The effect of antifibrotic agents on acute respiratory failure in COVID-19 patients: a retrospective cohort study from TriNetX US collaborative networks

The present retrospective multi-institutional study was conducted by the U.S. The Collaborative Research Network has demonstrated that the novel antifibrotic agents nintedanib and pirfenidone effectively reduce the 1-year mortality rate among COVID-19 patients suffering from acute respiratory failure. Remarkably, this study represents, to our knowledge, the first instance of survival benefit observed.

We observed significantly better 1-year survival in patient receiving nintedanib compared to those receiving pirfenidone. However, only 39 patients received pirfenidone in our cohort, indicating that small sample size may have contributed to insignificant results. Likewise, the small sample size during Alpha strain and Delta strain periods could also have led to insignificant findings. The characteristics of the Omicron strain, including its tendency to infect the upper respiratory tract rather than the lower respiratory tract and its lower IL-6 secretion, may have influenced the effectiveness of antifibrotic agents [18]. However, due to limitations of the TriNetX database, which does not specify the virus strain patients were infected with, comparing the effects of antifibrotic treatment across different strains was challenging. There likely were cases of mixed-strain infection across the four time frames. As a result, we are unable to ascertain the actual effect of antifibrotic agents on different virus strain. Further studies are warranted to validate these findings.

Our result revealed a higher percentage of patients in the antifibrotic group received Tocilizumab. Elevated IL-6 concentrations are associated with severe outcomes in COVID-19 [19]. Tocilizumab, an IL-6 receptor antagonist, has been demonstrated to reduce inflammatory responses and improve 28-day mortality in COVID-19 patients requiring oxygen therapy [20].Currently, the World Health Organization suggested using Tocilizumab in severe or critical COVID-19 patients who exhibit signs of desaturation in room air, severe respiratory distress, ARDS, require life-sustaining treatment, sepsis and septic shock [21]. However, Tocilizumab may also exacerbate bacterial infections in COVID-19 patients, which could restrict its usage. In the RECOVERY trial, 16% of patients in the Tocilizumab group ultimately did not receive this treatment [20]. Tocilizumab would be administered only to COVID-19 patients with higher severity and fewer signs of complicating bacterial infection. This observation may reflect a higher severity of illness among patients in the antifibrotic group.

Nintedanib functions by binding to intracellular ATP pockets and inhibiting profibrotic signaling pathways, including platelet-derived growth factor, fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor-beta (TGF-β) [10]. Similarly, pirfenidone regulates pro-fibrotic and pro-inflammatory cytokines such as TGF-β, tumor necrosis factor-α, interferon γ, interleukin-1β, and interleukin-6, thus inhibiting fibroblast proliferation and collagen synthesis [22, 23]. Moreover, pirfenidone has demonstrated a capacity to reduce ACE receptor expression, which is considered a major cellular receptor for SARS-CoV-2 virus entry [24]. Notably, case reports have indicated successful treatment outcomes using nintedanib for COVID-19-related ARDS [25, 26]. While ongoing studies on the treatment of COVID-19 patients with acute respiratory failure or pulmonary fibrosis exist, only limited published data are currently available. Umemura et al. observed that nintedanib significantly shortened the duration of mechanical ventilation and reduced the high attenuation area percentage on computed tomography volumetry in COVID-19 patients admitted to the ICU and requiring mechanical ventilation. However, no significant differences in 28-day mortality were found [27]. Similarly, Zhang et al. demonstrated that pirfenidone significantly decreased inflammatory biomarkers, including interleukin-2R, tumor necrosis factor-alpha (TNF-α), and D-dimer, although clinical parameters such as clinical improvement time, duration of oxygen therapy, time from randomization to death, and interstitial changes on CT images exhibited insignificant improvement [28].

Epithelial injury followed by a subsequent fibroproliferative cascade has been recognized as a key pathogenic mechanism of pulmonary fibrosis shared between COVID-19-related ARDS and idiopathic pulmonary fibrosis [29‐32]. Type 2 alveolar epithelial cells (ATII cells) plays a crucial role in IPF development [33, 34, 35, 36]. SARS-CoV-2 enters lower respiratory tract cells via the angiotensin-converting enzyme 2 (ACE2) receptor in conjunction with transmembrane protease serine 2, expressed by ATII cells. Inadequate responses of ATII cells to lung injury lead to aberrant tissue repair, characterized by fibroblast activation, collagen deposition, connective tissue accumulation, and angiogenesis [37, 38]. Both idiopathic pulmonary fibrosis and COVID-19-induced pulmonary fibrosis involve the renin-angiotensin system (RAS) in their disease progression. A pivotal player in this context, ACE2, interacts with other components of the RAS. ACE2-mediated SARS-CoV-2 entry into lung cells is believed to result in reduced ACE2 expression, disturbing the RAS system balance and subsequently triggering inflammation and fibrosis [39].

Dysregulation of microRNAs (miRNAs) has been implicated in the development of pulmonary fibrosis in COVID-19 patients, contributing to collagen deposition and myofibroblast transformation [40]. This miRNA imbalance has also been observed in idiopathic pulmonary fibrosis patients [41]. Lacedonia et al. analyzed the expression of exosomal miRNAs and confirmed the key involvement of a let-7d down-regulation and dysregulation of miR-16 in IPF [42]. Notably, Guiot et al. identified a total of 34 dysregulated miRNAs that overlapped between COVID-19 and idiopathic pulmonary fibrosis [40].

Despite the insightful findings, our study has certain limitations. The utilization of retrospective electronic records introduces inherent weaknesses. Lack of access to raw data prevents an accurate assessment of disease severity, identification of the causes of acute respiratory failure, determination of whether SARS-CoV-2 related pneumonia was presenting, specification of specific dosage and timing or the reasons for initiating antifibrotic treatment. Potential miscoding, inaccurate coding, or incomplete clinical information about comorbidities, socioeconomic status, and lifestyle habits may also introduce biases. Moreover, the TriNetX database lacks certain clinical information, such as ventilator-free days, ICU days, ventilator weaning rates, and hospitalization duration. Consequently, the efficacy of antifibrotic therapy cannot be adequately evaluated based on these parameters.