In our study, pulmonary fibrotic-like changes were frequently observed (75.2%) in patients with severe COVID-19 requiring MV. Low hemoglobin level (≤ 9 g/dL) was independently associated with pulmonary fibrosis development in these patients.
The reported incidence of pulmonary fibrosis in patients with COVID-19 varies from 25.5–84.1%,6, 7, 13–17 which could be attributed to the variations in disease severity among study participants, definitions of pulmonary fibrosis, and heterogeneity of the study periods. Although most patients in our study received antiviral and steroid treatment, the high prevalence of pulmonary fibrosis emphasized the need for post-recovery monitoring with follow-up CT in patients recovering from severe COVID-19. Further research is needed to explore MV strategies that may reduce the incidence of pulmonary fibrosis in patients with COVID-19 requiring MV.
Patient-related factors, such as older age, male sex, smoking, obesity, and underlying disease6, 7, 13–16 and laboratory findings including interleukin-6, interferon-gamma, and Krebs Von den Lungen-6 levels,18–20 have been suggested as risk factors for pulmonary fibrosis. Laboratory findings associated with the pathophysiology of COVID-19, including excessive proinflammatory cytokines and suppressed immune responses, including elevated CRP, D-dimer, LDH, and procalcitonin levels, as well as lymphopenia, leukocytosis have been linked to disease severity.21, 22 However, in our analysis, these variables did not exhibit a statistically significant association with pulmonary fibrosis. Instead, we observed that patients in the pulmonary fibrosis group exhibited lower SOFA scores, heart rates, and AST concentrations at the time of ICU admission than those in the no pulmonary fibrosis group. In our study, higher mortality in the no pulmonary fibrosis group, especially when applying strict criteria was applied for defining pulmonary fibrosis, and shorter interval between ICU admission and CT assessment in deceased patients compared to those of survivors suggested that patients with higher disease severity died prematurely before the development or progression of pulmonary fibrosis. The complex and multifactorial nature of pulmonary fibrosis development in COVID-19 may also explain these inconsistencies.23
A retrospective study conducted,24 involving 227 patients with COVID-19, Li et al. demonstrated a negative correlation between hemoglobin and pulmonary fibrosis (r = − 0.368, P < 0.001). In another study involving 159 patients, Zhang et al.25 reported that hemoglobin level can distinguish between patients with severe and non-severe COVID-19 infections, with an area under the curve of 0.79 in the receiver operating characteristic analysis, suggesting its utility in assessing disease severity. Furthermore, in a cross-sectional study involving 601 patients with COVID-19, Algassim et al.26 observed that lower hemoglobin levels are associated with a more severe course of disease and higher mortality in COVID-19. In the survival analysis, they observed a significant negative correlation between hemoglobin and length of hospital stay (r = − 0.25, P = 0.002) and higher mortality rate in patients with anemia (hemoglobin levels < 12.5 g/dL) than in those without anemia (HR: 1.882, 95% CI: 1.145–2.774: log-rank test, P = 0.0104). Consistent with these findings, our study also demonstrated an association between low hemoglobin levels and pulmonary fibrosis, supporting the importance of monitoring hemoglobin levels in patients with COVID-19. Anemia in ICU patients may have a multifactorial cause, including dysregulated iron homeostasis, inflammatory cytokines-medicated inhibition of erythroid cell differentiation, erythropoietin suppression, and a shortened erythrocyte half-life in the presence of systemic inflammation.27, 28 In our multivariable analysis, even after adjusting for laboratory findings reflecting systemic inflammation, low hemoglobin levels (≤ 9 g/dL) remained an independent risk factor for pulmonary fibrosis. This finding raised the question about the potential impact of correcting low hemoglobin abnormalities on reducing the incidence of pulmonary fibrosis. Further research is warranted to determine whether correcting hemoglobin abnormalities can reduce the incidence of pulmonary fibrosis and whether new transfusion strategies are required to reduce pulmonary fibrosis.
To the best of our knowledge, this is the first observational study investigating the characteristics and risk factors associated with pulmonary fibrosis in patients with severe COVID-19 requiring MV. Our study had some limitations. First, the retrospective nature of the study might have introduced potential bias, and the observational design prevented us from establishing causal relationships between the identified risk factors and pulmonary fibrosis development. Second, CT used to assess pulmonary fibrosis development was performed within a short period of time after ICU admission. Notably, long-term follow-up CT studies including patients with severe COVID-19 pneumonia have demonstrated that lung fibrosis can resolve over time.6, 13, 29 The lack of long-term follow up and assessment of pulmonary function in our study limited our understanding on progression or resolution of pulmonary fibrosis in patients with severe COVID-19. Despite these limitations, our study’s multicenter design and the inclusion of a large number of patients with severe COVID-19 increased the reliability of the results. The adjusted analyses for multiple variables revealed important risk factors associated with pulmonary fibrosis in patients with severe COVID-19, while taking into account the potential influence of confounding variables.