Respiratory Syncytial Virus Symptoms Research Articles

CROCuS, a Phase II Study Evaluating the Antiviral Activity, Clinical Outcomes, and Safety of Rilematovir in Children Aged ≥28 Days and ≤3 Years with Acute Respiratory Tract Infection Due to Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) causes significant morbidity and mortality in children aged ≤5 years and adults aged ≥60 years worldwide. Despite this, RSV-specific therapeutic options are limited. Rilematovir is an investigational, orally administered inhibitor of RSV fusion protein-mediated viral entry. To establish the antiviral activity, clinical outcomes, safety, and tolerability of rilematovir (low or high dose) in children aged ≥28days and ≤3years with RSV disease. CROCuS was a multicenter, international, double-blind, placebo-controlled, randomized, adaptive phase II study, wherein children aged ≥28 days and ≤3 years with confirmed RSV infection who were either hospitalized (Cohort 1) or treated as outpatients (Cohort 2) were randomized (1:1:1) to receive rilematovir (low or high dose) or placebo. Study treatment was administered daily as an oral suspension from days 1 to 7, with dosing based on weight and age groups. The primary objective was to establish antiviral activity of rilematovir by evaluating the area under the plasma concentration-time curve of RSV viral load in nasal secretions from baseline through day 5. Severity and duration of RSV signs and symptoms and the safety and tolerability of rilematovir were also assessed through day 28 (±3). In total, 246 patients were randomized, treated, and included in the safety analysis population (Cohort 1: 147; Cohort 2: 99). Of these, 231 were included in the intent-to-treat-infected analysis population (Cohort 1: 138; Cohort 2: 93). In both cohorts, demographics were generally similar across treatment groups. In both cohorts combined, the difference (95% confidence interval) in the mean area under the plasma concentration-time curve of RSV RNA viral load through day 5 was -1.25 (-2.672, 0.164) and -1.23 (-2.679, 0.227) log10 copies∙days/mL for the rilematovir low-dose group and the rilematovir high-dose group, respectively, when compared with placebo. The estimated Kaplan-Meier median (95% confidence interval) time to resolution of key RSV symptoms in the rilematovir low-dose, rilematovir high-dose, and placebo groups of Cohort 1 was 6.01 (4.24, 7.25), 5.82 (4.03, 8.18), and 7.05 (5.34, 8.97) days, respectively; in Cohort 2, estimates were 6.45 (4.81, 9.70), 6.26 (5.41, 7.84), and 5.85 (3.90, 8.27) days, respectively. A similar incidence of adverse events was reported in patients treated with rilematovir and placebo in Cohort 1 (rilematovir: 61.9%; placebo: 58.0%) and Cohort 2 (rilematovir: 50.8%; placebo: 47.1%), with most reported as grade 1 or 2 and none leading to study discontinuation. The study was terminated prematurely, as the sponsor made a non-safety-related strategic decision to discontinue rilematovir development prior to full recruitment of Cohort 2. Data from the combined cohort suggest that rilematovir has a small but favorable antiviral effect of indeterminate clinical relevance compared with placebo, as well as a favorable safety profile. Safe and effective therapeutic options for RSV in infants and young children remain an unmet need. EudraCT Number: 2016-003642-93; ClinicalTrials.gov Identifier: NCT03656510. First posted date: 4 September, 2018.

Respiratory syncytial virus knowledge, attitudes, and perceptions among adults in the United States

ABSTRACT Respiratory syncytial virus (RSV) is associated with considerable morbidity and mortality among older adults (aged ≥60 years) and adults with certain chronic conditions in the United States (US). Despite this burden, no previous studies have assessed the knowledge, attitudes, and perceptions (KAP) of RSV among these populations. This study evaluates RSV-related KAP among US adults at increased risk of severe RSV infection. A cross-sectional, web-based survey was administered from May to June 2022 to better understand respiratory infection- and RSV-related KAP among US adults who are at risk of severe RSV infection. The survey included ≥200 adults in each of 4 subgroups: adults aged 60–89 years, and adults aged 18–59 years with ≥1 chronic cardiovascular condition, chronic pulmonary condition, or diabetes mellitus. Survey responses were analyzed descriptively overall and by subgroup, with exploratory logistic regression modeling used to evaluate characteristics associated with RSV awareness and concern. Among the 827 survey respondents, only 43.3% had ever heard of RSV (n = 358/827). The study identified key knowledge gaps (e.g. bacterial vs. viral nature of respiratory infections, RSV seasonality, common RSV symptoms, extent to which RSV causes respiratory infections in specific patient populations). Although 33.7% of RSV-aware adults (n = 120/356) reported being worried/very worried about RSV, 67.3% (n = 241/358) rarely consider RSV as a potential cause of their cold/flu-like symptoms. Results from this study highlight important knowledge gaps related to RSV, perceived risk, and severity of RSV. Findings can be used to support the development of tailored education efforts to support RSV prevention.

Respiratory syncytial virus in children: epidemiology and clinical impact post-COVID-19.

Respiratory syncytial virus (RSV) remains a leading cause of mortality and morbidity worldwide. RSV seasonality was disrupted by COVID-19-associated nonpharmaceutical interventions (NPIs). We review RSV seasonality, molecular epidemiology, clinical manifestations, and community awareness to inform future prevention strategies. An initial reduction of RSV disease observed with NPIs, and subsequent global resurgence was associated with a collapse in genetic diversity. A lack of immunity is suggested to have contributed to the resurgence of RSV cases experienced post COVID-19. The median age of children admitted with RSV increased during the resurgence, likely secondary to the expanded cohort of RSV-immune naive children. The pandemic also played a role in increased community awareness, which can be utilized as part of a coordinated public health effort to introduce prevention strategies. Further education on signs and symptoms of RSV is still required. mAbs and maternal vaccines targeting RSV have the potential to reduce paediatric morbidity, however this new era of RSV prevention will require ongoing research to facilitate community awareness and engagement, and better respiratory surveillance. Tackling the global burden of RSV will require a coordinated effort and measures to ensure access and affordability of new prevention strategies.

A pilot phase 2a, randomized, double-blind, placebo-controlled study to explore the antiviral activity, clinical outcomes, safety, and tolerability of rilematovir at two dose levels in non-hospitalized adults with respiratory syncytial virus infection

ObjectivesTo assess the antiviral effect, clinical outcomes, and safety of the respiratory syncytial virus (RSV) fusion inhibitor rilematovir in non-hospitalized RSV-infected adults. MethodsThis phase 2a, double-blind, multicentre study randomly assigned RSV-positive adult outpatients ≤5 days from symptom onset 1:1:1 to receive rilematovir 500 mg, 80 mg, or placebo once-daily for 7 days. Antiviral effect was assessed by RSV RNA viral load (VL), measured by quantitative RT-PCR, and Kaplan-Meier (KM) estimates of time to undetectable VL. Clinical course was assessed by KM estimates of median time to resolution of key RSV symptoms assessed through patient-reported outcomes. ResultsRSV-positive patients (n = 72) were randomly assigned; 66 had confirmed RSV infection and received rilematovir 500 mg (n = 23), 80 mg (n = 21) or placebo (n = 22). Differences versus placebo in mean RSV RNA VL area under the curve (90% CI) through days 3, 5 and 8, respectively, were 0.09 (−0.837; 1.011), −0.10 (−2.171; 1.963), and −1.03 (−4.746; 2.682) log10 copies.day/mL for rilematovir 500 mg, and 1.25 (0.291; 2.204), 2.53 (0.430; 4.634), and 3.85 (0.097; 7.599) log10 copies.day/mL for rilematovir 80 mg. KM estimates of median (90% CI) time-to-first confirmed undetectable VL were 5.9 (3.85; 6.90), 8.0 (6.86; 12.80) and 7.0 (6.62; 10.88) days and 5.7 (2.93; 7.01), 8.1 (6.74; 12.80) and 7.9 (6.62; 11.74) days in patients with symptom onset ≤3 days, for rilematovir 500 mg, 80 mg, and placebo, respectively. KM estimates of median (90% CI) time to resolution of key RSV symptoms were 7.1 (5.03; 11.43), 7.6 (5.93; 8.32), and 9.6 (5.95; 14.00) days for rilematovir 500 mg, 80 mg, and placebo, respectively; and in patients with symptom onset ≤3 days, median 8.0, 7.6, and 11.8 days, respectively. DiscussionRilematovir use, initiated early, suggests a potential clinical benefit in RSV-infected adults, with data supporting development of RSV therapeutic options. Trial registrationThis study is registered with clinicaltrials.gov (NCT03379675).

Evaluation of symptoms in respiratory syncytial virus infection in adults: psychometric evaluation of the Respiratory Infection Intensity and Impact Questionnaire™ symptom scores

BackgroundThe Respiratory Infection Intensity and Impact Questionnaire (RiiQ™) is a patient-reported outcome measure designed to assess symptoms and impacts of respiratory syncytial virus (RSV) infection. This study evaluated the construct validity, reliability, and responsiveness of the RiiQ™ Respiratory and Systemic Symptoms Scale scores.MethodsProspective data were analyzed from a total of 1795 participants, including from non-hospitalized patients with acute respiratory infection (ARI) and no coinfections enrolled in a Phase 2b RSV vaccine study (RSV-positive: n = 60; RSV-negative: n = 1615), and two observational studies of patients hospitalized with RSV (n = 20; n = 100). Descriptive statistics, confirmatory factor analysis (CFA), test–retest intraclass correlation coefficients (ICCs), construct validity correlations (between a clinician-assessed clinical questionnaire and the RiiQ™ symptoms scale), known-groups validity, and responsiveness (correlations of change scores) were evaluated.ResultsMean patient age ranged from 66.5 to 71.5 years and the majority of patients were female. Initial assessments in the vaccine trial (ARI Day 1) were suggestive of less severe illness than in the observational studies with hospitalized patients. CFA loadings (> 0.40) supported summary scores. ICCs exceeding the recommended threshold of 0.70 supported test–retest reliability for Respiratory and Systemic Symptoms, except in the small observational study. At the scale level, correlations were moderate to strong (|r| ≥ 0.3) and positive between the Respiratory Symptoms Scale and the related clinical questionnaire scores, reflecting measurement of similar symptoms in support of convergent validity. Correlations with change in Patient Global Impression of Severity > 0.30 supported responsiveness.ConclusionsPsychometric tests applied to the RiiQ™ Symptoms scales provide evidence of its reliability, construct validity, discriminating ability, and responsiveness for use in clinical studies to assess the onset and severity of RSV symptoms.

Systematic literature review of the signs and symptoms of respiratory syncytial virus.

Respiratory syncytial virus (RSV) is responsible for over 30 million lower respiratory tract infections (LRTIs) and 3 million hospitalizations worldwide each year. Despite the risk RSV poses to young children, older adults, and individuals with comorbidities or suppressed immunity, there is limited understanding of RSV symptom presentation across these at-risk groups, and there is no vaccine for RSV. We conducted two systematic literature reviews (SLRs) of studies that document signs and symptoms (S&S) of RSV in (1) children aged ≤5years and (2) immunocompromised adolescents and adults, and adults at high risk for severe RSV due to age or comorbidities. Symptom duration and hospital length of stay (LOS) were explored. Electronic database searches were performed following PRISMA guidelines. Studies captured RSV S&S across community and hospital settings. Clinicians and caregivers reported (n = 25 studies) nasal discharge/congestion, cough, shortness of breath, feeding abnormalities, and fever in ≥40% of children across studies and settings. Median hospital stays for children ranged from 2days in the United States to 7.5days in China. High-risk adults with RSV (n = 6 studies) commonly (≥40% of adults) reported cough, sputum, dyspnea, and fever/feverishness. Median length of hospital stay in adults ranged from 6 to 15 days across studies. Caregivers and clinicians reported similar RSV S&S in young children, including upper and lower respiratory and systemic symptoms. In high-risk and immunocompromised adults, the most frequent (in multiple publications) and commonly reported RSV S&S were primarily LRTI symptoms. RSV symptoms could last for weeks and are variable based on geography.

Impact of the Coronavirus Disease 2019 Pandemic on the Clinical Features of Pediatric Respiratory Syncytial Virus Infection in Japan.

Mitigation measures implemented during the coronavirus disease 2019 (COVID-19) pandemic remarkably reduced the incidence of infectious diseases among children. However, a re-emergence of respiratory syncytial virus (RSV) infection was observed in 2021 in Japan. We compared the clinical characteristics of hospitalized patients with RSV infection before and during COVID-19. We retrospectively enrolled children aged <6 years who were hospitalized with RSV infection in 18 hospitals and compared their clinical characteristics before (January 2019 to April 2020, 1675 patients) and during COVID-19 (September 2020 to December 2021, 1297 patients). The mean age of patients with RSV infection was significantly higher during COVID-19 than before (17.4 vs 13.7 months, P < .001). Compared with before COVID-19, a 2.6-fold increase in RSV cases in the 2-5 years age group was observed from sentinel surveillance during COVID-19, whereas a 1.2-fold increase was noted in the same age group among hospitalized patients. On average for all patients, consolidation shadows obtained on radiography were less frequently observed (26.1 vs 29.6%, P = .04), and reduced respiratory assistance (42.2% vs 48.7%, P < .001) and hospitalization stay (5.7 vs 6.0 days, P < .001) was required in patients with RSV infection during COVID-19. Coronavirus disease 2019 and social activity restriction caused epidemiological changes in pediatric RSV infections, and a majority of patients with RSV infection aged ≥2 years did not develop severe symptoms requiring hospitalization. The RSV symptoms during the COVID-19 outbreak were equivalent to or milder than in the previous seasons.

Impact of respiratory syncytial virus disease on quality of life in adults aged ≥50 years: A qualitative patient experience cross-sectional study.

BackgroundInformation about the impact of respiratory syncytial virus (RSV) on quality of life in older adults is limited. This study characterized the patient experience of RSV illness in USA older adults and assessed the content validity of the InFLUenza Patient Reported Outcome (FLU‐PRO) in this population.MethodsThis qualitative, non‐interventional, cross‐sectional study included hybrid concept elicitation and cognitive debriefing interviews with 30 individuals (age ≥50 years) with polymerase chain reaction‐confirmed RSV diagnosed within 6 months of screening. Targeted literature review was first conducted to inform the development of interview materials. Webcam or telephone interviews were conducted by qualitative researchers using a semistructured interview guide. Interview transcripts were coded and analyzed using Excel and NVivo software.ResultsAll participants reported impacts on daily activities, social activities, and relationships during RSV disease. Physical functioning was impaired in 25 (83%) participants, and 18 (60%) reported not engaging in leisure activities/hobbies. All nine participants who were working reported major impacts on work. Most (n = 28; 93%) described emotional impacts. A majority (n = 19; 63%) reported symptoms lasting beyond the acute disease stage from a week to >1 month. Symptom concepts reported generally matched FLU‐PRO items and domains. Cognitive debriefing indicated that FLU‐PRO was easy to understand and captured participants' experiences of RSV illness.ConclusionsThis study indicates that RSV disease in adults aged ≥50 years in the USA has substantial impacts on daily life and that the concepts included in FLU‐PRO are appropriate and fit for purpose as a measure of RSV symptoms in this population.

Occurrence and disease burden of respiratory syncytial virus and other respiratory pathogens in adults aged ≥65 years in community: A prospective cohort study in Japan.

BackgroundThe frequency and clinical profile of respiratory syncytial virus (RSV)–acute respiratory disease (ARD) in older adults in Japan has not been well‐characterized.MethodsThis was a multicenter prospective observational cohort study to evaluate the occurrence rate of ARD in 1000 older adult participants (≥65 years) for 52 weeks during the 2019 to 2020 season. A multiplex polymerase chain reaction panel was used for pathogen detection in nasopharyngeal swab from participants diagnosed with ARD. Symptoms and impact of ARD was assessed using the Respiratory Infection Intensity and Impact Questionnaire (RiiQ™). The study was registered at UMIN (https://www.umin.ac.jp/ctr/): UMIN000037891.ResultsRSV–ARD was detected in 24/1000 (2.4%) participants and RSV‐lower respiratory tract disease in 8/1000 (0.8%) participants. The median duration of RSV–ARD was 18 days. All 24 participants had utilized the medical services of outpatient visits and only 1 (4.2%) participant was hospitalized for RSV–ARD. The most common viruses other than RSV that caused ARD (detected in >10 participants) were human rhinovirus/enterovirus, parainfluenza 3, coronavirus OC43, human metapneumovirus, and influenza A/H1. The most frequent symptoms of RSV–ARD were cough, sore throat, nasal congestion, and expectoration.ConclusionsRSV was reported as a major pathogen for respiratory infections in older adults in Japan.

Evaluation of a standardised protocol to measure the disease burden of respiratory syncytial virus infection in young children in primary care

BackgroundA better understanding of the burden of respiratory syncytial virus (RSV) infections in primary care is needed for policymakers to make informed decisions regarding new preventive measures and treatments. The aim of this study was to develop and evaluate a protocol for the standardised measurement of the disease burden of RSV infection in primary care in children aged < 5 years.MethodsThe standardised protocol was evaluated in Italy and the Netherlands during the 2019/20 winter. Children aged < 5 years who consulted their primary care physician, met the WHO acute respiratory infections (ARI) case definition, and had a laboratory confirmed positive test for RSV (RT-PCR) were included. RSV symptoms were collected at the time of swabbing. Health care use, duration of symptoms and socio-economic impact was measured 14 days after swabbing. Health related Quality of life (HRQoL) was measured using the parent-proxy report of the PedsQL™4.0 generic core scales (2–4 years) and PedsQL™4.0 infant scales (0–2 years) 30 days after swabbing. The standardised protocol was evaluated in terms of the feasibility of patient recruitment, data collection procedures and whether parents understood the questions.ResultsChildren were recruited via a network of paediatricians in Italy and a sentinel influenza surveillance network of general practitioners in the Netherlands. In Italy and the Netherlands, 293 and 152 children were swabbed respectively, 119 and 32 tested RSV positive; for 119 and 12 children the Day-14 questionnaire was completed and for 116 and 11 the Day-30 questionnaire. In Italy, 33% of the children had persistent symptoms after 14 days and in the Netherlands this figure was 67%. Parents had no problems completing questions concerning health care use, duration of symptoms and socio-economic impact, however, they had some difficulties scoring the HRQoL of their young children.ConclusionRSV symptoms are common after 14 days, and therefore, measuring disease burden outcomes like health care use, duration of symptoms, and socio-economic impact is also recommended at Day-30. The standardised protocol is suitable to measure the clinical and socio-economic disease burden of RSV in young children in primary care.

Predictive factors of continuous negative extrathoracic pressure management failure in children with moderate to severe respiratory syncytial virus infection

Continuous negative extrathoracic pressure (CNEP) might be beneficial for children with severe respiratory tract infections. However, there are no available data on the predictors of its failure among individuals with respiratory syncytial virus (RSV) infections. Here, we conducted a retrospective cohort study between October 1, 2015 and October 31, 2018 in hospitalized children with moderate to severe symptoms of respiratory syncytial virus (RSV) infections. We divided 45 children requiring CNEP ventilation with a non-fluctuating negative pressure of − 12 cm H2O into two groups. They were classified based on improvement or deterioration of their respiratory disorder under CNEP ventilation (responder group: n = 27, failure group: n = 18). Based on the univariate analysis, the responder and failure groups significantly differed in terms of median age, days elapsed from RSV onset to the initiation of CNEP, white blood cell count (WBC), titer of venous pCO2, body temperature at admission, and modified Wood-Downes Score (mWDS) 6 h after initiating CNEP. Based on a logistic regression analysis adjusted for age < 1 year upon admission, less than 5 days elapsed from RSV onset to the initiation of CNEP, not high value of WBC and body temperature at admission, and high values of mWDS 6 h after initiating CNEP were found to be significant independent risk factors for CNEP ventilation failure. The former two variables were associated with less failure (odds ratio was approximately 5), and the latter two variables are associated with more failure (odds ratio was approximately 8–9). Thus, CNEP could be a valid option for children with moderate to severe RSV infections, especially in those who were aged > 1 year, and specific clinical and laboratory findings.

Innate Type 2 Responses to Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is a common and contagious virus that results in acute respiratory tract infections in infants. In many cases, the symptoms of RSV remain mild, however, a subset of individuals develop severe RSV-associated bronchiolitis. As such, RSV is the chief cause of infant hospitalization within the United States. Typically, the immune response to RSV is a type 1 response that involves both the innate and adaptive immune systems. However, type 2 cytokines may also be produced as a result of infection of RSV and there is increasing evidence that children who develop severe RSV-associated bronchiolitis are at a greater risk of developing asthma later in life. This review summarizes the contribution of a newly described cell type, group 2 innate lymphoid cells (ILC2), and epithelial-derived alarmin proteins that activate ILC2, including IL-33, IL-25, thymic stromal lymphopoietin (TSLP), and high mobility group box 1 (HMGB1). ILC2 activation leads to the production of type 2 cytokines and the induction of a type 2 response during RSV infection. Intervening in this innate type 2 inflammatory pathway may have therapeutic implications for severe RSV-induced disease.

A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract.

BackgroundPresatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI).MethodsPatients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality.ResultsFrom January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (−1.12 vs −1.09 log10 copies/mL; treatment difference −0.02 log10 copies/mL, 95% confidence interval: −.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients.ConclusionsPresatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo.Clinical Trials Registration www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29

Estimates for quality of life loss due to Respiratory Syncytial Virus.

BackgroundIn children aged <5 years in whom severe respiratory syncytial virus (RSV) episodes predominantly occur, there are currently no appropriate standardised instruments to estimate quality of life years (QALY) loss.ObjectivesWe estimated the age‐specific QALY loss due to RSV by developing a regression model which predicts the QALY loss without the use of standardised instruments.MethodsWe conducted a surveillance study which targeted confirmed RSV episodes in children aged <5 years (confirmed cases) and their household members who experienced symptoms of RSV during the same time (suspected cases). All participants were asked to complete questions regarding their health during the infection, with the suspected cases additionally providing health‐related quality of life (HR‐QoL) loss estimates by completing EQ‐5D‐3L‐Y or EQ‐5D‐3L instruments. We used the responses from the suspected cases to calibrate a regression model which estimates the HR‐QoL and QALY loss due to infection.FindingsFor confirmed RSV cases in children under 5 years of age who sought health care, our model predicted a QALY loss per RSV episode of 3.823 × 10−3 (95% CI 0.492‐12.766 × 10−3), compared with 3.024 × 10−3 (95% CI 0.329‐10.098 × 10−3) for under fives who did not seek health care. Quality of life years loss per episode was less for older children and adults, estimated as 1.950 × 10−3 (0.185‐9.578 × 10−3) and 1.543 × 10−3 (0.136‐6.406 × 10−3) for those who seek or do not seek health care, respectively.ConclusionEvaluations of potential RSV vaccination programmes should consider their impact across the whole population, not just young child children.

PIN129 - ADAPTING INFLUENZA PATIENT-REPORTED OUTCOMES (PRO) MEASURES TO MONITOR RESPIRATORY SYNCYTIAL VIRUS (RSV) SYMPTOM SEVERITY IN ADULTS: QUALITATIVE EVIDENCE OF KEY CONCEPTS AND CONTENT VALIDITY

Influenza virus and Respiratory Syncytial Virus (RSV) cause acute respiratory tract infections that present with similar symptoms. Although no PRO measures have been developed to monitor the severity of RSV symptoms in adults, influenza symptom PRO measures may be useful for RSV severity assessment. This study was conducted to evaluate the content validity of RSV adaptations of the FLU-PRO™ and Flu-iiQ™ (RI-PRO™ and R-iiQ™, respectively) for research in inpatients and outpatients with RSV infection. Combined concept elicitation and cognitive debriefing interviews were conducted with 28 US-English-speaking adults recently diagnosed with RSV (n=18) or influenza (n=10). Atlas.Ti was used for thematic analysis of verbatim transcripts. Similar symptoms were reported for RSV and influenza: ‘cough’, ‘wheezing’ and ‘fever’ were discussed by >75% of RSV and influenza patients. Some RSV patients (17%) also noted ‘rapid heartbeat’, ‘dry nose’, and ‘dry eyes.’ RSV patients understood both measures and confirmed both PROs assessed most ‘core’ RSV symptoms. The RI-PRO™ assessed more symptoms patients reported including ‘body/systemic’, ‘nasal’, ‘eye’ and ‘pain’ than the R-iiQ™, but not ‘wheezing.’ The R-iiQ™ symptom assessment was less comprehensive and some impact items were not relevant for inpatients. When symptoms were most severe, most RSV patients stated it would have been difficult for them to complete either measure. Robustly measuring RSV severity in adults is challenging. Content validity of RI-PRO™ and R-iiQ™ was supported, but neither measure provided the ideal assessment of symptoms for use in both inpatient/outpatient settings. Regulatory and best-practice guidelines highlight the need for a comprehensive symptom assessment to support content validity must be balanced with patient burden (e.g., brief symptom diaries) to monitor symptom severity daily or more often for severely ill hospitalized patients. This study identified symptoms most important to patients to include in a symptom diary for RSV inpatients and outpatients.

Psychometric evaluation of a caregiver diary for the assessment of symptoms of respiratory syncytial virus

BackgroundThere are no clinical outcome assessment (COA) tools developed in accordance with Food and Drug Administration (FDA) guidance suitable for the evaluation of symptoms associated with respiratory syncytial virus (RSV) infection among infants. The Gilead RSV Caregiver Diary (GRCD) is being developed to fulfill this need; the present research evaluates the GRCD and documents its reliability, validity, and responsiveness among children < 24 months of age with acute RSV infection.MethodsA prospective, observational study was conducted in the United States during the 2014–2015 northern hemisphere winter season. Subjects were < 24-month, full-term, previously healthy infants with confirmed RSV infection and ≤5 days of symptoms. The GRCD was completed twice daily for 14 days by caregivers. Additional data were collected during the initial visit, subsequent visits, and end-of-study interview. Test-retest reliability (kappa and intraclass correlation coefficients [ICCs]), construct validity (correlations and factor analyses), discriminating ability (analyses of variance and chi-square), and responsiveness (effect sizes and standardized response means) were evaluated.ResultsA total of 103 subjects were enrolled (mean age 7.4 ± 5.3 months). GRCD items were grouped into different subscales according to question content, which, with the exception of the behavior impact domain (ICC = 0.43), demonstrated internal consistency (alphas = 0.78–0.94) and test-retest reliability (ICCs = 0.77–0.94). Hypothesized correlations with parent global ratings of RSV severity ranged from 0.45 to 0.70 and provided support for construct validity. Support for discriminating ability was limited. Effect sizes ranged from − 1.48 to − 4.40, indicating the GRCD was responsive to change.ConclusionsThese psychometric analyses support the validity, reliability, and responsiveness of the GRCD for assessing RSV symptoms in children < 24 months of age.

Development of a novel observer-reported outcome measure for the assessment of Respiratory Syncytial Virus (RSV) infection symptoms in pediatric clinical trials

BackgroundRespiratory syncytial virus (RSV) is a seasonal infection affecting most children by 2 years of age and the leading cause of lower respiratory tract infection requiring hospitalization in infants. Novel antiviral medications are in development to improve the clinical outcomes of RSV; however, no clinical outcome assessments (COAs) for RSV have been developed in alignment with the United States Food and Drug Administration patient-reported outcome guidance to assist in the evaluation of new therapies. To address this need, an observer-reported outcome (ObsRO) measure designed to assess observable RSV symptoms was created.MethodsThe literature was reviewed to evaluate existing COAs and identify constructs of interest. Individual caregiver interviews elicited concepts that informed item development, and candidate items were subsequently evaluated in two rounds of cognitive testing. Separate cohorts of caregivers of RSV-infected nonhospitalized and hospitalized infants participated. Therapeutic-area experts provided input throughout the instrument development process.ResultsCaregivers of 39 children < 24 months old with RSV (31 nonhospitalized, 8 hospitalized) participated in in-depth, individual interviews during concept elicitation and cognitive debriefing, resulting in 21 concepts identified as potentially observable and relevant to young children with RSV. The item pool was reduced to 12 cardinal symptoms and behavior impacts reported to be directly observable by caregivers, with 10 daytime and 9 nighttime symptoms to capture diurnal variation in severity.ConclusionsThe RSV Caregiver Diary assesses RSV symptom severity and change from the parent or caregiver perspective in a standardized manner to measure treatment benefit. Following psychometric evaluation and refinement, this tool is expected to be suitable for assisting in the clinical development of RSV therapeutics.

Vaccination strategies against respiratory syncytial virus

Respiratory syncytial virus (RSV) is the most common cause of US infant hospitalization. Additionally, RSV is responsible for 10,000 deaths annually among the elderly across the United States, and accounts for nearly as many hospitalizations as influenza. Currently, several RSV vaccine candidates are under development to target different age groups. To evaluate the potential effectiveness of age-specific vaccination strategies in averting RSV incidence, we developed a transmission model that integrates data on daily infectious viral load and changes of behavior associated with RSV symptoms. Calibrating to RSV weekly incidence rates in Texas, California, Colorado, and Pennsylvania, we show that in all states considered, an infected child under 5 y of age is more than twice as likely as a person over 50 y of age to transmit the virus. Geographic variability in the effectiveness of a vaccination program across states arises from interplay between seasonality patterns, population demography, vaccination uptake, and vaccine mechanism of action. Regardless of these variabilities, our analysis showed that allocating vaccine to children under 5 y of age would be the most efficient strategy per dose to avert RSV in both children and adults. Furthermore, due to substantial indirect protection, the targeting of children is even predicted to reduce RSV in the elderly more than directly vaccinating the elderly themselves. Our results can help inform ongoing clinical trials and future recommendations on RSV vaccination.

Lipopeptide-adjuvanted respiratory syncytial virus virosomes: A safe and immunogenic non-replicating vaccine formulation

Respiratory syncytial virus (RSV) causes severe respiratory disease in children and the elderly. There is no registered RSV vaccine. Early experimental non-replicating vaccines have been found to exacerbate RSV symptoms upon infection causing enhanced respiratory disease. Here we show that immunization of mice with reconstituted virosomes produced from RSV envelopes and containing the lipopeptide adjuvant (P3CSK4), induces high-titer virus-neutralizing antibodies, and the secretion of IFN-γ through both MHC-I and MHC-II presentation of antigen, with a balanced Th1/Th2 profile. Immunization with RSV virosomes provides sterilizing immunity to virus challenge in mice and cotton rats, while not producing symptoms of enhanced disease. Therefore, these virosomes represent a promising candidate inactivated RSV vaccine formulation.

Respiratory syncytial virus infections: Recent prospects for control

Respiratory syncytial virus (RSV) infections remain a significant public health problem throughout the world, although recently developed and clinically approved anti-RSV antibodies administered prophylactically to at-risk populations appear to have significantly affected the disease development. Much effort has been expended to develop effective anti-RSV therapies, using both in vitro assay systems and mouse, cotton rat, and primate models, with several products now in various stages of clinical study. Several products are also being considered for the treatment of clinical symptoms of RSV. In this review, updates on the status of the approved anti-RSV antibodies, ribavirin, and recent results of studies with potential new anti-RSV compounds are summarized and discussed.