Discussion
Our study showed that COVID-19 patients’ CRP, ferritin, and fibrinogen levels decreased with treatment, consistent with previous studies, while FEV1 and FVC values increased. The symptoms of restrictive lung disease observed at the start of treatment were improved on day 7 of treatment. Correlation analysis between the 7-day changes in laboratory parameters and pulmonary function tests showed that FEV1 and FVC values increased in correlation with the change in CRP and fibrinogen levels.
On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 a pandemic and as of December 15, 2020, more than 72 million cases had been confirmed worldwide [1]. Large-scale studies on COVID-19 have documented extensive lung damage both during and after the disease. In a recent report it was determined that COVID-19 pneumonia patients still showed abnormalities in lung CT scans after discharge, with ground-glass opacities being the most common pulmonary sequelae7. Survivors of other coronavirus pneumonias (SARS and MERS) are known to have pulmonary function and exercise capacity impairments persisting for months or even years5,8-10. To date, however, there have been few studies examining loss of pulmonary function in discharged COVID-19 patients.
SARS-CoV-2 infects the human airway and the vascular and immune cells, potentially leading to severe damage to the respiratory tract, especially within the lungs. Disease severity depends on the effectiveness of the immune system. Current evidence suggests that in some cases, viral infection can cause an exaggerated immune reaction in the host that is severe enough to be classified as the hyperinflammatory condition referred to as macrophage activation syndrome11.
Numerous proinflammatory cytokines are released in COVID-19 patients, primarily tumor necrosis factor alpha, interleukins 1, 2, 6 and 18, and nitric oxide. These cytokines can increase vascular permeability, resulting in impaired tissue perfusion, endothelial damage, and microthrombus formation. Increased vascular permeability causes fluid accumulation in the lung tissue and interstitial spaces, which manifests clinically with acute respiratory failure 2,3. Suppression of these proinflammatory cytokines has proven to be therapeutically beneficial in many inflammatory conditions, including viral infections. Increased cytokine levels in the lung cause alveolar epithelial damage, alveolar septal fibrous proliferation, hyaline membrane formation, and the development of pulmonary consolidation12. This is the main cause of the restrictive pathology and reduced diffusion capacity seen in the lungs of COVID-19 patients. Studies have shown that this process continues in association with regression even after discharge 13. In a study including 110 COVID-19 patients, evaluation of pulmonary function tests at discharge showed a reduction in diffusion capacity that was correlated with disease severity. However, a striking aspect of the study was that the diffusing capacity of the lung for carbon monoxide (DLCO) decreased more than the diffusing capacity divided by alveolar volume (DLCO/VA), suggesting that impairment of the diffusion membrane was a more important issue than low lung volume 6.
It was also observed that levels of D-dimer and acute phase reactants such as CRP, ferritin, and fibrinogen were elevated in COVID-19 patients after intense inflammatory cytokine discharge and that these parameters may be associated with morbidity and mortality 14. Among these parameters, levels of CRP, fibrinogen, and ferritin levels were found to be high and inversely correlated with FEV1and FVC levels 15-17. These acute phase reactants are elevated in most inflammatory diseases, and studies evaluating the relationship with parenchymal fibrosis in interstitial lung diseases have demonstrated increases in correlation with the extent of parenchymal fibrosis, highlighting their potential usefulness in follow-up 18,19.
In the present study, we observed that the restrictive pattern initially presented by COVID-19 patients due to parenchymal infiltration in the lungs resolved during follow-up with regression of the lung consolidation. Pulmonary function values increased with the decline in CRP and fibrinogen levels, suggesting the improvement was secondary to reduced inflammation. However, consistent with our experience with COVID-19, fibrosis may be permanent and patients may show a restrictive pattern with reduced diffusion in long-term follow-up. Plasma fibrogen level has been associated with increased parenchymal fibrosis in previous studies. Therefore, the decline in plasma fibrinogen levels during follow-up in COVID-19 suggests that this parameter may be useful in evaluating progression to parenchymal fibrosis in this disease, which is characterized by pathologies also observed in interstitial lung diseases, such as hyaline membrane formation and alveolar septal fibrous proliferation.
The most important limitation of our study was the inability to evaluate diffusion capacities and total lung capacities when evaluating the etiology of the restrictive pathology observed in pulmonary function tests. However, this was a result of the fact that only portable pulmonary function testing equipment could be placed in the negative pressure room established to minimize the chance of transmission.
In conclusion, although the assessment of laboratory parameters and radiological findings has become a convenient method for evaluating COVID-19 patients, the inability to evaluate patients’ pulmonary function due to risk prevention measures has become the biggest problem in follow-up and discharge. In this study examined the guiding potential of some of these easily obtained parameters, we observed that decline in both CRP and fibrinogen levels may be associated with improved pulmonary functional capacity.