Dengue FeverDengue Fever

Prof: Nooruddin JafferProf: Nooruddin Jaffer

HMCHMC

KarachiKarachi

Dengue FeverDengue Fever

Dengue virusDengue virus Most prevalent vector-Most prevalent vector-

borne viral illness in the borne viral illness in the worldworld

Main mosquito vector is Main mosquito vector is Aedes aegyptiAedes aegypti

Year round Year round transmissiontransmission

IncidenceIncidence

50-100 million dengue fever infections per 50-100 million dengue fever infections per year globallyyear globally

500,000 cases of severe dengue, dengue 500,000 cases of severe dengue, dengue hemorrhagic fever or dengue shock hemorrhagic fever or dengue shock syndrome syndrome

100-200 cases annually in U.S. 100-200 cases annually in U.S. Average case fatality 5% Average case fatality 5%

DistributionDistribution

Endemic in more than Endemic in more than 100 tropical and 100 tropical and subtropical countries subtropical countries

Pandemic began in Pandemic began in Southeast Asia after WW Southeast Asia after WW II with subsequent global II with subsequent global spread spread

Several epidemics since Several epidemics since 1980s1980s

Distribution is comparable Distribution is comparable to malariato malaria

Clinical PresentationClinical Presentation

Spectrum of illness Spectrum of illness • non-specific febrile illnessnon-specific febrile illness• classic dengueclassic dengue• dengue hemorrhagic feverdengue hemorrhagic fever• dengue shock syndromedengue shock syndrome• other (CNS dysfunction, liver failure, other (CNS dysfunction, liver failure,

myocarditis)myocarditis)

Classic DengueClassic Dengue Acute febrile illness with headache, retro-orbital Acute febrile illness with headache, retro-orbital

pain, myalgias, arthralgiaspain, myalgias, arthralgias ““Break-bone fever”Break-bone fever” High fever 5-7 daysHigh fever 5-7 days Second fever for 1-2 days in 5% patients Second fever for 1-2 days in 5% patients Followed by marked fatigue days to weeksFollowed by marked fatigue days to weeks Classic dengue 15-60% of infectionsClassic dengue 15-60% of infections Nausea, vomiting, diarrhea (30%)Nausea, vomiting, diarrhea (30%) Macular or maculopapular confluent rash (50%)Macular or maculopapular confluent rash (50%) Respiratory symptoms: cough, sore throat (30%)Respiratory symptoms: cough, sore throat (30%)

Dengue Hemorrhagic FeverDengue Hemorrhagic Fever

WHO classification of DHFWHO classification of DHF Thrombocytopenia (platelet count <100,000)Thrombocytopenia (platelet count <100,000) Fever 2-7 daysFever 2-7 days Hemorrhagic manifestations with a positive Hemorrhagic manifestations with a positive

tourniquet test, petechiae, ecchymoses or tourniquet test, petechiae, ecchymoses or mucosal bleeding. mucosal bleeding.

Hemoconcentration or evidence of plasma Hemoconcentration or evidence of plasma leakage (ascites, effusion, decreased albumin) leakage (ascites, effusion, decreased albumin)

Dengue Hemorrhagic FeverDengue Hemorrhagic Fever

Usually occurs in secondary infections after Usually occurs in secondary infections after actively or passively (maternal) acquired actively or passively (maternal) acquired immunity to a different viral serotypeimmunity to a different viral serotype

Only 2-4% of secondary infections result in Only 2-4% of secondary infections result in severe disease severe disease

Mortality is 10-20% if untreated, but decreases Mortality is 10-20% if untreated, but decreases to <1% if adequately treatedto <1% if adequately treated

Plasma leakage may progress to dengue shock Plasma leakage may progress to dengue shock syndromesyndrome

Physical ExamPhysical Exam

Nonspecific findingsNonspecific findings Conjunctival injection, Conjunctival injection,

pharyngeal erythema, pharyngeal erythema, lymphadenopathy, lymphadenopathy, hepatomegaly (20-hepatomegaly (20-50%)50%)

Macular or Macular or maculopapular rash maculopapular rash (50%)(50%)

Laboratory FindingsLaboratory Findings

LeukopeniaLeukopenia Thrombocytopenia (<100,000)Thrombocytopenia (<100,000) Modest liver enzyme elevation (2-5x nml)Modest liver enzyme elevation (2-5x nml) Serology:Serology:• Acute phase serum IgM (+6-90 days) ELISAAcute phase serum IgM (+6-90 days) ELISA• Acute and convalescent IgG (99% sens, 96% Acute and convalescent IgG (99% sens, 96%

spec) spec) • Hemagglutination inhibition assay (HI) is gold Hemagglutination inhibition assay (HI) is gold

standard. Paired acute and convalescent HI standard. Paired acute and convalescent HI assay, positive if >4 fold titer rise assay, positive if >4 fold titer rise

Virology Virology

Flavivirus familyFlavivirus family Small enveloped Small enveloped

viruses containing viruses containing single stranded single stranded positive RNA positive RNA

Four distinct viral Four distinct viral serotypes (Den-1, serotypes (Den-1, Den-2, Den-3, Den-4)Den-2, Den-3, Den-4)

PathophysiologyPathophysiology

Transmitted by the Transmitted by the bite of Aedes bite of Aedes mosquito (Aedes mosquito (Aedes aegypti) aegypti)

Incubation 3-14 days Incubation 3-14 days Acute illness and Acute illness and

viremia 3-7 daysviremia 3-7 days Recovery or Recovery or

progression to progression to leakage phaseleakage phase

PathophysiologyPathophysiology

Dengue virus enters and replicates within Dengue virus enters and replicates within monocytes, mast cells, fibroblastsmonocytes, mast cells, fibroblasts

Innate and adaptive immune responseInnate and adaptive immune response Cytokine release: TNF-a, IL-2, IL-6, IL-8Cytokine release: TNF-a, IL-2, IL-6, IL-8 Compliment activation Compliment activation Antibody dependent enhancement (ADE) Antibody dependent enhancement (ADE)

thought to contribute to severe infectionsthought to contribute to severe infections T-cell activation: CD4 and CD8 cells cytokine T-cell activation: CD4 and CD8 cells cytokine

productionproduction

PathophysiologyPathophysiology

Capillary Leak Syndrome:Capillary Leak Syndrome:• Transient increased capillary permeability due to Transient increased capillary permeability due to

endothelial cell dysfunctionendothelial cell dysfunction• Widening of tight junctionsWidening of tight junctions• Cytokine release and complement activationCytokine release and complement activationLeukopenia, Thrombocytopenia and Hemorrhagic Leukopenia, Thrombocytopenia and Hemorrhagic

diathesis:diathesis:• Direct viral bone marrow suppressionDirect viral bone marrow suppression• Platelet destruction in DHFPlatelet destruction in DHF• ?Molecular mimicry between viral protein and ?Molecular mimicry between viral protein and

coagulation factorscoagulation factors

Disease FactorsDisease Factors

Dengue-2 serotype most virulentDengue-2 serotype most virulent Increased severity with secondary infectionsIncreased severity with secondary infections Increased risk in children <15 years and elderly. Increased risk in children <15 years and elderly. Greatest risk of DHF in infants.Greatest risk of DHF in infants. More severe in femalesMore severe in females Increased mortality with comorbid conditions Increased mortality with comorbid conditions Less common in malnourished childrenLess common in malnourished children

Differential DiagnosisDifferential Diagnosis

ViraVirall: : Influenza, HIV, Hepatitis A, Yellow Fever, Influenza, HIV, Hepatitis A, Yellow Fever, Hantavirus, Measles, Rubella, Coxsackie and other Hantavirus, Measles, Rubella, Coxsackie and other enteroviruses, parvovirus B19, Chikungunya virus, EBVenteroviruses, parvovirus B19, Chikungunya virus, EBV

BacterialBacterial: : Typhoid, Scarlet fever, MeningococcemiaTyphoid, Scarlet fever, MeningococcemiaParasiticParasitic:: Malaria, Leptospirosis, Rickettsial disease, Malaria, Leptospirosis, Rickettsial disease,

Leishmaniasis, Chagas diseaseLeishmaniasis, Chagas diseaseFungal:Fungal: Cryptococcus, Blastomycosis, Histoplasmosis Cryptococcus, Blastomycosis, Histoplasmosis Non-InfectiousNon-Infectious: : Malignancy, rheumatic, vasculitis, drug Malignancy, rheumatic, vasculitis, drug

fever, other miscellaneous fever, other miscellaneous

Differential DiagnosisDifferential Diagnosis

Mosquito Borne IllnessesMosquito Borne Illnesses ProtozoaProtozoa: Malaria: Malaria RoundwormRoundworm: Filariasis, dirofilariasis: Filariasis, dirofilariasis AlphavirusesAlphaviruses: Chikungunya fever, Mayaro fever, Ross : Chikungunya fever, Mayaro fever, Ross

River fever, Eastern, Western, and Venezuelan equine River fever, Eastern, Western, and Venezuelan equine encephalitisencephalitis

FlavivirusesFlaviviruses: West Nile fever, Zika fever, St. Louis : West Nile fever, Zika fever, St. Louis encephalitis, Japanese encephalitis, Yellow Feverencephalitis, Japanese encephalitis, Yellow Fever

BunyavirusesBunyaviruses: LaCrosse encephalitis, Oropouche virus, : LaCrosse encephalitis, Oropouche virus, Bwamba fever, California encephalitis Bwamba fever, California encephalitis

TreatmentTreatment

No specific therapyNo specific therapy Supportive measures:Supportive measures: adequate hydration adequate hydration acetaminophen (if no liver dysfunction)acetaminophen (if no liver dysfunction) avoid ASA and NSAIDs avoid ASA and NSAIDs DHF or DHF w/ shock:DHF or DHF w/ shock: IV fluid resuscitation and hospitalizationIV fluid resuscitation and hospitalization blood or platelet transfusion as neededblood or platelet transfusion as needed

TreatmentTreatment Treatment with corticosteroids shown not to Treatment with corticosteroids shown not to

reduce mortality with severe dengue shock reduce mortality with severe dengue shock • 2 studies of 63 and 92 pediatric DHF shock pts 2 studies of 63 and 92 pediatric DHF shock pts

treated w/ hydrocortisone 50mg/kg x1 or treated w/ hydrocortisone 50mg/kg x1 or methylprednisolone 30mg/kg x1 dose vs methylprednisolone 30mg/kg x1 dose vs placebo.placebo.

• Study of 95 pediatric DHF shock pts treated with Study of 95 pediatric DHF shock pts treated with carbazochrome sodium sulfate (AC-17) vs B carbazochrome sodium sulfate (AC-17) vs B vitamins for 3 daysvitamins for 3 days

Ribavirin very weak in vitro and in vivo activity Ribavirin very weak in vitro and in vivo activity against flavivirusesagainst flaviviruses

VaccinationVaccination

No current dengue vaccineNo current dengue vaccine Estimated availability in 5-10 yearsEstimated availability in 5-10 years Vaccine development is problematic as the Vaccine development is problematic as the

vaccine must provide immunity to all 4 serotypesvaccine must provide immunity to all 4 serotypes Lack of dengue animal modelLack of dengue animal model Live attenuated tetravalent vaccines under Live attenuated tetravalent vaccines under

phase 2 trials phase 2 trials New approaches include infectious clone DNA New approaches include infectious clone DNA

and naked DNA vaccinesand naked DNA vaccines

PreventionPrevention

Personal:Personal: clothing to reduce exposed skinclothing to reduce exposed skin insect repellent especially in early morning, late afternoon. Bed netting is of little utility. insect repellent especially in early morning, late afternoon. Bed netting is of little utility.

Environmental:Environmental: reduced vector breeding sitesreduced vector breeding sites solid waste managementsolid waste management public educationpublic education

PreventionPrevention

Biological: Biological: Target larval stage of Aedes in large water Target larval stage of Aedes in large water

storage containers storage containers Larvivorous fish (Gambusia), endotoxin Larvivorous fish (Gambusia), endotoxin

producing bacteria (Bacillus), copepod producing bacteria (Bacillus), copepod crustaceans (mesocyclops) crustaceans (mesocyclops)

Chemical: Chemical: Insecticide treatment of water containersInsecticide treatment of water containers Space spraying (thermal fogs)Space spraying (thermal fogs)

Public HealthPublic Health

Major and escalating global public health Major and escalating global public health problemproblem

Global demographic changes: urbanization and Global demographic changes: urbanization and population growth with substandard housing, population growth with substandard housing, water, and waster management systemswater, and waster management systems

Deteriorating public health infrastructure with Deteriorating public health infrastructure with limited resources resulting in “crisis limited resources resulting in “crisis management” not preventionmanagement” not prevention

Increased travel Increased travel Lack of effective mosquito control Lack of effective mosquito control