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Vol. 223. Issue 8.
Pages 479-485 (October 2023)
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Vol. 223. Issue 8.
Pages 479-485 (October 2023)
Original article
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Impact of N-Acetylcysteine in the mortality of patients hospitalized with COVID-19: a retrospective cohort study
Efecto de la N-Acetilcisteína en la mortalidad de pacientes ingresados por COVID-19: estudio de cohorte retrospectivo
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M.A. Galindo-Andúgara,
Corresponding author
magalindo@sescam.jccm.es

Corresponding author.
, Á. Arias Ariasb, J. Alfonso García Guerrac, I. Fernández Visierd, J. Manuel Fernández Ibáñeze, A. Bellido Maldonadoc
a Servicio de Medicina Interna. Hospital General La Mancha Centro, Alcázar de San Juan (C. Real), Spain
b Unidad de Docencia, Investigación y Formación, Hospital General La Mancha Centro, Alcázar de San Juan (C. Real), Spain
c Sección de Neumología, Hospital General La Mancha Centro, Alcázar de San Juan (C. Real), Spain
d Sección de Aparato Digestivo, Hospital General La Mancha Centro, Alcázar de San Juan (C. Real), Spain
e Sección de Geriatría, Hospital General La Mancha Centro, Alcázar de San Juan (C. Real), Spain
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Figures (1)
Tables (3)
Table 1. Main characteristics of patients included in the study and comparison between patients who did and did not receive NAC.
Table 2. Clinical characteristics, radiological findings, and treatment regimens and comparison between patients who did and did not receive NAC.
Table 3. Multivariate analysis of risk factors of mortality, adjusted for the main comorbidities.
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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.

Keywords:
N-Acetylcysteine
COVID-19
SARS-CoV-2
Hospital mortality
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 años. 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 años; 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 clínicos aleatorizados deben confirmar el papel de la N-Acetilcisteína en pacientes con COVID-19.

Palabras clave:
N-Acetilcisteína
COVID-19
SARS-CoV-2
Mortalidad hospitalaria
Full Text
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.1 The disulfide bridges that form this interaction are fundamental, as is the equilibrium between the disulfide (SS) and thiol (-SH) groups.2

In the most severe forms of COVID-19, there is an excessive release of inflammatory mediators such as interleukin (IL)-1β, IL-2, IL-6, tumor necrosis factor (TNF)-α, and others. 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 Therefore, 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 pandemic 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 1200mg/day orally. This study aims to verify if the use of NAC had a positive impact on the progress of hospitalized patients and on reducing mortality due to COVID-19.

Patients and methodsDesign

This work is an observational, retrospective cohort study.

Patients

Adult patients admitted to the La Mancha Centro General 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 number 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 dexamethasone (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 regimens: 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 1200mg/day orally divided into two 600-mg doses. The main variables (including treatment received and mortality) 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 quantitative variables were described using mean±standard deviation (SD) or median±interquartile range (IQR) according to the variable’s distribution. Statistical methods (Kolmogorov-Smirnov or Shapiro-Wilk test) and graphic methods (histograms) were used to verify the variable’s normality.

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 qualitative 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, significant variables on the multivariate analysis, variables close to statistical significance (p<0.200), and adjustment or clinically 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 regression 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 ethical 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).

ResultsGeneral 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 similar and there are no statistically significant differences (Table 1).

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 
SexMale196 (51.9%)  89 (49.7%)  107 (53.8%)  0.432
Female182 (48.1%)  90 (50.3%)  92 (46.2%) 
Institutionalized51 (13.5%)  21 (11.7%)  30 (15.1%)  0.342 
ComorbiditiesHypertension  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 useNon-smoker288 (76.2%)  138 (77.1%)  150 (75.4%)  0.864
Active Smoker80 (21.2%)  37 (20.7%)  43 (21.6%) 
Former smoker10 (2.6%)  4 (2.2%)  6 (3%) 

NAC: N-acetylcysteine; SD: standard deviation; COPD: chronic obstructive pulmonary disease; VTD: venous thromboembolic disease.

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 differences among the eight treatment regimens used in both groups (Table 2). There were no differences in the blood tests performed.

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±6±7±0.002 
Chest XRNormal  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  – 
Maximum oxygen requiredNot 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 regimenHydroxychloroquine  15 (4%)  15 (8.4%)  <0.001
LMWH  42 (11.1%)  25 (14%)  17 (8.5%) 
Hydroxychloroquine+Azithromycin  10 (2.6%)  10 (5.6%) 
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%) 
All  161 (42.6%)  63 (35.2%)  98 (49.2%) 
Admission to the intensive care unit4 (1.1%)  1 (0.6%)  3 (1.5%)  0.625 
In-hospital death101 (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.

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 mortality 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 ventilation.

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).

Figure 1.

General survival curve (1A), survival curve according to age groups (1B) and according to N-acetylcysteine treatment (1C).

(0.18MB).
Risk factors and protective factors of mortality identified

Lastly, the multivariate logistic regression analysis adjusted for the different treatment regimens identified the following 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 (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).

Table 3.

Multivariate analysis of risk factors of mortality, adjusted for the main comorbidities.

OR (95%CI)  p 
Age65 years or youngerReference  – 
65 to 80 years2.442 (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 arrhythmia2.791 (1.255–6.207)  0.012 
Asthma0.190 (0.034–1.061)  0.058 
Chest x-rayNormal  Reference  – 
Mild  0.846 (0.370–1.931)  0.691 
Moderate+Severe  7.322 (3.179–16.863)  <0.001 
N-acetylcysteine0.566 (0.310−0.997)  0.049 

OR: Odds Ratio; CI: confidence interval. XR: x-ray.

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 1200mg per day was associated with lower mortality 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 corticosteroids 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 (≥1200mg/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 possible 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 duration 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 inflammatory 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 (1200mg/day orally) showed a reduction in mortality and the need for invasive mechanical ventilation.16 One of the studies with the largest number of cases included 2071 patients treated with NAC at a dose of 1800mg/day. It also showed lower mortality 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 1200mg/day orally is recommended. In patients with severe disease and respiratory compromise, an intravenous NAC dose of 100mg/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 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 observational 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 variable 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 number 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 exhaustive 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 characteristics.

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 profile 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 specific 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.

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