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.

Prevalence of thyroid dysfunction in healthy adults according to the estimated iodine intake in 24-hour urine samples: The SALMEX cohort.

PURPOSE: The aim of this study was to evaluate the prevalence of thyroid dysfunction in a cohort of healthy individuals in Mexico City, as well as to investigate the potential associations of these results with their estimated iodine intake (EII) as reflected by their 24-hour urinary iodine excretion (24-h UIE). METHODS: From the SALMEX cohort, 683 adults provided an appropriate 24-h urine sample. Thyroid function tests and thyroid antibody concentrations were determined in the participants' sera. We analyzed discrepancies between the commonly used urinary parameters to determine the iodine intake status and the performance of thyroglobulin (Tg) as a biomarker of its status in the adult population. RESULTS: The prevalence of dysthyroidism was high, being similar to other studies. Subclinical hypothyroidism was detected in 5.0% of individuals, clinical hypothyroidism in 1.8% of individuals, and sub-clinical hyperthyroidism in 2.8% of individuals. The median EII was 285 µg/d (IQR 215.0-369.0); 94% of individuals had EII >150 µg/d recommended daily allowance (RDA) in adults. The urinary iodine concentration (UIC) and the UIE had relative biases in their averages of 34.4%. The Tg median was 7.21 ng/mL. The prevalence of increased Tg was 6.15%. There was no correlation between Tg and EII (r= 0.019, p= 0.606). CONCLUSIONS: Thyroid dysfunction was highly prevalent in this population. Our cohort revealed a slight discrepancy between dysthyroidism manifestations and iodine intake markers; the latter represent a population with adequate iodine intake. Further studies are necessary to clearly define the prevalence of thyroid dysfunction as well as the iodine nutritional status in Mexico.

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).

Evaluation of bone densitometry by dual-energy x-ray absorptiometry as a fracture prediction tool in women with chronic kidney disease.

BACKGROUND: The 2017 KDIGO guidelines establish a 2B grade recommendation in favor of testing Bone Mineral Density (BMD) by DXA to assess osteoporotic fracture (OPF) risk in patients with CKD G3a-G5D. Still, controversy remains because large studies evaluating it for this particular population are lacking. AIM: To establish the clinical performance of BMD measured by DXA in the evaluation of fracture risk in women with CKD. METHODS: We conducted a 43 year retrospective cohort study with 218 women ≥18 years-old with CKD and BMD measurement by DXA of total hip and lumbar spine. Clinical (age, year of CKD onset, comorbidities, BMI, transplant status, treatment), and biochemical (PTH, corrected calcium, phosphate, vitamin D [25 (OH) D3], creatinine, and albumin), parameters were collected from hospital records. All osteoporotic fractures (as defined by the WHO) found in the clinical and radiologic files were registered. RESULTS: 218 women with a median age of 60 years (40-73 IQ range) and a CKD evolution time of 12 years (7-18 IQ range) were evaluated. Forty-eight (28.23%) presented an OPF. These women were older (57 vs 69 years, p =0.0072) and had a lower BMD. CKD stage did not influence fracture incidence. In the multivariate analysis we found that for each standard deviation decrease in hip and lumbar spine T-Score, the overall fracture risk was 2.7 and 2.04 times higher, respectively. More than 50% of fractures took place within the first ten years of follow-up, especially with GFR <30 mL/min/m2 and osteoporosis. Diabetes and hypothyroidism accelerated fracture onset, while renal transplant delayed it. In the ROC analysis, the AUC was largest with the total hip (0.7098, p = 0.000) and lumbar spine (0.6916, p = 0.000). CONCLUSIONS: BMD measured by DXA is a useful fracture prediction tool for women with CKD, having a sensibility and specificity similar to that in the general population. It seems to be appropriate for the diagnosis, treatment decisions, and follow-up of patients with renal failure.