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  • Severe dengue: the need for new case definitions

    The Lancet Infectious Diseases 2006; 6:297-302
    DOI:10.1016/S1473-3099(06)70465-0
    Severe dengue: the need for new case definitions Dr Jos? G Rigau-P?rezMD a

    Summary

    Dengue fever imposes a societal burden that is difficult to measure because of the disease's non-specific symptoms and the lack of easily applied case definitions for its more severe manifestations. An efficacy trial of a tetravalent vaccine is expected in the near future, but only one of the severe dengue syndromes?the continuum of dengue haemorrhagic fever and dengue shock syndrome?is well defined. One of the results of the focus on dengue haemorrhagic fever is the false perception of low disease burden in the Americas, which is an obstacle to the mobilisation of political and economic resources to fight the disease. Three improvements are necessary to standardise the dengue haemorrhagic fever definition and to allow it to do well in different populations: (1) redefine the threshold for thrombocytopenia, (2) clarify the standard practice and value of the tourniquet test, and (3) incorporate a criterion to measure intravenous fluid replacement. In addition, for an accurate estimation of dengue burden, locally appropriate definitions of severe dengue must be devised and standardised so they will be considered valid in the global research community.
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    Introduction

    Dengue fever imposes a societal burden that is difficult to measure because of the disease's non-specific symptoms and the lack of easily applied definitions for its more severe manifestations. Most overt cases develop a self-limited illness known as ?breakbone fever?, considered benign in the medical published work, but not by patients. A small proportion of infected people develop a potentially lethal condition known as dengue haemorrhagic fever. An efficacy trial of a tetravalent dengue vaccine is expected in the near future, but only one of the severe dengue syndromes?the continuum of dengue haemorrhagic fever and dengue shock syndrome?is well defined.1 The case definition, proven useful in clinical care and research (for which it was devised), has nevertheless been criticised by dengue researchers for decades.2?5 The current dengue haemorrhagic fever definition is mainly derived from experience in Bangkok up to 1975,6,7 and is not equally useful in all clinical care or epidemiological situations. It must be updated to reflect current practices in case treatment, hospital laboratory, and dengue diagnostic methods. The strict application of the definition, and its solitary use as the identifier of severe dengue, underestimates the number of dengue haemorrhagic fever cases and possibly makes it difficult for the clinician (and society) to realise the role of dengue in the patient's condition. The expansion of dengue transmission throughout the world, and the near possibility of vaccine trials also present the need for new definitions to identify and better study the other, non-dengue haemorrhagic fever/dengue shock syndrome severe dengue manifestations. The false perception of low disease burden in the Americas, resulting from the focus on dengue haemorrhagic fever, is an obstacle to the mobilisation of political and economic resources to fight dengue, and to establish viable vaccine testing sites.

    Dengue

    Benjamin Rush described an epidemic of breakbone fever in Philadelphia in 1780 in which patients showed some or all of the following symptoms: fever, headache, severe muscle and joint pain, nausea, vomiting, rash, haemorrhagic manifestations, and asthenia in convalescence. A similar syndrome in Madrid in 1801 was given the name of ?dengue? (meaning ?affectation? in Spanish) to describe the plaintive demeanor of patients.8 The dengue virus (figure) is transmitted by Aedes spp mosquitoes, usually Aedes aegypti. All four serotypes (DEN-1 to DEN-4) induce specific but not cross-protective long-term immunity, and all can cause severe disease.


    Click to enlarge image


    Figure. Colour-enhanced transmission electron micrograph of dengue virusChris Bjornberg/Science Photo Library



    In 1953, a haemorrhagic fever of children emerged in Manila, and dengue was recognised as its cause in 1956. In a relatively short time dengue haemorrhagic fever was detected throughout southeast Asia, and defined as an excessive capillary permeability that may lead to shock and death. There was little dengue in Central and South America after the A aegypti eradication campaign between 1947 and 1972, but the mosquito returned and international travel became faster, causing large epidemics, endemicity, and co-circulation of several viruses.9 The first case of dengue haemorrhagic fever was documented in Puerto Rico in 1975, and in 1981 there was a dengue epidemic in Cuba with many dengue haemorrhagic fever cases and deaths. Dengue haemorrhagic fever is now endemic in almost all tropical and subtropical regions of the Americas.6,10,11
    A case of dengue haemorrhagic fever, defined according to the current guidelines of the WHO and Pan American Health Organization,6,7 fulfills all of the following clinical criteria: fever, any haemorrhagic manifestation, thrombocytopenia (≤100 000 platelets per μL), and objective evidence of increased capillary permeability. The last must be documented by either haemoconcentration (an increase in haematocrit of 20% or greater from average, or decreased by an equivalent amount from baseline after intravenous fluid therapy), pleural or abdominal effusion (by radiography or other imaging method), or hypoalbuminaemia or hypoproteinaemia. When the only haemorrhagic manifestation is provoked (by a tourniquet test), the case is categorised as grade I dengue haemorrhagic fever, but a spontaneous haemorrhage, even if mild, indicates grade II illness. Grades III and IV dengue haemorrhagic fever (incipient and frank circulatory failure, respectively) represent dengue shock syndrome.6,7 A prospective study in Thailand found that about 15?20% of dengue haemorrhagic fever cases presented to hospital in grade I, 50% in grade II, 30% in grade III, and rare patients in frank shock, but in locations where dengue is not as promptly treated, the proportion of patients admitted in grades III and IV is likely to be higher.12 With early diagnosis and management, case fatality rates for dengue haemorrhagic fever may be less than 1%, but late recognition may increase it tenfold or more. ?Alarm signals? that precede the onset of dengue shock syndrome have been empirically identified and recommended as a tool to assist in decreasing dengue mortality throughout the world. Their use also needs to be prospectively evaluated.13
    Among the severe dengue syndromes identified since the emergence of dengue haemorrhagic fever are the so-called ?unusual manifestations? with bleak prognosis. These are encephalopathy and less often encephalitis, hepatic failure, cardiomyopathy, and dengue fever with severe haemorrhage.2,14,15 They are not identified by the WHO case definition, are not very well defined to date, and are not equally rare in all endemic locations. For example, the ratio of cases of encephalopathy per 1000 people with dengue haemorrhagic fever was 177 in Indonesia in 1975?77,16 eight in Thailand for 1995?99,17 and five in two different studies in Vietnam in 1995 and 1997?99.18,19 More recently reported unusual (and troublesome) manifestations include acute respiratory distress syndrome and acalculous cholecystitis.20,21

    Social construction

    Dengue haemorrhagic fever as a subject of inquiry has changed since its emergence in 1953 with the globalisation of severe disease and more information about its pathophysiology. Disease is a result of social resources, relations, and cultural ideas, in addition to biomedical conditions.22 The pre-eminence of dengue haemorrhagic fever as the indicator of severe dengue was justified by the syndrome's severity and novelty, and the intense scientific controversy about its cause. Two hypotheses were proposed to explain why only a small proportion of infected people develop dengue haemorrhagic fever: infection with particular virus strains, or a consequence of pre-existing dengue antibody.23?25 Cohort studies in southeast Asia, designed to resolve these issues, also produced important discoveries about the variability of the clinical manifestations of dengue. Most infected children and adults may be asymptomatic or minimally symptomatic, and the risk of development of dengue haemorrhagic fever has been estimated at only 1?125 cases out of every 1000 dengue infections in children.26?29 The current thinking is a convergence of both originally opposed theories.30 As explained by Halstead, ?[dengue haemorrhagic fever/dengue shock syndrome] occurs at epidemic proportions only when the second infecting serotype is of southeast Asian origin?.31

    Disease burden

    The investigation of dengue haemorrhagic fever incidence and causes was moulded by the social environment, tools, and study endpoints available in Asia, where the disease emerged. The application of these tools in the Americas, where non-dengue haemorrhagic fever syndromes are principally responsible for dengue-related morbidity, has provided additional insight into the causes of severe dengue, but results in an underestimation of the burden of dengue. The impression that even well-informed researchers would get from the medical published work and international disease report statistics is that dengue is a problem concentrated mostly in southeast Asia. This interpretation does not take into account the dramatic differences in surveillance infrastructure between Asia and the Americas. Social and economic factors have a very strong role in allowing the full development of dengue haemorrhagic fever. In locations with good quality and availability of medical care, dengue haemorrhagic fever cases and deaths will be few but at great cost (in terms of funds, personnel, training, and materials), and with an accompanying large number of days lost from work (which are also days of pain and fever, even if out of the hospital). It is interesting to compare selected country statistics for 1998, a year in which dengue epidemics were reported throughout the world (table 1).

    Click to view table


    Table 1. Comparison of 1998 dengue incidence reports in selected countries in southeast Asia and Latin America


    Although the number of cases reported in southeast Asian countries is impressive, the reported incidence is in the same order of magnitude as in the Americas. The public-health burden might still be considered worse in Asia because dengue haemorrhagic fever is all that is reported there, while it forms only a small proportion of dengue cases in the Americas, but one must consider that the use of dengue diagnostic testing varies from 3% of reported cases in southern Vietnam to 100% in Puerto Rico.35 The crucial indicator, population mortality rate, was not very different in Thailand and Puerto Rico. The similarities are borne out by studies using disability adjusted life years (DALYs; a measure of the loss of healthy days in a society due to death, pain, or incapacitation as a result of illness) as a standard measure of disease burden. Studies examining DALYs due to dengue per million inhabitants per year found a similar order of magnitude for dengue burden in Puerto Rico (658 DALYs, using data from 1984?94),36 southeast Asia (848 DALYs for 1988?92),37 Thailand (427 DALYs for 2001),38 and a model cohort of southeast Asian children born in 1999 (420 DALYs).39 Why is there such a gap between the incidence statistics and the measure of social cost?

    Dengue haemorrhagic fever definition

    The WHO case definition for dengue haemorrhagic fever, which has been in use since 1975, with periodic revisions, was devised for clinical diagnosis in locations without the benefit of virological or serological tests for dengue.7,40,41 For comparison, the implicit ?gold standard? to confirm the results of using the dengue haemorrhagic fever definition has involved not only the four clinical criteria outlined above, but also knowledge of their relative timing, virological or serological positivity for dengue, and the judgment of expert clinicians. Two recent studies provide best-case estimates of the sensitivity and specificity of the WHO case definition. In a study done in Thailand,12 28 patients were considered to have developed dengue haemorrhagic fever (table 2). Strict application of the definition's criteria captured only 23 out of the 28?ie, a sensitivity of 82%. The specificity was 94% (30/32). My analysis only considered the 60 laboratory-positive patients among the 203 patients enrolled in the study, thus biasing the study in favour of the definition. In a study carried out in Vietnam42 there were 631 laboratory-positive dengue patients with full clinical information, of whom 310 developed shock. The WHO definition, strictly applied, identified 253 of them (ie, a sensitivity of 82%). Specificity, although not stated, seems to have been 100%. If the sensitivity of the definition in prospective studies carried out by clinician researchers was 82%, clearly the dengue haemorrhagic fever detection rate in routine clinical care will be lower.

    Click to view table


    Table 2. Sensitivity and specificity of the WHO case definition for dengue haemorrhagic fever among laboratory-positive dengue cases12


    Some of the problems with the dengue haemorrhagic fever definition are extrinsic to the text of the WHO definition. Researchers who state they are following the WHO criteria frequently misquote them or adapt them. Inconsistency in the application of the dengue haemorrhagic fever definition is partly provoked by the lack of clarity and consistency in WHO documents themselves, and also because there are difficulties for its use outside a research protocol. The WHO definition requires different and repeated clinical tests (haematocrit, platelets, serum albumin or protein, radiographs, microscopic analysis of urine), which is a challenge for countries with limited resources. Furthermore, the definition relies on tests that reflected the situation in southeast Asia in the 1960s. For example, it does not use the current threshold for thrombocytopenia (≤150 000 platelets per μL), or a level established by risk analysis, but actually uses an estimate of platelet count (≤100 000 platelets per μL) when an average three or less petechiae per field are seen in the inspection of ten oil-immersion fields (100?magnification) of a blood smear.7,43 The tourniquet test is another stumbling block, because there is confusion in the definition of a positive result (either ten or 20 petechiae per square inch [6?45 cm2]), it is a long test (5 min) for a doctor's visit, and it feels even longer for the patients, since it is very uncomfortable.7,44,45
    The omission of the use of the tourniquet test has considerable impact on the detection of dengue haemorrhagic fever. Grade I dengue haemorrhagic fever, which might represent 15?20% of all dengue haemorrhagic fever cases, depends on tourniquet test positivity. Time is another factor in the definition, since many patients must be tested repeatedly over several days before they present the required findings. Finally, the dengue haemorrhagic fever definition also results in a paradox?early treatment will prevent fulfillment of the diagnostic criteria. Appropriately hydrated cases will not haemoconcentrate to the extreme required by the definition, and therefore will not be classified as dengue haemorrhagic fever patients unless expensive tests?eg, chest radiographs or ultrasound?are used to document the capillary leakage criterion.

    Recommendations

    When new diseases are identified, the emphasis is on the more severe cases, but as an epidemic expands, such a constricted definition is an impediment to the accurate measurement of disease burden, early control efforts, and community education.46 In addition, clinical care, research, and surveillance have different requirements for a well-defined case. One case definition for severe dengue does not fit all the life-threatening dengue syndromes. The WHO dengue haemorrhagic fever definition needs to be simplified, standardised, and tested, but additional definitions for other syndromes are also needed.
    Three basic improvements are needed to standardise the WHO dengue haemorrhagic fever definition. First, the threshold for thrombocytopenia must be redefined, either in reference to the pathophysiological process or to the easiest laboratory measure available locally. Second, the standard practice for the tourniquet test must be clarified and the value of the test defined. Third, and most important, the definition needs an additional criterion to incorporate a measure of treatment. The volume of intravenous solution infused to prevent hypotension or shock will depend not only on the patient's condition, but also on the expertise of clinicians and each country's treatment guidelines, therefore the timing and the relative volume of fluid (per body area or per kg of weight) must be specified, thus providing an indication of the underlying severity of disease even when prompt care prevents the manifestation of haemoconcentration or hypotension.
    To assure early treatment, a presumptive dengue haemorrhagic fever definition should have minimal requirements, and may include different criteria than those incorporated into the WHO case definition. For example, in Costa Rica, where (as in the rest of the Americas) dengue shock syndrome is seen in children and adults, intravenous fluid replacement is primarily guided by the non-invasive monitoring of mean arterial pressure, a rapid and direct marker of severity.47 We must nevertheless recognise that it is not easy to detect severe dengue using few, simple criteria, as has been shown by the evaluation of an algorithm for integrated management of childhood illnesses that include dengue.48 Ideally, the dengue haemorrhagic fever case definition should be useful for clinicians but simple and explicit enough to guide epidemiologists in case identification from reviews of data in hospital records. Plasma leakage is an indicator of risk, both for the individual and for the community. When it occurs in a person, prompt attention is necessary to prevent shock. When it occurs in a community, more cases of severe disease and fatalities are likely. For public-health surveillance, the WHO definition has great value, if resources allow the collection of all the necessary data. Unfortunately the data are frequently not collected in the hospital, by choice or lack of resources.
    By contrast, too simple a case definition would be inadequate for carrying out a vaccine trial. To demonstrate that a vaccine produces a significant reduction of a rare disease requires a large population of vaccinated and unvaccinated participants, but for a common disease, a small population will suffice. The selection of dengue haemorrhagic fever as the primary endpoint in a vaccine trial imposes much inefficiency. If we accept the largest risk estimate for dengue haemorrhagic fever among children with secondary infection (12?5%, 95% CI 5?24%),26 then even if the vaccine protects against every infection with dengue, the tally of successes (prevented dengue haemorrhagic fever) will only count, at most, 12?5% of the cases of vaccine-induced protection. Indeed, a study in Nicaragua49 found that the dengue haemorrhagic fever/dengue shock syndrome definition captured only 18% of adult dengue cases with one or more of the following severe disease manifestations: shock, plasma leakage, marked thrombocytopenia, or internal haemorrhage. The inclusion of additional endpoints for vaccine testing is therefore desirable for both study efficiency and patient benefit.
    A vaccine that prevents not only dengue haemorrhagic fever but dengue fever would lift a major burden of illness from travellers, the military, and countries where dengue is highly endemic. Unfortunately, the current reporting definition of dengue fever is highly insensitive and non-specific, and useless as a trial endpoint.50,51 It is therefore imperative that we define additional primary endpoints for severe dengue in children and adults, including standard definitions for severe dengue fever and the unusual manifestations in a way that allows consistency in international comparisons and clinical trials. It may be possible to define categories of certainty according to local resources?eg, a laboratory-positive case that fulfills the criteria of the WHO definition for dengue haemorrhagic fever (most certain); a laboratory-positive case with shock or fatal issue; a laboratory-positive case of dengue with hypotension or any other severe manifestation; a case that fulfills the criteria of the WHO definition for dengue haemorrhagic fever but has no laboratory diagnosis; and a case of severe dengue fever with no laboratory diagnosis (least certain).
    The adoption of locally useful but non-standardised case definitions for dengue haemorrhagic fever must be prevented. Minor variations in the application of the dengue haemorrhagic fever definition criteria could result in marked discrepancies in surveillance reports from place to place. For example, the use of a modification that considered either one haematocrit of 50% or over or haemoconcentration of 10% or over as criteria for plasma leakage doubled the number of dengue haemorrhagic fever cases identified (from 108 cases to 215) compared with the original WHO definition.52 To determine if the new definitions might have undesirable consequences on the quality of surveillance data, their sensitivity and specificity should be tested in a well-studied population of patients, or at least applied retrospectively to data from well-examined groups, like the cohort studied in Bangkok and Kamphaeng Phet, Thailand.12 The predictive positive value and predictive negative value should be defined in populations with different incidences of dengue haemorrhagic fever. The lessons from AIDS surveillance should not be forgotten?the adoption of expanded criteria for AIDS was preceded by a broad deliberative process and the publication of statistical projections, so that the result of the new definition?an increase by more than 100% in the number of cases reported in 1993 compared with 1992?could be anticipated.53
    In conclusion, although scientific research focused on dengue haemorrhagic fever and its determinants of incidence has been very productive, dengue researchers must consider that the measurement instrument (case definition) is affecting our estimation of dengue severity, and that additional clinical endpoints besides dengue haemorrhagic fever need to be defined. For an accurate estimation of dengue burden, locally appropriate definitions of severe dengue must be devised and standardised so they will be considered valid in the global dengue research community.

    Conflicts of interest
    I declare that I have no conflicts of interest.


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    <!--end simple-tail-->Affiliations

    a. Dengue Branch, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, San Juan, PR, USA

    Correspondence to: Dr Jos? G Rigau-P?rez, Dengue Branch, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1324 Calle Ca?ada, San Juan, PR 00920 3860, USA. Tel +1 787 706 2399; fax +1 787 706 2496

  • #2
    Re: Severe dengue: the need for new case definitions

    Comment


    • #3
      Table 1


      Table 1. Comparison of 1998 dengue incidence reports in selected countries in southeast Asia and Latin America

      ..=not reported.

      <!--start ce:table-footnote=-->
      *<!--start ce:note-para=-->Rates calculated using WHO country information (http://www.who.int/countries), except for Puerto Rico.<!--end ce:note-para--><!--end ce:table-footnote-->
      <!--start ce:table-footnote=-->
      ?<!--start ce:note-para=-->Estimated from <!--start ce:cross-ref=-->reference 5<!--end ce:cross-ref-->, assuming a mean 50% positivity rate for all cases with samples submitted to the national surveillance programme.

      Comment


      • #4
        Table 2


        Table 2. Sensitivity and specificity of the WHO case definition for dengue haemorrhagic fever among laboratory-positive dengue cases<!--start ce:cross-ref=--><!--start ce:sup=-->12<!--end ce:sup--><!--end ce:cross-ref-->

        DHF=dengue haemorrhagic fever. Sensitivity = (23 ? 100)/28 = 82% (95% CI 65?93%). Specificity = (30 ? 100)/32 = 94% (95% CI 81?99%)

        Comment

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