N-acetylcysteine for COVID-19: real-time analysis of all 15 studies

Effects of Different Inhalation Therapy on Ventilator-Associated Pneumonia in Ventilated COVID-19 Patients: A Randomized Controlled Trial

Delić et al., Microorganisms, doi:10.3390/microorganisms10061118

RCT mechanically ventilated patients in Croatia, 39 treated with N-acetylcysteine and 52 control patients, showing no significant difference in mortality with treatment. Treated patients showed a lower incidence of gram-positive or MRSA-caused ventilator-associated pneumonia.

risk of death, 9.7% lower, RR 0.90, p = 0.67, treatment 21 of 39 (53.8%), control 31 of 52 (59.6%), NNT 17.

Delić et al., 5/28/2022, Randomized Controlled Trial, Croatia, peer-reviewed, 12 authors, study period October 2020 - June 2021.

Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19

Izquierdo et al., Science Progress, doi:10.1177/00368504221074574

Retrospective 19,208 COVID+ hospitalized patients in Spain, 2,071 treated with high dose NAC, showing lower mortality with treatment. In multivariable analysis, authors adjust for corticosteroids, but do not adjust for HCQ use which was also significantly more common in the NAC group. NAC 600mg every 8 hours.

risk of death, 25.6% lower, RR 0.74, p < 0.001, treatment 136 of 2,071 (6.6%), control 1,935 of 17,137 (11.3%), adjusted, OR converted to RR, multivariable.

Excluded in after exclusion results of meta analysis: significant unadjusted confounding possible.

Izquierdo et al., 1/27/2022, retrospective, Spain, peer-reviewed, 7 authors, study period 1 March, 2020 - 24 January, 2021.

Inhibitory effects of specific combination of natural compounds against SARS-CoV-2 and its Alpha, Beta, Gamma, Delta, Kappa, and Mu variants

Goc et al., European Journal of Microbiology and Immunology, doi:10.1556/1886.2021.00022 (In Vitro)

In Vitro study testing combinations of plant extracts and micronutrients with several variants of SARS-CoV-2. A combination of vitamin C, N-acetylcysteine, curcumin, quercetin, resveratrol, theaflavin, naringenin, baicalin, and broccoli extract showed the highest inhibition of RBD binding, and also decreased RdRp, furin, and cathepsin L activity.

Goc et al., 1/21/2022, peer-reviewed, 5 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

The Effects of N-Acetylcysteine as Adjuvant Therapy To Reduce TNF-Α Level And Increase SPO2/FIO2 Ratio In Improving Hypoxemia In COVID-19 Patients

Ramadhan et al., Indonesian Journal of Tropical and Infectious Disease, 9:3

Prospective study with 75 NAC patients and 16 control patients, showing no significant difference in mortality.

risk of death, 134.7% higher, RR 2.35, p = 0.68, treatment 11 of 75 (14.7%), control 1 of 16 (6.2%), unadjusted.

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

Ramadhan et al., 12/27/2021, prospective, Indonesia, peer-reviewed, 6 authors, study period June 2020 - July 2021.

Impact of N-acetyl-l-cysteine on SARS-CoV-2 pneumonia and its sequelae: results from a large cohort study

Faverio et al., ERJ Open Research, doi:10.1183/23120541.00542-2021

Retrospective 1,083 consecutive hospitalized COVID patients in Italy, showing no significant differences with NAC treatment. The number of patients transferred to another facility exceeds the number of deaths, which may significantly affect results.

risk of death, 19.0% higher, RR 1.19, p = 0.33, treatment 91 of 572 (15.9%), control 44 of 329 (13.4%), propensity score weighting.

risk of ICU admission, 33.8% higher, RR 1.34, p = 0.08, treatment 107 of 572 (18.7%), control 46 of 329 (14.0%), propensity score weighting.

risk of no hospital discharge, 1.4% lower, RR 0.99, p = 0.94, treatment 180 of 572 (31.5%), control 105 of 329 (31.9%), NNT 224, propensity score weighting.

Faverio et al., 12/2/2021, retrospective, Italy, peer-reviewed, 10 authors, study period February 2020 - April 2021, trial NCT04424992 (history) (STORM).

Therapeutic possibilities of using an expectorant mucolytic agent with antioxidant properties in COVID-19 infection

Ignatova et al., Russian Medical Inquiry, doi:10.32364/2587-6821-2021-5-7-473-478

Retrospective 111 patients with moderate COVID-19 pneumonia, 56 treated with NAC, showing shorter hospitalization time with treatment. NAC 1200mg daily intravenous, divided into two doses.

hospitalization time, 20.3% lower, relative time 0.80, p < 0.05, treatment 56, control 55.

Ignatova et al., 11/10/2021, retrospective, Russia, peer-reviewed, median age 49.2, 12 authors, average treatment delay 4.6 days.

N-acetylcysteine for the treatment of COVID-19 among hospitalized patients

Avdeev et al., Journal of Infection, doi:10.1016/j.jinf.2021.07.003

Prospective study of 24 hospitalized COVID-19 patients in Russia treated with NAC, and 22 matched controls, showing significantly improved SpO₂/FiO₂, and significantly shorter hospitalization with treatment.

risk of death, 69.4% lower, RR 0.31, p = 0.34, treatment 1 of 24 (4.2%), control 3 of 22 (13.6%), NNT 11.

risk of mechanical ventilation, 77.1% lower, RR 0.23, p = 0.18, treatment 1 of 24 (4.2%), control 4 of 22 (18.2%), NNT 7.1.

risk of ICU admission, 77.1% lower, RR 0.23, p = 0.18, treatment 1 of 24 (4.2%), control 4 of 22 (18.2%), NNT 7.1.

hospitalization time, 15.4% lower, relative time 0.85, p = 0.01, treatment 24, control 22.

Avdeev et al., 7/9/2021, retrospective, Russia, peer-reviewed, 4 authors, study period 12 April, 2020 - 20 June, 2020, average treatment delay 7.2 days.

N-acetyl-cysteine reduces the risk for mechanical ventilation and mortality in patients with COVID-19 pneumonia: a two-center retrospective cohort study

Assimakopoulos et al., Infectious Diseases, doi:10.1080/23744235.2021.1945675

Retrospective 42 hospitalized PCR+ COVID-19 pneumonia patients treated with NAC, and a matched control group of 40 patients, showing significantly lower severe respiratory failure and significantly lower mortality with treatment. NAC 600 mg bid orally for 14 days.

risk of death, 97.1% lower, RR 0.03, p = 0.006, treatment 2 of 42 (4.8%), control 12 of 40 (30.0%), NNT 4.0, OR converted to RR.

Assimakopoulos et al., 6/29/2021, retrospective, Greece, peer-reviewed, 9 authors, study period 1 February, 2021 - 30 April, 2021.

Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19

Altay et al., Advanced Science, doi:10.1002/advs.202101222

RCT 304 low-risk outpatients, 229 treated with N-acetylcysteine, l-carnitine tartrate, nicotinamide riboside chloride, and serine, showing significantly faster recovery with treatment. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism were significantly improved in treated patients.

risk of hospitalization, 80.1% lower, RR 0.20, p = 0.25, treatment 0 of 229 (0.0%), control 1 of 76 (1.3%), NNT 76, relative risk is not 0 because of continuity correction due to zero events.

risk of no recovery, 82.7% lower, RR 0.17, p < 0.001, treatment 229, control 75, multivariate Cox regression.

Altay et al., 6/28/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Turkey, peer-reviewed, 18 authors, this trial uses multiple treatments in the treatment arm (combined with l-carnitine tartrate, nicotinamide riboside chloride, serine) - results of individual treatments may vary.

A pilot study on intravenous N-Acetylcysteine treatment in patients with mild-to-moderate COVID19-associated acute respiratory distress syndrome

Taher et al., Pharmacological Reports, doi:10.1007/s43440-021-00296-2

RCT 92 hospitalized patients, 47 treated with NAC, showing non-significant improvements in outcomes. IRCT20120215009014N355. NAC 40mg/kg/day intravenous for 3 days.

risk of death, 17.9% lower, RR 0.82, p = 0.65, treatment 12 of 47 (25.5%), control 14 of 45 (31.1%), NNT 18.

risk of mechanical ventilation, 13.8% lower, RR 0.86, p = 0.67, treatment 18 of 47 (38.3%), control 20 of 45 (44.4%), NNT 16.

ICU time, 20.0% lower, relative time 0.80, p = 0.48, treatment 47, control 45.

hospitalization time, 33.3% lower, relative time 0.67, p = 0.31, treatment 47, control 45.

risk of no recovery, 14.5% lower, RR 0.85, p = 0.41, treatment 25 of 47 (53.2%), control 28 of 45 (62.2%), NNT 11.

Taher et al., 6/10/2021, Double Blind Randomized Controlled Trial, Iran, peer-reviewed, 6 authors, average treatment delay 7.0 days.

Case Characteristics, Clinical Data, And Outcomes of Hospitalized COVID-19 Patients In Qom Province, Iran: A Prospective Cohort Study

Pourhoseingholi et al., Research Square, doi:10.21203/rs.3.rs-365321/v2 (Preprint)

Prospective study of 2,468 hospitalized COVID-19 patients in Iran, showing no significant difference with NAC treatment. IR.MUQ.REC.1399.013.

risk of death, 11.0% lower, HR 0.89, p = 0.43, treatment 65 of 309 (21.0%), control 274 of 2,159 (12.7%), adjusted, multivariable, Cox proportional hazards.

Pourhoseingholi et al., 5/26/2021, prospective, Iran, preprint, mean age 57.9, 11 authors, study period 2 February, 2020 - 20 July, 2020, average treatment delay 7.4 days.

A Retrospective Analysis of Outcomes Amongst COVID-19 Infected Patients with Acute Hepatitis Receiving N-Acetylcysteine Therapy in a Safety Net Hospital

Pellegrini et al., Gastroenterology, doi:10.1016/S0016-5085(21)02756-6

Retrospective 864 hospitalized late stage COVID-19 patients in the USA, 138 receiving NAC treatment for acute hepatitis, showing lower mortality with treatment. Results are adjusted for confounders, however details are not provided.

risk of death, 51.7% lower, OR 0.48, p < 0.001, treatment 138, control 726, adjusted, multivariable, RR approximated with OR.

Pellegrini et al., 5/23/2021, retrospective, USA, peer-reviewed, 10 authors, study period March 2020 - May 2020.

N-acetylcysteine as a part of complex treatment of moderate COVID-associated pneumonia

Gaynitdinova et al., Pulmonologiya, doi:10.18093/0869-0189-2021-31-1-21-29

RCT 46 hospitalized patients with moderate COVID-19 pneumonia, 24 treated wth N-acetylcysteine, showing significantly shorter hospitalization with treatment. NAC 1,200 – 1,500mg/day intravenously.

hospitalization time, 15.4% lower, relative time 0.85, p < 0.001, treatment 24, control 22.

relative improvement in lung Ct, 50.7% better, RR 0.49, p < 0.001, treatment 24, control 22.

Gaynitdinova et al., 2/19/2021, Randomized Controlled Trial, Russia, peer-reviewed, 6 authors, average treatment delay 7.0 days.

Double-blind, Randomized, Placebo-controlled Trial With N-acetylcysteine for Treatment of Severe Acute Respiratory Syndrome Caused by Coronavirus Disease 2019 (COVID-19)

de Alencar et al., Clinical Infectious Diseases, doi:10.1093/cid/ciaa1443

RCT 135 severe stage patients in Brazil, showing no significant differences. NAC 21g (~300mg/kg) for 20 hours. U1111-1250-356 [ensaiosclinicos.gov.br].

1. ensaiosclinicos.gov.br, http://www.ensaiosclinicos.gov.br/rg/RBR-8969zg/.

risk of death, 2.6% higher, RR 1.03, p = 0.94, treatment 9 of 67 (13.4%), control 9 of 68 (13.2%), OR converted to RR.

risk of mechanical ventilation, 16.0% higher, RR 1.16, p = 0.64, treatment 16 of 67 (23.9%), control 14 of 68 (20.6%), OR converted to RR.

risk of ICU admission, 8.5% lower, RR 0.91, p = 0.65, treatment 29 of 67 (43.3%), control 32 of 68 (47.1%), NNT 26, OR converted to RR.

ICU time, 12.5% higher, relative time 1.12, p = 0.56, treatment 67, control 68.

hospitalization time, 10.0% higher, relative time 1.10, p = 0.87, treatment 67, control 68.

de Alencar et al., 9/23/2020, Double Blind Randomized Controlled Trial, placebo-controlled, Brazil, peer-reviewed, median age 59.0, 65 authors, average treatment delay 7.0 days.

Association of previous medications with the risk of COVID-19: a nationwide claims-based study from South Korea

Huh et al., medRxiv, doi:10.1101/2020.05.04.20089904 (Preprint)

Retrospective database analysis of 65,149 in South Korea, showing significantly lower cases with existing N-acetylcysteine treatment. The journal version of this paper does not present the N-acetylcysteine results.

risk of case, 26.2% lower, RR 0.74, p < 0.001, treatment 710 of 13,788 (5.1%), control 4,462 of 51,361 (8.7%), adjusted, OR converted to RR, multivariable.

Huh et al., 5/4/2020, retrospective, database analysis, South Korea, preprint, 10 authors.

Antiandrogens	(meta)	Melatonin	(meta)
Aspirin	(meta)	Metformin	(meta)
Bamlaniv../e..	(meta)	Molnupiravir	(meta)
Bebtelovimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Cannabidiol	(meta)	Nitric Oxide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)
Lactoferrin	(meta)

Other Treatments		Global Adoption