A case of a 12 year old girl who was admitted because of high grade fever for 3 days.

After the
fever lysed, maculopapular rash appeared associated with abdominal pain. Stool was black and
tarry. Urine was pinkish. Patient complained of difficulty of breathing. BP-palpatory 60. Patient
deteriotaed and died on 7th day of hospitalization. Autopsy was performed.

(+) complete dse of dengvaxia.

PE on admission:

BP: 90/60 mmhg

CR: 90/min
RR: 20/min
Temperature: 39 C
Pale skin
(+) harsh breath sound
Regular cardiac rate and rhythm, (-) murmur
Flat abdomen, (-) masses
Grossly normal extremities

Laboratory :

1st HD 2nd HD 3rd HD 4th HD 5th HD

Hematocrit 0.34 0.38 0.50 0.40 0.32
(vol/vol)
Hemoglobin 12.6 14.3 15.9 14.6 11
(gl/l)
WBC count (x 6 4 3.8 3.2 4.0
10 9/L)
Neutrophils 64 50 44 40 31
Lymphocytes 34 48 56 57 66
Eosinophils 1 0 0 2 1
Monocytes 1 2 0 1 2
Platelets (x 10 280 230 100 60 20
12/L)
Urinalysis unremarkable +
erythrocytes

Autopsy:

(+) hepatomegaly
(+) multiorgan edema and minute hemorrhage

ETIOLOGY

A. Dengue Fever
▪ A benign syndrome caused by several arthropod-borne viruses and is characterized
by biphasic fever, myalgia or arthralgia, rash, leukopenia, and lymphadenopathy.
 ▪ Dengue virus is transmitted by female mosquitoes mainly of the species Aedes
aegypti and, to a lesser extent, Ae. albopictus.
▪ This mosquito also transmits chikungunya, yellow fever and Zika infection. Dengue is
widespread throughout the tropics, with local variations in risk influenced by rainfall,
temperature and unplanned rapid urbanization.
B. Serotypes
▪ 4 distinct serotypes of the virus that cause dengue (DEN-1, DEN-2, DEN-3 and DEN-
4). Recovery from infection by one provides lifelong immunity against that particular
serotype.
▪ However, cross-immunity to the other serotypes after recovery is only partial and
temporary. Subsequent infections by other serotypes increase the risk of developing
severe dengue.
C. A clinical diagnosis of dengue fever derives from:
▪ High index of suspicion and knowledge of the geographic distribution and
environmental cycles of causal viruses.
▪ Because clinical findings vary and there are many possible causative agents, the term
dengue-like disease should be used until a specific diagnosis is established.
▪ A case is confirmed by isolation of the virus, viral antigen, or genome by polymerase
chain reaction analysis, as well as demonstration of a 4-fold or greater increase in
antibody titers.
▪ A probable case is a typical acute febrile illness with supportive serology and
occurrence at a location where there are confirmed cases.

CLINICAL MANIFESTATIONS
I. Dengue Fever
▪ The incubation period is 1-7 days.
▪ The clinical manifestations are variable and are influenced by the age of the patient.
▪ May be undifferentiated or characterized by fever for 1-5 days, pharyngeal
inflammation, rhinitis, and mild cough.
▪ Majority experience sudden onset of fever, with temperature rapidly increasing to
39.4-41.1°C (103-106°F), usually accompanied by frontal or retroorbital pain,
particularly when pressure is applied to the eyes. Occasionally, severe back pain
precedes the fever (back-break fever). A transient, macular, generalized rash that
blanches under pressure may be seen during the 1 st 24-48 hr of fever.
▪ The pulse rate may be slow relative to the degree of fever. Myalgia and arthralgia
occur soon after the onset of fevers and increase in severity over time.
▪ From the 2nd-6th day of fever, nausea and vomiting are apt to occur, and generalized
lymphadenopathy, cutaneous hyperesthesia or hyperalgesia, taste aberrations, and
pronounced anorexia may develop.
▪ Approximately 1-2 days after defervescence, a generalized, morbilliform,
maculopapular rash appears that spares the palms and soles.
▪ It disappears in 1-5 days; desquamation may occur. Rarely there is edema of the
palms and soles. About the time this second rash appears, the body temperature,
which has previously decreased to normal, may become slightly elevated and
demonstrate the characteristic biphasic temperature pattern.

II. DENGUE HEMORRHAGIC FEVER

 ▪ All of the following criteria is fulfilled:
▪ Biphasic Fever
▪ Minor or major hemorrhagic manifestations in the form of at least one of the
following: (increased capillary permeability >20%)
✓ A positive tourniquet test
✓ Petechiae, ecchymosis, or purpura
✓ Bleeding from the mucosa or injection sites
✓ Hematemesis, melena, hematochezia, hematuria, increased
menstrual flow
▪ Thrombocytopenia (<100,000/uL )
▪ Objective evidence of plasma leakage caused by increased vascular
permeability, as evidenced by one or more of the following
✓ A rise in the hematocrit (defined as >20% over baseline)
✓ A drop in hematocrit following volume replacement treatment <20%
of baseline
✓ Hypoalbuminemia
✓ Pleural effusion, ascites, or other effusions (by chest radiography or
UTZ)
✓ Poor perfusion (cold extremities)
III. DENGUE SHOCK SYNDROME
✓ Approximately 20-30% of cases of dengue hemorrhagic fever are complicated by
shock (dengue shock syndrome). Most patients who have DHF do not develop DSS.
DSS occurs during defervescence 3 to 6 days after the onset of symptoms
✓ Dengue shock: DHF plus evidence of circulatory failure manifested by shock or all of
the following
▪ Fewer than 10% of patients have Gross ecchymosis or gastrointestinal
bleeding, usually after a period of uncorrected shock.
▪ Bradycardia and ventricular extrasystoles are common during
convalescence
▪ Narrow pulse pressure (<20 mm Hg) or hypotension for age (systolic
pressure <80 mm Hg for children younger than 5 years of age or <90 mm
Hg for children 5 years of age and older)
▪ Respiratory distress (nelsons) that may be a harbinger of pulmonary edema
caused by overhydration, an all too common outcome of inexpert treatment
▪ Abrupt change of temperature from fever to hypothermia (Cold, clammy
skin)
▪ Altered mental status, including irritability, somnolence, or obtundation
▪ Capillary leakage and loss of intravascular volume result in shock rather than
in hemorrhage
▪ After a 24-36 hr period of crisis, convalescence is fairly rapid in the children
who recover. The temperature may return to normal before or during the
stage of shock.
▪
DENGUE CASE CLASSIFICATION AND LEVEL OF SEVERITY
B. Dengue illness is categorized according to level of severity as:
▪ Dengue without warning signs
▪ Dengue with warning signs
▪ Severe dengue
C. Dengue without warning warnings can be further classified according to signs and
symptoms and laboratory tests as suspect dengue, probable dengue and confirmed
dengue.
▪ Dengue without warning signs
▪ Suspect dengue
▪ a previously well individual with acute febrile illness of 1-7 days
duration plus two of the following: headache, body malaise, retro-
orbital pain, myalgia, arthralgia, anorexia, nausea, vomiting,
diarrhea, flushed skin, rash (petechial, Hermann’s sign)
▪ Probable dengue
▪ a suspect dengue case plus laboratory test: Dengue NS1 antigen
test and atleast CBC (leukopenia with or without
thrombocytopenia) or dengue IgM antibody test (optional)
▪ Confirmed dengue
▪ a suspect or probable dengue case with positive result of viral
culture and/or Polymerase Chain Reaction (PCR) and/or Nucleic
Acid Amplification Test- Loop Mediated Amplification Assay
(NAAT-LAMP) and/ or Plaque Reduction Neutralization Test
(PRNT)
▪ Dengue with warning signs
 ▪ a previously well person with acute febrile illness of 1-7 days plus any of
the following: abdominial pain or tenderness, persistent vomiting, clinical
signs of fluid accumulation (ascites), mucosal bleeding, lethargy or
restlessness, liver enlargement, increase in haematocrit and/or
decreasing platelet count
▪ Severe dengue
▪ Severe plasma leakage leading to
▪ shock (DSS)
▪ fluid accumulation with respiratory distress
▪ Severe bleeding
▪ as evaluated by clinician
▪ Severe organ impairment
▪ Liver: AST or ALT ≥ 1000
▪ CNS: e.g. seizures, impaired consciousness
▪ Heart: and other organs (i.e. myocarditis, renal failure)

PHASES OF DENGUE INFECTION

**CRITICAL PHASE
▪ Dengue without Warning Signs: those who will improve after defervescence
▪ Those who will deteriorate will manifest warning signs and will be categorized as Dengue
with Warning Signs or some may progress to Severe Dengue.
▪ When warning signs occurs, severe dengue may follow near the time of Defervescence
which usually happens between 24 to 48 hours.
DIFFERENTIAL DIAGNOSIS

measles  Erythematous  Prodromal stage Coryza, cough

maculopapular and conjunctivitis(the “3 Cs”)
rash  Enanthem of the buccal cavity with Koplik
Usually begins spots after 3 days
on the face,  Exanthem stage: high fever, malaise,
frequently generalized lymphadenopathy
behind the ears
→
disseminates to morbilliform refers to a rash that looks like measles.
the rest of the The rash consists of macular lesions that are red and
body (palms usually 2–10 mm in diameter but may be ...
and soles
typically
spared)

 Exanthem
begins to fade
after ∼5 days,
with a brown
discoloration
and
desquamation

 

Adverse  Fever  Itching

drug  Maculopapular  Facial edema
reactions rash  topical application of drug
Type 4  Hepatomegaly  Antiepileptic
sensitivity  Diffuse lymphade drugs (e.g., phenobarbital, carbamazepine, lam
reactions nopathy otrigine)Antibiotics (e.g. sulfonamide) Allopurinol
 Often leads  Eosinophilia
to multiorgan 
failure
 Thrombocytopeni
a
 Atypical lymphoc
ytosis

Rule In Rule Out

Malaria  Hemoglobinuria  Rashes
 Anemia  No petechial
 Abdominal pain hemorrhage
 Slight
hepatomegaly

Differentials Rule In Rule Out

Leptospirosis  High Fever  Jaundice (hallmark)
(Wiels Disease)  Abdominal Pain  Conjunctival
 Difficulty of suffusion (redness
Breathing of conjunctiva)
 Haemorrhage (  Severe Headache
intestines,lung)  Meningeal irritation
(Second phase)
 Anuria or oliguria
 Cough,haemoptysis
 Cardiac arrhythmia

Rule In Rule out

ITP  Thrombocytopenia  Bleeding into the skin
 onset is usually sudden takes the form of
 Blood in urine purpura or petechiae
 Bruises
 Non-feverish
 Splenomegaly
 Bloody stool

Rule in Rule out

Rubella (German measles)
• Thrombocytopenia
• Leukopenia
• Neutropenia
• Fever
• Rash
• Hematuria
• Hepatomegaly
• Low grade fever
• Sore throat
• Inflamed, red eyes
• Stuffy or runny nose
• Cough
• Forchheimer spots
(petechial
hemorrhages on the
soft palate)

Rule In Rule out

Chikungunya • Incubation period: 3 – • Intermittent fever
7 days • Pinkish urine
• Fever(>39°C) • Black tarry stool
• Rash • Lymphocytosis
• Neutropenia
• Thrombocytopenia
• Hemoconcentration

LABORATORY TESTS
Dengue NS1 RDT Requested between 1-5 days of illness

Use to detect dengue virus antigen during early

phase of acute dengue infection

Test is for free in all health centers and selected

public hospitals nationwide

As early as 1 day post onset of symptoms (DPO),

and up to 18 DPO.

useful for differential diagnostics between

flaviviruses because of the specificity of the
assay.

Dengue IgM/IgG Requested beyond five days of illness

Use to detect dengue antibodies during acute

late stage of dengue infection (IgM) and to
determine previous infection (IgG)

May give false positive result due to antibodies

induced by dengue vaccine

Samples with a negative IgG in the acute phase

and a positive IgG in the convalescent phase of
the infection are primary dengue infections.

A positive IgG in the acute phase and a 4-fold

rise in IgG titer in the convalescent phase (with at
least a 7 day interval between the two samples)
is a secondary dengue infection.

May cross react with other arboviral diseases

such as Chikungunya and Zika

DOH augmentation is limited to selected

government hospitals only
Polymerase Chain Reaction (PCR) One of the gold standard laboratory tests to
confirm dengue virus.

Molecular based test confirmatory test

Available only in dengue sub-national and

national reference laboratories

RT–PCR has become a primary tool to detect

virus early in the course of illness

A positive PCR result is a definite proof of current

infection and it usually confirms the infecting
serotype as well.

a negative result is interpreted as

“indeterminate”

Negative results before 5 days of illness are

usually asked to submit a second serum sample
for serological confirmation after the 5th day of
illness

Nucleic Acid Amplification Test- Loop Mediated A novel molecular-based confirmatory test used
Isothermal Amplification Assay (NAAT-LAMP) to detect dengue virus.

Work just like PCR but cheaper and simpler in

nature.

In the pipeline to be introduced under the

National Dengue Prevention and Control Program
in district and provincial hospitals

Plaque Reduction Neutralization Test (PRNT) Gold standard to characterize and quantify
circulating level of anti-DENV neutralizing
antibody (NAb)

Most specific serological tool for the

determination of dengue antibodies

used to determine the infecting serotype in

convalescent sera.

measures the titer of the neutralizing antibodies

in the serum of the infected individual and
determines the level of protective antibodies this
individual has towards the infecting virus.

based on the principle of interaction of virus and

antibody resulting in inactivation of virus such
 that it is no longer able to infect and replicate in
cell culture.

Available only at the dengue national reference

laboratory

Total While Blood Cell (WBC) count Routinely used in hospitals as standard dengue
diagnostic tests
-Platelet
Look for trend of decreasing WBC, decreasing
-Hematocrit platelet and increasing hematocrit

Complete Blood Cell Count

• Leukopenia, often with lymphopenia, is observed near the end of the febrile phase of
illness
o Lymphocytosis, with atypical lymphocytes, commonly develops before
defervescence or shock.
o Significantly lower total WBC, neutrophil, and platelet counts than patients
• A hematocrit level increases greater than 20% is a sign of hemoconcentration and
precedes shock.
o The hematocrit level should be monitored at least every 24 hours to facilitate
early recognition of dengue hemorrhagic fever and every 3-4 hours in severe
cases of dengue hemorrhagic fever or dengue shock syndrome.
• Thrombocytopenia has been demonstrated in up to 50% of dengue fever cases. Platelet
counts less than 100,000 cells/μL are seen in dengue hemorrhagic fever or dengue
shock syndrome and occur before defervescence and the onset of shock.
o The platelet count should be monitored at least every 24 hours to facilitate early
recognition of dengue hemorrhagic fever..

Coagulation studies may help to guide therapy in patients with severe hemorrhagic manifestations.
Findings are as follows:
• Prothrombin time is prolonged
• Activated partial thromboplastin time is prolonged
• Low fibrinogen and elevated fibrin degradation product levels are signs of disseminated
intravascular coagulation
• Signs of early coagulopathy may be as subtle as a guaiac test that is positive for occult blood
in the stool. Guaiac testing should be performed on all patients in whom dengue virus
infection is suspected
Serum Studies
• Serum specimens should be sent to the laboratory for serodiagnosis, PCR, and viral
isolation.
o Because the signs and symptoms of dengue fever are nonspecific, attempting
laboratory confirmation of dengue infection is important.
o Serodiagnosis is made based on a rise in antibody titer in paired specimens
obtained during the acute stage and during convalescence.
 o Results vary depending on whether the infection is primary or secondary.
• Early in the illness (≤5 days after symptom onset), laboratory confirmation can be made
from a single acute-phase serum specimen by detecting dengue virus genomic sequences
with RT-PCR or DENV nonstructural protein 1 (NS1) antigen via immunoassay.
o Later in the illness, IgM anti-DENV can be detected with ELISA. The CDC currently
recommends that, within the first week of illness, diagnostic testing should include a
test for dengue virus (RT-PCR or NS1) and IgM anti-DENV.
o For patients seen more than one week after fever onset, IgM anti-DENV, such as the
MAC-ELISA, is more useful, although NS1 may still be positive up to 12 days after
fever onset.

PHARMACOLOGIC/NON-PHARMACOLOGIC TREATMENTS

Non Pharmacologic (Uncomplicated Dengue fever)

▪ Bed rest

▪ Cold sponging to keep body temp below 38.5 0C

▪ Herbal Medicine (I.e. Papaya Leaf juice, “Tawa-tawa” extract etc)

Pharmacologic

▪ Supportive therapy (Fluid Replacement):

▪ Ringers Lactate10-20mL/kg for 1hour

▪ Plasma expanders (Starch, Dextran 40, or albumin 5%) 10-20mL/kg

▪ Platelet and Fresh Frozen Plasma (for severe bleeding)

▪ Complications:

▪ Hypervolemia which may contribute to cardiac failure, is heralded by a decrease in

hematocrit (<40%) with wide pulse pressure (Give diuretics to control)

▪ Anagesics (For myalgia and fever):

▪ Acetaminophen 500mg or 10mg/kg in children monitored for 24-48hrs

▪ Contraindications:

▪ Aspirin and NSAIDS/Ibprofen (may cause gastritis, vomiting, acidosis, severe

bleeding)

Criteria For discharge:

▪ Afebrile for 24hrs without antipyretics

▪ Good appetite
 ▪ Adequater urine output

▪ Stable Hematocrit level (38-46%)

▪ At least 48 hrs after recovery from shock

▪ No respiratory Distress

▪ Platelet >50,000 cells/uL

Algorithm

References:

Nelsons Pediatrics

Handbook For Clinical Management of Dengue by WHO

http://www.nrhmhp.gov.in/sites/default/files/files/Guidelines_Dengue.pdf

https://www.cdc.gov/leptospirosis/symptoms/index.html

https://emedicine.medscape.com/article/215840-overview

https://www.who.int/zoonoses/diseases/Leptospirosissurveillance.pdf