Impact of COVID-19 Therapeutics on the Development of Post-Infectious Lung Fibrosis

Yong Jun Choi¹Ji Eun Nam²Chul Hwan Park²Ji Ye Jung³Eun Hye LEE⁴Hye Jung Park¹Chi Young Kim¹Jae Hwa Cho¹Min Kwang Byun^1*

• ¹Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
• ²Department of Radiology and the Research Institute of Radiological Science, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
• ³Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, Seoul, Republic of Korea
• ⁴Division of Pulmonology, Allergy and Critical Care Medicine, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea, Seoul, Republic of Korea

ABSTRACT Background: Post-COVID-19 pulmonary fibrosis (PCPF) is a significant long-term complication in survivors of COVID-19. In this study, we aimed to identify clinical risk factors for PCPF and evaluate the impact of COVID-19–related therapies. Methods: We retrospectively studied hospitalized adults with confirmed COVID-19 across three hospitals in South Korea from 2020 to 2022. Inclusion required chest computed tomography (CT) imaging both before and after COVID-19 infection. PCPF was defined as fibrotic changes seen on follow-up CT performed at least one month after recovery. Results: Among 5,720 hospitalized adults with COVID-19, 688 met the inclusion criteria, and 87 (12.6%) developed PCPF based on follow-up CT. In the multivariate logistic regression, pre-existing renal disease (adjusted odds ratio [aOR] 3.287; 95% confidential interval [CI]: 1.260–8.580; p = 0.014), higher hemoglobin levels (aOR: 1.194; 95% CI: 1.032–1.387; p = 0.018) and elevated CRP (aOR: 1.005; 95% CI: 1.001–1.009; p = 0.022) were independently associated with increased risk of PCPF. Remdesivir use was significantly associated with a reduced risk of PCPF (aOR: 0.359; 95% CI: 0.176–0.734; p = 0.005), whereas baricitinib use was associated with an increased risk (aOR: 5.633; 95% CI: 1.642– 19.548; p = 0.006). Conclusion: PCPF remains a relevant sequela in COVID-19 survivors. Remdesivir and baricitinib use were associated with a reduced and increased risk of PCPF, respectively. Although adjusted for multiple confounders, residual indication bias of each treatment cannot be completely excluded. Therefore, prospective studies are needed to validate these associations.