Olaf Horstick

Towards a global dengue research agenda.

Dengue is the most rapidly advancing vector-borne disease with an estimated 50 million dengue infections occurring annually. As a result of major demographic changes rapid urbanization on a massive scale global travel and environmental change the world - particularly the tropical world - faces enormous challenges from emerging infectious diseases. Dengue epitomizes these challenges. In the early years of the 21st century we are collectively failing to meet the threat posed by dengue as the disease spreads unabated and almost 40% of the worlds population now live at risk of contracting it. Because of the rapidly increasing public health importance of dengue the 2002 World Health Assembly Resolution (WHA55.17) urged greater commitment among Member States and WHO to dengue control; of particular significance is the 2005 Revision of the International Health Regulations (WHA58.3) which includes dengue fever as an example of a disease that may constitute an international public health emergency. (excerpt)

What does dengue disease surveillance contribute to predicting and detecting outbreaks and describing trends

Objective  To review the evidence on the application of tools for dengue outbreak prediction/detection and trend monitoring in passive and active disease surveillance systems in order to develop recommendations for endemic countries and identify research needs.

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.

Bacillus thuringiensis israelensis (Bti) for the control of dengue vectors: systematic literature review.

To systematically review the literature on the effectiveness of Bacillus thuringiensis israelensis (Bti), when used as a single agent in the field, for the control of dengue vectors.

The potential for malaria control with the biological larvicide Bacillus thuringiensis israelensis (Bti) in Peru and Ecuador

A study on the efficacy of Bti spraying in mosquito breeding places was undertaken in the Pacific coast of Peru and Ecuador and in the Amazon area of Peru. It was shown that Bti is a powerful larvicide for Anopheles larvae, although it sinks quickly, whereas Anopheles larvae feed at the water surface. The duration of its effect was less than 7 days with the exception of the Amazon area of Peru, where it was approximately 10 days. In two study areas, Bti was sprayed weekly over periods of 10 and 7 weeks, respectively, and the adult mosquito densities were monitored. The Anopheles adult density (bites per person per hour on human baits) was reduced by an average of 70% in one area and by up to 50% in the other. This means that Bti spraying can potentially be an important component of a modified malaria control strategy.

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 disease surveillance: an updated systematic literature review

To review the evidence for the application of tools for dengue outbreak prediction/detection and trend monitoring in passive and active disease surveillance systems in order to develop recommendations for endemic countries and identify important research needs.

Reviewing Dengue: Still a Neglected Tropical Disease?

Dengue is currently listed as a “neglected tropical disease” (NTD). But is dengue still an NTD or not? Classifying dengue as an NTD may carry advantages, but is it justified? This review considers the criteria for the definition of an NTD, the current diverse lists of NTDs by different stakeholders, and the commonalities and differences of dengue with other NTDs. We also review the current research gaps and research activities and the adequacy of funding for dengue research and development (R&D) (2003–2013). NTD definitions have been developed to a higher precision since the early 2000s, with the following main features: NTDs are characterised as a) poverty related, b) endemic to the tropics and subtropics, c) lacking public health attention, d) having poor research funding and shortcomings in R&D, e) usually associated with high morbidity but low mortality, and f) often having no specific treatment available. Dengue meets most of these criteria, but not all. Although dengue predominantly affects resource-limited countries, it does not necessarily only target the poor and marginalised in those countries. Dengue increasingly attracts public health attention, and in some affected countries it is now a high profile disease. Research funding for dengue has increased exponentially in the past two decades, in particular in the area of dengue vaccine development. However, despite advances in dengue research, dengue epidemics are increasing in frequency and magnitude, and dengue is expanding to new areas. Specific treatment and a highly effective vaccine remain elusive. Major research gaps exist in the area of integrated surveillance and vector control. Hence, although dengue differs from many of the NTDs, it still meets important criteria commonly used for NTDs. The current need for increased R&D spending, shared by dengue and other NTDs, is perhaps the key reason why dengue should continue to be considered an NTD.

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.