The most important findings of our study are that EGFR involvement and severity of pulmonary fibrosis are associated with CRP, d.dimer, and length of stay in the intensive care unit. The dose of methylprednisolone used did not make a significant difference in the severity of fibrosis.
The alveolar epithelial surface consists of alveolar type I (ATI) and type II (ATII) cells. Acute alveolar injury (ALI) occurs when SARS-CoV-2 enters these cells [2, 3]. The barrier function of the cells is lost, and the permeability of the alveolo-capillary membrane increases. Barrier function is essential for rapid and efficient restoration of the alveolar epithelium, and the barrier function is activated by the Human Epidermal Growth Factor Receptor (HER) family [11, 12]. Initial epithelial repair events in ALI include proliferation, proliferation, and migration of ATII cells. Then differentiation into ATI cells develops.
If damage persists, there is unregulated and excessive ATII cell proliferation. Fibroblasts and myofibroblasts proliferate. Extracellular matrix, including collagen and fibronectin, is stored excessively and irregularly, eliminating the original tissue. With the failure of normal ATII regeneration, pulmonary fibrosis develops. The barrier function of epithelial cells is crucial for ATI restoration and inhibition of fibrosis. The HER family that regulates barrier function is activated by tyrosine kinase and is of four types in humans: HER 1 or EGFR, HER 2, HER 3 and HER 4 . In our study, EGFR involvement was not detected in 11 (22%) patients, while there was mild in 20 (40%) patients, moderate in 13 (26%) patients, and severe involvement in 6 (12%) patients. We could not find any previous study examining EGFR uptake in pulmonary tissue in Covid 19 pneumonia with post mortem biopsy. Our study is the first study on this subject as far as we can research. In a study examining pulmonary fibrosis by Masson trichrome staining of biopsy material in patients with ARDS, the presence of fibrosis was associated with the death of the disease . Although not related to Covid-19, it can be considered to support our study as it also examines ARDS that develops in patients with Covid-19 pneumonia.
In the study of Huang et al., it was said that radiologically, more than one-third of patients who recovered from Covid pneumonia developed fibrotic abnormalities upon discharge from the hospital . However, this study included severe covid 19 pneumonia survivors, and the EGFR was not studied. In our research, post-mortem 78% of the patients had pulmonary fibrosis radiologically and pathologically. The extent of involvement considered radiologically, and EGFR involvement was correlated.
CRP is a non-specific acute phase protein induced by Interleukin 6, with a potent proinflammatory effect. A sensitive biomarker indicates inflammation, infection, and tissue damage . In this study, CRP averages were significantly different between groups separated according to the severity of EGFR involvement. Our data also supported the study of Yu et al., with 32 patients with confirmed Covid-19 pneumonia, examining signs of fibrosis on thorax CT . In the study of Huang et al. based on radiological data, CRP was statistically significantly higher in the group with fibrosis than in the group without fibrosis . However, pathological data were not included in these two studies. Although our sample group was small, the cutoff value was 161 mg/L. In Liu et al.’s study of 141 cases with Covid 19 pneumonia, the probability of developing severe disease was higher in patients with CRP > 41.8 mg/L . We could not find any previous study on the risk of death in this regard.
Coagulation steps are activated as a result of tissue damage in ALI due to Covid-19. Thrombus develops in small vessels. D.dimer rises as a marker of fibrin disruption and abnormal coagulation balance . In our study, the severity of EGFR involvement and the prevalence of radiological involvement were associated with d.dimer elevation. We have confirmed the studies discussing the relationship between d.dimer and pulmonary fibrosis with thorax CT by performing a pathological examination [15, 19].
ARDS, which can develop in SARS and MERS infections, is partially caused by host immune responses. Corticosteroids suppress inflammation in the lung. However, it also inhibits pathogen virus's immune response and clearance . Wu et al., in their study with 201 patients with covid 19 pneumonia, stated that the use of methylprednisolone in patients with ARDS reduced the risk of death . Methylprednisolone was used in the treatment of 92% of our patients since the World Health Organization also recommended the use of corticosteroids in patients with severe covid 19 pneumonia . In our study, there was no significant difference in the occurrence of pulmonary fibrosis between patients who did not receive methylprednisolone, who received 80 mg/day, and those who received 250 mg/day. Chen et al. reported no difference in in-hospital mortality rates among covid 19 patients receiving low, medium, and high-dose methylprednisolone . However, we could not find a study examining methylprednisolone doses and pulmonary fibrosis rates in patients with Covid 19 pneumonia.
There are studies indicating that age, male gender, smoking, comorbidities, leukocytosis, lymphopenia, and high lactate dehydrogenase (LDH) are risk factors for the development of pulmonary fibrosis [15, 17, 24]. These studies were evaluated according to thorax CT findings and in surviving patients. In our research, pathologically, age, gender, smoking, comorbidity, leukocytosis, lymphopenia, and high LDH did not affect the severity of pulmonary fibrosis in severe covid 19 pneumonia.
The limitations of our study can be listed as follows; First of all, our case number is relatively small. Studies with a larger sample group and perhaps autopsy material may provide more information. We did not have the authority to treat our patients before death in the ICU. Our colleagues who administered the treatment were blind to our study. We think that studies to be conducted by comparing treatment options, including antifibrotic therapy, will shed light on the treatment of pulmonary fibrosis that may develop after Covid-19.
CRP and d.dimer values can guide the severity of pulmonary fibrosis that may develop in patients followed up in the ICU due to Covid 19 pneumonia. The data of our study is that the dose of methylprednisolone used does not make a significant difference in the severity of fibrosis. This study, in which EGFR uptake is monitored in Covid 19 pneumonia, maybe a preliminary idea for studies that will examine the indications of antifibrotic drugs in pulmonary fibrosis due to Covid 19.