Pyridostigmine reduces mortality of patients with severe SARS-CoV-2 infection: A phase 2/3 randomized controlled trial.

BACKGROUND: Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19. METHODS: We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described. RESULTS: We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44-64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24-0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively). CONCLUSION: Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.

Seroepidemiology of SARS-CoV-2 in healthcare personnel working at the largest tertiary COVID-19 referral hospitals in Mexico City.

INTRODUCTION: We performed a longitudinal SARS-CoV-2 seroepidemiological study in healthcare personnel of the two largest tertiary COVID-19 referral hospitals in Mexico City. METHODS: All healthcare personnel, including staff physicians, physicians in training, nurses, laboratory technicians, researchers, students, housekeeping, maintenance, security, and administrative staff were invited to voluntarily participate, after written informed consent. Participants answered a computer-assisted self-administered interview and donated blood samples for antibody testing every three weeks from October 2020 to June 2021. RESULTS: A total of 883 participants (out of 3639 registered employees) contributed with at least one blood sample. The median age was 36 years (interquartile range: 28-46) and 70% were women. The most common occupations were nurse (28%), physician (24%), and administrative staff (22%). Two hundred and ninety participants (32.8%) had a positive-test result in any of the visits, yielding an overall adjusted prevalence of 33.5% for the whole study-period. Two hundred and thirty-five positive tests were identified at the baseline visit (prevalent cases), the remaining 55 positive tests were incident cases. Prevalent cases showed associations with both occupational (institution 2 vs. 1: adjusted odds ratio [aOR] = 2.24, 95% confidence interval [CI]: 1.54-3.25; laboratory technician vs. physician: aOR = 4.38, 95% CI: 1.75-10.93) and community (municipality of residence Xochimilco vs. Tlalpan: aOR = 2.03, 95% CI: 1.09-3.79) risk-factors. The incidence rate was 3.0 cases per 100 person-months. Incident cases were associated with community-acquired risk, due to contact with suspect/confirmed COVID-19 cases (HR = 2.45, 95% CI: 1.21-5.00). CONCLUSIONS: We observed that between October 2020 and June 2021, healthcare workers of the two largest tertiary COVID-19 referral centers in Mexico City had similar level of exposure to SARS-CoV-2 than the general population. Most variables associated with exposure in this setting pointed toward community rather than occupational risk. Our observations are consistent with successful occupational medicine programs for SARS-CoV-2 infection control in the participating institutions but suggest the need to strengthen mitigation strategies in the community.

Clinical Characteristics and Mortality of Health-Care Workers With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Mexico City.

BACKGROUND: We evaluated the risk of death for health-care workers (HCW) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Mexico City during the coronavirus disease 2019 (COVID-19) pandemic, and describe the associated factors in hospitalized HCW, compared with non-HCW. METHODS: We analyzed data from laboratory-confirmed SARS-CoV-2 cases registered from 27 February-31 August 2020 in Mexico City's public database. Individuals were classified as non-HCW or HCW (subcategorized as physicians, nurses, and other HCW). In hospitalized individuals, a multivariate logistic regression model was used to analyze the potential factors associated with death and compare mortality risks among groups. RESULTS: A total of 125 665 patients were included. Of these, 13.1% were HCW (28% physicians, 38% nurses, and 34% other HCW). Compared with non-HCW, HCW were more frequently female, were younger, and had fewer comorbidities. Overall, 25 771 (20.5%) were treated as inpatients and 11 182 (8.9%) deaths were reported. Deaths in the total population (9.9% vs 1.9%, respectively; P < .001) and in hospitalized patients (39.6% vs 19.3%, respectively; P < .001) were significantly higher in non-HCW than in HCW. In hospitalized patients, using a multivariate model, the risk of death was lower in HCW in general (odds ratio [OR], 0.53) than in non-HCW, and the risks were also lower by specific occupation (OR for physicians, 0.60; OR for nurses, 0.29; OR for other HCW 0.61). CONCLUSIONS: HCW represent an important proportion of individuals with SARS-CoV-2 infection in Mexico City. While the mortality risk is lower in HCW compared to non-HCW, a high mortality rate in hospitalized patients was observed in this study. Among HCW, nurses had a lower risk of death compared to physicians and other HCW.

Impact of RT-PCR Test False-Negative Results for SARS-CoV-2 Surveillance in Mexico.

Background: Underestimation of the number of cases during the coronavirus disease 2019 (COVID-19) pandemic has been a constant concern worldwide. Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA using realtime reverse-transcription polymerase chain reaction (RT-PCR) is the most common method to confirm a case. However, these tests have suboptimal sensitivity. Objective: The objective of the study was to estimate the number of COVID-19 confirmed cases, intensive care unit (ICU) admissions and deaths in Mexico, accounting for the probabilities of false-negative tests. Methods: We used publicly available, national databases of all SARS-CoV-2 tests performed at public laboratories in Mexico between February 27 and October 31, 2020. We used the estimated probabilities of false-negative tests based on the day of clinical sample collection after symptom initiation calculated previously. With the resulting model, we estimated the corrected daily number of cases, ICU admissions, and deaths. Results: Among 2,024,822 people tested in Mexico between February 27 and October 31 with an available result, we estimated 1,248,583 (95% confidence interval 1,094,850-1,572,818) cases, compared to 902,343 cases reported with positive tests. ICU admissions and deaths were 15% and 8% higher than reported, respectively. Conclusion: Accounting for SARS-CoV-2 RT-PCR-based diagnostic tests' precision is a simple way to improve estimations for the true number of COVID-19 cases among tested persons.

A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the Pyridostigmine In Severe COvid-19 (PISCO) trial protocol.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19. METHODS: A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. DISCUSSION: This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04343963 (registered on April 14, 2020).