Severe Respiratory Infection Research Articles

The bidirectional interplay of obstructive sleep apnea and viral respiratory infections in children: A novel opportunity for primary prevention.

Obstructive sleep apnea (OSA) and viral respiratory infections are highly prevalent conditions in children and a major cause of respiratory morbidity in this age group. Severe viral respiratory infections are a known risk factor for pediatric OSA, which is primarily caused by hypertrophy of upper airway lymphoid tissues (adenoids and tonsils). This review examines recent progress in understanding early-life development of lymphoid tissues in the human upper airway, with a particular focus on how respiratory viruses may influence this process and contribute to OSA pathogenesis. It also explores the bidirectional relationship between OSA and severe viral infections, highlighting the need for ongoing monitoring and novel primary prevention strategies to address these interconnected conditions.

A-315 Cardiac Troponin Concentrations in Pediatric Patients Infected with Respiratory Syncytial Virus

Abstract Background Respiratory syncytial virus (RSV) is associated with considerable morbidity and mortality in pediatric patients. Cardiac troponin I (TnI) has been shown to increase in patients with acute respiratory illness, including COVID-19. The impact of RSV infection on circulating TnI has been formally demonstrated in the literature. The goal of this study was to assess the relationship between TnI and respiratory syncytial virus (RSV) in pediatric patients. Methods A prospective study was conducted at St. Louis Children’s Hospital from October 2023 to February 2024. Patients older than 6 months who presented to the ED and had a CBC ordered within 6 hours of testing positive for RSV on the Biofire® FilmArray® Respiratory Panel were enrolled. Patients with Rhinovirus, Enterovirus, Streptococcus pneumoniae, or Adenovirus infections were included as controls. Remnant EDTA specimens were tested on an Abbott ARCHITECT i2000 for high sensitivity TnI (hs-TnI) with a limit of detection of 1.4 ng/L and a limit of quantitation of 3.5 ng/L. 99% upper reference limits from the CALIPER database on the Abbott of <7 ng/L were used as a threshold for positive results. The electronic medical record (EPIC) was assessed for demographic information and outcomes including length of stay (LOS), intensive care unit (ICU) length of stay, requirement of supplemental oxygen, white blood cell count (WBC), and creatinine. Results A total of 103 patients had RSV and 35 had other respiratory infections (ORI). The average age for the RSV positive group was 2.3 and for the ORI group was 2.4. Males made up 61% of the RSV+ group and 51% of the ORIs. 93 patients in the RSV group were admitted. The median TnI for RSV patients was 1.4 (IQR, 1.2-2.9) and for ORIs was 1.4 (IQR, 1.4-6.8). TnI was measurable in 58% of those with RSV and 54% in ORIs. We next assessed the correlation between hospital LOS and TnI in RSV+ patients, with a Pearson r of 0.42 (95% CI= 0.23-0.58). There was no correlation between WBC and LOS (r=-0.04, 95% CI=-0.25-0.17). There was also no correlation between TnI and WBCs or creatinine. Of admitted patients, 44 (47%) in the RSV group were in the ICU compared to 18 (51.4%) in those with ORIs. RSV+ patients that required ICU treatment had comparable TnI (1.4, IQR, 0.9-3.5) to those that didn’t require ICU stay (1.4, IQR, 0.75-1.5). There was no correlation between ICU LOS and TnI in RSV+ patients (r=-0.08, 95% CI=-0.39-0.24). There was a significant difference in mean TnI concentrations in RSV+ patients that required supplemental oxygen (8.7, 95% CI: 0-19) versus those that did not (1.7, 95% CI: 1.1-2.4). Conclusions There was no difference in TnI in patients hospitalized for RSV relative to ORIs. While TnI concentration was associated with LOS, there were minimally other associations between TnI and outcomes in patients hospitalized with RSV. While TnI elevations are associated with acute respiratory infections in adults, the impact on pediatric patients is not as clear. Future investigation is needed to understand how severe respiratory infections impact pediatric cardiac function.

Aging enhances pro-atrogenic gene expression and skeletal muscle loss following respiratory syncytial virus infection.

Aging and many age-related health conditions are associated with skeletal muscle loss. Furthermore, older adults are more susceptible to severe respiratory infections, which can in turn lead to muscle wasting. The mechanisms by which respiratory viral infection can impact skeletal muscle in older adults are not well understood. We determined the effects of acute infection with respiratory syncytial virus (RSV) on the lung and skeletal muscle of aged mice. RSV infection caused more severe disease in aged mice with enhanced weight loss, reduced feeding, higher viral load, and greater airway inflammation. Aged but not young mice showed decreased leg muscle weight at the peak of illness and decreased size of leg muscle fibers. Aged mice increased muscle-specific expression of atrophy-promoting enzymes (Atrogin-1 and MuRF-1) and failed to increase the rate of muscle protein synthesis during RSV infection. In aged mice, the changes in Atrogin-1 and MuRF-1 gene expression in skeletal muscle correlated with IL-6 levels in the lungs. These findings indicate that RSV infection of aged mice provides a model for studying the diverse adverse systemic consequences of respiratory viral infections on health and wellbeing in older adults.

Oral Cavity Microbiome Impact on Respiratory Infections Among Children.

The respiratory system, traditionally considered antiseptic, harbors a diverse and dynamic bacterial microbiome. Recent advancements in microbiome research have revealed its significant influence on both innate and adaptive immunity, particularly in the context of respiratory infections in children. This article also provides an overview of the types of bacteria that commonly affect the respiratory system, including Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae. These bacteria are prevalent in pediatric populations and significantly contribute to the development and severity of respiratory tract infections (RTIs). This review aims to evaluate the impact of the oral cavity and upper respiratory microbiome on the susceptibility and severity of respiratory infections in pediatric populations. We specifically focus on how early colonization patterns of bacteria such as Moraxella and Streptococcus contribute to the development of respiratory tract infections in children from birth through adolescence. A thorough literature review was performed, focusing on studies publishing between 2004 and 2023. The review included research exploring the role of the upper respiratory microbiome in pediatric populations, with a specific focus on children aged birth to 18 years. Emphasis was placed on microbial characterization, the modulation of immune responses in respiratory tract infections, and the potential therapeutic applications of microbiome-targeted interventions. The findings suggest that the composition and disruption of the upper respiratory microbiome significantly influence clinical outcomes in children with respiratory infections. Notably, dysbiosis in the microbiome has been linked to increased susceptibility to repeated infections, highlighting the importance of maintaining microbial balance for optimal respiratory health. Understanding the impact of oral cavity and upper respiratory microbiome could lead to improved management and prevention strategies for respiratory infections in children. This review underscores the potential of microbiome modulation, including the use of probiotics as a therapeutic approach to enhance clinical outcomes in pediatric respiratory infections.

Impact of respiratory tract infections on spinal muscular atrophy with focus on respiratory syncytial virus infections: a single-centre cohort study.

Spinal muscular atrophy (SMA) is a degenerative neuromuscular disorder leading to muscle hypotonia, weakness, and respiratory and bulbar impairment. Infants with SMA have an increased risk of respiratory tract infections (RTI) including severe respiratory syncytial virus (RSV) infections. Therefore, guidelines for the treatment of SMA recommend RSV prophylaxis with palivizumab for patients aged below two years who have compromised motor functions ("non-sitters"). Since palivizumab is not approved for RSV prophylaxis in SMA patients in Switzerland, payers usually do not grant cost approvals for this indication. Therefore, this study aimed to investigate the frequency of severe RTI among SMA patients focusing on RSV infections requiring hospital treatment and to determine the long-term impact of RSV infections on the natural history of SMA. A single-centre cohort study at the tertiary paediatric Neuromuscular Centre Zurich, Switzerland, including data of SMA patients with a genetic-based therapy initiated below two years of age between May 2019 and December 2022. All hospitalisations were analysed with a focus on severe RTI and especially RSV infections, and their impact on nutritional and respiratory function. The costs of inpatient treatment of RSV infections were determined and compared with estimated expenses for RSV prophylaxis with palivizumab. 12 SMA patients (median age at treatment initiation: 3.5 months, range: 0-17 months) were followed for a cumulative period of 25.75 years (7 SMA type 1; 5 SMA type 2 including one presymptomatic individual). With an incidence rate of 2.34 per patient-year, the risk of severe RTI was especially high in SMA type 1 (versus 0.1 in SMA type 2, p = 0.044). A total of 37 hospitalisations (279 hospital days) was necessary for the treatment of RTI in general; 9 of them were attributed to RSV infections (in 5 SMA type 1 patients; 84 hospital days). Only 3/12 SMA patients had received seasonal RSV prophylaxis with palivizumab. No RSV infections requiring hospital treatment occurred in patients while receiving seasonal RSV prophylaxis. During RTI, nutritional support had to be commonly initiated and continued after discharge. In 3/7 SMA type 1 patients, non-invasive ventilation was started during acute treatment for RTI and continued to the end of follow-up. We observed a high risk of RTI, especially RSV infections, among young SMA patients. Failure to adhere to established care protocols, for example by omitting RSV prophylaxis, may be linked to a heightened risk of morbidity in these children.

Functional evaluation of TMEM176B and its predictive role for severe respiratory viral infection through integrated analysis of single-cell and bulk RNA-sequencing.

Transmembrane protein 176B (TMEM176B), localized mainly on the endosomal membrane, has been reported as an immune regulatory factor in malignant diseases. However, the biological function of this molecule remains undetermined during respiratory viral infections. To investigate the functions and prognostic value of this gene, six gene sets were selected from the Gene Expression Omnibus database for research. First, the function of TMEM176B and its co-expressed genes were evaluated at different levels (cell, peripheral blood, lung tissue). Afterwards, a machine learning algorithm was utilized to analyze the relationship between TMEM176B and its interacting genes with prognosis. After importance evaluation and variable screening, a prognostic model was established. Finally, the reliability of the model was further verified through external data sets. In vitro experiments were conducted to validate the function of TMEM176B. TMEM176B and its co-expressed genes are involved in multiple processes such as inflammasome activation, myeloid immune cell development, and immune cell infiltration. Machine learning further screened 27 interacting gene modules including TMEM176B as prognostic models for severe respiratory viral infections, with the area under the ROC curve (AUCs) of 0.986 and 0.905 in derivation and external validation sets, respectively. We further confirmed that viral load as well as NLRP3 activation and cell death were significantly enhanced in TMEM176B-/- THP-1-differentiated macrophages via in vitro experiments. Our study revealed that TMEM176B is involved in a wide range of biological functions in respiratory viral infections and has potential prognostic value, which is expected to bring new insights into the clinical management of severe respiratory viral infection hosts.

IFN-γ and YAP lead epithelial cells astray after severe respiratory infection.

Ineffective recovery from pneumonia can lead to interstitial lung disease characterized by aberrant epithelial cells in fibrotic regions. In this issue of the JCI, Lin et al. define molecular pathways leading to the development and persistence of keratin 5+ (Krt5+) epithelial cells in the alveolar parenchyma when mice struggle to recover from influenza infection. The receptor for IFN-γ on lung epithelium was essential for the formation of aberrant Krt5+ cells and fibrotic lung disease. The transcription factor Yes-associated protein 1 (YAP) was necessary for persistence of these Krt5+ cells, and IFN-γ activated YAP in lung epithelial cells via JAK, focal adhesion kinase (FAK), and Src kinases. These findings establish a targetable pathway underlying some of the pulmonary postacute sequelae of pneumonia.

Evaluation of A Non-Nucleoside Inhibitor of the RSV RNA-Dependent RNA Polymerase in Translatable Animals Models

Respiratory Syncytial Virus (RSV) causes severe respiratory infections and concomitant disease resulting in significant morbidity and mortality in infants, elderly, and immunocompromised adults. Vaccines, monoclonal antibodies, and small molecule antivirals are now either available, or in development, to prevent and treat RSV infections. Although, rodent and non-rodent preclinical animal models have been used to evaluate these emerging agents there is still a need to improve our understanding of the pharmacokinetic (PK)-pharmacodynamic (PD) relationships, within and between animal models to enable better design of human challenge studies and clinical trials. Herein, we report a PKPD evaluation of MRK-1, a novel small molecule non-nucleoside inhibitor of the RSV L polymerase protein, in the semi-permissive cotton rat and African green monkey models of RSV infection. These studies demonstrate a strong relationship between in vitro activity, in vivo drug exposure, and pharmacodynamic efficacy as well as revealing limitations of the cotton rat RSV model. Additionally, we report unexpected horizontal transmission of human RSV between co-housed African green monkeys, as well as a lack of drug specific resistant mutant generation. Taken together these studies further our understanding of these semi-permissive animal models and offer the potential for expansion of their preclinical utility in evaluating novel RSV therapeutic agents.

Intracellular delivery of antiviral shRNA using penetratin-based complexes effectively inhibits respiratory syncytial virus replication and host cell apoptosis

BackgroundCell-penetrating peptides (CPPs) are effective for delivering therapeutic molecules with minimal toxicity. This study focuses on the use of penetratin, a well-characterized CPP, to deliver a DNA vector encoding short hairpin RNA (shRNA) targeting the respiratory syncytial virus (RSV) F gene into infected cells. RSV is known to cause severe lower respiratory infections in infants and poses significant risks to immunocompromised individuals and the elderly. We evaluated the antiviral efficacy of the penetratin-shRNA complex by comparing its ability to inhibit RSV replication and induce apoptosis with ribavirin treatment.MethodsPenetratin-shRNA complexes were prepared at different ratios and analyzed using gel retardation assays, dynamic light scattering, and zeta potential measurements. The complexes were tested in HEp-2 and A549 cells for transfection efficiency, cytotoxicity, viral load, and apoptosis using plaque assays, real-time reverse transcription-polymerase chain reaction (RT-PCR), DNA fragmentation, propidium iodide staining, and caspase 3/7 activation assays.ResultsThe gel shift assay determined that a 20:1 CPP-to-shRNA ratio was optimal for effective complexation, resulting in particles with a size of 164 nm and a zeta potential of 8.7 mV. Transfection efficiency in HEp-2 cells was highest at this ratio, reaching up to 93%. The penetratin-shRNA complex effectively silenced the RSV F gene, reduced viral titers, and decreased DNA fragmentation and apoptosis in infected cells.ConclusionPenetratin effectively delivers shRNA targeting the RSV F gene, significantly reducing viral load and preventing apoptosis without toxicity. This approach surpasses Lipofectamine and shows potential for future therapeutic interventions, especially when combined with ribavirin, against RSV infection.Graphical

Clinical and economic inpatient burden of respiratory syncytial virus (RSV) infections in children < 2 years of age in Germany, 2014-2019: a retrospective health claims analysis.

Respiratory syncytial virus (RSV) is a common cause for severe lower respiratory tract infections (LRTI) in children < 2 years of age in Germany - though little is known about the clinical and economic burden of RSV in children with and without risk factors per month of life. In a retrospective health claims analysis, we identified RSV inpatient cases between 2014 and 2019. We assessed incidence rates, mortality rate, healthcare resource utilization, associated direct costs per case and excess costs for 30, 90 and 365 days after hospital admission matched to a control group. The outcomes are reported separately for the first and second year of life (i.e., for infants and toddlers) and were stratified by month of life, preterm and risk status (i.e., presence of underlying disease: chronic respiratory or cardiac disease, immunosuppression, neurological diseases, diabetes, conditions originating in the perinatal period). RSV-attributable hospital incidence rate was higher in infants (30.25/1,000) than toddlers (14.52/1,000), highest in the first three months of life (44.21/1,000), in infants born preterm (64.76/1,000) or with any underlying disease (54.85/1,000). Mortality rate was also higher for infants (0.08/1,000) than toddlers (0.04/1,000). Mean 30-day excess costs ranged from 2,953 € for infants born full-term at no risk, hospitalized for 5 days, to 6,694 € for infants born extremely premature, hospitalized for 7 days. In Germany, the clinical and economic burden of RSV is substantial, especially in the most vulnerable population, that is, very young infants, those born premature and/or those with an underlying disease.

Severe acute respiratory infections: An epidemiological analysis of surveillance data in Bahrain, 2018-2022.

Severe acute respiratory tract infections (SARI) pose a health threat to children and adults worldwide. The SARI surveillance program was initiated in 2018 in Bahrain to monitor the activity of respiratory pathogens. Salmaniya Medical Complex (SMC) was chosen as the sentinel site for the SARI surveillance program. This study aimed to describe the epidemiology of SARI patients admitted to SMC from 2018 to 2022. Patients meeting the World Health Organization definition of SARI and presenting with cough and fever within the last 10 days and admitted to SMC from January 2018 until December 2022 were included in the study. Epidemiological data on SARI cases were collected from SARI surveillance data and analyzed using SPSS version 25 and Excel. A total of 1362 SARI cases were enrolled from January 2018 to the end of December 2022; the majority were males (57.7%, n = 786). The highest SARI incidence rates were recorded among individuals over 65 years old (155.5 per 100,000) in 2021 and among those under 5 years old (887 per 100,000) in 2020. About half of the patients had at least one comorbidity (54.0%, n = 735), with diabetes (23.0%, n = 313) and hypertension (17.2%, n = 234) being the most common. The highest number of cases was observed in 2021 (27%, n = 373), followed by 2018 (20%, n = 267). A viral pathogen was detected in 30.7% (n = 418) of the SARI patients. The most prevalent pathogen was influenza A (11.5%, n = 156), followed by SARS-CoV-2 (9.7%, n = 132), respiratory syncytial virus (RSV) (5.1%, n = 69), and influenza B (3.9%, n = 53). The highest percentage of SARI cases was recorded in the winter months, mainly January (17%, n = 236). The percentages of influenza A and RSV cases were highest in December, at 22% (n = 39) and 14% (n = 25), respectively. Influenza B cases were recorded predominantly in March (9%, n = 11). The incidence of SARI was highest among patients above 65 years old. The majority had comorbidities. Influenza and respiratory syncytial viruses were the most frequent causes of SARI, with influenza A being the most prevalent. December and January were the months with the highest SARI cases and viral detection rates. Promoting vaccination, timely testing, and prompt treatment, especially for the elderly and those with comorbidities, is key to reducing SARI-related morbidity and mortality, especially during peak seasons.

Poor stress resilience in adolescence predicts higher risk of severe COVID-19 and other respiratory infections: A prospective cohort study of 1.4 million Swedish men

ObjectivesTo investigate the associations between stress resilience in late adolescence and later risk of severe COVID-19 and other lower respiratory infections. A secondary aim was to examine potential confounding between low cardiorespiratory fitness (CRF) and stress resilience in relation to respiratory infection. MethodsWe conducted a registry-based cohort study of 1.4 million Swedish men, undergoing military conscription between 1968 and 2005. All were assessed by a psychologist for stress resilience, receiving a score between 1 and 9. The outcomes were hospitalization or death due to COVID-19 from March 2020 to September 2021 and hospitalization due to bacterial or viral pneumonia from conscription until January 2020. A secondary aim was to examine potential confounding between low cardiorespiratory fitness (CRF) and stress resilience in relation to respiratory infection. ResultsPoor stress resilience in late adolescence is associated with later risk of severe lower respiratory infections. Using a high resilience score as the reference, the hazard ratio (95 % CI) for death due to COVID-19 for the lowest scores was 1.49 (1.01–2.18) adjusted for CRF and other confounders. The corresponding adjusted hazard ratios for hospitalization due to bacterial pneumonia were 2.28 (2.03–2.57) and for viral pneumonia 1.92 (1.33–2.79). No significant interaction was seen between stress resilience and CRF in the analysis. ConclusionsPoor stress resilience is a prospective factor for severe COVID-19 as well as for bacterial and viral respiratory pneumonia endpoints, independent of CRF. These findings imply an effect of late adolescent stress resilience on the immune system later in life.

Research progress on T-cell immunity in patients infected with SARS-CoV-2

Patients with SARS-CoV-2 infection often exhibit significant changes in T cells, particularly a reduction in CD4+T and CD8+T cells in peripheral blood, which has become a key feature of severe respiratory infection. These immune changes in T lymphocytes are closely associated with disease progression, but the specific mechanisms remain unclear and warrant further investigation. This paper reviewed the changes in the number and function of T cells in respiratory viral infections, with a focus on SARS-CoV-2, and summarized related therapeutic explorations. We believe that improving and enhancing the number and function of T lymphocytes in infected hosts is a promising strategy for the treatment of respiratory viral infections, although more systematic and in-depth scientific research is still needed.

The Role of the CX3CR1-CX3CL1 Axis in Respiratory Syncytial Virus Infection and the Triggered Immune Response.

Respiratory syncytial virus (RSV) is a common respiratory pathogen that causes respiratory illnesses, ranging from mild symptoms to severe lower respiratory tract infections in infants and older adults. This virus is responsible for one-third of pneumonia deaths in the pediatric population; however, there are currently only a few effective vaccines. A better understanding of the RSV-host relationship at the molecular level may lead to a more effective management of RSV-related symptoms. The fractalkine (CX3CL1) receptor (CX3CR1) is a co-receptor for RSV expressed by airway epithelial cells and diverse immune cells. RSV G protein binds to the CX3CR1 receptor via a highly conserved amino acid motif (CX3C motif), which is also present in CX3CL1. The CX3CL1-CX3CR1 axis is involved in the activation and infiltration of immune cells into the infected lung. The presence of the RSV G protein alters the natural functions of the CX3CR1-CX3CL1 axis and modifies the host's immune response, an aspects that need to be considered in the development of an efficient vaccine and specific pharmacological treatment.

A robust mouse model of HPIV-3 infection and efficacy of GS-441524 against virus-induced lung pathology

Human parainfluenza virus type 3 (HPIV-3) can cause severe respiratory tract infections. There are no convenient small-animal infection models. Here, we show viral replication in the upper and lower airways of AG129 mice (double IFNα/β and IFNγ receptor knockout mice) upon intranasal inoculation. By multiplex fluorescence RNAscope and immunohistochemistry followed by confocal microscopy, we demonstrate viral tropism to ciliated cells and club cells of the bronchiolar epithelium. HPIV-3 causes a marked lung pathology. No virus transmission of the virus was observed by cohousing HPIV-3-infected AG129 mice with other mice. Oral treatment with GS-441524, the parent nucleoside of remdesivir, reduced infectious virus titers in the lung, with a relatively normal histology. Intranasal treatment also affords an antiviral effect. Thus, AG129 mice serve as a robust preclinical model for developing therapeutic and prophylactic strategies against HPIV-3. We suggest further investigation of GS-441524 and its prodrug forms to treat HPIV-3 infection in humans.

Cefotaxime Versus Ceftriaxone: A Comprehensive Comparative Review.

Cefotaxime and ceftriaxone are two prominent third-generation cephalosporin antibiotics, which are a class of antimicrobial agents with overlapping antibacterial spectra and therapeutic indications, commonly used in treating severe bacterial infections, including meningitis, sepsis, and respiratory tract infections. Despite their shared antibacterial coverage, these antibiotics differ significantly in their pharmacokinetic characteristics such as half-life, protein binding, and tissue penetration. This comprehensive review systematically compares the pharmacokinetic profiles, pharmacological attributes, clinical efficacy, and safety profiles of cefotaxime and ceftriaxone. It further highlights the importance of understanding the nuanced differences between cefotaxime and ceftriaxone, particularly in clinical settings such as intensive care units or during pediatric treatment, where rapid bactericidal action or prolonged drug activity might influence therapeutic outcomes. While their overlapping spectrums offer versatility, clinicians should consider these distinct pharmacokinetic attributes and associated clinical outcomes to guide optimal antibiotic selection.

Influenza A (H1N1) in Hospitalized Children.

Influenza A (H1N1) is a contagious respiratory infection caused by the influenza A virus. In the majority of cases, H1N1 influenza is benign. However, it can be dangerous for infants and children with underlying chronic diseases. The severity of influenza depends on various factors, including the virulence of the virus strain, preexisting immunity level, and individual health conditions. The aim of this study is to describe the clinical profile of H1N1 influenza in hospitalized infants and children. This is a prospective and descriptive study conducted from November 1, 2018, to January 31, 2024. In this study, we included all children under 14 years old hospitalized for suspected severe lower respiratory infection who had gone through virological testing. We used a multiplex polymerase chain reaction (PCR) kit: the Film Array-Respiratory Panel. Due to the depletion of multiplex PCR kits, this study continued using rapid influenza diagnostic tests based on immunochromatographic technique. We report 45 confirmed cases of H1N1 influenza, collected during the period from November 1, 2018, to January 31, 2024. The average age was 2 years and 4 months. The main reason for admission was respiratory distress found in all patients. In 53% of the cases, there was an associated comorbidity, including asthma (17 cases), prematurity (2 cases), congenital adrenal hyperplasia (2 cases), cystic fibrosis (1 case), undetermined etiology bronchial dilation (1 case), and Basedow's disease (1 case). The clinical presentation included viral bronchiolitis (17 cases), moderate asthma exacerbation (10 cases), severe asthma exacerbation (7 cases), pneumonia (9 cases), bronchial dilation exacerbation (1 case), and flu-like syndrome with adrenal insufficiency (1 case). Fever was present in 31 patients. Gastrointestinal symptoms such as diarrhea and vomiting were present in 20 cases. Three patients required intensive care, with 2 children being intubated and ventilated (one severe acute asthma and one severe viral bronchiolitis). Two cases were treated with oseltamivir. The average length of hospital stay was 7.5 days, ranging from 3 to 20 days. All cases showed favorable evolution. We conclude that preventive measures remain crucial, and influenza vaccination is highly recommended in cases of underlying morbidity.

An attachment glycoprotein nanoparticle elicits broadly neutralizing antibodies and protects against lethal Nipah virus infection

Nipah virus (NiV) is a zoonotic emergent paramyxovirus that can cause severe encephalitis and respiratory infections in humans, with a high fatality rate ranging from 40% to 75%. Currently, there are no approved human vaccines or antiviral drugs against NiV. Here, we designed a ferritin-based self-assembling nanoparticle displaying the NiV G head domain on the surface (NiV G-ferritin) and assessed immune responses elicited by the soluble NiV G head domain (NiV sG) or NiV G-ferritin. Immunization with NiV G-ferritin or NiV sG conferred complete protection against lethal NiV challenge without detection of viral RNA in Syrian golden hamsters. Compared to NiV sG, NiV G-ferritin induced significantly faster, broader, and higher serum neutralizing responses against three pathogenic henipaviruses (NiV-Malaysia, NiV-Bangladesh, and Hendra virus). Moreover, NiV G-ferritin induced a durable neutralizing immunity in mice as antisera potently inhibited NiV infection even after six months of the third immunization. Additionally, we isolated a panel of 27 NiV G-binding monoclonal antibodies (mAbs) from NiV G-ferritin immunized mice and found that these mAbs targeted four distinct antigenic sites on NiV G head domain with two sites that have not been defined previously. Notably, 25 isolated mAbs have potent neutralizing activity with 50% inhibitory concentrations less than 10 ng/mL against NiV pseudovirus. Collectively, these findings provide new insights into the immunogenicity of NiV G protein and reveal that NiV G-ferritin is a safe and highly effective vaccine candidate against Nipah virus infection.

A Phase 1/2a Study Evaluating Safety and Immunogenicity of Ad26.RSV.preF in RSV-seronegative Toddlers Aged 12-24 Months.

Respiratory syncytial virus (RSV) causes serious illness in children. The Ad26.RSV.preF vaccine candidate was immunogenic with acceptable safety in a phase 1/2a study of RSV-seropositive children. Here, we assessed its safety and immunogenicity in RSV-seronegative children. In this randomized, observer-blinded, placebo-controlled, phase 1/2a study (NCT03606512; https://www.clinicaltrials.gov/ct2/show/NCT03606512), RSV-seronegative toddlers aged 12-24 months received Ad26.RSV.preF (2.5 × 1010 viral particles) or placebo on days 1, 29, and 57 (a meningococcal vaccine [Nimenrix] could substitute for day 57 placebo). Primary endpoints were solicited local and systemic adverse events (AEs; 7 days after each vaccination), unsolicited AEs (28 days postvaccination), and serious AEs (first vaccination until study end). Participants were monitored for RSV-respiratory tract infection to assess infection rates and for severe RSV-lower respiratory tract infection as an indication of enhanced disease. RSV-A2 neutralizing, RSV (A and B) preF binding, and RSV postF immunoglobulin G-binding antibodies were evaluated on days 1 (predose), 8, and 85, and after RSV season 1. Thirty-eight participants were enrolled and vaccinated (Ad26.RSV.preF, n = 20; placebo, placebo/Nimenrix, n = 18). Solicited AEs were more common following Ad26.RSV.preF than placebo; most were mild/moderate. No vaccine-related serious AEs were reported. Five of 19 participants receiving Ad26.RSV.preF and 2/18 receiving placebo or placebo/Nimenrix had confirmed RSV-respiratory tract infection or RSV-associated otitis media; none were considered severe. At the final season 1 study visit, most Ad26.RSV.preF recipients had ≥2-fold increases from baseline in RSV-A2 neutralizing, RSV A and B preF binding, and RSV postF antibodies. Ad26.RSV.preF was well tolerated and immunogenic in RSV-seronegative toddlers.

Development and validation of an individual risk prediction tool for severe respiratory syncytial virus infection among children under five years in China

Objective: To construct a predictive model to assess the risk of severe respiratory syncytial virus infection among children under five years in China, conduct preliminary validation of this model by using external data, and develop an individual risk assessment tool available for their parents. Methods: The admission after RSV infection was used as a marker of severe infection. Based on the evidence of RSV hospitalization-related risk factors and real-world data, such as the prevalence of various risk factors in children under five years old in China, a Monte Carlo-based individual RSV hospitalization risk prediction model for children under five years old was constructed. Taking Suzhou City as an example, the model was externally validated, and an interactive risk prediction tool (RSV HeaRT) was developed on the WeChat mini-program platform. Results: The estimation model showed that in children under five years old in China if the population did not have any risk factors for severe RSV infection, the RSV annual hospitalization rate was 2.2/1 000 (95%CI: 0.9/1 000-7.5/1 000). Based on this baseline hospitalization rate and the prevalence of related risk factors in Suzhou, the model predicted an RSV hospitalization rate of 8.0/1 000 (95%CI: 4.6/1 000-24.4/1 000) for children under five years old annually in Suzhou, which was close to the reported RSV hospitalization rate in literature (10/1 000-20/1 000). In the developed RSV HeaRT WeChat mini-program, target users (such as parents of children) could input basic information, disease history, and social environmental factors of the child into the mini-program, and the tool could provide real-time feedback on the following predicted results: First, the relative risk of hospitalization due to RSV infection in current children compared to general children; Second, the probability of hospitalization due to RSV infection within the next year; Third, the relative risk of adverse outcomes during hospitalization in the event of RSV infection. Conclusion: This study is based on real-world evidence related to RSV hospitalization risk and constructs an RSV hospitalization risk prediction model suitable for Chinese children based on the combination of the current prevalence of risk factors in children under five years old in China. The accuracy of the prediction model results has been preliminarily demonstrated. Based on this design, the RSV HeaRT developed can facilitate parents to evaluate the hospitalization risk of children.