Dengue illnesses praman

1. DENGUE ILLNESSES
By
Dr Praman Kushwah
Guide : Dr Girish Nanoti

2. Introduction
• Today, dengue ranks as the most important mosquito-borne
viral disease in the world
• The World Health Organization (WHO) estimates that 50–100
million dengue infections occur each year
• About 500,000 DHF patients require hospitalization and
approximately 12,500 of those die each year (case fatality rate
[CFR] of 2.5%)
• Although dengue has been predominantly a disease of
children, it now affects all age groups worldwide. It has been
reported in India that approximately 20% of cases had
occurred in infants less than 1 year of age

3. • India one of the worst hit contries
• Hyperendemicity that is circulation of multiple serotypes has
become frequent
• Dengue viral infections can present with a wide spectrum of
clinical illnesses from the common dengue fever (DF) to the
more severe presentations of dengue hemorrhagic fever
(DHF) and dengue shock syndrome (DSS)
• WHO add a classification of expanded dengue syndrome (EDS)
(or unusual manifestation of dengue, UD), which includes
severe CNS, liver, myocardial, or abdominal dysfunction

4. The Virus

5. • genus Flavivirus
• family Flaviviridae
• contain single stranded RNA and are small in size (50 nm)
• genome codes for
– three structural proteins (capsid protein [C], membrane-associated protein [M], and envelope
protein [E])
– seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5). NS1 (45 kDa)
• four dengue virus serotypes which are designated as
– DENV-1
– DENV-2 (more likely to cause shock)
– DENV-3 (more liver involvement)
– DENV-4
• Infection with any one serotype confers lifelong immunity to the virus serotype
and temporary cross-protection (months) to secondary infection with one of the
other serotypes
• does not afford protection from the infection by a heterotopous serotype
• Secondary infections are associated with elevated risks of severe disease outcomes

6. Vector

7. • Dengue is transmitted by the female mosquitoes
1. Aedes aegypti and
2. Aedes albopictus
• virus can also be transmitted through blood transfusion, organ
transplantation and by vertical transmission in late pregnancy
• day time feeder ,can fly up to a limited distance of 400 metres
• most active just after sunrise and just before sunset
• Incubation period
– Extrinsic (in mosquito)  8-12 days
– intrinsic (in humans)  4-6 days (range 3–14 days).
• patient with dengue is infectious for mosquitoes from just
before to just after the febrile period

8. • breeds almost entirely in domestic man-made water
receptacles found in and around households,
– water storage containers,
– water reservoirs, overhead tanks, desert coolers, unused
tyres,
– coconut shells, disposable cups, unused grinding stones,
– industrial and domestic junk, construction sites, etc
• disease has a seasonal pattern ( period July–November)
• cases peak after the monsoons and are not uniformly
distributed throughout the year

9. Immuno-pathogenesis

11. 1. Capillary leakage and shock
1. Anti-NS1 antibody acts as auto antibodies that cross-
react with platelets and noninfected endothelial
cells
2. disturbance in the function of the endothelial
glycocalyx layer
3. Plasma leakage
4. mild and transient hypotension or progress to
profound shock
5. haemoconcentration, pleural effusion or Ascites
6. evident on 3 to 7 day of illness and patients may be
afebrile

12. 2. Coagulopathy in dengue
1. mechanisms still remain unclear
2. increase in activated Partial Thromboplastin Time
(aPTT)
3. reduction in fibrinogen concentrations
4. Thrombocytopenia associated
5. Release of heparin sulphate or chondroitin
sulphate from the glycocalyx

13. 3. Causes of Bleeding in DF/DHF
1. Abnormal coagulogram
2. Thrombocytopenia
3. Platelet dysfunction
4. Prothombin complex deficiency
5. secondary to Liver involvement
6. Endothelial injury
7. DIC and Prolong Aptt
8. Decrease fibrinogen level
9. Increase level of fibrinogen degradation product (FDP)
10. Increase level of D-Dimer
11. Consumptive coagulopathy (activation of mononuclear phagocytes)
12. Sequestration of platelets

14. 4. Causes of Thrombocytopenia
1. Destruction of platelet (anti platelet antibodies)
2. DIC
3. Bone marrow suppression in early stage
4. Peripheral sequestration of Platelets

15. Antibody- Dependent Enhancement

16. • Enhancement of immune activation during secondary dengue
infection leads to an exaggerated cytokine response resulting
in increased vascular permeability
• memory T cells produce early IFN- γ and CD40L in the
Dendritic Cell microenvironment, leading to greater DC
activation, T-cell stimulation, and cytokine release (especially
IL-12).

17. The risk factors for DHF/DSS
– Virus strain—DENV-2 > DENV-3, DENV-4 > DENV-1
– Pre existing anti dengue antibody
– Age of host—younger children are at increased
risk
– Secondary infection
– Genetic predisposition
– Hyperendemicity—two or more virus serotypes
circulating simultaneously at high level

18. Dengue classification

19. 1997 World Health Organization classification of dengue infections

20. 2009 Revised WHO classification of dengue infections

21. Pertaining to the new guidelines dengue is now classified into
three categories
1 dengue
2 dengue with warning signs and
3 severe dengue
whereas the clinical course of the disease is divided in three phases e febrile, critical, and recovery.

22. Positive tourniquet test
• The tourniquet test is performed by inflating a blood pressure cuff to a
midpoint between the systolic and diastolic pressure and maintain for five
minutes.
• The test is considered positive when 10 or more petechiae per one square
inch area over forearm are observed.
• In DHF, the test usually gives a definite positive test with 20 petechiae or
more.

23. Clinical manifestations

24. Dengue fever
• Most patients with dengue recover following a
self-limiting non-severe clinical course, a small
proportion progress to severe disease
• Maculopapular rash may or may not appear
during fever or defervescence.
• The clinical course of illness passes through the
following three phases:
1. Febrile phase
2. Critical phase
3. Convalescent phase

25. Febrile phase
1. dengue fever is usually biphasic,
2. lasting 2-7 days
3. headache, flushing and rash.
4. pain in retro-orbital area, muscles,
joint or bone.
5. maculopapular or rubelliform rash
6. usually appear after 3 or 4 day of
fever
7. generally fades away in the later part
of the febrile phase.
8. cluster of petechiae over upper and
lower limbs.
9. haemorrhagic manifestation may be
seen rarely in case with co-morbid
illness

27. Critical phase
(Leakage phase)
1. after 3 to 4 days of onset of fever.
2. plasma leakage and high
haemoconcentration
3. Abnormal haemostasis and
leakage of plasma leads to shock,
4. bleeding, accumulation of fluid in
pleural and abdominal cavity.
5. High morbidity and mortality in
DHF/DSS are
6. commonly associated with various
organ involvements and metabolic
derangement.
7. period of plasma leakage usually
persists for 36-48 hrs

28. Convalescent phase (recovery phase)
1. usually after 6-7 days of fever and last for 2-3 days
2. fluid returns to the circulatory system
3. signs and symptoms improve.
4. Patient may develop pulmonary oedema if the fluid
replacement is not optimized
5. Some patients have a confluent erythematous or
petechial rash with small areas of normal skin,
described as “isles of white in the sea of red”.
6. Some may experience generalized pruritus
7. Bradycardia and electrocardiographic changes are
common during this stage

30. Dengue Fever with warning signs and
symptoms
• Recurrent vomiting
• Pleural effusion/ ascites/ gall bladder oedema on imaging
• Minor bleeding from different sites, scanty haemoptysis, haematemesis,
• haematuria, increase menstrual flow, gum bleeding, etc.
• •Abdominal pain or discomfort
• Palpitation, breathlessness
• Hepatic dysfunction or hepatomegaly
• Decrease urinary output
• HighHCT(>45%)
• Rapid fall in platelet count
• Cold clammy extremities
• Narrow pulse pressure
• Rapid pulse
• Hypotension

31. Severe dengue
• defined as a suspected dengue patient with one
or more of the following:
• (i) Severe plasma leakage that leads to shock
(dengue shock) and/or fluid accumulation with
respiratory distress
• (ii) Severe bleeding
• (iii) Severe organ impairment
– Hepatic (transaminases > 1000)
– Neurological involvement
– Cardiac involvement

32. Clinical Criteria for DF / DHF/DSS

33. Dengue shock syndrome (DSS)

34. Differential Diagnosis of DF/DHF
• Malaria
• Enteric fever
• Pharyngitis
• Tonsillitis
• Influenza
• Leptospirosis
• Meningococcal infection
• Chikungunya fever
• Epidemic typhus/ scrub typhus
• Crimean-Congo haemorrhagic fever
• Ebola haemorrhagic fever

35. DIAGNOSIS
• WHO criteria for suspected dengue infection require
the presence of fever together with two of the
following findings
1. Headache
2. Retro-orbital pain
3. Myalgia
4. Arthralgia or bone pain
5. Rash
6. Bleeding manifestations
7. Leukopenia
8. Rising hematocrit (Hct) 5%-10%
9. Platelet count ≤150,000 cells/mm3

36. LABORATORY DIAGNOSIS
1. ELISA-based NS1 antigen tests
1. NS1 enables detection of the cases early, i.e. in the viremic stage
2. useful for differential diagnostics between flaviviruses because of
the specificity of the assay
2. IgM-capture enzyme-linked immunosorbent assay (MAC-ELISA)
1. usually detectable by day 5 of the illness
2. in most patients it wanes to an undetectable level by 60 days
3. Isolation of dengue virus
1. provided that the sample is taken in the first five days of illness
2. From acute phase serum, plasma or washed buffy coat from the
patient, autopsy tissues
4. Polymerase chain reaction (PCR)
1. nested RT-PCR, nucleic acid sequence-based amplification (NASBA)
or real-time RT-PCR has gradually replaced the virus isolation

37. 5. IgG-ELISA
1. used to differentiate primary and secondary dengue
infections
6. Serological tests
1. HI, complement fixation (CF) and neutralization test (NT).
2. These are not commonly used due
7. RDTs
1. number of commercial RDT kits for anti-dengue IgM/IgG
antibodies and NS1 antigen are commercially available,
which give the results within 15 to 25 minutes

38. Indications for
Observation/Admission
1. Shock or impending shock
1. Narrow pulse pressure (≤20 mm Hg) is commonly observed in children and
is usually due to plasma leakage.
2. Hypotension is commonly observed in adults and patients with significant
bleeding. Older children and adults may present with postural hypotension.
3. Some patients may present with clinical signs of shock, that is, rapid and
weak pulse, delayed capillary refill time (>2 seconds), cold-clammy skin, or
skin mottling with normal blood pressure.( Note that shock in dengue
patients may not be due to plasma leakage, but rather to other conditions,
such as hypoglycemia or excessive vomiting)
2. Rising Hct ≥ 20% and thrombocytopenia
3. Clinical deterioration during defervescence
4. Leukopenia and/or thrombocytopenia with poor clinical condition, poor
appetite, or other warning signs
5. Significant bleeding

39. • Some patients may be observed or admitted to the
hospital earlier than the usual on the basis of the
following indications:
1. High risk patients: Prolonged shock, obesity, infants, the
elderly, pregnancy, bleeding, comorbidities, altered
mental status, or behavioral change
2. No care-takers at home
3. Unreliable follow-up

40. CLINICAL MANAGEMENT

41. Group A: Outpatient management
with instructions
1. should be reviewed daily with a clinical examination and laboratory
assessment.
2. encouraged to take oral rehydration solution and fruit juice to replace
losses
3. Paracetamol is the preferred antipyretic with a minimum dosing interval
of 6 h.
4. Non-steroidal anti-inflammatory drugs may aggravate gastritis and/or
bleeding and are to be avoided.
5. Caregivers must be informed that the patient should be brought to
hospital immediately if any of the following occur:
1. no clinical improvement,
2. deterioration around the time of defervescence,
3. severe abdominal pain, persistent vomiting, cold and clammy extremities,
4. lethargy or irritability/restlessness,
5. bleeding (e.g., black stools or coffee-ground vomiting)
6. failure to pass urine for more than 4 - 6 h.

42. Group B: those who should be
admitted to hospital
1. group includes those with warning signs, co-
morbid conditions or social situations where
adequate home care cannot be ensured.
2. Choice of intravenous fluids –
– The current WHO guidelines recommend the use
of either isotonic crystalloid or colloid fluids for
the treatment of hypotensive shock.

43. Group C: those who require emergency treatment
for severe dengue
1. Urgent intravenous resuscitation with crystalloids or colloids, aimed at
maintaining adequate perfusion and urine output and improving tachycardia.
2. In patients with compensated shock, fluids are started at a rate of 5-10 ml/kg/h
and titrated based on clinical response and serial hematocrit measurements.
3. Patients with hypotensive shock should receive boluses of intravenous isotonic
crystalloid or colloid solution at a rate of 10 - 20 ml/kg over 15 min.
4. Further fluids are adjusted based on the response and serial hematocrit
measurements.
5. A falling hematocrit at this stage may indicate hemorrhage and should be treated
with blood transfusion (fresh whole blood or packed red blood cells).
6. There are three stages of shock in dengue e compensated shock, hypotensive
shock and refractory shock

46. Management of refractory shock
• Step 1
1. Stabilize, maintain ABC
2. High flow oxygen, consider intubation
3. Give colloids 10e20 ml/kg 2e3 boluses
4. Correct the correctable causes like
hypoglycemia, hypocalcemia and acidosis
5. Repeat hematocrit
6. Under ideal circumstances, invasive monitoring
(CVP/ABP) to be done

47. Step 2
• If shock persisted after boluses
• Look for hematocrit and CVP and look for co-
morbidities
If CVP low and HCT normal to
high
If CVP normal/high and HCT
normal
If CVP low and HCT low
1. Titrate crystalloid/colloid till
target CVP/HCT
2. Watch for respiratory distress
3. Provide positive pressure
ventilation
4. Watch for SBP and 2D ECHO
5. Start Inotropes/Vasopressor
if indicated
1. Consider
inotropes/vasopressor
according to SBP
2. Dopamine/Adrenaline (if SBP
low)
3. Dobutamine (SBP normal/high)
4. Check for raised intra
abdominal pressure
5. Controlled ascitic fluid tapping
1. Check for
occult/overt bleeding
2. Consider blood
transfusion to break
3. anemia-acidosis-
shock cycle

48. Step 3
• Look for unrecognized morbidities
1. Occult bleed
2. Myocardial dysfunction (systolic or diastolic)
3. Elevated intra abdominal pressure
4. Co existing bacterial shock/malaria
5. Positive pressure ventilation contributing to
poor cardiac output
6. Wide spread hypoxic ischemic injury with
terminal vasoplegic shock (no treatment
effective)

49. Severe bleeding
1. The most important intervention for a patient
with dengue shock and life threatening bleeding
is restoration of oxygen carrying capacity.
2. Transfuse fresh whole blood or fresh packed red
blood cells.
3. Platelets, FFP or cryoprecipitate are not
indicated in majority of patients of severe
bleeding, as they may contribute to volume
overload.
4. They are indicated only if bleeding is ongoing
despite 2- 3 aliquots of blood transfusion

50. Fluid overload
1. Indications - severe respiratory distress/hypoxemic respiratory failure,
pulmonary edema, tense ascites and irreversible shock (heart failure,
often in combination with ongoing hypovolemia).
2. investigations and monitoring like chest X-ray, ECG, echocardiography,
cardiac enzymes assay and intra abdominal pressure measurement
3. oxygen therapy or positive pressure ventilation, decreasing or stopping
intravenous fluids and oral or intravenous furosemide 0.1-0.5
mg/kg/dose or a continuous infusion of furosemide 0.1 mg/kg/hour.
4. Patient in shock state with signs of fluid overload may have occult
hemorrhage . Fresh whole blood transfusion is to be given as soon as
possible
5. Rapid drainage of pleural and ascitic fluid may cause sudden
hemodynamic instability and catastrophic hemorrhage

51. Indication of Platelet transfusion
1. Platelet count less than 10000/cu.mm in
absence of bleeding manifestations
(Prophylactic platelet transfusion).
2. Haemorrhage with or without
thrombocytopenia

52. Management of neonatal dengue
1. After delivery, the newborn may go into shock
which may be confused with septic shock or
birth trauma.
2. In this case, history of febrile illness during
pregnancy is important which may help to
diagnose Dengue Shock Syndrome among
neonates and infants.
3. Close observation, symptomatic and supportive
treatment are the mainstay of management.

53. Criteria for discharge of patients
• The admitted patients who have recovered
from acute dengue infection having
1. no fever for atleast 24 hours,
2. normal blood pressure,
3. adequate urine output,
4. no respiratory distress,
5. persistent platelet count >50,000/cu.mm
--should be discharged from hospital.

54. Vaccine for dengue infection
1. Till now there is no licensed vaccine available
against dengue viral infection.
2. Several trials are ongoing in the world for the
development of tetravalent dengue vaccine.
3. So far phase III trials of a recombinant, live
attenuated tetravalent dengue vaccine (CYD-
TDV) has completed in Five Asian countries in
children which may be promising in
preventing dengue infection in near future

55. references
1. Diagnosis and management of dengue in children:
Recommendations and IAP ID chapter plan of action (Accepted 28 July 2014
Available online 15 August 2014)
2. National Guidelines for Clinical Management of Dengue Fever
©World Health Organization 2015
3. fifth edition of the Rogers' Textbook of Pediatric Intensive Care
4. IAP textbook of paediatric Infectious diseases 2013
5. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL.
The global distribution and burden of dengue. Nature.
2013;496:504e507.
6. WHO. Handbook for Clinical Management of Dengue, WHO.
Geneva: World Health Organization; 2012