N-Acetylcysteine reduces mortality in patients hospitalized with COVID-19: A retrospective cohort study

Abstract

Introduction and aim:
N-acetylcysteine has been proposed for the treatment of COVID-19 thanks to its mucolytic, antioxidant and anti-inflammatory effects. Our aim is to evaluate its effect on patients admitted with COVID-19 in mortality terms.

Material and methods:
Retrospective single-center cohort study. All patients admitted to our hospital for COVID-19 from March to April 2020 have been considered.

Results:
A total of 378 patients were included, being 196 (51.9%) men, with an average age of 73.3 ± 14.5 years. 52.6% (199) received treatment with N-Acetylcysteine. More than 70% presented coughs, fever, and/or dyspnea. The global hospital mortality was 26.7%. A multivariate analysis through logistic regression identified the age of patients [older than 80; OR: 8.4 (CI95%:3-23.4)], a moderate or severe radiologic affectation measured by the RALE score [OR:7.3 (CI95%:3.2-16.9)], the tobacco consumption [OR:2.8 (CI95%:1.3-6.1)] and previous arrhythmia [OR 2.8 (CI95%: 1.3-6.2)]as risk factor that were independently associated with mortality during the admission. The treatment with N-Acetylcysteine was identified as a protective factor [OR: 0.57 (CI95%: 0.31-0.99)]. Asthma also seems to have a certain protective factor although it was not statistically significant in our study [OR: 0.19 (CI95%: 0.03-1.06)].

Conclusions:
Patients with COVID-19 treated with N-acetylcysteine have presented a lower mortality and a better evolution in this study. Future prospective studies or randomized clinical trials must confirm the impact of N-Acetylcysteine on COVID-19 patients.

Full text

ARTICLE IN PRESS
+Model
RCENG-2128;
No.
of
Pages
8
Revista
Clínica
Española
xxx
(xxxx)
xxx---xxx
www.elsevier.es/rce
Revista
Clínica
Española
ORIGINAL
ARTICLE
Impact
of
N-Acetylcysteine
in
the
mortality
of
patients
hospitalized
with
COVID-19:
a
retrospective
cohort
study
M.A.
Galindo-Andúgara,∗,
Á.
Arias
Ariasb,
J.
Alfonso
García
Guerrac,
I.
Fernández
Visierd,
J.
Manuel
Fernández
Ibá˜
neze,
A.
Bellido
Maldonadoc
aServicio
de
Medicina
Interna.
Hospital
General
La
Mancha
Centro,
Alcázar
de
San
Juan
(C.
Real),
Spain
bUnidad
de
Docencia,
Investigación
y
Formación,
Hospital
General
La
Mancha
Centro,
Alcázar
de
San
Juan
(C.
Real),
Spain
cSección
de
Neumología,
Hospital
General
La
Mancha
Centro,
Alcázar
de
San
Juan
(C.
Real),
Spain
dSección
de
Aparato
Digestivo,
Hospital
General
La
Mancha
Centro,
Alcázar
de
San
Juan
(C.
Real),
Spain
eSección
de
Geriatría,
Hospital
General
La
Mancha
Centro,
Alcázar
de
San
Juan
(C.
Real),
Spain
Received
8
February
2023;
accepted
8
July
2023
KEYWORDS
N-Acetylcysteine;
COVID-19;
SARS-CoV-2;
Hospital
mortality
Abstract
Introduction
and
aim:
N-Acetylcysteine
has
been
proposed
for
the
treatment
of
COVID-19
thanks
to
its
mucolytic,
antioxidant
and
anti-inflammatory
effects.
Our
aim
is
to
evaluate
its
effect
on
patients
admitted
with
COVID-19
in
mortality
terms.
Material
and
methods:
Retrospective
single-center
cohort
study.
All
patients
admitted
to
our
hospital
for
COVID-19
from
March
to
April
2020
have
been
considered.
Results:
A
total
of
378
patients
were
included,
being
196
(51.9%)
men,
with
an
average
age
of
73.3
±
14.5
years.
52.6%
(199)
received
treatment
with
N-Acetylcysteine.
More
than
70%
presented
coughs,
fever,
and/or
dyspnea.
The
global
hospital
mortality
was
26.7%.
A
multi-
variate
analysis
through
logistic
regression
identified
the
age
of
patients
[older
than
80;
OR:
8.4
(CI95%:3−23.4)],
a
moderate
or
severe
radiologic
affectation
measured
by
the
RALE
score
[OR:7.3
(CI95%:3.2---16.9)],
the
tobacco
consumption
[OR:2.8
(CI95%:1.3---6.1)]
and
previous
arrhythmia
[OR
2.8
(CI95%:
1.3---6.2)]
as
risk
factor
that
were
independently
associated
with
mortality
during
the
admission.
The
treatment
with
N-Acetylcysteine
was
identified
as
a
pro-
tective
factor
[OR:
0.57
(CI95%:
0.31−0.99)].
Asthma
also
seems
to
have
a
certain
protective
factor
although
it
was
not
statistically
significant
in
our
study
[OR:
0.19
(CI95%:
0.03---1.06)].
∗Corresponding
author.
E-mail
address:
magalindo@sescam.jccm.es
(M.A.
Galindo-Andúgar).
https://doi.org/10.1016/j.rceng.2023.07.006
2254-8874/©
2023
Elsevier
Espa˜
na,
S.L.U.
and
Sociedad
Espa˜
nola
de
Medicina
Interna
(SEMI).
All
rights
reserved.
Please
cite
this
article
as:
M.A.
Galindo-Andúgar,
Á.
Arias
Arias,
J.
Alfonso
García
Guerra
et
al.,
Impact
of
N-
Acetylcysteine
in
the
mortality
of
patients
hospitalized
with
COVID-19:
a
retrospective
cohort
study,
Revista
Clínica
Española,
https://doi.org/10.1016/j.rceng.2023.07.006

ARTICLE IN PRESS
+Model
RCENG-2128;
No.
of
Pages
8
M.A.
Galindo-Andúgar,
Á.
Arias
Arias,
J.
Alfonso
García
Guerra
et
al.
Conclusions:
Patients
with
COVID-19
treated
with
N-acetylcysteine
have
presented
a
lower
mor-
tality
and
a
better
evolution
in
this
study.
Future
prospective
studies
or
randomized
clinical
trials
must
confirm
the
impact
of
N-Acetylcysteine
on
COVID-19
patients.
©
2023
Elsevier
Espa˜
na,
S.L.U.
and
Sociedad
Espa˜
nola
de
Medicina
Interna
(SEMI).
All
rights
reserved.
PALABRAS
CLAVE
N-Acetilcisteína;
COVID-19;
SARS-CoV-2;
Mortalidad
hospitalaria
Efecto
de
la
N-Acetilcisteína
en
la
mortalidad
de
pacientes
ingresados
por
COVID-19:
estudio
de
cohorte
retrospectivo
Resumen
Introducción
y
objetivo:
La
N-Acetilcisteína
se
ha
propuesto
para
el
tratamiento
de
COVID-19
gracias
a
sus
efectos
mucolítico,
antioxidante
y
antiinflamatorio.
El
presente
estudio
tiene
como
objetivo
evaluar
su
efecto
en
pacientes
ingresados
con
COVID-19,
en
términos
de
mortalidad.
Material
y
métodos:
Estudio
de
cohorte
retrospectivo
unicéntrico.
Se
incluyeron
todos
los
pacientes
ingresados
por
COVD-19
entre
marzo
y
abril
de
2020
en
nuestro
hospital.
Resultados:
Un
total
de
378
pacientes
fueron
incluidos,
de
ellos
196
(51,9%)
fueron
hombres,
la
edad
media
fue
de
73,3
±
14,5
a˜
nos.
199
(52,6%)
pacientes
recibieron
tratamiento
con
N-
Acetilcisteína.
Más
del
70%
tuvieron
tos,
fiebre
y/o
disnea.
La
mortalidad
hospitalaria
global
fue
del
26,7%.
Un
análisis
multivariante
mediante
regresión
logística
identificó
la
edad
de
los
pacientes
[mayores
de
80
a˜
nos;
OR:
8,4
(IC95%:
3---23,4)],
una
afectación
radiológica
moderada
o
grave
medida
por
la
escala
RALE
[OR:
7,3
(IC95%:
3,2---16,9)],
el
consumo
de
tabaco
[OR:
2,8
(IC95%:
1,3---6,1)]
y
arritmia
previa
[OR:
2,8
(IC95%:
1,3---6,2)]
como
factores
de
riego
que
se
asociaron
independientemente
con
la
mortalidad
durante
el
ingreso.
El
tratamiento
con
N-
acetilcisteína
fue
identificado
como
factor
protector
[(OR:
0,57
(IC95%:
0,31---0,99)].
El
asma
podría
representar
asimismo
un
factor
protector
de
mortalidad,
aunque
en
el
presente
estudio
no
alcanza
significación
estadística
[(OR:
0,19
(IC95%:
0,03---1,06)].
Conclusiones:
Los
pacientes
con
COVID-19
tratados
con
N-Acetilcisteína
presentaron
una
menor
mortalidad
y
mejor
evolución
en
nuestro
estudio.
Futuros
estudios
prospectivos
o
ensayos
clíni-
cos
aleatorizados
deben
confirmar
el
papel
de
la
N-Acetilcisteína
en
pacientes
con
COVID-19.
©
2023
Elsevier
Espa˜
na,
S.L.U.
y
Sociedad
Espa˜
nola
de
Medicina
Interna
(SEMI).
Todos
los
derechos
reservados.
Introduction
Since
2019,
the
world
has
faced
a
pandemic
caused
by
a
coronavirus
called
SARS-CoV-2.
This
betacoronavirus
uses
angiotensin-converting
enzyme
2
(ACE2)
to
enter
cells
through
its
interaction
with
protein
S.1The
disulfide
bridges
that
form
this
interaction
are
fundamental,
as
is
the
equi-
librium
between
the
disulfide
(SS)
and
thiol
(-SH)
groups.2
In
the
most
severe
forms
of
COVID-19,
there
is
an
exces-
sive
release
of
inflammatory
mediators
such
as
interleukin
(IL)-1␤,
IL-2,
IL-6,
tumor
necrosis
factor
(TNF)-␣,
and
oth-
ers.
This
is
known
as
the
‘‘cytokine
storm.’’3,4 This
leads
to
a
massive
release
of
free
radicals,
with
the
development
of
oxidative
stress
and
a
decrease
in
levels
of
glutathione,
which
plays
an
important
role
in
tissue
damage.5,6 There-
fore,
substances
with
an
antioxidant
effect
have
been
proposed
as
treatment
options,
including
ascorbic
acid,
zinc,
vitamin
D,
and
N-acetylcysteine
(NAC).7 --- 9
NAC
is
a
precursor
of
glutathione
derived
from
l-cysteine
and
has
antioxidant
action.
There
is
extensive
experience
in
its
use
in
other
diseases
such
as
chronic
obstructive
pulmonary
disease.
It
has
been
suggested
for
use
in
COVID-
19
thanks
to
its
multiple
effects.
Its
mucolytic
action
is
due
to
its
capacity
to
break
the
disulfide
bridges
of
the
glycoprotein
matrix.
Its
antioxidant
effect
is
thanks
to
its
capacity
to
replenish
thiol
and
glutathione
levels
and
to
neutralize
free
radicals.10 Lastly,
its
anti-inflammatory
action
is
due
to
its
ability
to
inhibit
cytokines
such
as
IL-6
and
promote
lymphocyte
proliferation
(which
is
inversely
affected
by
oxidative
stress
and
low
levels
of
glutathione.11,12
Spain
was
one
of
the
countries
most
affected
by
the
pan-
demic
in
the
first
wave
(from
January
31
to
June
21,
2020).
The
worst
months
were
March
and
April,
which
was
also
true
in
our
center.13 Given
the
lack
of
a
specific
treatment
for
COVID-19,
one
of
the
adjuvant
treatments
proposed
was
NAC
at
a
dose
of
1200
mg/day
orally.
This
study
aims
to
ver-
ify
if
the
use
of
NAC
had
a
positive
impact
on
the
progress
of
hospitalized
patients
and
on
reducing
mortality
due
to
COVID-19.
2

ARTICLE IN PRESS
+Model
RCENG-2128;
No.
of
Pages
8
Revista
Clínica
Española
xxx
(xxxx)
xxx---xxx
Table
1
Main
characteristics
of
patients
included
in
the
study
and
comparison
between
patients
who
did
and
did
not
receive
NAC.
Overall
(n
=
378)
No
NAC
(n
=
179)
NAC
(n
=
199)
p
Mean
age
±
SD
(range) 73.3
±
14.5
(22---100)
73.9
±
15.4 72.8
±
13.7 0.482
Sex Male
196
(51.9%)
89
(49.7%)
107
(53.8%) 0.432
Female
182
(48.1%)
90
(50.3%)
92
(46.2%)
Institutionalized
51
(13.5%)
21
(11.7%)
30
(15.1%)
0.342
Comorbidities Hypertension
246
(65.3%)
122
(68.5%)
124
(62.3%)
0.205
Dyslipidemia
144
(38.1%)
66
(36.9%)
78
(39.2%)
0.642
Diabetes
124
(32.8%)
52
(29.1%)
72
(36.2%)
0.140
COPD
40
(10.6%) 21
(11.7%) 19
(9.5%)
0.491
Asthma
24
(6.3%)
12
(6.7%)
12
(6%)
0.789
Ischemic
heart
disease
49
(13%)
22
(12.3%)
27
(13.6%)
0.712
Previous
arrhythmia
51
(13.5%) 24
(13.4%)
27
(13.6%)
0.635
Cognitive
impairment
65
(17.2%) 34
(19%) 31
(15.6%)
0.379
Previous
VTD
39
(10.3%)
23
(12.8%)
16
(8%)
0.125
Kidney
failure
54
(14.3%)
31
(17.3%)
23
(11.6%)
0.110
Solid
tumor
45
(11.9%)
26
(14.5%)
19
(9.5%)
0.136
Hematologic
tumor
9
(2.4%)
6
(3.3%)
3
(1.5%)
0.605
Tobacco
use Non-smoker
288
(76.2%)
138
(77.1%)
150
(75.4%) 0.864
Active
Smoker
80
(21.2%)
37
(20.7%)
43
(21.6%)
Former
smoker
10
(2.6%)
4
(2.2%)
6
(3%)
NAC:
N-acetylcysteine;
SD:
standard
deviation;
COPD:
chronic
obstructive
pulmonary
disease;
VTD:
venous
thromboembolic
disease.
Patients
and
methods
Design
This
work
is
an
observational,
retrospective
cohort
study.
Patients
Adult
patients
admitted
to
the
La
Mancha
Centro
Gen-
eral
Hospital
due
to
COVID-19
confirmed
by
means
of
a
PCR
test
of
nasopharyngeal
exudate
between
March
9
and
April
30,
2020
were
included.
Patients
were
excluded
if
they
received
treatment
regimens
with
a
low
num-
ber
of
patients
(<10);
this
included
restricted-use
drugs
such
as
IL-1
inhibitors
(anakinra)
or
IL-6
(tocilizumab),
lopinavir/ritonavir,
emtricitabine/tenofovir,
and
apheresis.
Patients
were
also
excluded
if
they
were
treated
with
dex-
amethasone
(its
use
began
at
the
end
of
April)
and/or
calcifediol,
due
to
their
low
numbers.
Procedure/data
collection
Patients
were
treated
according
to
protocol
in
force
at
the
center.
There
were
various
treatment
regi-
mens:
hydroxychloroquine
±
azithromycin
±
low-molecular-
weight
heparin
±
glucocorticoids
±
NAC.
The
choice
of
NAC
as
a
treatment
was
at
the
attending
physician’s
discretion
in
accordance
with
his/her
clinical
judgment.
The
NAC
dose
used
was
1200
mg/day
orally
divided
into
two
600-mg
doses.
The
main
variables
(including
treatment
received
and
mor-
tality)
were
gathered
from
the
electronic
medical
record
and
electronic
records
from
the
Radiology,
Pharmacy,
and
Laboratory
Departments.
The
Radiographic
Assessment
of
Lung
Edema
(RALE)
scale
was
used
to
measure
the
degree
of
lung
involvement
on
the
chest
x-ray:
0
points
(normal),
1 --- 2
(mild
involvement),
3 --- 6
(moderate
involvement),
and
7 --- 8
(severe
involvement).
Statistical
analysis
A
descriptive
analysis
was
performed
on
all
the
variables
included
in
the
study.
Qualitative
variables
were
described
using
absolute
and
relative
frequencies
whereas
quan-
titative
variables
were
described
using
mean
±
standard
deviation
(SD)
or
median
±
interquartile
range
(IQR)
accord-
ing
to
the
variable’s
distribution.
Statistical
methods
(Kolmogorov-Smirnov
or
Shapiro-Wilk
test)
and
graphic
methods
(histograms)
were
used
to
verify
the
variable’s
nor-
mality.
3

ARTICLE IN PRESS
+Model
RCENG-2128;
No.
of
Pages
8
M.A.
Galindo-Andúgar,
Á.
Arias
Arias,
J.
Alfonso
García
Guerra
et
al.
Table
2
Clinical
characteristics,
radiological
findings,
and
treatment
regimens
and
comparison
between
patients
who
did
and
did
not
receive
NAC.
Overall
(n
=
378)
No
NAC
(n
=
179)
NAC
(n
=
199)
p
Length
of
hospital
stay
(median
±
IQR) 7
±
46
±
57
±
5 0.002
Chest
XR Normal
79
(21.5%) 43
(24.7%) 36
(18.6%) 0.274
Mild
(RALE
score
1---2)
163
(44.3%)
78
(44.8%)
85
(43.8%)
Moderate
(RALE
score
3---6)
111
(30.2%)
45
(25.9%)
66
(34%)
Severe
(RALE
score
7---8)
15
(4.1%)
8
(4.6%)
7
(3.6%)
Not
performed 10
5
5
---
Maximum
oxygen
required
Not
required
38
(10.1%)
21
(11.7%)
17
(8.6%) 0.100
Nasal
cannula
258
(68.3%)
112
(62.7%)
146
(73.3%)
Venturi
face
mask
26
(6.8%)
14
(7.8%)
12
(6%)
Non-rebreather
mask
51
(13.5%)
30
(16.7%)
21
(10.6%)
NIMV
5
(1.3%) 2
(1.1%) 3
(1.5%)
Treatment
regimen
Hydroxychloroquine
15
(4%)
15
(8.4%)
0<0.001
LMWH
42
(11.1%) 25
(14%) 17
(8.5%)
Hydroxychloroquine
+
Azithromycin
10
(2.6%) 10
(5.6%)
0
Hydroxychloroquine
+
LMWH
45
(11.9%)
23
(12.8%)
22
(11.1%)
Glucocorticoids
+
LMWH
45
(11.9%)
13
(7.3%)
32
(16.1%)
Hydroxychloroquine
+
Azithromycin
+
LMWH
48
(12.7%)
18
(10.1%)
30
(15.1%)
Hydroxychloroquine
+
Glucocorticoids
+
LMWH
12
(3.2%)
12
(6.7%)
0
All
161
(42.6%)
63
(35.2%)
98
(49.2%)
Admission
to
the
intensive
care
unit
4
(1.1%)
1
(0.6%)
3
(1.5%)
0.625
In-hospital
death
101
(26.7%)
56
(31.3%)
45
(22.6%)
0.057
NAC:
N-acetylcysteine;
IQR:
interquartile
range;
XR:
x-ray;
RALE:
Radiographic
Assessment
of
Lung
Edema;
NIMV:
non-invasive
mechanical
ventilation.
LMWH:
low-molecular-weight
heparin.
A
bivariate
analysis
was
used
to
make
comparisons
between
groups
(NAC
vs
no
NAC
and
death
vs
discharge).
The
chi-square
test
or
Fisher’s
exact
test
was
used
for
qualita-
tive
variables
and
the
Student’s
t-test
or
the
Mann-Whitney
U
test
was
used
for
quantitative
variables
according
to
the
variable’s
normality.
Lastly,
a
multivariate
analysis
was
performed
by
means
of
a
logistic
regression
in
order
to
independently
identify
possible
risk
factors
and
protective
factors.
The
odds
ratio
(OR)
and
95%
confidence
intervals
(95%CI)
were
calculated
for
the
significant
variables.
To
build
the
final
model,
signif-
icant
variables
on
the
multivariate
analysis,
variables
close
to
statistical
significance
(p
<
0.200),
and
adjustment
or
clin-
ically
relevant
variables
were
used.
Once
the
larger
model
was
built,
variables
that
did
not
reach
statistical
significance
and
were
not
adjustment,
effect
modifier,
or
confounding
variables
were
removed.
In
this
same
manner,
a
Cox
regres-
sion
model
was
created,
calculating
the
hazard
ratios
(HR)
and
95%CI.
All
calculations
were
performed
using
the
SPSS
program
version
18.
The
value
of
p
<
0.05
was
defined
as
statistically
significant.
Ethical
considerations
The
study
was
conducted
in
accordance
with
the
ethi-
cal
principles
of
the
Declaration
of
Helsinki.
Approval
was
granted
from
the
Drug
Research
Ethics
Committee
of
the
La
Mancha
Centro
General
Hospital
(ref.
147-C).
Results
General
characteristics
of
patients
and
comparisons
between
patients
with
and
without
NAC
A
total
of
378
patients
were
included.
The
percentage
of
men
was
slightly
higher;
there
were
199
men
(52.6%),
the
mean
age
was
73.3
±
14.5
years.
Respiratory
symptoms
were
the
most
common----70%
reported
cough,
fever,
and/or
dyspnea----followed
by
asthenia
(34.4%).
Half
of
patients
(52.6%)
received
treatment
with
NAC
(n
=
199).
Comparing
their
characteristics
with
those
of
the
group
which
did
not
receive
NAC,
they
were
observed
to
be
4

ARTICLE IN PRESS
+Model
RCENG-2128;
No.
of
Pages
8
Revista
Clínica
Española
xxx
(xxxx)
xxx---xxx
Figure
1
General
survival
curve
(1A),
survival
curve
according
to
age
groups
(1B)
and
according
to
N-acetylcysteine
treatment
(1C).
similar
and
there
are
no
statistically
significant
differences
(Table
1).
It
was
observed
that
patients
with
or
without
treatment
with
NAC
were
similar
in
regard
to
the
radiological
severity
upon
admission
and
maximum
oxygen
required.
The
overall
mortality
rate
was
26.7%.
There
was
a
trend
toward
greater
mortality
in
the
group
which
did
not
receive
NAC
(31.3%
vs
22.6%;
p
=
0.057).
There
were
statistically
significant
dif-
ferences
among
the
eight
treatment
regimens
used
in
both
groups
(Table
2).
There
were
no
differences
in
the
blood
tests
performed.
Flow
chart
of
patients
included
in
the
study
The
in-hospital
mortality
rate
was
26.7%.
Patients
who
died
were
older
than
those
who
were
discharged
(81.3
±
11.5
vs
70.4
±
14.5
years,
p
<
0.001).
In
regard
to
the
x-ray
upon
admission,
greater
mortal-
ity
was
observed
among
those
with
greater
radiological
involvement:
the
mortality
rate
was
<20%
in
patients
with
a
normal
x-ray
or
mild
involvement,
increased
to
41.4%
in
patients
with
a
moderate
RALE
score,
and
was
80%
in
patients
with
severe
involvement.
Greater
mortality
was
also
observed
among
those
with
greater
maximum
oxygen
requirements.
The
mortality
rate
was
2.6%
in
patients
who
did
not
require
oxygen,
17.1%
in
patients
with
nasal
cannula,
50%
in
patients
with
a
Venturi
mask,
and
80%
in
patients
with
a
non-rebreather
mask
or
non-invasive
mechanical
ventila-
tion.
The
median
survival
time
was
28
(19.5---36.5)
days
(Fig.
1A).
Comparing
the
various
age
groups,
it
was
observed
that
the
median
survival
decreased
significantly
among
those
who
were
older
(p
<
0.001):
it
was
13
(8.8---17.2)
days
in
patients
older
than
80
years
(Fig.
1B).
In
addition,
it
was
observed
that
the
median
survival
time
was
significantly
greater
in
patients
treated
with
NAC
(p
=
0.013),
who
had
30
(17.2---42.8)
days
of
survival,
compared
to
patients
who
did
not
receive
it,
who
had
23
(8.4---37.6)
days
(Fig.
1C).
Risk
factors
and
protective
factors
of
mortality
identified
Lastly,
the
multivariate
logistic
regression
analysis
adjusted
for
the
different
treatment
regimens
identified
the
follow-
ing
risk
factors
of
mortality:
the
patient’s
age
(patients
older
than
80
years:
OR:
8.4
(95%CI:
3---23.4)),
moderate
or
severe
x-ray
involvement
measured
by
the
RALE
scale
(OR:
7.3
5

ARTICLE IN PRESS
+Model
RCENG-2128;
No.
of
Pages
8
M.A.
Galindo-Andúgar,
Á.
Arias
Arias,
J.
Alfonso
García
Guerra
et
al.
Table
3
Multivariate
analysis
of
risk
factors
of
mortality,
adjusted
for
the
main
comorbidities.
OR
(95%CI)
p
Age 65
years
or
younger
Reference
---
65
to
80
years
2.442
(0.894---6.667)
0.082
Older
than
80
years.
8.429
(3.029---23.453)
<0.001
Tobacco
use
(smoker
+
former
smoker
vs
non-smoker)
2.816
(1.1310---6.056)
0.008
Previous
arrhythmia
2.791
(1.255---6.207)
0.012
Asthma
0.190
(0.034---1.061)
0.058
Chest
x-ray Normal
Reference
---
Mild
0.846
(0.370---1.931)
0.691
Moderate
+
Severe
7.322
(3.179---16.863)
<0.001
N-acetylcysteine
0.566
(0.310−0.997)
0.049
OR:
Odds
Ratio;
CI:
confidence
interval.
XR:
x-ray.
(95%CI:
3.2---16.9)),
tobacco
use
(OR:
2.8
(95%CI:
1.3---6.1)),
and
previous
arrhythmia
(OR:
2.8
(95%CI:
1.3---6.2)).
On
the
contrary,
treatment
with
NAC
was
identified
as
a
protective
factor
(OR:
0.57
(95%CI:
0.31---0.99)).
Asthma
also
seemed
to
be
a
protective
factor
to
a
certain
degree,
though
this
finding
was
not
statistically
significant
(OR:
0.19
(95%CI:
0.03---1.06))
(Table
3).
Similar
results
were
found
in
the
Cox
regression
analysis
(Supplementary
material,
Table
A.4)
Discussion
This
study
showed
that
the
oral
administration
of
NAC
at
a
dose
of
1200
mg
per
day
was
associated
with
lower
mortal-
ity
in
patients
hospitalized
due
to
COVID-19.
The
risk
factors
identified
by
means
of
logistic
regression
were
age,
greater
radiological
involvement,
tobacco
use,
and
presence
of
prior
arrhythmia
whereas
treatment
with
NAC
was
a
protective
factor.
In
regard
to
asthma,
the
use
of
inhaled
corticos-
teroids
seemed
to
confer
a
certain
degree
of
protection
against
SARS-CoV-2,
as
it
reduced
ACE2
receptor
expression
in
the
lungs.14,15
As
shown
in
other
studies,
the
use
of
NAC
at
high
doses
(≥1200
mg/day)
may
have
beneficial
effects
due
to
its
antioxidant
and
anti-inflammatory
action.
This
would
help
prevent
production
of
oxygen
free
radicals
and
the
cytokine
storm
in
COVID-19.16,17 On
the
other
hand,
NAC
may
have
a
modulating
role
in
ACE2
receptors,
hindering
the
binding
of
SARS-CoV-2
to
protein
S
and
its
entry
into
the
cell.18 This
effect
is
maintained
even
with
the
new
variants,
including
Delta
and
Omicron.19 Findings
have
recently
been
published
on
its
role
in
reducing
inflammasomes
in
samples
obtained
through
tracheal
biopsy
in
severe
patients
with
COVID-19
treated
with
NAC.20
The
low
cost
of
NAC
and
its
good
safety
profile----with
very
few
side
effects
even
at
high
doses----make
it
pos-
sible
to
consider
it
as
a
treatment
option.
Nevertheless,
there
are
contradictory
results
on
its
therapeutic
effect.
Most
studies
include
only
a
small
percentage
of
patients
treated
with
NAC
and
the
doses
used
as
well
as
the
dura-
tion
and
route
of
administration
vary
among
the
different
works.
A
study
conducted
in
Brazil
on
135
severe
patients
who
received
intravenous
NAC
in
two
initial
doses
showed
no
differences
in
regard
to
progress
and
mortality.21 Other
studies
have
reported
improvements
in
mortality
and
inflam-
matory
patterns,
although
findings
were
not
statistically
significant.22,23 A
Greek
study
on
82
patients
who
received
the
same
dose
of
NAC
as
in
this
study
(1200
mg/day
orally)
showed
a
reduction
in
mortality
and
the
need
for
inva-
sive
mechanical
ventilation.16 One
of
the
studies
with
the
largest
number
of
cases
included
2071
patients
treated
with
NAC
at
a
dose
of
1800
mg/day.
It
also
showed
lower
mor-
tality
in
those
who
received
NAC,
though
there
were
no
statistically
significant
differences
in
regard
to
the
need
for
invasive
mechanical
ventilation.17 One
of
the
difficulties
is
establishing
the
most
suitable
dose
(in
terms
of
safety
and
efficacy),
considering
that
the
effects
of
NAC
are
highly
dependent
on
the
dose
administered.
In
general,
a
minimum
NAC
dose
of
1200
mg/day
orally
is
recommended.
In
patients
with
severe
disease
and
respiratory
compromise,
an
intra-
venous
NAC
dose
of
100
mg/kg
can
be
used
for
at
least
three
days.24
Two
meta-analyses
have
recently
been
published.
The
work
by
Paraskevas25 included
eight
studies
and
showed
no
significant
differences
in
favor
of
NAC,
though
the
authors
6

ARTICLE IN PRESS
+Model
RCENG-2128;
No.
of
Pages
8
Revista
Clínica
Española
xxx
(xxxx)
xxx---xxx
recognize
the
low
level
of
evidence
(mainly
due
to
the
small
number
of
patients)
and
the
need
for
future
research.
The
work
by
Chen26 also
showed
no
differences
in
mortality,
need
for
intubation,
or
length
of
hospital
stay.
However,
the
clinical
trial
by
Panahi
which
included
250
patients
and
in
which
the
treatment
group
received
nebulized
NAC
did
show
benefits
in
the
decrease
in
mortality
and
inflammatory
parameters.27 At
present,
there
are
various
clinical
trials
on
the
use
of
NAC
in
COVID-19
which
will
help
clarify
these
issues.28
This
study
has
several
limitations.
First,
it
is
an
obser-
vational
study.
Therefore,
the
results
obtained
must
be
confirmed
by
future
randomized,
controlled
clinical
trials.
Second,
patients
were
treated
according
to
the
protocols
in
force
at
the
hospital,
which
included
other
drugs
with
a
possible
beneficial
effect
in
COVID-19.
To
minimize
this
limitation,
patients
were
divided
into
treatment
subgroups
according
to
whether
they
received
NAC
or
not
and
this
vari-
able
was
used
to
adjust
the
multivariate
analysis.
Third,
patients
with
the
new
Delta
and
Omicron
variants
were
not
included,
though
the
available
evidence
shows
that
NAC
may
have
the
same
effect
on
these
variants.19,24 This
study
also
had
strengths.
The
sample
included
a
large
num-
ber
of
patients
and
it
was
homogeneous
and
representative
of
patients
in
the
first
wave,
in
which
the
effect
of
NAC
could
be
studied
as
there
were
no
specific
treatments
for
these
patients
yet.
The
information
collected
was
exhaus-
tive
and
all
data
were
reviewed
and
verified,
especially
data
regarding
treatment
received.
Grouping
patients
with
similar
treatments
made
it
possible
to
note
the
effect
of
NAC.
At
present,
thanks
to
the
evolution
of
COVID-19,
it
is
difficult
to
recruit
a
group
of
patients
with
these
character-
istics.
In
conclusion,
the
use
of
NAC
at
high
doses
in
patients
with
COVID-19
decreased
mortality
and
was
associated
with
more
favorable
progress.
Future
randomized
clinical
trials
or
prospective
studies
may
help
confirm
the
role
of
NAC
in
these
patients.
Until
then,
the
low
cost
and
good
safety
pro-
file
of
NAC
make
it
a
reasonable
choice
as
an
associated
treatment.
Ethical
considerations
This
work
was
conducted
in
accordance
with
the
ethics
code
of
the
World
Medical
Association
(Declaration
of
Helsinki).
The
study
protocol
was
approved
by
the
Drug
Research
Ethics
Committee
(DREC)
of
the
Comprehensive
Care
Management
of
Alcázar
de
San
Juan.
Funding
This
research
has
received
neither
finantial
support
nor
spe-
cific
grants
from
agencies
in
the
public,
commercial,
or
non-profit
sectors.
Conflicts
of
interest
The
authors
declare
that
they
do
not
have
any
conflicts
of
interest.
References
1.
De
Flora
S,
Balansky
R,
La
Maestra
S.
Rationale
for
the
use
of
N-acetylcysteine
in
both
prevention
and
adjuvant
therapy
of
COVID-19.
FASEB
J.
2020;34:13185---93.
2.
Suhail
S,
Zajac
J,
Fossum
C,
Lowater
H,
McCracken
C,
Sev-
erson
N,
et
al.
Role
of
oxidative
stress
on
SARS-CoV
(SARS)
and
SARS-CoV-2
(COVID-19)
infection:
a
review.
Protein
J.
2020;39:644---56.
3.
Nasi
A,
McArdle
S,
Gaudernack
G,
Westman
G,
Melief
C,
Rock-
berg
J,
et
al.
Reactive
oxygen
species
as
an
initiator
of
toxic
innate
immune
responses
in
retort
to
SARS-CoV-2
in
an
age-
ing
population,
consider
N-acetylcysteine
as
early
therapeutic
intervention.
Toxicol
Rep.
2020;7:768---71.
4.
Mohanty
RR,
Padhy
BM,
Das
S,
Meher
BR.
Therapeutic
poten-
tial
of
N-acetyl
cysteine
(NAC)
in
preventing
cytokine
storm
in
COVID-19:
review
of
current
evidence.
Eur
Rev
Med
Pharmacol
Sci.
2021;25:2802---7.
5.
Santos
AF,
Póvoa
P,
Paixão
P,
Mendonc¸a
A,
Taborda-Barata
L.
Changes
in
glycolytic
pathway
in
SARS-COV
2
infection
and
their
importance
in
understanding
the
severity
of
COVID-19.
Front
Chem.
2021;9:685196.
6.
Poe
FL,
Corn
J.
N-Acetylcysteine:
a
potential
therapeutic
agent
for
SARS-CoV-2.
Med
Hypotheses.
2020;143:109862.
7.
Bauer
SR,
Kapoor
A,
Rath
M,
Thomas
SA.
What
is
the
role
of
supplementation
with
ascorbic
acid,
zinc,
vitamin
D,
or
N-
acetylcysteine
for
prevention
or
treatment
of
COVID-19?
Cleve
Clin
J
Med.
2020,
doi:10.3949/ccjm.87a.ccc046.
8.
Akhter
J,
Quéromès
G,
Pillai
K,
Kepenekian
V,
Badar
S,
Mekkawy
AH,
et
al.
The
combination
of
bromelain
and
acetylcys-
teine
(BromAc)
synergistically
inactivates
SARS-CoV-2.
Viruses.
2021;13:425.
9.
Fratta
Pasini
AM,
Stranieri
C,
Cominacini
L,
Mozzini
C.
Potential
role
of
antioxidant
and
anti-inflammatory
therapies
to
pre-
vent
severe
SARS-Cov-2
complications.
Antioxidants
(Basel).
2021;10:272.
10.
Dominari
A,
Hathaway
Iii
D,
Kapasi
A,
Paul
T,
Makkar
SS,
Cas-
taneda
V,
et
al.
Bottom-up
analysis
of
emergent
properties
of
N-acetylcysteine
as
an
adjuvant
therapy
for
COVID-19.
World
J
Virol.
2021;10:34---52.
11.
Shi
Z,
Puyo
CA.
N-Acetylcysteine
to
combat
COVID-19:
an
evi-
dence
review.
Ther
Clin
Risk
Manag.
2020;16:1047---55.
12.
Schwalfenberg
GK.
N-Acetylcysteine:
a
review
of
clinical
usefulness
(an
old
drug
with
new
tricks).
J
Nutr
Metab.
2021;2021:9949453.
13.
Casas-Rojo
JM,
Antón-Santos
JM,
Millán-Nú˜
nez-Cortés
J,
Lumbreras-Bermejo
C,
Ramos-Rincón
JM,
Roy-Vallejo
E,
et
al.
Clinical
characteristics
of
patients
hospitalized
with
COVID-19
in
Spain:
Results
from
the
SEMI-COVID-19
Registry.
Rev
Clin
Esp.
2020;220:480---94.
14.
Adir
Y,
Saliba
W,
Beurnier
A,
Humbert
M.
Asthma
and
COVID-19:
an
update.
Eur
Respir
Rev.
2021;30:210152.
15.
Izquierdo
JL,
Almonacid
C,
González
Y,
Del
Rio-Bermudez
C,
Ancochea
J,
Cárdenas
R,
et
al.
The
impact
of
COVID-19
on
patients
with
asthma.
Eur
Respir
J.
2021;57:2003142.
16.
Assimakopoulos
SF,
Aretha
D,
Komninos
D,
Dimitropoulou
D,
Lagadinou
M,
Leonidou
L,
et
al.
N-acetyl-cysteine
reduces
the
risk
for
mechanical
ventilation
and
mortality
in
patients
with
COVID-19
pneumonia:
a
two-center
retrospective
cohort
study.
Infect
Dis
(Lond).
2021;53:847---54.
17.
Izquierdo
JL,
Soriano
JB,
González
Y,
Lumbreras
S,
Ancochea
J,
Echeverry
C,
et
al.
Use
of
N-Acetylcysteine
at
high
doses
as
an
oral
treatment
for
patients
hospitalized
with
COVID-19.
Sci
Prog.
2022;105:00368504221074574.
18.
Manˇ
cek-Keber
M,
Hafner-Bratkoviˇ
c
I,
Lainˇ
sˇ
cek
D,
Benˇ
cina
M,
Govednik
T,
Orehek
S,
et
al.
Disruption
of
disulfides
within
RBD
of
SARS-CoV-2
spike
protein
prevents
fusion
and
represents
a
7

ARTICLE IN PRESS
+Model
RCENG-2128;
No.
of
Pages
8
M.A.
Galindo-Andúgar,
Á.
Arias
Arias,
J.
Alfonso
García
Guerra
et
al.
target
for
viral
entry
inhibition
by
registered
drugs.
FASEB
J.
2021;35:e21651.
19.
La
Maestra
S,
Garibaldi
S,
Balansky
R,
D’Agostini
F,
Micale
RT,
De
Flora
S.
Inhibition
of
the
cell
uptake
of
delta
and
omicron
SARS-CoV-2
pseudoviruses
by
N-acetylcysteine
irre-
spective
of
the
oxidoreductive
environment.
Cells.
2022;11:
3313.
20.
Milara
J,
Martínez-Expósito
F,
Montero
P,
Roger
I,
Bayarri
MA,
Ribera
P,
et
al.
N-acetylcysteine
reduces
inflammasome
acti-
vation
induced
by
SARS-CoV-2
proteins
in
vitro.
Int
J
Mol
Sci.
2022;23:14518.
21.
de
Alencar
JCG,
Moreira
C
de
L,
Müller
AD,
Chaves
CE,
Fukuhara
MA,
da
Silva
EA,
et
al.
Double-blind,
randomized,
placebo-controlled
trial
with
N-acetylcysteine
for
treatment
of
severe
acute
respiratory
syndrome
caused
by
coron-
avirus
disease
2019
(COVID-19).
Clin
Infect
Dis.
2021;72:
e736---41.
22.
Taher
A,
Lashgari
M,
Sedighi
L,
Rahimi-Bashar
F,
Pooro-
lajal
J,
Mehrpooya
M.
A
pilot
study
on
intravenous
N-
acetylcysteine
treatment
in
patients
with
mild-to-moderate
COVID19-associated
acute
respiratory
distress
syndrome.
Phar-
macol
Rep.
2021;73:1650---9.
23.
Avdeev
SN,
Gaynitdinova
VV,
Merzhoeva
ZM,
Berikkhanov
ZG-M.
N-acetylcysteine
for
the
treatment
of
COVID-19
among
hospi-
talized
patients.
Journal
of
Infection.
2022;84:94---118.
24.
Izquierdo-Alonso
JL,
Pérez-Rial
S,
Rivera
CG,
Peces-Barba
G.
N-acetylcysteine
for
prevention
and
treatment
of
COVID-19:
current
state
of
evidence
and
future
directions.
J
Infect
Public
Health.
2022;15:1477---83.
25.
Paraskevas
T,
Kantanis
A,
Karalis
I,
Michailides
C,
Karamouzos
V,
Koniari
I,
et
al.
N-acetylcysteine
efficacy
in
patients
hos-
pitalized
with
COVID-19
pneumonia:
a
systematic
review
and
meta-analysis.
Rom
J
Intern
Med.
2023;61:41---52.
26.
Chen
C-H,
Hung
K-F,
Huang
C-Y,
Leong
J-L,
Chu
Y-C,
Chang
C-
Y,
et
al.
Is
N-acetylcysteine
effective
in
treating
patients
with
coronavirus
disease
2019?
A
meta-analysis.
J
Chin
Med
Assoc.
2023;86:274.
27.
Panahi
Y,
Ghanei
M,
Rahimi
M,
Samim
A,
Vahedian-Azimi
A,
Atkin
SL,
et
al.
Evaluation
the
efficacy
and
safety
of
N-acetylcysteine
inhalation
spray
in
controlling
the
symptoms
of
patients
with
COVID-19:
an
open-label
randomized
controlled
clinical
trial.
J
Med
Virol.
2023;95:e28393.
28.
https://clinicaltrials.gov/ct2/results?term=acetylcysteine+
%20AND%20+Covid&Search.
(Accessed
19
June
2023).
8