Antioxidants, Vol. 11, Pages 2298: Impact of N-Acetyl Cysteine (NAC) on Tuberculosis (TB) Patients—A Systematic Review

1. IntroductionTuberculosis (TB) remains a leading cause of morbidity and mortality in people with pulmonary and extra-pulmonary forms of the disease, and has only recently been surpassed by the COVID-19 pandemic [1]. The pandemic has compromised the TB control program, including both human and financial resources for the fight against TB, as the results dropped between 2019 and 2021 [1]. Despite well-established and widely-publicized methods of prevention and treatment, the TB disease still affects people all over the world. The main causes of its persistence include HIV infection and poverty. The World Health Organization (WHO) estimated that there were 10.6 million incident TB cases and 1.6 million fatalities in 2021 [1]. Additionally, it has been observed that 85% of reported cases of TB are successfully treated [2]. Despite an apparent microbiologic cure, studies have shown that TB patients with a follow-up of at least 24 months still have some sort of persistent pulmonary impairment [3]. According to Ravimohan et al., (2018), pulmonary tuberculosis is a risk factor for long-term lung impairment and yet is frequently overlooked despite its high prevalence and link to a lower quality of life [4].Sustained TB infection elicits an immunological process whereby the cellular immune response by alveolar macrophages, dendritic cells, and neutrophils as first-line defending cells acts on M. tb by engulfing, processing, and presenting peptides to naïve T cells that differentiate into T helper 1 cells (Th1), which undergo maturation and produce interferon gamma (IFN-γ), and activate macrophages and neutrophils to produce anti-microbial peptides including the reactive oxygen species (ROS), tumor necrosis alpha (TNF-α), and induced nitrogen species (iNOS) as part of the defense mechanism [5,6]. However, excessive production of ROS destroys lung tissues through the oxidation process [7,8].Glutathione (GSH) is a non-protein thiol consisting of a tripeptide of glycine, cysteine, and glutamic acid, which are produced naturally by body cells. GSH has been found to be a free radical scavenger [9]. GSH has also been shown to protect against ROS and reactive nitrogen species by neutralizing free radicals and converting them into oxidized glutathione (GSSG) and water (2GSH + O-GSSG + H2O), a reaction that consumes GSH [10,11,12]. Cysteine amino acid as a precursor to GSH synthesis is required. Although it is considered conditionally essential, human synthetic capacity and dietary content are also limited.NAC is a synthetic form of cysteine, a sulfur-containing amino acid that is temperature stable, a supplement required to replenish GSH [13]. It has been used routinely in the treatment of acetaminophen toxicity, which protects against fatal liver injuries [14]. Several studies have been conducted to evaluate and identify the use of NAC as a drug supplement in the treatment of several diseases, including the recent COVID-19 pandemic. NAC is a mucolytic and antioxidant drug is found to reduce the viscosity of the sputum, clean the bronchi, help to relieve dyspnea, and improve lung function [15,16]. Researchers went further to evaluate the effects of NAC against microbial activity and anti-TB drug effects during and after TB treatment [17,18,19,20]. The current review looked at study designs, methods, countries of origin, benefits for TB patients, Adverse events, and immunological responses. The review’s second goal was to identify the in vivo and in vitro study designs conducted to assess the effects of NAC on TB disease progression, including treatment reduction, sputum culture conversion rate, lung function, and GSH expression. 1.1. What Is Already Known on This Topic?

NAC serves as a precursor for GSH biosynthesis. The product was approved by the WHO for the treatment of acetaminophen intoxication. Studies are researching the product’s potential to treat a number of illnesses, such as the recent COVID-19 pandemic, TB, COPD, chronic bronchitis, and others.

1.2. What Does This Present Study Add?

The present review has found that few studies have been conducted to find out the effects of NAC in TB treatment and therefore highlights the importance of conducting more clinical trials on the use of NAC in TB treatment in order to demonstrate the general effect of adjunctive NAC in TB treatment.

2. Materials and Methods

The present systematic review was conducted by using a systematical literature search for all available NAC articles in the databases. Search terms were created following the population, concepts, and context (PCC) format. We categorized our review title into two parts, whereas the–“TB patients’ treatment” part of the research title was categorized as population, “the effect of adjunctive NAC” part was categorized as an intervention. The first group comprised search terms related to population targeting:

“tuberculosis treatment”[All Fields] OR “lung cavitation”[All Fields] OR “lung exacerbations” [All Fields] OR “COPD”[All Fields] OR “Respiratory problems”[All Fields] OR “lung impairment”[All Fields] OR “lung disorder” [All Fields] OR “interferon gamma”[MeSH] OR “inflammatory cytokines”[All Fields] OR “ROS”[All Fields] OR “Reactive oxygen-species”[All Fields] OR “lung inflammation”[All Fields] OR “Tuberculosis-disease”[All Fields] OR “lung-TB”[All Fields] OR “Standard anti-TB” OR “TB regimen”[All Fields] OR “relapse TB”[All Fields] OR “host-directed therapy”[All Fields].

The Cysteine group comprised the intervention concepts for the TB disease. The search terms were:

“GSH”[All Fields] AND “pulmonary-TB”[All Fields] OR (“Antioxidant”[All Fields] OR “Glutathione”[All Fields]) OR “pulmonary tuberculosis”[All Fields] OR “COPD”[All Fields] AND “TB”[All Fields] OR “pulmonary-tb”[All Fields] OR “Cysteine”[All Fields] OR “NAC”[All Fields] OR “acetyl-cysteine”[All Fields] OR “Precursor”[All Fields] OR “n-acetyl cysteine”[All Fields] OR “N-acetyl-cysteine”[All Fields] OR “Sulfur-containing”[All Fields] OR “Amino-acid”[All Fields] OR (“adjunct”[All Fields] OR “TB-treatment”[All Fields] OR “adjunctive”[All Fields] OR “replenish-GSH”[All Fields] OR “NAC impact”[All Fields] OR “NAC effects”[All Fields] OR “NAC-supplement”[All Fields]) OR “non-thiol”[All Fields] OR “Cysteine”[All Fields] OR “N-Acetyl cysteine”[All Fields] OR “Glycine”[All Fields] OR “cysteine”[MeSH Terms] OR “glutamine”[All Fields] OR “glutamic acid”[All Fields] OR “Hepatotoxicity”[All Fields] OR “DiLI”[All Fields].

We conducted a search of the identified terms in PubMed, Google Scholar, SciFinder, and Wiley online library databases. Each group of search terms were identified either in Abstracts, Free Full Text, full text, books and documents, case reports, clinical studies, clinical trials, in phase 1–4, clinical trial protocols, comparative studies, Meta-Analysis, observational studies, randomized controlled trials, research support, US Government, Reviews and systematic Reviews, and human subjects. We identified 42,205 results in the first group (as a population) and 113,106 results from the second group (as an intervention). Further searching using #1AND#2 was done by combining the results of the population and an intervention, as identified above. The initial database searches were performed on 12 April 2022, and updated on 31 May 2022. Twenty-four studies were selected for full-text review based on the abstracts obtained by this search approach. In addition, we looked through the reference lists of all the papers and reviews we obtained to see if there were any other studies that were relevant prior to data extraction. The articles included reported on clinical trials: randomized, double-blind or open-label, placebo-controlled, prospective, pilot, and case studies of oral, inhalation, and intravenous NAC supplementation taken on a regular basis during the course of TB treatment. We also included experimental studies investigating the in vitro effects of NAC on the harvested cells, either from humans or experimental animals, and studies conducted in the trial of NAC used in combination with other approved drugs. Review articles on the effects of NAC were included in this review as well see (Tables 1–4). We excluded trials of NAC conducted in other diseases apart from TB. See (Figure 1).

The present review work was not registered, and the protocol was not prepared.

The primary outcome measures of the review were to evaluate clinical trials on the effects of NAC on the progression of TB disease, such as improved lung function, sputum culture conversion, increased levels of GSH expression, and changes in cytokine production, specifically IL-10 and TNF-α. NAC supplement dosage and treatment duration were also assessed. The secondary outcome measures were to determine whether a protective effect or adverse event resulted from the course of NAC usage during and/or after TB treatment.

Statistical Methods

Unadjusted meta-analyses were conducted for each intervention, comparison group, and outcome using a random effect model in STATA software (version 16, STATA Corporation, College Station, TX, 4905 Lakeway Drive, USA). Relative risk was used when the outcome was culture conversion, and risk difference was used when the outcomes were adverse events. I2 statistics were used to assess heterogeneity between studies. The values of I2 statistics greater than 50% represented high heterogeneity. For all analyses, the p-value for statistical significance was set at 0.05.

3. ResultsAfter searching 37 citations and 8035 full-text papers, and by removing the duplicates and irrelevant articles using the Covidence tool, 207 articles were assessed for eligibility. Finally, 24 articles were included, of which 1 article was not yet published but rather was an accepted manuscript. The articles were searched from 1960, when NAC use began, until 2022. Of the identified and included articles, 100% were disseminated after 2004, 53.8% of the articles were published between 2016 and 2020, and 19.2% of the articles were already published from 2021 to 31st May 2022. Most of the articles were reported from North America (34.8%) and (13.04%) reported from Brazil or Iran. Furthermore, 8.7% of the identified articles are from the United Kingdom, India, South Africa, and China separately. Five (20.8%) of the identified articles were clinical trials, seven (29.2%) were systematic literature reviews or in vitro study designs, four (16.7%) were experimental animal model designed studies, and one (4.2%) was a case report. Almost all articles found that the NAC replenished GSH, which boosted host immunological function and improved TB treatment, including lung function and reduced time to sputum culture positivity, with minimal or minor side effects; see (Figure 1) and (Table 1, Table 2, Table 3 and Table 4). 3.1. Data Charting

The data charting process was completed after data extraction conducted by the use of the online COVIDENCE program tool, which was freely offered to be used by the organization team. The tools automatically identify duplicates and ease the data extraction process.

Table 1 presents the in vitro studies that were carried out to assess the effect of NAC on TB.Table 2 presents studies using experimental animal models to examine the effect of NAC on TB.Table 3 presents clinical trials and a case study that was done to assess the impact of NAC on TB.Table 4 presents studies on NAC’s impact on TB. 3.2. NAC Effect on Sputum Culture ConversionUnderstanding NAC’s mucolytic property and that it may have an effect on microbial activity, the review looked into studies that reported on the effect of NAC in TB, with a focus on sputum culture conversion. We found two studies from Mahakalkar et al. [17] and Safe I.P [19], which both looked into the effect of NAC on sputum culture conversion (Table 5). The forest plot from two studies on the use of NAC in TB is shown below.Table 5 presents sputum culture conversion from two studies. The overall effect of the NAC intervention group was not significantly different from the control, with a pooled RR of 1.10 and a 95% CI of 0.98–1.23. As for the heterogeneity between the studies, since the I2 is 0%, this suggests no important heterogeneity was observed between studies. Although the Mahakalkar paper reported that in the NAC group, 23 patients achieved sputum negativity in three weeks, while 14 patients were in the PLACEBO group and Safe. P reported 11 (61.1%) patients in the NAC group had a negative culture at week 8, while only 7 (33.3%) were in the control group. 3.3. Adverse Events of NAC in TB SubjectsNAC has been investigated as a supplementary drug for patients and reduces hepatotoxicity. The present review identified mild adverse events that were reported by Izabella P. Safe et al. [31], including nausea, vomiting, and hepatotoxicity. However, the article reported that up to 30% patients were experiencing hepatotoxicity are living with HIV, and the infection appeared to be one of the risk factors. Baniasadi et al. [29] reported that NAC protects against drug-induced hepatotoxicity caused by the standard anti-TB drugs therapy (INH, RIF, and PZA combination) in elderly populations. Again, milder adverse events were reported in a case study by Fox et al [32], Oral NAC was associated with nausea and vomiting, suggesting further investigation in clinical trials being required. Three studies identified by Kranzer et al. [34] reported that NAC reduced ototoxicity in 146 patients with end-stage renal failure receiving aminoglycosides, while eighty-three studies described how the administration of NAC for more than 6 weeks increased abdominal pain, nausea and vomiting, diarrhea, and arthralgia in 1.4–2.2 times. The meta-analysis from three studies were conducted to evaluate the adverse events was represented by a forest plot below (Table 6).Table 6 presents adverse events between the control and NAC groups from three studies. The results showed a risk difference between the two groups with a 95% CI of −0.03 (95% CI: −0.42–0.35), although there was significant inter-study heterogeneity. 3.4. Immunological ResponsesA pilot study conducted by Guerra et al. examined the effects of NAC (alone and in combination with IL-2 and IL-12) on up-regulating NK cell cytotoxic receptors and determined the levels of GSH in NK cells derived from HIV-positive, as well as the survival of H37Rv M. tb strain in monocytes cultured in the presence of NK cells (both from HIV-positive individuals). Findings treating NK cells with IL-2, IL-12, and NAC, inhibited the growth of H37Rv. When combined with GSH, it improved the ability of NK cells to control M. tb infection. Lin et al [21]. discovered that NAC inhibits the expression of TNF-α and caspase-9 genes as well as the translation of apoptotic proteins. Also Venketaraman et al. (2008) [24] showed that NAC decreased the levels of IL-10, IL-6, TNF-α, and IL-1 in blood cultures derived from TB patients and also showed the efficient control of intracellular M. tb infection in blood cultures derived from healthy subjects compared to TB patients. 3.5. GSH Expression LevelsWe also looked into the effect of NAC on GSH expression. Two studies conducted by Mahakalkar et al. (2017) [17] in a clinical trial to investigate the effect of NAC on the production of glutathione peroxidase, an enzyme that catalyzes the oxidation and dimerization of GSH. The finding was that 600 mg NAC taken twice a day significantly raised Glutathione Peroxidase levels. A clinical study by Safe. P. et al. [31] measured the effect of 600 mg NAC taken twice a day on the GSH expression study found GSH levels were elevated only in RIPENAC patients at 60 days compared to levels found at the baseline. Furthermore, GSH levels were higher in RIPENAC patients compared to the RIPE group at day 60. It has been observed that NAC enhanced GSH levels by 2-fold in the RIPENAC group compared to the control at 60 days of treatment. It is possible that restoring GSH may negatively impact other markers, as the generation of ROS has been proposed as a mechanism of action for both macrophages and TB drugs. The current study did not explain how this effect will translate to clinical outcomes. 3.6. Lung FunctionTB disease impairs normal lung function, and the effect persists even after the microbiological cure [3]. In several studies on lung disease, spirometry is the gold standard for measuring airway obstruction [5]. Researchers have reported that half of TB survivors present with some form of lung impairment [3,40]. NAC is now used as a food supplement and some clinical trials have investigated the role played by NAC in improving lung function impaired during TB infection. Forced expiratory volume (FEV1) has been very extensively studied in this regard; even small decreases in FEV1 are associated with increased standardized mortality risks. Conversely, there is a known long-term FEV1 benefit and a possible short-term benefit from treatment shortening. It is also possible that only some patients will benefit from NAC. The present review did not identify any studies or research on the use of NAC in improving lung outcomes in TB patients.

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