DENGUE FEVER AND ALIKE

PGI Deepak GhimireSHH - Department of Medicine

Primary Sources: WHO Dengue guidelines for diagnosis, treatment, prevention and control ,2009

Dengue Fever

• One of the viral hemorrhagic fever

• Most rapidly spreading mosquito-borne viral disease

• In the last 50 years, incidence has increased 30-fold

• Increasing geographic expansion

– New countries

– From urban (OLD) to rural settings (NOW)

https://www.interhealthworldwide.org

Viral hemorrhagic fever

Dengue Fever

• DOH - 41% increase in cases of dengue fever

– January 2016 to June 2016 compared with the same period in 2015

• Average: 220 dengue cases/Day (2010-2015)

• Peak : July - November (few month after rainy season)

https://www.interhealthworldwide.org

DOH records

DOH records

DENGUE

• Definition:

• DENV is an single stranded RNA positive-strand virus of the family Flaviviridae; genus Flavivirus

DENGUE VIRUS

Aedes aegypti

Mosquito-borne tropical disease caused by Dengue Virus

Modes of transmission

• Which of the following are modes of transmission of Dengue virus ?

1. Mosquito bite (vector borne)

2. Blood transfusion

3. Vertical transmission

4. Needle prick injury

5. Feco-oral

Vector of Dengue Fever

• Principal vector: Aedes aegypti• Tropical & subtropical species

• Relatively uncommon above 1000 metres

• May spend their lifetime in or around the houses

• Immature stages are found in water-filled habitats

• several species: outbreak

– Aedes albopictus

– Aedes polynesiensis

AGE DISTRIBUTION

• 2000-2010 (DOH)

– 1-4 y0: (15-31%)

– 5-14 yo (28-50%)--- Highest proportion :

– 15-49yo: (21-37%)

Visayas (2015,DOH) : wider distribution in >21 y.o

Why is that dengue predominantly affects children in endemic area?

• In endemic areas, children and in coming tourists may be only person to acquire overt dengue fever, WHY ?

– Usually Adults have become immune

Is dengue virus racist ?

• Answer TRUE/FALSE :

A. DENGUE IS MORE COMMON IN WHITES & ASIANS

B. DENGUE IS MORE COMMON IN BLACK

Like malaria, severe dengue is also very rare in individual of African ancestry.

DUE TO UNDISCOVERED GENETIC RESISTANCE

Area of involvement & vector

• o'nyong'nyong virus– usually involves villages/small town

– Transmitted by Anopheles mosquito

– polyarthritis, rash and fever

– self-limiting & No fatalities

• dengue/ & chikungunya– causes urban outbreaks

– spread by Aedes albopictus & Aedes aegypti.

DENGUE FEVER AND ALIKE

DENGUE VIRUS PATHWAY

Dengue Virus: 3 structural proteins

Dengue Virus

73

How many serotypes of Dengue virus are known ?

• Previously recognized: 4 serotypes

– Serotypes

• DEN-1

• DEN-2

• DEN-3

• DEN -4

•The fifth variant DENV-5 has been isolated in October 2013 ( Malaysia outbreak ,2007)• DENV-5 follows the sylvatic cycle unlike the other 4 serotypes •Has potential for human infection (few incidence; Malaysia, Singapore)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297835/

Which serotypes of most dangerous ? Den-2

How to determine dengue serotype?

• Plaque reduction neutralization test (PRNT)

– detection of serotype-specific IgG antibody

– gold standard for detecting the neutralization activity of antibodies against DENV

• RT-PCR based method

Fig. PRNT

Why some dengue are too serious ?

• DHF occurs if multiple serotypes of dengue virus are transmitted; simultaneously or sequentially ( secondary dengue)

• First infections, called primary infections are usually mild symptoms

• In areas of high endemicity secondary infections are frequent, but not all 2ndry infections are dangerous

• Immunological status also plays major role

When can primary infections be severe ?

• Severe dengue (DHF) can occur during primary dengue infection most commonly in infants whose mothers are immune to dengue

• WHY ?

•Circulation of infection enhancing antibodies at the time of infection is strongest risk factor

•Absence of cross reactive neutralizing antibody

Pathogenesis

• Q. COMPLETE PATHOGENESIS OF DENGUE (SEVERE DENGUE) IS UNDERSTOOD

• ANSWER: NO

• But epidemiologic studies suggest it is usually associated with second heterotropicinfections of DENG 1-4

• Viremia level predicts disease severity

Is there any immune suppression in dengue ?

• Answer YES OR NO

Pathogenesis of DF

• Dengue virus – immune complex attaches to marcophages Fc receptors

• Signals to suppress innate immunity

• Results in enhanced viral production

Pathogenesis of Secondary dengue infection

• Rapid activation of complement system

• TNF receptor, INF-y, IL-2 level are elevated

• C3 catabolic rates are elevated & c1q,c3,c4,c5-8 , c3 proactivators are depressed

Why is there increased vascular permeability ?

• complement activation

• Virus itself or NS1-Ag interacts with endothelial cells, blood clotting factors & platelet

• These interactions increase vascular permeability

What is the mechanism of bleeding in dengue ?

• Not known

• Synergy of ff :

–Mild DIC

–Liver damage

–Thrombocytopenia

What is mechanism behind hemoconcentrations & hypovolemia ?

• Capillary leakage – Fluids, electrolyre, albumin & even RBC leaks into

extravascular spaces

• Fluid deficit– Fasting, thristing, vomiting

• These factors lead to hemoconcentration, hypovolemia, tissue hypoxia, metabolic acidosis and hyponatremia

Biopsy of death patient, what do you expect to find ?

• usually NO PATHOLOGICAL lesions are found– GI or Intracranial hemorrhage (few case)– Petechial hemorrhage of inteventricular septum of

Heart, myocarditis (very rare) – Focal hemorrhage in lungs, liver, adrenal,

subarachnoid space– Liver might have fatty changes’– Blood tinged effusions in body cavity (75% cases)– DENGUE VIRUS is frequently absent in tissues – Viral antigen/RNA can be localized to hepatocyte and

macrophages in liver, spleen, lung, lymphatics

Headache Body Malaise Myalgia Arthralgia Retro-orbital pain

Anorexia Nausea Vomiting Diarrhea Flushed skin Rash (Petechial,

Hermann’s sign)

PROBABLE DENGUE

PLUS any TWO (2) of the following:

And LABORATORY TESTS CBC (leukopenia with or without

thrombocytopenia) and/or Dengue NS1 Antigen test or Dengue IgM antibody test (optional)

Lives in or travel to dengue-endemic area, with fever lasting 2-7 days,

LABORATORY CONFIRMED DENGUE•Viral culture Isolation•PCR •Dengue serology

TOURNIQUET TEST

• (+) TT increases the probability of dengue

• (+) hemorrhagic manifestations

HOW TO DO A TORNIQUET TEST

• Take the patient’s blood pressure and record it– For example, 100/70mmHG

• Inflate the cuff to a point MIDWAY between SBP and DBP, and maintain for 5 minutes, (100+70)/2= 85mmHg

• Reduce and wait 2minutes

• Count petechial below antecubital fossa

• POSITIVE TEST : – 10 or more petechiae /square inch

CLINICAL DIAGNOSIS OF DENGUE

• THINGS TO CONSIDER:

– Exposure Hx.

– S/sx. consistent with Dengue

• R/O other diseases exposure

• R/O other Acute febrile illnesses

– Clinical laboratory findings consistent with dengue

DENGUE SIGNS AND CLINICAL SYMPTOMS

• Incubation Period: 4-10 days (usually 4-7 days)

• Sudden onset of high fever

• Three Phases

1. Febrile phase

2. Critical Phase

3. Recovery phase

Febrile Phase

Critical Phase

Recovery Phase

PHASES OF DENGUE FEVER

FEBRILE PHASE

• Usually lasts 2-7 days

• Monitoring warning signs: recognize progression to Critical Phase

• Mild hemorrhagic manifestations: Petechiae and mucosal bleeding may be seen

• Earliest Abnormality in CBC: total WBC

CLINICAL SIGNS AND SYMPTOMS

Headache Body Malaise Myalgia Arthralgia Retro-orbital pain Anorexia Nausea Vomiting Diarrhea Flushed skin Rash (Petechial, Hermann’s

sign)

LABORATORY TESTS

• CBC

– Leukopenia

with or without thrombocytopenia) and/or

• Tourniquet test

• Dengue NS1 Antigen test or

• Dengue IgM antibody test (optional)

COMPLICATIONS : DEHYDRATION

Mimics of Dengue fever

, Zika virus

Disease transmitted by Aedes aegypti

Thrombocytopenia Small joints painstooped posture

Laboratory test for Dengue Fever

Laboratory test for Dengue Fever

Primary and secondary Dengue infection

Other Laboratory test for Dengue Fever

• Liver enzymes (AlT > AST)

• Creatinine

• Cardiac enzymes *

– myocarditis

– atrioventricular conduction disorders

– supraventricular arrhythmia

Diagnosis of Chikungunya

Illness <5 days : RT-PCR Illness 5-7 days : RT-PCR + serology (IgM ELISA)Illness >7 days : serology (4 x rise is titer)

PHASES OF DENGUE FEVER

CRITICAL PHASE

• DEFERVESCENCE: DAY 3-7 of illness; when Temp. drops to 37.5-38’C or less, and remains below this level

• Pt. can either IMPROVE or DETERIORATE IMPROVE: Dengue without

Warning signs DETERIORATE:

Dengue With Warning signs Severe Dengue

WARNING SIGNS

• Abdominal pain or tenderness

• Persistent Vomiting

• Mucosal Bleeding

• Clinical signs of Fluid accumulation

• Lethargy, restlessness

• Liver enlargement

• Laboratory: – INCREASE in Hct (20%)

and/or

– DECREASE Platelet count <100,000/ul

COMPLICATIONS: SHOCK, BLEEDING / ORGAN IMPAIRMENT

Mimics of Dengue fever

PHASES OF DENGUE FEVER

RECOVERY PHASE

In the next 48-72hrs: Gradual re-absorption of extravasatedfluid from intravascular to extravascular space thru Lymphatics.

Improvement of well-being

Stable hemodynamic status

Diuresis

Appearance of Classical rash: “isles of white in the sea of red”

Hct stablize/ lower due to dilution effect of reabsorbed fluids

WBC- rises soon after defervescence (1st), then Platelet Count normalizes

COMPLICATIONS : HYPERVOLEMIA

RECOVERY PHASE

“isles of white in the sea of red”

DENGUE CLASSIFICATION

WHO 1997 classification

1. Undifferentiated Fever

2. Dengue Fever (DF)

3. Dengue Hemorrhagic Fever (DHF)- Grade I,II,III,IV(DSS)

Revised WHO classification (2009)

1.Dengue WITHOUT

warning signs

2.Dengue WITH

warnings signs

3.SEVERE Dengue

Headache Body Malaise Myalgia Arthralgia Retro-orbital pain Anorexia Nausea Vomiting Diarrhea Flushed skin Rash (Petechial,

Hermann’s sign)

DENGUE WITHOUTWARNING SIGNS

DENGUE WITHWARNING SIGNS SEVERE DENGUE

PLUS any TWO (2) of the following:

And LABORATORY TESTS CBC (leukopenia with or

without thrombocytopenia) and/or

Dengue NS1 Antigen test or Dengue IgM antibody test

(optional)

Lives in or travel to dengue-endemic area, with fever lasting 2-7 days,

PLUS any ONE (1) of the following:

Abdominal pain or tenderness

Persistent vomiting Clinical signs of fluid

accumulation Mucosal bleeding Lethargy, restlessness Liver enlargement Laboratory: INCREASE in Hct

and/or DECREASE Platelet count <100,000/ul

CONFIRMED DENGUEViral culture IsolationPCR, dengue serology

Dengue with or without warning signs, PLUS any of the following:

Severe Plasma Leakage, leading to:-shock-fluid accumulation with respiratory distress

Severe BleedingSevere Organ Impairment

- Liver: AST or ALT ≥1000-CNS: seizure, impaired consciousness-Heart: Myocarditis-Kidneys: renal failure

DENGUE

WITH/WITHOUT WARNING SIGNS

Lives in or travel to dengue-endemic area, with fever lasting 2-7 days,

PLUS any ONE (1) of the following:

Abdominal pain or tenderness Persistent vomiting Clinical signs of fluid accumulation Mucosal bleeding Lethargy, restlessness Liver enlargement Laboratory: INCREASE in Hct and/or DECREASE

Platelet count <100,000/ul

SEVERE DENGUE

Lives in or travel to dengue-endemic area, with fever lasting 2-7 days,

and any of the above clinical manifestations for dengue with or without warning signs, PLUS any of the following:

Severe Plasma Leakage, leading to:-shock-fluid accumulation with respiratory distress

Severe BleedingSevere Organ Impairment

- Liver: AST or ALT ≥1000-CNS: seizure, impaired consciousness-Heart: Myocarditis-Kidneys: renal failure

TREATMENT

• Treatment of uncomplicated dengue fever is supportive

• Bed rest is advised during the febrile period.

• Antipyretics should be used to keep body temperature < 40 ° C (104 ° F)

• Analgesics or mild sedation may be required to control pain

• Aspirin is contraindicated

• Fluid and electrolyte replacement - required for deficits caused by sweating, fasting, thirsting, vomiting, and diarrhea

DENGUE CASE MANAGEMENT: GROUP A ( OPD/home care)

GROUP CRITERIA : Px. With out warning signs AND who are able: • To tolerate adequate volumes of oral fluids • To pass urine at least once every 6 hours

LABORATORY TESTS• Complete blood count (CBC)• Haematocrit (HCT) – px. With stable HCT can be sent home

TREATMENT• Adequate bed rest• Adequate fluid intake• Paracetamol, 4 gram maximum per day in adults and accordingly in children.

MONITORING : Daily review for disease progression:• Decreasing white blood cell count• Defervescence• warning signs (until out of critical period)

INSTRUCTIONS: •Advice for immediate return to hospital if development of any warning signs, and• written advice for management (e.g. home care card for dengue).

DENGUE CASE MANAGEMENT: GROUP B (In-hospital care)

GROUP CRITERIA : Px. With WARNING SIGNS OR• co-existing conditions :pregnancy,infancy, old age,diabetes mellitus,renal failure• social circumstances : living alone, living far

TREATMENT: Obtain reference HCT before fluid therapy•Give isotonic solutions such as 0.9 % saline, ringer’s lactate.

•Start with 5–7 ml/kg/hr for 1–2 hours then •Reduce to 3–5 ml/kg/hr for 2–4 hr, and then •Reduce to 2–3 ml/kg/hr or less according to clinical response

REASSESS CLINICAL STATUS AND REPEAT HCT:• if HCT remains STABLE continue with 2–3 ml/kg/ hr for another 2–4 hours;• if vital signs Worsens & HCT rises rapidly increase rate to 5–10 ml/kg/hr for 1–2 hours

REASSEMENT IVF RATE: reduce intravenous fluids gradually when the rate of plasma leakage decreases towards the end of the critical phase

• Adequate urine output and/or fluid intake•HCT deceases below the baseline value in a stable patient.

MONITOR: •vital signs and peripheral perfusion (1–4 hourly until patient is out of critical phase• urine output (4–6 hourly)• HCT (before and after fluid replacement, then 6–12 hourly)• blood glucose• other organ functions (renal profile, liver profile, coagulation profile, as indicated).

DENGUE CASE MANAGEMENT: GROUP C (Needs Emergency care)

GROUP CRITERIA : Px. With WARNING SIGNS & any of the following features:•severe plasma leakage with shock and/or fluid accumulation with respiratory distress•severe bleeding • severe organ impairment

Severe dengue

Compensated shock

Hypotensiveshock

Severe bleeding

• signs of Compensation •Signs of poor perfusion•Normal B.P

•Signs of shock•Narrowed pulse pressure•Hypotension •Met. Acidosis

•Drop in Hct (20% or >) •Or frank hemorrhage•GI bleed•Epistaxis

DENGUE CASE MANAGEMENT: GROUP C (Needs Emergency care)

COMPENSATED SHOCK : Fluid challenge for 24-48 hours

•Start isotonic crystalloids at 5–10 ml/kg/hr over 1 hour. •Reassess condition.

IF PATIENT IMPROVES:• IV fluids should be reduced gradually

•5–7 ml/kg/hr for 1–2 hours•3–5 ml/kg/hr for 2–4 hours•2-3 ml/kg/hr for 2–4 hours

•Reduced further depending on haemodynamic status;

IF PATIENT IS STILL UNSTABLE: check HCT after first bolus;• If HCT increases/still high (>50%), repeat a 2nd bolus of crystalloids (10-20 ml/kg/hr for 1 hr)

•If (+) improvement after 2nd bolus reduce rate to 7–10 ml/kg/hr for 1-2 hrs

• continue to reduce as above;

COMPENSATED SHOCK

•IF HCT DECREASES, this indicates bleeding •need to cross-match and transfuse blood as soon as possible.

DENGUE CASE MANAGEMENT: GROUP C (Needs Emergency care)

HYPOTENSIVE SHOCK:

TREATMENT OF HYPOTENSIVE SHOCK :•Initiate IV fluid resuscitation with crystalloids or colloids at 20 ml/kg as a bolus for 15 min

IF PATIENT IMPROVES:• give a crystalloid/colloid solution of 10 ml/kg/hr for 1 hour, then reduce gradually as above.

IF PATIENT IS STILL UNSTABLE: Review the HCT taken before the fi rst bolus

IF HCT WAS LOW (<40% in children and adult females, <45% in adult males) •Indicates bleeding cross-match and transfuse

IF HCT WAS HIGH COMPARED TO BASELINE VALUE•Change to IV colloids at 10–20 ml/kg as a second bolus over 30 minutes to 1 hour

•Reassess after second bolus. •IF PATIENT IS IMPROVING reduce the rate to 7–10ml/kg/hr for 1–2 hours, then back to IV cystalloids and reduce rates as above; •IF PATIENT’S CONDITION IS STILL UNSTABLErepeat HCT after second bolus.

If HCT decreases, this indicates bleeding

IF HCT INCREASES/REMAINS HIGH (>50%)•continue colloid infusion at 10–20 ml/kg as a third bolus over 1 hour, then reduce to 7–10 ml/kg/h 1–2 hours, then change back to crystalloid solution and reduce rate as above.

DENGUE CASE MANAGEENT: GROUP C (Needs Emergency care)

SEVERE BLEEDING:

TREATMENT OF HAEMORRHAGIC COMPLICATIONS:

•Give 5–10 ml/kg of fresh packed red cells

OR

•10–20 ml/kg of fresh whole blood.

Hematocrit of <30% as a trigger for blood transfusion, as recommended in the Surviving Sepsis Campaign Guideline (15), is not applicable to severe dengue.

When is platelet transfusion indicated in Dengue ?

There is little evidence to support the practice of transfusing platelet concentrates and/or fresh-frozen plasma for severe bleeding.

ALGORITHM FOR FLUID MANAGEMENT IN HYPOTENSIVE SHOCK

INFANTS. CHILDREN AND ADULTS

TREATEMENT OF HEMORRHAGIC COMPLICATIONS

• Mucosal bleed

– If stable with fluid resuscitation; consider it minor

• Profound thrombocytopenia

– Strict bedrest and protection from trauma

• Do NOT give IM injections

– avoid hematoma

• Watch out for BLACK STOOL:

– GI Bleed or Internal bleed

Complications in Dengue

• Dehydration

• Bleeding

• hyperglycaemia or hypoglycaemia

• Bradyarrythmia

• Electrolyte and acid-base imbalances

• co-infections (URTI, Iv site, FBC ?)

• Hypervolemiamost frequent cause of death

DEATH IN DENGUE: HYPERVOLEMIA

• Early clinical features of fluid overload:– Respiratory distress, difficulty in breathing;– Rapid breathing;– Chest wall in-drawing;– Wheezing (rather than crepitations);– Large pleural effusions;– Tense ascites;– Increased jugular venous pressure (JVP).

• Late clinical features:– pulmonary edema

– irreversible shock (heart failure)

Disease notification

• In dengue-endemic countries, cases of suspected, probable and confirmed dengue should be notified as soon as possible so that appropriate public health measures can be initiated.

• Laboratory confirmation is not necessary before notification but should be obtained.

• In non-endemic countries, usually only confirmed cases will be notified.

DISCHARGE CRITERIA

Prevention

• Sanitation

• Vector control

• Dengue Vaccine

Status of Vaccine Development

• CYD-TDV is a live recombinant tetravalentdengue vaccine that has been evaluated as a 3-dose series on a 0/6/12 month schedule inPhase III clinical studies.

• It has been registered for use in individuals 9-45years of age living in endemic areas.

• Protection rate of 56-60 % in Phase III clinicalstudies

• CYD-TDV is currently not prequalified by WHO

Good morning !