2. INTRODUCTION
• It is the most prevalent arthropod borne viral disease
worldwide, causing 400 million infections each year
• Out of which 100 million cause critical illnesses.
• Vector- Most commonly , Aedes aegypti (Day biter , prefers
fresh water), Aedes albopictus
• Incubation period is 3 to 14 days, symptoms occur 4-7 days
after bite
3. DENGUE VIRUS
• Genus- flavivirus, Single stranded, positive sense RNA virus.
• Types of dengue serotypes- DENV-1, DENV-2, DENV-3, DENV-4,
DENV-5
• Viron consists of 3 structural (core, membrane associated,
envelope) and 7 non structural (NS1, NS2a, NS2b, NS3, NS4a, NS4b,
NS5) proteins.
• Envelope protein is the one that binds to host receptor to allow
viral transport .It is also responsible for neutralisation of
erythrocytes , Induction of neutralising Ab and protective immune
responses.
• NS1 is does not form a part of the viron instead is secreted on the
surface of infected cell. Its titres corelate with severity of disease.
5. Epidemiology
• Dengue is Endemic to >100
countries worldwide
• Endemicity in south East Asia,
Highest in
India,Indonesia,Myanmar,Srila
nka , Thialand
• Highest endemicity worldwide-
Brazil
• Circulating strains- DENV-2 in
Maharashtra and Karnataka
and DENV-1 in Delhi
6. Aedes aegypticus
• Vectors for most viral fevers are found in rural areas, for which
dengue is a exception.
• Dengue fever epidemics depend on temperature, higher
temperature accelerates the development of larvae.
• Temperature <15 and >36 degrees Celsius reduce mosquito
feeding, peak transmission is at 32 degree Celsius.
• Peak relative humidity is a stronger predictor and hence, incidence
is higher at areas of heavy rainfall.
• Mortality is 10-20 % in DF and in case of DSS it an reach upto 40%
10. Pathology
• Key pathological changes - Leaky capillaries with coagulopathy.
• Cross infection for the second time runs a more severe course due to-
1. Halestead’s theory-
Ineffective neutralisation by antibodies,Antibody dependent enhancement of viral
replication.
1. Hoskin effect/Original antigen sin-
If body is affected by pathogen 1 – immune response with memory is developed
Second infection with pathogen 2 (similar but different spectrum of illness)-immune
response is one similar to pathogen 1 and hence an ineffective one leading to severe
response
• Note- if same pathogen 1 is infected with again- some immunity is
provided due to immune memory.
11. Pathogenesis
• Antibody dependent enhancement- After a primary infection there are
antibodies against the proteins. These antibodies are known to induce
endothelial cell apoptosis in a caspase dependent manner.
• Cellular immune response- both CD 4 and CD 8 are infected which augment
release of cytokines
• Cytokine responses-
1. virus infected monocytes, B lymphocytes, mast cells produce cytokines. Th1: TNF alpha, IL
2, IL 6, INF gamma are highest in first 3 days. Th2 :IL 10,IL 5, IL 4 appear later.
2. TGF Beta corelate with disease severity.
3. These cytokines cause increased vascular permeability and shock.
4. IL 6 (endogenous pyrogen) is also seen to be increased in DF stage
• Activated neutrophils secrete elastase which activated compliment , coagulation
and fibrinolytic systems.
12. Thrombocytopenia in Dengue
• Bone Marrow Suppression
• Anti NS1 antibody mediated destruction
• Cytoadherence to endothelial membrane leading to sequestration
• Immune complex mediated , antiplatelet antibodies
• Complement mediated
• Macrophage activation
• DIC
13. Bleeding in Dengue
• Thrombocytopenia.
• Platelet dysfunction and sequestration
• Prothrombin defect- partial prothrombin time is prolonged.
• Endothelial injury
• DIC
oLow fibrinogen
oRaised FDP
oRaised D-dimer
14. Clinical course
•80% people mildly
symptomatic and
0.5-1 % develop
severe dengue.
•Phases –
1. Febrile
2. Critical phase
3. Recovery phase
15. Febrile phase
• Period of viremia
• It lasts 2-7 days
• Its sudden onset, high grade fever (>38.5 degree celcius
),frontal/retro orbital pain,anorexia , severe myalgias, scleral
injections.
• Defervescence- When body temperature drops to less than
38 degree Celsius and remains below it.
16. Critical phase
• Onset is identified by-
Defervescence
Rapid fall in platelet and rise in Hct( leukopenia develops 24 hrs
prior to platelet drop)
Development of warning signs
( Severe abdominal pain, persistent vomiting, Fluid accumulation,
mucosal bleeds, lethargy , hepatomegaly)
• It lasts 24-48 hrs.
• Capillary leak starts extravasation of fluid fluid loss state
17. Recovery phase
• Gradual reabsorption of extravascular fluid come back to
intravascular space.
• Takes place from 48-72 hrs and diuresis ensues.
• Only oral fluid guided by thirst and urinary output must be
administered carefully
18. Rash of dengue-
• Often transient, near
the time of
defervescence, on D3-
D5 a maculopapular
rash develops on the
trunk and spreads over
to the extremities and
face, associated with
pruritis
• More common in
primary infection
• Seen in 50% cases.
19. History
• Onset of fever
• Hydration status-
oral intake
Urine output ( normal 0.5 to 1.5 cc urine/kg/hr)
Vomiting ,Anorexia , Diarrhea
• Warning symptoms
• Other relevant history-
Sick person contact
Exposure to water,rat etc ( to rule out leptospirosis)
comorbidities
20. Examination
• Tachycardia
• Hypotension-
1. SBP <90mmHg
2. MAP <70 mmHg
3. Drop in SBP >40mmHg or <2 SD below normal for age
• Reduced skin turgor.
• Reduced bilateral lung entry.
• Hepatomegaly.
• Change in mental status due to –
1. Infection itself
2. Shock
3. Hyponatremia
4. Liver dysfunction
5. Encephalopathy
22. Diagnosis
1. Probable DF or DHF-
• A case compatible with clinical description of DF during outbreak
OR
• Non-ELISA base NSI antigen/IgM positive.(A positive RDT is considered
probable due to its poor sensitivity)
2. Confirmed case –Fever with one of the following-
a) Virus culture positive in serum,plasma,leucocytes
b) Single serum sample showing IgM antibody
c) Single serum sample showing viral antigen by NSI-ELISA
d) IgG seroconversion in paired sea after 2 weeks with 4 fold rise of
IgG titre
e) Viral nucleic acid detected by PCR
23. Laboratory findings
• WBC-Leukopenia
• PLATELET-Thrombocytopenia
• LFT-Moderate elevation of aminotransferase without normal hepatic
dysfunction.-ALT OR AST >1000 units/L. AST is twice the amount of ALT.
• HEMATOCRIT- HCT rises >20% from baseline
• SERUM PROTEIN- Low
• URINE- microscopic haematuria
• ESR/CRP- Normal to low ( VS bacterial infections)
• Diagnosis in first 5 days, by Viral nucleic acid detection by PCR is Sp but
costly.
• Detection of viral antigen nonstrustural protein NS1 positive during first 7
days, which is Sn ( 90% in primary infection and 60-80% in secondary
infection)
• IgM can be detected as early as 4 days after onset of illness by lateral flow
immunoassay or ELISA
26. Dengue fever (break bone fever)/ Dengue
without warning signs
Fever for 2-7 days along with 2 or more of the following :
• Headache
• Retro orbital/orbital pain
• Myalgia
• Arthralgia
• Hemorrhagic manifestations(positive torniquet
test,petechiae,purpura,echymosis,epistaxis,gum
bleeding,hematemesis,hematuria,hematochezia,malena,vaginal
bleeding)
• Leukopenia
27. Dengue haemorrhagic fever/ Dengue with
warning signs
• Cardinal feature of DHF is plasma leak due to
increased vascular permeability
• Red flags-intense abdominal pain,persistent vomiting,
marked restlessness or lethargy.
28. Dengue haemorrhagic fever / Dengue with
warning signs
Diagnosing DHF requires all of the following to be present-
• Fever or history of fever for 2-7 days, usually biphasic.
• Haemorrhagic tendencies as evident by 1 or more of the following-
1. Positive torniquet test(may be negative or mildly positive in state of
shock), HESS test :>10/sq. inch
2. Petechiae,echymosis,purpura.
3. Bleeding from mucosa,injectiin sites,GIT(Hematemesis/malena)
• Thrombocytopenia(<100,000 cells per cumm)
• Evidence of plasma leakage
1. Hct rise 20% above baseline for the age and sex
2. Drop in Hct following volume replacement treatment >20% from
baseline
3. Signs of plasma leakage like Pleural effusion,Ascites,hypoprotenemia,gall
bladder edema on USG
29. Torniquet test/ HESS test
• Marker of capillary fragility.
• A positive test is >10/sq. inch
area in the antecubital area.
• May be negative or mildly
positive in state of shock.
• May be positive closer to
defervescence.
• May be positive in other viral
illnesses like measles and
Influenza.
30. Dengue shock syndrome
• DSS is DHF with marked plasma leak.
• To diagnose as DSS all criteria of DHF along with one to signal
circulatory failure should be present-
1. Rapid and weak pulse
2. Narrow pulse pressure (20mmHg) early in phase and
hypotension(<80mmHg in less than 5 years and <90mmHg in more
than 5 years of age) later in phase
3. Cold,clammy skin and restlessness
31. Severe dengue
• Severe plasma leakage-
1. Shock
2. Fluid accumulation
• Severe bleeding
• Severe organ involvement-
1. Hepatomegaly >2cm, Mild hepatic injury due to hypoxia and
shock.
2. CNS- altered mental status, seizures,encephalopathy
3. Cardiac- arrythmias, myocardial impairement corresponds to
degree of plasma leakage, rarely myocarditis
4. Renal – AKI due to endocapillary proliferative
glomerulonephritis, shock , rhabdomyolysis and ATN
5. Ocular dysfunction- retinal vasculitis
6. Secondary hemophagocytic lymphohistiocytosis- fatal
33. Management of DF
• General principals-
1. No NSAIDs line Aspirin, can give antipyretic like PCM.
2. No IM Injections
3. Laxatives
4. Avoid brushing teeth
5. Maintain good hydration
• When to transfuse platelet -
1. If no bleeding transfuse at 10,000
2. If bleeding present,transfuse regardless of count
34. Intravenous fluids
• IVF should be given to maintain good perfusion to organs
and to have a target urine output of 0.5ml/kg/hr.
• Isotonic Ringer lactate or normal saline is used.
• Reduce fluids gradually when plasma leakage decreases
towards end of critical phase. This is indicated by-
1. Increasing Urine output and adequate oral fluids.
2. HCT decreases below baseline in a stable patient.
35. Indication for colloids
• Failure of crystalloids to normalize blood pressure or
pulse.
• Development of shock along with fluid overload
states.
• Given at 10ml/hg over 1 hour
• 10% Dextran 40 in normal saline over 24 hours ( 3
doses)
• 6% starch over 24 hours ( 5 doses)
42. ABCS- cause of refractory hypotension
• A - Acidosis
• B - Bleeding
• C - Calcium, Sodium, Potassium abnormalities
• S – Sugar (Hpoglycemia)
43. Discharge criteria
• No fever without antipyretics for 24 hours
• No respiratory distress
• Platelet count >50,000/cu.mm
• Minimun of 2-3 days of recovery from shock
• Visible clinical improvement
1. Good appetite
2. Normal BP
3. Hemodynamically stable
4. Urine output
44. Preventive measures
• Personal protection-
1. Repellents like DEET (broad spectrum), picardin, PMD(p-menthane-3,8-diol),
BioUD,metofluthrin, Permethrin treated clothes.
2. Insectiside spraying- spraying insecticide on curtains was previously being done,
currently not being used much.
• Mosquito control–
1. Reducing breeding sites- community based education to reducing accumulating of
standing water.
2. Larva control- Seeding water vessels with copepods that feed on mosquitoes
3. Endosymbiotic control – A novel strategy by releasing mosquitoes infected with
Wolbachia a obligate intracellular bacterium, this makes them less susceptible to
DENV
45. Vaccine
• DENGVAXIA/ CYD-TVD- licensed in 2015 in 20 countries
• Live attenuated tetravalent chimeric vaccine (YFV as backbone).
• Approved for 9-45 years of age with history of dengue in past
• Not approved in India
• Efficacy- 60-80%
• 2. TRK-008 – Tetravalent live attenuated with DEN 2 as backbone
46. Cause of death in Dengue
• Unrecognized disease
• Unrecognized or prolonged shock
• Unrecognized occult hemorrhage
• Fluid overload
• Nosocomial sepsis in elderly
47. Differential Diagnosis-Infective
• Other Viral haemorrhagic fevers- differentiated with
epidemiology and PCR
1. Ebola
2. Marburg
3. Lassa
4. Yellow fever virus
5. Hantavirus
6. Severe fever with thrombocytopenia virus (SFTSV)
• Chikungunya-joint pain and swelling more common, vs
dengue who has more abdominal pain, thrombocytopenia
and bleeding.
48. Differential Diagnosis-Infective
• Zika- Has more conjunctivitis incidence.
• Malaria-Myalgia is not that severe . No rash or
leukopenia.Diagnosed by RDT or Peripheral smear
showing parasite.
• Typhoid –diagnosed by stool or blood culture.
• Leptospirosis- Develops hyperbilirubinemia,
Leucocytosis and anemia.
• Rickettsial infection
50. Summery
• Dengue fever is the leading cause of
arbovirus apart from Zika virus and
Yellow fever virus.
• Most cases have mild infection.
• Identifying the warning signs at
earliest and giving appropriate
treatment is key to management .
51. Bibliography
• National guidelines for clinical management of Dengue fever NVBDCP
• CDC
• UpToDate
• Harrison's Principles of Internal Medicine
• Dengue viral infections, G N Malavige et al, University Hospital,
Nottingham NG7 2UH, UK .
http://dx.doi.org/10.1136/pgmj.2004.019638
