Confirmed Respiratory Syncytial Virus Infection 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.

Effectiveness of Nirsevimab Immunoprophylaxis Administered at Birth to Prevent Infant Hospitalisation for Respiratory Syncytial Virus Infection: A Population-Based Cohort Study.

Respiratory syncytial virus (RSV) infection is a frequent cause of hospitalisation in the first few months of life; however, this risk rapidly decreases with age. Nirsevimab immunoprophylaxis was approved in the European Union for the prevention of RSV-associated lower respiratory tract disease in infants during their first RSV season. We evaluated the effectiveness of nirsevimab in preventing hospitalisations for confirmed RSV infection and the impact of a strategy of immunisation at birth. A population-based cohort study was performed in Navarre, Spain, where nirsevimab was offered at birth to all children born from October to December 2023. Cox regression was used to estimate the hazard ratio of hospitalisation for PCR-confirmed RSV infection between infants who received and did not receive nirsevimab. Of 1177 infants studied, 1083 (92.0%) received nirsevimab. The risk of hospitalisation for RSV was 8.5% (8/94) among non-immunised infants versus 0.7% (8/1083) in those that were immunised. The estimated effectiveness of nirsevimab was 88.7% (95% confidence interval, 69.6-95.8). Immunisation at birth of infants born between October and December 2023 prevented one hospitalisation for every 15.3 immunised infants. Immunisation of children born from September to January might prevent 77.5% of preventable hospitalisations for RSV in infants born in 2023-2024. These results support the recommendation of nirsevimab immunisation at birth to children born during the RSV epidemic or in the months immediately before to prevent severe RSV infections and alleviate the overload of paediatric hospital resources.

Disease burden attributable to respiratory syncytial virus outbreaks in long-term care.

Respiratory syncytial virus (RSV) disease burden is significant among children; however, RSV can also cause excess morbidity and mortality among older adults. Populations in long-term care homes (LTCHs) may be at greater risk of exposure and increased infection severity. The objectives of this article are to identify evidence regarding disease burden and outcome severity attributable to RSV outbreaks among residents and staff in LTCHs; and to highlight reported population and outbreak characteristics. All types of evidence were eligible for inclusion. Data utilized by included studies was between the end of the 2010 H1N1 influenza pandemic and the beginning of the coronavirus disease 2019 (COVID-19) pandemic. Evidence from the following countries was considered: G7, the European Union, Australia and New Zealand. A total of 167 articles were identified; 58 full texts were analyzed and four sources of evidence were eligible for inclusion. Data related to population characteristics, outbreak type and resident and staff outcomes were manually charted. There is a paucity of evidence sources pertaining to RSV outbreak burden among residents and staff in LTCHs. Outbreak duration ranged from 13 to 21 days. For each outbreak, 4-7 residents had confirmed RSV infection. Attack rates ranged from 12% to 38%. A spectrum of disease attributable to RSV outbreaks in LTCHs was identified, ranging from mild cold-like symptoms to death. Integration of RSV into existing respiratory pathogen surveillance programs is important to characterize susceptibility, transmissibility and virulence of RSV in at-risk populations. There is a need for public health organizations to publish the findings from outbreak investigations to provide evidence to inform RSV outbreak prevention and response in LTCH settings.

Age-specific predictors of disease severity in children with respiratory syncytial virus infection beyond infancy and through the first 5 years of age.

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. 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. 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. 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.

Respiratory syncytial virus disease morbidity in Australian infants aged 0 to 6 months: a systematic review with narrative synthesis

BackgroundA significant proportion of the global respiratory syncytial virus (RSV) associated morbidity is accounted for by infants aged 0 to 6 months, who are particularly vulnerable to severe disease. In 2015, 44% of global hospitalisations in infants in this age group were secondary to RSV. The objective of this systematic review is to appraise and synthesise the local evidence of RSV infection morbidity among Australian infants aged 0 to 6 months and to assess the implications for future immunisation strategies.MethodsElectronic databases (Medline, Embase, Pubmed and Global Health) were searched for full-text articles published between 2000 and 2023 in English language. Studies that examined markers of RSV disease morbidity in infants aged 0 to 6 months in Australia who had laboratory confirmed RSV infection were eligible for inclusion. The outcomes of interest were incidence, prevalence, testing rate, positivity rate, mortality, emergency department visits, community health visits, hospitalisation, intensive care unit admission, supplementary oxygen use, mechanical ventilation, risk factors for disease severity and monoclonal antibody use.ResultsThe database search identified 469 studies. After removal of duplicates and full-text review, 17 articles were eligible for inclusion. This review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Synthesis without meta-analysis guidelines.ConclusionsQualitative analysis of the included studies showed that Australian infants aged 0 to 6 months have higher rates of RSV testing, positivity and incidence; and more likely to develop severe disease that requires hospitalisation, intensive care unit admission or respiratory support, compared to children and adults of all ages. Aboriginal and Torres Strait Islander infants aged 0 to 6 months demonstrated higher rates of RSV infection and hospitalisation, compared to non-Indigenous infants. Age-related trends persisted in geographic areas with varying seasonal transmission of RSV, and during the SARS-CoV-2 pandemic. Passive immunisation strategies targeting infants in their first 6 months of life, either via vaccination of pregnant women or administration of long-acting monoclonal antibody during infancy, could effectively reduce RSV disease burden in Australia.

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).

A randomized controlled trial of presatovir for respiratory syncytial virus after lung transplant

Respiratory syncytial virus (RSV) infection in lung transplant recipients is associated with high morbidity. This study evaluated the RSV fusion inhibitor presatovir in RSV-infected lung transplant recipients. In this international Phase 2b, randomized, double-blind, placebo-controlled trial (NCT02534350), adult lung transplant recipients with symptomatic confirmed RSV infection for ≤7 days received oral presatovir 200 mg on day 1 and 100 mg daily on days 2 to 14, or placebo (2:1), with follow-up through day 28. There were 2 coprimary endpoints: time-weighted average change in nasal RSV load from day 1 to 7, calculated from nasal swabs, in the full analysis set ([FAS]; all patients who received study drug and had quantifiable baseline nasal RSV load) and time-weighted average change in nasal RSV load from day 1 to 7 in the subset of patients with pretreatment symptom duration at the median or shorter of the FAS. Secondary endpoints were changes in respiratory infection symptoms assessed using the Influenza Patient-Reported Outcomes questionnaire and lung function measured by spirometry. Sixty-one patients were randomized, 40 received presatovir, 20 placebo, and 54 were included in efficacy analyses. Presatovir did not significantly improve the primary endpoint in the FAS (treatment difference [95% CI], 0.10 [-0.43, 0.63] log10 copies/ml; p=0.72) or the shorter symptom-duration subgroup (-0.12 [-0.94, 0.69] log10 copies/ml; p=0.76). Secondary endpoints were not different between presatovir and placebo groups. Presatovir was generally well tolerated. Presatovir treatment did not significantly improve change in nasal RSV load, symptoms, or lung function in lung transplant recipients.

Clinical and Socioeconomic Burden of Respiratory Syncytial Virus in Iceland.

Respiratory syncytial virus (RSV), a very common pathogen, causes variable disease severity. In addition to considerable clinical burden on children, their families and healthcare facilities, RSV infections in children also carry significant direct and indirect socioeconomic burden. We analyzed data from 5 consecutive RSV seasons (2015-2020) and used virologically confirmed RSV infections and age <5 years as case definition. Clinical information was retrieved from electronic patient records. Costs were estimated by assuming an annual 30% attack rate and a combination of direct medical costs and calculations of societal costs of lost productivity. A total of 716 children younger than 5 years of age had confirmed RSV infection of which 254 needed hospitalizations, most of whom were previously healthy. The median length of admission was 3.6 days and 13 patients needed intensive care. The hospital admission incidence rate was 2.5/1000 children/year, but 9.1 for children younger than 1 years of age. The total annual cost of RSV was estimated at €4.3 million, of which 10% was direct healthcare costs. The clinical and socioeconomic disease burden of RSV in Iceland is substantial despite slightly lower hospital admission rates than other high-income countries. The prevention of RSV in young children, either through maternal or infant vaccination, has the potential to decrease both clinical and financial impact of the annual epidemics.

Risk factors associated with severe disease in respiratory syncytial virus infected children under 5 years of age.

ObjectiveTo evaluate risk factors for severe disease in children under 59 months of age hospitalized with respiratory syncytial virus (RSV) infection.Study designWe prospectively enrolled 1,096 cases of laboratory confirmed RSV infection during three consecutive RSV seasons in 2015–2018. Potential risk factors for severe disease were retrieved through patient questionnaires and linkage to national health registries. Need for respiratory support (invasive ventilation, bi-level positive airway pressure, or continuous positive airway pressure), and length of stay exceeding 72 h were used as measures of disease severity. Associations were investigated using multivariable logistic regression analyses. Multiple imputation was used to avoid bias and inference induced by missing data.ResultsRisk factors associated with a need for respiratory support included age younger than 3 months of age [aOR: 6.73 (95% CI 2.71–16.7)], having siblings [aOR: 1.65 (95% CI 1.05–2.59)] and comorbidity [aOR: 2.40 (95% CI 1.35–4.24)]. The length of hospital stay >72 h was significantly associated with being younger than 3 months of age [aOR: 3.52 (95% CI 1.65–7.54)], having siblings [aOR: 1.45 (95% CI 1.01–2.08)], and comorbidity [aOR: 2.18 (95% CI 1.31–3.61)]. Sub-group analysis of children younger than 6 months of age confirmed the association between both young age and having siblings and the need for respiratory support.ConclusionIn a large cohort of children <59 months hospitalized with RSV infection, young age, comorbidity, and having siblings were associated with more severe disease.

Effectiveness of palivizumab immunoprophylaxis in infants with respiratory syncytial virus disease in Colombia.

Respiratory syncytial virus (RSV) is one of the most important childhood infections. To evaluate the effectiveness and safety of palivizumab immunoprophylaxis in preterm infants at a high risk of severe respiratory syncytial virus infection during the RSV season in Colombia. A prospective observational non-comparative multicenter study in six Colombian cities. At the beginning of the RSV infection season, palivizumab prophylaxis, up to five doses, was administered to infants born at ≤32 weeks of gestation, infants younger than six months, infants under one year of age with bronchopulmonary dysplasia (BPD), infants one year or less of age with hemodynamically significant acyanotic and non-acyanotic congenital heart disease (CHD), and with follow-up during the immunoprophylaxis until one month after the last dose. The study enrolled 600 patients, 91.8% of which were born at ≤ 32 weeks of gestation. BPD was observed in 54.9% of infants. 49% were born at < 32 weeks gestation and presented BPD. 6.9% had hemodynamically significant acyanotic and non-acyanotic CHD 53.3% received three or more doses of palivizumab. The mean interval between doses was 39.6 days. 1.8% of patients were hospitalized due to a confirmed RSV infection. Overall mortality was 1.2%, whereas the mortality by RSV in infants undergoing prophylaxis was 0.2%. Palivizumab was a clinically effective, well-tolerated treatment in the Colombian population. The safety profile of palivizumab reflects the findings from previous studies in developed countries.

Erratum: Risk Factors for Respiratory Syncytial Virus Infections in Moderate/Late Premature Infants in Turkey: A Prospective Multicenter Epidemiological Study.

Objective Respiratory syncytial virus (RSV) is one of the most prevalent causes of lower respiratory tract infection (LRTI). The primary objective of this study is to provide the risk modelling of confirmed RSV infection in children who were born preterm at 29 to 35 weeks of gestational age and presented with LRTI. Study Design This prospective, multicenter study was performed between October 2015 and March 2017. Premature infants born with gestational age between 29 and 35 weeks that were ≤2 years of age at the beginning of the RSV season and admitted to the hospital with clinical findings of LRTI during the season were included. RSV-positive and -negative infants were compared in terms of demographic features, risk factors, and requirement of hospitalization. Results RSV positive group was lower than RSV negative group and ratio of ≤3 months age at admission was significant higher in RSV (+) group. RSV-positive infants were found to be significantly born during or 3 months prior to RSV season. The rate and duration of hospitalization and need for mechanical ventilation were significantly higher in RSV positive infants. The rate and duration of hospitalization in RSV positive patients was related to the chronological age. Conclusion This study showed that preterm infants with RSV-associated LRTI significantly needed more hospitalization, intensive care admission, and mechanical ventilation. In addition need of hospitalization and duration of hospitalization were significant higher in ≤3 months of age. Therefore, we suggest the importance of palivizumab prophylaxis in infants ≤ 3 months chronological age, especially during the RSV season.

Risk Factors for Respiratory Syncytial Virus Infections in Moderate/Late Premature Infants in Turkey: A Prospective Multicenter Epidemiological Study.

Respiratory syncytial virus (RSV) is one of the most prevalent causes of lower respiratory tract infection (LRTI). The primary objective of this study is to provide the risk modelling of confirmed RSV infection in children who were born preterm at 29 to 35 weeks of gestational age and presented with LRTI. This prospective, multicenter study was performed between October 2015 and March 2017. Premature infants born with gestational age between 29 and 35 weeks that were ≤2 years of age at the beginning of the RSV season and admitted to the hospital with clinical findings of LRTI during the season were included. RSV-positive and -negative infants were compared in terms of demographic features, risk factors, and requirement of hospitalization. RSV positive group was lower than RSV negative group and ratio of ≤3 months age at admission was significant higher in RSV (+) group. RSV-positive infants were found to be significantly born during or 3 months prior to RSV season. The rate and duration of hospitalization and need for mechanical ventilation were significantly higher in RSV positive infants. The rate and duration of hospitalization in RSV positive patients was related to the chronological age. This study showed that preterm infants with RSV-associated LRTI significantly needed more hospitalization, intensive care admission, and mechanical ventilation. In addition need of hospitalization and duration of hospitalization were significant higher in ≤3 months of age. Therefore, we suggest the importance of palivizumab prophylaxis in infants ≤ 3 months chronological age, especially during the RSV season.

Evaluation of the protective potential of antibody and T cell responses elicited by a novel preventative vaccine towards respiratory syncytial virus small hydrophobic protein

ABSTRACT The small hydrophobic (SH) glycoprotein of human respiratory syncytial virus (RSV) is a transmembrane protein that is poorly accessible by antibodies on the virion but has an ectodomain (SHe) that is accessible and expressed on infected cells. The SHe from RSV strain A has been formulated in DPX, a unique delivery platform containing an adjuvant, and is being evaluated as an RSV vaccine candidate. The proposed mechanism of protection is the immune-mediated clearance of infected cells rather than neutralization of the virion. Our phase I clinical trial data clearly showed that vaccination resulted in robust antibody responses, but it was unclear if these immune responses have any correlation to immune responses to natural infection with RSV. Therefore, we embarked on this study to examine these immune responses in older adults with confirmed RSV infection. We compared vaccine-induced (DPX-RSV(A)) immune responses from participants in a Phase 1 clinical trial to paired acute and convalescent titers from older adults with symptomatic laboratory-confirmed RSV infection. Serum samples were tested for anti-SHe IgG titers and the isotypes determined. T cell responses were evaluated by IFN-γ ELISPOT. Anti-SHe titers were detected in 8 of 42 (19%) in the acute phase and 16 of 42 (38%) of convalescent serum samples. IgG1, IgG3, and IgA were the prevalent isotypes generated by both vaccination and infection. Antigen-specific T cell responses were detected in 9 of 16 (56%) of vaccinated participants. Depletion of CD4+ but not CD8+ T cells abrogated the IFN-γ ELISPOT response supporting the involvement of CD4+ T cells in the immune response to vaccination. The data showed that an immune response like that induced by DPX-RSV(A) could be seen in a subset of participants with confirmed RSV infection. These findings show that older adults with clinically significant infection as well as vaccinated adults generate a humoral response to SHe. The induction of both SHe-specific antibody and cellular responses support further clinical development of the DPX-RSV(A) vaccine.

Antibiotic Overuse in Children with Respiratory Syncytial Virus Lower Respiratory Tract Infection

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections (LRTI) during the first year of life. Antibiotic treatment is recommended in cases suspected of bacterial coinfection. The aim of this prospective study was to estimate the incidence of bacterial coinfections and the amount of antibiotic overuse in children infected with RSV using expert panel diagnosis. Children 1 month of age and over with LRTI or fever without source were prospectively recruited in hospitals in the Netherlands and Israel. Children with confirmed RSV infection by Polymerase Chain Reaction (PCR) on nasal swabs were evaluated by an expert panel as reference standard diagnosis. Three experienced pediatricians distinguished bacterial coinfection from simple viral infection using all available clinical information, including all microbiologic evaluations and a 28-day follow-up evaluation. A total of 188 children (24% of all 784 recruited patients) were positive for RSV. From these, 92 (49%) were treated with antibiotics. All 27 children (29%) with bacterial coinfection were treated with antibiotics. Fifty-seven patients (62%) were treated with antibiotics without a diagnosis of bacterial coinfection. In 8 of the 92 (9%), the expert panel could not distinguish simple viral infection from bacterial coinfection. This is the first prospective international multicenter RSV study using an expert panel as reference standard to identify children with and without bacterial coinfection. All cases of bacterial coinfections are treated, whereas as many as one-third of all children with RSV LRTI are treated unnecessarily with antibiotics.

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.

Respiratory syncytial virus subtype ON1/NA1/BA9 predominates in hospitalized children with lower respiratory tract infections.

Respiratory syncytial virus (RSV) infection is the leading cause of acute respiratory tract disease in children less than 5 years old. The aim of this study was to further elucidate the molecular properties and clinical characteristics of RSV infection. The study sample included 238 patients <5 years old who were hospitalized with clinical symptoms of upper or lower respiratory tract infection (URTI or LRTI) in the Pediatric Department at the First People's Hospital of Chenzhou, South China in 2014. We subjected nasopharyngeal aspirate (NPA) or nasal swab (NS) samples from the patients to indirect fluorescence assay screens. RSV G genes were amplified by reverse transcription‐PCR (RT‐PCR) and sequenced. Of the 238 patients screened, 64 (26.8%) were confirmed to have RSV infections. Of those 64 confirmed RSV infection cases, 39 (60.9%) had subtype BA9, 13 (20.3%) had the recently identified subtype ON1, 11 (17.2%) had subtype NA1, and 1 (1.6%) had subtype GB2. The predominant presentation was LRTI with coughing, sputum production, fever, and wheezing. RSV subtype NA1 and BA9 infections were found mostly in infants, whereas the age distribution of subtype ON1 infections was more uniform across the age bands. Phylogenetic analysis indicated that, compared with the prototype strain A2, all ON1 and most NA1 isolates had lost one potential N‐glycosylation site at amino acid 251 and 249 due to T251K and N249Y substitution, respectively. These findings suggest that NA1, BA9, and ON1 are the dominant RSV subtypes causing respiratory tract infections in young children presenting to the hospital in South China. J. Med. Virol. 89:213–221, 2017. © 2016 Wiley Periodicals, Inc.

Cytokine responses in primary and secondary respiratory syncytial virus infections.

Primary respiratory syncytial virus (RSV) infections are characterized by high levels of IL-8 and an intense neutrophilia. Little is known about the cytokine responses in secondary infections. Preschool children experiencing RSV secondary infections were recruited from the siblings of infants admitted to hospital with RSV acute bronchiolitis. Fifty-one infants with acute bronchiolitis (39 RSV positive, 12 RSV negative) and 20 age-matched control infants were recruited. In addition, seven older siblings of infants from the RSV-positive cohort and confirmed RSV infection were recruited. Samples of nasal secretions were obtained using a flocked swab, and secretions extracted using centrifugation. Cytokine bead array was used to obtain levels of interleukin (IL)-17A, IL-8, IL-6, IL-21, and tumor necrosis factor-α. Levels of IL-8 and IL-6 were significantly lower in the RSV-positive siblings compared with the RSV-positive infants. There were no significant differences between levels of the other cytokines in the primary and secondary infections. The very high levels of IL-8 and IL-6 response characteristic of the primary RSV infection was not observed in secondary RSV-positive infections and this did not appear to be due to a global reduction in cytokine production.

Systematic review and meta-analysis of respiratory syncytial virus infection epidemiology in Latin America.

Respiratory syncytial virus (RSV) is a frequent cause of acute respiratory infection and the most common cause of bronchiolitis in infants. The aim of this systematic review and meta-analysis was to obtain a comprehensive epidemiological picture of the data available on disease burden, surveillance, and use of resources in Latin America. Pooled estimates are useful for cross-country comparisons. Data from published studies reporting patients with probable or confirmed RSV infection in medical databases and gray literature were included from 74 studies selected from the 291 initially identified. When considering all countries, the largest pooled percentage RSV in low respiratory tract infection patients was found in the group between 0 and 11 months old, 41.5% (95% CI 32.0–51.4). In all countries, percentages were increasingly lower as older children were included in the analyses. The pooled percentage of RSV in LRTIs in the elderly people was 12.6 (95% CI 4.2–24.6). The percentage of RSV infection in hospitalized newborns was 40.9% (95% CI 28.28–54.34). The pooled case fatality ratio for RSV infection was 1.74% (95% CI 1.2–2.4) in the first 2 years of life. The average length of stay excluding intensive care unit admissions among children with risk factors for severe disease was 12.8 (95% CI 8.9–16.7) days, whereas it averaged 7.3 (95% CI 6.1/8.5) days in otherwise healthy children.We could conclude that infants in their first year of age were the most vulnerable population. To our knowledge, this is the first systematic review on RSV disease burden and use of health resources in Latin America.

Editorial Commentary: Respiratory Syncytial Virus: A Global Pathogen in an Aging World

Respiratory syncytial virus (RSV) was identified in 1957 as a cause of infant bronchiolitis and is now recognized as the major cause of hospitalizations for respiratory infection in young children [1]. Shortly after its discovery, mild illness in adults with RSV reinfection was observed and since the 1980s evidence has been slowly mounting that the burden of adult RSV disease is substantial [2, 3]. Groups at highest risk for severe infection include the elderly, persons with chronic cardiopulmonary diseases, and those with immunosuppression [4, 5]. Despite the currently available epidemiologic data, RSV infection is rarely considered by internists evaluating patients with respiratory illness in their offices or in the hospital. In addition, health agencies and industry remain uncertain as to whether adult RSV disease warrants programs to develop therapeutics and vaccines. The reason for the adult RSV “identity crisis” is in large part because physicians rarely make a specific viral diagnosis in an individual patient and thus, they are unable to personalize the disease. Insensitive pointof-care diagnostics, the lack of a distinct clinical syndrome, and a broad epidemic curve that overlaps with influenza and other respiratory viruses all contribute to this lack of recognition of the problem. The development of new sensitive molecular diagnostics have dramatically altered epidemiologic research involving respiratory viruses, and recent studies now provide a more accurate picture of the burden of RSV disease [6, 7]. Yet, here too, the global community cannot personalize the problem to their own region or countries as most studies to date are from Europe and North America. Unless a disease is demonstrated in one’s own backyard, there is a natural tendency to ignore or minimize the problem. In this issue of Clinical Infectious Diseases, Lee and colleagues [8] present data from a large, 3-year study of adults hospitalized with respiratory illness in Hong Kong, China. In this study, the clinical and radiologic features of 607 adults with confirmed RSV infection are compared and contrasted to patients with seasonal influenza infection. The findings clearly demonstrate significant morbidity and mortality in older persons associated with RSV infection, which is comparable to influenza. RSV accounted for 6%–9% of respiratory illnesses during seasonal peaks; 72% of those admitted with RSV had lower respiratory tract complications, 11% required ventilatory support, and 9% died within 30 days. Similar to previous reports, infected patients were elderly (mean age, 75 years), and most had underlying medical conditions with chronic lung disease reported in 36%. Of note, although substantial proportions of both RSV and influenza patients had underlyin g medical conditions, RSV patients had significantly more lung disease and major systemic comorbidities. This observation may reflect the very large sample size of the current study allowing detection of more subtle differences in patient groups than previous reports. Importantly, there was no significant difference in the overall outcomes of survival and duration of hospitalization of RSV- and influenza-infected patients. Although a number of the observations

High Morbidity and Mortality in Adults Hospitalized for Respiratory Syncytial Virus Infections

Better understanding of complications and outcomes of adults hospitalized with respiratory syncytial virus (RSV) infection is necessary. A retrospective cohort study was conducted on all adults (≥ 18 years) admitted to 3 acute care general hospitals in Hong Kong with virologically confirmed RSV infection during 2009-2011 (N = 607). Adults hospitalized for seasonal influenza during the period were used for comparison (n = 547). Both infections were prospectively diagnosed following a standard protocol. Independent reviews of chest radiographs were performed by radiologists. Main outcome measures were all-cause death, respiratory failure requiring ventilatory support, and hospitalization duration. Cox proportional hazards models were used for analyses. The mean age of RSV patients was 75 (SD, 16) years; 87% had underlying conditions. Lower respiratory and cardiovascular complications were diagnosed in 71.9% (pneumonia, 42.3%; acute bronchitis, 21.9%; chronic obstructive pulmonary disease/asthma exacerbation, 27.3%) and 14.3% of patients, respectively; 12.5% had bacterial superinfections. Supplemental oxygen and ventilatory support were required in 67.9% and 11.1%, respectively. Crude all-cause mortality was 9.1% and 11.9% within 30 days and 60 days, respectively; mean length of stay of survivors was 12 (SD, 13) days. Advanced age, radiographic pneumonia, requirement for ventilation, bacterial superinfection, and elevated urea level and white blood cell count were independently associated with poorer survival. Systemic corticosteroid use was associated with longer hospitalization and secondary infections. The overall outcomes of survival and length of stay were not significantly different from those in influenza. RSV can cause severe lower respiratory complications in older adults, resulting in respiratory failure, prolonged hospitalization, and high mortality similar to seasonal influenza. Corticosteroids did not seem to improve outcomes. The unmet need for antiviral therapy and vaccination against RSV in adults should be promptly addressed.