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Clincal Features of Dengue

Tomas Jelinek

MD PhD DTM&H FFTM FRCP(Glas)

• Medical Director, Berlin Center for Travel & Tropical Medicine

• Scientific Director, Center of Travel Medicine, Düsseldorf

• Ass. Professor, Institute for Social Medicine, Epidemiology and

Health Economics, Charité, Berlin

• Consultant, Armed Forces Hospital Berlin

• Berlin Airport Physician

• Expert Consultant to WHO

Source: RKI SurvStat

0

200

400

600

800

2001 2003 2005 2007 2009 2011

Dengue in Germany: reported cases

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Woman in her fifties

• No medical history of earlier illness

• Frequent visits to South-East Asia

• Immunizations from 2000

• No chemoprophylaxis

Thailand

3

Development of symptoms

Teleph d 4

Headache

Fever 39°C

Myalgias

Vomiting

Teleph d 4

Headache

Fever 39°C

Myalgias

Vomiting

Teleph d 8

Fever >39°C

Not feeling ok

Teleph d 8

Fever >39°C

Not feeling ok

Med care center d 9

Fever (37,4)

Headache

Neck stiffness

Vomiting

Dyspnoe

Med care center d 9

Fever (37,4)

Headache

Neck stiffness

Vomiting

Dyspnoe

Cabin d 9

Tachypnoe

Chills

Temp 34,5°C

Dyspnoe

Cabin d 9

Tachypnoe

Chills

Temp 34,5°C

Dyspnoe

Care center d 10

Confusion

Lethargy

Cold extremities

Cyanosis

HR 30-100

BP?

SaO2?

Care center d 10

Confusion

Lethargy

Cold extremities

Cyanosis

HR 30-100

BP?

SaO2?Viral infection

Ibuprofen

Paracetamol

Viral infection

Ibuprofen

Paracetamol

Hospital admittance

• At 06:40 am

• No radial pulsation, no BP measurable

• Cardiac arrest within 3 minutes

4

Rescusitation

• Aggressive fluid therapy (io, iv)

• Lactic acidosis (pH 6,62, lactate 18)

• Abnormal bleeding from perforated skin locations

• Cardiac rhytm established after 25 minutes

Intensive care unit

• Biochemistry• Hb 15-7, Trc 120, INR 2,8, Hct 49, kreat 98

• Lactic acidosis (pH 7,12)

• Therapy• Crystalloids (7000ml over 2,5 h)

• Pressor (Noradrenalin®, Dopamin®, Glypressin®)

• Buffer (Tribonat®)

• Erythrocytes (SAG®)

• Plasma proteins (Octaplas®)

• Antibiotics (Benzylpenicillin, Tobramycin, Metronidazole)

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Complications

• Circulatory failure

• Acidosis

• Respiratory failure

• Hypovolemic shock

• Massive bleeding from endotracheal tube

• Death occured 2,5 h after admittance

What was treated?

• Circulatory collapse in patient with infection

• Returned traveller from Thailand (10 days before)

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Differential diagoses

MalariaMalaria

Bacterial sepsisBacterial sepsis

RickettsiosisRickettsiosis

Dengue viral infectionDengue viral infection

LeptospirosisLeptospirosis

Bacterial meningitisBacterial meningitis

Something else?Something else?

PneumoniaPneumonia

Dengue diagnostics

• Rapid serological test: IgM positive, IgG negative

• Confirmed by ELISA

• Dengue RNA PCR positive

• Only minor viremia

• Serotype 1 (DEN-1)

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What makes this case unique?

• Dengue shock syndrome (DSS)

• Primary dengue infection

• No hemorrhagic manifestations

• Unfulfilled WHO case criteria of DHF

• Woman in her fifties

• Rapid shock initiation

• Fatal outcome

4 Serotypes: I-IVTransmission: mosquitos (Aedes aegypti & albopictus)Incubation period: 2-7 days

Symptomshigh fever, frequently biphasicpronounced myalgias and arthralgiasheadacherash

Complications:Dengue Hemorrhagic Fever (DHF)Dengue Schock Syndrome (DSS)

Dengue-Fever (DF)Dengue-Fever (DF)

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Dengue Fever

• Fever (sudden onset)

• Headache

• Myalgia & Arthralgia, „break bone fever“

• Rash (< 50%)

• Leuco-, Thrombozytopenia

CLINICAL FEATURES

Fever 92.7%Headache 69.4%Fatigue 56.6%Rash 53 %Muscle pain 49.8%Retroorbital

pain 43.8%Bleeding

disorder* 26 %

Unusual clinical findings: blurred vision / atrial fibrillation

*including positive tourniquet test

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TropNetEurop: Signs and Symptoms of Travel-Acquired Dengue Infections in 465 Europeans and Immigrants to Europe (multiple entries possible)

Fever

Headache

Myalgia/Arthralgia

Fatigue

Rash

Diarrhea

Vomiting

Lymphadenopathy

Respiratory Symptoms

ENT Symptoms

Neurological Symptoms

Psychological Symptoms

Other

0 10 20 30 40 50 60 70 80 90 100

% Jelinek et al. CID 2002

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RashRash::

„„ whitewhite islandsislandsin a in a

red red seasea““

Dengue Hemorrhagic FeverDengue Hemorrhagic Fever

Source: Farrar, Wood, Innes,

Tubbs. Infectious Diseases. Mosby Int. 1995

Petechial exanthema

positive Tourniquet-test

Hemorrhages

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Diagnostic Criteriaas DHF plusRR-decrease

Therapy:Thrombocytes ICUShock management

Note: Mortality up to 44%!

Dengue Shock Syndrome (DSS)Dengue Shock Syndrome (DSS)

Bleeding with Dengue

• In many cases minor bleeding occurs at sites of trauma only

• There is NO thrombotic tendency clinically

• Significant mucosal bleeding (usually GI) is associated with:-�Severe or prolonged shock�Older age/adults

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DHF/DSS-Risk and Viral Factors

• Virus Serotype– DEN-2 > DEN-3 >> DEN-4 and DEN-1

• Virus-Strain (Sub-/Genotype)

• Regions with circulation of 2 or moreserotypes

DHF/DSS-Risk and Host Factors

• Higher risk in secondary infections

• Pre-existing DEN-antibodies– previous infection– maternal antibodies in babies

• Age

• genetic factors– Asians + Caucasians >> Africans

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Antibody Dependent Enhancement

� Life-long protection againt homologous serotype

�No or only brief protection against heterologousserotypes

�Consecutive infection with a different serotype:

�Heterologous antibodies enhance viral replication: „antibody dependend enhancement“ (ADE)

�Increased Risk for DHF/DSS

-

1

Dengue 1 Virus1

HomologousHomologousantibodies form antibodies form nonnon-- infectious complexesinfectious complexes

-Non neutralising antibodies

1

1

1 Complex of neutralisiing AB + Virus

1Neutralising antibodies against DEN Virus

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Dengue 2 Virus

2

2

2

HeterologousHeterologous antibodies form antibodies form infectious complexesinfectious complexes

1 AB to Dengue Virus

2 2

Complex of AB + Virus2

Infectious Ab/VirusInfectious Ab/Virus--complexes bind to FCcomplexes bind to FC--receptors of monocytes,receptors of monocytes,enhancing enhancing

replicationreplication

Non-neutralizing antibody

2

2

Dengue 2 Virus2

2

2

Complex of antibody and DengueVirus

2

2

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First infection withany

Dengue-Serotype

Dengue-Fever

Remission, life-longimmunity to that particular

serotype

2nd, (3rd, 4th) infection withany other dengue serotype

Immune enhancement: virus and preexistingantibodies against other serotypes form complexes

Invasion of monocytes is enhanced, increased viralreplication

Release of vasoactive mediators from T-cells, increase of vascular permeability, extravasation,

haemorrhagies

DHF DSS

Mortality: 12-44%Mortality: 1-5%

DHF and DSS: PathophysiologyDHF and DSS: Pathophysiology

Grading of DHF and DSS (WHO-Classification)

• Grade 1DF, TZ ↓, Tourniquet +

• Grade 2grade 1 + spontaneous hemorrhages

• Grade 3 (DSS)imminent shock(tachycardia, hypotension, etc.)

• Grade 4 (DSS)shock

- DSS: signs of capillary leakage• HK (> 20%), Hypalbuminemea, pleural effusions

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Candidate list of explanatory variables for riskfactor analysis or „warning signs“

• Categorical:– Abdominal pain or abdominal tenderness present– Persistent vomiting present (> 5 times per day)– Restlessness– Lethargy– Chest pain– Watery stools– Skin flush– Generalized rash– Fainting (only for age > 5y)– Jaundice– Liver enlarged (>= 2cm)– Any bleeding present– Any mucosal bleeding present– Tourniquet test positive– Abnormal Coma Score (GCS or BCS)– Any past medical history

• Continous:– Hct (highest per day)– Platelets (lowest per day)– WBC– Atypical lymphocytes– AST/ALT– Albumin– Bilirubin– Syst. BP (lowest of the day)

Based on values being present 1 day before onset of severe disease (based on the administration of a severe intervention)

The risk of progressing towards severedisease is ~5% - no significant differencebetween mild group and moderate group

510.04-0.080.06From moderate to severe

320.03-0.060.04From mild to severe

830.04-0.060.05Transition to severe

N95% CIRisk

• 144 patients were grade of intervention 3 on their day of enrollment

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Possible warning signs for severedisease

2

9

25

27

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1 1

010

2030

Nu

mbe

r of

pat

ien

ts

1 2 3 4 5 6 7 8 9day of illness (of first worst day)

Severe cases with minus 1 data available

Possible warning signs before onset of severedisease by intervention category

controlled for age group (</>=15y), continent and day of intervention

2.87 (0.002)Mucosal bleeding

10.69 (<0.001)Lethargy

1.19 (<0.001)Platelet decrease(per 10,000)

3.53 (<0.001)Abdominal pain / tenderness

1.00 (0.983)Hematocrit increase (%)

Multivariable OR (p-value)

1 day before onset of severity

(pooled from day of illness 4-7)Variable

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SEVERE DENGUE

1.Severe plasma leakage2.Severe haemorrhage3.Severe organ impairment

Warning Signs

DENGUE ± Warning Signs

Dengue Classification (WHO meeting Sept. 2008)

WithoutWith

Warning Signs*• Abdominal pain or tenderness• Persistent vomiting• Clinical fluid accumulation• Mucosal bleeding• Lethargy; restlessness• Liver enlargement >2cm• Laboratory: Increase in HCT concurrent with rapid decrease in platelet count

1. Severe plasma leakage leading to • Shock (DSS)• Fluid accumulation with respiratory distress

2. Severe bleedingas evaluated by clinician

3. Severe organ involvement� Liver: AST or ALT>=1000 � CNS: Impaired consciousness � Heart and other organs

Presumptive Diagnosis• Fever• Anorexia and nausea • Rash• Aches and pains• ± Warning signs• Leucopenia• Tourniquet test +

Neighbourhooddengue/history of travel to dengue endemic area * Requiring strict observation and medical intervention

Surveillance on dengue within TropNetEurop

� Between 1999 – 2003: 483 cases notified including 13 cases (2.7%) of dengue hemorrhagic fever (DHF)

� Non-Europeans (immigrants and foreign visitors) � 4-times higherrisk to develop DHF[95% CI 1.4–13.5]

(Wichmann et al. Dengue Bull 2003)

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Results: Patients‘ characteristics

� 219 travellers with dengue (median age 32yrs)

� 8% non-Europeans (n=17), all born in dengue endemic countries

� 17% secondary infections*

� Non-European more secondary infections (50% vs. 14%, P = 0.001)

� DHF (WHO-case def.): 2 persons (0.9%)

� 1 atrial fibrillation, 1 blurred vision (2 months)*Exclusion of travellers with previous flavivirus immunization (JEV, YF, TBE)

Origin of dengue in 219 travellers

� Single countries: India (23%), Thailand (17%)� Median travel duration: 24 days� First trip to dengue-endemic country: 39%

Southeast Asia

Indian subcontinent

South-Central America

Caribbean

Africa

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0 10 20 30 40 50 60 70

ALAT >3-fold incr.

ASAT >3-fold incr.

Thrombo&Leucopenia

Shock

Spont. Bleeding

Petechiae

Pos. Tourniquet

Rash

Clinical & laboratory features of dengue in travellers during the acute phase (n=176)

n=37/84

[%]

nose/gum (n=11)skin bleeding (n=4)internal hemorrhage (n=4)

Platelets <50,000/mm3

(n=18)

Associations with severe infection

� 23 (11%) with severe disease

� Univariate analysis:

% OR 95%CI

secondary dengue 44 5.1 (1.4–17.7)non-European origin 23 3.8 (1.0–13.9)>3-fold ASAT-increase 55 3.5 (1.2–10.0)

� No association: travel to Asia, travel >28d

� Multivariate analysis: secondary dengue infection & > 3-fold increased ASAT

� 34% first visit to dengue-endemic country

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Associations with spontaneous bleeding

� 17 (8%) with spontaneous bleeding�Univariate analysis:

% OR 95%CIsecondary dengue infection 46 5.3 (1.4–20.8)non-European origin 24 3.7 (0.9–15.2)>3-fold ASAT-increase 56 3.5 (1.1–11.4)>3-fold ALAT-increase 47 3.3 (1.1–10.4)Platelets < 100,000/mm3 71 3.1 (0.95–10.7)

�No association: travel to Asia, travel >28d�Multivariate analysis: secondary infection, non-European

origin, >3-fold ALAT-increase� 29% first visit to dengue-endemic country

Diagnosis

Dengue

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� Culture� Isolation of virus in tissue-culture is only 50%

sensitive in acute phase samples� PCR� NS1-Antigen

� Serological methods� Detection of specific IgM � Significant rise of IgG in paired serum samples

�Antibody testing might fail at that early stage�Take convalescent samples

�Confirmed dengue� Virus detection by isolation,

immunohistochemistry in necropsy tissue, or � an at least four-fold increase of antibody titers

using a type-specific plaque reduction neutralization test

� Samples positive for IgM antibody alone should only be reported as “probable” dengue infections

Diagnosis of Dengue

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Dengue Fever IgMand IgGDengue Fever IgMand IgGRapid immunochromatographic Test Rapid immunochromatographic Test

IgMIgM positivepositive NegativeNegative

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Confirmed denguevirus detection by isolation, PCR, orfourfold or greater change in reciprocal IgM or IgGantibody titres in paired serum samples

Probable denguesingle positive IgM antibody test on a acute or convalescent-phase serum specimen

Suspected denguediagnosis based entirely on clinical features and travel history

Diagnosis of “suspected”, “probable”, and “confirmed”dengue infection according to WHO classifications

Dengue-Fever (DF): TherapyDengue-Fever (DF): Therapy

symptomatic:RestAntipyreticsAnalgetics

Be careful with ASS!

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Quelle: www.pdvi.org

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Questions?