Clinical Progression Scale-Pediatrics: A Potential Metric of Respiratory Syncytial Virus Severity and Progression in Children

Résumé fourni par la source

(See the Major Article by Ess and Rostad on pages 1283–91.) Respiratory syncytial virus (RSV) has a high burden of disease in infants and young children worldwide, causing an estimated 33 million acute lower respiratory infections and 3.6 million associated hospitalizations each year [1]. In 2023, two products became available in the United States for the prevention of RSV-associated lower respiratory tract infections in infants. The first, nirsevimab, is a monoclonal antibody targeting the RSV prefusion F protein, which is recommended for all infants under 8 months of age born during or entering their first RSV season and certain higher-risk infants entering their second RSV season [2]. The second product, Abrysvo, is a bivalent prefusion F-protein–based vaccine given to pregnant individuals between 32 and 36 weeks gestation [3]. The Advisory Committee on Immunization Practices (ACIP) recommends that all infants receive protection from RSV during their first respiratory season, through either maternal RSV vaccination or infant nirsevimab immunization. While these products were found to be safe and efficacious, uptake has been impeded, in part due to high cost and limited accessibility. As a result, many infants remain unprotected against RSV. Meanwhile, toddlers and young children who are not eligible for nirsevimab are also at risk for RSV-associated lower respiratory tract disease. There is an unmet need for RSV antivirals for children who become infected [4, 5]. However, studying the efficacy of therapeutics in clinical trials has been difficult with current outcome measurements like length of hospital stay (LOS) or ventilator-free days as they require a large sample size to detect differences in clinical improvements between treatment groups. Thus, there has been an ongoing need for standardized, clinically meaningful outcome metrics for RSV clinical trials of both vaccines and treatments in the pediatric population. The study by Leland et al published in this issue of The Journal of Infectious Diseases utilized the Clinical Progression Scale-Pediatrics (CPS-Ped) score, an ordinal severity score to assess the clinical improvement of infants hospitalized for RSV-related critical illness [6]. The authors analyzed data from 600 prospectively enrolled infants admitted to 39 pediatric intensive care units (PICUs) across 27 US states and included 585 in the analysis. The CPS-Ped score, which measures severity ranging from 0 (meaning discharged home at their respiratory baseline) to 8 (death) was calculated for each participant at admission, and days 2–7, 10, and 14 of hospitalization. Clinical improvement was defined as a score of 2 or less, meaning that a participant no longer required acute respiratory support, or a decrease in score by at least 3 points from admission. Almost two-thirds of infants (380/585, 65%) clinically improved as defined by CPS-Ped at day 7 compared to admission. Characteristics associated with a failure to clinically improve by day 7 included age <3 months at admission, prematurity (more strongly for infants born before 29 weeks gestational age), underlying respiratory conditions, and invasive mechanical ventilation within 24 hours of admission. Leland et al also calculated the estimated sample size at 80% power needed to detect a 15% relative improvement in the percentage of participants who clinically improved at day 7 using CPS-Ped or in LOS between treatment groups and found that 584 participants were needed per treatment group to detect a 15% relative improvement using CPS-Ped compared to 1645 participants per group using LOS as an outcome measurement [6]. Limitations of the study included that only infants were analyzed, and only during a single respiratory season, and some practice variabilities in PICU admission and respiratory support modalities were observed between the sites. A standardized and clinically meaningful outcome metric for pediatric RSV like the CPS-Ped score could be a helpful tool for the development of RSV treatments and vaccines. While the concept of a composite ordinal clinical score is not new, RSV severity scores to date have not been deemed sufficiently validated [7]. The CPS-Ped score described in this study was developed based on the World Health Organization Clinical Progression Scale (WHO-CPS) for adults [8]. The WHO-CPS score was developed through a WHO-led international collaborative response to coronavirus disease 2019 (COVID-19) in 2020 as a minimal set of data to collect in all COVID-19 clinical trials and research studies with the goal of facilitating aggregation and comparison of data across studies and health care systems. The ordinal score aimed to capture the virologic outcome, burden on the health care system, and spectrum and progression of clinical disease from asymptomatic infection to death. The WHO-CPS score was utilized in multiple adult studies throughout the COVID-19 pandemic, including as a criterion for phase 3 clinical trial entry and as a primary trial end point [9, 10]. The CPS-Ped score differs from the WHO-CPS score in a few key ways. First, it was developed by multisite investigators within the Pediatric Acute Lung and Sepsis Investigator's Network Pediatric Intensive Care Influenza Study Group (PALISI PICFLU) and Overcoming COVID-19 network [11]. Secondly, the scale does not include a virologic outcome, although this was only utilized to differentiate a score of 0 or 1 in the WHO-CPS score. As a result, 2 mild/ambulatory categories were removed. And lastly, CPS-Ped relies upon the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome to stratify severe outcomes [12]. While the CPS-Ped score has not previously been applied to cohorts with RSV or utilized in prospective studies, it has been applied retrospectively to cohorts with both influenza and COVID-19 [11]. Strengths of the score include that it can capture clinical progression and health care utilization over time, which may be advantageous for therapeutic clinical trials. It also captures multiple levels of respiratory support, including high-flow nasal cannula, which has been increasingly utilized for bronchiolitis [13]. There is also potential that variables in the score could be directly downloaded from the electronic health record using medical informatics approaches, as has been done for WHO-CPS [14], enabling studies of larger databases. Weaknesses include that it captures treatment administration rather than some patient-specific signs and symptoms (eg, nasal cannula utilization rather than patient oxygen saturation; high-flow nasal cannula utilization rather than signs of respiratory distress), which may render it more subjective to practice variability than other respiratory scores or outcome metrics. These aspects may render it less useful as a predictive tool for clinical decision making, as some other scores have been utilized [15]. If CPS-Ped is adequately validated, it could provide a useful outcome metric or entry criterion for future pediatric RSV clinical trials and could facilitate monitoring disease progression in epidemiologic studies. Sheikh et al suggested that at least 2 independent external validation studies with a low bias rating should be utilized to adequately validate an RSV severity score [7]. As the clinical progression of respiratory infections differs across age groups, understanding how the score performs prospectively by pathogen in the age group being studied over time is also important. Pursuing these evaluation steps could be worthwhile, as such a score could reduce the sample size needed per treatment group and make enrollment into RSV clinical trials more feasible. Currently, multiple RSV antiviral therapeutics are in development, including drug candidates targeting the RSV L or F proteins [5]. Studying RSV antivirals is challenged by low enrollment rates into cl

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