With the duration of While the COVID-19 pandemic is getting prolonged, it is necessary to perform studies aim- ing to achieve a more comprehensive understanding of the COVID-19 pathogenesis because such information can be helpful in developing more effective medications and re- ducing mortality. In some patients, severe inflammation, cytokine storm, and severely disrupted immune responses may lead to ARDS, ALI, or death ( 17 ). Considering the need for saving time and costs in the current situation caused by the COVID-19 pandemic, drug repurposing is very valuable compared to the development or discovery of new drugs ( 18 ). Thus, several clinical trials have been conducted on various drugs and therapies that modulate the immune system ( 19 , 20 ). Among all these drugs, NLRP3 Inflammasome in- hibitors have been investigated in many studies, yielding promising results ( 21 ). For example, a clinical trial found that colchicine, as an adjuvant medication along with the standard treatment, could shorten the length of treatment and improve the clinical condition of the patients with COVID-19 (TrialTroveID-379443). Another inhibitor of the NLRP3 inflammasome, low-dose melatonin was inves- tigated by some clinical trials as a potential treatment for COVID-19 (NCT04409522), leading to improvements in the clinical condition and plain radiographs of the patients ( 22 ). Recently, in another study, we showed that quercetin (NLRP3 inhibitor) is effective in lowering the serum lev- els of q-CRP, and LDH as critical markers involved in COVID-19 severity ( 23 ). Other NLRP3 inflammasome in- hibitors and immunomodulators investigated in the clini- cal trials as potential COVID-19 treatments include statins, sirolimus, azithromycin, cyclosporine, oridonin, quercetin, and curcumin ( 24 , 25 ), as well as Tranilast, which was eval- uated in the present study. According to our results, a daily dose of 300 mg Trani- last during the first seven days of hospitalization could improve the clinical symptoms of weakness and fatigue in the patients with severe COVID-19 who are under treat- ment with antivirals and supportive care. It is worth noting that several studies have reported long-term fatigue in pa- tients with COVID-19. Thus, alleviating these symptoms is of great importance ( 26 ). The presence of long-term and severe fatigue, which greatly impacts the patients’ quality of life, can be due to the extension of inflamma- tion to the CNS, leading to the cerebral accumulation of pro-inflammatory cytokines ( 27–29 ). The effect of Trani- last on this important symptom can be explained by its role in causing a significant reduction in the inflammatory factors and pro-inflammatory cytokines, such as IL-1 and TNF. Moreover, increased activation of neutrophils and NE- Tosis is a potentially destructive mechanism in the in- flammation and thrombosis, which especially occurs in the lungs of the patients with severe COVID-19 and those be- ing infected with some other viral infections leading to pul- monary inflammation, such as influenza ( 30 , 31 ). Interest- ingly, IL-1, as a product of NLRP3 inflammasome, exacer- bates this extensive NETosis ( 32 , 33 ). Several studies have noted the increased levels of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF, in patients with COVID-19 ( 34–37 ). NLR, CRP, LDH, and d-dimer also have a diag- nostic and predictive role in some inflammatory diseases, including the COVID-19 ( 38–44 ). According to our re-
sults, Tranilast could reduce the NLR, CRP, and d-dimer in the intervention group compared to the control group, highlighting its effect on preventing severe and destructive inflammation, especially in the inflammatory phase of the disease. Considering the destruction and necrosis observed due to neutrophils in vascular inflammation, thrombosis, and COVID-19 exacerbation, these findings are potentially beneficial in preventing the disease exacerbation and de- velopment of respiratory distress. There are some hepatic and renal adverse effects re- ported for the Tranilast in some studies ( 12 ). Therefore, we evaluated the levels of Cr, BUN, SGOT, and SGPT in both study groups during the intervention and follow- up and There was no significant difference between the two groups. Moreover, Tranilast could lead to significant reductions in the levels of inflammatory markers in the in- tervention group compared to the control group. Therefore, in addition to its effect on the disease severity, it could in- crease the effect of antiviral drugs, leading to clinical im- provements with fewer complications and dose-dependent toxicity. Although this trial included statistically insignificant findings in primary binary outcomes (in two of three pri- mary outcomes), the efficacy of intervention cannot be re- jected since the effect size indicator of RR was not in the trivial range in two outcomes based on reduction in deaths or hospitalization in ICU or the number of long hospital- ization cases. However, the power of statistical analyses based on binary outcomes is obviously lower than statis- tical analyses based on continuous quantitative outcomes, and this fact should be considered in the design and imple- mentation of trials that include both continuous quantitative and binary outcomes. In addition, the findings for the quantitative outcome of O2 saturation indicated that intervention could create significant effectiveness, and even a moderate efficacy was obtained by the effect size indicator of SMD. The present study had some limitations due to the critical situation in the hospitals and for the healthcare personnel. These limi- tations include the small sample size and the short duration of follow-up, increasing the possibility of bias. According to the above points, it seems that repeating this trial using the confirmatory approach and preferably designing multi- center trials with higher sample sizes and higher general- izability is an effective solution and to confirm the present study results in the future.
