The decline of dengue in the Americas in 2017: discussion of multiple hypotheses.

OBJECTIVE: Since the 1980s, dengue incidence has increased 30-fold. However, in 2017, there was a noticeable reduction in reported dengue incidence cases within the Americas, including severe and fatal cases. Understanding the mechanism underlying dengue's incidence and decline in the Americas is vital for public health planning. We aimed to provide plausible explanations for the decline in 2017. METHODS: An expert panel of representatives from scientific and academic institutions, Ministry of Health officials from Latin America and PAHO/WHO staff met in October 2017 to propose hypotheses. The meeting employed six moderated plenary discussions in which participants reviewed epidemiological evidence, suggested explanatory hypotheses, offered their expert opinions on each and developed a consensus. RESULTS: The expert group established that in 2017, there was a generalised decreased incidence, severity and number of deaths due to dengue in the Americas, accompanied by a reduction in reported cases of both Zika and chikungunya virus infections, with no change in distribution among age groups affected. This decline was determined to be unlikely due to changes in epidemiological surveillance systems, as similar designs of surveillance systems exist across the region. Although sudden surveillance disruption is possible at a country or regional level, it is unlikely to occur in all countries simultaneously. Retrospective modelling with epidemiological, immunological and entomological information is needed. Host or immunological factors may have influenced the decline in dengue cases at the population level through immunity; however, herd protection requires additional evidence. Uncertainty remains regarding the effect on the outcome of sequential infections of different dengue virus (DENV) types and Zika virus (ZIKV), and vice versa. Future studies were recommended that examine the epidemiological effect of prior DENV infection on Zika incidence and severity, the epidemiological effect of prior Zika virus infection on dengue incidence and severity, immune correlates based on new-generation ELISA assays, and impact of prior DENV/other arbovirus infection on ZIKV immune response in relation to number of infections and the duration of antibodies in relation to interval of protection. Follow-up studies should also investigate whether increased vector control intensification activities contributed to the decline in transmission of one or more of these arboviruses. Additionally, proposed studies should focus on the potential role of vector competence when simultaneously exposed to various arboviruses, and on entomological surveillance and its impact on circulating vector species, with a goal of applying specific measures that mitigate seasonal occurrence or outbreaks. CONCLUSIONS: Multifactorial events may have accounted for the decline in dengue seen in 2017. Differing elements might explain the reduction in dengue including elements of immunity, increased vector control, and even vector and\or viruses changes or adaptations. Most of the results of this expert consensus group meeting are hypothetical and based on limited evidence. Further studies are needed.

OBJECTIF: Depuis les années 1980, l'incidence de la dengue a été multipliée par 30. Cependant, en 2017, il y a eu une réduction notable du nombre de cas d'incidence de dengue rapportés dans les Amériques. Nous voulions fournir des explications plausibles à la baisse en 2017. MÉTHODES: Un groupe d'experts constitué de représentants d'institutions scientifiques et académiques, d'officiels des Ministères de la Santé d'Amérique Latine et de membres du personnel de l'OPS/OMS s'est réuni en octobre 2017 pour proposer et évaluer des hypothèses. RÉSULTATS: En 2017, il y a eu une baisse généralisée de l'incidence, de la sévérité et du nombre de décès dus à la dengue dans les Amériques, accompagnée d'une réduction des cas rapportés d'infections par le virus Zika et par le virus du chikungunya, sans modification dans la répartition entre les groupes d'âge affectés. Il a été déterminé que ce déclin était peu probablement dû aux changements dans les systèmes de surveillance épidémiologique, étant donné que des systèmes de surveillance similaires existaient dans toute la région. Bien que des perturbations soudaines dans la surveillance soient possibles au niveau national ou régional, il est peu probable que cela se produise simultanément dans tous les pays. Une modélisation rétrospective avec des informations épidémiologiques, immunologiques et entomologiques est nécessaire. Des facteurs liés à l'hôte ou immunologiques peuvent avoir influencé le déclin des cas de dengue au niveau de la population par le biais de l'immunité; cependant, l'évidence d'une protection conférée par l'effet du troupeau nécessite des données supplémentaires. Une incertitude subsiste quant à l'effet sur le résultat des infections séquentielles de différents types du virus de la dengue (DENV) et du virus Zika (ZIKV), et vice-versa. Les études à venir devraient examiner (1) l'effet épidémiologique d'une infection antérieure par le DENV sur l'incidence et la sévérité du virus Zika, (2) l'effet épidémiologique d'une infection antérieure par le virus Zika sur l'incidence et la sévérité de la dengue, (3) les corrélats immunitaires basés sur des tests ELISA de nouvelle génération, (4) l' impact d'une infection antérieure à DENV/autres arbovirus sur la réponse immunitaire au ZIKV en fonction du nombre d'infections et de la durée des anticorps en fonction de l'intervalle de protection, (5) si des activités d'intensification de la lutte antivectorielle ont contribué à la diminution de la transmission d'un ou plusieurs de ces arbovirus, (6) le rôle potentiel de la compétence vectorielle lorsqu'ils sont exposés simultanément à différents arbovirus, (7) la surveillance entomologique et son impact sur la circulation d'espèces de vecteurs, dans le but d'appliquer des mesures spécifiques qui réduisent l'occurrence saisonnière d'épidémies. CONCLUSIONS: Des événements multifactoriels pourraient expliquer le déclin observé de la dengue en 2017. La plupart des résultats de cette réunion du groupe de consensus d'experts sont hypothétiques, reposent sur des données limitées et requièrent des investigations supplémentaires.

Improved tools and strategies for the prevention and control of arboviral diseases: A research-to-policy forum.

BACKGROUND: Research has been conducted on interventions to control dengue transmission and respond to outbreaks. A summary of the available evidence will help inform disease control policy decisions and research directions, both for dengue and, more broadly, for all Aedes-borne arboviral diseases. METHOD: A research-to-policy forum was convened by TDR, the Special Programme for Research and Training in Tropical Diseases, with researchers and representatives from ministries of health, in order to review research findings and discuss their implications for policy and research. RESULTS: The participants reviewed findings of research supported by TDR and others. Surveillance and early outbreak warning. Systematic reviews and country studies identify the critical characteristics that an alert system should have to document trends reliably and trigger timely responses (i.e., early enough to prevent the epidemic spread of the virus) to dengue outbreaks. A range of variables that, according to the literature, either indicate risk of forthcoming dengue transmission or predict dengue outbreaks were tested and some of them could be successfully applied in an Early Warning and Response System (EWARS). Entomological surveillance and vector management. A summary of the published literature shows that controlling Aedes vectors requires complex interventions and points to the need for more rigorous, standardised study designs, with disease reduction as the primary outcome to be measured. House screening and targeted vector interventions are promising vector management approaches. Sampling vector populations, both for surveillance purposes and evaluation of control activities, is usually conducted in an unsystematic way, limiting the potentials of entomological surveillance for outbreak prediction. Combining outbreak alert and improved approaches of vector management will help to overcome the present uncertainties about major risk groups or areas where outbreak response should be initiated and where resources for vector management should be allocated during the interepidemic period. CONCLUSIONS: The Forum concluded that the evidence collected can inform policy decisions, but also that important research gaps have yet to be filled.

Adverse Drug Reactions to Antiretroviral Therapy in HIV-Infected Patients at the Largest Public Hospital in Nicaragua.

OBJECTIVE: Adverse drug reactions (ADRs) to antiretroviral therapy (ART) are an important cause of hospitalization, treatment discontinuation, and regimen changes in both developed and developing countries. This study is the first to examine and understand ADRs in HIV-infected patients in Nicaragua. METHODS: A retrospective descriptive study was conducted from May 2010 to March 2011, in a cohort of HIV-infected patients receiving ART at the largest public hospital in Managua, Nicaragua. Patients were identified based on ADRs reporting on a standardized antiretroviral pharmacotherapy form. Subsequently, chart reviews of these patients were performed in order to document the specific ADRs. RESULTS: Six hundred ninety-two patients on ART were included. The incidence of ADRs was 6.4% (95% confidence interval [CI] 4.5-8.2). Females demonstrated a higher incidence, that is, 10.2% (95% CI 5.3-15.1, P = .020). Patients treated with combinations of zidovudine (ZDV)/lamivudine (3TC) and emtricitabine (FTC)/tenofovir (TDF) had fewer ADRs (P < .01) than those using other combinations. Five patients were hospitalized or had a prolonged hospitalization secondary to ADRs, with no mortality attributed to ADR. The most common manifestations of ADRs were central nervous system (20 of 44), gastrointestinal (12 of 44), and dermatologic (8 of 44) reactions. Adverse drug reactions were classified as "likely ADRs" (25 of 44) and "possible ADRs" (19 of 44). No ADRs were preventable. CONCLUSION: Adverse drug reactions most frequently affected the central nervous system. No ADR was life threatening. The frequency of ADRs in this Nicaraguan patient population was less than that reported from other studies in resource-limited settings.

Symptomatic versus inapparent outcome in repeat dengue virus infections is influenced by the time interval between infections and study year.

Four dengue virus serotypes (DENV1-4) circulate globally, causing more human illness than any other arthropod-borne virus. Dengue can present as a range of clinical manifestations from undifferentiated fever to Dengue Fever to severe, life-threatening syndromes. However, most DENV infections are inapparent. Yet, little is known about determinants of inapparent versus symptomatic DENV infection outcome. Here, we analyzed over 2,000 DENV infections from 2004 to 2011 in a prospective pediatric cohort study in Managua, Nicaragua. Symptomatic cases were captured at the study health center, and paired healthy annual samples were examined on a yearly basis using serological methods to identify inapparent DENV infections. Overall, inapparent and symptomatic DENV infections were equally distributed by sex. The mean age of infection was 1.2 years higher for symptomatic DENV infections as compared to inapparent infections. Although inapparent versus symptomatic outcome did not differ by infection number (first, second or third/post-second DENV infections), substantial variation in the proportion of symptomatic DENV infections among all DENV infections was observed across study years. In participants with repeat DENV infections, the time interval between a first inapparent DENV infection and a second inapparent infection was significantly shorter than the interval between a first inapparent and a second symptomatic infection. This difference was not observed in subsequent infections. This result was confirmed using two different serological techniques that measure total anti-DENV antibodies and serotype-specific neutralizing antibodies, respectively. Taken together, these findings show that, in this study, age, study year and time interval between consecutive DENV infections influence inapparent versus symptomatic infection outcome, while sex and infection number had no significant effect. Moreover, these results suggest that the window of cross-protection induced by a first infection with DENV against a second symptomatic infection is approximately 2 years. These findings are important for modeling dengue epidemics and development of vaccines.

Evaluation of the diagnostic utility of the traditional and revised WHO dengue case definitions.

Dengue, a mosquito-borne viral illness, is a major public health problem worldwide, and its incidence continues to increase. In 2009, the World Health Organization published guidelines that included a revision of the dengue case definition. Compared to the traditional definition, the revised case definition relies more on signs than on symptoms, making it more applicable to young children. We evaluated the diagnostic utility of both case definitions in two studies of pediatric dengue in Managua, Nicaragua. In a community-based cohort study, we included data from 3,407 suspected dengue cases, of which 476 were laboratory-confirmed. In the second study, we collected information from 1,160 participants recruited at the national pediatric reference hospital (723 laboratory-confirmed). In the cohort study, the traditional definition had 89.3% sensitivity and 43.1% specificity, while the revised definition yielded similar sensitivity (86.6%) and higher specificity (55.2%, p<0.001). In the hospital study, the traditional case definition yielded 96.7% sensitivity and 22.0% specificity, whereas the revised case definition had higher sensitivity (99.3%, p<0.001) but lower specificity (8.5%, p<0.001). We then evaluated the performance of two diagnostic models based on the signs/symptoms included in each definition by analyzing the effect of increasing numbers of signs/symptoms on the sensitivity and specificity of case capture. Receiver operating characteristic analysis showed a slightly better performance for the revised model in both studies. Interestingly, despite containing less symptoms that cannot be readily expressed by children aged less than 4 years, the revised definition did not perform better in this age group. Overall, our results indicate that both case definitions have similar capacity to diagnose dengue. Owing to their high sensitivity and low specificity, they should be primarily used for screening purposes. However, in a primary care setting, neither of the case definitions performed well as a screening test in younger children.

Evaluation of the traditional and revised WHO classifications of Dengue disease severity.

Dengue is a major public health problem worldwide and continues to increase in incidence. Dengue virus (DENV) infection leads to a range of outcomes, including subclinical infection, undifferentiated febrile illness, Dengue Fever (DF), life-threatening syndromes with fluid loss and hypotensive shock, or other severe manifestations such as bleeding and organ failure. The long-standing World Health Organization (WHO) dengue classification and management scheme was recently revised, replacing DF, Dengue Hemorrhagic Fever (DHF), and Dengue Shock Syndrome (DSS) with Dengue without Warning Signs, Dengue with Warning Signs (abdominal pain, persistent vomiting, fluid accumulation, mucosal bleeding, lethargy, liver enlargement, increasing hematocrit with decreasing platelets) and Severe Dengue (SD; dengue with severe plasma leakage, severe bleeding, or organ failure). We evaluated the traditional and revised classification schemes against clinical intervention levels to determine how each captures disease severity using data from five years (2005-2010) of a hospital-based study of pediatric dengue in Managua, Nicaragua. Laboratory-confirmed dengue cases (n = 544) were categorized using both classification schemes and by level of care (I-III). Category I was out-patient care, Category II was in-patient care that did not meet criteria for Category III, which included ICU admission, ventilation, administration of inotropic drugs, or organ failure. Sensitivity and specificity to capture Category III care for DHF/DSS were 39.0% and 75.5%, respectively; sensitivity and specificity for SD were 92.1% and 78.5%, respectively. In this data set, DENV-2 was found to be significantly associated with DHF/DSS; however, this association was not observed with the revised classification. Among dengue-confirmed cases, the revised WHO classification for severe dengue appears to have higher sensitivity and specificity to identify cases in need of heightened care, although it is no longer as specific for a particular pathogenic entity as was the traditional schema.

Unusual dengue virus 3 epidemic in Nicaragua, 2009.

The four dengue virus serotypes (DENV1-4) cause the most prevalent mosquito-borne viral disease affecting humans worldwide. In 2009, Nicaragua experienced the largest dengue epidemic in over a decade, marked by unusual clinical presentation, as observed in two prospective studies of pediatric dengue in Managua. From August 2009-January 2010, 212 dengue cases were confirmed among 396 study participants at the National Pediatric Reference Hospital. In our parallel community-based cohort study, 170 dengue cases were recorded in 2009-10, compared to 13-65 cases in 2004-9. In both studies, significantly more patients experienced "compensated shock" (poor capillary refill plus cold extremities, tachycardia, tachypnea, and/or weak pulse) in 2009-10 than in previous years (42.5% [90/212] vs. 24.7% [82/332] in the hospital study (p<0.001) and 17% [29/170] vs. 2.2% [4/181] in the cohort study (p<0.001). Signs of poor peripheral perfusion presented significantly earlier (1-2 days) in 2009-10 than in previous years according to Kaplan-Meier survival analysis. In the hospital study, 19.8% of subjects were transferred to intensive care, compared to 7.1% in previous years - similar to the cohort study. DENV-3 predominated in 2008-9, 2009-10, and 2010-11, and full-length sequencing revealed no major genetic changes from 2008-9 to 2010-11. In 2008-9 and 2010-11, typical dengue was observed; only in 2009-10 was unusual presentation noted. Multivariate analysis revealed only "2009-10" as a significant risk factor for Dengue Fever with Compensated Shock. Interestingly, circulation of pandemic influenza A-H1N1 2009 in Managua was shifted such that it overlapped with the dengue epidemic. We hypothesize that prior influenza A H1N1 2009 infection may have modulated subsequent DENV infection, and initial results of an ongoing study suggest increased risk of shock among children with anti-H1N1-2009 antibodies. This study demonstrates that parameters other than serotype, viral genomic sequence, immune status, and sequence of serotypes can play a role in modulating dengue disease outcome.

Severe coinfections of dengue and pandemic influenza A H1N1 viruses.

Here we report on 4 hospitalized patients with dengue-influenza virus coinfections. All patients were RT-PCR positive for dengue virus and pandemic influenza A H1N1. Clinical findings at presentation ranged from influenza-like illness to severe dengue. Clinical progression of the infections varied, but all developed dengue symptoms and had interstitial infiltrates. Three cases required intensive care management and 1 case was fatal.