MAJOR ARTICLE

Dengue Hemorrhagic Fever: The Sensitivity and Specicity of the World Health Organization Denition for Identication of Severe Cases of Dengue in Thailand, 19942005
Anon Srikiatkhachorn,1 Robert V. Gibbons,4 Sharone Green,1 Daniel H. Libraty,1 Stephen J. Thomas,4 Timothy P. Endy,2 David W. Vaughn,3,a Ananda Nisalak,4 Francis A. Ennis,1 Alan L. Rothman,1 Suchitra Nimmannitaya,5 and Siripen Kalayanarooj5
1

University of Massachusetts Medical School, Worcester; 2State University of New York, Upstate Medical University, Syracuse; 3Military Infectious Diseases Research Program, US Army Medical Research and Material Command, Fort Detrick, Maryland; 4Armed Forces Research Institute of Medical Sciences and 5Queen Sirikit National Institute of Child Health, Bangkok, Thailand

Background. Dengue virus infection causes a spectrum of clinical manifestations, usually classied according to the World Health Organization (WHO) guidelines into dengue fever (DF) and dengue hemorrhagic fever (DHF). The ability of these guidelines to categorize severe dengue illness has recently been questioned. Methods. We evaluated dengue case denitions in a prospective study at a pediatric hospital in Bangkok, Thailand, during 19942005. One thousand thirteen children were enrolled within the rst 3 days after onset of fever and observed with standardized data collection. Cases were classied on the basis of application of the strict WHO criteria. All dengue virus infections were laboratory conrmed. We retrospectively grouped patients on the basis of whether they received signicant intervention based on uid replacement and/or requirements for blood transfusion. Results. Eighty-ve (58%) of 150 persons with DHF, 40 (15%) of 264 with DF, and 73 (12%) of 599 with other febrile illnesses (OFIs) received signicant intervention. Sixty-eight percent of dengue cases requiring intervention met strict WHO criteria for DHF. In contrast, only 1% of OFI cases met WHO criteria for DHF. Plasma leakage and thrombocytopenia were the 2 components contributing to the specicity of the WHO case denition and identied dengue cases that required intervention. Hemorrhagic tendency did not reliably differentiate DF and DHF. In DF cases, thrombocytopenia and bleeding were associated with severity. Conclusions. Dengue illness is heterogeneous in severity, and severe clinical features occurred in patients whose cases were not characterized as DHF. The WHO case denition of DHF demonstrated sensitivity of 62% and specicity of 92% for identication of dengue illness requiring intervention, without the need for laboratory conrmation of dengue virus infection, in an area of endemicity. Dengue hemorrhagic fever (DHF) is the leading cause of viral hemorrhagic fever worldwide [1, 2]. The classication of dengue illness was developed by clinical experts largely on the basis of experience in children in Thailand and was originally published by the World Health Organization (WHO) in 1975 and updated in 1997 [1, 2]. Dengue illness is classied into undifferentiated febrile illness, dengue fever (DF), and DHF. The case denition of DHF requires 4 diagnostic components: fever, hemorrhagic manifestation (positive tourniquet test result, skin bleeding [petcchiae or ecchymosis], and mucosal bleeding, including gastrointestinal bleeding, epistaxis, and menorrhagia), thrombocytopenia (thrombocyte count, 100,000 cells/mm3), and evidence of plasma leakage (pleural effusion, ascites, hemoconcentration 20%, or hypoproteinemia) [2]. Dengue shock

Received 30 July 2009; accepted 16 December 2009; electronically published 5 March 2010. a Present afliation: GlaxoSmithKline Biologicals, North America, King of Prussia, Pennsylvania. Reprints or correspondence: Dr Anon Srikiatkhachorn, Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, 55 Lake Ave N, Rm S6-862, Worcester, MA 01655 (anon.srikiatkhachorn@umassmed .edu). Clinical Infectious Diseases 2010; 50:11351143 2010 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2010/5008-0008$15.00 DOI: 10.1086/651268

WHO Case Denitions of Dengue Illness CID 2010:50 (15 April) 1135

syndrome (DSS) is dened as DHF with circulatory failure [2]. The WHO classication has aided in the assessment of global dengue disease burden. and in the development of treatment algorithms, resulting in an improvement in the mortality rate of DHF [3]. However, the classication system categorizes cases based upon clinical manifestations and laboratory values. Its ability to categorize severe dengue illness has not been critically evaluated and recently been questioned [4]; several studies have reported that a number of severe dengue cases have failed to meet the case denition of DHF [412]. Here, we address whether the WHO case denition of DHF can identify severe dengue cases, as determined by the requirement for uid replacement and blood transfusion. The sensitivity and specicity of each component of the WHO case denition in identifying severe cases were evaluated.

METHODS Participants and procedures. Data collected from a prospective study of children in Bangkok, Thailand, with suspected dengue virus infection during the period 19942005 were analyzed [13]. Children between 6 months and 15 years of age with fever of !3 days duration and without an obvious source of infection were recruited. Exclusion criteria included known chronic disease or signs of shock on presentation. Subjects were monitored as inpatients until clinically stable for at least 1 day after defervescence. Data, including vital signs, hemorrhagic manifestations, presence of pleural effusions (detected by right lateral decubitus chest radiography) or ascites (detected by physical examinations), tourniquet test results [13], complete blood count, and albumin level, were collected daily. Blood samples were obtained for dengue serologic testing 59 days after discharge. The study was approved by the hospital institutional review board, the Thai Ministry of Public Health, the US Army Surgeon General, and the University of Massachusetts Medical School. Patients were treated in accordance with well-established clinical protocols, which generally follow WHO guidelines [1]. In lieu of early intravenous uid treatment, patients were encouraged to drink. Intravenous uid was initiated if any of the following characteristics were present: (1) signs suggestive of dehydration (eg, dry mucous membranes or poor urine output) with poor oral intake; (2) signs of poor peripheral perfusion, including persistent tachycardia, delayed capillary rell (12 s), or narrow pulse pressure (!20 mm Hg); or (3) a need for blood or colloid solution transfusion. A right lateral decubitus chest radiograph was performed 1 day after defervescence. The size of the effusion was expressed as pleural effusion index (PEI), which equaled the vertical dimension of the uid/the width of the hemithorax times 100 [13].
1136 CID 2010:50 (15 April) Srikiatkhachorn et al

Laboratory tests. Virus was identied in plasma samples by virus isolation in mosquitoes and/or by a serotype-specic reverse-transcription polymerase chain reaction, as described elsewhere [14, 15]. The serotypes of isolated viruses were identied by typing enzyme-linked immunosorbent assay [16]. Cases were classied as having primary or secondary dengue virus infection on the basis of the ratio of dengue-specic immunoglobulin (Ig) G and IgM and by hemagglutination inhibition test on paired samples, as previously published [17]. Hematocrits were obtained by nger stick at least every 6 h during the rst 18 h after defervescence. The percentage hematocrit change was calculated as (highest hematocrit during hospitalization hematocrit at convalescence)/hematocrit at convalescence 100 [18]. Clinical classication. Patients without virologic or serologic evidence of dengue virus infection were classied as other febrile illness (OFIs). Dengue cases were classied into DF or DHF grade 14 on the basis of strict application of the WHO case denitions [2]. In addition, case records from conrmed dengue cases were reviewed by a physician expert who did not participate in patient care (S.N.), and dengue cases were classied as DF or DHF grade 14. Although the experts designation was based on the WHO case denitions, the expert physician took into consideration the patients clinical course and interventions that might have affected the parameters used in the classication. For example, the physician may have used the lowest hematocrit reading obtained prior to defervescence as a baseline or may not apply the strict hematocrit criteria if the clinical course was complicated by bleeding or if intravenous uid was administered, which may lower the hematocrit readings. To evaluate the association between case designation and disease severity, we classied dengue cases on the basis of intervention requirements. Patients were classied as having dengue that required intervention (DRI) or dengue that did not require intervention (DNRI) on the basis of requirement for signicant interventions, dened as (1) use of intravenous uid, (2) receipt of uid resuscitation (combined oral and intravenous uid or oral uid alone equal to or exceeding a combined volume of maintenance uid and 5% volume decit on any day during the hospitalization) [19, 20], or (3) transfusion of whole blood or blood products. Statistical analysis. Comparisons of continuous variables were performed using the Student t test. The x2 test was used to evaluate statistical differences in categorical variables between groups. All statistical analyses were performed using the SPSS statistical package, version 14.0.0 (SPSS).

RESULTS Characteristics of the study population. Among 1013 chil-

dren recruited, 264 (26%), 150 (15%), and 599 (59%) were classiedaccording to the strict WHO criteria and the laboratory diagnosisas having DF, DHF, or OFI, respectively (Table 1). There were 12, 128, 9, and 1 cases of DHF grade 1 4, respectively. Patients were classied according to the experts opinion as having DF in 265 cases (26%), DHF in 149 cases (15%), and OFI in 599 cases (59%) (Appendix, Table A1). The concordance between the strictly applied WHO criteria and the experts opinion in classifying dengue cases into DF and DHF was 88%. The experts classied 16% of WHO-classied DHF cases as DF and 9% of WHO-classied DF cases as DHF. The dengue virus serotypes in this series were DENV-1 (35%), DENV-2 (24%), DENV-3 (26%), DENV-4 (13%), and unidentied (2%). The majority of WHO-dened DHF cases (91%) were secondary virus infections. WHO case denitions and disease severity. There were no deaths in this study. Among all 414 dengue cases, 125 (30%) were classied as DRI (Table 2). Sixty-eight percent of DRI cases met the strict WHO case denitions for DHF (Table 3); this represented a 75% agreement between the strict WHO diagnosis of DHF and the intervention requirement. Fifty-seven percent of the WHO-dened DHF cases required intervention, compared with 15% of DF cases and 12% of OFI cases (Table 2). The proportions of cases with a low pulse pressure (!20 mm Hg) at any time during the hospitalization were higher for cases of DHF (P ! .01) (Table 1). Two of 3 patients with DF and low pulse pressure received blood transfusion. The remaining patient with DF case who had a narrow pulse pressure had hemoconcentration without thrombocytopenia. Among 6 patients with OFI who had a narrow pulse pressure, small pleural effusions were found in 2 patients. The hypotension resolved without signicant uid resuscitation in all but 1 case. Contribution of individual components of DHF case denitions to clinical classications. Bleeding manifestations were
Table 1. Clinical Characteristics of Study Participants

common in both DF and DHF (Table 3). A positive tourniquet test result differentiated dengue from OFI with 77% specicity. Hematemesis and melena were more common in patients with DHF (23% and 11%, respectively) than in those with DF (4% and 4%, respectively; P ! .01) (Appendix, Table A2). The specicities of bleeding in differentiating DHF from DF and DRI from DNRI were low (15% and 11%, respectively) (Table 4). Seven study subjects received blood transfusions; 5 had DHF, and 2 had DF (P p .12). The high incidence of hemorrhage among persons with OFI was mostly due to petechiae and minor epistaxis, which were detected by close observation. The mean ( standard error of the mean) of the minimum platelet counts for patients with DHF, DF, and OFI were 46,763 2145, 123,327 3694, and 230,866 5758 platelets/mm3, respectively (P ! .01). The specicity of thrombocytopenia (thrombocyte count, !100,000 cells/mm3) for differentiating DHF from DF was 64%; for differentiating DHF from DF and OFI, it was 89% (Table 4). The cutoff value that best differentiated DRI from DNRI was 62,900 cells/mm3, with 69% sensitivity and 79% specicity (data not shown). Pleural effusions were the most common sign of plasma leakage in persons with DHF (79%) (Table 3). Ascites was detected in 34% of patients with DHF, and 96% of these persons also had pleural effusions (Table 3). Nine percent and 15% of patients with DF and OFI, respectively, had small pleural effusions (mean PEI standard error of the mean p 4.41% 1.4% and 2.2% 0.1%, respectively), which were signicantly smaller than those found in patients with DHF (19.4% 1.6%; P ! .001). Hemoconcentration (20% increase in hematocrit) was found in 69% of patients with DHF and was the only sign of plasma leakage in 19% (Table 3). Thirteen percent and 11% of patients with DF and OFI, respectively, had hemoconcentration 20% without any accompanying direct evidence of plasma leakage.

Clinical diagnosis Characteristic Number of patients Age, mean years SE Sex, no. of patients Male Female Duration of fever duration at presentation, mean days SE Duration of fever after study entry, mean days SE No. (%) of patients who received uid intervention No. (%) of patients with narrow pulse pressure (!20 mm Hg) or signs of shock DF 264 8.31 0.18 152 112 1.9 0.1b 2.4 0.1 40 (15) 3 (1) DHF 150 8.73 0.25 80 70 2.1 0.1 2.4 0.1 85 (57) 10 (7) OFI 599 6.72 0.12a 322 277 1.7 0.0 1.9 0.5 73 (12) 6 (1)

NOTE. DF , dengue fever; DHF , dengue hemorrhagic fever; OFI, other febrile illness; SE, standard error.
a b

The mean age of patients with OFI was lower than that of patients with dengue infection (P ! .05). The mean durations of fever at presentation were greater in DHF group than in the DF and OFI groups (P ! .001).

WHO Case Denitions of Dengue Illness CID 2010:50 (15 April) 1137

Table 2. Patient Classications Based on World Health Organization Case Denitions and Fluid Intervention
No. (%) of patients No IV uid and less than M+5% 526 (88) 224 (85) 65 (43) 6 (50) 59 (46) 0 (0) 0 (0) 815 (81) IV uid and less than M+5% 37 (6) 28 (10.5) 62 (42) 5 (42) 51 (40) 5 (56) 1 (100) 127 (12) No IV uid and M+5% 33 (5.5) 8 (3) 3 (2) 0 (0) 3 (2) 0 (0) 0 (0) 44 (4) IV uid and M+5% 3 (0.5) 4 (1.5) 20 (13) 1 (8) 15 (12) 4 (44) 0 (0) 27 (3)

Clinical diagnosis OFI DF DHF All Grade 1 Grade 2 Grade 3 Grade 4 Total

Total 599 264 150 12 128 9 1 1013

NOTE. Patients were classied on the basis of uid interventions received into (1) those who did not receive any intravenous uid and for whom the total uid on any day during hospitalization was less than the combined volume of maintenance uid and 5% decit (M + 5%); (2) those who received intravenous uid but for whom the volume of daily uid intake was less than the volume of M + 5% decit; (3) those who did not receive intravenous uid intervention but for whom uid intake exceeded the combined volume for at least 1 day during the illness; and (4) those who received intravenous uid for whom the uid intake exceeded the combined volume for at least 1 day during the illness. Patients with dengue in the last 3 groups were classied as having dengue requiring intervention in this analysis. The rest of patients with dengue were classied as dengue not requiring intervention. DF , dengue fever; DHF , dengue hemorrhagic fever; OFI, other febrile illness.

Pleural effusion alone provided sensitivity and specicity of 79% and 91%, respectively, for discriminating DF from DHF (Appendix, Table A3). Inclusion of evidence of plasma leakage other than pleural effusion increased the sensitivity to 100% but decreased the specicity to 76%. Pleural effusion yielded 64% sensitivity and 78% specicity for differentiating DRI from DNRI. When other signs of plasma leakage were included, the sensitivity increased to 75% and the specicity declined to 58% (Appendix, Table A3). Contribution of criteria to the WHO classication. Plasma leakage and thrombocytopenia were the main diagnostic components contributing to the specicity of the case denitions in classifying dengue cases (76% and 64% specicity, respectively), and pleural effusion was the key component identifying plasma leakage (Table 4; Appendix, Table A3). The combination of thrombocytopenia and plasma leakage had a specicity of 98% in differentiating DHF from DF (Table 4). The specicity did not change signicantly when hemorrhage was added to plasma leakage and thrombocytopenia (from 98% to 100%). When patients with dengue were classied on the basis of the requirement for intervention, plasma leakage alone had a sensitivity of 75% and specicity of 58% (Table 4). The addition of hemorrhage did not signicantly change the sensitivity (74%) or the specicity (62%). The sensitivity and the specicity for DRI of combined plasma leakage and thrombocytopenia criteria were 68% and 75%, respectively (Table 4).

Thrombocytopenia alone or the combination of thrombocytopenia and plasma leakage differentiated dengue from OFI with 94% and 98% specicity, respectively (Table 4). Only 1% of OFI cases met the denitions of DHF (ie, plasma leakage, thrombocytopenia, and hemorrhage). A signicant number of patients with DF did receive signicant intervention. To examine the characteristic differences among DF cases that differed in intervention requirement, we compared the frequencies of components of the case denitions in DF cases classied as either DRI or DNRI. The prevalence of plasma leakage, bleeding, and the combination of these 2 were not signicantly different between the 2 groups (Figure 1). However, thrombocytopenia was more common among patients with DF who required intervention than among those who did not (53% and 34%, respectively; P ! .05). The frequencies of patients with combined thrombocytopenia and bleeding were also higher for patients with DF who required intervention (50%) than among those who did not (29%; P ! .01). DISCUSSION Recent studies have questioned whether the WHO clinical classication scheme optimally identies severe dengue cases [4, 5, 9, 12, 2123]. To answer these questions, we analyzed data collected over a 12-year period from a prospective study con-

1138 CID 2010:50 (15 April) Srikiatkhachorn et al

Table 3. Clinical and Laboratory Findings in Dengue and Nondengue Diagnostic Categories and in Cases Classied on the Basis of the Requirement for Signicant Intervention
Percentage of patients OFI (n p 599) DF (n p 264) DHF/DSS (n p 150) Grade 1 or 2 DHF ( p 140) Grade 3 or 4 DSS (n p 10) No intervention (n p 815) DRI (n p 125)

Clinical nding Bleeding manifestation Positive tourniquet test result Spontaneous bleeding Positive tourniquet test result or spontaneous bleeding Thrombocytopenia (platelet count, !100,000 platelets/mm3) Signs of plasma leakage Pleural effusion Ascites Hemoconcentration Pleural effusion, ascites, or hemoconcentration Pleural effusion only Combinations of ndings Thrombocyopenia plus a positive tourniquet test result or spontaneous bleeding Pleural effusion, ascites, or hemoconcentration plus thrombocyopenia Pleural effusion, ascites, or hemoconcentration plus a positive tourniquet test result or spontaneous bleeding Pleural effusion, ascites, or hemoconcentration; thrombocyopenia; and a positive tourniquet test result or spontaneous bleeding

23 50 62 6

71 68 85 36

84 91 100 100

80 91 100 100

100 80 100 100

39 56 70 20

88 86 95 85

15 1 13 26 12

9 3 15 24 7

79 34 69 100 24

78 32 67 100 26

100 70 90 100 0

17 1 17 31 12

64 45 53 75 11

4 2

32 2

100 100

100 100

100 100

17 9

84 68

17

20

100

100

100

24

74

100

100

100

68

NOTE. Numbers denote the percentages of cases with the indicated ndings in each diagnostic category. Spontaneous bleeding includes all signs of bleeding except bleeding elicited by trauma or tourniquet test. A positive tourniquet test result was dened as petechiae of 20 spots in a 2.5-cm2 area on the forearm after application of pressure at the midpoint between systolic and diastolic pressure for 5 min using a sphygmomanometer. Patients were classied as having dengue requiring intervention (DRI) if they received intravenous uid or their total uid intake on any day exceeded the combined volume of maintenance uid and 5% decit or received blood transfusion. DF , dengue fever; DHF , dengue hemorrhagic fever; DSS, dengue shock syndrome; OFI, other febrile illness.

ducted at a referral center for dengue with a well-established intervention guideline. The study design allowed us to collect serial clinical and laboratory data and to use the levels of interventions as a measure of disease severity independent of the WHO classication. Our study showed that DHF, as dened by the WHO criteria, correlated strongly with the need for intervention. DHF constituted 68% of dengue cases that received signicant intervention. However, 42% of DHF cases did not require intervention. In contrast, 15% of DF and 12% of OFI cases did require signicant intervention. This nding demonstrates the heterogeneity in severity in each disease category. Dehydration from fever and poor oral intake may be the common underlying cause of the requirement for uid replacement in both DF and OFI cases. Furthermore, hemorrhage (sometimes severe) has been well recognized to occur in persons with DF and has led to a separate category of DF with unusual hemorrhage in the WHO classication scheme. The majority of patients with

DF cases who received signicant intervention had thrombocytopenia or thrombocytopenia and bleeding (DRI-DF) (Figure 1). In addition, 2 patients with severe cases who received blood transfusion had DF. A number of studies have shown that a signicant proportion of patients with dengue who experience shock did not fulll the WHO DHF case denition [4, 7, 9, 11, 12, 24]. In this study, 10 (76%) of 13 dengue cases with documented narrow pulse pressure were classied as DHF by the WHO case denitions. Two of the 3 patients with DF with hypotension had signicant hemorrhage and required blood transfusion. This suggests that hemorrhage may contribute to severity in DF cases. Other possible explanations for the failure of the DHF case denition to detect shock cases include the lack of data on platelet counts, hematocrits, or lateral decubitus chest radiogram at critical time points. Delays in treatment of dehydration and metabolic disturbances may result in disease severity irrespective of dengue case denitions. In addition, some

WHO Case Denitions of Dengue Illness CID 2010:50 (15 April) 1139

Table 4. The Sensitivity and Specicity of Each Component of the Current World Health Organization Case Denitions and the Combinations of These Components in Distinguishing Dengue Hemorrhagic Fever (DHF) from Dengue Fever (DF) and non-DHF Cases (DF and Other Febrile Illness [OFI] Combined) and Dengue (DHF+DF) from OFI and in Classifying Disease Severity in Dengue Cases Based on Intervention Requirement
Case denition components Classication, parameter DHF vs DF Sensitivity, % Specicity, % DHF vs DF plus OFI Sensitivity, % Specicity, % DHF plus DF vs OFI Sensitivity, % Specicity, % DRI vs DNRI Sensitivity, % Specicity, % DRI vs DNRI plus OFI Sensitivity, % Specicity, % Leak 100 76 100 75 52 74 75 58 75 69 Bleed 100 15 100 31 90 38 95 11 95 30 Plt 100 64 100 89 59 94 85 52 85 80 Leak plus bleed 100 80 100 82 49 83 74 62 74 76 Leak plus Plt 100 98 100 98 37 98 68 75 68 90 Bleed plus Plt 100 68 100 87 57 96 84 55 84 83 Leak, bleed, and Plt 100 100 100 96 36 99 68 78 68 92

NOTE. Leak was dened as plasma leakage (pleural effusion, ascites, and/or hemoconcentration), bleed was dened as bleeding including a positive tourniquet test result, and plt was dened as thrombocytopenia (platelet count, !100,000 platelets/mm3). DRI, dengue requiring intervention, DNRI, dengue not requiring intervention, OFI, other febrile illnesses.

severe cases might not have met the strictly applied criteria for DHF because of discordance between the presence of plasma leakage, bleeding, and the severity of thrombocytopenia. Plasma leakage was a major component that contributed to the specicity of the case denition and correlated with intervention requirement in dengue cases. Our study demonstrated that the presence of signicant (PEI, 14%) pleural uid was the most sensitive and specic evidence of plasma leakage in DHF. We have previously demonstrated by serial ultrasonograms that, in contrast to the progressive nature of plasma leakage in DHF, ultrasound evidence of plasma leakage in nonDHF cases was not progressive and rapidly resolved [25]. Our study demonstrated that thrombocytopenia is an important discriminating factor for both DHF and disease severity. Thrombocytopenia also discriminated dengue from OFI with 94% specicity (Table 3). Importantly, thrombocytopenia is also a marker of severity in patients with dengue who did not fulll the WHO case denition of DHF. Studies have shown that platelet counts inversely correlated with plasma viral load, which has been shown to correlate with the extent of plasma leakage [26]. Hemorrhagic manifestations did not alter the sensitivity or specicity of the case denitions because of the high incidence in both DF and DHF, as has been previously reported in Viet1140 CID 2010:50 (15 April) Srikiatkhachorn et al

nam [9]. Although the tourniquet test had low specicity in differentiating DHF from DF, as previously described [5, 7], it distinguished dengue from OFI with a reasonable specicity (77%). Even in a well-dened population and with frequent monitoring, the WHO case denition, when strictly applied, demonstrated only 88% concordance rate with diagnoses assigned by a physician expert. This discordance was largely related to differences in the determination of hemoconcentration; for application of strict WHO criteria, the peak hematocrit was compared with the convalescent hematocrit as a baseline whereas the pattern of hematocrits over the entire hospital course was utilized by the clinician. Signicant discordance between the grading of DHF cases by the expert and by strict WHO criteria was also noted. The expert physician used clinical impression, the presence of rapid pulse, and signs of poor peripheral perfusion as indicators of severity, whereas the grading based on WHO case denitions in this study relied only on documented pulse pressure, which may result in undergrading of some DHF cases. Dengue is endemic in many countries where conrmatory laboratory tests for dengue virus infection may not be widely available. Simple and practical tools that help differentiate dengue from OFI and identify potentially severe dengue cases are

Figure 1. Frequencies of the components of case denitions for dengue hemorrhagic fever (DHF)plasma leakage (left upper circles), thrombocytopenia (right upper circles), and bleeding including a positive tourniquet test result (lower circles)in various patient populations. DF, dengue fever; DNRI, dengue not requiring intervention; DNRI-DF, DF cases not requiring intervention; DRI, dengue requiring intervention; DRI-DF, DF cases requiring intervention; OFI, other febrile illness.

indispensable for case management. Our study demonstrated that tourniquet test and thrombocytopenia are useful for differentiating dengue from OFI (Table 3). Plasma leakage and thrombocytopeniaindividually or in combinationfurther identied patients with dengue who were at risk for severe illness requiring uid or blood replacement. We did not detect in our patients other severe manifestations, such as encephalitis/encephalopathy and myocarditis, as has been reported elsewhere [2123, 27, 28]. It is possible that these manifestations were complications from shock and might have been prevented by early treatment in our study [29]. Alternatively, these severe manifestations might be due to associated infectious conditions or represent distinct manifestations in different populations. Our patient population likely differed from patients with dengue seen in general practice. The early recruitment (after !3 days of illness) and close observation in our study might have resulted in fewer severe dengue cases. Although we have found the current WHO case denition to be effective in identifying severe dengue cases our ndings will need to be validated in other settings and in populations with different ethnicity. Our ndings have implications for the classication of dengue. First, the current WHO criteria identify the majority (68%)but not allpatients with dengue who required in-

tervention. It showed excellent specicity (99%) (Table 4) in differentiating dengue from nondengue illness. This supports the use of these criteria for case reporting in the absence of serological or virological conrmation of dengue infection, a practical issue for resource-poor countries. Second, plasma leakage and thrombocytopenia are the 2 components of the case denitions that discriminate DHF from DF and severe cases from milder cases. Although serial hematocrits and platelet counts remain important monitoring tools, clinical or laboratory indicators capable of predicting disease severity are needed. The development of such tools requires a proper classication of patients. For this purpose, the current classication system appears to be suitable.
Acknowledgments
We thank the arbovirology and molecular sections of the Armed Forces Research Institute of Medical Sciences for diagnostic testing; doctors and nurses of Queen Sirikit National Institute of Child Health and the staff of the Armed Forces Research Institute of Medical Sciences for patient care and sample collection. Financial support. The National Institutes of Health (NIHP01AI34533) 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 ofcial or reecting the view of the US Government. Potential conicts of interest. All authors: no conicts.

WHO Case Denitions of Dengue Illness CID 2010:50 (15 April) 1141

APPENDIX

Table A1. Case Classication Based on World Health Organization (WHO) Case Denitions and Expert Physicians Opinion Physician diagnosis DHF WHO criteria DF DHF Grade 1 Grade 2 Grade 3 Grade 4 3 22 0 0 7 0 0 0 0 89 0 0 2 17 9 0 0 0 0 1 12 128 9 1 DF 240 Grade 1 6 Grade 2 18 Grade 3 0 Grade 4 0 Total 264

NOTE. DF , dengue fever; DHF , dengue hemorrhagic fever; OFI, other febrile illness.

Table A2.

Bleeding Observed during Hospitalization No. (%) of patients

Clinical diagnosis DHF All Grade 1 Grade 2 Grade 3 Grade 4 DF OFI

a

Epistaxis

Hematemesis

Melena

Other

Skina

Positive tourniquet test result only

41 (28) 0 (0) 40 (31) 1 (11) 0 (0) 50 (19) 75 (13)

34 (23) 0 (0) 29 (23) 4 (44) 1 (100) 11 (4) 12 (2)

16 (11) 0 (0) 14 (11) 2 (22) 0 (0) 11 (4) 17 (3)

7 (4) 0 (0) 7 (5) 0 (0) 0 (0) 3 (1) 3 (1)

115 (78) 0 (0) 110 (86) 4 (44) 1 (100) 154 (58) 245 (40)

12 (9) 12 (100) 0 (0) 2 (22) 0 (0) 46 (17) 72 (12)

NOTE. DF , dengue fever; DHF , dengue hemorrhagic fever; OFI, other febrile illness. Skin bleeding, including petechiae, ecchymosis, and easy to bruise.

Table A3. Sensitivity and Specicity of Individual and Combinations of Signs of Plasma Leakage in Dengue Hemorrhagic Fever (DHF) and Dengue Fever (DF) Patients Classied on the Basis of the World Health Organization Case Denitions and Patients Classied on the Basis of Intervention Requirement Intervention requirement Clinical classication, parameter DHF vs DF Sensitivity, % Specicity, % DRI vs no intervention (dengue cases) Sensitivity, % Specicity, % 64 78 45 99 53 74 9 99 12 93 2 100 32 100 75 58 79 91 35 97 69 85 7 98 22 99 1 100 27 100 100 76 P A H P+A P+H A+H P+A+H (P + A) or H

NOTE. A, ascites; H, hemoconcentration; P , pleural effusion.

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