N-acetylcysteine (NAC) has been considered one of the most effective drugs against viral infections of various kinds for decades. Today, its name has acquired special significance in the context of the pandemic, as its efficacy is being studied in patients with advanced respiratory symptoms of COVID-19.
Efficacy of N-Acetylcysteine in Respiratory Diseases
This research, in turn, was derived from previous studies on the efficacy of N-acetylcysteine in other respiratory diseases unrelated to Sars-Cov-2.
The country has not lagged behind in research progress. In early 2020, Zambon Colombia SA, a subsidiary of Zambon SpA, with support from Grupo Proyéctame, conducted a comprehensive meta-analysis titled “Efficacy and safety of the use of parenteral N-acetylcysteine in the management of patients with adult respiratory distress syndrome (ARDS)” focusing on the use of NAC in patients with acute respiratory distress syndrome, which was later recognized by the international medical community as the most common indication in individuals with late-stage COVID-19.
The development of ARDS, as in other diseases, depends on the immune response of the particular organism. In the case of a low or moderate response, 3 basic processes are triggered in the body: Overproduction of mucus, exaggerated inflammatory response – cytokine storm, coagulopathies and endotheliopathies. The phenomena are identical to those seen in COVID-19 sufferers and are due to the inflammatory response that the virus causes in the human body.
The mucus plug that results from the infection blocks the airways and obstructs the passage of air. When infected with Sars-Cov-2, it changes its consistency to a thicker, more viscous one that eventually becomes completely adherent to the tissues. The sepsis-causing cytokine storm is believed to be another effect of the new disease, a product of ongoing viral replication.
According to research published in Cell Press, the cytokine excess fits conventional models of antiviral induction, but it is not known whether immune system hyperactivity or failure to resolve the inflammatory response – a consequence of viral replication – underlies the severe disease. However, reports from the medical community indicate that increased thrombus formation and endothelial cell death occur in COVID-19 patients, the latter characteristic process having already been mentioned.
In the meta-analysis performed by Zambon Colombia SA in non-COVID patients with ARDS, the following medical evidence was selected according to the AMSTAR model:
The results showed that the mucolytic, antioxidant and anti-inflammatory effects were more effective when administered parenterally to critically ill patients (intensive care unit). N-acetylcysteine, as a mucolytic agent, dissolves the dense, excess mucus produced, loosens the mucus plug stuck in the airways, and thus enables expectoration and facilitates air passage.
As for the antioxidant effect, it acts directly on TNFa, IL-1, IL-6 and IL-8, reducing the pro-inflammatory cytokines produced during the syndrome, and finally it reduces platelet aggregation and arterial thrombi due to the antithrombotic effect of the drug.
When using NAC as a concomitant drug, the meta-analysis showed that the use of intravenous N-acetylcysteine at a dose of 200 mg per kg per day for at least 5 days reduces the length of stay in the ICU by 18.4%, that is, the length of stay in the ICU is reduced by 4.47 days.
Because the drug does not act directly on the causative agents of ARDS, it cannot be considered a general treatment for the syndrome.
Although the high safety profile of N-acetylcysteine is emphasized, no significant reduction in the mortality rate associated with its use was observed under these particular circumstances. That is, as a complementary drug in the comprehensive treatment of the syndrome in the intensive care unit.
Further Evidence Points to the Same Outcome
Since the WHO announced the Sars Cov-2 pandemic on March 11, the medical and scientific community has been desperate to find a definitive cure. In the process, N-acetylcysteine has been highlighted in COVID-19 trials conducted in more than 19 countries, including the United States, England, Spain, Russia and China.
In April, a month after the Zambon Colombia SA meta-analysis was completed and in the first month of the pandemic, the British Medical Journal (BMJ) published a meta-analysis and systematic review of the use of mucoactives for acute respiratory failure in critically ill patients, including intravenous NAC and nebulized NAC.
The analysis focused on five specific aspects-in addition to the selected literature review and risk assessment: duration of mechanical ventilation, length of ICU stay, length of hospital stay, ventilator-free days, and mortality.
- Duration of mechanical ventilation: 7 of the analyzed studies (n=1226) reported the use of these adjuvants, but no beneficial effect was found with the administration of highly heterogeneous mucoactive agents.
- Ventilator-free days: according to the data analyzed, three studies reported ventilator-free days: two at day 28 and one at day 30, but no difference in ventilator-free days was observed. For clarification, the expert group responsible for the meta-analysis mentioned that in one study, the average number of ventilator-free days was 11 in patients treated with mucoactives versus 3 ventilator-free days in patients treated with placebo. However, it was not included in the meta-analysis because the mean SD could not be determined.
- Hospitalization: as stated above, there was no significant change in hospitalization. This conclusion was reached after reviewing the information from four studies in the meta-analysis.
The main finding of this meta-analysis, ICU stay, confirms the conclusions of the Zambon Colombia ZA meta-analysis. None shared their sources.
According to the data presented, intravenous administration of N-acetylcysteine reduced the duration of ICU stay by 4.7 days. The result is quite close to that of Zambon Colombia ZA, despite the different I2 heterogeneity percentages of the two.
The BMJ study has an I2 of 25%, compared with the I2 of 44% in the pharmaceutical company meta-analysis. In other words, the confirmation of the results comes from a more accurate study (published in BMJ).
Mortality is the second aspect consistent with the analysis conducted by Zambon Colombia SA. To this end, the researchers note in the analysis published in the British journal that mucoactives have no effect on mortality in patients with acute respiratory failure. When the data were divided into subgroups, there was no evidence of a change with the use of intravenous NAC.
It is worth noting that the population studied by Anand included individuals with hypoxic respiratory failure (type 1), acute hypercapnic respiratory failure (type 2), ARDS, and acute lung injury. However, the evaluation of the efficacy and safety of N-acetylcysteine was performed only for use in patients with ARDS. Because this study was not available until after the cutoff date of the Zambon-Columbia study, local investigators did not consider the data already presented.
Does NAC Play a Key Role in the Treatment of Patients with COVID-19?
In July, the journal ELSEVIER published the article “Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine” (name translated into English), describing the clinical case of a 44-year-old man treated with COVID-19 in New York who initially received a single dose of hydroxychloroquine 400 mg the day after hospitalization and was treated intravenously with NAC 10 days after hospitalization because there was no improvement and he had to be intubated.
Immediate improvement in hemolysis rates was seen with the first application. In a second round, a sustained decrease in bilirubin levels was noted as an effect of the drug. In addition, the physicians conducting the study noted that inflammatory markers were dramatically lowered by taking NAC, even though steroids had been administered concurrently.
When N-acetylcysteine treatment was repeated in 9 additional subjects, a significant overall decrease in inflammatory markers (CRP, ferritin, and neutrophil/lymphocyte ratio) was observed during intravenous NAC administration. A rebound effect was observed in 6 patients after treatment discontinuation, whereas no additional effects occurred in the remaining 3 patients. However, the conclusion was the same in all cases: intravenous administration of NAC significantly lowered inflammatory markers and allowed patients to be discharged more quickly due to significant improvement in their symptoms.
This table shows that with an intravenous dosage of 30000 – 20000 mg, the patient can leave the ICU after 2 days. If the drug is administered at a dose of less than 200 mg/kg/day, the length of stay is prolonged. The results presented here support the feasibility of using NAC in high doses, as documented in the meta-analysis by Zambon Colombia SA.
Recently, on August 5, the Journal of Personalized Medicine published the article “Postulated Adjuvant Therapeutic Strategies for COVID-19″ mentioning some adjuvant strategies for COVID-19. The study focused on 12 agents selected for their pharmacologic mechanism of action against one or more of the seven alterations caused by Sars-Cov-2 infection: Immune system dysregulation, viral invasion of healthy cells, viral replication, excessive inflammatory response, oxidative stress, thrombosis, and endothelial damage.
To evaluate the efficacy of the selected drugs, a previous classification was used that divides the development of COVID-19 into three phases, depending on the severity of symptoms experienced by infected individuals.
Stages II and III correspond to the intermediate and advanced stages of the disease. Although pulmonary complications are already known to develop between days 5 and 12, this also represents a window of 7 days that may be critical to the recovery process. In the absence of established clinical guidelines to date, there is a risk that the virus will mature and trigger a multisystemic inflammatory process from which thousands of infected individuals will not recover.
Among the most important complications associated with COVID-19, the study lists acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), a theme in the research mentioned above. On this basis, the expert team presents a table of recommended adjuvant drugs for current treatment. For N-acetylcysteine, 560 mg is recommended, divided into 3 daily doses (one every 8 hours).
The following specific functions of N-acetylcysteine in COVID-19 infection were identified:
- Reduction of virus entry into the cell: N-acetylcysteine contains the DPP4R inhibitor. It is now known that mRNA and protein expression of DPP4 is inversely related to lung function and diffusion capacity parameters, which would explain the propensity of smokers and people with chronic obstructive pulmonary disease (COPD) to develop COVID-19.
- TLR7 activation/type 1 interferon response: according to the research findings, N-acetylcysteine may contribute to the prevention or control of RNA virus infections, as the drug enhances the signaling functions of TLR7 and mitochondrial antiviral signaling protein (MAVS) in the production of type 1 IFN. As mentioned in the article, IFNs are able to inhibit the replication of SARS-like coronavirus, so they may be useful for the treatment of COVID-19. In addition, activation of TLR7 by single-stranded viral RNA entrapped in endosomes is a key stimulus for induction of type 1 IFN by RNA virus.
- Assists in reducing oxidative stress: Sars-Cov-2 triggers a recurrent mechanism in viral infections: It activates a pro-oxidant response of macrophages through TLR stimulation, leading to TNF-α activation of NADPH, which in turn mediates ROS production. To reduce ROS, important antioxidants such as glutathione (GSH) and glutathione peroxidase (GPx) are needed to neutralize these substances and convert them into products that are non-toxic to the body. Intake of N-acetylcysteine increases glutathione production, especially in the elderly, as plasma levels of the antioxidant and cysteine decrease with age.
Although the mucolytic effect of N-acetylcysteine was not considered in this study, its antioxidant and anti-inflammatory effects are most important. That is, it can be used as a preventive measure before COVID-19 symptoms develop unfavorably and lead to ICU stay, or it can be administered in more severe patients.
By and large, the evidence presented here shows that the effect of N-acetylcysteine supports the recovery process in all types of patients. However, it cannot be dismissed that administering the drug – as a support to standard treatment – to patients in the ICU leads to an improvement in their symptoms, eliminating the need for invasive treatment and minimizing the resulting sequelae.
It also cannot be overlooked that the use of NAC reduces the number of days patients spend in the ICU, opening up the possibility of providing quality care in a shorter time to those who need it, without compromising the availability of beds or the infrastructure that such departments need to function properly.
Currently, Colombia applies the Methodological Guide for the Development of Clinical Practice Guidelines (CPG) to make recommendations for health professionals. Among the requirements established, the submission of high-quality scientific evidence is one of the most important. In this regard, it should be noted that the reviews included in the Columbia meta-analysis and the additional studies performed a quality assessment of the included clinical trials using the Cochrane Collaboration’s Risk of Bias tool. Currently, the use of N-acetylcysteine as an adjuvant treatment is not regulated, nor are there any uses other than those commonly approved by Invima.