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.