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Dengue Hemorrhagic Fever: The Sensitivity and Specificity of the World Health Organization Definition for Identification of Severe Cases of Dengue in Thailand, 1994–2005

  1. Anon Srikiatkhachorn1,
  2. Robert V. Gibbons4,
  3. Sharone Green1,
  4. Daniel H. Libraty1,
  5. Stephen J. Thomas4,
  6. Timothy P. Endy2,
  7. David W. Vaughn3,a,
  8. Ananda Nisalak4,
  9. Francis A. Ennis1,
  10. Alan L. Rothman1,
  11. Suchitra Nimmannitaya5, and
  12. Siripen Kalayanarooj5
  1. 1University of Massachusetts Medical School, Worcester
  2. 2State University of New York, Upstate Medical University, Syracuse
  3. 3Military Infectious Diseases Research Program, US Army Medical Research and Material Command, Fort Detrick, Maryland
  4. 4Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
  5. 5Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
  1. 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{at}umassmed.edu).

  • ↵a Present affiliation: GlaxoSmithKline Biologicals, North America, King of Prussia, Pennsylvania.

 
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Abstract

Background. Dengue virus infection causes a spectrum of clinical manifestations, usually classified 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 definitions in a prospective study at a pediatric hospital in Bangkok, Thailand, during 1994–2005. One thousand thirteen children were enrolled within the first 3 days after onset of fever and observed with standardized data collection. Cases were classified on the basis of application of the strict WHO criteria. All dengue virus infections were laboratory confirmed. We retrospectively grouped patients on the basis of whether they received significant intervention based on fluid replacement and/or requirements for blood transfusion.

Results. Eighty-five (58%) of 150 persons with DHF, 40 (15%) of 264 with DF, and 73 (12%) of 599 with other febrile illnesses (OFIs) received significant 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 specificity of the WHO case definition and identified 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 definition of DHF demonstrated sensitivity of 62% and specificity of 92% for identification of dengue illness requiring intervention, without the need for laboratory confirmation 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 classification 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 classified into undifferentiated febrile illness, dengue fever (DF), and DHF. The case definition 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 syndrome (DSS) is defined as DHF with circulatory failure [2].

The WHO classification 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 classification 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 definition of DHF [4–12].

Here, we address whether the WHO case definition of DHF can identify “severe” dengue cases, as determined by the requirement for fluid replacement and blood transfusion. The sensitivity and specificity of each component of the WHO case definition in identifying severe cases were evaluated.

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Methods

Participants and procedures. Data collected from a prospective study of children in Bangkok, Thailand, with suspected dengue virus infection during the period 1994–2005 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 5–9 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 fluid treatment, patients were encouraged to drink. Intravenous fluid 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 refill (>2 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 fluid/the width of the hemithorax times 100 [13].

Laboratory tests. Virus was identified in plasma samples by virus isolation in mosquitoes and/or by a serotype-specific reverse-transcription polymerase chain reaction, as described elsewhere [14, 15]. The serotypes of isolated viruses were identified by typing enzyme-linked immunosorbent assay [16]. Cases were classified as having primary or secondary dengue virus infection on the basis of the ratio of dengue-specific immunoglobulin (Ig) G and IgM and by hemagglutination inhibition test on paired samples, as previously published [17].

Hematocrits were obtained by finger stick at least every 6 h during the first 18 h after defervescence. The percentage hematocrit change was calculated as (highest hematocrit during hospitalization − hematocrit at convalescence)/hematocrit at convalescence × 100 [18].

Clinical classification. Patients without virologic or serologic evidence of dengue virus infection were classified as other febrile illness (OFIs). Dengue cases were classified into DF or DHF grade 1–4 on the basis of strict application of the WHO case definitions [2]. In addition, case records from confirmed dengue cases were reviewed by a physician expert who did not participate in patient care (S.N.), and dengue cases were classified as DF or DHF grade 1–4. Although the expert∼s designation was based on the WHO case definitions, the expert physician took into consideration the patient's clinical course and interventions that might have affected the parameters used in the classification. 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 fluid was administered, which may lower the hematocrit readings.

To evaluate the association between case designation and disease severity, we classified dengue cases on the basis of intervention requirements. Patients were classified as having dengue that required intervention (DRI) or dengue that did not require intervention (DNRI) on the basis of requirement for significant interventions, defined as (1) use of intravenous fluid, (2) receipt of fluid resuscitation (combined oral and intravenous fluid or oral fluid alone equal to or exceeding a combined volume of maintenance fluid and 5% volume deficit 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).

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Results

Characteristics of the study population. Among 1013 children recruited, 264 (26%), 150 (15%), and 599 (59%) were classified—according to the strict WHO criteria and the laboratory diagnosis—as having DF, DHF, or OFI, respectively (Table 1). There were 12, 128, 9, and 1 cases of DHF grade 1–4, respectively. Patients were classified according to the expert's 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 expert∼s opinion in classifying dengue cases into DF and DHF was 88%. The experts classified 16% of WHO-classified DHF cases as DF and 9% of WHO-classified DF cases as DHF.

Table 1.
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Table 1.

Clinical Characteristics of Study Participants

The dengue virus serotypes in this series were DENV-1 (35%), DENV-2 (24%), DENV-3 (26%), DENV-4 (13%), and unidentified (2%). The majority of WHO-defined DHF cases (91%) were secondary virus infections.

WHO case definitions and disease severity. There were no deaths in this study. Among all 414 dengue cases, 125 (30%) were classified as DRI (Table 2). Sixty-eight percent of DRI cases met the strict WHO case definitions 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-defined 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 significant fluid resuscitation in all but 1 case.

Table 2.
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Table 2.

Patient Classifications Based on World Health Organization Case Definitions and Fluid Intervention

Table 3.
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Table 3.

Clinical and Laboratory Findings in Dengue and Nondengue Diagnostic Categories and in Cases Classified on the Basis of the Requirement for Significant Intervention

Contribution of individual components of DHF case definitions to clinical classifications. Bleeding manifestations were common in both DF and DHF (Table 3). A positive tourniquet test result differentiated dengue from OFI with 77% specificity. 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 specificities 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 2had DF (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.

Table 4.
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Table 4.

The Sensitivity and Specificity of Each Component of the Current World Health Organization Case Definitions 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

Figure 1.
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Figure 1.

Frequencies of the components of case definitions 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.

Table A1.
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Table A1.

Case Classification Based on World Health Organization (WHO) Case Definitions and Expert Physicians' Opinion

Table A2.
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Table A2.

Bleeding Observed during Hospitalization

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 specificity 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% specificity (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 = 4.41% ±1.4% and 2.2% ± 0.1%, respectively), which were significantly 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.

Pleural effusion alone provided sensitivity and specificity 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 specificity to 76%. Pleural effusion yielded 64% sensitivity and 78% specificity for differentiating DRI from DNRI. When other signs of plasma leakage were included, the sensitivity increased to 75% and the specificity declined to 58% (Appendix, Table A3).

Table A3.
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Table A3.

Sensitivity and Specificity of Individual and Combinations of Signs of Plasma Leakage in Dengue Hemorrhagic Fever (DHF) and Dengue Fever (DF) Patients Classified on the Basis of the World Health Organization Case Definitions and Patients Classified on the Basis of Intervention Requirement

Contribution of criteria to the WHO classification. Plasma leakage and thrombocytopenia were the main diagnostic components contributing to the specificity of the case definitions in classifying dengue cases (76% and 64% specificity, 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 specificity of 98% in differentiating DHF from DF (Table 4). The specificity did not change significantly when hemorrhage was added to plasma leakage and thrombocytopenia (from 98% to 100%).

When patients with dengue were classified on the basis of the requirement for intervention, plasma leakage alone had a sensitivity of 75% and specificity of 58% (Table 4). The addition of hemorrhage did not significantly change the sensitivity (74%) or the specificity (62%). The sensitivity and the specificity 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% specificity, respectively (Table 4). Only 1% of OFI cases met the definitions of DHF (ie, plasma leakage, thrombocytopenia, and hemorrhage).

A significant number of patients with DF did receive significant intervention. To examine the characteristic differences among DF cases that differed in intervention requirement, we compared the frequencies of components of the case definitions in DF cases classified as either DRI or DNRI. The prevalence of plasma leakage, bleeding, and the combination of these 2 were not significantly 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).

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Discussion

Recent studies have questioned whether the WHO clinical classification scheme optimally identifies severe dengue cases [4, 5, 9, 12, 21–23]. To answer these questions, we analyzed data collected over a 12-year period from a prospective study conducted 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 classification.

Our study showed that DHF, as defined by the WHO criteria, correlated strongly with the need for intervention. DHF constituted 68% of dengue cases that received significant intervention. However, 42% of DHF cases did not require intervention. In contrast, 15% of DF and 12% of OFI cases did require significant intervention. This finding 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 fluid 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 classification scheme. The majority of patients with DF cases who received significant 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 significant proportion of patients with dengue who experience shock did not fulfill the WHO DHF case definition [4, 7, 9, 11, 12, 24]. In this study, 10 (76%) of 13 dengue cases with documented narrow pulse pressure were classified as DHF by the WHO case definitions. Two of the 3 patients with DF with hypotension had significant 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 definition 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 definitions. In addition, some 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 specificity of the case definition and correlated with intervention requirement in dengue cases. Our study demonstrated that the presence of significant (PEI, >14%) pleural fluid was the most sensitive and specific 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 non- DHF 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% specificity (Table 3). Importantly, thrombocytopenia is also a marker of severity in patients with dengue who did not fulfill the WHO case definition 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 specificity of the case definitions because of the high incidence in both DF and DHF, as has been previously reported in Viet nam [9]. Although the tourniquet test had low specificity in differentiating DHF from DF, as previously described [5, 7], it distinguished dengue from OFI with a reasonable specificity (77%).

Even in a well-defined population and with frequent monitoring, the WHO case definition, 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. Significant 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 definitions 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 confirmatory 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 indispensable for case management. Our study demonstrated that tourniquet test and thrombocytopenia are useful for differentiating dengue from OFI (Table 3). Plasma leakage and thrombocytopenia—individually or in combination—further identified patients with dengue who were at risk for severe illness requiring fluid or blood replacement.

We did not detect in our patients other severe manifestations, such as encephalitis/encephalopathy and myocarditis, as has been reported elsewhere [21–23, 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 definition to be effective in identifying severe dengue cases our findings will need to be validated in other settings and in populations with different ethnicity.

Our findings have implications for the classification of dengue. First, the current WHO criteria identify the majority (68%)—but not all—patients with dengue who required intervention. It showed excellent specificity (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 confirmation of dengue infection, a practical issue for resource-poor countries. Second, plasma leakage and thrombocytopenia are the 2 components of the case definitions 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 classification of patients. For this purpose, the current classification system appears to be suitable.

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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 official or reflecting the view of the US Government.

Potential conflicts of interest. All authors: no conflicts.

  • Received July 30, 2009.
  • Accepted December 16, 2009.
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  1. Clinical Infectious Diseases
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