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 Dengue in Germany: reported cases 800 600 400 00 0 001 003 005 007 009 011 Source: RKI SurvStat 1
Woman in her fifties No medical history of earlier illness Frequent visits to South-East Asia Immunizations from 000 No chemoprophylaxis Thailand
Development of symptoms Teleph d 4 Headache Fever 39 C Myalgias Vomiting Teleph d 8 Fever >39 C Not feeling ok Med care center d 9 Fever (37,4) Headache Neck stiffness Vomiting Dyspnoe Viral infection Ibuprofen Paracetamol Cabin d 9 Tachypnoe Chills Temp 34,5 C Dyspnoe Care center d 10 Confusion Lethargy Cold extremities Cyanosis HR 30-100 BP? SaO? Hospital admittance At 06:40 am No radial pulsation, no BP measurable Cardiac arrest within 3 minutes 3
Rescusitation Aggressive fluid therapy (io, iv) Lactic acidosis (ph 6,6, lactate 18) Abnormal bleeding from perforated skin locations Cardiac rhytm established after 5 minutes Biochemistry Therapy Intensive care unit Hb 15-7, Trc 10, INR,8, Hct 49, kreat 98 Lactic acidosis (ph 7,1) Crystalloids (7000ml over,5 h) Pressor (Noradrenalin, Dopamin, Glypressin ) Buffer (Tribonat ) Erythrocytes (SAG ) Plasma proteins (Octaplas ) Antibiotics (Benzylpenicillin, Tobramycin, Metronidazole) 4
Complications Circulatory failure Acidosis Respiratory failure Hypovolemic shock Massive bleeding from endotracheal tube Death occured,5 h after admittance What was treated? Circulatory collapse in patient with infection Returned traveller from Thailand (10 days before) 5
Differential diagoses Malaria Bacterial meningitis Rickettsiosis Leptospirosis Pneumonia Something else? Bacterial sepsis Dengue viral infection Dengue diagnostics Rapid serological test: IgM positive, IgG negative Confirmed by ELISA Dengue RNA PCR positive Only minor viremia Serotype 1 (DEN-1) 6
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 Dengue-Fever (DF) 4 Serotypes: I-IV Transmission: mosquitos (Aedes aegypti & albopictus) Incubation period: -7 days Symptoms high fever, frequently biphasic pronounced myalgias and arthralgias headache rash Complications: Dengue Hemorrhagic Fever (DHF) Dengue Schock Syndrome (DSS) 7
Dengue Fever Fever (sudden onset) Headache Myalgia & Arthralgia, break bone fever Rash (< 50%) Leuco-, Thrombozytopenia CLINICAL FEATURES Fever 9.7% Headache 69.4% Fatigue 56.6% Rash 53 % Muscle pain 49.8% Retroorbital pain 43.8% Bleeding disorder* 6 % Unusual clinical findings: blurred vision / atrial fibrillation *including positive tourniquet test 8
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 0 30 40 50 60 70 80 90 100 % Jelinek et al. CID 00 9
Rash: white islands in a red sea Dengue Hemorrhagic Fever Petechial exanthema positive Tourniquet-test Source: Farrar, Wood, Innes, Tubbs. Infectious Diseases. Mosby Int. 1995 Hemorrhages 10
Dengue Shock Syndrome (DSS) Diagnostic Criteria as DHF plus RR-decrease Therapy: Thrombocytes ICU Shock management Note: Mortality up to 44%! 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 11
DHF/DSS-Risk and Viral Factors Virus Serotype DEN- > DEN-3 >> DEN-4 and DEN-1 Virus-Strain (Sub-/Genotype) Regions with circulation of or more serotypes 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 1
Antibody Dependent Enhancement Life-long protection againt homologous serotype No or only brief protection against heterologous serotypes Consecutive infection with a different serotype: Heterologous antibodies enhance viral replication: antibody dependend enhancement (ADE) Increased Risk for DHF/DSS Homologous antibodies form non-infectious complexes 1 1 1 1 1 Dengue 1 Virus Neutralising antibodies against DEN-1 Virus Non -neutralising antibodies Complex of neutralisiing AB + Virus 13
Heterologous antibodies form infectious complexes Dengue Virus AB to Dengue 1 Virus Complex of AB + Virus Infectious Ab/Virus-complexes bind to FC- receptors of monocytes, enhancing replication Dengue Virus Non-neutralizing antibody Complex of antibody and Dengue Virus 14
DHF and DSS: Pathophysiology First infection with any Dengue-Serotype nd, (3rd, 4th) infection with any other dengue serotype Immune enhancement: virus and preexisting antibodies against other serotypes form complexes Dengue-Fever Remission, life-long immunity to that particular serotype Invasion of monocytes is enhanced, increased viral replication Release of vasoactive mediators from T-cells, increase of vascular permeability, extravasation, haemorrhagies DHF DSS Mortality: 1-5% Mortality: 1-44% Grading of DHF and DSS (WHO-Classification) Grade 1 DF, TZ, Tourniquet + Grade grade 1 + spontaneous hemorrhages Grade 3 (DSS) imminent shock (tachycardia, hypotension, etc.) Grade 4 (DSS) shock - DSS: signs of capillary leakage HK (> 0%), Hypalbuminemea, pleural effusions 15
Candidate list of explanatory variables for risk factor 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 (>= cm) 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 severe disease is ~5% - no significant difference between mild group and moderate group Risk 95% CI N Transition to severe 0.05 0.04-0.06 83 From mild to severe 0.04 0.03-0.06 3 From moderate to severe 0.06 0.04-0.08 51 144 patients were grade of intervention 3 on their day of enrollment 16
Possible warning signs for severe disease Severe cases with minus 1 data available Number of patients 0 10 0 30 9 5 7 18 1 1 1 3 4 5 6 7 8 9 day of illness (of first worst day) Possible warning signs before onset of severe disease by intervention category controlled for age group (</>=15y), continent and day of intervention Mucosal bleeding Lethargy Variable Abdominal pain / tenderness Platelet decrease (per 10,000) Hematocrit increase (%) 1 day before onset of severity (pooled from day of illness 4-7) Multivariable OR (p-value) 3.53 (<0.001).87 (0.00) 1.19 (<0.001) 10.69 (<0.001) 1.00 (0.983) 17
Dengue Classification (WHO meeting Sept. 008) DENGUE ± Warning Signs SEVERE DENGUE Without With Warning Signs 1.Severe plasma leakage.severe haemorrhage 3.Severe organ impairment Presumptive Diagnosis Fever Anorexia and nausea Rash Aches and pains ± Warning signs Leucopenia Tourniquet test + Neighbourhood dengue/history of travel to dengue endemic area Warning Signs* Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation Mucosal bleeding Lethargy; restlessness Liver enlargement >cm Laboratory: Increase in HCT concurrent with rapid decrease in platelet count * Requiring strict observation and medical intervention 1. Severe plasma leakage leading to Shock (DSS) Fluid accumulation with respiratory distress. Severe bleeding as evaluated by clinician 3. Severe organ involvement Liver: AST or ALT>=1000 CNS: Impaired consciousness Heart and other organs Surveillance on dengue within TropNetEurop Between 1999 003: 483 cases notified including 13 cases (.7%) of dengue hemorrhagic fever (DHF) Non-Europeans (immigrants and foreign visitors) 4-times higher risk to develop DHF [95% CI 1.4 13.5] (Wichmann et al. Dengue Bull 003) 18
Results: Patients characteristics 19 travellers with dengue (median age 3yrs) 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.): persons (0.9%) 1 atrial fibrillation, 1 blurred vision ( months) *Exclusion of travellers with previous flavivirus immunization (JEV, YF, TBE) Origin of dengue in 19 travellers Southeast Asia Indian subcontinent South-Central America Caribbean Africa Single countries: India (3%), Thailand (17%) Median travel duration: 4 days First trip to dengue-endemic country: 39% 19
Clinical & laboratory features of dengue in travellers during the acute phase (n=176) Rash Pos. Tourniquet Petechiae Spont. Bleeding Shock n=37/84 nose/gum (n=11) skin bleeding (n=4) internal hemorrhage (n=4) Thrombo&Leucopenia ASAT >3-fold incr. Platelets <50,000/mm 3 (n=18) ALAT >3-fold incr. [%] 0 10 0 30 40 50 60 70 Associations with severe infection 3 (11%) with severe disease Univariate analysis: % OR 95%CI secondary dengue 44 5.1 (1.4 17.7) non-european origin 3 3.8 (1.0 13.9) >3-fold ASAT-increase 55 3.5 (1. 10.0) No association: travel to Asia, travel >8d Multivariate analysis: secondary dengue infection & > 3- fold increased ASAT 34% first visit to dengue-endemic country 0
Associations with spontaneous bleeding 17 (8%) with spontaneous bleeding Univariate analysis: % OR 95%CI secondary dengue infection 46 5.3 (1.4 0.8) non-european origin 4 3.7 (0.9 15.) >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/mm 3 71 3.1 (0.95 10.7) No association: travel to Asia, travel >8d Multivariate analysis: secondary infection, non-european origin, >3-fold ALAT-increase 9% first visit to dengue-endemic country Dengue Diagnosis 1
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 Diagnosis of Dengue 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
Dengue Fever IgM and IgG Rapid immunochromatographic Test IgM positive Negative 3
Diagnosis of suspected, probable, and confirmed dengue infection according to WHO classifications Confirmed dengue virus detection by isolation, PCR, or fourfold or greater change in reciprocal IgM or IgG antibody titres in paired serum samples Probable dengue single positive IgM antibody test on a acute or convalescent-phase serum specimen Suspected dengue diagnosis based entirely on clinical features and travel history Dengue-Fever (DF): Therapy symptomatic: Rest Antipyretics Analgetics Be careful with ASS! 4
??? Quelle: www.pdvi.org 5
Questions? 6