Clincal Features of DengueALAT >3-fold incr. ASAT >3-fold incr. Thrombo&Leucopenia Shock Spont....
Transcript of Clincal Features of DengueALAT >3-fold incr. ASAT >3-fold incr. Thrombo&Leucopenia Shock Spont....
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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
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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
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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
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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
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% 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
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Dengue 1 Virus1
HomologousHomologousantibodies form antibodies form nonnon-- infectious complexesinfectious complexes
-Non neutralising antibodies
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1
1 Complex of neutralisiing AB + Virus
1Neutralising antibodies against DEN Virus
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Dengue 2 Virus
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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
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Dengue 2 Virus2
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2
Complex of antibody and DengueVirus
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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
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1 1
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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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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?