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Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI), hospital admission, and mortality in children worldwide. Early-life RSV LRTI has also been associated with subsequent long-term respiratory sequelae, including recurrent LRTI, recurrent wheezing, asthma, and lung function impairment, and these effects can persist into adulthood as chronic respiratory disease. New preventive measures (maternal vaccine or long-acting monoclonal antibodies) have been licensed to reduce the burden of acute RSV LRTI in infants and children at high risk through passive immunisation. Studies of these RSV prevention products show high efficacy and effectiveness, particularly for preventing severe RSV LRTI, with implementation in many high-income countries, but limited access in low-income and middle-income countries (LMICs). These interventions might also reduce the risk of additional health outcomes and long-term morbidity. This Series paper provides the evidence for the long-term effects of early-life RSV disease, discusses mechanisms of disease development, and addresses the potential full public health value of prevention of RSV illness. Further research is needed to determine whether prevention of RSV LRTI or delay of RSV illness in early life might prevent or ameliorate the development of associated long-term respiratory disease. This potential further underscores the urgency for access and availability of new interventions to prevent early-life RSV LRTI in LMICs., Competing Interests: Declaration of interests HJZ is supported by the South African Medical Research Council; reports grants from AstraZeneca, Merck, and Pfizer for trials of RSV prevention and from the Gates Foundation for studies in childhood pneumonia (including RSV); has served on advisory boards of Merck and Pfizer on RSV prevention; has received speaker fees from Pfizer; serves on a data safety monitoring board for Moderna outside of the submitted work; and has served on the WHO Technical Advisory Group on new RSV preventive interventions. FC is supported by a National Institutes of Health (NIH) grant (NIH T32 ES007028). AM reports funding support from NIH, Merck, and Jansen; has served on advisory boards for Merck, Pfizer, Sanofi-Pasteur, AstraZeneca, Enanta, and Moderna outside of the submitted work; and has received speaker fees and travel and meeting support from Pfizer and Sanofi-Pasteur for educational lectures. RTS reports having received honoraria for advisory board meetings and pharma-sponsored symposia from Pfizer, Sanofi, Moderna, AstraZeneca, and OM-Pharma. TVH reports grants from the NIH; fees from the American Thoracic Society, the Parker B Francis Council of Scientific Advisors, and the NIH National Health Lung and Blood Institute for serving on council, and from Pfizer for serving on vaccine data safety monitoring boards; and speaker fees for invited talks from the American Academy of Allergy, Asthma and Immunology, and for an invited respiratory forum from Sanofi outside of the submitted work. JRO reports grants from the NIH and The Vaccine Company for research support and for participation on a data safety monitoring board. JRO is on scientific advisory boards for GSK, Moderna, and Pfizer. He has received personal funding from the France Foundation to develop RSV-continuing medical education materials. His institution has received RSV research funds from the Bill & Melinda Gates Foundation and the World Health Organization. TK declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Rhinoviruses (RVs) are a leading cause of acute respiratory infections (ARI) in children. The relationship between RV viral loads (VL), RV/viral-co-detections and disease severity, is incompletely understood. We studied children and adolescents ≤21 years with RV-ARI that were identified as inpatients or outpatients using a PCR panel from 2011-2013. RV VL were stratified according to cycle threshold (CT) values in high (≤25), intermediate (26-32) and low (>32). Adjusted analyses were performed to assess the role RV VL and RV/viral codetections on hospital admission, oxygen requirement, PICU care, and length of stay. Of 1,899 children with RV-ARI, 78% had chronic comorbidities and 24% RV/viral co-detections. Single RV vs RV/viral co-detections was associated with higher VL (24.74 vs 26.62 CT; p = 0.001) and older age (14.9 vs 9.5 months; p = 0.0001). Frequency of RV/viral co-detections were inversely proportional to RV loads: 32% with low; 28% with intermediate, and 19% with high VL, p = 0.0001. Underlying conditions were independently associated with all clinical outcomes, high VL with PICU care, and single RV-ARI with higher odds of hospitalization. In summary, single RV vs RV/viral co-detections were associated with higher VL and older age. Underlying diseases, rather than RV loads or RV/viral co-detections, consistently predicted worse clinical outcomes., (© 2024 Wiley Periodicals LLC.)

Objective: Long COVID, marked by persistent, recurring, or new symptoms post-COVID-19 infection, impacts children's well-being yet lacks a unified clinical definition. This study evaluates the performance of an empirically derived Long COVID case identification algorithm, or computable phenotype, with manual chart review in a pediatric sample. This approach aims to facilitate large-scale research efforts to understand this condition better., Methods: The algorithm, composed of diagnostic codes empirically associated with Long COVID, was applied to a cohort of pediatric patients with SARS-CoV-2 infection in the RECOVER PCORnet EHR database. The algorithm classified 31,781 patients with conclusive, probable, or possible Long COVID and 307,686 patients without evidence of Long COVID. A chart review was performed on a subset of patients (n=651) to determine the overlap between the two methods. Instances of discordance were reviewed to understand the reasons for differences., Results: The sample comprised 651 pediatric patients (339 females, M age = 10.10 years) across 16 hospital systems. Results showed moderate overlap between phenotype and chart review Long COVID identification (accuracy = 0.62, PPV = 0.49, NPV = 0.75); however, there were also numerous cases of disagreement. No notable differences were found when the analyses were stratified by age at infection or era of infection. Further examination of the discordant cases revealed that the most common cause of disagreement was the clinician reviewers' tendency to attribute Long COVID-like symptoms to prior medical conditions. The performance of the phenotype improved when prior medical conditions were considered (accuracy = 0.71, PPV = 0.65, NPV = 0.74)., Conclusions: Although there was moderate overlap between the two methods, the discrepancies between the two sources are likely attributed to the lack of consensus on a Long COVID clinical definition. It is essential to consider the strengths and limitations of each method when developing Long COVID classification algorithms.

Objectives: This study seeks to identify demographic and clinical factors prompting clinician prescribing of nirmatrelvir/ritonavir to pediatric patients for management of coronavirus disease 2019 (COVID-19) infection., Methods: Patients aged 12 to 17 years with a COVID-19 infection and nirmatrelvir/ritonavir prescription during an outpatient clinical encounter within a PEDSnet-affiliated institution between January 2022 and August 2023 were identified using electronic health record data. A multivariate logistic regression analysis was used to estimate odds of nirmatrelvir/ritonavir prescription after adjusting for various factors., Results: A total of 20 959 patients aged 12 to 17 years were diagnosed with a COVID-19 infection on the basis of an electronic health record-documented positive polymerase chain reaction or antigen test or diagnosis during an outpatient clinical visit. Of these patients, 408 received a nirmatrelvir/ritonavir prescription within 5 days of diagnosis. Higher odds of nirmatrelvir/ritonavir treatment were associated with having chronic or complex chronic disease (chronic: odds ratio [OR] 2.50 [95% confidence interval (CI) 1.83-3.38]; complex chronic: OR 2.21 [95% CI 1.58-3.08]). Among patients with chronic disease, each additional body system conferred 1.18 times higher odds of treatment (95% CI 1.10-1.26). Compared with non-Hispanic white patients, Hispanic patients (OR 0.61 [95% CI 0.44-0.83]) had lower odds of treatment., Conclusions: Children with chronic conditions are more likely than those without to receive nirmatrelvir/ritonavir prescriptions. However, nirmatrelvir/ritonavir prescribing to children with chronic conditions remains infrequent. Pediatric data concerning nirmatrelvir/ritonavir safety and effectiveness in preventing severe disease and hospitalization are critical optimizing clinical decision-making and use among children.

From 2001 to 2023, 17 (14%) of 120 neonates with confirmed herpes simplex virus infection tested positive for herpes simplex virus by polymerase chain reaction (PCR) from only mucosal sites without a clinical mucosal lesion. Whether mucosal PCR positivity reflects early infection that may lead to recognizable disease, transient colonization, or a false-positive PCR result remains a clinical conundrum and warrants further study., Competing Interests: Declaration of Competing Interest A.M. has received fees for participation in Advisory Boards from Janssen, Merck, Pfizer, AstraZeneca and Sanofi-Pasteur as well as research grants from NIH, Merck, and Janssen. None contributed to study design, collection, analysis, and interpretation of data, writing of the report, and decision to submit the manuscript for publication. Other authors have no conflict of interest relevant to this article to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This review article will summarize the vaccines and monoclonal antibodies currently under evaluation for the prevention of RSV disease in older infants, toddlers and young children. We will review the rationale for passive protection during the first months of life, and the role of active immunization afterwards, either with live attenuated, protein-based or mRNA vaccines., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Respiratory syncytial virus (RSV) is among the most common causes of lower respiratory tract infection (LRTI) and hospitalization in infants. However, the mechanisms of immune control in infants remain incompletely understood. Antibody profiling against attachment (G) and fusion (F) proteins in children less than 2 years of age, with mild (outpatients) or severe (inpatients) RSV disease, indicated substantial age-dependent differences in RSV-specific immunity. Maternal antibodies were detectable for the first 3 months of life, followed by a long window of immune vulnerability between 3 and 6 months and a rapid evolution of FcγR-recruiting immunity after 6 months of age. Acutely ill hospitalized children exhibited lower G-specific antibodies compared with healthy controls. With disease resolution, RSV-infected infants generated broad functional RSV strain-specific G-responses and evolved cross-reactive F-responses, with minimal maternal imprinting. These data suggest an age-independent RSV G-specific functional humoral correlate of protection, and the evolution of RSV F-specific functional immunity with disease resolution., Competing Interests: Declaration of interests G.A. is an employee of Moderna Therapeutics and also holds equity in Leyden Labs and Systems Seromyx. A.M. has received research grants from Janssen and Merck, fees for participation in advisory boards from Janssen, Merck, Sanofi Pasteur, Pfizer, and Moderna, and fees for lectures from Sanofi Pasteur, Pfizer, and Astra Zeneca. O.R. has received research grants from the Bill & Melinda Gates Foundation, Merck, and Janssen; fees for participation in advisory boards from Merck, Sanofi Pasteur, and Pfizer; and fees for lectures from Pfizer, AstraZeneca, and Sanofi Pasteur., (Published by Elsevier Inc.)

Lower respiratory tract infections, commonly caused by respiratory syncytial virus (RSV) or Streptococcus pneumoniae (pneumococcus), pose a substantial global health burden, especially in children younger than 5 years of age. A deeper understanding of the relationship between RSV and pneumococcus would aid the development of health-care approaches to disease prevention and management. We completed a systematic review to identify and assess evidence pertaining to the relationship between RSV and pneumococcus in the pathogenesis of childhood respiratory infections. We found mechanistic evidence for direct pathogen-pathogen interactions and for indirect interactions involving host modulation. We found a strong seasonal epidemiological association between these two pathogens, which was recently confirmed by a parallel decrease and a subsequent resurgence of both RSV and pneumococcus-associated disease during the COVID-19 pandemic. Importantly, we found that pneumococcal vaccination was associated with reduced RSV hospitalisations in infants, further supporting the relevance of their interaction in modulating severe disease. Overall evidence supports a broad biological and clinical interaction between pneumococcus and RSV in the pathogenesis of childhood respiratory infections. We hypothesise that the implementation of next-generation pneumococcal and RSV vaccines and monoclonal antibodies targeting RSV will act synergistically to reduce global morbidity and mortality related to childhood respiratory infections., Competing Interests: Declaration of interests LB and RD obtained a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme (MSD) to cover the costs of Violicom's searches and screening of the data. LB is the founding chairman of the Respiratory Syncytial Virus Foundation (ReSViNET Foundation); he has regular interactions with pharmaceutical and other industrial partners, but he has not received personal fees or other personal benefits. LB reports the following funding to his institution: funding for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics; funding for the RSV GOLD study from the Bill & Melinda Gates Foundation; funding as part of the Innovative Medicines Initiative-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi; funding for participation in clinical studies sponsored by MedImmune and Pfizer from Julius Clinical; and consulting fees and fees for invited lectures from AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, and Janssen. AM has received research grants to her institution from Janssen, Merck, and the US National Institutes of Health (NIH); fees for participation on advisory boards from Janssen, Sanofi Pasteur, Merck, Pfizer, and AstraZeneca; and fees for lectures from Sanofi Pasteur and AstraZeneca. OR has received research grants to his institution from Janssen, Merck, NIH, and the Bill & Melinda Gates Foundation; fees for participation on advisory boards from Sanofi Pasteur, Merck, and Pfizer; and fees for lectures from Pfizer, Sanofi Pasteur, and AstraZeneca. DMW is supported by a grant from the NIH National Institute of Allergy and Infectious Diseases (R01AI137093) and has received consulting fees from Pfizer, Merck, and GSK/Affinivax for work unrelated to this manuscript; he is the principal investigator on grants from Pfizer and Merck to his institution for work unrelated to this manuscript. RD has received grants to his institution from Pfizer, MSD, and MedImmune/AstraZeneca; consulting fees and fees for participation on advisory boards from Pfizer and MSD; payment for speakers bureaus from Pfizer, MSD, Sanofi Pasteur, and GSK; and payment for expert testimony from Pfizer. SBB and DB declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Multisystem inflammatory syndrome in children (MIS-C) represents a hyperinflammatory state that can result in multi-organ dysfunction and death. Myeloid-derived suppressor cells (MDSC) are an immunosuppressive cell population that expands under inflammatory conditions and suppresses T cell function. We hypothesized that MDSC would be increased in children with MIS-C and that MDSC expansion would be associated with T cell lymphopenia., Methods: We conducted a prospective, observational study. Initial blood samples were collected within 48 h of admission. Age-matched healthy controls underwent sampling once. MDSC and T cell populations were identified by flow cytometric methods., Results: We enrolled 22 children with MIS-C (12 ICU, 10 ward) and 21 healthy controls (HC). Children with MIS-C demonstrated significantly higher MDSC compared to HC, and MDSC expansion persisted for >3 weeks in the ICU group. Children with MIS-C admitted to the ICU demonstrated significantly lower absolute numbers of T cells and natural killer cells. There were no significant associations between MDSC and cardiac dysfunction, duration of hospitalization, or vasoactive inotrope score., Conclusions: Our study suggests that children critically ill with MIS-C have expansion of MDSC and associated decreased T cell and NK cell populations. Our results did not demonstrate associations between MDSC and clinical outcomes., Impact: Multisystem inflammatory syndrome in children (MIS-C) is a dysregulated immune response occurring several weeks after SARS-CoV-2 infection that can result in multi-organ dysfunction and death. Children severely ill with MIS-C demonstrated increased myeloid-derived suppressor cells and decreased absolute numbers of CD4+ and CD8 + T cells and NK cells compared to healthy controls. There was no significant association between MDSC numbers and clinical outcomes; including cardiac dysfunction, length of stay, or requirement of vasoactive support, in children with MIS-C., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Infants and young children born prematurely are at high risk of severe acute lower respiratory infection (ALRI) caused by respiratory syncytial virus (RSV). In this study, we aimed to assess the global disease burden of and risk factors for RSV-associated ALRI in infants and young children born before 37 weeks of gestation., Methods: We conducted a systematic review and meta-analysis of aggregated data from studies published between Jan 1, 1995, and Dec 31, 2021, identified from MEDLINE, Embase, and Global Health, and individual participant data shared by the Respiratory Virus Global Epidemiology Network on respiratory infectious diseases. We estimated RSV-associated ALRI incidence in community, hospital admission, in-hospital mortality, and overall mortality among children younger than 2 years born prematurely. We conducted two-stage random-effects meta-regression analyses accounting for chronological age groups, gestational age bands (early preterm, <32 weeks gestational age [wGA], and late preterm, 32 to <37 wGA), and changes over 5-year intervals from 2000 to 2019. Using individual participant data, we assessed perinatal, sociodemographic, and household factors, and underlying medical conditions for RSV-associated ALRI incidence, hospital admission, and three severity outcome groups (longer hospital stay [>4 days], use of supplemental oxygen and mechanical ventilation, or intensive care unit admission) by estimating pooled odds ratios (ORs) through a two-stage meta-analysis (multivariate logistic regression and random-effects meta-analysis). This study is registered with PROSPERO, CRD42021269742., Findings: We included 47 studies from the literature and 17 studies with individual participant-level data contributed by the participating investigators. We estimated that, in 2019, 1 650 000 (95% uncertainty range [UR] 1 350 000-1 990 000) RSV-associated ALRI episodes, 533 000 (385 000-730 000) RSV-associated hospital admissions, 3050 (1080-8620) RSV-associated in-hospital deaths, and 26 760 (11 190-46 240) RSV-attributable deaths occurred in preterm infants worldwide. Among early preterm infants, the RSV-associated ALRI incidence rate and hospitalisation rate were significantly higher (rate ratio [RR] ranging from 1·69 to 3·87 across different age groups and outcomes) than for all infants born at any gestational age. In the second year of life, early preterm infants and young children had a similar incidence rate but still a significantly higher hospitalisation rate (RR 2·26 [95% UR 1·27-3·98]) compared with all infants and young children. Although late preterm infants had RSV-associated ALRI incidence rates similar to that of all infants younger than 1 year, they had higher RSV-associated ALRI hospitalisation rate in the first 6 months (RR 1·93 [1·11-3·26]). Overall, preterm infants accounted for 25% (95% UR 16-37) of RSV-associated ALRI hospitalisations in all infants of any gestational age. RSV-associated ALRI in-hospital case fatality ratio in preterm infants was similar to all infants. The factors identified to be associated with RSV-associated ALRI incidence were mainly perinatal and sociodemographic characteristics, and factors associated with severe outcomes from infection were mainly underlying medical conditions including congenital heart disease, tracheostomy, bronchopulmonary dysplasia, chronic lung disease, or Down syndrome (with ORs ranging from 1·40 to 4·23)., Interpretation: Preterm infants face a disproportionately high burden of RSV-associated disease, accounting for 25% of RSV hospitalisation burden. Early preterm infants have a substantial RSV hospitalisation burden persisting into the second year of life. Preventive products for RSV can have a substantial public health impact by preventing RSV-associated ALRI and severe outcomes from infection in preterm infants., Funding: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe., Competing Interests: Declaration of interests YM and ES were affiliated with the University of Edinburgh when this work was conducted. YM is currently affiliated to the School of Public Health, Wuhan University, Wuhan, China and ES is employed by University College Hospital, University College Hospitals NHS Foundation Trust, London, UK. XW reports grants from GSK to their institution and personal fees from Pfizer, outside the submitted work. YL reports grants from Wellcome Trust, WHO, and GSK paid to their institution, and personal fees from Pfizer, outside the submitted work. TS reports grants from Royal Society of Edinburgh outside the submitted work. LJB reports regular interactions with AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Genzyme, MeMed Diagnostics, and Janssen but has not received personal fees or other personal benefits; being the founding chairman of the ReSViNET Foundation; their affiliation (University Medical Centre Utrecht) has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics; major funding for the RSV GOLD study from the Bill & Melinda Gates Foundation; major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi; major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer; and minor funding (€1000–€25 000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, and Janssen. HYC reports consulting for Ellume, Pfizer, and the Gates Foundation; serving on advisory boards for Vir, Merck, and AbbVie; conducting continuing medical education teaching with Medscape, Vindico, Cataylst CME, and Clinical Care Options; research funding from Gates Ventures; and receiving support and reagents from Ellume and Cepheid, all outside of the submitted work. HJZ reports grants from the Gates Foundation, AstraZeneca, MSD, and Pfizer paid to their institution outside the submitted work, and serving on advisory boards for MSD. TH reports personal fees from Janssen, Sanofi, Enanta, MSD, and Moderna, all outside of the submitted work. MHJ reports personal fees from AstraZeneca, OM-Pharma, Chiesi, GSK, and Boehringer Ingelheim, outside the submitted work. MCN reports grants from the Gates Foundation, European & Developing Countries Clinical Trials Partnership, Pfizer, AstraZeneca, and Sanofi; and serving on advisory boards for Sanofi, all outside the submitted work. BR received honoraria due to lectures from AbbVie, Germania, Sanofi, AstraZeneca, Milupa, Nestle, and Fresenius, outside the submitted work; and travel support from AbbVie, Chiesi, AstraZeneca, Sanofi, and Nestle. HN reports grants from the Innovative Medicines Initiative related to the submitted work; grants from WHO, the National Institute for Health Research, Pfizer, and Icosavax; and personal fees from the Gates Foundation, Pfizer, ReViral, GSK, Merck, Icosavax, Sanofi, Novavax, and AbbVie, outside the submitted work. CFY reports grants from National Medical Research Council Singapore and Wellcome Trust, and funding to attend conferences and honorarium from Sanofi, Pfizer, and Takeda, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

We present a rare case of pan-valvular involvement in a 5-month-old female with Kawasaki disease shock syndrome despite early treatment with intravenous immunoglobulin and corticosteroids. She experienced a favorable outcome after the addition of infliximab, which was guided based on clinical, laboratory and echocardiogram findings, rather than recrudescence of fever, the most common indicator of intravenous immunoglobulin resistance., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The main objective of this report was to comprehensively analyze the clinical characteristics of children hospitalized with respiratory syncytial virus (RSV) infections in 2021 during the coronavirus disease 2019 (COVID-19) pandemic and to compare them with those in the five previous RSV seasons. We hypothesized that the clinical and demographic features of children hospitalized with RSV infection in 2021 were different from those hospitalized in previous respiratory seasons., Study Design: In this retrospective observational study, children younger than 2 years hospitalized with RSV bronchiolitis from January 1, 2015, to December 31, 2021, at the Department of Pediatrics of the Hospital Gregorio Marañón, Madrid, Spain, were included. We compared the clinical characteristics of children hospitalized with RSV bronchiolitis in the five seasons before the COVID-19 pandemic and during the subsequent off-seasonal surge of RSV infections., Results: We found a significant reduction in hospitalizations for RSV bronchiolitis during the usual winter epidemic period due to the COVID-19 pandemic. Children hospitalized with RSV infection in 2021, during the COVID-19 pandemic, were older than children hospitalized in the prepandemic period (2015-2020; 4.0 [1.6-9.2] vs. 3 [1.5-6.5] months; p  < 0.01). We also found shorter duration of oxygen days during the COVID-19 period compared with previous respiratory seasons (3 [2-5] vs. 4 [2-6] days; p  = 0.02)., Conclusion: The COVID-19 pandemic modified the RSV seasonality with a significant reduction in RSV hospitalizations during the expected 2020-2021 season and a reappearance of RSV 7 months later than expected. We also found changes in the median age of children with RSV bronchiolitis during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic compared with the prepandemic RSV seasons and shorter duration of oxygen days suggesting a modest reduction in disease severity. We hypothesize that this observation reflects the lack of RSV circulation in the previous months (April 2020-March 2021), with a larger pool of vulnerable infants that had not been previously infected., Key Points: · The COVID-19 pandemic shifted RSV seasonality.. · RSV children hospitalized during the pandemic were older.. · Modest reduction in disease severity was observed during the pandemic.., Competing Interests: R. R.-F. has received fees for lectures from AbbVie, AstraZeneca, and Sanofi; fees for participation in Advisory Boards from Sanofi, AstraZeneca, and Merck; and research grants from FIS (Fondo de Investigaciones Sanitarias). O. R. has received research grants to institution from Janssen, Merck, NIH, and the Bill & Melinda Gates Foundation; and fees for participation in Advisory Boards from Sanofi-Pasteur, Merck, Lilly, Adagios, and Pfizer and for lectures from Pfizer, Sanofi-Pasteur, and AstraZeneca. A. M. has received fees for participation in Advisory Boards from Janssen, Merck, and Sanofi-Pasteur; grants to institution from Merck and Janssen; and fees for lectures from Sanofi-Pasteur and AstraZeneca., (Thieme. All rights reserved.)

Importance: Induced hypothermia, the standard treatment for hypoxic-ischemic encephalopathy (HIE) in high-income countries (HICs), is less effective in the low-income populations in South Asia, who have the highest disease burden., Objective: To investigate the differences in blood genome expression profiles of neonates with HIE from an HIC vs neonates with HIE from South Asia., Design, Setting, and Participants: This case-control study analyzed data from (1) a prospective observational study involving neonates with moderate or severe HIE who underwent whole-body hypothermia between January 2017 and June 2019 and age-matched term healthy controls in Italy and (2) a randomized clinical trial involving neonates with moderate or severe HIE in India, Sri Lanka, and Bangladesh recruited between August 2015 and February 2019. Data were analyzed between October 2020 and August 2023., Exposure: Whole-blood RNA that underwent next-generation sequencing., Main Outcome and Measures: The primary outcomes were whole-blood genome expression profile at birth associated with adverse outcome (death or disability at 18 months) after HIE in the HIC and South Asia cohorts and changes in whole-genome expression profile during the first 72 hours after birth in neonates with HIE and healthy controls from the HIC cohort. Blood samples for RNA extraction were collected before whole-body hypothermia at 4 time points (6, 24, 48, and 72 hours after birth) for the HIC cohort. Only 1 blood sample was drawn within 6 hours after birth for the South Asia cohort., Results: The HIC cohort was composed of 35 neonates (21 females [60.0%]) with a median (IQR) birth weight of 3.3 (3.0-3.6) kg and gestational age of 40.0 (39.0-40.6) weeks. The South Asia cohort consisted of 99 neonates (57 males [57.6%]) with a median (IQR) birth weight of 2.9 (2.7-3.3) kg and gestational age of 39.0 (38.0-40.0) weeks. Healthy controls included 14 neonates (9 females [64.3%]) with a median (IQR) birth weight of 3.4 (3.2-3.7) kg and gestational age of 39.2 (38.9-40.4) weeks. A total of 1793 significant genes in the HIC cohort and 99 significant genes in the South Asia cohort were associated with adverse outcome (false discovery rate <0.05). Only 11 of these genes were in common, and all had opposite direction in fold change. The most significant pathways associated with adverse outcome were downregulation of eukaryotic translation initiation factor 2 signaling in the HIC cohort (z score = -4.56; P < .001) and aldosterone signaling in epithelial cells in the South Asia cohort (z score = null; P < .001). The genome expression profile of neonates with HIE (n = 35) at birth, 24 hours, 48 hours, and 72 hours remained significantly different from that of age-matched healthy controls in the HIC cohort (n = 14)., Conclusions and Relevance: This case-control study found that disease mechanisms underlying HIE were primarily associated with acute hypoxia in the HIC cohort and nonacute hypoxia in the South Asia cohort. This finding might explain the lack of hypothermic neuroprotection.

Background: Respiratory syncytial virus (RSV) infection is associated with significant morbidity in infants. Risk factors for severe disease beyond the first 2 years of life have not been fully defined., Methods: Children <5 years hospitalized with virologically confirmed RSV infection were identified over six respiratory seasons (10/2012-4/2018) and their medical records manually reviewed. Multivariable analyses were performed to define the age-specific (<6, 6-24, and >24-59 months) risk factors associated with oxygen administration, PICU admission, mechanical ventilation, and duration of hospitalization., Results: We identified 5143 children hospitalized with RSV infection: 53.5% (n = 2749) <6 months; 31.7% (n = 1631) 6-24 months; and 14.8% (n = 763) >24-59 months. Rates of ICU admission were high (35%-36%) and comparable across age groups, while children >24-59 and 6-24 versus those <6 months required supplemental oxygen more frequently (73%; 71%; 68%, respectively; p = .003). The presence of comorbidities increased with age (25%, <6 months; 46%, 6-24 months; 70%, >24-59 months; p < .001). Specifically, neuromuscular disorders, chronic lung disease, and reactive airway disease/asthma were predictive of worse clinical outcomes in children aged 6-24 and >24-59 months, while RSV-viral codetections increased the risk of severe outcomes in children aged <6 and 6-24 months of age., Conclusions: Almost half of children hospitalized with RSV infection were >6 months. Underlying comorbidities increased with age and remained associated with severe disease in older children, while RSV-viral codetections were predictive of worse clinical outcomes in the youngest age groups. These data suggest the importance of defining the clinical phenotype associated with severe RSV according to age, and the persistent burden associated with RSV beyond infancy., (© 2024 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Enterovirus-D68 (EV-D68) has appeared biennially in the United States following the 2014 outbreak. It has gained epidemiologic and clinical relevance and was identified as an important pathogen associated with severe respiratory and central nervous system diseases. We aim to describe the clinical and molecular characteristics of the post-pandemic 2022 Enterovirus-D68 outbreak in children evaluated in a tertiary pediatric hospital in Columbus, Ohio., Methods: EV-D68 RT-PCR was performed on nasopharyngeal specimens collected during Jun-Nov 2022 from children (<18 years), identified by 1) physician-order or 2) random selection of 10-15 specimens weekly that were Rhinovirus/Enterovirus-positive by physician-ordered respiratory virus panel. Patients who tested positive for EV-D68 were identified and clinical data and outcomes were analyzed. Partial viral VP1 region was sequenced and characterized., Results: Forty-four children positive for EV-D68 were identified, among which 88.6 % of patients presented with respiratory symptoms and 61.4 % required PICU admission. Two patients presented with AFM that was attributed to EV-D68. EV-D68 sequences from 2022 clustered within the B3 subclade., Conclusions: A significant proportion of children identified with EV-D68 during the 2022 outbreak had respiratory compromise requiring PICU admission. As the virus continues evolving, it is important to monitor the activity of EV-D68, characterizing these strains clinically and genetically, which will help to understand the viral pathogenicity and virulence., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ALL has received research grants from BioFire, Cepheid, Luminex, and Diasorin, and consulting fees from Medscape, Biorad and BioFire. AM has received research grants from NIH, Janssen and Merck to institution, fees for participation in advisory boards from Janssen, Sanofi-Pasteur, Pfizer and Merck and fees for educational lectures from Sanofi-Pasteur and AstraZeneca. The remaining authors have no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We analyzed the frequency, clinical impact and severity of respiratory syncytial virus (RSV) and SARS-CoV-2 coinfections in a single pediatric center between March 2020 and January 2023. Compared to single RSV infections, RSV/SARS-CoV-2 coinfections were uncommon (2.1%), occurred more frequently during circulation of omicron, and were associated with increased disease severity as defined by longer hospitalization and increased need for high-flow nasal cannula., Competing Interests: R.R-.F. has received fees for lectures from Abbvie, Astra Zeneca, Pfizer and Sanofi, fees for participation in Advisory Boards from Sanofi, Astra Zeneca and Merck, and research grants from FIS (Fondo de Investigaciones Sanitarias). O.R. has received research grants to institution from Janssen, Merck, NIH and the Bill & Melinda Gates foundation; and fees for participation in Advisory Boards from Sanofi-Pasteur, Merck, Lilly, Adagios and Pfizer and for lectures from Pfizer, Sanofi-Pasteur and Astra-Zeneca. A.M. has received fees for participation in Advisory Boards from Janssen, Merck, Pfizer and Sanofi-Pasteur, grants to institution from Merck and Janssen, and fees for lectures from Sanofi-Pasteur and Astra-Zeneca. The other authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Multi-system inflammatory syndrome in children (MIS-C) is a severe post-acute sequela of SARS-CoV-2 infection in children, and there is a critical need to unfold its highly heterogeneous disease patterns. Our objective was to characterize the illness spectrum of MIS-C for improved recognition and management. We conducted a retrospective cohort study using data from March 1, 2020-September 30, 2022, in 8 pediatric medical centers from PEDSnet. We included 1139 children hospitalized with MIS-C and used their demographics, symptoms, conditions, laboratory values, and medications for analyses. We applied heterogeneity-adaptive latent class analyses and identified three latent classes. We further characterized the sociodemographic and clinical characteristics of the latent classes and evaluated their temporal patterns. Class 1 (47.9%) represented children with the most severe presentation, with more admission to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 (23.3%) represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 (28.8%) represented a mild presentation. Our results indicated that MIS-C has a spectrum of clinical severity ranging from mild to severe and the proportion of severe or critical MIS-C decreased over time., (© 2023. The Author(s).)

Competing Interests: Potential conflicts of interest. OR has received research grants to institution from Janssen, Merck, NIH, and the Bill & Melinda Gates foundation; and fees for participation in Advisory Boards from Sanofi-Pasteur, Merck, Lilly, Adagios, and Pfizer and for lectures from Pfizer, Sanofi-Pasteur, and Astra-Zeneca. AM has received fees for participation in Advisory Boards from Janssen, Merck, and Sanofi-Pasteur, grants to institution from Merck and Janssen, and fees for lectures from Sanofi-Pasteur and Astra-Zeneca. RR-F has received fees for lectures from Abbvie, Astra Zeneca, and Sanofi; fees for participation in Advisory Boards from Sanofi, Astra Zeneca and Merck; and research grants from FIS (Fondo de Investigaciones Sanitarias). Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Background: Respiratory viruses such as respiratory syncytial virus (RSV), influenza, parainfluenza and human metapneumovirus are well-established etiologies of acute lower respiratory tract infections (ALRIs; LRI-viruses). In contrast, adenovirus (AdV), rhinovirus/enterovirus (RV/EV) and seasonal human coronaviruses (CoV), collectively termed AdV/RV/CoV, are detected both in healthy children and children with ALRI., Methods: The methods include a prospective longitudinal case-control study, assessing the prevalence of LRI-viruses versus AdV/RV/CoV in ALRI [community-acquired alveolar pneumonia (CAAP) and bronchiolitis] during hospitalization (visit 1), 7-14 days (visit 2) and 28-35 days (visit 3) in 2-17-month-old children. Controls were 2-27-month-old children hospitalized for elective surgery during the same respiratory seasons., Results: We enrolled 99 infants (37 CAAP, 38 bronchiolitis and 24 controls) and obtained 211 nasopharyngeal swabs. Overall, 163 (77%) had greater than or equal to 1 viruses detected; RV/EV (n = 94; 45%) and RSV (n = 71; 34%) were the most frequently detected viruses. In CAAP, the overall LRI-virus prevalence was 78.4%, 32.4% and 5.4% in visits 1, 2 and 3, respectively; the respective rates in bronchiolitis were 73.7%, 34.5% and 8.0%. In controls, no LRI-viruses were detected. In contrast, the overall AdV/RV/CoV prevalence was high among controls (70.8%) and similar among CAAP (48.6%, 40.5% and 40.5%) and bronchiolitis (47.4, 58.6% and 64.0%) across visits., Conclusions: Among ALRI cases, LRI-viruses dominated during the acute disease, with prevalence declining within 28-35 days, suggesting their causative role. In contrast, AdV/RV/CoV prevalence was similar during all 3 visits and in controls, suggesting that carriage of these viruses is common during the viral respiratory season. The current study is relatively small and of short duration; however, the findings are supported by other recent studies., Competing Interests: S.B.-S. has received grants from Pfizer, fees as scientific consultant, participation in advisory board, and educational lectures from Pfizer and MSD, and fees for educational lectures from GSK. O.R. has received research grants from NIH, the Bill & Melinda Gates Foundation, Merck and Janssen to institution; fees for participation in advisory boards from Merck, Sanofi-Pasteur, Adagio, Lilly and Pfizer; and fees for lectures from Pfizer, Sanofi-Pasteur and AstraZeneca. A.L.L. has received research grants from Biofire, Cephied, Luminex, and Diasorin, and consulting fees from Medscape, Biorad and Biofire. A.M. has received research grants from, NIH, Janssen and Merck to institution, fees for participation in advisory boards from Janssen, Sanofi-Pasteur, and Merck and fees for educational lectures from Sanofi-Pasteur and AstraZeneca. R.D. has received grants from Pfizer, MSD, MedImmune/AstraZeneca, fees as scientific consultant, participation in advisory board, and educational lectures from Pfizer and MSD, as well as fees for educational lectures from Sanofi-Pasteur. The remaining authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Beginning in late 2021, we observed a significant increase in SARS-CoV-2 reinfections in pediatric patients evaluated at our institution. We aimed to characterize the children with SARS-CoV-2 reinfection, determine the number of SARS-CoV-2 reinfections, and characterize the intervals between two infections in our patient population., Methods: From March 2020 to September 2022, we identified children ≤21 years old who had ≥2 SARS-CoV-2 infections using laboratory reports. We then defined the type of SARS-CoV-2 variant in the first and subsequent infections by mutation-specific typing or local epidemiology data. Clinical outcomes and the intervals between SARS-CoV-2 infections were assessed., Results: We identified 541 children with ≥2 SARS-CoV-2 infections. The median interval between two infections was 229 days. The hospitalization rate was lower in the second infection. Reinfection counts were higher during the periods that Omicron variants predominated. Reinfection occurred more rapidly when Omicron variants were circulating with some occurring in less than 90 days., Conclusions: As SARS-CoV-2 continues to evolve, there is a need for ongoing surveillance to identify the frequency and time interval between reinfections and to re-evaluate the definition of SARS-CoV-2 reinfections., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Using electronic health record data combined with primary chart review, we identified seven children across nine participant pediatric medical centers with a diagnosis of Multisystem Inflammatory Syndrome in Children (MIS-C) managed exclusively as outpatients. These findings should raise awareness of mild presentations of MIS-C and the option of outpatient management., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Post-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect conditions and symptoms associated with pediatric PASC., Materials and Methods: We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) ( N  = 1309) to children with ( N  = 6545) and without ( N  = 6545) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls., Results: We found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise., Discussion: Our study addresses methodological limitations of prior studies that rely on prespecified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes., Conclusion: We identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: Nonpharmaceutical interventions to prevent the spread of coronavirus disease 2019 also decreased the spread of respiratory syncytial virus (RSV) and influenza. Viral diagnostic testing in patients with respiratory tract infections (RTI) is a necessary tool for patient management; therefore, sensitive and specific tests are required. This scoping literature review aimed to summarize the study characteristics of commercially available sample-to-answer RSV tests., Content: PubMed and Embase were queried for studies reporting on the diagnostic performance of tests for RSV in patients with RTI (published January 2005-January 2021). Information on study design, patient and setting characteristics, and published diagnostic performance of RSV tests were extracted from 77 studies that met predefined inclusion criteria. A literature gap was identified for studies of RSV tests conducted in adult-only populations (5.3% of total subrecords) and in outpatient (7.5%) or household (0.8%) settings. Overall, RSV tests with analytical time >30 min had higher published sensitivity (62.5%-100%) vs RSV tests with analytical time ≤30 min (25.7%-100%); this sensitivity range could be partially attributed to the different modalities (antigen vs molecular) used. Molecular-based rapid RSV tests had higher published sensitivity (66.7%-100%) and specificity (94.3%-100%) than antigen-based RSV tests (sensitivity: 25.7%-100%; specificity:80.3%-100%)., Summary: This scoping review reveals a paucity of literature on studies of RSV tests in specific populations and settings, highlighting the need for further assessments. Considering the implications of these results in the current pandemic landscape, the authors preliminarily suggest adopting molecular-based RSV tests for first-line use in these settings., (© American Association for Clinical Chemistry 2022.)

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results., Competing Interests: Declaration of interests UMCU received minor funding from The Bill & Melinda Gates Medical Research Institute. DMW has received consulting fees from Pfizer, Merck, Affinivax, and Matrivax, unrelated to this manuscript; and is a principal investigator with grant support from Pfizer and Merck to Yale University, unrelated to this manuscript. NIM has regular interaction with pharameutical and other industrial partners: UMC Utrecht has received fees for invited lectures by Abbvie, Merck, and Sanofi. LB has regular interaction with pharmaceutical and other industrial partners. BSG is an inventor of patents for RSV vaccines using the stabilised prefusion F protein. AM has received research grants from National Institutes of Health, Janssen, and Merck institution; fees for participation in advisory boards from Janssen, Sanofi-Pasteur, and Merck; and fees for educational lectures from Sanofi-Pasteur and AstraZeneca. TJR was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. BSG was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. UJB was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. UMCU has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, Janssen, Pfizer, the Bill & Melinda Gates Foundation, and MeMed Diagnostics. UMCU has received major cash or in-kind funding as part of the public private partnership IMI-funded RESCEU project from GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding by Julius Clinical for participating in the INFORM study sponsored by MedImmune. UMCU has received minor funding for participation in trials by Regeneron and Janssen from 2015-17 (total annual estimate less than €20 000). UMCU received minor funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, Novavax, Pfizer, and Janssen (total annual estimate less than €20 000). Dr. Bont is the founding chairman of the ReSViNET Foundation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The interplay among respiratory syncytial virus (RSV) loads, mucosal interferons (IFN), and disease severity in RSV-infected children is poorly understood., Methods: Children <2 years of age with mild (outpatients) or severe (inpatients) RSV infection and healthy controls were enrolled, and nasopharyngeal samples obtained for RSV loads and innate cytokines quantification. Patients were stratified by age (0-6 and >6-24 months) and multivariable analyses performed to identify predictors of disease severity., Results: In 2015-2019 we enrolled 219 RSV-infected children (78 outpatients; 141 inpatients) and 34 healthy controls. Type I, II, and III IFN concentrations were higher in children aged >6 versus 0-6 months and, like CXCL10, they were higher in outpatients than inpatients and correlated with RSV loads (P < .05). Higher IL6 concentrations increased the odds of hospitalization (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.07-5.36) only in children >6 months, while higher IFN-λ2/3 concentrations had the opposite effect irrespective of age (OR, 0.38; 95% CI, .15-.86). Likewise, higher CXCL10 concentrations decreased the odds of hospitalization (OR, 0.21; 95% CI, .08-.48), oxygen administration (OR, 0.42; 95% CI, .21-.80),PICU admission (OR, 0.39; 95% CI, .20-.73), and prolonged hospitalization (OR, 0.57; 95% CI, .32-.98) irrespective of age., Conclusions: Children with milder RSV infection and those aged >6 months had higher concentrations of mucosal IFNs, suggesting that maturation of mucosal IFN responses are associated with protection against severe RSV disease., Competing Interests: Potential conflicts of interest. A. M. has received research grants from NIH, Janssen, and Merck; fees for participation in advisory boards from Janssen, Merck, and Sanofi-Pasteur; and fees for lectures from Sanofi-Pasteur and Astra-Zeneca. O. R. has received research grants from NIH, the Bill and Melinda Gates Foundation, Merck, and Janssen; fees for participation in advisory boards from Merck, Sanofi-Pasteur, Lilly, Pfizer, and Adagio; and fees for lectures from Pfizer, Astra-Zeneca, and Sanofi-Pasteur. M. E. P. has received research grants from NIH, the Cystic Fibrosis Foundation, and Janssen. None of these fees were related to the research described in this article. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The high burden of respiratory syncytial virus (RSV) infection in young children disproportionately occurs in low- and middle-income countries (LMICs). The PROUD (Preventing RespiratOry syncytial virUs in unDerdeveloped countries) Taskforce of 24 RSV worldwide experts assessed key needs for RSV prevention in LMICs, including vaccine and newer preventive measures., Methods: A global, survey-based study was undertaken in 2021. An online questionnaire was developed following three meetings of the Taskforce panellists wherein factors related to RSV infection, its prevention and management were identified using iterative questioning. Each factor was scored, by non-panellists interested in RSV, on a scale of zero (very-low-relevance) to 100 (very-high-relevance) within two scenarios: (1) Current and (2) Future expectations for RSV management., Results: Ninety questionnaires were completed: 70 by respondents (71.4% physicians; 27.1% researchers/scientists) from 16 LMICs and 20 from nine high-income (HI) countries (90.0% physicians; 5.0% researchers/scientists), as a reference group. Within LMICs, RSV awareness was perceived to be low, and management was not prioritised. Of the 100 factors scored, those related to improved diagnosis particularly access to affordable point-of-care diagnostics, disease burden data generation, clinical and general education, prompt access to new interventions, and engagement with policymakers/payers were identified of paramount importance. There was a strong need for clinical education and local data generation in the lowest economies, whereas upper-middle income countries were more closely aligned with HI countries in terms of current RSV service provision., Conclusion: Seven key actions for improving RSV prevention and management in LMICs are proposed., Competing Interests: The reviewer PAP declared a past co-authorship with the author(s) FMT to the handling. XCE and BP have received research funding and/or compensation as advisor/lecturer from AbbVie and AstraZeneca. JF and BRG, working for Violicom and former company, have previously received payment from AbbVie and AstraZeneca for work on various projects. MCN reports grants from the Bill & Melinda Gates Foundation, European & Developing Countries Clinical Trials Partnership, Pfizer, AstraZeneca and Sanofi-Pasteur; and personal fees from Pfizer and Sanofi-Pasteur. RTS has received fees for Advisory Board meetings and lectures for Sanofi-Pasteur, AstraZeneca, Janssen, and AbbVie. QB serves in the Independent Data Monitoring Committee (IDMC) for Respiratory Syncytial Virus (RSV) vaccine development for the protection of infants (since October 2015) (GlaxoSmithKline -GSK). JP reports grants to his institution from MedImmune, Merck, Sanofi Pasteur and AbbVie, and personal fees from AbbVie, Merck and AstraZeneca. JMP reports grants to his institution from MedImmune. HJZ has received funding for RSV-related research studies from Pfizer, AstraZeneca, Merck and the Bill & Melinda Gates Foundation. AM has received research funding from Merck and Janssen and compensation as advisor/lecturer from Sanofi-Pasteur and AstraZeneca. IM has been an investigator on studies funded by MedImmune, Regeneron, and Boehringer. MAS has received research funding from Janssen and compensation as advisor/lecturer from AbbVie, Sanofi-Pasteur and AstraZeneca. All declarations made by authors outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Carbonell-Estrany, Simões, Bont, Gentile, Homaira, Scotta, Stein, Torres, Sheikh, Broor, Khuri-Bulos, Nokes, Munywoki, Bassat, Sharma, Basnet, Garba, De Jesus-Cornejo, Lupisan, Nunes, Divarathna, Fullarton, Rodgers-Gray, Keary, Reñosa, Verwey, Moore, Noordeen, Kabra, do Vale, Paternina-De La Ossa, Mariño, Figueras-Aloy, Krilov, Berezin, Zar, Paudel, Safadi, Dbaibo, Jroundi, Jha, Rafeek, Pinheiro, Bracht, Muthugala, Lanari, Martinón-Torres, Mitchell, Irimu, Pandey, Krishnan, Mejias, Santos Corrêa Da Costa, Shrestha, Pernica, Cotrim de Carvalho, Jalango, Ibrahim, Ewa, Ensinck, Ulloa-Gutierrez, Miralha, Lucion, Hassan, Akhtar, Aleem, Chowdhury, Rojo, Sande, Musau, Zaman, Arlant, Ghimire, Price, Subedi, Brenes-Chacon, Goswami, Rahman, Hossain, Chisti, Vain, Lim, Chiu, Papenburg, Juarez, Senaratne, Arunasalam, Strand, Ayuk, Ogunrinde, Tavares, Garba, Garba, Dawa, Gordon, Osoro, Agoti, Nyawanda, Ngama, Tabu, Mathew, Cornacchia, Rai, Jain, Giongo and Paes.)

Since the COVID-19 pandemic began, different SARS-CoV-2 variants have been identified and associated with higher transmissibility than the ancestral nonvariant strain. During January 1, 2021-January 15, 2022, we assessed differences in clinical and viral parameters in a convenience sample of COVID-19 outpatients and inpatients 0-21 years of age in Columbus, Ohio, USA, according to the infecting variant, identified using a mutation-specific reverse transcription PCR assay. Of the 676 patients in the study, 17.75% were infected with nonvariant strains, 18.49% with the Alpha variant, 41.72% with Delta, and 16.42% with Omicron. Rates of SARS-COV-2/viral co-infections were 15.66%-29.41% and were comparable across infecting variants. Inpatients with acute Delta and Omicron infections had lower SARS-CoV-2 cycle threshold values and more frequent fever and respiratory symptoms than those with nonvariant strain infections. In addition, SARS-COV-2/viral co-infections and the presence of underlying conditions were independently associated with worse clinical outcomes, irrespective of the infecting variant.

Rationale: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes long-term pulmonary sequelae in adults, but little is known about pulmonary outcomes in pediatrics., Objective(s): The aim of this study was to describe long-term subjective and objective pulmonary abnormalities after SARS-CoV-2 infection in pediatric populations., Methods: Single-center, retrospective cohort of patients seen in post-coronavirus disease 2019 (COVID-19) pulmonary clinic in 2021. Subjects evaluated had persistent pulmonary symptoms 4 weeks or more after initial infection. Clinical testing included a 6-min walk test (6MWT), chest X-ray, pre- and postbronchodilator spirometry, plethysmography, and diffusion capacity. Patients were followed 2-to-3-months after the initial visit with repeat testing. The primary outcome was the presence of abnormal pulmonary function testing. Secondary measures included variables associated with pulmonary outcomes., Results: Eighty-two adolescents were seen at a median of 3.5 months postinfection, with approximately 80% reporting two or more symptoms at clinic presentation (cough, chest pain, dyspnea at rest, and exertional dyspnea). At follow-up (~6.5 months) exertional dyspnea persisted for most (67%). Spirometry was normal in 77% of patients, but 31% had a positive bronchodilator response. No abnormalities were noted on plethysmography or diffusion capacity. Clinical phenotypes identified included inhaled corticosteroid responsiveness, paradoxical vocal fold motion disorder, deconditioning, and dysautonomia. Multivariable modeling demonstrated that obesity, anxiety, and resting dyspnea were associated with reduced 6MWT, while female sex and resting dyspnea were associated with higher Borg Dyspnea and Fatigues scores., Conclusions: This is the largest study to date of pediatric patients with long-term pulmonary sequelae post-COVID-19. Identified clinical phenotypes and risk factors warrant further study and treatment., (© 2022 Wiley Periodicals LLC.)

Importance: The postacute sequelae of SARS-CoV-2 infection (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited., Objective: To identify diagnosed symptoms, diagnosed health conditions, and medications associated with PASC in children., Design, Setting and Participants: This retrospective cohort study used electronic health records from 9 US children's hospitals for individuals younger than 21 years who underwent antigen or reverse transcriptase-polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020, and October 31, 2021, and had at least 1 encounter in the 3 years before testing., Exposures: SARS-CoV-2 positivity by viral test (antigen or RT-PCR)., Main Outcomes and Measures: Syndromic (symptoms), systemic (conditions), and medication PASC features were identified in the 28 to 179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting viral test-positive groups with viral test-negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race and ethnicity, and time period of cohort entrance. The incidence proportion for any syndromic, systemic, or medication PASC feature was estimated in the 2 groups to obtain a burden of PASC estimate., Results: Among 659 286 children in the study sample, 348 091 (52.8%) were male, and the mean (SD) age was 8.1 (5.7) years. A total of 59 893 (9.1%) tested positive by viral test for SARS-CoV-2, and 599 393 (90.9%) tested negative. Most were tested in outpatient testing facility settings (322 813 [50.3%]) or office settings (162 138 [24.6%]). The most common syndromic, systemic, and medication features were loss of taste or smell (aHR, 1.96; 95% CI, 1.16-3.32), myocarditis (aHR, 3.10; 95% CI, 1.94-4.96), and cough and cold preparations (aHR, 1.52; 95% CI, 1.18-1.96), respectively. The incidence of at least 1 systemic, syndromic, or medication feature of PASC was 41.9% (95% CI, 41.4-42.4) among viral test-positive children vs 38.2% (95% CI, 38.1-38.4) among viral test-negative children, with an incidence proportion difference of 3.7% (95% CI, 3.2-4.2). A higher strength of association for PASC was identified in those cared for in the intensive care unit during the acute illness phase, children younger than 5 years, and individuals with complex chronic conditions., Conclusions and Relevance: In this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC.

Objective: To identify associations between weight status and clinical outcomes in children with lower respiratory tract infection (LRTI) or asthma requiring hospitalization., Methods: We performed a retrospective cohort study of 2 to 17 year old children hospitalized for LRTI and/or asthma from 2009 to 2019 using electronic health record data from the PEDSnet clinical research network. Children <2 years, those with medical complexity, and those without a calculable BMI were excluded. Children were classified as having underweight, normal weight, overweight, or class 1, 2, or 3 obesity based on Body Mass Index percentile for age and sex. Primary outcomes were need for positive pressure respiratory support and ICU admission. Subgroup analyses were performed for children with a primary diagnosis of asthma. Outcomes were modeled with mixed-effects multivariable logistic regression incorporating age, sex, and payer as fixed effects., Results: We identified 65 132 hospitalizations; 6.7% with underweight, 57.8% normal weight, 14.6% overweight, 13.2% class 1 obesity, 5.0% class 2 obesity, and 2.8% class 3 obesity. Overweight and obesity were associated with positive pressure respiratory support (class 3 obesity versus normal weight odds ratio [OR] 1.62 [1.38-1.89]) and ICU admission (class 3 obesity versus normal weight OR 1.26 [1.12-1.42]), with significant associations for all categories of overweight and obesity. Underweight was also associated with positive pressure respiratory support (OR 1.39 [1.24-1.56]) and ICU admission (1.40 [1.30-1.52])., Conclusions: Both underweight and overweight or obesity are associated with increased severity of LRTI or asthma in hospitalized children., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis. Precise and updated information about demographic characteristics, clinical manifestations, and risk factors for severe disease are needed for optimal implementation of upcoming new therapeutic and preventive interventions., Objectives: The main goals of this study were to define the epidemiology of acute bronchiolitis in hospitalized young children during 5 calendar years in Spain; evaluate the differences in clinical manifestations between children hospitalized with RSV infection and those hospitalized with non-RSV infection; and identify demographic characteristics, clinical parameters, and risk factors associated with disease severity., Methods: We performed a retrospective review of the medical records of children younger than 2 years who were hospitalized with bronchiolitis between January 2015 and December 2019. We constructed multivariable models to identify independent predictors of disease severity defined as length of hospital stay (LOS), pediatric intensive care unit (PICU) admission, and need for a high-flow-nasal canula (HFNC)., Results: From January 2015 to December 2019, 1437 children were hospitalized with bronchiolitis and met the inclusion criteria. The proportion of children hospitalized with bronchiolitis caused by RSV increased significantly during the study period, from 60% to 65% ( P  = .03). The children with RSV bronchiolitis were younger than those with non-RSV bronchiolitis (median age = 3 months [interquartile range = 1.5-6.5 months] vs 4 months [interquartile range = 2-7.5 months], respectively ( P  < .01). The children younger than 6 months with RSV bronchiolitis had enhanced disease severity compared with those with non-RSV bronchiolitis, as defined by an LOS of more than 4 days, severity scores, need for an HFNC, intravenous fluids, enteral feeding, and PICU admissions ( P  < .01). Age younger than 6 months and RSV-positive etiology were independently associated with greater odds of PICU admission, need for an HFNC, and longer LOS., Conclusion: This study identified differences in disease severity between young children with RSV bronchiolitis and those with non-RSV bronchiolitis. These differences are particularly significant in children younger than 6 months, who comprise a group of infants with suboptimal innate immunity to RSV and may benefit from new preventive strategies., (© 2022 The Authors.)

Competing Interests: Conflicts of interest AM has received research grants from NIH, Janssen and Merck (to institution), fees for CME lectures from Sanofi-Pasteur and Astra-Zeneca and participation in advisory boards from Janssen, Sanofi-Pasteur, and Merck. OR has received research grants from NIH, the Bill & Melinda Gates Foundation and Janssen; and fees for participation in advisory boards from Merck, MedImmune/Sanofi-Pasteur, Lilly and Pfizer; and fees for lectures from Pfizer. Those fees were not related to the research described in this manuscript.

Background: Although children with COVID-19 account for fewer hospitalizations than adults, many develop severe disease requiring intensive care treatment. Critical illness due to COVID-19 has been associated with lymphopenia and functional immune suppression. Myeloid-derived suppressor cells (MDSCs) potently suppress T cells and are significantly increased in adults with severe COVID-19. The role of MDSCs in the immune response of children with COVID-19 is unknown., Aims: We hypothesized that children with severe COVID-19 will have expansion of MDSC populations compared to those with milder disease, and that higher proportions of MDSCs will correlate with clinical outcomes., Methods: We conducted a prospective, observational study on a convenience sample of children hospitalized with PCR-confirmed COVID-19 and pre-pandemic, uninfected healthy controls (HC). Blood samples were obtained within 48 h of admission and analyzed for MDSCs, T cells, and natural killer (NK) cells by flow cytometry. Demographic information and clinical outcomes were obtained from the electronic medical record and a dedicated survey built for this study., Results: Fifty children admitted to the hospital were enrolled; 28 diagnosed with symptomatic COVID-19 (10 requiring ICU admission) and 22 detected by universal screening (6 requiring ICU admission). We found that children with severe COVID-19 had a significantly higher percentage of MDSCs than those admitted to the ward and uninfected healthy controls. Increased percentages of MDSCs in peripheral blood mononuclear cells (PBMC) were associated with CD4+ T cell lymphopenia. MDSC expansion was associated with longer hospitalizations and need for respiratory support in children admitted with acute COVID-19., Conclusion: These findings suggest that MDSCs are part of the dysregulated immune responses observed in children with severe COVID-19 and may play a role in disease pathogenesis. Future mechanistic studies are required to further understand the function of MDSCs in the setting of SARS-CoV-2 infection in children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bline, Andrews, Moore-Clingenpeel, Mertz, Ye, Best, Sayegh, Tomatis-Souverbielle, Quintero, Maynard, Glowinski, Mejias and Ramilo.)

Background: Pneumonia has a major impact on childhood health and health care costs. This study was designed to obtain contemporary information on the clinical characteristics and etiology of community-acquired pneumonia (CAP) in children from both inpatient and outpatient settings in the USA., Methods: We conducted a prospective, multicenter, observational study of CAP among previously healthy children 2 months to 18 years of age in 6 children's hospitals in Ohio from 2015 to 2018. For pathogen detection, nasopharyngeal swabs were collected from all subjects. Blood and pleural fluid cultures were available per standard of care., Results: We enrolled a convenience sample of 441 patients: 380 hospitalized and 61 outpatients. Tachypnea and radiologic findings of consolidation and pleural effusion were more frequent among inpatients than outpatients. A pathogen was detected in 64.6% of patients: viruses in 55.6%, atypical bacteria in 8.8% and pyogenic bacteria in 4.3%. Eighteen (4.1%) patients had both viruses and bacteria detected. Rhinovirus/enterovirus (RV; 18.6%) and respiratory syncytial virus (RSV; 16.8%) were the viruses most frequently detected, and Mycoplasma pneumoniae (8.2%) and Streptococcus pneumoniae (2.3%) were the most common bacteria. Except for S. pneumoniae, which was identified more frequently in inpatients, there were no significant differences between inpatients and outpatients in the proportions of children with specific pathogens detected., Conclusions: Rhinovirus/enterovirus and RSV among viruses and M. pneumoniae and S. pneumoniae among bacteria were the most common pathogens detected in children with CAP. Tachypnea and chest radiographs with consolidation and/or pleural effusion were associated with hospitalization., Competing Interests: A.M. has received research grants from the NIH and Janssen and fees from Janssen and Roche for participation in advisory boards. O.R. has received research grants from Janssen, NIH, and the Bill & Melinda and Gates Foundation; fees from Merck, Sanofi/Medimmune, and Pfizer for participation in advisory boards; and fees from Pfizer for educational lectures. A.L.L. has received research funding and participated in advisory boards for BioFire Diagnostics. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This national study evaluated trends in illness severity among 82 798 children with coronavirus disease 2019 from March 1, 2020, to December 30, 2021., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Mejias reports funding from Janssen, Sanofi, and Merck for advisory board participation; and Dr Rao reports grant support from GSK and Biofire. The remaining authors have indicated they have no conflicts of interest relevant to this article to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: The fusion (F) glycoprotein of respiratory syncytial virus (RSV) represents the major neutralizing antigen, and antibodies against the pre-F conformation have the most potent neutralizing activity. This study aimed to assess the correlation between maternal antibody titers against the pre-F, post-F, and G glycoproteins and the child's risk of developing severe RSV bronchiolitis early in infancy., Methods: We identified previously healthy term infants <3 months of age hospitalized with RSV bronchiolitis from December 2015 to March 2016. We measured IgG antibody titers to pre-F, post-F, and G proteins in maternal sera obtained at 9-12 weeks of pregnancy of these hospitalized infants' mothers (n = 94) and compared them with serum antibody titers of control pregnant mothers (n = 130) whose children were not hospitalized., Results: All maternal samples (n = 224) had detectable pre-F antibodies. Pre-F antibody titers were significantly lower in mothers whose infants were hospitalized with RSV bronchiolitis compared with those mothers whose infants were not hospitalized (23.9 [range (or antibody titer range), 1.4-273.7] µg/L vs 30.6 [XXX, 3.4-220.0] µg/L; P = .0026). There were no significant differences in maternal post-F and G antibody titers between hospitalized and nonhospitalized infants., Conclusions: Our findings indicate that maternal pre-F antibodies are fundamental for providing immune protection to the infant., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The role of nasopharyngeal bacteria in respiratory syncytial virus (RSV) disease has been underestimated. We measured the frequency and burden of respiratory bacteria in the upper respiratory tract of infants with RSV infection over 7 respiratory seasons, and their impact on clinical outcomes., Methods: Children <2 years old with mild (outpatients, n=115) or severe (inpatients, n=566) RSV infection, and matched healthy controls (n=161) were enrolled. Nasopharyngeal samples were obtained for RSV, Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, and Haemophilus influenzae detection and quantitation by PCR. Multivariable models were constructed to identify variables predictive of severe disease., Results: S. pneumoniae, H. influenzae, and M. catarrhalis, but not S. aureus, were detected more frequently in RSV-infected children (84%) than healthy controls (46%; P<.001). Detection of S. pneumoniae and/or H. influenzae was associated with fever, more frequent antibiotic treatment, worse radiologic findings, and higher neutrophil counts (P<.01). In adjusted analyses, S. pneumoniae/H. influenzae codetection was independentlyassociated with greater odds of hospitalization, higher disease severity scores, need for supplemental oxygen, and longer hospitalization., Conclusions: Nasopharyngeal codetection of S. pneumoniae and H. influenzae in infants with RSV infection is associated with increased disease severity., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Influenza immunization during pregnancy provides protection to the mother and the infant. Studies in adults and children with inactivated influenza vaccine have identified changes in immune gene expression that were correlated with antibody responses. The current study was performed to define baseline blood transcriptional profiles and changes induced by inactivated influenza vaccine in pregnant women and to identify correlates with antibody responses., Methods: Pregnant women were immunized with inactivated influenza vaccine during the 2013-2014 and 2014-2015 seasons. Blood samples were collected on day 0 (before vaccination) and on days 1 and 7 after vaccination for transcriptional profile analyses, and on days 0 and 30, along with delivery and cord blood samples, to measure antibody titers., Results: Transcriptional analysis demonstrated overexpression of interferon-stimulated genes (ISGs) on day 1 and of plasma cell genes on day 7. Prevaccination ISG expression and ISGs overexpressed on day 1 were significantly correlated with increased H3N2, B Yamagata, and B Victoria antibody titers. Plasma cell gene expression on day 7 was correlated with increased B Yamagata and B Victoria antibody titers. Compared with women who were vaccinated during the previous influenza season, those who were not showed more frequent significant correlations between ISGs and antibody titers., Conclusions: Influenza vaccination in pregnant women resulted in enhanced expression of ISGs and plasma cell genes correlated with antibody responses. Brief summary: This study identified gene expression profiles of interferon-stimulated genes and plasma cells before vaccination and early after vaccination that were correlated with antibody responses in pregnant women vaccinated for influenza., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The burden of coronavirus disease 2019 (COVID-19) in children represents a fraction of cases worldwide, yet a subset of those infected are at risk for severe disease. We measured plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in a cohort of 103 children hospitalized with COVID-19 with diverse clinical manifestations. SARS-CoV-2 RNAemia was detected in 27 (26%) of these children, lasted for a median of 6 (interquartile range, 2-9) days, and was associated with higher rates of oxygen administration, admission to the intensive care unit, and longer hospitalization., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: The airway microbiota has been linked to specific paediatric respiratory diseases, but studies are often small. It remains unclear whether particular bacteria are associated with a given disease, or if a more general, non-specific microbiota association with disease exists, as suggested for the gut. We investigated overarching patterns of bacterial association with acute and chronic paediatric respiratory disease in an individual participant data (IPD) meta-analysis of 16S rRNA gene sequences from published respiratory microbiota studies. Methods: We obtained raw microbiota data from public repositories or via communication with corresponding authors. Cross-sectional analyses of the paediatric (<18 years) microbiota in acute and chronic respiratory conditions, with >10 case subjects were included. Sequence data were processed using a uniform bioinformatics pipeline, removing a potentially substantial source of variation. Microbiota differences across diagnoses were assessed using alpha- and beta-diversity approaches, machine learning, and biomarker analyses. Results: We ultimately included 20 studies containing individual data from 2624 children. Disease was associated with lower bacterial diversity in nasal and lower airway samples and higher relative abundances of specific nasal taxa including Streptococcus and Haemophilus . Machine learning success in assigning samples to diagnostic groupings varied with anatomical site, with positive predictive value and sensitivity ranging from 43 to 100 and 8 to 99%, respectively. Conclusion: IPD meta-analysis of the respiratory microbiota across multiple diseases allowed identification of a non-specific disease association which cannot be recognised by studying a single disease. Whilst imperfect, machine learning offers promise as a potential additional tool to aid clinical diagnosis., Competing Interests: MPi reports personal fees from Mérieux Université, grants from Abacus Diagnostica, outside the submitted work. AM reports grants and personal fees from Janssen, personal fees from Merck, personal fees from Sanofi-Pasteur, personal fees from Roche, outside the submitted work. EZ reports grants and personal fees from Cystic Fibrosis Foundation, outside the submitted work. OS is an employee of Nestlé Research – Societé des Produits Nestlé S.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Broderick, Waite, Marsh, Camargo, Cardenas, Chang, Cookson, Cuthbertson, Dai, Everard, Gervaix, Harris, Hasegawa, Hoffman, Hong, Josset, Kelly, Kim, Kong, Li, Mansbach, Mejias, O’Toole, Paalanen, Pérez-Losada, Pettigrew, Pichon, Ramilo, Ruokolainen, Sakwinska, Seed, van der Gast, Wagner, Yi, Zemanick, Zheng, Pillarisetti and Taylor.)