Dengue viral infection. The most rapidly spreading

1
Dengue infection

• Suwatthiya Siriboon
• Medicine, Sapprasithiprasong Hospital

2
Dengue viral infection

• The most rapidly spreading mosquito-borne viral
  disease in the world
• Dengue virus
• 4 serotypes DEN1, DEN2,DEN3, and DEN4
• Family Flaviviridae
• Genus Flavivirus
• Single stranded RNA virus
• Asian genotypes of DEN-2 and DEN-3 frequently
  associated with severe disease accompanying
  secondary dengue infections

3
Dengue Virus Infection

• Immunity long lasting in same serotype, partial
  and transient to other serotypes
• Primary infection, secondary infection
• Greater risk of serious symptoms in secondary
  infection
• Plasma leakage distinguishes dengue fever from
  dengue hemorrhagic fever

4
Dengue hemorrhagic fever

• Usually associated with secondary dengue
  infection
• But can appear during primary infection,
  especially in infants who possess maternal IgG
  dengue antibody
• A second attack of DHF is very rare 0.5 of
  cases in a study over a 16 year period at
  Childrens Hospital in Bangkok

Nimmannitya et al. Symposium on Dengue and Dengue
Hemorrhagic Fever, Bangkok. 1990
5
(No Transcript)
6
Figure 1.2 Average annual number of DF and DHF
cases reported to WHO, and of countries reporting
dengue, 19552007
Dengue Guidelines for diagnosis, treatment,
prevention and control. WHO 2009
7
Dengue

• Thailand
• All 4 regions Northern, Central, North-Eastern
  and Southern
• June 2007, outbreaks from Trat, Bangkok,
  Chiangrai, Phetchabun, Phitsanulok, Khamkaeng
  Phet, Nakhon Sawan and Phit Chit
• 58,836 cases (Jan. to Nov. 2007)
• Fatality rate in Thailand is below 0.2

8
Dengue Virus Infection Clinical Syndromes

• Undifferentiated fever
• Dengue fever fever, headache, muscle pain,
  nausea/vomiting, rash
• DHF
• DSS

Gr I, II
Plasma leakage
Gr III, IV
9
Definition of Dengue Hemorrhagic Fever
4 necessary criteria

• Fever, or recent history of acute fever
• Hemorrhagic manifestations
• Low platelet count (100,000/mm3 or less)
• Objective evidence of leaky capillaries
• elevated hematocrit (20 or more over baseline)
• pleural or other effusions

10
Definition of Dengue Shock Syndrone

• 4 criteria for DHF
• Evidence of circulatory failure manifested
  indirectly by all of the following
• Rapid and weak pulse
• Narrow pulse pressure (lt 20 mm Hg) OR hypotension
  for age
• Cold, clammy skin and altered mental status
• Frank shock is direct evidence of circulatory
  failure

11
WHO classification

• Undifferentiated fever
• Dengue fever (DF)
• Dengue haemorrhagic fever (DHF)
• 4 severity grades
• grades III and IV dengue shock syndrome (DSS)
• Currently the classification into DF/DHF/DSS
  continues to be widely used

12
WHO classification
Dengue haemorrhagic fever diagnosis, treatment,
prevention and control. 2nd edition. Geneva
World Health Organization. 1997
13

• patients with non-severe dengue
• patients with warning signs
• patients without warning signs
• dengue is one disease entity with different
  clinical presentations and often with
  unpredictable clinical evolution and outcome

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Suggested dengue case classification and levels
of severity
Dengue Guidelines for diagnosis, treatment,
prevention and control. WHO 2009
15
Vectors

• Aedes aegypti

Stegomyia aegypti (formerly Aedes aegypti)
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Dengue

• incubation period of 4-10 days
• wide spectrum of illness (most, asymptomatic or
  subclinical)
• Primary infection induce lifelong protective
  immunity to the infecting serotype
• Individuals suffering an infection are protected
  from clinical illness with a different serotype
  within 2-3 months of the primary infection
• no long-term cross-protective immunity

17
Risk factors determine the severity of disease
and secondary infection

• Age
• Ethnicity
• Possibly chronic diseases (bronchial asthma,
  sickle cell anemia and DM)
• Young children (less able to compensate for
  capillary leakage and are consequently at greater
  risk of dengue shock)
• Secondary heterotypic infection as risk factor
  for severe dengue

18
The course of dengue illness
Dengue Guidelines for diagnosis, treatment,
prevention and control. WHO 2009
19
Febrile phase

• High-grade fever, 27 days
• facial flushing, skin erythema, body ache,
  myalgia, arthralgia, headache and N/V
• Some, sore throat, injected pharynx and
  conjunctival injection
• Positive tourniquet test
• indistinguishable between severe and non-severe
  dengue cases
• Monitoring for warning signs
• Mild hemorrhagic manifestations petechiae and
  mucosal membrane bleeding (e.g. nose and gums)
• Massive vaginal bleeding and GI bleeding may
  occur
• Liver often enlarged and tender after a few days
  of fever
• The earliest abnormality in CBC progressive
  decrease in WBC

20
The course of dengue illness
Dengue Guidelines for diagnosis, treatment,
prevention and control. WHO 2009
21
Critical phase

• Around the time of defervescence, temperature
  drops to lt37.538 C
• days 37 of illness
• increase in capillary permeability, ?Hct
• clinically significant plasma leakage usually
  lasts 2448 hours
• Progressive leukopenia ? rapid ?platelet count?
  plasma leakage
• Patients without ?capillary permeability will
  improve
• Patients with ?capillary permeability worse,
  lost plasma volume
• Pleural effusion and ascites
• The degree of increase above the baseline HCT
  reflects severity of plasma leakage

22
Critical phase

• Shock
• Prolonged shock, organ impairment, metabolic
  acidosis and DIC
• severe hemorrhage causing ?HCT in severe shock
• WBC may increase in patients with severe bleeding
• severe organ impairment severe hepatitis,
  encephalitis or myocarditis and/or severe
  bleeding

23
The course of dengue illness
Dengue Guidelines for diagnosis, treatment,
prevention and control. WHO 2009
24
Recovery phase

• If the patient survives the 2448 hour critical
  phase
• gradual reabsorption of extravascular compartment
  fluid takes place in the following 4872 hours
• well-being improves, appetite returns, GI
  symptoms abate, hemodynamic status stabilizes and
  diuresis ensues
• Rash isles of white in the sea of red Some
  may experience generalized pruritus
• Bradycardia
• Hct stabilizes or lower due to the dilutional
  effect of reabsorbed fluid
• WBC usually rise soon after defervescence but the
  recovery of platelet count is typically later
  than that of WBC

25
Febrile, critical and recovery phases in dengue
Dengue Guidelines for diagnosis, treatment,
prevention and control. WHO 2009
26
Severe dengue

• Fever of 27 days plus any of the following
• Evidence of plasma leakage
• high or progressively rising Hct
• pleural effusions or ascites
• circulatory compromise or shock (tachycardia,
  cold and clammy extremities, capillary refill
  time gt 3 seconds, weak or undetectable pulse,
  narrow PP or, in late shock, unrecordable BP)
• Significant bleeding
• Altered level of consciousness (lethargy or
  restlessness, coma, convulsions)
• Severe GI involvement (persistent vomiting,
  increasing or intense abdominal pain, jaundice)
• Severe organ impairment (acute liver failure,
  ARF, encephalopathy or encephalitis, or other
  unusual manifestations, cardiomyopathy)

27
Diagnosis of Dengue Infection

• Antibody detection
• Hemagglutination Inhibition (HAI)
• ELISA (IgG/IgM)
• Rapid test (IgG/IgM)
• Antigen detection
• NS1
• RNA detection
• PCR
• Viral isolation

28
Diagnosis

• Approximate time-line of primary and secondary
  dengue virus infections and the diagnostic
  methods that can be used to detect infection

Dengue Guidelines for diagnosis, treatment,
prevention and control. WHO 2009
29
Interpretation of dengue diagnostic tests
adapted from Dengue and Control (DENCO) study
Dengue Guidelines for diagnosis, treatment,
prevention and control. WHO 2009
30
Primary Infection

• NS1 antigen Day 1 after onset of fever and up
  to day 9
• IgM antibody
• Day 5 of infection, sometimes as early as Day 3
• IgM levels peak in 2 weeks, followed by a 2
  week rapid decay
• Undetectable 2 to 3 months after infection
• Low levels of IgG are detected in the early
  convalescent phase, not during the acute phase

31
Secondary Infection

• NS1 antigen day 1 after onset of fever and up
  to day 9
• IgM response is more varied
• Usually preceded by IgG and appears quite late
  during the febrile phase
• Minority of patients will show no detectable
  levels of IgM
• May not be produced until 20 days after onset of
  infection
• May be produced at low or undetectable levels
• High levels of IgG are detectable during the
  acute phase
• Reach levels above those found in primary or past
  infection
• IgG may be detectable by Day 3 of symptoms, but
  generally detectable day 5-6
• Persist for 30-40 days then decline to levels
  found in primary or past infection

1.Innis BL (1997). Antibody Response to Virus
Infection. In Gubler DJ and Kuno G, Dengue and
Dengue Hemorrhagic Fever, CAB International, NY,
USA 2.Vornham V and Juno G (1997) Laboratory
diagnosis of dengue virus infections. In Gubler
DJ and Kuno G,Dengue and Dengue Hemorrhagic
Fever, CAB International, NY, USA
32
Hemagglutination Inhibition Test
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ELISA Test for Dengue Infection
34
Atypical manifestations of dengue
35
Atypical neurological manifestations of dengue

• Neurologic abnormalities uncommon during dengue
  fever
• DHF, encephalopathy is well recognized, from
  several factors
• cerebral anoxia
• cerebral edema
• cerebral hemorrhage
• hyponatremia
• toxicity secondary to liver failure
• Studies in southeast Asia, encephalopathy
  associated with classic DF can occur in up to
  half of the cases

Am. J. Trop. Med. Hyg., 54(3), 1996, 153-55
36
Atypical neurological manifestations of dengue

• Can occur during either dengue fever or DHF
• Meningitis, encephalitis, mononeuropathy, and
  polyneuropathy
• Can occur during earlier stage of disease or as a
  postinfection manifestation

Am. J. Trop. Med. Hyg. 48(6), 1993, 793-802
37
Atypical gastrointestinal manifestations of dengue

• Hepatitis
• Hepatomegaly, jaundice and raised
  aminotransferase levels (ASTgtALT)
• caused by the dengue virus and /or Hypoxia and
  tissue ischemia in cases of shock
• Fulminant hepatic failure
• rare
• Severe hepatic dysfunction (ALT and AST gt10x
  normal) was seen with DHF associated with
  spontaneous bleeding tendencies
• tends to occur more often in DHF or DSS compared
  to classic dengue infections
• Acalculous cholecystitis
• Acute pancreatitis

38
Atypical cardiovascular manifestations of dengue
fever

• uncommon
• Cardiac rhythm disorders
• atrioventricular blocks
• atrial fibrillation
• sinus node dysfunction
• ectopic ventricular beats
• Most are asymptomatic, benign self limiting
  course with resolution of infection
• These arrythmias have been attributed to viral
  myocarditis
• An exact mechanism has not been elucidated

Tropical Medicine and International Health
2007121087-1095
39
Atypical cardiovascular manifestations of dengue
fever

• Pericardial effusions have been reported
  previously, but did not contribute to the shock
  status

40
Atypical respiratory manifestations of dengue

• ARDS
• Pulmonary hemorrhage thrombocytopenia, changes
  in vascular permeability, platelet dysfunction

41
Atypical renal manifestations of dengue

• proteinuria, haematuria, generalized edema and HT
  associated with low C3 and C4 suggests an
  immune-mediated acute glomerular injury
• ARF and multiple organ failure can also be a
  manifestation of rhabdomyolysis

42
Dengue myositis

• Dengue fever break bone fever, severe muscle,
  joint and bone pain
• Acute benign myositis elevated SGOT, SGPT, and
  CPK
• Dengue virus infection may also cause persisting,
  severe, myositis for weeks

43
Lymphoreticular complications of dengue

• Dengue virus antigen is found predominantly in
  cells of the spleen, thymus and lymph nodes
• DHF, lymphadenopathy is observed in half of the
  cases
• Splenomegaly is rarely observed in small infants
• Splenic rupture and lymph node infarction in DHF
  are rare

Tropical Medicine and International Health
2007121087-1095
44
Dengue infection in pregnancy

• Women in a highly endemic area has estimated the
  risk of exposure to be almost 1 during pregnancy
  
• Vertical transmission is a relatively low 1.6
• The seropositivity rate increased with advancing
  maternal age, indicating that younger women were
  more at risk to contract the disease during
  pregnancy
• While the older patients were more likely to have
  preexisting protective immunity

Travel Medicine and Infectious Disease (2007) 5,
183-88 OBSTETRICS GYNECOLOGY VOL.111, NO.5, MAY
2008
Journal of Infection (2005) 51, 287-93
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Management of Dengue Infection

• Dengue is a dynamic disease and presented in 3
  phases febrile phase, critical phase and
  recovery phase
• Clinical deterioration often occurs in the
  critical phase and is marked by plasma leakage
  and rising HCT
• Look out for warning signs which may indicate
  severe dengue or high possibility of rapid
  progression or shock
• Recognition of shock in its early stage and
  prompt fluid resuscitation with close monitoring
  of fluid adjustment will give a good clinical
  outcome
• There is no evidence to support prophylactic use
  of platelet transfusion

46
Management of dengue infection

• Early recognition of the disease
• Management
• referral when necessary

47
A stepwise approach to the management of dengue
48
History taking

• date of onset of fever/illness
• quantity of oral intake
• assessment for warning signs
• diarrhea
• change in mental state/seizure/dizziness
• urine output
• other important relevant histories, such as
  family or neighbourhood dengue
• travel to dengue endemic areas
• co-existing conditions (e.g. infancy, pregnancy,
  obesity, DM, HT)

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Physical examinaion

• assessment of mental state
• assessment of hydration status
• assessment of hemodynamic status
• checking for tachypnea/acidotic breathing/pleural
  effusion
• checking for abdominal tenderness/hepatomegaly/asc
  ites
• examination for rash and bleeding manifestations
• tourniquet test (repeat if previously negative or
  if there is no bleeding manifestation)

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Investigation

• CBC Hct, ?Wbc, ?platelet
• Other LFT, glucose, electrolytes, BUN/Cr,
  bicarbonate or lactate, cardiac enzymes, ECG and
  urine specific gravity

51
A stepwise approach to the management of dengue
52

• Clinician should be able to determine
• Dengue diagnosis (provisional)
• Phase of dengue illness if dengue is suspected
  (febrile/critical/recovery)
• Hydration and hemodynamic status of patient (in
  shock or not)
• Whether the patient requires admission

53
A stepwise approach to the management of dengue
54

• Plan of management
• Notification is required
• If admission is indicated, refer to prerequisites
  for transfer
• If admission is not indicated
• Daily or more frequent follow up is necessary
  especially from day 3 onwards until the patient
  becomes afebrile for at least 24 - 48 hours
  without antipyretics
• Serial CBC/HCT must be monitored as disease
  progresses

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Admission criteria
56
Calculations for normal maintenance of
intravenous fluid infusion
Normal maintenance fluid per hour can be
calculated on the basis of the following
formula(equivalent to Holliday-Segar formula)
4 mL/kg/h for first 10 kg body weight 2
mL/kg/h for next 10 kg body weight 1 mL/kg/h
for subsequent kg body weight For
overweight/obese patients calculate normal
maintenance fluid based on ideal body weight (IBW)
IBW for overweight/obese adults can be estimated
on the basis of the following formula Female
45.5 kg 0.91(height -152.4) cm Male 50.0 kg
0.91(height -152.4) cm
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Management of dengue infection
PRESUMPTIVE DIAGNOSIS Live in/travel to dengue
endemic area Fever and two of the following
criteria Anorexia and nausea Rash Aches
and pains Warning signs Leukopenia
Tourniquet test positive Laboratory confirmed
dengue (important when no sign of plasma leakage)
WARNING SIGNS Abdominal pain or tenderness
Persistent vomiting Clinical fluid
accumulation Mucosal bleed Lethargy,
restlessness Liver enlargment gt2 cm
Laboratory increase in HCT concurrent with rapid
decrease in platelet count (requiring strict
observation and medical intervention)
NEGATIVE
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NEGATIVE
Group A( may be sent home) Group
criteria Patients who do not have warning
signs AND who are able to tolerate adequate
volumes of oral fluids to pass urine at least
once every 6 hours Laboratory tests CBC
HCT Treatment Advice for adequate bed rest
adequate fluid intake Paracetamol, 4 gram
maximum per day in adults and accordingly in
children Patients with stable HCT can be sent
home Monitoring Daily review for disease
progression decreasing WBC count
defervescence warning signs (until out of
critical period) Advice for immediate return to
hospital if development of any warning signs,
and written advice for management (e.g. home
care card for dengue)

• Co-existing conditions
• Social circumstances

NEGATIVE
DENGUE WITHOUT WARNING SIGNS
59
NEGATIVE
POSITIVE

• Co-existing conditions
• Social circumstances

DENGUE WITH WARNING SIGNS
NEGATIVE
DENGUE WITHOUT WARNING SIGNS
60
POSITIVE
SEVERE DENGUE
61
Algorithm for fluid management in compensated
shock
Compensated shock (SBP maintained but has signs
of reduced perfusion)
Fluid resuscitation with isotonic crystalloid
510 ml/kg/hr over 1 hour
Improvement
YES
NO
Check HCT
HCT?
HCT? or high

• IV crystalloid 57 ml/kg/hr for 12
• hours, then
• reduce to 35 ml/kg/hr for 24 hours
• reduce to 23 ml/kg/hr for 24 hours.
• If patient continues to improve, fluid can be
• further reduced.
• Monitor HCT 68 hourly.
• If the patient is not stable, act according
• to HCT levels
• if HCT ?, consider bolus fluid
  administration or increase fluid administration
• if HCT ?, consider transfusion with fresh
  whole transfusion.
• Stop at 48 hours.

Consider significant occult/overt bleed Initiate
transfusion with fresh whole blood
Administer 2nd bolus of fluid 1020 ml/kg/hr for
1 hour
Improvement
NO
YES
If patient improves, reduce to 710 ml/kg/hr for
12 hours Then reduce further
62
Algorithm for fluid management in hypotensive
shock
Hypotensive shock Fluid resuscitation with 20
ml/kg isotonic crystalloid or colloid over 15
minutes. Try to obtain a HCT level before fluid
resuscitation
Improvement
NO
YES
Review 1st HCT

• Crystalloid/colloid 10 ml/kg/hr for 1 hour, then
  continue with
• IV crystalloid 57 ml/kg/hr for 1 2 hours
• reduce to 35 ml/kg/hr for 24 hours
• reduce to 23 ml/kg/hr for 24 hours.
• If patient continues to improve, fluid can be
• further reduced.
• Monitor HCT 6-hourly.
• If the patient is not stable, act according
• to HCT levels
• if HCT ?, consider bolus fluid
  administration or increase fluid administration
• if HCT ?, consider transfusion with fresh
  whole transfusion.
• Stop at 48 hours.

HCT?
HCT? or high
Consider significant occult/overt bleed Initiate
transfusion with fresh whole blood
Administer 2nd bolus fluid (colloid) 1020 ml/kg
over ½-1 hour
Improvement
NO
YES
Repeat 2nd HCT
HCT?
HCT? or high
Administer 3rd bolus fluid (colloid) 1020 ml/kg
over 1 hour
Improvement
YES
NO
Repeat 3rd HCT
63
Treatment of hemorrhagic complications

• Mucosal bleeding
• if patient remains stable with fluid
  resuscitation/replacement, considered as minor
• Bleeding improves rapidly during recovery phase
• Patients with profound thrombocytopenia
• strict bed rest and protect from trauma
• not give im injections (avoid hematoma)
• prophylactic platelet transfusions for severe
  thrombocytopaenia in hemodynamically stable
  patients not shown to be effective and not
  necessary
• If major bleeding occurs, usually from GI tract,
  and/or vagina in adult females

64
Management of Dengue Infection

• No hemorrhagic manifestations and patient is
  well-hydrated
• home treatment
• Hemorrhagic manifestations or hydration
  borderline
• outpatient observation center or hospitalization
• Warning signs (even without profound shock) or
  DSS
• hospitalize

65
Patients Monitoring

• Patients treated at home
• Instruction regarding danger signs
• Consider repeat clinical evaluation
• Patients with bleeding manifestations
• Serial hematocrit and platelets at least daily
  until defervescence for 1 to 2 days

66
Treatment of Dengue Fever

• Fluids
• Rest
• Antipyretics (avoid aspirin and NSAIDs)
• Monitor blood pressure, hematocrit, platelet
  count, level of consciousness