Nasal cathelicidin is expressed in early life and is increased during mild, but not severe respiratory syncytial virus infection.

Respiratory syncytial virus is the major cause of acute lower respiratory tract infections in young children, causing extensive mortality and morbidity globally, with limited therapeutic or preventative options. Cathelicidins are innate immune antimicrobial host defence peptides and have antiviral activity against RSV. However, upper respiratory tract cathelicidin expression and the relationship with host and environment factors in early life, are unknown. Infant cohorts were analysed to characterise early life nasal cathelicidin levels, revealing low expression levels in the first week of life, with increased levels at 9 months which are comparable to 2-year-olds and healthy adults. No impact of prematurity on nasal cathelicidin expression was observed, nor were there effects of sex or birth mode, however, nasal cathelicidin expression was lower in the first week-of-life in winter births. Nasal cathelicidin levels were positively associated with specific inflammatory markers and demonstrated to be associated with microbial community composition. Importantly, levels of nasal cathelicidin expression were elevated in infants with mild RSV infection, but, in contrast, were not upregulated in infants hospitalised with severe RSV infection. These data suggest important relationships between nasal cathelicidin, upper airway microbiota, inflammation, and immunity against RSV infection, with interventional potential.

Asymptomatic Viral Presence in Early Life Precedes Recurrence of Respiratory Tract Infections.

BACKGROUND: Respiratory tract infections (RTIs) in infants are often caused by viruses. Although respiratory syncytial virus (RSV), influenza virus and human metapneumovirus (hMPV) can be considered the most pathogenic viruses in children, rhinovirus (RV) is often found in asymptomatic infants as well. Little is known about the health consequences of viral presence, especially early in life. We aimed to examine the dynamics of (a)symptomatic viral presence and relate early viral detection to susceptibility to RTIs in infants. METHODS: In a prospective birth cohort of 117 infants, we tested 1304 nasopharyngeal samples obtained from 11 consecutive regular sampling moments, and during acute RTIs across the first year of life for 17 respiratory viruses by quantitative PCR. Associations between viral presence, viral (sub)type, viral load, viral co-detection and symptoms were tested by generalized estimating equation (GEE) models. RESULTS: RV was the most detected virus. RV was negatively associated [GEE: adjusted odds ratio (aOR) 0.41 (95% CI 0.18-0.92)], and hMPV, RSV, parainfluenza 2 and 4 and human coronavirus HKU1 were positively associated with an acute RTI. Asymptomatic RV in early life was, however, associated with increased susceptibility to and recurrence of RTIs later in the first year of life (Kaplan-Meier survival analysis: P = 0.022). CONCLUSIONS: Respiratory viruses, including the seasonal human coronaviruses, are often detected in infants, and are often asymptomatic. Early life RV presence is, though negatively associated with an acute RTI, associated with future susceptibility to and recurrence of RTIs. Further studies on potential ecologic or immunologic mechanisms are needed to understand these observations.

The burden of respiratory syncytial virus in healthy term-born infants in Europe: a prospective birth cohort study.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of hospitalisation in infants. The burden of RSV infection in healthy term infants has not yet been established. Accurate health-care burden data in healthy infants are necessary to determine RSV immunisation policy when RSV immunisation becomes available. METHODS: We performed a multicentre, prospective, observational birth cohort study in healthy term-born infants (≥37 weeks of gestation) in five sites located in different European countries to determine the health-care burden of RSV. The incidence of RSV-associated hospitalisations in the first year of life was determined by parental questionnaires and hospital chart reviews. We performed active RSV surveillance in a nested cohort to determine the incidence of medically attended RSV infections. The study is registered with ClinicalTrials.gov, NCT03627572. FINDINGS: In total, 9154 infants born between July 1, 2017, and April 1, 2020, were followed up during the first year of life and 993 participated in the nested active surveillance cohort. The incidence of RSV-associated hospitalisations in the total cohort was 1·8% (95% CI 1·6-2·1). There were eight paediatric intensive care unit admissions, corresponding to 5·5% of 145 RSV-associated hospitalisations and 0·09% of the total cohort. Incidence of RSV infection in the active surveillance cohort confirmed by any diagnostic assay was 26·2% (24·0-28·6) and that of medically attended RSV infection was 14·1% (12·3-16·0). INTERPRETATION: RSV-associated acute respiratory infection causes substantial morbidity, leading to the hospitalisation of one in every 56 healthy term-born infants in high-income settings. Immunisation of pregnant women or healthy term-born infants during their first winter season could have a major effect on the health-care burden caused by RSV infections. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking, with support from the EU's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations.

Performance Assessment of a Rapid Molecular Respiratory Syncytial Virus Point-of-Care Test: A Prospective Community Study in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) causes a substantial burden in older adults. Viral load in RSV-infected adults is generally lower compared to young children, which could result in suboptimal sensitivity of RSV diagnostics. Although the Xpert® Xpress Flu/RSV assay has been used in routine clinical care, its sensitivity to diagnose RSV infection in older adults is largely unknown. We aimed to compare the performance of the Xpert® Xpress Flu/RSV assay with real-time reverse-transcription polymerase chain reaction (RT-PCR) in home-dwelling older adults (≥60 years of age). METHODS: Nasopharyngeal swabs were tested with Xpert® Xpress Flu/RSV and compared to RSV RT-PCR in older adults with acute respiratory tract infections with different levels of disease severity. RESULTS: We studied 758 respiratory samples from 561 older adults from 2 consecutive RSV seasons. Thirty-five (4.6%) samples tested positive for RSV by at least 1 of the assays, of which 2 samples were negative by Xpert® Xpress Flu/RSV and 3 samples by real-time RT-PCR. The positive percentage agreement (PPA) was 90.9% (95% confidence interval [CI], 76.4%-96.8%) and negative percentage agreement was 99.7% (95% CI, 99.0%-99.9%). Viral loads were low (≤103 copies/mL or cycle threshold value ≥34) in all cases with discordant results for the 2 assays. CONCLUSIONS: The PPA of Xpert® Xpress Flu/RSV compared to routine RT-PCR is high for RSV detection in home-dwelling older adults. The assay is fast and easy to use at the point of care. CLINICAL TRIALS REGISTRATION: NCT03621930.

Respiratory Syncytial Virus Consortium in Europe (RESCEU) Birth Cohort Study: Defining the Burden of Infant Respiratory Syncytial Virus Disease in Europe.

BACKGROUND: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although prematurity and cardiopulmonary disease are risk factors for severe disease, the majority of infants hospitalized with RSV are previously healthy. Various vaccines and therapeutics are under development and expected to be available in the near future. To inform the use of these new vaccines and therapeutics, it is necessary to determine the burden of RSV disease in Europe. We will prospectively follow-up a birth cohort to obtain incidence data on RSV acute respiratory tract infection (ARTI). METHODS: Multicenter prospective study of a birth cohort consisting of 10 000 healthy infants, recruited during 3 consecutive years. RSV associated hospitalization in the first year of life will be determined by questionnaires and hospital chart reviews. A nested cohort of 1000 infants will be actively followed. In case of ARTI, a respiratory sample will be collected for RSV molecular diagnosis. RESULTS: The primary outcome is the incidence rate of RSV-associated hospitalization in the first year of life. In the active cohort the primary outcome is RSV associated ARTI and MA-ARTI. CONCLUSIONS: We will provide key information to fill the gaps in knowledge about the burden of RSV disease in healthy infants. CLINICAL TRIALS REGISTRATION: NCT03627572.

Low Sensitivity of BinaxNOW RSV in Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants. Early detection of RSV can optimize clinical management and minimize use of antibiotics. BinaxNOW RSV (BN) is a rapid antigen detection test that is widely used. We aimed to validate the sensitivity of BN in hospitalized and nonhospitalized infants against the gold standard of molecular diagnosis. METHODS: We evaluated the performance of BN in infants with acute respiratory tract infections with different degrees of disease severity. Diagnostic accuracy of BN test results were compared with molecular diagnosis as reference standard. RESULTS: One hundred sixty-two respiratory samples from 148 children from October 2017 to February 2019 were studied. Sixty-six (40.7%) samples tested positive for RSV (30 hospitalizations, 31 medically attended episodes not requiring hospitalization, and 5 nonmedically attended episodes). Five of these samples tested positive with BN, leading to an overall sensitivity of BN of 7.6% (95% confidence interval [CI], 3.3%-16.5%) and a specificity of 100% (95% CI, 96.2%-100%). Sensitivity was low in all subgroups. CONCLUSIONS: We found a low sensitivity of BN for point-of-care detection of RSV infection. BinaxNOW RSV should be used and interpreted with caution.

Differentiation Between Pediatric Irritable Bowel Syndrome and Inflammatory Bowel Disease Based on Fecal Scent: Proof of Principle Study.

Background: The diagnostic work-up of pediatric irritable bowel syndrome (IBS) and functional abdominal pain-not otherwise specified (FAP-NOS) commonly includes invasive tests for discrimination from inflammatory bowel disease (IBD). As this carries a high burden on patients, an ongoing need exists for development of noninvasive diagnostic biomarkers for IBS and FAP-NOS. Several studies have shown microbiota alterations in IBS/FAP, which are considered to be reflected by fecal volatile organic compounds (VOCs). The object of the study was to evaluate whether pediatric IBS/FAP-NOS could be discriminated from IBD and healthy controls by fecal VOC analysis. Methods: IBS/FAP-NOS was diagnosed according to the ROME IV criteria, and de novo IBD patients and healthy controls (HCs) aged 4 to 17 years were matched on age and sex. Fecal VOCs were analyzed by means of field asymmetric ion mobility spectrometry. Results: Fecal VOCs of 15 IBS/FAP-NOS, 30 IBD (15 ulcerative colitis, 15 Crohn's disease) patients and 30 HCs were analyzed and compared. Differentiation between IBS/FAP-NOS and IBD was feasible with high accuracy (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.88-1; P < 0.00001). IBS/FAP-NOS profiles could not be differentiated from HCs (AUC, 0.59; 95% CI, 0.41-0.77; P = 0.167), whereas IBD profiles could with high accuracy (AUC, 0.96; 95% CI, 0.93-1; P < 0.00001). Conclusion: Pediatric IBS/FAP-NOS could be differentiated from IBD by fecal VOC analysis with high accuracy, but not from healthy controls. The latter finding limits the potential of fecal VOCs to serve as a diagnostic biomarker for IBS/FAP-NOS. However, VOC could possibly serve as additional noninvasive biomarker to differentiate IBS/FAP-NOS from IBD. 10.1093/ibd/izy151_video1izy151.video15786446046001.