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

Lubis Department of Pediatrics Faculty of Medicine, University of North Sumatera

Prevalence of Clinical Spectrums of Dengue Infection in Dengue Model

5%
Population Infection

76%

Asymptomatic Infection

24% Clinical
Cases

DF 94%(Non-DHF)

6% DHF/DSS

99.2% Survive 0.8%

Death

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

Countries and Areas at Risk of Dengue Transmission

2.5 billion in endemic countries 50 100 million dengue cases 500.000 DHF Morbidity 1 3 weeks 20.000 deaths

DHF INCIDENCE RATE

Dengue Bull. 2006; 30: 1-14

DHF MORBIDITY & MORTALITY IN INDONESIA FROM 1968 - 2005

Dengue Bull. 2006; 30: 1-14

6

DENGUE MANIFESTATIONS

Case Definition for DHF WHO 1997

DENGUE FEVER

DENGUE HEMORRHAGIC FEVER

DENGUE SHOCK SYNDROME

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

WHO DENGUE FEVER

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

DENGUE MANIFESTATIONS

Case Definition for DHF WHO 1997

DENGUE FEVER

DENGUE HEMORRHAGIC FEVER

DENGUE SHOCK SYNDROME

Fever lasts 2-7 days,occasionally biphasic Hemorrhagic tendencies Thrombocytopenia (< 100,000 /mm3) Evidence of plasma leakage, manifested by : - rise in haematocrit > 20% - drop in haematocrit following volume replacement - signs of plasma leakage

WHO DENGUE HEMORRHAGIC FEVER

J Pediatr. 2007; 83(2): 22-35.
8

Dengue Hemorrhagic Fever

Grading Symptoms

1997

Grade I

Grade II Grade III

Grade IV

Hemoconcentration, fever, non specific constitutional symptoms, only positive tourniquet test Spontaneous bleeding in addition to the manifestation from Grade I Circulatory failure, rapid & weak pulse, narrow pulse pressure, cold clammy skin, hypotension by age, oliguria, restlessness Profound shock, hypotension or unrecordable blood pressure
9

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

DENGUE MANIFESTATIONS

Case Definition for DHF WHO 1997

DENGUE FEVER

DENGUE HEMORRHAGIC FEVER

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

WHO DENGUE SHOCK SYNDROME

J Pediatr. 2007; 83(2): 22-35.
10

The 3rd edition of the WHO dengue guidelines

http://whqlibdoc.who.int/publications/2009/9 789241547871_eng.pdf

11

WHO 2009 Dengue Case Classification and Levels of Severity

Dengue + Warning Signs
1. 2. 3.

Severe Dengue
Severe plasma leakage Severe haemorrhage Severe organ impairment

without

with warning signs

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

12

Criteria for Dengue + Warning Signs Probable Dengue Live in/travel to dengue endemic area Fever and 2 of the following criteria : - Nausea, vomiting - Rash - Aches and pain - Tourniquet test positive - Leukopenia - Any warning sign Laboratory-Confirmed Dengue Important when no sign of plasma leakage
Nathan MB. Dengue: guidelines for diagnosis, treatment, prevention and control. 2009. p3-21.
13

Warning Signs - Abdominal pain or tenderness - Persistent vomiting - Clinical fluid accumulation - Mucosal bleed - Lethargy, restlessness - Liver enlargement > 2 cm - Laboratory: increase in HCT concurrent with rapid decrease in platelet count

Criteria for Severe Dengue Severe Plasma Leakage Leading to : - Shock (DSS) - Fluid accumulation with respiratory distress Severe Bleeding As 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.

14

Revised and expanded edition of dengue guideline

This edition have been extensively revised and expanded by the WHO Southeast Asian Region Office, with the focus on new/additional topics of current relevance to Member States of the South-East Asia Region.

15

2011 WHO-SEARO Dengue Case Classification

16

WHO Classification of Dengue Infections and Grading of Severity of Dengue

17

What is expanded dengue syndrome ?

Uncommon manifestation Neurological, hepatic, renal and other isolated organ involvement CNS manifestations : Convulsions, spasticity, changes in consciousness and transient paresis Limited evidences showed dengue viruses may cross the blood-brain barrier and cause encephalitis

18

Expanded dengue syndrome

System
Neurological

Unusual or atypical manifestations

Febrile seizures in young children Encephalopathy Encephalitis / aseptic meningitis Intracranial haemorrhages / thrombosis Subdural effusions Mononeuropathies / polyneuropathies / Guillaine-Barre syndrome Transverse myelitis Hepatitis / fulminant hepatic failure Acalculous cholecystitis Acute pancreatitis Hyperplasia of Peyers patches Acute parotitis Acute failure Hemolytic uremic syndrome Conduction abnormalities Myocarditis Pericarditis

Gastrointestinal / hepatic

Renal Cardiac

19

Expanded dengue syndrome (continue..)

System
Respiratory Lymphoreticular / bone marrow

Unusual or atypical manifestations

Acute respiratory distress syndrome Pulmonary hemorrhage Infection associated haemophagocytic syndrome IAHS or Haemophagocytic lymphohisiocytosis (HLH), idiopathic thrombocytopenic purpura (ITP) Spontaneous splenic rupture Lymph node infarction Macular haemorrhage Impaired visual acuity Optic neuritis Post infectious fatigue syndrome, depression, hallucinations, psychosis, alopecia

Eye

Others

Gulati S, Maheswari A. Atypical manifestation of dengue. Trop Med Int Health. 2007; 12(9): 1087-95

20

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
21

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
22

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.

23

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
classification by expert reviewer

Revised classification by expert reviewer Total Not Dengue classifia ble WS negative WS positive 23 57 268 (100%) (8.6%) (21.3%) (13.7% of all)
7 551 1317 (100%) (0.5%) (41.8%) (67.1% of all) 2 8 289 (100%) (0.7%) (2.8%) (14.7% of all)

Severe Dengue

Not classifiable

159 (59.3%)

29 (10.8%)

DF

684 (51.9%)

75 (5.7%)

DHF (grades 1 and 2)

240 (83.0%)

39 (13.5%)

13.7% ofBMC dengue cases could be classified by DSS 0 0 not 12 Barniol J, et al. Infectious Diseases 2011, 11:106 doi:10.1186/1471-2334-11-106. 88 (100%) experienced reviewers as compared to 1.6% who (DHF grades 3and 4) (0%) (0%) (13.6%) could not classified with (4.5% of all) the revised classification

76 (86.4%)
24

Perceived advantages and disadvantages regarding the revised dengue case classification (N=1413 comments in 1288 staff questionnaires) [1]
Advantages of the revised classification It helps improving management and treatment More simple and practical Easier to classify according to severity Easier to understand It helps improving triage and referral No disadvantages of the revised classification Other advantages Total of positive responses N (%) 319 (22.6%) 199 (14.0%) 176 (12.6%) 71 (5.0%) 45 (3.2%) 191 (13.5%) 72 (5.0%) 1073(75.9%)

25

Perceived advantages and disadvantages regarding the revised dengue case classification (N=1413 comments in 1288 staff questionnaires) [2]
Disadvantages of the revised classification No advantages of the revised classification Needs more training and dissemination It's less specific. Needs more clinical entities and concise protocols Lack of manpower and resources Over diagnosis of dengue (saturation of hospitals) Warning signs: Too many, subjective, also in other diseases Lack of laboratory support Other disadvantages Total of negative responses
Barniol J, et al. BMC Infectious Diseases 2011, 11:106 doi:10.1186/1471-2334-11-106. 26

N (%) 25 (1.8%) 67 (4.7%) 54 (3.8%) 45 (3.2%) 32 (2.3%)

24 (1.7%) 10 (0.7%) 83 (5.9%)

340 (24.1%)

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.

27

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.
28

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

29

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

30

Global distribution of dengue virus serotypes, 1970

Global distribution of dengue virus serotypes, 2004

Gubler DJ. Comp Immunol Microbiol Infect Dis. 2004.

31

Clinical and laboratory findings for DHF by dengue serotype

Southeast Asian J Trop Med Public Health. 2005; 36(6): 1432-8.

32

 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 viruses 2. The antibody-dependent enhancement theory
Comp Immun Microbiol Infect Dis. 2007; 30: 329-40.

33

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.

34

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
35

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
36

Antibody-dependent enhancement (ADE) is the process in which certain strains of dengue virus, complexed with these nonneutralizing antibodies, can enter a greater proportion of the mononuclear cells where the virus replicates unchecked, thus increasing virus production and producing a massive infection

37

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.
38

Vascular Permeability
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 suggested induce endothelial permeability : IL-1, IL1, IL-2, IL-6, IL-8, TNF-, IFN-, histamine, platelet-activating factor, vascular endothelial growth factor (VEGF)
39

Halstead SB. Dengue. 2008. p285-326.

40

The course of dengue illness

McCall P, Lloyd L, Nathan MB. Dengue: guidelines for diagnosis, treatment, prevention and control. 2009. p59-87.

41

Febrile, critical and recovery phases in dengue

Febrile phase
Dehydration, high fever may cause neurological disturbance and febrile seizures in young children

Critical phase

Shock from plasma leakage, severe haemorrhage, organ impairment

Recovery phase

Hypervolemia (only if intravenous fluid therapy has been excessive and/or has extended into this period)
42

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

Course of dengue infection and timings of diagnosis

Lancet. 2007; 370: 1644-52.

43

Laboratory Diagnosis
Early illness tests
Virus isolation Nucleic acid detection Detection of antigens
Buchy P, Peeling R.Dengue: guidelines for diagnosis, treatment, prevention and control. 2009. p91-107.
44

Late illness tests

Serological tests

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.

45

Relationship between day of illness and NS1 sensitivity

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

46

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.

47

IgG titers in primary vs secondary dengue fever depending on the day of serum collection

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

48

Immune response to dengue infection

49

Suspect of Dengue Infection

High fever, < 7 days Malaise, no ARI Emergency signs (+)
Shock Seizure Encephalopathy Bleeding

Emergency signs (-)

Tourniquet test

Positive Leucocyte < 4.000/uL

Negative

Inpatient
One day observation Observe for 24 hours Symptoms & lab

Normal leucocyte

Outpatient Control until fever(-) Advice the parent

+ Thrombocyte < 100.000/uL + Rise of Ht > 10%

Fever persist > 3 days Check Hb, Ht, leucocyte & thrombocyte
50

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 & ibuprofen are contraindicated Diazepam Domperidon 1 mg/kgBB, 3 dose, 1-2 days H2 blocker (ranitidine, cimetidine) Antibiotic is not given Steroid is not effective
51

Treatment of DHF without shock (DHF grade I and II)

Able to drink Unable to drink Vomit
Infuse D5%:NaCl 0,9% = 3:1 Maintenance drips Check Hb, Ht, thrombocyte every 6-12 hours

Drink 2 L/day Paracetamol Anticonvulsive, if necessary

Evaluate the symptoms & lab Signs of shock Diuresis Bleeding Hb, Ht, thrombocyte every 6-12 hours Discharge Improve Worsen Change to RL D5%
52

Treatment of DHF grade I and II

Improvement Initial fluid 6 8 ml/kg/hour RLD5% or RAD5%
No Improvement

Monitor the vital signs Not agitated Hb, Ht, thrombocyte every 6-12 hours Agitated Strong pulse Respiratory distress Stable BP HR increase Ht decrease Ht increase Diuresis 1 ml/kg/hour Pulse pressure < 20mmHg Diuresis <1 ml/kg/hr Fluid decrease to 5 ml/kg/hour Fluid increase to 10-15 ml/kg/hour 3 ml/kg/hour Evaluate in 12-24 hours Stop in 24-48 hours
Treatment of DSS Unable vital signs

53

SHOCK

O2 2-4 L/min Isotonic fluid 20 ml/kg/hour RL/RA/NS in 30 min Evaluate in 30 minute, has the shock resolved? Yes No Continue the RL + Kolloid + Correct acidosis Evaluate in 1 hour Ht Not resolved Increase Kolloid No improvement
54

Adjust the fluid Monitor Stable

Shock has resolved

Decrease Transfusion Inotropic

Stop the fluid not more than 48 hours after the shock has resolved

55

Rate of infusion in DSS

56

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 weeks for platelet count to become normal. In most uncomplicated cases, platelet rises to normal within 3 5 days

57

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