Infectious Diseases

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/infd20

N-acetyl-cysteine reduces the risk for mechanical

ventilation and mortality in patients with
COVID-19 pneumonia: a two-center retrospective
cohort study

Stelios F. Assimakopoulos, Diamanto Aretha, Dimitris Komninos, Dimitra

Dimitropoulou, Maria Lagadinou, Lydia Leonidou, Ioanna Oikonomou,
Athanasia Mouzaki & Markos Marangos

To cite this article: Stelios F. Assimakopoulos, Diamanto Aretha, Dimitris Komninos, Dimitra
Dimitropoulou, Maria Lagadinou, Lydia Leonidou, Ioanna Oikonomou, Athanasia Mouzaki & Markos
Marangos (2021) N-acetyl-cysteine reduces the risk for mechanical ventilation and mortality in
patients with COVID-19 pneumonia: a two-center retrospective cohort study, Infectious Diseases,
53:11, 847-854, DOI: 10.1080/23744235.2021.1945675

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INFECTIOUS DISEASES, https://doi.org/10.1080/23744235.2021.1945675
2021; VOL. 53,
NO. 11, 847–854

ORIGINAL ARTICLE

N-acetyl-cysteine reduces the risk for mechanical ventilation and mortality in

patients with COVID-19 pneumonia: a two-center retrospective cohort study

Stelios F. Assimakopoulosa , Diamanto Arethab, Dimitris Komninosc, Dimitra Dimitropoulouc,

Maria Lagadinoua, Lydia Leonidoua, Ioanna Oikonomoua, Athanasia Mouzakid and Markos Marangosa
a
Department of Internal Medicine, University of Patras Medical School, Patras, Greece; bDepartment of Anesthesiology and
Intensive Care Medicine, University of Patras Medical School, Patras, Greece; cDepartment of Internal Medicine, “St Andrews”
State General Hospital, Patras, Greece; dDivision of Hematology, Department of Internal Medicine, University of Patras Medical
School, Patras, Greece

ABSTRACT
Background: N-acetyl-cysteine (NAC) has been previously shown to exert beneficial effects in diverse respiratory diseases,
through antioxidant and anti-inflammatory actions. Our aim was to evaluate NAC potential impact in hospitalised patients
with COVID-19 pneumonia, in terms of progression to severe respiratory failure (SRF) and mortality.
Patients and Methods: This retrospective, two-centre cohort study included consecutive patients hospitalised with moder-
ate or severe COVID-19 pneumonia. Patients who received standard of care were compared with patients who additionally
received NAC 600 mg bid orally for 14 days. Patients’ clinical course was recorded regarding (i) the development of SRF
(PO2/FiO2 <150) requiring mechanical ventilation support and (ii) mortality at 14 and 28 days.
Results: A total of 82 patients were included, 42 in the NAC group and 40 in the control group. Treatment with oral NAC
led to significantly lower rates of progression to SRF as compared to the control group (p < .01). Patients in the NAC group
presented significantly lower 14- and 28-day mortality as compared to controls (p < .001 and p < .01 respectively). NAC
treatment significantly reduced 14- and 28-day mortality in patients with severe disease (p < .001, respectively). NAC
improved over time the PO2/FiO2 ratio and decreased the white blood cell, CRP, D-dimers and LDH levels. In the multivari-
able logistic regression analysis, non-severe illness and NAC administration were independent predictors of 28-
days survival.
Conclusion: Oral NAC administration (1200 mg/d) in patients with COVID-19 pneumonia reduces the risk for mechanical
ventilation and mortality. Our findings need to be confirmed by properly designed prospective clinical trials.

KEYWORDS ARTICLE HISTORY CONTACT

COVID-19 Received 25 May 2021 Stelios F. Assimakopoulos
pneumonia Revised 14 June 2021 sassim@upatras.gr
N-acetyl-cysteine Accepted 16 June 2021 Department of Internal Medicine and Division
antioxidant of Infectious Diseases, University of Patras
mortality Medical School, Patras 26504, Greece
ARDS

ß 2021 Society for Scandinavian Journal of Infectious Diseases

848 S. F. ASSIMAKOPOULOS ET AL.

Introduction positive real time RT-PCR of a nasopharyngeal swab

sample [3]. Patient’s disease severity classification to
The world scientific community has currently intensified
moderate and severe, was based on the National
its research efforts for the development of an effective
Institute of Health (NIH) criteria [3]. Specifically, moder-
treatment for COVID-19. Although COVID-19 is usually a
ate illness was defined as evidence of lower respiratory
mild disease, a minority of patients might develop a
disease during clinical assessment or imaging, with
severe clinical course associated with acute respiratory
SpO2
94% on room air at sea level, while severe dis-
distress syndrome (ARDS), multiple organ failure and
ease was defined as any of the following: SpO2 < 94%
increased mortality. This severe form of COVID-19 is
on room air at sea level, a respiratory rate >30 breaths/
characterised by a ‘cytokine storm’ with excessive
min, PaO2/FiO2 < 300 mmHg, or lung infiltrates >50%.
release of interleukin (IL)-1b, IL-2, IL-6, IL-7, tumour
All patients enrolled should have a PO2/
necrosis factor (TNF)-a, granulocyte colony stimulating
FiO2
150 mmHg on admission. The PO2/FiO2 ratio dur-
factor, interferon-c inducible protein 10, monocyte
ing hospitalisation was determined by serial arterial
chemoattractant protein 1 and macrophage inflamma-
blood gas analyses. We included a series of consecutive
tory protein 1-a [1]. These inflammatory mediators pro-
adult patients who received N-acetyl-cysteine (NAC)
mote organ injury not only in the lung, but in heart,
600 mg bid orally for 14 days or until hospital discharge
endothelium, kidney, brain, liver and intestinal tissue as
(whatever comes first) plus standard of care. The com-
well. Oxidative stress seems to constitute an important
parison group consisted of patients that were selected
pathogenetic factor of tissue injury in SARS-CoV-
by random sampling amongst those admitted at the
2 infection.
same hospitals the same period and received standard
N-acetylcysteine was introduced in the 1960s as a
of care, matched 1:1 by age and sex. The NAC/Control
mucolytic agent in respiratory infections and has also
enrolment ratio between the two participating hospitals
been used in paracetamol toxicity. NAC is a thiol-con-
was not significantly different (18/22 vs. 24/18). Standard
taining free-radical scavenger and a precursor of gluta-
of care consisted of supplemental oxygen, antibiotic
thione which exerts potent antioxidant effects in diverse
agents and intravenous fluids and electrolytes as neces-
pathological states. Reactive oxygen species and oxida-
sary, prophylactic low molecular weight heparin, while
tive stress activate important redox-sensitive transcrip-
patients with SpO2  94% on room air requiring supple-
tion factors like NF-jB and activator protein-1, which
mental oxygen were additionally given remdesivir
lead to the co-ordinate expression of proinflammatory
200 mg IV once, then 100 mg IV QD for 4 days and dexa-
genes of IL-6, IL-8, and TNF-a [2]. There is ample evi-
methasone 6 mg IV or PO QD for 10 days or until dis-
dence in preclinical and clinical studies that NAC can
charge, according to the National Institutes of Health
attenuate immune activation and prevent cyto-
and the National (Greek) Public Health Organisation
kine release.
treatment guidelines [3]. Exclusion criteria for this study
Taking into consideration the antioxidant and anti-
included age <18 years, severe respiratory failure requir-
inflammatory actions of NAC, the present retrospective
ing mechanical ventilation on admission, administration
study evaluated its potential clinical impact in patients
of IL-1 or IL-6 inhibitors (anakinra or tocilizumab respect-
hospitalised with COVID-19 pneumonia, in terms of pro-
ively). The study protocol was approved by the Regional
gression to severe respiratory failure and mortality.
Research Ethics Committee (no.214/06-04-2021). Our
study was carried out in accordance with the ethical
Patients and methods guidelines of the 2003 Declaration of Helsinki.
Patients
Study drug
This is an observational, retrospective study on patients
with moderate or severe COVID-19 pneumonia hospital- Granules for suspension of NAC (Trebon N; 600 mg/
ised during the third pandemic wave from February 1st sachet, Unipharma Pharmaceutical Laboratories S.A.,
to April 30th, 2021 at the Patras University Hospital, an Greece) was dissolved in half a glass of water and
academic 750 bed hospital, and ‘St. Andrew’ General administered orally twice per day. The NAC dosage
Hospital of Patras, a regional 400 bed hospital. Diagnosis selection was based on previous studies in respiratory
of COVID-19 pneumonia was based on established crite- diseases, demonstrating that 1200 mg/d of oral NAC
ria, requiring confirmation of SARS-CoV-2 infection by prevents chronic obstructive pulmonary disease
 INFECTIOUS DISEASES 849

exacerbations and exerts antioxidant and anti-inflamma-
tory actions in community-acquired pneumonia [4,5].
There is also extensive clinical experience in diverse clin-
ical entities, showing the high tolerability and safety of
this drug, even at much higher doses and for longer
periods of administration than the commonly prescribed
dose of 600 mg/d as a mucolytic agent [6].
Outcome measures
Two major clinical end-points of patients’ clinical course
were recorded: (a) development of severe respiratory
failure (SRF) (defined as PO2/FiO2 <150) requiring inva-
sive or non-invasive mechanical ventilation, within
14 days from hospital admission (patients with SRF
underwent computed tomographic pulmonary angiog-
raphy for exclusion of thromboembolic disease) and (b)
mortality at 14 and 28 days.
Statistical analysis
Data were analysed using the SPSS statistical package
for Windows (version 25.0; IBM, Armonk, USA) and the
GraphPad Prism Software (La Jolla, CA, version 9.1.0.).
Normality of data was tested using the Shapiro-Wilk
test. All parameters exhibited non-normal distribution
except leucocytes, fibrinogen and PLT. Normally distrib-
uted data that measured at different time points were
compared, between and within groups, using repeated
analysis of variance (ANOVA Repeated Measures-General
Linear Model) followed by post-hoc Student’s t-test while
Bonferroni correction was used to adjust the level of sig-
nificance for multiple comparisons. Similarly, for non-
normally distributed data, the nonparametric analysis of
variance (Kruskal-Wallis test) followed by a post-hoc
Mann-Whitney U-test was used and the level of
significance for multiple comparisons was adjusted with
Dunn’s test. The chi-squared test was used to compare
the proportional and categorical data. Uni-and multivari-
able logistic regression was used to identify predictors
of mortality at 28 days. Variables with p-values <.02 in
the univariate regression were included in the multivari-
able model while the choice of variables was also based
on scientific knowledge and considered potential collin-
earity. Multicollinearity issues were tested using the vari-
ance inflation factor (VIF). The possibility of survival and
non-development of severe respiratory failure at 28 days
were also assessed with survival analysis (Kaplan-Meier
curves). In all cases, p-values <.05 were considered
significant.
Results
Patients’ baseline characteristics
A total of 82 patients were included in the study: 42 in
the NAC (treatment) group and 40 in the control group.
The baseline characteristics of the patients including
age, gender, and Charlson co-morbidity index were simi-
lar between groups (p < .05) (Table 1). Significantly more
patients in the NAC group presented with severe disease
(p ¼ .004).
Differences in patients’ clinico-laboratory parameters
over time
Cohort differences in patients’ clinico-laboratory parame-
ters measured at different time points are presented in
Figure 1. There were no statistically significant differen-
ces between the two study groups at baseline (day 1),
while at day 7 and 14 there were statistically significant
differences for PO2/FiO2, WBCs, CRP, D-dimers and LDH.

Table 1. Patients’ clinico-laboratory baseline characteristics in the control and the NAC study groups.
Group
Pts Characteristics NAC Control p-value
Number 42 40
Gender (male/Female) 28/14 27/13 .93
Age (years) 61 (16) 64 (17) .3
Charlson co-morbidity Index 2 (4–1) 3 (5–2) .09
Severe illness (pt no, %) 26 (68.4) 12 (31.6) .004
PO2/FiO2 ratio 297 (339–247) 271 (372–188) .37
WBCs (absolute number/mm3) 5.665 (7.185–3.898) 6.120 (8.640–4.925) .15
Lymphocytes (absolute number/mm3) 1.017 (702) 1.270 (1.253) .26
CRP (mg/dl) 4 (7–2) 7 (13–3) .07
Ferritin (ng/ml) 515 (1200–298) 767.5 (1388–396) .46
D-dimers (lg/l) 630 (1205–455) 1.150 (1665–492) .13
Fibrinogen (mg/dl) 496 (140) 554 (160) .18
LDH (U/l) 256 (319–222) 314 (423–221) .11
PLT (x103/ll) 214 (459) 208 (911) .70
Continuous data are presented as mean (SD) or median (interquartile range). NAC: N-acetylcysteine, SRF: severe respiratory failure; WBC: white
blood cells. P-values <.05 were considered significant.
850 S. F. ASSIMAKOPOULOS ET AL.

Figure 1. Cohort differences in patients’ characteristics measured at different time points. WBCs: white blood cells, CRP: C-reactive protein;
SRF: severe respiratory failure.

Specifically, PO2/FiO2 ratio was higher in the NAC group

as compared to controls (p < .001 at 7 days and p < .05
at 14 days, respectively). Patients in the NAC group had
lower levels of WBCs (p < .05 at 7 days and p < .05 at
14 days respectively), CRP (p < .001 at 7 days and p < .05
at 14 days respectively), D-dimers (p < .001 both at 7
and 14 days) and LDH (p < .001 both at 7 and 14 days),
compared to patients in the control group. No differen-
ces in ferritin values between the two groups at 1, 7
and 14 days were detected.

Need for mechanical ventilation and mortality

Treatment with oral NAC led to significantly lower rates
of progression to SRF with need for mechanical ventila-
tion support as compared to the control group (p < .01)
(Figure 2). Patients in the NAC group presented signifi-
cantly lower 14- and 28-day mortality (p < .001 and
p < .01 respectively) compared to patients in the control
group (Figure 3(A)). When patients in the two study
groups were stratified according to their disease severity
at admission (moderate vs severe), mortality was signifi-
cantly reduced by NAC in patients with severe disease
(p < .001 for both 14 and 28 days) (Figure 3(B)).
Survival analysis (Kaplan-Meier curves) revealed statis-
tically significant differences between groups in prob-
ability of 28-day survival and mechanical ventilation free
survival (p < .001 respectively) (Figure 4).
Figure 2. Progression to severe respiratory failure (SRF) (PO2/
FiO2 < 150) within 14 days from admission in the control and NAC
study groups.
Uni- and multi-variate logistic regression for mortality
Univariate logistic regression revealed several factors
that were associated with an increased risk of 28-day
mortality (Table 2). Increased age (odds ratio (OR) 1.17;
95% confidence interval (95%CI): 1.05-1.2), higher
Charlson co-morbidity index (OR 2; 95%CI: 1.4-3.1),
severe illness (OR 3.5; 95%CI: 1.1-1.14), control (standard
of care) group (OR 8.5; 95%CI: 2.1-57.8) and lower lym-
phocytes levels (OR 0.99; 95%CI: 0.99-0.99) were all pre-
dictors of 28-day mortality. In the multivariate logistic
regression level, severe illness (adjusted odds ratio (aOR)
15.3; 95%CI: 1.5-335) and control group (aOR 48; 95%CI:

Figure 3. Mortality at 14- and 28-days after admission in the control and the NAC study groups (A). Mortality differences between groups
according to baseline disease severity (moderate vs. severe) (B). NAC: N-acetylcysteine, no: number.
4.4-1436) were independent predictors of
days mortality.
Discussion
The present study showed that orally administered NAC
at a dose of 1200 mg per day in hospitalised patients
with moderate or severe COVID-19 pneumonia, prevents
their clinical deterioration to severe respiratory failure
requiring invasive or non-invasive mechanical ventilation
and reduces 14- and 28-day mortality. Advanced age,
multiple comorbidities, low lymphocyte count, disease
severity and standard of care treatment were identified
as significant factors associated with mortality in univari-
ate regression analysis. In multivariate regression ana-
lysis, only severe disease and standard of care treatment
(without NAC) were associated with increased mortality.
In the control group, with a mean age of 64 years, a
high 28-day mortality rate of 30% was recorded. Similar
INFECTIOUS DISEASES 851
28- death rates for age-comparable hospitalised patients
with COVID-19 pneumonia have been previously
reported [7,8]. Amongst the 12 deceased patients in the
control group, 4 had multiple comorbidities with a
Charlson co-morbidity index
7 and 7 patients were

75 years old. Moreover 8/12 patients progressed to
severe respiratory failure and required invasive mechan-
ical ventilation, which is associated with increased mor-
tality [9]. It is noteworthy that the NAC group included
significantly more patients in severe condition as com-
pared to the standard of care group, although there was
no significant difference in baseline PO2/FiO2 values
between the two study groups. This might be explained
by the fact that PO2/FiO2 ratio was not the only deter-
minant of severe disease according to the severity classi-
fication criteria used in the present study [3], while its
range in severe patients was wide (150  299 mmHg).
NAC survival benefit was mainly attributed to signifi-
cantly reduced mortality in patients with severe COVID-
852 S. F. ASSIMAKOPOULOS ET AL.

19 pneumonia (2/42 in NAC vs 8/40 in standard of care).
Regarding patients with moderate disease at admission
0/16 died in the NAC group, while in the control group
3/28 patients died within the first 14 days and one add-
itional patient died within 28 days; however this trend
for mortality reduction by NAC did not reach statistical
significance owing to small number of moderately ill
patients. According to the presented results NAC
Figure 4. Kaplan-Meier curves for 28 days survival (A) and mechan-
ical ventilation free survival (B), for the control and NAC study
groups. NAC: N-acetylcysteine
administration improved oxygenation over time, and
reduced leukocytes, CRP and d-dimers levels, which is
suggestive of its anti-inflammatory action. The finding of
absence of ferritin reduction at 7 and 14 days after NAC
treatment initiation might be potentially explained by a
slowest kinetic alteration of ferritin as compared to
other inflammatory indices. Previous studies in sepsis
have demonstrated that although CRP and ferritin were
elevated analogously, their drop after treatment was not
paralleled and ferritin declined more slowly than CRP
possibly because of its longer half-life time [10].
Previous studies have demonstrated that NAC exerts
beneficial actions in diverse respiratory diseases. NAC
administration at a daily dose of 1200 mg has been
shown to prevent exacerbations of chronic obstructive
pulmonary disease [5]. A recent study including patients
with community-acquired pneumonia, showed that the
addition of 1200 mg/d of NAC to conventional treatment
reduced oxidative stress and the inflammatory response
[4]. Nasogastric administration of 1200 mg/d NAC has
been shown to prevent the development of ventilator-
associated pneumonia in intubated patients and leading
to shorter duration of hospital and intensive care unit
(ICU) stay [11].
The potential mechanisms of NAC beneficial actions
have been investigated in several in vitro and in vivo
studies. Beyond its well established action as a precursor
of glutathione, diverse additional mechanisms have
been described for its antioxidant and anti-inflammatory
actions; (i) NAC downregulates the mRNA expression of
the inflammasome NLRP3 thus decreasing the proinflam-
matory cytokine expression and release from activated
mononuclear phagocytes [12], (ii) inhibits the endotoxin-
induced release of IL-1b, IL-8, and TNF-a [13], (iii)
improves gut barrier dysfunction thus preventing sys-
temic endotoxemia and inflammatory response, while

Table 2. Predictors of mortality at 28 days based on an uni- and multi-variable logistic regression model.
Death at 28 days Univariate regression Multivariate regression
Variable Yes No OR (95% CI) p Value aOR (95% CI) p Value
Age (mean, SD) 77.5 (10) 59 (15) 1.17 (1.05–1.2) <.001 1.1 (0.98–1.3) .13
Gender (male/female) 8/6 47/21 1.6 (0.5–5.4) .38
Charlson Index (median, IQR) 4 (3.75–6.25) 2 (4–1) 2 (1.4–3.1) <.001 1.4 (0.7–3.3) .32
Severity of illness (severe, pts no) 10 28 3.5 (1.1–14) <.001 15.3 (1.5–335) .04
Group (NAC/control) 2/12 40/28 8.5 (2.1–57.8) .007 48 (4.4–1436) .006
Baseline measurements
PO2/FiO2 ratio (median/IQR) 239 (302–159) 303 (348–230) 0.99 (0.98–1) .16
WBCs (absolute number/mm3, median/IQR) 7400 (9890–5290) 5840 (7295–4070) 1 (0.9–1) .53
Lymphocytes (absolute number/mm3, mean/SD) 825 (366) 1202 (1079) 0.99 (0.99–0.991) .01 0.99 (0.99–0.99) .05
CRP (mg/dl, median/IQR) 7.5 (13–3.5) 4.4 (8.6–2.2) 1 (0.9–1.1) .2
Ferritin (ng/ml, median/IQR) 771 (1811–418) 614 (1273–299) 1 (0.9–1) .37
D-dimers (lg/l, median/IQR) 1160 (2400–540) 645 (1285–423) 1 (1–1) .19
LDH (U/l, median/IQR) 382 (667–245) 287 (375–239) 1.01 (1.01–1.01) .02
OR: Odds-Ratio; 95%CI: 95% Confidence interval; aOR: adjusted Odds-Ratio; WBCs: white blood cells; CRP: C-reactive protein; IQR: Interquartile range.
Factors that were included in the multivariate regression. p-values <.05 in multivariate logistic regression are considered significant.

previous studies have shown that COVID-19 has been
associated with gut barrier dysfunction and systemic
endotoxemia [14,15] (iii) downregulates programmed
cell death protein 1 expression in CD4þ and CD8þ lym-
phocytes thus increasing their longevity and counts [16].
Additionally, NAC may exert a direct antiviral action
against SARS-CoV-2. A previous in vitro study has dem-
onstrated that NAC inhibits the replication of other
respiratory viruses like influenza A and B and respiratory
syncytial virus in human pulmonary epithelial cells [17].
Replication of RNA viruses, including human coronavi-
ruses, in epithelial cells requires an active NF-jB path-
way. NAC has been demonstrated to inhibit NF-jB thus
exhibiting the theoretical potential to inhibit SARS-CoV-2
replication [18].
Despite the pathophysiological rationale for the
potential value of NAC in COVID-19, there is very limited
data regarding its clinical impact in this disease. To the
best of our knowledge, there is only one double-blind,
placebo-controlled randomised unicentric trial, con-
ducted in Brazil, where 135 patients diagnosed with
severe COVID-19 beyond standard of care were assigned
1:1 to either 21 g of IV NAC (14 g in the first 4 h and 7 g
in the next 16 h) or placebo [19]. This study found no
difference regarding the progression to severe respira-
tory failure requiring invasive or non-invasive mechanical
ventilation, admission to ICU and mortality. However, in
accordance with our positive results, previous case
reports and series of patients with COVID-19 have
shown that NAC administered at 1200 mg/d induced a
positive clinical impact [20,21]. A potential explanation
for these contradictory results might have been the
short treatment duration with NAC (20 h) in the Brazilian
study, as compared to its repeated daily administration
for 14 days in the present study. It has been previously
shown that early NAC discontinuation in COVID-19 was
associated with relapse of laboratory indices of inflam-
mation [21]. An additional explanation might have been
the significantly different doses of NAC used in the pre-
sent and the Brazilian study (1.2 vs. 21 g). Very higher
doses of intravenous NAC (200 mg/kg/d) have been
used clinically for the treatment of ARDS and a meta-
analysis of randomised clinical trials on this field failed
to demonstrate a survival benefit by high NAC dose
administration, although length of ICU stay was
decreased [22]. It should not be neglected that it has
been previously shown that high doses of other free
radical scavengers like beta-carotene, vitamin E, and
vitamin C have led to enhanced oxidative stress [23].
Regarding thiol containing compounds, the interaction
INFECTIOUS DISEASES 853
of thiols with reactive radicals can generate thiyl radi-
cals, depending on the baseline levels of oxidative stress
[24]. Previous in vitro and experimental animal studies
have shown that higher doses of NAC may exert a
prooxidant action, depending on the nature of the radi-
cals generated by the biological system [24–26].
Specifically, high NAC doses have been shown to
enhance the Fe2þ/H2O2-dependent oxidative stress and
increase superoxide radical formation [24,25].
Some limitations of the current study should be
acknowledged. First, the presented study is retrospective
with a limited number of patients. Second, patients
were not matched for disease severity, although this did
not affect the NAC positive impact in COVID-19-related
pneumonia because patients who received NAC had a
higher severity disease. Third, even though the basis of
NAC use in COVID-19 was its antioxidant action, this fac-
tor was not investigated by appropriate indices meas-
urements. Therefore, the mechanisms of the observed
clinical results could only be discussed on a theoret-
ical basis.
In conclusion, the present study provides evidence
that 1200 mg/d of oral NAC administration in patients
with COVID-19 pneumonia prevents development of
severe respiratory failure and improves survival. Our
findings need to be confirmed by properly designed
prospective clinical trials. In addition, the optimal time
for NAC treatment initiation (e.g. early after symptoms
onset or later in the disease course) remains to be eluci-
dated. Until then, considering the excellent safety profile
and low cost of oral NAC, its use as adjunctive therapy
in COVID-19 might be of reasonable value.
Disclosure statement
The authors declare that they have no conflict of interest.
ORCID
Stelios F. Assimakopoulos http://orcid.org/0000-0002-
6901-3681
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