الفهرس 
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Abstract
Summary
Coronavirus Disease 2019 (COVID-19) is a contagious respiratory illness caused by a novel coronavirus that was first identified in Wuhan, China in December 2019. The virus has spread since then to many countries around the world (Di Gennaro et al., 2020). Symptoms of COVID- 19 can range from mild to severe symptoms and include fever, cough, and difficulty breathing. In severe cases, the pneumonia caused by the virus become complicated and may cause acute respiratory distress syndrome or spread to other organs causing heart, kidney failure, stroke and might lead to sepsis (Hatmi, 2021).
The virus is primarily spread through respiratory droplets when an infected person coughs, sneezes or talks. These droplets can land in the mouths or noses of people who are nearby or can be inhaled directly to the lungs (Wilson et al., 2020). The risk of getting more severe symptoms of the infection rises with increasing age and the presence of comorbidities mainly hypertension, Diabetes and cardiovascular diseases (CDC COVID-19 Response Team, 2020; Schiffrin et al., 2020).
Polymerase chain reaction (PCR) is the gold standard for COVID-19 diagnosis. Yet, since the test has varying sensitivity, Chest CT along with blood tests aid in the diagnosis (Wiersinga et al., 2020).
When the virus spike protein reaches the lower airways, it binds to the angiotensin-converting enzyme 2 (ACE2) receptor and uses it to penetrate the alveolar cells, which results in decreased expression of the enzyme and accumulation of angiotensin II. Its accumulation promotes inflammatory as well as oxidative stress since they are strictly related to each other (Medina-Enríquez et al., 2020). Glutathione peroxidase enzyme appears to be lower in COVID-19 compared to healthy individuals (Muhammad et al., 2021) . Moreover, Patients with COVID-19 have high levels of inflammatory cytokines mainly IL-6 and TNF-α.
The higher the levels of these cytokines the higher the risk of more complicated disease (Hu et al., 2020). Increasing the anti-oxidant potentials of the body as well as targeting inflammation might be an appropriate therapeutic approach to help speedy recovery from the infection.
The management of COVID-19 infections includes adequate isolation to prevent the spread of the disease along with symptomatic treatment according to the patients’ presenting symptoms. The decision to use antivirals, corticosteroids and monoclonal antibodies depends on the patient’s disease severity and risk factors (National Institutes of Health, 2021).
N-acetylcysteine (NAC) is considered a well-tolerated and safe medication that has been used all across the world in variety of medical conditions for the past several decades (Paintlia et al., 2008). Besides its known mucolytic activity, NAC has anti-oxidants and anti-inflammatory effects. The drug exhibits its antioxidant property in several ways including interaction with the electrophilic groups of reactive oxygen species (ROSs) and being a glutathione (GSH) precursor. In addition, it inhibits the induction of the pro-inflammatory transcription factor NF-ƙB activated in response to oxidative stress (Guerini et al., 2022).
The objective of this trial was to assess the efficacy and tolerability of adding 1800 mg of oral NAC to the institutional protocol for moderate COVID-19 management through the measurement of plasma glutathione peroxidase, IL-6 and TNF-α along with the patients’ need for oxygenation, the duration on oxygen, length of hospital stay and incidence of adverse events.
The present study was a prospective, randomized, controlled study. Patients were recruited from El-Asema Hospital, Cairo, Egypt, from the period of March 2021 to April 2022. COVID-19 cases were confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab. COVID-19 pneumonia was confirmed by chest Computed tomography (CT) scan.
All COVID -19 patients admitted to the isolation ward were assessed for eligibility and were included if presented with moderate COVID-19 infection according to the management protocol of the Egyptian Ministry of Health and Population. Patients were excluded if they were; < 18 years, pregnant or lactating, allergic to NAC, critically ill or mechanically ventilated.
According to the management protocol of the Egyptian Ministry of Health and Population, COVID-19 infections were classified into mild, moderate or severe infection. Mild COVID-19 defines as respiratory symptoms without evidence of pneumonia or hypoxia, while moderate cases have pneumonia findings on radiology along with symptoms. Severe cases show clinical signs of pneumonia with one of the following: respiratory rate > 30 breaths/min; SaO2 < 92 at room air, PaO2/FiO2 ratio < 300 (Masoud et al., 2020).
Before the initiation of the study, it was approved by the Scientific Research Ethics Committee of the Faculty of Pharmacy, Ain Shams University and was registered on clinical trial.gov (NCT04792021). A written informed consent was obtained from all patients or their surrogates.
At baseline, all the participants were thoroughly evaluated via history talking, clinical assessment and laboratory assessment. Glutathione peroxidase, IL-6 and TNF-α levels were measured in their plasma at baseline and at the end of the study prior to patient’s discharge.
Oxidative stress was assessed by measuring the level of plasma glutathione peroxidase activity via a colorimetric assay kit. While the level of plasma IL-6 and TNF-α were estimated by means of ELISA technique. All the participants were assessed daily for adverse drug reactions.
The addition of NAC to the institutional protocol resulted in a decrease in the TNF-α level (p< 0.001) while that of glutathione peroxidase was markedly elevated in the NAC treated group (p=0.001). No significant difference was noted in levels of IL-6, CRP nor TLC levels between both groups (p-values,0.810 0.474, 0.050) respectively. The duration on oxygen support was significantly decreased in the NAC treated group (p=0.005). On the contrary, the length of hospital stay and the need for oxygen support was not affected by the addition of NAC (p- values, 0.45, 0.42) respectively. The mortality rate was comparable in both groups
There were no distinctive medication adverse effects observed except for one patient in the NAC group who refused to continue taking the medication due to its bitter after-taste.
In conclusion, this trial showed that NAC supplementation in moderate severity COVID-19 patients significantly decreased the level of TNF-α with no effect on IL-6 level. Moreover, NAC caused a significant increase in the glutathione peroxidase level which ameliorated the antioxidant capacity of the body. Furthermore, addition of NAC to the institutional protocol decreased the duration of oxygen for those who were in need with no effect on the number of patients who needed oxygen supplementation nor the length of hospital stay.