key: cord-0826561-04jih410
authors: Wong, Kon Ken; Lee, Shaun Wen Huey; Kua, Kok Pim
title: N-Acetylcysteine as Adjuvant Therapy for COVID-19 – A Perspective on the Current State of the Evidence
date: 2021-07-06
journal: J Inflamm Res
DOI: 10.2147/jir.s306849
sha: 64aad19bb94e2218fc0a390f453ecc8f46d05547
doc_id: 826561
cord_uid: 04jih410

The looming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a long-lasting pandemic of coronavirus disease 2019 (COVID-19) around the globe with substantial morbidity and mortality. N-acetylcysteine, being a nutraceutical precursor of an important antioxidant glutathione, can perform several biological functions in mammals and microbes. It has consequently garnered a growing interest as a potential adjunctive therapy for coronavirus disease. Here, we review evidence concerning the effects of N-acetylcysteine in respiratory viral infections based on currently available in vitro, in vivo, and human clinical investigations. The repurposing of a known drug such as N-acetylcysteine may significantly hasten the deployment of a novel approach for COVID-19. Since the drug candidate has already been translated into the clinic for several decades, its established pharmacological properties and safety and side-effect profiles expedite preclinical and clinical assessment for the treatment of COVID-19. In vitro data have depicted that N-acetylcysteine increases antioxidant capacity, interferes with virus replication, and suppresses expression of pro-inflammatory cytokines in cells infected with influenza viruses or respiratory syncytial virus. Furthermore, findings from in vivo studies have displayed that, by virtue of immune modulation and anti-inflammatory mechanism, N-acetylcysteine reduces the mortality rate in influenza-infected mice animal models. The promising in vitro and in vivo results have prompted the initiation of human subject research for the treatment of COVID-19, including severe pneumonia and acute respiratory distress syndrome. Albeit some evidence of benefits has been observed in clinical outcomes of patients, precision nanoparticle design of N-acetylcysteine may allow for greater therapeutic efficacy.

The acute respiratory disease COVID-19 caused by the novel coronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has spawned a global pandemic with untold morbidity and mortality, accompanied by devastating disruption to all facets of society, economy, and health care system. 1,2 SARS-CoV-2 is a single-stranded, positive-sense RNA virus that was initially identified in Wuhan city in China in December 2019 from an outbreak of pneumonia cases in connection with Huanan Seafood Wholesale Market. 3 It is closely related to other tremendously pathogenic beta-coronaviruses that have emanated in this century, namely severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV). 4 Unlike SARS-CoV-1 and MERS-CoV that exhibit only limited human-to-human transmissions, 5 a person being infected with SARS-CoV-2 who is just mildly ill or even asymptomatic can spread the disease to an average of two or three others, resulting in an exponential rate of increase in infection cases. SARS-CoV-2 virus has engendered 10fold higher in the number of cases than the 2003 SARS epidemic in a quarter of the time. 6 The rapid transmission of this highly pathogenic virus has warranted a pressing global need for the instantaneous development and deployment of therapeutic approaches and preventive measures against the disease. 7 Common hematological manifestations of COVID-19 infection include lymphocytopenia associated with intensification of the inflammatory process and direct infection of lymphocytes and destruction of lymphoid organs, increased ferritin levels owing to inflammation, and a higher rate of erythrocyte sedimentation in severe disease. Blood group A and males are more likely to become infected. Male sex, older age, and the presence of comorbidities are correlated with increased risk of COVID-19-related mortality. 8, 9 The development of thrombocytopenia may occur in severe disease due to reduced platelet production and increased destruction or consumption of platelets. Elevated D-dimer levels concomitant with high levels of fibrin degradation products and low antithrombin activity render COVID-19 patients to be at risk of hypercoagulability and thrombotic complications. Neutrophil-to-lymphocyte ratio and plasma D-dimer concentrations are relatively easy to quantify and possess clinical value for disease prognosis. 10 High levels of proinflammatory cytokines and chemokines, including interleukin (IL)-6, IL-2, IL-2 receptor, IL-10, tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) may cause multiorgan damage as well as cardiovascular complications. 11 Cardiac arrhythmia has also been reported and is associated with a cytokine storm-triggered systemic hyperinflammatory state and immune response that may cause injury to cardiac monocytes, resulting in myocardial dysfunction and the ensuing development of arrhythmia. Similarly, infection of alveolar pneumocytes cells by SARS-CoV-2 virus triggers the initiation of systemic inflammation and elevated immunoreactivity that potentiate T-cell and macrophage activation infiltrating infected myocardial tissues, leading to cardiovascular damage and myocarditis.

Additionally, atherosclerotic plaques can be destabilized by systemic inflammatory response which happens simultaneously with pro-inflammatory and pro-oxidative effects of SARS-CoV-2, thereby giving rise to acute coronary syndrome and ischemic heart disease among COVID-19 patients. 12 Previous research with coronaviruses using both in vitro and in vivo experimental designs has contributed to a valuable guiding foundation for elucidating therapeutic strategies for the treatment of COVID-19. On top of understanding the microbial pathogenesis and the molecular and cellular mechanisms of disease biology, activity of a therapeutic agent in a translational research, be it either in vitro or in vivo, is critical to proffer advancement to first-in-human clinical trials based on laboratory findings of pharmacology, toxicology, and immunology. 13 For COVID-19 repurposing of an existing clinically approved drug, it is pivotal to demonstrate its antiviral, antiinflammatory, and related effects against SARS-CoV-2 in cell-based systems in vitro. The assessment of drug potency may be impacted by the type of the virus (eg, fulllength wildtype, reporter viruses, or sub-genomic replicons, etc.) and the cell culture utilized (eg, Vero E6, Huh7, FRhK, or human airway epithelial cells), thus, necessitating high quality and standardized cellular assays, or at least with robust and universally accepted control groups. 14 Recent randomized controlled trials depict that repurposed antiviral drugs such as remdesivir, lopinavir, and interferon beta-1α regimens have small or null effect on hospitalized patients with COVID-19, as determined by outcomes such as overall mortality, initiation of mechanical ventilation, and duration of hospitalization. 15, 16 Combination treatment of remdesivir with antiinflammatory drug baricitinib is associated with shorter time to recovery and accelerated improvement in clinical status, notably among those receiving high-flow oxygen or non-invasive ventilation. 17 Treatment with dexamethasone reduces 28-day mortality in patients who are receiving invasive mechanical ventilation or oxygen without invasive mechanical ventilation, however, no discernible benefit and the possibility of causing harm have been found among those who are not receiving respiratory support. 18 Neutralizing antibody bamlanivimab results in fewer hospitalizations and a lower symptom burden. 19 25 The overwhelming impact of the COVID-19 crisis has driven the push for reimagining and repositioning of previously approved medical treatments for other indications to speed up the discovery and development of safe and efficacious agents to enlarge the alternatives for adjunctive treatment or prevention of progression into severe COVID-19 illness. 14 From the clinical front, it is presently worrisome to have no effective antimicrobial agents to treat the infected individuals and, optimally, eliminate viral shedding and the ensuing transmission cascades.

N-acetylcysteine is a mucolytic drug which exhibits antioxidant and anti-inflammatory effects. 26 The compound has been available in clinical practice for several decades to treat various medical conditions, including bronchitis, acute respiratory distress syndrome, paracetamol intoxication, chemotherapy-related toxicity, doxorubicin cardiotoxicity, heavy metal intoxication, ischemia-reperfusion cardiac injury, human immunodeficiency virus infection or acquired immunodeficiency syndrome, and neuropsychiatric disorders. N-acetylcysteine is also marketed as a dietary supplement that is suggested to possess antioxidant and hepatic-protecting effects. The antioxidant characteristic of N-acetylcysteine has been ascribable to its reactivity with •OH, CO 3 • − , •NO 2 , and thiyl radicals, the ability to repair oxidative damaged key cellular molecules, and activity as a precursor for biosynthesis of glutathione. 27 There is a growing body of evidence that highlights the intrinsic antimicrobial and antibiofilm activities in many respiratory pathogens, including Escherichia, Pseudomonas, Staphylococcus, Acinetobacter, Haemophilus, and Klebsiella. 26, [28] [29] [30] High concentrations of N-acetylcysteine do not carry the risk of adverse interactions with most commonly used antibiotics and can exert intrinsic antimicrobial activity against Haemophilus influenza. 26 Being a precursor for glutathione biosynthesis which is a crucial determinant of antimicrobial activity against bacteria, N-acetylcysteine is often prescribed as a mucolytic agent in conjunction with antibiotic treatment in respiratory tract infections to improve the outcomes of the course of therapy. 31 N-acetylcysteine has recently been suggested as an adjunctive therapy to the standard care for SARS-CoV-2 infection considering the favorable risk and benefit ratio and its effects on synthesizing glutathione, improving immune function, and modulating inflammatory response. 32-34 It achieves the therapeutic effects through two main activities: 1) mucolytic action conferred by the free sulfhydryl group which reduces disulfide bonds in the cross-linked mucus glycoproteins matrix, thus decreasing the viscosity of mucus; 2) antioxidative action attributable to a direct interaction with free radicals, an indirect effect as a precursor to cysteine which is required for glutathione biosynthesis, and a replenishment of thiol pools that is central to redox regulation and control. 35 In light of these properties, we hypothesize that N-acetylcysteine plays a role in the treatment of COVID-19 infection by the following postulated mechanisms of action ( Figure 1 ):

1. Envelope (E) and spike (S) proteins have a triple cysteine structural motif located directly after the E protein's transmembrane domain (NH 2 -… L-Cys-A-Y-Cys-Cys-N … -COOH) and a similar motif located in the carboxy terminus of the S protein (NH 2 -… S-Cys-G-S-Cys-Cys-K … -COOH). The position, orientation, and composition of these two motifs may serve as a center for the structural link between the E and S proteins which is mediated by the formation of disulfide bonds between the corresponding cysteine residues. 36 Previous studies have indicated that the entry of viral glycoprotein is affected by thiol-disulfide balance within the viral surface and the cell-surface of the host. 37, 38 Any perturbations in the thioldisulfide interchange equilibrium would deter the entry of the virus into host cells. 39, 40 Cleavage of disulfide bridges by N-acetylcysteine disrupts the structural components of the interacting proteins, thereby impairing receptor binding affinity and infectivity. 2. N-acetylcysteine is a chemical reducer of disulfide bonds via its free sulfhydryl groups may interact with the extracellular disulfide bridges of angiotensin II receptor, alter its tertiary structure, and inhibit the binding of angiotensin II to its surface receptors (AT 1a receptors) with subsequent attenuation of signal transduction and cell action. The AT 1a receptors possess two sets of disulfide bridges at the extracellular domain of the receptors: C18-C274 and C101-C180. N-acetylcysteine can reduce the disulfide bonds in a dose-dependent manner, 41 

actions to angiotensin II), thus protecting against lung inflammation and fibrosis. 43 3. The sulfhydryl group of N-acetylcysteine inhibits angiotensin converting enzyme, reducing production of angiotensin II. 44 In human lungs, angiotensin converting enzyme is expressed in lower lungs on type I and II alveolar epithelial cells. Following infection, viral entry begins with the attachment of spike (S) protein expressed on the viral envelope to angiotensin converting enzyme on the alveolar surface. Hence, N-acetylcysteine may prevent viral entry by limiting viral protein angiotensin converting enzyme interaction and internalization of the receptor-ligand complex. 45 It also protects against oxidative stress and prevents glycosylation of proteins which may confer protection against respiratory disease syndrome and lung failure. 4. The antioxidant effect of N-acetylcysteine ameliorates oxidative stress and inflammatory response in COVID-19. 46 It amplifies the signaling functions of toll-like receptor 7 protein and mitochondrial antiviral-signaling protein for boosting type 1 interferon production. 47 Type I interferon functions to induce expression of various interferon-stimulated genes that exert antiviral activities to host cells. (sRAGE, a decoy receptor) are positively associated with acute respiratory distress syndrome severity and mortality risk, whereas reduction in circulating levels of sRAGE drop results in disease resolution. 49 Advanced glycation end products are formed by a reaction of the dicarbonyl compounds methylglyoxal and glyoxal with amino acids in proteins during glycolysis. Methylglyoxal and methylglyoxal-derived AGE can further activate inflammatory cells by binding to RAGE. 50 N-acetylcysteine induces endogenous glutathione and hydrogen sulfide synthesis, thus attenuating methylglyoxal-induced protein glycation and additional glycosylation events in SARS-CoV-2 which may then inhibit the virus's infectivity and associated pathologies. 51 6. N-acetylcysteine inhibits NF-κB activation by suppressing TNF-induced IκB kinases, followed by impediment of proteasome-dependent degradation. 52 This prevents translocation of NF-κB from cytoplasm to the nucleus and block expression of pro-inflammatory cytokines and chemokines which have been correlated with severity and lethality in various acute respiratory viral infections, including Influenza A H5N1, highly pathogenic H1N1, SARS-CoV, MERS-CoV, and SARS-CoV -2. 53

In vitro studies show that N-acetylcysteine holds therapeutic promise in numerous viral respiratory tract infections.

In H5N1-infected A549 cells, N-acetylcysteine was found to attenuate H5N1-induced cytopathogenic effects, apoptosis, and virus yields. In addition, it decreased proinflammatory cytokine levels of CXCL8, CXCL10, CCL5, and interleukin-6. It was posited that the antiviral and anti-inflammatory effects of N-acetylcysteine were mediated by the inhibition of the oxidative metabolic pathway including transcription factor NF-κB and mitogen activated protein kinase p38. 54 In another study, N-acetylcysteine was demonstrated to have immune-modulating properties by increasing influenza virus-specific cytotoxic T-lymphocyte clones and interferon-γ generation. 55 In an in vitro A549 model infected with influenza (strains A and B), N-acetylcysteine was shown to inhibit expression and release of MUC5AC, IL6, and TNF-α, reduce intracellular hydrogen peroxide level, restore intracellular pool of total thiols, diminish NF-κB translocation to the cell nucleus, attenuate activation of mitogen activated protein kinase p38, and prevent replication of the viruses. 56 N-acetylcysteine also prevented apoptosis in H1N1-infected cell lines. 57 In Vero cells (ATCC CCL-81) infected with porcine H1N1 strain, N-acetylcysteine was reported to exert a dose-dependent inhibition on virus replication. However, the inhibitory effect of N-acetylcysteine was significantly less than that observed with H5N1, suggesting the susceptibility is strain-dependent. 58 

In in vitro modeling of RSV infection carried out in cultures of primary normal human bronchial epithelial cells, N-acetylcysteine significantly inhibited viral infection, re-established the number of beating cells, restored the virus-induced decrease in expression of β-tubulin and genes involved in ciliagenesis such as DNAI2 and FOXJ1, inhibited IL-13, MUC5AC, and GOB5 upregulation, inhibited ICAM1 expression, increased heme-oxygenase 1 expression which correlated with the restoration of cellular antioxidant capacity, and enhanced intracellular hydrogen peroxide and glutathione concentrations. 59 In another experiment, N-acetylcysteine significantly reduced MUC5AC expression in RSV-infected A549 cells. It also diminished induction of TNF-α and IL-6, decreased NF-κB nuclear translocation and p38 mitogen activated protein kinase phosphorylation, abolished intracellular hydrogen peroxide production, restored intracellular thiol levels, and reduced virus titre. 56 Likewise, RSV infection of A549 epithelial cell lines showed the inhibitory effects of N-acetylcysteine on virusinduced chemokine expression and DNA-binding activity of NF-κB subunits of p50 and p65. 60

In vivo studies depict some beneficial effects of N-acetylcysteine in numerous viral respiratory tract infections.

In mice following intranasal infection with a lethal dose of influenza A virus A/PR/8, the use of N-acetylcysteine increased survival rate from 58% (ribavirin monotherapy) to 92% (N-acetylcysteine and ribavirin), suggesting the antioxidant's role in improving host defense mechanism and preventing pathogenesis of lung inflammation. 61, 62 Further experiment depicted that survival rates of mice were 20% in the N-acetylcysteine group, 60% in the oseltamivir group, and 100% in combination treatment of N-acetylcysteine and oseltamivir. 63 In these three models, the mice were infected with 2-3 LD 50 of influenza virus and N-acetylcysteine was administered as a single daily dose of 1,000 mg/kg. 61-63 N-acetylcysteine increased survival by contributing to host defense mechanisms or by direct antioxidant effect against oxidative stress associated with viral infection. 63 On the contrary, mice infected intranasally with a deadly dose of porcine A/swine/Iowa/4 (H1N1) influenza strain showed no significant difference in percent survival and mean survival time between N-acetylcysteine and control groups, showing that different virus strains resulted in different susceptibilities to N-acetylcysteine. 58 The porcine A/swine/Iowa/4 (H1N1) strain was found to be more resistant to N-acetylcysteine than the human strain A/PR/8 (H1N1) deployed in other animal models. [61] [62] [63] The lack of treatment effect was possibly due to the virus phenotypic susceptibility to N-acetylcysteine and the viral pathotype. 64 Findings from H9N2 swine influenza virus-infected murine model indicated that N-acetylcysteine ameliorated pulmonary edema and inflammatory response, reduced myeloperoxidase activity in the lungs, decreased total and differential cell counts, neutrophils, macrophages, IL-6, IL-1β, TNF-α, and CXCL-10 in the bronchoalveolar lavage fluid, and inhibited protein expression of TLR4 and its mRNA in the lungs. 65 In an experiment of H3N2-infected mice, N-acetylcysteine decreased pulmonary responsiveness and increased immune cytokine expression of IFN-γ in comparison to saline controls, with no effect on virus titers and expression of IL-4, IL-13, and IL-12p40. 66 

Currently, there have been several clinical studies to measure the effects of N-acetylcysteine on viral respiratory tract infections. A randomized controlled trial demonstrated long-term N-acetylcysteine regimen resulted in significantly lower episodes of influenza and influenza-like illness, disease severity, and duration of confinement to bed due to respiratory diseases. Only 25% of the virusinfected subjects in the N-acetylcysteine arm developed symptoms compared to 79% receiving placebo. 67 Benefits were also documented in patients diagnosed with community acquired pneumonia whose plasma levels of malondialdehyde (oxidative stress parameter) and TNF-α (inflammatory mediator) were decreased and total antioxidant capacity was increased significantly among those treated with N-acetylcysteine. 68 Moreover, N-acetylcysteine resulted in a lower rate of ventilatorassociated-pneumonia compared with placebo. Patients treated with N-acetylcysteine had significantly shorter length of stay in the ICU, reduced time to hospital discharge, and a higher rate of complete recovery. 69 A clinical case study revealed that combination therapy of oseltamivir and N-acetylcysteine improved clinical outcomes in a woman with H1N1 influenza pneumonia, with clearance of pulmonary infiltrates, decreased requirement for oxygen supplementation, and lower plasma level of C-reactive protein. 70 Nonetheless, the majority of human studies utilizing N-acetylcysteine in COVID-19 infection have been small in scale, non-randomized, and lack appropriate comparison groups ( Table 1 ). In a single-center, randomized, doubleblind, placebo-controlled trial conducted at the Emergency Department of a hospital in Brazil, 140 patients with severe COVID-19 infection and oxyhemoglobin saturation of less than 94% or respiratory rate higher than 24 breaths/ minute were randomized to receive N-acetylcysteine 21,000 mg (approximately 300 mg/kg) for 20 hours or dextrose 5% (placebo). Of the intention-to-treat population comprising 135 patients, 16 patients (24%) receiving placebo required endotracheal intubation and invasive mechanical ventilation compared to 14 patients (21%) in the N-acetylcysteine group (P=0.675). No differences were noted in the duration of mechanical ventilation, death rate, rate of ICU admission, duration of stay in the ICU, and hospital stay. 71 A single-center, randomized, double-blind, placebocontrolled trial evaluating a combined metabolic cofactors supplementation encompassing L-serine, N-acetylcysteine, nicotinamide riboside, and L-carnitine tartrate in 309 adult patients with laboratory-confirmed COVID-19 infection reported that mean recovery time in the intervention group was significantly shorter compared to the placebo group (5.7 vs 9. 

cofactors supplementation showed a greater magnitude of decrease in plasma level of downregulated cytokines compared with placebo group on Day 14. The plasma levels of cytokines associated with inflammatory reactions (CSF-1, IL-15RA, IL18, MCP-1, and TNF) were significantly downregulated in the intervention group compared to the placebo group on Day 14. Only two patients in the intervention group (2.8%) reported a similar adverse event of mild rash on the upper part of the body. 72 A case report of a 54-year-old male patient with preexisting hypertension, hyperlipidemia, and obesity who was tested positive for COVID-19 11 days prior to admission to Holy Family Hospital in Massachusetts showed that combination therapy of hydroxychloroquine and N-acetylcysteine led to a progressive clinical improvement and a decrease in inflammatory markers for inflammation, for instance, C-reactive protein and lactic acid. The patient was mechanically ventilated for only 3 days, was then transferred from the ICU to the general ward on Day 7, and was finally discharged from the hospital on Day 12 with stable vital signs and normalized laboratory results. 73 In another case report, a 64-year-old man presented with acute respiratory distress syndrome due to COVID-19 severe pneumonia and secondary bacterial lung infection was admitted to Taihe Hospital in Shiyan, China and was given repeated bedside bronchoscopy at intervals of 1 day or 2 days with a large dose of 10,000-15,000 mg/ time of N-acetylcysteine nebulized inhalation solution lavage combined with routine nebulization and sputum suction airway management. The patient's refractory hypercapnia was gradually improved and was cured and discharged after 46 days of hospitalization. 74 Similar clinical benefit was noted in a case study of a 44-year-old man presented to the emergency department of NYU Langone, New York, with a previously diagnosed G6PD deficiency and a current COVID-19 infection with a redisposed risk of hemolysis. The use of intravenous N-acetylcysteine at 30,000 mg in three divided doses over 24 hours was associated with an immediate improvement in hemolysis indices (direct bilirubin levels), liver enzyme levels (alanine aminotransferase and aspartate aminotransferase), resolution of hemolysis as quantified by a sustained reduction in total and direct bilirubin and an elevated haptoglobin, and a sustained decrease in neutrophil to lymphocyte ratio which was an inflammatory predictor. Furthermore, patient's oxygenation continued to improve and his veno-venous extracorporeal membrane oxygenator was discontinued after 2 weeks. It was observed that the combination of corticosteroids and intravenous N-acetylcysteine resulted in a marked reduction in inflammatory markers (C-reactive protein and ferritin) and the patient was finally discharged home after 41 days of hospital stay. Following these encouraging outcomes, a cohort of nine COVID-19 patients without G6PD deficiency were prescribed with intravenous N-acetylcysteine and demonstrated a significant overall reduction in inflammatory markers (C-reactive protein and ferritin), whereas a rebound inflammation was noted in six patients following discontinuation of the therapy. The median C-reactive protein level during IV N-acetylcysteine administration was 55 mg/dL which was considerably lower compared to the time before administration (143 mg/dL) or after N-acetylcysteine discontinuation (69 mg/dL). N-acetylcysteine was found to mitigate COVID-19associated cytokine storm, elicit progressive clinical improvement, and facilitate hospital discharge readiness. 75 A retrospective case series study in the inpatient department of Medical College Kolkata, India revealed that two out of 148 patients with pre-existing comorbidities and laboratory-confirmed COVID-19 infection were treated with triple combination therapy of Ivermectin, Atorvastatin, and N-acetylcysteine, and the regimen was found to be a useful adjunct to standard of care (oxygenation, restricted fluid therapy, anticoagulation, and corticosteroid). It had no apparent adverse effects and could potentially reduce mortality in patients with COVID-19. 76 A multicenter, retrospective, cohort study in Clinic Bascoy and Clínica Arvila Magna, Spain assessed the effectiveness of an ImmunoFormulation containing N-acetylcysteine versus standard care in 40 patients with laboratory-confirmed COVID-19 infection. Ninety percent of patients in the ImmunoFormulation cohort recovered from the infection as compared to 47% in the control cohort (P=0.006). The mean recovery time for the ImmunoFormulation cohort was significantly shorter in comparison to the control cohort for patients with mild symptoms (11.22 vs 28.00 days), moderate symptoms (17.57 vs 28.00 days), and severe symptoms (16.00 vs 25.42 days). The duration of symptoms was also significantly shorter in the ImmunoFormulation cohort compared to the control group, notably for fever ( 

except for the loss of taste or smell (19.73 days) that was recognized as a long-term complication of COVID-19. No patient experienced any adverse drug reactions. The ImmunoFormulation containing 560 mg N-acetylcysteine daily was an effective adjuvant therapy on evolution of symptomatology in COVID-19 patients. 77 Notwithstanding the inconsistencies on the degree of efficacy of N-acetylcysteine as an adjunct in COVID-19 infection, all reported studies support the apparent safety profile of N-acetylcysteine irrespective of the dose and route of administration. There are many more clinical studies that are currently underway to generate the necessary evidence of its efficacy to inform future patient care and clinical action ( Table 2) . [78] [79] [80] [81] [82] [83] 

There has been no in vitro or in vivo research that specifically examines the effect of N-acetylcysteine on COVID-19 infection. The potential use of N-acetylcysteine in COVID-19 is largely inferred from previous research on other viruses such as influenza and respiratory syncytial virus. Promising results have been noted in the ability of N-acetylcysteine to synthesize glutathione, improve T lymphocyte proliferative response, and modulate the inflammatory pathway. Glutathione precursors such as N-acetylcysteine are suggested as a potential therapeutic approach for blocking NF-κB activation and addressing cytokine storm syndrome and respiratory distress in patients suffering from COVID-19 pneumonia. 84 In plasma, N-acetylcysteine reacts with cystine, reducing it to cysteine and yielding diacetylcystine and N-acetylcysteine-cysteine via redox exchange reactions, and subsequently enters human erythrocytes and sustains glutathione synthesis. 85 Additional research has illuminated the action of N-acetylcysteine on T-cell proliferation and IL-2 secretion which implies intracellular thiols regulate selective signaling pathways for a novel target of immunoregulation. 86 Furthermore, in vitro treatment of murine T-cells with N-acetylcysteine induces reactive oxygen species scavenging and initiates NFAT expression and nuclear translocation. Addition of N-acetylcysteine to Cd4cre-Gclc T-cells increases Myc expression and CD98 production. Indeed, intrinsic Gclc expression in T-cells is necessary for antigen-specific immunity to virus infections. The antioxidative glutathione pathway is found to be central to metabolic integration and reprogramming in inflammatory responses mediated by T-cells. 87 In this regard, high-dose N-acetylcysteine has been exemplified to replenish depleted pulmonary glutathione concentrations and yield concomitant favorable effects on lung function. 88 The therapy also increases glutathione levels in peripheral blood T lymphocytes and disrupts the mammalian target of rapamycin activation in chronic inflammatory disease. 89 Given that severe COVID-19 possesses shareable dominant risk factors with idiopathic pulmonary fibrosis, the effectiveness of N-acetylcysteine for slowing the rate of deterioration of vital capacity and single-breath lung diffusion capacity for carbon monoxide presents a rational option for treating patients infected with COVID-19. 88,90 Therefore, it is conjectured that high dose N-acetylcysteine can enhance innate and adaptive immunity by elevating stores of glutathione levels in T lymphocytes, along with modulating immune-system responses to alleviate the degree of severity of COVID-19 infection and thus improve patient outcomes. Future in vitro studies to test candidate therapeutic compound in COVID-19 should deploy standardized assays, for example, Vero cells that can competently replicate and isolate the virus readily, whereas in vivo studies should utilize transgenic mice and Syrian hamsters, or cats and ferrets if opting for larger experimental animals. 91 Of note, one of the important regulators of inflammation in COVID-19 is IL-6. 92 Elevations in serum IL-6 concentrations have been identified under critical conditions such as sepsis, acute respiratory distress syndrome, and COVID-19. 93,94 IL-6 is crucial for innate and adaptive immunity, efficient pathogen clearance, and physiological functions such as regulation of acute-phase response, hematopoiesis, lipid homeostasis, metabolism, and neural development. 95 In essence, anti-inflammatory, proresolution, and antimicrobial activities of IL-6 are facilitated by classical signalling, whilst pro-inflammatory activities of IL-6 are facilitated by trans-signalling. 96 Targeting the pathological effects of IL-6-mediated inflammation should avoid the unintentional concurrent abolition of its anti-inflammatory and pro-resolution functions. 93 Blockade of IL-6 and the consequent reduction of downstream effects on inflammation and the innate immune response may have beneficial effects on clinical outcomes in patients with COVID-19, including those with acute hypoxemic respiratory failure. 97 pharmacotherapy to selectively inhibit the trans-signalling pathway through which IL-6 signals.

Oral and intravenous N-acetylcysteine regimens are associated with adverse events such as diarrhea, nausea, vomiting, and mild-to-moderate hypersensitivity reactions such as urticaria, rash, angioedema, and wheezing. 98, 99 Such adverse events are dose-related and antihistamines are effective for treating and preventing recurrence of the anaphylactic reactions. Urticaria should be treated with antihistamine and N-acetylcysteine can be continued after symptom resolution. Angioedema and respiratory symptoms require the administration of antihistamine, corticosteroid, or symptomatic management. 100 In such cases, N-acetylcysteine should be discontinued, and if necessary, it can be re-started 1 hour after the administration of antihistamine in the absence of signs and symptoms of anaphylaxis. 101, 102 Patients with a history of atopy (asthma and allergy) are recommended to receive prophylactic antihistamine 15 minutes prior to N-acetylcysteine administration to eliminate the excess risk of adverse reactions. 102, 103 At present, there are six registered clinical trials evaluating the potential therapeutic value of N-acetylcysteine against COVID-19. [78] [79] [80] [81] [82] [83] The findings will build on in vitro and early in vivo evidence for the use of N-acetylcysteine as an adjuvant therapy for COVID-19. Similar to clinical trials on other infectious respiratory illnesses, study endpoints should appropriately encompass changes in SARS-CoV-2 associated blood cytokine levels, change in peripheralblood lymphocyte count and activation, improvement in clinical status, hospital length of stay, time to recovery, safety outcomes, and overall mortality. While SARS-CoV-2 variants appear to occur sporadically in different geographical locations across the globe, they do not culminate in more severe diseases than the ancestral strain, albeit altered virus virulence, pathogenesis, and transmissibility have been documented. 104, 105 Future trials in patients infected with mutated SARS-CoV-2 strains may help to confirm or refute the possibility of a treatment benefit with N-acetylcysteine.

It is noteworthy that molecular attraction forces between chitin found on the exoskeleton of mites on human skin (Demodecidae or Pyemotidae species) and lipids present on the viral envelope cause interactions between arthropod and coronavirus which play a major role in the transmission of SARS-CoV-2. 106 Natural small molecules, namely cyclodextrins and phytosterols, may hinder viral lipid-dependent attachment to host cells and thus reduce infectivity of the virus. 107 Nowadays, these natural compounds exist in various forms of dietary supplements. 107 Their potential to exhibit antiviral effects invigorates additional research to create novel biomedical applications for the treatment and prevention of COVID-19. This also implies the possibility that N-acetylcysteine has a role in inhibiting arthropod-coronavirus interaction and producing antimicrobial effect on endosymbionts of Demodex folliculorum. 108 Ivermectin is a broad-spectrum anti-parasitic drug which elicits anti-inflammatory and acaricidal actions against Demodex mites, 109, 110 in addition to antiviral activity against a range of viruses. 111 Possible mechanisms include downregulation of the expression of pro-inflammatory genes, including those of IL-8, TNF-α, and cathelicidin LL-37 and downregulation of the ACE-2 receptor and viral entry into the cells of the respiratory epithelium and olfactory bulb. 112 As a free radical scavenger, N-acetylcysteine can prevent ivermectin-induced cell death due to reactive oxygen species generation, 113 suggestive of potential benefits with their combined use. However, current clinical findings do not support the use of ivermectin for the treatment of COVID-19 as it does not significantly improve the time to resolution of symptoms. 114 Patients with COVID-19 pneumonia can present with blood coagulation abnormalities, commonly manifested by elevated levels of fibrinogen and D-dimer in tandem with mild thrombocytopenia. 115, 116 Rise in D-dimer levels has been linked to poorer prognosis and higher mortality rate. 117,118 D-dimer levels, lung inflammation, and pulmonary hemorrhage are influenced by neutrophil elastase activity. 119, 120 As such, suppression of elastase and neutrophil activation may be helpful in hemorrhagic or thrombotic complications associated with COVID-19. 121 N-acetylcysteine has been found to inhibit release of elastase and modulate neutrophil activity when used at high concentrations. 122 In neutrophilic airway inflammation in cystic fibrosis, high-dose N-acetylcysteine decreases the neutrophil burden in airways and the number of airway neutrophils actively releasing elastase-rich granules. 123 Treatment with N-acetylcysteine can also attenuate lung emphysema induced by elastase as depicted in amelioration of airspace enlargements, partial recovery of expiratory flows, and normalization of lung collagen content. 124 This evidence sheds light on the possible role of N-acetylcysteine on mediating inflammation-mediated lung injury and abnormalities of blood coagulation in severe COVID-19. 

Novel formulations have recently been discovered to overcome the low bioavailability and short plasma halflife of N-acetylcysteine. 125 Loading of N-acetylcysteine into lipid-based and polymer-based nanoparticles can improve muco-penetrating properties in pulmonary and oral delivery and hence the drug efficacy. 126, 127 A detailed in vivo and in vitro investigation is warranted to derive their applicability and efficacy in clinical settings.

As the most commonly approved nanomedicines by the US FDA, 128 lipid-based nanoparticles afford many advantages such as relatively simple formulation, self-assembled structure, biocompatibility, drug load capacity, and adjustable physicochemical properties to suit biological characteristics. 129 However, the lipid nanoparticle system is limited by low physicochemical stability and low-tomoderate encapsulation efficiency for N-acetylcysteine. 130 A liposomal formulation of co-encapsulated azithromycin and N-acetylcysteine has been demonstrated to have a synergistic effect against bacterial strains. 131 The high cellular membrane permeability and targeting accuracy associated with such a delivery system illuminates a potential implication for the co-formulation strategy of N-acetylcysteine with antiviral drug.

Recent evidence shows that polymer-based nanoparticles like N-acetylcysteine-loaded poly(lactic-coglycolic acid) have desirable efficacy in preventing acute lung injury by mitigating the effects of reactive oxygen species and inflammation. The formulation delivers N-acetylcysteine directly to the lungs with increased pulmonary deposition and higher pulmonary concentrations with a lower dose of N-acetylcysteine. 132 Polymer-based nanoparticle enhances pharmacokinetic and pharmacodynamics properties of encapsulated drug via prolonged drug release and particle retention. 133, 134 While poly(lactic-coglycolic acid) is one of the most commonly used biodegradable polymers, its poor drug loading requires higher polymer load to facilitate dose delivery. 135 Polymer-based nanoparticles are biodegradable, water soluble, biocompatible, biomimetic, and stable during storage. The surfaces can be easily modified for additional targeting. Disadvantages comprise higher risk of particle aggregation and toxicity. 127 To date, N-acetylcysteine has been used intranasally for the treatment of non-allergic chronic rhinitis with goblet cell metaplasia in which significant reduction in neutrophils, lymphocytes, goblet cells, bacterial count, turbinate hypertrophy, nasal symptoms, and rhinorrhea have been observed. The benefits are attributed to N-acetylcysteine's mucolytic activity, the ability to restore surface ciliary activity at the nasal epithelium, and modulation of inflammatory response which is central to the immune defence mechanism of nasal mucosa. 136 Likewise, acute recurrent rhinosinusitis treated with nasal douche consisting of flunisolide (corticosteroid) and N-acetylcysteine has been associated with a less stuffy nose, reduction in severity of symptoms and rhinosinus signs as assessed by endoscopy, improved cytological grading of neutrophil and eosinophil cells, less exacerbations, and increased mucociliary motility. 137 In addition, topical intranasal drug combining tuaminoheptane sulphate (vasoconstrictor) and N-acetylcysteine exhibits a rapid decongestant effect with a significant decrease of resistance and increase of inspiratory flow. 138 Topical delivery of N-acetylcysteine in the nostrils has also been investigated in ragweed sensitive patients and discovered that late phase allergic response mediated nasal symptoms can be reduced. 139 In vivo studies have demonstrated nasal application of N-acetylcysteine in rats can reduce goblet cell loss and inflammation as well as promote wound healing of nasal mucosa, 140 and combination of N-acetylcysteine and non-ionic surfactant (polyoxyethylene (C25) lauryl ether) can improve nasal bioavailability as a result of mucolytic activity of N-acetylcysteine in decreasing mucus viscosity. 141 Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption. 142

The COVID-19 pandemic has highlighted the critical need for new drugs to complement existing therapies. In view of the widespread recognition of the safety and efficacy of N-acetylcysteine in numerous diseases over several decades, the aroused scientific interest has prompted the evaluation of its efficacy in COVID-19 clinical trials. As such, it opens a window for drug discovery with additional advantages, comprising the known pharmacological and human safety profiles. Advances in nanoparticle design are foreseen to have an impact on optimizing drug delivery and targeted activity of N-acetylcysteine in coronavirus disease. Currently, there is some evidence supporting the use of N-acetylcysteine as an adjunctive therapy for COVID-19. increased bioavailability or target-oriented delivery, ascertain optimal dosage and route of administration, and conduct well-controlled, adequately powered, randomized clinical trials to determine the safety and efficacy of N-acetylcysteine in patients with COVID-19.

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The authors received no specific funding for this work.

The authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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