Respiratory Syncytial Virus Lower Respiratory Tract 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.

Risk Analysis of Respiratory Syncytial Virus Among Infants in the United States by Birth Month.

Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality among U.S. infants. A child's calendar birth month determines their age at first exposure(s) to RSV. We estimated birth month-specific risk of medically attended (MA) RSV lower respiratory tract infection (LRTI) among infants during their first RSV season and first year of life. We analyzed infants born in the USA between July 2016 and February 2020 using three insurance claims databases (two commercial, one Medicaid). We classified infants' first MA RSV LRTI episode by highest level of care incurred (outpatient, emergency department, or inpatient), employing specific and sensitive diagnostic coding algorithms to define index RSV diagnoses. In our main analysis we focused on infants' first RSV season. In our secondary analysis we compared the risk of MA RSV LRTI during infants' first RSV season to that of their first year of life. Infants born from May through September generally had the highest risk of first-season MA RSV LRTI-approximately 6%-10% under the specific RSV index diagnosis definition and 16%-26% under the sensitive. Infants born between October and December had the highest risk of RSV-related hospitalization during their first season. The proportion of MA RSV LRTI events classified as inpatient ranged from 9%-54% (specific) and 5%-33% (sensitive) across birth month and comorbidity group. Through the first year of life, the overall risk of MA RSV LRTI is comparable across birth months within each claims database (6%-11% under the specific definition, 17%-30% under the sensitive), with additional cases progressing to care at outpatient or ED settings. Our data support recent national recommendations for the use of nirsevimab in the USA. For infants born at the tail end of an RSV season who do not receive nirsevimab, a dose administered prior to the onset of their second RSV season could reduce the incidence of outpatient and ED-related events.

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.

Implications of Food and Drug Administration Approval of Respiratory Syncytial Virus Prophylactic Medication.

Therapies for prevention of respiratory syncytial virus (RSV), a major cause of lower respiratory tract infections (LRTIs) among infants and toddlers, are expanding. The Food and Drug Administration (FDA) recently approved administration of nirsevimab, a monoclonal antibody aimed at preventing medically attended RSV LRTIs, for all infants and especially those at high risk.

Approaches to the Prevention and Treatment of Respiratory Syncytial Virus Infection in Children: Rationale and Progress to Date.

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection (LRTI) in children, and is associated with long-term pulmonary sequelae for up to 30 years after infection. The mainstay of RSV management is supportive therapy such as supplemental oxygen. Palivizumab (Synagis™-AstraZeneca), a monoclonal antibody targeting the RSV F protein site II, has been licensed for the prevention of RSV in high-risk groups since 1998. There has been recent promising progress in preventative strategies that include vaccines and long-acting, high-potency monoclonal antibodies. Nirsevimab (Beyfortus™-AstraZeneca/Sanofi), a monoclonal antibody with an extended half-life, has recently been registered in the European Union and granted licensure by the US Food and Drug Administration. Furthermore, a pre-fusion sub-unit protein vaccine has been granted licensure for pregnant women, aimed at protecting their young infants, following established safety and efficacy in clinical trials (Abrysvo™-Pfizer). Also, multiple novel antiviral therapeutic options are in early phase clinical trials. The next few years have the potential to change the landscape of LRTI through improvements in the prevention and management of RSV LRTI. Here, we discuss these new approaches, current research, and clinical trials in novel therapeutics, monoclonal antibodies, and vaccines against RSV infection in infants and children.

Safety, Tolerability, and Pharmacokinetics of Nirsevimab for the Prevention of RSV Disease in Immunocompromised Children Aged ≤24 Months: Music, an Open Label, Phase 2 Trial

Background Immunocompromised children are at increased risk for severe respiratory syncytial virus (RSV)-associated lower respiratory tract infections (LRTIs), which can lead to poor outcomes, including death. Nirsevimab, an extended half-life monoclonal antibody that targets the RSV prefusion F protein, is approved in Canada, the EU, Great Britain, and the US for the prevention of RSV lower respiratory tract disease in neonates and infants during their first RSV season. In Canada and the US, approval extends to the second season for children remaining at higher risk for severe RSV disease. Here, we present the full analysis of the MUSIC trial (NCT04484935), a 12-month, Phase 2, open-label, uncontrolled, single-dose study of nirsevimab, designed to evaluate the safety, pharmacokinetics (PK), and emergence of antidrug antibodies (ADA) in immunocompromised children ≤24 months of age. Methods Children aged ≤24 months with ≥1 immunocompromising condition received a single intramuscular injection of nirsevimab 50 mg (if weight &amp;lt;5 kg) or 100 mg (if weight ≥5 kg) prior to their first RSV season or 200 mg if entering their second RSV season (Table 1). Safety, ADA, and PK were evaluated to Day 361 (final database lock April 18, 2023). Adverse events of special interest (AESIs) included immediate hypersensitivity (including anaphylaxis), immune complex disease, or thrombocytopenia. Results One hundred children (first RSV season n=46, second RSV season n=54) were enrolled from 8 countries (Table 1). Immunocompromising conditions included primary immunodeficiency (n=33), systemic high-dose corticosteroid therapy, (n=29), immunosuppressive chemotherapy, (n=20), history of organ or bone marrow transplantation (n=16), other immunosuppressive therapy (n=15), and human immunodeficiency virus infection (n=8; children may have had more than one condition). Six children experienced 8 treatment-related adverse events (AEs; pyrexia n=4, abdominal pain n=1, erythema n=1, rash n=2); all were Grade 1 severity , except 1 event of Grade 2 pyrexia, and occurred within 7 days of dosing. No treatment-related serious AEs or new onset chronic diseases were observed. Six AESIs were reported in 5 children; all were Grade 1 hypersensitivity events limited to cutaneous findings (food allergy n=2, contrast media allergy n=1, urticaria n=2, erythema n=1), with 1 considered treatment-related (erythema). Three deaths occurred (LRTI, septic shock, and suspected tumor hemorrhage); all were determined to be unrelated to treatment. Eleven children developed treatment-emergent ADAs (median titer 200.0; Day 31 n=1, Day 151 n=1, and Day 361 n=9); none experienced a treatment-related serious AE, AESI, or skin hypersensitivity reaction. Of the children who were ADA-positive on Day 361, 1 experienced a treatment-related AE (Grade 1 pyrexia within 60 minutes of dosing), and 1 experienced a Grade 1 rash on Day 104, determined to be unrelated to treatment. Children who were ADA-positive on Day 361 were more likely to have nirsevimab levels below the limit of detection versus ADA-negative children, suggesting an influence of ADA on PK between Days 151 and 361. Nirsevimab serum exposures at Day 151 were similar to levels demonstrated to be effective in preventing medically attended RSV LRTI in healthy children enrolled in the Phase 3 MELODY trial (Figure 1). Fourteen children demonstrated a rapid decline in serum concentrations through Day 151 compared with the rest of the children; a review of their medical histories revealed evidence for protein-losing conditions, including graft versus host disease, chronic liver disease, and nephrotic syndrome, in 9 of the 14 children. Although none met protocol-defined case criteria for medically attended RSV LRTI, 3 children had an RSV-positive LRTI (central or local test) requiring medical attendance (in an inpatient or outpatient setting; all after Day 151), of whom 1 was hospitalized. Conclusions In immunocompromised children aged ≤24 months, a single dose of nirsevimab was well tolerated and no safety concerns arose over 361 days. Levels of ADA were low, with minimal effects on PK and no apparent impact on safety outcomes. Nirsevimab serum exposure was consistent with previous studies in healthy children and supportive of efficacy in this population at risk of severe RSV disease. Some children with underlying protein-losing conditions had a rapid decline in nirsevimab serum concentrations.

2712. Respiratory syncytial virus (RSV) pre-fusion F antibody titers in hematopoietic cell transplant recipients with upper versus lower respiratory tract infections

Abstract Background Humoral immune responses to respiratory syncytial virus (RSV) infection in hematopoietic cell transplant (HCT) recipients have not been well characterized. We measured RSV pre-fusion F antibody (RSVpreF) titers in HCT recipients in 3 groups: upper respiratory tract infections (URTI) only, lower respiratory tract infections (LRTI) only, and those who progressed from URTI to LRTIs (progressors). Methods We evaluated adult and pediatric allogeneic HCT recipients who acquired RSV from 12/2011 to 12/2019. Prospective and leftover clinical serum specimens were collected from the Fred Hutchinson Cancer Center. Samples included baseline prior to infection, at RSV URTI or LRTI diagnosis, and after infection (both 4-6 and &amp;gt;8 weeks). Quantitative RSVpreF titers were determined using the MesoScale Discovery electrochemiluminescence assay. We compared longitudinal log10 RSVpreF titers among groups using linear mixed effect models with restricted cubic splines. Results A total of 129 samples from 39 patients were analyzed; 24 with URTI only, 8 progressors, and 7 with LRTI only. The median age at infection was 45 years, but HCT recipients with LRTI only had an overall higher median age of 54 (range 23-63) (Table 1). Most had acute leukemia (n=18, 46%) and received peripheral blood stem cells (n=27, 69%) as their cell source (Table 1). Median RSVpreF values were similar across the 3 different groups at each timepoint (Table 2). Trajectories of RSVpreF titers over time for each patient trended towards an increase following RSV diagnosis in all groups (Figure 1a). Predicted curves in RSVpreF titers over time did not differ significantly by group (Figure 1b, p=0.38).Table 2.Summary of RSVpreF titers among allogeneic transplant recipients before and after a post-HCT RSV infection. RSVpreF titers were obtained utilizing Meso Scale Discovery chemiluminescence assays. (A) RSVpreF titers for allogeneic HCT recipients with RSV infection. Each line represents a patient. The top panel shows patients with RSV URTI only, the middle panel shows patients who progressed from URTI to LRTI, and the bottom panel shows patients who presented with RSV LRTI. Open circles represent time points prior to RSV diagnosis, filled circles represent time points just prior to, on or after URTI, and asterisks represent time points just prior to, on, or after LRTI. (B) RSVpreF titers plotted by days from RSV diagnosis. Open circles represent observed values and lines represent model predicted trajectories. Black circles and lines correspond to patients with RSV URTI only, blue corresponds to patients who progressed from RSV URTI to LRTI, and dark orange represents patient who presented with RSV LRTI at diagnosis. An outlying observation at day -53 was excluded. Conclusion Among allogeneic HCT recipients with RSV infection, RSVpreF titers increased in response to RSV infection, but did not differ among patients with URTI only, progressors, or those with LRTI only across pre and post infection time points. Our novel immunoassay results are similar to those from previously described RSV neutralization assays, but extended the observation period beyond 4 weeks after infection, revealing a modest increase in RSVpreF titers. Further characterization of RSV humoral immunity, including mucosal immunity, is needed. Disclosures chikara Ogimi, MD, bioMerieux Japan Ltd.: Honoraria|Horiba: Honoraria|Pfizer: Honoraria Janet A. Englund, MD, Ark Biopharma: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Emily T. Martin, PhD, MPH, Merck: Grant/Research Support Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Symbio: Advisor/Consultant Alpana Waghmare, MD, Allovir: Grant/Research Support|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|GlaxoKlineSmith/Vir: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Pfizer: Grant/Research Support|Vir Biotechnology: Advisor/Consultant

89. The Impact of Nirsevimab on an RSV Season in All Infants: Data From The HARMONIE Study

Abstract Background RSV is an extremely common respiratory pathogen and a leading cause of infant hospitalisation. An estimated 1 in 7 infants will develop an RSV lower respiratory tract infection (LRTI) requiring medical attention. The majority of infants hospitalised have no comorbidities and were born at term. Nirsevimab is the only preventative option designed to provide protection to all infants from RSV LRTI, from the start of their first RSV season, for the duration of that season. In the HARMONIE trial conducted in the UK, France, and Germany (EudraCT 2022-000099-20), we evaluated the impact of nirsevimab on all cause LRTI hospitalisations, as well as RSV LRTI specifically. Analyses looked at the efficacy of nirsevimab across subgroups that constitute the all infant population, all of whom are vulnerable throughout their first RSV season. Methods Individually randomised infants (≥29 weeks gestational age) received a single intramuscular injection of nirsevimab (&amp;lt; 5 kg 50 mg; ≥5 kg 100 mg), or no intervention (standard of care) before or during the RSV season. Following a single physical visit participants were monitored remotely for all cause LRTI hospitalisation (secondary endpoint, defined as treating physician decision to admit to in-patient care for &amp;gt;24 hours). Efficacy was evaluated through the RSV season. Adverse events (AEs) continue to be monitored for 365 days. Results 8058 infants were randomized, 4037 to the nirsevimab group and 4021 to the no intervention group. Efficacy against RSV LRTI was 83.21% (CI 67.77-92.04%) across all countries. Efficacy was consistent across infant subgroups, in those born at term (≥ 37 weeks: 84.41% (CI 64.92-94.10%)) or prematurely (&amp;lt; 37 weeks: 78.31% (CI 33.49-94.69%)) and not impacted by infant weight at randomisation (&amp;lt; 5kg: 82.12% CI 59.14-93.30% and ≥ 5kg 85.16% CI 57.01-96.25%). Efficacy against all cause LRTI hospitalisation was 58.04% (39.693- 71.19). Conclusion A single dose of nirsevimab given before or during the RSV season demonstrated a significant and sustained impact on RSV LRTI hospitalisations for the entire RSV season. Consistent efficacy was shown across subgroups comprising the all infant population.The potential impact of nirsevimab was reinforced by a reduction in all cause LRTI hospitalisations. Disclosures Saul N. Faust, FRCPCH PhD, AstraZeneca, Janssen, Pfizer, Moderna, GlaxoSmithKline, Novavax, Sanofi, Seqirus, Medimmune, Merck, MSD, Iliad and Valneva: Advisor/Consultant|AstraZeneca, Janssen, Pfizer, Moderna, GlaxoSmithKline, Novavax, Sanofi, Seqirus, Medimmune, Merck, MSD, Iliad and Valneva: Investigator Katrina Cathie, MBE, FRCPCH, AstraZeneca: Advisor/Consultant|GSK: Advisor/Consultant|Iliad: Advisor/Consultant|Janssen: Advisor/Consultant|MedImmune: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant|Sanofi: Advisor/Consultant|Valneva: Advisor/Consultant SB Drysdale, FRCPCH, PhD, AstraZeneca: Advisor/Consultant|iLiAD: Advisor/Consultant|Janssen: Advisor/Consultant|Moderna: Advisor/Consultant|MSD: Advisor/Consultant|Pfizer: Advisor/Consultant|Sanofi: Advisor/Consultant|Valneva: Advisor/Consultant S Royal, FRCGP, Sanofi: Advisor/Consultant C Felter, MD, Sanofi: Employee NC Vassilouthis, MD, Sanofi: Employee Mathieu Bangert, PhD, Sanofi: Staff member K Mari, PhD, Sanofi: Employee R Nteene, MD, Sanofi: Employee M Roberts, MD, Sanofi: Employee P Tissieres, MD, Baxter: Advisor/Consultant|PAion: Advisor/Consultant|Sanofi: Advisor/Consultant|Sedana: Advisor/Consultant

Are maternal vaccines effective and safe for mothers and infants? A systematic review and meta-analysis of randomised controlled trials

IntroductionMaternal vaccination is a promising strategy to reduce the burden of vaccine-preventable diseases for mothers and infants. We aimed to provide an up-to-date overview of the efficacy and safety of...

Nirsevimab for the prevention of respiratory syncytial virus disease in children. Statement of the Spanish Society of Paediatric Infectious Disease (SEIP)

IntroductionNirsevimab, a monoclonal antibody for the prevention of disease caused by respiratory syncytial virus (RSV), has recently been approved for use in Europe and Spain. ObjectivesTo provide recommendations for the administration of nirsevimab for prevention of RSV disease. MethodsThe approach chosen to develop these recommendations involved a critical review of the literature and the use of the Delphi and GRADE methods. An expert group was formed. The group engaged in three rounds to define the questions, express support or opposition, grade recommendations and establish the agreement or disagreement with the conclusions. ResultsIn the general neonatal population, routine administration of nirsevimab is recommended to reduce the frequency of illness and hospitalisation for bronchiolitis and RSV lower respiratory tract infection. Nirsevimab is recommended for all infants born in high-incidence RSV season and infants aged less than 6 months at the season onset. In infants born preterm between 29 and 35 weeks of gestation, with haemodynamically significant heart disease or with chronic lung disease, routine administration of nirsevimab is recommended to reduce the incidence of disease and hospitalisation due to bronchiolitis and RSV lower respiratory tract infection. In patients in whom palivizumab is currently indicated, its substitution by nirsevimab is recommended to reduce the burden of bronchiolitis. ConclusionsRoutine administration of nirsevimab to all infants aged less than 6 months born during the RSV season or aged less than 6 months at the start of the winter season is recommended to reduce the burden of disease and the frequency of hospitalization due to bronchiolitis.

Nirsevimab para la prevención de la enfermedad por virus respiratorio sincitial en niños. Posicionamiento de la Sociedad Española de Infectología Pediátrica

IntroductionNirsevimab, a monoclonal antibody for the prevention of disease caused by respiratory syncytial virus (RSV), has recently been approved for use in Europe and Spain. ObjectivesTo provide recommendations for the administration of nirsevimab for prevention of RSV disease. MethodsThe approach chosen to develop these recommendations involved a critical review of the literature and the use of the Delphi and GRADE methods. An expert group was formed. The group engaged in three rounds to define the questions, express support or opposition, grade recommendations and establish the agreement or disagreement with the conclusions. ResultsIn the general neonatal population, routine administration of nirsevimab is recommended to reduce the frequency of illness and hospitalisation for bronchiolitis and RSV lower respiratory tract infection. Nirsevimab is recommended for all infants born in high-incidence RSV season and infants aged less than 6 months at the season onset. In infants born preterm between 29 and 35 weeks of gestation, with haemodynamically significant heart disease or with chronic lung disease, routine administration of nirsevimab is recommended to reduce the incidence of disease and hospitalisation due to bronchiolitis and RSV lower respiratory tract infection. In patients in whom palivizumab is currently indicated, its substitution by nirsevimab is recommended to reduce the burden of bronchiolitis. ConclusionsRoutine administration of nirsevimab to all infants aged less than 6 months born during the RSV season or aged less than 6 months at the start of the winter season is recommended to reduce the burden of disease and the frequency of hospitalization due to bronchiolitis.

Comparative analysis of clinical features of lower respiratory tract infection with respiratory syncytial virus and influenza virus in adults: a retrospective study

BackgroundRespiratory syncytial virus (RSV) infection in adults remains less recognized and understood, both socially and clinically, compared to influenza virus infection. This retrospective study aims to delineate and compare the clinical manifestations of adult RSV and influenza virus infections in the lower respiratory tract, thereby enhancing awareness of RSV lower respiratory tract infection and providing strategic insights for its prevention and treatment.MethodsClinical data from January 2019 to December 2020 were analyzed for 74 patients with RSV and 129 patients with influenza A/B virus lower respiratory tract infections who were admitted to respiratory or intensive care units. All patients had complete clinical data with positive IgM and negative IgG viral antibodies. Comparison parameters included onset timing, baseline data, clinical manifestations, supplementary examination results, treatment methods, and prognosis, while logistic regression was employed to ascertain the correlation of clinical features between the two patient groups.ResultsIn comparison to the influenza group, the RSV group presented less frequently with fever at admission but exhibited a higher incidence of dyspnea and wheezing on pulmonary auscultation (P < 0.01). RSV infection was more prevalent among patients with underlying diseases, particularly chronic obstructive pulmonary disease (COPD) and demonstrated a higher probability of co-infections, most notably with Mycoplasma (P < 0.01). The RSV group had significantly higher lymphocyte counts (P < 0.01) and exhibited more incidences of pleural thickening, pulmonary fibrosis, and emphysema (P < 0.05). The use of non-invasive mechanical ventilation was more common, and hospital stays were longer in the RSV group compared to the influenza group (P < 0.05). Logistic multivariate regression analysis further revealed that age and tachypnea incidence were significantly higher in the RSV group (P < 0.05).ConclusionCompared to influenza virus infection, adults with COPD are more susceptible to RSV infection. Moreover, RSV infection elevates the risk of co-infection with Mycoplasma and may lead to conditions such as pleural thickening, pulmonary fibrosis, and emphysema. The requirement for non-invasive mechanical ventilation is higher in RSV-infected patients, who also tend to have longer hospital stays. Therefore, greater awareness and preventive strategies against RSV infection are imperative.

Infants Admitted to US Intensive Care Units for RSV Infection During the 2022 Seasonal Peak

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) and infant hospitalization worldwide. To evaluate the characteristics and outcomes of RSV-related critical illness in US infants during peak 2022 RSV transmission. This cross-sectional study used a public health prospective surveillance registry in 39 pediatric hospitals across 27 US states. Participants were infants admitted for 24 or more hours between October 17 and December 16, 2022, to a unit providing intensive care due to laboratory-confirmed RSV infection. Respiratory syncytial virus. Data were captured on demographics, clinical characteristics, signs and symptoms, laboratory values, severity measures, and clinical outcomes, including receipt of noninvasive respiratory support, invasive mechanical ventilation, vasopressors or extracorporeal membrane oxygenation, and death. Mixed-effects multivariable log-binomial regression models were used to assess associations between intubation status and demographic factors, gestational age, and underlying conditions, including hospital as a random effect to account for between-site heterogeneity. The first 15 to 20 consecutive eligible infants from each site were included for a target sample size of 600. Among the 600 infants, the median (IQR) age was 2.6 (1.4-6.0) months; 361 (60.2%) were male, 169 (28.9%) were born prematurely, and 487 (81.2%) had no underlying medical conditions. Primary reasons for admission included LRTI (594 infants [99.0%]) and apnea or bradycardia (77 infants [12.8%]). Overall, 143 infants (23.8%) received invasive mechanical ventilation (median [IQR], 6.0 [4.0-10.0] days). The highest level of respiratory support for nonintubated infants was high-flow nasal cannula (243 infants [40.5%]), followed by bilevel positive airway pressure (150 infants [25.0%]) and continuous positive airway pressure (52 infants [8.7%]). Infants younger than 3 months, those born prematurely (gestational age <37 weeks), or those publicly insured were at higher risk for intubation. Four infants (0.7%) received extracorporeal membrane oxygenation, and 2 died. The median (IQR) length of hospitalization for survivors was 5 (4-10) days. In this cross-sectional study, most US infants who required intensive care for RSV LRTIs were young, healthy, and born at term. These findings highlight the need for RSV preventive interventions targeting all infants to reduce the burden of severe RSV illness.

Evaluation of Clinical Case Definitions for Respiratory Syncytial Virus Lower Respiratory Tract Infection in Young Children.

Various case definitions of respiratory syncytial virus lower respiratory tract infection (RSV-LRTI) are currently proposed. We assessed the performance of 3 clinical case definitions against the World Health Organization definition recommended in 2015 (WHO 2015). In this prospective cohort study conducted in 8 countries, 2401 children were followed up for 2 years from birth. Suspected LRTIs were detected via active and passive surveillance, followed by in-person clinical evaluation including single timepoint respiratory rate and oxygen saturation (by pulse oximetry) assessment, and nasopharyngeal sampling for RSV testing by polymerase chain reaction. Agreement between case definitions was evaluated using Cohen's κ statistics. Of 1652 suspected LRTIs, 227 met the WHO 2015 criteria for RSV-LRTI; 73 were classified as severe. All alternative definitions were highly concordant with the WHO 2015 definition for RSV-LRTI (κ: 0.95-1.00), but less concordant for severe RSV-LRTI (κ: 0.47-0.82). Tachypnea was present for 196/226 (86.7%) WHO 2015 RSV-LRTIs and 168/243 (69.1%) LRTI/bronchiolitis/pneumonia cases, clinically diagnosed by nonstudy physicians. Low oxygen saturation levels were observed in only 55/226 (24.3%) WHO 2015 RSV-LRTIs. Three case definitions for RSV-LRTI showed high concordance with the WHO 2015 definition, while agreement was lower for severe RSV-LRTI. In contrast to increased respiratory rate, low oxygen saturation was not a consistent finding in RSV-LRTIs and severe RSV-LRTIs. This study demonstrates that current definitions are highly concordant for RSV-LRTIs, but a standard definition is still needed for severe RSV-LRTI. NCT01995175.

Optimizing next-generation RSV prevention in Mali: A cost-effectiveness analysis of pediatric vaccination, maternal vaccination, and extended half-life monoclonal antibody immunoprophylaxis.

Respiratory syncytial virus (RSV) is the most common cause of early childhood lower respiratory tract infection (LRTI) in low- and middle-income countries (LMICs). Maternal vaccines, birth-dose extended half-life monoclonal antibodies (mAbs), and pediatric vaccines are under development for prevention of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in young children. We analyzed the health and economic impact of RSV interventions used alone or in combinations in Mali. We modeled age-specific and season-specific risks of RSV LRTI in children through three years, using WHO Preferred Product Characteristics and data generated in Mali. Health outcomes included RSV LRTI cases, hospitalizations, deaths, and disability-adjusted life-years (DALYs). We identified the optimal combination of products across a range of scenarios. We found that mAb delivered at birth could avert 878 DALYs per birth cohort at an incremental cost-effectiveness ratio (ICER) of $597 per DALY averted compared to no intervention if the product were available at $1 per dose. Combining mAb with pediatric vaccine administered at 10/14 weeks, 1947 DALYs would be prevented. The ICER of this combination strategy is $1514 per DALY averted compared to mAb alone. Incorporating parameter uncertainty, mAb alone is likely to be optimal from the societal perspective at efficacy against RSV LRTI above 66%. The optimal strategy was sensitive to economic considerations, including product prices and willingness-to-pay for DALYs. For example, the combination of mAb and pediatric vaccine would be optimal from the government perspective at a willingness-to-pay above $775 per DALY. Maternal vaccine alone or in combination with other interventions was never the optimal strategy, even for high vaccine efficacy. The same was true for pediatric vaccine administered at 6/7 months. At prices comparable to existing vaccine products, extended half-life RSV mAbs would be impactful and efficient components of prevention strategies in LMICs such as Mali.

Model-estimated impacts of pediatric respiratory syncytial virus prevention programs in Mali on asthma prevalence.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) in young children and is associated with subsequent recurrent wheezing illness and asthma (wheeze/asthma). RSV prevention may therefore reduce wheeze/asthma prevalence. We estimated the contribution of RSV LRTI and the impact of RSV prevention on recurrent wheeze/asthma in Mali. We simulated 12 consecutive monthly birth cohorts in Mali and estimated RSV LRTI cases through 2 years and recurrent wheeze/asthma prevalence at 6 years under different RSV prevention scenarios: status quo, seasonal birth-dose extended half-life mAb, and seasonal birth-dose extended half-life mAb followed by 2 doses of pediatric vaccine (mAb+ vaccine). We used World Health Organization (WHO) Preferred Product Characteristics for RSV prevention, demographic and RSV epidemiologic data from Mali, regional recurrent wheeze/asthma prevalence, and relative risk of recurrent wheeze/asthma given early childhood RSV LRTI. Among the simulated cohort of 778,680 live births, 10.0% had RSV LRTI by 2 years and 89.6% survived to 6 years. We estimated that 13.4% of all recurrent wheeze/asthma at 6 years was attributable to RSV LRTI. Recurrent wheeze/asthma prevalence at 6 years was 145.0 per 10,000 persons (RSV LRTI attributable) and 1084.2 per 10,000 persons (total). In mAb and mAb+ vaccine scenarios, RSV LRTI cases decreased by 11.8% and 44.4%, respectively, and recurrent wheeze/asthma prevalence decreased by 11.8% and 44.4% (RSV LRTI attributable) and 1.6% and 5.9% (total). In Mali, RSV prevention programs may have a meaningful impact on chronic respiratory disease, strengthening the case for investment in RSV prevention.

Pulmonary sequelae in 2-year-old children after hospitalisation for respiratory syncytial virus lower respiratory tract infection during infancy: an observational study

BackgroundRespiratory syncytial virus (RSV) is the most common cause of hospitalisation for lower respiratory tract infection (LRTI) in children. RSV LRTI during early childhood may increase susceptibility to recurrent wheezing...

Review and Update of Active and Passive Immunization Against Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection (LRTI) in children, causing approximately 3.6 million hospitalizations per year, and has been associated with long-term pulmonary sequelae for up to 30years after infection, yet preventative strategies and active treatment options remain elusive. The associated morbidity and healthcare related costs could be decreased substantially with the development of these much-needed medications. After an initial false start in the development of an RSV vaccine, gradual progress is now being made with the development of multiple vaccine candidates using numerous different mechanisms of action. Furthermore, nirsevimab, a new monoclonal antibody for the prevention of RSV, has recently been registered in the European Union. New novel treatments for RSV infection are also in the pipeline, which would provide the clinician with much needed ammunition in the management of the acute disease. The next few years have the potential to change the landscape of LRTI forever through the prevention and management of RSV LRTI and thereby decrease the mortality and morbidity associated with it. In this review, we discuss these new approaches, current research, and clinical trials in monoclonal antibody and vaccine development against RSV.

Evolutionary dynamics of respiratory syncytial virus in Buenos Aires: Viral diversity, migration, and subgroup replacement.

Globally, the human respiratory syncytial virus (RSV) is one of the major causes of lower respiratory tract infections (LRTIs) in children. The scarcity of complete genome data limits our understanding of RSV spatiotemporal distribution, evolution, and viral variant emergence. Nasopharyngeal samples collected from hospitalized pediatric patients from Buenos Aires tested positive for RSV LRTI during four consecutive outbreaks (2014-2017) were randomly subsampled for RSV complete genome sequencing. Phylodynamic studies and viral population characterization of genomic variability, diversity, and migration of viruses to and from Argentina during the study period were performed. Our sequencing effort resulted in one of the largest collections of RSV genomes from a given location (141 RSV-A and 135 RSV-B) published so far. RSV-B was dominant during the 2014-2016 outbreaks (60 per cent of cases) but was abruptly replaced by RSV-A in 2017, with RSV-A accounting for 90 per cent of sequenced samples. A significant decrease in RSV genomic diversity-represented by both a reduction in genetic lineages detected and the predominance of viral variants defined by signature amino acids-was observed in Buenos Aires in 2016, the year prior to the RSV subgroup predominance replacement. Multiple introductions to Buenos Aires were detected, some with persistent detection over seasons, and also, RSV was observed to migrate from Buenos Aires to other countries. Our results suggest that the decrease in viral diversity may have allowed the dramatic predominance switch from RSV-B to RSV-A in 2017. The immune pressure generated against circulating viruses with limited diversity during a given outbreak may have created a fertile ground for an antigenically divergent RSV variant to be introduced and successfully spread in the subsequent outbreak. Overall, our RSV genomic analysis of intra- and inter-outbreak diversity provides an opportunity to better understand the epochal evolutionary dynamics of RSV.

Efficacy of nirsevimab against respiratory syncytial virus lower respiratory tract infections in preterm and term infants, and pharmacokinetic extrapolation to infants with congenital heart disease and chronic lung disease: a pooled analysis of randomised controlled trials

In a phase 2b trial and the phase 3 MELODY trial, nirsevimab, an extended half-life, monoclonal antibody against respiratory syncytial virus (RSV), protected healthy infants born preterm or at full term against medically attended RSV lower respiratory tract infection (LRTI). In the MEDLEY phase 2-3 trial in infants at higher risk for severe RSV infection, nirsevimab showed a similar safety profile to that of palivizumab. The aim of the current analysis was to assess the efficacy of nirsevimab using a weight-banded dosing regimen in infants born between 29 weeks gestational age and full term. Infants enrolled in the phase 2b and MELODY trials were randomised (2:1) to receive a single intramuscular injection of nirsevimab (infants weighing <5 kg received 50 mg; those weighing ≥5 kg received 100 mg) or placebo before the RSV season. Infants in MEDLEY were randomised (2:1) to receive one dose of nirsevimab (infants weighing <5 kg received 50 mg; those weighing ≥5 kg received 100 mg) followed by four monthly placebo doses, or five once-a-month intramuscular doses of palivizumab. We report a prespecified pooled efficacy analysis assessing the weight-banded dosing regimen proposed on the basis of the phase 2b and MELODY trials, in addition to extrapolated efficacy in infants with chronic lung disease, congenital heart disease, or extreme preterm birth (<29 weeks' gestational age) based on pharmacokinetic data from the phase 2-3 MEDLEY safety trial. For the pooled efficacy analysis, the primary endpoint was incidence of medically attended RSV LRTI through 150 days post-dose. The secondary efficacy endpoint was number of admissions to hospital for medically attended RSV LRTI. The incidence of very severe RSV LRTI was an exploratory endpoint, defined as cases of hospital admission for medically attended RSV LRTI that required supplemental oxygen or intravenous fluids. We also did a prespecified exploratory analysis of medically attended LRTI of any cause (in the investigator's judgement) and hospital admission for respiratory illness of any cause (defined as any upper respiratory tract infection or LRTI leading to hospital admission). Post hoc exploratory analyses of outpatient visits and antibiotic use were also done. Nirsevimab serum concentrations in MEDLEY were assessed using population pharmacokinetic methods and the pooled data from the phase 2b and MELODY trials. An exposure target was defined on the basis of an exposure-response analysis. To successfully demonstrate extrapolation, more than 80% of infants in MEDLEY had to achieve serum nirsevimab exposures at or above the predicted efficacious target. Overall, 2350 infants (1564 in the nirsevimab group and 786 in the placebo group) in the phase 2b and MELODY trials were included in the pooled analysis. Nirsevimab showed efficacy versus placebo with respect to the primary endpoint of medically attended RSV LRTI (19 [1%] nirsevimab recipients vs 51 [6%] placebo recipients; relative risk reduction [RRR] 79·5% [95% CI 65·9-87·7]). Consistent efficacy was shown for additional endpoints of RSV LRTI hospital admission (nine [1%] nirsevimab recipients vs 21 [3%] placebo recipients; 77·3% [50·3-89·7]) and very severe RSV (five [<1%] vs 18 [2%]; 86·0% [62·5-94·8]). Nirsevimab recipients had fewer hospital admissions for any-cause respiratory illness (RRR 43·8% [18·8-61·1]), any-cause medically attended LRTI (35·4% [21·5-46·9]), LRTI outpatient visits (41·9% [25·7-54·6]), and antibiotic prescriptions (23·6% [3·8-39·3]). Among infants with chronic lung disease, congenital heart disease, or extreme preterm birth in MEDLEY, nirsevimab serum exposures were similar to those found in the pooled data; exposures were above the target in more than 80% of the overall MEDLEY trial population (94%), including infants with chronic lung disease (94%) or congenital heart disease (80%) and those born extremely preterm (94%). A single dose of nirsevimab protected healthy infants born at term or preterm from medically attended RSV LRTI, associated hospital admission, and severe RSV. Pharmacokinetic data support efficacy extrapolation to infants with chronic lung disease, congenital heart disease, or extreme prematurity. Together, these data suggest that nirsevimab has the potential to change the landscape of infant RSV disease by reducing a major cause of infant morbidity and the consequent burden on caregivers, clinicians, and health-care providers. AstraZeneca and Sanofi.