Respiratory syncytial virus infection in adults: Differences with influenza.

INTRODUCTION: Respiratory syncytial virus (RSV) causes an acute respiratory illness similar to influenza, although there are few data comparing both of them in adults. The existence of clinical differences between these two infections could have implications for their management. MATERIALS AND METHODS: Retrospective observational cohort study including 63 adults with positive PCR for RSV and 221 for influenza during winter 2018-2019. Epidemiological, clinical characteristics and outcomes were contrasted between both groups. RESULTS: Compared to influenza, RSV-positive patients presented a higher association with active neoplasia (OR=2.9; 95% CI: 1.2-6.9), dependence for basic activities of daily living (OR=3.4; 95% CI: 1.4-8.2) and immunosuppression due to chronic glucocorticoid administration (OR=7.6; 95% CI: 1.6-36.1). At diagnosis, fever was less common (OR=0.3; 95% CI: 0.2-0.7), and C-reactive protein level ≥100mg/l was more frequent (OR=2.1; 95% CI: 1.0-4.5). They developed bacterial co-infection by Staphylococcus aureus in a higher proportion (OR=8.3; 95% CI: 1.5-46.9) and presented a greater need for admission to the intensive care unit (OR=5.4; 95% CI: 1.4-19.2). CONCLUSION: RSV is an important cause of respiratory illness in adults during the influenza season. It especially affects vulnerable patients with chronic underlying diseases, and has a higher morbidity than influenza. For all these reasons, specific detection, prevention and treatment of RSV is necessary in order to reduce the consumption of health care resources due to RSV disease in adults.

Respiratory syncytial virus burden and risk factors for severe disease in patients presenting to the emergency department with flu-like symptoms or acute respiratory failure.

BACKGROUND: Predictors of Respiratory Syncytial Virus (RSV) infection and determinants of RSV unfavorable outcomes are still unclear. We assessed RSV burden and investigated the risk factors associated with RSV positive swab and RSV severe disease. METHODS: A retrospective, single center, cohort study included all consecutive patients referred to the emergency department of L. Sacco University Hospital (Milan) with flu-like symptoms or acute respiratory failure (aRF) tested per protocol for SARS-CoV-2, RSV, Influenza A (InvA) during the 2022-2023 autumn/winter season. Clinical characteristics and patients' outcomes were registered. Respiratory failure, need for respiratory support, shock, sepsis or in-hospital death defined severe disease. MAIN FINDINGS: The analysis included 717 patients (65.1% negative swab, 14.1% InvA, 8.5% RSV, 8.6% SARS-CoV-2, 3.6% other viruses). Compared with the study cohort, RSV patients had the highest occurrence of aRF (62.7%) and severe disease (70.5%); mortality was similar to InvA (6.6% vs 5.9%, p = 0.874). Compared with InvA patients, RSV patients were older (p = 0.009), had higher Charlson index (p = 0.001), higher prevalence of chronic heart failure (p = 0.001) and were more frequently on ICS (p = 0.026) and immunosuppressants (p = 0.018). Heart failure [OR (95%CI):3.286 (1.031-10.835); p = 0.041], chronic exposure to ICS [OR (95%CI):2.377 (1.254-4.505); p = 0.008] and immunosuppressants [OR (95%CI):3.661 (1.246-10.754); p = 0.018] predicted RSV infection. Glycaemia ≥120 mg/dL [OR (95%CI):5.839 (1.155-29.519); p = 0.033], leucocytes ≥8000 cells/µL [OR (95%CI):5.929 (1.090-32.268); p = 0.039], and past/active smoking [OR (95%CI):7.347 (1.301-41.500); p = 0.024] predicted severe RSV disease. CONCLUSIONS: RSV infection is associated with significant mortality and morbidity. Preventive strategies for RSV infection such as vaccination are highly warranted, especially in older patients with cardiovascular and chronic respiratory conditions.

Risk Factors for Severe Respiratory Syncytial Virus Infection in Hospitalized Children.

BACKGROUND: RSV often leads to hospitalization, and accurate knowledge of risk factors is crucial. METHODS: We retrospectively analyzed laboratory-confirmed RSV hospitalizations regarding pregnancy factors, birth status, cigarette smoke exposure, nutrition, social conditions, clinical presentation, and severe disease defined as a need for passive oxygen therapy (pO2Tx), the presence of pneumonia, respiratory failure, intensive care unit (ICU) transfer, and prolonged hospitalization. RESULTS: A univariate analysis included 594 children (median age 4 months) and revealed a pO2Tx relationship with age ≤ 3 months (OR = 1.56), prematurity (OR = 1.71), being born during RSV season (OR = 1.72), smoke exposure during pregnancy (both parents (OR = 2.41, father (OR = 1.8)), dyspnea (OR = 5.09), and presence of apnea (OR = 5.81). Pneumonia was associated with maternal smoke exposure (OR = 5.01), fever (OR = 3.92), dyspnea (OR = 1.62), history of aspiration (OR = 4.63), and inversely with age ≤ 3 months (OR = 0.45). Respiratory failure was associated with prematurity (OR = 3.13) and apnea (OR = 18.78), while the lower odds were associated with older age (OR = 0.57 per month) and presence of fever (OR = 0.11). ICU transfer was associated with apnea (OR = 17.18), but an inverse association was observed with age (OR = 0.54) and fever (OR = 0.11). A prolonged hospital stay was associated with prematurity (OR = 1.76), low birth weight (OR = 2.89), aspiration (OR = 4.93), and presence of fever (OR = 1.51). CONCLUSIONS: Age (up to 3 months), prematurity, and presence of apnea are risk factors for a severe RSV course.

Proteomics endotyping of infants with severe bronchiolitis and risk of childhood asthma.

BACKGROUND: Bronchiolitis is the leading cause of hospitalization in U.S. infants and a major risk factor for childhood asthma. Growing evidence supports clinical heterogeneity within bronchiolitis. We aimed to identify endotypes of infant bronchiolitis by integrating clinical, virus, and serum proteome data, and examine their relationships with asthma development. METHODS: This is a multicenter prospective cohort study of infants hospitalized for physician-diagnosis of bronchiolitis. We identified bronchiolitis endotypes by applying unsupervised machine learning (clustering) approaches to integrated clinical, virus (respiratory syncytial virus [RSV], rhinovirus [RV]), and serum proteome data measured at hospitalization. We then examined their longitudinal association with the risk for developing asthma by age 6 years. RESULTS: In 140 infants hospitalized with bronchiolitis, we identified three endotypes: (1) clinicalatopic virusRV proteomeNFκB-dysregulated , (2) clinicalnon-atopic virusRSV/RV proteomeTNF-dysregulated , and (3) clinicalclassic virusRSV proteomeNFκB/TNF-regulated endotypes. Endotype 1 infants were characterized by high proportion of IgE sensitization and RV infection. These endotype 1 infants also had dysregulated NFκB pathways (FDR < 0.001) and significantly higher risks for developing asthma (53% vs. 22%; adjOR 4.04; 95% CI, 1.49-11.0; p = 0.006), compared with endotype 3 (clinically resembling "classic" bronchiolitis). Likewise, endotype 2 infants were characterized by low proportion of IgE sensitization and high proportion of RSV or RV infection. These endotype 2 infants had dysregulated tumor necrosis factor (TNF)-mediated signaling pathway (FDR <0.001) and significantly higher risks for developing asthma (44% vs. 22%; adjOR 2.71; 95% CI, 1.03-7.11, p = 0.04). CONCLUSION: In this multicenter cohort, integrated clustering of clinical, virus, and proteome data identified biologically distinct endotypes of bronchiolitis that have differential risks of asthma development.

A Retrospective Cohort Study on Infant Respiratory Tract Infection Hospitalizations and Recurrent Wheeze and Asthma Risk: Impact of Respiratory Syncytial Virus.

BACKGROUND: Infant respiratory syncytial virus infection (RSV) has been associated with asthma later in life. We explored the risk of recurrent wheeze or asthma in children with infant RSV-associated hospitalization compared to other respiratory infections. METHODS: We performed a retrospective cohort study using Danish national hospital discharge registers. Infants younger than 6 months, born between January 1995 and October 2018, and with a RSV hospital admission were compared to infants hospitalized for injuries, non-RSV acute upper respiratory tract infection (AURTI), pneumonia and other respiratory pathogens, nonpathogen-coded lower respiratory tract infections (LRTI), pertussis, or nonspecific respiratory infections. Infants were followed until recurrent wheeze or asthma diagnosis, death, migration, age 10 years, or study end. We estimated cumulative incidence rate ratios (CIRR) and hazard ratios (HR) adjusted for sex, age at inclusion, hospital length of stay (LOS), maternal smoking, 5-minute APGAR score (APGAR5), prematurity, and congenital risk factors (CRF). RESULTS: We included 68 130 infants, of whom 20 920 (30.7%) had RSV hospitalization. The cumulative incidence rate of recurrent wheeze or asthma was 16.6 per 1000 person-years after RSV hospitalization, higher than after injury (CIRR, 2.69; 95% confidence interval [CI], 2.48-2.92), AURTI (CIRR, 1.48; 95% CI, 1.34-1.58), or pertussis (CIRR, 2.32; 95% CI, 1.85-2.91), similar to pneumonia and other respiratory pathogens (CIRR, 1.15; 95% CI, .99-1.34) and LRTI (CIRR, 0.79; 95% CI, .60-1.04), but lower than nonspecific respiratory infections (CIRR, 0.79; 95% CI, .73-.87). Adjusted HRs for recurrent wheeze or asthma after RSV hospitalization compared to injuries decreased from 2.37 (95% CI, 2.08-2.70) for 0 to <1 year to 1.23 (95% CI, .88-1.73) for 6 to <10 years for term-born children, and from 1.48 (95% CI, 1.09-2.00) to 0.60 (95% CI, .25-1.43) for preterm-born children. Sex, maternal smoking, LOS, CRF, and APGAR5 were independent risk factors. CONCLUSIONS: Infant RSV hospitalization is associated with recurrent wheeze and asthma hospitalization, predominantly at preschool age. If causal, RSV prophylaxis, including vaccines, may significantly reduce disease burden of wheeze and asthma.

ITGB4 deficiency induces mucus hypersecretion by upregulating MUC5AC in RSV-infected airway epithelial cells.

Respiratory syncytial virus (RSV) infection is the main cause of bronchiolitis in children. Excessive mucus secretion is one of the primary symbols in RSV related lower respiratory tract infections (RSV-related LRTI), which is closely associated with the occurrence and development of asthma in later life. Integrin ß4 (ITGB4) is down-regulated in the airway epithelial cells (AECs) of asthma patients which plays a critical role in the pathogenesis of asthma. However, whether ITGB4 is involved in the pathological processes of RSV infection remains unclear. In this study, we found that decreased expression of ITGB4 was negatively correlated with the level of MUC5AC in childhood AECs following RSV infection. Moreover, ITGB4 deficiency led to mucus hypersecretion and MUC5AC overexpression in the small airway of RSV-infected mice. MUC5AC expression was upregulated by ITGB4 in HBE cells through EGFR, ERK and c-Jun pathways. EGFR inhibitors treatment inhibited mucus hypersecretion and MUC5AC overexpression in ITGB4-deficient mice after RSV infection. Together, these results demonstrated that epithelial ITGB4 deficiency induces mucus hypersecretion by upregulating the expression of MUC5AC through EGFR/ERK/c-Jun pathway, which further associated with RSV-related LRTI.

Exchange Protein Directly Activated by cAMP 2 Enhances Respiratory Syncytial Virus-Induced Pulmonary Disease in Mice.

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in young children. It is also a significant contributor to upper respiratory tract infections, therefore, a major cause for visits to the pediatrician. High morbidity and mortality are associated with high-risk populations including premature infants, the elderly, and the immunocompromised. However, no effective and specific treatment is available. Recently, we discovered that an exchange protein directly activated by cyclic AMP 2 (EPAC2) can serve as a potential therapeutic target for RSV. In both lower and upper epithelial cells, EPAC2 promotes RSV replication and pro-inflammatory cytokine/chemokine induction. However, the overall role of EPAC2 in the pulmonary responses to RSV has not been investigated. Herein, we found that EPAC2-deficient mice (KO) or mice treated with an EPAC2-specific inhibitor showed a significant decrease in body weight loss, airway hyperresponsiveness, and pulmonary inflammation, compared with wild-type (WT) or vehicle-treated mice. Overall, this study demonstrates the critical contribution of the EPAC2-mediated pathway to airway diseases in experimental RSV infection, suggesting the possibility to target EPAC2 as a promising treatment modality for RSV.

Mild encephalitis/encephalopathy with a reversible splenial lesion associated with respiratory syncytial virus infection in infants.

Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a clinicoradiologic syndrome typically characterized by transient mild encephalitis or encephalopathy with reversible lesions being found in the splenium of corpus callosum (SCC) by magnetic resonance imaging (MRI). A variety of pathogens including influenza virus, rotavirus, and adenovirus associated with MERS have been reported. However, respiratory syncytial virus (RSV)-related MERS is relatively rare in infants. In this study, we report two Chinese infants who suffered from RSV-related MERS. Both infants manifested as fever, seizure, and altered states of consciousness with confirmed detections of RSV-RNA in the specimens from throat swab. Clinical symptoms/signs such as apnea and shallow breathing were also noted in these two infants. Furthermore, brain MRI images indicated reversible isolated lesions with transiently reduced diffusion in the SCC. Fortunately, both of these two infants recovered completely following treatment within a month. Our study suggests that RSV may serve as a novel causative agent for MERS in infants. Clinicians should focus more attention on RSV-related MERS in infants in order to improve early accurate diagnosis and therapeutic decision making.

Respiratory syncytial virus nonstructural protein 1 breaks immune tolerance in mice by downregulating Tregs through TSLP-OX40/OX40L-mTOR axis.

Respiratory syncytial virus (RSV) infection in early life is associated strongly with the subsequent development and exacerbation of asthma, however, the mechanism is still ambiguous. In this study, we identified that RSV nonstructural protein (NS) 1 plays a critical role. Plasmid-mediated overexpression of NS1 induced significant airway hyperresponsiveness, eosinophilia, and mucus hyperproduction in mice. In the pNS1 group, there were markedly elevated proportions of Th2 and Th17 cells, while Th1 and Foxp3+ regulatory T cells (Tregs) significantly declined compared with the control group. Serum concentrations of interleukin (IL)-4, IL-5, IL-6, IL-17, transforming growth factor-beta, and tumor necrosis factor-alpha increased but levels of interferon-gamma and interleukin-10 declined in pNS1 group. Besides, NS1 caused a significant rise of serum thymic stromal lymphopoietin (TSLP) and OX40L levels, and a neutralizing mAb anti-OX40L was capable of promoting RSV clearance and attenuating the airway allergic inflammation caused by pNS1. Otherwise, OX40L-blocking counteracts the inhibitory effect of pNS1 on Tregs in the spleen. RSV NS1 caused elevated levels of phospho-AKT, phospho-mTOR, and phospho-S6K1, which were partially attenuated by anti-OX40L. Moreover, a specific inhibitor of mTORC1 significantly relieved the inhibition of Foxp3 expression and Tregs differentiation. Together, the data indicate that RSV NS1 protein breaks immune tolerance and induces airway inflammation and hyperresponsiveness in mice. In this process, NS1-stimulated TSLP and OX40L play a major role by inhibiting the induction of Tregs, which is at least partially mediated by modulating AKT-mTOR signaling pathways.

COPD Is Associated with Elevated IFN-ß Production by Bronchial Epithelial Cells Infected with RSV or hMPV.

IFN treatment may be a viable option for treating COPD exacerbations based on evidence of IFN deficiency in COPD. However, in vitro studies have used primarily influenza and rhinoviruses to investigate IFN responses. This study aims to investigate the susceptibility to infection and IFN response of primary bronchial epithelial cells (BECs) from COPD donors to infection with RSV and hMPV. BECs from five COPD and five healthy donors were used to establish both submerged monolayer and well-differentiated (WD) cultures. Two isolates of both RSV and hMPV were used to infect cells. COPD was not associated with elevated susceptibility to infection and there was no evidence of an intrinsic defect in IFN production in either cell model to either virus. Conversely, COPD was associated with significantly elevated IFN-ß production in response to both viruses in both cell models. Only in WD-BECs infected with RSV was elevated IFN-ß associated with reduced viral shedding. The role of elevated epithelial cell IFN-ß production in the pathogenesis of COPD is not clear and warrants further investigation. Viruses vary in the responses that they induce in BECs, and so conclusions regarding antiviral responses associated with disease cannot be made based on single viral infections.

Deficiency in ST2 signaling ameliorates RSV-associated pulmonary hypertension.

Pulmonary hypertension (PH) observed during respiratory syncytial virus (RSV) bronchiolitis is associated with morbidity and mortality, especially in children with congenital heart disease. Yet, the pathophysiological mechanisms of RSV-associated PH remain unclear. Therefore, this study aimed to investigate the pathophysiological mechanism of RSV-associated PH. We used a translational mouse model of RSV-associated PH, in which wild-type (WT) and suppression of tumorigenicity 2 (ST2) knockout neonatal mice were infected with RSV at 5 days old and reinfected 4 wk later. The development of PH in WT mice following RSV reinfection was evidenced by elevated right ventricle systolic pressure, shortened pulmonary artery acceleration time (PAT), and decreased PAT/ejection time (ET) ratio. It coincided with the augmentation of periostin and IL-13 expression and increased arginase bioactivity by both arginase 1 and 2 as well as induction of nitric oxide synthase (NOS) uncoupling. Absence of ST2 signaling prevented RSV-reinfected mice from developing PH by suppressing NOS uncoupling. In summary, ST2 signaling was involved in the development of RSV-associated PH. ST2 signaling inhibition may be a novel therapeutic target for RSV-associated PH.NEW & NOTEWORTHY We report that the pathogenic role of ST2-mediated type 2 immunity and mechanisms contribute to RSV-associated pulmonary hypertension. Inhibiting ST2 signaling may be a novel therapeutic target for this condition.

Letalidad en lactantes con cardiopatías congénitas hospitalizados por virus respiratorio sincicial / Case fatality in infants with congenital heart disease hospitalized for respiratory syncytial virus

INTRODUCCIÓN. Las cardiopatías congénitas son un factor de riesgo para desarrollar enfermedad severa por virus respiratorio sincicial (VRS). En Chile no se conoce la hospitalización o letalidad por esta causa. El objetivo de este estudio fue determinar la letalidad de niños menores de 2 años con cardiopatías congénitas hospitalizados por infección por VRS en el hospital de niños Roberto del Río, Santiago, Chile. MÉTODO. Estudio descriptivo retrospectivo de revisión de fichas clínicas de niños menores de 24 meses con cardiopatía congénita, hospitalizados por infección respiratoria baja por VRS. Se registró edad, género, tipo de cardiopatía congénita, comorbilidades, días de hospitalización, ingreso a unidad de paciente crítico y letalidad en Hospital Roberto del Río durante los años 2014 a 2016. Se analizaron resultados mediante Stata 13. Aprobado por Comité de ética del Servicio de Salud Metropolitano Norte RESULTADOS: Se estudian 94 pacientes hospitalizados, mediana de edad de 7,3 meses, 45 (48%) hombres. Los casos de cardiopatía congénita cianótica fueron 7 (7,4%), obstructivas izquierdas 3 (3,2%) y no obstructivas 84 (89,3%). Las comorbilidades fueron: 17 (18,08%) trisomía 21, 10 (10,6%) patología neurológica, 6 (6,38%) reflujo gastroesofágico. Sin comorbilidad 48 pacientes (51,06%). La mediana de hospitalización es 8 días y la necesidad de ventilación mecánica de 1 día, siendo mayor en las cianóticas. Requieren ingreso a unidad de paciente crítico 49 (52,12%). La letalidad fue de un 8,5%. CONCLUSIÓN: La morbimortalidad de la infección por VRS observada en pacientes con cardiópatas congénitas es elevada, por lo que la prevención con anticuerpos monoclonales podría tener impacto. En el 2019 Chile implementa el uso de anticuerpos monoclonales anti VRS en niños con cardiopatías congénitas por lo que será interesante medir el impacto de esta medida.

INTRODUCTION. Congenital heart disease is a risk factor for developing severe disease due to respiratory syncytial virus (RSV). In Chile the rate of hospitalization or lethality due to this cause is not known. The objective of this study was to determine lethality of infants with congenital heart disease hospitalized for RSV infection. METHOD. Retrospective descriptive study, through review of clinical records of infants under 24 months with congenital heart disease, hospitalized due to low RSV respiratory infection. We recorded age, gender, type of congenital heart disease, comorbidities, days of hospitalization, admission to a critical patient unit and lethality in Roberto del Río Hospital between 2014 to 2016. The research had approved bay the ethical Comitee Servicio de Salud Metropolitano Norte. Results were analyzed through Stata 13. RESULTS. 94 hospitalized patients were studied, median age of 7.3 months, 45 (48%) men. The cases of congenital cyanotic heart disease were 7 (7.4%), left obstructive 3 (3.2%) and non-obstructive 84 (89.3%). The comorbidities were: 17 (18.08%) trisomy 21, 10 (10.6%) neurological pathology, 6 (6.38%) gastroesophageal reflux and 48 patients (51.06%) did not present. The hospitalization median is 8 days and the need for 1-day mechanical ventilation is greater in cyanotic patients. They require admission to the critical patient unit 49 (52.12%). The lethality is 8.5%. CONCLUSION: The lethality of RSV infection observed in patients with congenital heart disease is high. In 2019 Chile implemented the use of RSV monoclonal antibodies congenital heart disease. New studies are needed to measure the impact of this new policy. Keywords: congenital heart disease, respiratory syncytial virus

Asociación temporal entre la circulación de virus respiratorios y hospitalizaciones por enfermedad de Kawasaki / Temporal association between the circulation of respiratory viruses and hospitalizations due to Kawasaki disease

INTRODUCCIÓN: La etiología de la enfermedad de Kawasaki (EK) es desconocida, planteándose que infecciones virales la gatillan en pacientes susceptibles. OBJETIVO: Estudiar la asociación temporal entre la circulación de virus respiratorios y hospitalizaciones por EK en la Región Metropolitana (RM), Chile, entre 2010-2017. METODOLOGÍA: Estudio ecológico retrospectivo de casos de EK en pacientes bajo 18 años de edad, en base a egresos hospitalarios. La circulación de virus se analizó mediante el reporte de la red de vigilancia metropolitana. Se utilizaron promedios móviles para EK (PMEK) y virus respiratorios (PMVR). RESULTADOS: Se registraron 14.902 casos de infecciones virales respiratorias entre 2010-2017. Se observó correlación directa entre PMVR-virus respiratorio sincicial (VRS) de un mes y año y PMEK del mes subsiguiente (coeficiente de correlación (ρ) = +0,441; p < 0,001), y una asociación similar para PMVR-influenza A (FLU A) (ρ = +0,362; p < 0,001). PMVR-influenza B (FLU B) y PMVR-metapneumovirus (MPV) presentan correlaciones directas con PMEK (ρ = +0,443; p < 0,001 y ρ = +0,412; p < 0,001, respectivamente), siendo contemporáneo en mes y año con EK para FLU B, mientras que MPV presenta un desfase de un mes entre PMVR y PMEK. CONCLUSIÓN: Existe correlación temporal directa entre la circulación de VRS, FLU A, FLU B y MPV con EK en niños de la RM, Chile.

BACKGROUND: The etiology of Kawasaki disease (KD) is unknown. It is believed that viral infections could trigger the disease in susceptible patients. AIM: To study the temporal association between the circulation of respiratory viruses and KD hospitalizations in the Metropolitan Region (MR), Chile, between 2010-2017. METHODS: Ecologic study consisting of a review of KD cases in children under 18 years of age based on hospital discharges. The circulation of respiratory viruses was analyzed using the report of the metropolitan surveillance network. Moving averages for KD (MAKD) and respiratory viruses (MARV) were used. RESULTS: 14,902 cases of respiratory virus infections were recorded between 2010-2017. A direct correlation was found between MARV-respiratory syncytial virus (RSV) of one month and year and MAKD of the subsequent month (correlation coefficient (ρ) = +0.441; p < 0.001). A similar association was found for MARV-influenza A (FLU A) (ρ = + 0.362; p < 0.001). MARV-influenza B (FLU B) and MARV-metapneumovirus (MPV) had direct correlations with MAKD (ρ = +0.443; p < 0.001 and ρ = +0.412; p < 0.001, respectively), being FLU B contemporary in month and year with KD, and MPV presenting a one-month lag. CONCLUSION: There is a direct temporal correlation between RSV, FLU A, FLU B and MPV circulation and KD in children from RM, Chile.

Comparison of clinical characteristics and outcomes between respiratory syncytial virus and influenza-related pneumonia in China from 2013 to 2019.

This study aims to compare clinical characteristics and severity between adults with respiratory syncytial virus (RSV-p) and influenza-related pneumonia (Flu-p). A total of 127 patients with RSV-p, 693 patients with influenza A-related pneumonia (FluA-p), and 386 patients with influenza B-related pneumonia (FluB-p) were retrospectively reviewed from 2013 through 2019 in five teaching hospitals in China. A multivariate logistic regression model indicated that age ≥ 50 years, cerebrovascular disease, chronic kidney disease, solid malignant tumor, nasal congestion, myalgia, sputum production, respiratory rates ≥ 30 beats/min, lymphocytes < 0.8×109/L, and blood albumin < 35 g/L were predictors that differentiated RSV-p from Flu-p. After adjusting for confounders, a multivariate logistic regression analysis confirmed that, relative to RSV-p, FluA-p (OR 2.313, 95% CI 1.377-3.885, p = 0.002) incurred an increased risk for severe outcomes, including invasive ventilation, ICU admission, and 30-day mortality; FluB-p (OR 1.630, 95% CI 0.958-2.741, p = 0.071) was not associated with increased risk. Some clinical variables were useful for discriminating RSV-p from Flu-p. The severity of RSV-p was less than that of FluA-p, but was comparable to FluB-p.

The burden of respiratory syncytial virus infections among children with sickle cell disease.

BACKGROUND: Although respiratory syncytial virus (RSV) is the leading cause of pediatric lower respiratory tract infections, the burden of RSV in children with sickle cell disease (SCD) is unknown. METHODS: We conducted a retrospective, nested, case-control study of children with SCD <18 years who had respiratory viral panels (RVPs) performed at Children's Healthcare of Atlanta from 2012 to 2019. We abstracted the medical records to describe the demographics, clinical features, and outcomes of children who tested positive for RSV (cases) versus children who tested negative (controls). We calculated the annual incidence of RSV and related hospitalization rates with 95% confidence intervals (CIs) and used multivariate logistic regression to evaluate associations. RESULTS: We identified 3676 RVP tests performed on 2636 patients over seven respiratory seasons resulting in 219/3676 (6.0%) RSV-positive tests among 160/2636 (6.1%) patients. The average annual incidence of laboratory-confirmed RSV infection among children with SCD was 34.3 (95% CI 18.7-49.8) and 3.8 (95% CI 0.5-7.0) cases per 1000 person-years for those <5 years and 5-18 years, respectively. The RSV-related hospitalization rate for children <5 years was 20.7 (95% CI 8.5-32.8) per 1000 person-years. RSV-positive cases were significantly younger than RSV-negative patients (3.8 years vs 7.6 years, P < .001). Of RSV-positive cases, 22 (13.8%) developed acute chest syndrome and nine (5.6%) required intensive care, which was not significantly different from RSV-negative children with SCD. CONCLUSION: RSV infections are common in children with SCD with higher burden in younger patients. RSV is associated with considerable morbidity, including higher rates of hospitalization compared to the general population.

SARS-CoV-2 viral clearance during bone marrow aplasia after allogeneic hematopoietic stem cell transplantation-A case report.

Respiratory viral infections are known causes of mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we report a unique case of a child with viral pneumonia caused by coinfection with human metapneumovirus (MPV), respiratory syncytial virus (RSV), and SARS-CoV-2 after HSCT. A 9-year-old girl with acute lymphoblastic leukemia underwent allogeneic HSCT from a matched, unrelated donor. During the post-transplant period, in profound leukopenia (below 10 leukocytes/µL), she was diagnosed with SARS-CoV-2, MPV, and RSV pneumonia and was treated with ribavirin and chloroquine. Before leukocyte recovery, the girl became asymptomatic, and SARS-CoV-2 and RSV clearance was achieved. The shedding of SARS-CoV-2 stopped before immune system recovery, and one may hypothesize that the lack of an inflammatory response might have been a contributing factor to the mild clinical course. Post-transplant care in HSCT recipients with COVID-19 infection is feasible in regular transplant units, provided the patient does not present with respiratory failure. Early and repeated testing for SARS-CoV-2 in post-transplant patients with concomitant infection mitigation strategies should be considered in children after HSCT who develop fever, respiratory symptoms, and perhaps gastrointestinal symptoms to control the spread of COVID-19 both in patients and in healthcare workers in hospital environments. Training of staff and the availability of personal protective equipment are crucial for containing SARS-CoV-2 infection.

CEACAM3 decreases asthma exacerbations and modulates respiratory syncytial virus latent infection in children.

BACKGROUND: Respiratory syncytial virus (RSV) is associated with childhood asthma. Nevertheless, not all children exposed to RSV develop asthma symptoms, possibly because genes modulate the effects of RSV on asthma exacerbations. OBJECTIVE: The purpose of this study was to identify genes that modulate the effect of RSV latent infection on asthma exacerbations. METHODS: We performed a meta-analysis to investigate differentially expressed genes (DEGs) of RSV infection from Gene Expression Omnibus datasets. Expression quantitative trait loci (eQTL) methods were applied to select single nucleotide polymorphisms (SNPs) that were associated with DEGs. Gene-based analysis was used to identify SNPs that were significantly associated with asthma exacerbations in the Taiwanese Consortium of Childhood Asthma Study (TCCAS), and validation was attempted in an independent cohort, the Childhood Asthma Management Program (CAMP). Gene-RSV interaction analyses were performed to investigate the association between the interaction of SNPs and RSV latent infection on asthma exacerbations. RESULTS: A total of 352 significant DEGs were found by meta-analysis of RSV-related genes. We used 38 123 SNPs related to DEGs to investigate the genetic main effects on asthma exacerbations. We found that eight RSV-related genes (GADD45A, GYPB, MS4A3, NFE2, RNASE3, EPB41L3, CEACAM6 and CEACAM3) were significantly associated with asthma exacerbations in TCCAS and also validated in CAMP. In TCCAS, rs7251960 (CEACAM3) significantly modulated the effect of RSV latent infection on asthma exacerbations (false-discovery rate <0.05). The rs7251960 variant was associated with CEACAM3 mRNA expression in lung tissue (p for trend=1.2×10-7). CEACAM3 mRNA was reduced in nasal mucosa from subjects with asthma exacerbations in two independent datasets. CONCLUSIONS: rs7251960 is an eQTL for CEACAM3, and CEACAM3 mRNA expression is reduced in subjects experiencing asthma exacerbations. CEACAM3 may be a modulator of RSV latent infection on asthma exacerbations.

Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants. METHODS: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%). RESULTS: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups. CONCLUSIONS: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).

Bronquiolitis aguda: tratamiento de la insuficiencia respiratoria / Acute bronchiolitis: treatment of respiratory insufficiency

The severe respiratory insufficiency (SRI) caused by acute bronchitis whose main etiology is the respiratory syncytial virus is the main cause of under 2-year-old children hospitalization during the winter months, especially in the risk groups. Its treatment is mainly based in general measures, administration of respiratory support with standard oxygen therapy, non-invasive ventilation, invasive mechanical ventilation or the emerging high flow nasal cannula therapy, which these past few years has become an easy alternative of use, well tolerated, secure to be used in emergency rooms, basic rooms and pediatric intensive care units. The election of therapy will depend of the patient severity, the level of complexity of the healthcare center and the experience in the different treatment modalities of the health team. It is essential to carry out protocols and guidelines for the management of SRI treatment caused by acute bronchitis for emergency services, basic rooms and pediatric intensive care.

La insuficiencia respiratoria aguda (IRA) causada por bronquiolitis aguda (BA), cuya principal etiología es el virus respiratorio sincicial (VRS), es la principal causa de hospitalizaciones en menores de 2 años durante los meses de invierno, especialmente en grupos de riesgo. Su manejo se basa principalmente en medidas generales, administración de soporte respiratorio con oxigenoterapia estándar, ventilación no invasiva (VNI), ventilación mecánica invasiva (VMI) o la emergente terapia con cánula nasal de alto flujo (CNAF), que se ha transformado en los últimos años en una alternativa de fácil uso, bien tolerada, segura para ser usada en los servicios de urgencia, salas básicas y unidades de cuidados intensivos pediátricos (UCIP). La elección de la terapia a utilizar dependerá de la gravedad del paciente, del nivel de complejidad del centro asistencial y de la experiencia en las distintas modalidades de tratamiento del equipo de salud. Es fundamental realizar protocolos y guías de manejo de tratamiento de la IRA causada por BA tanto para servicios de urgencia, salas básicas como cuidados intensivos pediátricos.

Impaired tumor necrosis factor-α secretion by CD4 T cells during respiratory syncytial virus bronchiolitis associated with recurrent wheeze.

BACKGROUND: Infants with severe respiratory syncytial virus (RSV) bronchiolitis have an increased risk of recurrent wheezing and asthma. We aimed to evaluate the relationships between regulatory T cell (Treg) percentage and cytokine production of in vitro-stimulated CD4+ T cells during acute bronchiolitis and the development of recurrent wheezing in the first 3 years of life. METHODS: We obtained peripheral blood from 166 infants hospitalized with their first episode of RSV-confirmed bronchiolitis. Granzyme B (GZB) expression, and interleukin-10, interferon-γ, tumor necrosis factor-α (TNF-α), IL-4, and IL-5 production by in vitro anti-CD3/CD28- and anti-CD3/CD46-activated CD4+ T cells, and percentage of peripheral Treg (CD4+CD25hi Foxp3hi ) cells were measured by flow cytometry. Wheezing was assessed every 6 months. Recurrent wheezing was defined as three or more episodes following the initial RSV bronchiolitis. RESULTS: Sixty-seven percent (n = 111) of children had wheezing after their initial RSV infection, with 30% having recurrent wheezing. The percentage of peripheral Treg (CD4+CD25hi Foxp3hi ) cells was not significantly different between the wheezing groups. Decreased TNF-α production from anti-CD3/CD28- and anti-CD3/CD46- activated CD4+ T cells was observed in the recurrent wheezers, compared with nonwheezers (p = .048 and .03, respectively). There were no significant differences in the GZB+ CD4+ T cells and production of other inflammatory cytokines between these groups. CONCLUSIONS: We demonstrated lower TNF-α production by in vitro stimulated CD4+ T cells during severe RSV bronchiolitis in children that subsequently developed recurrent wheezing, compared with children with no subsequent wheeze. These findings support the role of CD4+ T cell immunity in the development of subsequent wheezing in these children.