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\begin{document}

\title{Evaluation of the Efficacy and Safety of Oral N-acetylcysteine in
Patients With COVID-19 Receiving the Routine Antiviral and
Hydroxychloroquine Protocol: A Randomized Controlled Clinical Trial}



\author[1]{Najmolsadat Atefi}%
\author[1]{Azadeh Goodarzi}%
\author[1]{taghi riahi}%
\author[1]{niloofar khodabandehloo}%
\author[1]{mahshid talebitaher}%
\author[1]{niloofar najar nobari}%
\author[1]{farnoosh seirafianpour}%
\author[1]{zeinab mahdi}%
\author[1]{amir baghestani}%
\author[1]{rohollah valizadeh}%
\affil[1]{Iran University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
ABSTRACT The current absence of gold-standard or all-aspect favorable
therapies for COVID-19 renders a focus on multipotential drugs proposed
to prevent or treat this infection or ameliorate its signs and symptoms
vitally important. The present well-designed randomized controlled trial
sought to evaluate the efficacy and safety of N-acetylcysteine as
adjuvant therapy in hospitalized Iranian patients with COVID-19. Four
different diets in 60 patients include; Kaletra (lopinavir/ritonavir) +
hydroxychloroquine with/without N-acetylcysteine (600 mg TDS) and
atazanavir/ritonavir + hydroxychloroquine with/without N-acetylcysteine
(600 mg TDS), were administered in the study. At the end of the study, a
further decrease in C-reactive protein was observed in groups with
N-acetylcysteine (P =0.008), and no death occurred in the
atazanavir/ritonavir + hydroxychloroquine + N-acetylcysteine group,
showing that the combination of these drugs may reduce mortality. A
significant rise in O2 saturation was observed in
atazanavir/ritonavir+hydroxychloroquine+N-acetylcysteine group (P
\textless{}0.05). Accordingly, oral or intravenous N-acetylcysteine, may
enhance O2 saturation, blunt the inflammation trend (by reducing
C-reactive protein), and reduce mortality in hospitalized patients with
COVID-19. The N-acetylcysteine could be more effective as prophylactic
or adjuvant therapy in stable and 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.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

\textbf{Background:} The first case of severe acute respiratory
coronavirus syndrome (SARS-CoV-2) was reported in late November 2019 in
Wuhan, China. By then, many patients had been admitted to the hospital
for acute pneumonia of unknown origin. On March 11, the World Health
Organization (WHO) announced the outbreak of COVID-19 and declared it to
be an epidemic (1, 2). The virus is transmitted through respiratory
droplets or aerosols (3). One of the theories concerning the coronavirus
pathogenesis is that the virus binds to host cells through
angiotensin-converting enzyme 2 (ACE2). ACE2 is expressed by the
epithelial cells of the lung, intestine, kidney, and blood vessels (4).
Diabetes, ACE inhibitors, and angiotensin II receptor blockers (ARBs),
which are used for hypertension control, increase ACE2 expression and
COVID-19 risk (4). The symptoms of COVID-19 include dry coughs; malaise;
fever; dyspnea; multiorgan failure; acute respiratory distress syndrome
(ARDS) requiring mechanical ventilation and oxygen therapy in the
intensive care unit (ICU); coagulopathy with thrombosis; systemic
manifestations such as sepsis, septic shocks, and multiorgan dysfunction
syndrome; and mucocutaneous involvement (5, 6). Therefore, COVID-19 is
considered a disease with a thousand faces (7, 8).

Diversity in the clinical manifestations of COVID-19 is related to the
interaction between the coronavirus and the immune system (6, 9).
Inflammatory responses, cytokine storms, and chemokines are critical
issues allied to the complications of COVID-19 (10, 11). About 33\% of
the patients with COVID-19 require ICU admission, with a mortality rate
of 20\% reported in some investigations (12, 13). Additionally, a
mortality rate of 49.0\% has been reported among critical patients with
comorbid cardiovascular diseases, hypertension, diabetes, chronic
respiratory diseases, or cancer (12). Polymerase chain reaction (PCR)
tests of the upper respiratory tract samples, lung computed tomography
(CT) scans, and blood tests are accepted by the WHO for the diagnosis of
COVID-19 (3, 14). N-acetylcysteine (NAC) is a multipotential drug
suggested by the literature for the prevention and treatment of COVID-19
(1, 15-24). NAC is antioxidant glutathione with a wide variety of use in
different medical conditions, including loosening thick mucus and
treating a wide range of diseases such as acetaminophen overdose,
pulmonary disorders, cystic fibrosis, idiopathic pulmonary fibrosis,
ARDS, bronchitis, chronic obstructive pulmonary disease, and pneumonia
(6, 24). Evidence indicates the important roles of NAC in the prevention
and treatment of COVID-19 by regulating oxidative and apoptotic
responses, boosting the immune system, reducing cytokines and
interleukins in the wake of COVID-19 infection, suppressing viral
replication (especially via the mucolytic properties of NAC, diluting
the viral load in the respiratory system), preventing and alleviating
pulmonary disorders, augmenting oxygenation, supporting the therapeutic
course of patients with sepsis hospitalized in the ICU, diminishing
comorbidities, decreasing the likelihood of non-pulmonary end-organ
damage or failure and liver failure, and facilitating oxygenation and
circulation (24-26). COVID-19 can manifest itself through neurological
disorders such as Guillain--Barre syndrome, seizure, headache, and
stroke (27). NAC is capable of exerting protective effects on the
nervous system and helps prevent or treat these manifestations (5).
Liver failure can develop in patients with COVID-19 for several reasons,
including metabolic acidosis and complications induced by certain drugs
such as remdesivir, which is one of the most commonly used drugs in
these patients. In this regard, one of the most well-known effects of
NAC is the prevention and treatment of hepatotoxicity (28-30).

\textbf{A Gap of Knowledge:}

Despite numerous studies on COVID-19, no gold-standard treatment for
this disease has been found yet, hence the current use of supportive
therapies. The best way to manage the disease is through prevention,
with vaccination already underway around the world; nonetheless, many
cases of COVID-19--related infection and death are still reported.

Most COVID-19 supportive drugs modulate the immune system to regulate
inflammatory storms (5). Many of the immune modulators have
immunosuppressive properties that may not work properly in viral
disorders (5). NAC is one of the few immune modulators without
immunosuppressive properties (31). However, all the articles suggesting
the use of NAC in the treatment of COVID-19 recommend further
well-designed randomized controlled clinical trials (RCTs).

\textbf{Aim:}

This double-blind (secondary assessor- and analyst-blinded) RCT was
designed to evaluate the effects of oral NAC on the treatment of
hospitalized patients with COVID-19.

Although it seems that NAC confers significant benefits in patients with
mild COVID-19 before hospitalization, the present study focused solely
on inpatients. The current study is one of the well-designed RCTs to
evaluate the efficacy and safety of NAC as adjuvant therapy in
hospitalized patients with COVID-19.

\textbf{METHODS}

\textbf{Design and Settings}

The present double-blind RCT was performed in Rasool Akram Medical
Complex, Tehran, Iran, on 60 patients with COVID-19. The diagnosis of
COVID-19 was established according to the opinion of the treating
physician, based on clinical signs and PCR or paraclinical or laboratory
findings.

\textbf{Sampling and Allocation}

The sampling convenience method was employed. Eligible participants were
classified by stratified blocked randomization and based on diet therapy
(4 regimens). Thereafter, they were randomly assigned to either the
intervention group or the routine treatment regimen group. Randomization
was done separately within each group. The size of the blocks was 4; in
other words, 2 allocations to the intervention group and 2 allocations
to the routine treatment group were considered.

\textbf{Eligibility Criteria}

The indication for hospitalization according to the national protocol
was as follows: fever above 39\selectlanguage{ngerman}° or being toxic in the examination,
respiratory distress, the use of respiratory muscle relaxants, the use
of suprasternal or intercostal retraction, a respiratory rate greater
than 30 per minute, a heart rate higher than 120 beats per minute, a
peripheral blood O\textsubscript{2} saturation level less than 93\%,
having an underlying disease (eg, diabetes, hypertension, heart failure,
immune system disorders, renal or hepatic impairment, a history of
asthma or chronic obstructive pulmonary disease, and smoking), age over
50 years in the case of being symptomatic, and the involvement of
one-third of 3 to 5 pulmonary lobes. The exclusion criteria were
composed of being a child, having unstable vital signs, being either
intubated or needing intubation, being admitted to the ICU, having
decreased levels of consciousness, having a respiratory rate greater
than 24, having a blood pressure level below 90/60 mm Hg, exhibiting
multi-lobular infiltration on CT scans or chest X-rays, having permanent
hypoxia, being pregnant or lactating, and having previous allergies to
NAC or glutathione-based drugs. The withdrawal criteria were comprised
of drug intolerance, severe complications probably related to NAC during
treatment, and unwillingness to continue collaboration with the study at
any point and for any reason.

\textbf{Interventions and Follow-up}

Two 30-person diets, comprising 15 single diets of Kaletra
(lopinavir/ritonavir) + hydroxychloroquine (HCQ) with/without NAC (600
mg TDS) and atazanavir/ritonavir + HCQ with/without NAC (600 mg TDS),
were administered in the study. Sixty patients completed the study. (15
patient: Kaletra + HCQ / 15 patient: Kaletra + HCQ + NAC / 15 patient:
atazanavir/ritonavir + HCQ / 15 patient: atazanavir/ritonavir + HCQ +
NAC) The control and intervention groups received the national protocol
treatment, and NAC was added to the treatment of the intervention group.
Since the eligible patients had no contraindications for NAC, the
protocol was 600 mg orally every 8 hours for 14 days.

\textbf{Blinding}

The secondary assessor and the data analyst were blinded to the
treatment regimens.

\textbf{Paraclinical Data}

Laboratory parameters were evaluated by using the peripheral blood
samples of the patients. Additionally, lactate dehydrogenase (LDH),
tumor necrosis factor-\selectlanguage{greek}α, \selectlanguage{english}interleukin-6, complete blood count (CBC),
erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) tests
were performed daily for the patients, and the course of laboratory
changes was monitored. Radiological examinations of lungs were performed
by CT scanning twice: at admission and discharge, and differences in
radiological findings were recorded and compared. In the patients with
minor underlying problems or gastrointestinal intolerance, 600 mg of
oral tablets every 12 or 24 hours were given.

\textbf{Response to Treatment Criteria}

\begin{itemize}
\tightlist
\item
  Time of improvement in symptoms such as coughs, shortness of breath,
  and lethargy
\item
  Improvements in O\textsubscript{2} saturation without changes in the
  treatment protocol and reductions in the need for O\textsubscript{2}
\item
  Duration of hospitalization according to the course of symptom
  improvement
\item
  Re-admission after discharge
\item
  Serial evaluations of laboratory parameters, consisting of LDH, tumor
  necrosis factor-\selectlanguage{greek}α, \selectlanguage{english}interleukin-6, CBC, ESR, and CRP, and comparison of
  parameters at hospitalization, during hospitalization, and at
  discharge
\item
  Investigation of changes in anti-inflammatory parameters
\item
  Examination of radiological changes at the beginning of
  hospitalization and during hospitalization
\item
  Need for ICU admission during hospitalization
\end{itemize}

\textbf{Primary and Secondary Outcomes}

The primary outcomes of the study were the efficacy and side effects of
NAC, and the secondary outcomes were drug tolerance and treatment
satisfaction. The effectiveness of treatment was evaluated according to
the duration of hospitalization; improvement in
O\textsubscript{2}saturation, laboratory and paraclinical findings, and
clinical symptoms; and the assessment of complications based on a
questionnaire.

\textbf{Ethical Considerations}

The research adhered to the tenets of the Declaration of Helsinki. The
study protocol was approved by the Ethics Committee of Iran University
of Medical Sciences (ethical code \# IR.IUMS.REC.1399.206 registered on
August 16, 2020), and the study protocol was registered in the Iranian
Registry of Clinical Trials (\#IRCT20200623047897N1;
https://en.irct.ir/trial/49277). Written informed consent was obtained
from all the patients.

\textbf{RESULTS}

In this study, the mean age of the patients was 57.82 \selectlanguage{ngerman}± 18.23 years, and
the mean hospitalization duration was 10.13 ± 6.07 days. In respect of
sex, 31 patients (51.7\%) were female, without any significant
differences between the groups. Table 1 and Table 2 present the clinical
and paraclinical characteristics of the study population at admission
and discharge showing that CRP (F =9.102, \emph{P} =0.008), alkaline
phosphatase (ALP) (F =7.650, \emph{P} =0.001), and diff\_segment (F
=5.156, \emph{P} =0.007) at discharge were different between the 4
groups in such a way that the atazanavir/ritonavir + HCQ + NAC group had
the lowest value concerning CRP. Regarding ALP at discharge, the Kaletra
+ HCQ + NAC group had the highest value. Furthermore, diff\_segment had
the highest value in the atazanavir/ritonavir + HCQ + NAC group.

According to the \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test, 6 patients in the Kaletra +
HCQ group received intravenous immune globulin (IVIG), while the
atazanavir/ritonavir + HCQ + NAC group did not receive any IVIG, with
the difference constituting statistical significance (\emph{P} =0.015).
Given that the patients were randomly divided into 4 groups, the groups
were different with respect to fatigue and anorexia, cardiovascular
diseases, and hypertension (Table 3). Regarding binary variables, most
cases of fever were reported in the atazanavir/ritonavir + HCQ + NAC
group (n =12), most cases of cough in the atazanavir/ritonavir + HCQ +
NAC group (n =13) most cases of dyspnea in the atazanavir/ritonavir +
HCQ + NAC group (n =13), and most cases of fatigue in the
atazanavir/ritonavir + HCQ + NAC group (n =13) and the
atazanavir/ritonavir + HCQ group (n =13). Additionally, 12 cases of body
aches were reported in the atazanavir/ritonavir + HCQ group, 4 cases of
diarrhea in the Kaletra + HCQ group, 7 cases of sore throat in the
atazanavir/ritonavir + HCQ+ NAC group, 7 cases of chest discomfort in
the Kaletra + HCQ group, 7 cases of headache in the atazanavir/ritonavir
+ HCQ group, 14 cases of dizziness in the Kaletra + HCQ group + NAC,
only 1 case of seizure in the atazanavir/ritonavir + HCQ + NAC group, 6
cases of olfactory dysfunction in the Kaletra + HCQ + NAC group (fewest
cases of olfactory dysfunction were observed in the Kaletra + HCQ + NAC
group and the atazanavir/ritonavir + HCQ + NAC group), and 5 cases of
taste disorders in the Kaletra + HCQ + NAC group.

The administration of dexamethasone, acetaminophen, azithromycin,
ceftriaxone, interferon-\selectlanguage{greek}β, \selectlanguage{english}and levofloxacin was not the same across the
4 groups. For instance, 6 patients in each of the atazanavir/ritonavir +
HCQ and atazanavir/ritonavir + HCQ + NAC groups received interferon-\selectlanguage{greek}β
\selectlanguage{english}(\emph{P} =.002), indicating that the zero mortality in the
atazanavir/ritonavir + HCQ + NAC. Two patients in the Kaletra + HCQ
group, 1 patient in the atazanavir/ritonavir + HCQ group, and 1 patient
in the Kaletra + HCQ + NAC died; this difference, however, was not
statistically significant (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} =2.134, \emph{P} =.896).
All the patients in the atazanavir/ritonavir + HCQ + NAC group were
discharged in good condition (Table 4).

According to the linear regression model, performed to predict the
length of stay at the ICU, the use of IVIG, creatine phosphokinase (CPK)
elevation, and ESR decrease were correlated with an increased length of
stay at the ICU (Table 5). None of the used drugs had a significant
difference regarding mortality (Table 6).

Apropos of improvement in O\textsubscript{2} saturation with the 4 types
of medicine, the results showed that such improvement with
atazanavir/ritonavir + HCQ + NAC (\emph{P} =.001) and
atazanavir/ritonavir + HCQ (\emph{P} =0.008) was significant insofar as
these 2 groups had a high level of O\textsubscript{2} saturation after
treatment by comparison with the primary O\textsubscript{2} saturation
level (before intervention) (Table 7). No statistically significant
differences in this regard were observed between the 4 groups
(\emph{P}\textgreater{}0.05) (Table 8 and Fig. 2).

\textbf{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 (\emph{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 (\emph{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 (\emph{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-\selectlanguage{ngerman}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
(\emph{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 O\textsubscript{2} 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
O\textsubscript{2} saturation level of the groups that received NAC
(\emph{P} \textless{}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
\textless{}94\% or respiratory rate \textgreater{}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
O\textsubscript{2} 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 \selectlanguage{greek}α-\selectlanguage{english}lipoic
acid might represent a novel treatment approach to blocking NF-\selectlanguage{greek}κ\selectlanguage{english}B 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 O\textsubscript{2} saturation, ameliorate inflammation by lowering
CRP, and lessen mortality.

\textbf{CONCLUSIONS}

Given the current absence of any gold-standard therapy for the treatment
of COVID-19 or its associated complications, multipotential drugs with
anti-inflammatory, antioxidant and anti-apoptotic properties could have
promising results if indicated or used in a proper setting. We designed
one of the best-designed RCTs to date to evaluate the efficacy and
safety of NAC in the treatment of patients with COVID-19. The salient
findings of this RCT were that at the end of the study, a further drop
in C-reactive protein was detected in the NAC group (\emph{P} =0.008),
and no death occurred in the atazanavir/ritonavir + HCQ + NAC group,
indicating that the combination of these drugs may lessen mortality.
Moreover, the atazanavir/ritonavir + HCQ and atazanavir/ritonavir + HCQ
+ NAC groups had the highest O\textsubscript{2} saturation at the end of
the study and a significant elevation in O\textsubscript{2} saturation
after the start of the intervention, including NAC
(\emph{P}\textless{}0.05). In light of the findings of the present RCT,
we can conclude that oral or intravenous NAC, if indicated, may boost
O\textsubscript{2} saturation, blunt the inflammation trend (by reducing
C-reactive protein), and decline mortality in hospitalized patients with
COVID-19. The 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.

\textbf{Author's Contributions:}

All authors contributed to the preparation of data and the finalization
of this article. All the figures have been produced by the authors of
this article and are personal data.

\textbf{Acknowledgments:}

The authors would like to thank the Clinical Research Development Center
of Rasool Akram Medical Complex for its technical and editorial
assistance.

\textbf{Funding} :

The authors received no funding for this project.

\textbf{Declaration of Conflict of Interest:}

The authors declare there is no conflict of interests.

\textbf{Data Availability:}

The data supporting the findings of this study are available from the
corresponding author upon reasonable requests.

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