Mycobacterium manresensis induces trained immunity in vitro.

The COVID-19 pandemic posed a global health crisis, with new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants weakening vaccine-driven protection. Trained immunity could help tackle COVID-19 disease. Our objective was to analyze whether heat-killed Mycobacterium manresensis (hkMm), an environmental mycobacterium, induces trained immunity and confers protection against SARS-CoV-2 infection. To this end, THP-1 cells and primary monocytes were trained with hkMm. The increased secretion of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1ß, and IL-10, metabolic activity, and changes in epigenetic marks suggested hkMm-induced trained immunity in vitro. Healthcare workers at risk of SARS-CoV-2 infection were enrolled into the MANRECOVID19 clinical trial (NCT04452773) and were administered Nyaditum resae (NR, containing hkMm) or placebo. No significant differences in monocyte inflammatory responses or the incidence of SARS-CoV-2 infection were found between the groups, although NR modified the profile of circulating immune cell populations. Our results show that M. manresensis induces trained immunity in vitro but not in vivo when orally administered as NR daily for 14 days.

Atherosclerosis, Cardiovascular Disease, and COVID-19: A Narrative Review.

Atherosclerosis is a chronic inflammatory and degenerative process that mainly occurs in large- and medium-sized arteries and is morphologically characterized by asymmetric focal thickenings of the innermost layer of the artery, the intima. This process is the basis of cardiovascular diseases (CVDs), the most common cause of death worldwide. Some studies suggest a bidirectional link between atherosclerosis and the consequent CVD with COVID-19. The aims of this narrative review are (1) to provide an overview of the most recent studies that point out a bidirectional relation between COVID-19 and atherosclerosis and (2) to summarize the impact of cardiovascular drugs on COVID-19 outcomes. A growing body of evidence shows that COVID-19 prognosis in individuals with CVD is worse compared with those without. Moreover, various studies have reported the emergence of newly diagnosed patients with CVD after COVID-19. The most common treatments for CVD may influence COVID-19 outcomes. Thus, their implication in the infection process is briefly discussed in this review. A better understanding of the link among atherosclerosis, CVD, and COVID-19 could proactively identify risk factors and, as a result, develop strategies to improve the prognosis for these patients.

Effectiveness of antitussives, anticholinergics, and honey versus usual care in adults with uncomplicated acute bronchitis: a multiarm randomized clinical trial.

BACKGROUND: Despite the frequent use of symptomatic therapies in cough, evidence of their benefits is lacking. OBJECTIVE: We compared the effectiveness of 3 symptomatic therapies and usual care in acute bronchitis. METHODS: Multicenter, pragmatic, multiarm parallel group, open randomized trial in primary care (ClinicalTrials.gov, Identifier: NCT03738917) was conducted in Catalonia. Patients ≥18 with uncomplicated acute bronchitis, with cough<3 weeks as the main symptom, scoring ≥4 in either daytime or nocturnal cough (7-point Likert scale), were randomized to usual care, dextromethorphan 15 mg t.i.d., ipratropium bromide inhaler 20 µg 2 puffs t.i.d, or 30 mg of honey t.i.d., all taken for up to 14 days. The main outcome measure was the number of days with moderate-to-severe cough. A symptom diary was given. A second visit was scheduled at days 2-3 for assessing evolution, with 2 more visits at days 15 and 29 for clinical assessment, evaluation of adverse effects, re-attendance, and complications. RESULTS: We failed to achieve the sample size scheduled due to the COVID-19 pandemic. We finally recruited 194 patients. The median number of days with moderate-to-severe cough (score ≥ 3) in the usual care arm was 5 (interquartile range [IQR], 4, 8.75), 5 in the ipratropium bromide arm (IQR, 3, 8), 5 in the dextromethorphan arm (IQR, 4, 9.75), and 6 in the honey arm (IQR, 3.5, 7). The same results were obtained in the Kaplan-Meier survival analysis for the median survival time of each arm with the usual care as the reference group. CONCLUSION: The symptomatic treatment evaluated has shown to be ineffective against cough.

Cough is the most frequent symptom reported by patients with lower respiratory tract infections. Despite being a defense mechanism, cough is unpleasant and negatively affects sleep and overall well-being. Accordingly, many patients with acute cough seek medical help to mitigate symptoms and reduce their duration despite the typically self-limiting nature of the condition. In this randomized clinical trial, we explored the benefit of 3 common symptomatic treatments recommended in some guidelines for relieving this symptom during the course of uncomplicated acute bronchitis, a cough suppressant, an inhaler, and honey intake. Although the total number of patients initially expected could not be achieved due to the disruption caused by the COVID-19 pandemic, the results of our study demonstrate a lack of efficacy of these products as the number of days of severe-to-moderate cough was similar in the 3 arms and comparable to the group of patients allocated to usual care.

Antidiabetic treatment and COVID-19 Outcomes: A population-based cohort study in primary health care in Catalonia during the first wave of the pandemic.

AIMS: To analyse if antidiabetic treatment was associated with better COVID-19 outcomes in type 2 diabetic patients, measured by hospital admission and mortality rates as severe outcomes. METHODS: Cohort study including COVID-19 patients registered in the Primary Care electronic records, in March-June 2020, comparing exposed to metformin in monotherapy with exposed to any other antidiabetic. DATA SOURCE: SIDIAP (Information System for Research in Primary Care), which captures clinical information of 5,8 million people from Catalonia, Spain. RESULTS: We included 31,006 diabetic patients infected with COVID-19, 43.7% previously exposed to metformin, 45.5% of them in monotherapy. 16.4% were admitted to hospital and 15.1% died. Users of insulin in monotherapy (OR 1.29, 95% CI 1.11-1.50), combined with metformin (OR 1.38, 1.13-1.69) or IDPP4 alone (OR 1.29, 1.03-1.63) had higher risk of severe outcomes than those in metformin monotherapy. Users of any insulin (OR 1.61, 1.32-1.97) or combined with metformin (OR 1.69, 1.30-2.20) had a higher risk of mortality. CONCLUSIONS: Patients receiving metformin monotherapy in our study showed a lower risk of hospitalization and death in comparison to those treated with other frequent antidiabetic agents. We cannot distinguish if better outcomes are related with the antidiabetic therapy or with other factors, such as metabolic control or interventions applied during the hospital admission.

Outcomes of COVID-19 Infection in People Previously Vaccinated Against Influenza: Population-Based Cohort Study Using Primary Health Care Electronic Records.

BACKGROUND: A possible link between influenza immunization and susceptibility to the complications of COVID-19 infection has been previously suggested owing to a boost in the immunity against SARS-CoV-2. OBJECTIVE: This study aimed to investigate whether individuals with COVID-19 could have benefited from vaccination against influenza. We hypothesized that the immunity resulting from the previous influenza vaccination would boost part of the immunity against SARS-CoV-2. METHODS: We performed a population-based cohort study including all patients with COVID-19 with registered entries in the primary health care (PHC) electronic records during the first wave of the COVID-19 pandemic (March 1 to June 30, 2020) in Catalonia, Spain. We compared individuals who took an influenza vaccine before being infected with COVID-19, with those who had not taken one. Data were obtained from Information System for Research in Primary Care, capturing PHC information of 5.8 million people from Catalonia. The main outcomes assessed during follow-up were a diagnosis of pneumonia, hospital admission, and mortality. RESULTS: We included 309,039 individuals with COVID-19 and compared them on the basis of their influenza immunization status, with 114,181 (36.9%) having been vaccinated at least once and 194,858 (63.1%) having never been vaccinated. In total, 21,721 (19%) vaccinated individuals and 11,000 (5.7%) unvaccinated individuals had at least one of their outcomes assessed. Those vaccinated against influenza at any time (odds ratio [OR] 1.14, 95% CI 1.10-1.19), recently (OR 1.13, 95% CI 1.10-1.18), or recurrently (OR 1.10, 95% CI 1.05-1.15) before being infected with COVID-19 had a higher risk of presenting at least one of the outcomes than did unvaccinated individuals. When we excluded people living in long-term care facilities, the results were similar. CONCLUSIONS: We could not establish a protective role of the immunity conferred by the influenza vaccine on the outcomes of COVID-19 infection, as the risk of COVID-19 complications was higher in vaccinated than in unvaccinated individuals. Our results correspond to the first wave of the COVID-19 pandemic, where more complications and mortalities due to COVID-19 had occurred. Despite that, our study adds more evidence for the analysis of a possible link between the quality of immunity and COVID-19 outcomes, particularly in the PHC setting.

Antidiabetic treatment and COVID-19 Outcomes: a population-based cohort study in Primary Health Care in Catalonia during the first wave of the pandemic

Aims To analyse if antidiabetic treatment was associated with better COVID-19 outcomes in type 2 diabetic patients, measured by hospital admission and mortality rates as severe outcomes. Methods Cohort study including COVID-19 patients registered in the Primary Care electronic records, in March-June 2020, comparing exposed to metformin in monotherapy with exposed to any other antidiabetic. Data source: SIDIAP (Information System for Research in Primary Care), which captures clinical information of 5,8 million people from Catalonia, Spain. Results We included 31,006 diabetic patients infected with COVID-19, 43.7% previously exposed to metformin, 45.5% of them in monotherapy. 16.4% were admitted to hospital and 15.1% died. Users of insulin in monotherapy (OR 1.29, 95% CI 1.11-1.50), combined with metformin (OR 1.38, 1.13-1.69) or IDPP4 alone (OR 1.29, 1.03-1.63) had higher risk of severe outcomes than those in metformin monotherapy. Users of any insulin (OR 1.61, 1.32-1.97) or combined with metformin (OR 1.69, 1.30-2.20) had a higher risk of mortality. Conclusions Patients receiving metformin monotherapy in our study showed a lower risk of hospitalization and death in comparison to those treated with other frequent antidiabetic agents. We cannot distinguish if better outcomes are related with the antidiabetic therapy or with other factors, such as metabolic control or interventions applied during the hospital admission.

Risk of thrombotic events and other complications in anticoagulant users infected with SARS-CoV-2: an observational cohort study in primary health care in SIDIAP (Catalonia, Spain).

BACKGROUND: The risk of thromboembolic events and COVID-19 complications in anticoagulated patients once hospitalized has been widely analyzed. We aim to assess these outcomes in primary health care (PHC) patients chronically treated with oral anticoagulants (OAC) in comparison with non-treated. METHODS: Cohort study including adults with COVID-19 diagnosis in the PHC records in Catalonia, Spain; from March to June 2020. Patients were matched between exposed and non-exposed to OAC based on age and gender in a 1:2 design. Data source is the Information System for Research in Primary Care (SIDIAP). RESULTS: We included 311,542 individuals with COVID-19. After propensity score matching, we obtained a cohort of 20,360 people, 10,180 exposed and 10,180 non-exposed to OAC. Their mean age was 79.9 and 52.1% were women. Patients exposed to OAC had a higher frequency of comorbidities than non-exposed. Anticoagulated patients had a higher risk of hospital admission (IRR 1.16, 95% CI 1.03-1.29), and of stroke and pulmonary embolism than non-anticoagulated (IRR 1,80, 95% CI 1.06-3.06). The risk of pneumonia was not different between groups (IRR 1.04, 95% CI 0.84-1.30). We found a lower risk of death in patients exposed to OAC (IRR 0.60, 95% CI 0.55-0.65). CONCLUSIONS: OAC users in our study had more comorbidities and were older than non-users, well known risks for hospitalization being confirmed with our results. We also found in our study that OAC exposure was not associated to an increased risk in the mortality rate, and it was associated with higher risks of hospital admission and thromboembolic events, although we cannot assess the effect of the interventions applied during hospital admission on the outcomes studied, as our database is a PHC database. TRIAL REGISTRATION: EUPAS register: EUPAS37205 .

Clinical effectiveness and bacteriological eradication of three different Short-COurse antibiotic regimens and single-dose fosfomycin for uncomplicated lower Urinary Tract infections in adult women (SCOUT study): study protocol for a randomised clinical trial.

INTRODUCTION: Uncomplicated lower urinary tract infections (uLUTI) are a common problem in primary care. Current local guidelines recommend the use of a single 3 g dose of fosfomycin. However, most general practitioners (GP) prefer short-course therapies to single-dose therapy. No study has compared head-to-head short-course antimicrobial agents for uLUTIs. Therefore, the aim of this randomised clinical trial is to compare three different short-course antibiotic therapies with a single-dose of fosfomycin for these infections. METHODS AND ANALYSIS: This will be a pragmatic, multicentre, parallel group, open trial. Women aged 18 or older and with symptoms of uLUTI and a positive urine dipstick analysis will be randomised to one of the following four groups: a single dose of 3 g of fosfomycin, 2 days of 3 g of fosfomycin o.d., 3 days of pivmecillinam 400 mg three times per day (t.i.d) or 5 days of nitrofurantoin 100 mg t.i.d. A total sample of 1120 patients was calculated. The primary endpoint is clinical effectiveness at day 7, defined as cure of symptoms reported by the patients in a diary including four symptoms: dysuria, urgency, frequency and suprapubic pain, which will be scored on a 4-point severity scale (not present/mild/moderate/severe). Follow-up visits are scheduled at days 7 (phone call), 14 and 28 for assessing evolution. Urine samples will be collected in the three on-site visits and urine cultures performed. If positive, antibiograms for the three antibiotics studied will be performed. Bacterial eradication will be measured at days 14 and 28. ETHICS AND DISSEMINATION: The study was approved by the Ethical Board of IDIAP Jordi Gol (reference number: 21/173-AC) and Spanish Agency of Medicines and Medical Devices. The findings of this trial will be disseminated through research conferences and peer-review journals. TRIAL REGISTRATION NUMBER: NCT04959331; EudraCT Number: 2021-001332-26. TIME SCHEDULE: January 2022 to April 2023.

Correlation between Previous Antibiotic Exposure and COVID-19 Severity. A Population-Based Cohort Study.

We examined the correlation between previous antibiotic exposure and COVID-19 severity using a population-based observational matched cohort study with patient level data obtained for more than 5.8 million people registered in SIDIAP in Catalonia, Spain. We included all patients newly diagnosed with COVID-19 from March to June 2020 and identified all their antibiotic prescriptions in the previous two years. We used a composite severity endpoint, including pneumonia, hospital admission and death due to COVID-19. We examined the influence of high antibiotic exposure (>4 regimens), exposure to highest priority critically important antimicrobials (HPCIA) and recent exposure. Potential confounders were adjusted by logistic regression. A total of 280,679 patients were diagnosed with COVID-19, 146,656 of whom were exposed to at least one antibiotic course (52.3%) during the preceding two years. A total of 25,222 presented severe COVID-19 infection (9%), and the risk of severity was highest among those exposed to antibiotics (OR 1.12; 95% CI: 1.04-1.21). Among all individuals exposed to antibiotics, high, recent and exposure to HPCIAs were correlated with increased COVID severity (OR 1.19; 95% CI: 1.14-1.26; 1.41; 95% CI: 1.36-1.46; and 1.35; 95% CI: 1.30-1.40, respectively). Our findings confirm a significant correlation between previous antibiotic exposure and increased severity of COVID-19 disease.