Therapeutic effect of N-acetylcysteine in severe or critical coronavirus disease 2019 pneumonia: A retrospective cohort study

Abstract

Background

Severe or critical coronavirus disease 2019 pneumonia is associated with a high mortality rate and considerable treatment cost. Although a few reports have shown that N-acetylcysteine may shorten recovery time in patients with severe acute respiratory syndrome coronavirus 2 infection, its effect on mortality or disease progression in patients with severe or critical coronavirus disease 2019 pneumonia has not been investigated. This study aimed to evaluate the effect of N-acetylcysteine on mortality or disease progression, hospital stay, and hospitalization costs in patients with severe or critical coronavirus disease 2019 pneumonia.

Methods

This single-center, retrospective cohort study included 221 patients with severe or critical coronavirus disease 2019 pneumonia who were hospitalized at the Department of Respiratory and Critical Care Medicine, Huashan Hospital from December 2022 to January 2023. After 1:1 propensity score matching, 176 patients were divided into two groups based on whether oral N-acetylcysteine was administered for at least 3 days. Binary logistic regression was used to analyze the effect of N-acetylcysteine on mortality or disease progression, whereas its effect on 28- or 90-day mortality was analyzed using Cox regression.

Results

Binary logistic regression analysis showed that N-acetylcysteine was associated with a reduced risk of the composite endpoint of mortality or disease progression during hospitalization (odds ratio = 0.288, 95% confidence interval: 0.147–0.793, p = 0.011). However, N-acetylcysteine was not significantly associated with hospitalization costs, length of hospital stay, or the use of high-flow oxygen or mechanical ventilation. In addition, no significant association was observed between N-acetylcysteine use and 28- or 90-day mortality. Given the retrospective design and potential residual confounding, these findings should be interpreted as exploratory.

Conclusions

In this retrospective cohort study, treatment with N-acetylcysteine for at least 3 days was associated with a possible reduction in mortality or disease progression during hospitalization in patients with severe or critical coronavirus disease 2019 pneumonia. Prospective studies are needed to confirm these observations.

Keywords

N-acetylcysteine coronavirus disease 2019 pneumonia severe acute respiratory syndrome coronavirus 2

Introduction

Coronavirus disease 2019 (COVID-19) is an infectious disease with high transmissibility, high morbidity, high severe rate, and high mortality, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.¹ COVID-19 can range from asymptomatic infection to critical illness and death, with severe and critical cases accounting for 20% of all cases. Mortality is extremely high in severe and critically ill patients with COVID-19 owing to a high risk of respiratory failure, sepsis shock, and multiorgans failure.^2,3 The lungs are the most affected organs in patients with COVID-19 and are characterized by diffuse exudation, inflammatory storm, inflammatory cell infiltration, fibrosis, and severe hypoxia or respiratory failure.^4–6 Therefore, it is necessary to study and identify more adjuvant drugs in addition to antivirus drugs to reduce organ injury and mortality in patients with severe and critical COVID-19 pneumonia.

SARS-CoV-2 upregulates intracellular reactive oxygen species (ROS) levels by binding virus spike (S) proteins with the angiotensin-converting enzyme 2 (ACE2) expressed in alveolar cells.^7–9 In addition, SARS-CoV-2 can inactivate ACE2, which leads to an redox imbalance in the cells.^10,11 Ultimately, increased ROS may facilitate SARS-CoV-2 replication and aggravate pulmonary injury.^12–14

Glutathione (GSH), the major scavenger of ROS in cells is synthesized from cysteine, glutamate, and glycine. N-acetylcysteine (NAC), a type of antioxidant and free radical scavenger, acts primarily by promoting the synthesis of GSH by hydrolyzing to cysteine in cells.^15–17 In contrast, NAC also maintains a redox balance by inhibiting ACE2 activity.¹⁸ Several meta-analyses have assessed the role of NAC in COVID-19; however, the findings remain heterogeneous.¹⁹ Some studies have suggested that intravenous NAC shortens hospital stay and improves symptoms without reducing the intensive care unit (ICU) admission or 28-day mortality rates,²⁰ whereas others report benefits in terms of improvement in inflammatory markers and oxygen saturation, which are associated with reduced mortality.²¹ Mechanistic studies have reported that NAC may inhibit the replication and intracellular invasion of SARS-CoV-2 and reduce the production of proinflammatory mediators,^22–26 and several clinical studies have suggested reduced mortality.^27,28 Despite these findings, most existing studies have notable limitations: they often pooled patients across all disease severities, were predominantly conducted in Western populations, and primarily relied on randomized controlled trials (RCTs) with stringent eligibility criteria. Consequently, the effect of NAC on mortality or disease progression specifically in severe or critically ill patients, a high-risk population with substantially worse outcomes, remains less well characterized, particularly in East Asian real-world settings. To address the abovementioned gaps, this retrospective cohort study aimed to investigate the effect of NAC on the composite endpoint mortality and disease progression as well as secondary outcomes, including hospital stay, hospitalization costs, and use of high-flow nasal cannula oxygen therapy (HFNC) or mechanical ventilation, in patients with severe or critical COVID-19 pneumonia in China.

Methods

Study design and participants

This single-center retrospective cohort study included patients who met the following inclusion criteria: (a) clinical manifestations consistent with SARS-CoV-2 infection; (b) a positive result for either SARS-CoV-2 RNA or antigen test; and (c) hospitalization for severe or critical COVID-19 pneumonia at Huashan Hospital between December 2022 and February 2023. Severe COVID-19 pneumonia was defined as meeting at least one of the following criteria: (a) respiratory rate ≥30 breaths/min; (b) oxygen saturation ≤93% at rest; (c) partial pressure of arterial oxygen(PaO₂)/fraction of inspired oxygen (FiO₂) ≤300 mmHg; or (d) progressive symptoms with chest computed tomography (CT) findings indicating >50% lesion progression within 24–48 h. Critical COVID-19 pneumonia was defined as meeting any of the following criteria: (a) respiratory failure and requirement of mechanical ventilation; (b) sepsis shock; and (c) requirement of ICU monitoring for the multiorgan failure.²

Propensity score matching (PSM)

In total, 221 patients with severe or critical COVID-19 pneumonia hospitalized at Huashan Hospital from December 2022 to January 2023 were initially enrolled (Figure 1). Patients were divided into NAC (0.2 g thrice daily for ≥3 days, n = 95) and non-NAC (n = 126) groups. To minimize confounding, we performed 1:1 PSM using a logistic regression model, which included sex, age (>75 vs. ≤75 years), COVID-19 vaccination history (yes/no), modified early warning score (MEWS; ≥2 vs. 0–1), chronic disease (yes/no, including chronic respiratory disease, chronic cardiovascular disease, and chronic kidney disease), use of paxlovid (yes/no), and need for oxygen therapy at admission (yes/no) at admission. Matching was nearest neighbor without replacement (caliper = 0.2 × SD of logit propensity score (PS)). Balance was assessed using standardized mean differences (SMDs, <0.1 acceptable). The overlap of propensity score distributions was visually confirmed. Post-admission variables (glucocorticoid use and prone positioning) were not included in the PSM model. After matching, 176 patients (88 per group) were included (Figure 1).

Figure 1.

Flow diagram of patient selection and propensity score matching.

Outcomes

The primary outcome was the composite endpoint of mortality or disease progression during hospitalization. Secondary outcomes included total hospitalization cost, length of hospital stay, use of HFNC or mechanical ventilation, and 28- and 90-day mortality.

Statistical analyses

Univariate and multivariable binary logistic regression were used for the composite endpoint and HFNC/mechanical ventilation. For binary outcomes, variables with p <0.05 in the univariate analysis were included in the multivariable model, along with age and MEWS (the two PSM-imbalanced variables). Multivariable linear regression was (log10-transformed cost and untransformed length of stay) adjusted for age, sex, MEWS, chronic disease, vaccination, paxlovid, oxygen therapy, prone positioning, and glucocorticoid use. The effect of NAC on 28- and 90-day mortality was analyzed using Cox proportional hazards regression. All tests were two-sided with p <0.05 considered significant. Analyses were performed using the Statistical Package for Social Sciences (SPSS) software (version 20, IBM Corp.; Armonk, NY, USA).

Reporting guideline

This study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline for cohort studies. A completed STROBE checklist is provided in the Supplementary Materials.

Results

Clinical characteristics of patients

Among the 221 patients with severe or critical COVID-19 pneumonia, 95 received oral NAC for ≥3 days, whereas 126 did not (non-NAC group). Baseline characteristics of the study participants are presented in Table 1. Before PSM, imbalances were observed in paxlovid use (SMD = 0.312), COVID-19 vaccination history (SMD = 0.112), NEWS (SMD = 0.240), and age distribution (SMD = 0.232). After 1:1 matching, 176 patients (88 per group) were included. Balance was assessed using SMD (<0.1 acceptable). As shown in Table 1(SMD > 0.1 bolded), most covariates were well-balanced. However, residual imbalance remained for age (SMD = 0.136) and MEWS (SMD = 0.223), with the NAC group having a higher proportion of patients with MEWS ≥2 (26.1% vs. 17.0%) and age ≤75 years (53.4% vs. 46.6%). Therefore, age and MEWS were adjusted for in multivariable models. All other covariates, including paxlovid use, were well-balanced after matching.

Table 1.

Clinical characteristics of patients before and after propensity score matching.

	Before matching			After matching
	Non-NAC group (N = 126)	NAC group (N = 95)	SMD	Non-NAC group (N = 88)	NAC group (N = 88)	SMD
Sex (%)			0.091			0.092
Female	52 (41.3)	35 (36.8)		36 (40.9)	32 (36.4)
Male	74 (58.7)	60 (63.2)		52 (59.1)	56 (63.6)
Age (%)			0 . 232			0.136
≤75 years	57 (45.2)	54 (56.8)		41 (46.6)	47 (53.4)
>75 years	69 (54.8)	41 (43.2)		47 (53.4)	41 (46.6)
COVID-19 vaccination history (%)			0.112			0.069
No	70 (55.6)	58 (61.1)		52 (59.1)	55 (62.5)
Yes	56 (44.4)	37 (38.9)		36 (40.9)	33 (37.5)
Chronic disease (%)			0.06			0.046
0–1	56 (44.4)	45 (47.4)		44 (50.0)	42 (47.7)
≥2	70 (55.6)	50 (52.6)		44 (50.0)	46 (52.3)
Smoking status (%)			0.032			0.091
No	119 (94.4)	89 (93.7)		81 (92.0)	83 (94.3)
Yes	7 (5.6)	6 (6.3)		7 (8.0)	5 (5.7)
MEWS (%)			0.24			0.223
0–1	104 (82.5)	69 (72.6)		73 (83.0)	65 (73.9)
≥2	22 (17.5)	26 (27.4)		15 (17.0)	23 (26.1)
Gammaglobulin use^a (%)			0.07			0.03
No	108 (85.7)	79 (83.2)		74 (84.1)	73 (83.0)
Yes	18 (14.3)	16 (16.8)		14 (15.9)	15 (17.0)
Paxlovid use (%)			0.312			0.022
No	79 (62.7)	45 (47.4)		45 (51.1)	44 (50.0)
Yes	47 (37.3)	50 (52.6)		43 (48.9)	44 (50.0)
Glucocorticoid use^a (%)			0.111			0.162
No	56 (44.4)	37 (38.9)		41 (46.6)	34 (38.6)
Yes	70 (55.6)	58 (61.1)		47 (53.4)	54 (61.4)
HFNC or mechanical ventilation^a (%)			0.069			0
No	100 (79.4)	78 (82.1)		72 (81.8)	72 (81.8)
Yes	26 (20.6)	17 (17.9)		16 (18.2)	16 (18.2)
Prone position ventilation^a (%)			0.363			0.287
No	103 (81.7)	63 (66.3)		70 (79.5)	59 (67.0)
Yes	23 (18.3)	32 (33.7)		18 (20.5)	29 (33.0)

SMD <0.1 indicates acceptable balance. Variables marked with ^a are post-admission interventions not included in the PSM model.

Bolded values indicate statistical significance (p < 0.05).

HFNC: high-flow nasal cannula; MEWS: modified early warning score; NAC: N-acetylcysteine; SMD: standardized mean difference; COVID-19: coronavirus disease 2019; PSM: propensity score matching.

NAC might reduce the composite endpoint mortality or disease progression in patients with severe or critical COVID-19 pneumonia

Univariate binary logistic regression analysis showed that NAC use and COVID-19 vaccination history were associated with a lower risk of mortality or disease progression during hospitalization in patients with severe or critical COVID-19 pneumonia, whereas age >75 years and use of HFNC or mechanical ventilation were associated with a higher risk (Table 2). Multivariable binary logistic regression identified age >75 years (odds ratio (OR) = 2.335, 95% confidence interval (CI): 0.932–5.854, p = 0.070), use of HFNC or mechanical ventilation (OR = 6.506, 95% CI: 2.497–16.955, p < 0.0001), and NAC (OR = 0.292, 95% CI: 0.112–0.763, p = 0.012) as independent risk factors for the composite endpoint (Table 2). However, Cox regression analysis suggested that only high-flow oxygen or mechanical ventilation was an independent risk factor for 28- and 90-day mortality (STable 1 and 2).

Table 2.

Logistic regression analysis of the effect of N-acetylcysteine on the composite endpoint mortality or disease progression in patients with severe or critical COVID-19 pneumonia.

Characteristics	Comparison for OR	Univariate analysis		Multivariate analysis
Characteristics	Comparison for OR	OR (95% CI)	p-value	OR (95% CI)	p-value
Sex	Male vs. female	2.029 (0.850–4.843)	0.111
Age (years)	>75 vs. ≤75	2.926 (1.261–6.788)	0 . 012	2.335 (0.932–5.854)	0.070
COVID-19 vaccination history	Yes vs. no	0.39 (0.158–0.964)	0.041	0.432 (0.159–1.174)	0.100
Smoking	Yes vs. no	1.619 (0.412–6.362)	0.49
Chronic disease	≥2 vs. 0–1	1.65 (0.747–3.646)	0.216
MEWS	≥2 vs. 0–1	1.333 (0.542–3.277)	0.531	1.577 (0.545–4.560)	0.432
Gammaglobulin use	Yes vs. no	0.97 (0.338–2.778)	0.954
Paxlovid use	Yes vs. no	0.693 (0.316–1.518)	0.359
Glucocorticoid use	Yes vs. no	1.034 (0.471–2.269)	0.933
High-flow oxygen or mechanical ventilation	Yes vs. no	7.059 (2.965–16.803)	<0.0001	6.506 (2.497–16.955)	<0.0001
Prone position ventilation	Yes vs. no	1.152 (0.488–2.720)	0.747
NAC use	Yes vs. no	0.342 (0.147–0.793)	0.012	0.292 (0.112–0.763)	0.012

COVID-19: coronavirus disease 2019; MEWS: Modified Early Warning score; OR: odds ratio; CI: confidence interval; NAC: N-acetylcysteine.

Bolded values indicate statistical significance (p < 0.05).

NAC might not reduce hospitalization costs for patients with severe or critical COVID-19 pneumonia

Multivariable linear regression analysis (Table 3) showed that age >75 years (B = 0.159, 95% CI: 0.067–0.251, p = 0.001), gamma globulin use (B = 0.323, 95% CI: 0.198–0.448, p < 0.001), paxlovid use (B = 0.103, 95% CI: 0.009–0.196, p = 0.031), and HFNC or mechanical ventilation (B = 0.293, 95% CI: 0.171–0.415, p < 0.001) were independently associated with higher hospitalization costs. In contrast, COVID-19 vaccination history was associated with lower hospitalization costs (B = −0.136, 95% CI: −0.230 to −0.042, p = 0.005). N-acetylcysteine (NAC) use did not show a statistically significant association with hospitalization costs (B = 0.059, 95% CI: −0.031 to 0.149, p = 0.195).

Table 3.

Multivariable linear regression analysis of the effect of N-acetylcysteine on the hospitalization cost of patients with severe or critical COVID-19 pneumonia.

Characteristics	Unstandardized coef		Standardized coef	t	P	95% CI		Collinearity diagnostics
Characteristics	B	SE	β	t	P	lower limit	upper limit	tolerance	VIF
Sex (male vs. female)	0.045	0.048	0.061	0.937	0.350	−0.050	0.140	0.901	1.109
Age (>75 vs. ≤75 years)	0.159	0.047	0.221	3.420	0.001	0.067	0.251	0.916	1.092
COVID-19 vaccination history (yes vs. no)	−0.136	0.048	−0.185	−2.861	0.005	−0.230	−0.042	0.915	1.093
Smoking status (yes vs. no)	0.150	0.094	0.105	1.589	0.114	−0.036	0.336	0.874	1.144
Chronic disease (≥2 vs. 0–1)	0.012	0.019	0.040	0.632	0.529	−0.025	0.049	0.928	1.078
MEWS (≥2 vs. 0–1)	−0.005	0.058	−0.006	−0.091	0.927	−0.120	0.110	0.862	1.161
Gamma globulin use (yes vs. no)	0.323	0.063	0.332	5.105	0.000	0.198	0.448	0.900	1.112
Paxlovid use (yes vs. no)	0.103	0.047	0.142	2.172	0.031	0.009	0.196	0.887	1.128
Glucocorticoid use (yes vs. no)	0.007	0.048	0.010	0.152	0.880	−0.087	0.101	0.892	1.121
High-flow oxygen or mechanical ventilation (yes vs. no)	0.293	0.062	0.314	4.728	0.000	0.171	0.415	0.867	1.153
Prone position ventilation (yes vs. no)	−0.059	0.054	−0.072	−1.086	0.279	−0.165	0.048	0.867	1.154
NAC use (yes vs. no)	0.059	0.046	0.082	1.301	0.195	−0.031	0.149	0.952	1.051

Hospital cost was natural log-transformed to approximate normality.

Bolded values indicate statistical significance (p < 0.05).

CI: confidence interval; SE: standard error; COVID-19: coronavirus disease 2019; coef: coefficient; VIF: variance inflation factor; MEWS: Modified Early Warning score; NAC: N-acetylcysteine.

NAC had no significant effect on the hospital stay of patients with severe or critical COVID-19 pneumonia

Multivariable linear regression analysis (Table 4) showed that age >75 years (B = 3.834, 95% CI: 1.396–6.272, p = 0.002), paxlovid use (B = 3.425, 95% CI: 0.947–5.904, p = 0.007), and HFNC or mechanical ventilation (B = 6.248, 95% CI: 3.001–9.496, p < 0.001) were independently associated with longer hospital stays. COVID-19 vaccination history was associated with shorter hospital stays (B = −2.615, 95% CI: −5.114 to −0.116, p = 0.040). N-acetylcysteine (NAC) use did not show a statistically significant association with hospital stays (B = 0.966, 95% CI: −1.426 to 3.357, p = 0.427). Other covariates, including sex, smoking status, chronic disease, MEWS, gamma globulin use, glucocorticoid use, and prone positioning, were not significantly associated with length of stay (all p > 0.05).

Table 4.

Multivariate linear regression analysis of the effect of N-acetylcysteine on hospital stay in patients with severe or critical COVID-19 pneumonia.

Characteristics	Unstandardized coef		Standardized coef	t	P	95% CI		Collinearity diagnostics
Characteristics	B	SE	β	t	P	lower limit	upper limit	tolerance	VIF
Sex (male vs. female)	−1.514	1.278	−0.085	−1.184	0.238	−4.037	1.010	0.901	1.109
Age (>75 vs. ≤75)	3.834	1.235	0.221	3.105	0.002	1.396	6.272	0.916	1.092
COVID-19 vaccination history (yes vs. no)	−2.615	1.265	−0.147	−2.067	0.040	−5.114	−0.116	0.915	1.093
Smoking status (yes vs. no)	2.325	2.507	0.068	0.927	0.355	−2.625	7.274	0.874	1.144
Chronic disease (≥2 vs. 0–1)	−0.088	0.495	−0.013	−0.177	0.859	−1.065	0.890	0.928	1.078
MEWS (≥2 vs. 0–1)	−1.211	1.547	−0.057	−0.783	0.435	−4.265	1.844	0.862	1.161
Gamma globulin use (yes vs. no)	1.438	1.679	0.061	0.857	0.393	−1.877	4.754	0.900	1.112
Paxlovid use (yes vs. no)	3.425	1.255	0.197	2.730	0.007	0.947	5.904	0.887	1.128
Glucocorticoid use (yes vs. no)	2.359	1.265	0.134	1.865	0.064	−0.138	4.856	0.892	1.121
High-flow oxygen or mechanical ventilation (yes vs. no)	6.248	1.645	0.278	3.799	0.000	3.001	9.496	0.867	1.153
Prone position ventilation (yes vs. no)	−2.273	1.434	−0.116	−1.584	0.115	−5.105	0.560	0.867	1.154
NAC use (yes vs. no)	0.966	1.211	0.056	0.797	0.427	−1.426	3.357	0.952	1.051

CI: confidence interval; SE: standard error; COVID-19: coronavirus disease 2019; coef: coefficient; VIF: variance inflation factor; MEWS: Modified Early Warning score; NAC: N-acetylcysteine.

Bolded values indicate statistical significance (p < 0.05).

NAC had no significant effect on the application proportion of HFNC or mechanical ventilation in patients with severe or critical COVID-19 pneumonia

The results of univariate logistic regression analysis found that male sex, MEWS value, and glucocorticoid use were related to higher rates of HFNC or mechanical ventilation, whereas NAC (OR = 1.000, 95% CI = 0.465–2.151, p = 1.000) had no significant effect on the usage proportion of HFNC or mechanical ventilation in patients with severe or critical COVID-19 pneumonia (Table 5). Consistent with the above, male sex (OR = 2.715, 95% CI: 1.074–6.866, p = 0.035) and glucocorticoid use (OR = 2.633, 95% CI: 1.080–6.42, p = 0.033) were independent risk factors of higher application proportion of HFNC or mechanical ventilation in patients with severe or critical COVID-19 pneumonia according to multivariate logistic regression (Table 5).

Table 5.

Logistic regression analysis of the effect of N-acetylcysteine on the application proportion of HFNC or mechanical ventilation in patients with severe or critically ill COVID-19 pneumonia.

Characteristics	Comparison for OR	Univariate analysis		Multivariate analysis
Characteristics	Comparison for OR	OR (95% CI)	p-value	OR (95% CI)	p-value
Sex	Male vs. female	2.625 (1.066–6.462)	0 . 036	2.715 (1.074–6.866)	0.035
Age (years)	＞75 vs. ≤75	1.589 (0.730–3.457)	0.243	1.986 (0.871–4.530)	0.103
COVID-19 vaccination history	Yes vs. No	0.454 (0.191–1.078)	0.073
Smoking	Yes vs. No	1.552 (0.396–6.087)	0.529
Chronic disease	≥2 vs. 0–1	1.503 (0.691–3.270)	0.305
MEWS	≥2 vs. 0–1	1.883 (0.802–4.423)	0.146	2.138 (0.860–5.316)	0.102
Gamma globulin	Yes vs. No	1.952 (0.775–4.920)	0.156
Paxlovid	Yes vs. No	1.633 (0.751–3.555)	0.216
Glucocorticoid use	Yes vs. No	2.610 (1.100–6.197)	0.030	2.633 (1.080–6.420)	0.033
Prone position ventilation	Yes vs. No	2.214 (0.991–4.944)	0.053
NAC use	Yes vs. No	1.000 (0.465–2.151)	1.000	0.879 (0.388–1.992)	0.757

OR: odds ratio; CI: confidence interval; COVID-19: coronavirus disease 2019; MEWS: Modified Early Warning score; NAC: N-acetylcysteine; HFNC: high-flow nasal cannula oxygen therapy.

Bolded values indicate statistical significance (p < 0.05).

Discussion

Considering the high incidence of COVID-19 and the elevated mortality among patients with severe or critical COVID-19 pneumonia, further research is urgently needed to lower the mortality rate in this population. Although antiviral therapies such as paxlovid and VV116 have been shown to reduce disease severity in high-risk patients,^29–31 additional therapeutic drugs may be required to potentially reduce the mortality rate among patients with severe or critical COVID-19 pneumonia.

NAC, a nutraceutical precursor of the important antioxidant GSH, plays multiple biological roles in mammals and microbes.²² It may induce GSH synthesis, thereby enhancing antioxidant effect and reducing glycation of intracellular proteins; it also inhibits nuclear factor kappa B (NF-κB), which in turn suppresses the production of proinflammatory cytokines and chemokines.²²

Clinical studies on NAC in COVID-19 have yielded inconsistent results. Izquierdo et al.²⁷ reported that high-doses NAC (600 mg every 8 h) are associated with significantly lower mortality, with no effect on the mean hospital stay or need for invasive mechanical ventilation. In an open-label RCT, Panahi et al.²⁸ found that NAC inhaler spray (one puff per 12 h for 7 days) reduced the mortality rate but did not affect the length of hospital stay. In contrast, Taher et al.³² observed no significant difference in the 28-day mortality between NAC and placebo groups among COVID-19–associated acute respiratory distress syndrome (ARDS) patients. Faverio et al.³³ reported no difference in in-hospital mortality, but noted a shorter length of hospital stay, whereas Alencar et al.³⁴ reported that high-dose NAC does not affect the need for mechanical ventilation. Thus, although several studies have examined the effect of NAC use on mortality, hospital length of stay, and mechanical ventilation in COVID-19 patients, the results vary considerably. This heterogeneity may be explained by differences in the inclusion/exclusion criteria (disease severity, comorbidities, and age), study design (prospective vs. retrospective, few RCTs), substantial variation in NAC dosage, treatment duration, and route of administration as well as limited sample sizes in some reports.

Despite the above, no reliable study has specifically evaluated the effect of NAC on disease progression and mortality in severe COVID-19 pneumonia. In our study, oral NAC (0.2 g three times daily) for ≥3 days was associated with a reduced risk of the composite endpoint of mortality or disease progression during hospitalization in patients with severe or critical COVID-19 pneumonia. However, NAC use was not significantly associated with total hospitalization costs, length of stay, the need for HFNC or mechanical ventilation, or 28- and 90-day mortality. Our findings extend the previous meta-analyses in several ways. First, although prior studies have suggested benefits in terms of recovery time and inflammatory markers, we provide preliminary evidence that NAC may reduce a clinically meaningful composite endpoint not systematically assessed before. Second, we focused exclusively on the high-risk subgroup of severe/critically ill patients, whereas many previous analyses pooled heterogeneous patient populations. Third, our real-world data from an East Asian cohort complement the predominantly Western literature and enhance the generalizability of evidence on NAC use in COVID-19 patients. Notably, the lack of significant effects on costs, length of stay, and short-term mortality helps define the boundaries of NAC's therapeutic benefits and prevents an overestimation of its efficacy.

This study has certain limitations. First, it was a single-center retrospective study, inherently subject to selection bias and residual confounding despite PSM. Some residual imbalance (e.g. MEWS and age) remained, although we adjusted for it in multivariable models. Second, the composite endpoint combined mortality and disease progression. Although this increased the statistical power of the analyses, it assumes comparable clinical importance of both components. The observed benefit was driven primarily by a reduction in nonfatal events (disease progression), which is consistent with NAC's anti-inflammatory mechanism; however, this interpretation remains speculative and requires prospective validation with predefined hierarchical endpoints. Third, NAC was used at a standard mucolytic dose (0.2 g three times daily) reflecting real-world practice, which is lower than the doses used in other regimens shown to more effectively target oxidative stress in previous studies. Therefore, the absence of a significant mortality benefit may, at least in part, be attributable to dose selection, and future dose-optimization studies are warranted. Fourth, several effect estimates had wide CIs, reflecting the modest sample size and low event rates in certain subgroups. Thus, our findings should be considered exploratory and hypothesis-generating, requiring confirmation in larger cohorts. Fifth, we could not adjust for COVID-19 vaccination status (type/doses) or primary infection versus reinfection, as these data were not systematically captured in electronic medical records during the study period, which may have introduced residual confounding. Given these limitations, future multicenter prospective RCTs with larger sample size are needed to further investigate and potentially validate our therapeutic observations.

Supplemental Material

sj-doc-1-imr-10.1177_03000605261463447 - Supplemental material for Therapeutic effect of N-acetylcysteine in severe or critical coronavirus disease 2019 pneumonia: A retrospective cohort study

Supplemental material, sj-doc-1-imr-10.1177_03000605261463447 for Therapeutic effect of N-acetylcysteine in severe or critical coronavirus disease 2019 pneumonia: A retrospective cohort study by Xin Jin, Yu Zhao and Xiaofei Jiang in Journal of International Medical Research

Supplemental Material

sj-docx-1-imr-10.1177_03000605261463447 - Supplemental material for Therapeutic effect of N-acetylcysteine in severe or critical coronavirus disease 2019 pneumonia: A retrospective cohort study

Supplemental material, sj-docx-1-imr-10.1177_03000605261463447 for Therapeutic effect of N-acetylcysteine in severe or critical coronavirus disease 2019 pneumonia: A retrospective cohort study by Xin Jin, Yu Zhao and Xiaofei Jiang in Journal of International Medical Research

Footnotes

Acknowledgments

We thank all the patients who participated in this study.

ORCID iDs

Xin Jin

Ethical statement

This study was approved by the Institutional Review Board of Huashan Hospital, affiliated to Fudan University. In this retrospective study, the data are anonymous, and the requirement for informed consent was therefore waived.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental material

Supplemental material for this article is available online.

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