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Hematopoiesis The formation and maturation of blood cells
Bone Marrow H&E stained Under normal conditions, Hematopoiesis occurs in the bone marrow.
section There are three basic components to the bone marrow: bony trabeculae, adipose tissue (fat),
and hematopoietic cells.
When looking at bone marrow, it is important to determine the cellularity which is the area of
the marrow space that is occupied by the hematopoietic cells.
Cellularity varies with age:
o younger patients have more hematopoietic cells and less fat
EX An infinant’s cellularity would approach 100%
o older patients have less hematopoietic cells and more fat
EX A patient in their 7th decade of life the cellularity would be about 30%
Hematopoietic Cells Several types of hematopoietic cells
o Myeloid cells have 4 types:
Neutrophils, Eosinophils, Basophils, and Monocytes
Where Neutrophils, Eosinophils, and Basophils are often referred to as Granulocytes
because the cells have granules in their cytoplasm
o Erythrocytes (Red Blood Cells)
o Megakaryocytes
largest cell in the bone marrow which produces platelets
o Lymphoid cells (B or T lymphocytes)
Myeloid Cell Maturation The Neutrophil starts out as an Myeloblast (aka Blast cell)
(EX‐Neutrophil) o immature cell
o large cell with a very large nucleus and a small amount of
cytoplasm
Blast cells mature into a Myelocyte
o large cell with a rounded nucleus
Myelocyte matures into a Late Myelocyte (Early
Metamyelocyte)
o nucleus beginning to indent
Late Myelocyte matures into a Metamyelocyte
o indented nucleus
o the color of the cytoplasm changes to a light‐pink with
granules
Metamyelocyte matures into a Band cell
o much thinner nucleus that is shaped like a horseshoe
Band cell matures into a Segmented (mature) Neutrophil
White Blood Cells Two peripheral blood smears
Band (Stab) Cells
o indented nucleus that is shaped like a horseshoe
o With a light‐pink granular cytoplasm
o Band cells are normally not circulating within the
peripheral blood, but are restricted to the bone marrow,
but in times of stress (ex infection) the bone marrow will
release Band cells to help fight the infection
Segmented Neutrophil
o the nucleus normally has three to five lobes
Eosinophils
o bilobed nucleus
o bright pink granules within the cytoplasm
Basophil
contains a Blue/purple cytoplasm that is filled with granules
that obscure the nucleus
Lymphocyte
o relatively small cells and about the size of a red blood cell
(yellow box)
Monocyte
o much larger than a red blood cell (green box)
o nucleus is indented (kidney bean in shape or reniform)
o cytoplasm is grey/blue
H&E Stained Sections Neutrophils
o You can see the neutrophils with their multilobed nucleus (red box) with light‐pink
cytoplasm
Eosinophils
o Green box – eosinophil with a bilobed nucleus and the bright pink granules are noticeable
Lymphocytes
o Lymphocytes with a small nucleus and about the same size as red blood cells within the blood
vessel (red box)
Plasma Cells
o Plasma cells are mature B lymphocytes and they have a nucleus that is off to the side (green box)
‐the chromatin inside of the nucleus is clumped and restricted to the periphery of the nucleus
called Clock Face Chromatin
Red Blood Cells and Platelets
o This is a peripheral blood smear containing red blood cells (which are the most numerous cells within
our peripheral blood)
a mature red blood cells does not have a nucleus but instead has an area of central pallor (which is
normally 1/3 the diameter of the cell)
o Platelets are also distributed within the peripheral blood
not technically cells but are derived from Megakaryocytes
Megakaryocyte
o The large cells are the megakaryocytes (green box)
located next to the sinusoids which are small blood vessels within the bone marrow
fragments of the megakaryocytes break off which form platelets
Question Based on these representative sections of normal bone marrows, can you identify the bone
marrow from the younger patient and the bone marrow from an older patient?
o Image on the left is from a young patient there are more hematopoietic cells and less
adipose tissue
o Image of the right is from an older patient there are fewer hematopoietic cells and more
adipose tissue
Pathology of Anemia
Hematopoiesis Series of events in which pluripotent stem cells mature into functional blood cells Pluripotent stem cell is
precursor of all blood cell lines:
o red blood cells (RBCs), white blood cells (WBCs), platelets
o RBC maturation occurs in the bone marrow except for T‐cell maturation which occurs in the thymus
Red Blood Cells Bulk of the formed elements in blood
(erythrocytes) o anucleate biconcave discs that carry oxygen to the tissues and return to the lungs carrying carbon dioxide
Peripheral Blood Smear Formed blood elements are visualized by means of the peripheral blood smear
(High Power) o Drop of blood is smeared on a glass slide
o Dried smear is stained
Evaluation of hematopoiesis is accomplished by a bone marrow aspirate and biopsy
Red cell maturation Reticulocyte is usually first stage of red blood cell released from marrow into peripheral blood
sequence o Where cytoplasm may be slightly bluish‐pink due to residual RNA (polychromasia)
Majority of RBCs in peripheral blood are mature biconcave discs with a normal life‐span of about 120 days
RBC Membrane Phospholipid bilayer combined with glycolipids and cholesterol
o integral proteins span the bilayer
UNIQUE to RBC contains a Membrane skeleton controls biconcave shape and cell deformability
(qualities essential for travel through microcirculation)
Hemoglobin Hemoglobin synthesis involves 2 biosynthetic pathways
o Synthesis of heme
o Synthesis of globin chains
Heme Heme consists of 4 pyrrole groups joined into large ring (porphyrin ring) with ferrous ion incorporated into center
o Heme is composed of iron and protoporphyrin
Heme Synthesis Heme synthesis occurs in almost all tissues because heme proteins include not
only hemoglobin and myoglobin but all the cytochromes (electron transport
chain, cytochrome P‐450, cytochrome b5) as well as the enzymes catalase,
peroxidase, and the soluble guanylate cyclase stimulated by nitric oxide.
The pathway producing heme is controlled independently in different tissues
o In the liver, the rate‐limiting enzyme is delta‐aminolevulinate synthase (ALA)
which is repressed by the production of heme
ALA synthase converts Glycine and Succinyl‐CoA into delta‐Aminolevulinic
acid using B6 as a cofactor. The reaction occurs within the mitochondria
ALA synthase is inhibited by heme
ALA dehydratase converts delta‐Aminolevulinic acid into Porphobilinogen
ALA dehydratase is inhibited by lead (Pb)
Porphobilinogen deaminase (Hydroxymethylbilane synthase) converts
Porphobilinogen into Hydroxymethylbilane
A mutation in the enzyme Porphobilinogen deaminase results in Acute
Intermittent Porphyria (Autosomal dominant)
Uroporphyrinogen 3 synthase converts Hydroxymethylbilane into
Uroporphyrinogen 3
Uroporphyrinogen decarboxylase converts Uroporphyrinogen 3 into
Coproporphyrinogen 3
A mutation in the enzyme Uroporphyrinogen decarboxylase results in
Porphyria Cutanea Tarda (Autosomal dominant – most common
porphyria)
Coproporphyrinogen 3 is converted into Protoporphyrin 9
Ferrochelatase converts Protoporphyrin 9 and Fe2+ into Heme
Ferrochelatase is inhibited by lead (Pb)
Globin Chains Globin chains contain approximately 150 amino acids and each chain is arranged in a “knotted
sausage” fashion
o heme binds to a specific region of each globin chain
Alpha, beta, delta, gamma
Hemoglobin A (HbA) = alpha2‐beta2
Hemoglobin A2 (HbA2) = alpha2‐delta2
Hemoglobin F (HbF) = alpha2‐gamma2
Iron plus protoporphyrin plus two globin dimers form hemoglobin.
o Most important hemoglobin is hemoglobin A (a2b2), comprising more than 95% of the hemoglobin in the normal adult red
cell
RBC Catabolism Aging RBCs are largely removed by mononuclear phagocytic engulfment in the spleen
Heme and globin chains are separated;
o heme is divided into iron (which is recycled)
o porphyrin rings (eliminated as bilirubin)
o globin is dismantled into amino acids
Accelerated RBC destruction is called “hemolysis”
Anemia‐Definition Reduced oxygen carrying capacity of blood
Anemia may be defined as reduction below normal limits of the total circulating red cell mass
Hemoglobin (Hb), Hematocrit (Hct), and RBC count are used as surrogates for RBC mass:
Anemia is defined as:
Hb < 13.5 g/dL (males) Normal = 13.5‐17.5 g/dL
Hb < 12.5 g/dL (females) Normal = 12.5‐16.0 g/dL
Classification of Anemia Blood loss
o Acute
o chronic
Increased Rate of Destruction (Hemolytic Anemias)
o Intrinsic (intracorpuscular) abnormalities of RBCs
Hereditary
Red cell membrane disorders Hereditary spherocytosis
Red cell enzyme deficiencies G6PD deficiency
Disorders of hemoglobin synthesis
o structurally abnormal globin synthesis Sickle cell anemia
o deficient globin synthesis Thalassemia
Acquired
Paroxysmal Nocturnal Hemoglobinuria (PNH)
o Extrinsic (extracorpuscular) abnormalities of RBCs
Antibody‐mediated immune hemolytic anemias
Mechanical trauma microangiopathic hemolytic anemia
Infections malaria
Chemical injury lead poisoning
Sequestration hypersplenism
o Impaired red cell production (diminished erythropoiesis)
Disturbances of proliferation/differentiation of erythroblasts
Deficient heme synthesis iron deficiency anemia
Deficient DNA synthesis megaloblastic anemia: B12/folate
Multiple mechanisms anemia of chronic disease
Disturbances of proliferation/maturation of stem cells aplastic anemia
Red cell indices Mean cell volume (MCV)
o Measures the average volume of a red blood cell
Mean cell hemoglobin (MCH)
o Measures the average mass of hemoglobin per red blood cell
o MCH value is low in hypochromic anemias
hypochromic cells have an increased area of central pallor and a decrease in redness is due to a disproportionate reduction
of red cell hemoglobin in proportion to the volume of the cell.
Hypochromia is clinically defined as
o below the normal MHC reference range of 27‐33 picograms/cell in adults
o below the normal MCHC reference range of 33‐36 g/dL in adults
o It is calculated by dividing the total mass of hemoglobin by the number of red blood cells in a volume of blood.
MCH=(Hgb*10)/RBC
o A normal value in humans is 27 to 31 picograms/cell and depends on hemoglobin synthesis
MCH decreases when Hb synthesis is reduced
MCH remains falsely normal when both Hb and RBC counts are reduced
Mean cell hemoglobin concentration (MCHC)
o Measures the hemoglobin concentration in a given volume of red blood cells
o Calculated by dividing the haemoglobin by the haematocrit
o Reference ranges for blood tests are 32 to 36 g/dL or between 19.9 and 22.3 mmol/L
Elevated MCHC = polychromatic
As seen in:
o hereditary spherocytosis
o sickle cell disease
o homozygous haemoglobin C disease
MCHC can be falsely elevated when there is agglutination of red cells (falsely lowering the measured RBC) or when there
is opacifaction of the plasma (falsely increasing the measured hemoglobin).
Causes of plasma opacification that can falsely increase the MCHC associated with
o Hyperbilirubinemia
o Hypertriglyceridemia
o free hemoglobin in the plasma (due to hemolysis).
RBC distribution width (RDW)
o coefficient of variation of red cell volume, measures anisocytosis
Classification based on MVC Microcytic Anemia
o MCV <80 fL
iron deficiency
thalassemia
anemia of chronic disease
Normocytic Anemia
o MCV = 80‐100 fL
Macrocytic Anemia
o MCV >100 fL
Megaloblastic anemia (Vitamin B12/folate deficiency)
alcoholism
Sideroblastic anemia Not a specific entity—outdated term
Presence of abnormal erythroid precursors in the bone marrow: “ring sideroblasts”
Seen in anemias due to many different causes
o Hereditary ALAS2 mutation (rare)
o Lead poisoning
o Vitamin B6 (pyridoxine) deficiency
o Drugs (e.g. Isoniazid)
o Chronic alcoholism
o Myelodysplastic syndrome (malignant)
Microcytic, normocytic or macrocytic depending on cause
Hemolysis (Intrinsic or Hemolytic anemias are characterized by:
Extrinsic) o Shortening of normal RBC life span (premature destruction of RBCs)
o Accumulation of products of hemoglobin catabolism
o Marked compensatory increase in erythropoiesis within the bone marrow
Intravascular
o RBCs are destroyed within the vascular compartment resulting in
Hemoglobinemia
Hemoglobinuria
Hemosiderinuria
o Free hemoglobin forms complexes mostly with haptoglobin (levels usually become low) and is removed by the liver
Extravascular
o RBCs are destroyed primarily by tissue macrophages (as in normal RBC catabolism, but exaggerated)
o Does not usually result in significant hemoglobinemia or hemoglobinuria, but often the reticuloendothelial system is
hyperactive, resulting in splenomegaly
o More common than intravascular hemolysis
Microcytic Anemia Iron Deficiency Anemia
Anemia of Chronic Disease
Sideroblastic Anemia
Thalassemia Alpha‐Thalassemia Hereditary – structurally abnormal globin
Beta‐Thalassemia – Minor synthesis
Beta‐Thalassemia – Major
Lead Poisoning
Macrocytic Anemia Folate Deficiency
Vitamin B12 Deficiency
Normocytic Anemia Extravascular Hereditary Spherocytosis Hereditary – red cell membrane disorder
Hemolysis Sickle Cell Anemia
Hemoglobin C
Intravascular Paroxysmal Nocturnal Hemoglobinuria Acquired
Hemolysis Glucose‐6‐Phosphate Dehydrogenase Hereditary – red cell enzyme deficiency
Deficiency
Immune Hemolytic Anemia
Microangiopathic Hemolytic Anemia
Malaria
Anemia due to Aplastic Anemia
Underproduction
Reticulocyte Count Correction = (Hct/45)* Reticulocyte count
o If >3% = the bone marrow IS responding appropriately
o If <2% = the bone marrow is NOT responding
Microcytic Anemias
Basic Principles Anemia with MCV < 80 fL
Microcytic anemias are due to a decreased production of hemoglobin
o Red Blood Cell (RBC) progenitor cells in the bone marrow are large and normally divide multiple times to produce smaller
mature cells to cause a normal MCV range from 80 – 100 fL
o Microcytosis is die due to an “extra” division which occurs to maintain hemoglobin concentration
Hemoglobin is made of heme and globin
o Heme is composed of iron and protoporphyrin
o Where a decrease in heme, globin, iron, or protoporphyrin leads to microcytic anemia
Microcytic anemias include:
o Iron deficiency anemia
o Anemia of chronic disease
o Sideroblastic anemia
o Thalassemia
Laboratory Findings
State Ferritin TIBC Serum Iron % Saturation
Normal 2‐30 g/dL (male) 300 micro‐gram/dL 100 micro‐gram/dL 33%
2‐20 g/dL (female)
Iron Deficiency Anemia Low High Low Low
Anemia of Chronic Disease High Low Low Low
Sideroblastic Anemia High Low High High
Iron Deficiency anemia Due to decreased levels of iron
o Decreased iron leads to decreases heme
Causes decreased hemoglobin
Resulting in Microcytic anemia
Most common type of anemia
o The lack of iron is the most common nutritional deficiency in the world, affecting 1/3 of the population
Iron is consumed in the form of meat‐derived heme and vegetable‐derived non‐heme formats
o Absorption occurs in the duodenum
Enterocytes have heme and non‐heme (DMT1) transporters
Where the heme (meat‐derived) form is more readily absorbed
o Enterocytes (simple columnar epithelial cells found in the small intestine) transport iron across the cell membrane into blood
via Ferroportin
o Transferrin transports iron in the blood and delivers it to the liver and bone marrow for intracellular storage in macrophages
o Stored intracellular iron is bound to Ferritin
Which prevents iron from forming free radicals via the Fenton reaction
Laboratory measurements of iron status
o Serum iron – measure of iron in the blood ~100 micro‐gram/dL
o Serum ferritin – reflects iron stores in macrophages and in the liver screening test
o Total Iron Binding Capacity (TIBC) – measure of transferrin molecules in the blood
o With Low iron stores increased transferrin synthesis by the liver increased TIBC
o Percent Saturation – percentage of transferrin molecules that are bound by serum iron
Normal % Saturation = (100/300) *100% = 33%
Iron deficiency is usually cause by dietary lack or blood loss
o Infants – breast feeding because human milk is low in iron
o Children – poor diet
o Adults (20‐50 years old):
peptic ulcer disease in males
menorrhagia or pregnancy in females
o Elderly:
colon polyps/carcinoma in the western world
hookworm (Ancylostoma duodenale and Necator americanus) in the developing world
o Other causes of iron deficiency include:
Malnutrition
Malabsorption
Gastrectomy – acid aids in iron absorption by maintaining the Fe2+(ferrous) state, which is more readily absorbed than
Fe3+(ferric)
Stages of iron deficiency
o Storage iron is depleted
Causes a decrease in serum ferritin
o Serum iron is depleted
decreased circulating iron, causes a decreased serum iron
which causes an increase total iron binding capacity (TIBC) and a decrease in % saturation
o Normocytic anemia where the bone marrow makes fewer, but normal‐sized RBC
o Microcytic, hypochromic anemia where the bone marrow makes smaller and fewer RBC
Clinical features of iron deficiency include:
o Anemia
o Koilonychia – the nails have lost their convexity, becoming flat or even concave in shape “Spoon
Nails”
o Pica – craving and chewing substances that have no nutritional value, such as ice, clay, soil, or paper
o Oral epithelial atrophy – if Plummer‐Vinson syndrome is present
Plummer‐Vinson syndrome is iron deficiency anemia with esophageal web and atrophic glossitis
Presentation includes:
o Anemia – fatigue and conjunctival pallor (Hct < 6g)
o Dysphagia
o Beefy‐red tongue
Laboratory findings include
o Microcytosis and hypochromasia (central pallor >33% of the cell) RBC with increased red cell distribution
width (RDW)
Ferritin TIBC Serum Iron % Saturation Free Erythrocyte Protoporphyrin (FEP)
Decreased Increased Decreased Decreased Increased
Treatment:
o Supplemental iron in the form of ferrous sulfate
Anemia of Chronic Disease Anemia associated with:
o chronic inflammation – endocarditis or autoimmune diseases
because the body responds to inflammation as if it was an infection
bacteria increase their reproduction with iron so the body tries to keep the iron away from the bacteria
o Malignancies Cancer
Most common type of anemia in hospitalized patients
Chronic disease results in production of acute phase reactants from the liver, including hepcidin
o Hepcidin sequesters iron in storage sites by
Limiting iron transfer from macrophages to erythroid precursors
Suppressing erythropoietin (EPO) production
o The aim is to prevent bacteria from accessing iron which is necessary for their survival
Decreased available iron
o Causes decreased heme which leads to a decrease in hemoglobin
Resulting in microcytic anemia
Laboratory findings include:
Ferritin TIBC Serum Iron % Saturation Free Erythrocyte Protoporphyrin (FEP)
Increased Decreased Decreased Decreased Increased
Treatment:
o Addressing the underlying cause
Sideroblastic Anemia Anemia due to defective protoporphyrin synthesis
o Where a decreased protoporphyrin leads to decreased heme
Causes decreased hemoglobin leasing to Microcytic anemia
Protoporphyrin is synthesized via a series of reaction
o Aminolevulinic acid synthetase (ALAS) converts succinyl CoA to aminolevulinic acid (ALA) using Vitamin B6 (Pyridoxine) as a
cofactor rate limiting step
o Aminolevulinic acid dehydratase (ALAD) converts ALA to porphobilinogen
o Additional reactions convert porphobilinogen to protoporphyrin
o Ferrochelatase attaches protoporphyrin to iron to make heme this is the final reaction that occurs in the mitochondria
Iron is transferred to erythroid precursors and enters the mitochondria to form heme
o If protoporphyrin is deficient
Iron remains trapped in the mitochondria
Iron‐laden mitochondria form a ring around the nucleus of erythroid precursors
o These cells are called Ringed Sideroblasts (Prussian blue–stained mitochondria seen in the
bone marrow)
Sideroblastic anemia can be congenital or acquired
o Congenital defect
Most commonly involves the ALAS rate limiting enzyme
o Acquired causes include:
Alcoholism – mitochondrial poison
Lead poisoning – inhibits ALAD and Ferrochelatase
Vitamin B6 deficiency – required cofactor for the ALAS enzyme and is most commonly seen as a side effect of Isoniazid
treatment for tuberculosis
Laboratory findings include: Iron‐Overload State
Ferritin TIBC Serum Iron % Saturation Free Erythrocyte Protoporphyrin (FEP)
Increased Decreased Increased Increased Decreased
Thalassemia Anemia due to decreased synthesis of globin chains of hemoglobin
o Where a decrease in globin causes a decrease in hemoglobin
Resulting in Microcytic anemia
Inherited mutation
o Where carriers are protected against Plasmodium falciparum malaria
Divided into alpha and beta thalassemia based on decreased production of alpha or beta globin chains
o Normal types of hemoglobin are:
HbF (alpha2‐gamma2)
HbA (alpha1‐beta2)
HbA2 (alpha2‐delta2)
Alpha‐Thalassemia is usually due to gene deletion
o Normally the 4 alpha genes are present on chromosome 16
Silent carrier:
If one gene is deleted – asymptomatic
Alpha‐Thalassemia trait:
If two genes are deleted – cause mild anemia with an increased RBC count
o Where cis deletion is associated with an increased risk of severe thalassemia in offspring
Cis deletion is when both deletions occur on the same chromosome seen in Asians (0,0/alpha,alpha)
Trans deletion is when one deletion occurs on each chromosome seen in Africans and African Americans
(0,alpha/0,alpha)
HbH Disease:
If three genes are deleted – causes severe anemia
o Where beta chains form tetramers (HbH) that damage RBCs
o HbH can be seen on electrophoresis
Hydrops fetalis:
If four genes are deleted – this is lethal in utero
o Where the gamma chains form tetramers (Hb Barts) that damage RBCs
o Hb Barts can be seen on electrophoresis
Beta‐Thalassemia is usually due to gene mutations point mutation in the promoter or splicing sites
o Seen in individuals of Africana and Mediterranean descent
o Two beta genes are present on Chromosome 11
Where mutations results in absent (beta‐zero) or diminished (beta‐positive) production of the beta‐globin chain
Beta‐Thalassemia minor (Beta/Beta‐positive) is the mildest form of the disease
o Presentation is usually asymptomatic with an increased RBC count
o Microcytic, hypochromic RBCs and Target cells are seen on blood smear ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐>
Must be distinguished from ion deficiency
o Hemoglobin electrophoresis shows:
decreased HbA
increased HbA2 (5% where normal is 2.5%)
increased HbF (2% where normal is 1%)
Beta‐Thalassemia major (Beta‐zero/Beta‐zero) is the most severe form of the disease
o Presents with severe anemia a few months after birth where a high HbF (alpha2‐gamma2) at birth is temporarily protective
Unpaired alpha chains precipitate and damage RBC membranes
Resulting in ineffective erythropoiesis and extravascular hemolysis (removal of circulating RBCs by the spleen)
Massive erythroid hyperplasia ensues resulting in:
expansion of hematopoiesis into
o the skull reactive bone formation leads to “crewcut” appearance on x‐ray ‐‐‐‐‐‐‐‐‐>
o the facial bones chipmunk facies
extramedullary hematopoiesis with hepatosplenomegaly
risk of aplastic crisis with parvovirus B19 infection of erythroid precursors
Chronic transfusions are often necessary
Leads to an increased risk for secondary hemochromatosis
Smear shows microcytic, hypochromic RBCs with target cells and nucleated red blood cells
Electrophoresis shows HbA2 and HbF with little or no HbA
Lead Poisoning Lead inhibits ferrochelatase and ALA dehydratase which causes…
o Decrease in heme synthesis
o Increase in RBC protoporphyrin.
Also inhibits rRNA degradation
o Which causes RBCs to retain aggregates of rRNA (basophilic stippling).
Symptoms of LEAD poisoning:
o Lead Lines on gingivae (Burton lines) and on metaphyses of long bones on x‐ray.
o Encephalopathy and Erythrocyte basophilic stippling.
o Abdominal colic and sideroblastic Anemia.
o Drops—wrist and foot drop.
Treatment
o Dimercaprol and EDTA are 1st line of treatment.
o Dimercaptosuccinic acid (DMSA), also called succimer, is a medication used to treat lead, mercury, and arsenic poisoning
Used for chelation in children
Exposure risk increases in old houses with chipped paint.
Macrocytic Anemia
Folate Deficiency
Vitamin B12 Deficiency
Basic Principles Anemia with MCV > 100 fL
o most commonly due to folate or vitamin Bl2 deficiency (megaloblastic anemia)
Folate and vitamin Bl2 are necessary for synthesis of DNA precursors.
o Folate circulates in the serum as methyltetrahydrofolate (methyl THF)
Where the removal of the methyl group allows for participation in the synthesis of DNA precursors.
o Methyl group is transferred to vitamin B12 (cobalamin).
o Vitamin B12 then transfers the methyl group to homocysteine
producing Methionine.
Lack of folate or vitamin Bl2 impairs synthesis of DNA precursors.
o Impaired division and enlargement of RBC precursors
Which leads to Megaloblastic anemia.
o Impaired division of granulocytic precursors
Which leads to hyper‐segmented neutrophils.
o Megaloblastic change is also seen in rapidly‐dividing (EX – intestinal) epithelial cells.
Other causes of macrocytic anemia (without megaloblastic change) include:
o Alcoholism, liver disease, drugs – chemotherapy (5‐FU)
Folate Deficiency Dietary folate is obtained from green vegetables and from some fruits
o Folate is absorbed in the jejunum
Folate deficiency develops within months, because the body stores are minimal
Causes include:
o Poor diet – alcoolics and elderly
o Increased demand – pregnancy, cancer, and hemolytic anemia
o Folate antagonists – Methotrexate which inhibits Dihydrofolate Reductase
Clinical and laboratory findings include:
o Macrocytic RBCs MCV > 100 fL
o Hypersegmented neutrophils >5 lobes
o Glossitis
o Decreased serum folate
o Increased serum homocysteine which causes an increased risk for thrombosis
o Normal methylmalonic acid
o No CNS abnormalities
Vitamin B12 Deficiency Dietary vitamin B12 is complexed to animal‐derived proteins
o Salivary gland enzymes (EX – amylase) liberate vitamin B12, which is then bound by R‐binder (also from the
salivary gland) and is carried through the stomach
o Pancreatic proteases in the duodenum detach vitamin B12 from the R‐binder
o Vitamin B12 binds to the Intrinsic Factor (made by gastric parietal cells) in the small bowel
The intrinsic factor‐vitamin B12 complex is absorbed in the ileum
Vitamin B12 deficiency is less common than folate deficiency and takes years to develop due to the large hepatic stores of
vitamin B12
Pernicious anemia is the most common cause of vitamin B12 deficiency
o Autoimmune destruction of parietal cells (located in the stomach)
Leads to intrinsic factor deficiency
Other causes of vitamin B12 deficiency include:
o Pancreatic insufficiency
o Damage to the terminal ileum due to
Crohn disease
Diphyllobothrium latum – fish tapeworm
Dietary deficiencies are rare except in vegans
Clinical and laboratory findings include:
o Macrocytic RBCs MCV > 100 Fl
o Hypersegmented neutrophils
o Glossitis
o Subacute combines degeneration of the spinal cord CNS abnormalities
Vitamin B12 is a cofactor for the conversion of methylmalonic acid to succinyl CoA important in fatty acid metabolism
Vitamin B12 deficiency results in
Increased levels of methylmalonic acid which impairs spinal cord myelinization
Damage results in
poor proprioception and vibratory sensation due to injury of the posterior columns
spastic paresis due to injury of the lateral corticospinal tract
o Decreased serum vitamin B12
o Increased serum homocysteine
Which is similar in folate deficiency that causes an increased risk for thrombosis
o Increased methylmalonic acid
Which is different in folate deficiency
Normocytic Anemia
Basic Principles Anemia with a normal sized RBC MCV = 80 – 100 fL
Due to an increased peripheral destruction or underproduction of RBCs
o Therefore, the reticulocyte count helps to distinguish between these two etiologies
Reticulocytes Reticulocytes are young RBCs are released from the bone marrow
o Can be identified on blood smear as larger cells with a bluish cytoplasm due to residual RNA
Normal reticulocyte count (RC) = 1‐2%
o RBC lifespan is 120 days
Where each day roughly 1‐2% of the RBCs are removed from the circulation and replaced by reticulocytes
A properly functioning marrow responds to anemia by increasing the Reticulocyte count to >3%
However, the Reticulocyte count is falsely elevated in anemia
o Because the reticulocyte count is measured as a percentage of total RBC
Where a decrease in total RBCs falsely elevates the percentage of reticulocytes
o Corrected Reticulocyte count is the measured reticulocyte count times Hct/45
If the corrected count > 3%
This indicates good bone marrow response and suggests a peripheral destruction
If the corrected count < 2%
This indicates poor bone marrow response and suggest underproduction
Peripheral RBC Destruction Divided into:
(Hemolysis) o Extravascular hemolysis
o Intravascular hemolysis
Where both results in anemia with a good marrow response
Extravascular hemolysis Extravascular hemolysis involves RBC destruction by the reticuloendothelial system
overview o Which is associated with macrophages of the spleen, liver, and lymph nodes
Macrophages consume RBCs and break down hemoglobin
o Globin is broken down into amino acids
o Heme is broken down into iron and protoporphyrin
Iron is recycled
Protoporphyrin is broken down into unconjugated bilirubin
Which is bound to serum albumin and delivered to the liver for conjugation and excretion as bile
Clinical and laboratory findings include:
o Anemia with
Splenomegaly
Jaundice due to unconjugated bilirubin
Increased risk for bilirubin gallstones
o Marrow hyperplasia with corrected reticulocyte > 3%
Intravascular hemolysis Intravascular hemolysis involves destruction of RBC within vessels
overview Clinical and laboratory findings include:
o Hemoglobinemia
o Hemoglobinuria
o Hemosiderinuria:
renal tubular cells pick up some of the hemoglobin that is filtered into the urine and break it down into iron, which
accumulates as hemosiderin
tubular cells are eventually shed resulting in hemosiderinuria
o Decreased serum haptoglobin
Normocytic Anemia – Extravascular Hemolysis
Hereditary Spherocytosis Inherited defect of RBC cytoskeleton‐membrane tethering proteins
o Most commonly involves:
Spectrin – forms the membrane skeleton that is attached to the lipid bilayer by Ankyrin
Ankyrin – anchors the spectrin protein to the membrane
Band 3.1 – integral membrane protein
Membrane blebs are formed and lost over time
o Loss of membrane renders cells round (Spherocytes) instead of disc‐shaped
o Spherocytes are less able to maneuver through splenic sinusoids and are consumed by splenic macrophages
resulting in anemia
Clinical and laboratory findings include
o Spherocytes with loss of central pallor
o Increased RDW
o Increased Mean Corpuscular Hemoglobin Concentration (MCHC)
o Splenomegaly
o Jaundice with unconjugated bilirubin
o Increased risk for bilirubin gallstones
o Increased risk for aplastic crisis with parvovirus B19 infection of erythroid precursors
Diagnosed by osmotic fragility test
o Which reveals increased spherocyte fragility in hypotonic solution
Treatment is splenectomy
o Anemia resolves, but spherocytes persist and Howell‐Jolly bodies emerge on blood smear
Howell‐Jolly bodies are fragments of nuclear material in RBCs
Sickle Cell Anemia Autosomal recessive mutation of the beta chain of hemoglobin
o Where a single amino acid change replaces normal glutamic acid (hydrophilic AA) with valine (hydrophobic AA) at the sixth
position of the beta‐globin gene, resulting in Hemoglobin S (HbS)
The mutated gene is carried by 8‐10% of individuals of African descent
o Likely due to the protective role sickly cell anemia has against falciparum malaria
Sickle cell trait:
o arises when one abnormal beta gene is present
Sickle cell disease:
o arises when two abnormal beta genes are present
Which results in >90% HbS in RBCs
HbS polymerizes when deoxygenated causing polymers aggregate into needle‐like structures
o Resulting in sickle cells
Where an increased risk of sickling occurs with:
Hypoxemia
Dehydration
Acidosis
Fetal hemoglobin (HbF) protects against sickling
Where high HbF at birth is protective for the first few months of life
Treatment with Hydroxyurea increases levels of HbF
Cells continuously sickle and de‐sickle while passing through the microcirculation resulting in complications related to RBC
membrane damage
o Extravascular hemolysis:
Reticuloendothelial system removes RBCs with damaged membranes
Leasing to anemia, jaundice with unconjugated hyperbilirubinemia, and increased risk for bilirubin gallstones
o Intravascular hemolysis:
RBCs with damaged membranes dehydrate leading to hemolysis with decreased haptoglobin and target cells on blood
smear
o Massive erythroid hyperplasia ensues resulting in
Expansion of hematopoiesis into the
skull to give a “crewcut” appearance on x‐ray
facial bones to give a “chipmunk facies”
Extramedullary hematopoiesis with hepatomegaly
Risk of aplastic crisis with parvovirus B19 infection of erythroid precursors
Extensive sickling leads to complications of vaso‐occlusion
o Dactylitis – swollen hands and feet due to vaso‐occlusive infarcts in bones
Common presentation sign in infants
o Auto‐splenectomy (Asplenia) – shrunken, fibrotic spleen
Consequences include:
Increased risk of infection with encapsulated organisms such as:
o Streptococcus pneumoniae
o Haemophilus influenzae most common cause of death in children
Affected children should be vaccinated by 5 years of age
Increased risk of Salmonella paratyphi osteomyelitis
Howell‐Jolly bodies on blood smear
Howell‐Jolly bodies are small dense particles seen in the cytoplasm of this erythroid precursor.
o Acute chest syndrome – vaso‐occlusion in pulmonary microcirculation
Presents with:
chest pain
shortness of breath
lung infiltrates
Often precipitated by pneumonia
Most common cause of death in adult patients
o Pain crisis –
o Renal papillary necrosis – results in gross hematuria and proteinuria
Sickle cell trait is the presence of ONE mutated beta chain and ONE normal beta chain which results in <50% HbS in RBC
because HbA is slightly more efficiently produced than HbS
Generally asymptomatic with no anemia
o RBC with <50% HbS do not sickle in vivo except in the renal medulla
Extreme hypoxia and hypertonicity of the medulla cause sickling
which results in microinfarctions
o leading to microscopic hematuria resulting in a decreased ability to concentrate the urine
Laboratory findings
o Sickle cells and target cells are seen on blood smear in sickle cell disease, but NOT in sickle cell trait
o Metabisulfite screen causes cells with any amount of HbS to sickle positive in both disease and trait
o Hb electrophoresis confirms the presence and amount of HbS
Disease:
0% HbA; 90% HbS; 8% HbF; 2% HbA2 NO HbA
Trait:
55% HbA; 43% HbS; 0% HbF; 2% HbA2
Hemoglobin C Autosomal recessive mutation in the beta chain of hemoglobin
o Normal glutamic acid is replaced by Lysine
o Less common than sickle cell disease
Presents with:
o Mild anemia due to extravascular hemolysis
Characteristic HbC crystals are seen in RBCs on blood smear
o Numerous target cells and scattered hemoglobin C crystals in a patient with hemoglobin C
disease. Hemoglobin C crystals are dense rectangular structures composed of precipitated
hemoglobin C. Target cells form when there is an excess of membrane in relation to cytosol. Microcytic target cells can be
seen in thalassemia and other hemoglobinopathies. Macrocytic target cells can be seen in liver disease. Target cells can also
be seen in hyposplenic patients, or as an artifact of slide preparation.
Normocytic Anemia – Intravascular Hemolysis
Paroxysmal Nocturnal Acquired defect in myeloid stem cells resulting in absent
Hemoglobinuria (PNH) glycosylphosphatidylinositol (GPI) renders cells susceptible to destruction
by complement
o Blood cells coexist with complement
o Decay accelerating factor (DAF) on the surface of blood cells protects
against complement‐mediated damage by inhibiting C3 convertase
o DAF is secured to the cell membrane by GPI an anchoring glycolipid
o The absence of GPI leads to absence of DAF:
rendering cells susceptible to complement‐mediated damage
Intravascular hemolysis occurs episodically often at night during sleep
o Mild respiratory acidosis develops with shallow breathing during sleep and activates complement
Where RBC, WBC, and platelets are lysed
o Intravascular hemolysis leads to hemoglobinemia and hemoglobinuria especially in the morning
Where hemosiderinuria is seen days after hemolysis
Laboratory findings
o Sucrose test is used to screen for disease
o Confirmatory test = Acidified serum test OR flow cytometry to detect the lack of CD55 (DAF) on blood cells
Main cause of death is thrombosis of the hepatic, portal, or cerebral veins
o Destroyed platelets release cytoplasmic contents into the circulation which inducing thrombosis
Complications include:
o Iron deficiency anemia – due to chronic loss of hemoglobin in the urine
o Acute myeloid leukemia (AML) – which develops in 10% of patients
Glucose‐6‐Phosphate X‐linked recessive disorder resulting in reduced half‐life of G6PD which renders cells
Dehydrogenase (G6PD) susceptible to oxidative stress
Deficiency o RBC are normally exposed to oxidative stress in particular from peroxide (H2O2)
o Glutathione (an antioxidant) neutralized peroxides but becomes oxidized in the process
o NADPH (a by‐product of G6PD) is needed to regenerate reduced glutathione
Decreased G6PD
o Leads to decreased NADPH
Which causes decreased glutathione and peroxide to accumulate
Resulting in oxidative injury to the sulfhydryl groups within globin chains by peroxides
o causing intravascular hemolysis
G6PF deficiency has two major variants
o African variant – mildly reduced half‐life of G6PD leading to mild intravascular hemolysis with oxidative stress
o Mediterranean variant – markedly reduced half‐life of G6PD leading to marked intravascular hemolysis with oxidative stress
o Higher carrier frequency in both populations is likely due to the protective role G6PD deficiency has against falciparum malaria
Oxidative stress precipitates hemoglobin as Heinz bodies
o causes of oxidative stress includes:
infections
drugs – primaquine, sulfa drugs, and dapsone
fava beans
o Heinz bodies are removed from RBC by splenic macrophages resulting in bite cells
Which leads to predominantly intravascular hemolysis
o Image:
The RBC deformity (arrow) shown in this image is referred to as a bite cell. This abnormality can be seen in when
hemoglobin precipitates (Heinz bodies noted on supravital staining) attach to the RBC membrane and are removed when
these cells pass through the spleen. Disorders associated with this abnormality include α thalassemia (β chain tetramers)
and G6PD deficiency manifested after oxidant drug exposure.
Presents with hemoglobinuria and back pain hours after exposure to oxidative stress
Drug‐induced hemolysis is acute with variable severity
o intravascular hemolysis, characterized by hemoglobinema, hemoglobinuria and decreased hematocrit, typically develops after
two or three days after exposure to oxidative stress
Heinz preparation is used to screen for disease
o Precipitated hemoglobin can only be seen with a special Heinz stain called
crystal violet stain
Enzyme studies confirm deficiency which is performed weeks after hemolytic
episode resolves
Immune Hemolytic Anemia Antibody‐mediated (IgG or IgM) destruction of RBC
(IHA) IgG‐mediated disease usually involves extravascular hemolysis
o IgG binds RBC in the relatively warm temperature of the central body warm agglutinin
Membrane of antibody‐coated RBC is consumed by splenic macrophages resulting in spherocytes
o Associated with:
SLE – most common cause
CLL – Chronic Lymphocytic Leukemia
Certain drugs – classically penicillin and cephalosporins
The drug may attach to the RBC membrane with subsequent binding of antibody to drug‐membrane complex
The drug may also induce production of autoantibodies (EX – alpha‐methyldopa) that bind to self‐antigens on RBC
o Treatment involves:
cessation of the offending drug
give steroids, IVIG and if necessary splenectomy
IgM‐mediated disease also usually involves extravascular hemolysis
o IgM binds to RBC and fixes complement in the relatively cold temperature of the extremities cold agglutinin
o RBC inactivate complement, but residual C3b serves as an opsonin for splenic macrophages resulting in spherocytes
Extreme activation of complement can lead to intravascular hemolysis
o Associated with Mycoplasma pneumoniae and infectious mononucleosis
Coombs test is used to diagnose IHA
o Direct Coombs test confirms the presence of antibody‐coated RBC or complement‐coated RBC
When anti‐IgG/complement is added to patient’s RBC
agglutination occurs if RBC are already coated with IgG or complement
This is the most important test for IHA
o Indirect Coombs test confirms the presence of antibodies in patient serum
Anti‐IgG and test RBCs are mixed with the patient’s serum
Agglutination occurs if serum antibodies are present
Microangiopathic Intravascular hemolysis that results from vascular pathology
Hemolytic Anemia o RBC are destroyed as they pass through the obstructed or narrowed vessel lumina within the circulation
Iron deficiency anemia occurs with chronic hemolysis
Occurs with:
o microthrombi associated with TTP‐HUS, DIC, and HELLP
o prosthetic heart valves due to mechanical trauma
o aortic stenosis
when present, microthrombi produce schistocytes on blood smear
Malaria infection of the RBCs and liver with Plasmodium
o transmitted by the female Anopheles mosquito
RBCs rupture as part of the Plasmodium life cycle resulting in intravascular hemolysis and
cyclical fever
o Plasmodium falciparum – daily fever
o Plasmodium vivax and Plasmodium ovale – fever every other day
Spleen also consumes some infected RBCs results in mild extravascular hemolysis with
splenomegaly
Anemia due to Underproduction
Basic Principles Decreased production of RBC by the bone marrow
o Characterized by a low corrected reticulocyte count
Etiologies include:
o Causes of microcytic and macrocytic anemia
o Renal failure – decreased production of EPO by peritubular interstitial cells
o Damage to bone marrow precursor cells may result in anemia or pancytopenia
Parvovirus B19 Infects progenitor red cells and temporarily halts erythropoiesis
o Leads to significant anemia in the setting of preexisting marrow stress EX – sickle cell anemia
Treatment is supportive the infection is self‐limited
Aplastic Anemia Damage to hematopoietic stem cells
o results in pancytopenia (anemia, thrombocytopenia and leukopenia) with a low reticulocyte count
Etiologies include:
o Frequently idiopathic
o Whole body irradiation
o Drugs or chemicals
o Viral infection
o Autoimmune damage
Bone Marrow Biopsy reveals and empty, fatty marrow
o Bone marrow typically is hypocellular with increased fat and small foci of lymphocytes and plasma cells
o
Treatment
o includes cessation of any causative drugs and supportive care with transfusion and marrow‐stimulating factors, including
erythropoietin, GM‐CSF, and G‐CSF
Immunosuppression may be helpful as some idiopathic cases are due to abnormal T‐cell activation with released of
cytokines
May require bone marrow transplantation as a last report
Myelophthisic Process Pathologic process (ex metastatic cancer) that replaces bone marrow
o Hematopoiesis is impaired
which results in a pancytopenia
Transfusion Part 1
Blood Donors and Medicine 15 million donations collected in the US annually
9.2 million donors
38% of US population eligible to donate
Less than 6% of eligible population do so
Next American Red Cross blood drives will be held on 11/22 from 9am‐3pm in the Stritch gym
Blood Types Most people are O positive and A positive
Do you know yours? Type US Population (%)
A positive 30
A negative 6
B positive 9
B negative 2
AB positive 4
AB negative 1
O positive 39
O negative 9
Formation of the A antigen
Formation of the B antigen
ABO Type Test
ABO Type Expected (pre‐formed) Isoagglutinins in Plasma
A Anti‐B
B Anti‐A
O Anti‐A, Anti‐B, and anti‐AB
AB Neither anti‐A or anti‐B (Universal Plasma)
Why? Genetics – Over 600 antigens in RBC’s
Response to Genetics
o Isoagglutinins – antibodies produced by an individual that cause agglutination of red blood cells in other individuals.
o Alloantibodies – antibodies to foreign pathogen
o Autoantibodies – antibodies to self tissues
RBC Isoagglutinins Antibody against dominant polysaccharide
Naturally occurring: made against bacteria which share polysaccharide epitopes
IgM
Activate complement
Intravascular hemolysis (fast)
ABO Group System ABO blood typing is a uniform first step in all
tissue transplantation because ABO
incompatibilities will cause hyper acute graft
rejection in the host. The ABO blood group
antigens are a group of glycoprotein molecules
expressed on the surface of erythrocytes and
endothelial cells. Natural isohemagglutinins
(IgM antibodies that will agglutinate the
glycoprotein molecules on the red blood cells
of nonidentical individuals) are produced in
response to similar molecules expressed on the
intestinal normal flora. A person is protected
by self‐tolerance from producing antibodies
that would agglutinate his own red blood cells,
but will produce those agglutinins that will
react with the red blood cells from other individuals.
Alloantibodies Antibodies against antigens we lack
Requires exposure to antigen on RBC’s
o Pregnancy
o Transfusion
o Transplantation
Mostly composed of IgG
o Most do not bind Complement
o Occurs via Extravascular hemolysis (slow process)
Types of Hemolysis Extravascular Hemolysis:
o In extravascular hemolysis RBCs are phagocytized by macrophages in
the spleen and liver. Causes include RBC membrane abnormalities
such as bound immunoglobulin, or physical abnormalities restricting
RBC deformability that prevent egress from the spleen. Extravascular
hemolysis is characterized by spherocytes.
Intravascular Hemolysis:
o In intravascular hemolysis RBCs lyse in the circulation releasing
hemoglobin into the plasma. Causes include mechanical trauma,
complement fixation, and other toxic damage to the RBC. The
fragmented RBCs are called schistocytes.
Autoantibodies Antibodies against generic (non‐specific) RBC membrane antigens
Common – increase with each decade of life
Usually “silent”
Can be detected in plasma of normal individuals
Some can cause hemolysis
Autoantibodies React at 37 degrees C
Warm IgG
Coat patient’s RBC’s or circulate in plasma
Positive DAT and/or IAT
Autoantibodies IgM
Cold Do activate complement
Positive DAT and/or IAT
Blood Transfusion Blood
o Biological product
o Pharmaceutical product
FDA regulated
Think of blood that is a “Liquid transplant”
Requires a doctor’s order
Transfusion Therapy
Pre‐Transfusion Testing Patient identification
Specimen identification
Type and screen
Type and crossmatch
When a properly labelled specimen is
received at the blood bank
o The blood is first typed and screen
Forward and Reverse Typing
Antibody Screen
To detect for any alloantibodies the patient may have
If the antibody screen is negative, then the ABO type is determined
Then an ABO compatible donor unit is selected
Then the recipient plasma is mixed with a sample of donor RBCs
If no hemolysis or agglutination is observed, then the donor RBC unit is issued
Blood Type ABO and Rh typing
o Forward Typing:
This test is used to detect the presence or absence of A and/or B antigens on an individual's red blood cells.
An individual's ABO group is determined by testing the red blood cells with reagent anti‐A and anti‐B sera. Agglutination
of the individual's red cells by the appropriate antisera signifies the presence of the antigen on the red cell while no
agglutination with the antisera signifies its absence.
o Reverse Typing:
This test is used to detect ABO antibodies in an individual's serum, and is used to confirm the ABO Forward Typing.
The patient's serum is mixed with reagent group A cells and group B cells.
Agglutination indicates the presence of Anti‐A or Anti‐B in the patient's serum.
Antibody Screen Patient’s serum with set of three reagent RBC’s with known antigens
RBC’s have about 600 serologically defined surface antigens
33 blood group systems
D antigen of the Rh blood group is the most immunogenic after A and B
Other Rh antigens: C, c, E, e
o Kell: K, k
o Duffy: Fya, Fyb
o Kidd: Jka, Jkb
o MNS: M, N, S, s
o Lutheran: Lua, Lub
Unexpected Alloantibodies Found in patients who lack the corresponding antigen
Stimulated by exposure to another person’s RBC’s
Most IgG
Most do not bind complement
Extravascular hemolysis (slow), destruction of RBC’s in 10‐14 days
Antibody Screen: The indirect Coombs test is designed to identify Rh‐negative mothers who are producing anti‐
Indirect Coombs Test Rh antibodies of the IgG isotype, which may be transferred across the placenta harming Rh‐
positive fetuses.
o The indirect Coombs is also used in the diagnosis of transfusion reactions.
Antibody Screen: The direct Coombs is designed to identify maternal anti‐Rh antibodies that are
Direct Coombs Test already bound to infant RBCs or antibodies bound to RBCs in patients with
autoimmune hemolytic anemia.
Seen in the following
o Delayed hemolytic transfusion reactions
o Autoimmune hemolytic anemia
o Hemolytic diseases of the newborn
o Acute hemolytic transfusion reactions
Agglutination Agglutination tests are widespread in clinical medicine and are simply a variation on
precipitation reactions.
In agglutination reactions, the antigen is a particulate antigen such as RBCs or latex
beads.
Both will clump up to form of a lattice of antibody‐bound particles in the presence of
appropriate antibodies.
o Latex bead agglutination tests are available for the diagnosis of cerebrospinal
infections such as Haemophilus, pneumococcus, meningococcus, and Cryptococcus.
In each of these cases, antibodies against these organisms are conjugated to latex beads, and the presence of microbial
antigens in the CSF is detected by the subsequent agglutination of those beads.
o RBC agglutination reactions are important in defining ABO blood groups, diagnosing Epstein‐Barr virus infection (the
monospot test), and identifying Coombs test for Rh incompatibility.
Pre‐Transfusion Before transfusion, the recipient’s and the donor’s blood are typed and cross‐matched to avoid hemolytic transfusion reactions.
Compatibility Testing o Although many antigen systems are present on red blood cells,
only the ABO and Rh systems are specifically tested prior to all transfusions.
o The A and B antigens are the most important
because everyone who lacks one or both red cell antigens has IgM isoantibodies (called isoagglutinins) in his or her plasma
against the missing antigen(s).
The isoagglutinins activate complement and can cause rapid intravascular lysis of the incompatible red blood cells.
In emergencies, type O/Rh‐negative blood can be given to any recipient, but only packed cells should be given to avoid
transfusion of donor plasma containing anti‐A and anti‐B antibodies.
The other important antigen routinely tested for is the D antigen of the Rh system.
o Approximately 15% of the population lacks this antigen.
In patients lacking the antigen, anti‐D antibodies are not naturally present, but the antigen is highly immunogenic.
A recipient whose red cells lack D and who receives D‐positive (Rh+) blood may develop anti‐D antibodies that can cause
severe lysis of subsequent transfusions of D‐positive red cells.
Blood typing includes a crossmatch assay of recipient serum for unusual alloantibodies directed against donor red blood cells
o Which is done by mixing recipient serum with panels of red blood cells representing commonly occurring minor red cell
antigens
o The screening is particularly important if the recipient has had previous transfusions or pregnancy.
Process:
o Type: ABO and Rh
o Screen: Tests for unexpected alloantibodies
o Crossmatch: Donor and recipient compatibility
If a patient is going to receive RBC:
Major Cross‐match is performed to test the recipient’s plasma with donor cells
If a patient is going to receive plasma and not RBC
Minor Cross‐match is performed to test the donor’s plasma with recipient cells
Only order it when transfusion is required
72 hour hold for the unit
Summary How blood types are determined and their importance
Pre‐transfusion testing
DAT vs IAT
Differences between isoagglutinins, alloantibodies, and autoantibodies
Why we screen for unexpected antibodies
Compared TAS to TXM
Transfusion Part 2
Hemolytic Disease of the The Rhesus (Rh) system classifies blood by the presence or absence of the Rh (D) antigen on the
Fetus/Newborn (HDN) surface of RBC’s. In this test, a patient’s RBCs are mixed with serum containing anti‐Rh (D)
antibodies and are observed for clumping. If clumping occurs, the Rh (D) antigen is present, and
the patient’s blood is typed Rh positive; if clumping doesn’t occur, the antigen is absent, and the
patient’s blood is typed Rh‐negative.
Purpose of Rhesus Typing
o To establish blood type according to the Rh system.
o To help determine the donor’s compatibility before transfusion.
o To determine if the patient will require an Rh (D) immune globulin injection.
Normal Results
o If the D antigen is present, that person is Rh positive.
o If the D antigen is absent, that person is Rh negative.
o Antibodies to Rh antigens develop only as an immune response after a transfusion or during pregnancy.
Abnormal Results
o Rh incompatibility is the most common and severe cause of HDN, possible when Rh‐negative woman and an Rh‐positive man
produce an Rh positive baby.
Pre‐requisites Mother lacks the Rh antigen AND is exposed by pregnancy/transfusions
Fetus possesses the antigen and it’s well developed in utero (most RBC antigens are, except for ABO, I, P, Lewis, Cartwright: ABO
NOT FULLY EXPRESSED)
Mother produces the IgG antibody – will cross the placenta, but IgM can NOT cross the placenta
Pathogenesis Fetomaternal hemorrhage (FMH) always occur: as early as 8 weeks‐most at delivery
o During the first pregnancy, the mother (Rh negative) is exposed during delivery
Which causes an immune response to form antibodies to the Rh positive antigen and
produce B cells
The Rh‐specific B cells will form memory cells
o During the second pregnancy, if the fetus is Rh positive and the mother is exposed
The Rh‐specific memory cells will recognize the fetal antigen and produce IgG antibodies
which can cross the placenta and attack the fetal RBC causing erythroblastosis fetalis
Immunization risk increases with FMH volume
Risk factors that may induce formation of the antibodies include:
o Trauma, procedures, abortion
o Always avoid using father’s blood when the mom needs a transfusion
In the Rh System:
o D most immunogenic (severe HDN)
o Other blood groups can cause an immune response:
Anti‐K, anti‐Fya, anti‐S
ABO groups are not fully formed in utero
o Group O (contains Anti‐A and Ant‐B) mom with an A‐antigen fetus (mild if any HDN)
o ABO HDN: 15% of pregnancies
o Treatment is exposure under ultraviolet light
Clinical Findings Fetal Hemolysis
o Fetal Anemia = “anemia neonatorum”
o Fetal Jaundice = “icterus gravis/ icterus praecox”
Accelerated red cell destruction‐Compensation
o Accelerated RBC production with increased extramedullary erythropoiesis and circulating nucleated RBCs called
“erythroblastosis fetalis”
This can occur in the liver, kidney
o With increased erythropoiesis in the liver, this causes Hepatomegaly
Hepatomegaly can lead to Edema‐Decompensation
o Generalized edema (called Anasarca) leading to hydrops fetalis
Hydrops fetalis (fetal hydrops) is a serious fetal condition defined as abnormal accumulation of fluid in two or more fetal
compartments, including:
ascites, pleural effusion, pericardial effusion, and skin edema.
In some patients, it may also be associated with polyhydramnios and placental edema.
o CHF, hemorrhage, enlarged placenta
Severe anemia: Fetal death
Bilirubinemia
o Fetus in utero:
Bilirubin from the fetus is processed in the Mom’s liver to conjugate the bilirubin
o Newborn: Liver is immature and is unable to process bilirubin
This buildup of bilirubin may lead to kernicterus
Kernicterus is a very rare type of brain damage that occurs in a newborn with severe jaundice. It happens when bilirubin
builds up to very high levels and spreads into the brain tissues. This causes permanent brain damage.
Pre‐Natal Testing ABO
Rh
Antibody screen: because HDN can occur with other ABO blood groups
o If positive, we do serial titration of the antibody through out the pregnancy
History
Assessing Risk to Fetus Antibody titer comparison
Amniocentesis:
o good indicator of intrauterine hemorrhage
Liley’s Graph: checks the optical density in the amniotic fluid to correlate with levels of bilirubin
PUBS, (percutaneous umbilical blood sampling) or cordocentesis: direct measure of fetal hemoglobin
Intrauterine Transfusion To correct fetal anemia
o Intrauterine transfusions can start at 24‐26 weeks of gestation from an Rh negative donor, even if the fetus is Rh positive
o Done periodically (every 2 weeks) until delivery
HDN Prevention What is it?
Rh Immune Globulin (RhIg) o Concentrate of IgG anti D
o Developed from pools of human plasma
o Trade names: RhoGam, Rophylac
How does it work?
o Antigen blocking‐antibody mediated immunosuppression
RhIg Dosage: 1 ml = 300 ug
o This dose is sufficient to prevent immunization from 15 ml of RBCs or 30 ml of whole blood
Can be given IM (RhoGam) or IV (Rophylac)
At 28 weeks
Within 72 hrs postpartum after determining volume of FMH to neutralize any fetal cells that are within the mother’s
circulation
Also given during:
o Abortions
o Trauma
o Procedures
o During emergencies: Transfusion of Rh+ products (with RhoGam) to an Rh‐ woman of child bearing age
HDN Summary Prevention= RhIg at 28 weeks and 72 hrs post partum, others
Clinical Finding Pathogenesis Treatment
Anemia Alloimmune hemolysis Intrauterine, exchange and or simple
transfusions
Jaundice Hemolysis Phototherapy
Erythroblastosis Extramedullary erythropoiesis in the Transfusion
liver
Anasarca (Generalized Hypoalbuminemia‐CHF Exchange transfusion
edema)
CHF Anemia Transfusion
AutoImmune Hemolytic Auto‐Antibodies against RBC antigens
Anemia (AIHA) Most are not significant
Some cause hemolysis
Risk increases with each decade of life
AIHA can develop from:
o Idiopathic
o SLE, CLL, Lymphomas, malignancies
o Cold agglutinin disease usually transient in children
Cause Crossmatch incompatibility with all RBC units
Labs With anemia there is a Decreased Hg/Htc
o Since Hb is decreased there is an Increased Bilirubin
o Increased LDH due to lysing of RBC
+DAT
+Ab Screen using Indirect Antigobulin Test (IAT)
Low or absent haptoglobin
Peripheral smear with
o Spherocytes
o Polychromasia
o Circulating nucleated RBCs
AIHA Disease Associations Ig Clearance of Hemolysis DAT/IAT
Warm ‐Autoimmune diseases IgG (Ab‐Ag reaction Extravascular (Fc receptors Both IgG and C3:
Autoimmune HA ‐Lymphoid malignancies at 37 C) in liver and spleen) +DAT
+IAT (Ab Screen)
Cold Agglutinin ‐Post infection (mycoplasma, IgM (Ab‐Ag reaction Extravascular (C3 receptors +DAT (C’ only)
Disease Infectious mononucleosis) at 25 C or colder) in liver) +IAT
‐Lymphoid malignancies
Drug Associated Drug associated Usually IgG Extravascular IgG +DAT in the presence
HA of the drug in plasma
AIHA Treatment Warm Autoimmune HA
o Steroids, IVIG, Immunosuppression, Splenectomy
Cold Autoimmune HA
o Supportive care, Keep patient warm, Treat underlying disease
Drug induced
o Stop drug exposure
Transfusion Reactions ANY unfavorable consequence is considered an adverse effect of blood transfusion.
It is also referred to as a TRANSFUSION REACTION
Response Immunologic Non‐Immunologic
Acute (<24 hours) Hemolytic Circulatory Overload
Febrile Non‐hemolytic Hemolytic (physical or chemical destruction of
Allergic RBCs)
Anaphylactic Air Embolus
TRALI (Transfusion Related Acute Lung Hypocalcemia
Injury) Hypothermia
Delayed (>24 Hemolytic (anamnestic response) Iron Overload
hours) Graft vs. Host Disease
Post‐Transfusion Purpura
Other considerations:
o Infectious Complications of Blood Transfusion leading to Septis
o Other Consequences of Blood Transfusion (immunomodulation, refractoriness)
Acute Transfusion Acute Hemolytic Transfusion Reaction
Reactions o Incidence: 1 in 76,000
Immunologic o Fatal: 1 in 1.8 million
o Cause: Red Cell Incompatibility Intravascular hemolysis that starts after pre‐formed antibodies activate complement to
completion in the vasculature
Signs and Symptoms:
o Onset within minutes to hours
o Release of cytokines leading to fever, hypotension, shock
o Pain along infusion site and patient anxiety
o Coagulopathy that may progress to DIC (disseminated intravascular coagulopathy)
o Renal failure with oliguria and anuria
due to Hgb and RBC stroma
resulting in free Hemoglobin in serum and urine
Prevention:
o Give ABO Compatible Blood
Febrile Non‐Hemolytic Transfusion Reactions
o Incidence: 1:17 to 1:200 RBCs and 1:3 to 1:100 platelets.
Down to about 1‐2% after universal leukoreduction, (from ~30%)
Cause: Increase in temperature of 1C (2 F)
due to recipient antibodies against donor leukocyte antigens, and/or accumulated cytokines
Signs and Symptoms:
o Usually mild fever
But may lead to chills, rigors, headaches, vomiting
o Seen in multiply transfused patients, multiple pregnancies
Must rule out:
o Hemolytic transfusion reaction is dose dependent
o Bacterial contamination
Prevention:
o Leukoreduction of cellular blood products (antipyretics)
is the removal of white blood cells (or leukocytes) from the blood or blood components supplied for blood transfusion. After
the removal of the leukocytes, the blood product is said to be leukoreduced
Leukoreduction of Blood Leukocyte‐reduced RBCs
Products o At least 85% of original RBCs
o < 5 x 10^6 WBCs in 95% of units tested
Leukocyte‐reduced Platelet Concentrates:
o At least 5.5 x 1010 platelets in 75% of units tested
o < 8.3 x 10^5 WBCs in 95% of units tested
Leukocyte‐reduced Apheresis Platelets:
o At least 3.0 x 1011 platelets in 90% of units tested
o < 5.0 x 10^6 WBCs 95% of units tested
Allergic (Urticarial) Transfusion Reaction
o May re‐start the unit slowly after treatment, if symptoms resolve
Incidence:
o 1:33 to 1:100
Cause:
o Recipient antibodies against donor plasma proteins or other allergens (food, medications)
Signs and Symptoms:
o Begins within minutes of infusion, release of histamine
leading to rash, itching and hives (called urticaria)
o Must be sure that the only reaction is the urticaria
Prevention:
o Pre‐treatment with anti‐histamines to avoid the reaction
Anaphylactic Transfusion Reaction
Incidence:
o 1:20,000 to 1:50,000
Cause:
o Recipient is IgA deficient and has anti‐IgA in serum that reacts to even small amounts of donor IgA in the plasma of any blood
component
Signs and Symptoms:
o Sudden onset of symptoms. Life threatening!!!!
o Hypotension leading to shock, loss of consciousness, and death
o Difficulty breathing and bronchospasms leading to cyanosis
o Nausea and vomiting, severe abdominal cramps, diarrhea
Prevention:
o STOP transfusion Immediately
o Wash cellular blood products or give IgA deficient products
Transfusion Related Acute Lung Injury (TRALI)
Acute onset of respiratory distress
o That occurs during or within 6 hours of the transfusion
Clinical Features
o Hypoxemia
o Dyspnea
o Non‐cardiogenic Pulmonary edema
o Hypotension
o Fever
o Bilateral lung infiltrates on CXR
Incidence:
o 1:1,200 to 1:190,000
o Can contribute to mortality in 1 in 200,000 transfusion recipients
(leading cause of death)
Cause:
o Donor HLA antibodies match the antigen against recipient WBCs:
antibodies bind to antigen in PMN causing aggregation and adhesion to capillary endothelium in the lungs
causing complement activation and resulting in edema
Previous Research
o 15‐20% of female donors have HLA antibodies
1 pregnancy causes a 10% risk of HLA alloimmunization, 2 pregnancies 20%, etc..
75% fatalities were linked to female donors with HLA Antibodies
25% of fatal cases have no demonstrable Ab trigger and may be related to “storage lesion” and patient factors
o <1% of male donors have HLA antibodies
o There is a 5‐7 fold greater TRALI occurrence with high volume plasma products:
Such as Fresh Frozen Plasma/plasma frozen (greater risk) > Platelets > Red cells
Acute Transfusion Circulatory Overload (TACO)
Reactions Incidence:
Non‐Immunologic o ~1%. Elderly and pediatric patients at risk
Cause:
o Rapid increase in blood volume to a patient with compromised cardiac or pulmonary function
Signs and Symptoms:
o Dyspnea
o Cyanosis
o Severe headaches
o Hypertension unique to TACO)
o congestive heart failure
Prevention:
o Stop infusion and place patient in a sitting position
o Slow down future infusions
Other types:
o Physically or Chemically induced hemolysis
o Hypothermia
o Hypocalcemia – citrate is within the blood products which traps calcium
o Air embolism
Infectious Complications of Bacterial Contamination
Blood Transfusion Most often seen from platelets transfusions (room temperature)
If bacteria are present Red cell units will look dark
Symptoms:
o Rapid onset
o Fever, shaking chills, hypotension, muscle pain
o Nausea and vomiting, abdominal cramps, diarrhea, hemoglobinuria, shock, renal failure and DIC
Stop transfusion immediately
Gram stain and blood cultures on unit, patient and infusion set samples
IV broad spectrum antibiotics
Prevention:
o Maintain standards of donor selection, blood collection and maintenance of collected blood components
Estimated Residual Risk HIV 1:2,000,000
After Currently Mandated HTLV 1:2,900,00
Testing Hepatitis B 1:1,000,000
Hepatitis C 1:1,150,000
Bacterial contamination 1:2,000 to 1:4,000 and <1:10,000 culture
WNV 11 cases reported since 2002
Transfusion Reaction Work What to do FIRST if an Acute Transfusion Reaction is suspected (within 15 minutes)
up o STOP THE TRANSFUSION!!!!!!!
o Keep the line open with saline solution
o Notify the Blood Bank and Physician immediately
Post‐transfusion blood samples to be collected:
o Clotted specimen:
Repeat ABO, Rh, IAT and Crossmatch.
o EDTA specimen:
Direct antiglobulin test
If DAT is negative then will need to Visual check for hemolysis comparing with pre‐transfusion sample
o Clotted specimen:
collect 5‐7 hours after transfusion to check bilirubin levels
Recipient diagnosis
Information to collect
o Prior history of pregnancy or transfusions
o Current medications
o Signs and symptoms during transfusion reaction
o How many ml’s of blood product were infused
o Was a blood warmer used? Infusion pump?
o Was the component manipulated in any way?
o Other solutions/medications given concomitantly?
o Pre and Post transfusion vital signs?
Suspected Transfusion Verify all patient identification and unit identification Misidentified patients is one of the leading causes of transfusion related
Reaction deaths in the United States
If misidentification is found, search the floor/unit for other patients receiving blood and verify their identification and unit
Even today 1:10,000 units are Txed to the wrong Pt
Always double check the patient identifiers with the unit tags before spiking the bag
Recognize the symptoms
Observation within 15 minutes of start is critical for detection of an acute reaction
STOP the transfusion when symptoms occur!
Clinical Approach to Anemia (Online)
Red blood cell disorders There are two types of red blood cell disorders.
The first is anemia, which refers to a decrease in the number of red blood cells. It is actually, however, defined as a reduction in
oxygen transporting capacity of the blood. Anemias are very common.
The second type of red blood cell disorder is polycythemia, which is also known as erythrocytosis.
o This condition is an increase in the total number of red blood cells.
o Polycythemia overall is much less common than anemia.
o Two types of Polycythemia:
Primary polycythemia (also referred to as Polycythemia Vera) is a primary abnormality of the bone marrow categorized as a
myeloproliferative syndrome.
Secondary polycythemia can occur people who smoke or who live at high altitude.
Classifications of Anemia There are several ways in which to classify anemia:
o via morphologic changes in the red blood cells
o via functional changes and
o via mechanism
MORPHOLOGY Anemia can be classified by morphology which refers to the size of the red blood cell.
The 3 categories are:
o Microcytic
o Macrocytic
o Normocytic.
Clinically, this is measured by the MCV or the Mean Corpuscular Volume.
o Anemias with a low MCV (<85 fL) are considered microcytic.
Examples of these anemias include the following:
Iron deficiency (late stages)
Thalassemias
Lead poisoning
Sideroblastic anemia
Anemia of chronic disease (late stages)
o Anemias with a high MCV (>100 fL) are considered macrocytic.
Macrocytic anemias can be further classified as
Megaloblastic
o A megaloblast is an unusually large red blood cell; see image ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
o Examples of these anemias include the following:
Megaloblastic:
Folate deficiency
B12 deficiency
Non‐megaloblastic:
o Liver disease
o Alcoholism
o Reticulocytosis ‐ is a condition where there is an increase in reticulocytes, immature red blood cell
o Anemias with normal MCV (85‐95 fL)are considered normocytic.
Examples of these anemias include the following.
Iron deficiency (early)
Anemia of chronic disease and chronic inflammation
Chronic kidney disease
Aplastic anemia (marrow failure)
Clinically an anemia may begin in one category and transfer into another with progression of the disease.
o For example, in early iron deficiency anemia,
the MCV may be normal
but as the iron levels continue to decline over time
o the anemia will often become microcytic.
o In addition, there can be several processes occurring at the same time which can skew the interpretation
for example, if patients have an iron deficiency (low MCV) and B12 deficiency (high MCV)
the patient's actual MCV may be high, low, or normal.
FUNCTIONAL Anemia can be classified by function.
o This typically refers to either a hyperproliferative or a hypoproliferative state.
o This is measured clinically by the reticulocyte count.
Reticulocytes are immature red blood cells.
They are produced in the bone marrow, released into the blood stream, and in about one day become mature red blood
cells.
o The reticulocyte count reflects the bone marrow's response to anemia.
A high reticulocyte count reflects
an adequate response of the bone marrow to the anemia.
A low reticulocyte count indicates
an underproduction or an inadequate response of the bone marrow.
Clinically, however, the reticulocyte count itself is not the most useful measure of the bone marrow response
o because it is usually reported as a percentage of total red blood cells.
Because anemia is associated with a total reduction in the number of red blood cells, the percentage of reticulocytes may be
artificially elevated.
There are two alternative clinical values that are more useful:
o Reticulocyte index (RI) or Corrected Reticulocyte Count:
% Pt Hematocrit
% of reticulocytes
%
Where in the equation, 45% is the normal hematocrit in
males; 40% in females
Normal RI is 0.5% ‐ 2.0%
RI < 2% indicates hypoproliferation
RI > 2% indicates hyperproliferation
o Most often, a reticulocyte count is performed with an
automated instrument (hematology analyzer) and can be done
simultaneously with a CBC, which includes an RBC count,
hemoglobin and hematocrit.
Either an absolute number of reticulocytes and/or a
percentage of reticulocytes can be reported.
For a percentage, the number of reticulocytes is compared to the total number of RBCs:
Reticulocyte % Number of Reticulocytes/Number of total RBC x 100%
o Absolute reticulocyte count (ARC)
Measured by flow cytometry
Normally, the ARC should be greater than 25,000‐75,000µL
Low: ARC < 50,000 µL
Normal: ARC = 50,000 – 100,000 µL
High: ARC > 100,000 µL
Comparing Hyperproliferative to Hypoproliferative Anemia
Hyperproliferative Anemias Hypoproliferative Anemias
Acute blood loss Deficiency of essential red blood cell producing substrates Iron,
B12, and Folate
Hereditary Hemolytic Anemia: Anemia of chronic disease
Thalassemia, Sickle Cell Disease, and Hereditary
Spherocytosis
Acquired disorders: Anemia due to endocrine disorders
Immune hemolytic anemias (IHA), Malaria, and Valvular
heart disease
Anemia due to marrow infiltration and stem cell disorders
Intrinsic and extrinsic hemolytic anemias Aplastic anemia
MECHANISM Anemia can also be classified by the cause:
o Blood loss (acute or chronic)
o Decreased production (ie bone marrow failure issues)
o Increased destruction (ie hemolytic anemias)
Approach to the Patient History
o One must always obtain a thorough history to help determine the cause of the anemia and appropriate treatment.
o Commonly reported symptoms in all types of anemia include the following:
Shortness of breath
Weakness
Fatigue
Insomnia
Children ‐ growth retardation and failure to thrive
By asking additional questions you may be able to determine potential contributing causes:
o Blood loss anemia
ask about any signs of recent bleeding
Nutritional deficiencies:
o Screen for decreased B12, folate, or iron consumption (ie red meats, dark leafy greens, beans, eggs, dairy)
Ask about reasons for malabsorption: (ie history of gastric bypass, Celiac disease)
Ask about excess consumption of alcohol
Ask if the patient has Pica
Pica is the persistent eating of substances such as dirt, clay or chalk that have no nutritional value
Pica may be seen in patients with severe iron deficiency anemia
Chronic illnesses:
o Liver disease
o Chronic kidney disease
o Cancer
o Chronic infections such as tuberculosis, osteomyelitis
Recent acute illnesses or infections:
o Parvovirus B19 ‐ a virus which replicates in erythroid precursor cells and kills them.
The virus is notorious for causing aplastic anemia in persons with chronic (hemolytic) anemias
o Diarrheal illness ‐ think possible hemolytic‐uremic syndrome with infection with E Coli, Shigella, or Salmonella
o Malaria
Signs of hemolysis
o Darkening of urine
o Yellowing of skin or eyes
o Presence of prosthetic heart valves
The list above is by no means exhaustive. However, it demonstrates some of the different symptoms, signs, and causes of
anemia that you should consider and learn to ask in your interview as you begin to encounter and care for patients with different
types of anemia.
Approach to the Patient Physical Exam
o A thorough physical exam is just as crucial as a complete history in determining the underlying cause of anemia.
If you have a good eye, you may just have the answer before you even get to the laboratory evaluation.
The images below show some characteristic physical exam findings of different types of anemia.
Conjunctival Pallor ‐ There is usually a marked difference between the red anterior and creamy
posterior parts. This difference is absent when significant anemia is present.
Kiolonychia – spooning of the nail bed associated with severe iron deficiency
Papillary atrophy – note the smooth surfaces on the periphery on the tongue with reflects the
loss of normal papillae. Can be seen with Vitamin B12 deficiency
Angular stomatitis – can be seen with nutritional deficiencies such as iron or B12
Typical slapped cheek rash in Parvovirus infection
Scleral icterus – seen with hemolytic anemias
Jaundice – typical yellowing of the skin
Clinical Indices
o We previously discussed the MCV, reticulocyte index, and absolute reticulocyte count.
However, when encountering a patient with anemia there are additional laboratory values that are important and merit
discussion here.
o As shown in the table, the hemoglobin, hematocrit, and red cell count have a lower range of normal in women than in men.
Element Male Adult Female Adult
Hemoglobin 14‐18 g/dL 12‐16 g/dL
Hematocrit 42‐50% 37‐47%
Red blood cell count (RBC) 4.6‐6.0x106/L 4.2‐5.4x106/L
MCV 80‐100 fL 80‐100 fL
MCH 27‐31 pg 27‐31 pg
MCHC 32‐36 g/dL 32‐36 g/dL
RDW 11.9‐15.5% 11.9‐15.5%
o The MCV or mean corpuscular volume is a measure of the average volume of the red blood cell.
MCV is used to determine if a red blood cell is normal size, too big, or too small.
Can be calculated from hematocrit and the red blood cell count (RBC)
/
fL 1000
10 /
Where 1 L = 1x10^6 micro‐L
o The MCH or mean corpuscular hemoglobin is the average mass of hemoglobin per red blood cell.
Hemoglobin 10
RBC
o The MCHC or mean corpuscular hemoglobin concentration is a measure of the concentration of hemoglobin in a given volume
of red blood cells.
Hemoglobin
Hematocrit
o Where MCH and MCHC are relevant in the discussion of hypochromic and hyperchromic anemias.
Hypochromic anemias are anemias in which the red cell looks pale on a blood smear
o hypo = decreased, chromic = color
The cell looks pale because there is less hemoglobin in the cell than normal.
Therefore, both MCH and MCHC are decreased in hypochromic anemias.
The most common hypochromic anemias are iron deficiency and thalassemia.
o In the image:
On the left are normal red blood cells in terms of color and size.
The photo on the right shows cells that are smaller in size (microcytic) and have central pallor
(hypochromic).
This is a blood smear that would be commonly seen in iron deficiency anemia.
Hyperchromic anemias are anemias in which the red blood cell appears darker and deeper in
color on a blood smear.
o This occurs because there is more hemoglobin relative to the volume of the red blood cell.
MCHC is elevated in hyperchromic anemias.
EX – hereditary spherocytosis:
a familial hemolytic anemia in which the red cell membranes are weak due to one of
several mutations.
o As a result, the cells become smaller and darker in appearance as evidenced the
picture below.
o Importantly, the MCHC is normal in macrocytic anemias.
Why? Although the amount of hemoglobin is elevated (MCH is high) the cell itself is also large, so the total concentration of
hemoglobin relative to cell volume remains normal.
RDW, or red cell distribution width, is a measure of variation in red cell sizes.
o RDW is high in
iron deficiency anemias
macrocytic anemias.
o RDW is normal in
Thalassemias
anemias of chronic disorders.
Peripheral blood smear Use the following steps to evaluate a peripheral blood smear:
o Characterize the size of the RBCs
microcytic, normocytic, or macrocytic
o Characterize the hemoglobin density:
hypochromic, normochromic, or hyperchromic
o Evaluate for variations in
size (anisocytosis)
shape (poikylocytosis)
o Evaluate for any abnormal forms:
schistocytes, target cells, spherocytes, acanthocytes, etc
We have reviewed images for the size and hemoglobin density of red blood cells on prior pages. Let's now look at some
examples of variations in size and learn to recognize abnormal forms.
Anisocytosis refers to a variation in red blood cell size.
o RDW (red cell distribution width) is a quantitative measure of anisocytosis.
The picture below demonstrates this.
Poikylocytosis: refers to a variation in red blood cell shape
o There are many different shapes red blood cells depending on the underlying pathology.
Acanthocyte (acantho = "spiny") or spur cell.
Have multiple tiny projections seen all over their surface.
Seen in liver disease.
Echinocyte or burr cell:
o These cells are often confused with spur cells.
o The projections on burr cells are smaller and more evenly spaced than spur cells.
o They also show a small area of central pallor as compared to spur cells.
o These cells are often present in chronic kidney disease.
Bite cell:
o Seen in a G6PD deficiency.
This is an X‐linked condition resulting in a deficiency of the enzyme G6PD (glucose‐6‐
phosphate‐dehydrogenase) in RBCs.
After episodes of stress including infections, exposure to certain drugs, or exposure to fava
beans, a hemolytic anemia is triggered.
Red blood cells typically form Heinz bodies (image on left), which are small round inclusions in
the cell, made up of denatured hemoglobin.
As this atypical cell passes through the spleen, it removes the Heinz body and the result is a
bite cell (image on right).
Schistocyte or helmet cell:
o These are irregularly shaped often jagged fragments of red blood cells.
o They are seen in hemolytic anemias.
Sickle cell:
o These cells are seen in sickle cell anemia;
this is a very serious disorder in which abnormal hemoglobin molecules within the red blood
cell cause them to take on a sickle or a crescent shape.
o Because the cells are abnormal they also have a shorter half life than typical red blood cells
which produces the anemia.
o The abnormally shaped red blood cells get stuck in smaller blood vessels and cause many of the
characteristic symptoms of this condition including pain crises.
Dacrocyte or teardrop cell:
o These cells are typically seen in myleofibrosis (bone marrow fibrosis) or infiltration of the bone
marrow by a process like metastatic cancer.
o These cells take on a teardrop shape because they are forced to squeeze themselves in narrow
spaces in a fibrosed bone marrow or marrow crowded with cancer cells.
Codocyte or target cell:
o These cells are named as such because they appear with a central, darker area surrounded by a
white ring, giving them the appearance of a bull's eye.
o These cells are typically seen in liver disease and thalassemia.
Bone Marrow Biopsy In some cases clinical presentation, laboratory values, and peripheral smear examination are not sufficient to confirm a
suspected diagnosis or cause of anemia.
o In these situations, patients will often go on to have a bone marrow biopsy.
When the marrow is examined, it usually involves two parts: a bone
marrow aspirate and a bone marrow biopsy.
o A bone marrow aspirate contains spicules of bone marrow that allow
for easy assessment of multiple cell types and lineages.
However, many pathologic processes like fibrosis are missed on an
aspirate and require a biopsy.
o Biopsies provide better assessments of overall cellularity.
The picture on the left shows a normal bone marrow aspirate
showing multiple different cell types and different stages of maturation.
The picture below on the right shows a normal bone marrow biopsy which shows bone, fat, and cellular elements.
Review: Approach to the Patient
o Now that we have discussed a thorough history, physical exam, review of laboratory values, and evaluation of a peripheral
smear, let's put it all together and practice with some cases. Below is an algorithm that you can follow to evaluate a patient
with anemia in a standard manner:
Anemia – Is anemia associated with other hematologic abnormalities that warrant bone marrow examination? EX – abnormal
WBC, abnormal platelet count, abnormal or immature cells on peripheral blood smear
o Yes:
Do bone marrow examination and evaluate for:
leukemia, lymphoma, myelodysplasia, aplastic anemia, myelofibrosis, myelophthisis, megaloblastic anemia, anemia of
chronic disease, infection, or congenital anemias
o No: Is there an appropriate reticulocyte response to anemia?
Yes: Is there evidence of hemolysis? (history of jaundice, increased serum bilirubin, increased serum LDH, decreased serum
haptoglobin, blood smear abnormalities (spherocytes, schistocytes), or hemosiderinuria)
Yes: Is direct antiglobulin test (DAT) positive?
o Yes:
Evaluate for immune hemolytic anemias (IHA) including:
SLE, Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), drug‐induced (alpha‐methyldopa, penicillin,
cephalosporins)
o No:
Evaluate for inherited hemolytic disorders (HS, HE, G6PD deficiency, PK deficiency, hemoglobinopathies) and
acquired nonimmunohemolytic anemia (MAHA, PNH, infectious agents such as malaria, oxidant drugs and
chemicals)
No:
o Evaluate for acute or chronic blood loss
No: Check MCV
If MCV > 100 fL
o Evaluate for macrocytic anemia including:
Megaloblastic anemia (B12 and/or folate deficiency), alcoholism, liver disease, myelodysplasia, drugs and toxins
(zidovudine, methotrexate, arsenic), infections (HIV), hypothyroidism
If MCV = 80‐100 fl
o Evaluate for normocytic anemia including:
Anemia of chronic disease, pure red cell apasia, chronic renal insufficiency, liver disease, endocrine disorders
(androgen deficiency)
If MCV < 80 fL
o Evaluate for microcytic anemia:
Iron deficiency, thalassemia, sideroblastic anemia, hemoglobin E disease, anemia of chronic disease, lead poisoning
Case 1
Ms E. is a 41 yo Caucasian woman who presents with several months of fatigue. She notes that her sleep has been fine. She denies shortness of breath except
that she feels a little more winded now when carrying her laundry up and down the stairs; she does not exercise regularly. She has no chest pain and no
palpitations. On further questioning, she reports that her menses have been heavier over the last year but she denies any other symptoms of bleeding including
epistaxis, melena, and hematochezia. She has no allergies and takes only a multivitamin; she only sporadically will use ibuprofen for relief of menstrual cramps.
She has no significant past medical history.
o Epistaxis: bleeding from the nose
o Melena: dark sticky feces containing partly digested blood
o Hematochezia: is the passage of fresh blood through the anus, usually in or with stools
With regards to her family history, her parents are both from Italy, her mother has hypothyroidism and uterine fibroids, and her father died young in a car
accident.
Physical exam is as follows:
o Vitals: BP 120/60, HR 88, Respiration 12/min, orthostatics were negative
o Gen: no acute distress, well‐nourished
o Skin: no bruises or petechiae
o HEENT: + conjunctival pallor, no scleral icterus, mucous membranes are moist, no noted epistaxis or bleeding gums
o Neck: thyroid is normal without nodules or tenderness
o LAD: no supraclavicular, cervical, or axillary lymphadenopathy
o Chest: clear to auscultation bilaterally
o CV: regular rate and rhythm, soft I/VI systolic murmur
o Abdomen: soft, non‐tender, non‐distended, no hepatosplenomegaly
o GU: normal external genitalia, normal vaginal mucosa without discharge, cervix appeared normal, bimanual exam normal
o Rectal: brown stool in vault, no palpable or visible hemorrhoids
o Ext: no clubbing, cyanosis, or edema
o Neuro: normal
Complete blood count:
Patient's Result Normal Range
WBC 8.2 4.8-10.8 x 103/μL
Hgb 8.0 12-15.6 g/dL
Hct 24% 35-46%
RBC 2.8 3.8-5 x 106/μL
MCV 60 80-96.1 fL/red cell
MCH 20 27.5-33.2 pg/red cell
MCHC 33 33.4-35.5 g/L
RDW 16.5 11.5-14.5
Platelets 500,000 150-400,000 μL
Reticulocyte count 1% 0.5-1%
Absolute reticulocyte count 40,000 25,000-75,000 μL
LDH 210 U/L 0-304 U/L
The patient’s blood smear:
Question: Based on the above clinical information, how would you classify this anemia?
Answer: Microcytic, Hypochromic, and Hypoproliferative
o The MCV is low which suggests that it is microcytic, and this is confirmed on the peripheral smear showing small red blood cells.
o The MCH and MCHC are also low which suggests that it is hypochromic; this is also visible on the peripheral smear as evidenced by the central pallor of most
of the red blood cells.
o Since the absolute reticulocyte count is normal (not elevated), this patient has a hypoproliferative anemia.
Question: Which anemias are characteristically microcytic and hypochromic?
Answer: Iron deficiency, Anemia of chronic disease, and Thalassemia minor
o Anemia of chronic disease may first present as a normocytic anemia and then progress to microcytic anemia.
o Iron deficiency anemia may first present as a normcoytic anemia and then progress to microcytic anemia.
o Thalassemia minor is microcytic, hypochromic anemia
The above blood smear also demonstrates poikylocytosis which is confirmed by the elevated RDW.
You can help differentiate between iron deficiency anemia, anemia of chronic disease, and thalassemia minor based on further laboratory studies. These values
are summarized in the table below.
Anemia of Chronic Thalassemia
Normal Iron Deficiency Disease (minor)
Ferritin 18-300 ng/mL Low <12nm/mL NL / elevated NL / elevated
Serum iron 40-180mcg/dL Low <40mcg/dL Low NL / elevated
Elevated
TIBC 250-450mcg/dL >350mcg/dL Low <30 mcg/dL NL to high
Transferrin Saturation
(Iron/TIBC ratio) 25-35% <15% >15% Normal
RDW NL High / NL NL NL
MCV NL Low Low / normal Low
Ferritin represents the amount of iron stored in the body.
o Ferritin is low in iron deficiency.
o Ferritin is often elevated in anemia of chronic disease as it is a marker of overall body inflammation in this case. Thus, ferritin is an "acute phase reactant".
TIBC is the total iron binding capacity;
o this measures the body's ability to bind iron to transferrin which is the protein that transports iron through the blood.
TIBC is high in iron deficiency as there is very little iron in the blood so a lot of transferrin is available to bind iron.
TIBC tends to be low in anemia of chronic disease because the production of transferrin is decreased in states of chronic inflammation.
The transferrin saturation is the ratio of serum iron to TIBC;
o this indicates how much of the transferrin that is available in the blood is actually bound to iron.
The transferrin saturaiton is low in iron deficiency as there are low levels of iron and high levels of transferrin
The transferrin saturation is elevated in anemia of chronic disease because there are low levels of circulating iron in the blood and very low levels of
available transferrin.
As reviewed previously, the RDW is high in iron deficiency, and normal in anemia of chronic disease and thalassemia.
Ms. E.'s iron studies are as follows:
Serum iron 30mcg/dL
TIBC 375mg/dL
Transferrin saturation 8%
Ferritin 9ng/mL
In addition, three stool samples are submitted for fecal occult blood testing and these are negative, indicating that she is unlikely to be losing blood through her
GI tract.
Question: Based on all of the above information and the iron studies, what is the most likely cause of Ms. E’s anemia?
Answer: Iron deficiency anemia
o This is a very common clinical scenario. Ms. E is a young woman who has regular menstrual cycles that have been heavier in the last year. In addition, she has
a family history of fibroids which can cause heavy bleeding. All of her studies are consistent with the diagnosis of iron deficiency anemia: a microcytic,
hypochromic anemia (low MCV, low MCH and MCHC), anisocytosis on her smear confirmed by an elevated RDW, and low reticulocyte count due to a low level
of both circulating serum iron and stored iron (ferritin).
She is diagnosed with iron deficiency anemia and started on ferrous sulfate 325mg three times per day.
Three months later her repeat lab studies show a normalized hemoglobin, a low‐normal MCV, and a ferritin level of 45. She continues to have some heavy
bleeding and is evaluated by her gynecologist for treatment of the fibroids but opts for watchful waiting and continuation of oral iron therapy.
Case 2
Mrs. R is a 37yo woman who was incidentally found to be anemic during her evaluation for infertility. She has no complaints except some intermittent trouble
sleeping. Her menstrual cycle is regular and light. Her only other medical history is vitiligo and Hashimoto's thyroiditis. She has no past surgical history.
Her family history is notable for a maternal grandmother with rheumatoid arthritis and a father with diabetes mellitus. She has no allergies.
Her only medication is 100mcg of synthroid daily. Her physical exam:
Vitals: BP 106/72, HR 68, Respiration 12/min Gen: no acute distress, well‐nourished
Skin: vitiligo on her hands (see image below) HEENT: + conjunctival pallor
Neck: thyroid is mildly enlarged and rubbery, no discrete nodules LAD: no supraclavicular, cervical, or axillary lymphadenopathy
Chest: clear to auscultation bilaterally
CV: regular rate and rhythm, no murmurs
Abdomen: soft, non‐tender, non‐distended, no hepatosplenomegaly Ext: no clubbing, cyanosis, or edema
Neuro: normal
Vitiligo is a skin condition that involves depigmentation of the skin. It is caused by destruction of the melanocytes in the skin, and
results in patches of white skin and hair loss. Below is a typical presentation of vitiligo:
Her complete blood count is as follows:
The patient's blood smear is shown:
Question: Based on the above clinical scenario, how would you classify this anemia?
Answer: Macrocytic, Normochromic, Hypoproliferative
Question: Given that the above findings suggest a macrocytic anemia, which of the following conditions would be on your differential diagnosis?
Answer: B12 and folate deficiency would be expected to produce a macrocytosis (elevated MCV).
o There are two main causes of megaloblastic anemias: B12 (cobalamin) deficiency and folate deficiency (early myelodysplastic syndrome is another less
common cause)
o B12 deficiency can be related to the following:
Inadequate dietary intake (found usually in animal products like meat, fish, and dairy products) Malabsorption
Intrinsic factor deficiency
Terminal ileum disorders
o Folate deficiency can be related to the following:
Inadequate dietary intake (found in most foods but most highly in liver, yeast, spinach, other greens, and nuts) Increased folate requirements (such as
pregnancy)
Malabsorption
Impaired metabolism (inhibitors of DHFR)
Additional laboratory studies are sent, and the results are as follows:
Based on the above, her anemia is likely from B12 deficiency caused by underlying pernicious anemia, which is evidenced by the presence of intrinsic factor
antibodies.
o Both B12 and folate are critical for DNA synthesis;
without them a patient will develop ineffective erythropoiesis that produces the megaloblastic anemia and characteristic hypersegmented neutrophils (see
right picture under peripheral blood smear above).
o Metabolism of cobalamin (vitamin B12):
Digested cobalamin forms a complex with the R‐binding protein in the stomach.
This protein is digested by enzymes in the small intestine, and the cobalamin then binds to intrinsic factor.
Intrinsic factor is produced by the parietal cells in the fundus and body of the stomach.
In the ileum the cobalamin‐ intrinsic factor complex enters the cells, the intrinsic factor is destroyed, and the cobalamin becomes available for use in the
blood.
Dietary folate is rapidly absorbed from the upper small intestine.
This patient has pernicious anemia ‐ autoimmune condition that results in the atrophy of the parietal cells in the stomach.
o There are three types of associated autoantibodies in pernicious anemia:
Antibodies
that block the cobalamin from binding to intrinsic factor
that bind to the intrinsic factor and do not allow attachment in the ileum and
directed against the parietal cells themselves.
o As a result, minimal amounts of intrinsic factor are available
thus cobalamin cannot be absorbed in the small intestine.
o This condition is common among Northern Europeans but can be seen in any ethnic group.
o The ratio of incidence in men and women is ~1:1.6, and the peak age of onset is 60;
o However, the average age of onset is lower among black individual and Latin Americans.
Importantly, this condition occurs more commonly in individuals with other autoimmune conditions like thyroid disorders, vitiligo, Addison's disease, and
hypoparathyroidism.
o Treatment for pernicious anemia is B12 replacement.
Traditionally, this is accomplished by weekly then monthly IM injections of B12;
however, in some cases, very large oral doses may be equally effective.
With adequate treatment, you should see a rise in reticulocytes, normalization of the hemoglobin and B12 levels, and disappearance of the
hypersegmented neutrophils.
Case 3
Mr B. is a 66yo African American man who presents to clinic with new onset dyspnea x 2 weeks. He has no past medical history and has not seen a physician
regularly for years. Since his shortness of breath developed two weeks ago, his wife has been telling him that his eyes look yellow.
He had a tonsillectomy as a child.
He is a retired lawyer, does not drink any alcohol, and has no history of drug use.
He has no allergies and takes no medications. On review of systems, he notes some fatigue and darkening of his urine. His physical exam is as follows:
Vitals: BP 144/90, HR 106, Respiration 14/min Gen: appears fatigued
Skin: no jaundice
HEENT: + conjunctival pallor, + scleral icterus, + sublingual jaundice Neck: no thyromegaly, no nodules
LAD: no supraclavicular, cervical, or axillary lymphadenopathy Chest: clear to auscultation bilaterally
CV: tachy but regular, no murmurs
Abdomen: soft, non‐tender, non‐distended, + splenomegaly Ext: no clubbing, cyanosis, or edema
Neuro: normal
His complete blood count is as follows:
The patient's blood smear is shown:
Question: Based on the above clinical scenario, how would you classify this anemia?
Answer: Normocytic, Normochromic, Hyperproliferative
Question: What does a hyperproliferative anemia signify?
Answer: bone marrow is attempting to compensate for red blood cell loss
Question: The laboratory values indicate hyperproliferative anemia; they also show an elevated LDH and low haptoglobin. Based on these clinical findings, what
is the most likely cause of this patient's anemia?
Answer: Hemolytic anemia: LDH is a marker of cell turnover; given that LDH is elevated, this suggests increased cell destruction. In addition, haptoglobin is a
protein that binds free hemoglobin; in cases of hemolytic anemia, the red cells break and free hemoglobin is released which binds the available haptoglobin,
thus reducing the levels of haptoglobin.
o Hemolytic anemias are anemias due to increased destruction of red blood cells.
These anemias may be hereditary or acquired.
In addition, they may be the result of intracorpuscular defects or extracorpuscular factors, and the site of destruction may be intravascular or extravascular.
Most hereditary hemolytic anemias are associated with intracorpuscular defects, and most acquired hemolytic anemias are associated with
extracorpuscular factors.
The following table lists examples of each:
Intracorpuscular Defects Extracorpuscular Factors
Hereditary Hemoglobinopathies Familial hemolytic uremia syndrome
Enzymopathies
Membrane‐cytoskeletal defects
Acquired Paroxysmal nocturnal hemoglobinuria (PNH) Mechanical destruction
Toxic agents
Drugs
Infectious
Autoimmune
o The main laboratory feature of hemolytic anemia is the presence of reticulocytes which is the primary sign of the erythropoietic response of the bone
marrow. In addition, you may see an elevation in indirect bilirubin and LDH.
o In autoimmune hemolytic anemias, there is an antibody that binds to the surface of the red blood cells and causes their destruction.
o A laboratory test that can help distinguish between an autoimmune cause or another cause of hemolytic anemia by the detection of these antibodies is
known as the Coomb's test or the antiglobulin test.
o There is a direct and an indirect form of this test.
In the direct test, an animal anti‐IgG or anti‐C3 is added to the patient's serum.
If the patient's red blood cells are coated with an antibody or complement, they
will agglutinate.
In the indirect test, the patient's serum is added to a sample of red cells
expressing a known set of blood group antigens, followed by the addition anti‐
human immunoglobulin. If agglutination occurs, this test is positive.
o In either form of the Cooomb's test, agglutination signifies the presence of
antibodies in the patient's serum that are the cause of the hemolysis. This test is
depicted in the image.
Mr. B.'s direct Coomb's test is positive.
There are many causes of autoimmune hemolytic anemias including
o Lupus
o Lymphoma
o Chronic lymphocytic leukemia (CLL)
Based on the patient's elevated white blood cell count and abnormal blood smear showing mature lymphocytes with a high nuclear to cytoplasmic ratio, CLL is
suspected. The patient is referred to a hematologist for further management.
What is CLL? What are the cells that are depicted in this blood smear?
o CLL is a B‐cell neoplasm of small lymphocytes ‐ the predominant white blood cell type in the image.
o Smudge cells, which are the three light purple large cells, noted.
o These cells are CLL cells that are ruptured during preparation of the slide.
Case 4
Mr. G. is a 68yo African American man with a history of hypertension, hyperlipidemia, diabetes mellitus, and coronary artery disease who presents with
generalized weakness. He notes that he last felt himself about 5 months ago. At that time, he was very active; he would walk at least 1 mile per day with his wife
and dog. He would go to the gym and try to swim 1‐2 days per week. Now he can only walk a few blocks without having to stop because of weakness and
shortness of breath. He has noticed a 10lb weight loss during these months despite no changes to his dietary intake. He denies fevers, chills, blood in his stool,
or any other source of bleeding. He denies weak urinary stream, nocturia, and urinary frequency.
His other past medical history is notable for occasional heartburn and osteoarthritis in both of his knees.
His family history is notable for his father who died of a heart attack at age 63, and his mother who died of a stroke in her 80s.
He is a retired truck driver, married, has three grown children, and five grandchildren. He has smoked 1 pack of cigarettes per day for 35 years. He drinks alcohol
maybe twice per year on special occasions, and he has no history of illicit drug use.
He is allergic to penicillins.
o His current medication regimen is as follows:
Aspirin 81mg daily
Losartan 100mg daily
Hydrochlorothiazide 25mg daily
Metoprolol succinate 100mg daily
Rosuvastatin 20mg daily
Metformin 1000mg twice per day
Calcium carbonate as needed
Acetaminophen 325mg as needed
With regards to his health maintenance, his PSA (prostate specific antigen) two years ago was normal, and he had a normal colonoscopy at age 50. He is up‐to‐
date on his immunizations.
His physical exam is as follows:
o Vitals: BP 118/74, HR 62, Respiration 12/min
o Gen: no acute distress, somewhat thin body habitus
o Skin: no rashes, bruises; + venous stasis changes over both his lower legs
o HEENT: + conjunctival pallor, no scleral icterus, mucous membranes are moist, no noted epistaxis or bleeding gums Neck: thyroid is normal without nodules
or tenderness
o LAD: no supraclavicular, cervical, or axillary lymphadenopathy was noted
o Chest: breath sounds are a little distant and overall air movement is somewhat decreased but there are no audible wheezes, rales, or rhonchi CV: regular rate
and rhythm, III/VI systolic murmur heard best at the right upper sternal border
o Abdomen: soft, non‐tender, non‐distended, no hepatosplenomegaly Rectal: brown stool in vault, no palpable lesions, no hemorrhoids noted Ext: no clubbing,
cyanosis, or edema
o Neuro: normal
His complete blood count is as follows:
His peripheral blood smear is as shown:
Question: Based on the above clinical information, how would you classify this anemia?
Answer: Microcytic, Hypochromic, Hypoproliferative
Additional laboratory studies are sent and are as follows:
This patient's cbc, iron studies, and blood smear appear consistent with iron deficiency anemia. In addition, to the small, pale red blood cells on the smear, there
is also an increase in the number of platelets which is another common finding in this anemia.
Question: Based on the clinical history and finding of iron deficiency anemia, what is the most likely source of this patient's anemia?
Answer: Gastrointestinal blood losses: GI losses would be the most common source of slow blood loss resulting in an iron deficiency
anemia. Given his long smoking history, an underlying malignancy would be very high on the differential.
o KEY PRINCIPLE:
o Any man or post‐menopausal woman diagnosed with iron defieciency anemia MUST be evaluated
o for the presence for gastrointestinal blood loss as the etiology of the anemia.
o He undergoes EGD and colonoscopy for further evaluation; the findings are as follows:
Mr. G's esophagus shows inflamed and erythematous mucosa consistent with esophagitis.
His colonoscopy revealed a large sigmoid mass.
Mr. G is referred to a colorectal surgeon and oncologist for further management. This is another classic case of iron deficiency anemia
caused by slow blood loss. In this case, the patient had an underlying gastrointestinal malignancy. In addition, he had evidence of
esophagitis which can also cause slow blood loss resulting in an iron deficiency anemia.
Question: This patient had a normal colonoscopy at age 50. Based on that finding, what is the appropriate screening interval?
Answer: With a normal colonoscopy, a patient should be told to have a repeat in 10 years for continued surveillance. This patient was well overdue for his
repeat colonoscopy.
Case 5
Mrs. Z. is a 75yo Hispanic woman with a history of hypertension, hyperlipidemia, coronary artery disease, and uncontrolled diabetes mellitus who presents with
complaint of palpitations and insomnia. She has noticed short episodes of fast heart rate with only mild exertion. For example, she tells you that she was
vacuuming the stairs the day prior and half‐way through she had to stop because her heart was beating so fast. She denied chest pain, noted a little shortness of
breath, and also noted some dizziness. She has never fainted. She denies any bleeding and has normal bowel movements. She has had difficulty sleeping most of
her life, but in the last year or so it has become increasingly worse.
Her surgical history is notable for a total abdominal hysterectomy with bilateral salpingoophorectomy at the age of 52 for fibroids. Her family history is notable
for two parents with diabetes who both passed in their 80s.
She does not drink, smoke, and has no history of illicit drug use. She is a retired teacher, and currently helps care for her young grandchildren. She has no known
drug allergies.
Her medications are as follows:
o Aspirin 81mg daily
o Lisinopril 40mg daily
o Metoprolol succinate 100mg daily
o Furosemide 40mg daily
o Rosuvastatin 40mg daily
o Lantus insulin 40 units SQ at night
o Humalog insulin 2 units SQ with meals + correction factor
o Glipizide 10mg daily
o Acetaminophen 325mg as needed
Her physical exam is as follows:
o Vitals: BP 146/88, HR 68, Respiration 12/min Gen: no acute distress, obese body habitus
o Skin: no bruises or rashes noted
o HEENT: + conjunctival pallor
o Neck: thyroid is normal without nodules or tenderness
o LAD: no supraclavicular, cervical, or axillary lymphadenopathy was noted
o Chest: clear to auscultation bilaterally
o CV: regular rate and rhythm, II/VI systolic murmur heard best at R/LUSB
o Abdomen: soft, non‐tender, non‐distended, no hepatosplenomegaly
o Ext: trace pitting edema b/l
Her complete blood count is as follows:
Her peripheral blood smear is as follows:
Question: Based on the above clinical information, how would you classify this anemia?
Answer: Normocytic, Normochromic, Hypoproliferative
Question: What type of atypical cell is present on the above blood smear?
Answer: Burr cell
Question: Based on the above clinical information, what is the most likely cause of this patient’s anemia?
Answer: Chronic kidney disease
Patient's additional laboratory values are as follows:
This patient has an elevated creatinine level suggesting chronic kidney disease. Her erythropoietin (epo) level is relatively low given
the degree of anemia; in other words, you would expect the epo level to be higher in response to her anemia.
While the erythropoietin level is shown in this case for teaching purposes, levels are not routinely measured because the expense of
the test, and it does not ultimately aid in treatment decisions.
Anemia is a very common comorbidity in patient's with chronic kidney disease. In fact, the level of anemia correlates with the stage of CKD as evidenced by the
graph.
Anemia in chronic kidney disease is due to a decreased production of erythropoietin by the kidney. In addition, the red blood cells seem to have a shorter
lifespan in patients with CKD. Iron studies can be used to help differentiate anemia of CKD from other hypoproliferative anemias.
In anemia associated with chronic kidney disease:
o iron levels, ferritin levels, and TIBC are usually normal.
Interestingly, however, many patients who are on chronic hemodialysis may develop iron deficiency anemia from acute blood loss associated with this
procedure; iron must be appropriately replaced in these patients.
Patients with anemia and CKD are often treated with erythropoietin injections with the goal being to increase their hemoglobin levels to > 11g/dL.
Mrs. Z.'s chronic kidney disease is likely the result of uncontrolled diabetes and long‐standing hypertension. She is referred to a nephrologist and started on
erythropoietin. Her hemoglobin levels, creatinine, and iron studies are monitored closely going forward.
Sample Questions
Why do patients who smoke or live at high altitude develop polycythemia?
o Low blood oxygen levels stimulate erythropoietin production which leads to the increased production of red blood cells and hemoglobin concentration.
Where does the name reticulocyte originate from?
o The name is derived from the mesh‐like or reticular ribosomal RNA that is visible under the microscope
What questions would you ask a patient to elicit the presence of blood loss anemia?
o Have you had dark, tarry stools?
Called Melena which suggests upper gastrointestinal bleeding
o Do you have any bright red blood in your stool?
Called Hematochezia
o Have you been coughing up blood?
Called Hemoptysis
o Do you have blood in your urine?
Called Hematuria
o Have you been taking drugs such as non‐steroid anti‐inflammatory drugs or aspirin?
Which can cause GI ulcers
o For women – Do you have heavy or prolonged menses?
How do prosthetic heart valves contribute to hemolysis?
o They can cause physical breakage of red blood cells
At what serum bilirubin level can you typically begin to detect scleral icterus?
o Some people can detect scleral icterus at as little as 2.5 mg/dL of bilirubin, but typically it becomes more evident around 4 mg/dL
Matching:
G6PD Deficiency = Symptoms may develop upon treatment for malaria
Sickle cell anemia = patients at risk for infections with encapsulated bacteria
Hereditary Spherocytosis = Defect in spectrin
Megalobastic anemia = hypersegmented neutrophils
G6PD Deficiency = Bite Cells
Microangiopathic hemolytic anemia = schistocytes
Bone Marrow infiltration = tear drop cells
Normocytic Anemias
o Iron deficiency – early
o Aplastic anemia
o Chronic disease – early
o Chronic kidney disease
Macrocytic Anemias
o B12 deficiency
o Folate deficiency
o Alcohol related
o Reticulocytosis
Microcytic Anemias
o Iron deficiency – late
o Lead poisoning
o Thalassemia
o Chronic disease – late
Red Cell Shapes
Abnormal size Anisocytosis
Abnormal shape Poikilocytosis
Type Seen In
Elliptocytes Hereditary elliptocytosis
Spherocytes Hereditary spherocytosis
Autoimmune Hemolytic Anemia
Target cells Hemoglobinopathies – Sickle Cell, Hemoglobin C
Thalassemia – Beta minor, Beta major
Liver disease
Acanthocytes Abetalipoproteinemia
Echinocytes (Burr cells) Uremia
More commonly as an artifact
Schisocytes Microangiopathic Hemolytic Anemia
Macroangiopathic anemia
Traumatic Hemolysis
Bite cells Glucose‐6‐Phosphate Dehydrogenase Deficiency
Teardrop cells (dacrocytes) Thalassemia
Myelofibrosis
Sickle cells (drepanocytes) Sickle Cell Anemia
Rouleaux (stack of coins) Multiple Myeloma
Red Cell Inclusions
Type Results from Seen in
Basophilic stippling Cytoplasmic remnants of RNA May indicate reticulocytosis
Lead poisoning
Howell‐Jolly Bodies Remnants of nuclear chromatin Severe anemias
Patients without spleen
Papenheimer Bodes Composed of iron May be found in peripheral blood following splenectomy
Ring sideroblasts Iron trapped abnormally in mitochondria forming a ring around the nucleus Sideroblastic anemia
Heinz Bodies Denatured hemoglobin Glucose‐6‐Phosphate Dehydrogenase Deficiency
Primary Immunodeficiency Diseases
Defects of Phagocytic Cells
Disease Molecular Defect Symptoms
Chronic Granulomatous Disease Deficiency of NADPH oxidase (any one of 4 Recurrent infections with catalase positive bacteria and
(CGD) component proteins) fungi
Failure to generate superoxide anion and other
O2 radicals
Leukocyte Adhesion Deficiency Absence of CD18 a common beta chain of the Recurrent and chronic infections
leukocyte integrins Failure to form pus
The 3 integrins that contain CD18 are: Delayed separation of umbilical cord stump
o LFA‐1, MAC‐1, and GP150/95
Chediak‐Higashi Syndrome Nonsence mutation in the lysosomal trafficking Recurrent infection with bacteria
regulator CHS1/LYST leads to aberrant fusion Chemotactic and degranulation defects
of vesicles Absent NK activity
Partial albinism
Glucose‐6‐phosphate Deficiency of essential enzyme in hexose Recurrent infections with catalase positive bacteria and
Dehydrogenase (G6PD) monophosphate shunt fungi
Anemia
Deficiency
Myeloperoxidase deficiency Defect in MPO affects the ability to convert Mild or none
hydrogen peroxide to hypochlorite
Hyperimmunoglobulin E Defects in JAK‐STAT signaling pathway leads Characteristic facies, severe, recurrent sinusopulmonary
Syndrome (Job Syndrome) to impaired Th17 function causes a decreased infections, pathologic bone fractures, retention of primary
IFN‐gamma production teeth, increased IgE, eczematous rash
Defects of Humoral Immunity
Disease Molecular Defect Signs/Symptoms Treatment
Bruton (X‐linked) Deficiency of the Bruton tyrosine Increased susceptibility to encapsulated Monthly gamma‐globulin
Agammaglobulinemia kinase (btk) which promotes bacteria and bloodborne viruses replacement
pre‐B cell expansion Low immunoglobulins of all isotypes Antibiotics for infection
Faulty B‐cell development Absent or low levels of circulating B‐cells
B‐cell maturation does not progress past
the pre‐B cell stage while maintaining cell‐
mediated immunity
X‐linked Hyper IgM Syndrome Deficiency of CD40L on activated T‐ High serum titers of IgM without other Antibiotics and gamma‐
cells isotypes globulins
Normal B‐cell and T‐cell numbers
Susceptibility to encapsulated bacteria and
opportunistic pathogens
Selective IgA Deficiency Multiple genetic causes Decreased IgA Antibiotics
Normal IgM and IgG NOT immunoglobulins
Elevation of IgE
Repeated sinopulmonary and
gastrointestinal infection
Increased atopy heightened immune
responses to common allergens
Common Variable Collection of syndromes Onset in late teens and early twenties Antibiotics
Immunodeficiency Several associated genetic defects B‐cells present in peripheral blood
Immunoglobulin levels decrease with time
Increased autoimmunity
Transient Delayed onset of normal IgG Detected in 5th to 6th month of life Antibiotics
Hypogammaglobulinemia of synthesis Resolves by 16‐30 months In severe cases gamma‐
Susceptibility to pyogenic bacteria globulin replacement
Infancy
Deficiencies of Complement or its Regulation
Deficiencies in Complement Components Deficiency Signs/Diagnosis
Classic Pathway C1q, C1r, C1s, C4, and C2 Marked increase in immune complex diseases
Increased infections with pyogenic bacteria
Both Pathways C3 Recurrent bacterial infections
Immune complex disease
C5, C6, C7, C8, or C9 Recurrent meningococcal and gonococcal infections
Deficiencies in Complement Regulatory Proteins C1‐INH (Hereditary Angioedema) Overuse of C1, C4, or C2
Edema at mucosal surfaces
T‐Cell Deficiencies and Combined Deficiencies
Category Disease Defect Clinical Manifestation
Selective T‐cell Deficiency DiGeorge Syndrome Heterozygous deletion of Characteristic facies
chromosome 22q11 Clinical triad of:
Failure of formation of 3rd and 4th o Cardiac malformations
pharyngeal pouches o Hypocalcemia
Thymic aplasia o Hypoplastic thymus
MHC Class 1 Deficiency Failure of TAP 1 molecules to CD8+ T‐cells deficient
transport peptides to endoplasmic CD4+ T‐cells normal
reticulum Recurring viral infections
Normal DTH
Normal Ab production
Combined Partial B‐cell and Wiskott‐Aldritch Syndrome Defect in the WAS protein which Defective responses to bacterial
T‐cell Deficiency plays a critic al role in actin polysaccharides and depressed IgM
cytoskeleton rearrangement Gradual loss of humoral and
cellular responses
Thrombocytopenia
Eczema
IgA and IgE may be elevated
Ataxia telangiectasia Defect in the ATM kinase involved Ataxia – gait abnormalities
in the detection of DNA damage Telangiectasia – capillary
and progression through the cell distortions in the eye
cycle Deficiency of IgA and IgE
production
Complete Functional B‐cell Severe Combined Defects in common gamma chain of Chronic diarrhea
and T‐cell Deficiency Immunodeficiency (SCID) IL‐2 receptor present in Skin, mouth, and throat lesions
receptors for IL‐4, IL‐7, IL‐9, IL‐15 Opportunistic (fungal) infections
X‐linked Low levels of circulating
lymphocytes
Cells unresponsive to mitogens
Adenosine deaminase deficiency Clinical overall with X‐linked SCID
results in toxic metabolic products plus neurologic deficiency
in cells
rag1 or rag2 gene nonsense total absence of B‐cells and T‐cells
mutations
Bare Lymphocyte Syndrome/MHC Failure of MHC class 2 expression T‐cells present and responsive to
Class 2 Deficiency Defects in transcription factors nonspecific mitogens
No GVHD
Deficient in CD4+ T‐cells
Hypogammaglobulinemia
Clinically observed as a severe
combined immunodeficiency
When to Suspect 8 or more new ear infections within one year
Immunodeficiency 2 or more serious sinus infections within 1 year
Two or more months on antibiotics with little effect
2 or more pneumonias within 1 year
Failure of an infant to gain weight or grow normally
Recurrent, deep skin or or organ abscesses
Persistent thrush in mouth or elsewhere on skin, after age 1
Need for IV antibiotics to clear infections
2 or more deep‐seated infections
A family history of primary immunodeficiency disease
Clinical Patterns “Recurrent Clinical manifestation Most likely PID
Symptoms” Recurrent ear and sinopulmonary infections with response to Antibody
antibiotics defects/complement/innate/neutropenia
Recurrent adenitis CGD
Pneumonia
Recurrent boils (MSSA) CDG, HIES, Innate
Pneumonia
Recurrent candidiasis SCID, CID, CMC APECED, HIES
Recurrent meningitis Complement
Recurrent Giardia and diarrhea Antibody and CID
Recurrent parotitis IgE deficiency, HIV
Recurrent fevers Diseases of immune dysregulation
Microbial “Red Flags” in PID Pathogen Most likely PID
Pneumocystis j. SCID, HIGM, HIV, XLA
Serratia marcescens CGD
Pseudomonas sepsis Antibody defects, Complement
Meningococcus Complement
Mycobacteria/Salmonella IFN‐gamma/IL‐12 pathway, CGD
Aspergillus CGD
X‐linked Mutation in a signaling tyrosine receptor that is mandatory for growth and development of B cells‐specifically BTK‐critical for the
agammaglobulinemia pre‐BCR signal
(XLA) also called Bruton’s Males
Disease Ig not detectable in serum
B cells absent in marrow, blood and lymphoid tissue
This is the only “pure” B cell defect
Can be treated successfully with pooled IVIg on a monthly cycle
4 y/o male in ER last month for pneumonia
Referred for allergies and asthma
Hx of recurrent otitis media and purulent rhinorrhea
Receives abs 6‐8x/yr and always gets better
Growth is in 25%
No tonsils
Fx Hx ‐ negative Two maternal uncles dies 14 mo and 28 mo of infection and diarrhea in hospital
Dx ‐ XLA
Chronic Granulomatous Childhood disease ( can be diagnosed as late as 3rd decade of life)
Disease (CGD) NADPH oxidase deficiency results in a reduction in leukocyte oxidative burst that is responsible for killing bacteria and fungi after
phagocytosis
Recurrent infections ( S. aureus, Bulkholderia, Serratia, Nocardia, Aspergillus)
Diagnosis ‐ abnormal nitroblue tetrazolium test( respiratory burst assay) or flow cytometry DHR(dihydrorhodamine‐1, 2, 3) assay
Tx ‐ antimicrobial prophylaxis (TMP/SMX, itraconazole; +/‐ interferon gamma
7 mo old female admitted with lymphadenitis
PMHx
labial abscess with MRSA
pneumonia age 4.5 mo
pneumonia age 6 mo
Culture ‐ Serratia
Dx‐ CGD p67 mutation
Common Variable Bimodal distribution of age of onset of symptoms‐ <5 years of age and 25‐35 years of age
Immunodeficiency (CVID) Recurrent bacterial infections ‐ respiratory with encapsulated bacteria and GI‐ Giardia
Diagnosis ‐ low Ig levels or one of it's subsets
Poor response to vaccines ‐ check pneumococcal and tetanus antibody tiers
Increased risk of autoimmune disease, malignancy (B‐cell lymphoma, gastric cancer), and interstitial lung disease
Tx ‐ regular IV or subQ Ig infusions
42 y/o female
Well until age 37 dx ITP
Recurrent bronchitis and Dx asthma
Age 40 dx with lymphadenopathy and HSM
CT pulmonary nodules dx sarcoidosis
Bx lymph node ‐ follicular hyperplasia and non‐caseating granulomas
Immunoglobulin level
IgG ‐ 149 (694‐1,618 mg/dl)
IgM ‐ 13 (82‐453mg/dl)
IgA ‐ <6 (46‐304mg/dl)
DX ‐ CVID
Severe Combined Most severe of all
Immunodeficiency (SCID) Sick from birth
Multiple sites for the mutation have been found:
o mutations in the gene encoding the common γ (γc) chain shared by the receptors for the cytokines IL‐2, IL‐4, IL‐7, IL‐9, and IL‐
15
o including common IL2 R‐(JAK‐3), Rag 1 & 2, adenosine deaminase deficiency
Treatment usually will require a stem cell transplant or gene insertion
If ADA deficiency is present and stem cell/gene therapy, enzyme replacement possible
4 mo male, 28 weeks twin B 2.8 kg
3 weeks oral candidiasis
4.5 weeks vomiting, diarrhea, wt loss, oral candidiasis
3 mo admitted with vomiting, diarrhea, thrush and severe weight loss. Rotavirus positive
Dx: SCID
Family Hx: XSCID
X‐linked Mutation in a signaling tyrosine receptor that is mandatory for growth and development of B cells‐specifically BTK‐critical for the
agammaglobulinemia pre‐BCR signal
(XLA) Males
Ig not detectable in serum
B cells absent in marrow, blood and lymphoid tissue
Can be treated successfully with pooled IVIg on a monthly cycle
16 mo male with a 2 day history of enlarging spider bite to R hand, rash on his right calf and vomiting with decreased oral intake
and decreased urine output
PMHx ‐ History of mastoiditis (culture S. pneumonia) at 11 mo, several episodes of otitis media and tymphanostomy with ear
tube placement
WBC 3.9, neutrophils‐3.9%, bands‐0%, lymphs‐29%, monos‐68%, ANC‐117, ALC‐113
Blood culture positive for Pseudomonas
Dx ‐ XLA
Physical Signs of Dysmorphic facies: look for midline defects, listen for heart murmur
Immunodeficiencies Failure to thrive
Head: microcephaly
Mouth: oral thrush, teeth, oral sores, gingival disease
Oropharynx: absence of tonsils tissue
Skin: atypical atopic dermatitis/erythroderma
Lymphatics: absence of palpable lymph nodes, lymphadenopathy/organomegaly
Telangiectasia's
Wiskott‐Aldrich Syndrome Eczema
Thrombocytopenia
Moderate T cell deficiency
Decreased IgM and inability to make antibody to polysaccharides
X linked recessive mutation of the WAS gene (cytoskeletal regulation), so females are carriers, boys
have disease
High incidence autoimmune diseases
Thymic aplasia or DiGeorge Infants very sick from birth with fungal infections
syndrome Structural mutations in the 3rd and 4th branchial pouches (also called pharyngeal arches)
There will always be associated abnormalities in the CVS –usually Tetralogy of Fallot or pulmonary stenosis
Facial dysmorphism
Absent or deficient parathyroid glands and symptomatic hypocalcemia
Paracortical regions of lymph nodes are depleted
Diagnosis of Thymic aplasia
o No thymic shadow on chest film
o Severe lymphopenia
o Decreased lymphoid tissue
o Ig levels will be normal at birth because they reflect maternal Ig
o Genetic‐usually sporadic deletion on 22q11
Ataxia‐Telangiectasia Early cerebellar dysfunction
Oculocutaneous telangiectasia
Recurrent infection of all kinds
High rate of neoplasia‐leukemia/lymphoma
Extreme sensitivity to radiation‐induced DNA damage and faulty repair
Defective apoptosis
Pale medullary sinuses surrounding darker medullary cords. You can see many stellate reticular cells which, with reticular fibers,
make a meshwork through the sinuses. Lymph “percolates” though the meshes of the sinuses while debris of foreign matter in it
is phagocytized.
o Primary Lymphoid Follicles:
contain mature B‐Cells (able to respond to an antigen, but they are naïve so they have not had the opportunity to do so).
Once a naïve B‐cell is exposed to an antigen, it becomes activated and it goes to the center of the follicle and it proliferates
and forms the germinal center (lighter staining, surrounded by darker staining mantle zone). Germinal centers are the sites
of B‐Cell proliferation.
o Secondary Lymphoid Follicles:
Once a germinal center is formed in a follicle, you now call it a secondary follicle (the germinal center will be lighter in color).
Spleen
The primary function of the spleen is to be the site of destruction of old red blood cells. It is also a site for processing and
capturing antigens. It does this because it has two compartments. There is a central artery.
o Red Pulp:
consists of open sinuses and cellular cords.
Blood travels into the spleen through progressively smaller vessels, eventually into sinuses. Sinuses in the spleen are
surrounded by cellular cords, which contain macrophages. Macrophages sample anything in the blood that looks foreign.
When they find it, they take it into their cytoplasm and destroy it via phagocytosis. The red pulp appears red because it is:
sort of "sponge" which filters antigens and particulate materials, engulfs aged erythrocytes and serves as a reservoir for
erythrocytes and platelets.
o White Pulp:
blood travels to the spleen through progressively smaller blood vessels. Once the blood vessels get to the arterioles, they
become surrounded by a sheath of lymphoid cells in the spleen. These are called the periarteriolar lymph sheath (PALS).
The cells that make up the PALS are T‐Cells and often are off to the side or to the periphery of the artery and we call it a
lymphoid follicle. Lymphoid follicles in the spleen can be primary or secondary. They are defined in the same way as they are
in the lymph node. They have the same function as they do in the lymph node.
Mucosal Associated Lymphoid follicles that are distributed throughout the body along the mucosa and into certain organs. They
Lymphoid Tissue (MALT) are responsible for surveying and sampling the material that flows along the mucosal surfaces of the GI tract,
the Respiratory tract, the GU tract, and the Conjunctiva. In the ilium, these are called Pyre’s Patches. Note
that they have germinal centers and they are surrounded by the mantel zone.
Quiz
1. Match the items. The task is to match the lettered items with the correct numbered items. Appearing below is a list of lettered items. Following that is a list of
numbered items. Each numbered item is followed by a drop‐down. Select the letter in the drop down that best matches the numbered item with the lettered
alternatives.
Secondary follicle.
o (B) The secondary follicle arises from primary follicle that develops germinal centers due to antigenic
stimulation of B cells and production of antibodies and is surrounded by mantle zone and marginal zone
lymphocytes.
Contains cords, sinuses and vessels but minimal number of follicles along with small B and T lymphocytes, Plasmacytoid
lymphocytes, plasmablasts and plasma cells.
o (D) The medulla contains the medullary cords, sinuses and vessels but minimal number of follicles. The medullary cords are
found in hilar region between the sinuses, composed mostly of small B and T lymphocytes, plasmacytoid lymphocytes,
plasmablasts and plasma cells. The medullary sinuses carry lymph from afferent to efferent lymphatics and have macrophages
and plasma cells.
Contains thin fibrous and smooth muscle connective tissue.
o (A) The capsule is a thin fibrous / smooth muscle connective tissue covering of lymph node that is connected to fibrous
trabeculae which penetrate the node.
Primary follicle
o (C) The primary follicle is comprised of round aggregates of small, dark staining inactive (naïve) B lymphocytes, usually near
the capsule, within a network of follicular dendritic cell processes. No germinal center is present in primary follicles.
2. Lymph nodes are a primary lymphoid organ where B and T cells proliferate in response to exogenous antigen.
True
False (CORRECT)
o Primary lymphoid organs are bone marrow and thymus involved in the production and early clonal selection of lymphocyte
tissues (generate lymphocytes from progenitor cells). Lymph nodes, spleen and Peyers patches of the intestine are secondary
lymphoid organs, where B and T cells mature and proliferate in response to exogenous antigen. Tertiary lymphoid organs are
accumulations of lymphoid cells in chronic inflammation that resemble lymph nodes in their cellular content and organization.
3. Drag items from the left column to the correct order in the right column. Outline the path of LYMPH through a lymph node:
a. Medullary sinuses >> Subcapsular sinuses >> Efferent lymphatic vessel >> Peritrabecular sinuses >> Afferent lymphatic vessels.
b. Afferent lymphatic vessels >> Subcapsular sinuses >> Peritrabecular sinuses >> Medullary sinuses >> Efferent lymphatic vessel
(CORRECT)
4. Leukemia is cancer originating in the lymphoid organs, while lymphoma originates in the bone marrow.
a. True
b. False (CORRECT) Leukemia is cancer originating in the bone marrow, while lymphoma originates in the lymphoid organs.
5. Mucosa‐associated lymphoid tissue (MALT) is present in which of the following organs?
GI tract (CORRECT) The mucosa‐associated lymphoid tissue (MALT) is the diffusion system of small concentrations of lymphoid
tissue found in various sites, such as the GI tract, thyroid, breast, lung, salivary glands, eye and skin.
Thyroid (CORRECT)
Breast (CORRECT)
Lung (CORRECT)
Brain
Salivary glands (CORRECT)
Skin (CORRECT)
Ovary
6. Organ A. The thymus continues to grow until puberty then gradually atrophies. In elderly individuals, a large portion of the thymus tissue is replaced by
adipose tissue. Organ B. Continued stasis and trapping of abnormal sickled red blood cells leads to infarctions that eventually reduce the size of the spleen
tremendously by adolescence.
True (CORRECT)
o Organ A. The thymus continues to grow until puberty then gradually atrophies. In elderly individuals, a large portion of the
thymus tissue is replaced by adipose tissue.
o
o Organ B. Continued stasis and trapping of abnormal sickled red blood cells leads to infarctions that eventually reduce the size
of the spleen tremendously by adolescence.
o
False
7. Which is true of the splenic histology below?
a. The area labeled "A" forms sheaths of lymphoid cells around arteries (periarteriolar lymphatic sheath),
composed of T cells and lymphoid follicles (B cells). (CORRECT)
b. The area labeled "B" filters old / damaged red blood cells
c. The area labeled "A" serves as a reservoir for erythrocytes and platelets (CORRECT) Red pulp (A) filters old /
damaged red blood cells and serves as a reservoir for erythrocytes and platelets. It is traversed by thin walled venous sinusoids
lined by littoral cells, a type of endothelial cell which also stains with histiocytic markers and has a discontinuous wall, allowing
passing of red blood cells between sinus and cords. The sinuses are separated by splenic cords (cords of Billroth) containing a
labyrinth of splenic macrophages, which filter red blood cells and ingest old (normal lifespan is 120 days), damaged (seen in
hereditary spherocytosis, sickle cell anemia) or antibody coated red blood cells. It also removes Heinz bodies or other red blood
cell inclusions (peripheral blood has Howell‐Jolly bodies if no functional spleen is present). White pulp (B) forms sheaths of
lymphoid cells around arteries (periarteriolar lymphatic sheath), composed of T cells and lymphoid follicles (B cells) with
surrounding mantle zone (proliferating B cells) and outer marginal zone (memory B cells) in order to trap antigens for processing.
8. Match the items.
Thymic medulla (B)
Thymic cortex (A)
9. What is the structure seen below on histology? (please type in all lower case)
a. Hassall’s Body/Corpuscle
10. Match the items.
a. Highly vascularized lymphoid organ organized into two components (a) an immune component and (b) a component that
filters antigens and particulate materials and engulfs aged erythrocytes. (3)
b. The primary lymphoid organ for maturation of T‐cells. (1)
c. Plays important roles in circulating filtering lymph, defending against microbial invasion and providing a place for lymphocytes
to meet antigens (2)
Hematopoetic Pathology
Reactive Changes In White Blood Cells
Leukocytosis Characterized by an elevated white blood cell count with the following features
o Increased neutrophils (neutrophilia)
o Increased eosinophils (eosinophilia)
o Increased monocytes (monocytosis)
o Increased lymphocytes (lymphocytosis)
o Increased basophils (Basophilia)
Neutrophilia
o Increased bone marrow production is seen with acute inflammation associated with pyogenic bacterial infection or tissue
necrosis
o Increased release from bone marrow storage pool may be cause by corticosteroids, stress, or endotoxin
o Increased bands (Left Shift) is noted in peripheral circulation
o Reactive changes include:
Dohle bodies – aggregates of rough endoplasmic reticulum
Toxic granulations – prominent granules
Cytoplasmic vacuoles of neutrophils
Eosinophilia
o Occurs with:
Allergies and asthma – type 1 hypersensitivity reaction
Parasitic infection
Patients on medications – especially in hospitals
Certain skin diseases and cancers – adenocarcinomas and Hodgkin disease
Monocytosis
o Occurs with:
Certain chronic diseases – collagen vascular diseases and Inflammatory Bowel Disease (IBD)
Certain infections – especially TB (but the monocytes are called macrophages inside the tissue
Lymphocytosis
o Occurs with
Acute (viral) diseases – Infectious Mononucleosis (IM) because lymphocytes attacks viruses
Chronic inflammatory processes
Infectious Mononucleosis
o An example of a viral disease that causes lymphocytosis
o The most common cause is Epstein‐Barr virus (a herpesvirus)
Sequence of events
EBV invades B‐lymphocytes via CD21 (CR1) receptor
Cytotoxic (CD8) T‐lymphocytes respond against invaded B‐cells and form atypical lymphocytes called Downey cells
o Which are enlarged lymphocytes that have abundant cytoplasm condensed peripherally Ballerina skirt appearance
o Similar in appearance to monocytes
Diagnosis is by antibody production
Heterophil antibodies are the basis of the Paul‐Bunnell reaction that is used as the monospot test (which is repeated if the
initial test is negative during the first week)
Affects adolescents and young adults Kissing Disease
Classic triad of symptoms:
Fever
Sore throat with gray‐white membrane on tonsils
Lymphadenitis – bilateral cervical lymphadenopathy posterior auricular nodes
Another sign is hepatosplenomegaly
Acute, self‐limited disease, which usually resolves in 4‐6 weeks
Complications include:
Hepatic dysfunction
Splenic rupture
Rash – if treated with ampicillin
o Less common causes are other viruses
Cytomegalovirus (CMV) causes Heterophile‐negative infectious Mononucleosis
Does not cause sore throat as with EBV
Basophilia
o Occurs with:
Chronic myeloproliferative disorders
Polycythemia vera
Chronic myelogenous leukemia (CML)
Leukopenia Is characterized by a decrease white blood cell count which has the following features:
o Decreased neutrophils may be due to…
Decreased production
Aplastic anemia
Chemotherapy
Increased destruction
Infections
Autoimmune diseases – Systemic lupus erythematosus (SLE)
Activation of neutrophil adhesion molecules on endothelium
Due to endotoxins during septic shock
o Decreased eosinophils may be due to…
Increased cortisol
Which causes sequestering of eosinophils in lymph nodes
Examples include:
o Cushing syndrome
o Exogenous corticosteroids
o Decreased lymphocytes may be due to…
Immunodeficiency syndromes
HIV
DiGeorge syndrome – T‐cell deficiency causes viral infections due to hypoplasia of the thymus (T‐cells are not able to
mature)
Severe combined immunodeficiency (SCID) – B‐cell and T‐cell deficiency
Occurs secondary to
immune destruction – SLE
corticosteroids
radiation – lymphocytes are the most sensitive cells to radiation
atypical lymphocytes – found in the peripheral blood and T‐cell areas of the lymph nodes (paracortex)
Normal Lymph Node Follicles are only located within the Cortex
o Inside the follicle are B‐cells
Medulla contains the sinusoids
Paracortex is where the T‐cells are located
Lymphadenopathy Is lymph node enlargement due to reactive conditions or neoplasia
Acute Nonspecific Lymphadenitis
o Produces tender enlargement of lymph nodes
Where focal involvement is seen with bacterial lymphadenitis
o Microscopically
There may be neutrophils within the lymph node
o Associated with:
Cat‐scratch Fever
Due to Bartonella henselae
o Which causes stellate microabscesses
Generalized involvement of lymph nodes is seen with viral infections
Chronic Nonspecific Lymphadenitis
o Causes nontender enlargement of lymph nodes
o Follicular hyperplasia involves B lymphocytes and may be seen with
Rheumatoid arthritis
Toxoplasmosis
Early HIV infections
o Paracortical lymphoid hyperplasia involves T‐cells and may be seen with
Virus
Drugs – Dilantin
SLE
o Sinus histiocytosis involves macrophages and in most cases is nonspecific
Histiocytes within the lymph node are the macrophages
Causes dilated sinusoids that are filled with histiocytes which is a reactive condition that is secondary to the lymph node
draining a cancer
If a person has cancer and a enlarged lymph node can’t assume that the enlarged node is metastasis
The enlarged lymph node maybe Sinus histiocytosis secondary to the tumor
Neoplasia
o Usually causes nontender enlargement of lymph nodes
o Most common tumor to involve lymph nodes is metastatic cancer (breast, lung, malignant melanoma, stomach, and colon)
Which is initially seen under the lymph node capsule (sub‐capsule sinus)
o Malignant lymphoma and infiltration by leukemias are another important cause for lymphoadenopathy
Lymphoid Neoplasms
Acute Leukemias The peripheral blood has decreased mature forms and increased immature forms called Blasts
o Which have immature chromatin with nucleoli
o Image:
3‐5x the size of a red blood cells
The red blood cells in the image are microcytic and hyperchromic (anemia)
There is also a decreased number of platelets (thrombocytopenia)
The bone marrow has increased immature cells (blasts)
o Diagnostic criteria are greater than 30% blasts in the bone marrow
o The marrow will be hyperplastic with increased hematopoietic cells and very few fat cells on byopsy
Acute symptoms are secondary to marrow failure which can produce
o Decreased erythrocytes causing anemia and fatigue
o Decreased leukocytes causing infections and fever
o Decreased platelets causes bleeding
Lymphoid Neoplasia Revised European‐American Classification of Lymphomas (REAL)
Classifications o Precursor
B‐cell neoplasms (immature B‐cells)
T‐cell neoplasms (immature T‐cells)
o Peripheral
B‐cell neoplasms (mature B‐cells)
T‐cell neoplasms (mature T‐cels)
Lymphoid neoplasms were grouped together because some lymphomas look just like some leukemias due to the same cell
o A cell in a lymph node = Lymphoma
o A cell in a peripheral blood smear = Leukemia
Precursor B‐cell and T‐cell Neoplasms (Immature)
B‐cell CD markers are >10
T‐cell CD markers are <10
Acute Lymphoblastic Lymphoblasts are positive for:
Leukemia (ALL) o Terminal deoxytransferase (TdT) – a marker for precursor B and T cells
o PAS stain
o Hyperploidy – greater than 50 chromosomes better prognosis in patients
o Polyploidy: Associated with translocations
t(12;21) –
t(4;11) –
t(9;22) – Philadelphia chromosome which is normally associated with CML
But if patients with ALL have the Philadelphia chromosome poor prognosis in patients
o Acid phosphatase
Immunologic Classification of ALL
o B‐cell Lineage
Classification is based on the presence or absence of cytoplasmic or surface markers including:
Presence of Surface Immunoglobulin (sIg) mature B‐ALL
Presence of cytoplasmic mu () pre ‐B‐ALL
B‐cell tumors express B‐cell molecules CD19 and CD10
Early pre‐B‐ALL is the most common type of ALL
Seen primarily in children
Rapid onset of symptoms
due to marrow involvement and pancytopenia (decrease in WBC, RBC, and platelets)
o T‐cell Lineage
T‐ALL is associated with mediastinal mass in young (adolescent) adult males
Express CD1, CD3, and CD7
Image
o Lymphoblasts looks like large lymphocytes with a large round nucleus and scant cytoplasm with NO granules
Clinical Correlate
o ALL is associated with infiltration of the CNS and Testes called Sanctuary sites
Where prophylactic radiation and or chemotherapy to the CNS is used
because malignant cells in the brain are protected from chemotherapy by the blood‐brain barrier
Lymphoblastic Lymphoma Majority of cases are T‐cells and are aggressive and rapidly progressive
Most patients are
o young males with mediastinal lymphadenopathy or a mediastinal mass
The leukemic phase of lymphoblastic lymphoma is similar to T‐ALL
o Positive for Terminal deoxytransferase (TdT)
Most cells express CD1, CD2, CD5, and CD7
Peripheral B‐cell and T‐cell Neoplasms (Mature)
Chronic Lymphocytic Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) are very similar
Leukemia (CLL) o Where both represent an abnormal proliferation of B‐cells
Small Lymphocytic Patients who present with….
Lymphoma (SLL) o Lymph node findings SLL
o Blood findings CLL
50% of CLL patients also have lymph node involvement
CLL and SLL can be categorized by the markers present on B cells
o B‐CLL cells (95% of cases) have
B‐cell markers CD19 and CD20
T‐cell marker CD5
Importantly the cells are CD23 positive and CD10 negative
o T‐CLL cells (5% of cases) have
T‐cell markers
o The histology of affected lymph nodes reveals only diffuse pattern with small lymphocytes (not see sinusoids or follicles called
effacement of the lymph node architecture)
But proliferation centers may also be present
o Peripheral blood findings show:
Increased numbers of normal‐appearing lymphocytes
Numerous smudge cells (Parachute cells) are also present
Smudge cells result from the fact that the neoplastic lymphocytes are unusually fragile
o Bone marrow biopsy show numerous normal‐appearing neoplastic lymphocytes
Clinical Characteristics of CLL
o CLL is the most slow growing of all of the leukemias
Patient may be asymptomatic
Heard to treat
o Mean age at time of diagnosis is age 60
o Because the B‐cells are neoplastic (nonfunctional), they will not turn into plasma cells and make antibodies
So patients develop hypogammaglobulinemia
Leading to an increased risk of pyogenic infections
o Because antibodies attach pyogenic bacteria
CLL is associated with warm autoimmune hemolytic anemia (AIHA) in 10% of cases
Because the normal B‐cells becomes overreactive and become plasma cells to make tons of antibodies
Which causes spherocytes to be observed in the peripheral blood
o CLL rarely transforms into a worse disease such as
Prolymphocytic leukemia
Large cell lymphoma called Richter Syndrome
o Image
Peripheral blood smear for CLL where the lymphocytes are the same size or slightly larger and a red blood
cell you can tell that these are lymphocytes and NOT lymphoblasts
Smudge cells are located in the bottom of the image which are fragile and smudge during the peripheral
smear
Hairy Cell Leukemia Rare B‐cell neoplasm that causes indolent disease in middle‐aged Caucasian men.
There can be a “dry‐tap” with bone marrow aspiration
o Because the cells are so packed into the marrow, you can not aspirate normal marrow elements
Lymphocytes have “hair like” cytoplasmic projections
The diagnostic stain is positive tartrate‐resistant acid phosphatase (TRAP)
Physical exam:
o shows a markedly enlarged spleen (splenomegaly)
due to infiltration of red pulp by malignant cells
Treatment
o is 2‐chloro‐deoxyadenosine (2‐CdA or Cladribine) which inhibits adenosine deaminase (ADA) and increases the levels of toxic
deoxyadenosine.
Follicular Lymphoma (FL) Well‐differentiated B‐cell lymphoma with follicular architecture
o Follicles will be present in the cortex and medulla
Most common form of non‐Hodgkin lymphoma in the US
All follicular lymphomas are derived from B‐lymphocytes
o Positive for CD10, CD19 and CD20
Characteristic translocation t(14;18)
o Chromosome 14: Immunoglobulin heavy‐chain genes
o Chromosome 18: bcl‐2 gene where activation of bcl‐2 inhibits apoptosis by blocking the bax channel
Clinical Features:
o Commonly presents with disseminated disease (advanced stage)
o Has a better prognosis than diffuse lymphomas
But does not respond to therapy unlike more aggressive diffuse lymphomas
o Up to 50% of cases will progress to diffuse large‐cell Non‐Hodgkin Lymphoma (NHL)
Diffuse Large B‐Cell High grade large B‐cell lymphoma with a diffuse growth pattern
Lymphoma (DLBCL) o Large cells with prominent nucleoli
Associated with:
o Immunocompromised: HIV patients
o Autoimmune diseases:
Hashimoto thyroiditis ‐ is an autoimmune disease in which the thyroid gland is gradually destroyed. Early on there may be
no symptoms. Over time the thyroid may enlarge forming a painless goitre
Sjogren syndrome – which presents as unilateral enlargement of the parotid glands
An aggressive, rapidly proliferating tumor that may respond to therapy
Special subtypes include:
o Immunodeficiency‐associated B‐cell lymphomas often infected with EBV
o Body‐cavity large B‐cell lymphomas some of which are associated with human herpes virus (HHV‐8)
Small Noncleaved High grade B‐cell lymphoma composed of intermediate‐sized lymphoid cells
Lymphoma (Burkitt Microscopically:
Lymphoma) o Shows a “starry‐sky” appearance due to numerous reactive tangible‐body macrophages (light
areas) phagocytosis of apoptotic tumor cells
o Dark cells are the malignant Burkitt cells
o Mitotic figures are also seen aggressive tumor
Characteristic t(8;14) translocation
o Chromosome 14: immunoglobin heavy‐chain gene
o Chromosome 8: oncogene c‐myc
Both endemic and sporadic forms of Burkitt lymphoma largely occur in children and young adults
o African type is endemic form
Involvement of mandible or maxilla is characteristic
Associated with EBV presenting with a large jaw
o American type is nonendemic, sporadic form
Involvement of the abdomen (bowel, retroperitoneum, or ovaries)
Has a high incidence in AIDS patients
Mantle Cell Lymphoma Also called Intermediate Differentiated Lymphocytic Lymphoma
(MCL) Tumor cells arise from mantle zone B‐lymphocytes
o Positive for CD19, CD20, and CD5 similar to CLL
o However, Negative for CD23
Characteristic translocation is t(11;14)
o Chromosome 11: bcl‐1 (cyclin D)
o Chromosome 14: immunoglobulin heav‐chain gene
Marginal Zone Diverse group of B‐cell neoplasms that arise within
Lymphoma (MALToma) o Lymph nodes
o Spleen
o Extranodal tissue ‐ Stomach
Associated with Mucosa‐Associated Lymphoid Tissue (MALTomas)
The lesion begins as a reactive polyclonal reaction and may be associated with a previous autoimmune disorder or infectious
disease
o Sjogren disease
o Hashimoto thyroiditis
o Helicobacter gastritis
The lymphoma remains localized for long periods of time
Multiple Myeloma Is a malignant neoplasm of plasma cells
o Most common primary tumor arising in the bone marrow of adults
Patient is an elderly male that presents with low back pain
o Differential includes:
Metastatic prostate cancer
Abdominal Aortic Aneurysm
Lab studies show
o increased serum protein with normal serum albumin
o M spike in serum electrophoresis is a monoclonal immunoglobulin spike most commonly IgG
(60%) or IgA (20%)
o Bence Jones proteins are light chains that are small and can be filtered into the urine
Histology
o Bone Marrow Biopsy:
Shows increased proliferation of plasma cells (>20% is characteristic)
Results in normal marrow elements being pushed out like leukemias where the patient can present with Pancytopenia
o Peripheral blood:
May show Rouleaux formation (stack of coins)
IgG attached to RBC which allows for the RBC to attach to each other creating a stack of
coins
Image shows stacks of coins and a central plasma cells (nucleus is eccentric (pushed to one
side) there is also a light area called a perinuclear hoff which is the Golgi apparatus
Multiple lytic bone lesions due to osteoclastic activating factor
o Appear as punched out lesions in the skull or vertebra
Lytic bone lesions cause
o Hypercalcemia – osteoclasts reabsorb bone for calcium
o Bone pain
o Increased risk for fracture
Complications include:
o Increased risk of infection – most common cause of death
o Renal disease – myeloma nephrosis
o Primary amyloidosis – occurs in 10% of patients due to amyloid light (AL) chains
o Increased amount of IL‐6
Associated with poorer prognosis because survival of myeloma cells depends on IL‐6
Plasmacytoma Solitary myeloma (1 lesion) within the bone or soft tissue
o Within Bone:
Precursor lesion that can later develop into myeloma
o Outside Bone (extramedullary):
Usually found within the upper respiratory tract and is not a precursor lesion for myeloma
Monoclonal Serum M protein is found in 1‐3% of asymptomatic individuals over the age of 50
Gammopathy of o The incidence increases with increasing age
Undetermined Annual risk of developing a plasma cell dyscrasia (usually multiple myeloma) is 1‐2% per year
Significance (MGUS) MGUS may also evolve into
o Lymphoplasmacytic Lymphoma (Waldenstrom macroglobulinemia)
o Primary amyloidosis
o B‐cell lymphoma
o CLL
Lymphoplasmacytic A small lymphocytic lymphoma with plasmacytic differentiation
Lymphoma (Waldenstrom o Is a cross between multiple myeloma and SLL
Macroglobulinemia) Like Myeloma
o Serum electrophoresis shows an M spike but with IgM (large pentamer)
Like SLL (unlike Myeloma)
o The neoplastic cells infiltrate many organs lymph nodes, spleen, bone marrow called Reticuloendothelial System (RES)
Unlike Multiple Myeloma
o There are no lytic bone lesions
o No increase in serum calcium
Russell bodies (cytoplasmic immunoglobulin) and Dutcher bodies (intranuclear immunoglobulin) may be present
Because IgM is so large there may be hyperviscosity syndrome
o Visual abnormalities:
may be due to vascular dilations and hemorrhages in the retina
o Neurologic symptoms include
Headaches
Confusion
o Bleeding and cryoglobulinemia can be due to abnormal globulins, which precipitate at low temperatures and may cause
Raynaud phenomenon
Peripheral T‐cell and Natural Killer Cell Neoplasms
Peripheral T‐Cell A diagnosis of exclusion
Lymphoma (Unspecified)
Adult T‐Cell A malignant T‐cell disorder CD4 T‐cells
Leukemia/Lymphoma o Due to HTLV‐1 infection
(ATLL) o Often seen in Japan and the Caribbean
Clinical symptoms include:
o Skin lesions
o Hypercalcemia
o Enlarged lymph nodes
o Hepatomegaly
o Splenomegaly
Microscopic characteristics:
o Hyperlobated “4‐leaf clover” lymphocytes found in the peripheral blood
Mycosis Fungoides and Mycosis Fungoides is a malignant T‐cell disorder post‐thymic CD4+ cells
Sezary Syndrome o That has a better prognosis than ATLL
Clinical presentation:
o Generalized pruritic erythematous rash which develops as a sequence of skin changes
Since the lymphoma cells are found in the skin and presents like a fungal infection
Inflammatory eczematous stage plaque stage tumor nodule stage
o NO hypercalcemia
Microscopic characteristics:
o Atypical PAS‐positive lymphocytes are present in the epidermis called Epidermotropism
o Aggregates of these cells are called Pautrier microabscesses
o If there is erythroderma and cerebriform Sezary cells present in peripheral blood (it is not a leukemia)
The condition is called Sezary Syndrome associated with generalized exfoliative skin rash
Lymphoma – Hodgkin versus Non‐Hodgkin Lymphomas
Hodgkin lymphoma has some characteristics that are different from non‐Hodgkin lymphoma
o Clinically, Hodgkin lymphoma may present similar to an infection (with fever)
o The spread is contiguous (spread is in order/sequence) to adjacent node groups unlike Non‐Hodgkin lymphoma which can
jump around to different lymph nodes in the body
o Classification is based on inflammatory response and not the malignant cell
o No leukemic state
o Extranodal spread is uncommon
Hodgkin Lymphoma Diagnostic cells are Reed‐Sternburg cells
o which are intermixed with reactive inflammatory cells
Reed‐Sternburg cells are B‐cells
o Large malignant tumor cells that have a bilobed nucleus with a prominent large inclusion‐like nucleolus in each lobe
o Positive for CD15 (Leu‐M1) and CD30 (Ki‐1)
Except for lymphocyte predominate Hodgkin Lymphoma
which stains for B‐cell markers and is negative for CD15 and CD30
o Microscopically:
With two Owls‐Eye in appearance
If there is a SINGLE owls‐eye this is CMV
In the center is a bilobed nucleus with an Owls‐Eye appearance
Hodgkin Lymphoma Lymphocyte‐Rich:
Classification o Rare
o Composed primarily of reactive lymphocytes associated with Epstein‐Barr virus in 40% of cases
o Immunophenotype: CD45 negative, CD15 positive, CD30 positive
Lymphocyte‐Predominant:
o Good prognosis lots of lymphocytes and few Reed‐Sternburg cells (bad guy)
o Has lympho‐histocytic variants of the Reed‐Sternburg cell called “popcorn cells”
Because the nucleus looks like a popcorn kernel
o UNIQUE Immunophenotype: CD45 Positive, CD15 Negative, CD30 Negative, and CD20 Positive
Mixed Cellularity:
o Occurs in middle‐aged and older males
o Composed of eosinophils and plasma cells in associated with the Reed‐Sternburg cells
The increased number of eosinophils is related to IL‐5 secretion
o Immunophenotype: CD45 negative, CD15 positive, CD30 positive
Lymphocyte‐Depleted:
o Presents with abdominal adenopathy
o Has very few lymphocytes and many Reed‐Sternberg cells worst prognosis
o Immunophenotype: CD45 negative, CD15 positive, CD30 positive
Nodular Sclerosis:
o Most common subtype in 65‐70% of cases
Where there are Reed‐Sternburg cells that are separated by scar tissue
o Only type which affects females more than males
o Microscopically:
Lymph node has broad collagen bands
Reed‐Sternberg cell has clear space in the cytoplasm called Lacunar cell
o Immunophenotype: CD45 negative, CD15 positive, CD30 positive
Etiology Bimodal age group distribution late 20s and >50
o Typically a young male that presents with fever, weight loss and night sweats
Differential diagnosis includes:
Hodgkin Lymphoma, HIV, TB
Patients usually present with painless enlargement of lymph node
Patients who have B‐cell symptoms (below) have a worst prognosis:
o Fever
o Weight loss > 10%
o Night sweats
Poor prognosis is directly proportional to the number of Reed‐Sternburg cells present
Treatment:
o Treatment above the diaphragm is with radiation (Stage 1 and 2)
o Treatment below the diaphragm is with chemotherapy (Stage 3 and 4)
o In order to separate stage 2 and 3
If the spleen is involved Stage 3
Those who survive chemotherapy and radiotherapy have an increased risk for cancer
o Secondary Non‐Hodgkin lymphoma
o Acute Leukemia
Myeloid Neoplasms
Acute Myelogenous Is a cancer of the myeloid line of blood cells
Leukemia (AML) Median age at diagnosis is age 50
Patient can present with Pancytopenia
Symptoms include:
o Fatigue
o Unusual bleeding
o Infections
Lab findings:
o Myeloid blasts or Promyelocytes represent at least 20% of the marrow cells.
Myeloblasts are very large with abundant cytoplasm containing granules which are NOT found in lymphoblasts
Lymphoblasts usually show scant basophilic cytoplasm (high N:C ratio) and fine nuclear chromatin (not clumpy), often
nuclear convolutions.
o In both B‐ and T‐ALL, the tumor cells have scant basophilic cytoplasm and nuclei somewhat larger than those of small
lymphocytes.
o The nuclear chromatin is delicate and finely stippled, and nucleoli are usually small and often demarcated by a rim
of condensed chromatin.
o In many cases the nuclear membrane is deeply subdivided, imparting a convoluted appearance. In keeping with the
aggressive clinical behavior, the mitotic rate is high.
o Myeloid blasts may have intracytoplasmic rods called Auer rods
Auer rods are…
composed of abnormal lysosomes that are pathognomonic of myeloblasts and not found in ALL
stain positive with myeloperoxidase or Sudan‐black B stain
o Neutrophils use myeloperoxidase to turn hydrogen peroxide into super oxygen species
are most commonly found in M3 AML
Tissue form of AML is called granulocytic sarcoma (chloroma)
French‐American‐British (FAB) Classification
o M0 – undifferentiated
o M1 – myeloblastic leukemia without maturation
o M2 – myeloblastic leukemia with maturation
o M3 – hypergranular (microgranular) promyelocytic leukemia
Microscopically, has numerous cytoplasmic granules and numerous Auer rods
May develop into DIC, sepsis, epistaxis
Due to the release of thromboplastic substances in granules especially when therapy kills the leukemic cells
Characteristic translocation is t(15;17)
Chromosome 15 has the PML gene
Chromosome 17 has the retinoic acid receptor alpha gene (RAR‐alpha)
This translocation forms an abnormal retinoic acid receptor thus therapy is All‐Trans‐Retinoic Acid (ATRA)
o M4 – myelomonocytic leukemia has both myeloblasts and monoblasts
o M5 – monocytic leukemia may have gingival infiltrates
o M6 – erythroleukemia Di Guglielmo disease
Due to abnormal erythroid precursors
Which causes binucleate and megaloblastic changes
o M7 – Acute Megakaryocytic Leukemia
Associated with acute myelofibrosis
Due to the release of platelet‐derived growth factor (PDGF)
Myelodysplastic Classified according to the number of blasts in the marrow
Syndromes (MDS) o Typically blasts in the marrow are less than 30%
Blasts are present but not enough to meet the criteria for acute leukemia
Dysplastic changes include:
o Pelger‐Huet cells aviator glasses nuclei
o Ring sideroblasts
o Nuclear budding
o Pawn ball megakaryocytes
MDS are considered preleukemias
o Where patients have an increased risk of developing acute leukemia if the number of blasts reaches 30% or higher
Clinical Presentation:
o MDS mainly affects older adults (age 50‐70)
o Predispose to infection, hemorrhage, and anemia
o Transformation to AML is common
Myeloproliferative MPS are clonal neoplastic proliferations of multipotent myeloid stem cells
Disorders (MPD) o The bone marrow is usually markedly hypercellular hence the name of myeloproliferative
o All cell lines are increased in number:
Erythroid
Myeloid
Megakaryocytes
o The various MPS cannot be distinguished by the histologic appearance of the bone marrow
Chronic Myelogenous CML is a clonal proliferation of pluripotent granulocytic precursor stem cells
Leukemia (CML) A unique characteristic is the chromosomal translocation (BCR‐ABL fusion gene) called the Philadelphia (Ph) chromosome which
has the translocation of t(9;22)
o Chromosome 9 has c‐ABL gene which is an oncogene
o Chromosome 22 has BCR gene (Breakpoint Cluster Region)
o This translocation forms a new protein P210 that has tyrosine kinase activity
Clinically
o CML has an insidious onset and massive splenomegaly
Microscopically
o The bone marrow is hypercellular with all cell lines increased in number
o Peripheral leukocytosis is present, including:
Markedly increased neutrophils and bands and metamyelocytes
Increased eosinophils and basophils like the other MPS
Labs
o Decreased leukocyte alkaline phosphatase (LAP) activity is diagnostic compared with leukemoid reaction, which has
increased LAP
Leukemoid reaction – with severe bacterial reaction, the bone marrow will release neutrophils and bands
in addition the bone marrow will release myocytes, myeloblasts, and metamyelocytes
o where a bone marrow smear will look like CML
In a leukemoid reaction, LAP will be increased because these cells are non‐neoplastic and make LAP
Difference between CML and LR LAP
CML Decreased
Leukemoid Reaction Increased
In the Peripheral blood smear of CML, you see the maturation of the Granulocytic series including:
o Myeloblasts – 3‐5x the size of a RBC
o Band cells
o Neutrophils
Treatment:
o Imatinib mesylate – to block the P210 tyrosine kinase protein production by the translocation
o Bone marrow transplant
Progression is typically slow 50% develop accelerated phase in <5 years
o Unless blast crisis develops looks like AML which is throwing out blasts
Blast Crisis has a very poor prognosis and doesn’t respond to chemotherapy
In blast crisis, 70% of cases show myeloid blasts and 30% shows lymphoid blasts
Polycythemia Vera A stem cell disorder with trilineage proliferation including:
o Erythroid
o Granulocytic
o Megakaryocytic
May develop into a “spent phase” with myelofibrosis where the bone marrow makes a ton of cells and then burns out and
produces scars to give the name myelofibrosis (fibrosis of the bone marrow)
o Which causes an increased risk for acute leukemia
Treatment:
o Phlebotomy
Characteristic findings include:
o Increased erythroid precursors with increased RBC
o Increased hematocrit
o Increased blood viscosity which can cause deep vein thrombosis and infarcts
o Decreased erythropoietin
but RBC have increased sensitivity to erythropoietin and over proliferate
o Increased basophils
Histamine release from basophils can cause intense pruritus and gastric ulcer (bleeding may cause iron deficiency)
Patients may present with Urticaria (hives) due to degranulation by mass cell
o Increased eosinophils like all of the MPS
o Increased LAP due to the increased in the number of WBC
o Splenomegaly due to high cell turnover can cause hyperuricemia resulting in gout
o Other clinical characteristics include:
Plethora – redness
Cyanosis – blue
Essential Characterized by
Thrombocythemia o Increased megakaryocytes (and other cell lines) in the bone marrow
o Megakaryocytes produce platelets
Peripheral blood smear shows
o increased platelets (>1,000,000), some with abnormal shapes
o increased leukocytes
Clinical characteristics include:
o Excessive bleeding
o Occlusion of small vessels
Myelofibrosis (MF) with Myeloid Metaplasia
Unknown etiology agnogenic
Marrow fibrosis is secondary to factors released from megakaryocytes platelet‐derived growth factor (PDGF)
o Bone marrow aspiration may be a dry tap just like Hairy cell leukemia
o Biopsy specimen shows hypocellular marrow with fibrosis increased reticulin
The fibroblasts are a polyclonal proliferation and are NOT neoplastic
There is an enlarged spleen
o Due to extramedullary hematopoiesis myeloid metaplasia
o High cell turnover causes hyperuricemia resulting in gout
Peripheral smear shows
o Leukoerythroblastosis – immature white cells and nucleated red cells
o Teardrop RBC
Natural History of the Myeloproliferative Disorders (MPD)
Polycythemia vera and essential thrombocytosis can lead to myelofibrosis
All can lead to acute leukemia as a complication
Diseases of Histiocytes and Dendritic Cells
Langerhans histiocytosis Proliferation of Langerhan histiocytes from the epidermis
Common in children
Can affect many sites including:
o Skin
o Bone
o CNS – diabetes insipidus
o Lungs
Biopsy is required for diagnosis
Langerhans cells are CD1a positive
Electron microscopy
o Shows cytoplasmic Birbeck granules tennis racket‐shaped organelles
Multisystem Variant:
o Letterer‐Siwe disease:
Malignant histiocytosis seen in children <2 years
Marrow involvement can be fatal (50% mortality rate)
Hand‐Schuller‐Christian:
o triad includes:
Calvarial involvement, Diabetes insipidus, Exophthalmos
o Malignant histiocytosis that mainly affects children
o Prognosis is intermediate
Unisystem variant:
o Eosinophilic granuloma most often found in bone
Benign histiocytosis that occurs in adolescents and young adults
Mast Cell Diseases
Mastocytosis Mast cells have metachromatic granules that stain with Toluidine blue
o Their diseases are associated with pruritic and swelling of tissues secondary to histamine release
Occurs from birth to adulthood
o But adult‐onset cases are more severe
The WHO separates mastocytosis into three categories:
o Cutaneous Mastocytosis
o Solitary Mastocytoma (infants) – characterized by localized mast cell hyperplasia with release of mediators
o Urticaria pigmentosum – skin disease with increased dermal mast cells
o Systemic Mastocytosis – mast cell infiltrations in multiple organs
o Localized Extracutaneous Mast Cell Neoplasms
Cutaneous Mastocytosis
Seen in children and regresses over time
Mast cell degranulation enzymes (histamine and tryptase) cause Pruritis
Systemic Mastocytosis
Is a clonal proliferation of mast cells with release of mediators
o associated with a KIT mutation
More than one organs are involved
o including the skin and bone marrow
The WHO classifies systemic mastocytosis as one of the myeloproliferative neoplasms
o Variants include some rare leukemias
o Diagnosis is made with
bone marrow biopsy
molecular analysis
Localized Extracutaneous Mast Cell Neoplasms
can be benign Mastocytoma
can be malignant Sarcoma
Diseases of the Spleen and Thymus
Splenomegaly Splenic enlargement can be cause by multiple things:
o Vascular congestion associated with
Portal hypertension
o Reactive hyperplasia of white pulp associated with
Autoimmune disorders
Infectious mononucleosis
Malaria
o Infiltrative diseases associated with:
Metastatic non‐Hodgkin Lymphoma
Primary amyloidosis
Leukemias
o Accumulated macrophages in the red pulp associated with:
Gaucher
Niemann‐Pick disease
o Extravascular hemolysis
o Extramedullary hematopoiesis in splenic sinusoids seen in the MPD
Hypersplenism will result in thrombocytopenia
Splenic dysfunction
Will result in a loss of the ability to remove damaged red cells
o Which leads to Howell‐Jolly bodies in peripheral red blood cells
o Also associated with hemolytic anemia
Patients Increased risk for infection associated with sepsis and peritonitis include
o Splenectomized
o Asplenic
o Hyposplenic
Infections are particularly due to
o Streptococcus
o Haemophilus
o Salmonella
Thymomas
Low‐grade tumors of the thymic epithelium with many histologic patterns
Recent large case series has shown that tumor behavior does not always correlate with histopathological features
True Thymic Hyperplasia
Is enlargement of a histologically normal thymus
o Which can occur as a complication of chemotherapy
Thymic Lymphoid hyperplasia
Shows a germinal center hyperplasia
Mycology
Background Mycology is the study of fungi which includes:
o Molds, yeasts, and mushrooms
All fungi are:
o Eukaryotic – true nucleus, 80S ribosomes, mitochondria, as are humans
o Complex carbohydrate cell walls chitin, glucan, and mannan
o Ergosterol = Major membrane sterol
Imidazole antifungals inhibit synthesis of ergosterol
Polyene antifungals bind more tightly to ergosterol than cholesterol
Fungal Growth and Fungi usually reproduce without sex
Reproduction o Single‐celled yeasts—budding
Fungi that make hyphae can reproduce asexually as well
o Bits of the hyphae can break off and continue to grow as separate entities, or can form stalks containing seed‐like spores.
Fungi can produce spores sexually
o Two mating cells from hyphae of different strains of fungi can mate by fusing together and forming a spore stalk.
o less common
Structural Characteristics Yeast are unicellular and reproduce by asexually by processes termed blastoconidia formation (budding)
or fission.
Pseudohyphae are chains of blastoconidia that have not separated (exagerated form of budding).
Most fungi have branching threadlike tubular filaments called hyphae that elongates at their tips by a
process called apical extension.
These filamentous structures are either hollow and multinucleated (coenocytic) or divided by partitions
or septations.
The collective term for a mass of hyphae is mycelium which is synonymous with mold.
Sporangium is an enclosed sac that contains asexual spores. Conidiophore is a specialized hyphal
structure that bear condidia
Arthroconidia – Asexual form by breaking up of hypha at the point of septation.
Coccidiomycosis – soil
Chlamydoconidia – Enlarged, rounded conidum that is thick walled and contains stored food.
Paracoccidioddes and phaeohyphomycosis
Macro and Microconidia – Small and large types of conidia in a fungus. Asexual form
Dimorphic Fungi Fungi that are able to convert from hyphal to yeast or yeast‐like forms
Thermally dimorphic: in the cold are the mold form
o Yeast like cells at 35 C
o Mold form at 25 C
Examples
o Histoplasma capsulatum
o Blastomyces dermatitidis
o Coccidioides immitis
o Sporothrix schenckii
o Paracoccidioides brasiliensis
o Penicillium marneffei
Mycology: Human disease Mycotoxins
Hypersensitivity diseases
Superficial, cutaneous and subcutaneous mycoses
Systemic mycoses
Opportunistic mycoses
Epidemiology of Fungi Person to person
o Athletes’ foot
Contact with environment
o Inhalation of spores
o Traumatic inoculation
Contact with animals
o Inhalation of bird droppings
o Touch infected skin/hair of dogs
Pathogenesis of Fungi Adherence
o Fungal adhesins that mediate colonization of epithelial surfaces
Invasion of natural barriers
o Trauma (rose thorns)
o Inhalation of spores (Coccidioides in dust)
o Breakdown of mucosal barriers (catheters)
Avoid phagocytosis
o Histoplasma yeast multiply in macrophages
o Cryptococcus has capsule
Host immunity
o Humoral immunity not protective
o Cellular immunity required to eradicate infection
Candidiasis – p56
Immunocompromised patient, overuse of antibiotics—thrush, spread down GI tract, septicemia
IV drug abusers—endocarditis
Germ tube test demonstrates pseudohyphae and hyphae
Most common opportunistic fungal pathogen
Normal flora of GI and GU tracts
Oval budding yeasts in body fluids
Yeasts with pseudohyphae in tissues
Colonies resemble bacteria in culture
Medically Important Candida albicans (germ tube +)
Candida Spp. o >60% of clinically significant isolates
o Laboratory Diagnosis
Direct exam by Gram stain or calcofluor
Difficult to implicate Candida as pathogen where it is normal flora
Isolate from blood cultures and tissue
Candida albicans strains produce white to cream colored, pasty, smooth colonies on Sabouraud dextrose agar
Test yeast for production of germ tube
Germ tubes are the beginning of true hyphae and observed by microscopic examination upon
inoculation of the strain in serum.
The two Candida spp. that produce germ tube are Candida albicans and Candida dubliniensis.
Perform biochemical battery
No serology tests available
o Calcofluor Stain
Calcofluor white is a fluorescent brightener that binds to chitin
o Gram Stain
Candida albicans produces clusters of round blastoconidia along the hyphae and particularly at points of
septa.
Pseudohyphae and true hyphae are also observed.
o Histopathology
Periodic Acid‐Schiff (PAS) stained section of post‐mortem esophagus showing invasion of blood vessel by
C. albicans.
Grocott's methenamine silver (GMS) stain
Note blastoconidia and branched pseudohyphae.
Candida dubliniensis
o Highest prevalence from oral or fecal specimens of HIV‐positive patients
Candida glabrata
o No pseudohyphae
o Associated with UTI’s, occasionally vaginitis
o Higher rates of resistance to fluconazole
Candida krusei
o Resistant to fluconazole
o Colonization/infection in BMT
Candida lusitaniae
o Opportunistic blood, urine, and respiratory tract pathogen
o Resistance to amphotericin B
Candida parapsilosis
o Endocarditis (25%), post‐surgical endophthalmitis
Candida tropicalis
o Disease in patients with lymphoreticular malignancies
Candida ‐ Pathogenesis Adheres to mucosal cells
Binds to fibronectin, collagen, and other extracellular components using adhesin
Lytic enzymes:
o C. albicans produce phospholipases
o C. albicans, C. tropicalis, and C. parapsilosis produce proteases that are lytic for keratin facilitating invasion of epithelial
surfaces
Candidiasis – Host Defenses Intact integument – Candida do not normally grow on skin and normally found in low numbers in GI tract
Normal bacterial flora (especially normal gut flora)
Cell wall mannan
o activates the alternate complement pathway leading to enhanced phagocytosis and killing of Candida
o Mannan is antigenic, causes antibody formation, nearly all human sera contain IgG antibody against mannan
Cell wall glycoproteins and mannans elicit delayed hypersensitivitiy and cell mediated immunity
Neutrophils and macrophages are key in defense against Candida infections
Mucocutaneous forms of candidiasis are associated with defects in cell‐mediated immunity, while system spread is generally
associated with neutropenia. Reason why systemic spread of esophageal candidiasis in AIDS patients is uncommon
Risk Factors for Candida Antibiotic therapy
Infection o Part of endogenous flora (oral, GI, GU tract)
o Loss of normal flora and overgrowth of yeasts
Corticosteroid use
Decreased T cell function
Diabetes
Candida Skin and Nail Change in the texture color and structure of the nail.
infections o Nailed sometimes red.
o Sides of the nails are yellowish gray and shoe distal onycholysis.
The skin has a fairly sharp but irregular erythematous area with easily detachable cigarette paper like scaling.
Treatment:
o Candida infection oral antifungal (grespeg, lamisil)
o Dermatophyte: topicals (clotrimazole, topical lamisil)
Clinical Manifestations Mucocutaneous infection
o Thrush is a yeast infection that causes white patches in the mouth and on the tongue.
Oral:
o creamy white areas of membranous exudates the tongue or buccal mucosa that can easily be removed.
o
Skin:
o fairly sharp but irregularly demarcated erythematous area with easily detachable cigarette‐paper like scaling that follows the
borders of the lesion, occasionally circular, resulting in a scaling collar.
o
Vulvovaginal candidiasis
o Candida can overgrow due to
Stress, pregnancy, and illnesses that affect the immune system
Certain medicines eg. birth control pills and steroids.
Antibiotics can kill "good" bacteria that normally keep the growth of Candida in the vagina in check.
Women who have diabetes that isn't controlled are at a higher risk for yeast infections.
Chronic mucocutaneous candidiasis
o Hereditary immunodeficiency disorder due to malfunction of T cells
o Candida infections develop and persist, usually beginning during infancy
o In infants, first symptoms are often thrush that is difficult to treat, diaper rash, or both. Severity varies. May cause a
disfiguring rash that covers the face and scalp.
o
Candida endopthalmitis
o Exogenous ‐ trauma or a surgical procedure on eye with direct inoculation of organism into the anterior chamber.
o Endogenous ‐ candidemia with hematogenous seeding of retina and choroid
o If untreated, both forms progress to endophthalmitis, in which the vitreous is infected, and can result in loss of sight
o
Candida Esophagitis
o there is a creamy white thick exudates on the surface of the esophagus
o
Candida infections Systemic
o Fungemia
o Endocarditis
o Pulmonary infection
o Urinary tract infection
o Meningitis
Diagnosis KOH: pseudohyphae, true hyphae, budding yeasts
Septicemia: culture lab identification: biochemical tests/formation of germ tubes
Treatment Topical imidazoles or oral imidazoles; nystatin
Disseminated: Amphotericin B or fluconazole
Aspergillosis – p55
Patient with asthma, cystic fib osis—growing mucous plugs in lung
Patient with cavitary lung lesions—fungus ball
Patient with burns—cellulitis, invasion
Immunocompromised patient—pneumonia, meningitis
Septate hyphae branch at acute angles
Roman Catholic Church. a brush or instrument for sprinkling holy water; aspersorium.
Origin: 1640–50; < Neo‐Latin, equivalent to Latin asperg ( ere ) to be sprinkled
Characteristics of Rapidly growing mold
Aspergillus Found in soil, air, construction dust
Dichotomous branching—Y shaped, acute angle
Septate hyphae
Most important species: Aspergillus fumigatus
ID according to color and structures
Pathogenesis of Aspergillus Inhale spores / conidia
Conidia bind to fibronectin
A. fumigatus inhibits alternate complement pathway and interferes with opsonization
Clinical Manifestations Allergic aspergillosis
o Sinus infection on CT
o
Fungus ball in pre‐existing cavity (TB, emphysema)
o Fungus ball in lung
o
Invasive apergillosis
Dissemination infection
Can be angioinvasive
Common Aspergillus Aspergillus Fumigatus
Species o ID according to color and structures
o
Monomorphic filamentous fungus
o Dichotomously branching
o Generally acute angles
o Frequent septate hyphae with 45° angles
o One of our major recyclers: compost pits, moldy marijuana
Diseases/Predisposing Allergic bronchopulmonary aspergillosis (ABPA)/asthma, cystic fibrosis (growing in mucous plugs in the lung but not penetrating
Conditions the lung tissue)
Fungus ball: free in preformed lung cavities (surgical removal to reduce coughing, which may induce pulmonary hemorrhage)
Invasive aspergillosis/severe neutropenia, CGD, CF, burns
o Invades tissues causing infarcts and hemorrhage.
o Nasal colonization → pneumonia or meningi s
o Cellulitis/in burn patients; may also disseminate
Treatment Voriconazole for invasive and aspergilloma, glucocorticoids + itraconazole for ABPA
Mucormycosis – Mucor, Rhizopus, Absidia (Zygomycophyta) – p58
Ketoacidotic diabetic or leukemic patient with rhinocerebral infection
Biopsy with nonseptate, irregular width hyphae branching at 90‐degree angles
Mucormycosis refers to angiotropic (blood vessel‐invading) infection produced by various fungi in the orders Mucorales and
Entomophthorales.
Previously, the term zygomycosis was used to denote invasive fungal infections caused by fungi belonging to phylum
Zygomycota, class Zygomycetes, orders Mucorales and Entomophthorales.
The Mucorales order contains 2 families—Mucoraceae and Cunninghamellacea. Since majority of human infections are caused
by Mucorales fungi, the term Mucormycosis is now used to designate this infection
Mucormycosis – Habitat Agents of mucormycosis commonly found on fruit, bread, and in soil and are common components of decaying organic debris
Ubiquitous and generally saprophytic, rarely causing disease in immunocompetent hosts,
3rd most common cause of invasive fungal infection in immunocompromised patients, especially stem cell transplant recipients
and patients with underlying hematologic malignancies
Mucormycosis – Host risk Acidotic diabetics
factors Malnourished children
Severely burned patients
Severe leucopenia
Immunosuppressive disorders (leukemia, lymphoma, AIDS)
Use of immunosuppressive therapy such as corticosteroids
Mucormycosis – Inhalation of spores
Pathogenesis Deposition of spores in the nasal turbinates
Direct inoculation of abraded skin
Spore germination
Generally acute and rapidly developing in debilitated patients.
Infection typically involves rhino‐facial‐cranial area, lungs, gastrointestinal tract, skin, or less commonly other organ systems.
Predilection for vessel (arterial) invasion resulting in embolization and necrosis of surrounding tissue.
Infections are typically acute and fulminant.
Mucormycosis – Clinical Rhinocerebral mucormycosis
Syndromes o Most frequent presentation overall and classically affects diabetics with ketoacidosis
o Usually presents with facial and/or eye pain, proptosis and progressive signs of involvement of orbital structures (muscles,
nerves and vessels)
Case of a periorbital mucormycosis
Dangerous fungal infection usually occurring in immuno‐compromised patient, affecting the regions of the eye, nose, and
through its growth and destruction of the periorbital tissues, it will eventually invade the brain cavity.
o Usually results in death, often within a few days. Mortality rate is approximately 85%.
Pulmonary
o Occurs most frequently among neutropenic patients
o Presents with nonspecific symptoms such as fever, cough and dyspnea; hemoptysis may occur with vascular invasion
GI tract
o Usually affects patients with severe malnutrition
o May involve the stomach, ileum, and colon
o Clinical picture mimics intra‐abdominal abscess. The diagnosis is often made at autopsy.
Cutaneous
o Reported with minor trauma, insect bites, non sterile dressing, wounds, and burns
o Necrotic lesions progressively evolve from the epidermis into dermis and even muscle.
Disseminated disease
o Angioinvasion
o Ischemia, necrosis of tissue
Mucormycosis – The Rhizopus species from the Mucoraceae family are the most commonly identified etiologic agents of mucormycosis in humans.
Organisms The species most commonly associated with mucormycosis is Rhizopus arrhizus
Other organisms causing mucormycosis include
o Mucor
o Cunninghamella
o Apophysomyces
o Lichtheimia (Absidia)
o Saksenaea
o Rhizomucor
o Entomophthora
o Conidiobolus
o Basidiobolus
Rhizopus arrhizus
Infections caused by R. arrhizus (synonym: R. oryzae) are frequently acute and rapidly fatal despite early diagnosis and
treatment.
R. arrhizus have a predilection for invading major blood vessels, with ensuing ischemia, necrosis, and infarction of adjacent
tissues, resulting in the production of black pus.
Persons at risk include patients with granulocytopenia, hematopoietic stem cell transplant and solid organ transplant recipients,
and patients with underlying acidosis.
Mucormycosis: Diagnosis Cytologic or tissue confirmation important
Tissue reaction
o usually slight
o acute suppurative inflammation predominates with focal areas of granulomatous inflammation
Hyphae
o broad, vary from 6‐50 um in diameter
o Asepate or sparsely septate
o irregularly branched
o ribbon‐like
o 90° branching
Microscopic examination of tissues for broad, non septated hyphae
Growth is woolly white to grey
o
Examination of culture for characteristic sporangia
o
Mortality Overall mortality approx 50%
Hematologic malignancy 65%
Hematopoietic stem cell transplant 90%
Treatment Strategies Early Diagnosis
o Treatment initiated within five days of diagnosis
o CT and MRI can be useful, although not very sensitive
o Mortality was reduced in one study from 83% to 59% if diagnosed < 5 days
Reversal of underlying predisposing factors
o stop immunosuppressive therapy if possible
o restore euglycemia
o do not administer iron and/or blood products
Surgical management
o Debridement of necrotic tissue for complete eradication
o Often extensive and extremely disfiguring
o Far higher mortality in those who do not undergo debridement than those who do
Mucormycosis Aspergillosis
Dermatophytosis – Ringworm, Tinea – p54
Patient with scaly, pruritic ring‐like lesions of skin. May involve hair shaft or nails.
KOH scraping shows arthroconidia and hyphae.
Fungal Infection of keratinized tissues (skin, hair, nails) caused by a group of specialized fungi, the dermatophytes
Onychomycosis—nail infections caused by any fungus
Invasion of subcutaneous or deep tissues is very rare
Slow growing in culture (25 C)
Transmission requires close personal contact
Dermatophytes‐ Classified into 3 genera
Classification Species Infects Skin Infects Hair Infects Nails
Epidermophyton – 2 species X X
Microsporum – 16 species X X
Trichophyton – 24 species X X X
Dermatophytes Inflammation often greatest at the advancing margin leaving a central area with some clearing
Clinical Manifestations The name “ringworm” follows from the irregular inflammatory border of the skin lesion
Naming of clinical disease is done by appending a Latin term designating body site to the word, tinea
Tinea pedis (Athlete’s foot) – most common dermatophyte infection
o Begins as weeping, peeling lesion between 4th and 5th toes. May extend to other toes
o In toe webs, scaling, fissuring, maceration, and erythema may be associated with an itching or burning
sensation
o Most common species: T. rubrum, T. mentagrophytes, E. floccosum
Tinea capitis (ringworm of the scalp)
o Dermatophytosis of scalp due to invasion of hair
o Hair becomes dull, lusterless and tends to break off 1‐2 mm above hair follicle orifice
o Infection may be patchy or extensive and with time may involve entire scalp
o Predominant cause of tinea capitis in USA is T. tonsurans
Tinea corporis (Dermatophytosis of glabrous skin)
o Most commonly occurs in children and may be seen on face, shoulder, arms, or other surfaces
o Lesions variable in size, annular, sharply marginated, exhibit raised, red, serpiginous border (“ringworm”)
o Agents of tinea corporis include: M. canis, M. gypseum, T. mentagrophytes, T. rubrum
Tinea cruris (jock itch)
o Infection of groin, perineum, scrotum, perianal area. More common in men
o Erythema, pustule formation, hyperpigmentation of affected areas associated with chronic infection
o Itiching or burning common
o Common agents are T. rubrum and E. floccosum
Pathogenesis of Inoculation via minor trauma
Dermatophytes Penetrates stratum corneum and proliferates
Infection spreads laterally, not deeper
Spread to other keratinized structures
Cell mediated immunity for resolution
Chronic infection associated with decreased T cell function
Lab Diagnosis of Direct exam of leading edge of skin lesion by KOH or calcofluor
Dermatophytosis Examine hair under Wood’s light
o Damaged hair fluoresces
o Remove infected hair at shaft for culture
Culture to rule out other pathogens
o
ID by color, growth, conidia shape
KOH Preparation/Mount
o 20% potassium hydroxide
o Rapid detection of fungal elements from a clinical specimen
o Sample is placed on a slide with KOH solution
o Solution slowly dissolves the skin cells but not the fungus. The fungus can then be seen with a microscope
o Scrape leading edge of skin lesion
o
Treatment Topical imidazoles or tolnaftate
Oral imidazoles or griseofulvin where hairs are infected, or skin contact hurts
Keep areas dry.
Cryptococcosis
Crytococcus neoformans
o Pigeon breeder with acute pulmonary symptoms
o Hodgkins/AIDS patient with meningitis
o India ink mount of CSF with encapsulated yeasts
Crytococcus neoformans Yeast (4‐6 micrometers) with polysaccharide capsule
Yeast cells are round, no oval
Found throughout the world
Associated with pigeon droppings and soil
Prevalence and Genus Cryptococcus includes 37 species
Epidemiology Cryptococcus neoformans and Cryptococcus gattii are only species that are pathogenic and the only pathogenic encapsulated
yeast
Cryptococcus found in weathered quano from pigeons and other birds
neoformans Found in soil, wood, rotting vegetation, and fruit juice (first identification in nature from peach
juice samples)
Cryptococcus gattii limited global distribution
Endemic in Southern California and Mexico
Recovered from animals and humans living in Pacific Northwest
May be endemic to other regions of US
World‐wide distribution, skin testing indicates many persons exposed, but few develop illness
Can cause disease in normal and Immunocompromised hosts
o Disease occurs in 7‐8% of AIDS patients in U.S.
o More than 50% of total number of cases of cryptococcosis reported annually in the U.S. occur in AIDS patients
Most common predisposing factor in non‐AIDS patients is
o receipt of large doses of adrenal corticosteroids
o Sarcoidosis and lymphoma also predispose to infection
Cryptococcus gattii found largely in immunocompetent hosts
Pathogenesis Infection acquired by inhalation into the lungs from an environmental source, but case clustering not observed
Animals can be infected but transmission to humans does not occur
Pulmonary infection is asymptomatic or symptomatic
o but typically, self‐limited in immunocompetent patients
Hematogenous spread to CNS and other organs occurs even with subclinical pulmonary infection
Conidia inhaled from environment lung CNS
Capsule blocks phagocytosis
Capsule interferes with complement pathway
Activated T cells required for clearing infection
Recovery associated with humoral immunity
Clinical Manifestions Most patients will have meningoencephalitis at presentation
Present with
o Headache
o Nausea
o Gait abnormalities
o Dementia
o Irritability
o Cranial nerve abnormalities and hydrocephalus
due to basilar meningitis occur
o Fever and nuchal rigidity may be mild
Deepening coma eventually results in untreated patients, and death occurs from 2 weeks to years after onset of symptoms
Pulmonary involvement cough and chest pain
CXR will show one or more well‐localized infiltrates
Other organs involved include:
o skin, bone, prostate and other GU sites, hepatitis, pericarditis, endocarditis, and endophthalmitis
Raised skin lesions resulting from dissemination of the yeast in an immuno‐compromised patient
Laboratory Diagnosis Colonies are fast growing, soft, glistening to dull, smooth, usually mucoid, and cream to slightly pink or yellowish brown in color.
The growth rate is somewhat slower than Candida and usually takes 48 to 72 h.
Ability to grow at 37°C is one of the features that differentiates Cryptococcus neoformans from other Cryptococcus spp.
Encapsulated yeast in India ink preparation.
o The small round structure in the center of the white area is the yeast cell. 400X.
Cryptococcal Antigen Latex Agglutination or Lateral Flow Assay
o Highly sensitive and specific
o Can detect antigen in CSF and serum
o Has diagnostic and prognostic value
o Method of choice for diagnosing patients with cryptococcal meningitis
Cryptococcus in Gram Stain
Histopathology Methenamine silver (GMS) stained tissue section of lung showing non‐encapsulated yeast cells of C. neoformans.
Encapsulated yeast cells in brain tissue.
Mucicarmine stain, 630X
Treatment AMB+5FC (flucytosine) until afebrile and culture negative (minimum of 10 weeks), then fluconazole
Dimorphic Fungi
Mold in the cold and Yeast in the Heat
o Yeast like cells at 35 C
o Mold form at 25 C
Examples
o Histoplasma capsulatum
o Blastomyces dermatitidis
o Coccidioides immitis
o Sporothrix schenckii
o Paracoccidioides brasiliensis
o Talaromyces (Penicillium) marneffei
Histoplasmosis
Histoplasma capsulatum
o Normal patient with acute pulmonary; immunocompromised patient with chronic pulmonary or disseminated infection
o States following drainages of Great Lakes to Gulf of Mexico
o Exposure to bird or bat excrement
o Sputum or blood cultures with mononuclear cells packed with yeast cells
Characteristics Dimorphic fungus
o Yeast phase (2‐4 um) found in macrophages
o Mold phase has tuberculate macroconidia
No capsule
Found in soil, bird and bat droppings
Concentrated in Ohio / Mississippi River Valleys
Clinical Manifestations Asymptomatic (antibody present)
Pulmonary
o Infiltrates, mediastinal lymphadenopathy
o May progress to cavitating lesion
o Fever, night sweat, weight loss (like TB)
Disseminated
o Febrile illness
o Spread to CNS, skin, adrenals
o Enlarged liver and spleen
Pathogenesis Hallmark = Infection of reticuloendothelial (RE) by yeasts growing in macrophages
Conidia inhaled by host & converts to yeast
Yeasts phagocytosed by macrophages
Yeasts multiply and spread to liver, spleen, and bone marrow
Primary lesion = granuloma in lung
Lab Diagnosis Culture of bone marrow, biopsy, BAL
o Convert mold to yeast phase
o DNA probe of colony
Skin test with histoplasmin
o Positive test shows past exposure
o Not to diagnose acute infection
Urine Antigen Test
At 25°C
o Colonies are slow growing and granular to cottony in appearance.
o Color is white initially and usually becomes buff brown with age; reverse, is yellow or yellowish orange.
o
o Hyphae are septate and hyaline.
Has both macro‐ and microconidia.
Macroconidia are tuberculate, thick‐walled, round, unicellular, hyaline, large and often have fingerlike projections on the
surface.
Histology Intracellular budding yeast cells are typical
Histoplasma capsulatum predominates at central portion of lesions. Thus, selection of tissue section to be excised for
histopathologic and mycologic examination is of particular significance.
o multinucleate giant cell
o
o Intracellular yeast form in a multinucleate giant cell. H&E, spleen, 1000X
o
Treatment Itraconazole for mild
Amphotericin B for severe
Blastomycosis
Blastomyces dermatitidis (“Chicago Disease”)
o Normal patient with acute pulmonary symptoms
o Immunocompromised patient with chronic pulmonary or disseminated infection
o North and South Carolina (otherwise coexists with Histoplasma)
o Sputum has broad‐based, budding yeasts with double, refractile cell walls
Characteristics Dimorphic fungus
o Large thick wall yeasts with broad based buds
o
o Mold phase not unique
Found in central U.S.
o
Associated with soil
and wood
Clinical Manifestations Pulmonary
o Fever, chest pain, cough with sputum
o Hilar lymphadenopathy, nodular lesion
Skin lesions (necrosis and fibrosis)
Lytic bone lesions
Disseminated disease
Some patients have an acute self‐limited pneumonia, with resolution of fever, cough, myalgias, and malaise within
1 month
Most patients have chronic pneumonia with indolent onset and progressive course.
o CXR is abnormal in 2/3s, with alveolar or nodular infiltrates
o
Skin lesions are common and may progress to large ulcers
Mucus membrane lesions are also common and may mimic CA
Osteolytic lesions with draining sinuses are not infrequent
GU tract disease (prostatitis, epididymitis) mimics that seen with tuberculosis
Blastomyces Yeast and Yeast
Mold Phases
Mold
Histology Tissue sections showing large, broad‐base, budding yeast‐like cells, 8‐15mm in diameter.
Note: tissue sections need to be stained by Gomori's methenamine silver (GMS) stain or periodic acid‐Schiff (PAS) stain to
clearly see the yeast‐like cells, which are often difficult to observe in H&E stained preps.
Laboratory Diagnosis Broad‐based budding yeast on KOH Prep
At 25°C
o The growth rate is slow to moderately rapid.
o The colony diameter is 0.5 to 3 cm following incubation for 7 days on potato glucose agar.
o The texture is membranous and downy to woolly.
o The surface color is white to beige and reverse is pale to brownish.
o
o Septate hyaline hyphae and unbranched short conidiophores are observed.
o Conidiophores arise at right angles to the hyphae. Conidia are hyaline and unicellular. They are solitary and pyriform to
globose in shape (Lollipop).
o
At 37°C
o After incubation at 37°C on an enriched medium or in infected tissue sections, the fungus appears as budding yeast cells.
o The yeast cells (8‐12 µm in diameter) typically have double‐contoured refractile walls and a broad base attaching the bud to
the parent cell
o
o
Broad Base Budding = Blastomycosis
Treatment Itraconazole for mild
Amphotericin B for severe
Coccidioidomycosis
Coccidioides immitis/posadasii (“Valley Fever”)
o Normal patient with erythema nodosum or self‐resolving pneumonia
o Immunocompromised patient with calcifying chronic pulmonary or disseminated infections
o Pregnant female in third trimester, disseminated infection
o Desert southwest
o Sputum has spherules with endospores
Characteristics Dimorphic fungus
o In tissue: spherule filled with endospores
o In culture: mold with barrel shaped arthroconidia
Coccidioides immitis (typically in California) and Coccidioides posadasii (typically outside of California)
Thought to be Geographically restricted to desert climate (Southwest U.S.)
Not transmitted person‐to‐person
Pathogenesis Inhalation of arthroconidia bypasses upper airway into alveoli
Monocytes ingest arthroconidia
Arthroconidia converts to spherule
Clinical Manifestations Primary infection characterized by fever, cough, chest pain, malaise and occasionally hypersensitivity reactions.
CXR shows infiltrate, hilar adenopathy, or pleural effusion. Mild eosinophilia may be seen
Most cases resolve spontaneously with complete recovery
Dissemination to bone, skin, squamous and mucosal tissues, meninges, joints and other sites can follow primary pulmonary
infection
Dissemination occurs more frequently in African Americans, Filipinos, Native American, Mexican‐Americans, Pregnant women,
and immunocompromised patients
Erythema nodosum
o The rash is a immunologic response to the fungus. It is most commonly seen in Caucasian women.
o
Lab Diagnosis Microscopic exam to detect spherules
Culture
o Demonstrate alternating arthroconidia
o DNA probe of colony
Skin test turns positive 1‐4 weeks
Serology useful unless anergic
o Antibody decrease as disease resolves
Colonies grow rapidly.
Macroscopic morphology may be very variable.
At 25 or 37°C and on Sabouraud dextrose agar, the colonies are moist, glabrous, membranous, and grayish initially, later
producing white and cottony aerial mycelium. With age, colonies become tan to brown in color.
At 25°C
o Arthroconidia are thick‐walled, barrel‐shaped, 2‐4 x 3‐6µm in size.
o Typically, these arthroconidia alternate with empty disjunctor cells.
o On the released arthroconidia, annular frills that are the remnants of the disjunctor cells are observed.
o
Histology Spherules containing endospores are typical structures formed in infected tissues.
Treatment Azoles for mild to moderate (itraconazole, etc.)
Amphotericin B for severe
Subcutaneous Mycoses
Involves infection of skin and underlying tissues (without dissemination)
Humans often accidental hosts (trauma with saprophytic fungi)
Subspecies includes:
o Sporotrichosis
o Chromoblastomycosis
o Mycetoma
o Rhinosporidiosis
o Lobomycosis
o Phaeohyphomycosis
Sporotrichosis
Sporothrix schenckii
o Patient with subcutaneous/lymphocutaneous mycetoma
o Gardener, florist, basket weaver
o Cigar‐shaped yeasts in pus
Characteristics Dimorphic fungus
o Cigar shaped yeast at 37 C
o Mold with daisy like conidiophore at 25 C
Found in soil
Associated with rose thorns and moss
Clinical Manifestations Papular skin lesion enlarges and ulcerates
Appearance of subcutaneous firm nodules that progress along dermal and lymphatic vessels.
o It is also called nodular lymphangiitis
Multiple ulcers
Disseminates to bones, lungs, eyes, CNS
Pathogenesis Inhalation of conidia or traumatic inoculation of skin
Organism multiplies at local site
Pyogenic and granulomatous response
Infection spreads via the lymphatics
Pulmonary sporotrichosis is rare
Lab Diagnosis Sporothrix in culture and microscopic mold findings
Sporothrix Yeast Phase
Treatment Itraconazole or amphotericin B
Chromoblastomycosis
Characteristics Posttraumatic chronic infection of subcutaneous tissue
Papules verrucous cauliflower‐like lesions on lower extremities
Systemic invasion is very rare
Etiologic Agents Phialophora verrucosa
Fonsecaea pedrosoi
Fonsecaea compacta
Cladophialophora carrionii
Rhinocladiella aquaspera
Histology Presence of dark‐walled, or dematiaceous (melanized) septate hyphae = Copper pennies
Opportunistic Fungi
Species Key Vignette Clues
Aspergillus fumigatus Patient with asthma, cystic fibrosis – growing mucous plugs in lung
Patient with cavitary lung lesions – fungus ball
Patient with burns—cellulitis, invasion
Immunocompromised patient – pneumonia, meningitis
Septate hyphae branch at acute angles
Candida albicans Immunocompromised patient, overuse of antibiotics ‐ thrush, spread down GI tract,
septicemia
IV drug abusers – endocarditis
Germ tube test demonstrates pseudohyphae and hyphae
Cryptococcus neoformans Pigeon breeder with acute pulmonary symptoms
Hodgkins/AIDS patient with meningitis
India ink mount of CSF with encapsulated yeasts
Mucormycoses (Mucor, Rhizopus, Ketoacidotic diabetic or leukemic patient with rhinocerebral infection
Absidia) Biopsy with non‐septate, irregular width hyphae branching at 90‐degree angles
Pneumocystis jiroveci Premature infant or AIDS patient with atypical pneumonia
Biopsy with honeycomb exudate and silver‐staining cysts
X‐ray: ground glass
GRAM POSITIVE BACILLI
GENUS: Mycobacterium
Sub‐Species Diseases Treatment
M. tuberculosis Primary Pulmonary TB First 2 months: Rifampin + Isoniazid + Pyrazinamide + Ethambutol (RIPE)
Next 4 months: Rifampin and Isoniazid
M. leprae Leprosy Dapsone and Rifampin for tuberculoid form
Clofazimine is added for lepromatous form
M. avium‐intracellular Localized pulmonary disease Clarithromycin or azithromycin combined with rifabutin or ethambutol
M. kansasii
M. marinum Fish tank granuloma Isonazide
Rifampin or Ethambutol
M. ulcerans Buruli ulcer Rifampin and Streptomycin
M. scrofulaceum Cervical lymphadenitis in children Isoniazid, Rifampin and Streptomycin
GENUS Features:
Acid fast rods with waxy cell wall
Obligate aerobe
Cell wall
o Unique: high concentration of lipids containing long chain fatty acids called mycolic acids
o Wall makes mycobacteria highly resistant to desiccation and many chemicals (including NaOH used to kill other bacteria in sputa before
neutralizing and culturing)
Sensitive to UV
Mycobacterium tuberculosis
High‐risk patient (poverty, HIV+, IV drug user)
Chronic cough, weight loss
Ghon complex
Auramine‐rhodamine staining, acid fast bacilli in sputum
Produce niacin, heat‐sensitive catalase
Positive PPD
Facultative intracellular
Distinguishing Features:
Auramine‐rhodamine staining bacilli (fluorescent apple green) no antibody is involved
Acid fast (true) bacilli in sputum
Aerobic, slow growing on Lowenstein‐Jensen medium grows faster in broths with palmitic acid
Produces niacin
Produces a heat‐sensitive catalase:
o at standard testing conditions (68 C) = negative
o at body temperature (36 C) = positive
Habitat/Reservoir:
Human lungs
Transmission:
Respiratory droplets
Pathogenesis:
Facultative intracellular organism Most important
Sulfatides Surface glycolipids inhibit phagosome‐lysosome fusion
Allowing intracellular survival
If fusion occurs waxy nature of cell envelope reduces killing effect
Cord factor Composed of Trehalose dimycolate creates a serpentine cord appearance in virulent strains
Inhibits leukocyte migration
Disrupts mitochondrial respiration and oxidative phosphorylation
Tuberculin and Mycolic Acid A surface proteins that cause delayed Hypersensitivity and Cell‐Mediated Immunity (CMI)
CMI mediates formation of granulomas and caseation
No exotoxins or endotoxins
Damage is done by the immune system
Diseases:
Primary Pulmonary TB Symptoms: fever, dry cough
Organism replicates in naïve alveolar macrophages (mid to lower lobes), killing the macrophages until CMI is
established called Ghon focus
Macrophages transport the bacilli to the regional lymph nodes (Hilar nodes)
Ghon complex = Hilar nodes + Ghon focus
Organisms that are walled off within the Ghon complex remain viable less treated
Secondary TB (Reactivational TB) Symptoms: fever, hemoptysis, night sweats, weight loss
Erosion of granulomas into airway (high oxygen) later in life under conditions of reduced T‐cell immunity which can lead
to mycobacterial replication and disease symptoms
Resulting in a complex disease with the potential of infecting any organ system
Caseating granulomas with central necrosis and Langhans giant cells are characteristic
Miliary TB Associated with dissemination to the:
o brain (meninges)
o spine (Pott disease ‐ a form of tuberculous arthritis of the intervertebral joints)
o lungs
o lymph nodes
o liver
o spleen
o adrenal gland
o joints and long bones
Diagnosis:
Microscopy of sputum: screen with Auramine‐Rhodamine stain (fluorescent apple‐green) no antibody involved and very sensitive
o If positive, confirm with acid fast stain
PPD skin test (Mantoux): measure zone of induration at 48‐72 hours
o If positive:
o >5 mm in HIV+ or anyone with recent TB exposure; AIDS patients have reduced ability to mount skin test
o >10 mm in high‐risk population: IV drug users, people living in poverty, or immigrants from high TB areas
o >15 mm in low‐risk population
Positive skin test indicates only exposure but not necessarily active disease
Quantiferon‐TB Gold Test: measures interferon‐gamma production when leukocytes are exposed to TB antigens; fever false positives from BCG vaccination
Slow growing (3‐6 weeks) colonies on Lowenstein‐Jensen medium
Organisms produce niacin and are catalase‐negative at 68 C
No serodiagnosis
Treatment:
Often resistant to multiple drugs
Standard observed short‐term therapy for uncomplicated pulmonary TB if area acquired has <4% drug‐resistant mycobacteria
o First 2 months: Rifampin + Isoniazid + Pyrazinamide + Ethambutol (RIPE)
o Next 4 months: Rifampin and Isoniazid
Streptomycin added for possible drug‐resistant cases until susceptibility test are back if area acquired has >4% drug‐resistant mycobacteria
For Multiple Drug Resistance (MDR) TB: use 3‐5 previously unused drugs including Aminoglycosides, Fluorowuinolones, Thioamide, Cycloserine, Bedaquiline
Prevention:
Isoniazid taken for 9 months can prevent TB in person swith infection but no clinical symptoms
Bacille Calmette‐Guerin (BCG) vaccine containing live, attenuated organisms may prevent disseminated disease not used in the US
UV light or HEPA filter used to treat potentially contaminated air
Mycobacteria Other Than Tuberculosis (MOTTS)
M. tuberculosis in HIV patient with normal count or low CD4 count (disseminated)
MAI only in late HIV patient with low CD4 count
Distinguishing Features:
Atypical mycobacteria
Non‐contagious
Habitat/Reservoir:
Found in surface waters, soil, and cigarettes
Organism Disease Transmission Clinical Presentation Treatment
M. avium‐intracellular (MAI) Pulmonary, GI, Disseminated Respiratory, Ingestion AIDS patients: causes Prophylaxis: Azithromycin
disseminated non‐TB disease with AIDS patients
prophylaxis when CD4+ count
M. kansasii is <50 cells/mm3
Treatment: Azithromycin or
clarithromycin plus
ethambutol
M. ulcerans Buruli ulcer (Africa) Wound contamination Ulcer Rifampin and Streptomycin
M. marinum Soft tissue infections “Fish Abrasions Cutaneous granulomas with Heat‐sensitive bacteria: hot
tank granuloma” tropical fish enthusiasts compress applied to area
Isonazide
Rifampin or Ethambutol
M. scrofulaceum Cervical lymphadenitis in Respiratory, Ingestion Rare Isoniazid, Rifampin and
children Streptomycin
Mycobacterium leprae (Hansen disease)
Acid fast bacilli in punch biopsy
Immigrant patient with sensory loss in extremities
Distinguishing Features:
Acid fast rods seen in punch biopsy
Obligate intracellular parasite cannot be cultured in vitro
Optimal growth at less than body temperature
Habitat/Reservoir:
Armadillos in the US
Organism likes cool temperatures and often infects the skin and superficial nerves glove and stocking loss of sensation
Transmission:
Nasal discharge from untreated lepromatous leprosy patent
Pathogenesis:
Obligate intracellular parasite Prefers cooler parts of the body to infect: skin and perifpheral nerves
Diseases:
Hansen disease has two forms but usually starts out with an indeterminate stage called “borderline”
Tuberculoid Borderline Lepromatous
Cell‐mediated immune system Strong Cell‐Mediated Immunity due to Th1 immune Weak Cell‐Mediated Immunity due to Th1
response immune response
Lepromin skin test Positive Negative
Number of organisms in tissue Low High (foam cells totally filled)
Damage from Immune response due to CMI killing infected cells Large number of intracellular organisms
Granuloma formation causes nerve enlargement Nerve damage from overgrowth of bacteria in
and damage cells
Loss of sensation causes burns and trauma Loss of sensation causes burns and trauma
Number of lesions and other Fewer lesions: macular Numerous lesions becoming nodular
symptoms Nerve enlargement Loss of eyebrows
Paresthesia Destruction of nasal septum
Paresthesia
Leonine (Lon‐like) facies
Diagnosis:
Punch biopsy or sasal scrapings
Acid fast stain
Lepromin skin test is positive in the tuberculoid but not in the lepromatous form
No cultures
Treatment:
Tuberculoid form: Dapsone and Rifampin
Lepromatous form: Clofazimine is added
Prevention:
Dapsone for close family contacts
Lecture Notes
Global TB Perspective 1/3 world infected with TB
10.4 million new TB cases
(11% in HIV+ pts)
1.4 million deaths (0.4 m w/HIV)
History in the US In the early 1900’s, TB was the most common cause of death in the U.S.
New England 1800’s: MORTALITY = 1,600/100,000
Translated to Chicago today ‐‐ >100,000 deaths/year
National TB Perspective ~10 million Americans are infected (positive skin tests)
Only 7‐10% infected people develop disease in their lifetimes
o the remainder have latent infections
(spread of infection is controlled; not active TB disease)
AIDS patients — of those who are infected with TB, 10% per year will develop active disease
Persons who are more Close contacts of an active case
likely to be infected with TB Foreign‐born persons from areas where TB is common
Medically underserved, low income populations
Residents of long‐term care facilities
Persons who inject drugs
Migrant farm workers and homeless persons
Occupationally exposed persons ‐ e.g., health care workers
Persons who are more HIV infection
likely to progress to disease Recently infected with TB (within the past 2 years)
Certain medical conditions – silicosis, gastrectomy, jejuno‐ileal bypass, weight of 10% of more below ideal body weight, chronic
renal failure, diabetes mellitus, chronic immunosuppressive therapy (e.g., prolonged, high‐dose corticosteroids), leukemia,
lymphoma, and other malignancies
Injection drug use
History of inadequately treated TB
TB Transmission Almost exclusively airborne
Close contacts are at greatest risk (approx.. 20%)
AIDS ‐ the only Opportunistic Infection transmitted to normal people
Nosocomial ‐ (in health care setting)
Extrapulmonary TB is rarely contagious
Transmission by ingestion ‐ very rare now
TB Pathogenesis “Droplet nucleus” ‐ alveolar macrophage access
Regional lymph node and blood‐borne spread
“Ghon focus” ‐ primary site of lung infection
o also known as a granuloma, there can be a caseating necrosis
o Located at the periphery of the lung
“Ranke complex” – calcified Ghon complex = Ghon focus + mediastinal lymph nodes
Immunopathogenesis – TB antigens lymphoproliferation, cytokine production, granuloma formation, tissue destruction;
positive PPD skin test and Quantiferon assay
“Primary” (initial) TB infection – results in either:
o Latent TB infection (LTBI) > 90% initial infections
o Primary progression to active TB (mostly HIV/AIDS)
“Secondary” disease (reactivation) < 10% infections
o Usually (80‐90% of 2° disease) ‐ upper lung infiltrate/cavitation
o Less commonly (10‐15% of 2° disease) – “extrapulmonary” sites of reactivation from initial blood borne spread of infection
(e.g., brain [meninges], heart [pericardium], bone, GU)
Lung Granuloma Palisading epithelial cells
Multinucleated giant cells
Amorphous necrotic material with central necrosis
Ghon Complex Ghon focus – Organism replicates in naïve alveolar macrophages (mid to lower lobes), killing the macrophages
until Cell‐Mediated Immunity is established
Hilar Node – Macrophages transport the bacilli to the regional lymph nodes
Ghon complex = Hilar nodes + Ghon focus
o Organisms that are walled off within the Ghon complex remain less treated
Ghon focus
Cavity Lung Disease Occurs at the apex of the lung due to relatively poor pymphatic drainage and high oxygen tension
TB Diagnosis Recient immigrant, cough, fever, weight loss, traveled from an area with active TB
Medical history – nonspecific symptom complex
Physical examination – nonspecific or NO findings
Radiographic examination – upper lung field infiltrates, cavities, +/‐ lesions in other organs called Extrapulmonary TB
Extrapulmonary TB (XPTB) Mechanism and incidence:
o Sites that progress from original, bacteremic phase: brain, epiphyses of long bones, kidneys, vertebral bodies, lymph nodes
o Many XPTB pts have co‐existing pulm TB
o Immunocompetent pts: ~85% pulm ~15% only XPTB
o AIDS pts ~1/3 pulm TB, ~1/3 only XPTB, ~1/3 both (i.e., increased XPTB)
Sites of infection (think TB w/ lymphocyte‐predominant fluids)
o CNS TB – peak incidence in children, 0‐4 yr of age
o TB Pericarditis – more common in older pts (50% >55 yr old)
o Osteomyelitis of spine: “Pott’s disease”; lower thoracic, upper lumbar
o TB Peritonitis – inflammation of the peritoneum (inner abdominal wall)
o GU/Gyne – local symptoms; genital TB – female > male
TB – Differential Diagnosis Medical history – TB exposure; risk groups
Physical examination – nothing specific to help
Other chronic granulomatous infections:
o Nontuberculous mycobacterial infections
o Fungal infections
TB Diagnosis – Tuberculin Tuberculin Skin test (TST)
(PPD) Skin Test o The TST attempts to measure cell‐mediated immunity in the form of a delayed‐type hypersensitivity
response to the purified protein derivative (PPD). The PPD is a crude mixture of antigens, many of which
are shared among M tuberculosis, Mycobacterium bovis BCG, and several non‐tuberculous mycobacteria
(NTM)
Interferon (IFN)‐gamma Release Assays (IGRA) Quantiferon Gold Assay:
o This assay is an indirect test for M. tuberculosis infection that is based on measurement of a cell‐mediated immune response.
o A cocktail of 3 mycobacterial proteins (ESAT‐6, CFP‐10, and TB 7.7) stimulate the patient's T‐cells in vitro to release interferon‐
gamma, which is then measured using ELISA technology.
o The test detects infections produced by the M. tuberculosis complex (including M. tuberculosis, M. bovis, and M. africanum
infections).
o BCG strains and the majority of other non‐tuberculosis mycobacteria do not harbor ESAT‐6, CFP‐10, and TB 7.7 proteins
thus, patients either vaccinated with BCG or infected with most environmental mycobacteria should test negative.
TB Diagnosis – Microbiology Sputum Acid‐fast bacilli (AFB) smears; cultures from otherwise sterile sites
Sputum – nucleic acid amplification testing (NAAT)
Multiple culture techniques:
o Solid media ‐‐> colony morphology
o Liquid media ‐‐> rapid detection
HPLC ‐ mycolic acids ‐‐> speciation
Molecular diagnostics ‐‐> Genetic probes; PCR
Antibiotic susceptibility testing
TB Diagnosis ‐ Sputum AFB Acid Fast (Zehel‐Nelson) Stain
Stain and Molecular
Diagnostics (NAAT)
Auramine‐Rhodamine Fluorescence
Nontuberculous environmental pathogens that affect predisposed hosts (found everywhere)
Mycobacteria (NTM)
Environmental Sources of Bioaerosols
NTM Water ‐ fresh, salt, domestic, hot tubs, swimming pools
Soil ‐ 80% of soil samples (especially, SE U.S.)
Nosocomial sources
o Rapid growers ‐ most common pathogens identified
o Slow growers ‐ MAC, M. xenopi ‐ hospital water supplies
Predisposing Conditions for Pre‐existing, underlying lung abnormalities:
NTM Lung Disease o COPD ‐ emphysema
o Bronchiectasis – dilated, scarred airways (Increased AFB colonization)
o Previous chest radiotherapy (e.g., for breast Cancer lung fibrosis)
o Interstitial pulmonary fibrosis (IPF/ILD)
o Congenital cystic abnormalities
o Previous pulmonary emboli/infarction
o Recurrent aspiration pneumonia (source of bronchiectasis)
Common theme: structural lung abnormality = predisposing factor
Contrast of NTM Infections NTM = environmental in origin (not human‐to‐human transmission)
with TB NTM infections “require” an underlying predisposition to cause dis.
NTM infections do not have a prolonged latent phase.
NTM infections do not disseminate outside the lung (except in AIDS patients).
Skin testing and Quantiferon testing are not available for NTM.
Radiographic presentations of NTM lung disease may differ from TB.
72 yo male smoker with Progressive cavity like lesions
emphysema and cavitary
MAI disease
Need to do AFB stain plus NAAT
Female nonsmoker with
mid‐lung bronchiectasis and
NTM disease
Magnified portion shows scared airways
Mycology Seminar
Case 1
Chicago Man with Bilateral Pulmonary Infiltrates:
A 35‐year‐old man presented to his primary care physician with a 2 days history of fever and cough productive of purulent sputum. He had no other complaints. He
had no known medical problems. On exam in the physician’s office vitals were: T 101ºF, blood pressure 110/75 (baseline BP’s were 112‐118/80), pulse 90, respiratory
rate 16, oxygen saturation 95% on room air. The patient appeared fatigued. On lung exam, there were bronchial breath sounds in the right mid lung with egophony.
Note that there appears to be some form of consolidation, also there are air bronchograms on the chest x‐ray.
You cannot see the right heart border, so it is likely lobar pneumonia.
This is a young, otherwise healthy guy.
Treat the symptoms of bacterial pneumonia Moxifloxacin is a good respiratory fluoroquinolone.
o No reason to think he has TB.
o The most common cause of pneumonia is strep pneumoniae.
o The most commonly prescribed drug for outpatient community acquired pneumonia is Azithromycin.
However, only 70% of strep pneumoniae are susceptible to azithromycin.
This is not a statistic that all physicians are aware of.
There is growing interest in using fluoroquinolones.
o Especially the respiratory ones.
o Levofloxacin can be used too (Moxifloxacin is more likely to cause c diff infections).
Levofloxacin is renal excreted, so most of it pools in the bladder.
o Moxifloxacin is excreted in the bile and it ends up in the intestines.
It does mass destruction there.
Moxifloxacin is the only fluoroquinolone that has good anaerobic activity.
There are mostly anaerobes in the gut.
There is a strain of c diff that is fluoroquinolone resistant now in the US.
Q1. There was dullness to percussion of the right mid lung field. What would you do next?
A. Obtain CT of the chest
B. Obtain sputum specimen for bacterial culture and prescribe a course of moxifloxacin (CORRECT)
C. Refer patient to pulmonary medicine
D. Obtain a sputum specimen for fungal cultures
E. Perform TB skin test
Q2. At 7‐day follow‐up he felt minimally better. He had no fevers but his cough persisted. He felt fatigued. Three weeks later the
patient presented with worsened cough and shortness of breath. He had diffuse course breath sounds on lung exam and multiple
new skin lesions. Chest X‐ray showed bilateral pulmonary infiltrates and a right pleural effusion. What would you do next?
A. Perform biopsy of skin lesion (CORRECT)
B. Perform lung biopsy
C. Obtain pleural fluid for microbiology culture
D. Refer patient to pulmonary medicine for bronchoscopy
This is the least invasive option. You could do the pleural fluid, but this is a better option. There are no other signs for empyema or cancer, so we don’t
need to drain the fluid.
The slide shows many neutrophils and broad based budding yeast. Those are the white, non‐staining structures. Where they are budding, they have a
large base attachment. The pathologist would then do a fungal stain to confirm the diagnosis. The GMS silver stain shows all fungi. Note the outline of a
budding yeast that is connected at the base with a broad attachment. Only the culture would be a definitive test.
Q3. GMS: Bronchoscopy specimens demonstrated similar yeast forms. What organism does this represent?
a. Blastomyces dermatitidis (CORRECT)
b. Aspergillus fumigatus
c. Coccidioides immitis
d. Cryptococcus neoformans
e. Histoplasma capsulatum
Q4. What is the geographic distribution of this fungus in the U.S.
A. Southeastern states
B. Southwestern states
C. Upper Midwest including Chicago area (CORRECT)
D. Ohio and Mississippi River basin
E. Pacific Northwest
Ohio and Mississippi River Valley Regions. Chicago land is an area of high incidence. Exposure to soil and warm moist wooded areas rich in organic debris.
Inhalation of conidia and conversion to yeast phase in the lung provides the most common portal of entry.
Q5. What additional tests would you perform?
A. EIA for HIV antibody (CORRECT)
B. Sputum for AFB
C. PPD
D. Immunoelectrophoresis
About half the patients with this are not symptomatic, so it would be a good idea to make sure that this patient is not immunocompromised. AFB is
looking for mycobacteria. PPD is looking for TB. Immunoelectrophoresis would be looking for immune deficiency in general.
Q6. What therapy would you recommend for this patient?
A. Amphotericin B
B. Oral Itraconazole (CORRECT)
C. Caspofungin
D. Vancomycin
E. Piperacillin‐Tazobactam
Amphotericin B is preferred for severely ill patients or immunocompromised patients with systemic disease (especially with CNS involvement) due to
Amphotericin B fungicidal properties.
Itraconazole is preferred for immunocompetent patients with mild to moderate disease that is NOT involving the CNS
Q7. What is the most common serious adverse effect of amphotericin?
A. Fever/Chills
B. Nephrotoxicity (CORRECT)
C. Gynecomastia
D. Bone marrow suppression
Blastomycosis Summary
Tissue Phase: Broad Based Bud = Blastomyces
Mold Phase: Lollipop conidia
Endemic in Ohio‐Mississippi river valley with the epicenter in Chicago
CASE 2
Cc: “I have had the most awful headache for more than 1 week.”
A 30 year‐old man with HIV infection presented to the hospital with fever and intractable diffuse headache for 10 days. The headache pain averaged 7‐8/10 in
severity. On the day of admission, he developed nausea and vomited bilious material several times. Overall he felt fatigued. He had
no recent head trauma. He had no focal weakness or paresthesias or photophobia. His remembered that his last CD4 count four
months ago was 75. His medications include zidovudine, lamivudine, efavirenz, azithromycin and trimethoprim/sulfamethoxazole. He
stated that he was compliant with his medications.
On examination his temperature was 39.5C, Pulse ‐ 102, Blood pressure ‐ 100/62, Respiratory rate ‐14. He appeared thin. Pupils were
equal and reactive. There was no evidence of papilledema on funduscopic exam. There were white plaques on his buccal mucosa
and oropharynx. His neck range of motion was mildly decreased. His lung, heart, and cardiovascular exams were normal. Complete
neurologic exam revealed no motor or sensory deficits. Kernig’s and Brudzinski’s signs were not elicited.
Q1. Would you order a CTH2 ‐ CT HEAD WITHOUT CONTRAST?
a. Yes (CORRECT)
b. No
He is at risk for many things and he is having a profound headache, so you would want to know if something is happening, also want to look at his CSF.
EXAM: CTH2 ‐ CT HEAD WITHOUT CONTRAST. THERE IS MODERATE GENERALIZED ATROPHY, PROMINENT FOR A PATIENT OF THIS AGE. THERE IS NO EVIDENCE OF AN
ACUTE INTRACRANIAL BLEED OR EXTRAAXIAL FLUID COLLECTION. THERE IS NO EVIDENCE OF AN INTRACRANIAL MASS. AS SEEN ON THESE IMAGES, THE PARANASAL
SINUSES AND MASTOID AIR CELLS APPEAR NORMALLY AERATED. (THE RIGHT FRONTAL SINUS IS APLASTIC.). IMPRESSION: MODERATE GENERALIZED CEREBRAL
ATROPHY.
Q2. Differential Diagnosis?
A. Viral meningitis
B. Aseptic meningitis
C. Fungal meningitis
D. Early bacterial meningitis
E. All of the above (CORRECT)
Q3. What Additional CSF Studies Would You Order?
A. CSF gram stain and culture
B. CSF Fungal culture
C. Cryptococcal Latex Antigen
D. CSF Viral culture
E. All of the above (CORRECT)
Q4. Which of the following microorganisms has a particular trophism for the CNS?
A. Blastomyces dermatitidis
B. Aspergillus fumigatus
C. Coccidioides immitis
D. Cryptococcus neoformans (CORRECT)
E. Histoplasma capsulatum
Laboratory Diagnosis of Cryptococcosis neoformans
Cryptococcal Antigen Latex Agglutination
o Highly sensitive and specific
o Can detect antigen in CSF and serum
o Has diagnostic and prognostic value
o Method of choice for diagnosing patients with cryptococcal meningitis
o Historically india ink prep with a Mucicarmine stain was used to diagnose
Point of Entry 2. India Ink Prep 1. Mucicarmine stain
Inhalation
o Soil, pigeon droppings
o Ironically pulmonary disease is not common
Hematogenous dissemination
Why HIV patients?
Cell mediated immune defect
Cryptococcal meningitis usually occurs in HIV patients with CD4 cell counts < 100.
Treatment
Induction therapy: Amphotericin + flucytosine
Fluconazole
Q5. What would the pathogen look like?
A. 1 (CORRECT)
B. 2
C. 3
Number One are yeast producing buds (Cryptococcosis)
Number Two is composed of hyphae that have septae and branching at a 45º angle (Actinomyces).
Number Three is non‐septaed hyphae that are ribbon like and branching at 90º angles (Mucormycetes).
Cryptococcus Summary
Only Encapsulated Yeast
Tropism for CNS
Associated with pigeon droppings
T cell immunity required for resolution
More than 50% of total number of cases of cryptococcosis reported annually in the U.S. occur in AIDS patients
Most common predisposing factor in non‐AIDS patients is receipt of large doses of adrenal corticosteroids.
Case 3
45 Y.O. with Sinus Infection: A 45‐year old woman with difficult to control insulin requiring diabetes mellitus and multiple
admissions for diabetic ketoacidosis is being treated for chronic sinusitis. Her symptoms have worsened despite a 6‐week course
of broad spectrum antibiotics. She presents to ED unable to open her right eye. On admission she had a white cell count of
22,000/mm3, with 84 percent neutrophils and bands and a moderate degree of metabolic acidosis (blood pH, 7.22; plasma
bicarbonate concentration, 8 mmol per liter). A computed tomographic scan of the head showed involvement of the paranasal
sinuses and periorbital soft tissues.
Q1. The physician should be most concerned for infection with which of the following organisms?
a. Actinomyces
b. Aspergillus
c. Cryptococcus
d. Mucor (CORRECT)
e. Coccidioides
Actinomyces would not be common in this setting as a bacteria.
Aspergillus usually starts as a pulmonary thing,
Cryptococcus is usually CNS.
Coccidioides is really pulmonary.
Q2. What are the morphologic features that separate Mucormycetes from Aspergillus?
a. Broad, ribbon‐like, non‐septate hyphae (CORRECT).
b. Dichotomous 45º branching
c. Conidia produced from phialidsa attached to vesicle
d. Rapid growing blue‐green mold
B, C, and D are all features of aspergillus.
NOTE:
o Sinusitis: Viral, Bacterial. One step back.
o Sinusitis Complications: Orbital and periorbital extension usually from the ethmoid, occasionally from frontal sinus.
Orbital and periorbital extension
usually from the ethmoid , occasionally from frontal sinus
Intracranial extension
meningitis, subdural or epidural abscess, or brain abscess.
Dural sinus thrombosis rare
o Intracranial extension: meningitis, subdural or epidural abscess, or brain abscess.
o Dural sinus thrombosis rare.
Strong link between patients with brittle diabetes and chronic sinusitis
o due to Mucormycetes, including Mucor and Rhizopus “rhinocerebral mucormycosis”
Suspect mucormycosis in any patient with
chronic sinusitis
who appears unusually ill
does not respond to antibiotic therapy
Treatment
high‐dose amphotericin B
Surgical debridement of necrotic tissue.
Fungi can spread rapidly from the sinuses to skull bones and brain, potentially causing massive tissue destruction and death.
Case 4
68 Y.O. Cotton mill worker: A 68‐year‐old North Carolina man with diabetes mellitus was admitted for evaluation of a persistent right lower lobe infiltrate and
treatment of diabetic ketoacidosis. Three weeks prior to admission, he presented to an outside physician for evaluation of fever, chills, weight loss, and anorexia. A
chest radiograph demonstrated a right lower lobe infiltrate. He was treated with azithromycin, but his condition worsened. His PPD test was negative, and three
sputum specimens were negative for AFB on smear. Sputum specimens were sent for fungal culture. The patient works in a cotton mill in the so‐called “opening
room,” where he opens bundles of cotton received from the southwestern U.S.
Initially treated for diabetic ketoacidosis. Cultures of sputum and blood grew a whitish mold with following microscopic appearance
Q1. What is the fungus causing this man’s illness?
a. Candida albicans
b. Coccidioides immitis (CORRECT)
c. Cryptococcus neoformans
d. Blastomyces dermatitidis
e. Histoplasma capsulatum
Q2. What is the geographical distribution of this fungus in U.S.
a. Southeastern states
b. Southwestern states (CORRECT)
c. Upper Midwest including Chicago area
d. Ohio and Mississippi River basin
e. Pacific Northwest
Q3. If this man did not live or travel to an area endemic for this fungus, how might he have become infected?
Likely that patient inhaled arthroconidia of Coccidioides immitis which were present in the cotton he was handling
Cotton has been shown to be a vehicle for this infection in regions remote from the endemic area
Q4. Which characteristic of this agent makes it highly infectious?
Ability to produce easily aerosolized arthroconidia is reason for its highly infectious nature
Arthroconidia are formed by fragmentation of hyphae during sporulation
Mycelial growth is seen at ambient temperature, and it is the hyphal fragmentation into arthroconidia at this temperature that makes organism so
dangerous
How does organism differ when grown in the environment and in a human host?
When growing in human host, organism produces yeastlike phase described as an endosporulating spherule
In vivo yeast‐like phase of C. immitis is not infectious to others
Pulmonary Review
Response to Exercise
Exercise Physiology Increased CO2 production (VCO2) and Oxygen consumption (VO2)
o Normally at rest
VCO2 = 200 mL/min
VO2 = 250 mL/min
o The respiratory quotient (RQ) is a dimensionless number used in calculations of basal metabolic rate (BMR) when estimated
from carbon dioxide production.
Defined as the ratio of the volume of carbon dioxide evolved to that of oxygen consumed by an organism, tissue, or cell in a
given time.
RQ = VCO2/VO2 = 0.8
o With exercise, there will be an:
Increases in the content of CO2 in the venous blood (CvCO2)
Decreases in the content of O2 in the venous blood (CvO2)
o What happens in terms of heart and lung at rest
TV/RR/MV all increase
TV – tidal volume = 500 mL
RR – respiratory rate = 10 breaths per minute 5 breaths in 30 seconds
MV – minute ventilation = 5 liters per minute
SV/HR/CO all increase
SV – stroke volume = 75 mL
HR – heart rate = 70 beats per minute
CO – cardiac output = 5 liters per minute
o CO = SV*HR
Including pulmonary blood flow
Exercise in Health:
o When glucose is metabolized aerobically (with Oxygen) this generates 32 ATP, but when glucose is metabolized anaerobically
(without Oxygen) this generates 2 ATP
o Oxygen consumption (VO2) increases until oxygen delivery fails to meet oxidative phosphorylation requirements at anaerobic
threshold
Anaerobic threshold is when ATP is generated anaerobically
resulting in metabolic acidosis
due to the accumulation of lactic acid
Use Winter’s formula to see if Metabolic acidosis is
compensated
PCO2 = 1.5*HCO3 + 8 +/‐ 2
if Given = Expected Compensated
if Given > Expected Respiratory acidosis
If Given < Expected Respiratory alkalosis
o When does anaerobic threshold occurs?
At 50% of exercise capacity
Max Heart rate = 220 – Age
o Compensatory mechanisms of the lungs and heart
TV/RR/MV all increase
TV – tidal volume = 500 mL 3L
RR – respiratory rate = 10 breaths per minute 40 bpm
MV – minute ventilation = 5 liters per minute 120 lpm
SV/HR/CO all increase (including pulmonary blood flow)
SV – stroke volume = 75 mL 125 mL
HR – heart rate = 70 beats per minute max heart rate = 220‐age
CO – cardiac output = 5 liters per minute 25 lpm
o NO CHANGE IN ARTERIAL GASES (PaO2, PaCO2)
Healthy people at peak exercise are NOT hypoxic (you do not desaturate)
Because when you send venous blood through the lungs, the deoxygenated blood, gets saturated very quickly.
When you examine a patient who’s complaint is dyspnea on exertion
o Compare the patients SaO2 at rest and when the patient is walking
Because if the patient does desaturate on exertion this is pathologic and almost always suggests a lung disease
Decrease Dead Space
Pulmonary Transmural pressures
o The pressure changes across the lung and across the chest wall are defined as transmural pressure
o For the lung, this transmural pressure is called the transpulmonary pressure
o Transpulmonary pressure (PL) is defined as the pressure difference between
alveolar pressure (PA) ‐ the pressure in the air spaces
pleural pressure (PPL) ‐ pressure surrounding the lung
760 756 4
o The transmural pressure across the chest wall (PW) is the difference between
Pleural pressure
Pressure surrounding the chest wall (Pb) – the barometric pressure or body surface pressure
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o During inspiration, the chest wall expands to a larger volume
Because the pleural pressure is negative relative to atmospheric
pressure during quiet breathing the transmural pressure across the
chest wall is negative
o The pressure across the respiratory system (PRS) is the sum of the
pressure across the lung and the pressure across the chest wall
o The alveolar pressure is the sum of the pleural pressure and the elastic
recoil pressure of the lung
o Substituting PA into the equation for PL
In general, the transpulmonary pressure (PL) is the pressure distending the lung, whereas the elastic recoil pressure is
tending to collapse the lung.
o Pneumothorax
Is when the alveoli near the lung surface ruptures and air escapes into the pleural space
o
Pulmonary Compliance Respiratory System Compliance:
o Change in Volume divided by the change in pressure
Normal:
o 60 to 100 mL/cm H2O
Tidal volume = 500 mL
Pleural pressure (at rest) = ‐5 cm H2O
Increased Compliance = A
o Loss of elastic recoil due to hyperinflation as seen in
Emphysema
Decreased Compliance = B = Low Compliance
o Increased elastic recoil due to additional tissue in the
interstitium making the lungs stiffer as seen in Pulmonary
Fibrosis creating small lungs
Dead Space Definition:
o Volume of inspired gas that does not partake in gas exchange (ventilated but not perfused)
Anatomic: Major Trachea/Bronchi
Composed of the volume of gas that fills the conducting airways that is not gas exchanged
Physiologic: Zone 1 of the lung (Top of the Lung)
Composed of the volume of air which is inhaled that does not take part in the gas exchange,
either because it remains in the conducting airways, or it reaches alveoli that are not
perfused or poorly perfused.
Therefore, tidal volume consists of dead space and alveolar space
o How much dead space is present normally?
Zone 1: Represent the lung apex, where the pulmonary arterial pressure (Pa) is so low that it can be exceeded by the
pulmonary alveolar pressure (PA)
This causes the capillaries to collapse
o Because of the greater external pulmonary alveolar pressure
Which causes the blood flow to stop
Under normal conditions
o Zone 1 does not exist Physiologic Dead Space
Dead Space can be calculated
Vd = Vt (PaCO2 – PeCO2)/PaCO2
o Where VD = Dead Space Volume, Vt = Tidal volume, PaCO2 = arterial partial pressure of CO2, PeCO2 = expiatory
partial pressure of CO2
Vd/Vt = the fraction of each tidal volume that is “wasted”
o Normal:
Dead Space = Vd = 1 ml/lb or 150 mL
Tidal Volume = Vt = 500 mL
Vd/Vt = 150 mL/500 mL * 100% = 30%
During exercise, the percent of the dead space per tidal volume (Vd/Vt) = decreases
Because the anatomic dead space remains constant and the tidal volume increases
o Increased pulmonary blood flow
Causes an increase in perfusion to the apex (Zone 1) reducing Zone 1
Resulting in a decrease in Vd/Vt
Normally the dead space decreases from 30% to less than 15% during exercise
Disease States of increased dead space (Vd/Vt)
Decreased perfusion of ventilated lung
o Pulmonary Emboli:
a clot that blocks a part of the vasculature of the lung, so the section is ventilated, but blood is not perfusing that
section of lung
which increases the percentage of the dead space
o Volume depletion:
Normal vasculature, but there is no blood in the vasculature
Volume depleted causes a lower perfusion pressure
o Pulmonary Arterial Hypertension:
Thickening of the arterial walls before the alvoli, where a narrow pulmonary artery would cause a decrease in
perfusion
Increased Alveolar Pressures:
Mechanical Ventilation (PEEP – Positive End‐Expiratory Pressure)
o Causes the alveoli to dilate and crush the capillary
Causing a decrease in perfusion
Which increases the percentage of dead space
Consequences of Increased Vd/Vt
Reduced CO2 elimination Hypercapnia = excessive CO2 in the bloodstream
Increased Work of Breathing (WOB) Dyspnea = difficult or labored breathing
Minute PaCO2
Ventilation
At rest 5 L/min 40 mmHg (Normal)
Exercise Increased Normal
Panic Attack Increased Decreased
Increased Dead Space with intact CNS Increased (WOB) Normal
Increased Dead Space without intact CNS (stroke, Normal Increased (Hypercapnic)
overly sedated, spinal cord injury)
Pulmonary Embolism Increased (WOB) Decreased (Despite increased Vd/Vt due to an
even greater increase in MV)
Panic attack – there is increased breathing (i.e. minute ventilation), but with normal CO2 production
Resulting in a decreased PaCO2
o causing the cerebral blood flow to constrict
Resulting in passing out
Pulmonary embolism increases the dead space (perfusion alveoli that are still being ventilated)
During a pulmonary embolism there is an increase in minute ventilation
o Causes the PaCO2 to decrease
If a patient has a high PaCO2 (Hypercapnic)
May be due to:
o Increase in dead space
o Increase in CO2 production resulting in a Respiratory acidosis
o Decrease in minute ventilation
If a patient has a normal PaCO2
But has an increased minute ventilation
o Because a higher than normal fraction of the tidal volume is waster
O2 Pressure, Saturation, PaO2 = Partial pressure of O2 [75 – 100 mmHg]
and Content o Depends on the atmospheric pressure to create the driving force for Oxygen transfer
At sea level 760 mmHg with 21% Oxygen and 79% Nitrogen
PO2 = 159.6 mmHg
PN2 = 600.4 mmHg
o Poor solubility coefficient for O2 Henry’s Law = 0.003
o Only one variable for pO2
Driving force partial pressure of O2
SaO2 = Saturation of Hemoglobin (Hgb)
o Each gram of hemoglobin can bind 1.34 mL of O2
o There are two variable for saturation:
Partial pressure of O2 Driving force
Available Hemoglobin binding sites
CaO2 = Content of O2 in a dL of blood
o CaO2 = (SaO2)(1.34)(Hgb) + (PaO2)(0.003)
Normal values:
Hgb = 15 gm/dL
SxO2 = 100%
CaO2 = 20 mL of O2 per dL of Blood
o Where there are three determinants: PaO2 (mmHg) SaO2 (%)
Saturation, Pressure. Hemoglobin 27 50
At rest: PaO2 = 40 mmHg = PvO2 Hgb = 75% 40 (normal PvO2) 75
With exercise: PvO2 decreases 60 90
PaO2 = 60 mmHg Hgb = 90%
With a pulse oximeter measuring SaO2 > 90% = acceptable
This is the minimal oxygenation of the blood
o DaO2 = Oxygen delivery to the tissues
DaO2 = CO * CaO2
DaO2 = (5 L Blood/min) * (20 mL O2/dL)(10 dL/1 L) = 1,000 mL O2/min
PaO2 SpO2 CaO2 DaO2
Normal 100 mmHg 100% 20 mL O2/dL 1000 mL/min
Lung Disease Low Low Low Low
Altitude Low Low Low Low
CO Poisoning Normal Low (Normal by pulse oximetry) Low Low
Anemia (Colon Cancer) Normal Normal Low Low
Cardiomyopathy (Heart failure) Normal Normal Normal Low
o Lung diseases there is an issue with getting Oxygen into the lung
This causes a low oxygen delivery unless the cardiac output is increases
o CO Poisoning decreases the number of hemoglobin binding sites for oxygen
o Anemia there is less hemoglobin available to bind oxygen, but the percent saturated is relative
The Alveolar‐Arterial The Alveolar‐Arterial gradient is the difference between the expected alveolar concentration and the measured arterial
Oxygen Gradient concentration
o Alveolar carbon dioxide (PACO2) and arterial carbon dioxide
(PaCO2) partial pressures ARE EQUAL, but this is not true for
oxygen.
o In normal individuals, the alveolar partial pressure of oxygen
(PAO2) is greater than the arterial partial pressure of oxygen
(PaO2).
o This difference is called the Alveolar‐arterial Partial Pressure of
Oxygen Difference (AaDO2)
AaDO2 = PAO2 – PaO2
PAO2 = PIO2 – PACO2/RQ
PIO2 = Interstitial Partial Pressure
PACO2 = Alveolar Partial Pressure from ABG = 40 mmHg
RQ = Respiratory Quotient = VCO2/VO2
o Normal diet RQ = 0.8
If Pure fat diet RQ = 0.7
If Pure carbohydrate diet RQ = 1.0
o VCO2 = Volume of CO2 produced
o VO2 = Volume of O2 consumed
PIO2 = (Pb – PH2O)*FiO2
o PIO2 = (760 ‐ 47)*0.21 = 150 mmHg
o PAO2 = 150 – 40/0.8 = 102 mmHg
PaO2 = Alveolar Partial Pressure from ABG
o Arterial partial pressure of oxygen is measured by blood gas analysis
Normal values:
Alveolar (mmHg) at RQ = 0.8 arterial (mmHg) A‐a Gradient (mmHg)
Oxygen 102 90 12
Carbon Dioxide 40 40
o The Alveolar‐arterial Partial Pressure of Oxygen Difference
AaDO2 = PAO2 – PaO2 = 102 – 90 = 12 mmHg
o The mean AaDO2 rises about 3‐4 mmHg per decade of life A‐a < Age(year)/4 + 4
If the patient is 24 years old
A‐a = 24/4 + 4 = 10 mmHg
So you can have a gradient between the calculated Alveolar O2 and the arterial O2 of approximately 10 mmHg
If the patient is 34 years old
A‐a = 34/4 + 4 = 13 mmHg
A‐a gradient increases with most lung diseases
But NOT with:
Altitude
Decrease in FiO2
Hypercapnia
o Hypercapnia = excessive carbon dioxide in the bloodstream, typically caused by inadequate respiration
When you fly in an airplane, the cabin is pressurized to 8,000 ft which is equal to a total pressure of 540 mmHg
PIO2 = (Pb – PH2O)*FiO2
PIO2 = (564 ‐ 47)*0.21 = 109
PAO2 = 109 – 40/0.8 = 59 mmHg this is less than 60 mmHg = Hypoxic
Hypoxic Pulmonary In other tissues:
Vasoconstriction o Hypoxia results in dilation of arteries vascular resistance to decrease
In the lungs:
o Hypoxia results in pulmonary arterial vasoconstriction vascular resistance to increase
In order to redirect the blood to better ventilated areas in the lung
o This is useful if there is a localized (focal) pulmonary hypoxia (i.e. lobar pneumonia)
o Not useful if you are living at altitude, because lungs will vasoconstrict everywhere
Causes diffuse hypoxia
Resulting in Pulmonary Hypertension or Cor Pulmonale
At Altitude = Low PaO2 Low PaCO2 (breathing more) resulting in a respiratory alkalosis
o Over time, the kidneys will respond to the alkalosis by wasting bicarbonate to bring up the pH
NORMAL FIO2 (21%) but a reduced Barometric Pressure
o At 15,000 feet, Total pressure = 450 mmHg
AaDO2 = [(450 ‐ 47)*.21 – PACO2/0.8] – PaO2
PIO2 = (450 ‐ 47)*.21 = 85 mmHg
PAO2 = PIO2 – PACO2/0.8 = 85 – 40/0.8 = 35 mmHg
Hypoxia due to Decreased Barometric Pressure
What does the body do? Immediately the body tries to compensate Compensatory Hyperventilation
o Results in respiratory alkalosis
pH increases (more basic)
HCO3 decreased
o Then after a few days, the kidneys will waste bicarbonate to increase the pH
Other Physiologic Consequences:
o Increased erythropoietin (EPO)
Causes an increase in hematocrit (Hct)
o Increased 2,3 DPG
Binds to Hgb
Causes the release of more O2 in the periphery
o Increased mitochondria metabolism
Hypoxic pulmonary vasoconstriction
o Acute: High Altitude Pulmonary Edema
o Chronic: Pulmonary Hypertension
High Altitude Cerebral Edema
o If a patient is going to travel at high altitude can be given a carbonic anhydrase inhibitor
This will waste bicarbonate in the kidneys
Causes the pH to increase inducing acidosis
When the patient is in acidosis
o Respiration rate increases Decreases the PaCO2
o Resulting in an increase in PaO2
Oxygen‐Hemoglobin Shift to the right:
Dissociation Curve o Causes a decreased O2 affinity to Hbg
Results in an increase in PCO2, temp, H+, altitude, 23 DPG
Bohr Effect:
o Peripheral acidosis shifts curve to the right, unloading O2
Haldane Effect:
o In the lungs, oxygenation of Hgb
results in CO2 release from RBC’s
Pulmonary Hypertension Normal Pulmonary Artery Systolic Pressure (PASP): < 25 mmHg/5 mmHg
o Primary Hypertension (PHTN) = pulmonary pressure is > 25/5
Symptoms:
Dyspnea (SOB), Chest Pain, Syncope looks just like Aortic Stenosis
Physiology:
Increased VD/VT (so increased WOB)
RV strain / Cor Pulmonale / Reduced Cardiac Output
Secondary Hypertension is due to causes
WHO Class 1: Pulmonary Idiopathic (IPAH)
Arterial Hypertension Heritable (HPAH)
o Bone morphogenetic protein receptor type 2 (BMPR2)
o Activin receptor‐like kinase 1 gene (ALK1), endoglin (with or without haemorrhagic
telangiectasia)
o Unknown
Drug‐ and toxin‐induced: fin‐fin
Associated with (APAH):
o Connective tissue diseases: Lupus
o Human immunodeficiency virus (HIV) infection
o Portal hypertension – cirrhosis
o Congenital heart disease (CHD)
o Schistosomiasis – most common
o Chronic haemolytic anaemia
Persistent pulmonary hypertension of the newborn (PPHN)
WHO Class 2: Pulmonary Systolic dysfunction
hypertension due to left Diastolic dysfunction
heart diseases Valvular disease
WHO Class 3: Pulmonary Chronic obstructive pulmonary disease (COPD)
hypertension due to lung Interstitial lung disease (ILD)
diseases and/or Other pulmonary diseases with mixed restrictive and obstructive pattern
hypoxemia Sleep‐disordered breathing (SDB)
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Developmental abnormalities
WHO Class 4: Chronic After a single pulmonary embolism can result in vascular remodeling leading to chronic
thromboembolic pulmonary hypertension
pulmonary hypertension
(CTEPH)
WHO Class 5: PHTN with Haematological disorders: myeloproliferative disorders, splenectomy
unclear multifactorial Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis,
mechanisms lymphangioleiomyomatosis, neurofibromatosis, vasculitis
Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis
o Destruction of lung parenchyma (emphysema)
o Decreased vasculature (PE)
o Left to right shunt …. Shear stres…..endothelial injury
o Hypoxic vasoconstriction (altitude, OSA)
Mechanisms of Hypoxia Increased A‐a Gradient
o Common: 95% of the time
VQ Mismatch
Shunt
o Other less common:
Diffusion Impairment
Diffusion‐Perfusion Impairment
Normal A‐a Gradient:
o Common:
Hypoventilation
o Other less common:
Altitude
Decreased FIO2 (rarely encountered clinically)
VQ Mismatch
o Decreased Ventilation relative to blood flowrate
Because O2 exits alveolus more quickly than enters via bronchi
Causes a MILD Hypoxia
o Hypoxia improves with supplemental O2 PaO2 will increase
o Diseases that cause VQ mismatch include:
Asthma, COPD = narrowing of the airways
Pulmonary Emboli
Interstitial Lung Disease (ILD) = Pulmonary Fibrosis
Shunt
o No O2 reaches some set of pulmonary capillaries
Which results in SEVERE Hypoxia
o Hypoxia does NOT improve with supplemental O2
o Diseases that causes:
Pulmonary Shunt:
NO ventilation to alveoli that are still perfused
o Blood:
RBC from alveoli hemorrhage
o Pus:
WBC from pneumonia
o Water:
Pulmonary Edema – from Left heart failure or ARDS
Acute Respiratory Distress Syndrome (ARDS) – where the capillaries leak fluid into the alveoli due to sepsis
o Atelectasis:
is the collapse or closure of a lung resulting in reduced or absent gas‐exchange
Pulmonary Arteriovenous malformation (AVM):
is an abnormal connection between arteries and veins, bypassing the capillary system.
Cardiac Shunt:
Atrial Septal Defects (ASD):
o Atrial septal defects are a group of congenital heart diseases that enables communication between atria of the heart
due to a deficiency in the interatrial septum
Patent Foramen Ovale (PFO):
o is a remnant of the fetal foramen ovale, which normally closes at birth
Ventricular Septal Defect (VSD):
o is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart.
Diffusion Impairment:
o NOT a common problem
Blood is normally fully oxygenated within 25% of its transit through the alveolar capillaries.
Therefore, even if slowed by a diffusion barrier, blood usually reaches full saturation
o Hypoxia is MILD
Hypoxia improves with supplemental O2
Diffusion‐Perfusion Impairment called Hepatopulmonary Syndrome
o caused by vasodilation in the lungs of patients with liver disease cirrhosis.
Dyspnea and hypoxemia are worse in the upright position (which is called platypnea and orthodeoxia,
respectively).
Causes dilated capillaries pose an impairment to full oxygenation
The dilation of these blood vessels causes overperfusion relative to ventilation, leading to
ventilation‐perfusion mismatch and hypoxemia.
There is an increased gradient between the partial pressure of oxygen in the alveoli of the lung and
adjacent arteries (alveolar‐arterial [A‐a] gradient) while breathing room air.
Additionally, late in cirrhosis, it is common to develop high output failure, which would lead to less time in capillaries per
red blood cell, exacerbating the hypoxemia.
Question 1. Which of these things increase during exercise?
A. Dead Space
B. Venous CO2 content
C. pH
D. Venous O2 content
Question 2: The pressure‐volume curve B describes which disease process:
A. Emphysema
B. Pulmonary Fibrosis
C. Cystic Fibrosis – is really cystic fibrosis of the pancreas which causes bronchial obstruction
D. Bronchial Asthma – not due to compliance but due to airway narrowing
Question 3: What accounts for the difference between minute ventilation and alveolar ventilation
A. Tidal volume ‐ The volume of air that is moved with each quiet breath
B. Respiratory rate – The number of breaths per minute
C. Functional residual capacity ‐ Is the volume of air in the lung at the end of exhalation during quiet breathing
D. Residual volume ‐ Is the air remaining in the lung after a complete exhalation
E. Dead space
Question 4: A 65 yo M has these arterial blood gas findings: Normal PaO2, Normal O2 Saturation, Low O2 Content. Which disease state best explains these results:
A. Anemia
B. Asthma
C. High Altitude
D. Emphysema
E. Cyanide Poisoning
Question 5. A 25 yo living in Maywood reports dyspnea and has a PaO2 = 70 (low should be 90 mmHg) and PaCO2 = 32 (low; should be 40 mmHg). Which of the
following is increased:
A. Alveolar‐Arterial Oxygen Gradient
a. A‐a = ([760‐47]*0.21 – 32/0.8) – 70 = 40 mmHg
b. Expected A‐a = Age/4 + 4 = 25/4 + 4 = 10 mmHg
c. A‐a Given > A‐a Expected
B. Peripheral Oxygen Consumption
a. would not lead to hypoxia by itself would need to have a lung disease in addition
C. Left to Right Cardiac Shunting
a. Left sided blood has a normal PaO2, so sending this blood through the lungs again would not increase the PaO2
b. Right to Left Shunting WOULD, because the right side venous blood would shunt into the left side arterial blood causing a decrease in PaO2
D. Lung Diffusion Capacity
a. Increasing the diffusion capacity of gasses to diffuse across the lungs would not lower the PaO2 the PaO2 would increase
Question 6: In which organ would this graph be expected:
A. Heart
B. Lung
C. Brain
D. Kidney
E. Skin
Question 7: Your classmate spent her ISI in Peru where, after 1 week, she was evaluated for dyspnea.
Which ABG findings would you expect to see?
A. A
B. B
C. C
D. D
Pulmonary Histology (Online)
Conducting Portion Function of the conducting portion
o Transports
o Warms
o Humidifies
o Filters
Upper Airway: bone, cartilage, and fibrous tissue lined by stratified squamous and ciliated pseudostratified columnar epithelia
o Nasal Cavity
o Pharynx
Nasopharynx
Oropharynx
o Larynx
Epiglottis: elastic cartilage
Vocal cords: striated skeletal muscle / elastic fibers
Lower Airway: lined by respiratory epithelium
o Trachea: C‐shaped cartilage with smooth muscle
o Bronchi
Extrapulmonary/ primary bronchi: begin at the bifurcation of trachea and lead to lungs: extensions of the trachea
Intrapulmonary/secondary and tertiary bronchi: begin at lung hilum. Smooth muscle and hyaline cartilage plates
o Bronchioles: no cartilage and gain Clara cells
o Terminal bronchioles: increased Clara cells
Conducting portion: Lower Trachea: connects larynx to primary bronchi
Airway o Starting at the Lumen
Mucosa: respiratory epithelium = ciliated pseudostratified columnar
epithelium and lamina propria
Ciliated cells, goblet cells, basal cells, and neuroendocrine cells
Submucosa:
dense connective tissue and seromucousglands
Hyaline cartilage:
C‐shaped; some smooth muscle (trachealis) to stabilize opening
Adventitia: 1. Trachea
connective tissue that covers cartilage
Trachea –Respiratory Columnar cells at the top of the image with cilia to help move secretions
Epithelium
High power of columnar cells with cilia, there are goblet cells that contains mucus for release on the mucosal surface
Conducting portion: Lower Main / Primary Bronchi (extrapulmonary bronchi)
Airway o Similar structure to trachea
o Right is wider and more vertical than the left
Secondary /Tertiary (Intrapulmonary ) Bronchi
o Begin at the hilum of the lung
o Mucosa: respiratory epithelium as seen in trachea and primary bronchi
o But below the mucosa is a Smooth muscle band between submucosa and mucosa
Innervated by the sympathetic and parasympathetic systems and allows the airway to be reactive by these systems
o Submucosa: seromucous glands
o Hyaline cartilage plates
o Adventitia
Bronchus, secondary You can see the luminal surface with the mucosa
Blue arrow is pointing to the smooth muscle band that is below the mucosa
Red arrow is pointing to the hyaline cartilage plates
Conducting portion: Mucosa: lined by respiratory epithelium with Clara cells replacing goblet cells
Bronchioles o Dome shaped cells without cilia secrete glycosaminoglycans and secretory proteins
Clara cells increase as bronchioles give rise to terminal bronchioles
Epithelium gradually become mostly clara cells with cuboidal rather than ciliated epithelium as the terminal bronchioles
near the respiratory bronchioles
Smooth muscle layer
No cartilage unique
Adventitia
An electron microscope(EM) uses an electron beam to illuminate a specimen and produce a magnified image. Is able to achieve
magnifications up to 10,000,000 x thus it is very useful to look at the ultrastructural characteristics of a cell.
Electron micrograph (EM) of the respiratory mucosa. You can see the ciliated cells with interspersed Clara cells.
Bronchiole You can see the mucosal lining along with a very small smooth muscle lining
Remember that the bronchiole has NO CARTILAGE!!
Terminal bronchiole Clara cells create a cuboidal lining rather than the columnar lining
Respiratory portion Function:
o Gas exchange
Respiratory bronchioles:
o tubes between alveoli
o Alveolar ducts/alveolar sacs: arise from respiratory bronchioles but have more alveoli and terminate as blind pouches
Alveoli:
o Thin‐walled pouches lined by type I / type II pneumocytes
Respiratory Portion: Tertiary bronchioles give rise to respiratory bronchioles
Respiratory Bronchioles First airways to function in gas exchange
Lined by cuboidal cells and connect to alveoli and alveolar ducts
Respiratory bronchioles, b = respiratory bronchiole with alveolus (a) in its wall.
alveolar ducts, and alveoli Most of the wall of the bronchiole has a definite line of dark along it, signifying a cuboidal epithelium d & c = alveolar duct.
o Its wall consists almost entirely of alveoli, which have only a simple squamous lining, too flat to be visible here.
e = alveoli (the smallest respiratory units)
f = blood vessel (branch of pulmonary artery still)
Respiratory Portion: Ducts are lined by squamous alveolar cells (type I pneumocytes) with knobs of cuboidal cells
Alveolar ducts and alveoli o Each duct functions as a corridor to connect several alveoli
Alveoli
o Mostly lined by Type I pneumocytes (95%‐97%):
flat dark oval nucleus and thin cytoplasm
o Small percentage of Type II pneumocytes:
These cells can divide and replace type I cells
large polygonal cells at corner of alveoli.
Secrete components of pulmonary surfactant.
o Lined by septa = blood‐air barrier for case exchange formed by delicate connective tissue and capillaries
o Alveolar macrophages: aka dust cells, located in septa, often contain phagocytized material
Alveolar Macrophages The alveolar macrophages are frequently pigmented with their debris
Alveolar spaces ‐Septa Type 1 pneumocyte have a very flat nucleus and the cytoplasm is making up the alveolar wall and connected through tight
junctions
Type 2 pneumocytes tend to be at the edge of the alveolar septa and tend to be more cuboidal in shape
Illustrative EM EM showing
o basal lamina (1) between squamous alveolar epithelium (2 = Type I cell) and capillary endothelium (3).
o The nucleus at upper right belongs to the endothelial cell lining the capillary.
o The dark structure is a red blood cell.
o The capillary plus the alveolar linings on both sides constitute the inter alveolar septum that lies between two alveolar spaces.
Normal Lung, Congenital Anomalies and Acute Lung Injury
Anatomy and Histology The major function of the lung is to replenish oxygen and excrete carbon dioxide from blood.
o The anatomy and the intricate histology of the lung is uniquely designed to facilitate this function
The right and left lungs are surrounded by the visceral pleura with an approximately weight of 300‐450
grams
Development of the Lung
The respiratory system is The midline trachea develops into two lateral out pockets called lung buds.
an outgrowth from the o The right lung bud divides into three main bronchi
ventral wall of the foregut o The left lung bud divides into two main bronchi
Giving rise to the three lobes in the right lung and two lobes in the left lung
The lingual represents the anterior inferior division of the upper lobe and is a counter part of
the middle lobe
The development of the Pseudoglandular Stage (7‐17 weeks):
respiratory system during o During this period, growth and branching allows for the development of pulmonary structures EXCEPT those elements needed
the fetal period is divided for gas exchange
into several stages Canalicular Stage (17‐27 weeks):
o In this phase, the canaliculi branch out of the terminal
bronchiole.
o The canaliculi compose the proper respiratory part of the
lungs, called the pulmonary parenchyma.
o All of the air spaces that are derive from a terminal
bronchiole form an acinus.
The acinus includes an alveolar duct which then develops
into an alveolar sac.
o The essential characteristic of the canalicular phase is the differentiation of epithelium into cuboidal secretory cells (Type 2
pneumocytes).
o The capillaries surround the acini and thus form the foundation for the later exchange of
gases.
Saccular‐Alveolar Stage (27‐40 weeks):
o In this phase, the respiratory part of the bronchopulmonary tree develops with the
formation of alveolar sacs which are separated by primary septa.
o The alveolar sacs will be progressively divided into smaller subunits by secondary septa,
leading to the formation of alveoli.
Airways of the Lung
Trachea The trachea divides into a right and left main bronchus.
Each major bronchus then subdivides into smaller airway passages referred to as bronchi.
The airway passages become smaller and are referred to as bronchioles.
Eventually the bronchioles terminate into small collections of air sacs known as alveoli, which is where the
actual exchange of CO2 and Oxygen occur.
Trachea Bronchus Bronchi Bronchioles Alveoli
Bronchus The right main bronchus deviates only 20‐30 degrees off the main stem bronchus
The left main bronchus deviates 40‐60 degrees off the main
In an upright position, this predisposes a person to aspirate foreign material into the right main bronchus often.
Bronchi and Bronchioles Connective tissues, smooth muscle, and cartilage provide the basic structural framework.
o The main bronchi branch dichotomously giving rise to progressively smaller airways called bronchioles
o Difference between Bronchiole and Bronchi
Bronchiole has no cartilage, no sub‐mucous glands, and go goblet cells
o With progressive branching of bronchi
Cartilage decreases
Smooth muscle increases
Cell Types Trachea, Bronchus, and Bronchi are lined by pseudostratified ciliated columnar epithelium
o Which is comprised of 4 major types of cells
Ciliated cells, Goblet cells, Basal cells, Neuroendocrine cells
Ciliated Cells:
Are a key component of the mucociliary escalator
o On top of the airway epithelium, is a thin film of mucus that is produced by the
goblet cells to trap foreign particles
o The ratio of ciliated to goblet cells is between 7‐25 to 1
In case of acute bronchial irritation
o The number of goblet cells increases
o To produce more mucus
o To help clear the irritation
Goblet cells:
A goblet cell is a glandular, modified simple columnar epithelial cell whose function is to secrete gel‐forming mucins, the
major components of mucus.
The goblet cell is highly polarised with the nucleus and other organelles concentrated at the base of the cell. The
remainder of the cell's cytoplasm is occupied by membrane‐bound secretory granules containing mucin.
Basal Cells:
Are pluripotential reserve cells that can differentiate into ciliated and non‐ciliated cells
To repopulate the epithelium after a bronchial injury
Pulmonary Neuroendocrine cells (PNEC)
The cells are bottle‐ or flask‐like in shape, and reach from the basement membrane to the lumen with chemoreceptors
for hypoxia detection
The source of several types of lung cancer‐ most notably, small cell carcinoma of the lung, and bronchial carcinoid tumor
Bronchiole
o The bronchioles do not contain cartilage, sub‐mucous glands, or goblet cells
o The distal part of the terminal bronchiole is called the Acinus
The Acinus is comprised of:
Respiratory bronchioles
Alveolar ducts
Alveolar sacs
Alveoli
Alveoli
o The alveoli are the main site of gas exchange
o The microscopic structure of the alveolar walls called alveolar septa include:
Capillary endothelium and basement membrane
Pulmonary interstitium
Composed of:
o Fine elastic fibers, Small bundles of collagen, Few fibroblast‐like cells,
Smooth muscle cells, Mast cells, and Mononuclear cells (rare)
The pulmonary interstitium is most prominent in the thicker portions of the alveolar septum.
Alveolar epithelium contains a continuous layer of two principle cells types:
Type 1 pneumocytes:
o flat, plate‐like cells that cover 95% of the alveolar surface
Type 2 pneumocytes:
o round cells that synthesize surfactant and act as stem cells that repair the alveolar epithelium
after damage to Type 1 pneumocytes
The alveolar walls are perforated by pores of Kohn
o Allowing passage of air, bacteria, and exudates between adjacent alveoli
A few alveolar macrophages are present within the alveolar space
o In an adult, these macrophages often contain phagocytosed carbon particles
Congenital Anomalies
Agenesis: Complete absence of lung tissue beyond the trachea or mainstem bronchus.
Agenesis can be unilateral, bilateral or lobar.
o Bilateral agenesis is incompatible with life.
o Unilateral agenesis is frequently associated with cardiovascular anomalies including
Atrial Septal Defect (ASD)
Patent Ductus Arteriosus (PDA)
Abnormal pulmonary venous return
Hypoplasia: Incomplete or defective development of the lung
o resulting in diminished size.
In majority of the cases, the deformity is attributable to an associated malformation that directly or indirectly
compromises the thoracic space available for lung growth.
o Examples of common associations include:
Decreased intrathoracic space (renal cystic disease, Diaphragmatic Hernia)
Prolonged Oligohydramnios
Decreased breathing movements (anencephaly, musculoskeletal disorders)
Tracheoesophageal fistula Tracheoesophageal fistula (TOF) is an abnormal connection (fistula) between the esophagus and
and Esophageal atresia: the trachea.
Esophageal atresia is when the upper esophagus ends and does not connect with the lower
esophagus and stomach.
These frequently go hand in hand.
o Suspect esophageal atresia with or without TOF
if there is maternal polyhydramnios = an excess of amniotic fluid in the amniotic sac.
if infant has excessive oral or pharyngeal secretions
if there is choking, cyanosis, or coughing at feeding
o Most common variety is esophageal atresia with TOF to the distal esophageal segment
Bronchogenic cyst: Recall that the respiratory system is an outgrowth from the ventral wall of the foregut
o Bronchogenic cysts are foregut buds that have separated and disconnected from the tracheobronchial
tree enlarging and forming a cystic mass.
Children, young adults, no sex predilection.
Chest x‐ray shows spherical, well‐marginated masses, usually located in the mid mediastinum.
Forming unilocular cysts
o Which are filled with clear fluid Lined by cuboidal to columnar ciliated epithelium
o Which may contain cartilage and glands (like submucosal glands)
o At risk for infection
Congenital Pulmonary Also known as Congenital Cystic Adenomatoid Malformation (CCAM)
Airway Malformation Forming “hamartomatous lesions”, which can be separated into five types based on clinical,
(CPAM) radiolographic and pathologic features.
o Hamartoma
is defined as a common benign tumor in an organ composed of tissue elements normally found at
that site but that are growing in a disorganized mass.
o The lesions are composed of multiple, irregular varying sized acinar structures lined by cuboidal,
ciliated pseudostratified columnar or alveolar epithelium.
o There is a slight male predominance
o Onset is most commonly seen in new born and up to first 2 years of life.
Infants (0‐1 year) may present with signs of infection (cough, fever) or with respiratory distress,
depending on the size of the lesion.
Sequestration Discrete mass of lung tissue that is not connected to the tracheobronchial tree.
Types include:
o Extralobar Pulmonary Sequestration:
Due to an abnormal budding from the foregut
Lies outside the normal lung
Completely surrounded by its own visceral pleura
Onset within the first 6 months of life
With a male predominance.
Presents with
Dyspnea, Cyanosis, and feeding difficulties due to the mass
Located in the media left lower lobe and presents as a soft tissue mass.
Receives and drains into the systemic circulation rather than pulmonary circulation.
Histologically
can look normal or show dilated bronchioles or inflammation or a co‐existing CPAM.
o Intralobar Sequestration:
Is acquired as a result of obstruction of the bronchial tree and to the vascular supply to the
affected segment of lung
Contained within normal lung pleura
Occurs 98% of the cases are located in the medial left lower lobe
Presents in the 2nd or 3rd decade associated with recurrent infections
Show evidence of chronic infection
including lymphoid hyperplasia, accumulation of foamy macrophages, and fibrosis.
Acute lung injury (ALI) also The term Acute Lung Injury encompasses a spectrum of bilateral pulmonary damage (endothelial and epithelial)
called Non‐Cardiogenic Pathophysiology:
Pulmonary Edema o Parenchymal disease that causes an increase resistance to expansion
which can be initiated by numerous conditions:
o Clinically
Acute onset of dyspnea
Decreased arterial oxygen pressure (hypoxemia)
Development of bilateral pulmonary infiltrates in the absence of primary left‐sided heart failure.
Where pulmonary infiltrates are usually caused by damage to the alveolar capillary membrane called noncardiogenic
pulmonary edema
o Direct Lung Injury
Pneumonia
Aspiration
Trauma
Fat embolism
Near drowning
Inhalation injury
Reperfusion injury after lung transplantation
Drug overdose
o Indirect Lung Injury
Sepsis
Severe trauma with shock
Acute pancreatitis
Drug overdose
Uremia
DIC
o Acute lung injury can progress to the more severe Acute Respiratory Distress Syndrome (ARDS)
Acute respiratory distress is a clinical syndrome caused by diffuse alveolar capillary and epithelial damage.
syndrome (ARDS) Characterized by
o rapid onset (<24 hours) of life threatening respiratory insufficiency
o cyanosis
o severe arterial hypoxemia that is refractory to oxygen therapy and may progress to multisystem organ failure
Normal PaO2/FiO2 = 100/0.21 = 475
PaO2/FiO2 < 200 ARDS
PaO2/FiO2 < 300 ALI
ARDS – Etiology Direct Injury
o *Pneumonia (40% occurrence)
Diffuse pulmonary infections: viral and mycoplasma
o Aspiration (15%)
*Gastric aspiration
o Inhaled Irritants
Oxygen toxicity, Smoke, Irritant gases and chemicals
o Physical Injury
Pulmonary contusions, Near drowning
Indirect Injury
o Infection
*Sepsis (25%)
o Physical Injury
*Mechanical trauma, *Head injuries, Fractures with fat embolism, Burns, Ionizing radiation
o Chemical Injury
Heroin or methadone overdose, Acetylsalicylic acid (Aspirin), Barbiturate overdose, Paraquat – weed killer
Hematologic Conditions
o Multiple transfusions associated with:
Transfusion Related Acute Lung Injury (TRALI)
TRALI is characterized by the acute onset of non‐cardiogenic pulmonary edema following transfusion of blood products
The primary symptoms of TRALI are
o sudden dyspnea
o severe hypoxemia
o hypotension
o fever within 6 hours after the transfusion
Transfusion Associated Circulatory Overload (TACO)
TACO is a transfusion reaction (an adverse effect of blood transfusion) that occurs due to a rapid transfusion of a large
volume of blood.
The primary symptoms of TACO are
o Dyspnea
o Orthopnea
o peripheral edema
o rapid increase of blood pressure
o Disseminated Intravascular Coagulation (DIC)
ARDS Etiology in a Nutshell
o A – Aspiration, acute pancreatitis, air/amniotic fluid embolism
o R – Radiation
o D – Drug overdose, DIC, drowning
o S – Shock, sepsis, smoke inhalation
ARDS ‐ Clinically Incidence
o 1.5 to 8.3 per 100.000 people/year
o 7% of all ICU admissions
o 40$ mortality rate
Onset:
o 24‐72 hrs of precipitating event
Symptoms:
o Tachypnea, Dyspnea, cyanosis (due to hypoxemia)
o Bilateral lung infiltrates in the absence of cardiac dysfunction
Approach to diagnosis:
o clinical history
o imaging studies (X‐ray, CT)
o bronchoscopy (r/o aspiration, hemorrhage, infection malignancy)
Treatment:
o Primarily supportive with a goal to maintain gas exchange
o Treat underlying condition + supportive care
ARDS – X‐Ray Findings No cardiomegaly – enlarged heart
No pleural effusions
No Kerley B lines
o These are short parallel lines at the lung periphery which represent the interlobular septa
o They may be seen in any zone but are most frequently observed at the lung bases at the
costophrenic angles on the PA radiograph, and in the substernal region on lateral radiographs.
Delay in onset of any x‐ray findings for at least 12 hours post‐insult
o Between 12 and 24 hours
Patchy alveolar infiltrates in both lungs
o Between 24 and 48 hours
Coalesce to produce massive air‐space consolidation of both lungs
o From 5 to 7 days
Clearing is frequently 2° effects of CPP ventilation rather than true healing
Pneumonia may superimpose
Difficult to recognize but look for new focal infiltrates and pleural effusion
o More than one week
Coarse reticular interstitial disease which may lead to fibrosis
ARDS – histologic Manifestations in the lungs is pathological known as Diffuse Alveolar Damage (DAD).
o ARDS can occur in a multitude of clinical settings and is associated with either direct injury to
the lung or indirect injury in the setting of a systemic process.
o Micro:
alveolar capillaries are engorge
intra‐alveolar pink granular precipitate is seen
Hemosiderin‐laden macrophages
o Gross:
Soggy, firm, brown lung = brown induration, which predisposes to infection.
ARDS – Pathogenesis: In ARDS, the integrity of alveolar‐capillary membrane barrier is
compromised
o by either endothelial or epithelial injury, or, more commonly, both.
The acute consequences of damage to the alveolar capillary
membrane include:
o increased vascular permeability and alveolar flooding
o loss of diffusion capacity
o widespread surfactant abnormalities
caused by damage to type II pneumocytes
Lung injury is caused by an imbalance of pro‐inflammatory and anti‐
inflammatory mediators.
o After an acute insult, macrophages secrete:
IL‐8 – neutrophil chemotactic and activating agent
o Release of IL‐8, IL‐1, and tumor necrosis factor (TNF), leads to
endothelial activation as well as sequestration and activation of
neutrophils in pulmonary capillaries.
o Activated neutrophils release oxidants, proteases, leukotrienes and platelet‐activating factor that damage the alveolar
epithelium and endothelium.
Resulting in:
Pneumocyte and endothelial cell necrosis
Edema
Hyaline membrane formation (begins Day 2 and peaks Day 4‐5)
Inflammation is sparse
Organizing interstitial fibrosis, and type 2 pneumocyte proliferation
The damage can be counteracted by
o endogenous antiproteases
o antioxidants
o anti‐inflammatory cytokines (e.g., IL‐10).
Resulting in either
o Restoration of normal lung architecture
o Progression to fibrosis – end stage honeycomb fibrosis
ARDS ‐ Pathology Early Exudative Phase (Acute)
o In the acute phase of ARDS, the lungs are dark red, firm, airless, and heavy.
o Microscopic examination reveals
capillary congestion
necrosis of alveolar epithelial cells
interstitial and intra‐alveolar edema and hemorrhage
collections of neutrophils in capillaries particularly with sepsis
o The most characteristic finding is the presence of hyaline membranes, particularly lining the
distended alveolar ducts.
hyaline membranes consist of fibrin‐rich edema fluid admixed with remnants of necrotic epithelial cells.
Subacute Proliferative Phase (Organizing)
o In the organizing stage, vigorous proliferation of type II pneumocytes occurs in an attempt to regenerate the alveolar lining.
Fibrotic Phase (Late)
o Resolution is unusual; more commonly, there is organization of the fibrin exudates, with resultant intra‐alveolar fibrosis.
o Marked thickening of the alveolar septa ensues, caused by proliferation of interstitial cells and deposition of collagen.
o late proliferative and fibrosis stages.
(A) The cellular late proliferative phase of ARDS may evolve to (B)
fibrosis, with cellular fibroblastic proliferation and collagen deposition.
Neonate Respiratory There are many causes of respiratory distress in a newborn,
Distress Syndrome (NRDS) o Etiology Includes:
excessive sedation of the mother
fetal head injury during delivery
aspiration of blood or amniotic fluid
intrauterine hypoxia secondary to compression from coiling of the umbilical cord about the neck
The most common cause is Respiratory Distress Syndrome (RDS)
o also known as Hyaline Membrane Disease, Infant respiratory distress syndrome (IRDS), Respiratory distress syndrome of
newborn
where small pulmonary vessels engorged
causes the leakage of blood into the alveoli
leading to the formation of intra‐alveolar hyaline membranes
consisting of fibrin and cellular debris
Incidence: 24,000 cases/year
Incidence inversely proportional to the gestation age
o 60 % < 28 weeks
o 15‐20% < 32‐36 weeks
o < 5% >37 weeks
Predisposing factors: Prematurity
o Surfactant can be secreted as early as 20 weeks, but surfactant is not produced in sufficient amounts till 34 weeks
o Therefore, insufficient pulmonary surfactant production by immature lungs results in failure of lungs to inflate after birth
maternal diabetes
o high levels of insulin counteract the effects of steroids to decrease the risk for RDS
C‐section
o cesarean section performed before the onset of labor may be associated with increased risk for RDS
Surfactant Surfactant is synthesized in type II pneumocyte
Composition:
o dipalmitoyl phosphatidylcholine/ lecithin (DPPC), unsaturated phosphatidyl cholines (PC) and phosphatidylglycerol (PG) and
surfactant specific proteins SP‐A, SP‐B, SP‐C and SP‐D.
Function:
o Stabilizing the lung by reducing surface tension
o Host defense mechanism as a barrier for inhaled particles
Surfactant Deficiency
o Surfactant can be secreted as early as 20 weeks but is not produced in sufficient
amounts till 34 weeks
o Decreased surfactant
Causes an increased surface tension, an increased resistance to inflation, and
collapse
Causes ventilation perfusion mismatch
o Which may result in hypoxia, endothelial and epithelial injury, increased
capillary permeability, epithelial necrosis, and hyaline membranes
Image of hyaline membrane disease which shows numerous hyaline membranes
lining the alveolar ducts. Interstitial fibroblasts and congested alveolar capillaries
thicken the alveolar septa.
Image of yellow hyaline membranes that may be observed in kernicteric infants with respiratory
distress syndrome.
Surfactant synthesis is modulated by:
o Stressed Induced
Under stress conditions, Glucocorticoids are released which increases the production of surfactant lipids and associated
proteins.
which results in a lower the risk of developing RDS.
Stressors include: labor, prolactin, thyroxine, and TGF‐beta
o Suppressed
High blood levels of insulin in infants of diabetic mothers
Because insulin counteracts the effects of steroids
Control and treatment of Prevention and treatment
NRDS o Delaying labor if possible to permit fetal lung maturity
Oxygen is given with a small amount of continuous positive airway pressure (CPAP)
Intravenous fluids are administered to stabilize the blood sugar, blood salts, and blood pressure
o Prophylactic administration of exogenous surfactant (infants less than 28 weeks) will reduced the incidence and
complications of RDS.
o Assess maturation of fetal lungs:
Amniotic fluid assay:
Lecithin to sphingomyelin ratio (>2:1)
Amniotic fluid:
Lamellar body counts.
NRDS Complications Complications of oxygen therapy used in NRDS:
o Retrolental fibroplasia (retinopathy of permaturity)
Retinopathy of prematurity (ROP) is abnormal blood vessel development in the retina of the eye in a premature infant.
o Bronchopulmonary dysplasia
Bronchopulmonary dysplasia (BPD) is a chronic lung disorder that is most common among children who were born
prematurely, with low birth weights and who received prolonged mechanical ventilation to treat respiratory distress
syndrome.
The classic diagnosis of BPD may be assigned at 28 days of life if the following criteria are met:
Positive pressure ventilation (CPAP) during the first 2 weeks of life for a minimum of 3 days.
Clinical signs of abnormal respiratory function.
Requirements for supplemental oxygen for longer than 28 days of age to maintain PaO2 above 50 mm Hg.
Chest radiograph with diffuse abnormal findings characteristic of BPD.
Other complications due to prematurity:
o Patent Ductus Arteriosus (PDA)
o Intraventricular hemorrhage (IVH)
o Necrotizing enterocolitis (NEC)
ARDS Compared to NRDS ARDS NRDS
Etiology Numerous, direct and indirect injury to the Prematurity, fetal injury during delivery, aspiration of blood
lung and amniotic fluid, cord compression
Pathophysiology Imbalance of pro‐inflammatory and anti‐ Surfactant deficiency
inflammatory mediators
Age Adults Premature infants
Symptoms Tachypnea (fast breathing), dyspnea Tachypnea, tachycardia, cyanosis
(shortness of breath)
Histology DAD, hyaline membrane formation DAD, hyaline membrane formation
Treatment Treat underlying cause plus supportive CPAP, surfactant, IVF
measures
Acute Interstitial Clinicopathologic term (aka Hamman‐Rich syndrome)
Pneumonia Rapidly progressive disease clinically similar to ARDS with no identifiable cause
o death usually within 2 months
Adults with influenza‐like illness followed by shortness of breath
Microscopically resembles diffuse alveolar damage (DAD) with brisk interstitial fibroblastic proliferation
Pulmonary Edema Edema = increased fluid in the interstitial tissue spaces
Causes: Increased hydrostatic pressure; Reduced osmotic pressure; lymphatic obstruction; Sodium retention; Inflammation
Different Types of Most Common Cause is Hemodynamic or cardiogenic edema
Pulmonary Edema o Due to:
Left side heart failure; Volume overload
Edema due to microvascular injury (alveolar injury)
o leakage of flluids and proteins into interstitial space and in severe cases into the alveoli. If diffuse leads to ARDS.
o Caused by:
Infections; Liquid aspiration, drugs, chemicals; Radiation, transfusion
Edema of undetermined origin
o High altitude
o Neurogenic edema
In cases of hemodynamic rising pressure in the pulmonary veins
edema o cause back pressure changes
resulting in congestion and edema
The increase in the hydrostatic pressure of the venules of the visceral pleura
o results in pleural effusion.
Where the lungs become boggy and heavy
There is perivascular and interstitial transudates, alveolar septal edema, and edema fluid within alveolar
spaces on microscopy.
Variable number of red cells extravagate from the leaky capillaries which are then phagocytosed by
macrophages.
o The hemoglobin from the red cells is broken down
resulting in hemosiderin laden macrophages (also called heart failure cells)
which is a reflection of previous episodes of pulmonary edema.
Atelectasis or Collapse Atelectasis, also known as collapse,
o is loss of lung volume caused by inadequate expansion of air spaces
results in shunting of inadequately oxygenated blood from pulmonary arteries
into veins
thus giving rise to a ventilation‐perfusion imbalance and hypoxia.
o Neonatal
Incomplete expansion
o Acquired
Resorption or obstruction (mediastinum shifts towards affected lung)
Asthma, COPD, bronchiectasis, aspiration, postop patients
Compression (Mediastinum shifts away from the affected lung)
Effusions, air, tumors, CHF
Contraction (can not be corrected)
Fibrosis of lung/pleura
Atelectasis is classified Resorption atelectasis:
into three forms o Resorption atelectasis occurs when an obstruction prevents air from reaching distal airways.
The air already present gradually becomes absorbed, and alveolar collapse follows.
Depending on the level of airway obstruction, an entire lung, a complete lobe, or one or more segments may be involved.
o The most common cause is obstruction of a bronchus
by a mucous or mucopurulent plug.
This frequently occurs postoperatively but also may complicated by:
o bronchial asthma, bronchiectasis, chronic bronchitis, tumor, or foreign body aspiration, particularly in children.
Compression atelectasis:
o Compression atelectasis (sometimes called passive or relaxation atelectasis) is usually associated with accumulation of fluid,
blood, or air within the pleural cavity, which mechanically collapses the adjacent lung.
o This is a frequent occurrence with pleural effusion
caused most commonly by congestive heart failure (CHF)
o Leakage of air into the pleural cavity (pneumothorax) also leads to compression atelectasis.
o Basal atelectasis resulting from the elevated position of the diaphragm
commonly occurs in bedridden patients, in patients with ascites, and during and after surgery.
Contraction atelectasis:
o Contraction (or cicatrization) atelectasis occurs when either local or generalized fibrotic changes in the lung or pleura hamper
expansion and increase elastic recoil during expiration.
Mediastinum Shift Resorption:
o Mediastinum shifts towards affected lung because the lung volume is diminished.
Oxygen trapped distal to the obstruction is eventually reabsorbed
leading to collapse of the obstructive segment.
Obstruction can be caused by excessive secretions, therefore most often found in astma, chronic bronchitis, rarely foreign
body aspiration
Compressive:
o Mediastinum shifts away from the affected lung
Pleural cavity filled with fluid, blood air
Contraction:
o Fibrotic changes in lung or pleura
Atelectasis (except when caused by contraction) is potentially reversible and should be treated promptly to prevent hypoxemia
and superimposed infection of the collapsed lung
Histology
Pneumothorax Types:
o Spontaneous
o Traumatic
Pathophysiology:
o Causes compression and atelectasis, leading to respiratory distress
Most commonly associated with:
o Emphysema, asthma, TB
Spontaneous idiopathic form:
o in younger people, rupture of peripheral small pleural blebs
Symptoms: Sudden sharp chest pain, made worse by a deep breath or a cough
Shortness of breath
Chest tightness
Easy fatigue
Rapid heart rate
Bluish color of the skin caused by lack of oxygen
Tension pneumothorax Defect acts as a flap, air enters in during inspiration, but the flap
closes up, and does not allow air to escape during expiration.
X‐ray Image
o The visceral‐pleura white line. (as marked by the white dots)
o Loss of pulmonary markings over the left lung.
o The mediastinum is shifted to the right and the diaphragm over
the left side is pushed downwards.
Treatment for
o small pneumo: nothing
o large: chest tube
Question 1
A 30‐year‐old woman develops multiple organ failure, bleeding diathesis post‐partum (DIC and increased risk for ARDS). Sputum
and blood cultures are negative. Nevertheless, she requires intubation with mechanical ventilation, but it becomes progressively
more difficult to maintain her oxygen saturations. Ventilatory pressures must be increased. A portable chest radiograph shows
increasing opacification of all lung fields (bilateral disease). Capillary wedge pressure is normal (no cardio pulmonary edema, if
capillary wedge pressure was increased there would be pulmonary edema).
the lungs look wet (boggie) and distended, with rib impressions
Which of the following pathologic processes is most likely now to be present in her lungs?
A. Emphysema no infiltrates
B. Diffuse alveolar damage due to amniotic fluid embolism
C. Extensive neutrophilic alveolar exudates (i.e. Pneumonia) cultures are negative
D. Extensive intra‐alveolar fluid (i.e. pulmonary edema) wedge pressure would be increasing
E. Normal lung
Pulmonary Pathology Part 2
Diffuse Pulmonary Diseases
Obstructive Limitation of airflow
Increase in resistance
o due to partial or complete obstruction at any level
Associated with a decrease in FEV1/FVC
o Emphysema
o Chronic bronchitis
o Bronchiectasis
o Asthma
o Tumor
o Foreign body
Restrictive Reduced expansion of lung parenchyma with decrease in total lung capacity
o Parenchyma ‐ the functional tissue of an organ as distinguished from the connective and supporting tissue
Associated with a decreased TLC and normal FEV1
o Due to chest wall disorders including:
Polio
Obesity
Pleural disease
Kyphoscoliosis
o Due to interstitial or infiltrative diseases including:
ARDS
Dust diseases
Interstitial fibrosis
Pulmonary Function Tests
Assess nature and severity To quantify the progression of disease and the response to therapy
of lung disease Assessment of pulmonary functions in people who are exposed to toxins includes tobacco
Spirometry Measuring air flow – Spirogram
o Commonly used clinical tests have the patient inhale
maximally to TLC and then exhale as rapidly and
completely as possible to RV.
o The results are displayed either as a spirogram or as a
flow‐volume curve/loop
Spirogram
o A spirogram displays the volume of gas exhaled against
time and provides four major test results
o Forced vital capacity (FVC)
The total volume of air that is exhaled during a maximal
forced exhalation from TLC to RV
o Forced expiratory volume in 1 second (FEV1)
The volume of air that is exhaled in the first second during the maneuver
Normal = 75‐80% of FVC can be exhaled in the first second
o Ratio of FEV1 to FVC (FEV1/FVC)
Normal = greater than 75‐80%
Less than 75% suggests difficulty exhaling due to an obstruction obstructive
pulmonary disease
o Average mid maximal expiratory flow (FEF25‐75)
The forced expiratory flow from 25% to 75% of Vital Capacity (VC)
Flow‐Volume Loop A flow‐volume curve or loop is created by displaying the instantaneous flow rate during a forced
maneuver as a function of the volume of gas.
This instantaneous flow rate can be plotted during exhalation (top of loop) and during inspiration
(bottom of loop).
o Expiratory flow rates are displayed above the horizontal line
o Inspiratory flow rates are displayed below the horizontal line
Gives three main pulmonary function tests
o FVC = RV ‐ TLC
o Peak expiratory flow rate (PEFR) – the greatest flowrate achieved during the expiratory maneuver
Normally occurs within the first 20% of the cycle
Expiratory flow limitation ‐ Flow rates decrease toward RV
Performed three forced expiratory maneuvers with increasing effort
As effort increases,
o Peak expiratory flow rate increases
o However, the flow rates at lower lung volumes converge
This indicates that with modest effort, maximal expiratory flow is achieved
In other words, no matter how much effort you put in, the flow rates decrease as lung volume decreases
o Therefore, expiratory flow rate at lower lung volumes are “effort independent” and “Flow limited”
In contrast, events early in the expiratory maneuver are “effort dependent”
o Increasing effort generates increasing flow rate
Associated with the first 20% of the flow in the expiratory flow‐volume loop.
Forced Expiratory Flow (FEF25) is the instantaneous flow rate at which 25% of the VC remains to be exhaled.
This is also calculated at 50% and 75%.
Peak Inspiratory flow rate (PIFR) – the greatest flowrate achieved during the inspiratory maneuver
When lung volume increases
o Forces of inspiratory muscles decrease
o Lung recoil pressure increases
o Airway resistance decreases
Maximum Inspiratory Flow – half way between TLC and RV
Obstructive Pulmonary Disease
Overview Key players
o Asthma
o Chronic Obstructive Pulmonary Disease (COPD)
Chronic Bronchitis
Emphysema
o Bronchiectasis
Asthma Intermittent and reversible airway obstruction
o Key thing to remember is that asthma is reversible airway obstruction and episodic.
Asthma is due to hyper reactivity of airways.
Where the stimuli that trigger the attacks in patients may or may not have any role in triggering attacks in patients with
normal airways.
o Increased responsiveness of the tracheobronchial tree to various stimuli
o Complex disorder in which multiple susceptibilty genes interact with environmental factors to initiate pathologic reaction
o Associated with:
Chronic bronchial inflammation
with eosinophils (bilobed), expanded lamina propria thickened basement membrane *type 1 hypersensitivity)
Bronchial smooth muscle hypertrophy hyper‐reactivity
Increased mucus production
Symptoms: Wheezing
Breathlessness
Chest tightness
Cough
Incidence: Occurs in 5% of the US population
There has been an increased incidence in the western world in the past 4 decades
o “Hygiene hypothesis”: eradication of infections, alteration of immune homeostasis and altered/allergic/harmful immune
response
Stimulus: Infections
Environmental irritants
Cold air
Stress
Exercise
Types of Asthma ‐ Atopic Immune Mediated: Type I hypersensitivity reaction involving IgE bound to mast cells
o Sequence of an Allergic Response
Contact with an allergen is usually mucosal (respiratory or gastrointestinal), but can be cutaneous or systemic.
Uptake of allergen by antigen presenting cells (dendritic cells) through allergic TLR that induces the dendritic cell to produce
IL‐4 instead of IL‐12
Presentation of the allergen as an immunodominant peptide in a Class II MHC groove.
The nature of the peptide and the unique presentation will dictate a dominant IgE response
Allergic responses are dependent on Th2 activation
Presentation of this antigen by a dendritic cell in the absence of Th1‐TLR binding or by an allergic TLR
o Where the absence of the Th1 initiator cytokine IL‐12 or presence of IL‐4 then leads to presentation to a Th2 T cell by
default
Early release of IL‐4 from mast cells or basophils
o Which is commonly caused by an innate immune response of these cells to a parasite
Any situation where IL‐4 is the dominant cytokine at the time of the antigen appearance
Th2 T cell then provides the critical IL‐4 signal to an allergen specific B cell
Which causes the accelerated production of Th2 cytokines IL‐4 and IL‐13
Promotion of IgE class switching occurs by the up regulation of CD23 (which is the Fc‐epsilon II receptor) on mast cells and
basophils
Which increase their production of IL‐4 and IL‐13
o Due to the strong influence by gene influenced polymorphisms
IL‐4 from Th2 T cells, Basophils, and Mast cells activate epsilon germ‐line transcription in B cells and results in IgE synthesis
Begins in childhood, triggered by environmental allergens (dust, pollen etc.)
Family history of asthma, atopy
o Positive family history, asthmatic attacks are preceded by allergic rhinitis, urticaria or eczema.
Tests: Skin reaction to allergen
o Allergen sensitization test by Serum radioallergosorbent tests Positive showing IgE for various antigens
Types of Asthma – Non‐ Associated with non‐immune triggering mechanisms
Atopic o respiratory viruses
o air pollutants like ozone
Hyperirritable bronchial tree
o virus induced inflammation of the respiratory mucosa
lowers the threshold of subepithelial vagal receptors to irritants
Mechanisms not as well understood as atopic asthma
o however, final pathways probably converge
Tests:
o Skin and serum tests are negative
Types of Asthma – Drug Several drugs
Induced Asthma o aspirin most striking example
Presumed mechanism with Aspirin
Cyclooxygenase pathway of arachidonic acid is inhibited more than lipooxygenase pathway
o resulting in bronchial spasm
Patients with recurrent rhinitis and nasal polyps
Drugs might induce skin reaction (urticaria) in addition to asthma
Types of Asthma – Fumes
Occupational Asthma o epoxy resins, plastics
organic chemical dusts
o wood, cotton, platinum
gases
o toluene
Asthma develops after repeated exposure to inciting agent
Pathogenesis of Asthma Th2 dominated response favoring IgE production and eosinophil recruitment
Secondary exposure leads to bronchospasm
o increased vascular permeability, mucus production and mediator release
Asthma Genetics Chromosome 5q has several susceptibility genes
o IL‐13:
Mutations causes genetic polymorphisms which increases the susceptibility for atopic
asthma
o CD‐14:
Single Nucleotide Polymorphisms (SNP) associated with occupational asthma
ADAM33 gene
o Located on chromosome 20q
o ADAM33 is a member of the metalloproteinase family
Where mutations cause polymorphisms
Which accelerate bronchial smooth muscle proliferation
Pathology of Asthma Normal tissue structure
Bronchial asthma tissue structure
Status asthmaticus:
o a severe condition in which asthma attacks follow one another without pause
causes hyperinflated lungs
o Productive cough containing
Spiral‐shaped mucus plugs called Curschmann spirals
Gross
Histologic Curschmann spirals
o Twisted mucus plugs admixed with sloughed epithelium
Eosinophil‐derived crystals called Charcot‐Leyden crystals
Charcot‐Leyden crystals are crystal aggregates of eosinophil major basic protein
Complications of Asthma Status asthmaticus prolonged bout of asthma lasting for days, responding poorly to treatment
Emphysema
Chronic bronchitis
Pneumonia
Bronchiectasis
Cor pulmonale
Chronic Bronchitis Persistent productive cough for at least three consecutive months in at least two consecutive years
Population
o Smokers
o Urban dwellers, smog‐ridden cities
o Most common in middle aged men
o Complication: Cor pulmonale and heart failure
Morphology:
o Hypertrophy of mucus secreting glands
Resulting in Goblet cell metaplasia
Inflammation
Fibrosis and obliterative changes in bronchioles
Bronchioloitis obliterans: Obliteration of the lumen due to fibrosis
o Which may lead to atypical metaplasia/dysplasia of the respiratory epithelium
Metaplasia is the reversible replacement of one differentiated cell type with another mature differentiated cell type.
o The change from one type of cell to another is generally caused by some sort of abnormal stimulus.
o In simplistic terms, it is as if the original cells are not robust enough to withstand the new environment, and so they change
into another type more suited to the new environment.
o If the stimulus that caused metaplasia is removed or ceases, tissues return to their normal pattern of differentiation.
o Metaplasia is not synonymous with dysplasia and is not directly considered carcinogenic
Dysplasia is a term used in pathology to refer to an abnormality in maturation of cells within a tissue.
o This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of
mature cells.
o Dysplasia is often indicative of an early neoplastic process.
o The term dysplasia is typically used when the cellular abnormality is restricted to the originating tissue, as in the case of an
early, in‐situ neoplasm.
Disease of the large Such as the bronchus, that is lined with respiratory epithelium that is pseudo stratified where some nuclei are located high in the
airways cell and some nuclei are located low in the cell.
o Respiratory epithelium is called pseudo stratified because all of the cells touch the basement membrane
o The pseudo stratified cells are columnar (tall) and ciliated
Under the basement membrane is the lamina propria
o Containing large blood vessels which brings warm blood into the
region to allow the air to be warmed before the air travels to the
bottom of the lung for gas exchange
Under the lamina propria is the submucosa
o Containing two types of glands:
Serous gland which produces a watery fluid that helps to humidify
the air before the air travels down into the lung
Mucinous gland which produces a mucus like fluid which lines the
epithelial surface acting like a filter for particles that are breathed in
during inspiration
Under the submucosa is cartilage
Normally the thickness of the mucinous glands to the thickness of the
entire wall (from the mucous layer down to the cartilage) is 40%
o If a person smokes, there will be a ton of foreign particles introduced
into the lungs
Where the lungs will respond by increasing the amount of mucus
that is produced.
Resulting in hyperplasia and hypertrophy of the mucinous glands
relative to the thickness of the wall greater than 50% called Reed
Index
o The Reed Index measures the thickness of the mucinous
glands relative to the thickness of the wall
Where in Chronic Bronchitis the Reed Index is greater than
50%
Characterized by Leads to increased thickness of mucus glands relative to overall bronchial wall thickness
hypertrophy of bronchial Reid index increases to > 50%
mucinous glands o Where the normal is < 40%
Image:
o Respiratory epithelium (yellow)
o Basement membrane (red)
o Blood vessel (blue) to warm and humidify the air
o Mucinous glands (green)
Clinical features of Productive cough due to excessive mucus production:
Chronic Bronchitis o Which causes an increases PaCO2 and decreases PaO2
Presenting as Cyanosis called blue bloaters
Normal lung function, within the alveolar air sac there is a partial pressure of oxygen (PAO2) where oxygen diffuses across
into the blood vessel to create an arteriole partial pressure of oxygen (PaO2)
Mucus plugs trap carbon dioxide in the alveolar air sac which causes the partial pressure of CO2 to increase
Then due to Dalton’s Law, the alveolar partial pressure of oxygen will decrease
o Resulting in a decrease in the arteriole partial pressure of oxygen
Complications of Chronic Increased risk of infection because anywhere there is a block, there is an increased risk of infection behind the block
Bronchitis Increased risk of cor pulmonale:
o Recall that the blood vessels in the lung are designed to vasoconstrict when there is a lack of oxygen in a specific region of the
lung to shunt the blood to another region for gas exchange
o Where in a disease state, the blood vessels in different parts of the lung will vasoconstrict which causes increased pressure on
the right ventricle
Which will initially cause right ventricular hypertrophy leading to right heart failure called Cor pulmonale
Bronchogenic carcinoma
Emphysema Destruction of walls of airspaces distal to terminal bronchioles
o leading to permanent abnormal enlargement of air spaces.
Clinically characterized
o by increased AP diameter of chest
increased total vital capacity
resulting in hypoxia, cyanosis and respiratory acidosis
In most pts there is an association with heavy smoking, 10% pts are nonsmokers
Types of Emphysema Centriacinar (centrilobular)
o Affecting the Respiratory bronchioles (proximal portion of
the acinus)
In the Upper lobes
o Male smokers
o Often associated with chronic bronchitis
o Coal‐workers pneumoconiosis
Panacinar (panlobular)
o Affecting the Lower lobes (entire acinus)
o Associated with a alpha1‐antitrypsin deficiency
Affecting the whole acinus
Distal acinar (paraseptal)
o Affects the Distal acinus
Along pleura and lobular septa
Adjacent to areas of fibrosis, scarring, atelectasis (collapse)
can form multiple, contiguous, enlarged air spaces, can form cysts (bullae)
o Could lead to spontaneous pneumothorax in young adults
Irregular
o Acini irregularly involved
o Associated with scarring/ healed inflammatory lesions
produces no visible pattern
o Mostly asymptomatic (probably most common)
Other types of Compensatory:
Emphysema o Dilatation of alveoli, but not destruction of septal walls in response to loss of lung substance elsewhere.
Senile:
o emphysema consequent upon the physiologic atrophy of old age.
Obstructive hyperinflation:
o due to a tumor or a foreign object
o Ball‐valve action where air enters during inspiration but can’t exit on expiration.
o Ventilation from through collaterals may bring air from behind the obstruction
Bullous (> 1 cm in diameter)
o is composed of lesions > 1 cm in diameter, and can be associated with any type of emphysema
Interstitial ‐ not in the lung but in the soft tissue
o Entrance of air into the connective tissue stroma, mediastinum, or connective tissue stroma
Pathogenesis of Mild chronic inflammation macrophages, CD8+ T
Emphysema lymphocytes, and neutrophils
Protease ‐ antiprotease theory:
o The walls of acinus are destroyed when there is an
imbalance between proteases and anti‐proteases in the
lung.
Protease is an enzyme like elastase, which can digest
connective tissue elements.
Proteases are found throughout the body, especially in
PMNs (neutrophils and macrophages)
Where alpha1‐antitrypsin (alpha1AT) inhibits proteases
Any stimuli which
o increases the number of pmn
o causing degranulation of pmn
o increases proteolytic activity
o any stimulus inhibiting anti‐proteases
o anti‐elastase
Will increase proteolysis
Polymorphisms in TGF‐beta
o increases the risk for developing COPD
by altering susceptibility of MMP
Smoking increases the level of lung proteases while impairing the action of anti‐proteases.
Patients with panacinar emphysema may lack alpha1‐antitrypsin
Pathology of Emphysema Emphysema causes destruction of alveolar walls without fibrosis
o Which causes:
enlarged air spaces
Number of alveolar capillaries are reduced
Collapse of the bronchioles with expiration due to the loss of support from the surrounding parenchyma
Gross examination
o Hyperinflated lungs with formation of bullae looks like bubble wrap
o Centrilobular Emphysema : With marked upper lobe predominance
Destruction of alveolar walls, Note: There is no fibrosis
Alpha‐1 Antitrypsin Genetic deficiency of alpha‐1 antitrypsin
Deficiency o Alpha‐1 antitrypsin is the principle antielastase in serum and interstitial tissue Synthesized in the liver
o Alpha‐1 antitrypsin is encoded by codominant expressed genes on the Pi locus of chromosome 14
o Normal phenotype of alpha 1 antitrypsin PiMM.
Most common form in its deficiency is PiZZ
o >80% of the PIZZ individuals develop emphysema.
Chronic Bronchitis versus Chronic Bronchitis affects
Emphysema o Large airways
Trachea and bronchi
Causing mucus hypersecretion and inflammation
o Small airways
Bronchioles
Causing peribronchiolar fibrosis and airway obstruction
Emphysema affects
o Gas exchange associated with the Acinus
Respiratory bronchiole, alveolar ducts, and alveoli
Causing loss of elastic recoil
Predominant Bronchitis Predominant Emphysema
Age 40‐45 50‐75
Dyspnea Mild; late Severe; early
Cough Early; copious sputum Late’ scantly sputum
Infection Common Occasional
Respiratory insufficiency Repeated Terminal
Cor Pulmonale Common Rare; terminal
Airway resistance Increased Normal or slightly increased
Elastic recoil Normal Low
Chest radiograph Prominent vessels; large heart Hyperinflation; small heart
Appearance Blue bloater Pink Puffer
Bronchitis Blue bloaters: mild cyanosis, hypercapnia, hypoxia
Emphysema Pink Puffers: over ventilate, well oxygenated
Bronchiectasis Permanent dilatation of bronchi and bronchioles
o caused by destruction of the muscle and elastic tissue
caused by chronic necrotizing inflammation.
Symptoms: Cough
Fever
Copious amounts of foul‐smelling purulent sputum
Dyspnea
Etiology and predisposing Obstruction (tumor, foreign bodies)
conditions: Infection (TB, Aspergillus)
Congenital/Hereditary
o Cystic fibrosis
o Kartagener’s syndrome
o Immunodeficiency states
Other (Rheumatoid arthritis, lupus, Graft versus Host Disease)
Pathogenesis Obstruction
o Causes impaired clearing mechanisms due to pooling of secretions distal to obstruction
Resulting in inflammation of the airways with necrosis, fibrosis, and eventual dilation
Gross examination, bronchiectasis shows dilated bronchi and bronchioles extending out to the pleura
o These changes can also be seen on chest x‐ray
Complications of Respiratory insufficiency
Bronchiectasis Cor pulmonale
Brain abscesses
Amyloidosis due to AL
o Where AA amylodoisis is due to infection
Cystic Fibrosis Severe bronchiectasis
Primary defect in Chloride transport causing accumulation of viscous secretions obstructing the airways
Mutation occurs in the CFTR gene, found at the q31.2 locus of chromosome 7,
Increased susceptibility to repeated infections, and wide spread damage to the airway walls
CFTR Gene
o Cystic fibrosis transmembrane conductance regulator
o Protein Function: CFTR protein product is a chloride channel protein found in membranes of cells that line
passageways of the lungs, liver, pancreas, intestines, reproductive tract, and skin. CFTR is also involved in
the regulation of other transport pathways.
o Associated Disorders: Defective versions of this protein, caused by CFTR gene mutations, can lead to CF and
congenital bilateral aplasia of the vas deferens.
o About 70% of mutations observed in CF patients result from deletion of three base pairs in CFTR's nucleotide sequence (delta
F508).
Kartagener Syndrome Autosomal‐recessive with variable penetrance
Caused by immotile cilia due to a defect of dynein arms primary
ciliary dyskinesia
Associated with
o Sinusitis
o Bronchiectasis
o Situs inversus – a congenital condition where the major visceral
organs are anatomically reversed compared with their normal
anatomical positions
o Infertility
Summary of COPD Emphysema Destruction and dilatation of acini
Centriacinar: smoking
Panacinar: alpha 1 antitypsin deficiency
“Pink Puffers”
Chronic Bronchitis Cough
Hypersecretion of mucus
Smoking, pollutants
Large and Small airway disease
“Blue bloaters”
Bronchiectasis Damage to and dilatation of bronchial wall
Permanent
Infections, purulent mucus
Bronchial Asthma Episodes of bronchospasm
Atopic or allergic
Nonatopic (viruses and pollutants)
Eosinophils, mucus plugs (Charcot‐Leyden crystals and Curschmann’s spirals)
Clinical Term Anatomic Major Pathologic Changes Etiology Signs/Symptoms
Site
Chronic bronchitis Bronchus Mucous gland hyperplasia, Tobacco smoke, air Cough, sputum
hypertension pollutants production
Bronchiectasis Bronchus Airway dilation and scaring Persistent or severe Cough, purulent
infections sputum, fever
Emphysema Acinus Airspace enlargement, wall Tobacco smoke Dyspnea
destruction
Small‐Airway Bronchiole Inflammatory Tobacco smoke, air Cough, dyspnea
Disease, Bronchiolitis scarring/obliteration pollutants,
miscellaneous
Restrictive Lung Diseases
Basic Principles Restricted lung expansion causes decrease in lung volumes
o Decrease in TLC
o Decrease FEV1
o Major decrease in FVC
o Increase in the FEV1/FVC ratio
Underlying pathogenic factor is injury to the alveoli with activation of macrophages and the release of fibrogenic cytokines (TGF‐
beta)
Two broad categories:
o Interstitial lung disease
Pulmonary decreased diffusing capacity, increased A‐a gradient
o Chest wall disease
Extrapulmonary, peripheral hypoventilation, normal A‐a gradient
Organization of Interstitial Group of disorders that result in inflammation and fibrosis of alveolar walls (septa) with similar clinical,
Lung Disease radiographic, and physiologic features
o Symptoms:
Dyspnea
o Physical exam:
Tachypnea, fine “dry” crackles, NO wheezing
o Physiology:
Reduced oxygen diffusing capacity, decreased lung volume and compliance
Secondary pulmonary hypertension can result in right sided heart failure (cor pulmonale)
o Chest Radiography:
Diffuse infiltration by small nodules, irregular lines, or ground glass shadows
o End stage disease results in “honeycomb lung”
repeated cycles of lung injury and wound healing with increase collagen deposition, “honeycomb” lung appearance and
digital clubbing
Major categories
Fibrosing Diseases: Idiopathic Pulmonary Fibrosis
Pneumoconioses Coal Worker’s Pneumoconiosis
Silicosis
Berylliosis
Asbestosis
Drug‐ and Radiation‐Induced Pulmonary Diseases
Granulomatous Diseases: Sarcoidosis
Hypersensitivity Pneumonitis
Pulmonary Eosinophilia: Loeffler Syndrome
Smoking‐Related Interstitial Diseases: Desquamative Interstitial Pneumonia
Respiratory Bronchiolitis
Fibrosing Diseases
Idiopathic Pulmonary Also known as “usual interstitial pneumonia (UIP)” or “cryptogenic fibrosing alveolitis”
Fibrosis (IPF)
Pathogenesis The current concept is that IPF is caused by “repeated cycles” of epithelial
activation/injury by some unidentified agent.
Histopathologic features include:
o inflammation and induction of TH2 type T cell response with eosinophils,
mast cells, IL‐4, and IL‐13 in the lesions
o Abnormal epithelial repair at the sites of damage and inflammation gives
rise to exuberant fibroblastic or myofibroblastic proliferation
leading to the characteristic fibroblastic foci.
TGF‐beta1 is released from injured type I pneumocytes
o Which induces transformation of fibroblasts into myofibroblasts
leading to excessive and continuing deposition of collagen and ECM.
Familial IPF have mutations that shorten telomeres
o leading to rapid senescence and apoptosis of pneumocytes.
TGF‐beta1 inhibits caveolin‐1 in fibroblast
o which inhibits the deposition of collagen and ECM
inhibiting pulmonary fibrosis
Morphology Grossly, the pleural surfaces of the lung have the appearance of cobblestones
o because of the retraction of scars along the interlobular septa.
The cut surface shows fibrosis (firm, rubbery white areas), with lower lobe predominance
and a distinctive distribution in the subpleural regions and along the interlobular septa.
The pattern of fibrosis in IPF is referred to as Usual Interstitial Pneumonia (UIP).
o The histologic hallmark of UIP is patchy interstitial fibrosis
which varies in intensity (is more pronounced in the subpleural region) and worsens
with time.
The earliest lesions demonstrate exuberant fibroblastic proliferation and appear as fibroblastic focus which is running parallel to
the surface and bluish myxoid extracellular matrix
o
o Over time these areas become more collagenous and less cellular.
Quite typical is the existence of both early and late lesions called temporal heterogeneity
o The dense fibrosis causes
collapse of alveolar walls
formation of cystic spaces which are lined by either hyperplastic type II pneumocytes or bronchiolar epithelium called
honeycomb fibrosis
The interstitial inflammation usually is patchy
o Consisting of alveolar septal infiltrate of mostly lymphocytes and occasional plasma cells, mast cells, and eosinophils.
Secondary pulmonary hypertensive changes
o Associated with intimal fibrosis and medial thickening of pulmonary arteries are also often present.
Trichrome stain: stains areas of fibrosis blue to highlight collagen
o
Clinicopathologic Affects individuals 40‐70 years of age
Correlation o Affects Men more than women
Symptoms:
o Dyspnea on exertion
o Dry cough (nonproductive)
o Velcro crackles during inspiration
Later stages of the disease may develop
o Cyanosis, cor pulmonale, and peripheral edema
The clinical and radiologic findings often are diagnostic
o surgical lung biopsy is needed for diagnosis in selected cases
Progressive deterioration of IPF is associated with a mean survival is 3 years or less
o Where lung transplantation is the only definitive therapy available.
Pneumoconioses Describes the accumulation of inhaled mineral dust in the lungs and the tissue reaction to its presence
o Which includes diseases induced by
particulates, chemical fume, vapor‐induced non‐neoplastic lung diseases
The following pathologic conditions associated with each mineral dust and the major industries in which the dust exposure is
sufficient to produce disease
Agent Disease Exposure
Coal dust Simple Coal Worker’s Pneumoconiosis: Coal mining
associated with macules and nodules
Complicated Coal Worker’s
Pneumoconiosis: associated with
Progressive Massive Fibrosis (PMF)
Silica Silicosis Sandblasting, quarrying, mining, stone
cutting, foundry work, ceramics
Asbestos Asbestosis, pleural effusions, pleural Ship building, roofing, plumbing,
plaques, or diffuse fibrosis Installation and removal of insulation
Mesothelioma
Carcinoma of the lung and larynx
Beryllium Berylliosis Mining, fabrication
Iron Oxide Siderosis Welding
Barium sulfate Baritosis Mining
Tin oxide Stannosis Mining
Pathogenesis The reaction of the lung to mineral dusts depends on many variables, including:
o size, shape, solubility, and reactivity of the particles
Particles greater than 5 to 10 μm are unlikely to reach distal airways
Particles smaller than 0.5 μm move into and out of alveoli, often without substantial deposition and injury.
Particles that are 1 to 5 μm in diameter are the most dangerous
because they get lodged at the bifurcation of the distal airways
Coal dust:
o is relatively inert, and large amounts must be deposited in the lungs before lung disease is clinically detectable.
Silica, asbestos, and beryllium are more reactive than coal dust
o resulting in fibrotic reactions at lower concentrations.
Most inhaled dust is entrapped in the mucus blanket and rapidly removed from the lung by ciliary movement.
o However, some of the particles become impacted at alveolar duct bifurcations
where macrophages accumulate and engulf the trapped particulates
The pulmonary alveolar macrophage is a key in the initiation and perpetuation of lung injury and fibrosis.
o Many particles activate the inflammasome and induce IL‐1 production
o The more reactive particles trigger the macrophages to release cytokines that mediate an inflammatory response and initiate
fibroblast proliferation and collagen deposition.
o Some of the inhaled particles may reach the lymphatics
by direct drainage
within migrating macrophages
o thereby initiate an immune response to components of the particulates and/or to self‐proteins that are modified by the
particles.
o This then leads to an amplification and extension of the local reaction
Tobacco smoking worsens the effects of all inhaled mineral dusts, more so with asbestos than with any other particle.
Coal Worker’s Worldwide dust reduction in coal mines has greatly reduced the incidence of coal dust–induced disease. The spectrum of lung
Pneumoconiosis (CWP) findings in coal workers ranges from:
o Asymptomatic anthracosis pigment accumulates without a perceptible cellular reaction
o Simple coal worker’s pneumoconiosis (CWP) accumulations of macrophages occur with little to no pulmonary dysfunction
less than 10% of cases of simple CWP progress to PMF
o Complicated CWP or progressive massive fibrosis (PMF) fibrosis is extensive and lung function is compromised
PMF is a generic term that applies to a confluent fibrosing reaction in the lung
Although coal is mainly carbon
o coal mine dust contains a variety of trace metals, inorganic minerals, and crystalline silica
o The ratio of carbon to contaminating chemicals and minerals (“coal rank”) increases from bituminous to anthracite coal
o in general, anthracite mining has been associated with a higher risk of CWP.
Morphology Pulmonary anthracosis is the most innocuous coal induced pulmonary lesion in coal miners
commonly seen in
o all urban dwellers and tobacco smokers
Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages
o which then accumulate in the connective tissue along the lymphatics, including the
pleural lymphatics, or in lymph nodes
Simple Coal Worker’s Characterized by:
Pneumoconiosis o coal macules and the somewhat larger coal nodule
Coal macule consists of dust‐laden macrophages
Coal nodule contains small amounts of collagen fibers arrayed in a delicate network.
The upper lobes and upper zones of the lower lobes are more heavily involved
o Where centrilobular emphysema can occur
o emphysema is more common in the United Kingdom and Europe, probably because the
coal rank is higher than in the United States.
Complicated Coal Worker’s occurs on a background of simple CWP
Pneumoconiosis (Progressive o by coalescence of coal nodules
Massive Fibrosis) o generally requires many years to develop
Characterized by:
o multiple, intensely blackened scars larger than 2 cm
o On microscopic examination the lesions are seen to consist of dense
collagen and pigment
Clinical Features Usually a benign disease that produces little decrement in lung function
If PMF develops
o there is increasing:
pulmonary dysfunction
pulmonary hypertension
cor pulmonale
o Progression from CWP to PMF has been linked to a variety of conditions including
coal dust exposure level
total dust burden
But can progress even in the absence of further exposure
Once smoking‐related risk has been taken into account
o there is no increased frequency of lung carcinoma in coal miners, a feature that distinguishes CWP from both silica and
asbestos exposures
Silicosis The most prevalent chronic occupational disease in the world
Caused by inhalation of crystalline silica, mostly in occupational settings
o Workers involved in sandblasting and hard‐rock mining are at particular risk
Silica occurs in both crystalline and amorphous forms
o but crystalline forms (including quartz, cristobalite, and tridymite) are the most toxic and fibrogenic
where quartz is most commonly implicated in silicosis
After inhalation:
o the particles cause activation and release of mediators by pulmonary macrophages, including:
IL‐1, TNF, fibronectin, lipid mediators, oxygen‐derived free radicals, and fibrogenic cytokines
Morphology Silicotic nodules
o characterized grossly in their early stages by:
tiny, barely palpable, discrete, pale‐to‐blackened (if coal dust is also present) nodules in the upper zones of
the lungs
Microscopically:
o Concentrically arranged hyalinized collagen fibers surrounding an amorphous center
This “whorled” appearance of the collagen fibers is quite distinctive for silicosis
o Polarized light shows
weakly birefringent silica particles, primarily in the center of the nodules
As the disease progresses
o nodules may coalesce into hard, collagenous scars, with eventual progression to PMF
where the intervening lung parenchyma may be compressed or over expanded, and a
honeycomb pattern may develop.
o Fibrotic lesions may also occur in the hilar lymph nodes and pleura.
o Thin sheets of calcification may occur in the lymph nodes seen by x‐ray as “eggshell”
calcification (e.g., calcium surrounding a zone lacking calcification).
Clinical Features Detected on routine chest radiographs obtained in asymptomatic workers
o And show a fine nodularity in the upper zones of the lung
o but pulmonary function is either normal or moderately affected
Most patients do not develop shortness of breath until late in the course, after PMF is present
Many patients with PMF develop pulmonary hypertension and cor pulmonale
o as a result of chronic hypoxia‐induced vasoconstriction and parenchymal destruction
The disease is slow to kill
o but impaired pulmonary function may severely limit activity
Associated with an increased susceptibility to tuberculosis
o Where silicosis results in a depression of cell mediated immunity, and crystalline silica may inhibit the ability of pulmonary
macrophages to kill phagocytosed mycobacteria
o Nodules of silicotuberculosis often contain a central zone of caseation
Asbestosis Asbestos is a family of crystalline hydrated silicates with a fibrous geometry.
On the basis of epidemiologic studies, occupational exposure to asbestos is linked to
o parenchymal interstitial fibrosis (asbestosis)
o localized fibrous plaques or, rarely, diffuse fibrosis in the pleura
o pleural effusions
o lung carcinomas
o malignant pleural and peritoneal mesotheliomas
o laryngeal carcinoma
There is an increased incidence of asbestos‐related cancers in family members of asbestos workers
Pathogenesis Concentration, size, shape, and solubility of the different forms of asbestos determine whether inhalation of the material will
cause disease.
There are two distinct forms of asbestos:
o Serpentine the fiber is curly and flexible
Where serpentine chrysotile accounts for most of the asbestos used in industry
o Amphibole the fiber is straight, stiff, and brittle
Amphiboles are less prevalent but more pathogenic than the serpentine chrysotile
o Both types can produce:
Asbestosis
lung cancer
mesothelioma
The greater pathogenicity of straight and stiff amphiboles is related to their structure
o Whereas the serpentine chrysotiles, are likely to become impacted in the upper respiratory passages and be removed by the
mucociliary elevator.
Serpentine chrysotiles that are trapped in the lungs are gradually leached from the tissues
because they are more soluble than amphiboles.
Amphiboles align themselves in the airstream and are delivered deeper into the lungs
where they may penetrate epithelial cells to reach the interstitium
o Despite these differences, both asbestos forms are
Fibrogenic and increasing exposure to either is associated with a higher incidence of all asbestos‐related diseases.
Complications of Asbestosis
o Causes fibrosis through a process between particulates and lung macrophages
o Functions as a tumor initiator and a promoter
oncogenic effects of asbestos on the mesothelium are mediated by the free radicals that are generated by asbestos fibers
which preferentially localize in the distal lung close to the mesothelial layer
o Chemicals that are adsorbed onto the asbestos fibers also contribute to the pathogenicity of the fibers
For example, the adsorption of carcinogens in tobacco smoke onto asbestos fibers provide evidence between tobacco
smoking and the development of lung carcinoma in asbestos workers
Morphology Asbestosis is marked by diffuse pulmonary interstitial fibrosis
o These changes are indistinguishable from UIP
except for the presence of asbestos bodies seen as golden brown, fusiform or beaded rods
with a translucent center.
Asbestos bodies are formed when macrophages attempt to phagocytose asbestos fibers
o Where the iron comes from phagocyte ferritin
o Asbestos bodies can be found in normal lungs 1. High‐power detail of an asbestos body, revealing
the typical beading and knobbed ends (arrow).
but in much lower concentrations
without an accompanying interstitial fibrosis
In contrast with CWP and silicosis
o Asbestosis begins in the lower lobes and subpleurally
but the middle and upper lobes of the lungs become affected as fibrosis progresses
o Contraction of the fibrous tissue distorts the normal architecture
creating enlarged air spaces enclosed within thick fibrous walls affected regions become
honeycombed
o Simultaneously, fibrosis develops in the visceral pleura
causing adhesions between the lungs and the chest wall
this scarring may trap and narrow pulmonary arteries and arterioles
o causing pulmonary hypertension and cor pulmonale
Pleural plaques are the most common manifestation of asbestos exposure and are well‐circumscribed
plaques of dense collagen often containing calcium 2. Asbestosis. Markedly thickened visceral
pleura covers the lateral and diaphragmatic
o They develop most frequently on the anterior and posterolateral aspects of the parietal pleura and surface of lung. Note also severe interstitial
fibrosis diffusely affecting the lower lobe of
over the domes of the diaphragm. the lung.
o They do not contain asbestos bodies
o Only rarely occur in persons with no history or evidence of asbestos exposure
Uncommonly does asbestos exposure induce pleural effusion or diffuse pleural fibrosis.
Clinical Features The clinical findings in asbestosis are indistinguishable from those of any other chronic interstitial lung disease.
o Progressively worsening dyspnea 10 to 20 years after exposure
o Accompanied by a cough associated with production of sputum
o May progress to congestive heart failure, cor pulmonale, and death
Pleural plaques are usually asymptomatic and are detected on radiographs as circumscribed densities
Both lung carcinoma and malignant mesothelioma develop in workers exposed to asbestos.
The risk of lung carcinoma increases five‐fold for asbestos workers
o the relative risk for mesothelioma, normally a very rare tumor (2 to 17 cases per 1 million persons), is more than 1000 times
greater.
o Concomitant cigarette smoking greatly increases the risk of lung carcinoma but not that of mesothelioma.
o Lung or pleural cancer associated with asbestos exposure carries a particularly grim prognosis.
Drug‐ and Radiation‐ Drugs can cause a variety of both acute and chronic alterations in respiratory structure and function
Induced Pulmonary o Bleomycin, an anticancer agent, causes pneumonitis and interstitial fibrosis, as a result of direct toxicity of the drug and by
Diseases stimulating the influx of inflammatory cells into the alveoli
o Amiodarone, an antiarrhythmic agent, also is associated with risk for pneumonitis and fibrosis.
Radiation pneumonitis is a well‐known complication of therapeutic irradiation of pulmonary and other thoracic tumors
o Acute radiation pneumonitis, occurs 1 to 6 months after therapy in as many as 20% of the patients
manifested by fever, dyspnea out of proportion to the volume of irradiated lung, pleural effusion, and development of
pulmonary infiltrates within the area of radiation.
These signs and symptoms may resolve with corticosteroid therapy or progress to chronic radiation pneumonitis,
associated with pulmonary fibrosis.
Granulomatous Disease
Sarcoidosis Sarcoidosis is considered an example of a restrictive lung disease, but also a multisystem disease of unknown etiology
Characterized by
o Noncaseating granulomas in many tissues and organs
Other diseases, mycobacterial or fungal infections and berylliosis, also produce noncaseating granulomas
o therefore, the histologic diagnosis of sarcoidosis is one of exclusion.
o Bilateral hilar lymphadenopathy visible on chest radiographs is the major presenting manifestation in most cases.
o Eye and skin involvement each occurs in about 25% of cases, and either may occasionally be the presenting feature of the
disease.
Epidemiology Sarcoidosis occurs throughout the world
o affecting both genders and all races and age groups
Interesting epidemiologic trends includes:
o Affects adults <40 years of age.
o High incidence in Danish and Swedish populations, and in the United States among African Americans
o Has a higher prevalence among nonsmokers.
Etiology Although the etiology of sarcoidosis remains unknown, several lines of evidence suggest that it is a disease of disordered
immune regulation in genetically predisposed persons exposed to certain environmental agents.
Pathogenesis Several immunologic abnormalities in sarcoidosis suggest the development of a cell‐mediated response to an unidentified
antigen.
o Where the process is driven by CD4+ helper T cells.
Abnormalities include:
o Intra‐alveolar and interstitial accumulation of CD4+ TH1 cells
o Oligoclonal expansion of T cell subsets as determined by analysis of T cell receptor rearrangement
o Increases in T cell–derived TH1 cytokines such as IL‐2 and IFN‐gamma
resulting in T cell expansion and macrophage activation, respectively
o Increases in several cytokines in the local environment (IL‐8, TNF, macrophage inflammatory protein‐1‐alpha)
Which favors recruitment of T cells and monocytes and contributes to the formation of granulomas
o Anergy to common skin test antigens such as Candida or purified protein derivative (PPD)
Resulting from pulmonary recruitment of CD4+ T cells and consequent peripheral depletion
o Polyclonal hypergammaglobulinemia, another manifestation of TH cell dysregulation
o The role of genetic factors is suggested by familial and racial clustering of cases and association with certain human leukocyte
antigen (HLA) genotypes (e.g., class I HLA‐A1 and HLA‐B8).
o After lung transplantation, sarcoidosis recurs in the new lungs in 75% of patients
o Several putative “antigens” have been proposed as the inciting agent for sarcoidosis (e.g., viruses, mycobacteria, Borrelia,
pollen)
but no evidence suggests that sarcoidosis is caused by an infectious agent.
Morphology The diagnostic histopathologic feature of sarcoidosis is the noncaseating epithelioid granuloma,
irrespective of the organ involved.
Characterized by:
o Peribronchial noncaseating granulomas with many giant cells.
Which is a discrete, compact collection of epithelioid cells rimmed by an outer zone of largely
CD4+ T cells
The epithelioid cells are derived from macrophages and are characterized by abundant
eosinophilic cytoplasm and vesicular nuclei. 3. Sarcoid. Characteristic peribronchial noncaseating
granulomas with many giant cells
o A thin layer of laminated fibroblasts are present peripheral to the granuloma
Where over time, these proliferate and lay down collagen that replaces the entire granuloma with a hyalinized scar.
o Two other microscopic features are sometimes seen in the granulomas:
Schaumann bodies:
laminated concretions composed of calcium and proteins
Asteroid bodies
stellate inclusions enclosed within giant cells.
o Rarely, foci of central necrosis may be present in sarcoid granulomas, suggesting an infectious process.
Where caseation necrosis typical of tuberculosis is absent.
The granulomas predominantly involve the interstitium rather than air spaces
o To localize in the connective tissue around bronchioles, pulmonary venules, and in the pleura (“lymphangitic” distribution).
Where the bronchoalveolar lavage fluid contains abundant CD4+ T cells
In 5% to 15% of patients, the granulomas are replaced by diffuse interstitial fibrosis honeycomb lung.
Intrathoracic hilar and paratracheal lymph nodes are enlarged
in 75% to 90% of patients
o Where a third present with peripheral lymphadenopathy.
The nodes are characteristically painless and have a firm,
rubbery texture.
o Unlike in tuberculosis, lymph nodes in sarcoidosis are
non‐matted (non‐adherent)
do not ulcerate
Skin lesions are encountered in approximately 25% of patients.
o Erythema nodosum, the hallmark of acute sarcoidosis
consists of raised, red, tender nodules on the anterior
aspects of the legs
Sarcoidal granulomas are uncommon in these lesions
o Discrete painless subcutaneous nodules usually reveal
abundant noncaseating granulomas.
Eye and lacrimal gland lesions occurs in about one fifth to one half of patients
o Iritis or iridocyclitis
Can be unilateral or bilateral
Resulting in corneal opacities, glaucoma, and (less commonly) total loss of vision.
o The posterior uveal tract also is affected
Resulting in choroiditis, retinitis, and optic nerve involvement
o Ocular lesions are frequently accompanied by inflammation in the lacrimal glands
Resulting in suppression of lacrimation (sicca syndrome)
Sicca Syndrome also known as Sjogren syndrome characterized by dry eyes and dry mouth
Unilateral or bilateral parotitis with painful enlargement of the parotid glands occurs in less than 10% of patients with
sarcoidosis
some go on to develop xerostomia (dry mouth). Combined uveoparotid involvement is designated Mikulicz syndrome.
The spleen may appear unaffected grossly
o but in about three fourths of cases, it contains granulomas
o In approximately 10%, it becomes clinically enlarged.
The liver demonstrates microscopic granulomatous lesions
o usually in the portal triads
o only one third of the patients demonstrate hepatomegaly or abnormal liver function.
Sarcoid involvement of bone marrow is reported in as many as 40% of patients, although it rarely causes severe manifestations.
Other findings may include
o Hypercalcemia and Hypercalciuria
o These changes are not related to bone destruction
caused by increased calcium absorption secondary to production of active vitamin D by the mononuclear phagocytes in the
granulomas.
Clinical Features Often presents asymptomatic
o Only discovered on routine chest films as bilateral hilar adenopathy or as an incidental finding at autopsy
Associations include:
o Peripheral lymphadenopathy, cutaneous lesions, eye involvement, splenomegaly, or hepatomegaly
o Respiratory symptoms (shortness of breath, dry cough, or vague substernal discomfort)
o constitutional signs and symptoms (fever, fatigue, weight loss, anorexia, night sweats).
Lung and Lymph node biopsy shows the presence of noncaseating granulomas
Sarcoidosis follows an unpredictable course characterized by either progressive chronicity or periods of activity interspersed
with remissions.
o The remissions may be spontaneous or initiated by steroid therapy and often are permanent.
o Overall, 65% to 70% of affected persons recover with minimal or no residual manifestations.
o Another 20% develop permanent lung dysfunction or visual impairment.
o Of the remaining 10% to 15%, most succumb to progressive pulmonary fibrosis and cor pulmonale.
Hypersensitivity Hypersensitivity pneumonitis is an immunologically mediated inflammatory lung disease that primarily affects the alveoli and is
Pneumonitis therefore often called allergic alveolitis. Most often it is an occupational disease that results from heightened sensitivity to
inhaled antigens such as in moldy hay.
Syndrome Exposure Antigens
Fungal and Bacterial Antigens
Farmer’s lung Moldy hay Micropolyspora faeni
Bagassosis Moldy pressed sugar cane (bagasse) Thermophilic actinomycetes
Maple bark disease Moldy maple bark Cryptostroma corticale
Humidifier lung Cool‐mist humidifier Thermophilic actinomycetes, Aureobasidium pullulans
Malt worker’s lung Moldy barley Aspergillus clavatus
Cheese washer’s lung Moldy cheese Penicillium casei
Insect Products
Miller’s lung Dust‐contaminated grain Sitophilus granarius (wheat weevil)
Animal Products
Pigeon breeder’s lung Pigeon droppings Pigeon serum proteins in droppings
Chemicals
Chemical worker’s lung Chemical industry Trimellitic anhydride, isocyanates
The damage in hypersensitivity pneumonitis occurs at the level of alveoli.
o Manifests as a predominantly restrictive lung disease with
decreased diffusion capacity, lung compliance, and total lung volume.
Evidence suggest that hypersensitivity pneumonitis is an immunologically mediated disease:
o Bronchoalveolar lavage specimens consistently demonstrate increased numbers of T lymphocytes of both CD4+ and CD8+
phenotype.
o Most patients with hypersensitivity pneumonitis have specific precipitating antibodies in their serum, and complement and
immunoglobulins have been demonstrated within the vessel walls by immunofluorescence, indicating type III hypersensitivity.
o The presence of noncaseating granulomas in two thirds of patients with this disorder suggests a role for type IV
hypersensitivity as well.
In summary, hypersensitivity pneumonitis is an immunologically mediated response to an extrinsic antigen that involves both
immune complex and delayed‐type hypersensitivity reactions.
Morphology The histopathologic picture in both acute and chronic forms of hypersensitivity pneumonitis
includes
o patchy mononuclear cell infiltrates in the pulmonary interstitium, with a characteristic
peribronchiolar accentuation.
Lymphocytes predominate
but plasma cells and epithelioid cells also are present.
In acute forms of the disease
o variable numbers of neutrophils may also be seen 4. Hypersensitivity pneumonitis, histologic appearance. Loosely
formed interstitial granulomas and chronic inflammation are
o Interstitial noncaseating granulomas are present in more than two thirds of cases, usually in characteristic.
a peribronchiolar location.
In advanced chronic cases
o diffuse interstitial fibrosis occurs.
Clinical Features Hypersensitivity pneumonitis may manifest either as an
o Acute reaction
fever, cough, dyspnea, and constitutional signs and symptoms
arising 4 to 8 hours after exposure
o Chronic disease characterized by
insidious onset of cough, dyspnea, malaise, and weight loss
Removal of the antigenic exposure after acute attacks of the disease
o complete resolution of pulmonary symptoms occurs within days
But failure to remove the inciting agent from the environment
o results in an irreversible chronic interstitial pulmonary disease.
Pulmonary Eosinophilia
Characterized by
o an infiltration and activation of eosinophils
o latter by elevated levels of alveolar IL‐5.
These diverse diseases generally are of immunologic origin, but the etiology is not understood.
Pulmonary eosinophilia is divided into the following five categories:
Acute eosinophilic Characterized by
pneumonia with respiratory o rapid onset of fever, dyspnea, hypoxia, and diffuse pulmonary infiltrates on chest radiographs.
failure The bronchoalveolar lavage fluid typically contains more than 25% eosinophils.
There is prompt response to corticosteroids.
Simple pulmonary characterized by
eosinophilia (Loeffler o transient pulmonary lesions, eosinophilia in the blood, and a benign clinical course.
syndrome) o The alveolar septa are thickened by an infiltrate containing eosinophils and occasional giant cells.
Tropical eosinophilia caused by infection with microfilariae and helminthic parasites
Secondary eosinophilia associated with asthma, drug allergies, and certain forms of vasculitis
Idiopathic chronic characterized by
eosinophilic pneumonia o aggregates of lymphocytes and eosinophils within the septal walls and the alveolar spaces
typically in the periphery of the lung fields
o High fever, night sweats, and dyspnea
This is a disease of exclusion, once other causes of pulmonary eosinophilia have been ruled out.
Smoking‐Related Interstitial Diseases
Smoking also is associated with restrictive or interstitial lung diseases.
Desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis are the two related examples of smoking‐associated
interstitial lung disease.
Desquamative interstitial The most striking histologic feature of DIP is the accumulation of large numbers of macrophages with
pneumonia abundant cytoplasm containing dusty‐brown pigment (smoker’s macrophages) in the air spaces.
(DIP) The alveolar septa are thickened by a sparse inflammatory infiltrate (usually lymphocytes)
interstitial fibrosis is mild.
Pulmonary functions usually show a mild restrictive abnormality, and patients with DIP typically have a good prognosis with
excellent response to steroid therapy and smoking cessation.
Respiratory Bronchiolitis Respiratory bronchiolitis is a common histologic lesion found in smokers
characterized by the presence of pigmented intraluminal macrophages akin to those in DIP, but in a “bronchiolocentric”
distribution (first‐ and second‐order respiratory bronchioles).
Mild peribronchiolar fibrosis also is seen. As with DIP, affected patients present with gradual onset of dyspnea and dry cough,
and the symptoms recede with cessation of smoking.
Lung Tumors
Estimated New Cancer Men
Cases in the US (2014) o Lung – most common
o Prostate
o Colon and rectum
Women
o Lung – most common
o Breast
o Colon and rectum
Estimated Cancer Deaths in Men
the US (2014) o Prostate – most common
o Lung
o Colon and rectum
Women
o Breast – most common
o Lung
o Colon and rectum
Overview Although lungs frequently are the site of metastases from cancers arising in extrathoracic organs
o primary lung cancer is also a common disease
95% of primary lung tumors are carcinomas
5% constitute a miscellaneous group that includes
Carcinoids
mesenchymal malignancies (e.g., fibrosarcomas, leiomyomas)
lymphomas
benign lesions
o The most common benign tumor is a spherical, small (3 to 4 cm), discrete “hamartoma”
Also called coin lesion on chest radiographs
Consists mainly of mature cartilage, mixed with fat, fibrous tissue, and blood vessels in various proportions.
If Clonal cytogenic abnormalities are found indicating that it is a benign neoplasm; the neoplasm is still called a
hamartoma.
Carcinomas
The incidence among males is gradually decreasing, but it continues to increase among females, with more women dying each
year from lung cancer than from breast cancers, since 1987.
o These statistics undoubtedly reflect the causal relationship of cigarette smoking and lung cancer.
The peak incidence of lung cancer is in persons in their 50s and 60s.
At diagnosis:
o >50% of patients already have distant metastatic disease, while a fourth have disease in the regional lymph nodes.
The prognosis with lung cancer is dismal:
o The 5‐year survival rate for all stages of lung cancer combined is about 16%, a figure that has not changed much over the last
30 years; even with disease localized to the lung, a 5‐year survival rate of only 45% is typical.
The four major histologic types of carcinomas of the lung are:
o Adenocarcinoma
o Squamous cell carcinoma
o Small cell carcinoma
o Large cell carcinoma.
Non‐Small Cell Lung Carcinoma (NSCLC): Acinar, papillary, micropapillary, solid, lepidic predominant,
Adenocarcinoma mucinous subtypes
Non‐Small Cell Lung Carcinoma (NSCLC): Squamous cell carcinoma
Large Cell Carcinoma Large Cell Neuroendocrine Carcinoma
Small Cell Carcinoma Combined Small Cell Carcinoma
Adeno‐squamous Carcinoma
Carcinomas with pleomorphic, sarcomatoid, or Spindle cell carcinoma
sarcomatous elements Giant cell carcinoma
Carcinoid tumor Typical
Atypical
Carcinomas of salivary gland type
Unclassified carcinoma
In some cases there is a combination of histologic patterns (e.g., small cell carcinoma and adenocarcinoma)
o Where squamous cell and small cell carcinomas show the strongest association with smoking
Due to changes in smoking patterns in the U.S.
Where adenocarcinoma has replaced squamous cell carcinoma as the most common primary lung tumor in recent years.
Adenocarcinomas also are by far the most common primary tumors arising in
o Women
o Never‐smokers
o Persons younger than 45 years.
Carcinomas of the lung were classified into two broad groups:
o Small cell lung cancer (SCLC) 15%
Virtually all SCLCs have metastasized by the time of diagnosis and hence are not curable by surgery.
Best treated by chemotherapy, with or without radiation therapy
o Non–small cell lung cancer (NSCLC) 85%
which includes:
adenocarcinoma (40%); squamous cell carcinoma (30%); large cell carcinoma (10%); carcinoid tumor (5)
NSCLCs are more likely to be resectable and usually responded poorly to chemotherapy
But there are new therapies that target specific mutated gene products present in the various subtypes of NSCLC
o mainly in adenocarcinomas
Etiology and Pathogenesis Smoking‐related carcinomas of the lung arise by a stepwise accumulation of a multitude of genetic abnormalities (estimated to
be in the thousands for small cell carcinoma) that result in transformation of benign progenitor cells in the lung into neoplastic
cells.
The sequence of molecular changes is not random but follows a predictable sequence that parallels the histologic progression
toward cancer
o Early events include
Inactivation of tumor suppressor genes located on the short arm of chromosome 3 (3p)
o Late events include
TP53 mutations
activation of the KRAS oncogene
o More important, loss of chromosomal material on 3p, can be found in
benign bronchial epithelium of persons with lung cancer
respiratory epithelium of smokers without lung cancer
o suggesting that large areas of the respiratory mucosa are mutagenized after exposure to carcinogens (“field effect”).
A subset of adenocarcinomas:
o Associated with:
Non‐smoking
Women
Asian (Far East origin)
o Contain activating mutations of the epidermal growth factor receptor (EGFR)
where tumors are sensitive to a class of agents that inhibit EGFR signaling but the response often is short‐lived
o EGFR and K‐RAS mutations (occur in 30% of adenocarcinomas) are mutually exclusive
o Other mutations occurring in 4% to 6% of adenocarcinomas are:
EML4‐ALK tyrosine kinase fusion genes
c‐MET tyrosine kinase gene amplifications
o Where abnormalities can be targeted with tyrosine kinase inhibitors
With regard to carcinogenic influences, there is strong evidence that cigarette smoking and, to a much lesser extent, other
environmental insults are the main culprits responsible for the genetic changes that give rise to lung cancers.
About 90% of lung cancers occur in active smokers or those who stopped recently
o A direct correlation between the frequency of lung cancer and pack‐years of cigarette smoking.
With a 60 times greater risk among habitual heavy smokers (two packs a day for 20 years) than among nonsmokers.
11% of heavy smokers develop lung cancer
o Where other predisposing factors include:
women have a higher susceptibility to carcinogens in tobacco than men
cessation of smoking decreases the risk of developing lung cancer over time but never return to baseline levels
Passive smoking (proximity to cigarette smokers) increases the risk of developing lung cancer two‐fold that of nonsmokers
Smoking of pipes and cigars increases the risk, but only modestly.
Other influences include:
miners of radioactive ores
asbestos exposure
o increases the risk of lung cancer five‐fold in nonsmokers.
o heavy smokers exposed to asbestos have an approximately 55 times greater risk for development of lung cancer
than that for nonsmokers not exposed to asbestos.
workers exposed to dusts containing:
o arsenic, chromium, uranium, nickel, vinyl chloride, and mustard gas
The mutagenic effect of carcinogens is conditioned by hereditary (genetic) factors
o Where procarcinogens require metabolic activation via the P‐450 monooxygenase enzyme system for conversion into active
carcinogens
Where specific genetic polymorphisms involving the P‐450 genes have an increased capacity to metabolize procarcinogens
derived from cigarette smoke
incur the greatest risk for development of lung cancer
o Persons whose peripheral blood lymphocytes undergo chromosomal breakages after exposure to tobacco‐related carcinogens
(mutagen sensitivity genotype)
have >10‐fold risk of developing lung cancer
The sequential changes leading to cancer have been best documented for squamous cell carcinomas
o With linear correlation between the intensity of exposure to cigarette smoke and the appearance of ever more worrisome
epithelial changes that begin with
basal cell hyperplasia and squamous metaplasia and progress to squamous dysplasia and carcinoma in situ, before
culminating in invasive cancer
o Among the major histologic subtypes of lung cancer, squamous and small‐cell carcinomas show the strongest association
with tobacco exposure.
Morphology Carcinomas of the lung
o begin as small mucosal lesions typically are firm and gray‐white
Associated with:
intraluminal masses can
o invade the bronchial mucosa
o form large bulky masses pushing into adjacent lung parenchyma.
large masses may undergo
o cavitation secondary to central necrosis or develop focal areas of hemorrhage
o Invade the pleural cavity and chest wall and spread to adjacent intrathoracic structures
More distant spread can occur through lymphatics or the hematogenous route.
Squamous cell Association:
carcinomas o Most common tumor in male smokers
Location:
o Centrally in major bronchi and eventually spread to local hilar nodes, but they disseminate outside the thorax 1. Well‐differentiated
squamous cell carcinoma
later than do other histologic types. showing keratinization and
Characteristic Histology: pearls
o Well differentiated tumors show invasive nests of squamous cell with keratin pearls and intercellular bridges
Comment:
o Squamous cell carcinomas are preceded by the development of
squamous metaplasia squamous dysplasia carcinoma in situ invasive carcinoma 2. Intercellular Bridges
Where atypical cells may be identified although the lesion is asymptomatic and undetectable on
radiographs.
o Eventually, the small neoplasm reaches a symptomatic stage
when a well‐defined tumor mass begins to obstruct the lumen of a major bronchus, often producing distal 3. Squamous cell carcinoma
usually begins as a central
atelectasis and infection. (hilar) mass and grows
contiguously into the
o Simultaneously, the lesion invades surrounding pulmonary substance peripheral parenchyma
Adenocarcinomas Association:
o Most common tumor in non‐smokers and female smokers
Location:
o Peripheral gray‐white mass
o Tumor may develop in area of parenchymal scarring called scar carcinoma
Characteristic Histology:
o May assume a variety of forms, including
acinar (gland‐forming) 4. Gland‐forming adenocarcinoma. inset shows thyroid
transcription factor 1 (TTF‐1) positivity, which is seen in a
papillary (mucinous) majority of pulmonary adenocarcinomas
formerly called mucinous bronchioloalveolar carcinoma multifocal and may present as
pneumonia‐like consolidation on imaging
Comment:
o In general, adenocarcinomas grow slowly and form smaller masses than do the other subtypes, but they tend to metastasize
widely at an early stage.
Atypical Adenomatous The initial lesion of peripheral adenocarcinomas is an atypical adenomatous hyperplasia (AAH)
Hyperplasia (AAH) o which progresses to adenocarcinoma in situ (formerly bronchioloalveolar carcinoma)
which can be classified as:
minimally invasive adenocarcinoma
o tumor less than 3 cm with an invasive component measuring 5 mm or less
invasive adenocarcinoma
o tumor of any size that has invaded to depths greater than 5 mm
o May arise through the following sequence of differentiation: 5. Atypical adenomatous hyperplasia with cuboidal
atypical adenomatous hyperplasia ‐ adenocarcinoma in situ ‐ invasive epithelium and mild interstitial fibrosis
adenocarcinoma
Histology:
o well‐demarcated focus of epithelial proliferation (with a thickness of 5 mm or less)
o composed of cuboidal to low‐columnar cells
which shows cytologic atypia of variable degree such as:
nuclear hyperchromasia; pleomorphism; prominent nucleoli
Genetic analyses:
o Lesions are monoclonal; K‐RAS mutations
Adenocarcinoma in situ Location:
(AIS) [also called o Peripheral parts of the lung, as a single nodule
bronchioloalveolar Characteristic Histology:
carcinoma] o Key features include:
diameter of 3 cm or less; columnar cell growth along preexisting structures (bronchioles and
alveoli); preservation of alveolar architecture
Comment:
o The tumor cells may be 6. AIS mucinous subtype, with characteristic growth along
preexisting alveolar septa, without invasion
non‐mucinous, mucinous, or mixed
grow in a monolayer along the alveolar septa
which serves as a scaffold called “lepidic”
o which is a growth pattern of neoplastic cells that looks like butterflies sitting on a fence
o AIS does not show destruction of alveolar architecture or stromal invasion with desmoplasia
Which are features of adenocarcinoma
Large cell carcinomas Association:
o Smoking
Location:
o Central or Peripheral
Characteristic Histology:
o Poorly differentiated large cells
No keratin pearls
No intercellular bridges
No glands
No mucin
o The cells typically have:
large nuclei
prominent nucleoli
moderate amount of cytoplasm.
Comment:
o Poor prognosis
o Large cell carcinomas probably represent squamous cell or adenocarcinomas that are so undifferentiated that they can no
longer be recognized by means of light microscopy.
o Immunohistochemistry for TTF‐1 (adenocarcinomas), p40 (squamous), or chromogranin (neuroendocrine) may allow for more
specific classification
Small cell lung Association:
carcinomas (SCLCs) o Male smokers
Location:
o Central – with extension into the lung parenchyma and early involvement of the hilar and
mediastinal nodes
Characteristic Histology:
o Poorly differentiated small cells, pale gray in color
Tumor cells characterized as:
7. Small cell carcinoma with small deeply basophilic cells and areas
round to fusiform shape of necrosis (top left). Note basophilic staining of vascular walls due
to deposit by DNA from necrotic tumor cells (Azzopardi effect).
scant cytoplasm
finely granular chromatin
Mitotic figures frequently are seen
o Arises from neuroendocrine (Kulchitsky) cells and chromogranin positive
Comment:
o Despite the appellation of small, the neoplastic cells are usually twice the size of resting lymphocytes.
o Necrosis is invariably present and may be extensive.
o The tumor cells are markedly fragile and often show fragmentation and “crush artifact” in small biopsy specimens.
o These tumors often:
express a variety of neuroendocrine markers (Table)
secreting a host of polypeptide hormones that may result in paraneoplastic syndromes
Feature Small Cell Lung Carcinoma (SCLC) Non‐Small Cell Lung Carcinoma (NSCLC)
Histology Scant cytoplasm; small, hyperchromatic Abundant cytoplasm; pleomorphic
nuclei with fine chromatin pattern; nuclei nuclei with coarse chromatin pattern;
indistinct; diffuse sheets of cells nucleoli often prominent; glandular or
squamous architecture
Neuroendocrine dense core granules on Usually present Usually absent
markers electron microscopy;
expression of
chromogranin, neuron‐
specific enolase, and
synaptophysin
Epithelial markers epithelial membrane Present Present
antigen, carcinoembryonic
antigen, and cytokeratin
intermediate filaments
Mucin Absent Present in adenocarcinomas
Peptide hormone production Adrenocorticotropic hormone (ACTH) Parathyroid hormone‐related peptide
Antidiuretic hormone (ADH) (PTH‐rp) in squamous cell carcinoma
Gastrin‐releasing hormone (GRP)
Calcitonin hormone – released from C‐cells
Tumor suppressor 3p deletions >90% >80%
gene abnormalities Rb mutations 90% 20%
p16/CDKN2A mutations 10% >50
p53 mutations >90% >50%
Dominant KRAS mutations Rare 30% (adenocarcinomas)
oncogene EGFR mutations Absent 20% (adenocarcinomas, nonsmokers,
abnormalities women)
ALK rearrangements Absent 4‐6% adenocarcinomas, nonsmokers,
often have signet ring morphology
Response to chemotherapy and radiotherapy Often complete response but recur Uncommonly, complete response
invariably
Surgical resection Usually not amenable (treated with chemo Usually amenable
and radiation)
Intrathoracic spread Intrathoracic spread of lung cancer to the lymph nodes, particularly:
o hilar, bronchial, tracheal, and mediastinal
Involvement of the left supraclavicular node (Virchow node) is particularly characteristic of an occult primary tumor.
Extend into the pleural or pericardial space adenocarcinoma
o leading to inflammation and effusion
They may compress or infiltrate the superior vena cava to cause either
venous congestion
vena caval syndrome: characterized by
o distended head and neck veins, plethora (dilation of superficial blood vessels), and facial and upper arm edema
Apical neoplasms may invade the brachial or cervical sympathetic plexus
o severe pain in the ulnar nerve
o produces Horner syndrome
which causes ipsilateral
enophthalmos (posterior displacement of the eyeball due to ptosis)
ptosis
miosis
anhidrosis).
o Such apical neoplasms sometimes are called Pancoast tumors, and the combination of clinical findings is known as Pancoast
syndrome.
Pancoast tumor often is accompanied by
destruction of the first and second ribs and sometimes thoracic vertebrae
Clinical Course Carcinomas of the lung are silent, insidious lesions that in many cases have spread so as to be unresectable before they produce
symptoms.
Presentation:
o chronic cough and expectoration (sputum production)
o hoarseness
o chest pain
o superior vena cava syndrome
o pericardial or pleural effusion
o persistent segmental atelectasis or pneumonia
Prognosis is grim
o The tumor presents with symptoms coming from metastatic spread to the
brain (mental or neurologic changes)
liver (hepatomegaly)
bones (pain)
o Adrenal insufficiency (Addison disease) is uncommon, because islands of cortical cells sufficient to maintain adrenal function
usually persist.
Overall, NSCLCs carry a better prognosis than SCLCs.
When NSCLCs (squamous cell carcinomas or adenocarcinomas) are detected
o before metastasis or local spread cure is possible by lobectomy or pneumonectomy
SCLCs have invariably spread by the time they are first detected
o even if the primary tumor appears small and localized surgical resection is not a viable treatment
o Very sensitive to chemotherapy but invariably recur
o Median survival even with treatment is 1 year.
Paraneoplastic Include:
Syndromes o Hypercalcemia
caused by secretion of a PTH‐rp
osteolytic lesions may also cause hypercalcemia, but this would not be a paraneoplastic syndrome
o Cushing syndrome:
from increased production of adrenocorticotropic hormone (ACTH)
o Syndrome of Inappropriate secretion of Antidiuretic Hormone (SIADH)
cause by secretion of ADH
o Neuromuscular syndromes, including:
myasthenic syndrome
peripheral neuropathy
polymyositis
o Hypertrophic pulmonary osteoarthropathy
Characterized by periosteal new bone formation with clubbing and arthritis
o Coagulation abnormalities, including
migratory thrombophlebitis
nonbacterial endocarditis
disseminated intravascular coagulation
Secretion of calcitonin and other ectopic hormones also has been documented by assays, but these products usually do not
provoke distinctive syndromes.
Hypercalcemia with squamous cell neoplasms
Hematologic syndromes with adenocarcinomas.
The remaining syndromes are much more common with small cell neoplasms, but exceptions abound.
Carcinoid Tumors
Carcinoid tumors are malignant tumors composed of cells that contain:
o dense‐core neurosecretory granules in their cytoplasm
o may secrete hormonally active polypeptides
Classified into:
o Typical (low‐grade) carcinoids
o Atypical (intermediate‐grade) carcinoids – more aggressive than Typical carcinoid
Prognosis:
o Both are often resectable and curable
Bronchial carcinoids:
o occur at an early age (mean 40 years) and represent about 5% of all pulmonary neoplasms.
Morphology Association:
o Not significantly related to smoking
Location:
o Central – forms a polyp‐like mass in the bronchus
o Peripheral – less common
Originate in main bronchi and grow in one of two patterns:
o Obstructing polypoid, spherical, intraluminal mass
o Mucosal plaque penetrating the bronchial wall to fan out in the peribronchial tissue—the so‐called collar‐ 8. Bronchial carcinoid. Carcinoid
growing as a spherical, pale mass
button lesion. (arrow) protruding into the lumen of
the bronchus.
Even these penetrating lesions push into the lung substance along a broad front
o Reasonably well demarcated.
o 5% to 15% of carcinoids have metastasized to the hilar nodes at presentation, distant
metastases are rare.
Characteristic Histology
o Typical carcinoids:
composed of nests of uniform cells with regular round nuclei with “salt‐and‐pepper”
chromatin 9. Histologic appearance demonstrating small, rounded, uniform
absent or rare mitoses nuclei and moderate cytoplasm.
little pleomorphism
o Atypical carcinoid:
display a higher mitotic rate (but less than small or large cell carcinomas)
focal necrosis.
Atypical tumors have a higher incidence of lymph node and distant metastasis than typical carcinoids.
o Unlike typical carcinoids, the atypical subset demonstrates TP53 mutations in 20% to 40% of cases.
Typical carcinoid, atypical carcinoid, and small cell carcinoma can be considered to represent a continuum of increasing
histologic aggressiveness and malignant potential within the spectrum of pulmonary neuroendocrine neoplasms.
Clinical Findings Signs and symptoms include:
o Cough
o Hemoptysis
o Recurrent bronchial and pulmonary infections
Peripheral tumors
o often asymptomatic being discovered incidentally on chest radiographs
o Only rarely induce the carcinoid syndrome
Which is characterized by
intermittent attacks of
o diarrhea
o flushing
o cyanosis
The reported 5‐ and 10‐year survival rates
o Typical carcinoids are above 85%
o Atypical carcinoids are 56% and 35%, respectively
o Only 5% of patients with the most aggressive neuroendocrine lung tumor—SCLC—are alive at 10 years.
Pleural Lesions
Pathologic involvement of the pleura is
o a secondary complication of an underlying pulmonary disease
where evidence of secondary infection and pleural adhesions are particularly common findings at autopsy
Important primary disorders are
o primary intrapleural bacterial infections
o malignant mesothelioma – primary neoplasm of the pleura
Pleural Effusion and Pleural effusion
Pleuritis o Which is the presence of fluid in the pleural space characterized as
transudate
the condition is called Hydrothorax
o Hydrothorax from CHF probably is the most common cause of fluid accumulation in the pleural cavity
exudate
Characterized by protein >2.9 gm/dL and inflammatory cells causes Pleuritis.
The four principal causes of pleural exudate formation are
o Microbial invasion through either direct extension of a pulmonary infection or blood‐borne seeding causes
Suppurative Pleuritis or Empyema (refers to pus in the pleural space)
o Cancer – lung carcinoma, metastatic neoplasms to the lung or pleural surface, mesothelioma
o Pulmonary infarction
o Viral pleuritis
Other, less common causes of exudative pleural effusions are
o systemic lupus erythematosus, rheumatoid arthritis, and uremia, as well as previous thoracic surgery.
o Malignant effusions characteristically are large and frequently bloody Hemorrhagic Pleuritis
Where cytologic examination may reveal malignant and inflammatory cells.
Transudates and Serous Exudates
o usually are resorbed without residual effects
if the inciting cause is controlled or remits.
Fibrinous, Hemorrhagic, and Suppurative Exudates
o Lead to fibrous organization
Causing adhesions, fibrous pleural thickening, and calcifications.
Pneumothorax, Pneumothorax
Hemothorax, and o refers to presence of air or other gas in the pleural sac
Chylothorax Due to a traumatic penetrating chest wall injuries
Due to spontaneous rupture of apical blebs in typically tall young adults Simple or Spontaneous Pneumothorax
Secondary Pneumothorax
o Is the result of some thoracic or lung disorder
such as emphysema or a fractured rib
o Secondary pneumothorax is the consequence of rupture of any pulmonary lesion situated close to the pleural surface that
allows inspired air to gain access to the pleural cavity
Such pulmonary lesions include emphysema, lung abscess, tuberculosis, carcinoma, and many other, less common
processes.
Mechanical ventilatory support with high pressure also may trigger secondary pneumothorax.
Complications of pneumothorax include:
o A ball‐valve leak may create a tension pneumothorax that shifts the mediastinum away from the collapsed lung
Compromise of the pulmonary circulation may follow and may even be fatal
If the leak seals and the lung is not re‐expanded within a few weeks scarring may occur to never fully re‐expanded the lung.
Which causes serous fluid to collect in the pleural cavity
o creating hydropneumothorax
With prolonged collapse
the lung and pleural cavity becomes vulnerable to infection,
Empyema is thus an important complication of pneumothorax called Pyopneumothorax
Hemothorax
o the collection of whole blood (which may clot) in the pleural cavity due to…
Trauma – common cause
complication of a ruptured intrathoracic aortic aneurysm almost always fatal.
o Hypotension and a shift of the trachea to the unaffected side
Chylothorax
o is lymphatic fluid containing microglobules of lipid in the pleural cavity
o Is always significant because it implies obstruction of the major lymph ducts, usually by an intrathoracic cancer (e.g., a primary
or secondary mediastinal neoplasm, such as a lymphoma).
Malignant Mesothelioma Is a rare cancer of mesothelial cells
o arising in the parietal or visceral pleura or much less commonly, in the peritoneum and pericardium
related to occupational exposure to asbestos in the air
o where 50% have a history of exposure to asbestos
associated with those who work directly with asbestos:
shipyard workers, miners, insulators are at greatest risk
In persons whose only exposure was
living in proximity to an asbestos factory
being a relative of an asbestos worker
Developing malignant mesothelioma is often 25 to 40 years after initial asbestos exposure
o Where multiple somatic genetic events are required for neoplastic conversion of a mesothelial cell
The combination of cigarette smoking and asbestos exposure greatly increases the risk of lung carcinoma
o but it does not increase the risk of developing malignant mesothelioma.
Morphology Malignant mesotheliomas
o are often preceded by extensive pleural fibrosis and plaque formation seen on CT.
Start in a localized area
o Where over time spread widely, either by
contiguous growth
diffusely seeding the pleural surfaces
o The affected lung typically is covered by a yellow‐white, firm, sometimes gelatinous layer of tumor
that obliterates the pleural space
Distant metastases are rare. 10. Malignant mesothelioma. Note the thick,
firm, white pleural tumor that ensheathes
The neoplasm may directly invade the thoracic wall or the subpleural lung tissue. this bisected lung.
Normal mesothelial cells are biphasic
o giving rise to pleural lining cells as well as the underlying fibrous tissue.
Histologically:
o mesotheliomas conform to one of three patterns:
Epithelial:
in which cuboidal cells line tubular and microcystic spaces
o where small papillary buds project into
this is the most common pattern and also the one most likely to be confused with a pulmonary adenocarcinoma
Sarcomatous:
in which spindled and sometimes fibroblastic‐appearing cells grow in nondistinctive sheets
Biphasic:
having both sarcomatous and epithelial areas.
Clinical Asbestos is not removed or metabolized from the lung fibers remain in the body for life
Lifetime risk after exposure does not diminish over time
Asbestos fibers preferentially gather near the mesothelial cell layer
o to generate reactive oxygen species
which cause DNA damage
Somatic mutations of two tumor suppressor genes have been observed in malignant mesotheliomas:
o p16/CDKN2A, at chromosomal locus 9p21
o NF2, at chromosomal locus 22q12
Pulmonary Function Tests (PFT’s)
PFT’s Provide information Flow Rates
regarding: Lung Volumes
Gas Exchange
Other:
o Airway Resistance
o Respiratory Muscle Strength
Used to answer the Question:
o Is there a pulmonary explanation for dyspnea?
o If so….
Is there Obstruction?
Is there Restriction?
Is there a Diffusion Defect?
CC: Dyspnea History:
o How Bad?
With Moderate/Significant Exertion
With Minimal Effort / Activities of Daily Living (ADL’s)
At rest
o When?
Always vs Intermittent vs Nocturnal vs Specific Environments/Activities
o Associated Symptoms?
Cough, Hemoptysis, Chest Pain, Wheezing
o Risk Factors?
Cigarettes, Occupational, Environmental
Physical Exam
o Big Lungs vs Small Lungs
o Crackles vs Wheezing
Labs:
o CXR/CT, Exercise Desaturation
o PFT’s
Three Main Components Spirometry
o To identify obstruction
Lung Volume Determination
o To identify restriction
Diffusion Capacity Measurement
o To identify a diffusion defect
Calculate expected/predicted values:
o Age
o Height
o Sex
o Race
Measure patient values
Compare Measured to Predicted values:
o “normal” is defined by measured values that are between 80% and 120% of the predicted values
Spirometry After a full inspiration, patient blows out as forcefully as possible until all air has been exhaled.
The volume and rate of air exhaled are measured and reported as both a
o “Flow‐Volume Loop”
o “Volume‐Time Curve”
o
Flow Volume Loop At High Lung Volumes, both elastic recoil and airway diameter are maximal and thus flow rate is highest.
As Lung Volumes decrease during the course of exhalation, both elastic recoil and airway diameter are reduced, so flow rate
decreases.
Hence, one can plot Flow at any given Lung Volume graphically resulting in a “Flow Volume Loop”
Flow (L/sec)
Expiration
Inspiration
Volume Time Curve
Normal Spirometry
> 0.8 age 20‐39
> 0.7 age 60‐80
Obstruction
Obstruction is identified if:
o Reduced RATIO of FEV1 to FVC (not just a decreased FEV1)
< 0.70
o “Scooping” of the Flow Volume Loop
FEV1 percent predicted determines severity, but there is no clear consensus
Mild Moderate Severe Very Severe
50‐80% 50‐30% <30%
65‐80% 50‐65% <50%
60‐80% 40‐60% <40%
Reversibility
o Bronchodilator FEV1 INCREASES by 200cc AND 12%
Hyperreactivity
o FEV1 DECREASES by 20% in response to methacholine
o
Other Spirometry Values
Obstructive Diseases Common:
o Asthma
o COPD
o Bronchiectasis
Uncommon:
o Bronchiolitis
o Lymphangioleiomyomatosis (LAM)
o Toxic inhalation
o Upper Airway Obstruction (UAO)
Lower versus Upper Airway Lower (Small) Airway Obstruction
Obstruction o Obstruction worsens during exhalation as lung volume decreases
Bronchioles lack cartilage
During exhalation, small airway diameter gradually decreases
o Results in gradually decreasing airflow
o
Upper (Large) Airway Obstruction
o Airflow is reduced even at high lung volumes
Where bronchioles should be maximally open
o
Upper Airway Obstruction Three types:
o Fixed
Intra‐thoracic pressure changes do NOT affect the degree of obstruction (a)
Both Inspiratory and Expiratory limbs of the FVL are affected
Obstruction may be located either intra‐ or extra‐thoracic
o Variable
Intra‐thoracic pressure changes DO affect the degree of obstruction
Inspiratory limb affected = Extra‐thoracic obstruction (b)
Expiratory limb affected = Intra‐thoracic obstruction (c)
“Fixed” Upper Airway Both Inspiratory and Expiratory limbs affected.
Obstruction Site of obstruction may be either intra‐ or extra‐thoracic.
“Variable” Intrathoracic Only the Expiratory limb is affected.
Upper Airway Obstruction Site of obstruction is Intra‐thoracic tracheomalacia
“Variable” Extrathoracic Only the Inspiratory limb is affected.
Upper Airway Obstruction Site of obstruction is Extra‐thoracic vocal cord dysfunction
Spirometry Identifies Why not Restriction?
Obstruction o No defined upper limit of normal for FEV1/FVC ratio, and
o “Loops” of normal and restriction look similar
o
Restrictive Lung Disease Requires measurement of lung volumes:
o Helium Dilution
o Body Box Plethysmography
Three Main Lung Volumes
Total Lung Capacity (TLC): Determined by Lung Elastic Recoil
Functional Residual Capacity (FRC): Determined by the balance between Elastic Recoil of the Lung (in) vs Chest Wall (out)
Residual Volume (RV): the volume of gas trapped due to airway closure
Why do we care about lung If Low:
volumes? o Decreased TLC = a RESTRICTIVE process
Interstitial Lung Disease
Chest Wall Disease
Neuromuscular Disease
If High:
o Increased TLC = Hyperinflation:
Loss of lung elastic recoil
Emphysema
o Increased RV = Gas Trapping
Any obstructive process
Restrictive Lung Disease
o Decreased TLC (< 80% Predicted)
o Three Categories of Restriction
Interstitial Lung Disease (Increased Lung Elastic Recoil) most common 95%
Sarcoid
Hypersensitivity Pneumonitis (chronic)
Idiopathic Inflammatory Pneumonitis / Idiopathic Pulmonary Fibrosis (IPF)
Tumor / TB (scarring)
Failure / Fungal (granulomata)
Aspiration/Asbestosis
Connective Tissue Diseases
Environmental
Drugs
Chest Wall Disease (Decreased Chest Wall Elastic Recoil)
Kyphoscoliosis
Ascites
Pleural Effusions
Obesity – Chest wall recoil (out) is decreased where
o severe obesity decreases TLC
o mild obesity decreases FRC
Neuromuscular Disease: ()
Examples:
o Amyotrophic Lateral Sclerosis (ALS)
o Muscular Dystrophy (MD)
o Myopathies
Decreased TLC, Increased RV, Normal FRC
Prove by measuring strength:
o Negative Inspiratory Force (NIF)
o Positive Expiratory Force (PEF)
Diffusion Capacity Assesses Alveolar‐Capillary Surface Area available for gas exchange.
o DLCO = Diffusion capacity of the Lung for Carbon Monoxide
There are 2 terms that describe the dynamics of the transfer of individual substances between the interstitium and the
capillary:
If the substance equilibrates between the capillary and interstitium, it is said to be in a perfusion‐limited situation.
If the substance does not equilibrate between the capillary and interstitium, it is said to be in a diffusion‐limited situation.
Carbon monoxide is a unique gas in that it typically doesn’t equilibrate between the alveolar air and the capillary blood.
Thus, it is a diffusion‐limited gas.
This is taken advantage of clinically, and the measurement of the uptake of CO in mL/min/mm Hg is referred to as the
diffusing capacity of the lung.
It is an index of the lung’s structural features.
Carbon Monoxide: A Gas That Is Always Diffusion Limited
o Carbon monoxide has an extremely high affinity for hemoglobin. When it is present in the blood, it
rapidly combines with hemoglobin, and the amount dissolved in the plasma is close to zero (therefore,
partial pressure in the plasma is considered zero).
o Thus, the alveolar partial pressure gradient (P1 – P2) is simply P1 (alveolar partial pressure), since P2 is
considered to be zero.
o At a constant and known alveolar partial pressure, the uptake of carbon monoxide depends only on
the structural features of the lung, as illustrated in Figure.
This measured uptake of carbon monoxide is called the diffusing capacity of the lung (DLCO;
mL/min/mm Hg).
It is an index of overall surface area and membrane thickness.
With a structural problem, it correlates with the extent of lung damage and is particularly useful
when measured serially over time.
DL (rate of CO diffusion) decreases in emphysema and fibrosis but increases during exercise.
Equations DLCO = [CO]inhaled ‐ [CO]exhaled
o Normal is 25 mL/min/mmHg
DLCO corrected= DLCO x (15/Hgb)
o Where DLCO corrected sometimes called “DLCO adjusted” or “DL Adj”
o This equation corrects for patient’s Hgb
o In anemia
DLCO is low but DLCO corrected is normal
DL/VA = DLCO corrected / Alveolar Volume
o Corrects for patient’s lung volume
o Post‐resection
DLCO is low but DL/VA is normal
Which value to use?
o No consensus.
Abnormal DLCO Reduced DLCO:
o Loss of alveoli
Both Emphysema and Interstitial Lung Disease
o Loss of blood flow to the alveoli
Pulmonary Hypertension
o Anemia
Increased DLCO:
o Alveolar Hemorrhage
o Congestive Heart Failure
o Polycythemia
DLCO Summary Expected DLCO to be low in any disease with loss of either alveoli or capillaries
o Can occur in both obstruction (emphysema) and restriction (pulmonary fibrosis)
Suspect Pulmonary Hypertension when
o DLCO is low but spirometry, lung volumes, and hemoglobin are all normal called “Isolated Low DLCO”
PFT’s: A Practical Approach
Decrease in FEV1/FVC Obstruction
Ratio < 0.7 o Occurs in Asthma, COPD, Bronchiectasis
Decreased TLC Restriction
TLC < 80% Predicted o Occurs in Interstitial Disease, Chest Wall Disease, Neuromuscular Disease
Decreased DLCO Diffusion Defect
DLCO < 80% Predicted o Occurs in COPD and/or Interstitial Lung Disease
o If “Isolated” consider Pulmonary Hypertension
If all normal Normal PFT, but does not rule out Asthma or Mixed Defects
PFT Examples (and Normal
expectations) Obstructive Lung Disease
o Asthma
o COPD
o Upper Airway Obstruction
Fixed
Variable
Intra‐thoracic
Extra‐thoracic
Restrictive Lung Disease
o ILD
o Obesity
o Neuromuscular Disease
Decreased Diffusion Capacity
o Associated with either Emphysema or ILD
o Isolated suggesting Pulmonary Hypertension
Normal
Obstructive – Asthma
(Hyperreactivity)
Obstructive – Asthma
(Obstruction +
Bronchodilator Response)
Obstructive ‐ COPD Obstruction / NO Bronchodilator Response
Also Hyperinflation / Gas Trapping / Low DLCO
Obstructive – Upper Airway
Obstruction – Variable
Extrathoracic
Restriction
Restriction
Restriction
Sleep Apnea
Sleep Disordered Breathing Obstructive Sleep Apnea (OSA)
o Due to obstruction of the upper airway
Central Sleep Apnea
o Failure of the brain to initiate respiration
Obesity‐Hypoventilation Syndrome
o Almost all also have OSA
o Hypo‐ventilate even when awake
Obstructive Sleep Apnea Respiratory effort against airway obstruction
(OSA) o Caused by excess parapharyngeal tissue in adults, adenotonsillar hypertrophy in children
Due to obstruction of the upper airway. Upper Airway Obstruction with preserved chest/abdominal effort
Central Sleep Apnea Failure of the brain to initiate respiration
Risk Factors:
o CHF
o CNS Diseases
Obesity‐Hypoventilation Almost all also have OSA
Syndrome Hypo‐ventilate even when awake
Great Overlap:
o Often mixed Obstructive and Central
o Most OHVS also have OSA
Diagnosis:
o Polysomnography (Sleep Study)
o
Apnea‐Hypopnea Index (AHI):
o The combined number of 10‐second episodes per hour of:
Apnea: Complete cessation of airflow
Hypopopnea: Partial reduction in airflow.
Severity:
o Normal: <5.
o Mild: 5‐15.
o Moderate: 16‐30.
o Severe: > 30.
Risk Factors:
o Obesity
o Neck Circumference (>17 in)
o Hypertension
o Male Gender
o Increasing Age
o Smoking
o Retrognathia
Epidemiology:
o 5% of adults overall
o US White Males with BMI 25‐28
1 in 5 have an AHI>5
1 in 15 have AHI>15
o 1% change in body weight:
results in 3% change in AHI.
o 10% increase in weight:
results in 6X risk of progressing from mild to moderate OSA
Consequences:
o Fragmented Sleep;
Daytime Hypersomnolence;
Intellectual Impairment;
o Repeated Episodes of Hypoxia;
Pulmonary Hypertension;
Polycythemia;
o Other:
HTN (Even Mild OSA Increases Risk of HTN)
Stroke
Arrhythmia
Glucose Intolerance
Immune System Activation.
Epworth Sleepiness Scale
o Survey that determines the likelihood to fall asleep in different situations
o
Score results:
1‐6: Normal
7‐8: Average
9 or more: Seek medical advice immediately!
Treatment:
o treatment of OSA may improve CHF.
o
o Why are there Cardiovascular effects?
o
o General:
weight loss
avoid sedatives
treat nasal congestion
avoid supine sleeping position
o Nasal CPAP/BiPAP:
continuous vs Bileval positive Airway pressure.
o ENT Eval:
oral devices
UPPP (uveul…)
tracheostomy (if super severe).
Lung Cancer Screening Leading cause of cancer death for men and women
o More than colon, breast, and prostate combined
Overall five‐year survival remains 14%
o Only liver and pancreas are worse
brain, leukemia, multiple myeloma, melanoma, esophagus are all better
15 years of life lost per lung cancer death
Screening Rationale: 5‐year Survival
Catch Cancer Early 100
80
70
60
40
14
20
0
Overall Stage I
Rarely Presents Early
10 0 88
80
60
40
20
12
0
S t age I S t a ge I I , I I I , I V
Stage I is almost never symptomatic
> 95% of patients presenting with symptoms will die of their disease
Between 1 and 3 cm, the chance of metastases increases from 30 to 60 %.
Tumors less than 0.5 cm have a less than 20% chance.
Screening has to work? From the 1950’s through the 1970’s
o Four nonrandomized uncontrolled studies of CXR’s
Philadelphia Pulmonary Neoplasm Research Project
VA Trial
Tokyo Metropolitan Government Study
South London Lung Cancer Study
o Two nonrandomized but controlled studies of CXR’s
North London Cancer Study
Erfurt County Study
o Four randomized trials of CXR’s and Sputum Cytology
Johns Hopkins Lung Project
Memorial Sloan‐Kettering Lung Project
Mayo Lung Project (MLP)
Czechoslovakian Study
But screening didn’t work Screening identified:
o More cancers
o More early stage cancers
o More resectable cancers
And screening resulted in a better 5‐yr survival
BUT NO reduction in Lung Cancer Mortality
o Screened patients had a higher likelihood of being diagnosed and living longer from the time of diagnosis
o BUT just as many screened patients ultimately died of cancer.
Lead‐Time Bias
In the example shown, the diagnosis of disease is made earlier in the screened group, resulting in an apparent increase in
survival time (lead‐time bias), although the time of death is the same in both groups.
Length‐Time Bias
The probability of detecting disease is related to the growth rate of the tumor. Aggressive, rapidly growing tumors have a short
potential screening period (the interval between possible detection and the occurrence of symptoms). Thus, unless the
screening test is repeated frequently, patients with aggressive tumors are more likely to present with symptoms. More slowly
growing tumors have a longer potential screening period and are more likely to be detected when they are asymptomatic. As a
result, a higher proportion of indolent tumors is found in the screened group, causing an apparent improvement in survival.
Overdiagnosis Bias
Overdiagnosis bias is an extreme form of length‐time bias. The detection of very indolent tumors in the screened group produces
apparent increases in the number of cases of lung cancer (three in the screened group in the figure and one in the control group)
and in survival (two of three patients in the screened group were treated and died of natural causes, without evidence of disease
[66 percent survival], and the one patient in the control group did not survive [0 percent survival]), with no effect on mortality
(one death from lung cancer in each group). Two patients in the control group died with undiagnosed lung cancer that did not
affect their natural life span.
USPSTF Recommendations AGAINST screening for lung cancer (up until 1999)
Early Lung Cancer Action 1000 patients
Program (ELCAP) o Entry Criteria
Age > 60
> 10 pack year cigarette use
o Actual Mean Patient
Age = 67
45 pack years
Low Dose CT (LDCT) and CXR
Results:
o 233/1000 patients at least 1 Non‐Calcified Nodule (NCN) on LDCT
i.e. “Positive” Scan
o 27/233 were Malignant
CXR missed 20 of these
o 26/27 were Resectable
Theoretically curable due to early detection
Stage of the 27 Malignant 85% Stage I
Nodules o 83% missed by CXR
Overall, 96% resectable
Proves CT’s can find small cancers
o BUT no control group
AND what about all the “False Positives”
o 233 “positive” scans but only 27 cancers
o Therefore, 206 “False Positives”
USPSTF Recommendations INDETERMINATE support for LDCT to screen for lung cancer (up until 2014)
Other ELCAP Findings: 70 Chance of Malignancy vs Size of Largest NCN
60
% 50
1%
Size Matters 40
30
24%
20 33%
10 80%
0
2-5 6-10 11-20
Size of Largest NCN in mm
>20
Fleischner Guidelines Text
Size Low Risk High Risk
<4 mm No further evaluation 1 follow up CT in 1 year
4 – 6 1 follow up CT in 1 year 2 follow up CT’s in 6‐12 months and then again 8‐24
mm months
6 – 8 2 follow up CT’s in 6‐12 months and then again 8‐24 3 follow up CT’s in 3‐6 months, 9‐12 months, and at 24
mm months months
>8 mm PET Scan (then biopsy/resection versus follow up CT in 3 months, 9 months, and 24 months
Journal Article from NEJM Reduced lung cancer mortality with Low dose CT Screening by the National Lung Screening Trial (NLST) Research Team
o Compared LDCT with CXR’s annually for 3 years
o 53,454 “High Risk” Individuals
Age 55‐74
30 Pack Year Smoking History
Could not have stopped smoking more than 15 years ago
o Study stopped early after a median f/u of 6.5 years
NLST Results Reduced lung cancer death rate!
o 20% Relative Risk Reduction (CI 3.8‐26.7)
o Absolute Risk Reduction of death from lung cancer of 0.313%
320 scans to prevent 1 lung cancer death
NSLT Limitations LDCT compared to CXR?
“Healthy Volunteer” Effect
o > 30% had college or higher level education
Expertise of Radiologists and Surgeons in the study compared to community
Costs
o Impact on Smoking Cessation rates
Could help / Could hinder
USPSTF ‐ December 2013: The USPSTF recommends
o annual screening for lung cancer with low‐dose computed tomography in adults ages 55 to 80 years who have a 30 pack‐year
smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person
has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness
to have curative lung surgery.
o Grade: B recommendation.
Canadian Task Force on Preventive Health Care:
o For adults aged 55‐74 years with at least a 30 pack‐year smoking history who currently smoke or quit less than 15 years ago,
we recommend annual screening with LDCT up to three consecutive times. Screening should ONLY be carried out in health
care settings with expertise in early diagnosis and treatment of lung cancer.
Clinical Obstructive and Restrictive Lung Disease
General Categories of Cardiac
Dyspnea Pulmonary
o Obstructive
o Restriction
o Pulmonary Hypertension
Other:
o Renal (Acidosis)
o Anemia
o Neuromuscular
“Obstruction vs Restriction” Both present with Dyspnea
Why Does It Matter? However…
o Different Pathophysiology
o Different Prognosis
o Different Treatment Options
Obstruction:
o Increased Airway Resistance (Raw)
o Large Lungs
o Wheezing
o Decreased FEV1/FVC
Restriction:
o Abnormal Elastic Recoil (ER)/Strength
o Small Lungs
o Crackles
o Decreased TLC
Both presents with:
o SOB
o DOE
o Cough
Obstructive Lung Diseases Diseases:
o Asthma
o COPD
o Bronchiectasis
Symptoms:
o SOB/DOE, Cough, Tightness, Audible Wheezing
Signs:
o Poor Air Movement, Wheezing
CXR:
o Hyperinflation
PFT’s:
o Decreased FEV1/FVC ratio
Asthma Submucosal edema/inflammation, mucous gland hyperplasia, smooth muscle hypertrophy
o Potential for “airway remodeling”
5% of adults…
o occurs at any age
Episodic …
o obstruction / bronchial hyper‐reactivity
Episodic …
o SOB/DOE
o Wheezing
o Cough
o Chest Tightness
Asthma: Diagnosis Typical History and Physical Exam
o Clinical Response to Treatment
PFT’s
o Obstruction with a significant Bronchodilator Response
Normal but a positive Methacholine Challenge Test
Classification...
o Mild Intermittent
<2*, <2, >80%, <20%
*DAYTIME symptoms/wk, NIGHTTIME symptoms/mo, Baseline FEV1 or
Peak Expiratory Flow Rate (PEFR), PEFR variability
o Mild Persistent
3‐6, 3‐4, >80, 20‐30
o Moderate Persistent
Daily, >5, 60‐80, >30
o Severe Persistent
Continual, Frequent, <60, >30
o Peak Flow < 80%
…. MORE Rx!
o Peak Flow < 50%
….SEVERE!
Asthma: Treatment Relievers:
o As Needed (PRN) Use
o Bronchodilators
Controllers:
o Regular Use
o Anti‐Inflammatory
Relievers Mainly Short Acting Beta‐agonists
o Routes:
Metered Dose Inhalers (MDI’s)
Nebulizers (Neb)
PO, Subcutaneous, IV, per ETT
o Most Commonly:
Albuterol MDI…2 Puffs PRN
Pirbuterol MDI…2 Puffs PRN
o Alternatively:
Levalbuterol, MDI or nebulizer, PRN
Ipratropium, MDI or nebulizer, PRN (anticholinergic)
Controllers First Line Therapy = Inhaled Corticosteroids
o Beclomethasone
o Budesonide
o Ciclesonide
o Fluticasone
o Mometasone
Must be taken regularly
Common Side Effects’s:
o Oral‐Pharyngeal (prevented with spacer)
SE’s of Unclear Significance:
o HPA (Hypothalamus‐Pituitary‐Adrenal) Axis, Bone, Cataracts
Second Line Therapy – along WITH inhaled corticosteroids (ICS)
o Long Acting Beta‐Agonists:
Salmeterol
Formoterol
often combined with ICS’s
o Anti‐Leukotrienes:
Montelukast
Zafirlukast
Zileutin
o Less Common:
Cromolyn
Theophylline
Anti‐Cholinergics
Omalizumab
o Last Resort:
Chronic oral steroids
o Experimental:
Thermoplasty
Stepwise Approach for Managing Asthma in Youths >12 Years of Age and Adults
Special Considerations Cough‐Variant Asthma
o Sometimes the only symptom of asthma
o 1 of the 3 most common causes of chronic cough, along with Post‐Nasal Drip (PND) and GERD
Can’t control Asthma without control of PND/GERD as well
Exercise‐Induced Asthma also called Exercise‐Induced Bronchospasm (EIB)
o Increased minute ventilation results in mucosal ‘dehydration’ and mast cell degranulation
o Worse in cold, dry air
o Either exercise in humid conditions, or
o Albuterol pre‐exercise
Occupational Asthma
o Due to inhalational trigger in work environment
Sensitizer‐induced specific immunologic response (IgE related)
Irritant‐induced not requiring sensitization
o Symptoms/PF’s
worsen during work day/work week
improve weekends/vacations
Reactive Airways Dysfunction Syndrome (RADS)
o NO prior asthma
o “big bang” exposure with others affected
o Rx: Steroids
o Typically better in 6 months
Churg‐Strauss Vasculitis
o Small Vessel Vasculitis
o Mononeuropathies
o Increased Eosinophils
o Rx: Steroids
Aspirin Sensitivity
o Samter’s Triad
Asthma
Nasal Polyposis
ASA Sensitivity (and other NSAIDs)
o Rx: anti‐leukotrienes
Allergic Bronchopulmonary Aspergillosis (ABPA)
o Diagnosis: Asthma Plus
Central Bronchiectasis
Migratory Pulmonary Infiltrates
Peripheral Eosinophilia
Immediate Skin Test Reaction
High IgE
IgE/IgG to Aspergillus
o Treatment
Steroids
Asthma Summary Episodic:
o Dyspnea
o Wheezing
o Cough
o Chest Tightness
Inflammatory Etiology
Inhaled Corticosteroids
o The Mainstay of Therapy
Chronic Obstructive Chronic Obstruction that is Secondary to:
Pulmonary Disease (COPD) o Emphysema:
Permanent distention of the distal air spaces with destruction of alveolar septa
o Chronic Bronchitis:
Excessive sputum production
Emphysema:
o Pink Puffer
o
o Maintains a normal PaCO2
‘Huffs and Puffs’
‘Burns calories’
o Therefore, maintains a normal PaO2
Appears ‘pink’
Chronic Bronchitis
o Blue Bloater
o
o “Accepts” Hypercapnea
Less tachypneic
Doesn’t burn calories
o Results in Hypoxia (Cyanosis)
Appears ‘blue’
Hypoxic Pulmonary Vasoconstriction
Edematous
“Bloated”
o Lots of Mucous
Presentation: Insidious onset of
o SOB/DOE
o Cough
MINIMAL day to day variability
Diagnosis: Typical History and Physical
o Clinical Response to Therapy
PFT’s:
o (1) Obstruction with minimal bronchodilator response
o (2) Hyperinflation
o (3) Reduced Diffusing Capacity
Treatment: Stop Smoking!
o
Medications
o Short‐Acting Bronchodilators (MDI or Neb)
Anti‐cholinergics:
Ipratropium
Beta‐agonists:
Albuterol
Pirbuerol
Levalbuterol
Combination:
Ipratropium and Albuterol
o Long‐Acting Bronchodilators (MDI or Neb)
Anti‐cholinergics:
Tiotropium
Aclidinium
Umeclidinium
Beta‐agonists:
Salmeterol
Formoterol
Indacaterol
Arformoterol
Combinations now available
o Other:
Corticosteroids (inhaled > PO)
Azithromycin
Theophylline
Staging and Treatment Stage Disease Diagnosis Treatment
Stage 0 At Risk Normal Spirometry Smoking Cessation
Stage 1 Mild COPD FEV1/FVC < 0.7 Short‐Acting Bronchodilators
Normal FEV1
Stage 2 Moderate COPD FEV1 = 50‐80% predicted Long‐Acting Bronchodilators
Stage 3 Moderately Severe COPD FEV1 = 30‐50% predicted Add ICS’s
Stage 4 Severe COPD FEV1 < 30% predicted Methylxanthines
Long‐Term Oxygen Therapy
o
o
Cardiopulmonary Rehabilitation
Other:
o Transplantation
o Check alpha‐1‐antitrypsin level
Bronchiectasis Pathology:
o A suppurative lung disease characterized by permanent abnormal dilation of the bronchi
o
Pathogenesis: Cole’s Vicious Cycle of Inflammation Model
o Cole proposed that an environmental insult often on a background of genetic susceptibility (impaired
mucociliary clearance) resulting in persistence of microbes in the sinobronchial tree and microbial
colonization
o The microbial infection caused by chronic inflammation resulting in tissue damage and impaired
mucociliary motility
o In turn this led to more infection with a cycle of progressive inflammation causing lung damage
o The current view is that the two factors required for the development of this condition are persistent infection and a defect in
host defense
o The dominant cell types involved in the inflammation process in bronchiectasis are neutrophils, lymphocytes, and
macrophages.
Neutrophils are the most prominent cell types in the bronchial lumen and release mediators, particularly proteases/elastase
which cause bronchial dilation bronchiectasis
o The infiltrate in the cell wall is predominantly composed of macrophages and lymphocytes
o Studies have reported that the main lymphocyte is the T cell and these are cells that are likely to produce the lymphoid
follicles described by Whitwell
Bacteria Colonization
o Gram‐Negative Bacteria
P. aeruginosa
H. influenzae
M. catarrhalis
o G‐positives
o NTM (non‐tuberculous mycobacterium)
Symptoms:
o SOB/DOE
o Daily copious sputum production
Though occasionally “Dry Bronchiectasis”
Associated Causes:
o Pneumonia
o Common Variable Immune Deficiency
o Cystic Fibrosis
o ABPA
o Kartagener’s
o Rheumatoid Arthritis
o Often coexistent sinusitis
Diagnosis:
o Clinical
Obstructed PFT’s with Daily Copious Sputum
o Radiographic demonstration of abnormal airways (CXR or CT)
“Signet Ring Sign”
The internal diameter of the bronchus is larger than that of its accompanying vessel
“Tram Tracking”
The bronchus fails to taper in the periphery of the chest.
Goals of Therapy:
o Break the vicious cycle of mucus stasis, infection, inflammation, and airway destruction
Airway Clearance Therapy
CPT (chest percussion therapy)
7% Hypertonic Saline
Bronchodilators
Antibiotic Therapy
Suppressive vs Eradication
Anti‐inflammatory Therapy
Inhaled corticosteroids, Macrolides
Transplantation
Obstructive Lung Diseases The Big Three
Summary o Asthma
o COPD
Emphysema
Chronic Bronchitis
o Bronchiectasis
Rare/Others
o Bronchiolitis Obliterans
o Lymphangioleiomyomatosis (LAM)
o Toxic Inhalation
o (“Airway” Sarcoid)
Restrictive Lung Disease Restriction = decrease TLC
Three Categories
o Interstitial Lung Disease = 95%
increase Lung ER
o Chest Wall Disease
decrease Chest Wall ER
Examples
Kyphoscoliosis
Obesity
Ascites
o Neuromuscular Disease
normal FRC, decreased TLC, increased RV
Examples
ALS
Muscular Dystrophy
Myopathies
Interstitial Lung Disease Definition:
o Chronic, non‐malignant, non‐infectious inflammation and/or derangement of the alveolar walls
“stuff in the interstitium”
o Increased Elastic Recoil
Includes:
o Pulmonary Fibrosis
o Sarcoidosis
o Pneumoconiosis
o ARDS (“healed” fibroproliferative phase)
o Drug Toxicities
o Collagen Vascular Diseases
Pneumoconiosis
o Associated with:
Asbestosis
Coal Worker’s Lung
Farmer’s Lung
Silicosis
Talcosis
Kaolinosis (clay)
Stannosis (tin)
Berylliosis
Bagassosis (sugar cane)
Popcorn Lung
Pneumosparklyosis
Pneumosparklyosis
o Also known as Glitter lung
o A respiratory disease caused by the chronic inhalation of precision‐cut iridescent, metallizated
particles
o Populations most at risk:
Elementary‐school art teachers and transgendered “drag queen” entertainers are the
o Pathophysiology:
Airborne glitter enters through the nose and mouth. First attracted to glue‐like mucous
membranes, the glitter then settles into the lungs
Glitter deposits cause scarring, inflammation, and twinkling of the lungs, leading to bedazzlemia
Bedazzlemia is a condition in which alveoli are so sparkly that oxygen molecules are reflected away from the bloodstream
Eventually, the alveoli becomes completely decorated and are unable to function, leading to massive system failure due to
oxygen starvation.
Although the damgers of glitter lung are just now becoming known, the body’s intolerance of shiny substances has been
studied for decades
Idiopathic Interstitial Histologic Patterns Associations
Pneumonias (IIP) Usual Interstitial Pneumonitis (UIP) Idiopathic Pulmonary Fibrosis (IPF)
Non‐Specific Interstitial Pneumonitis (NSIP) Connective Tissue Disease (CTD); Hypersensitivity
Pneumonitis (HP); Exposures (remember that ANA and
Rheumatoid Factor are non‐specific)
Cryptogenic Organizing Pneumonia (COP); Bronchiolitis CTD, Drugs, Radiation, Infection (Responds to Prednisone)
Obliterans with Organizing Pneumonia (BOOP)
Desquamative Interstitial Pneumonitis (DIP) Smokers
Respiratory Bronchiolitis‐Associated Interstitial Pneumonitis Smokers
(RB‐ILD)
Acute Interstitial Pneumonitis (AIP) Hammon Rich Syndrome
Lymphocytic Interstitial Pneumonitis (LIP) HIV, Lymphoma, Sjogren’s
Causes of Interstitial Lung Diseases
o Sarcoid
o Hypersensitivity Pneumonitis
o Idiopathic Pulmonary Fibrosis/ “IIP’s”
o Tuberculosis
o Fungal
o Aspiration / Asbestosis
o Connective Tissue Diseases / (Cancer)
o Eosinophilic Granuloma
o Drugs
Amiodarone
Nitrofurantoin
Bleomycin
o Plus Pneumoconioses
Presentation:
o SOB/DOE
o Cough
Signs:
o Crackles
o Small Lungs
o +/‐ Clubbing
CXR:
o Reduced Volumes
o Interstitial Markings
PFT’s:
o Decreased TLC
Normal or Increased FEV1/FVC ratio
FEV1 and FVC are BOTH decreased
Diagnosis:
o Restrictive PFT’s
o Consistent CXR/HRCT
If no evidence of ILD on HRCT, consider the other two categories of restrictive lung disease;
Chest Wall Disease
Neuromuscular Disease
o Biopsy:
Transbronchial (TBBx)
Open Lung
Thoracoscopic
Sarcoid Non‐Specific Tissue Reaction
Non‐Caseating Granulomata
Any age, sex, race
o (increased risk in young, female, AA)
Pulmonary Involvement:
o Lymphadenopathy
o Interstitial Lung Disease
Non‐Pulmonary Involvement:
o Ocular, Cardiac, CNS, Bone, Skin, Hypercalcemia
CXR “Staging” Stage 0 = Normal
Stage 1 = Lymphadenopathy (LAD)
Stage 2 = LAD + ILD (Classically an upper lobe predominance)
Stage 3 = ILD (Classically an upper lobe predominance)
Stage 4 = ESLD with honeycombing
Sarcoid: Treatment
o Options:
Corticosteroids
Other:
Methotrexate
Cyclosporine
Azathioprine
o When:
CNS, Ocular, Cardiac, Hypercalcemia, Disfiguring Skin Changes
Pulmonary SYMPTOMS or Worsening PFT’s
NOT just for asymptomatic lymphadenopathy
Idiopathic Pulmonary Etiology Unknown
Fibrosis (IPF) Middle‐Aged/Elderly
Insidious DOE progressing to SOB at rest
Cough (can be quite severe)
Mean Survival = 2.5 to 5 years
Diagnosis
o “Typical” Presentation:
Typical Patient, Symptoms, Exam, PFT’s
Typical High Resolution CT (HRCT) findings:
Sub‐pleural fibrosis progressing to honeycomb
o Biopsy if atypical clinical presentation
Video‐Assisted Thoracoscopic Surgery (VATS) or Open Lung BIopsy
(Not by TBBx)
Pathology = “U.I.P.”
Treatment
o Symptomatic / Palliative Care
i.e., oxygen, opiates, anti‐tussives
o PREVIOUSLY no proven therapy
Many agents tried without evidence:
Steroids, Colchicine, Cyclophosphamide, Azathioprine, Interferon, NAC (N‐acetyl cysteine)
o NOW (as of November 2014):
Pirfenidone
Nintedanib
o Consider Transplantation
Clinical Approach to History
Dyspnea o SOB:
Summary: Always vs Intermittent
At Rest, With Exertion (? Intensity), At Night
o Associated Cough, Sputum, Chest Pain
o Tobacco or Occupational Risks
Physical
o Big Lungs vs Small Lungs
o Crackles vs Wheezing
Work‐Up
o CXR
Hyperinflation vs Small Lungs
“Extra Lines and Dots”
o PFT’s
Obstruction (decreased FEV1/FVC) vs Restriction (decreased TLC)
Pleural Disease
Outline Brief Anatomy/Physiology Review
Pleural Effusions
o Classification
o Treatment Options
Pneumothorax
Pleural Anatomy & Normally, less than 10cc fluid
Physiology o Pleural Effusion = Excess Pleural Fluid Accumulation
Only parietal pleural is innervated
Blood Supply (confusing at best)
o Visceral Pleura:
Arterial supply is from the bronchial and pulmonary arteries
Venous drainage is through the pulmonary veins (to LA)
o Parietal Pleura:
Arterial supply is from intercostals off the aorta
Venous drainage is through the IVC (to RA)
SVC
RA RV PA
pulm
cap
PV LA LV
Visceral Pleura
IVC
Parietal Pleura
SVC = Superior Vena Cava; IVC = Inferior Vena Cava; RA = Right Atrium; RV = Right Ventricle;
PA = Pulmonary Artery; PV = Pulmonary Vein; LA = Left Atrium; LV = Left Ventricle
Left Heart Failure leads to Pulmonary Edema and/or Pleural Effusions and/or Both
Primary Left
Heart Failure
EDEMA
RV LV
Visceral Pleura
EFFUSION
Parietal Pleura
Pulmonary Hypertension leads to Cor Pulmonale BUT NOT pulmonary edema or effusions
o Note: Since the parietal pleura drains into the IVC/RA, PHTN might WORSEN an effusion caused by left heart failure but PHTN
won’t cause an effusion independently.
Pulmonary Arterial
Hypertension
RV LV
Visceral Pleura
Parietal Pleura
Cor Pulmonale
Sub‐atmospheric pleural pressure (Ppl)
o Is approximately ‐5 cm H2O at mid‐thorax resulting from the
Elastic Recoil of the lung pulling in
Elastic Recoil (ER) of the chest wall pulling out
Pleural Fluid Formation Q = K [(Pcap ‐ Ppl) ‐ R(PIcap ‐ PIpl)]
o Q = Rate of Fluid Formation
o K = Filtration Coefficient of the pleura
o Pcap and Ppl = the capillary and pleural Hydrostatic Pressures
o R = Solute Reflection Coefficient of the pleura
o PIcap and PIpl = the capillary and pleural Oncotic Pressures
Causes of EXCESS pleural Increase in Filtration Coefficient of the pleura (K)
fluid formation: o Due to Infection/Inflammation/Cancer
Increased in Capillary Hydrostatic Pressure (Pcap)
o Due to LV failure
Decreased in Pleural Hydrostatic Pressure (Ppl)
o Due to Atelectasis
Decrease Capillary Oncotic Pressure (PIcap)
o Due to NS, Cirrhosis, Malnutrition
Direct entry of ascitic fluid, blood, lymph, gastric fluid
Pleural Effusions Definition:
o Excessive fluid accumulation in the pleural space
Symptoms:
o None
o Pain
o Dyspnea
o Respiratory Failure
Physical Exam Signs:
o Dullness to Percussion
o Decreased Breath Sounds and Tactile Fremitus
o Egophony
Chest X‐ray (CXR):
o “blunting of the angle” when the costophrenic angle is no longer sharp
o “meniscus”
o “white‐out”
with shift of mediastinum away
o “lateral decubitus” shows “layering”
o “loculations”
Evaluation of Effusions H & P
Thoracentesis
o Diagnostic
Approximately 50cc
o Therapeutic
for relief of symptoms
post‐thoracentesis pulmonary edema (> 1.5L)
Transudates vs Exudates Transudates:
o occurs in normal pleura when
Increase in Capillary Hydrostatic Pressure (Pcap)
Decrease in Pleural Hydrostatic Pressure (Ppl)
Decrease in Capillary Oncotic Pressure (PIcap)
o As a result of
LV failure
Atelectasis
Low albumin
Nephrosis
Cirrhosis
Malnutrition
Exudates
o Occurs in leaky pleura when
Increase in Filtration Coefficient of the Pleura (K)
o As a result of
Infection
Inflammation
Cancer
o Occurs as a direct entry of Ascitic fluid, Blood, Lymph, or GI secretions
Criteria for exudates: Criteria Test Result
Light’s Criteria for Exudates: Any one [Total Protein of the Pleural (TPpl)] / [Total Protein of the > 0.5
criteria classify the effusion as an exudate Serum (TPserum)]
[Lactate Dehydrogenase of the Pleural (LDHpl)] / [Lactate > 0.6
Dehydrogenase of the Serum (LDHserum)]
Lactate Dehydrogenase of the Pleural (LDHpl) > 200 (or 2/3
upper normal)
Revised Criteria: Either one criteria classify Lactate Dehydrogenase of the Pleural (LDHpl) > 200 (or 2/3
the effusion as an exudate upper normal)
Cholesterol of the Pleural > 45
Cholesterol Pleural Fluid Cholesterol (pf CHOL) cutoffs vary between 43 and 65
o Could have a role in “diuresed heart failure”
Parameters Sensitivity (%) Specificity (%) PPV (%) NPV (%) P value
Protein ratio 81.4 82.6 89.7 70.4 <0.0001
LDH ratio 86 94.7 97.4 75 <0.0001
pf LDH 100 57.8 84.3 100 <0.0001
pf CHOL 97.7 100 100 95 <0.0001
Differential Diagnosis Transudative Effusions
o CHF
o Cirrhosis
o Nephrotic Syndrome
o Atelectasis
o Hypothyroidism
o Pulmonary Embolism (15%)
o Peritoneal Dialysis
Exudative Effusions
o Cancer
o Infections (Empyema)
o Parapneumonic Effusions
o Pulmonary Embolism (85%)
o Connective Tissue Diseases
o Esophageal Rupture
o Drug Induced Disease
o Post‐MI
o Post‐Pericardiotomy
o Uremia
o Asbestos
o Meig’s Syndrome
o Yellow Nail Syndrome
o Hemothorax
o Chylothorax
Additional Pleural Fluid pH
Tests o normally, slightly higher than serum
due to active transport of bicarbonate
o low pH may be seen with
Infection (empyema)
Malignancy
Esophageal Rupture
Glucose
o low in RA, TB, Cancer, Empyema
Cell Count
o Total WBC
not very important unless frank pus
differential normally mainly macrophages
lots of PMNs suggests acute infection
lots of lymphocytes suggests TB or fungus
more than 5% mesothelial cells speaks against TB
o Total RBC
“Hematocrit” > 1/2 peripheral = hemothorax
Cytology
o sensitivity only 60%
Gram Stain
Culture & Sensitivities
ADA (adenosine deaminase) = TB
Amylase
o pancreatitis and/or esophageal rupture
Patterns TB: Exudative
Lymphocytic
< 5% mesothelial cells
+ADA
PPD may be negative early
Malignant Effusions: Exudative
Lymphocytic
RBC’s
+/‐ low pH/Glucose, Large
Pulmonary Embolism: 85% are small, unilateral, and exudative
+/‐ bloody
Esophageal Rupture: Left sided
low pH
high amylase
Endometriosis: Bloody
+/‐ associated with Pneumothoraces/Hemoptysis
“Hepatic” Effusions: Underlying cirrhosis
Transudative
R > L sided
rapid re‐accumulation
“Milky” Effusions: Chylothorax (Triglycerides > 110)
o Malignancy
o Trauma
o Mediastinal Disease (ruptured thoracic duct)
Pseudochylothorax (Triglycerides >100 AND Chol > 200)
o Chronic Inflammatory Conditions (breakdown of cell walls)
Empyema
Final Classification Transudates
Exudates
o “Uncomplicated”
o “Complicated” Exudates
very low pH and/or glucose
very high LDH
at risk of becoming an empyema
Empyema
o Positive Gram Stain
o Positive Culture
o Pus
Treatment Transudates: Treat the Cause
Exudates – Uncomplicated Treat the cause
Exudates – Complicated Serial Thoracenteses
Empyema Chest tube
Loculations +/‐ Thrombolytics
Multiple Loculations/Pleural Peel Video‐Assisted Thoracoscopic Surgery (VATS)/Thoracotomy
Pleurodesis Definition:
o Chemical or mechanical irritation of the visceral and parietal pleura to create adhesion and obliteration of the pleural space
Why?
o Prevents re‐accumulation of fluid
How?
o Chemical
talc, bleomycin, doxicycline
o Mechanical
gauze via VATS
Pneumothorax Definition:
o air in the pleural space
Mechanisms:
o alveolar air escapes into the pleural space
o air enters via a hole in the chest wall into the pleural space
The Result:
o Air enters the pleural space until Ppl = Patm
o Lung Collapses Inward
o Chest Wall Expands
If ball‐valve mechanism, may develop supra‐atmospheric Ppl with “tension”
o Leads to a decreased venous return and hypotension
Ball‐Valve Mechanism is when air enters the pleura during inspiration through a flap that closes
during expiration, trapping ever more air/pressure in the pleural space
Symptoms:
o Often Asymptomatic
o Chest Pain
o Dyspnea
o Cough
o Shock (if tension)
Physical Exam
o Unilateral Hyperinflation
o Decreased Breath Sounds and Tactile Fremitus
o Hyper‐resonance (“tympanitic”)
Chest X‐ray
o Hyperlucent lung fields
o Lack of “lung markings”
o Thin white pleural line
o Shift of mediastinum if tension
Test
Test
Test
Test
Test
Classification Spontaneous vs Traumatic/Iatrogenic
Primary vs Secondary
Treatment Observation
o +/‐ supplemental FiO2
o Room Air Pneumothorax Space:
PptxO2 = 159 mmHg (PB x FIO2)
PptxN2 = 600 mmHg (PB x FIN2)
o Capillaries lining the PTx space on RA:
PcapO2 = 40 mmHg
PcapN2 = 550 mmHg
o Capillaries on 100%FIO2:
PcapO2 = 40 mmHg
PcapN2 = 0 mmHg
Where the difference between PptxN2 and PcapN2 (RA) is the minimal Gradient for Reabsorption
Where the difference between PptxN2 and PcapN2 (100% FiO2) is the increased gradient for reabsorption
Only if small, asymptomatic, and there is no underlying lung disease do you use:
o Observation
+/‐ supplemental FiO2
o Needle/Syringe Drainage
o “Chest Tube”
Small Bore
Large Bore
+/‐ “suction”
VATS/Thoracotomy
Disorders of the Pulmonary Circulation
Outline Pulmonary edema
o High pressure
o Low pressure
Pulmonary embolism
Pulmonary hypertension
Pulmonary Edema
Pulmonary Edema Fluid accumulation within the lungs, usually due to an imbalance of Starling forces or
endothelial injury
o Pulmonary edema due to increased hydrostatic pressure can be seen in:
left‐sided heart failure
mitral valve stenosis
high altitude pulmonary edema
fluid overload
o Pulmonary edema due to decreased oncotic pressure can be seen in:
nephrotic syndrome
liver disease
o Pulmonary edema due to increased capillary permeability can be due to:
Infections
Drugs – bleomycin, heroin
Shock
Radiation
High Pressure Pulmonary Also called Cardiogenic pulmonary edema.
Edema Elevated Left Ventricular End Diastolic Pressure (LVEDP)
o causes elevated hydrostatic pressures
which result in increased edema formation.
Edema occurs in stages:
Stage 1 Interstitial pulmonary edema
Stage 2 Crescentic filling of the alveoli
Stage 3 Alveolar flooding
Associated with other signs of elevated LVEDP and cardiac dysfunction.
o Physical exam findings
JVD
S3
Hepatomegaly
Edema
Cool extremities
Thready pulse
o Chest x‐ray findings
vascular engorgement
perihilar infiltrates
cephalization
Kerley B lines
pleural effusions are common.
Causes include:
o LV systolic or diastolic dysfunction
o mitral valve disease
o hypervolemia with normal cardiac function (acute renal failure)
Histology:
o Engorged alveolar capillaries, intraalveolar pink grany precipitate, hemosiderin‐laden macrophages (heart failure cells)
o
Chest X‐ray
11/21/2008
12/2/2008
Treatment:
o Oxygen, non‐invasive mask ventilation
o Decrease preload (Pulmonary Capillary Wedge Pressure [PCWP)) using
Nitrates
Diuretics
Venodilators
o Decrease afterload using
ACE inhibitors
Hydralazine
o Increase contractility using
Dobutamine
Milrinone
Low Pressure Pulmonary Also called Acute Respiratory Distress Syndrome (ARDS) or Acute Lung Injury (ALI).
Edema Increased permeability (leaky capillaries)
o causes increased edema.
Follows any of a number of insults.
o Most common are due to:
Sepsis
Trauma
Pancreatitis
Edema has protein concentration approaching serum.
ARDS Definition
Timing Within 1 week of a known clinical insult or new or worsening respiratory symptoms
Chest imaging Bilateral opacities – not fully explained by effusions, lobar/lung collapse, or nodules
Origin of edema Respiratory failure not fully explained by cardiac failure or fluid overload
Need objective assessment (e.g. echocardiography) to exclude hydrostatic edema if no risk
factors are present
Oxygenation Mild 200 mmHg < PaO2/FiO2 < 300 mmHg with PEEP or CPAP > 5 cm H2O
Moderate 100 mmHg < PaO2/FiO2 < 200 mmHg with PEEP > 5 cm H2O
Severe PaO2/FiO2 < 100 mmHg with PEEP > 5 cm H2O
Physical Exam is typically notable for:
o Lack of signs of elevated filling pressures.
o If sepsis is the underlying cause, there are typically warm extremities, bounding pulses and a wide pulse pressure.
Refractory hypoxemia is usually the early problem, later in the course of the disease hypercapnia becomes more problematic.
Pathology of ARDS
o Diffuse alveolar damage with the following features
Interstitial (alveolar septal) edema
Fibroblastic proliferation in alveolar septa
Alveolar edema
Alveolar fibrin and cellular debris +/‐ hyaline membranes
Reactive Type 2 pneumocytes
CXR shows diffuse four quadrant fluffy infiltrates.
Pleural effusions and cardiomegaly are rare.
Swan‐Ganz Catheter
o Pulmonary wedge pressure, sometimes called pulmonary capillary wedge pressure, is measured from
the tip of a Swan‐Ganz catheter, which, after passing through the right heart, has been wedged in a small
pulmonary artery.
o The tip is pointing downstream toward the pulmonary capillaries, and the pressure measured at the tip
is probably very close to pulmonary capillary pressure.
o Since the vessel is occluded and assuming minimal flow, the pressure is probably also very close to the
left atrial pressure as well. A rise in pulmonary capillary wedge pressure is evidence of an increased in preload on the left
ventricle.
o In some cases, such as in mitral stenosis, it is not a good index of left ventricular preload.
Treatment
o Fix the underlying problem
o Lower the hydrostatic pressures
o Oxygen (but recognize that this is shunt)
o Mechanical Ventilation
High PEEP
Low tidal volumes
o Salvage therapy – Extra Corporeal Membrane Oxygenation (ECMO)
ECMO
Differentiating Between Finding High Pressure Pulmonary Edema Low Pressure Pulmonary Edema
High Pressure and Low Neck veins Elevated Flat
Pressure Edema Clinically Extra heart sounds +S3 None
Breath sounds Crackles Crackles or Clear
Peripheral edema Present None
Extremities Cool Warm and well perfused
Pulse pressure Narrow Wide
Wedge pressure >20 <18
Edema protein concentration Low High
Pulmonary Embolism
Pathophysiology Hypercoagulability, venous stasis, and/or intimal injury lead to thrombus formation.
Clot may propagate proximally.
DVT may dislodge and embolize.
Pulmonary arterial obstruction leads to:
o increased PVR
o redistribution of blood flow V/Q mismatch
o hyperventilation
o RV pressure overload, ischemia
Epidemiology Approximately 600,000 DVTs per year.
Approximately 10‐30% of DVTs lead to pulmonary embolus if not treated.
PE mortality is 30% untreated.
With therapy, mortality decreases to ~5%.
Autopsy studies as late as 1988 suggest that only 30% of PEs are diagnosed antemortem.
Risk Factors Active cancer
Previous VTE (with the exclusion of superficial vein thrombosis)
o Venous thromboembolism (VTE) is a disease that includes deep vein thrombosis (DVT) and pulmonary embolism (PE)
Reduced mobility
Already known thrombophilic condition
Recent (<1 month) trauma and/or surgery
Elderly age (>70)
Heart and/or respiratory failure
Acute myocardial infarction or ischemic stroke
Acute infection and/or rheumatologic disorder
Obesity (BMI>30)
Ongoing hormonal treatment
Clinical Presentation Symptoms
o Chest pain (88%)
Pleuritic (74%)
Non‐pleuritic (14%)
o Dyspnea (84%)
o Apprehension (59%)
o Cough (53%)
o Hemoptysis (30%)
o Syncope (13%)
Signs
o Respiration rate >16/min (92%)
o Rales (58%)
o Increased S2P (53%)
o Pulse >100/min (44%)
o Temperature > 37.8 C (43%)
o Phlebitis (32%)
o Gallop (34%)
o Diaphoresis (36%)
o Edema (24%)
o Murmur (23%)
o Cyanosis (19%)
Pathology Typically shows a hemorrhagic wedge‐shaped infarct. The infarction heals by regeneration or scar formation
Chest X‐rays Cardiomegaly (27%)
Normal (24%)
Pleural effusions (23%)
Elevated hemidiaphragm (20%)
PA enlargement (19%)
Atelectasis (18%)
No finding was sensitive or specific or correlated with echo findings.
Diagnostic Testing D‐ Dimer would be elevated
o sensitive, but not specific (good at ruling disease out)
Lower extremity ultrasonography
o specific, but not sensitive (good at ruling disease in)
o
V/Q scan shows V/Q mismatch
o
Pulmonary angiography
o
CT Angiography
o
Therapy Prevention
Anticoagulation This is appropriate initial therapy in almost everyone, unless there is a contraindication
o Heparin
o Coumadin (vitamin K antagonist) for at least 3 months
o New oral anticoagulants (NOACs) which are either
direct thrombin inhibitors:
dabigatran
factor Xa inhibitors
rivaroxaban
apixaban
IVC filter
o Reduce the rate of recurrent PE without improving survival
o Indicated if an absolute contraindication to anticoagulation
Thrombolytics
o Only proven to improve survival in shock
Surgical/Catheter Thrombectomy
Pulmonary Hypertension
The RV is a low pressure, high volume system.
o Normal PA pressures run 20/10.
Acutely the RV cannot generate pressures over 40 mmHg.
Chronically, pulmonary pressures approaching systemic can be generated, but not without consequences.
PH is mean PA pressure > 25 mmHg
Classification Group 1: Pulmonary Arterial Hypertension (PAH)
o Idiopathic PAH
o Heritable (Primary Pulmonary Hypertension (PPH))
BMPR2
ALK1, endoglin (+/‐ hereditary hemorrhagic telanglectasia
Unknown
o Drug and toxin induced
Aminorex; Fenflurimina; Rapeseed oil; Amphetamines; Cocaine
o Associated with
Connective tissue disease
Scleroderma; Lupus
HIV infection
Portal hypertension
Congenital heart disease
Schistosomiasis
Chronic hemolytic anemia
o Persistent pulmonary hypertension of the newborn
Group 2: Pulmonary Hypertension due to left heart disease
o Systolic dysfunction
o Diastolic dysfunction
o Valvular disease
Group 3: Pulmonary Hypertension due to lung disease/hypoxia
o Chronic obstructive pulmonary disease
o Interstitial lung disease
o Other pulmonary diseases with mixed restrictive and obstructive patterns
o Sleep‐disordered breathing
o Alveolar hypoventilation disorders
o Chronic exposure to high altitude
o Developmental abnormalities
Group 4: Chronic Thromboembolic Pulmonary Hypertension
o No subtypes
Group 5: Pulmonary Hypertension with unclear mechanisms
o Hematologic disorders: myeloproliferative disorders, splenectomy
o Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis (lymphangiolelomyomatosis, neurofibromatosis,
vasculitis)
o Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
o Other: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis
Pathology Medial Hypertrophy
o
Plexiform Lesions
o
Treatment Pulmonary rehabilitation.
Oxygen if needed.
~10% of patients can have a response to calcium channel blockers
All other vasodilators cause systemic hypotension before pulmonary vasodilation.
Targeted Therapies
o Endothelin receptor antagonists – inhibits Endothelin
Ambrisentan
Bosentan
Macitentan
o Phosphodiesterase type 5 inhibitor – inhibits cGMP
Sildenafil
Tadalafil
o Exogenous nitric oxide – stimulates cGMP
Soluble Guanylate Cyclase Stimulator—Riociguat
o Prostacyclin derivatives – stimulates cAMP
Epoprostenol
Iloprost
Treprostinil
Other treatment options
o Consider anticoagulation
o Diuretics (with caution)
o Digoxin?
o Lung Transplant can be a treatment option if the patient is otherwise stable.
Sepsis
Outline History of sepsis
Definitions
Epidemiology
Pathophysiology
Signs and symptoms
Management
Case
History of Sepsis Sepsis is defined as the body’s inflammatory response to an infectious precipitant. Sepsis originates from the Greek word “sepo”
which means “I rot.” Hippocrates described sepsis as a process in which “flesh rots, swamps generate foul airs and wounds
fester.” At first, it was thought that the profound inflammation seen with sepsis was due to the overwhelming bacterial load but
patients continued to die despite the introduction of antibiotics. Therefore, it was determined that it was body’s response to the
pathogen that drove the pathogenesis of sepsis.
In this session we will review the current concepts of pathogenesis of the systemic inflammatory response syndrome due to
infection. We will also review the epidemiology, clinical manifestations, and an approach to diagnosis and treatment.
Definitions Systemic Inflammatory Response Syndrome (SIRS):
o Massive inflammatory reaction from systemic cytokine release. Defined as two or more of the following clinical manifestations
present at the same time:
Temperature of >38 C or <36 C
Heart rate >90 beats per minute
Respiratory rate > 20 breaths per minute or PaCO2 <32 mm Hg
WBC count of >12,000/mm3 or <4,000/mm3 or >10% immature forms (bands)
Sepsis:
o SIRS plus a suspected or documented infection
Severe sepsis:
o Sepsis plus organ dysfunction (including but not limited to lactic acidosis (>2mmol/L), acute kidney injury (Cr >2mg/dL),
oliguria, respiratory failure, altered mental status) or hypotension (SBP<90 or MAP<65)
Septic shock:
o Severe sepsis plus persistent hypotension (despite fluid resuscitation) or lactate ≥ 4mmol/L
Systemic Inflammatory First described in 1983 by a trauma surgeon
Response Syndrome (SIRS): Reintroduced in 1991 by Dr. Roger Bone with the goal of aiding in the early detection of sepsis
Important to differentiate SIRS (body’s inflammatory response) from SIRS secondary to infection (sepsis)
Defined as cytokine release occurs in response to numerous insults. In addition to bacterial infection, SIRS is commonly seen in
the following settings:
o Burn injury
o Trauma or hemorrhage
o Acute pancreatitis
o Acute adrenal insufficiency
o Ischemic tissue injury including liver or muscle
o Venous thrombosis/pulmonary emboli
o Others: fat or amniotic fluid emboli, transfusion reaction, adverse drug reactions
Septic Shock A type of distributive shock = severe peripheral vasodilation
o “Distributive” comes from the fact that blood flow is unevenly distributed to various tissues
Hyperdynamic shock
o MAP = CO x SVR
o Cardiac output will increase to compensate for low SVR leading to bounding pulses, warm, flushed skin
On the other hand, cytokine‐induced myocardial depression can also occur in some patients
o Patients have depressed ejection fraction and a shift of Frank Starling curve down and to the right
Epidemiology of bacteremia Estimated 750,000 episodes each year with more than 100,000 deaths
and sepsis: Incidence of sepsis is increasing:
o In 2000, there were 620,000 patient hospitalized with sepsis compared to over 1.1million people in 2008
o Reason for rising incidence is likely due to more immunosuppression (organ transplant, bone marrow transplant, cancer
patients), more indwelling catheters, artificial valves, joints, etc.
However, mortality from sepsis has been on the decline over the past 20‐25 years
o 30‐40% mortality in 1990s to around 20‐25% in the last 2000s
o Most recent papers show an average mortality of 18‐20%
Published series disclose that about 1/3 of patients with sepsis have positive blood cultures.
A publication of 14,000 septic patients in 75 countries found Gram negative bacteria on 62%, Gram positive in 47% and fungi in
19% of positive blood cultures.
The lung is the most common site of infection with pneumonia causing about 50% of the cases of severe sepsis
o Intra‐abdominal and genitourinary tract are other common sources of infection
Pathophysiology The body’s response to infection is characterized by both a proinflammatory response and an anti‐inflammatory response
o The severity of these responses is determined by host factors (age, comorbidities) and by pathogen (microbial load and
virulence).
PROINFLAMMATORY: There are 4 main classes of pattern‐recognition receptors on surface of immune cells:
o Toll‐like receptors (TLR) most important one
o C‐type lectin receptors (CLR)
o Retinoic acid inducible gene 1‐like receptors (RLR)
o Nucleotide‐binding oligomerization domain‐like receptors (NLR)
Pattern‐recognition receptors recognize pathogen‐associated molecular patterns (PAMPs).
o PAMPS are structures that are conserved among microbial species
Examples of PAMPs include:
o Lipopolysaccharide (LPS)
Which are an outer membrane surface associated molecule associated with Gram negative bacteria
Recognized by TLR‐4
o Peptidoglycan
Which are cell wall fragment of gram positive bacteria
Recognized by TLR‐2
o Beta‐glucans of candida
Recognized by TLR‐2
When pattern‐recognition receptors (such as TLR) bind to PAMPs, this activates the cytosolic transcription factor nuclear factor
kapa‐B (NF‐kappaB) which then moves from the cytoplasm to the nucleus and activates innate immunity:
o Upregulation of transcription of proinflammatory cytokines such as:
tumor necrosis factor‐alpha (TNF‐alpha)
interleukin‐1 (IL‐1)
interleukin‐6 (IL‐6).
o Complement activation
Cell death releases damage‐associated molecular patterns (DAMPs)
o DAMPs are also recognized by receptors such as TLR and can trigger further inflammation.
o DAMPs can also be released following burns or trauma
which explains why a similar response (SIRS) can be seen without sepsis
Mechanism of organ failure in sepsis:
Increased thrombosis of small vessels:
o The release of Cytokines
Which causes an increased production of tissue factor
Causes increased fibrin deposition
o Resulting increased thrombus formation
o Increased expression of PAI‐1 (plasminogen activator inhibitor type 1)
causes decreased fibrinolysis
Resulting in further thrombus formation and DIC
o Other anti‐coagulant factors such as, are also decreased
tissue factor pathway inhibitor
antithrombin
activated protein C
Vasodilation causes hypotension:
o Cytokines increase the activity of inducible nitric oxide synthase (iNOS)
which increases the synthesis of nitric oxide (NO) a potent vasodilator
Increased fibrin‐rich thrombi in the small vessels along with hypotension
o leads to hypoperfusion of tissues
Loss of barrier function and capillary leak:
o PAR‐1 (protease activated receptor 1):
In the setting of
low dose thrombin or activated protein C PAR‐1 is cytoprotective
But in the setting of
high dose thrombin PAR‐1 becomes disruptive to the endothelial cell barrier
o Pro‐inflammatory cytokines also disrupt the capillary endothelium
leading to loss of barrier function
o The loss of barrier function
leads to capillary leak and third spacing of fluid with increased interstitial edema
which is the mechanism of ARDS
Mitochondrial dysfunction:
o Cytokines also cause the release of reactive oxygen species (ROS)
Where oxidative stress
leads to mitochondrial dysfunction and decreased O2 consumption by tissues
The combination of
o tissue hypoperfusion (from small vessel thrombus and vasodilation/hypotension)
o loss of barrier function
o decreased O2 consumption from mitochondrial dysfunction
o leads to tissue hypoxia and organ failure
ANTIINFLAMMATORY: Roger Bone hypothesized that a powerful anti‐inflammatory response already existed to balance the pro‐inflammatory response
and that anything that upset the balance too far in either direction (too much inflammation or failure to defend against invading
organisms) led to death
Anti‐inflammatory responses include:
o “Neuro‐inflammatory reflex”
Vagus nerve stimulates norepinephrine release from spleen
Norepinephrine causes acetylcholine release
Which inhibits the release of pro‐inflammatory cytokines
o IL‐10 production is increased
Which regulates T cell populations
Down‐regulates TNF‐alpha
o Extensive apoptosis of CD4+ T cells and B cells in spleen and lymph nodes
The combination of these anti‐inflammatory responses
o leads to immunosuppression with increased susceptibility to secondary infection
Summary on Pathogenesis The host responses to infection with both proinflammatory and anti‐inflammatory responses.
o The goal of the proinflammatory response is to eliminate invading pathogens
o The goal of the anti‐inflammatory response is to limit tissue injury
o A disruption of the balance in either direction can lead to death.
Clinical Features of Sepsis Organ system Mechanism Effect in Sepsis Signs and Symptoms
Lungs Capillary leak and edema Acute Respiratory Distress Syndrome Tachypnea
(ARDS) Hypoxia
Respiratory failure
Cardiac Reduction in cardiac Decreased cardiac output Tachycardia
contractility Mottled skin
Poor capillary refill
Troponin elevation
Renal Renal hypoperfusion, Acute tubular necrosis Decreased urine output
hypoxemia Acute renal failure
Microcirculatory dysfunction
Adrenals Decreased synthetic capacity Adrenal insufficiency Hypotension not
responsive to fluids
CNS Alterations in cell signaling Encephalopathy Confusion
Dysfunction of blood brain
barrier
Coagulation Thrombus formation Disseminated intravascular Thrombocytopenia
Consumption of clotting coagulation (DIC) Elevated INR, fibrinogen, D‐
factors and platelets dimer
Bleeding, petechiae,
purpura
Liver Hypoperfusion Dysfunction of reticuloendothelial Hyperbilirubinemia
system jaundice
“Shock liver” Transaminitis
Elevated INR
Confusion
Pancreas Increased gluconeogenesis Poor glucose control Hyperglycemia or
Insulin release suppressed Neutrophil function suppressed hyoglycemia
Insulin resistance
GI tract Depression of gut barrier Translocation of bacteria from gut into Paralytic ileus
function systemic circulation
Immune Apoptosis of lymphocytes Increased susceptibility to secondary New infection
System Suppression of infection
proinflammatory cytokines
Acute Respiratory Distress Acute (within one week of inciting event)
Syndrome (ARDS) Bilateral opacities on CXR
NOT due to pulmonary edema
Moderate to severe hypoxemia
o PaO2/FiO2 ratio <300mmHg
Example: PaO2 of 100mmHg on 0.50 FiO2 P/F ratio = 200
Warning Signs and Fever or hypothermia: > 38°C or < 36°C
Symptoms Tachycardia
Tachypnea, dyspnea and/or hypoxia
Hypotension (Systolic BP <90, MAP <65)
Confusion, alteration in mental status
Appearance:
o Initially, skin will be warm, well perfused, flushed with bounding pulses
o But as shock progresses, blood is shunted to core organs and the skin becomes cool and mottled
Lab abnormalities: Elevated (>12,000) or depressed (<4000) WBC count
Hyperglycemia or hypoglycemia in absence of diabetes
Transaminitis
o Ischemic hepatitis or “shock liver”
AST and ALT are >1000 international unit/L
Hyperbilirubinemia
Acute renal failure
Thrombocytopenia
Elevated INR
Elevated lactate
Positive cultures
Look for signs or infection Pneumonia
of history and physical: o Productive cough
o Dyspnea
o Rhonchi on lung exam
Abdominal infection
o Nausea, vomiting, diarrhea
o Focal abdominal pain
o Rebound, guarding on abdominal exam
Urinary tract infection
o Dysuria, urinary frequency
o Costovertebral angle (CVA) tenderness on exam
o Cloudy urine
Cellulitis
o Skin warmth, erythema, focal tenderness
o Look for evidence of abscess or crepitus on exam
Management of Sepsis The most important management aspect of sepsis is the ability to recognize signs/symptoms of sepsis and also identity the
deteriorating patient.
Stabilize airway and Supplemental oxygen to help with O2 delivery to tissues
breathing: Many patients will require intubation due to:
o Increased work of breathing
Lactic acidosis metabolic acidosis respiratory compensation (hyperventilation)
o Airway protection
due to altered mental status
3‐hour bundle (needs to Obtain cultures prior to administration of antibiotics
be completed with 3 Administer broad spectrum antibiotics
hours of “time zero”) Measure lactate level
Administer 30ml/kg crystalloid IV fluids
o for hypotension or lactate ≥4mmol/L
6‐hour bundle (needs to Apply vasopressors
be completed with 6 o for hypotension that does not respond to initial fluid resuscitation
hours of “time zero”) to maintain a mean arterial pressure (MAP) ≥65mmHg
Re‐measure lactate if initial lactate elevated >2mmol/L
Re‐assess volume status and tissue perfusion
Identification of source Cultures all potential sources (blood, urine, ascites, wounds)
and eradication of Remove chronic IV lines
infection Drain abscesses
Debride, amputate soft tissue sources
Early antibiotics are KEY! For every hour from the onset of septic shock that antibiotics are delayed
o leads to an average decrease in survival of almost 8%.
If antibiotics are delivered within the first hour survival is 80%
Empirical – choice based on patient assessment, hospital antimicrobial susceptibility patterns
Spectrum – should cover anticipated pathogens
Lactic acidosis: Shock leads to tissue hypoxia
Intracellular aerobic respiration is replaced by anaerobic glycolysis with excessive production of lactic acid
Lactate level is an independent predictor of mortality:
o Retrospective analysis on cohort of 300 septic shock (hypotensive) patients divided up based on lactate level (< 2.5 or > 2.5)
Those with lactate <2.5 had lower NE doses, lower mortality (7.7% vs 43%), less severe organ dysfunction
o On the other hand, normotensive septic patients with high lactates (>4mmol/L) had higher mortality than normotensive
patients with lactate <4mmol/L
Repeat lactate if elevated >2mmol/L to determine if your current management is adequate
IV fluid resuscitation: Only required if patient is
o Hypotensive
o lactate ≥ 4
Crystalloid is the preferred fluid
o lactated ringers, 0.9% normal saline or plasmalyte
Recommended amount = 30 cc/kg body weight
Average patient in septic shock requires 4‐6 liters of fluid in the first 24 hours
Vasopressors: Start vasopressors
o if the patient has received fluid resuscitation and MAP remains <65mmHg
Vasopressors bind to alpha‐receptors leading to vasoconstriction
o 1st choice = Norepinephrine
o 2nd choice = Vasopressin or Epinephrine
Corticosteroids Studies support use of hydrocortisone 200 mg daily in patients in whom hypotension persists despite adequate fluid
resuscitation and vasopressor therapy
Does not improve survival but hastens recovery from shock
Reassessment It is important to go back and reassess your patient to determine volume status and whether organ perfusion is improving
Assess volume status:
o Physical exam:
Is the patient still dry on exam?
o Echocardiogram:
IVC collapsibility with respiration indicates that the patient still may more fluid
o Passive leg raise:
mimics a transient 200‐300cc fluid bolus – if BP improves with passive leg raise, they may still need more fluid
Assess for improvement in organ hypoperfusion:
o Improving mentation (mental activity)
o Improving blood pressure
o Improving urine output
o Improving lactate
Cystic Fibrosis
History 1700’s‐ "Woe is the child kissed on the brow who tastes salty, for he is cursed and soon must die"
1905‐ Meconium ileus first described
1938‐ Dr. Dorothy Andersen said, "Cystic Fibrosis of the Pancreas and its relation to celiac disease: a clinical and pathological
study"
1940’s‐ Autosomal recessive
1953‐ Sweat electrolyte defect described during NYC heat wave
1959‐ Sweat test first described
1983‐ Sodium and Chloride transport abnormalities described
1989‐ CFTR cloned
o Positional cloning
Epidemiology 1:2000 to 1:17,000 live births depending on the population.
o 1:569 in Ohio Amish
o 1:2,500 American whites
o 1:17,000 in American blacks
o 1:90,000 in Hawaiian Asians
1 in 25 North American whites are carriers
Presentation Presenting features
o Acute/persistent pulmonary symptoms‐ 51%
o FTT/malnutrition‐ 43%
o Steatorrhea‐ 35%
o Meconium ileus‐ 19%
o Family history‐ 17%
Median age at diagnosis is 6 months
10% of diagnoses made after age 18.
CFTR Cystic Fibrosis Transmembrane Regulator
Present in epithelial cells of the:
o pancreas, salivary glands, sweat glands, intestine, respiratory and reproductive tracts
Gene is on the long arm (q‐arm) of chromosome 7, 250kB in length, 27 exons, 6.5 Kb
mRNA
Protein is 170 kD, 1480 amino acids
ATP Binding Cassette (ABC) Transport Family
Protein Kinase A
ATP regulated Chloride channel
Regulatory protein for other channels
Only 5‐10% activity needed for normal chloride transport
CFTR Function The primary defect in CF is
o abnormal function of an epithelial chloride channel protein encoded by the CF
transmembrane conductance regulator (CFTR) gene at chromosomal locus 7q31.2.
o where the changes in mucus are considered secondary to the disturbance in
transport of chloride ions.
In normal epithelia:
o the transport of chloride ions across the cell membrane occurs through
transmembrane proteins, such as CFTR, that form chloride channels.
Mutations in the CFTR gene render the epithelial membranes relatively impermeable
to chloride ions
o However, the impact of this defect on transport function is tissue‐specific. 1. Top, In cystic fibrosis (CF), a chloride channel defect
o Sweat Glands: in the sweat duct causes increased chloride and sodium
concentration in sweat. Bottom, Patients with CF have
The major function of the CFTR protein in the sweat gland ducts decreased chloride secretion and increased sodium and
is to reabsorb luminal chloride ions and augment sodium reabsorption through water reabsorption in the airways, leading to
the epithelial sodium channel (ENaC). dehydration of the mucus layer coating epithelial cells,
defective mucociliary action, and mucous plugging.
Therefore, in the sweat ducts, loss of CFTR function leads to CFTR, cystic fibrosis transmembrane conductance
decreased reabsorption of sodium chloride regulator; ENaC, epithelial sodium channel responsible
for intracellular sodium conduction.
o causes the production of hypertonic (“salty”) sweat (top).
o Respiratory and Intestinal
CFTR in the respiratory and intestinal epithelium is an active luminal secretion of chloride.
Where CFTR mutations result in
o loss or reduction of chloride secretion into the lumen (bottom).
o luminal sodium absorption through ENaCs is increased
Both of these ion changes increase passive water reabsorption from the lumen
o lowering the water content of the surface fluid layer coating mucosal cells
Unlike the sweat ducts, there is no difference in the salt concentration of the surface fluid layer coating the
respiratory and intestinal mucosal cells in normal persons and in those with CF
Instead, complications in CF comes from an isotonic but low‐volume surface fluid layer.
o In the lungs:
this dehydration leads to defective mucociliary action and the accumulation of concentrated, viscid secretions
which obstruct the air passages and predispose to recurrent pulmonary infections.
Other Regulatory Roles of Epithelial Na Channel (ENaC)
CFTR Electroneutral Na absorption
HCO3/Cl exchanger (pancreas)
ICOR Cl channel
Ca and swelling activated CL channel
ROM K2 K channel
Gap junction channels
Mucus secretion
ATP transport
Glutathione transport
AQP3,7 (water channel)
KCNN4 K channel
KVLQT1 K channel
CFTR Mutations Since the CFTR gene was cloned in 1989, more than 1300 disease‐causing mutations have been identified.
Mutations are classified as severe or mild, depending on the clinical phenotype:
o Severe mutations are
associated with complete loss of CFTR protein function
o Mild mutations
allow some residual CFTR protein function
The most common severe CFTR mutation is
o deletion of three nucleotides coding for phenylalanine at amino acid position 508 (ΔF508)
causes misfolding and total loss of the CFTR
Worldwide, ΔF508 mutation is found in approximately 88% of patients with CF 50% are homozygous
o Since CF is an autosomal recessive disease, affected persons harbor mutations on both alleles.
o Although CF remains one of the best‐known examples of the “one gene–one disease” axiom
there is increasing evidence that other genes modify the frequency and severity of organ‐specific manifestations.
Example – mannose‐binding lectin
o a key effector of innate immunity involved in phagocytosis of microorganisms
o where polymorphisms in one or both mannose‐binding lectin alleles produce lower circulating levels of the protein
are associated with a three‐fold higher risk of end‐stage lung disease
due to chronic bacterial infections.
Frequency depends on ethnicity
o In Ashkenazi Jews, W1282X is the most common mutation
Classes of Mutations
o Normal
o Class 1: No synthesis
o Class 2: No maturation
o Class 3: Blocked Regulation
o Class 4: Decreased Conductance
o Class 5: Decreased Abundance
Despite 20+ years of research, it has been difficult to connect how the CFTR defect leads to the pulmonary disease.
Why?
o Difficult to set up in vitro model of epith cells
o Variety of tissue specific roles of CFTR (too much focus on the sweat gland)
o Transgenic mouse model does not have spontaneous lung disease
o In vivo, difficult to measure Airway Surface Liquid (ASL) characteristics
Theories
o “ASL low volume” leads to mucus stasis, decreased ciliary beat, inhibited bacterial
clearance.
o “ASL too salty” and salt sensitive defensins don’t function.
o Abnormal submucosal gland secretions.
o Abnormal modulation of epithelial inflammation
High salt model
o This is what happens in the sweat gland, chloride cannot be reabsorbed, sodium and
water reabsorption are also decreased, ASL becomes very salty.
Low volume model
o Major defect is lack of regulation of ENaC, Na is hyper‐absorbed, Cl follows through
other pathways, water follows passively, low volume of ASL leads to increased mucus
concentrations, delayed transport, mucus adhesions.
Diagnosis Chest X‐ray
o Upper lobe predominant bronchiectasis
Signet ring
Tram tracking
o Peribronchial cuffing
o Nodules/mucous impaction
o Blebs, cysts
o
Morphology Pancreas:
The anatomic changes are highly variable and depend on which glands are affected and on the
severity of this involvement.
Pancreatic abnormalities are present in 85% to 90% of patients with CF.
o In the milder cases
there may be only accumulations of mucus in the small ducts, with some dilation of the
exocrine glands.
o In more advanced cases
usually seen in older children or adolescents
the ducts are totally plugged
causing atrophy of the exocrine glands and progressive fibrosis
The total loss of pancreatic exocrine secretion impairs
o Obstruction of ducts with inspissated secretions leads to dilation, destruction and fibrosis.
o Exocrine insufficiency/fat malabsorption
Small Intestine
Thick viscid plugs of mucus are found in the small intestine of infants and may
cause small bowel obstruction called meconium ileus.
Pulmonary:
The pulmonary changes are the most serious complications of this disease (Fig. 6–6).
These changes stem from obstruction and infection of the air passages secondary to the viscous mucus
secretions of the submucosal glands of the respiratory tree.
o Obstruction
The bronchioles often are distended with thick mucus
associated with marked hyperplasia and hypertrophy of the mucus‐secreting cells
o Infection
Superimposed infections can give rise to severe chronic bronchitis and bronchiectasis.
Development of lung abscesses is common.
Three Most Common bacteria include:
Staphylococcus aureus
Haemophilus influenzae
Pseudomonas aeruginosa
o High salt concentrations/defensins
o Pseudomonas exhibits changes in chronic infection
Mucoidy, biofilm
LPS changes
Loss of flagella dependent motility
Slower growth
Burkholderia cepacian is associated with rapid decline, and infection with this
organism has been associated with fulminant illness (“cepacia syndrome”).
Aspergillus fumigatus is commonly cultured (>50% of adults).
Emerging pathogens:
Stenotrophomonas maltophilia
Achromobacter xylosoxidans
Mycobacterium abscessus
Sinus effects:
o Hypertrophy/hyperplasia of secretory elements
o Inflammation and edema
o Polyps
o Transepithelial electric potential is raised.
Liver:
The liver involvement follows the same basic pattern.
o Bile canaliculi are plugged by mucinous material, accompanied by ductular proliferation and portal inflammation.
o Hepatic steatosis is a common finding in liver biopsies.
Over time, cirrhosis develops, resulting in diffuse hepatic nodularity.
o Such severe hepatic involvement is encountered in less than 10% of patients.
Reproductive:
Females
o Endocervicitis, mucus distended cervical glands
o Anovulatory
o 20% infertile
Males
o Azoospermia (A complete absence of sperm from the fluid ejaculated during orgasm) and infertility are found in 98% of the
affected males who survive to adulthood
Where Bilateral absence of the vas deferens is a frequent finding Failure in transport, not production (CBAVD)
In some males, this may be the only feature suggesting an underlying CFTR mutation.
MESA and ICSI
Summary of GI Effects GI Tract Effects
o Meconium ileus (5‐15% newborns)
o Distal intestinal obstruction syndrome
o Rectal prolapse
o Focal biliary cirrhosis (25%)
o Hypoplastic GB (25%), gallstones (10%)
o Fatty Liver (30%)
Pancreatic exocrine Diagnosis
insufficiency o Symptoms
o 72 hour fecal fat collection
o Fecal chymotrypsin or fecal elastase
o Vitamin ADEK levels
Therapy
o Enzyme replacement
o Dosing by fat intake, body weight or symptoms
CF Related Diabetes (CFRD) Pancreatic endocrine insufficiency
Symptoms‐ polyuria, polydipsia, weight loss, unexplained drop in lung function
Screen yearly
Bone and Joint Disease Osteopenia and osteoporosis in 40‐60%
Vitamin D deficiency, calcium malabsorption, accelerated bone loss, hypogonadism, inactivity, low BMI, medicine effects, ?
Direct CFTR effect
Episodic arthritis
Hypertrophic Pulm OsteoArthopathy
CF‐ Sweat glands Pronounced abnormality in Na, Cl homeostasis is well understood
o No obstruction
o No pathologic abnormalities
Increased sensitivity to dehydration in hot weather
Salty taste to sweat
Diagnosis Clinical evidence of CF
Laboratory evidence of CF includes:
o Sweat test; Genetic test; Nasal potential
Sweat test (quantitative pilocarpine iontopheresis)
o minimum 50 mg sweat
o Normal‐ sweat chloride <40 mmol/L, 40‐60 borderline, > 60 abnormal
o Needs to be done in an accredited lab
Genotyping
o Commercial testing panels (25‐97 most common mutations)
o Sensitive and specific in Caucasians with typical disease
o Less effective in the non‐white population, non‐classic phenotype
o Full sequencing of the CFTR gene available (30 day turn‐around time)
o Becoming more important to know the mutation for therapy
Newborn Screening
o Illinois and most other states have started screening all newborns for cystic fibrosis.
o Combination of a blood test, sweat test and mutation panel.
o Improves nutritional status, growth and intellectual outcomes.
o Fewer life threatening complications and hospitalizations.
o Families avoid the average 6‐15 month delay in diagnosis.
Therapy of CF Multidisciplinary team approach
Airway clearance
Antibiotics
o Chronic oral suppressive
o Cycled, nebulized antibiotics
Inhaled preservative free tobramycin (TOBI)
Randomized, double blind, trial of 520 patients, 300mg TOBI BID vs. placebo
28 days on therapy, 28 days off
FEV1 improved 10%
Also improvements in pseudomonas density, exacerbation rate
Inhaled Aztreonam Lysine (Cayston)
Nebulized Colistin
o IV antibiotics for exacerbations
Bronchodilators
Nutrition
o Calorie maintenance
o Enzyme replacement
o Vitamin replacement
Anti‐inflammatory
o Oral Steroids
delay progression of lung disease, BUT a high incidence of CFRD, growth suppression and cataracts
o Inhaled Steroids
50% of patients are on them, difficult to show a benefit
o NSAIDS
High dose ibuprofen‐ slowed decline in lung function, most evident in 5‐13 year olds with mild lung disease, have to monitor
serum levels
o Azithromycin
Mucolytics
o rhDNase (Dornase alpha, Pulmozyme)
Extracellular DNA from wbcs can compose up to 10% of CF secretions and increase viscosity
In studies, decreased age adjusted risk of exacerbation, improved spirometry, QOL, dyspnea scores
o Hypertonic saline
mechanism of action (increased height of ASL, induction of cough, combination of both)
In studies, slight improvement in spirometry, significant decrease in exacerbations
Lung Transplantation
o CF is the 3rd most common indication for transplant
o Slightly better outcomes
o Refer when FEV1 <30% predicted
o
The “Future” of Therapy for Therapy targeted at the specific defect caused by the mutation
CF Potentiators treat Class 3
o VX 770 (Ivacaftor)
Clinical trial of the potentiator VX 770 in CF patients with the G551D mutation
Correctors, Chaperones treat Class 2
o VX 809 (Lumacaftor)
Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR
Gene transfer
o Vehicle using adenovirus or liposomes
o Pros
Single gene defect
Only need 5‐10% activity for normal Cl transport function
Lung is accessible
Lungs are normal at birth
o Cons
Epithelium is difficult to transfect
Expression is short
Repeat administration not always possible
CFTR is multi‐functional and not all of the functions are equally easy to correct.
Clinical success is difficult to measure
o 20+ trials to date, most are proof of concept
Comparison of Therapies Improvement in FEV1 (%) Reduction in Exacerbation Cost/Month
Rate (%)
Azithro 4.4 40‐50 400
Flovent Unknown Unknown 150
Colistin 0.37 Unknown 3,600
Hypertonic Saline 3 56 75
rhDNase 5‐16 28‐37 2,500
TOBI 6‐10 26 5,700
Cayston 6‐10 NS‐45 5,800
Ivacaftor 10 55 24,000
Orkambi 2.5‐4 30‐40 21,600
Nutrition in CF Increased caloric demand
o May need to take in 3500‐4500 cal/day
Decreased intake
Malabsorption
CF related diabetes
Good nutritional status and weight >50% percentile associated with better outcomes
Old school teaching is quantity over quality
Oral supplements (Boost, Scandishakes—600 cal/8oz)
Tube feeds
o Place a feeding tube into the stomach
o Run feeds (50% caloric requirement) overnight
o Enzymes at the start of the feed
A Nutritionist’s Advice to CF Add calories by adding peanut butter or mayonnaise to foods
Patients Use gravies and sauces on vegetables, meats and starches
Use salad dressing to marinate meats
King sized candy bars are quick snacks for on‐the‐go
Use heavy cream in place of milk
Don’t push away the salt shaker
Fast foods and prepared foods help to simplify meals. They not only pack in a lot of calories and fat, but tend to be high in
sodium as well!
Conclusions Cystic fibrosis is an autosomal recessive disease caused by a mutation in the Cystic Fibrosis Transmembrane Conductance
Regulator gene.
The details of how that mutation leads to the pulmonary disease are still unclear.
Median survival is increasing into adulthood.
Therapy includes airway clearance, antibiotics, mucolytics and nutritional support.
Future therapy will focus on the processing and modulation of CFTR, restoring ion transport.
Gene therapy is still years away.
Pulmonary Ultrasound Lab
Case 1 – History A 22‐year old Male arrives to the Emergency Department by EMS after being stabbed by a knife during an altercation at a party.
He reports feeling pain to his left upper back and shortness of breath.
His PMHx and SurgHx are both negative.
He denies any taking medications or having any drug allergies.
Case 1 – Physical Exam Vitals
o Temp 37.1 BP 108/73 HR 114 RR 24 O2 sat 94% on RA
Physical exam
o Constitutional: Moderate distress
o Cardiac: Tachycardic, regular rhythm, no murmurs
o Pulmonary: Absent breath sounds on left, hyperresonance on percussion; clear breath sounds on right. Tachypneic, mild
respiratory distress
o Skin: 2 cm linear wound to left mid‐upper back
Case 1 – Workup What radiographic studies would you order on this patient?
o Answer:
CXR
Bedside US (eFAST)
o Can consider CT chest, but limitations include time, stability of patient and risk of decompensation, exposure to radiation
Case 1 – 1st CXR Describe the CXR findings in this patient.
o Answer:
Lack of pulmonary markings on left (air=black in pleural space)
Deep sulcus sign (costophrenic sulcus lower than contralateral side)
Atelectatic lung (due to recoiling of lung to its resting state when the negative intrathoracic pressure
is lost)
What is your suspected diagnosis?
o Answer
Pneumothorax on the left
Explain the cause behind these findings.
o Answer:
Normally, there is negative, vacuum‐like intrathoracic/intrapleural pressure caused by the competing natural forces
between the chest wall (wants to pull out) and the lungs (want to collapse).
A pneumothorax results when air enters the pleural space (between parietal and visceral pleura), allowing it to equalize with
atmospheric pressure ‐‐> lungs collapse, thoracic wall expands outward.
Case 1 – Lung Ultrasound As part of your eFAST (Extended Focused Assessment with Sonography in Trauma) exam, you obtain these findings.
Describe and demonstrate how to perform a complete eFAST exam on the mannequin and state what you would be looking for.
o Answer: see handout from PCM2 US lab
Subxiphoid view: Pericardial effusion
RUQ view: Anechoic fluid in morison’s pouch and above the diaphragm
LUQ view: Anechoid fluid in splenorenal recess, infra‐diaphragmatic region, above the diaphragm
Suprapubic view: Anechoic fluid in pouch of douglas (female) or in retrovesicular pouch (males)
Right and left thorax : eval for presence or absence of lung slide at pleural line, seashore sign vs barcode sign on M‐mode
What are the ultrasound findings of a normal lung?
o Answer:
Echogenic rib with posterior rib shadow
Hyperechoic (bright) pleural line between the ribs
"Lung slide" = "Ants marching" along the pleural line, indicating normal sliding of parietal and
visceral pleura on each other
On "M‐Mode" (motion mode), line across pleura would reveal "seashore sign"
A‐line and B‐lines
What are the ultrasound findings of a pneumothorax?
o Answer:
Lack of "lung slide" of the pleural line
M‐Mode would reveal "barcode sign" or "stratosphere sign"
Case 1 – Reassessment The nurse calls you back to reassess the patient as he appears to have deteriorated.
o New vitals: HR 142; BP 74/43
o PE: Neck: Right tracheal deviation, distended neck veins
Case 1 – 2nd CXR Describe the CXR findings.
o Answer:
Same findings as pneumothorax with additional finding:
Deviated mediastinum away from side of pneumothorax
Explain the cause of this patient’s deteriorated condition.
o Answer:
Air enters the pleural cavity (similar to pneumothorax), but is trapped during expiration, usual
due to a ball valve‐like mechanism. Air continues to build up resulting in increased intrathoracic
pressure on the affected side, collapsing the lung completely and shifting the mediastinum to the contralateral side.
Venous return to the heart is compromised, reducing cardiac output and risk of death
How would you manage this patient?
o Answer:
Needle decompression
Tube thoracostomy (smaller tube size needed, since only air)
Case 2
Case 2 – History A 52‐year old male arrives by EMS to the ED after falling 10 feet from to top of a ladder. He states the ladder slid out from
underneath him. He landed with his right upper back across the rungs of the ladder. His complaints include right sided chest
and back pain, as well as shortness of breath.
His PMH includes HTN and he is currently on lisinopril.
He has no PSurgHx.
Case 2 – Physical Exam Vitals
o Temp 36.4 BP 123/78 HR 134 RR 29 O2 sat 92% on RA
Physical exam
Constitutional: Moderate distress
o Cardiac: Tachycardic, regular rhythm, no murmurs
o Pulmonary: Diminished breath sounds on the right, dullness to percussion; normal breath sounds on left
o Chest: Subcutaneous emphysema on right
Case 2 – CXR Describe the CXR findings in this supine patient.
o Answer:
Since the patient is supine, blood has layered posteriorly and will have a hazy appearance on
the affected side
Upright CXR findings (Blood going to dependent portion of thorax)
Blunting of costophrenic angles
Large effusion can cause mediastinal shift and opacification
200ml needed to identify fluid on PA and 75ml on lateral (US can detect 20ml)
What can cause these physical exam findings?
o Answer:
Hemothorax
Pleural effusion
How would this finding appear on ultrasound?
o Answer:
Anechoic (black)
Case 2 – Ultrasound Describe and demonstrate how to assess for intrathoracic fluid using ultrasound.
o Answer:
Probe selection: lower frequency curvilinear or phased array transducer
Probe orientation: longitudinal with indicator towards head
Probe placement: coronal posterior axillary line at level of xiphoid process, or between 10‐
11th ribs on right, 9‐10th ribs on left
Evaluate above the diaphragm for anechoic (black) fluid
o Also, note ”spine sign” – visible vertebrae above the diaphragm;
normally can’t be seen since lung (air filled) will not allow transmission of ultrasound waves.
However, when fluid is present above diaphragm, which is a great US beam conductor, posterior structures (spine) can be
seen
What is the appropriate management for this patient?
o Answer:
Tube thoracostomy (would require bigger tube size than pneumothorax, since fluid can clog tube and hinder flow)
Case 3
Case 3 – History An 83‐year old patient presents to the ED with altered mental status.
She lives in a nursing home.
The patient is moaning and is unable to provide any information. EMS conveys that the nursing home staff noticed a change
from baseline yesterday, but did not comment on anything specific.
Reviewing the nursing home records reveals a PMH including stroke with residual dysarthria, dementia, hypertension and
diabetes mellitus.
Case 3 – Physical Exam Vitals
o Temp 39.4 C BP 93/69 HR 113 RR 34 O2 sat 89% on room air
Physical Exam
o Constitutional: Cachectic, somnolent in moderate distress
o Cardiac: Tachycardic, regular rhythm, normal S1 and S2, no murmur
o Pulmonary: Tachypneic, rhonchi right lung field; no rhonchi, rales or wheezing to left lung field
o Abdomen: Normal bowel sounds, soft, non‐tender, non‐distended
o Neurology: AAOx0
o Extremity: Contractured upper extremities
Case 3 – Workup What is your differential diagnosis?
o Pneumonia; Empyema; Viral URI; PE; Pleural effusion; CHF ;PTX; COPD; Urosepsis; Bacteremia; AMI; CVA (ischemic or
hemorrhage); Electrolyte abnormality
What radiologic studies would you order or perform on this patient?
o CXR
o US (Pulmonary, limited echo?)
o May consider CT scan (head, chest)
Case 3 – CXR Describe the CXR findings performed on this patient.
o Consolidation in right upper lobe.
o Air bronchogram seen
What is your suspected diagnosis?
o Right upper lobe pneumonia.
Most likely due to aspiration, given hx for stroke
Explain the pathology behind these CXR findings.
o Filling of alveoli with inflammatory fluid or pus consolidation
o Can be widespread, patchy or lobar
Case 3 – Ultrasound As you read about this diagnosis, you find that X‐ray is found to have a sensitivity ranging from 46‐77%, while US has a sensitivity
ranging from 93‐100% (using CT scan as the gold standard).
Armed with this information, you decide to perform a lung US.
Case 3 – Ultrasound (Left Describe the findings you see on the unaffected left lung. The probe is
Lung) placed at the midaxillary line at the level of T8.
o Hyperechoic rim of rib with shadow
o Hyperechoic pleural line with lung slide
o No visible lung parenchyma below pleural line (b/c air filled)
o ‐Spleen (visible at level where US placed)
Case 3 – Ultrasound (Right The probe is placed on the right posterolateral lung field. Describe the findings you see on
Lung) the affected right lung.
o Absence of pleural line between ribs
o ”hepatization” of lung
o Sonographic air bronchograms = hypoechoic pulmonary consolidation containing
hyperechoic lines and moving flecks with respiration
Most specific sign for dx of Pneumonia
Explain the cause of these findings.
o Inflammatory and purulent fluid fills the alveoli solid appearance of lung (”hepatization” of lung)
o Air bronchograms: Thought due to trapped air bubbles in small airways within a consolidation
Gross Morphology In lobar pneumonias, the inflammatory process leaves the affected lung airless and with a liver‐like consistency on gross exam ‐
Correlation: “Hepatization” “hepatization”
of the Lung
Case 3 – Management What is the most appropriate management of this patient?
o ABCs of resuscitation
o IV abx
o Admit
Case 3 – Limitations What are some limitations to using US when evaluating for pneumonia?
o Area of consolidation must involve some of the outer pleural surface
o Smaller consolidations may be difficult to detect
o Other causes of consolidation may appear similar (atelectasis, infarction, etc)
Define Point of Care Point of Care Ultrasound Definition:
Ultrasound. o Focused exam with specific goal and purpose
o Findings easily recognizable
o Easily learned skill
o Performed at bedside
o Performed quickly
Summarize its Utility in Utility in Patient Care:
Patient Care. o Improves patient care
o Reduce time to diagnosis
o Avoidance of radiation
o Decrease cost of healthcare
o Standard of care for procedures
Respiratory Tract Infections
Upper Respiratory Tract URI’s are the most common infections in the United States, with 75 million physician visits per year.
Infections (URIs) The syndromes under the designation of URI are
o Rhinitis; Sinusitis; Otitis; Pharyngitis; Laryngotracheitis; Epiglotitis; Bronchitis
There is a seasonal predisposition (fall/winter) to URIs.
The vast majority of these syndrome are viral and self‐limited and therefore do not require specific antimicrobial treatment.
Infectious Rhinitis “Rhinitis” refers to “a runny nose”
there are multiple potential causes of rhinitis – including
o infections
o allergies
o over‐use of nasal decongestants
o systemic diseases (such as granulomatosis with angiitis)
Infectious rhinitis is synonymous with the “common cold”.
Viruses are the etiologic agents in the vast majority of infectious rhinitis:
o Rhinovirus (30%)
o coronavirus (10%)
o parainfluenza
o influenza
o Respiratory Syncytial Virus (RSV)
o adenovirus
No etiologic agent is identified in >50% of patients with infectious rhinitis simply because
o the specific cause is not investigated
o knowing the specific cause will not change management.
Acute Sinusitis Acute sinusitis refers to an infection in the sinuses themselves.
o Where acute sinusitis commonly occurs after acute or chronic rhinitis.
Impairment of drainage of the sinuses
o by inflammatory edema of the mucosa is an important contributor to the pathogenesis of acute sinusitis.
The diagnosis for acute infection is a clinical diagnosis
o patients present with:
congestion
sinus tenderness
fevers
purulent nasal drainage
Obtaining sino‐nasal cultures in general is not helpful.
Most (>90%) are viral in etiology
o the minority are bacterial
which represents bacteria in the oronasal cavity:
S pneumonia
H. influenza
Moraxella
Oral anaerobes
Treatment:
o Because the majority of etiologic agents are Viral
the most appropriate treatment is NO antibiotics.
o However, antibiotics are, unfortunately, still frequently prescribed for patients presenting with acute sinusitis symptoms
resulting in inappropriate antibiotic overuse.
If there is strong clinical evidence or suspicion of bacterial sinusitis
o antibiotics with spectrum against upper airway bacteria are first line:
ampicillin
amoxicillin
trimethoprim‐sulfamethoxazole
amoxicillin‐clavulanate
Pharyngitis Pharyngitis refers to infection/inflammation of the pharynx.
Patients present with
o sore throat
o fever
The etiology is viral in 70% of cases.
“Strep throat” is pharyngitis caused by group A or B beta hemolytic streptococcus
o Presents with
high fevers
patchy tonsillar exudates.
o Treatment prevents the complications (rheumatic fever and post strep glomerulonephritis) but does not change the
course/duration of the pharyngitis itself.
If can be difficult to differentiate between viral and bacterial pharyngitis on the basis of clinical findings alone
o therefore a throat culture or rapid diagnostic test should be performed to detect Streptococcal infection.
Epiglottitis Epiglottitis is infection of the epiglottis.
Epiglottitis occurs most often in children 2‐7 years of age.
Patients present with
o high fever
o sore throat
o drooling
o sitting upright
o signs of systemic toxicity.
Swelling of the epiglottis and surrounding structures can result in airway compromise and complete airway obstruction which is
a medical emergency.
Radiographs of the lateral neck may show an enlarged epiglottis protruding from the anterior wall of the hypopharynx ‐ the so‐
called “thumb sign”.
Many patients will have positive blood cultures for the causative bacteria.
The most common etiologic organisms are
o Haemophilus influenzae
o Group A strep
o Haemophilus parainfluenzae.
Fortunately with immunization of infants against influenza B epiglottis is being seen less commonly.
Treatment:
o Emergent evaluation by an otolaryngologist to assess and secure the airway
o Antibiotic therapy:
amoxicillin‐clavulanate
ampicillin‐sulbactam
3rd generation cephalosporin
Acute Bronchitis Acute bronchitis refers to infection/inflammation of the large upper airways.
It is common
o the 9th most common cause of all outpatient visits
o incidence is higher in the fall/winter
Patients present with
o Cough for >5 days with purulent sputum production.
Etiologic agents are most commonly viral:
o Influenza
o Parainfluenza
o respiratory syncytial virus (RSV)
o coronavirus
o adenovirus
o rhinovirus
Bacterial causes include
o Mycoplasma
o Strep pneumoniae
o Haemophilus influenzae
o Bordetella pertussis.
In children, Bordetella pertussis presents as “whooping cough”.
In adults who are infected with B pertussis (because their protection from immunization has waned if not re‐immunized) can
present with a protracted cough. (presence of a wet cough lasting more than 4 weeks)
Treatment is effective only if diagnosed early.
Treatment:
o consists of supportive care (rest, drink fluids)
Routine antibiotics are not suggested since most cases of acute bronchitis are caused by viruses.
Cough syrups and anti‐tussives generally do not have much effect.
In large trials, mucolytics, which pull fluid into the airways to make the mucous less viscous and easier to cough up, have not
been shown to be of much effect either.
Lower Respiratory Tract Pneumonia refers to lower airway infection and inflammation
Infections (URIs) = Pathogens can reach the lungs by one of five routes:
Pneumonia o Direct inhalation
o aspiration of upper airway contents
o spread along the mucous membrane surface
o hematogenous spread
o rarely direct penetration
Epidemiology:
o There are 5.6 million cases of pneumonia annually and 1.7 million hospital admissions.
Despite the invention of penicillin
o the mortality rate of pneumonia has not improved over the years (outpatient morality 1‐5%; inpatient morality 15‐20%).
o Pneumonia and influenza are the 6th leading causes of death (and the leading causes of death from infection)
Clinical predisposing factors for pneumonia include:
o Old age
o Underlying pulmonary disease
o Smoking:
results in injury to mucociliary apparatus
resulting in decreased airway clearance
o Recent viral illness
results in injury to mucociliary apparatus
resulting in decreased airway clearance
o Diabetes mellitus
o Chronic kidney disease
o Immunodeficiency
Patients present with
o Cough
o sputum production
o shortness of breath
o fever
o patients may appear acutely ill or toxic.
Note that Elderly patients may not present with this typical constellation of symptoms.
o They may present with
mental status changes
“not acting quite themselves”
There may be signs of consolidation on exam
o Crackles
o Rhonchi
o increased bronchial breath sounds
o vocal fremitus
o dullness to percussion over the areas of consolidation
o leukocytosis.
Diagnostic testing:
o Chest‐xray will show a focal infiltrate.
If there is an associated Pleural Effusion
a thoracentesis should be performed to assure the pleural fluid is not infected (Empyema)
o The yield of blood and sputum cultures is generally low.
Image: Right upper lobe consolidation with air bronchograms
o
Pneumonias have been classified as bronchopneumonia and lobar pneumonia
o Bronchopneumonia is
Patchy consolidation
usually involves more than 1 lobe
represents infection that starts in the bronchioles and spreads to parenchyma.
Infecting organisms exhibit more variation than in lobar pneumonia and include:
Staphylococci
Streptococci
Haemophilus influenzae
Pseudomonas aeruginosa Nosocomial acquired
o Lobar pneumonia is
Contiguous
affects all or part of one lobe
mostly caused by
Streptococcus pneumoniae (95%) – rusty sputum
Klebsiella – alcoholics with mucoid sputum
o While these distinctions between bronchopneumonia and lobar pneumonia might make sense pathologically, clinically there
is much overlap, and so the move have been made to categorize pneumonias as pneumonia syndromes
Pneumonia is classically classified into 7 syndromes which will be discussed:
o Community:
acquired typical pneumonia
acquired atypical pneumonia
o Hospital‐acquired pneumonia
o Aspiration pneumonia
o Chronic pneumonia
o Necrotizing pneumonia and lung abscess
o Pneumonia in the immunocompromised host
UItimately, what is most important for patient care is
o knowing which microbial agents are most likely to be the etiologic agents for a given pneumonia syndrome
because this will determine the most appropriate empiric antimicrobial treatment
o If a specific etiologic agent is determined
treatment can be further tailored.
Pneumonia Syndromes Community acquired pneumonia refers to lung infection in individuals who develop infection from the normal environment
o contrast to those who acquire infection in the hospital or healthcare environment called Nosocomial
Community acquired pneumonia is further classified into
o typical pneumonia and atypical pneumonia.
Typical community Community Acquired Typical Pneumonia
acquired pneumonia o Presents with:
acute onset
cough
sputum
fever
shaking chills
o X‐ray findings include
focal infiltrates
o Sputum gram stains show
Many polymorphonuclear cells (PMNs) and bacteria
The most common etiologic agents of typical community acquired pneumonia:
o Strep pneumoniae:
it is the number 1 cause of typical community acquired pneumonia
Patients present with:
Fever
shaking chills (it may be a single chill)
RUSTY COLORED SPUTUM
shortness of breath
pleuritic chest pain
S. pneumoniae appear as lancet shaped diplococci on gram stain.
o H. influenza:
o Moraxella catarrhalis:
o Staphylococcus aureus:
No organism is found in 30‐50% of patients.
Treatment:
o Empiric therapy is selected based on the most common etiologic agents:
o Outpatient therapy:
Macrolides or doxycycline
If co‐morbid illness or recent antibiotic therapy ‐ respiratory fluoroquinolone
o Inpatient therapy:
If patients are sick enough to be in the hospital or ICU ‐ macrolide + beta lactam.
Duration of therapy is at least 5 days, longer if the patient is sick
Atypical community Atypical Community Acquired Pneumonias refers to a subacute onset of symptoms and a longer prodrome of milder symptoms.
acquired pneumonia o Where atypical pneumonia has been referred to as “walking pneumonia”.
When sputum produced is gram stained, often there are no organisms seen negative gram stain
Most frequent etiologic agents:
o Mycoplasma pneumoniae walking pneumonia
o Chlamydia pneumoniae
o Legionella pneumophilia
o Viruses
Therapy:
o Macrolide
o Doxycycline
o Respiratory fluoroquinolone
While the distinction between typical and atypical community acquired pneumonia is made, in reality there is significant overlap
in presentation and organisms.
o Therefore the antimicrobial management is essentially the same.
Legionella (also known as Patients present with:
Legionnaire’s disease and o Headache
Pontiac Fever) o Myalgias
o high fever
o cough
o sputum production.
the organisms flourish in artificial aquatic environments.
Transmission of the bacteria is NOT person to person but via exposure to inhalation of a contaminated water source.
Outbreaks can and have occurred.
Patients who present with pneumonia after a cruise or hotel stay – consider Legionella
o Legionella can progress to multiorgan system failure
o Legionella is NOT cultured from blood or sputum.
o The bacteria is diagnosed via urinary legionella antigen.
Viral pneumonias Generally seasonal and can be difficult to differentiate from bacterial pneumonias
o can develop into a secondary bacterial pneumonia
Most common viral causes of pneumonia include:
o Influenza
o Respiratory Syncytial Virus (RSV) – seen in young children
o Adenovirus – pneumonia with gastritis
o Cytomegalovirus (CMV) – immunocompromised patients
o Parainfluenza
Although specific viruses can be identified via PCR of respiratory secretions, only influenza has specific therapy.
Influenza: Patient presents with:
o Fever
o Cough
o Headache
o sore throat
o patients feel MISERABLE
Influenza infection can progress to
o Pneumonia
o respiratory failure
o death
During influenza season, it is best practice to test patients suspected to have influenza and isolate them from other patients
early to prevent spread of the infection.
Treatment:
o Antiviral therapies for influenza (oseltamivir or zanamivir) should be started within 48 hours of clinical symptoms
o It is best to prevent influenza with annual immunization.
Community Pneumonia in Children may not present with the typical symptoms of pneumonia.
the pediatric population o They may have
Tachypnea
Fever
Mild cough
Dyspnea
Etiologic agents to consider:
o Under 2 years of age:
Viral (RSV, rhinovirus)
o 5‐10 years old:
Mycoplasma
o 10‐16 years old:
S. pneumoniae
Chlamydia
Hospital acquired Hospital acquired pneumonias are defined as pulmonary infections acquired in the course of a hospital stay.
pneumonia o 1% of all hospitalized patients with develop pneumonia (more in the ICU).
Hospital acquired pneumonia increases the length of time patients need to stay in the hospital by 7‐9 days, increases costs and
markedly increases mortality.
Pathogenesis:
o Hospitalized patients will become colonized with gram negative rods that can be aspirated.
o The patient’s host defenses are lowered by the co‐existent illness (especially underlying lung disease, heart disease, or kidney
disease requiring dialysis).
o Anything that bypasses the natural defenses (endotracheal intubation, decreased mental status) will increase the risk of
developing pneumonia
Key Organisms to be considered as etiologic agents of hospital acquired pneumonia:
o Klebsiella pneumoniae
o E coli
o Enterobacter
o Proteus
o Serratia
o Pseudomonas
o Acinetobacter
Therapy:
o Early initiation of empiric antibiotic treatment is important
Where broad empiric therapy typically consists of
Anti‐pseudomonal cephalosporin
Antipseudomonal Carbapenem
Beta lactam + beta lactamase
IF there is a clinical concern for MRSA and the etiologic agent Vancomycin should be included
Treatment is subsequently narrowed based on culture results
Aspiration pneumonia Aspiration of gastric contents into the lung typically occurs in:
o Markedly debilitated patients
o Patients with loss of gag reflex or swallowing reflexes alcoholics due to reduced gag reflex (CN 9 and 10)
o Patients with repeated emesis
The right lower lung is most often involved
o due to anatomy (right main bronchus follows a more straight path down), particularly the lower segments of the right upper
lobe and the upper segments of the right lower lobe.
The resulting pneumonia is in part a chemical reaction from the irritating effects of the gastic acid (Chemical pneumonitis)
followed by bacterial infection.
Aspiration pneumonia can become necrotic and progress to abscess development
Etiologic Organisms:
o aspiration pneumonia is usually polymicrobial a mix of gram negative aerobes and anaerobes
Treatment:
o Therapy consists of broad spectrum antibiotiocs, covering gram negatives and anaerobes
beta lactam + beta lactamase
3rd generation cephalosporin + metronidazole for the anaerobes
Chronic pneumonia Chronic pneumonia is characterized by the subacute onset of symptoms, typically >6 weeks
It is caused by:
o Slow growing organisms:
Mycobacterium
Nocardia
Actinomyces
o Endemic fungi:
Histoplasmosis
Blastomycosis
Coccidiomycosis)
o Coxiella
o Tularemia
o an anatomic problem (obstructed airway)
Treatment is challenging because of the wide array of potential etiologies.
Attempts at culture and pathologic diagnosis are important in order to prescribe appropriate therapy and duration.
Lung abscess Abscess refers to a parenchymal infection that leads to tissue destruction, necrosis, suppuration and cavitation.
Abscesses can result from:
o any necrotizing pneumonia:
Staphylococcus aureus
Streptococcus pneumoniae
Klebsiella foul smelling sputum
Pseudomonas
o Aspiration
o Tooth abscess
o Septic emboli
Commonly isolated organisms include
o anaerobic mouth organisms:
bacteroides
fusobacterium
peptostreptococcus
o aerobic and anaerobic streptococcus
o gram negative rods.
Abscesses are often polymicrobial
Therapy:
o Piperacillin‐tazobactam
o Clindamycin – covers anaerobes above the diaphragm
o Duration of therapy is prolonged (up to 4‐6 weeks)
Complications include:
o Empyema
o Pulmonary hemorrhage
o Secondary amyloidosis
Empyema refers to infection that has spread into the pleural space.
Most will not be cured with antibiotics alone and will need to be drained.
Failure to drain the lung will result in organization of the empyema and fibrosis within the pleural space.
Pneumonia in the Pneumonia is a serious complication in patients with suppressed immune defenses.
immunocompromised A wide variety of infectious agents, some which do not cause infection in normal hosts, can be etiologic agents and are called
“opportunistic infections”.
Neutrophil dysfunction:
o Causes include:
Chemotherapy
Leukemia
Chronic Granulomatous Disease (CGD) Organisms:
gram negative rods
Staph
Aspergillus
Candida
T cell dysfunction:
o Causes include:
AIDS
T cell lymphoma
solid organ transplant
DiGeorge Syndrome
o Organisms include:
Cytomegalovirus (CMV)
Herpes Simplex Virus (HSV)
Pneumocystis
Listeria
Candida
Aspergillus
Cryptococcus
Mycobacteria
B cell dysfunction:
o Causes include:
Splenectomy
Lymphoma
Myeloma
Gamma globulin deficiency Organisms:
S pneumoniae
H flu
Neisseria
Klebsiella
E coli
Giardia
Additional Pearls: Some conditions or risk factors related to specific etiologic agents of pneumonia:
Exposure to bat or bird droppings Histoplasma capsulatum
Exposure to birds Chlamydophila psittaci
Exposure to rabbits Francisella tularensis (tularemia)
Exposure to farm animals Coxiella burnetti
Hotel or cruise ships Legionella
Travel to SW USA Coccidiosis
Structural lung disease Pseudomonas
Alcoholism Anaerobes, Klebsiella
Things to think about if no response to empiric therapy:
o Inadequate dosing of antibiotic
o Wrong antibiotic (resistant pathogen)
o Wrong diagnosis (maybe it is not pneumonia, but pulmonary embolism, ARDS, pulmonary edema or hemorrhage)
o Complication (empyema, abscess, drug fever, another infection).
o Host factors (older patients respond slower)
Summary Table: If bacteria are being considered as etiologic agents of respiratory tract infection
Condition Potential Etiologic Bacteria Empiric Antibiotic Options
Acute Sinusitis S pneumonia, Ampicillin
H. influenza Amoxicillin
Moraxella Trimethoprim‐Sulfamethoxazole
Pral anaerobes Amoxicillin‐clavulanate
Epiglottitis Haemophilus influenzae Amoxicillin‐clavulanate
Group A strep Ampicillin‐sulbactam
Haemophilus parainfluenzae 3rd generation cephalosporin
Community Acquired Pneumonia – Typical Strep pneumoniae Outpatient:
H. influenza o Macrolides
Moraxella catarrhalis o Doxycycline
Staphylococcus aureus Outpatient recent antibiotics or comorbid illness:
o Respiratory fluoroquinolone
Inpatient:
o Macrolide + Beta lactam
Community Acquired Pneumonia – Atypical Mycoplasma pneumoniae Macrolide
Chlamydia pneumoniae Doxycycline
Legionella Respiratory fluoroquinolone
Hospital Acquired Pneumonia Klebsiella pneumoniae Antipseudomonal cephalosporin
E coli Antipseudomonal carbapenem
Enterobacter Beta lactam‐beta lactamase
Proteus If MRSA suspected Vancomycin to be added
Serratia
Pseudomonas
Acinetobacter
MRSA
Aspiration Pneumonia Mix of gram negative aerobes and anaerobes Beta lactam + beta lactamase
3rd generation cephalosporin + metronidazole
Abscess Polymicrobial: Piperacillin‐tazobactam
o anaerobic mouth organisms: Clindamycin
bacteroides
fusobacterium
peptostreptococcus
o aerobic and anaerobic streptococcus
o gram negative rods