Dengue case definitions: what is

captured and what is missed

Kay M. Tomashek

Centers for Disease Control and Prevention

Dengue Branch, San Juan, Puerto Rico

Sabin Vaccine Institute and PAHO Workshop

June 11-13, 2014 Washington, D.C.

Overview of Issues

• Most DENV infections are asymptomatic

– Asymptomatic often combined with afebrile cases, undifferentiated fever, or absent <2 days in studies

• Febrile symptomatic cases are difficult to distinguish from other acute febrile illnesses (AFI)

– Mild illness

– Early in clinical course

• Severe cases more identifiable

– Atypical cases

– Cases not meeting all DHF criteria

Symptomatic Infections

All symptomatic

people with dengue

Symptomatic Infections

All symptomatic

people with dengue

All febrile people

with dengue

Who are these

afebrile

symptomatic

dengue cases?

Afebrile Symptomatic Cases

• Cluster study (Yoon 2013)

• 1599 children 6 months to 15 years old

• Lived 100m from PCR + febrile child or control from cohort

• Visited at day 0, 5, 10, and 15; blood draw days 0 and 15

• 126 infected; 102 symptomatic of which, 19 (18.6%) had no

fever history or history of antipyretic use:

� Symptoms among afebrile: rhinorrhea (47%), cough

(42%), abdominal pain (21%), and headache (16%)

� Used IgM to diagnose so illness may be unrelated

• Prospective study and nested serosurvey (Likosky1973)

• 2865 people (all ages) in households followed for 10 weeks

• 214 of 328 infected; 16 (7.5%) afebrile symptomatic

Symptomatic Infections

All symptomatic

people with dengue

All febrile people

with dengue

All

AFI

Acute Febrile Illness StudiesAuthor Country Inclusion Criteria N Proportion

Diagnosed

Leading Diagnoses

(% of all AFI)Mueller

(2014)

Cambodia;

3 outpatient

health

centers

Outpatients 7-49 years

with fever ≥38.0˚ or

history of fever < 8

days

1193 in 3

years

86% Malaria (57% PCR)

Leptospirosis (9% PCR)

Influenza (9% PCR)

Dengue (6% PCR)

Scrub typhus (4%)

Mayxay

(2013)

Laos;

2 hospitals

Admitted patients 5 -

49 years with fever

≥38.0˚ and no obvious

cause of fever

1938 in 2

years

41% Dengue (8% PCR or NS1)

Scrub typhus (7%)

Influenza (6% PCR)

Leptospirosis (6% PCR, Cx, MAT)

Japanese encephalitis (6% ELISA)

Bacteremia (2%)

Chheng

(2013)

Cambodia;

1 hospital

Admitted children <16

years with fever ≥38.0˚

1,225 in

one year

47% Dengue (11% IgM, 5% NS1)

Scrub typhus (8%)

Japanese encephalitis (6%)

Bacterial infection (11%)*

Other Rickettsioses (3%)

Leptospirosis (1% culture, NAAT)

Kasper

(2012)

Cambodia;

9 clinics

Patients >2 years with

fever >38.0˚ for >24

hours and <10 days;

9.9% admitted

9,997 in

3 years

38% Influenza (20%)

Dengue (9% PCR )

Malaria (7%)

Acute Febrile Illness StudiesAuthor Country Inclusion

Criteria

N Proportion

Diagnosed

Leading Diagnoses

(% of all AFI)Punjabi

(2012)

Indonesia;

1 hospital

Inpatients of all ages

with fever ≥38.0˚

and negative malaria

blood smear

226 in

3 years

35% Leptospirosis (9% PCR)

Rickettsioses (7%)

Typhoid fever (6%)

Dengue (4% seroconversion)

Manock

(2009)

Ecuador;

2 hospitals

Inpatients >5 years

with fever ≥38.0˚ for

<7 days without

focus of infection

304 in

3 years

40% Leptospirosis (13%)

Malaria (13%)

Rickettsioses (6%)

Dengue (5% seroconversion)

Q fever (5%)

* There were 76 (6.3%) bloodstream infections in this group. Staphlococcus aureus, Salmonella enterica serovar Typhi, Streptococcus

pneumoniae, Burkholderia pseudomallei, Escherichia coli lead list

Acute Febrile Illness Studies

• Capture all febrile dengue cases seeking care

– Most studies 35 to 45% of all AFI diagnosed

– Dengue lab confirmed in 4 to 11% of all AFI cases

– Co-infection rate in AFI studies 3 to 11%

• Need system to identify severe dengue cases

not presenting with fever

– Ask history of fever

Symptomatic Infections

All symptomatic

people with dengue

All febrile people

with dengueDengueDengue

Fever

Case DefinitionsDengue fever, 19971

• AFI with ≥2 of following:

– Headache

– Retro-orbital pain

– Myalgia

– Arthralgia

– Rash

– Leukopenia (WBC <5.0 x 109 /L)

– Hemorrhagic manifestation

• Case must have either supportive

serology or occurred in same

location and time as other lab

confirmed cases

Dengue, 20092

• A febrile illness with ≥2 of following: – Aches and pains

– Rash

– Leukopenia

– A positive tourniquet test

– Nausea, vomiting

• In patients who traveled to or lives in dengue endemic area

Dengue with warning signs• Abdominal pain or tenderness, persistent

vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, restlessness, liver enlargement, and an increase in hematocrit with decrease in platelet count

Aches and

pains

1World Health Organization (1997) Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd ed. Geneva: World Health Organization.2World Health Organization (2009) Dengue: guidelines for diagnosis, treatment, prevention and control. Geneva, Switzerland: World Health Organization.

Symptomatic Infections

All symptomatic

people with dengue

All febrile people

with dengueSevere

Dengue

DHF

Case DefinitionsDengue hemorrhagic fever, 19971

• An illness with the following:

– fever or history of fever of 2 to 7 days

duration

– hemorrhagic tendency

– Platelet count <100,000 cells per mm3

– Evidence of plasma leakage

Severe dengue, 20092

• An acute febrile illness of 2 to 7

days duration with any or all of

the following:

– Severe plasma leakage leading to shock

or fluid accumulation with respiratory

distress

– Severe bleeding as evaluated by clinician

– Severe organ involvement as evidenced

by elevated liver transaminases or

impaired consciousness

1World Health Organization (1997) Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd ed. Geneva: World Health Organization.2World Health Organization (2009) Dengue: guidelines for diagnosis, treatment, prevention and control. Geneva, Switzerland: World Health Organization.

Case Definition Evaluation

• Sensitivity = probability that LP cases are identified by test (case

definition) as having dengue; high sensitivity � few FN

• Specificity = probability that LN cases are identified by test as

not having dengue; high specificity � few FP

• Positive predictive value =

probability clinically diagnosed

case is a LP dengue case

• Negative predictive value =

probability that clinically diagnosed

non-dengue case is LN dengue case

Diagnostic Value of Case DefinitionsComparison of Outpatient and Inpatient Settings

• Pre-selected population that already met some of the criteria for

DF so increased sensitivity. Also, improved in inpatient setting,

which may be due to a difference in patient populations.

• Lower sensitivity in children < 4years old (values in parentheses)

• Higher PPV with increased incidence of disease (inpatient setting)

Author Study population Sensitivity Specificity PPV NPV

1997 2009 1997 2009 1997 2009 1997 2009Gutierrez

(2013)

Nicaragua

Prospective cohort of children 2 -

15 years; 3407 sought care and

suspected dengue and FUO cases

presenting in first 6 days of illness

are tested; 476 PCR positive cases

89%

(37%)

87%

(46%)

43% 55% 20% 24% 96% 96%

Gutierrez

(2013)

Nicaragua

Prospective inpatient study of 0.5-

14 years old; enrolled those with

fever <7 days and one or more

criteria for DF and no focus; 1160

cases and 723 PCR positive cases

97%

(87%)

99%

(97%)

22% 8.5% 67% 64% 80% 88%

Positive Predictive Value (PPV)

• What proportion of clinically diagnosed cases actually have

the disease?

From Assoc. of Faculties of Medicine of Canada. Accessed at http://phprimer.afmc.ca/Part2-MethodsStudyingHealth/Chapter6MethodsMeasuringHealth

Use of Case Definition to Identify CasesAmong Hospital Inpatients

Author Study population 1997 2009

DF DHF DSS UC D DWS SD UCMacedo

(2014)

Brazil

Retrospective review of

suspected dengue

inpatients 0 - 18 years old

from 3 hospitals during

outbreaks; 267 of 450

laboratory positive.

26 119 46 76 (29%)

• 7 D

• 50 DWS

• 19 SD

18 142 107 0

Gan

(2013)

Singapore

Retrospective review of

1278 PCR+ adult inpatients

at 1 hospital. All classified.

1061 183 34 0 617 457 204 0

* DF Dengue Fever; DHF Dengue Hemorrhagic Fever; DSS Dengue Shock Syndrome; UC Unclassified; D Dengue; DWS Dengue with

Warning Signs; SD Severe Dengue

Use of Case Definition to Diagnose CasesCohort Studies

Author Study population No.

AFI

No. (%)

Not Seen

No. (%)

Seen

No. (%)

cases

1997*

DF DHF UDFArunee

(2012)

Thailand

4-year

study

Prospective school

cohort of 3015 children

3-13 years + active

absentee surveillance;

fever >37.5C to report

to study hospital

5842 1558 (27%)†

not brought

to study

hospital by

parent

4284

(73%)

394 of

3401

tested

(12%)

142

(36%)

42

(11%)

210

(53%)

Biswas

(2012)

Nicaragua

5-year

study

Prospective community

cohort of 3800 kids 2-14

years old; >37.8C to

report to study hospital

22,778 20,804

(91%) other

cause

determined

1974

(9%)

181 (9%) 116

(64%)

19

(10%)

46 (25%)

* DF Dengue Fever; DHF Dengue Hemorrhagic Fever; UDF Undifferentiated Fever defined as a febrile illness not meeting case definitions for DF or DHF.† Half of these cases from the first 3 years were not seen at the study hospital reported not seeking care and were treated at home.

• Case definition missed many febrile dengue patients (UF cases)

• May be more UDF cases as 27% of AFI cases in Thailand study

did not go to study hospital and half of these cases never

sought care (i.e., mild AFI cases not tested for dengue).

Undifferentiated Fever Cases

• No age or sex difference between UDF vs. DF/DHF

• Had lower median peak temperature and shorter duration of fever than DF or DHF

• Most common symptoms among UDF: headache (89%), anorexia (81%), nausea/vomiting (68%), and myalgia (48%)

– Less likely to have petechiae and convalescent rash than DF or DHF cases

– More likely than to have lethargy and drowsiness more than 3 days

* Sirivichayakul, et. al. PLoS Neglected Trop Dis 2012; 6 (2):1-10

Final Thoughts

• There are some challenges in capturing all

dengue cases

– A lot of dengue may be mild and may not present

to hospital

• Clinic and hospital cases needed

– Many cases occur in children but not all

– Some cases have symptoms but no fever but may

contribute to transmission and burden of disease

• Even if they present they may not be captured

• These represent a small proportion of all dengue

Final Thoughts

• If we want to determine if dengue cases still

occurring post vaccine release, we would need

the most sensitive case definition

– Mild cases missed: 1997 case definition did not

capture 25 to 53% of all cases in cohorts in

Thailand and Nicaragua

– Cases among young children missed: 1997 and

2009 case definitions did not perform well among

children <4 years old in Nicaragua

Final Thoughts

• Existing surveillance systems could be adapted to detect acute febrile illnesses (AFI) and cases with recent fever history

– Would allow us to detect mild cases of undifferentiated fever

– Would capture cases in pre-verbal children

– Will enable us to detect atypical cases

• As case counts drop, sentinel AFI sites would augment existing passive surveillance including participatory surveillance systems

Final Thoughts

• As the clinical endpoint for a dengue vaccine is

dengue and not severe dengue, more work is

needed to better classify and distinguish DF

and some lesser degree of severe dengue as

not well defined