Dengue fever

Zhao zhixin The 3rd affiliated hospital of Sun Yat-Sen University zxzhao@21cn.com

WHAT IS DENGUE FEVER?



An acute ,self-limited, febrile disease . Dengue virus are maintained in a cycle that involves humans and Aedes aegypti primarily a disease of the tropics OCCURS IN two forms: Dengue fever(DF) Dengue haemorrhagic fever(DHF)

Clinical manifestations


DF: fever, headache, myalgias, bone pain.Lymphadenopathy, skin rash. Leukopenia DHF: high fever, haemorrhage, hepatomegaly evidences of leaky capillaries signs of circulatory failure(dengue shock syndrome,DSS.)

Why should we learn it ?



2500 million at risk from dengue per year. Epidemic in more than 100 countries in Africa, America, Eastern Mediterranean, South east Asia and the Western pacific. The global prevalence of DHF grown dramatically in recent decades: 1970/1995:4 fold increase. The most important mosquito-transmitted viral disease in term of mortality and morbidity.

Etiology
  

Dengue virus: enveloped RNA virus Classified : family of Flaviviridae. Serum type:1-4
 

causes closely related illness, severe and fatal disease but antigenically distinct

homotypic immunity: lifelong heterotypic immunity :short period but cross-response may worsen the second infection by a another serum type.

How DF transmitted?


Sources of infection: patients and anyone who with Covert infection

Transmitted vectors: Aedes aegypti is the most common vectors other Aedes mosquitos are less effiecitent : Ae.albopictus,Ae.polynesiesis Primarily a daytime feeder Lives around human habitation (Women and children summer time or rainny season)

The host: all susceptible if never came across dengue fever.

How dengue virus cause the disease?

(pathogenesis and clinical presentations)

Dengue virus

Blood stream

incubation Lymphadenopat hy,hepatomegly fever Bone pains,etc

Mononuclearphagocyte system
second viremia Antigen antibody complexes complement system Bone marrow depress Imfllamatory materials

Vascular permeability Rash, haemarrhagic

risk factors for DHF

Important risk factors for DHF include  Virus factors:
 

the serotype :2 is the predominating the strain: virulent strain genetic predisposition the age
 

Host factors:
 

Children : experienced a precious dengue infection Infants with waning levels of maternal dengue antibody.

immune status: if there are enhancing Ab.

Enchancing antibody


heterotypic antibodies


enhancement of virus replication in macrophages worsen the condition

A mechanism of DHF/DSS

Homologous Antibodies( ) Form Non-infectious Complexes

Dengue 1 virus Neutralizing antibody to Dengue 1 virus Non-neutralizing antibody Complex formed by neutralizing antibody and virus

Heterologous ( )Complexes Enter More Monocytes, Where Virus Replicates

Dengue 2 virus Non-neutralizing antibody Complex formed by nonneutralizing antibody and Dengue 2 virus

viral uptake and the replication in the mononuclear phagocytes.

First infection fail to neutralize virus of the other serum type infection

heterotypic antibodies the number of infected monocytes

rapid release of cytokines plasma leakage Haemoconcentration or shock

activation of cytotoxic lymphocytes

haemorrhage

pathophysiological changes occur in DHF/DSS: Increased vascular permeability haemoconcentration(Hct>20%) low pulse pressure other signs of shock. Disorder in haemostaisis : vascular changes thrombocytopenia coagulopathy.

CLINICAL PRESENTATIONS
Incubation: 5-8 days  Clinical features depend on the age of the patient: Infants and young children undifferentiated febrile disease, with maculapapular rash. Older children and adults either a mild febrile syndrome or the classic disease.


Manifestation Of Dengue Virus Infections

ASYMPTOMATIC
Undifferentiated Fever
Without haemorrhage

SYMPTOMATIC

Dengue Fever
With unusual haemorrhage

Dengue Haemorrhagic Fever

No shock DSS

Undifferentiated Fever


the most common manifestation of dengue

87% of students infected were either asymptomatic or mildly symptomatic

studies including all age- groups also demonstrate silent transmission

Dengue fever (DF)

1. fever
 

 

Abrupt onset, rising to 39.5-41.4 C Accompanied by frontal or retro-orbital headache Pain behind the eyes chillness Last 1-7 days Biphasic: defervesce for 1-2 days recurring with second rash but :T not as high

2. Bone pains
break bone fever is the another name of DF
   

After onset of fever May last several weeks Increase in severity Most common in legs, joints, and lumbar spine; With muscular and joint pains.

3. Rash
 

first rash: first 1-2 days of fever, transient, generalized, macular and blanching; Second rash
  

3-6 days. morbilliforms , maculopapular , rubella type Involving the trunk first, spreading to the face and extremities,

sparing palms and soles. other rash: petechiae

4. Hemorrhage


  

 

Skin hemorrhages: petechiae, purpura Gingival bleeding Nasal bleeding GI bleeding: hematemesis, melena, hematochezia Hematuria Increased menstrual flow

Physical exams(1)


Fever Conjunctival injection, pharyngeal erythema Rash: Measles-like rash over chest and upper limbs Generalized lymphadenopathy

Physical exams(2) :

Tourniquet Test


Method:
 

Inflate blood pressure cuff to a point: midway between systolic and diastolic pressure for 5 minutes

Positive test: 20 or more petechiae per 1 inch2 (6.25 cm2)

Clinical forms of DF(china)



Mild type Typical type Severe type: Unusual bleedings meningoencephalitis

Presentations of DHF/DSS(1)
  

high fever: remains >39 for 2-7days hepatomegaly : varies in size common haemorrhage
 

bleeding at venepuncture sites (coagulopathy) GI bleeding

Evidence of plasma leakage:  a rise in hematocrit (Hct):=>20%  pleural effusion ,ascites , hypoproteinemia a distinctive laboratory finding : Moderate to marked thrombocytopenia with concurrent haemoconcentration

DSS(2)=DHF+SHOCK
 

at the end of the febrile phase signs of circulatory disturbance

 

sweat, cool extremities rapid ,weak pulse

restless hypotension

varying severity
 

less severe: transient recover spontaneously more severe: uncorrected Shock ensues: metabolic acidosis, severe bleeding

Patient may dies or recovers within 12-24hours

finding

DF

DHF

(+1-25%,++26-50%,+++51-75%,++++76-100%)

Fever Petechiae Lymphadenopathy GI bleeding

++++ ++ ++ +

++++ ++ ++ +

finding
Maculopapular rash Myalgia/arthralgia Leukopenia Thrombocytopenia Positive tourniquet test Hepatomegaly Shock

DF
++ +++ ++++ ++ ++ 0 0

DHF
+ + ++ ++++ ++++ ++++ ++

Lab tests(1)


Clinical laboratory tests



CBC-- Leukopenia is typical; thrombocytopenia , hematocrit Liver function tests : Albumin Urine--check for microscopic hematuria

Lab tests(2) :Dengue-specific tests



serologic tests: Antibody assay useful for documenting: IgM and complement fixing (CF)Ab : short lived Fourfold increase in titer between acute and convalescent sera Viral antigen or viral RNA by PCR :

prove the diagnosis



Virus isolation: grown in vertebrate and mosquito cell lines Virus is best isolated from serum: febrile patients. but are difficult

ELISA Test for Serologic Diagnosis

Virus Isolation: Cell Culture

Virus Isolation: Mosquito Inoculation

Virus Isolation: Fluorescent Antibody Test

Diagnosis of DF
  

Epidemiological evidences Clinical presentations Lab tests:

  

Routine test: for monitoring the severity serologic tests: for clinical diagnosis Virus isolate: to distinguish the serum types.

four criteria for DHF

   

Fever , last for 2-7days at least one of Hemorrhage evidences Thrombocytopenia :PLT<100,000/mm3 Evidence of plasma leakage:  a rise in Hct:>=20%  pleural effusion ,ascites and hypoprotinemia

Diagnosis criteria for DSS

 

four criteria for DHF Evidence of shock  sweat, restless, cool extremities  rapid ,weak pulse  narrowing of pulse pressure<2.7kpa  hypotension

Differencial diagnosis
Include a wide spectrum of  viral


bacterial Parasitic infections

prognosis
 

Self-limit disease Convalescence may be prolonged

 

with weakness and mental depression Continued bone pains, bradycardia early hospitalization aggressive supportive care

Survival is related to
 

Treatment of DF
complicated, no specific trx
  

Fluid replacement: adequate hydration Bed Rest Antipyretics

  

acetaminophen (if no liver dysfunction) No aspirin(association with Reye syndrome ), steroids, avoid NSAIDS(anticoagulant properties).

Continuous Monitoring of
     

VS Diuresis,mental status Evidence of bleeding Hydration status Evidence of increased vascular permeability hematocrit, platelet count(manual)

Management for DHF



Prevent and Treatment of shock: mild to moderate isotonic dehydration (5%-8% deficit)
  

Iv crystalloids ; colloids; central line Correct electrolyte abnormalities and acidemia Monitor the vital signs:
avoid hypovolemia or fluid overload.

 

therapy for DIC: if indicated Unknown effective = steroid ,immune globulin platelet transfusions

prevention
Three operations must be conducted


isolation of patients. emergency mosquito control simultaneously Personal protection

 

vaccine
 

no vaccine currently available research is underway for the development of a vaccine. vaccine will not available for 5 to 10 years. as
 

it must provide immunity to all 4 serotypes Lack of dengue animal model

Personal protection


 

remain in well-screened or completely enclosed, air-conditioned areas; wear light-colored clothing with fulllength pant legs and sleeves; use insect repellent on exposed skin. Use netting when sleeping

Discharge criteria


afebrile for 24 h appetite clinical improvement shock Stable Hct Platelets u50,000/mm

3 days post

Eupnea: No respiratory distress from

Common Misconceptions about DHF

 Dengue + bleeding = DHF  Need 4 WHO criteria, capillary permeability  DHF kills only by hemorrhage  Patient dies as a result of shock  Poor management turns dengue into DHF  Poorly managed dengue can be more severe, but DHF is a distinct condition, which even well-treated patients may develop  Positive tourniquet test = DHF  Tourniquet test is a nonspecific indicator of capillary fragility

Rehydrating Patients Over 40 kg

Volume required: twice the recommended maintenance volume Formula for calculating maintenance volume: 1500 + 20 x (weight in kg - 20) For example


55 kg patient: maintenance volume : 1500 + 20 x (55-20) = 2200 ml For this patient, the rehydration volume would be 2 x 2200, or 4400 ml

Dengue virus infection symptomatic Asymptomatic dengue hemorrhagic fever (plasma leakage) DSS

Undifferentiat ed fever (viral syndrome)

dengue fever syndrome

no shock
Without hemorrhage

with unusual hemorrhage

DF

DHF

Fever

Dengue infection

heptomegaly

tournigeut test(+)

Increased vascular permeability

thrombocytopenia

Other haemorrhagic manifestations

Rising haematocrit Leakage of plasma Hypoproteinaemia Serous effusion coapulopathy

hypovolaemia DIC shock death Severe bleeding

Grade 1

1.Four Criteria for DHF

Antiinflamatory agents Monitor vital sings q2h Provide oral hydration

Grade 2

1+spontaneaous bleeding

Same as above + type and cross match Determine PT AND PTT

Grade 3

1+Sings of shock: hypotention

Same as above+ iv isotonic fluids, monitor q30mins, follow urine output

1+undetectalbe pulse Grade 4 and blood pressure

Same as above+ Iv colloids or plasma Provide critical care support