Jesper M. Weehuizen

BACKGROUND: The objective is to determine the impact of the Bacillus Calmette - Guérin (BCG) vaccine compared to placebo or no vaccine on COVID-19 infections and hospitalisations in healthcare workers. We are using a living and prospective approach to Individual-Participant-Data (IPD) meta-analysis of ongoing studies based on the Anytime Live and Leading Interim (ALL-IN) meta-analysis statistical methodology. METHODS: Planned and ongoing randomised controlled trials were identified from trial registries and by snowballing (final elicitation: Oct 3 2022). The methodology was specified prospectively – with no trial results available – for trial inclusion as well as statistical analysis. Inclusion decisions were made collaboratively based on a risk-of-bias assessment by an external protocol review committee (Cochrane risk-of-bias tool adjusted for use on protocols), expected homogeneity in treatment effect, and agreement with the predetermined event definitions. The co-primary endpoints were incidence of COVID-19 infection and COVID-19-related hospital admission. Accumulating IPD from included trials was analysed sequentially using the exact e -value logrank test (at level α = 0.5% for infections and level α = 4.5% for hospitalisations) and anytime-valid 95%-confidence intervals (CIs) for the hazard ratio (HR) for a predetermined fixed-effects approach to meta-analysis (no measures of statistical heterogeneity). Infections were included if demonstrated by PCR tests, antigen tests or suggestive lung CTs. Participants were censored at date of first COVID-19-specific vaccination and two-stage analyses were performed in calendar time, with a stratification factor per trial. RESULTS: Six trials were included in the primary analysis with 4 433 participants in total. The e -values showed no evidence of a favourable effect of minimal clinically relevance (HR < 0.8) in comparison to the null (HR = 1) for COVID-19 infections, nor for COVID-19 hospitalisations (HR < 0.7 vs HR = 1). COVID-19 infection was observed in 251 participants receiving BCG and 244 participants not receiving BCG, HR 1.02 (anytime-valid 95%-CI 0.78-1.35). COVID-19 hospitalisations were observed in 13 participants receiving BCG and 7 not receiving BCG, resulting in an uninformative estimate (HR 1.88; anytime-valid 95%-CI 0.26-13.40). DISCUSSION: It is highly unlikely that BCG has a clinically relevant effect on COVID-19 infections in healthcare workers. With only limited observations, no conclusion could be drawn for COVID-19 related hospitalisation. Due to the nature of ALL-IN meta-analysis, emerging data from new trials can be included without violating type - I error rates or interval coverage. We intend to keep this meta-analysis alive and up-to-date, as more trials report. For COVID-19 related hospitalisations, we do not expect enough future observations for a meaningful analysis. For BCG-mediated protection against COVID-19 infections, on the other hand, more observations could lead to a more precise estimate that concludes the meta-analysis for futility, meaning that the current interval excludes the HR of 0.8 predetermined as effect size of minimal clinical relevance. OTHER: No external funding. Preregistered at PROSPERO: CRD42021213069.

A causative role of Coxiella burnetii (the causative agent of Q fever) in the pathogenesis of B-cell non-Hodgkin lymphoma (NHL) has been suggested, although supporting studies show conflicting evidence. We assessed whether this association is present by performing a detailed analysis on the risk of mature B-cell NHL after Q fever during and after the largest Q fever outbreak reported worldwide in the entire Dutch population over a 16-year period. We performed an ecological analysis. The incidence of mature B-cell NHL in the entire Dutch population from 2002 until 2017 was studied and modelled with reported acute Q fever cases as the determinant. The adjusted relative risk of NHL after acute Q fever as the primary outcome measure was calculated using a Poisson regression. Between January 2002 and December 2017, 266 050 745 person-years were observed, with 61 424 diagnosed with mature B-cell NHL. In total, 4310 persons were diagnosed with acute Q fever, with the highest incidence in 2009. The adjusted relative risk of NHL after acute Q fever was 1.02 (95% CI 0.97–1.06, P = 0.49) and 0.98 (95% CI 0.89–1.07, P = 0.60), 0.99 (95% CI 0.87–1.12, P = 0.85) and 0.98 (95% 0.88–1.08, P = 0.67) for subgroups of diffuse large B-cell lymphoma, follicular lymphoma or B-cell chronic lymphocytic leukaemia, respectively. Modelling with lag times (1–4 years) did not change interpretation. We found no evidence for an association between C. burnetii and NHL after studying the risk of mature B-cell NHL after a large Q fever outbreak in Netherlands.

Background: the geographical similarities of the Dutch 2007–2010 Q fever outbreak and the start of the 2020 coronavirus disease 19 (COVID-19) outbreak in the Netherlands raised questions and provided a unique opportunity to study an association between Coxiella burnetii infection and the outcome following SARS-CoV-2 infection. Methods: We performed a retrospective cohort study in two Dutch hospitals. We assessed evidence of previous C. burnetii infection in COVID-19 patients diagnosed at the ED during the first COVID-19 wave and compared a combined outcome of in-hospital mortality and intensive care unit (ICU) admission using adjusted odds ratios (OR). Results: In total, 629 patients were included with a mean age of 68.0 years. Evidence of previous C. burnetii infection was found in 117 patients (18.6%). The combined primary outcome occurred in 40.2% and 40.4% of patients with and without evidence of previous C. burnetii infection respectively (adjusted OR of 0.926 (95% CI 0.605–1.416)). The adjusted OR of the secondary outcomes in-hospital mortality, ICU-admission and regular ward admission did not show an association either. Conclusion: no influence of previous C. burnetii infection on the risk of ICU admission and/or mortality for patients with COVID-19 presenting at the ED was observed.

Ghanem-Zoubi et al. [1] describe four patients with chronic Q fever vertebral osteomyelitis – which may be accompanied by discitis – and provide an extensive overview of literature. Chronic Q fever...