Severe Lower Respiratory Infection Research Articles

Risk factors for the development of severe or very severe respiratory syncytial virus-related lower respiratory tract infection in Indian infants: A cohort study in Melghat, India.

Respiratory syncytial virus (RSV) is undoubtedly the single most important cause of severe lower respiratory tract infection (LRTI) globally. While new prevention measures in young infants have become available, their use in developing countries is likely many years away. While risk factors for severe or very severe RSV LRTI in impoverished rural areas likely differ to urban areas, there are very few studies, especially those conducted in India, the major country contributing to the global burden of disease. Active surveillance for acute LRTI in enrolled infants and children <2 years of age, was conducted through weekly home visits in 93 villages of Melghat, India, from August 2016 to December 2020. Local hospitals and primary health centres were surveyed for admissions of enrolled subjects. Nasopharyngeal swabs were collected from children with severe, or very severe LRTIs and all who died, with RSV testing using nucleic acid tests at ICMR, National Institute of Virology Pune. Risk factors for both RSV associated and non-RSV associated, severe and very severe LRTI were identified through univariate and multivariate logistic regression. There were 483 severe or very severe RSV LRTI cases and 2807 non-RSV severe or very severe LRTI infections in a cohort of 13,318 children. Weight for age z-score ≤-2, the use of kerosene or wood for cooking, obtaining drinking water from a public tap and low gestational age significantly increased the risk of RSV LRTI. A higher wealth score index and water purification were protective. Comparison with non-RSV LRTI showed male sex as an additional risk factor. The analysis highlighted the risk of kerosene use [OR = 17.8 (3.0-104.4) (p ≤ 0.001)] and [OR = 3.4 (0.8-14.4) (p ≤ 0.05)] for RSV and non-RSV LRTIs, respectively. Nutritional status and environmental air quality are predisposing factors for developing an RSV LRI in young children, factors which are amenable to environmental and behavioural interventions.

RSV infection of humanized lung-only mice induces pathological changes resembling severe bronchiolitis and bronchopneumonia

Respiratory syncytial virus (RSV) is a substantial cause of severe lower respiratory tract infections in infants, young children, older adults, and immunocompromised individuals. There is a vital need for effective therapeutics to prevent and/or treat severe RSV infection in these high-risk individuals. The development and pre-clinical testing of candidate RSV therapeutics could be accelerated by their evaluation in animal models that recapitulate bronchiolitis and bronchopneumonia, both hallmark features of severe RSV infection in humans. Previously, we demonstrated that implanted human lung tissue in humanized lung-only mice (LoM) can be infected with RSV, resulting in sustained virus replication. Here we analyzed RSV-associated human lung pathology in the human lung implants of RSV-infected LoM. RSV-infected epithelial cells lining the airway and the alveolar regions of human lung implants result in hallmark histological features of RSV bronchiolitis and bronchopneumonia, including distal airway and alveolar lumens clogged with (1) sloughed and necrotic RSV-infected epithelial cells, (2) neutrophil-containing inflammatory infiltrates, and (3) MUC5B-dominated mucus secretions. We also show that treatment of LoM with a small molecule antiviral (ribavirin) or a neutralizing antibody (palivizumab) significantly suppressed and/or prevented RSV infection in vivo. Our data together show that RSV infection of human lung implants in vivo exhibits appropriate cellular tropism and results in the hallmark pathological characteristics of severe bronchiolitis and bronchopneumonia in humans. They also offer proof-of-principle of the utility of this model to evaluate novel approaches for the prevention/treatment of RSV infection.

RSV Severe Infection Risk Stratification in a French 5-Year Birth Cohort Using Machine-learning.

Respiratory syncytial virus (RSV) poses a substantial threat to infants, often leading to challenges in hospital capacity. With recent pharmaceutical developments to be used during the prenatal and perinatal periods aimed at decreasing the RSV burden, there is a pressing need to identify infants at risk of severe disease. We aimed to stratify the risk of developing a clinically severe RSV infection in infants under 1 year of age. This retrospective observational study was conducted at the Hospices Civils de Lyon, France, involving infants born between 2014 and 2018. This study focused on infants hospitalized with severe and very severe acute lower respiratory tract infections associated with RSV (SARI-WI group). Data collection included perinatal information and clinical data, with machine-learning algorithms used to discriminate SARI-WI cases from nonhospitalized infants. Of 42,069 infants, 555 developed SARI-WI. Infants born in November were very likely (>80%) predicted SARI-WI. Infants born in October were very likely predicted SARI-WI except for births at term by vaginal delivery and without siblings. Infants were very unlikely (<10%) predicted SARI-WI when all the following conditions were met: born in other months, at term, by vaginal delivery and without siblings. Other infants were possibly (10-30%) or probably (30-80%) predicted SARI-WI. Although RSV preventive measures are vital for all infants, and specific recommendations exist for patients with high-risk comorbidities, in situations where prioritization becomes necessary, infants born just before or within the early weeks of the epidemic should be considered as a risk group.

Respiratory Syncytial Virus–Associated Respiratory Diseases in Children and Adults.

Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections (LRTI), particularly in neonates, infants and young children, with approximately 33 million infections worldwide each year. 1-2% of episodes lead to hospitalization. There are hardly any reliable epidemiological figures on hospitalization in adults, whose burden of disease from RSV is probably markedly underestimated. This review is based on publications retrieved by a selective search in PubMed, with particular attention to recommendations for the prevention of RSV infection. There is no approved antiviral therapy for clinical practice, but preventive strategies are increasingly becoming available. Passive immunization in infants is well tolerated and highly effective, as is the active vaccination of pregnant women to prevent severe RSV infection in young infants. The former was found to lower the frequency of severe LRTI (5/4037 in the vaccination group vs. 19/4031 individuals in the placebo group), yielding an efficacy of 75.7%; for the latter, the corresponding findings were a reduction to 19/3682 in the vaccination group vs. 62/3676 in the placebo group, or 69.4% efficacy. For the active vaccination of older adults, both a recombinant vaccine with adjuvant and a bivalent vaccine have recently been approved. These, too, are well tolerated and highly effective: the former lowered the frequency of severe LRTI to 1/12466 in the vaccination group vs. 17/12494 in the placebo group (94.1% efficacy), while the latter lowered the frequency of LRTI with 3 or more manifestations to 2/17215 in the vaccination group vs. 14/17069 in the placebo group (85.7% efficacy). The approval of new RSV-specific monoclonal antibodies and active vaccinations enables targeted prevention of RSV infection in the main population groups at risk.

Respiratory Syncytial Virus and Influenza Infections in Children in Ulaanbaatar, Mongolia, 2015-2021.

Data available for RSV and influenza infections among children < 2 years in Mongolia are limited. We present data from four districts of Ulaanbaatar from April 2015 to June 2021. This study was nested in an enhanced surveillance project evaluating pneumococcal conjugate vaccine (PCV13) impact on the incidence of hospitalized lower respiratory tract infections (LRTIs). Our study was restricted to children aged < 2 years with arterial O2 saturation < 93% and children with radiological pneumonia. Nasopharyngeal (NP) swabs collected at admission were tested for RSV and influenza using qRT-PCR. NP swabs of all patients with radiological pneumonia and of a subset of randomly selected NP swabs were tested for S. pneumoniae (S.p.) by qPCR and for serotypes by culture and DNA microarray. Among 5705 patients, 2113 (37.0%) and 386 (6.8%) had RSV and influenza infections, respectively. Children aged 2-6 months had a higher percentage of very severe RSV infection compared to those older than 6 months (42.2% versus 31.4%, p-value Fisher's exact = 0.001). S.p. carriage was detected in 1073/2281 (47.0%) patients. Among S.p. carriage cases, 363/1073 (33.8%) had S.p. and RSV codetection, and 82/1073 (7.6%) had S.p. and influenza codetection. S.p. codetection with RSV/influenza was not associated with more severe LRTIs, compared to only RSV/influenza cases. In Mongolia, RSV is an important pathogen causing more severe LRTI in children under 6 months of age. Codetection of RSV or influenza virus and S.p. was not associated with increased severity.

Viral etiology of severe lower respiratory tract infections in SARS-CoV-2 negative hospitalized patients during the COVID-19 pandemic in Kuwait

BackgroundThe prevalence of respiratory infections is largely underexplored in Kuwait. The aim of our study is to determine the etiology of infections from patients who are SARS-CoV-2 negative hospitalized with severe lower respiratory tract infections (LRTIs) in Kuwait during the coronavirus disease 2019 (COVID-19) pandemic. MethodsWe conducted an observational cross-sectional study among severe LRTI patients between September 2021 and March 2022. Respiratory samples from 545 non-COVID-19 severe LRTIs patients were prospectively evaluated with FTD Respiratory 21 Plus® real-time PCR, targeting 20 different viruses and 1 atypical bacterial pathogen. ResultsAmong all 545 hospitalized cases, 411 (75.4 %) tested positive for at least one respiratory pathogen. The most common were rhinovirus (HRV) (32.7 %), respiratory syncytial virus (RSV) (20.9 %), metapneumovirus (HMPV) (14.1 %), bocavirus (13.2 %), and influenza A (12.7 %). The proportion of pathogens detected was highest in the under-5 age group, while HKU1 (44.4 %) predominated in the elderly (>50 years). ConclusionOur study reveals a high prevalence of respiratory viruses in severe acute lower respiratory tract infections among non-COVID-19 hospitalized patients in Kuwait. HRV remains the main etiology affecting the country, particularly in infants. These results underscore the necessity of employing multiplex PCR for accurate diagnosis and describing the epidemiology of infections among severe lower respiratory tract infections. This will facilitate the use of specific antiviral therapy and help avoid excessive or inappropriate antibiotic therapy.

Prenatal and early life exposure to air pollution and the risk of severe lower respiratory tract infections during early childhood: the Espoo Cohort Study

BackgroundThere is inconsistent evidence of the effects of exposure to ambient air pollution on the occurrence of lower respiratory tract infections (LRTIs) in early childhood. We assessed the effects of...

Cooperative interaction of interferon regulatory factor -1 and bromodomain-containing protein 4 on RNA polymerase activation for intrinsic innate immunity.

The human orthopneumovirus, Respiratory Syncytial Virus (RSV), is the causative agent of severe lower respiratory tract infections (LRTI) and exacerbations of chronic lung diseases. In immune competent hosts, RSV productively infects highly differentiated epithelial cells, where it elicits robust anti-viral, cytokine and remodeling programs. By contrast, basal cells are relatively resistant to RSV infection, in part, because of constitutive expression of an intrinsic innate immune response (IIR) consisting of a subgroup of interferon (IFN) responsive genes. The mechanisms controlling the intrinsic IIR are not known. Here, we use human small airway epithelial cell hSAECs as a multipotent airway stem cell model to examine regulatory control of an intrinsic IIR pathway. We find hSAECs express patterns of intrinsic IIRs, highly conserved with pluri- and multi-potent stem cells. We demonstrate a core intrinsic IIR network consisting of Bone Marrow Stromal Cell Antigen 2 (Bst2), Interferon Induced Transmembrane Protein 1 (IFITM1) and Toll-like receptor (TLR3) expression are directly under IRF1 control. Moreover, expression of this intrinsic core is rate-limited by ambient IRF1• phospho-Ser 2 CTD RNA Polymerase II (pSer2 Pol II) complexes binding to their proximal promoters. In response to RSV infection, the abundance of IRF1 and pSer2 Pol II binding is dramatically increased, with IRF1 complexing to the BRD4 chromatin remodeling complex (CRC). Using chromatin immunoprecipitation in IRF1 KD cells, we find that the binding of BRD4 is IRF1 independent. Using a small molecule inhibitor of the BRD4 acetyl lysine binding bromodomain (BRD4i), we further find that BRD4 bromodomain interactions are required for stable BRD4 promoter binding to the intrinsic IIR core promoters, as well as for RSV-inducible pSer2 Pol II recruitment. Surprisingly, BRD4i does not disrupt IRF1-BRD4 interactions, but disrupts both RSV-induced BRD4 and IRF1 interactions with pSer2 Pol II. We conclude that the IRF1 functions in two modes- in absence of infection, ambient IRF1 mediates constitutive expression of the intrinsic IIR, whereas in response to RSV infection, the BRD4 CRC independently activates pSer2 Pol II to mediates robust expression of the intrinsic IIR. These data provide insight into molecular control of anti-viral defenses of airway basal cells.

Exploring Clinical Predictors of Severe Human Metapneumovirus Respiratory Tract Infections in Children: Insights from a Recent Outbreak.

Human metapneumovirus (hMPV) is an important pathogen that causes both upper (URTIs) and lower respiratory tract infections (LRTIs) in children. The virus can be implicated in severe bronchiolitis and pneumonia, necessitating hospitalization, with certain cases requiring intensive care unit intervention. As part of a retrospective observational study, we aimed to identify indicators of severe hMPV respiratory tract infections in children referred to the University Children's Hospital Ljubljana and the Department of Infectious Diseases Ljubljana, Slovenia, during a recent outbreak. We analyzed clinical data from November 2022 to January 2023 and compared the characteristics of children presenting with URTIs and LRTIs. We also examined the characteristics of children with hMPV LRTIs, distinguishing between children with and without LRTI-associated hypoxemia. Of 78 hMPV-PCR-positive pediatric patients (mean age 3.1 years; 60.3% boys), 36% had a URTI, and 64% had an LRTI. Hospitalization was required in 64% (50/78), with 42% (21/50) requiring oxygen therapy. LRTI-associated hypoxemia was more common in patients with atopy who showed dyspnea, tachypnea, crackles, and wheezing on lung auscultation. In a multivariable logistic regression analysis, wheezing detected on lung auscultation was a significant predictive factor for hypoxemic hMPV-LRTI. Specifically, children presenting with wheezing were found to be ten times more likely to experience hypoxemia. Prematurity and chronic conditions did not influence the presentation or severity of hMPV infection. This study highlights wheezing and atopy as crucial indicators of severe hMPV LRTI in children, emphasizing the importance of early recognition and intervention.

Impact of pneumococcal conjugate vaccine 13 introduction on severe lower respiratory tract infections associated with respiratory syncytial virus or influenza virus in hospitalized children in Ulaanbaatar, Mongolia

ObjectivesLimited data indicate a beneficial effect of pneumococcal conjugate vaccines (PCVs) on respiratory syncytial virus (RSV) and influenza infections in young children. We evaluated the impact of 13-valent PCV (PCV13) introduction on the incidence of severe lower respiratory tract infections (LRTIs) associated with RSV or influenza in hospitalized children. MethodsOur study was restricted to children aged <2 years with arterial oxygen saturation <93% and children with radiologically confirmed pneumonia nested in a pneumonia surveillance project in four districts of Ulaanbaatar city, Mongolia. We tested nasopharyngeal swabs collected on admission for RSV and influenza using quantitative reverse transcription-polymerase chain reaction. The impact of PCV13 on the incidence of LRTI outcomes associated with RSV or with influenza for the period April 2015-March 2020 was estimated. Incidence rate ratios comparing pre- and post-vaccine periods were estimated for each outcome for each district using negative binomial models and for all districts combined with a mixed-effects negative binomial model. Adjusted models accounted for seasonality. Sensitivity analyses were conducted to assess the robustness of our findings. ResultsAmong 5577 tested cases, the adjusted incidence rate ratios showed a trend toward a reduction in RSV-associated outcomes: all LRTIs (0.77, 95% confidence interval [CI] 0.44-1.36), severe LRTIs (0.88, 95% CI 0.48-1.62), very severe LRTIs (0.76, 95% CI 0.42-1.38), and radiologically confirmed pneumonia (0.66, 95% CI 0.32-1.38) but inconsistent trends in outcomes associated with influenza. ConclusionsNo significant reductions were observed in any outcomes associated with RSV and influenza after PCV introduction.

Nirsevimab: A Review.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in people of all ages and is the leading cause of hospitalization among infants in the United States. The year 2023 was exciting for RSV prevention. The Food and Drug Administration (FDA) approved 3 new tools for preventing severe lower respiratory tract RSV infections in infants, young children, and elderly persons. In May 2023, the FDA approved 2 vaccines, RSVpreF3 (Arexvy™, GSK) and RSVpreF (Abrysvo™, Pfizer), for adults ages 60 years or older to be given as a single-dose intramuscular injection. July 2023 brought the approval of the first long-acting monoclonal antibody nirsevimab (Beyfortus™, Sanofi and AstraZeneca) for the prevention of RSV disease in infants and young children. Then in August, the FDA approved a vaccine (Abrysvo™, Pfizer) to be given to pregnant women to protect their newborns through passive immunity. This article focuses on nirsevemab that has been recommended by the Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) to be administered for all infants <8 months of age and for children 8 to 19 months of age who are at increased risk for severe RSV disease.

Personalized Infant Risk Prediction for Severe Respiratory Syncytial Virus Lower Respiratory Tract Infection Requiring Intensive Care Unit Admission.

Currently, there are no available tools to identify infants at the highest risk of significant morbidity and mortality from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) who would benefit most from RSV prevention products. The objective was to develop and internally validate a personalized risk prediction tool for use among all newborns that uses readily available birth/postnatal data to predict RSV LRTI requiring intensive care unit (ICU) admission. We conducted a population-based birth cohort study of infants born from 1995 to 2007, insured by the Tennessee Medicaid Program, and who did not receive RSV immunoprophylaxis during the first year of life. The primary outcome was severe RSV LRTI requiring ICU admission during the first year of life. We built a multivariable logistic regression model including demographic and clinical variables available at or shortly after birth to predict the primary outcome. In a population-based sample of 429 365 infants, 713 (0.2%) had severe RSV LRTI requiring ICU admission. The median age of admission was 66 days (interquartile range, 37-120). Our tool, including 19 variables, demonstrated good predictive accuracy (area under the curve, 0.78; 95% confidence interval, 0.77-0.80) and identified infants who did not qualify for palivizumab, based on American Academy of Pediatrics guidelines, but had higher predicted risk levels than infants who qualified (27% of noneligible infants with >0.16% predicted probabilities [lower quartile for eligible infants]). We developed a personalized tool that identified infants at increased risk for severe RSV LRTI requiring ICU admission, expected to benefit most from immunoprophylaxis.

Breath Markers of Oxidative Stress in Children with Severe Viral Lower Respiratory Tract Infection.

Severe viral lower respiratory tract infection (LRTI), resulting in both acute and long-term pulmonary disease, constitutes a substantial burden among young children. Viral LRTI triggers local oxidative stress pathways by infection and inflammation, and supportive care in the pediatric intensive care unit may further aggravate oxidative injury. The main goal of this exploratory study was to identify and monitor breath markers linked to oxidative stress in children over the disease course of severe viral LRTI. Exhaled breath was sampled during invasive ventilation, and volatile organic compounds (VOCs) were analyzed using gas chromatography and mass spectrometry. VOCs were selected in an untargeted principal component analysis and assessed for change over time. In addition, identified VOCs were correlated with clinical parameters. Seventy breath samples from 21 patients were analyzed. A total of 15 VOCs were identified that contributed the most to the explained variance of breath markers. Of these 15 VOCs, 10 were previously linked to pathways of oxidative stress. Eight VOCs, including seven alkanes and methyl alkanes, significantly decreased from the initial phase of ventilation to the day of extubation. No correlation was observed with the administered oxygen dose, whereas six VOCs showed a poor to strong positive correlation with driving pressure. In this prospective study of children with severe viral LRTI, the majority of VOCs that were most important for the explained variance mirrored clinical improvement. These breath markers could potentially help monitor the pulmonary oxidative status in these patients, but further research with other objective measures of pulmonary injury is required.

Efficacyand safety of respiratory syncytial virus vaccination during pregnancy to prevent lower respiratory tract illness in newborns and infants: a systematic review and meta-analysis of randomized controlled trials.

To evaluate the effectiveness and safety of respiratory syncytial virus (RSV) vaccination during pregnancy in preventing lower respiratory tract infection (LRTI) in infants and neonates, we conducted a systematic search of randomized controlled trials (RCTs) in five databases (PubMed, Embase and Cochrane Library, Web of Science, Cochrane Center Register of Controlled trial) until 1 May 2023. We performed a meta-analysis of the eligible trials using RevMan5.4.1 software. Our analysis included six articles and five RCTs. The meta-analysis revealed significant differences in the incidences of LRTI [risk ratio (RR): 0.64; 95% confidence interval (CI): 0.43, 0.96; p = 0.03)] and severe LRTI (RR: 0.37; 95% CI: 0.18, 0.79; p = 0.01) between the vaccine group and the placebo group for newborns and infants. These differences were observed at 90, 120, and 150 days after birth (p = 0.003, p = 0.05, p = 0.02, p = 0.03, p = 0.009, p = 0.05). At 180 days after birth, there was a significant difference observed in the incidence of LRTI between the two groups (RR: 0.43; 95% CI: 0.21, 0.90; p = 0.02). The safety results showed a significant difference in the incidence of common adverse events between the two groups (RR: 1.08; 95% CI: 1.04, 1.12; p < 0.0001). However, there was no significant difference observed in the incidence of serious adverse events (RR: 1.05; 95% CI: 0.97, 1.15; p = 0.23), common and serious adverse events (RR: 1.02; 95% CI: 0.96, 1.10; p = 0.23), or common and serious adverse events among pregnant women and newborns and infants (RR: 0.98; 95% CI: 0.93, 1.04; p = 0.52). In conclusion, maternal RSV vaccination is an effective and safe immunization strategy for preventing LRTI in postpartum infants, with greater efficacy observed within the first 150 days after birth.

Infants hospitalized with lower respiratory tract infections during the first two years of life have increased risk of pediatric obstructive sleep apnea.

Lower respiratory tract infections (LRTI) during the first 2 years of life increase the risk of pediatric obstructive sleep apnea (OSA), but whether this risk varies by LRTI severity is unknown. We analyzed data from 2962 children, aged 0-5 years, with early-life LRTI requiring hospitalization (severe LRTI, n = 235), treated as outpatients (mild LRTI, n = 394) and without LRTI (reference group, n = 2333) enrolled in the Boston Birth Cohort. Kaplan-Meier survival estimates and Cox proportional hazards models adjusted by pertinent covariables were used to evaluate the risk of pediatric OSA. Compared to children without LRTI, those with mild LRTI were at a higher risk of having OSA (hazard ratio [HR] 1.44, 95% confidence interval [CI]: 1.01-2.05), and those with severe LRTI were at the highest risk (HR 2.06, 95% CI: 1.41-3.02), independently of relevant covariables (including maternal age, race, gestational age, and type of delivery). Additional risk factors linked to a higher risk of OSA included prematurity (HR 1.34, 95% CI 1.01-1.77) and maternal obesity (HR 1.82, 95% CI 1.32-2.52). The time elapsed between LRTI and OSA diagnosis was similar in mild and severe LRTI cases, with medians of 23 and 25.5 months, respectively (p = .803). Infants with severe early-life LRTI have a higher risk of developing OSA, and surveillance strategies to identify OSA need to be particularly focused on this group. OSA monitoring should continue throughout the preschool years as it may develop months or years after the initial LRTI hospitalization.

Nirsevimab for Prevention of Hospitalizations Due to RSV in Infants

BackgroundThe safety of the monoclonal antibody nirsevimab and the effect of nirsevimab on hospitalizations for respiratory syncytial virus (RSV)–associated lower respiratory tract infection when administered in healthy infants are unclear.MethodsIn a pragmatic trial, we randomly assigned, in a 1:1 ratio, infants who were 12 months of age or younger, had been born at a gestational age of at least 29 weeks, and were entering their first RSV season in France, Germany, or the United Kingdom to receive either a single intramuscular injection of nirsevimab or standard care (no intervention) before or during the RSV season. The primary end point was hospitalization for RSV-associated lower respiratory tract infection, defined as hospital admission and an RSV-positive test result. A key secondary end point was very severe RSV-associated lower respiratory tract infection, defined as hospitalization for RSV-associated lower respiratory tract infection with an oxygen saturation of less than 90% and the need for supplemental oxygen.ResultsA total of 8058 infants were randomly assigned to receive nirsevimab (4037 infants) or standard care (4021 infants). Eleven infants (0.3%) in the nirsevimab group and 60 (1.5%) in the standard-care group were hospitalized for RSV-associated lower respiratory tract infection, which corresponded to a nirsevimab efficacy of 83.2% (95% confidence interval [CI], 67.8 to 92.0; P<0.001). Very severe RSV-associated lower respiratory tract infection occurred in 5 infants (0.1%) in the nirsevimab group and in 19 (0.5%) in the standard-care group, which represented a nirsevimab efficacy of 75.7% (95% CI, 32.8 to 92.9; P=0.004). The efficacy of nirsevimab against hospitalization for RSV-associated lower respiratory tract infection was 89.6% (adjusted 95% CI, 58.8 to 98.7; multiplicity-adjusted P<0.001) in France, 74.2% (adjusted 95% CI, 27.9 to 92.5; multiplicity-adjusted P=0.006) in Germany, and 83.4% (adjusted 95% CI, 34.3 to 97.6; multiplicity-adjusted P=0.003) in the United Kingdom. Treatment-related adverse events occurred in 86 infants (2.1%) in the nirsevimab group.ConclusionsNirsevimab protected infants against hospitalization for RSV-associated lower respiratory tract infection and against very severe RSV-associated lower respiratory tract infection in conditions that approximated real-world settings. (Funded by Sanofi and AstraZeneca; HARMONIE ClinicalTrials.gov number, NCT05437510).

Inter and intra-host diversity of RSV in hematopoietic stem cell transplant adults with normal and delayed viral clearance.

Respiratory syncytial virus (RSV) infection in immunocompromised individuals often leads to prolonged illness, progression to severe lower respiratory tract infection, and even death. How the host immune environment of the hematopoietic stem cell transplant (HCT) adults can affect viral genetic variation during an acute infection is not understood well. In the present study, we performed whole genome sequencing of RSV/A or RSV/B from samples collected longitudinally from HCT adults with normal (<14 days) and delayed (≥14 days) RSV clearance who were enrolled in a ribavirin trial. We determined the inter-host and intra-host genetic variation of RSV and the effect of mutations on putative glycosylation sites. The inter-host variation of RSV is centered in the attachment (G) and fusion (F) glycoprotein genes followed by polymerase (L) and matrix (M) genes. Interestingly, the overall genetic variation was constant between normal and delayed clearance groups for both RSV/A and RSV/B. Intra-host variation primarily occurred in the G gene followed by non-structural protein (NS1) and L genes; however, gain or loss of stop codons and frameshift mutations appeared only in the G gene and only in the delayed viral clearance group. Potential gain or loss of O-linked glycosylation sites in the G gene occurred both in RSV/A and RSV/B isolates. For RSV F gene, loss of N-linked glycosylation site occurred in three RSV/B isolates within an antigenic epitope. Both oral and aerosolized ribavirin did not cause any mutations in the L gene. In summary, prolonged viral shedding and immune deficiency resulted in RSV variation, especially in structural mutations in the G gene, possibly associated with immune evasion. Therefore, sequencing and monitoring of RSV isolates from immunocompromised patients are crucial as they can create escape mutants that can impact the effectiveness of upcoming vaccines and treatments.

The Respiratory Microbiome in Paediatric Chronic Wet Cough: What Is Known and Future Directions.

Chronic wet cough for longer than 4 weeks is a hallmark of chronic suppurative lung diseases (CSLD), including protracted bacterial bronchitis (PBB), and bronchiectasis in children. Severe lower respiratory infection early in life is a major risk factor of PBB and paediatric bronchiectasis. In these conditions, failure to clear an underlying endobronchial infection is hypothesised to drive ongoing inflammation and progressive tissue damage that culminates in irreversible bronchiectasis. Historically, the microbiology of paediatric chronic wet cough has been defined by culture-based studies focused on the detection and eradication of specific bacterial pathogens. Various 'omics technologies now allow for a more nuanced investigation of respiratory pathobiology and are enabling development of endotype-based models of care. Recent years have seen substantial advances in defining respiratory endotypes among adults with CSLD; however, less is understood about diseases affecting children. In this review, we explore the current understanding of the airway microbiome among children with chronic wet cough related to the PBB-bronchiectasis diagnostic continuum. We explore concepts emerging from the gut-lung axis and multi-omic studies that are expected to influence PBB and bronchiectasis endotyping efforts. We also consider how our evolving understanding of the airway microbiome is translating to new approaches in chronic wet cough diagnostics and treatments.

The Characteristics of Respiratory Bocavirus Infection in Acutely Sick Children Admitted to a Tertiary Hospital in Jordan.

The clinical manifestations of human bocavirus infections are diverse, ranging from mild common cold to severe lower respiratory tract infections. Bocaviruses have frequently been codetected with other respiratory viruses. We aimed to estimate the burden of bocavirus and multiple viral infections and to investigate the risk factors associated with these infections. This study was a retrospective chart review of admitted patients. The medical records of the included children were searched, and data on demographics, clinical presentation, imaging, laboratory and nasopharyngeal swab results were collected. A total of 157 patients were included. Most of the patients were males (62.1%) and under 6 months of age (52%). The 3 most common symptoms presented in the patients were cough (81.8%), rhinorrhea (58.6%) and fever (55.8%). Bocavirus DNA was detected in 12.66% of the patients, while 22.30% had multiple viruses. Age distribution was significantly different between bocavirus and nonbocavirus groups, with a lower proportion of bocavirus infection in all age groups (P = 0.032). The X-ray patterns significantly differed between the 2 study groups, with a lower number of patients in the bocavirus group having normal X-rays (P = 0.007). Patients infected with multiple viruses had more severe respiratory distress symptoms and diarrhea than those infected with only 1 virus. The prevalence of multiple viruses and bocavirus respiratory infections is significant. This study can guide physicians toward the clinical presentation and characteristics of children with respiratory bocavirus and multiple viral infections and propose future studies conducted in this regard.

Routine Metagenomics Service for ICU Patients with Respiratory Infection.

Rationale: Respiratory metagenomics (RMg) needs evaluation in a pilot service setting to determine utility and inform implementation into routine clinical practice. Objectives: Feasibility, performance, and clinical impacts on antimicrobial prescribing and infection control were recorded during a pilot RMg service. Methods: RMg was performed on 128 samples from 87 patients with suspected lower respiratory tract infection (LRTI) on two general and one specialist respiratory ICUs at Guy's and St Thomas' NHS Foundation Trust, London. Measurements and Main Results: During the first 15 weeks, RMg provided same-day results for 110 samples (86%), with a median turnaround time of 6.7 hours (interquartile range = 6.1-7.5 h). RMg was 93% sensitive and 81% specific for clinically relevant pathogens compared with routine testing. Forty-eight percent of RMg results informed antimicrobial prescribing changes (22% escalation; 26% deescalation) with escalation based on speciation in 20 out of 24 cases and detection of acquired-resistance genes in 4 out of 24 cases. Fastidious or unexpected organisms were reported in 21 samples, including anaerobes (n = 12), Mycobacterium tuberculosis, Tropheryma whipplei, cytomegalovirus, and Legionella pneumophila ST1326, which was subsequently isolated from the bedside water outlet. Application to consecutive severe community-acquired LRTI cases identified Staphylococcus aureus (two with SCCmec and three with luk F/S virulence determinants), Streptococcus pyogenes (emm1-M1uk clone), S. dysgalactiae subspecies equisimilis (STG62647A), and Aspergillus fumigatus with multiple treatments and public health impacts. Conclusions: This pilot study illustrates the potential of RMg testing to provide benefits for antimicrobial treatment, infection control, and public health when provided in a real-world critical care setting. Multicenter studies are now required to inform future translation into routine service.