Respiratory Syncytial Virus-related Community Chronic Obstructive Pulmonary Disease Exacerbations and Novel Diagnostics: A Binational Prospective Cohort Study

Abstract

Rationale: Respiratory syncytial virus (RSV) is a common global respiratory virus that is increasingly recognized as a major pathogen in frail older adults and as a cause of chronic obstructive pulmonary disease (COPD) exacerbations. There is no single test for RSV in adults that has acceptable diagnostic accuracy. Trials of RSV vaccines have recently shown excellent safety and efficacy against RSV in older adults; defining the frequency of RSV-related community infections and COPD exacerbations is important for vaccine deployment decisions. Objectives: This prospective study aimed to establish the frequency of outpatient-managed RSV-related exacerbations of COPD in two well-characterized patient cohorts using a combination of diagnostic methods. Methods: Participants were recruited at specialist clinics in London, United Kingdom, and Groningen, the Netherlands, beginning in 2017 and observed for three consecutive RSV seasons, during exacerbations, and at least twice yearly. RSV infections were detected by RT-PCR and serologic testing. Measurements and Main Results: A total of 377 patients with COPD attended 1,999 clinic visits and reported 310 exacerbations. There were 27 RSV-related exacerbations (8.7% of the total); of these, seven were detected only by PCR, 16 only by serology, and four by both methods. Increases in RSV-specific Nucleoprotein antibody were as sensitive as those in the antibody to Pre-Fusion or Post-Fusion for serodiagnosis of RSV-related exacerbations. Conclusions: RSV is associated with 8.7% of outpatient-managed COPD exacerbations in this study. Antibodies to RSV Nucleoprotein may have diagnostic value and are potentially important in a vaccinated population. The introduction of vaccines that prevent RSV is expected to benefit patients with COPD.

Keywords: chronic obstructive pulmonary disease; respiratory syncytial virus; rhinovirus.

Figure 1.

RESCEU (Respiratory Syncytial Virus Consortium in Europe) chronic obstructive pulmonary disease cohort study design and recruitment. (A) Study design at the London and Groningen recruitment sites. Some additional analyses were conducted at the London site (asterisks). (B) Consolidated Standards of Reporting Trials diagram for participant recruitment, retention, and observation of chronic obstructive pulmonary disease exacerbations. RSV = respiratory syncytial virus.

Figure 2.

(A) Respiratory syncytial virus (RSV) exacerbations are shorter than those caused by other pathogens. Time to recovery was assessed for all exacerbations, and durations were compared between exacerbation-associated pathogens (unknown, n  = 64; RSV, n = 16; rhinovirus, n = 30; influenza, n = 9; other virus, n = 16; bacteria, n = 24). Symptom duration was calculated from diary cards on which the data were complete. (B) Exacerbation severity is not related to diagnostic method. Time to recovery (in days) in RSV-associated exacerbations by diagnostic method (P = 0.947, Mann-Whitney U test; serology diagnosis, n = 11; PCR diagnosis, n = 5). FEV₁% change in RSV-associated exacerbations by diagnostic method (P = 0.947, Mann-Whitney U test; serology diagnosis, n = 11; PCR diagnosis, n = 5). Data in A were analyzed using a Kruskal-Wallis test with Dunn’s post hoc test, with P values denoting comparisons between RSV and all other exacerbation etiologies.

Figure 3.

Respiratory syncytial virus (RSV) exacerbations are associated with serological responses to diverse RSV proteins. Fold change in plasma IgG titer to RSV proteins (A) Glycoprotein a, (B) Glycoprotein b, (C) Post-Fusion, (D) Pre-Fusion, and (E) Nucleoprotein in RSV- and rhinovirus-associated exacerbations. (F) Correlation matrix of fold changes (before vs. after exacerbation) between antibody specificities. Significance was tested in A–E using Mann-Whitney U tests between groups, with the boxes representing medians and IQRs and whiskers representing ranges. (F) Spearman correlation values between paired data (*P < 0.05 and ***P < 0.001). F = Fusion; G = Glycoprotein; N = Nucleoprotein