The study findings were published in the peer reviewed journal: Respiratory Research (Springer).
https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-022-02166-8
In this multicenter prospective study of hospitalized patients with bilateral COVID-19 pneumonia of variable severity, we analyzed functional and radiological sequelae 12 months after hospital discharge, and we have found that reduced lung diffusion persisted in almost 40% of patients (DLCO < 80%) 1 year after acute COVID 19 infection. Furthermore, we identified radiological fibrotic-like changes on chest CT in almost 23% of our study cohort [n = 448]. However, these sequelae were not associated with other markers of severity previously described in ARDS cases [32], such as need for mechanical ventilation.
Along with an increasing number of people affected over time, survival has improved since the start of the pandemic [33], but with the consequence that millions of survivors could be affected by pulmonary sequelae of COVID-19, which could lead to a clear deterioration in quality of life.
Although functional recovery from severe COVID-19 pneumonia occurs within 1 year after discharge, approximately one third of patients (39.8%) still have decreased DLCO. These findings are in line with the results from a Chinese cohort [15], albeit excluding patients requiring invasive mechanical ventilation, and are consistent with a recently published meta-analysis [34].
Among our key findings is that although more severe patients showed higher diffusion impairment 2 months after discharge, this difference lost significance at 6 and 12 months. Furthermore, analyzing factors related to the persistence of DLCO deterioration, 1 year after discharge, we found association with age, female sex, body mass index and ferritin, but need of invasive mechanical ventilation (IMV) (most severe disease) was surprisingly not. The association between female sex and DLCO disturbances is consistent with previously published results at 6 [35, 36] and 12 months in COVID-19 pneumonia survivors [15], with no clear explanation forthcoming.
A recent systematic review showed that histopathological findings of diffuse alveolar damage caused by COVID-19 are indistinguishable from those provoked by other causes. At final, chronic/fibrotic phase was identified, showing a honeycomb lung with collagen fibrosis of the alveolar spaces and an interstitium with thickening of the alveolar wall together with squamous metaplasia of the alveoli [37]. These changes have been reported in 43% of 30 COVID-19 autopsies, and were associated with longer duration of illness and hospitalization and need for mechanical ventilation [38].
In our study cohort, any radiological abnormality at 12 months persisted in 27% [123/448] of patients. This percentage is similar to that obtained by Pan et al. (53/209) [14] and somewhat higher than that recently published by Wu et al. (24%), although patients with invasive mechanical ventilation were excluded in their cohort [15].
We define fibrotic-like changes as the presence of traction bronchiectasis, parenchymal bands and/or reticular pattern [25, 26, 39]. The analysis of fibrotic-like changes in our study population yielded results (23% [102/448]) similar to those found by a recent systematic review reporting radiological fibrotic-like sequelae in 21% of patients 1 year after discharge [40], although other meta-analyses have detected a higher percentage (29%) [34].
In our study, fibrotic-like changes were only associated with radiological involvement at admission and peak LDH levels. Although more severe patients (requiring IMV) had a significantly higher percentage of fibrotic sequelae than the mild group (84.2% [48/57] vs. 48.1% [39/81]), no significance was found between severity and fibrotic-like changes in the multivariable model [p = 0.15].
Mechanical ventilation is a recognized factor in fibrosis development [32], caused by mechanical stress and an induced “biotraumatic” inflammatory response involving cytokine, chemokine and growth factor release. This also supports our finding that radiological abnormalities were most common in the severe group.
Biomedical research proposes models in which the injury underlying viral infection in the lung induces fibrosis by various mechanisms. As mentioned, the elevated fibrogenesis-related biomarkers seen in these patients indicate that bilateral COVID-19 pneumonia may trigger certain biological pathways [36]. The SARS-CoV-2 infection damages the alveolar epithelium and induces cytokine production; this attracts macrophages that contribute to basement membrane damage and fibroblast activation. Furthermore, hemorrhage due to endothelial injury activates a coagulation cascade that culminates in fibrin deposition. All this contributes to fibrosis of the alveolar space [42].
Whether these changes involve scarring from the acute process or whether they might progress over time is still unclear [43]. Although the virus is eradicated in COVID-19 recovered patients, removing the cause of lung damage does not in itself preclude development of irreversible progressive and fibrotic interstitial lung disease [44].
This study has several limitations. Firstly, data on functional tests or CT scans prior to admission were not available for assessment of longitudinal changes. Secondly, following the study protocol, chest CT was performed initially only in patients with radiological or functional changes at 2 months, and at 12 months when initial CT was altered. This approach aimed to minimize radiological exposure and overload in radiology services during the pandemic, and follows guidelines recommended by several societies [28, 45].
In a small percentage of patients without previous resolution, chest CT at 1 year was not available, so the percentage of fibrotic sequelae could potentially be underestimated. Nonetheless, excluding patients with previous pulmonary interstitial disease or chronic obstructive pulmonary disease, and the fact that these are asymptomatic patients with no functional or chest X-ray alterations after discharge, seem unlikely to result in significant radiological alterations.
Likewise, altered DLCO has been described in 98% of patients with fibrosis at the time of initial evaluation, so the percentage of losses in cases of normal DLCO would potentially be low [46]. Another important limitation has been the loss of patients due to pandemic-related restrictions and security measures in pulmonary function laboratories. However, no differences were found between patients who underwent all tests compared to those who did not (Additional file 2: Table S2).
