DENGUE

EPIDEMIOLOGY

 4 serotypes of dengue virus transmitted in tropics (DEN1, DEN2, DEN3, DEN4)

- Area between 35N & 35S (Latitude)
- Directly proportional to the distribution of A. aegypti
 Principal vector: A. aegypti
 Others:
- A. albopictus
- A. polynesiensi (Tahiti)
- A. scutellaris hebrideus (N. Guinea)
- A. cooki (Niue)
 Definitive host: Human
 Reservoir: Human
 So, it is NOT a zoonosis
 After feeding on viraemic patient, viral replication in mosquito = 1-2 weeks (extrinsic
incubation period)
 Feed: Several times during 1-4 weeks life span
 A.aegypti
- Breed around humans
- Oviposits in stagnant water
- Adults -> shelter indoor bite during 1-2 hours intervals in mornings and late afternoons
- In endemic areas, 1 in 20 mosquitoes infected
- 0.8 – 2.0 km flying distance
 Transmission in tropical areas maintained throughout the year and  during rainy season
  humidity,  lifespan
  temperature,  extrinsic incubation period

Pathogenesis

 Usually Dengue Fever – self-limited infection

 Bite -> tissues (2-3 days, hematogenous)
 Virus circulate for 4-5 days in:
- Infected monocytes & macrophages
- B cells
- T cells
 Fever – viraemia
 Fever , viraemia  1 day later
Typify DF - ? cytokine response
 Myalgia – cardinal feature of DF
Histophatological Exmination:
- Perivascular mononuclear infiltrate + lipid accumulation
- Some cases – mitochondrial changes + muscle necrosis
- CPK  (creatinine phosphokinase)
  Musculoskeletal pain (breakbone fever)
People wonder whether there is viral infection of bone marrow. Because:
- Peripheral cytopenias
- Haemophagocytosis (+)
 Rash – lymphatic dermal vasculitis
  hepatic transaminases in 80%
Fatal cases
- Kuppfer cell hypertrophy
- Focal ballooning and necrosis of hepatocytes
- Mild fatty change
- Occasional councilman’s body
 Shock in DHF-DSS due t sudden extravasation of plasma into extravascular compartment
including pleura and abdominal cavity.
 Usually when fever has 
-  TNF
-  IL-8
-  IFN-gamma
- Complement activation
 Result: “loss” of fluid, and hypoproteinaemia/albuminaemia
 Reversal usually within 48 hours

Dengue Hemorrhagic Fever (DHF)

 Role of heterologous Abs in secondary infection

- Enchancing Abs
- i.e  uptake of virus and  replication in Fc-bearing cells
(Ab-mediated immune enhancement)
 TNF-alpha, CD8, IL-2
= Cross reactive CD4+ amd CD8+ cells 
= IFN-gamma  and IL-2 
 DHF -> Propensity after DEN-2 & DEN-3 infections (Pak Nasa: that’s for you to remember)

VIROLOGY

 Etiology
- Family: Arboviridae
- Genus: Flaviviridae
- Species: Dengue virus
- Serotypes: 4 (1,2,3,4)
 Virion
- Spheric/cubic
- 40-60 nm
- Consist of
i. Lipid enveolope
ii. Covered densely with surface projections (Membrane glycoproteins and
envelope glycoproteins)
 - E gp (envelope glycoproteins) organized as dimmers paired horizontally head to tail on
virion surface
 Viruses – unstable, sensitive to:-
- Heat
- UV
- Disinfectants (alcohol, iodine, etc)
- Acid/low pH
- Ether & deoxycholate
 (+) ssRNA of 11kb
 E gp exhibits important biological properties
- Viral-cellular attachment
- Endosomal membrane fusion
- Site for hemagglutination and neutralization

Clinical Features of Dengue Fever

Acute febrile disease with:

 Headache
 Musculoskeletal pain
 Rash (Hess test)

80% asymptomatic in infants/children

If ill:

 Fever
 Malaise
 Irritability
 Pharyngeal injection (URTI)
 Rash

Adult:

 > Sever & > acute

 Chills, severe frontal headache
 Retro-orbital pain
 Severe musculoskeletal pain
 Severe lumbal back pain
 Skin flushed
 General signs and symptoms

Then fever 

Second episode of fever and symptoms recur -> SADDLEBACK PATTERN

Followed by:

 Listlessness
  Fatigability
 Depression

DHF-DSS

 Hemorrhagic phenomena
 Hypovolaemic shock
o (Usually after fever has )
 Effusion
i. Pleura (80%)
ii. Ascites (>95%)
iii. Gallbladder oedema (>95%)
iv. Peri/parerenal (77%)
v. Heptaic/splenic
vi. Pericardial
 -> Myocardial dysfunction, metabolic acidosis, respiratory distress -> death
 Fatality rate
- Up to 50%
- Least reported 1%
 Encephalopathy -> CNS hemorrhage
 Liver & Renal failure

Laboratory Diagnosis

 Viral isolation
- 1st week after onset
- Serotype (Personal health reasons)
 Specimen
- Biopsy
- Autopsy
 Culture
- Suckling mice
- Mosquito cell lines (C6/36, AP61
- Vero
- LLCMK2
- PS, etc
 PCR
 Serology
- Blood/serum
- CSF
- Elisa (IgM, IgG)
i. 7-10 days after onset: 95% sensitive
ii. IgM & IgG -> 100% (as early as 4-5 days)
 Other tests
- IIF
- HA
Treatment

 Symptomatic
 Supportive

Prevention

 Mainstay
- Public health
- Personal (home)

Public Health

 Insecticidal fogging (? Usefulness)

 Vaccine – under development