ABSTRACT
Background: Hospitalized patients with severe COVID-19 have an increased risk of developing severe systemic inflammatory response, pulmonary damage, and acute respiratory distress syndrome (ARDS), resulting in end-organ damage and death. Acetylcholine modulates the acute inflammatory response through a neuro-immune mechanism known as the inflammatory reflex. Pyridostigmine, an acetylcholine-esterase inhibitor, increases the half-life of endogenous ACh, chemically stimulating the inflammatory reflex. This trial aimed to evaluate whether pyridostigmine could decrease invasive mechanical ventilation (IMV) and death in patients with severe COVID-19. Methods: We performed a parallel-group, multicenter, double-blinded, placebo-controlled, randomized clinical trial to evaluate if add-on pyridostigmine to standard treatment reduced the composite outcome of initiation of IMV and 28-day all-cause mortality among hospitalized patients with severe COVID-19. Results: 188 participants were randomly assigned to placebo (n=94) or pyridostigmine (n=94). The composite outcome occurred in 22 (23.4%) vs. 11 (11.7%) participants, respectively (hazard ratio 0.46, 95% confidence interval 0.22-0.96, p=0.03). Most of the adverse events were mild to moderate, with no serious adverse events related to pyridostigmine; discontinuation of the study drugs was similar in both groups. Conclusions: We provide evidence indicating that the addition of pyridostigmine to standard treatment resulted in a clinically significant reduction in the composite outcome (IMV/death) among patients hospitalized for severe COVID-19. (Funded by Consejo Nacional de Ciencia y Tecnologia, Mexico; ClinicalTrials.gov number: NCT04343963).
Subject(s)
COVID-19 , Lung Diseases , Death , Respiratory Distress SyndromeABSTRACT
Background: The development of mRNA vaccines to prevent SARS-CoV-2 has been remarkably successful, with highly effective vaccines available less than one year after confirming the first case. Due to the global burden of COVID-19 on health systems, emergency approval was attained after clinical trials with relatively small sample sizes and short follow-up periods. Limited information exists about the incidence of adverse events following immunisation (AEFI), particularly neurologic ones. Here, we describe the neurologic AEFI reported by recipients of the BNT162b2 mRNA COVID-19 vaccine. Methods: We conducted a prospective observational cohort using de-identified information from a database of all systemic and neurologic AEFI reported to the Mexican Ministry of Health throughout a passive Epidemiological Surveillance System by first-dose vaccine recipients, from December 24, 2020 to February 12, 2021. The cut-off date for this data was February 18, 2021. We performed descriptive analyses on demographics, timing from vaccination to AEFI development, event duration, and current outcome.Findings: Nationwide, 704 003 first-doses were administered; 6536 AEFI were reported. Among those, 4258 (65·1%) had at least one neurologic manifestation. Non-serious neurologic AEFI occurred in 99·6%. Headache (62·2%), transient sensory symptoms (3·5%), and weakness (1%) were the most frequent. Thirty-three serious AEFI were reported, of which 17 (2·4/100 000 doses) were neurologic, seven seizures, four functional syndromes, three Guillain-Barré syndrome (GBS) cases, and two of acute transverse myelitis. All GBS cases were related to a gastrointestinal infection before vaccination, 3/7 seizure episodes were related to poor antiepileptic drug compliance, and 2/7 to anaphylactic reactions. At the time of this report, 16/17 cases of serious neurologic AEFI had been discharged with no observed deaths.Interpretation: Our data suggest that the BNT162b2 mRNA vaccine is effective and safe. Their individual and societal benefits outweigh the low-percentage of serious neurologic and non-neurologic AEFI.Funding: Consejo Nacional de Ciencia y Tecnología, México.Declaration of Interest: None to declareEthical Approval: The study was revised and approved by the Ethics and Research Committees of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (Ref. NER-3667-2021) and the Mexican Ministry of Health.