dengue tropmed new sept'12

8/22/2019 Dengue TropMed New Sept'12

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Chairuddin P. Lubis, Syahril Pasaribu, Ayodhia P. Pasaribu,Inke Nadia D. Lubis

Department of Pediatrics

Faculty of Medicine, University of North Sumatera


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Prevalence of Clinical Spectrums of Dengue

Infection in Dengue Model

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Population Infection

AsymptomaticInfection

ClinicalCases

DF

(Non-DHF)

DHF/DSS

Survive

Death

5% 76%

24% 94%

6%99.2%

0.8%

Shepard DS. Vaccine. 2004; 22: 1275-80


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3

Countries and Areas at Risk of Dengue Transmission


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4

2.5 billion in endemic countries

50 100 million dengue cases

500.000 DHF

Morbidity 1 3 weeks

20.000 deaths


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DHF INCIDENCE RATE

Dengue Bull. 2006; 30: 1-14

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Dengue Bull. 2006; 30: 1-14

DHF MORBIDITY & MORTALITY IN INDONESIA

FROM 1968 - 2005

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DENGUEFEVER

DENGUE

HEMORRHAGIC

FEVER

DENGUE

SHOCK

SYNDROME

DENGUE MANIFESTATIONS

WHO

DENGUE FEVER

Acute onset febrile illness that lasts 2-7

days

With 2 or more following symptoms :

- headache - ptechiea- retro-orbital pain - tourniquet test (+)

- myalgia/arthralgia

- maculopapular rash

J Pediatr. 2007; 83(2): 22-35.

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Case Definition for DHFWHO 1997


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DENGUEFEVER

DENGUE

HEMORRHAGIC

FEVER

DENGUE

SHOCK

SYNDROME


WHO

DENGUEHEMORRHAGIC

FEVER

Fever lasts 2-7 days,occasionally biphasic

Hemorrhagic tendencies

Thrombocytopenia (< 100,000 /mm3)

Evidence of plasma leakage, manifestedby : - rise in haematocrit > 20%

- drop in haematocrit following

volume replacement

- signs of plasma leakage

J Pediatr. 2007; 83(2): 22-35.

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Dengue Hemorrhagic Fever

Grading SymptomsGrade I Hemoconcentration, fever, non specific

constitutional symptoms, only positive

tourniquet test

Grade II Spontaneous bleeding in addition to themanifestation from Grade I

Grade III Circulatory failure, rapid & weak pulse, narrow

pulse pressure, cold clammy skin, hypotension

by age, oliguria, restlessnessGrade IV Profound shock, hypotension or unrecordable

blood pressure

J Pediatr. 2007; 83(2): 22-35.

9

1997


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DENGUEFEVER

DENGUE

HEMORRHAGIC

FEVER

DENGUE

SHOCK

SYNDROME


WHO

DENGUE

SHOCK

SYNDROME

All four criteria of DHF must be present

Evidence of circulatory failure

manifested by :

- Rapid and weak pulse- Narrow pulse pressure (< 20 mmHg) or

- Hypotension for age, and

- Cold, clammy skin and restlessness J Pediatr. 2007; 83(2): 22-35.

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The 3rd edition of the WHO

dengue guidelines

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http://whqlibdoc.who.int/publications/2009/9

789241547871_eng.pdf


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WHO 2009 Dengue Case Classification and

Levels of Severity

Dengue + Warning Signs Severe Dengue

without

with

warningsigns

1. Severe plasma leakage

2. Severe haemorrhage3. Severe organ impairment

Nathan MB. Dengue: guidelines for diagnosis, treatment, prevention and control. 2009. p3-21.

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Criteria for Dengue + Warning Signs

Probable Dengue

Live in/travel to dengue endemic

areaFever and 2 of the following

criteria :

- Nausea, vomiting

- Rash

- Aches and pain- Tourniquet test positive

- Leukopenia

- Any warning sign

Warning Signs

- Abdominal pain or tenderness

- Persistent vomiting- Clinical fluid accumulation

- Mucosal bleed

- Lethargy, restlessness

- Liver enlargement > 2 cm

- Laboratory: increase in HCTconcurrent with rapid decrease

in platelet count

Laboratory-Confirmed DengueImportant when no sign of plasma

leakage

Nathan MB. Dengue: guidelines for diagnosis, treatment, prevention and control. 2009. p3-21.

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Criteria for Severe Dengue

Severe Plasma Leakage

Leading to :

- Shock (DSS)

- Fluid accumulation with respiratory distress

Severe BleedingAs evaluated by clinician

Severe Organ Involvement

- Liver : AST or ALT > 1000

- CNS : Impaired consciousness

- Heart and other organs

Nathan MB.Dengue: guidelines for diagnosis, treatment, prevention and control. 2009. p3-21.

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Revised and expanded

edition of dengueguideline

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This edition have been

extensively revised andexpanded by the WHO

Southeast Asian Region Office,

with the focus on

new/additional topics of current

relevance to Member States ofthe South-East Asia Region.


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2011 WHO-SEARO Dengue Case Classification

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WHO Cl ifi i f I f i d


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WHO Classification of Dengue Infections and

Grading of Severity of Dengue

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What is expanded dengue syndrome ?

Uncommon manifestation

Neurological, hepatic, renal and other isolated organ

involvement

CNS manifestations :

Convulsions, spasticity, changes in consciousness andtransient paresis

Limited evidences showed dengue viruses may cross the

blood-brain barrier and cause encephalitis

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Expanded dengue syndrome

System Unusual or atypical manifestations

Neurological Febrile seizures in young childrenEncephalopathy

Encephalitis / aseptic meningitis

Intracranial haemorrhages / thrombosis

Subdural effusions

Mononeuropathies / polyneuropathies / Guillaine-Barre

syndromeTransverse myelitis

Gastrointestinal / hepatic Hepatitis / fulminant hepatic failure

Acalculous cholecystitis

Acute pancreatitis

Hyperplasia ofPeyers patches

Acute parotitis

Renal Acute failure

Hemolytic uremic syndrome

Cardiac Conduction abnormalities

Myocarditis

Pericarditis 19


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Expanded dengue syndrome (continue..)

System Unusual or atypical manifestations

Respiratory Acute respiratory distress syndromePulmonary hemorrhage

Lymphoreticular / bone

marrow

Infection associated haemophagocytic syndrome

IAHS or Haemophagocytic lymphohisiocytosis (HLH),

idiopathic thrombocytopenic purpura (ITP)

Spontaneous splenic rupture

Lymph node infarction

Eye Macular haemorrhage

Impaired visual acuity

Optic neuritis

Others Post infectious fatigue syndrome, depression,

hallucinations, psychosis, alopecia

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Gulati S, Maheswari A. Atypical manifestation of dengue. Trop Med Int Health.

2007; 12(9): 1087-95


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High Risk Patients

Infants, and the elderly

Obesity

Pregnant women

Peptic ulcer disease

Women who have menstruation or abnormal

vaginal bleeding

Haemolytic diseases: G6PD deficiency,

thalassemia and other hemoglobinopathies

Congenital heart disease

Chronic diseases: DM, hypertension, asthma,ischaemic heart disease, chronic renal

failure, liver cirrhosis

Patients on steroid or NSAID treatment


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1997 vs 2009 WHO Dengue Classification

1997 WHO case classification was revised because of differences in geographical areas

and age groups affected

2009 classification is more sensitive in capturing severe disease than the 1997

guidelines (92% vs 39%)

1997 classification is recommended for continuing use because the 2009 classification

creates > 2x workload to health care personnel


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Usefulness and applicability of the revised

dengue case classification by disease:multi-centre study

in 18 countries

Judit Barniol, Roger Gaczkowski, Eliana Vega Barbato, Rivaldo V da Cunha, Doris Salgado, Eric

Martnez, Carmita Soria Segarra, Ernesto B Pleites Sandoval, Ajay Mishra, Ida Safitri Laksono, Lucy

CS Lum, Jos G Martnez, Andrea Nnez, Angel Balsameda, Ivan Allende, Gladys Ramrez, Efren

Dimaano, Kay Thomacheck, Naeema A Akbar, Eng E Ooi, Elci Villegas, Tran T Hien, Jeremy Farrar,

Olaf Horstick, Axel Kroeger and Thomas Jaenisch

BMC Infectious Diseases 2011, 11:106 doi:10.1186/1471-2334-11-106.


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Comparison of the current (DF/DHF/DSS) and the revised classification in 1962 prospective

chart reviews (130 charts with missing information excluded)

DF/DHF/DSS Revised classification by expert reviewer

Total

classification Not Dengue Severeby expert classifia Dengue

reviewer ble WS negative WS positive

Not classifiable 23 57 159 29

268 (100%) (8.6%) (21.3%) (59.3%) (10.8%)

(13.7% of all)

DF 7 551 684 75

1317 (100%)

(0.5%) (41.8%) (51.9%) (5.7%)

(67.1% of all)

DHF 2 8 240 39

289 (100%)(grades 1 and 2) (0.7%) (2.8%) (83.0%) (13.5%)

(14.7% of all)

DSS 0 0 12 76

88 (100%)

(DHF grades 3and 4) (0%) (0%) (13.6%) (86.4%)

(4.5% of all)

Barniol J, et al. BMC Infectious Diseases 2011, 11:106 doi:10.1186/1471-2334-11-106.13.7% of dengue cases could not be classified by

experienced reviewers as compared to 1.6% who

could not classified with the revised classification


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Perceived advantages and disadvantages regarding the

revised dengue case classification (N=1413 comments in

1288 staff questionnaires) [1]

Advantages of the revised classification N (%)

It helps improving management and treatment 319 (22.6%)

More simple and practical 199 (14.0%)

Easier to classify according to severity 176 (12.6%)Easier to understand 71 (5.0%)

It helps improving triage and referral 45 (3.2%)

No disadvantages of the revised classification 191 (13.5%)

Other advantages 72 (5.0%)

Total of positive responses 1073(75.9%)


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Perceived advantages and disadvantages regarding the revised

dengue case classification (N=1413 comments in 1288 staff

questionnaires) [2]

Disadvantages of the revised classification N (%)

No advantages of the revised classification 25 (1.8%)

Needs more training and dissemination 67 (4.7%)

It's less specific. Needs more clinical entities and

concise protocols 54 (3.8%)Lack of manpower and resources 45 (3.2%)

Over diagnosis of dengue (saturation of hospitals) 32 (2.3%)

Warning signs: Too many, subjective, also in other

diseases 24 (1.7%)

Lack of laboratory support 10 (0.7%)Other disadvantages 83 (5.9%)

Total of negative responses 340 (24.1%)

Barniol J, et al. BMC Infectious Diseases 2011, 11:106 doi:10.1186/1471-2334-11-106.


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The Tourniquet Test

Performed by inflating a blood pressure cuff

on the upper arm to a point midway between

the systolic and diastolic pressures for 5

minutes.

Positive when > 20 ptechiae per 2.5 cm.

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Is the tourniquet test a valuable predictor of DHF?

240 children in Delhi 40% positive in DF, 62% in DHF, 64%in DSS

110 adult DHF patients in North India 39.1% positive

172 Thai children 36% DF and 52% DHF have positive test

905 Vietnamese children 548 dengue confirmed

serologically, sensitivity 41.6%, specificity 94.4%, positive

predictive value 98.3%, negative predictive value 17.3%

Halstead SB. Dengue. 2008. p171-91.

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Prevalence of signs and symptoms in infants children and adults


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Prevalence of signs and symptoms in infants, children and adults,

with significant differences in prevalence noted between children

and infants and between children and adults

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Am J Trop Med Hyg. 2005; 73(6): 1063-70.

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Global

distribution of

dengue virus

serotypes, 1970

Global

distribution of

dengue virus

serotypes, 2004

Gubler DJ. Comp Immunol

Microbiol Infect Dis. 2004.


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Clinical and laboratory findings for DHF by dengue

serotype

Southeast Asian J TropMed Public Health.

2005; 36(6): 1432-8.

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The pathogenesis of DHF/DSS is still controversial.

Two theories that have been used to explain the

pathogenesis of DHF are :

1. The virulence of infecting dengue viruses2. The antibody-dependent enhancement theory

Comp Immun Microbiol Infect Dis. 2007; 30: 329-40.

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Risk factors of severe disease

Secondary infection with a different serotype

Sequentiality of serotypes in secondary infections

Association with specific genotypes

Time interval between first and second infection Age of host

Ethnicity of host

Underlying chronic diseases

J Clin Virol. 2003; 27: 1-13.

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Homologues antibodies form

non-infectious complexes

Person who have experienced a dengue infection develop serum

antibodies that can neutralize the dengue virus of that same

(homologous) serotype

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Heterologous antibodies form

infectious complexes

In a subsequent infection with a different virus serotype, the pre

existing heterologous antibodies form complexes with the new

virus, but these heterologous antibodies do not neutralize the

new serotype

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Antibody-dependent enhancement (ADE) is the process in which

certain strains of dengue virus, complexed with these non-

neutralizing antibodies, can enter a greater proportion of the

mononuclear cells where the virus replicates unchecked, thus

increasing virus production and producing a massive infection

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Heterologous complexes enter more monocytes,

where virus replicates

The infected monocytes release vasoactive mediators, resulting in

the increased vascular permeability and hemorrhagic

manifestations that characterize dengue hemorrhagic fever or

dengue shock syndrome.

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Vascular Permeability

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Intrinsic permeability is regulated by

endothelial surface glycocalyx, and also

endothelial cells themselves.

One of the dengue nonstructural proteins,

or one of the components of the immune

response may act directly with the

glycocalyx layer to alter temporarily the

characteristics of the fiber matrix.

Transient endothelial permeability is also

caused by one or more soluble mediators

released by the endothelium or by immune

cells.

Cytokines and mediators which suggestedinduce endothelial permeability : IL-1, IL-

1, IL-2, IL-6, IL-8, TNF-, IFN-, histamine,

platelet-activating factor, vascular

endothelial growth factor (VEGF)Halstead SB. Dengue. 2008. p285-326.


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The course of dengue illness

McCall P, Lloyd L, Nathan MB.

Dengue: guidelines for diagnosis,

treatment, prevention and

control. 2009. p59-87.

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Febrile, critical and recovery phases in dengue

Febrile phase

Critical phase

Recovery phase

Dehydration, high fever may cause

neurological disturbance and febrile

seizures in young children

Shock from plasma leakage,

severe haemorrhage, organ

impairment

Hypervolemia (only if intravenous

fluid therapy has been excessive

and/or has extended into this period)

McCall P, Lloyd L, Nathan MB.Dengue: guidelines for diagnosis,

treatment, prevention and control. 2009. p3-21. 42


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Course of dengue infection and timings of

diagnosis

Lancet. 2007; 370: 1644-52.

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Laboratory Diagnosis

Early illnesstests

Virus isolation

Nucleic aciddetection

Detection of

antigens

Late illnesstests

Serologicaltests

Buchy P, Peeling R.Dengue: guidelines for diagnosis, treatment,

prevention and control. 2009. p91-107.

44

i i li f i d d d


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Approximate time-line of primary and secondary dengue

virus infections and the diagnostic methods that can be used

to detect infection

Buchy P, Peeling R.Dengue:

guidelines for diagnosis,

treatment, prevention and

control. 2009. p91-107.

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Relationship between day of illness and NS1

sensitivity

Plosntds. 2009; 3(1): 360-7.

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Positive anti dengue IgM antibody results (%) in PD


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Positive anti-dengue IgM antibody results (%) in PD

and in SD patients depending on the day of serum

collection

J Clin Virol. 2004; 31: 179-84.

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IgG titers in primary vs secondary dengue fever depending

on the day of serum collection

J Clin Virol. 2004; 31: 179-84.

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Immune response to dengue infection

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Suspect of Dengue Infection

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High fever, < 7 days

Malaise, no ARI

Emergency signs (-)Emergency signs (+)

Shock

Seizure

Encephalopathy

Bleeding

Tourniquet test

Positive Negative

Inpatient

One day observation

Observe for 24 hours

Symptoms & lab

Leucocyte 10%

Outpatient

Control until fever(-)

Advice the parent

Fever persist > 3 days

Check Hb, Ht, leucocyte

& thrombocyte


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Treatment of DHF without shock

Fluid

Drink 2 litre/day to prevent dehydration Mineral water, juice, oralit

Symptomatic

Give antipiretic if high fever or history of febrile seizure

occured. Suggestion is paracetamol. Asetosal & ibuprofenare contraindicated

Diazepam

Domperidon 1 mg/kgBB, 3 dose, 1-2 days

H2 blocker(ranitidine, cimetidine)

Antibiotic is not given

Steroid is not effective

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T t t f DHF ith t h k


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Treatment of DHF without shock

(DHF grade I and II)

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Able to drink Unable to drinkVomit

Drink 2 L/day

Paracetamol

Anticonvulsive, if necessary

Infuse D5%:NaCl 0,9% = 3:1

Maintenance drips

Check Hb, Ht, thrombocyteevery 6-12 hours

Evaluate the symptoms & lab

Signs of shock

Diuresis

Bleeding

Hb, Ht, thrombocyte every 6-12 hours

Discharge Improve Worsen Change to

RL D5%


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Treatment of DHF grade I and II

Initial fluid 6 8 ml/kg/hour

RLD5% or RAD5%

Monitor the vital signs

Hb, Ht, thrombocyte every 6-12 hours

Improvement No ImprovementNot agitated

Strong pulse

Stable BP

Ht decrease

Diuresis 1 ml/kg/hour

Agitated

Respiratory distress

HR increase

Ht increase

Pulse pressure

< 20mmHg

Diuresis


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SHOCK O2 2-4 L/minIsotonic fluid 20 ml/kg/hour

RL/RA/NS

in 30 min

Evaluate in 30 minute, has the shock resolved?

Yes No

Adjust the fluid

Monitor

Stable

Stop the fluid not more

than 48 hours after the

shock has resolved

Continue the RL

+ Kolloid

+ Correct acidosis

Evaluate in 1 hourShock has

resolved

Not resolvedHt

Decrease Increase

Transfusion

Inotropic

Kolloid

No improvement


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Rate of infusion in DSS

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Criteria for discharging patients

Absence of fever for at least 24 hours without the use of anti fever

therapy

Return of appetite

Visible clinical improvement

Satisfactory urine output

A minimum of 2 3 days have elapsed after recovery from shock

No respiratory distress from pleural effusion and no ascites

Platelet count of more than 50.000/mm3. If not, patients can be

recommended to avoid traumatic activities for at least 1 2 weeksfor platelet count to become normal. In most uncomplicated cases,

platelet rises to normal within 3 5 days

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