Prior respiratory syncytial viral infection contributes to severe COVID‐19 illness: A nationwide cohort study
Authors: Hwan Jin Lee, Min Ji Kim, Jong Seung Kim, Yong Chul Lee, Jae Seok Jeong
Journal: Allergy (2024)

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a major threat to public health around the world.1 Recently, there has been a growing recognition of the influence that prior respiratory viral infections, such as influenza, have on the outcomes of COVID-19.2 However, little is known about the long-term effects of RSV infection in adults or how it affects the subsequent COVID-19. Here, we conducted a population-based nationwide cohort study to investigate the association between prior RSV infection and COVID-19 severity. In total, 18,535 of 8,644,520 individuals in the National Health Insurance Service cohort database had a record of RSV infection in the previous 3 years (2017–2019). Propensity score matching was conducted to select a matched non-infected group of equal size to the infection group (Figure S1). The primary outcomes of the study comprised COVID-19 susceptibility, hospitalization, and severity. Susceptibility was defined by confirmation of a positive SARS-CoV-2 result from a real-time reverse transcription polymerase chain reaction assay of a nasal or pharyngeal swab. Hospitalization was classified as admission of a COVID-19-infected patient. Finally, severe clinical outcomes of COVID-19 were defined as any of the following: (1) intensive care unit admission, (2) extracorporeal membrane oxygenation treatment, (3) mechanical ventilator use, or (4) death, as previously described.2 Methods are described in Data S1. First, the COVID-19 susceptibility was investigated within each group. The RSV infection group (1000 person years [PY]: 62.2) exhibited a significantly higher incidence of COVID-19 susceptibility than the non-infection group (1000 PY: 56.1; adjusted HR: 1.11, 95% confidence interval [CI]: 1.03–1.20; Figure 1A). This trend was more prominently observed in patients with underlying conditions such as angina (adjusted HR: 1.50, 95% CI: 1.20–1.89; Figure 1B). For the COVID-19-related hospitalization, 743 of 18,535 RSV infection group patients became infected with COVID-19. The COVID-19 group with a history of RSV infection (1000 PY: 1866.0) showed a significantly higher risk of hospitalization than that with no history of RSV infection (1000 PY: 1459.4; adjusted HR: 1.23, 95% CI: 1.02–1.48; Figure 1C). This trend was unaffected by factors such as age, sex, economic status, or underlying diseases, although those who had RSV infections within a year of COVID-19 infection had a more significant HR than controls (adjusted HR: 1.50, 95% CI: 1.09–2.09; Figure 1D). Regarding COVID-19 severity, the COVID-19 group with a history of RSV infection (1000 PY: 178.2) had a significantly higher risk of COVID-19 severity than the group with no RSV infection history (1000 PY: 70.5; adjusted HR: 3.13, 95% CI: 1.58–6.19; Figure 2A). The association with severity was more pronounced in individuals ≥65 years (adjusted HR: 5.35, 95% CI: 2.33–12.27), those with diabetes (adjusted HR: 2.92, 95% CI: 1.26–6.77), and patients with congestive heart failure (adjusted HR: 2.91, 95% CI: 1.17–7.23; Figure 2B). Furthermore, patients with RSV infections in the previous year had a greater HR than controls (adjusted HR: 5.16, 95% CI: 2.21–12.09). We conducted a further investigation focusing on the severity of RSV infection, where severe RSV infection was defined with any of the following: hospitalization, oxygen supply, dyspnea, pneumonia, or acute exacerbation of the respiratory system, confirmed by respiratory RSV infection. Interestingly, a significant increase in the severity of COVID-19 was observed in both the severe and non-severe RSV infection groups. These data suggest that RSV infection, regardless of its severity, independently increases the probability of adverse clinical progression of subsequent COVID-19, along with other host risk factors such as diabetes and congestive heart failure. Based on the observation that epithelial changes are an important factor in the initiation and progression of COVID-19 and immunological predispositions contribute to the development of severe COVID-19,3-7 this phenomenon implies that even a RSV infection that is clinically mild can lead to structural damage in the airways and localized and/or systemic immunological changes, which increase the risk of developing severe COVID-19. Further mechanistic studies are required to elucidate these interactions. Although the possible impact of ethnicity exists in our study, this study is, to our knowledge, the first to assess how previous RSV infections affect the clinical progression of future COVID-19 in the general population. Our data revealed that prior RSV infection increased susceptibility and hospitalization of COVID-19 patients. Notably, individuals who had an RSV infection within 3 years of COVID-19 development were at an increased risk of severe illness from SARS-CoV-2 infection. Therefore, our study suggests that recent RSV infection contributes to the burden of COVID-19. RSV vaccination, an effective public health control measure that has recently demonstrated efficacy in adults with underlying comorbidities, may be advantageous in the clinical course of COVID-19.8 HJL and JSJ interpreted the data and wrote the manuscript. JSK and MJK conducted the statistical plan and data analysis. JSJ, JSK, and YCL designed the study and supervised the project. All authors critically reviewed the manuscript and approved the final manuscript. This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (RS-2023-00236157; JSJ). This paper was supported by Fund of Biomedical Research Institute, Jeonbuk National University Hospital. No competing financial interests exist. The authors have no conflict of interest to declare. These data were derived from the following resources available in the public domain: NHIS 2022-1-623, https://nhiss.nhis.or.kr. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.