Summary Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. BCG vaccination trials for reducing SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last 5 years or did not. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (adjusted odds ratio [AOR] 0.58, p < 0.05), and lower incidence of extreme fatigue. In conclusion, recent BCG vaccination is safe, and large randomized trials are needed to reveal if BCG reduces the incidence and/or severity of SARS-CoV-2 infection.

Background Older age is associated with increased severity and death from respiratory infections, including coronavirus disease 2019 (Covid-19). The tuberculosis vaccine Bacille Calmette-Guérin (BCG) may provide heterologous protection against non-tuberculous infections, and has been proposed as a potential preventive strategy against Covid-19. Methods In this multicenter, placebo-controlled trial, we randomly assigned elderly individuals (60 years or older, n=2014) to intracutaneous vaccination with BCG (n=1008) or placebo (n=1006). The primary endpoint was the cumulative incidence of respiratory tract infections that required medical intervention, during 12 months of follow-up. Secondary endpoints included the incidence of Covid-19, and the effect of BCG vaccination on the cellular and humoral immune responses. Results The cumulative incidence of respiratory tract infection requiring medical intervention was 0.029 in the BCG-vaccinated group and 0.024 in the control group (subdistribution hazard ratio [SHR], 1.26; 98.2% confidence interval [CI], 0.65 to 2.44). 51 and 48 individuals tested positive for SARS-CoV-2 by PCR in the BCG and placebo group, respectively (SHR, 1.053; 95% CI, 0.71 to 1.56). No difference was observed in the frequency of adverse events. BCG vaccination was associated with enhanced cytokines responses after influenza, and partially also after SARS-CoV-2 stimulation. In patients diagnosed with Covid-19, antibody responses after infection were significantly stronger if the volunteers had previously received BCG. Conclusions BCG-vaccination had no effect on the incidence of respiratory tract infections, including SARS-CoV-2 infection, in elderly volunteers. However, BCG vaccination improved cytokine responses stimulated by influenza and SARS-CoV-2, and induced stronger antibody titers after Covid-19 infection.

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Background: Rapid initiation of antibiotic treatment is considered crucial in patients with severe infections such as septic shock and bacterial meningitis, but may not be as important for other infectious syndromes. A better understanding of which patients can tolerate a delay in start of therapy is important for antibiotic stewardship purposes. Objectives: To explore the existing evidence on the impact of time to antibiotics on clinical outcomes in patients presenting to the emergency department (ED) with bacterial infections of different severity of illness and source of infection. Sources: A literature search was performed in the PubMed/MEDLINE database using combined search terms for various infectious syndromes (sepsis/septic shock, bacterial meningitis, lower respiratory tract infections, urinary tract infections, intra-abdominal infections and skin and soft tissue infections), time to antibiotic treatment, and clinical outcome. Content: The literature search generated 8828 hits. After screening titles and abstracts and assessing potentially relevant full-text papers, 60 original articles (four randomized controlled trials, 43 observational studies) were included. Most articles addressed sepsis/septic shock, while few studies evaluated early initiation of therapy in mild to moderate disease. The lack of randomized trials and the risk of confounding factors and biases in observational studies warrant caution in the interpretation of results. We conclude that the literature supports prompt administration of effective antibiotics for septic shock and bacterial meningitis, but there is no clear evidence showing that a delayed start of therapy is associated with worse outcome for less severe infectious syndromes. Implications: For patients presenting with suspected bacterial infections, withholding antibiotic therapy until diagnostic results are available and a diagnosis has been established (e.g. by 4e8 h) seems acceptable in most cases unless septic shock or bacterial meningitis are suspected. This approach promotes the use of ecologically favourable antibiotics in the ED, reducing the risks of side effects and selection of resistance.

The original study and the current analysis were funded by Pfizer.

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Objectives The objectives of these two separate trials are: (1) to reduce health care workers (HCWs) absenteeism; and (2) to reduce hospital admission among the elderly during the COVID-19 pandemic through BCG vaccination. Trial design Two separate multi-centre placebo-controlled parallel group randomized trials Participants (1) Health care personnel working in the hospital or ambulance service where they will take care of patients with the COVID-19 infection and (2) elderly ≥60 years. The HCW trial is being undertaken in 9 hospitals. The elderly trial is being undertaken in locations in the community in Nijmegen, Utrecht, and Veghel, in the Netherlands, using senior citizen organisations to facilitate recruitment. Intervention and comparator For both trials the intervention group will be randomized to vaccination with 0.1 ml of the licensed BCG vaccine (Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated M. bovis). The placebo group consists of 0.1 ml 0.9% NaCl, which is the same amount, and has the same colour and appearance as the suspended BCG vaccine. Main outcomes (1) Number of days of unplanned work absenteeism in HCWs for any reason which can be continuously measured on a bi-weekly basis, and (2) the cumulative incidence of hospital admission due to documented COVID-19. Randomisation Participants will be randomized to BCG vaccine or placebo (1;1) centrally using a computer- based system, stratified by study centre. Blinding (masking) Subjects, investigators, physicians and outcome assessors are blinded for the intervention. Only the pharmacist assistant that prepares- and research personnel that administers- study medicines are unblinded. Numbers to be randomised (sample size) (1) The sample size for the first trial is N=1500 HCWs randomised 1:1 to either BCG vaccine (n=750) and placebo (n=750) and (2) The sample size for the second trial is N=1600 elderly persons randomised to BCG vaccine (n=800) and the placebo group (n=800). Trial Status HCW: version 4.0, 24-04-2020. Recruitment began 25-03-2020 and was completed on the 23-04-2020. Elderly: version 3.0, 04-04-2020. Recruitment began 16-04- 2020 and is ongoing. Trial registration The HCWs trial was registered 31-03-2020 at clinicaltrials.gov (identifier: NCT04328441) and registered 20-03-2020 at the Dutch Trial Registry (trialregister.nl, identifier Trial NL8477). The elderly trial was registered 22-04-2020 at the Dutch trial registry with number NL8547. Full protocol The full protocols will be attached as additional files, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

BackgroundWe aimed to evaluate health status and associated factors in community-dwelling elderly in the Netherlands.MethodsParticipants from a placebo-controlled double-blind randomized controlled trial conducted in the Netherlands were invited at the time of enrolment to participate in this study. Data were collected on comorbidities, socio-demographic background and health status, using EQ-5D-3L instrument. EQ-5D-3L summary index values (EQ-5D-indices) was derived using Dutch tariff. Regression analysis was conducted to identify factors associated with EQ-5D-indices and visual analogue scale (EQ-VAS).Results48,634 elderly (≥65 years) were included. The most frequently reported complaint was pain/discomfort (29.4%), but for the elder elderly (i.e. ≥85 years) it was mobility (52.9%). The proportion of persons reporting (multiple) problems increased with age from 31.5% for 65–69 years old subjects to 65.9% for elder elderly. The mean EQ-5D-indices and EQ-VAS decreased with age from 0.94 and 84, respectively in those 65 to 69 years old to 0.86 and 76, respectively, in ≥85 years old subjects. Increasing age, female gender, low education, geographic factors and comorbidities were associated with impaired health status.ConclusionsWithin community-dwelling elderly large differences in health status exist. Impairment increases rapidly with age, but health status is also associated with socio-demographic variables and comorbidities.Trial registrationClinicalTrials.gov, NCT00812084.Electronic supplementary materialThe online version of this article (doi:10.1186/s12955-016-0577-5) contains supplementary material, which is available to authorized users.