VIEWPOINT

DengueHow Best to Classify It

Anon Srikiatkhachorn,1 Alan L. Rothman,2 Robert V. Gibbons,3 Nopporn Sittisombut,4 Prida Malasit,5 Francis A. Ennis,1
Suchitra Nimmannitya,6 and Siripen Kalayanarooj6
1Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; 2Institute for Immunology and Informatics, University of Rhode Island,
Providence, Rhode Island; 3Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; 4Department of Microbiology, Faculty of
Medicine, Chiang Mai University, Chiangmai, Thailand; 5Medical Molecular Biology Unit, Siriraj Hopital, Mahidol University, Bangkok, Thailand; and 6Queen Sirikit
National Institute of Child Health, Bangkok, Thailand

The exponential increase in published

dengue research in recent years emphasizes the global importance of this infectious disease. Dengue is an important
health threat to a large proportion of the
worldwide population, with an estimated 3.6 billion persons at risk of this
infection [13]. In addition to wellknown areas of endemicity in Southeast
Asia, dengue has become endemic in
South and Central America. Dengue has
now been reported in areas not previously affected and areas where the
disease was thought to be controlled
[13]. Furthermore, dengue, previously
considered to be largely a pediatric illness, has been increasingly reported in
adults [47]. The expansion of dengue
geographically and demographically
Received 24 February 2011; accepted 16 June 2011.
Correspondence: Anon Srikiatkhachorn, MD, Department
of Medicine, University of Massachusetts Medical School,
55 Lake Ave North, Rm S6-862, Worcester, MA 01655
(anon.srikiatkhachorn@umassmed.edu).
Clinical Infectious Diseases 2011;53(6):563567
The Author 2011. Published by Oxford University Press
on behalf of the Infectious Diseases Society of America.
All rights reserved. For Permissions, please e-mail: journals.
permissions@oup.com.
1058-4838/2011/536-0010$14.00
DOI: 10.1093/cid/cir451

underscores the need for an appraisal of

the clinical classifications with regard to
their applicability and usefulness in
clinical management and research.
Historically, dengue was considered to
be a debilitating but not fatal illness.
During the late 1960s, outbreaks of fatal
dengue hemorrhagic fever in children in
Southeast Asia changed this perception
[811]. Clinical information from these
outbreaks formed the basis for a dengue
clinical classification published in the
World Health Organization (WHO)
guideline in 1975 and updated in 1997
[12, 13]. Clinical dengue is classified as
dengue fever (DF) and dengue hemorrhagic fever (DHF) (Figure 1). Dengue
fever is defined as a febrile illness with at
least 2 clinical findings, including nausea, vomiting, headache, arthralgia,
retro-orbital pain, rash, myalgia, hemorrhagic manifestations, and leukopenia.
Because of the lack of specificity of these
clinical signs and symptoms, laboratory
or epidemiological evidence of dengue
virus infection is required for a confirmed diagnosis. The definition of
DHF consists of 4 clinical criteria: fever,
a hemorrhagic tendency (spontaneous

bleeding or a positive tourniquet test

result), thrombocytopenia (platelet
count, #100 000 cells/mm3), and plasma
leakage as shown by pleural effusion,
ascites, or $20% hemoconcentration.
Of importance, the specificity of this
syndrome means that a diagnosis of
DHF does not require laboratory evidence of dengue virus infection.
Several criticisms have been raised
against the case definition of DHF. Reports have argued that the case definition of DHF is too rigid and too difficult
to apply in primary care or resourcelimited settings [1418]. Another criticism has been that the case definition
fails to identify a significant proportion
of severe dengue cases. For example,
severe manifestations, such as encephalopathy and hepatic failure, are not included in the DHF case definition. It has
also been questioned whether the case
definitions, which were developed primarily on the basis of data derived from
pediatric cases in southeast Asia, are
applicable to other regions and populations. Consequently, a multicenter
study to define clinical dengue was conducted (the Dengue Control [DENCO]

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Dengue has emerged as a major public health problem worldwide. Dengue virus infection causes a wide range of clinical
manifestations. Since the 1970s, clinical dengue has been classified according to the World Health Organization guideline as
dengue fever and dengue hemorrhagic fever. The classification has been criticized with regard to its usefulness and its
applicability. In 2009, the World Health Organization issued a new guideline that classifies clinical dengue as dengue and
severe dengue. The 2009 classification differs significantly from the previous classification in both conceptual and practical
levels. The impacts of the new classification on clinical practice, dengue research, and public health policy are discussed.

study), and on the basis of its findings,

a new clinical classification of dengue
disease has been published in the most
recent WHO guideline and subsequently
promulgated [19, 20]. Although an
effort to publish the findings is underway, the supporting data for the new

classification have been, up to this point,

largely inaccessible for evaluation [21]. A
recent follow-up study from the same
investigators indicates that the revised
classification is undergoing evaluation
regarding its applicability and usefulness
[22].

Figure 2. Dengue classification according to the World Health Organization guidelines issued in 2009. Dengue is classified as dengue with or without
warning signs and severe dengue. Diagnosis of dengue requires the presence of fever and at least 2 clinical findings or any warning signs.
Epidemiological or laboratory evidence is required to make the diagnosis. Severe dengue is defined as dengue with any of the following: (1) severe
plasma leakage leading to shock or respiratory distress, (2) severe hemorrhage, or (3) any organ failure.
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Figure 1. Dengue classification according to the World Health Organization guidelines issued in
1975 and 1997. Dengue is classified as (1) undifferentiated fever, (2) dengue fever (DF), and (3)
dengue hemorrhagic fever (DHF). In addition to fever and at least 2 clinical findings, diagnosis of DF
requires epidemiological or laboratory evidence supporting a dengue virus infection. To meet a case
definition of DHF, all 4 criteria are required: (1) fever, (2) hemorrhagic manifestations, (3)
thrombocytopenia (platelet count, #100 000 platelets/mm3), and (4) evidence of plasma leakage.
Diagnosis of DHF does not require laboratory support.

The new WHO guideline classifies

dengue as dengue and severe dengue
(Figure 2). The definition of (nonsevere)
dengue is somewhat similar to that of
DF: a combination of $2 signs and
symptoms in a febrile individual in an
area of endemicity. However, the signs
and symptoms listed in the revised
classification are more numerous and
less specific than those listed in the 1997
classification. They include aches and
pains, nausea, vomiting, and rash. In
addition, abdominal pain and tenderness,
persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy,
restlessness, and liver enlargement are
included in the list of clinical findings
suggestive of dengue and also serve as
warning signs for potentially severe dengue. Severe dengue is classified as cases
including any of the following: (1) plasma
leakage leading to shock or respiratory
distress, (2) severe bleeding, or (3) organ
failure (eg, elevated liver enzyme levels,
impaired consciousness, or heart failure).
The 2009 clinical classification represents a significant departure from the
prior classification. In contrast to the
previous classification, which defines
DHF as a clinical entity with plasma

than among those with DF. Therefore,

the case definition of DHF affords significant discriminating value for clinical
severity. Indeed, a recent study comparing the 2 classifications revealed that
the 2 classifications perform comparatively well in identifying severe dengue,
defined according to requirement for
intervention [33].
Another important aspect of the 2009
classification that reflects its intended
use as a case-management tool is the
inclusion of nonspecific warning signs as
diagnostic criteria for probable and potentially severe dengue cases. As such,
a patient presenting with abdominal
pain and vomiting in an area of endemicity during the dengue season will
qualify as a probable dengue case. On
the basis of the statistics from the outpatient department at Queen Sirikit
National Institute for Child Health in
Bangkok in 2008, the new case definition
would have qualified an additional
39 000 cases as probable dengue, whereas
only 1600 suspected dengue cases were
detected using a positive tourniquet test
result and leukopenia as screening tools
[34]. Among the latter, 76% were confirmed dengue cases by serologic testing
(unpublished data). Patients with
warning signs warrant close monitoring
according to the new guideline, posing
a significant burden for resource-poor
countries where dengue is highly endemic. In addition, the requirement for
laboratory confirmation is not clearly
stated for severe dengue in the 2009
classification. Without laboratory confirmation, an unknown number of cases
that qualify as severe dengue may not be
dengue, because of the nonspecific nature of the criteria. In contrast, the DHF
case definition excludes 99% of nondengue cases without the need for laboratory tests [32]. Implementation of
the 2009 case definitions of probable and
severe dengue without laboratory confirmation will certainly inflate the
number of dengue cases and further
complicate resource allocation and implementation of preventive measures.

The revised classification also poses

significant problems for dengue research. Because the revised classification
is designed primarily as a case-management tool, less emphasis is placed on the
underlying pathophysiology. In contrast
to the previous classification, which defined DHF as a clinical entity with
a common pathophysiological process,
the 2009 classification makes no such
distinction. This reflects the notion that
dengue is one disease entity with different clinical presentations and often
with unpredictable clinical evolution
and outcome, as indicated in the 2009
guideline [19, p. 11]. Consequently, severe dengue in the new classification
includes cases with diverse and potentially unrelated underlying mechanisms.
For instance, patients with highly elevated liver enzyme levels may be classified as having severe dengue regardless
of the presence of other clinical findings
(eg, plasma leakage or hemorrhage).
This poses a problem for research
studies that focus on specific manifestations (eg, plasma leakage) of dengue
disease, because patients classified as
having severe dengue may or may not
have manifestation(s) relevant to
a particular research question. This
would require more-specific designations of severe dengue for research
(eg, severe dengue with plasma leakage,
severe dengue with liver failure, or severe dengue with heart failure).
Although the severity-based classification is the central feature of the proposed classification, most of these severe
manifestations are not well defined in
the guideline and others are based on
arbitrary laboratory cutoff values. Indeed, the severity is based mostly on
clinical judgment and will lead to heterogeneity in the classified groups
because of variation in clinical practice.
This is in contrast to the previous classification, which depends on objective
findings only. Moreover, shock and severe organ involvement can be manifestations of the disease, complications
of delayed or inappropriate treatment,

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leakage as the cardinal feature that differentiates it from DF, the 2009 classification lists several clinical manifestations
as qualifiers for severe dengue. The improvement in dengue-associated mortality over the past decades has been
based on the understanding of the natural history of plasma leakage in DHF,
which occurs around the time of defervescence and coincides with the nadir
of the platelet count. Delayed detection
and treatment of plasma leakage is the
major cause of organ failure, listed as
severe manifestations in the 2009 classification. By listing severe organ involvement as a criterion for severity
separate from plasma leakage, the revised classification places emphasis on
isolated organ failure as a common and
significant cause of dengue severity.
With the exception of liver failure,
which has been reported to occur in
#1% in moderate to severe adult dengue
cases [23, 24], the frequencies of severe
organ impairment in the absence of
plasma leakage have not been well
documented. Most reports of isolated severe organ impairment consist of case reports or small case series [2531]. On the
basis of our prospective study involving
children, severe organ involvement in the
absence of plasma leakage is, in fact, uncommon [32]. In an attempt to include
these unusual dengue manifestations, the
2009 classification has unfortunately reduced the emphasis on the most important aspect of dengue disease and the
major factor contributing to fatality.
The 2009 severity-based classification
stems from an argument that DHF case
definition does not effectively identify
severe dengue. It is important to indicate
that the DHF case definition is based on
a combination of clinical and laboratory
findings to define a clinical syndrome
rather than disease severity. Consistent
with this, we found in a recent analysis
that patients with DHF are not uniformly severe [32]. However, the risk of
severe disease as defined by a requirement for intervention was significantly higher among patients with DHF

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Acknowledgments
Financial support. This work was supported by the National Institutes of Health
(grant NIH-P01AI34533) and the Military Infectious Disease Research Program.
The opinions or assertions contained herein
are the private ones of the authors and are not to
be construed as official or reflecting the view of
the US government.
Potential conflicts of interest. All authors:
No reported conflicts.
All authors have submitted the ICMJE Form
for Disclosure of Potential Conflicts of Interest.
Conflicts that the editors consider relevant to
the content of the manuscript have been disclosed in the Acknowledgments section.

References
1. Franco C, Hynes NA, Bouri N, Henderson
DA. The dengue threat to the United States.
Biosecur Bioterror 2010; 8:2736.
2. Center for Disease Control and Prevention
(CDC). Locally acquired DengueKey West,
Florida, 20092010. MMWR Morb Mortal
Wkly Rep 2010; 59:57781.
3. Morens DM, Fauci AS. Dengue and hemorrhagic fever: a potential threat to public
health in the United States. JAMA 2008;
299:2146.
4. Cummings DA, Iamsirithaworn S, Lessler JT,
et al. The impact of the demographic transition on dengue in Thailand: insights from
a statistical analysis and mathematical
modeling. PLoS Med 2009; 6:e1000139.
5. Saxena AK. Dengue in travelers. N Engl J
Med 2005; 353:25113; author reply -3.
6. Hammond SN, Balmaseda A, Perez L, et al.
Differences in dengue severity in infants,
children, and adults in a 3-year hospitalbased study in Nicaragua. Am J Trop Med
Hyg 2005; 73:106370.
7. Garcia-Rivera EJ, Rigau-Perez JG. Dengue
severity in the elderly in Puerto Rico. Rev
Panam Salud Publica 2003; 13:3628.
8. Nimmannitya S, Halstead SB, Cohen SN,
Margiotta MR. Dengue and chikungunya
virus infection in man in Thailand, 1962
1964. I. Observations on hospitalized patients with hemorrhagic fever. Am J Trop
Med Hyg 1969; 18:95471.
9. Nimmannitya S. Clinical spectrum and
management of dengue haemorrhagic fever.
Southeast Asian J Trop Med Public Health
1987; 18:3927.
10. Cohen SN, Halstead SB. Shock associated
with dengue infection. I. Clinical and
physiologic manifestations of dengue hemorrhagic fever in Thailand, 1964. J Pediatr
1966; 68:44856.
11. Pongpanich B, Kumponpant S. Studies of
dengue hemorrhagic fever. V. Hemodynamic studies of clinical shock associated
with dengue hemorrhagic fever. J Pediatr
1973; 83:10737.

Srikiatkhachorn et al

12. World health Organization. Technical

guides for diagnosis, treatment, surveillance, prevention and control of dengue
haemorrhagic fever. Geneva: WHO
(Southeast Asian and Western Pacific Regional Offices), 1975.
13. World health Organization. Dengue hemorrhagic fever: diagnosis, treatment, prevention
and control. 2nd ed. Geneva: WHO, 1997.
14. Balmaseda A, Hammond SN, Perez MA,
et al. Short report: assessment of the
World Health Organization scheme for
classification of dengue severity in Nicaragua. Am J Trop Med Hyg 2005; 73:
105962.
15. Bandyopadhyay S, Lum LC, Kroeger A.
Classifying dengue: a review of the difficulties in using the WHO case classification for
dengue haemorrhagic fever. Trop Med Int
Health 2006; 11:123855.
16. Phuong CX, Nhan NT, Kneen R, et al.
Clinical diagnosis and assessment of severity of confirmed dengue infections in
Vietnamese children: is the world health
organization classification system helpful?
Am J Trop Med Hyg 2004; 70:1729.
17. Rigau-Perez JG. Severe dengue: the need for
new case definitions. Lancet Infect Dis 2006;
6:297302.
18. Deen JL, Harris E, Wills B, et al. The WHO
dengue classification and case definitions:
time for a reassessment. Lancet 2006;
368:1703.
19. Dengue, guidelines for diagnosis, treatment,
prevention and control. Geneva, Switzerland: World Health Organization, 2009.
20. Anonymous. WHO issues new dengue
guidelines. TDR News 2010; 85:5.
21. Alexander N, Balmaseda A, Coelho IC, et al.
Multicentre prospective study on dengue
classification in four South-east Asian and
three Latin American countries. Trop Med
Int Health 2011; doi: 10.1111/j.1365-3156.
2011.02793.x.
22. Barniol J, Gaczkowski R, Vega Barbato E,
et al. Usefulness and applicability of the
revised dengue case classification by disease:
multi-centre study in 18 countries. BMC
Infect Dis 2011; 11:106.
23. Kuo CH, Tai DI, Chang-Chien CS, Lan CK,
Chiou SS, Liaw YF. Liver biochemical tests
and dengue fever. Am J Trop Med Hyg
1992; 47:26570.
24. Trung DT, Thao le TT, Hien TT, et al. Liver
involvement associated with dengue infection in adults in Vietnam. Am J Trop
Med Hyg 2010; 83:77480.
25. Anga G, Barnabas R, Kaminiel O, et al. The
aetiology, clinical presentations and outcome of febrile encephalopathy in children
in Papua New Guinea. Ann Trop Paediatr
2010; 30:10918.
26. Gasperino J, Yunen J, Guh A, Tanaka KE,
Kvetan V, Doyle H. Fulminant liver failure
secondary to haemorrhagic dengue in an
international traveller. Liver Int 2007;
27:114851.

Downloaded from cid.oxfordjournals.org at Universidade Federal Fluminense on August 27, 2011

underlying health conditions, or even

adverse effects of medications. For example, fluid accumulation with respiratory distress, listed as a criterion for
severity in the new classification, is often
a complication of overtreatment with
intravenous fluids. Because severity can
be modified by intervention, which
varies significantly from place to place,
the 2009 definition of severe dengue will
reflect the underlying disease severity
and the regional and local clinical practice. It is questionable whether such
a classification would be useful in research.
The dynamic nature of dengue demands close monitoring and repeated
clinical and laboratory evaluations.
Failure to obtain information, such as
hematocrit and platelet counts, at the
critical period is the primary reason for
the difficulties in applying the DF-DHF
classification. Unfortunately, this is
prevalent even in recent prospective
studies. For example, a subsequent study
by the DENCO investigators showed
that the maximum hematocrit reading
was available in only 12% of cases [22].
The inconsistent application of the DFDHF classification, largely because of the
lack of critical information, has led to
confusion and misunderstanding. It is
imperative that research studies include
sufficient detail on clinical data to justify
their conclusions. As dengue continues
to expand globally, the clinical classification will need to be reexamined and
modified. However, loosening of the
criteria for case classification and, in
particular, incorporation of heterogeneous disease manifestations and
mechanisms in a single classification, is
not helpful. Despite its limitations, the
DHF case classification has proved to be
useful for advancing important observations on dengue disease pathogenesis, such as the importance of secondary
dengue virus infection to the plasma
leakage phenomenon, and has been
instrumental in the development of
treatment regimens that have saved numerous lives.

27. George R, Liam CK, Chua CT, et al. Unusual clinical manifestations of dengue virus
infection. Southeast Asian J Trop Med
Public Health 1988; 19:58590.
28. Kankirawatana P, Chokephaibulkit K,
Puthavathana P, Yoksan S, Apintanapong
S, Pongthapisit V. Dengue infection presenting with central nervous system
manifestation. J Child Neurol 2000; 15:
5447.
29. Lum LC, Lam SK, George R, Devi S. Fulminant hepatitis in dengue infection. Southeast

Asian J Trop Med Public Health 1993; 24:

46771.
30. Solomon T, Dung NM, Vaughn DW, et al.
Neurological manifestations of dengue infection. Lancet 2000; 355:10539.
31. Vijayalakshmi AM, Devaprasath S. Fulminant hepatic failure in primary dengue infection. Indian Pediatr 2010; 47:280.
32. Srikiatkhachorn A, Gibbons RV, Green S,
et al. Dengue hemorrhagic fever: the sensitivity and specificity of the world health organization definition for identification of

severe cases of dengue in Thailand, 1994

2005. Clin Infect Dis 2010; 50:113543.
33. Basuki PS, Budiyanto , Puspitasari D, et al.
Application of revised dengue classification
criteria as a severity marker of dengue viral
infection in Indonesia. Southeast Asian
J Trop Med Public Health 2010; 41:
108894.
34. Kalayanarooj S, Nimmannitya S, Suntayakorn
S, et al. Can doctors make an accurate diagnosis of dengue infections at an early
stage? Dengue Bull 1999; 23:17.

Downloaded from cid.oxfordjournals.org at Universidade Federal Fluminense on August 27, 2011

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CID 2011:53 (15 September)

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