The effects of N-acetyl cysteine on acute viral respiratory infections in humans: A rapid review

Abstract

Current evidence suggests that N-Acetyl Cysteine (NAC) administration may help improve outcomes in people with acute respiratory distress syndrome and acute lung injury – conditions that closely resemble the signs and symptoms of COVID-19. Few mild and transient adverse events were reported in published randomised-controlled trials, indicating that NAC may be reasonably safe. These findings suggest that NAC may complement the management of COVID-19 infection, particularly when administered intravenously within an intensive care unit (ICU) environment.

Verdict

Current evidence suggests that N-Acetyl Cysteine (NAC) administration may help improve outcomes in people with acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) – conditions that closely resemble the signs and symptoms of COVID-19. In this rapid review, NAC was predominately administered intravenously to patients with ARDS or ALI, who were at risk of or requiring mechanical ventilation, and were admitted to a hospital intensive care unit. Findings indicated that NAC administration may assist in improving markers of inflammation or oxidation, systemic oxygenation, the need for / duration of ventilation, rate of patient recovery and clinical improvement score. The effects of NAC on patient length of stay, CT/x-ray images, mortality rate and pulmonary complications were inconclusive.

Few mild and transient adverse events were noted, indicating that NAC may be safe for use in acute respiratory distress syndrome or acute lung injury. Based on the evidence identified, and the similar symptomatic profiles of ARDS/ALI and COVID-19, the findings suggest that NAC may be used to complement the management of COVID-19 infection within an acute care setting. The safety and efficacy of orally administered NAC for the management of milder forms of COVID-19 infection within the community setting, remains uncertain. The current research evidence suggests NAC warrants further research for acute respiratory viral infections, including COVID-19.

1. Background

NAC is described as a mucolytic nutrient with anti-inflammatory, antioxidant and immunomodulating properties. NAC is reported to be used by naturopathic practitioners in some countries to assist in the management of some respiratory complaints. NAC has been found to be a glutathione (GSH) agonist with previous studies demonstrating that NAC administration increases GSH levels in red blood cells, granulocytes, and plasma of patients with acute respiratory distress syndrome or acute lung injury. Increasing GSH levels in the early phases of acute lung injury with NAC could reduce or limit the extent of epithelial and endothelial damage and improve the clinical course.

2. Search strategy

2.1. Research question

What are the effects of N-acetyl cysteine on acute respiratory viral infections (ARVI) and associated complications?

2.2. Inclusion/exclusion criteria

2.2.1. Inclusion criteria

Studies were included if they reported human prospective intervention studies sampling adults (aged 18 years and over) with reported acute respiratory viral infection (ARVI).

2.2.2. Exclusion criteria

Studies were excluded if the study sample was not reported as diagnosed with ARVI.

2.3. Databases

Medline (Ovid), AMED (Ovid), CINAHL (EBSCO), EMBASE (Ovid)

2.4. Search terms (example)

2.4.1. Medline (Ovid)

(( randomised Controlled Trials as Topic/ OR randomised controlled trial/ OR Random Allocation/ OR Double-Blind Method/ OR Single Blind Method/ OR clinical trial/ OR clinical trial, phase i.pt. OR clinical trial, phase ii.pt. OR clinical trial, phase iii.pt. OR clinical trial, phase iv.pt. OR controlled clinical trial.pt. OR randomised controlled trial.pt. OR multicenter study.pt. OR clinical trial.pt. OR exp Clinical Trials as topic/ OR (clinical adj trial$).tw. OR ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. OR PLACEBOS/ OR placebo$.tw. OR randomly allocated.tw. OR allocated adj2 random$).tw.) NOT (letter/ OR historical article/)) AND ((Acetylcysteine or N-Acetyl-l-cysteine or N-Acetylcysteine or NAC or N-AC or N-acetyl).af.) AND (Influenza, Human/ OR Influenza A Virus, H1N1 Subtype/ OR Influenza A virus/ OR Influenza A Virus, H3N2 Subtype/ OR H1N1.mp. OR breathing OR lung OR pulmonary OR respir$)

2.5. Critical appraisal

The risk of bias (RoB) of study findings was assessed using the revised Cochrane RoB tool for randomised trials (RoB 2) https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/current-version-of-rob-2?authuser=0.

3. Results

The search identified 640 citations. Seven duplicates were removed leaving 633 citations to be screened. After title and abstract reviews, 91 citations were left with 76 citations further excluded as they didn’t meet the inclusion and exclusion criteria [wrong patient population = 48, wrong study design = 13, wrong intervention = 7, paediatric population = 6, wrong comparator = 1 and wrong outcome = 1]. The remaining 13 articles were included in this rapid review. Table 1 show a summary of included studies.

Table 1.

Summary of studies examining the effect of NAC in acute viral respiratory infections humans.

Author		Country		WHO Region (see WHO tab)		Design (eg Cohort, cross-sectional)			Study duration		Study Population / Disease or Condition		Administration of NAC			Dose		Duration of Treatment		Control or Placebo		Total Number of Subjects		N in intervetion and placebo		Measure of Outcome			Outcome
Bernard, et al. [3]		USA, Canada		The Region of the Americas		DBPC RCT			March 17, 1992 to Feb 26, 1993		ICU, diagnosed with ARDS and needing ventilation		IV solution of 10 % NAC diluted with 5% dextrose in water			70 mg (0.4 mol)/kg body weight; OTZ, 63 mg (0.4 mol)/kg of body weight		30 min., every 8 h for a total of 30 doses during a 10-day treatment period		Placebo (5%dextrose in water)		n = 48		NAC: n = 14 OTZ: n = 17 Placebo: n = 15		RBC glutathione levels			NAC: increased from baseline 47 % (p < .05) OTZ: not significant Placebo: not significant
																										Mortality			No difference
																										Organ-failure free days			No difference
Domenighetti, et al. [4]		Switzerland		European		PC RCT			16-month period		ICU patients diagnosed with ARDS		IV solution			190 mg/kg/day of NAC or placebo		Continuous infusion over the first 3 days		Placebo (saline)		n = 42		NAC: n = 22; Placebo: n = 20		Incidence of ventilatory support			No difference
																										PaO2/FIO2			No difference
																										Lung Injury Score			NAC: 1.53 (SD 0.21) Placebo: 2.15 (SD 0.19) (p < .04)
																										Chest radiograph			No difference
Howe, et al. [5]		America USA		The Region of the Americas		DBPC RCT					ICU patients requiring mechanical ventilation		Enterally administered antioxidant supplementation via a bolus			Group 1: 5 mL dose of placebo; Group 2: 5 mL dose of vitamin E (100IU) and 5 mL dose of placebo; Group 3: rml dose of vitamin C (1000 mg), 5 mL dose of vitamin E (1000IU) and 5 mL dose of NAC (400 mg)		Bolus given every 8 h for 28 days or until they were weaned from mechanical ventilation (whichever was shorter)		Placebo		n = 72		C + E+NAC: n = 23; Placebo: n = 22; C + E n = 27		All-cause mortality			No difference
																										Days in ICU			No difference
																										Days in hospital			No difference
																										Number of days on mechanical ventilation			C + E group: Mean, 10 days C + E+NAC: Mean, 12 days Placebo: Mean, 19 days (p = .02)
Jepsen, et al. [6]		Denmark and Sweden		European		DBPC RCT					ICU patients diagnosed with ARDS		IV solution			NAC 150 mg/kg as a loading dose and then 20 mg/kg/hr		Initial dose was given for 30 min. on day one. Then continuous for the next 6 days		Placebo		n = 66		NAC: n = 32; Placebo: n = 34		Adverse events			NAC: a rash was observed in one patient after the loading dose.
																										Oxygenation			No difference
																										Administration of corticosteriods, prostaglandin E1 or NSAIDs			No difference
																										Time taken to recover from ARDS			No difference
																										Chest radiographs			No difference
Lai, et al. [1]		Hong Kong		South East Asia		Case report			Not applicable		One patient diagnosed with novel H1N1 influenza pneumonia, septic shock, type 1 respiratory failure		IV solution			NAC 100 mg/kg continuous IV infusion for 3 days.		Intial treatment with norepinephrine infusion, hdyrozortisone for septic shock. Oral oseltamivir 75 mg twice daily, IV antibiotics next day. Next day, oseltamivir 150 mg BD, IV NAC daily for 3 days.		None		n = 1		n = 1					Patient improved rapidly after high dose NAC therapy plus antiviral medications. CRP concentrations were also seen to decrease with the introduction of NAC high dose.
Laurent, et al. [7]		Switzerland		European		DB PC RCT					ICU patients diagnosed with severe ARDS		IV solution			190 mg/kg/day of NAC		Continuous infusion over the first 3 days		Placebo (isotonic saline solution)		n = 16		NAC n = 8; Placebo n = 8		Unstimulated oxygen radical production			No difference
																										Granulocyte GSH			Significantly higher in the NAC group compared to placebo (p < 0.01). Difference was abolished by day 5 (all treatment stopped on day 3).
																										Elastase release			No difference
Moradi, et al. [8]		Iran		Eastern Mediterranean		SB PC RCT			July 2005 and April 2006		Ventilated ICU patients with ALI/ARDS		IV solution			150 mg/kg at first day, followed by 50 mg/kg for 3 days		Initial dose was given for day one, then followed by continuous infusions for 3 days		Placebo (5%dextrose in water)		n = 30		NAC: n = 14; Placebo: n = 13		Mortality rate			NAC: 35.7 %; Placebo: 76.9 % (p = .03)
																										Duration of mechanical ventilation			No difference
																										Length of ICU stay			No difference
																										PaO2/FiO2 (Day 2)			NAC: 227.3 (SD 23.9); Placebo: 155.0 (SD 15.5) (p = .02)
																										PaO2/FiO2 (Day 3)			NAC: 344.0 (SD 38.3); Placebo: 166.5 (SD 119.0) (p < .001)
																										PaO2/FiO2 (Day 4)			NAC: 440.9 (SD 47.5); Placebo: 151.2 (SD 24.6) (p < .001)
Ortolani, et al. [11]		Italy		European		RCT			May 1995 to October 1997		ICU patients, diagnosed early ARDS requiring ventilation		IV solution of 5% NAC diluted with 5% dextrose in water alone or combined with Rutin 0.5 %			NAC 50 mg/kg OR NAC 50 mg/kg + Rutin 5 mg/kg every 8 h		9 days (trial length) then as long as artificial ventilation was needed		Control 250 mL 5% dextrose in water		n = 36		NAC: n = 12; NAC + Rutin: n = 12; Control: n = 12;		Oxidised and total glutathione in epithelial lining fluid (ELF)			No difference
																										Oxygenation			NAC: Improved
																										Lipid peroxidation (ethane expiration)			[Day 9] NAC: reduced 43 % NAC + Rutin: reduced 46 % Placebo: reduced 15 % (p < .01)
																										Polymorphonuclear (PMN) cell count in ELF			NAC: Reduced 50 % NAC + Rutin: Reduced 30 % Placebo: No change (p < .05)
																										Mortality [day 9 and day 30]			No difference
Sharafkhah, et al. [9]		Iran		Eastern Mediterranean		DBPC RDT			March 2014 to June 2016		Adult ICU admitted patients undergoing endotracheal intu-bation and mechanical ventilation		NAC (600 mg; water-soluble tablets) through nasogastric tube			Twice daily		Administered within the first 12 h of mechanical ventilation after hospital admission, and continued until performing extubation, tracheostomy, discharge, or death.		Placebo (water-soluble vitamin tablets)		n = 60		NAC: n = 30; Placebo: n = 30		Incidence of ventilator-associated pneumonia			NAC: 26.6 % Placebo: 46.6 % (p = .032)
																										Time to recovery			Patients who survived in the treatment group showed a more rapid recovery compared with the control group.
																										Incidence of ventilator associated pneumonia (VAP)			Patients treated with NAC were significantly less likely to develop clinically confirmed VAP compared with patients treated with placebo.
																										Time to VAP (days)			NAC: 6.42 (SD 1.9) Placebo: 3.46 (SD 2.53) (p = .002)
																										Duration of mechanical ventilation (days)			No difference
																										ICU stay (days)			NAC: 14.36 (SD 4.69) Placebo: 17.81 (SD 6.37) (p = .028)
																										Hospital stay (days)			NAC: 19.23 (SD 5.54 Placebo: 24.61 (SD 6.81) (p = .030)
																										Recovery rate of VAP			Complete - NAC: 56.6%; Placebo: 30% (p = .006) Modest – no difference Lack – NAC: 10.0%; Placebo: 26.6% (p = .040) Death: no difference
																										Adverse events			No adverse events related to NAC were identified.
Soltan-Sharifi, et al. [2]		Iran		Eastern Mediterranean		Controlled clinical trial			24 July 2005 and 30 April 2006		ICU patients with Illness known to be associated with ALI/ARDS who required mechanical ventilation		"Infused" NAC (150 mg/kg) diluted in 5% dextrose and and 50 mg/kg/day diluted in 5% dextrose			NAC (150 mg/kg) infused for 20 min the first day and then 50 mg/kg/day for three days.		3 days		None		n = 24		NAC: n = 14; Control: n = 10		Acute Physiology and Chronic Health Evaluation(APACHE II) score			NAC: Increased Placebo: Decreased (p < .01)
																										Intracellular glutathione (GSH) (48 h)			NAC: Increased 59 % Placebo: Decreased 23 % (p < .001)
																										GSH/GSSG ratio			NAC: Increased (22 vs 64.2) Placebo: No change (p < .01)
																										Total antioxidant power (TAP) (mmol/L) (72 h)			NAC: 3.6 (SD 0.38) Placebo: 1.8 (SD 0.25) (p = .013)
Suter, et al. [10]		Switzerland		European		DBPC RDT			12- month period		Patients with risk factors for ARDS, and presenting with mild-to-moderate acute lung injury		Continuous IV infusion			NAC 40 mg/kg/day		3 days		Placebo		n = 61		NAC: n = 32; Placebo: n = 29		Incidence of ventilatory support			NAC: Reduced (69 % vs 17 %) Placebo: Reduced (76 % vs 48 %) (p = .01)
																										FiO2 administered			NAC: Reduced (0.29 vs 0.48) Placebo: No difference (0.35 vs 0.48) (p < .05)
																										PaO2/FiO2			No difference
																										Lung injury score			NAC: Decreased (1.39 vs 0.67) Placebo: No difference (p < .01)
																										Chest radiograph score			NAC: No change at day 3; Decreased at discharge (1.8 vs 1.1) Placebo: Increased at day 3 (p < .05)
van Meenen, et al. [12]		Netherlands		European		RCT			June 22, 2014, to November 24, 2016		ICU patients receiving invasive ventilation		Nebulized 5 mL solution (300 mg acetylcysteine) administered alone or in combination with 5 mL solutions containing salbutamol (2.5 mg)			On demand nebulization group: 5 ml solutions containing acetylcysteine (300 mg) OR 5 ml solutions containing salbutamol (2.5 mg) dependent on patient presentation. Routine nebulization group: acetylcysteine (300 mg) with salbutamol (2.5 mg) four times daily		Maximum 28 days. On demand group were reassessed daily. Routine group - from start to end of invasive ventilation and, in the case of ventilation through a tracheostomy tube, until ventilator support was discontinued for longer than 24 h.		None		n = 842		On-demand group: n = 389; Routine group: n = 453		Number of ventilator-free days			No difference
																										Mortality			No difference
																										ICU and hospital length of stay			No difference
																										Adverse events			Total On demand: 13.8 % Routine: 29.3 % (p < .001) Tachyarrhythmia On demand: 12.5 % Routine: 25.9 % (p < .001) Agitation On demand: 0.2 % Routine: 4.3 % (p < .001)
Zhang, et al. [13]		China		Western Pacific Region		RCT			August 2016 and March 2017		All patients admitted to the hospital with community acquired pneumonia		Oral 600 mg tablet			NAC 1200 mg (600 mg tablet twice daily)		10 days		Standard care		n = 39		NAC: n = 21; Standard care: n = 18		Malondialdehyde (7 days)			NAC: +1.34 (SD 1.35) Non-NAC: +0.43 (SD 1.28) (p = .004)
																										Tumour-necrosis factor-α			NAC: +9.5 (SD 3.62) Non-NAC: 6.25 (SD 3.98) (p < .001)
																										Total antioxidant capacity			NAC: +4.16 (SD 2.95) Non-NAC: +1.78 (SD 3.21) (p = .005)
																										Superoxide dismutase			No difference
																										CT Image comparison			No difference

All but two studies were identified as randomised controlled trials (RCTs). The two non-RCTs comprised of a case report [1] and a controlled clinical trial [2]. Eight of the 13 (61.5 %) included trials were placebo-controlled [[3], [4], [5], [6], [7], [8], [9], [10]], and 6/13 (46.1 %) were double-blinded [3,[5], [6], [7],9,10].

Studies were conducted across five of six World Health Organisation (WHO) regions, with most undertaken in the European region (6/13 [46.2 %] [4,6,7,[10], [11], [12]]), followed by the Eastern Mediterranean (3/13 [23.0 %] [2,8,9];), Americas (2/13 [15.4 %] [3,5];), South East Asia (1/13 [7.7 %] [1];) and Western Pacific (1/13 [7.7 %] [13];) regions. All studies were conducted in a hospital setting, and all but two [1,13] were reportedly undertaken in an intensive care unit.

The 13 included studies comprised a total pool of 1337 subjects, with study sample sizes ranging from 1 to 842 (median 42). All subjects had an acute respiratory condition, with diagnoses including ALI/ARDS (7/13 [53.9 %]; [[2], [3], [4],[6], [7], [8],10]) or pneumonia (2/13 [15.4 %] [1,13];). Four studies (30.8 %) did not define the respiratory disorder [5,9,11,12].

N-Acetyl Cysteine (NAC) was predominantly administered intravenously (10/13 [76.9 %]; 40−480 mg/kg/day or 400 mg TDS via intravenous infusion; [[1], [2], [3], [4], [5], [6], [7], [8],10,11]), and to a lesser extent, as an oral tablet (2/13 [15.4 %]; 600 mg BD [9,13];) or via nebuliser (1/13 [7.7 %]; 300 mg QID or on demand [12];). Control interventions included 5% dextrose in water (3/13 [23.1 %] [3,8,11];), saline (2/13 [15.4 %] [4,7];), water-soluble vitamin tablets (1/13 [7.7 %] [9];), conventional treatment only (1/13 [7.7 %] [13];), and non-specified placebo (3/13 [23.1 %] [5,6,10];). The duration of treatment ranged from 3 to 28 days, with a median period of 3 days.

4. Critical appraisal

In the first Domain (randomisation process), two studies were rated as high risk of bias [1,4] with all other studies rated as low. For Domain 2 (treatment assignment), one trial was identified as high risk of bias [6], with seven trials rated as low [[2], [3], [4], [5],9,12]. Under Domain 3 (missing outcome data), two trials were considered to have high risk of bias [6,7], with eight trials rated as low [3,3,4,5,8,10,12,13]. For Domain 4 (measure of outcomes), all trials were rated as low risk of bias, except Lai et al. [1], which was assessed as having some concerns. In Domain 5 (selective reporting), one trial [11] was identified as high risk of bias, with the remaining trials rated as having some concerns or low risk of bias. Overall, five studies were judged as having high risk of bias [1,4,6,7,11], six rated as having some concerns [2,5,[8], [9], [10],13] and two judged as low risk of bias [3,12]. These judgements should be taken into consideration when interpreting the findings of this review.

5. Summary of findings

The 13 included studies reported on nine broad outcomes: markers of inflammation and oxidation, changes in CT or x-ray images, patient length of stay, mortality rate, pulmonary complications, ventilation-related issues, recovery rate, clinical improvement and adverse events.

Four RCTs [3,7,11,13] reported changes in markers of inflammation or oxidation. These studies reported significant improvements in GSH, tumour necrosis factor - α (TNF-α), malondialdehyde, total thioles, lipoperoxidation, total antioxidant power and polymorphonuclear cell activity following NAC administration when compared to controls. These findings were consistent with those reported in the two non-RCTs [1,2]). No differences between groups were reported for superoxide dismutase and elastase.

Changes in CT or x-ray images were measured in two RCTs [6,13]. Both studies found no differences in this outcome between NAC and control.

Three RCTs [5,9,12] assessed patient length of stay. Although one RCT [9] reported a significant reduction in ICU and hospital length of stay in the NAC group versus control, two studies [5,12] found no differences between groups in patient length of stay.

Mortality rate was measured in six RCTs [[3], [4], [5],8,10,12]. Four studies [3,5,10,12] reported no differences in mortality rates between NAC and control. The remaining studies reported conflicting results, with one RCT [8] revealing a reduction in the rate of mortality following NAC administration (relative to control), and the other RCT [4] reporting an increase in mortality rate with NAC administration.

Three RCTs [9,10,12] examined the efficacy of NAC in preventing pulmonary complications. When compared to control, NAC administration was associated with a significant reduction in ventilator-associated pneumonia and time to ventilator-associated pneumonia in 1 RCT [9]. However, in two RCTs [10,12], no difference was found between groups in the prevalence of pulmonary complications.

Ventilation-related issues were reported as an outcome in four RCTs [4,5,8,10]. NAC administration was associated with improvements in systemic oxygenation in two [8,10] of 3 RCTs, and a reduction in the need for / duration of ventilation in two [5,10] of three RCTs.

Four RCTs [3,6,9,11] and one case report [1] examined recovery rate following NAC administration. All but one study [6] reported a significant improvement in the rate of recovery from an acute respiratory condition with NAC administration when compared with control.

Clinical improvement was assessed in one controlled clinical trial [2]. The authors indicated that NAC administration was associated with an improvement in Acute Physiology and Chronic Health Evaluation (APACHE II) score – a measure of clinical improvement and a predictor of mortality risk.

Adverse event monitoring was reported in three RCTs [6,9,13]. Two studies [9,13] reported no adverse events with NAC administration, and 1 [6] reported a rash during the administration of a loading dose of NAC.

6. Clinical significance

From the evidence identified in this review, it is recommended that NAC could be used for people who have contracted Covid-19. At early stages of the disease, health practitioners could recommend oral NAC [600 mg BD] to assist in reducing respiratory mucus and inflammation, increasing systemic GSH levels and possibly averting hospital admission. As only three trials assessed the oral administration of NAC, and there were some concerns with the risk of bias of these studies, these suggestions need to be considered with caution until conclusive evidence becomes available. If health professionals have access and ability to administer NAC via nebuliser or IV, the review findings suggest that doses of NAC ranging from 40−480 mg/kg/day for at least 3 days may be suitable for patients who are deteriorating. Again, as two of the ten studies on IV administration of NAC were rated as high risk of bias, patients who are administered NAC intravenously need to be monitored closely.

Health practitioners are advised that these recommendations should complement, and not replace, standard medical care, and if required, the patient is recommended to obtain emergency care where needed.

Disclaimer

This article should not replace individual clinical judgement. The views expressed in this rapid review are the views of the authors and not necessarily from the host institutions. The views are not a substitute for professional medical advice.

Appendix A. Supplementary data

The following are Supplementary data to this article: