Characterization of type I interferon responses in dengue and severe dengue in children in Paraguay

BackgroundInfection with dengue virus (DENV) produces a wide spectrum of clinical illness ranging from asymptomatic infection to mild febrile illness, and to severe forms of the disease. Type I interferons (IFNs) represent an initial and essential host defense response against viruses. DENV has been reported to trigger a robust type I IFN response; however, IFN-α/β profile in the progression of disease is not well characterized.Objectives and study designIn this context, we conducted a retrospective study assessing the circulating serum levels of type I IFNs and related cytokines at different phases of illness in children during the 2011 outbreak of DENV in Paraguay. Demographic, clinical, laboratory and virological data were analyzed.ResultsDuring defervescence, significantly higher levels of IFN-β, IL-6 and MIP-1β, were detected in severe vs. non-severe dengue patients. Additionally, a significant positive correlation between INF-α and viremia was detected in children with severe dengue. A significant positive correlation was also observed between IFN-β serum levels and hematocrit during the febrile phase, whereas IFN-α levels negatively correlated with white blood cells during defervescence in severe dengue patients. Furthermore, previous serologic status of patients to DENV did not influence type I IFN production.ConclusionsThe distinct type I IFN profile in children with dengue and severe dengue, as well as its association with viral load, cytokine production and laboratory manifestations indicate differences in innate and adaptive immune responses that should be investigated further in order to unveil the association of immunological and physiological pathways that underlie in DENV infection.     

Transfusion transmission risk of dengue viruses in an endemic area

It is believed that dengue virus (DENV) is transfusion transmittable, only a few transfusion associated cases were reported so far in spite of at least 50 million dengue infections occur globally each year. The equation for calculating DENV transfusion transmission probability was proposed following the West Nile Virus model. In consideration of reported case number, population size in the region around the designated cases, symptomatic infection rate, blood donation rate, and mosquito biological characteristics together, a relative low rate of DENV transmittable donations was presumed in a low-grade endemic area. Both the apparent clinical presentation and the relative short viremia period of DENV infection prevent dengue viruses from being a highly potential transfusion transmittable agent. The geographically based selection and donor deferral strategy seems to effectively mitigate the potential risk of DENV transfusion transmission. The costly minipooled nucleic acid test (NAT) is therefore not recommended unless for ensuring enough safe blood donations in the dengue epidemic area.     

Diabetic patients suffering dengue are at risk for development of dengue shock syndrome/severe dengue: Emphasizing the impacts of co-existing comorbidity(ies) and glycemic control on dengue severity

Background/PurposeThe impact of type 2 diabetes mellitus (DM2) on clinical severity of dengue has not been fully understood. We aimed to assess risk factors for dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) and severe dengue (SD) (defined based on the World Health Organization 1997 and 2009 dengue classifications), and additionally identify, among DM2 patients, who are at risk for developing DHF/DSS and severe dengue.MethodsA retrospective analysis of dengue patients diagnosed between 2002 and 2010. Risk factors for development of DHF/DSS/SD were identified using multivariate analysis. To elucidate the impacts of coexisting comorbidity(ies) (i.e., hypertension, chronic kidney disease, old stroke, and/or ischemic heart disease) and glycemic control on clinical outcomes of dengue in DM2 patients, the overall DM2 patients and stratified DM2 patients (HbA1c < 7% vs. HbA1c ≧ 7%), with or without comorbidity(ies), were separately compared to controls (patients without any morbidity).ResultsOf 767 (146 DM2 and 621 controls) included patients, 1.4% suffered DSS and 3.3% SD. While DM2 was an independent risk factor for DSS (adjusted odds ratio [AOR] = 7.473; 95% confidence interval [CI] = 2.221–25.146) and SD (AOR = 6.207; 95% CI = 2.464–15.636), only DM2 patients with additional comorbidity(ies) and suboptimal glycemic control (HbA1c ≧ 7%) had significantly higher incidences of non-shock DHF (60.8% vs. 29%), DSS (8.7% vs. 0.8%) and SD (34.8% vs. 1.1%).ConclusionsThese data could help narrow down the number of targets in the triage for risky DM2 dengue patients to those with suboptimal glycemic control and co-existing comorbidity(ies).     

Correlation between increased platelet-associated IgG and thrombocytopenia in secondary dengue virus infections

Although the public health impact of dengue is increasing rapidly, the mechanism of thrombocytopenia in this disease remains unknown. To elucidate this mechanism, the relationship between platelet-associated IgG (PAIgG) and platelet count in 53 patients in the acute phase of secondary dengue virus infection was investigated in a prospective-hospital-based study. A significant inverse correlation between the two parameters was found in these patients, while no correlation was observed in healthy volunteers. The low baseline platelet counts during the acute phase in 12 patients with secondary dengue virus infection significantly increased during the convalescent phase, while the increased PAIgG levels during the acute phase in these patients significantly decreased during the convalescent phase. Anti-platelet IgG autoantibody was detected rarely in the plasma of 53 patients with secondary dengue infection. The involvement of anti-dengue virus IgG was also shown in platelets from all of 8 patients in the acute phase of secondary dengue virus infection. These findings suggest that PAIgG formation involving anti-dengue virus IgG plays a pivotal role in the induction of transient thrombocytopenia during the acute phase of secondary dengue virus infection.     

Analyses of clinical and laboratory characteristics of dengue adults at their hospital presentations based on the World Health Organization clinical-phase framework: Emphasizing risk of severe dengue in the elderly

Background/Purpose

Dengue clinically dynamically changes over time; the World Health Organization (WHO) dengue classification framework proposed 3 dengue clinical phases—febrile (days 1–3), critical (days 4–6) and recovery (days ≥7) phases. This study aimed to better understand clinical and laboratory characteristics in adults (≥18 years) suffering dengue in different clinical phases at their hospital presentations.

Immunopathogenesis of dengue hemorrhagic fever and shock syndrome: role of TAP and HPA gene polymorphism

Clinical outcomes of dengue infection such as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) could be attributed to host genetic factors. The transporters associated with antigen processing (TAP) genes are polymorphic genes located in the human leukocyte antigen (HLA) class II region and are essentially involved in class I antigen presentation. Therefore, these genes might grant susceptibility to severe dengue infection. Hence, the aim of the study was to type the TAP1 gene (using amplification refraction mutation system [ARMS] polymerase chain reaction [PCR]) and HPA1 and HPA2 gene polymorphism (by PCR–sequence specific primers) in different clinical spectrums of dengue infection. The study included 100 controls and 91 DF, 75 DHF, and 32 DSS patients. The results revealed that the frequencies of valine at TAP1 333 and HPA 1b at HPA1 were increased among DHF and DSS, respectively, in comparison to controls (p <0.05). The frequency of genotype TAP1 333 ILE/VAL (61.3%) was significantly higher in DHF compared with control (37%, p = 0.005) or DF (38.9%, p = 0.007) patients. A significantly greater proportion of DHF patients demonstrated HPA1a/1a and HPA 2a/2b genotypes than DF patients. DSS patients were more likely to be heterozygous at HPA1 than DHF (OR = 4.75, p = 0.003). A positive correlation existed between TAP1 333 and HPA1 in DHF (p = 0.017, r = 0.229). This first report on TAP and HPA gene polymorphism in dengue suggested that the heterozygous pattern at the TAP1 333 locus and HPA1a/1a and HPA2a/2b genotypes confer susceptibility to DHF and the HPA1a/1b genotype was determined to be a genetic risk factor for DSS.     

Association of increased platelet-associated immunoglobulins with thrombocytopenia and the severity of disease in secondary dengue virus infections

Severe thrombocytopenia and increased vascular permeability are two major characteristics of dengue haemorrhagic fever (DHF). To develop a better understanding of the roles of platelet-associated IgG (PAIgG) and IgM (PAIgM) in inducing thrombocytopenia and its severity of disease in patients with secondary dengue virus infection, the relationship between the PAIgG or PAIgM levels and disease severity as well as thrombocytopenia was examined in 78 patients with acute phase secondary infection in a prospective hospital-based study. The decrease in platelet count during the acute phase recovered significantly during the convalescent phase. In contrast, the increased levels of PAIgG or PAIgM that occurred during the acute phase of these patients decreased significantly during the convalescent phase. An inverse correlation between platelet count and PAIgG or PAIgM levels was found in these patients. Anti-dengue virus IgG and IgM activity was found in platelet eluates from 10 patients in an acute phase of secondary infection. Increased levels of PAIgG or PAIgM were significantly higher in DHF than those in dengue fever (DF). An increased level of PAIgM was associated independently with the development of DHF, representing a possible predictor of DHF with a high specificity. Our present data suggest that platelet-associated immunoglobulins involving antidengue virus activity play a pivotal role in the induction of thrombocytopenia and the severity of the disease in secondary dengue virus infections.     

Dengue virus and other arboviruses: a global view of risks

Arboviruses (arthropod-borne viruses) are an ecological group of viruses from different families (e.g. Bunyaviridae, Flaviviridae and Togaviridae) that use arthropods such as mosquitoes, flies and ticks as vectors for transmission between different hosts. The superb plasticity of these viruses allows propagation to different host systems including both invertebrates and vertebrates. More than 500 species of arbo-virus have been described and are listed in the International Catalogue of arbo-virus ( http://www.cdc.gov/nczved/divisions/dvbid/arbovirus.html ), many of which are of medical importance. Globally, arboviral infections have become increasingly common and human diseases caused by these infections have expanded their frontiers in the last few decades emerging in places with no previous history of epidemic activity or localised transmission of a specific arbovirus. One example is the recent arrival of West Nile virus (WNV) in the Western Hemisphere and its subsequent propagation in the Americas. Arboviral diseases are also re-emerging in places where the disease had previously been well-controlled or eradicated, resulting in an increasing number of cases and more severe forms of disease in endemic regions. Human infections with arboviruses are mostly asymptomatic, but symptomatic infections can range from malaise, mild febrile illness (with flu-like symptoms) to severe disease that may progress to long-term physical or cognitive impairment and/or mortality. Arboviral infections have an incubation period during which viral replication with a viremic phase takes place in the absence of symptoms. Viremic blood has the potential to transmit infection to blood recipients and therefore arboviruses can pose a threat to the safety of the blood supply. For instance, during an epidemic, asymptomatic individuals may donate blood and transmit the infection to blood component recipients. Among the arboviral infections that have been on the radar for increased activity in the last decade are: WNV, Dengue viruses (DENV) and Chikungunya virus (CHIKV). In addition, other arboviral infections such as Yellow Fever, Saint Louis encephalitis, Tick-borne encephalitis, Rift Valley fever, Japanese encephalitis, Powassan encephalitis, Murray Valley encephalitis and Zika fever have been reported as emerging or re-emerging in various areas around the globe. Alertness and surveillance are required to allow implementation of measures to mitigate risk of transmission to blood recipients including blood screening tests when available and appropriate. In addition, the evidence of increased arbovirus activity worldwide points to the critical need for the development of affordable diagnostic and screening assays with high sensitivity and specificity as well as new vaccines and therapies, since most populations at risk reside in less privileged parts of the world. The need for these tools is pressed by the imminent possibility of outbreaks in any part of the world due to the combination of expanding distribution of vectors and increased mobility of infected hosts by travel and trade.     

Predictive score for clinical complications during intra-hospital transports of infants treated in a neonatal unit

OBJECTIVE:

To develop and validate a predictive score for clinical complications during intra-hospital transport of infants treated in neonatal units.

METHODS:

This was a cross-sectional study nested in a prospective cohort of infants transported within a public university hospital from January 2001 to December 2008. Transports during even (n = 301) and odd (n = 394) years were compared to develop and validate a predictive score. The points attributed to each score variable were derived from multiple logistic regression analysis. The predictive performance and the score calibration were analyzed by a receiver operating characteristic (ROC) curve and Hosmer-Lemeshow test, respectively.

RESULTS:

Infants with a mean gestational age of 35±4 weeks and a birth weight of 2457±841 g were studied. In the derivation cohort, clinical complications occurred in 74 (24.6%) transports. Logistic regression analysis identified five variables associated with these complications and assigned corresponding point values: gestation at birth [<28 weeks (6 pts); 28-34 weeks (3 pts); >34 weeks (2 pts)]; pre-transport temperature [<36.3°C or >37°C (3 pts); 36.3-37.0°C (2 pts)]; underlying pathological condition [CNS malformation (4 pts); other (2 pts)]; transport destination [surgery (5 pts); magnetic resonance or computed tomography imaging (3 pts); other (2 pts)]; and pre-transport respiratory support [mechanical ventilation (8 pts); supplemental oxygen (7 pts); no oxygen (2 pts)]. For the derivation and validation cohorts, the areas under the ROC curve were 0.770 and 0.712, respectively. Expected and observed frequencies of complications were similar between the two cohorts.

CONCLUSION:

The predictive score developed and validated in this study presented adequate discriminative power and calibration. This score can help identify infants at risk of clinical complications during intra-hospital transports.     

Study of serum VEGF levels in patients with severe dengue infection admitted in a tertiary care hospital in Kolkata

Dengue is the most common arboviral infection globally, but its pathogenesis is poorly explored. Vascular endothelial growth factor (VEGF) has an essential role in the host defense against viral infection. However, not much information is available regarding its status in dengue patients from the eastern zone of India. In the present investigation, the level of VEGF was investigated for its possible utility as a dengue severity marker. Accordingly, confirmed dengue cases were enrolled during 2016-2018. Serum from all the study subjects was subjected to the standard enzyme-linked immunosorbent assay test for VEGF analysis. In addition, we assessed the association of VEGF to dengue severity. The study revealed that VEGF titers (P < .0001) were significantly increased in severe dengue (SD) patients in contrast to those with a milder form of dengue. An association was obtained between VEGF and increased SGOT (r = 0.517 with P < .0001) while VEGF had a negative correlation with platelets in SD patients (r = −0.331 with P = .001). Enhanced VEGF titers along with decreased platelets had a good association with SD. The investigation revealed that high VEGF titers are novel indicators of dengue severity. However, our results must be verified in a study evaluating a larger number of dengue patients.     

Application of nested multiplex polymerase chain reaction respiratory and pneumonia panels in children with severe community-acquired pneumonia

Community-acquired pneumonia (CAP) is a serious clinical concern. A lack of accurate diagnosis could hinder pathogen-directed therapeutic strategies. To solve this problem, we evaluated clinical application of nested multiplex polymerase chain reaction (PCR) in children with severe CAP. We prospectively enrolled 60 children with severe CAP requiring intensive care between December 2019 and November 2021 at a tertiary medical center. Nested multiplex PCR respiratory panel (RP) and pneumonia panel (PP) were performed on upper and lower respiratory tract specimens. We integrated standard-of-care tests and quantitative PCR for validation. The combination of RP, PP, and standard-of-care tests could detect at least one pathogen in 98% of cases and the mixed viral-bacterial detection rate was 65%. The positive percent agreement (PPA), and negative percent agreement (NPA) for RP were 94% and 99%; the PPA and NPA for PP were 89% and 98%. The distribution of pathogens was similar in the upper and lower respiratory tracts, and the DNA or RNA copies of pathogens in the lower respiratory tract were equal to or higher than those in the upper respiratory tract. PP detected bacterial pathogens in 40 (67%) cases, and clinicians tended to increase bacterial diagnosis and escalate antimicrobial therapy for them. RP and PP had satisfactory performance to help pediatricians make pathogenic diagnoses and establish therapy earlier. The pathogens in the upper respiratory tract had predictive diagnostic values for lower respiratory tract infections in children with severe CAP.     

Elevated plasma levels of the long pentraxin, pentraxin 3, in severe dengue virus infections

C-reactive protein is one of the most widely used indicators of the response of acute-phase proteins. The measurement of C-reactive protein in dengue, however, is clinically not useful, because of marginally elevated levels and absent association with disease severity. The prototypic long pentraxin, pentraxin 3, is an acute phase protein that is structurally related but distinct from C-reactive protein which has proven to correlate with the severity of bacterial infection in critically ill patients. The potential involvement of pentraxin 3 in dengue and its aptitude to predict more severe disease or poor clinical outcome has not been studied previously. We therefore measured pentraxin 3 plasma levels in 44 dengue virus infected patients. Pentraxin 3 levels were strikingly higher when compared to C-reactive protein levels, with highest pentraxin 3 values observed in the first 7 days after the onset of symptoms. Median pentraxin 3 levels at admission and peak levels during follow up were higher in patients suffering from dengue shock syndrome (at admission: 119.3 ng/ml [interquartile range 61.8--188.7], peak values during follow up: 147.9 ng/ml [interquartile range 85.7--204.3]) compared to levels found in patients with dengue fever and dengue hemorrhagic fever (at admission: 59.0 ng/ml [interquartile range 28.6--100.3], P=0.040; peak values during follow up: 80.8 ng/ml [interquartile range 36.1--168.1], P=0.020). Our results indicate that pentraxin 3 seems to be a marker of infection better than C-reactive protein in dengue. The role of pentraxin 3 in the pathogenesis of dengue and its potential as an early prognostic indicator of disease severity needs further assessment.     

Admission source and mortality in a pediatric intensive care unit

Background and Aims:

Studies carried out in different countries have shown that source of patient admission in Intensive Care Units (ICUs) is associated to death. Patients admitted from wards show a greater ICU mortality. The aim of the present study was to investigate the association between admission source and outcome in a Pediatric Intensive Care Unit (PICU).

Materials and Methods:

We studied all PICU admissions that took place between January 2002 and December 2005 in a tertiary hospital in Brazil. The major outcome studied was death while in the PICU. The independent variable analyzed was admission source, defined either as pediatric emergency room (PER), wards, operating room (OR) of the same hospital or other sources.

Results:

A total of 1823 admissions were studied. The overall expected mortality based on the Pediatric Index of Mortality 2 was 6.5% and the observed mortality was 10.3%. In adjusted analysis, the mortality was doubled in patients admitted from wards when compared with the PER patients.

Conclusions:

Observed mortality rates were higher in patients admitted from wards within the same hospital, even after adjustment.     

Use of exchange blood transfusion in the management of severe COVID-19 infection in pregnancy: experience from Lagos,Nigeria

Coronavirus disease 2019 (COVID-19) presents with symptoms that may be mild or severe. The individual with the severe form of the disease usually presents with a constellation of respiratory symptoms typical of acute respiratory distress syndrome. In this report, we present our experience of the successful management of an oxygen-dependent pregnant woman with severe COVID-19 infection who had 2 sessions of partial exchange blood transfusion. We discussed the principles that informed this intervention and the need to adopt this novel approach in the care of severe COVID-19 infection.     

Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects

Outbreaks of the Zika, dengue, and chikungunya viruses, especially in the Americas, pose a global threat due to their rapid spread and difficulty controlling the vector. Extreme phenotypes are often observed, from asymptomatic to severe clinical manifestations, which are well-studied in dengue. Host variations are also important contributors to disease outcomes, and many case-control studies have associated single nucleotide polymorphisms (SNPs) with severe dengue. Here, we found that the TC genotype and T-carriers for SNP rs1285933 in the C-type lectin superfamily member 5 (CLEC5A) gene was associated with severe dengue in a Northern Brazilian population (OR = 2.75 and p-value = 0.01, OR = 2.11 and p-value = 0.04, respectively). We also tested the functional effect of the CLEC5A protein and found that it is upregulated on the surface of human monocytes after in vitro dengue infection. CLEC5A was correlated with viral load inside the monocytes (Spearman r = 0.55, p = 0.008) and TNF production in culture supernatants (Spearman r = 0.72, p = 0.03). Analysis of mRNA in blood samples from DENV4-infected patients exhibiting mild symptoms showed that CLEC5A mRNA expression is correlated with TNF (r = 0.67, p = 0.0001) and other immune mediators. Monocytes from rs1285933 TT/TC individuals showed lower CLEC5A expression compared to CC genotypes. However, in these cells, CLEC5A was not correlated with TNF production. In summary, we confirmed that CLEC5A is genetically associated with dengue severity outcome, playing a central role during the immune response triggered by a dengue viral infection, and rs1285933 is a relevant SNP that is able to regulate signaling pathways after interactions between the dengue virus and CLEC5A receptors.     

A pediatric case of severe fever with thrombocytopenia syndrome in Zhejiang Province,China

This report describes a pediatric case of severe fever with thrombocytopenia syndrome (SFTS), which is an emerging disease that is caused by a novel bunyavirus. Interestingly, the previously reported SFTS cases typically involved elderly patients, while our case involved a 5-year-old child from Zhejiang Province, China. In this report, we describe our investigation of the clinical and epidemiological characteristics of this case, to improve our understanding of this emerging disease. Our principle finding was that the present case’s clinical symptoms were milder than those that have been reported in adult cases of SFTS. Therefore, we recommend more careful screening of pediatric patients who present with mild symptoms that are consistent with SFTS.     

Bloodstream infections in hospitalized adults with dengue fever: Clinical characteristics and recommended empirical therapy

Background

Dengue is an important mosquito-borne tropical viral disease and dual infection, though rare, has been regarded as a risk factor for severe disease and mortality. However, few studies focused on bloodstream infections (BSIs) and empirical antibiotic therapy rarely addressed.