N-Acetylcysteine to Combat COVID-19: An Evidence Review
The novel coronavirus disease (COVID-19) is caused by a virus (SARS-Cov-2) and is known for inducing multisystem organ dysfunction associated with significant morbidity and mortality. Current therapeutic strategies for COVID-19 have failed to effectively reduce mortality rate, especially for elderly patients. A newly developed vaccine against SARS-Cov-2 has been reported to induce the production of neutralizing antibodies in young volunteers. However, the vaccine has shown limited benefit in the elderly, suggesting an age-dependent immune response. As a result, exploring new applications of existing medications could potentially provide valuable treatments for COVID-19. N-acetylcysteine (NAC) has been used in clinical practice to treat critically ill septic patients, and more recently for COVID-19 patients. NAC has antioxidant, anti-inflammatory and immune-modulating characteristics that may prove beneficial in the treatment and prevention of SARS-Cov-2. This review offers a thorough analysis of NAC and discusses its potential use for treatment of COVID-19.
According to the CDC, most SARS-Cov-2 infected individuals can recover from the disease at home. However, this virus can also cause serious illness in immune-compromised individuals, elderly patients, and in those with certain preexisting health conditions, such as hypertension, diabetes, and cardiovascular disease.1 It takes approximately 7 days to develop computed tomography (CT)-confirmed pneumonia (COVID-19) from the onset symptoms, such as fever or dry cough, and another 2 days to progress to acute respiratory distress syndrome (ARDS).2 ARDS is the major cause of death for COVID-19 patients and is associated with dysregulated host immune responses following viral infection.
One of the early immune responses during viral infection is the production of cytokines and chemokines from immune cells. High levels of IL-8, a strong chemoattractant for neutrophils, has been detected early in infected SARS patients.3 Once activated by infection, neutrophils are rapidly recruited to sites of inflammation in the lungs, where they produce and secrete cytokines, enzymes, including elastase (NE), reactive oxygen species (ROS) by oxidative burst, and finally release DNA to form neutrophil extracellular traps (NETs).4 In severe COVID-19 patients, an increased number of neutrophils has been associated with disease severity,5 most likely due to the production of large amounts of proinflammatory cytokines, creating a “cytokine storm”.
In neutrophils, NE can degrade a wide variety of architecturally and functionally important molecules, such as clotting factors and complement proteins.6 NE activity may, in part, explain the significant increase of D-dimer and pulmonary hemorrhage observed in COVID-19 patients.2 Additionally, NET-bound NE can degrade local plasminogen without generating plasmin onto fibrin, thus resulting in impaired fibrinolysis. This suggests that NE-bound NETs have the potential to serve as a platform for activation and formation of intravascular coagulation,7,8 which partly explains why pulmonary embolism usually occurs in critical COVID-19 patients in the intensive care unit (ICU).9
In some critically ill COVID-19 patients, the coexistence of thrombosis and hemorrhage was observed,10 indicating that suppression of NE production by stabilizing neutrophils could be beneficial for either condition. For instance, inhibiting neutrophil activation by an IL-8 antibody can effectively combat acute lung injury.11,12 In other words, any measure that can suppress neutrophil activation might improve the outcomes of COVID-19 patients.
Cellular immunity is also required for a host to fight a viral infection, which is regulated by an oxidant-antioxidant balance. This balance is maintained by antioxidants including glutathione. In the immune cells of senior or immune-compromised individuals, ROS is increased due to decreased glutathione, which causes dysregulation of immune responses, particularly of T cell-mediated functions. This may explain the depressed cell-mediated immunity and increased mortality found in elderly persons as a result of infectious diseases, such as pneumonia.13,14
In fact, in addition to depressed functions, the number of lymphocytes, including both CD4+ and CD8+ T cells, was found to decrease linearly with age.15 Furthermore, a reduced number of T cells as a result of apoptosis was also observed in critical COVID-19 patients, which further compromised cellular immunity and was associated with the higher mortality for these populations.2,16Therefore, replenishing certain antioxidants may restore the normal responses of immune cells through inhibiting T cell apoptosis, potentially reducing incidence or severity of pneumonia due to virus infection.
Combining count changes of neutrophils and lymphocytes, several groups have recently revealed that a high neutrophil-to-lymphocyte ratio (NLR) predicts a more severe progression of the disease and worse outcomes for COVID-19 patients,17–19 suggesting that NLR may be used as a prognostic marker and a therapeutic guide during acute COVID-19 infection. Therefore, in addition to administration of anti-viral drugs, inhibiting neutrophil activation and protecting T cells could provide an effective therapeutic option for treating COVID-19 patients.
Theoretically, an effective vaccine would be the best solution to combat SARS-cov-2 infection. A recent study showed that a recombinant adenovirus type-5 (Ad5) vaccine was capable of inducing neutralizing antibodies at day 14 post-vaccination,20 suggesting that a quick control of the COVID-19 pandemic is a possibility. However, this study also found that the neutralizing antibodies were reduced between the ages of 45 to 60 when compared with younger people.
Since younger people are widely considered the major carriers and spreaders of SARS-Cov-2, effective vaccines are still desperately needed to reduce virus transmission. Meanwhile, exogenous neutralizing antibodies may help those not responsive to the SARS-Cov-2 vaccines. Unfortunately, both vaccines and neutralizing antibodies are still under development. Therefore, a multimodal approach may be necessary when treating COVID-19 in elderly patients or in those with preexisting conditions.
Evidence and Discussions
N-Acetylcysteine, a Forgotten Immune-Modulating Agent
N-acetylcysteine (NAC), a precursor of the antioxidant glutathione, has been used to loosen thick mucus in the lungs and treat acetaminophen overdose for decades. However, NAC can also boost the immune system, suppress viral replication, and reduce inflammation. Despite these valuable features, NAC has been mostly overlooked throughout SARS-Cov and MERS-Cov epidemics, as well as the current COVID-19 pandemic.
NAC Offers the Following Key Features to Combat COVID-19
Anti-Virus Functions of NAC
RNA viruses need active NF-κB pathway support within host cells in order to replicate. For human coronaviruses (HCoV-229E), suppression of NF-κB significantly reduced the replication rate.22 Therefore, drugs that inhibit NF-κB activation could potentially reduce viral replication.
NAC has been demonstrated to inhibit NF-κB, as well as the replication of human influenza viruses (H5N1, Vietnam/VN1203 strain) in human lung epithelial cells in a dose dependent manner (5 to 15 mM) (Figure 2). NAC also reduced the production of pro-inflammatory cytokines (IL-8, CXCL10, CCL5 and IL-6), thus reducing chemotactic migration of monocytes.23 In addition, NAC has also been showed to inhibit replication of other viruses, such as human immunodeficiency virus (HIV)24 and respiratory syncytial virus (RSV).25 This means that, theoretically, NAC has the potential to inhibit SARS-Cov-2 as well because of its ability to negatively regulate NF-κB.
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It has been demonstrated that NAC can change the redox balance towards reduced status inside neutrophils by replenishing reduced glutathione (GSH), which suppresses NF-κB activation at concentrations of 10mM or more, resulting in modulation of cytokine production and chemotactic signals.28 Moreover, neutrophils from healthy volunteers taking NAC (600 mg daily) for 14 days showed lower rates of oxidative burst and chemotaxis………Interestingly, NAC did not compromise other functions of neutrophils, such as phagocytosis and bacterial killing.30 Collectively this data supports the notion that 1200 mg of oral NAC can effectively reduce ROS production without compromising phagocytosis of SARS-Cov-2 in neutrophils.
N-Acetylcysteine Can Reduce the Incidence of Pneumonia
Given that oral NAC (600mg, bid) significantly decreased the frequency and severity of influenza, oral NAC may reduce the incidence of pneumonia as well. One study has demonstrated that about 37% of mechanically ventilated patients develop pneumonia, namely, ventilator-associated-pneumonia (VAP) in an intensive care unit. NAC (600 mg, bid) treated patients developed significantly less clinically confirmed pneumonia compared with placebo group patients (26.6% VS 46.6%).34 Another study showed that oral (600mg, bid) NAC significantly reduced the levels of TNF and malondialdehyde (MDA) and significantly improved oxidative stress.35 Modulation of the inflammatory process with antioxidants may have a mitigating effect in the development of pneumonia, potentially improving outcomes if high doses of NAC (1200mg, bid) are utilized.
N-acetylcysteine (NAC) is inexpensive, has very low toxicity, has been FDA approved for many years, and has the potential to improve therapeutic strategies for COVID-19. NAC administered intravenously, orally, or inhaled, may suppress SARS-CoV-2 replication and may improve outcomes if used timely. Potential therapeutic benefits of NAC include, extracellularly scavenging ROS radicals, replenishing intracellular GSH, suppression of cytokine storm, and T cell protection, thus mitigating inflammation and tissue injury. NAC administration in combination with other antiviral agents may dramatically reduce hospital admission rate, mechanical ventilation and mortality.