Evaluation of clinical and laboratory characteristics of dengue viral infection and risk factors of dengue hemorrhagic fever: a multi-center retrospective analysis.

BACKGROUND: Dengue Viral Infection (DVI) has become endemic in Pakistan since the first major outbreak in Karachi in 1996. Despite aggressive measures taken by relevant authorities, Pakistan has been dealing with a worsening dengue crisis for the past two decades. DHF is severe form of dengue infection which is linked with significant morbidity and mortality. Early identification of severe dengue infections can reduce the morbidity and mortality. In this context we planned current study in which we find out the different factors related with DHF as well as clinical laboratory features of DHF and compare them to DF so that patients can be best evaluated for DHF and managed accordingly at admission. METHODS: Retrospective study conducted over a period of 6 years (2013-2018) in two tertiary care hospitals in Pakistan. Data were collected by using a pre-structured data collection form. Data were statistically analyzed to determine the clinical and laboratory characteristics of DVI and risk factors of dengue hemorrhagic fever (DHF). RESULTS: A total 512 dengue cases (34.05 ± 15.08 years; Male 69.53%) were reviewed. Most common clinical manifestations of DVI were fever (99.60%), headache (89.1%), chills (86.5%), rigors (86.5%), myalgia (72.3%). Less common clinical manifestations were vomiting (52.5%), arthralgia (50.2%) and skin rashes (47.5%). Furthermore, nasal bleeding (44.1%), gum bleeding (32.6%), pleural effusion (13.9%) and hematuria (13.1%) were more profound clinical presentations among DHF patients. Mortality rate was 1.5% in this study. Logistic regression analysis indicated that delayed hospitalization (OR: 2.30) and diabetes mellitus (OR:2.71), shortness of breath (OR:2.21), association with risk groups i.e., living near stagnant water, travelling to endemic areas, living in endemic regions (OR:1.95), and presence of warning signs (OR:2.18) were identified as risk factors of DHF. Statistically we found that there is strong association of diabetes mellitus (DM) with DHF while the patient suffering from DM individually had higher odds (2.71) of developing DHF than patients without disease. CONCLUSIONS: The current study demonstrated that the clinical and laboratory profiles of DF and DHF are significantly distinct. Significant predictors of DHF were advanced age, diabetes mellitus, ascites, pleural effusion, thick gallbladder and delayed hospitalization. The identification of these factors at early stage provides opportunities for the clinicians to identify high risk patients and to reduce dengue-related morbidity and mortality.

Challenges and opportunities in controlling mosquito-borne infections.

Mosquito-borne diseases remain a major cause of morbidity and mortality across the tropical regions. Despite much progress in the control of malaria, malaria-associated morbidity remains high, whereas arboviruses-most notably dengue-are responsible for a rising burden of disease, even in middle-income countries that have almost completely eliminated malaria. Here I discuss how new interventions offer the promise of considerable future reductions in disease burden. However, I emphasize that intervention programmes need to be underpinned by rigorous trials and quantitative epidemiological analyses. Such analyses suggest that the long-term goal of elimination is more feasible for dengue than for malaria, even if malaria elimination would offer greater overall health benefit to the public.

Dengue and COVID-19, overlapping epidemics? An analysis from Colombia.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread throughout Latin America, a region swept by multiple previous and ongoing epidemics. There are significant concerns that the arrival of COVID-19 is currently overlapping with other viruses, particularly dengue, in various endo-epidemic regions across South America. In this report, we analyzed trends for both viral infections in Colombia during the first 20 epidemiological weeks (EWs) of 2020. From 1st January to 16th May 2020 (EWs, 1-20), a total of 52 679 cases of dengue and 14 943 cases of COVID-19 have been confirmed in Colombia. As both conditions may potentially lead to fatal outcomes, especially in patients with chronic co-morbidities, overlapping infections, and co-occurrence may increase the number of patients requiring intensive care and mechanical ventilation. In regions, such as Valle del Cauca, intensified preparation for such scenarios should be pondered, and further studies should be performed to address this critical issue in a timely matter.

Spatiotemporal distribution and socioeconomic disparities of dengue, chikungunya and Zika in two Latin American cities from 2007 to 2017.

OBJECTIVE: To assess the presence, pattern and magnitude of socioeconomic inequalities on dengue, chikungunya and Zika in Latin America, accounting for their spatiotemporal distribution. METHODS: Using longitudinal surveillance data (reported arboviruses) from Fortaleza, Brazil and Medellin, Colombia (2007-2017), we fit Bayesian hierarchical models with structured random effects to estimate: (i) spatiotemporally adjusted incidence rates; (ii) Relative Concentration Index and Absolute Concentration Index of inequality; (iii) temporal trends in RCIs; and (iv) socioeconomic-specific estimates of disease distribution. The spatial analysis was conducted at the neighbourhood level (urban settings). The socioeconomic measures were the median monthly household income (MMHI) for Brazil and the Socio-Economic Strata index (SES) in Colombia. RESULTS: There were 281 426 notified arboviral cases in Fortaleza and 40 887 in Medellin. We observed greater concentration of dengue among residents of low socioeconomic neighbourhoods in both cities: Relative Concentration Index = -0.12 (95% CI = -0.13, -0.10) in Fortaleza and Relative Concentration Index = -0.04 (95% CI = -0.05, -0.03) in Medellin. The magnitude of inequalities varied over time across sites and was larger during outbreaks. We identified a non-monotonic association between disease rates and socioeconomic measures, especially for chikungunya, that changed over time. The Relative Concentration Index and Absolute Concentration Index showed few if any inequalities for Zika. The socioeconomic-specific model showed increased disease rates at MMHI below US$400 in Brazil and at SES-index below level four, in Colombia. CONCLUSIONS: We provide robust quantitative estimates of socioeconomic inequalities in arboviruses for two Latin American cities. Our findings could inform policymaking by identifying spatial hotspots for arboviruses and targeting strategies to decrease disparities at the local level.

Clinical features of patients with Rocky Mountain spotted fever, dengue and chikungunya infection.

INTRODUCTION: Clinical distinction between arbovirus infections and those caused by rickettsia is crucial to initiate appropriate medical treatment. OBJECTIVE: To compare the differences between Rocky Mountain spotted fever (RMSF) and other vector-borne diseases (dengue and chikungunya) with similar clinical presentation, and to identify data that could aid rapid diagnosis of these diseases. METHODS: We evaluated sociodemographic, clinical and laboratory data of 399 patients from five hospitals and clinics of Sonora, Mexico, between 2004 and 2016, with laboratory-confirmed diagnosis of RMSF, dengue, or chikungunya. RESULTS: The RMSF group had the highest lethality (49/63 deaths, 77.8 %), followed by the chikungunya group (3/161, 1.9 %) and the dengue group (3/161, 1.9 %). Clinical differences included the presence of rash, edema, and pruritus; in addition, differences in multiple biomarkers such as platelets, hemoglobin, indirect bilirubin, and serum sodium levels were documented. CONCLUSION: Rash on the palms and soles, edema and absence of pruritus, together with high levels of direct bilirubin and severe thrombocytopenia could be useful indicators to differentiate patients at RMSF advanced stages from those with dengue and chikungunya.

INTRODUCCIÓN: La distinción clínica entre infecciones arbovirales y las provocadas por rickettsias es crucial para iniciar el tratamiento médico apropiado. OBJETIVO: Comparar las diferencias entre fiebre manchada de las montañas rocosas (FMMR) y otras enfermedades transmitidas por vector (dengue y chikungunya) con presentación clínica similar e identificar los datos que pudieran ayudar al diagnóstico rápido de esas enfermedades. MÉTODOS: Se evaluaron datos sociodemográficos, clínicos y de laboratorio de 399 pacientes de cinco hospitales y clínicas en Sonora, México, entre 2004 y 2016, con el diagnóstico confirmado por laboratorio de FMMR, dengue o chikungunya. RESULTADOS: El grupo con FMMR presentó la mayor letalidad (49/63 muertes, 77.8 %), seguido por el de chikungunya (3/161, 1.9 %) y el de dengue (3/161, 1.9 %). Las diferencias clínicas consistieron en la presencia de exantema, edema y prurito; además, se documentaron diferencias en múltiples biomarcadores como plaquetas, hemoglobina, bilirrubina indirecta y niveles de sodio sérico. CONCLUSIÓN: El exantema en palmas y plantas, edema y ausencia de prurito, aunados a niveles altos de bilirrubina directa y trombocitopenia severa pudieran ser indicadores útiles para diferenciar a pacientes con FMMR en etapas avanzadas de aquellos con dengue y chikungunya.

Travel-Associated and Locally Acquired Dengue Cases - United States, 2010-2017.

Dengue is a potentially fatal acute febrile illness caused by any of four mosquito-transmitted dengue viruses (DENV-1 to DENV-4) belonging to the family Flaviviridae and endemic throughout the tropics. Competent mosquito vectors of DENV are present in approximately one half of all U.S. counties. To describe epidemiologic trends in travel-associated and locally acquired dengue cases in the United States, CDC analyzed cases reported from the 50 states and District of Columbia to the national arboviral surveillance system (ArboNET). Cases are confirmed by detection of 1) virus RNA by reverse transcription-polymerase chain reaction (RT-PCR) in any body fluid or tissue, 2) DENV antigen in tissue by a validated assay, 3) DENV nonstructural protein 1 (NS1) antigen, or 4) immunoglobulin M (IgM) anti-DENV antibody if the patient did not report travel to an area with other circulating flaviviruses. When travel to an area with other flaviviruses was reported, IgM-positive cases were defined as probable. During 2010-2017, totals of 5,009 (93%) travel-associated and 378 (7%) locally acquired confirmed or probable dengue cases were reported to ArboNET. Cases were equally distributed between males and females, and median age was 41 years. Eighteen (three per 1,000) fatal cases were reported, all among travelers. Travelers should review country-specific recommendations (https://wwwnc.cdc.gov/travel/notices/watch/dengue-asia) for reducing their risk for DENV infection, including using insect repellent and staying in residences with air conditioning or screens on windows and doors.

Dengue viruses circulating in Indonesia: A systematic review and phylogenetic analysis of data from five decades.

Although epidemiological and molecular epidemiological (serotype, genotype, and lineage information) data are available for several major cities in Indonesia, there is yet to be a comprehensive national study of dengue in Indonesia over time. This study was conducted to provide a comprehensive epidemiology of circulating dengue viruses (DENV) in Indonesia between 1973 and 2016. This was conducted through a systematic review of the literature and phylogenetic analysis of available DENV sequences. Available data from National Disease Surveillance System have indicated an increasing trend of dengue incidence in Indonesia over the past 50 years. Incidence rates appear to be cyclic, peaking approximately every 6 to 8 years. In contrast, the case fatality rate has decreased approximately by half with each decade since 1980. Over this 50-year time span, serotype shifts, genotype displacement within DENV-1 and DENV-2, and introduction of DENV-1 and DENV-3 genotype from other countries occurred. These events were associated with increased incidence of dengue cases. Our study also provides a valuable national snapshot of DENV genetic diversity in Indonesia that may contribute to development of more effective dengue vaccine compositions for the region.

Dengue hepatitis with acute liver failure: Clinical, biochemical, histopathological characteristics and predictors of outcome.

BACKGROUND: Hepatitis infection from non-hepatotropic viruses such as dengue virus (DENV) is increasing worldwide. There is increasing recognition of the changing epidemiology and atypical presentations of DENV infection including acute liver failure (ALF). There is paucity of data regarding incidence, disease characteristics, and markers of prognosis in patients who develop DENV-related ALF. METHODS: We aimed to study the incidence, clinical features, laboratory characteristics, and determinants of outcome in patients of DENV presenting with ALF. We reviewed all patients with DENV infection and focused on DENV-related ALF from 2014 to 2017. Diagnosis of DENV and ALF was confirmed by serological tests and standard criteria, respectively. RESULTS: Thirty-six patients (20 men, mean age 32.3) developed ALF among 10 108 patients with DENV infection (0.35%). Twenty-one patients died (58.3%). Although bilirubin, aspartate and alanine aminotransferase, and international normalized ratio were markedly elevated in all patients with DENV ALF, there was no statistically significant difference between survivors and non-survivors. Lactate levels, pH at admission, and model for end-stage liver disease (MELD) score were the only predictors of mortality. Lactate levels were significantly higher in non-survivors (11.5 ± 4.2 mmol/L) than survivors (6.3 ± 3.6 mmol/L) (P < 0.001). MELD score in non-survivors (26.7 ± 10.2) was significantly higher than in survivors (20 ± 7.2) (P = 0.039). Receiver operator characteristic curve showed lactate or pH to be a superior prognostic marker than MELD with an area under the curve of 0.80, 0.79, and 0.70, respectively. CONCLUSION: Dengue hepatitis progressed to ALF in 0.35%. Development of ALF was associated with a high mortality (> 50%). Lactate level, pH, and MELD score at admission were significant determinants of outcome.

Factores clínicos y demográficos asociados con la mortalidad por dengue en Colombia: estudio de casos y controles.

Objetivo. Identificar factores demográficos y clínicos asociados con la mortalidad por dengue grave en cinco de-partamentos de Colombia. Material y métodos. Análisis secundario de un estudio de casos y controles basado en pa-cientes admitidos de 2009 a 2013. Los casos fueron pacientes que murieron por dengue y los controles fueron pacientes con dengue grave sobrevivientes a la enfermedad. Se utilizó el procedimiento de Mantel-Haenszel para identificar los factores. Resultados. Analizando 58 casos y 121 controles, cuatro factores fueron asociados con la mortalidad por den-gue: administración hospitalaria de dipirona (RMa=6.38 IC95% 2.41-16.86) y de acetaminofén (RMa=0.25 IC95% 0.10-0.61), presencia de comorbilidad (RMa=3.52 IC95% 1.51-8.18) y consulta previa por el mismo padecimiento (RMa=3.99 IC95% 1.63-9.77). Conclusiones. La administración de dipirona en pacientes con dengue grave se asoció con un aumento del riesgo de mortalidad. Si se considera que la dipirona fue retirada del mercado en 20 países por sus efectos secunda-rios, se puede desaconsejar su uso en el manejo del dengue.

30 years of fatal dengue cases in Brazil: a review.

BACKGROUND: Over the last 30 years, extensive dengue epidemics have occurred in Brazil, characterized by emergences and re-emergences of different serotypes, a change in the epidemiological profile and an increase in the number of severe and fatal cases. Here, we present a review on the dengue fatal cases that occurred in Brazil in 30 years (1986-2015). METHODS: We performed an ecological study by using secondary data on dengue fatal cases obtained in the National System of Reported Diseases (Sistema de Informação de Agravos de Notificação -SINAN) and in the Mortality Information System (SIM), both maintained by the Brazilian Ministry of Health. Cases were analyzed by region, demographic variables, clinical classification and complications based on the data available. RESULTS: In 30 years (1986-2015), the Southeast region reported 43% (n = 2225) of all dengue deaths in the country. The Midwest region was responsible for 18% of the fatal cases. After 2000, deaths occurred in almost all states, with the exception of Santa Catarina and Rio Grande do Sul, South region. From 2006 to 2010, the number of deaths increased, with higher rates of mortality, especially in Goiás and Mato Grosso. From 2011 to 2015, Goiás became the state with the highest mortality rate in the country, and Rio Grande do Sul reported its first dengue deaths. In 30 years, a total of 2682 dengue deaths occurred in males and 2455 in females, and an equal distribution between the sexes was observed. From 1986 to 2006, dengue deaths occurred predominantly in individuals over 15 years old, but this scenario changed in 2007-2008. After 2009, fatal cases on individuals above 15 years old became more frequent, with peaks in the years of 2010, 2013 and 2015. CONCLUSIONS: The Brazil is experiencing a hyperendemic scenario, which has resulted in the co-circulation of the four DENV serotypes and with the increasing occurrence of severe and fatal cases. The disease surveillance and studies characterizing what has been reported overtime, are still important tools to better understand the factors involved in the disease outcome.

REAL-WORLD EVIDENCE OF DENGUE BURDEN ON HOSPITALS IN MEXICO: INSIGHTS FROM THE AUTOMATED SUBSYSTEM OF HOSPITAL DISCHARGES (SAEH) DATABASE.

BACKGROUND: The incidence of dengue in Mexico has increased in recent decades. It has been suggested that dengue outbreaks may compromise treatment quality in hospitals. OBJECTIVE: The objective of the study was to quantify the burden imposed by dengue on hospital services in Mexico. METHODS: We analyzed 19.2 million records contained in the database of hospital services of the Mexican Ministry of Health between 2008 and 2014. The number of admissions due to dengue was compared to other potentially preventable hospitalizations. Hospital departments were categorized to reflect dengue-related activity as high dengue activity (HDA), low dengue activity (LDA), or zero dengue activity departments, and the impact of dengue activity on general in-hospital mortality in HDA departments was assessed. RESULTS: Dengue was the cause of more hospital admissions than most of the potentially preventable prevalent acute and chronic conditions and other infectious diseases. In HDA departments, dengue patient load was found to be a significant risk factor for overall in-hospital mortality. There was an approximately two-fold higher dengue case-fatality rate in LDA versus HDA departments, irrespective of dengue severity. CONCLUSIONS: This study confirms that dengue is an important cause of hospitalization in Mexico and highlights the impact of dengue activity not only on dengue case-fatality rate but also on the overall in-hospital mortality.

Burden of dengue in Kerala using disability-adjusted life years from 2006 to 2016.

BACKGROUND: State-specific disability-adjusted life years (DALYs) are seldom calculated. Understanding the health and disease trends in groups of states is useful for finding the heterogeneity of disease epidemiology in the country. OBJECTIVE: The objective of the study was to assess dengue burden in Kerala state, using DALY. METHODS: DALY was computed using the DALY package of R. Incidence was derived using reported and estimated dengue cases for 2006-2016. Mortality was calculated using reported deaths. We computed DALYs using the mortality estimates for the South-East Asia region (SEAR) also. Sensitivity and scenario analyses were done. RESULTS: The highest estimated relative DALY for dengue is 7.22 (95% confidence interval [CI]: 6.66-7.72) per lakh population. The DALY obtained using the mortality rates of SEAR ranged from 19.89 (95% CI: 8.44-29.45) per lakh population to 28.56 (95% CI: 17.04-38.05). We observed a cyclical pattern of increase in DALY every 2-3 years. The DALY in lower age groups is lesser. DALY in females was higher than males. CONCLUSIONS: The dengue-related DALY for the state of Kerala is lower than that of the global burden of disease due to lower mortality rates. Mortality reduction becomes the key to reducing burden, especially in areas of low incidence. The study also forms the benchmark for evaluating and implementing cost-effective measures for dengue control in the state.

30 years of dengue fatal cases in Brazil: a laboratorial-based investigation of 1047 cases.

BACKGROUND: Dengue viruses (DENV) have emerged and reemerged in Brazil in the past 30 years causing explosive epidemics. The disease may range from clinically asymptomatic infections to severe and fatal outcomes. We aimed to describe the epidemiological, clinical and laboratorial aspects of the dengue fatal cases received by a Regional Reference Laboratory, Brazil in 30 years. METHODS: A total of 1047 suspected fatal dengue cases were received from 1986 to 2015 and analyzed in the Laboratory of Flavivirus, FIOCRUZ. Suspected cases were submitted to viral detection, serological and molecular methods for cases confirmation. Influence of gender, age, serotype and type of infection (primary/secondary) on death outcome, as well the interactions between serotype and age or infection and age and type of infection were also studied. RESULTS: A total of 359 cases (34.2%) were confirmed and DENV-1 (11.1%), DENV-2 (43.9%), DENV-3 (32.8%) and DENV-4 (13.7%) were detected. Overall, fatal cases occurred more often in primary infections (59.3%, p = 0.001). However, in 2008, fatal cases were mainly associated to secondary infections (p = 0.003). In 2008 and 2011, deaths were more frequent on children and those infected by DENV-2 presented a higher risk for fatal outcome. Moreover, children with secondary infections had a 4-fold higher risk for death. CONCLUSIONS: Dengue is a multifactorial disease and, factors such as viral strain/serotype, occurrence of secondary infections and co-morbidities may lead to a severe outcome. However, the high dengue incidence and transmission during epidemics, such as those observed in Brazil may overwhelm and collapse the public health services, potentially impacting on increased disease severity and mortality.

Comorbidities increase in-hospital mortality in dengue patients in Brazil.

Dengue remains an unmet public health burden. We determined risk factors for dengue in-hospital mortality in Brazil. Of 326,380 hospitalised dengue cases in 9-45-year-old individuals, there were 971 deaths. Risk of dying was 11-times higher in the presence of underlying common comorbidities (renal, infectious, pulmonary disease and diabetes), similar to the risk of dying from severe dengue and much higher with the combination. Ensuring access to integrated dengue preventative measures in individuals aged ≥ 9 years including those with comorbidities may help achieve the WHO objective of 50% reduction in mortality and 25% reduction in morbidity due to dengue by 2020.

Clinical Profile, Hepatic Dysfunctions, and Outcome of Dengue Patients in a Tertiary Care Hospital of Eastern India.

Background: Dengue is one of the commonest tropical infections in India. This study was aimed to evaluate clinical profile, magnitude and spectrum of hepatic dysfunctions, outcome and clinical predictors of mortality in patients with dengue. Methods: In an observational study, data of 183 consecutive admitted dengue patients were prospectively collected. The magnitude of hepatitis and its association with outcome were studied. Results: The transaminases elevation was seen in 156 (85%) patients, with 21 (11.4%) patients had levels above 10 times the upper normal limit (UNL). Aspartate aminotransferase (AST) showed greater elevation as compared to Alanine aminotransferase (ALT) in 136 (87%) patients. Patients who died (n=8), compared with those who survived (n=175) had higher mean serum bilirubin (3.4 vs. 0.7 mg/dl, p= 0.01), median AST (8791 vs. 138 IU/L, p=0.02), median ALT (2692 vs 81 IU/L, p=0.02), median serum creatinine (2.0 vs 1.0 mg/dl, p=0.007), mean International normalized ratio (3.5 vs 1.1, p= 0.04), and lower median platelet count (20000 vs 60000/mm3, p <0.001). Among patients who died 87.5% (n= 7) had AST levels greater than 100 times UNL while among patients who survived 93% (n=162) had AST levels lower than 10 times UNL. In a multivariate analysis, serum bilirubin (≥2.2 mg/dl, OR 4.8) and creatinine (≥1.65 mg/dl, OR 2.8) were found to be independent predictors of mortality. Conclusions: Hepatitis is very frequent in patients with dengue. AST elevation is usually more than ALT elevation. Presence of jaundice and renal dysfunction at presentation are ominous signs in predicting mortality.

Case Management of Dengue: Lessons Learned.

The global burden of dengue and its geographic distribution have increased over the past several decades. The introduction of dengue in new areas has often been accompanied by high case-fatality rates. Drawing on the experience in managing dengue cases at the Queen Sirikit National Institute of Child Health in Bangkok, Thailand, this article provides the authors' perspectives on key clinical lessons to improve dengue-related outcomes. Parallels between this clinical experience and outcomes reported in randomized controlled trials, results of efforts to disseminate practice recommendations, and suggestions for areas for further research are also discussed.

Dengue fever in renal transplant patients: a systematic review of literature.

BACKGROUND: Dengue fever in renal transplanted patients has not been studied well, and we review all the literature about episodes dengue fever in renal transplant patients. METHODS: The aim was to describe clinico-pathological characteristics, immunosuppressive protocols, need renal outcome and mortality. PubMed, LILACS, Google Scholar and Research Gate were searched for "Dengue" and "Renal/Kidney Transplantation" with no date limits. Hits were analyzed by two researchers separately. RESULTS: Fever, myalgia, arthralgia and headache was significantly lower than normal population, while pleural effusions and ascites were observed more. Incidence of severe dengue is significantly higher among transplant patients in this review, as well as they had a significantly higher mortality (8.9% vs 3.7%, p = 0.031). Age, period after transplantation and immunosuppressive profile had no effect on disease severity, mortality or graft out come. Presence of new bleeding complications and ascites was associated with more severe disease (p < 0.001 and p = 0.005), death (p = 0.033) or graft loss (p = 0.035). Use of tacrolimus was associated with new bleeding complications (p = 0.027), and with ascites (p = 0.021), but not with thrombocytopenia. 25% of patients with primary disease fail to mount an IgG response by 15 weeks of the illness. 58.9% had graft dysfunction during illness. Postoperative transplanted patients were at risk of severe disease and unfavorable outcome. CONCLUSIONS: The physical and laboratory findings in dengue fever in renal transplanted patients differ from the general population. Some degree of graft dysfunction is common during the illness, but only a minority develops graft failure.

Surveillance of deaths caused by arboviruses in Brazil: from dengue to chikungunya.

Did death occur DUE TO dengue, or in a patient WITH dengue virus infection? It seems a matter of semantics, but in fact, it underscores how challenging it is to distinguish whether the disease contributed to death, or was itself the underlying cause of death. Can a death be attributed to chikungunya virus, when some deaths occur after the acute phase? Did the virus decompensate the underlying diseases, leading to death? Did prolonged hospitalisation lead to infection, resulting in the patient's progression to death? Were there iatrogenic complications during patient care? The dengue question, for which there has not yet been a definitive response, resurfaces prominently under the chikungunya surveillance scenario. We are facing an epidemic of a disease that seems to be more lethal than previously thought. The major challenge ahead is to investigate deaths suspected of occurring due to arbovirus infections and to understand the role of each infection in the unfavourable outcome.

Dengue fever in a municipality of West Bengal, India, 2015: An outbreak investigation.

BACKGROUND: In November 2015, death due to fever and increased number of fever cases were reported from Baranagar Municipality of North 24 Parganas district of West Bengal. OBJECTIVES: The episode was investigated with the objective to (1) confirm the existence of an outbreak, (2) describe it in terms of time, place, and person, (3) determine the cause of outbreak, and (4) recommend control measures. METHODS: Monthly incidence of dengue from 2012 to 2014 was calculated and compared with 2015 to confirm the outbreak. We used Integrated Disease Surveillance Programme definition and searched for suspect dengue cases going door-to-door in ward number one of Baranagar Municipality. Active case search was done in health facilities also. Information on date of onset, symptoms, sociodemographic, serological reports, and clinical outcome for suspected and confirmed dengue cases was collected. Blood specimens were collected for NS1 ELISA/monoclonal IgM antibody capture-ELISA test. Environmental and entomological surveys were done. RESULTS: Six hundred and seventy-one dengue cases (Overall attack rate = 3/1000), two deaths (Case fatality = 3/1000) were reported during September 14, 2015, till December 12, 2015. Out of 34 wards, attack rate was highest in ward number 1 (0.7%) and was 3 per 1000 among females. All age groups were affected. Thirty-two percent required hospitalization. NS1 ELISA was positive for 612 cases. Out of interviewed 31 dengue cases, 94% had headache, 90% had myalgia, followed by arthralgia, rash, and retro-orbital pain. Only in ward number 1, house index was >5%. CONCLUSION: We confirmed dengue outbreak. All age groups got affected. Deaths occurred in this outbreak. Potential breeding sources were present in ward number 1.

Dengue Virus Infection with Highly Neutralizing Levels of Cross-Reactive Antibodies Causes Acute Lethal Small Intestinal Pathology without a High Level of Viremia in Mice.

UNLABELLED: Severe dengue virus (DENV)-associated diseases can occur in patients who have preexisting DENV antibodies (Abs) through antibody-dependent enhancement (ADE) of infection. It is well established that during ADE, DENV-antibody immune complexes (ICs) infect Fcγ receptor-bearing cells and increase the systemic viral burden that can be measured in the blood. For protection against infection with DENV serotypes 1 to 4, strongly neutralizing Abs must be elicited to overcome the effect of ADE. Clinical observations in infants who have maternal DENV Abs or recent phase II/III clinical trials with a leading tetravalent dengue vaccine suggested a lack of correlation between Ab neutralization and in vivo disease prevention. In addressing this gap in knowledge, we found that inoculation of ICs formed with serotype cross-reactive Abs that are more than 98% neutralized in vitro promotes high mortality in AG129 mice even though peak viremia was lower than that in direct virus infection. This suggests that the serum viremia level is not always correlated with disease severity. We further demonstrated that infection with the ICs resulted in increased vascular permeability, specifically in the small intestine, accompanied with increased tissue viral load and cytokine production, which can be suppressed by anti-tumor necrosis factor alpha (anti-TNF-α) Abs. Flow cytometric analysis identified increased infection in CD11b(int) CD11c(int/hi) CD103(-) antigen-presenting cells by IC inoculation, suggesting that these infected cells may be responsible for the increase in TNF-α production and vascular permeability in the small intestine that lead to mortality in mice. Our findings may have important implications for the development of dengue therapeutics. IMPORTANCE: We examined the relationship between the neutralizing level of Abs at the time of infection and subsequent disease progression in a mouse model in order to understand why patients who are shown to have a neutralizing quantity of Abs still allow sufficient DENV replication to induce severe dengue manifestations, which sometimes do not correlate with viremia level. Strikingly, we found that high mortality was induced in AG129 mice by the increase in TNF-α-induced vascular permeability accompanied by an increased viral load, specifically in the small intestine, even when the initial infection level is suppressed to less than 5% and the peak viremia level is not enhanced. This suggests that ADE overcomes the protective efficacy of Abs in a tissue-dependent manner that leads to severe small intestinal pathology. Our findings may serve to address the pathogenic role of Abs on severe dengue disease and also help to develop safe Ab-based therapeutic strategies.