Impact of N-acetyl-l-cysteine on SARS-CoV-2 pneumonia and its sequelae: results from a large cohort study

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may cause pneumonia and acute respiratory distress syndrome (ARDS), whose pathogenesis has been partially related to an increased systemic inflammatory response with great production of pro-inflammatory cytokines causing a "cytokine storm" and an oxidative stress imbalance [1]. N-acetyl-L-cysteine (NAC) is a precursor of reduced glutathione [2] that has antioxidant, anti-inflammatory and immunomodulating properties that may prove beneficial in modulating the excessive inflammatory activation during coronavirus disease (COVID-19) [3]. Furthermore, NAC has been extensively used as a mucolytic agent to improve airway clearance in chronic respiratory diseases. During the COVID-19 pandemic research hypotheses on the role of NAC have been formulated and randomised control trials (RCT) are ongoing; however, to date only a few case reports have been published [3, 4]. The aim of our study is to evaluate the impact of NAC administered during hospitalisation for SARS-CoV-2 pneumonia on short-term and long-term outcomes. As short-term outcomes we considered in-hospital mortality, intensive care unit (ICU) admission, length of ICU stay and length of hospital stay (LOS) in patients discharged alive; as long-term outcomes we included diffusion capacity of the lung for carbon monoxide (D LCO ) impairment, chest radiography alterations, reduced distance walked in the 6-min walk test (6MWT) and dyspnoea score (modified Medical Research Council (mMRC) scale) at 6 months follow-up in a subset of patients included in a follow-up study. Furthermore, we will also evaluate the impact of NAC on the development of atelectasis during hospitalisation, a possible complication of SARS-CoV-2 pneumonia. We performed a retrospective monocentric study on 1083 consecutive adult patients hospitalised for SARS-CoV-2 pneumonia at the San Gerardo Hospital, Monza, Italy, between February 2020 and April 2021. Given that the aim was to evaluate the impact of a least 5 days of NAC administration, patients were excluded if they died or were discharged within 5 days from admission (n=177) to avoid immortal time bias. NAC was introduced, as per institutional protocol, on admission and administered at a dosage of 300 mg intravenously three times daily, switched to 600 mg per os twice daily once the patient reached clinical stability and continued until discharge. The study (STORM) was approved by the national Institutional Review Board (Spallanzani Hospital), and registered at ClinicalTrials.gov with identifier NCT04424992. As part of a multi-centre prospective study to evaluate pulmonary sequelae caused by SARS-CoV-2 pneumonia [5] (ClinicalTrials.gov identifier: NCT04435327), we also had available follow-up data on 102 patients from the original cohort alive at discharge. The follow-up consisted of a pneumological visit at 6 months including complete pulmonary function tests and D LCO , 6MWT, mMRC scale and..