Eric Martinez

Dengue: a continuing global threat

Dengue fever and dengue haemorrhagic fever are important arthropod-borne viral diseases. Each year, there are ∼50 million dengue infections and ∼500,000 individuals are hospitalized with dengue haemorrhagic fever, mainly in Southeast Asia, the Pacific and the Americas. Illness is produced by any of the four dengue virus serotypes. A global strategy aimed at increasing the capacity for surveillance and outbreak response, changing behaviours and reducing the disease burden using integrated vector management in conjunction with early and accurate diagnosis has been advocated. Antiviral drugs and vaccines that are currently under development could also make an important contribution to dengue control in the future.

Multicentre prospective study on dengue classification in four South-east Asian and three Latin American countries

Objective  To evaluate the existing WHO dengue classification across all age groups and a wide geographical range and to develop a revised evidence‐based classification that would better reflect clinical severity.

Multi-country evaluation of the sensitivity and specificity of two commercially-available NS1 ELISA assays for dengue diagnosis.

Background Early diagnosis of dengue can assist patient triage and management and prevent unnecessary treatments and interventions. Commercially available assays that detect the dengue virus protein NS1 in the plasma/serum of patients offers the possibility of early and rapid diagnosis. Methodology/Principal Findings The sensitivity and specificity of the Pan-E Dengue Early ELISA and the Platelia™ Dengue NS1 Ag assays were compared against a reference diagnosis in 1385 patients in 6 countries in Asia and the Americas. Platelia was more sensitive (66%) than Pan-E (52%) in confirmed dengue cases. Sensitivity varied by geographic region, with both assays generally being more sensitive in patients from SE Asia than the Americas. Both kits were more sensitive for specimens collected within the first few days of illness onset relative to later time points. Pan-E and Platelia were both 100% specific in febrile patients without evidence of acute dengue. In patients with other confirmed diagnoses and healthy blood donors, Platelia was more specific (100%) than Pan-E (90%). For Platelia, when either the NS1 test or the IgM test on the acute sample was positive, the sensitivity versus the reference result was 82% in samples collected in the first four days of fever. NS1 sensitivity was not associated to disease severity (DF or DHF) in the Platelia test, whereas a trend for higher sensitivity in DHF cases was seen in the Pan-E test (however combined with lower overall sensitivity). Conclusions/Significance Collectively, this multi-country study suggests that the best performing NS1 assay (Platelia) had moderate sensitivity (median 64%, range 34–76%) and high specificity (100%) for the diagnosis of dengue. The poor sensitivity of the evaluated assays in some geographical regions suggests further assessments are needed. The combination of NS1 and IgM detection in samples collected in the first few days of fever increased the overall dengue diagnostic sensitivity.

Comparing the Usefulness of the 1997 and 2009 WHO Dengue Case Classification: A Systematic Literature Review

The 1997 and 2009 WHO dengue case classifications were compared in a systematic review with 12 eligible studies (4 prospective). Ten expert opinion articles were used for discussion. For the 2009 WHO classification studies show: when determining severe dengue sensitivity ranges between 59–98% (88%/98%: prospective studies), specificity between 41–99% (99%: prospective study) - comparing the 1997 WHO classification: sensitivity 24.8–89.9% (24.8%/74%: prospective studies), specificity: 25%/100% (100%: prospective study). The application of the 2009 WHO classification is easy, however for (non-severe) dengue there may be a risk of monitoring increased case numbers. Warning signs validation studies are needed. For epidemiological/pathogenesis research use of the 2009 WHO classification, opinion papers show that ease of application, increased sensitivity (severe dengue) and international comparability are advantageous; 3 severe dengue criteria (severe plasma leakage, severe bleeding, severe organ manifestation) are useful research endpoints. The 2009 WHO classification has clear advantages for clinical use, use in epidemiology is promising and research use may at least not be a disadvantage.

Reviewing the development, evidence base, and application of the revised dengue case classification

Abstract With the example of dengue, an evidence-based approach to prospectively develop a case classification is described, gathering evidence for identifying strength and weaknesses of the existing model, collecting new data describing the disease as it occurs globally, further developing a new model that can be applied in practice and field testing the newly developed model in comparison to the previous model. For each step in this process, the highest available level of evidence has been applied. This process has been initiated by the World Health Organization’s (WHO) Special Programme for Research and Training in Tropical Diseases (TDR) and WHO’s Department for Control of Neglected Tropical Diseases (NTD), developing the following for dengue. Since the early 1970s, dengue has been classified into dengue fever, dengue haemorrhagic fever grades I and II and dengue shock syndrome grades III and IV (DF/DHF/DSS). However, in recent years, a growing number of dengue clinicians have questioned the shortcomings of this scheme. The issues have revolved around the complexity of confirming DHF in clinical practice, misclassifying severe cases as DF, and the emphasis on haemorrhage rather than plasma leakage as the underlying problem in most severe dengue cases. Step 1: A systematic literature review highlighted the shortcomings of the DF/DHF/DSS scheme: (1) difficulties in applying the criteria for DHF/DSS; (2) the tourniquet test has a low sensitivity for distinguishing between DHF and DF; and (3) most DHF criteria had a large variability in frequency of occurrence. Step 2: An analysis of regional and national dengue guidelines and their application in the clinical practice showed a need to re-evaluate and standardize guidelines as the actual ones showed a large variation of definitions, an inconsistent application by medical staff, and a lack of diagnostic facilities necessary for the DHF diagnosis in frontline services. Step 3: A prospective cohort study in seven countries, confirmed the difficulties in applying the DF/DHF/DSS criteria even in tertiary care hospitals, that DF/DHF/DSS do not represent levels of disease severity and that a clear distinction between severe dengue (defined by plasma leakage and/or severe haemorrhage, and/or organ failure) and (non-severe) dengue can be made using highly sensitive and specific criteria. In contrast, the sub-grouping of (non-severe) dengue into two further severity levels was only possible with criteria that gave approximately 70% sensitivity and specificity. Step 4: Three regional expert consensus groups in the Americas and Asia concluded that ‘dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome’ and that, revising the results of Step 3, DF/DHF/DSS is not related to disease severity. Step 5: In a global expert consensus meeting at WHO in Geneva/Switzerland the evidence collected in Steps 1–4 was reviewed and a revised scheme was developed and accepted, distinguishing: dengue with or without warning signs and severe dengue; the further field testing and acquisition of further prospective evidence of the revised scheme was recommended. Step 6: In 18 countries, the usefulness and applicability of the revised classification compared to the DF/DHF/DSS scheme were tested showing clear results in favour of the revised classification. Step 7: Studies are under way on the predictive value of warning signs for severe dengue and on criteria for the clinical diagnosis of dengue which will complete the evidence foundation of the revised classification. The analysis has shown that the revised dengue case classification is better able to standardize clinical management, raise awareness about unnecessary interventions, match patient categories with specific treatment instructions, and make the key messages of patient management understandable for all health care staff dealing with dengue patients. Furthermore, the evidence-based approach to develop prospectively the dengue case classification could be a model approach for other disease classifications.

Dengue in Nicaragua, 1994: reintroduction of serotype 3 in the Americas

The principal aim of this work was to report the reintroduction of dengue virus serotype 3 in the Americas after an absence of 17 years. In addition, it describes the most common symptoms associated with classical dengue and hemorrhagic dengue and presents data on the distribution of the epidemic in the various comprehensive local health care systems of Nicaragua. The study group consisted of 39 patients hospitalized in Managua and León for dengue with hemorrhagic manifestations and hemorrhagic dengue. Of these patients, 34 were classified as probable or confirmed cases of dengue. The most frequent symptoms were fever, headache, vomiting, and muscle and joint pains. The tourniquet test was positive and thrombocytopenia was confirmed in 56% and 44% of the patients, respectively. Epistaxis (67%) was the most common hemorrhagic sign. Of the 356 serum samples received through the dengue surveillance systems in October 1994, IgM antibodies were detected in 43%. The virus was isolated from 5 of 24 samples tested (serotype 3 from 3 and serotype 1 from 2). The reintroduction of serotype 3 of dengue into the Region was demonstrated, along with its ability to produce epidemics of hemorrhagic dengue. The countries are warned that if they do not quickly take the measures described in the guidelines for the prevention and control of dengue and dengue hemorrhagic fever, new epidemics may occur in the Americas, given the large number of persons susceptible to this serotype and the high density of the mosquito vector in most of the countries of the Region.

Relevance of Non-communicable Comorbidities for the Development of the Severe Forms of Dengue: A Systematic Literature Review

Patients with dengue fever and comorbidities seem to be at higher risk of developing complications and/or severe dengue compared to healthier individuals. This study systematically reviews the evidence related to comorbidities and dengue. A systematic literature review was performed in five databases (EMBASE, PUBMED, Global Health, SciELO, Cochrane) and grey literature for full-text articles since its inceptions until October 10, 2015. A total of 230 articles were retrieved. Sixteen studies were analysed after applying all inclusion and exclusion criteria. Seven case control studies and nine retrospective cohort studies showed that comorbidities may contribute to severe dengue, especially 1) cardiovascular disease, 2) stroke, 3) diabetes, 4) respiratory disease and 5) renal disease, as well as old age. However, due to heterogeneity in studies, the real estimate effect of comorbidities as modifiers of dengue severity could not be established. Further research in regions with high prevalence of dengue infection would contribute to a better understanding of the relevance of comorbidities in severe dengue, especially with a standardised protocol, for outcomes, specific comorbidities, study design—best using prospective designs—and sample sizes.

Dogma in Classifying Dengue Disease

In his recent perspective entitled Dengue: the Syndromic Basis to Pathogenesis Research, Inutility of the 2009 WHO Case Definition, Halstead expresses concern that adoption of the 2009 World Health Organization (WHO) classification scheme will compromise the “analytic clarity needed to understand mechanisms underlying dengue pathophysiology, pathogenesis, treatment, and therapeutics.”1 Leaving aside the important issue of how best to resolve the long running and convoluted debate on dengue case definitions and classification, two important misconceptions need to be addressed.

Comparison and critical appraisal of dengue clinical guidelines and their use in Asia and Latin America.

The World Health Organization (WHO) dengue classification scheme for dengue fever (DF) and dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS) has been adopted as the standard for diagnosis, clinical management and reporting. In recent years, difficulties in applying the WHO case classification have been reported in several countries. A multicenter study was carried out in Asia and Latin America to analyze the variation and utility of dengue clinical guidelines (DCGs) taking as reference the WHO/PAHO guidelines (1994) and the WHO/SEARO guidelines (1998). A document analysis of 13 dengue guidelines was followed by a questionnaire and Focus Group discussions (FGDs) with 858 health care providers in seven countries. Differences in DCGs of the 13 countries were identified including the concept of warning signs, case classification, use of treatment algorithms and grading into levels of severity. The questionnaires and FGDs revealed (1) inaccessibility of DCGs, (2) lack of training, (3) insufficient number of staff to correctly apply the DCGs at the frontline and (4) the unavailability of diagnostic tests. The differences of the DCGs and the inconsistency in their application suggest a need to re-evaluate and standardise DCGs. This applies especially to case classification and case management.

WHO Dengue Case Classification 2009 and its usefulness in practice: an expert consensus in the Americas

Abstract Introduction: In 2009, the new World Health Organization (WHO) dengue case classification – dengue/severe dengue (D/SD) – was introduced, replacing the 1997 WHO dengue case classification: dengue fever/dengue haemorrhagic fever/dengue shock syndrome (DF/DHF/DSS). Methods: A 2-day expert consensus meeting in La Habana/Cuba aimed to (1) share the experiences from Pan American Health Organization (PAHO) member states when applying D/SD, (2) present national and local data using D/SD, and (3) agree with the presented evidence on a list of recommendations for or against the use of D/SD for PAHO, and also globally. Results: Eight key questions were discussed, concluding: (1) D/SD is useful describing disease progression because it considers the dynamic nature of the disease, (2) D/SD helps defining dengue cases correctly for clinical studies, because it defines more precisely disease severity and allows evaluating dynamically the progression of cases, (3) D/SD describes correctly all clinical forms of severe dengue. Further standards need to be developed regionally, especially related to severe organ involvement, (4) D/SD allows for pathophysiological research identifying – in a sequential manner – the clinical manifestations of dengue related to pathophysiological events, (5) the warning signs help identifying early cases at risk of shock (children and adults), pathophysiology of the warning signs deserves further studies, (6) D/SD helps treating individual dengue cases and also the reorganization of health-care services for outbreak management, (7) D/SD helps diagnosing dengue, in presumptive diagnosis and follow-up of the disease, because of its high sensitivity and high negative predictive value (NPV), and (8) there is currently no update of the International Disease Classification10 (ICD10) to include the new classification of dengue (D/SD); therefore, there are not enough experiences of epidemiological reporting. Once D/SD has been implemented in epidemiological surveillance, D/SD allows to (1) identify severity of dengue cases in real time, for any decision-making on actions, (2) measure and compare morbidity and mortality in countries, and also globally, and (3) trigger contingency plans early, not only based on the number of reported cases but also on the reported severity of cases. Conclusion: The expert panel recommends to (1) update ICD10, (2) include D/SD in country epidemiological reports, and (3) implement studies improving sensitivity/specificity of the dengue case definition.