Febrile Phase Research Articles

Serum Ferritin As a Prognostic Indicator in Adult Dengue Patients.

Dengue virus (DENV) infection is increasing with rapid urbanization in India. Treatment of DENV infection is mainly supportive with no specific antiviral therapy. Although most patients show mild illness, some have a severe disease course such as dengue hemorrhagic syndrome, dengue shock, multi-organ failure, and death. The cause for severity is not fully understood. Currently, there are no methods available to predict the course of the illness. Hence, it is crucial to develop an early biomarker to predict the course of dengue illness which can aid in vigorous monitoring and early intervention. Here, we tried to establish a correlation between serum ferritin and severity of dengue illness. We measured ferritin levels in 100 dengue-positive cases on day 1 (D1) (febrile phase) and day 4 (D4) (defervescence or convalescent) of admissions to compare the levels with the severity of the disease. On D1, the serum ferritin level was a "good" predictor of severe dengue, with an area under the curve (AUC) of 0.863 with standard error (SE) = 0.043 and a 95% CI from 0.778 to 0.947 (P < 0.05). On D4, serum ferritin was an "excellent" predictor of severe dengue, with an AUC of 0.947 with SE = 0.021 and a 95% CI from 0.907 to 0.988 (P < 0.05). Serum ferritin is an inexpensive and easily accessible biomarker that can assist in monitoring and prognosticating the dengue-positive patients. This biomarker also directs us to explore the underlying pathogenetic mechanism in severe dengue, which can lay a foundation for future targeted therapeutic options to combat severe illness.

Higher Plasma Viremia in the Febrile Phase Is Associated With Adverse Dengue Outcomes Irrespective of Infecting Serotype or Host Immune Status: An Analysis of 5642 Vietnamese Cases.

BackgroundOne of the generally accepted constructs of dengue pathogenesis is that clinical disease severity is at least partially dependent upon plasma viremia, yet data on plasma viremia in primary versus secondary infections and in relation to clinically relevant endpoints remain limited and contradictory.MethodsUsing a large database comprising detailed clinical and laboratory characterization of Vietnamese participants enrolled in a series of research studies executed over a 15-year period, we explored relationships between plasma viremia measured by reverse transcription–polymerase chain reaction and 3 clinically relevant endpoints—severe dengue, plasma leakage, and hospitalization—in the dengue-confirmed cases. All 4 dengue serotypes and both primary and secondary infections were well represented. In our logistic regression models we allowed for a nonlinear effect of viremia and for associations between viremia and outcome to differ by age, serotype, host immune status, and illness day at study enrollment.ResultsAmong 5642 dengue-confirmed cases we identified 259 (4.6%) severe dengue cases, 701 (12.4%) patients with plasma leakage, and 1441 of 4008 (40.0%) patients recruited in outpatient settings who were subsequently hospitalized. From the early febrile phase onwards, higher viremia increased the risk of developing all 3 endpoints, but effect sizes were modest (ORs ranging from 1.12–1.27 per 1-log increase) compared with the effects of a secondary immune response (ORs, 1.67–7.76). The associations were consistent across age, serotype, and immune status groups, and in the various sensitivity and subgroup analyses we undertook.ConclusionsHigher plasma viremia is associated with increased dengue severity, regardless of serotype or immune status.

18F-fluorodeoxyglucose positron emission tomography as a window into human dengue pathophysiology

In mouse models of dengue virus (DENV) infection, 18F-FDG PET is able to sensitively detect tissue-specific sites of inflammation and disease activity, as well as track therapeutic response to anti- DENV agents. However, the use of 18F-FDG PET to study the pathogenesis of inflammation and disease activity in DENV infection in humans, has not been clinically validated. Here we report the 18F-FDG PET imaging results of two patients during the febrile phase of acute DENV infection, paired with serial serum viral load, NS1 and proinflammatory cytokine measurements. Our findings demonstrate that 18F-FDG PET is able to sensitively detect and quantify organ-specific inflammation in the lymph nodes and spleen, in classic acute dengue fever. This raises the potential for 18F-FDG PET to be used as a research tool that may provide further insights into disease pathogenesis.

Enhancing risk prediction of progression to severe disease during the febrile phase of dengue: A systematic review and meta-analysis

Background: Since no effective vaccine or specific treatment for dengue exists, the early prediction of progression to severe disease plays a keys role in patient triage and clinical management during the febrile phase. Without differentiating the time-course of the illness, previous systematic reviews and meta-analyses may have failed to identify early prognostic factors for progression to severe disease. This study aimed to identify the factors associated with progression to severe dengue disease, which are detectable specifically in the febrile phase. Methods and materials: We conducted a systematic review and meta-analysis to identify prognostic factors associated with disease progression identifiable during the febrile phase. Eight medical databases including MEDLINE, EMBASE, and Web of Science were searched for studies published from January 1997 to February 2018. The relevant studies were selected and assessed by three reviewers independenly with discrepancies resolved by consensus. We performed meta-analysis for factors reported in at least four studies. Meta-analysis were performed using random-effects models; heterogeneity and publication bias were also assessed. Results: In line with the 2009 WHO guidelines, we found that vomiting, abdominal pain and tenderness, spontaneous and mucosal bleeding, and clinical fluid accumulation were clinical features associated with severe disease. In addition, we found that the presence of specific pre-existing comorbidities (diabetes mellitus, hypertension and renal disease) were associated with progression to severe disease. We also found that individuals with a lower platelet count, lower serum albumin and higher aminotransferase levels (AST or ALT), detected during the first four days of the illness, were more prone to progress to severe disease. Dengue virus serotype 2 and secondary infections were also associated with progression to severe disease. Conclusion: This study supports the monitoring of the warning signs described in the 2009 WHO guidelines. In addition, testing for infecting serotype and monitoring platelet count, serum albumin, AST or ALT during the febrile phase of illness would improve the early prediction of severe dengue. This improvement would have major implications for the management of patients, particularly on presentation, and health care resource allocation in endemic areas.

Similarities and differences between the \u2018cytokine storms\u2019 in acute dengue and COVID-19

Severe pneumonia and multiorgan dysfunction in COVID-19 and dengue haemorrhagic fever (DHF) are two diseases that can associate with an altered immune response to the infecting virus. To determine the similarities and differences in the cytokine and chemokine responses in these two infections, we compared responses in patients with varying severity of COVID-19 and acute dengue at different time points of illness. During early disease, patients who proceeded to develop COVID-19 severe pneumonia (SP) and DHF had significantly higher levels of IL-6, IL-10 and MIP3α than those who developed mild illness. The lowest levels of IFNγ in early illness were seen in those who succumbed to their illness due to COVID-19. Levels of serum IL-10 (p = 0.0001), IL-6 (p = 0.002), MIP-3α (p = 0.02) and CD40-L levels (p = 0.002) significantly increased from 5 to 9 day of illness to 10–21 day of illness in patients with moderate-to-severe COVID-19, but not in those with mild illness. In contrast, these cytokine/chemokine levels remained unchanged in those with DHF or dengue fever (DF) during febrile and critical phases. Although IL-10 levels were significantly higher in COVID-19 patients with SP, patients with DHF had 25-fold higher levels, whereas IL-6 levels were 11-fold higher in those with COVID-19 SP. IL-10 and other cytokines were evaluated in a larger cohort of patients during early illness (≤ 4 days) who proceeded to develop DF (n = 71) or DHF (n = 64). Of the cytokines evaluated, IL-10 was significantly higher (p < 0.0001) in those who went on to develop DHF compared to DF. Low IFNγ response to the SARS-CoV2 and high levels of immunosuppressive IL-10 in both COVID-19 and dengue during early illness are indicators of an altered antiviral response potentially contributing to disease severity.

Zika Virus Disease Comparing Children and Adults in a Dengue-Endemic Setting

.Acute Zika virus (ZIKV) infection may mimic dengue virus (DENV) infection. We aimed to study the clinical difference of ZIKV disease among suspected non-severe DENV patients comparing children and adults. Patients with acute illness suspected of DENV disease plus no evidence of plasma leakage at the Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand, were enrolled from December 2016 to September 2018. Clinical data including DENV rapid diagnostic test (RDT) results were collected. Zika virus diagnosis was confirmed by real-time reverse transcription PCR on urine. Of 291 (180 pediatric and 111 adult) cases enrolled, 27 (10 pediatric and 17 adult) confirmed ZIKV cases were found. Rash was more frequent among pediatric ZIKV than pediatric non-ZIKV cases (100% versus 60%, P = 0.01). Rash, arthralgia, and conjunctivitis were more frequent among adult ZIKV than adult non-ZIKV cases (100% versus 29.8%, 64.7% versus 26.6%, 52.9% versus 9.7%, all P < 0.01, respectively). The median (interquartile range [IQR]) duration of rash was 4.5 (3.0, 7.25) days and 6.0 (4.5, 7.0) days in pediatric and adults ZIKV cases, respectively. Pediatric ZIKV cases had more fever (100% versus 58.5%, P = 0.03) but less arthralgia (20% versus 64.7%, P = 0.04) and less conjunctivitis (10% versus 52.9%, P = 0.04) than adult ZIKV cases. No ZIKV cases with DENV RDTs performed around day 3 of illness were positive for dengue nonstructural protein 1 (NS1) antigen. In dengue-endemic settings, rash and fever in children, and rash, arthralgia, and conjunctivitis in adults, particularly if rash persists for ≥ 3 days, plus negative dengue NS1 Ag during early febrile phase should prompt ZIKV diagnostic testing.

Dysfunctional Innate Immune Responses and Severe Dengue.

Although infection with the dengue virus (DENV) causes severe dengue, it causes a mild self-limiting illness in the majority of individuals. There is emerging evidence that an aberrant immune response in the initial stages of infection lead to severe disease. Many inflammatory cytokines, chemokines, and lipid mediators are significantly higher in patients with severe dengue compared to those who develop mild infection, during febrile phase of illness. Monocytes, mast cells, and many other cells of the immune system, when infected with the DENV, especially in the presence of poorly neutralizing antibodies, leads to production of pro-inflammatory cytokines and inhibition of interferon signaling pathways. In addition, production of immunosuppressive cytokines such as IL-10 further leads to inhibition of cellular antiviral responses. This dysregulated and aberrant immune response leads to reduced clearance of the virus, and severe dengue by inducing a vascular leak and excessive inflammation due to high levels of inflammatory cytokines. Individuals with comorbid illnesses could be prone to more severe dengue due to low grade endotoxemia, gut microbial dysbiosis and an altered phenotype of innate immune cells. The immunosuppressive and inflammatory lipid mediators and altered phenotype of monocytes are likely to further act on T cells and B cells leading to an impaired adaptive immune response to the virus. Therefore, in order to identify therapeutic targets for treatment of dengue, it would be important to further characterize these mechanisms in order for early intervention. In this review, we discuss the differences in the innate immune responses in those who progress to develop severe dengue, compared to those with milder disease in order to understand the mechanisms that lead to severe dengue.

Peripheral Follicular T Helper Cells and Mucosal-Associated Invariant T Cells Represent Activated Phenotypes During the Febrile Phase of Acute Dengue Virus Infection

Peripheral follicular helper T (pTfh) cells represent specialized CD4+ T cells that help B cells to secrete antibodies. Dengue infection appears to cause immune activation in a wide array of immune cells. Herein, we investigated the signatures of immune activation of circulating Tfh cells and mucosal-associated invariant T (MAIT) cells in adult subjects with confirmed acute clinical dengue virus (DENV) infection by multiparametric flow cytometry. The acute DENV infection induced a significant expansion of highly activated pTfh cells and circulating MAIT cells during acute febrile infection. We found a higher frequency of activated PD-1+ Tfh cells and CD38+ pTfh cells in clinical DENV infection. We also found similar activated and expanding phenotypes of MAIT cells in the patients tested. The total counts of activated pTfh cells and circulating MAIT cells were higher in dengue patients relative to healthy controls. We concluded that pTfh cells and circulating MAIT cells represent activated phenotypes in acute DENV infection.

Dengue viremia kinetics in asymptomatic and symptomatic infection

BackgroundDengue infection is a global health threat. While symptomatic cases contribute to morbidity and mortality, the majority of infected people are asymptomatic but serve as an important reservoir. However, the kinetics of viremia in asymptomatic infections remains unknown. MethodsWe enrolled 279 hospital-based symptomatic index cases and quantified dengue virus (DENV) RNA at enrollment and at the day of defervescence. To identify asymptomatic cases, 175 household members of index cases were monitored for clinical symptoms during follow-up, and blood was taken twice weekly to test for and quantify DENV RNA until cleared. ResultsWe detected DENV in thirteen asymptomatic household members (7.43%). Their DENV serotypes were primarily the same as those of their family index cases. The median peak DENV viremia in asymptomatic subjects was lower than that of symptomatic individuals during the febrile phase, and the viral decay rate was slower in asymptomatic infections. ConclusionsDENV level and kinetics in asymptomatic individuals differed significantly from those of symptomatic cases. Despite the lower viremia, the slower decay rate in asymptomatic infections could lead to their prolonging the infectious reservoir. The improvement of transmission control to prevent such long-lived asymptomatic infections from transmitting the DENV is needed.

Kinetics of CD4+ T Helper and CD8+ Effector T Cell Responses in Acute Dengue Patients.

Background: The protective or pathogenic role of T lymphocytes during the acute phase of dengue virus (DENV) infection has not been fully understood despite its importance in immunity and vaccine development.Objectives: This study aimed to clarify the kinetics of T lymphocyte subsets during the clinical course of acute dengue patients.Study design: In this hospital-based cohort study, 59 eligible Vietnamese dengue patients were recruited and admitted. They were investigated and monitored for T cell subsets and a panel of clinical and laboratory parameters every day until discharged and at post-discharge from the hospital.Results: We described for the first time the kinetics of T cell response during the clinical course of DENV infection. Severe cases showed significantly lower levels of effector CD8+ T cells compared to mild cases at day −1 (p = 0.017) and day 0 (p = 0.033) of defervescence. After defervescence, these cell counts in severe cases increased rapidly to equalize with the levels of mild cases. Our results also showed a decline in total CD4+ T, Th1, Th1/17 cells during febrile phase of dengue patients compared to normal controls or convalescent phase. On the other hand, Th2 cells increased during DENV infection until convalescent phase. Cytokines such as interferon-γ, IL-12p70, IL-5, IL-23, IL-17A showed tendency to decrease on day 0 and 1 compared with convalescence and only IL-5 showed significance indicating the production during acute phase was not systemic.Conclusion: With a rigorous study design, we uncovered the kinetics of T cells in natural DENV infection. Decreased number of effector CD8+ T cells in the early phase of infection and subsequent increment after defervescence day probably associated with the T cell migration in DENV infection.

Changes in Hemoglobin Level and Mean Corpuscular Volume During the Convalescent Phase of Acute Febrile Illness in Children: A Study of the Possible Role of Hemolysis

Fever is one of the most common clinical manifestations in children. During the early days of acute febrile illness, some decrease in hemoglobin levels occurs due to unspecified cause. 64 children aged 6 months to 12-year-old with a fever higher than 38° for more than one day and with a diagnosis of acute febrile illness were admitted. The values of MCV, ESR, CRP, and hepcidin were measured at baseline and then 7 to 10 days after the improvement of the fever. The levels of reticulocytes, LDH, and bilirubin were also measured in two stages. Data analysis was done using SPSS software. The mean hemoglobin level in the acute phase of febrile illness was significantly increased 7-10 days after discontinuation of the fever by 12.87±1.09 g/dl (P&lt;0.001). The MCV level also significantly increased (P&lt;0.001), and levels of CRP, ESR, LDH, bilirubin, and hepcidin showed significantly decreased during the convalescent phase compared to acute febrile phase, but the level of erythrocyte increased. The present study confirmed the decrease in hemoglobin in children with acute febrile illness. Increasing of bilirubin, LDH, hepcidin, level, and no bleeding was observed during acute febrile infection in children.

Blood pressure trend in hospitalized adult dengue patients.

BackgroundMonitoring of blood pressure is an important part of management of dengue illness. Large scale studies of temporal trend of blood pressure in adult dengue are lacking. In this study, we examined the differences in time trend of systolic (SBP) and diastolic blood pressure (DBP) in patients with and without severe dengue (SD), dengue hemorrhagic fever (DHF) and pre-existing hypertension, and elderly versus non-elderly patients.MethodsWe studied a retrospective cohort from 2005 to 2008 of 6,070 hospitalized adult dengue patients confirmed by polymerase chain reaction or clinical criteria plus positive dengue serology. Dengue severity was defined according to World Health Organization 1997 and 2009 guidelines. We used Bayesian hierarchical Markov models to compare the daily mean SBP and DBP between different subgroups. Analysis was conducted by day of defervescence (denoted as day 0), and day of illness onset (denoted as day 1) respectively.ResultsSBP decreased to a nadir during the critical phase before defervescence and was significantly lower for patients with SD or DHF, compared with patients without SD or DHF. DBP increased marginally more for patients with SD or DHF in the critical phase before defervescence. By day of defervescence, comparison of patients with and without SD showed significant difference in SBP from day -6 to day +6, except days +1, +3 and +5, and similarly in DBP except days 0, and +4 to +6. Comparison of patients with and without DHF showed significant difference in SBP from day -6 to day -1, but for DBP, significant difference was noted from day -6 to day +6, except day -2 to day 0. By day of illness, SBP differed significantly between patients with and without SD from illness days 1 to 10, and DBP from illness days 7 to 12. Between patients with and without DHF, SBP differed significantly on illness days 1, 2, 4 to 7, while DBP from days 7 to 12. On analysis by days of defervescence or by days of illness, elderly patients and those with hypertension showed consistently higher SBP and DBP throughout their hospitalization, as compared with their younger and non-hypertensive counterparts.ConclusionIn SD or DHF, SBP decreased to a nadir around the day of defervescence, and recovered to a level exceeding that in febrile phase by days 2 or 3 post-defervescence. Elderly patients and patients with pre-existing hypertension maintained higher SBP and DBP throughout the duration of dengue infection.

Antibody response patterns in chikungunya febrile phase predict protection versus progression to chronic arthritis

Chikungunya virus (CHIKV) infection causes acute febrile illness in humans, and some of these individuals develop a debilitating chronic arthritis that can persist for months to years for reasons that remain poorly understood. In this study from India, we characterized antibody response patterns in febrile chikungunya patients and further assessed the association of these initial febrile-phase antibody response patterns with protection versus progression to developing chronic arthritis. We found 5 distinct patterns of the antibody responses in the febrile phase: no CHIKV binding or neutralizing (NT) antibodies but PCR positive, IgM alone with no NT activity, IgM alone with NT activity, IgM and IgG without NT activity, and IgM and IgG with NT activity. A 20-month follow-up showed that appearance of NT activity regardless of antibody isotype or appearance of IgG regardless of NT activity during the initial febrile phase was associated with a robust protection against developing chronic arthritis in the future. These findings, while providing potentially novel insights on correlates of protective immunity against chikungunya-induced chronic arthritis, suggest that qualitative differences in the antibody response patterns that have evolved during the febrile phase can serve as biomarkers that allow prediction of protection or progression to chronic arthritis in the future.

Phenotype and functionality of follicular helper T cells in patients with acute dengue infection

BackgroundThe association of functionality and phenotype of follicular helper T cells (Tfh) with dengue virus (DENV) specific antibody responses and clinical disease severity has not been well studied.MethodsWe investigated the phenotype and functionality of Tfh cells and plasmablasts in adult patients (DF = 18, DHF = 22) with acute dengue (day 4 to 8 since onset of fever) of varying severity using multiparametric flowcytometry. The properties of Tfh cells were correlated with viraemia, disease severity, plasmablast responses and DENV-specific serum antibody responses. We further evaluated the kinetics of neutralizing antibodies (Neut50) throughout the course of illness in order to evaluate their association with clinical disease severity and viraemia.ResultsTfh cells (especially those producing IL-21 and co-expressing PD-1 and ICOS) were found to be significantly expanded (p < 0.0001) and highly activated in patients with DHF compared to those with DF. The frequency of Tfh cells significantly correlated with DENV-specific IgG, NS1-specific antibodies and Neut50 antibody titres in patients with DHF but not in those with DF. Although the Neut50 titres increased during the course of acute secondary DENV infection, they showed differences based on serotype. For instance, the Neut50 titres were significantly higher during the latter part of illness in patients with DF compared to DHF in DENV1 infection, while in DENV2, patients with DHF had significantly higher titres. The viral loads during early illness did not correlate with the subsequent rise in the Neut50 antibody titres during any time point of illness.ConclusionsThe expansion of Tfh cells is associated with DHF and DENV-specific IgG, NS1-specific and neutralizing antibodies. Neut50 titres did not associate with disease severity or viraemia at the point of first presentation during the febrile phase, but later titres do show differential association with severity in patients with DENV1 compared to DENV2.

Health-Related Quality of Life after Dengue Fever, Morelos, Mexico, 2016-2017.

We adapted the EQ-5D-3L questionnaire and visual analog scale to assess health-related quality of life (HRQOL) and persistent symptoms in 79 patients with laboratory-confirmed dengue in Morelos, Mexico. The lowest HRQOLs were 0.53 and 38.1 (febrile phase). Patients recovered baseline HRQOL in ≈2 months.

Quantitative and Selective Surface Plasmon Resonance Response Based on a Reduced Graphene Oxide-Polyamidoamine Nanocomposite for Detection of Dengue Virus E-Proteins.

Dengue viral infection is one of the most common deadliest diseases and has become a recurrent issue for public health in tropical countries. Although the spectrum of clinical diagnosis and treatment have recently been established, the efficient and rapid detection of dengue virus (DENV) during viremia and the early febrile phase is still a great challenge. In this study, a dithiobis (succinimidyl undecanoate, DSU)/amine-functionalized reduced graphene oxide-–polyamidoamine dendrimer (DSU/amine-functionalized rGO–PAMAM) thin film-based surface plasmon resonance (SPR) sensor was developed for the detection of DENV 2 E-proteins. Different concentrations of DENV 2 E-proteins were successfully tested by the developed SPR sensor-based system. The performance of the developed sensor showed increased shift in the SPR angle, narrow full-width–half-maximum of the SPR curve, high detection accuracy, excellent figure of merit and signal-to-noise ratio, good sensitivity values in the range of 0.08–0.5 pM (S = 0.2576°/pM, R2 = 0.92), and a high equilibrium association constant (KA) of 7.6452 TM−1. The developed sensor also showed a sensitive and selective response towards DENV 2 E-proteins compared to DENV 1 E-proteins and ZIKV (Zika virus) E-proteins. Overall, it was concluded that the Au/DSU/amine-functionalized rGO–PAMAM thin film-based SPR sensor has potential to serve as a rapid clinical diagnostic tool for DENV infection.

Impending Cardiac Tamponade and Hemorrhagic Pleural Effusion as Initial Presentations of Incomplete Kawasaki Disease: A Case Report

Kawasaki disease (KD) is an acute febrile illness that is characterized by systemic inflammation usually involving medium-sized arteries and multiple organs during the acute febrile phase, leading to associated clinical findings. The diagnosis is based on the principal clinical findings including fever, extremity changes, rash, conjunctivitis, oral changes, and cervical lymphadenopathy. However, KD diagnosis is sometimes overlooked or delayed because other systemic organ manifestations may predominate in acute phase of KD. As a cardiovascular manifestation, an acute pericarditis usually shows a small pericardial effusion, but large pericardial effusion showing clinical signs of cardiac tamponade is very rare. Here, we described a case of incomplete KD presenting with impending cardiac tamponade, and recurrent fever and pleural effusion. (J Rheum Dis 2020;27:68-72)

Diagnostic value of ferritin for the severity of dengue infection in children

Retracted by the Editor-In-Chief

Increase of Plasma TNF-α Is Associated with Decreased Levels of Blood Platelets in Clinical Dengue Infection.

Dengue virus (DENV) infection has become an increasingly common concern in tropical and subtropical regions. It has protean manifestations ranging from febrile phase to severe life-threatening illness. In this study, we estimated Th1 and Th2 cytokines and correlated the levels with dengue severity along with certain hematological and biochemical parameters. We also studied the seroprevalence of dengue between October and December 2017 at the Government Theni Medical College, India. Individuals with dengue fever (DF) were positive for either IgM or IgG, or both. The biochemical and hematological parameters along with plasma tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), granulocyte monocyte-colony stimulating factor (GM-CSF), interleukin (IL)-13, IL-12p70, IL-10, IL-5, IL-4, and IL-2 cytokines were estimated. The prevalence of DF was 42.9% during the study period. IL-2, TNF-α, IL-4, and IL-10 levels were significantly elevated (p < 0.005) in patients with secondary DENV infection, whereas the level of IL-13 remained unaltered during both primary and secondary infections. No statistically significant difference was noticed with IL-12p70, IL-5, IFN-γ, and GM-CSF between the healthy controls and the primary and secondary DENV-infected groups. Increase of 1 unit of TNF-α was associated with a decrease of 160 units of blood platelets. Together, the study suggests that TNF-α could play a key role in the pathogenesis of dengue, and despite the decrease in platelet levels, it remains to be seen whether any other inflammatory cells regulate the levels of TNF-α in DENV infection.

Distribution and Determinants of Chronic Kidney Disease of Unknown Etiology: A Brief Overview.

Globally, 33187000 DALYs and 956000 deaths are attributed to chronic kidney disease (CKD) every year. Diabetes and hypertension are the two most common causes of CKD. Another category of CKD without any known common causes, chronic kidney disease of unknown etiology (CKDu) is also increasingly reported from different regions of the world such as Central America, Sri Lanka, and India. They are predominately observed in agricultural communities where crops such as sugarcane and coconut are commonly cultivated. Young adults and males are at higher risk of developing CKDu. It mainly affects individuals belonging to lower socioeconomic status. Exposure to silica, arsenic, and fluoride might be associated with increased prevalence of CKDu. The role of heat stress in contributing to CKD through dehydration is unclear but cannot be ruled out. Mycotoxins such as aflatoxins and ochratoxins are also found to be associated with CKDu in some settings. Several studies have reported that CKDu has a significant positive association with pesticides used in agriculture such as HCH, Endosulfan, Alachlor, and Pendimethalin. There is also a possible role of infections by Hantavirus and Leptospirosis in acute febrile phase of CKDu. However, there is no conclusive evidence from studies conducted on CKDu regarding its causes and risk factors. Therefore, large-scale studies with better methodology need to be conducted to study the etiology and pathogenesis of CKDu in various settings.