Dengue viremia kinetics and effects on platelet count and clinical outcomes: An analysis of 2340 patients from Vietnam.

Background: Viremia is a critical factor in understanding the pathogenesis of dengue infection, but limited data exist on viremia kinetics. This study aimed to investigate the kinetics of viremia and its effects on subsequent platelet count, severe dengue, and plasma leakage. Methods: We pooled data from three studies conducted in Vietnam between 2000 and 2016, involving 2340 dengue patients with daily viremia measurements and platelet counts after symptom onset. Viremia kinetics were assessed using a random effects model that accounted for left-censored data. The effects of viremia on subsequent platelet count and clinical outcomes were examined using a landmark approach with a random effects model and logistic regression model with generalized estimating equations, respectively. The rate of viremia decline was derived from the model of viremia kinetics. Its effect on the clinical outcomes was assessed by logistic regression models. Results: Viremia levels rapidly decreased following symptom onset, with variations observed depending on the infecting serotype. DENV-1 exhibited the highest mean viremia levels during the first 5-6 days, while DENV-4 demonstrated the shortest clearance time. Higher viremia levels were associated with decreased subsequent platelet counts from day 6 onwards. Elevated viremia levels on each illness day increased the risk of developing severe dengue and plasma leakage. However, the effect size decreased with later illness days. A more rapid decline in viremia is associated with a reduced risk of the clinical outcomes. Conclusions: This study provides comprehensive insights into viremia kinetics and its effect on subsequent platelet count and clinical outcomes in dengue patients. Our findings underscore the importance of measuring viremia levels during the early febrile phase for dengue studies and support the use of viremia kinetics as outcome for phase-2 dengue therapeutic trials. Funding: Wellcome Trust and European Union Seventh Framework Programme.

Diagnostic performance of the bioline dengue duo rapid test on symptomatic patients assisted at Armed Forces Hospital (Hfa) in Brasília, Brazil.

Dengue necessitates accurate diagnosis. Rapid tests such as Bioline™ DENGUE DUO have gained traction, but validation in specific populations is essential. This study aimed to evaluate the performance of the Bioline™ test, alongside assessing the socio-epidemiological profile of symptomatic patients in a Brasília Military Hospital. The serum of 404 symptomatic patients was analyzed by the Bioline™ DENGUE DUO test, followed by Dengue virus detection and discrimination of the four serotypes by RT-qPCR. Accuracy was assessed using parameters including sensitivity (S), specificity (E), positive and negative predictive values (PPV and NPV), and positive (RV +) and negative (RV-) likelihood ratios. The NS1 component exhibited a sensitivity of 70.37%, a specificity of 97.30%, and an overall efficiency of 90.10% when compared to RT-qPCR as the gold standard. The IgM component demonstrated a sensitivity of 26.85%, a specificity of 89.53%, and an overall efficiency of 72.77% when compared to RT-qPCR as the gold standard. The IgG component demonstrated a sensitivity of 23.15%, a specificity of 68.92%, and an overall efficiency of 56.68% when compared to RT-qPCR as the gold standard. Several rapid tests are commercially available. However, considering variations across regions and demographic groups, it is important to question their accuracy in specific populations. Rapid tests are important screening tools, but they can have limitations for the certainty of diagnosis. Bioline™ DENGUE DUO displayed good specificity, but sensitivity was slightly below optimal levels. While helpful for confirming dengue, improvements are needed to effectively rule out the disease.

Dengue Virus and Zika Virus Seroprevalence in the South Pacific Populations of the Cook Islands and Vanuatu.

Arboviral diseases are serious threats to global health with increasing prevalence and potentially severe complications. Significant arthropod-borne viruses are the dengue viruses (DENV 1-4), the Zika virus (ZIKV), and the chikungunya virus (CHIKV). Among the areas most affected is the South Pacific Region (SPR). Here, arboviruses not only cause a high local burden of disease, but the region has also proven to contribute to their global spread. Outpatient serum samples collected between 08/2016 and 04/2017 on three islands of the island states of Vanuatu and the Cook Islands were tested for anti-DENV- and anti-ZIKV-specific antibodies (IgG) using enzyme-linked immunosorbent assays (ELISA). ELISA test results showed 89% of all test sera from the Cook Islands and 85% of the Vanuatu samples to be positive for anti-DENV-specific antibodies. Anti-ZIKV antibodies were identified in 66% and 52%, respectively, of the test populations. Statistically significant differences in standardized immunity levels were found only at the intranational level. Our results show that in both the Cook Islands and Vanuatu, residents were exposed to significant Flavivirus transmission. Compared to other seroprevalence studies, the marked difference between ZIKV immunity levels and previously published CHIKV seroprevalence rates in our study populations is surprising. We propose the timing of ZIKV and CHIKV emergence in relation to recurrent DENV outbreaks and the impact of seasonality as explanatory external factors for this observation. Our data add to the knowledge of arboviral epidemics in the SPR and contribute to a better understanding of virus spread, including external conditions with potential influence on outbreak dynamics. These data may support preventive and rapid response measures in the affected areas, travel-related risk assessment, and infection identification in locals and returning travelers.

A scoping literature review of global dengue age-stratified seroprevalence data: estimating dengue force of infection in endemic countries.

BACKGROUND: Dengue poses a significant burden worldwide, and a more comprehensive understanding of the heterogeneity in the intensity of dengue transmission within endemic countries is necessary to evaluate the potential impact of public health interventions. METHODS: This scoping literature review aimed to update a previous study of dengue transmission intensity by collating global age-stratified dengue seroprevalence data published in the Medline, Embase and Web of Science databases from 2014 to 2023. These data were then utilised to calibrate catalytic models and estimate the force of infection (FOI), which is the yearly per-capita risk of infection for a typical susceptible individual. FINDINGS: We found a total of 66 new publications containing 219 age-stratified seroprevalence datasets across 30 endemic countries. Together with the previously available average FOI estimates, there are now more than 250 dengue average FOI estimates obtained from seroprevalence studies from across the world. INTERPRETATION: The results show large heterogeneities in average dengue FOI both across and within countries. These new estimates can be used to inform ongoing modelling efforts to improve our understanding of the drivers of the heterogeneity in dengue transmission globally, which in turn can help inform the optimal implementation of public health interventions. FUNDING: UK Medical Research Council, Wellcome Trust, Community Jameel, Drugs for Neglected Disease initiative (DNDi) funded by the French Development Agency, Médecins Sans Frontières International; Swiss Agency for Development and Cooperation and UK aid.

Cytokine profiles in dengue fever and dengue hemorrhagic fever: A study from Indonesia.

Recent studies have demonstrated that cytokine dysregulation has a critical role in the pathogenesis of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The aim of this study was to investigate the association between tumor necrosis factor (TNF- α), interleukin 6 (IL-6), interleukin 10 (IL-10), and interleukin 17 (IL-17) with infection status, and severity of dengue. A prospective cross-sectional study was conducted at three hospitals in Gianyar regency and Denpasar municipality, Bali, Indonesia, from June to December 2022. Sixty-four dengue infected patients were involved. Patients' serum was tested for dengue infection using NS1 antigen rapid test, dengue virus immunoglobulin M (IgM) and immunoglobulin G (IgG) test, and reverse transcription polymerase chain reaction (RT-PCR). Cytokine levels (TNF-α, IL-6, IL-10, and IL-17) were measured using enzyme-linked immunosorbent assay (ELISA). Infection status was determined by combining serological and RT-PCR results, categorizing patients into primary and secondary infections. The present study found that DF patients had lower TNF-α, IL-6, and IL-17 but higher IL-10 levels compared to DHF patients (p<0.001). Elevated TNF-α, IL-6, and IL-17 levels were higher in secondary infection, while IL-10 level was higher in primary infection (p<0.001). In conclusion, cytokines play a crucial role in the interplay between cytokine dysregulation and dengue infection dynamics.

Development and assessment of a multiepitope synthetic antigen for the diagnosis of Dengue virus infection.

Immunodiagnostic tests for detecting dengue virus infections encounter challenges related to cross-reactivity with other related flaviviruses. Our research focuses on the development of a synthetic multiepitope antigen tailored for dengue immunodiagnostics. Selected dengue epitopes involved structural linearity and dissimilarity from the proteomes of Zika and Yellow fever viruses which served for computationally modeling the three-dimensional protein structure, resulting in the design of two proteins: rDME-C and rDME-BR. Both proteins consist of seven epitopes, separated by the GPGPG linker, and a carboxy-terminal 6 × -histidine tag. The molecular weights of the final proteins rDME-C and rDME-BR are 16.83 kDa and 16.80 kDa, respectively, both with an isoelectric point of 6.35. The distinguishing factor between the two proteins lies in the origin of their epitope sequences, where rDME-C is based on the reference dengue proteome, while rDME-BR utilizes sequences from prevalent Dengue genotypes in Brazil from 2008 to 2019. PyMol analysis revealed exposure of epitopes in the secondary structure. Successful expression of the antigens was achieved in soluble form and fluorescence experiments indicated a disordered structure. In subsequent testing, rDME-BR and rDME-C antigens were assessed using an indirect Elisa protocol against Dengue infected serum, previously examined with a commercial diagnostic test. Optimal concentrations for antigens were determined at 10 µg/mL for rDME-BR and 30 µg/mL for rDME-C, with serum dilutions ranging from 1:50 to 1:100. Both antigens effectively detected IgM and IgG antibodies in Dengue fever patients, with rDME-BR exhibiting higher sensitivity. Our in-house test showed a sensitivity of 77.3 % and 82.6 % and a specificity of 89.4 % and 71.4 % for rDME-C and rDEM-BR antigens. No cross-reactivity was observed with serum from Zika-infected mice but with COVID-19 serum samples. Our findings underscore the utility of synthetic biology in crafting Dengue-specific multiepitope proteins and hold promise for precise clinical diagnosis and monitoring responses to emerging Dengue vaccines.

Circulating serotypes and genotypes of dengue virus in North India: An observational study.

BACKGROUND OBJECTIVES: This study reports observation on circulating serotypes and genotypes of Dengue Virus in North India. METHODS: Serum samples were obtained from suspected cases of dengue referred to the virus diagnostic laboratory during 2014 to 2022. All samples were tested for anti-dengue virus IgM antibodies and NS1Ag by ELISA. NS1Ag positive samples were processed for serotyping and genotyping. RESULTS: Total 41,476 dengue suspected cases were referred to the laboratory of which 12,292 (29.6%) tested positive. Anti-Dengue Virus IgM antibodies, NS1Ag, both IgM and NS1Ag, were positive in 7007 (57.4%); 3200 (26.0%) and 2085 (16.0%) cases respectively. Total 762 strains were serotyped during 9-year period. DENV-1, DENV-2, DENV-3 and DENV-4 serotypes were found in 79 (10.37%), 506 (66.40%), 151 (19.82%) and 26 (3.41%) cases respectively. DENV-1, DENV-2 and DENV-3 were in circulation throughout. Total 105 strains were genotyped. Genotype IV of DENV-1 serotype was circulating till 2014 which was later replaced by genotype V. A distinct seasonality with increase in number of cases in post-monsoon period was seen. INTERPRETATION CONCLUSION: DENV-1, DENV-2 and DENV-3 were found to be in circulation in North India. Predominant serotype/genotype changed at times, but not at regular intervals.

Persistence of dengue serotype 2 viral RNA in blood cells of a returned traveler with dengue fever.

Dengue virus (DENV) is one of the most significant vector-borne pathogens worldwide. In this report, we describe clinical features and laboratory detection of dengue in a 45-year-old traveler to Nicaragua on return home to the United States in 2019. Clinical presentation was mild, with rash, headache, and fatigue, with only low-grade transient fever. Infection dynamics were documented by serology and PCR of serially collected body fluids. DENV serotype 2 was detected in whole blood 1 day after symptoms emerged, with viral RNA isolated to the red cell fraction, and remained detectable through day 89. DENV-2 RNA was detected in serum only on day 4, and IgM was undetectable on day 4 but evident by day 13. Viral RNA was also detected in urine. This report of DENV-2 RNA persistence in blood cells but only transient appearance in serum, supports the potential diagnostic value of whole blood over serum for PCR and opportunity of an expanded testing window. Informed testing approaches can improve diagnostic accuracy and inform strategies that preserve individual and public health.

Investigating the Association Between ABO Blood Groups and Rhesus Factors with Dengue and Chikungunya Virus Infections During the 2017 Outbreak in Bangladesh.

This retrospective study was conducted in 2017 during the dual dengue and chikungunya outbreak in Bangladesh. Febrile participants underwent blood tests for chikungunya, dengue, and ABO groups and rhesus (Rh) factors. Blood grouping information was gathered from healthy donors. Males and those aged between 18 and 49 years had a higher risk of contracting dengue and chikungunya. Blood group O exhibited the highest infection rates at ∼50%, whereas group AB had the lowest at ∼9% among the participants in the study. Yet, when considering the general population's blood group distribution, the combined odds of infection were 2.0, 3.5, and 1.4 times higher in groups B, O, and AB, respectively, than in group A. Infection rates were greater in Rh-negative people. Blood groups B, O, and AB showed higher susceptibility than blood group A according to adjusted odds ratios. Blood groups ABO and Rh factor hold significance in disease susceptibility and vaccine effectiveness. Keeping these implications in mind, further investigations are necessary to understand the mechanisms underlying these connections and their effects on the efficacy of dengue and chikungunya vaccines.

Seroprevalence of dengue and chikungunya viruses among urban refugees in Klang Valley, Malaysia.

BACKGROUND: Mosquito-borne diseases pose a significant global public health threat, with Malaysia's Klang Valley experiencing numerous outbreaks in densely populated urban areas. METHODS: This study aimed to estimate the seroprevalence of anti-dengue and anti-chikungunya antibodies among urban refugees in the Klang Valley, Malaysia, and identify associated risk factors. RESULTS: High seroprevalence of anti-dengue immunoglobulin G (IgG) and IgM (60.0% [confidence interval {CI} 55.39 to 64.48] and 9.2% [CI 6.77 to 12.25], respectively) were observed among refugees >18 years of age (χ22=11.720, p=0.003), Kachin ethnicity (χ28=72.253, p<0.001), without formal education (χ21=3.856, p=0.050), homes near waste disposal sites (χ21=10.378, p=0.001) and refugees who have experienced flooding (χ21=5.460, p=0.019). Meanwhile, the overall seroprevalence of anti-chikungunya IgG and IgM was 9.7% (CI 7.15 to 12.73) and 10.8% (CI 8.09 to 13.93), respectively, with ages 12-18 years (χ22=6.075, p=0.048), Rohingya ethnicity (χ28=31.631, p<0.001) and homes close to waste disposal sites (χ21=3.912, p=0.048) being significant risk factors. Results showed a link to poor environmental living conditions, with an increase in the vector population with higher availability of breeding sites and thus exposure to dengue and chikungunya virus. CONCLUSIONS: Health education among the community is the key to disease prevention, as there are no specific antiviral drugs for treatment and limited vaccine availability.

Utility of Atypical Lymphocytes and Large Immature Cells in Prediction of Dengue Severity.

Background: There is a clinical imperative to devise metrics to prognosticate dengue severity. Our objective was to determine the association between longitudinal trends in atypical lymphocytes and large immature cell count with platelet count and dengue severity. Materials and methods: Retrospective analysis of longitudinally measured clinical and hematological data from (n = 79) hospitalized dengue patients was done. Results: The cohort consisted of patients with dengue fever without warning signs (DFWOWS) (n = 40, females = 14, and age = 19.9 ± 14.6 years), dengue fever with warning signs (DFWWS) (n = 36, females = 13, and age = 16.1 ± 14.1 years) and severe dengue (n = 3, females = 2, and age = 5.3 ± 4 years). Platelet count increased at a rate of 11,524 cells/mm3/day, with a slower rate of rise as the severity increased (p = 0.001***). Concurrently hematocrit and neutrophil percentage decreased, while the lymphocyte percentage and white blood cell (WBC) count increased during the hospital stay. Every 1% increase in atypical lymphocyte count (ATY) was associated with a fall in platelet count by 16,963 cells/mm3 (p = 0.001***). A similar but weaker trend was found for large immature cells (LICs). Conclusion: The data support the usefulness of longitudinal tracking of atypical lymphocyte and large immature cell count for dengue prognosis. The time trends of the hematological parameters indicate the progression of patients from the critical to the recovery phase. How to cite this article: Peraka R, Koppula A, Muppala BS, et al. Utility of Atypical Lymphocytes and Large Immature Cells in Prediction of Dengue Severity. J Assoc Physicians India 2023;71(11):19-24.

First Report of the Detection of DENV1 in Human Blood Plasma with Near-Infrared Spectroscopy.

Dengue virus (DENV) is the world's most common arboviral infection, with an estimated 3.9 million people at risk of the infection, 100 million symptomatic cases and 10,000 deaths per year. Current diagnosis for DENV includes the use of molecular methods, such as polymerase chain reaction, which can be costly for routine use. The near-infrared spectroscopy (NIR) technique is a high throughput technique that involves shining a beam of infrared light on a biological sample, collecting a reflectance spectrum, and using machine learning algorithms to develop predictive algorithms. Here, we used NIR to detect DENV1 artificially introduced into whole blood, plasma, and serum collected from human donors. Machine learning algorithms were developed using artificial neural networks (ANN) and the resultant models were used to predict independent samples. DENV in plasma samples was detected with an overall accuracy, sensitivity, and specificity of 90% (N = 56), 88.5% (N = 28) and 92.3% (N = 28), respectively. However, a predictive sensitivity of 33.3% (N = 16) and 80% (N = 10) and specificity of 46.7% (N = 16) and 32% (N = 10) was achieved for detecting DENV1 in whole blood and serum samples, respectively. DENV1 peaks observed at 812 nm and 819 nm represent C-H stretch, peaks at 1130-1142 nm are related to methyl group and peaks at 2127 nm are related to saturated fatty groups. Our findings indicate the potential of NIR as a diagnostic tool for DENV, however, further work is recommended to assess its sensitivity for detecting DENV in people naturally infected with the virus and to determine its capacity to differentiate DENV serotypes and other arboviruses.

Hyperendemic Dengue and Possible Zika Circulation in the Westernmost Region of the Indonesian Archipelago.

The transmission of dengue and other medically important mosquito-borne viruses in the westernmost region of Indonesia is not well described. We assessed dengue and Zika virus seroprevalence in Aceh province, the westernmost area of the Indonesian archipelago. Serum samples collected from 199 randomly sampled healthy residents of Aceh Jaya in 2017 were analyzed for neutralizing antibodies by plaque reduction neutralization test (PRNT). Almost all study participants (198/199; 99.5%) presented with multitypic profiles of neutralizing antibodies to two or more DENV serotypes, indicating transmission of multiple DENV in the region prior to 2017. All residents were exposed to one or more DENV serotypes by the age of 30 years. The highest geometric mean titers were measured for DENV-4, followed by DENV-1, DENV-2 and DENV-3. Among a subset of 116 sera, 27 neutralized ZIKV with a high stringency (20 with PRNT90 > 10 and 7 with PRNT90 > 40). This study showed that DENV is hyperendemic in the westernmost region of the Indonesian archipelago and suggested that ZIKV may have circulated prior to 2017.

Seroprevalence of dengue, Zika, chikungunya and Ross River viruses across the Solomon Islands.

Across the Pacific, and including in the Solomon Islands, outbreaks of arboviruses such as dengue, chikungunya, and Zika are increasing in frequency, scale and impact. Outbreaks of mosquito-borne disease have the potential to overwhelm the health systems of small island nations. This study mapped the seroprevalence of dengue, Zika, chikungunya and Ross River viruses in 5 study sites in the Solomon Islands. Serum samples from 1,021 participants were analysed by ELISA. Overall, 56% of participants were flavivirus-seropositive for dengue (28%), Zika (1%) or both flaviviruses (27%); and 53% of participants were alphavirus-seropositive for chikungunya (3%), Ross River virus (31%) or both alphaviruses (18%). Seroprevalence for both flaviviruses and alphaviruses varied by village and age of the participant. The most prevalent arboviruses in the Solomon Islands were dengue and Ross River virus. The high seroprevalence of dengue suggests that herd immunity may be a driver of dengue outbreak dynamics in the Solomon Islands. Despite being undetected prior to this survey, serology results suggest that Ross River virus transmission is endemic. There is a real need to increase the diagnostic capacities for each of the arboviruses to support effective case management and to provide timely information to inform vector control efforts and other outbreak mitigation interventions.

Peptide Biomarkers for the Diagnosis of Dengue Infection.

In a world with an increasing population at risk of exposure to arthropod-borne flaviviruses, access to timely and accurate diagnostic tests would impact profoundly on the management of cases. Twenty peptides previously identified using a flavivirus proteome-wide microarray were evaluated to determine their discriminatory potential to detect dengue virus (DENV) infection. This included nine peptides recognized by IgM antibodies (PM peptides) and 11 peptides recognized by IgG antibodies (PG peptides). A bead-based multiplex peptide immunoassay (MPIA) using the Luminex technology was set-up to determine Ab binding levels to each of these peptides in a panel of 323 carefully selected human serum samples. Sera are derived from individuals either infected with different viruses, namely, the four DENV serotypes, Zika virus (ZIKV), yellow fever virus (YFV), chikungunya virus (CHIKV), West Nile virus (WNV) and Human immunodeficiency virus (HIV), or receiving vaccination against YFV, tick-borne encephalitis (TBEV), and Japanese encephalitis virus (JEV). Additionally, a set of healthy controls were included. We targeted a minimum specificity of 80% for all the analysis. The PG-9 peptide had the best sensitivity (73%) when testing DENV sera from acute patients (A-DENV; <8 days since symptom onset). With sera from convalescent DENV patients (C-DENV; >10 days since symptom onset) the FPG-1 peptide was the best seromarker with a sensitivity of 86%. When combining all A-DENV and C-DENV samples, peptides PM-22 and FPG-1 had the best-diagnostic performance with a sensitivity of 60 and 61.1%, and areas under the curve (AUC) of 0.7865 and 0.8131, respectively. A Random forest (RF) algorithm was used to select the best combination of peptides to classify DENV infection at a targeted specificity >80%. The best RF model for PM peptides that included A-DENV and C-DENV samples, reached a sensitivity of 72.3%, while for PG peptides, the best RF models for A-DENV only, C-DENV only and A-DENV + C-DENV reached a sensitivity of 88.9%, 89.1%, and 88.3%, respectively. In conclusion, the combination of multiple peptides constitutes a founding set of seromarkers for the discrimination of DENV infected individuals from other flavivirus infections.

A Population of CD4+CD8+ Double-Positive T Cells Associated with Risk of Plasma Leakage in Dengue Viral Infection.

According to the WHO 2009 classification, dengue with warning signs is at the risk of developing severe form of dengue disease. One of the most important warning signs is plasma leakage, which can be a serious complication associated with higher morbidity and mortality. We report that the frequency of CD4+CD8+ double-positive (DP) T cells is significantly increased in patients at risk of developing plasma leakage. Transcriptomic analysis demonstrated that CD4+CD8+ DP cells were distinct from CD4+ Single Positive (SP) T cells but co-clustered with CD8+ SP cells, indicating a largely similar transcriptional profile. Twenty significant differentially expressed (DE) genes were identified between CD4+CD8+ DP and CD8+ SP cells. These genes encode OX40 and CCR4 proteins as well as other molecules associated with cell signaling on the cell surface (NT5E, MXRA8, and PTPRK). While comparing the profile of gene expression in CD4+CD8+ DP cells from patients with and without warning signs of plasma leakage, similar expression profile was observed, implying a role of CD4+CD8+ DP cells in plasma leakage through a quantitative increase rather than functional alteration. This study provided novel insight into the host immune response during the acute febrile phase of DENV infection and the role of CD4+CD8+ DP T cells in the pathogenesis of plasma leakage.

Integrated view of molecular diagnosis and prognosis of dengue viral infection: future prospect of exosomes biomarkers.

Dengue viruses (DENVs) are the viruses responsible for dengue infection which affects lungs, liver, heart and also other organs of individuals. DENVs consist of the group of four serotypically diverse dengue viruses transmitted in tropical and sub-tropical countries of world. Aedes mosquito is the principal vector which spread the infection from infected person to healthy humans. DENVs can cause different syndromes depending on serotype of virus which range from undifferentiated mild fever to dengue hemorrhagic fever resulting in vascular leakage due to release of cytokine and Dengue shock syndrome with fluid loss and hypotensive shock, or other severe manifestations such as bleeding and organ failure. Increase in dengue cases in pediatric population is a major concern. Transmission of dengue depends on various factors like temperature, rainfall, and distribution of Aedes aegypti mosquitoes. The present review describes a comprehensive overview of dengue, pathophysiology, diagnosis, treatment with an emphasis on potential of exosomes as biomarkers for early prediction of dengue in pediatrics.

Dengue and Plasmodium falciparum Coinfection With Secondary Hemophagocytic Lymphohistiocytosis in a 3-Year-old Boy: A Clinical Conundrum.

Hemophagocytic lymphohistiocytosis (HLH) is a multisystem disease wherein there is an exaggerated immune system activation following a trigger such as infection, malignancy, or autoimmune diseases. Here we report a case of a 3-year-old boy who presented to us with fever, was diagnosed with dengue fever, and treatment started for the same. Clinical response was poor to treatment and high-grade fever persisted. Subsequent evaluation showed Plasmodium falciparum malaria and treatment was initiated with antimalarial drugs. Further clinical deterioration with poor trend of laboratory values over the next few days prompted evaluation for HLH; workup was positive satisfying the HLH-2004 criteria and IV dexamethasone was started. The child gradually improved and was discharged with normal counts on follow-up over the next 3 months. This article emphasizes on the importance of high degree of suspicion, early workup, and initiation of treatment for HLH for a better outcome.

Platelets in dengue infection: more than a numbers game.

Dengue virus (DENV) infection is responsible for the development of dengue illness, which can be either asymptomatic, present mild manifestations or evolve to severe dengue. Thrombocytopenia is an important characteristic during DENV infection, being observed both in mild and severe dengue, although the lowest platelet counts are encountered during severe cases. This review gathers information regarding several mechanisms that have been related to alterations in platelet number and function, leading to thrombocytopenia but also platelet-mediated immune and inflammatory response. On this regard, we highlight that the decrease in platelet counts may be due to bone marrow suppression or consumption of platelets at the periphery. We discuss the infection of hematopoietic progenitors and stromal cells as mechanisms involved in bone marrow suppression. Concerning peripheral consumption of platelets, we addressed the direct infection of platelets by DENV, adhesion of platelets to leukocytes and vascular endothelium and platelet clearance mediated by anti-platelet antibodies. We also focused on platelet involvement on the dengue immunity and pathogenesis through translation and secretion of viral and host factors and through platelet-leukocyte aggregates formation. Hence, the present review highlights important findings related to platelet activation and thrombocytopenia during dengue infection, and also exhibits different mechanisms associated with decreased platelet counts.Graphical abstract:Schematic mechanistic representation of platelet-mediated immune responses and thrombocytopenia during dengue infection. (A) DENV-infected platelets secrete cytokines and chemokines and also adhere to activated vascular endothelium. Platelets aggregate with leukocytes, inducing the secretion of NETs and inflammatory mediators by neutrophils and monocytes, respectively. (B) DENV directly infects stromal cells and hematopoietic precursors, including megakaryocytes, which compromises megakaryopoiesis. Both central and peripheric mechanisms contribute to DENV-associated thrombocytopenia.