RESPIRATORY TRACT DISEASES

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UPPER RESPIRATORY TRACT DISEASES

The respiratory tract is the most common site of infection by pathogens. Each year, children acquire between two and five upper respiratory tract infections and adults acquire one or two infections. The respiratory tract is a frequent site of infection because it comes in direct contact with the physical environment and is exposed to airborne microorganisms. A wide range of organisms can infect the respiratory tract, including viruses, bacteria, fungi, and parasites (Table -1).

Table R-1. Common Causes of Various Respiratory Diseases by Location Disease Location Disease Group of Pathogen Comments Upper respiratory tract Nasal passages Common cold Viruses Most common cause rhinovirus Nasal sinuses Rhinosinusitis Viruses Viruses are most Bacteria common cause of rhinosinusitis Pharynx Pharyngitis Viruses Viruses cause 90% of Streptococcus these infections pyogenes and Corynebacterium diphtheriae Respiratory airways Epiglottis Epiglottitis Bacteria Usually Haemophilus influenzae type b Click and bronchi Bronchitis, to edit Master subtitle style Trachea Viruses Usually caused by tracheobronchitis, viruses croup, laryngitis Bronchioles Bronchiolitis Viruses Most common cause is respiratory syncytial virus Lower respiratory tract Alveoli and alveolar Pneumonia Bacteria Most common cause sacs in adults is Streptococcus pneumoniae

Most of the surfaces of the upper respiratory tract (including nasal and oral passages, nasopharynx, oropharynx, and trachea) are colonized by normal flora, which are regular inhabitants and rarely cause disease. The normal flora of the upper respiratory tract has two main functions that are important in maintaining the healthy state of the host: (1) These organisms compete with pathogenic organisms for potential attachment sites, and (2) they can produce substances that are bactericidal and prevent infection by pathogens. There are no resident bacteria in the lower respiratory tract. Organisms that manage to enter the alveoli are usually eliminated by alveolar macrophages. Most bacteria (e.g., Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae) that

Protective Mechanisms

Normal flora: Commensal organisms Limited to the upper tract Mostly Gram positive or anaeorbic Microbial antagonist (competition)

Clearance of particles and organisms from the respiratory tract

Cilia and microvilli move particles up to the throat where they are swallowed. Alveolar macrophages migrate and engulf particles and bacteria in the alveoli deep in the lungs.

Other Protective Mechanisms

Nasal hair, nasal turbinates Mucus Involuntary responses (coughing) Secretory IgA Immune cells

There are two main obstruction a bacterium or virus must overcome in order to initiate an infection in the respiratory tract. The microorganism must avoid being caught up in the mucus layers of the upper respiratory tract, being transported to the back of the throat, and eventually being swallowed. If the invader has avoided the physical defense mechanisms of the upper respiratory tract, and is deposited in the lower respiratory tract or lung, it must either avoid phagocytosis, or be able to survive and multiply in the phagocytic cell. Mechanisms Used By Respiratory Tract Pathogens To Initiate Disease A. Before a respiratory disease can be established, the following conditions need to be met. There must be a sufficient number or sufficient "dose" of micob.

B. Once a respiratory tract pathogen is in the respiratory tract, it is essential that it colonize these surfaces before it can cause obvious disease. Most microorganisms cause disease by only a few pathogenic mechanisms. A few of these mechanisms, especially those used by respiratory tract pathogens are discussed below. Bacterial adherence factors = F and M proteins of Strep. pyogenes, Hemagglutinins of B. pertussis. Extracellular toxins = diphtheria toxin; pertussis toxin. Growth in host tissue = viruses, chlamydia sp. Evasion of host defense mechanism = capsules of Strep. pyogenes (also M protein), S. pneumoniae and H. influenzae by inhibiting phagocytosis.

Respiratory Tract Pathogens = Wide Ranges of Organisms Viruses = Rhinoviruses, RSV, Adenoviruses, Influenza, Parainfluenza Group A streptococci = pharyngitis Other streptococci = S. pneumoniae = sinusitis, Group B = pneumonia of infants Other microorganisms = C. diphtheriae, M. pneumoniae, Fungi Parasites Upper Respiratory Tract Pathogens Common cold = mostly viruses Acute otitis media = viral, bacterial, or fungal pathogens Sinusitis = Bacteria = S. pneumoniae, H. influenza Pharyngitis = 90% viruses, important bacteria = S. pyogenes and C. diphtheriae

I. The Common Cold

The common cold is caused by a multitude of organisms; about 90% of cases are due to viruses. Etiology Most cases of the common cold are caused by rhinoviruses; there are at least 100 immunologically distinct rhinoviruses. Other causes of the common cold Table URI-2. Some Infectious Agents that are listed in Table -2. Cause the Common Cold
Agents* Human Serotypes A, B, C 1, 2, 3, 4 1 (possibly 2) 1 1 > 100 types 24 6 31 (only types 11, 20, and 25 may cause respiratory illnesses) 34 (types 1, 2, 3, 5, 7, 14, and 21 are responsible for respiratory illnesses) Myxoviruses Influenza Parainfluenza Respiratory syncytial virus Human metapneumovirus Coronaviruses Picornaviruses Rhinoviruses (most common cause) Coxsackievirus A Coxsackievirus B Echoviruses Adenoviruses

Diagnosis Diagnosis of the common cold is dependent on the patients symptoms, localization of the disease process, time of year. Laboratory culture of the viruses and serologic testing is rarely performed. Therapy and Prevention The studies on the use of zinc acetate lozenges and nasal gel containing zinc gluconate are mixed. Others say they are of no help in treating patients with the common cold. Regular intake of large doses of vitamin C (0.2 gm/day) may shorten the duration of the illness and decrease the severity of symptoms of the common cold. Handwashing and disinfecting contaminated objects can help to avoid acquiring the common cold as well as avoiding contact with others during the cold season.

Pharyngitis
Pharyngitis (sore throat) can be caused by many different microorganisms; however, 90% of sore throats in adults and 6075% of sore throats in children are caused by viruses (Table -3). S pyogenes (-hemolytic group A Streptococcus) is Table URI-3. Some Viral Causes of Pharyngitis* the most common bacterial cause of acute Virus Associated Disorder or Symptom Occurrence in Pharyngitis pharyngitis. Common cold Rhinovirus Common
Coronavirus Adenovirus Common cold Common Common in military recruits and boarding schools Common Common in children Common Pharyngoconjunctival fever and acute respiratory disease Herpes simplex virust ypes 1 and Gingivostomatitis 2 Parainfluenza virus Cold and croup Coxsackie virus A Herpangina (high fever, vomiting, diarrhea, abdominal pain) and hand-foot-and-mouth disease Influenza A and B viruses Respiratory syncytial virus Epstein-Barr virus Influenza Bronchiolitis and croup Infectious mononucleosis

Common during flu season Common in children Common in adolescents during winter Less common Infrequent (homosexual males and heterosexual females at highest risk)

Cytomegalovirus CMV mononucleosis Human immunodeficiency virus Primary HIV infection *Viruses are the most common cause of pharyngitis.

Pathogenesis In viral pharyngitis, viruses gain access to the mucosal cells lining the nasopharynx and replicate in these cells. Damage to the host is often caused by damage to the cells where the viruses are replicating. In bacterial pharyngitis, S pyogenes attaches to the mucosal epithelial cells using M protein, lipoteichoic acid, and fibronectin-binding protein (protein F). It has a capsule composed of hyaluronic acid that prevents phagocytosis. Rheumatic fever and glomerulonephritis still occur following throat infections caused by S pyogenes. An autoimmune reaction occurs in some patients

Streptococcus pyogenes

Gram positive streptococci Carried and transmitted from the throat In Respiratory secretions

Group A Strep

Capsule -resistant to phagocytosis Enzymes damage host cells M protein adhesin

The M protein has many antigenic varieties and thus, different strain of S.pyogenes cause repeat infections

Strep Throat

Fever Tonsillitis Enlarged lymph nodes Middle-ear infection

Infected Middle Ear (otitis media)

Scarlet Fever
Caused by Erythrogenic Toxin secreted by S. pyogenes

Diagnosis Viral infections of the throat are rarely cultured because of the mild self-limiting. There are fewer cases of bacterial infections of the throat (compared to viral pharyngitis); however, delaying treatment of S pyogenes pharyngitis beyond 9 days after symptoms begin increases the patients chances of developing rheumatic fever . Therefore, strategies for diagnosis of acute pharyngitis infections are primarily directed at identifying patients with S pyogenes pharyngitis who require antimicrobial therapy. The best means of determining which etiologic agent is causing the pharyngitis is to swab the patients throat, culture the sample on blood agar plates, and demonstrate the growth of -hemolytic colonies that are catalase-negative, gram-positive cocci and are sensitive to bacitracin. S pyogenes rapid antigen

Therapy and Prevention Viral pharyngitis is treated with analgesics (e.g., acetaminophen), and warm saline gargles. These treatments will help lessen the pain Susceptible persons should be encouraged to limit contact with infected persons. An adenovirus vaccine is available for military personnel, but it is not permit for use in the general population. S pyogenes pharyngitis requires the use of an antimicrobial agent Penicillin remains the drug of choice to treat S pyogenes pharyngitis; erythromycin is the drug of choice for patients allergic to penicillin. Patients should be encouraged to limit contact with uninfected persons.

DIPHTHERIA Diphtheria is a bacterial disease that is now rarely seen because of successful universal vaccination. The vaccine does not affect the ability of the bacteria to colonize the oropharynx, however, but rather induces antibody production to inhibit diphtheria toxin. Etiology Corynebacterium diphtheriae is irregularly staining gram-positive, rod-shaped bacteria. Only strains of C diphtheriae that have toxin-producing lysogenic bacteriophage (b phage) can cause diphtheria. Manifestations Diphtheria results in pharyngeal pain, formation of a pseudomembrane seen on the tonsils and back of the oropharynx, regional lymphadenopathy (bull neck appearance), edema of the surrounding tissues, fetid breath, low-grade fever, and cough. Airway obstruction can occur.

Diphtheria

Transmitted by droplets or fomites Infects the upper respiratory tract Begins with severe sore throat, low-grade fever and swollen lymph nodes or with skin rash, 1-6 days after infection

Corynebacterium diphtheriae

Aerobic Gram + bacillus Toxin inhibits protein synthesis of cells to which it binds Destroyed cells and WBC form "pseudomembrane" which blocks airways

Diphtheria

An AB toxin B = binding subunit A = active subunit which binds to and inhibits a eucaryotic ribosomal translation factor Vaccine is diphtheria toxoid

Diagnosis Diagnosis of diphtheria includes observation of a pseudomembrane and bleeding upon removal of the membrane and severe cervical lymphadenopathy. The oropharynx should be swabbed and samples cultured for C diphtheriae. The C diphtheriae strain isolated by culture should be assayed for diphtheria toxin production using the Elek test (immunodiffusion assay) or by polymerase chain reaction (PCR). Treatment and Prevention A patient with diphtheria should be hospitalized, placed in isolation, and immediately treated with antiserum to the toxin. The second most immediate task is antimicrobial treatment with penicillin or erythromycin. The patient should also be given diphtheria vaccine to ensure immunity to the disease. Active immunization with the DTP vaccine for children and the DT vaccine for adults

Bacterial Pneumonia Bacterial, viral or fungal infection can cause Inflammation of the lung .

Pneumomoccal Pneumonia

Pneumococcal Pneumonia

Streptococcus pneumoniae Diagnosis by culturing bacteria Penicillin is drug of choice Leading cause of meningitis

Often secondary infection following influenza virus

Legionellosis
Legionella pneumophila: Gram-negative rod L. pneumophila is found in water Transmitted by inhaling aerosols, not transmitted from human to human Pontiac fever is a less deadly form of legionellosis Diagnosis: culturing bacteria Treatment: Erythromycin

Bordetella pertussis

Gram negative cocco-bacillus Capsule Adherence to ciliated cells Pertussis toxin is AB toxin

Pertussis (Whooping Cough)

Cough Violent coughing followed by whooping sound Vaccine it is made of purified components Not lifelong immunity adult carriers

Mycobacterium tuberculosis
Acid-fast bacillus complex cell wall with cord factor Causes TB: lungs bones, other organs Transmitted from human to human Airborne, Most commonly acquired by inhalation (milk, v. rare)

Mycobacterium tuberculosis

Thick lipid coat of Mycolic fatty acids Grows very slowly Resists killing by macrophages and grows in them

Tubercule formation
A tubercle in the lung is a consisting of a central core of TB bacteria inside an enlarged macrophage, and an outer wall of fibroblasts, lymphocytes, and neutrophils

granuloma

Tuberculosis

Primary Lung tubercles, caseous, tuberculin skin reaction Secondary (reactivation) Consumption: Coughing and chronic weight loss Dissemination Extrapulmonary TB (lymph nodes, kidneys, bones, genital tract, brain, meninges)

Tuberculosis

Elimination requires long antibiotic treatment with cocktail of antibiotics because of the resistance that develops. The two antibiotics most commonly used are rifampicin and isoniazid. TB requires much longer periods of treatment (around 6 to 24 months) to completely eliminate mycobacteria from the body

TB Skin Test

Tuberculin Skin Test

Injection of tuberculin protein

Cell-mediated immune response indicates previous exposure to TB

Delayed hypersensitivity reaction read in 48 hours The diameter of the lesion is measured (<10 mm is usually o.k.) Greater than 10 mm or raised could mean: current or previous infection, or vaccination followed by X-ray, acid-fast staining of sputum, culturing bacteria

Virus infections

Respiratory syncytial virus (RSV) Influenza virus

Fungal Infections
Coccidiodomycosis (Valley Fever) Coccidioides immitis Histoplasma capsulatum Opportunistic fungi involved in respiratory disease: Aspergillus Rhizopus Mucor

Respiratory Syncytial Virus

Enveloped (membrane) RNA virus Spread by respiratory droplets Community outbreaks in late fall to spring Upper respiratory tract infection epithelial cells May be fatal in infants Common in infants; 4500 deaths annually Causes cell fusion (syncytium) in cell culture Symptoms: coughing Diagnosis by serologic test for viruses and antibodies Treatment: Ribavirin

Influenza Virus

In virus classification influenza viruses are RNA viruses that make up three of the five genera of the family Orthomyxoviridae: Influenzavirus A Influenzavirus B Influenzavirus C Chills, fever, headache, muscle pain (no intestinal symptoms) 1% mortality due to secondary bacterial infections Treatment: Amantadine Vaccine for high-risk individuals

Influenza Virus

New human strains every year Mutations Pandemic strains Genetic Recombinant Viruses 1957 Asian Flu H2N2 1968 Hong Kong Flu H3N2 1977 Russian Flu H1N1 Bird Flu Directly from birds ?? H5N1

H1N1, which caused Spanish Flu in 1918, and Swine Flu in 2009 H2N2, which caused Asian Flu in 1957 H3N2, which caused Hong Kong Flu in 1968 H5N1, which caused Bird Flu in 2004 H7N7, which has unusual zoonotic potential H1N2, endemic in humans, pigs and birds H9N2 H7N2 H7N3 H10N7

H and N Flu Glycoproteins

H Hemagglutinin Hemagglutinin (H) spikes used for attachment to host cells Specific parts bind to host cells of the respiratory mucosa Different parts are recognized by the host antibodies Subject to changes N - Neuraminidase Breaks down protective mucous coating Neuraminidase (N) spikes used to release virus from cell Assist in viral release

Influenza

Antigenic shift Changes in H and N spikes Probably due to genetic recombination between different strains infecting the same cell Reason for deadly outbreaks Antigenic drift Mutations in genes encoding H or N spikes May involve only 1 amino acid Allows virus to avoid mucosal IgA antibodies

Common Cold vs Flu Common Cold adenoviruses, coronaviruses or rhinoviruses Rare Mild Slight Rare No Flu Influenza virus

Causative Organism: Chills: Fatigue: Aches: Fever: Vaccination possible:

Severity:

Sore throat: Stuffy nose: Can be diagnosed: Headache: Chest discomfort: Sneezing: Coughing:

Common Moderate to severe Usual and often severe Usually present Yes Serious health problems, such as Usually does not cause pneumonia, bacterial severe health problems infections, or hospitalizations can occur. Common Rare Common Rare No Yes Rare Common Mild to moderate Often severe Common Rare Hacking, productive Dry, unproductive

Coccidioides immitis

Soil fungus in American Southwest Cause of Valley Fever Highly infectious

Coccidioides immitis Life Cycle

Coccidioides immitis

Valley Fever usually a flu-like illness Can spread to bones, skin, meninges Transmitted by airborne arthrospores Diagnosis by serological tests or DNA probe Treatment: amphotericin B

Histoplasmosis

Histoplasma capsulatum, dimorphic fungus

(a) 37

(a) >35

Figure 24.17

Opportunistic fungi involved in respiratory disease:

Aspergillus Rhizopus Mucor

Mucor rouxii
Figure 12.2b, 12.4