Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has culminated in a global pandemic. As of 25 February 2022, a total of 430,257,564 cases and 5,922,049 deaths had been confirmed worldwide. Although the vast majority of patients experience mild-to-moderate symptoms, a large number of infected people continue to die from the disease.At present, clinical drug research for COVID-19 is predominantly focused on the development of new crown vaccines, antiviral therapy, and antibody neutralization therapy,[3–5] and to date, there are few studies on the therapeutic effects of N-acetylcysteine on COVID-19 patients .
The main cause of death from COVID-19 is acute respiratory distress syndrome (ARDS), and studies have shown that excessive immune activation and cytokine storm is the causes of COVID-19-related lung injury. It is currently believed that prolonged oxidative stress, increased production of reactive oxygen species (ROS), and decreased glutathione levels lead to an imbalance in redox homeostasis, thus leading to excessive immune activation and cytokine storms. It is used as a direct scavenger of ROS to regulate the redox state, regulate the inflammatory response, and exhibit indirect antioxidant properties. It has been confirmed by in vitro and in vivo studies, and it is widely used in clinics, for example, in the treatment of liver poisoning due to paracetamol toxicity, chronic obstructive pulmonary disease, and so on.
The first COVID-19 death autopsy in Chinawas conducted on an 85-year-old patient, and it revealed white foamy mucus in the trachea and jelly-like mucus in the bronchus lumen of the right lung, suggesting the presence of secretions in the airway of the COVID-19 patient. The secretions are considerably viscous and not easily discharged, possibly contributing to the acceleration of patient death. Therefore, the use of expectorant drugs has become an important part of the adjuvant treatment of patients with COVID-19. N-acetylcysteine (NAC) is an N-acetyl derivative of the natural amino acid L-cysteine. The active free -SH group in the NAC molecule potentially promotes the breakage of the acid glycoprotein polypeptide disulphide bond (-SS) in the sputum and directly splits the DNA molecular chain and mucin in the hydrolysed sputum, thereby decomposing the respiratory mucus. Keeping the respiratory tract moist may reduce irritation. In a prospective, randomized, controlled trial in Shandong Province, China,recruited adult patients with bronchiectasis who had experienced at least two acute exacerbations in the previous year. The results demonstrated that oral NAC (600 mg twice a day for 12 months) potentially reduces the risk of acute exacerbation.
In addition, the protective effect of NAC in influenza and other respiratory viral diseases has been confirmed, and it has been proven to reduce the incidence and severity of influenza and influenza-like diseases.The mechanism includes the inhibition of viral matrix protein expression, caspase activation, and fatty acid synthase upregulation, thereby inhibiting virus replication and reducing viral load. Simultaneously, it inhibits influenza A and B viruses as well as a respiratory syncytial virus by regulating the overexpression and release of MUC5AC and inhibiting the translocation of interleukin (IL)-8, IL-6, tumor necrosis factor-alpha, and nuclear factor kappa B to the nucleus as well as the phosphorylation of mitogen-activated protein kinase p38.53. The mechanism that leads to the production of ROS and release of mucin from epithelial cells increases inflammation and apoptosis events.
Based on the foregoing theory, we believe that NAC can play an important role in the treatment of COVID-19.
Clinical data sources include objective indicators such as laboratory tests, imaging tests, patient signs, and subjective indicators such as patient-reported outcomes (PROs). However, the use of clinical objective indicators alone may overlook a patient's certain symptoms and overestimate the effectiveness of medical interventions. The verbal characterization of the symptoms conveyed by the patient, and recorded by care providers is central to the practice of clinical medicine, and increasing importance is attached to patient-centered clinical care. The United States Food and Drug Administration defines a patient-reported outcomes as any report regarding the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. PROs is the only measure that can reflect the impact of the patient’s disease. It helps to obtain the patient’s treatment license and establishes beneficial communication between the patient and healthcare staff to determine treatment efficiency. Therefore, a measurement of any aspect of a patient's health status that comes directly from the patient (i.e., without the interpretation of the patient's responses by a physician or anyone else),PROs, necessarily need to be included to realistically assess the effectiveness and safety of the intervention.
The results of some foreign studies have shown that the St. George’s Respiratory Questionnaire (SGRQ) questionnaire correlates well with pulmonary function and clinical symptoms, [20–22]and most of the questions are required to be self-reported by patients, which is more realistic. Therefore, the SGRQ questionnaire was chosen to assess the quality of life of COVID-19 patients in this study. The SGRQ is a patient-reported questionnaire used to measure the impact of respiratory diseases and their treatment on the patient’s health-related quality of life (HRQoL). It has been used in patients with asthma, chronic obstructive pulmonary disease, bronchiectasis, interstitial lung disease, and lung transplantation. The SGRQ includes 50 items, divided into three parts: symptoms (frequency and severity), activities (activities that can cause shortness of breath or restricted activities), and impact on daily life (social impairment and psychological disorders caused by airway diseases). The SGRQ total score ranges from 0 to 100 points, with a lower score indicating superior HRQoL.
Therefore, we conducted a multi-center observational study (www.chictr.org.cn; number: ChiCTR2100049355). The main purpose of the study was to evaluate the effectiveness of NAC against COVID-19 and observe its impact on the patient-reported outcomes.