DISCUSSION
Evidence indicates some therapeutic effects for NAC on COVID-19 and its consequences. For instance, the oxidative-, immune-, and apoptotic-regulatory effects of NAC, as well as its special properties such as facilitation of oxygenation and circulation, can positively impact respiratory outcomes and prevent end-organ failure. Further, high-quality studies have reported the antioxidant and immunomodulatory roles of NAC in the treatment of viruses targeting the respiratory system (e.g., influenza [strains A and B] and respiratory syncytial virus) and the related acute injuries such as ARDS. Not only could NAC have a supportive role in patients hospitalized in the ICU, patients with sepsis, and patients with non-pulmonary end-organ damage or failure but also it could play a positive role in comorbidities. Moreover, NAC could be administered as a potential adjuvant therapy for COVID-19, considering patient status, indications, and contraindications (5, 32-34). Oral NAC may also be recommended as a preventive or therapeutic agent for disease-related outcomes in stable non-septic and non-intubated patients. The efficacy of IV NAC has been indicated in some moderate-to-severe or ICU-admitted cases of COVID-19 who have experienced complications like end-organ failure. There are many reports of the efficacy of NAC administration in cytokine storms, dyspnea, and ARDS related to COVID-19 (5). If indicated, the use of NAC via different administration routes varies case by case. Currently, based on studies with the highest level of evidence, it can be concluded that NAC may be most effective in stable patients when administered in the standard dose, and its preventive role (ie, to help non-infected patients or to help infected patients experience a better disease course) may be the most important aspect of this multipotential drug (35). To our knowledge, the present study is one of the best-designed RCTs to date for the evaluation of the efficacy and safety of NAC in hospitalized patients with COVID-19 infection. In summary, the findings of this RCT showed that the mean hospitalization duration (not merely in the ICU) was the shortest in the atazanavir/ritonavir + HCQ group (6.73 d) and longest in the Kaletra + HCQ + NAC group (11.87 d), with the difference between the 4 treatment groups in this regard failing to constitute statistical significance (P = 0.082). The mean length of ICU stay was the shortest in the atazanavir/ritonavir + HCQ + NAC group (1.8 d) and longest in the Kaletra + HCQ group (3.4 d), although these differences were not statistically meaningful (P =0.172). These results, albeit statistically nonsignificant, showed that the patients who received NAC had more total hospitalization days and fewer ICU hospitalization days, which means that these patients were more likely to have a stable general condition.
At hospitalization and before the commencement of the main treatment, CT scans and severity scores showed that ground glass opacification consolidation had the highest frequency (n =11) in the atazanavir/ritonavir + HCQ group and the lowest frequency (n =6) in the Kaletra + HCQ + NAC and Kaletra + HCQ groups. Bilateral opacification consolidation had the highest frequency in the atazanavir/ritonavir + group HCQ (n =8) and the lowest frequency in the Kaletra + HCQ + NAC group (n =5). Multifocal opacification consolidation exhibited the highest frequency in the atazanavir/ritonavir + HCQ group (n =7) and the lowest frequency in the Kaletra + HCQ group (n =4). None of the above was significantly different between the groups, denoting a normal distribution regarding lung involvement severity between the groups in this RCT.
At hospitalization and before the commencement of the main treatment, the 4 study groups were statistically significantly different in terms of seg_lymph_ratio, CRP, partial thromboplastin time (PTT), and LDH; nonetheless, at the end of the study, only CRP remained statistically meaningfully different between the groups. A further decrease in CRP was observed in the NAC group at the end of the study. Concerning CRP at discharge, the atazanavir/ritonavir + HCQ + NAC group had the lowest value (5.99), whereas the Kaletra + HCQ group had the highest value (40.00); therefore, the difference between the groups in CRP was statistically significant (P =0.008). In regard to ESR at discharge, the atazanavir/ritonavir + HCQ + NAC group exhibited the lowest value (9.00), while the Kaletra + HCQ + NAC group showed the highest value (65.50); there was, however, no statistically meaningful difference between the groups vis-à-vis ESR, indicating CRP changes are a more sensitive criterion for measuring response to treatment and reducing inflammation than ESR.
Other than CRP, in terms of the comparison of laboratory findings before the treatment of the hospitalized patients and at the time of discharge, the statistically significant findings are as follows:
With respect to diff_segment at discharge, whereas the Kaletra + HCQ + NAC group had the lowest value (62.97%), the atazanavir/ritonavir + HCQ + NAC group exhibited the highest value (79.96%). Conversely, apropos of ALP at discharge, the highest and lowest values were observed in the Kaletra + HCQ + NAC group and the atazanavir/ritonavir + HCQ + NAC group, respectively, and this difference was of statistical significance (P =0.001). It could be interpreted that the antiviral regimen exerted a more significant impact on diff_segment and ALP, so the improvement trend was more pronounced in the atazanavir/ritonavir regimen than in the Kaletra (lopinavir/ritonavir) regimen. As we know, in COVID-19 course we usually have leukopenia, lymphopenia and partial increase of segmented cell percentage but a lower total segmented cell count than the normal situation.
No death occurred in the atazanavir/ritonavir + HCQ + NAC group, indicating that the combination of these drugs might reduce mortality.
In regard to O2 saturation, the highest level was observed in the atazanavir/ritonavir + HCQ group and the atazanavir/ritonavir + HCQ + NAC group at the end of the study. Additionally, a significant increase occurred after intervention in the O2 saturation level of the groups that received NAC (P <0.05), which can be considered the most important finding of the current study.
A redox imbalance in alveolar epithelium cells causing apoptosis, increased inflammation and, consequently, impaired gas exchange has been documented in most COVID-19 cases. Many articles have reviewed the potential positive effects of NAC as a multipotential drug in the management of COVID-19 and its associated complications (5). In addition, some original studies including case reports, case series, and trials have focused on NAC for the treatment and management of patients with COVID-19 and its associated complications such as end-organ failure (especially, acute liver failure in the cases of remdesivir-induced liver failure, elevated liver enzymes, and intrahepatic hemorrhage), ARDS, and seizure (36, 37). In these complicated cases, NAC has usually been used as an IV infusion.
In an RCT conducted in Brazil to evaluate the efficacy and safety of IV NAC in admitted severe cases of COVID-19 (oxyhemoglobin saturation <94% or respiratory rate >24 breaths/minute), IV NAC failed to significantly reduce the need for mechanical ventilation by comparison with the control group in that 20.6% of the NAC group as opposed to 23.9% of the dexterous group required mechanical ventilation. Also in that study, the duration of mechanical ventilation, the rate of ICU admission, the length of ICU stays, and the rate of mortality were not statistically significantly different between the intervention and case groups, indicating that the administration of NAC in high doses did not affect the evolution of severe COVID-19 (35). The present study enrolled solely stable, moderate-to-severe, non-ICU admitted COVID-19 patients (N =60), among whom only 11 patients ultimately needed ICU admission during their disease course regardless of their therapeutic regimen. Accordingly, the severity score of patients and the administration route of NAC (IV vs oral) were different between the current RCT and the one in Brazil. Still, the interpretation of the results of these 2 trials indicates that NAC could be more effective as prophylactic or adjuvant therapy in stable non-severe cases of COVID-19 with a particularly positive role in the augmentation of O2 saturation and faster reduction of the CRP level and inflammation.
Aside from the therapeutic roles of NAC, not least as adjuvant therapy, the prophylactic roles of this multipotential drug in COVID-19 infection (38-40) and its related complications (41) have been discussed in many reviews (40, 42-47) and original studies (48, 49) all of which have focused mainly on the drug as an anti-inflammatory and anti-apoptotic agent.
In a very well-designed study on the treatment of COVID-19 patients with NAC, the drug in high doses failed to improve the outcomes of severe and ICU-admitted cases (35, 50). Another trial demonstrated that a combination of methylene blue, vitamin C, and N-acetyl cysteine increased the survival rate of COVID-19 patients (16). The results of a case series indicated that the oral and IV administration of glutathione, glutathione precursors (N-acetyl-cysteine), and α-lipoic acid might represent a novel treatment approach to blocking NF-κB and addressing cytokine storms and ARDS in patients with COVID-19 pneumonia (51). In a comprehensive study, a combination of copper, NAC, colchicine, and nitric oxide with candidate antiviral agents (viz. remdesivir or EIDD-2801) was used as a treatment for patients positive for SARS-CoV-2 (17). In the pandemic era of COVID-19, the authors of the present study have sought to assess the diagnostic, prognostic, and therapeutic concerns of this infection, focusing especially on dermatologic issues (52-63). They have also conducted comprehensive and systematic reviews and original articles. In their first review study, they discussed the potential drugs that could positively affect the COVID-19 course and outcome such as NAC (5). Since then, they have endeavored to conduct RCTs aimed at evaluating the efficacy and safety of multipotential drugs such as NAC. In light of the findings of the current RCT, we posit that the use of oral or IV NAC, if indicated, may boost O2 saturation, ameliorate inflammation by lowering CRP, and lessen mortality.