Associations of ABO and Rhesus D blood groups with phenome-wide disease incidence: A 41-year retrospective cohort study of 482,914 patients.

Background: Whether natural selection may have attributed to the observed blood group frequency differences between populations remains debatable. The ABO system has been associated with several diseases and recently also with susceptibility to COVID-19 infection. Associative studies of the RhD system and diseases are sparser. A large disease-wide risk analysis may further elucidate the relationship between the ABO/RhD blood groups and disease incidence. Methods: We performed a systematic log-linear quasi-Poisson regression analysis of the ABO/RhD blood groups across 1,312 phecode diagnoses. Unlike prior studies, we determined the incidence rate ratio for each individual ABO blood group relative to all other ABO blood groups as opposed to using blood group O as the reference. Moreover, we used up to 41 years of nationwide Danish follow-up data, and a disease categorization scheme specifically developed for diagnosis-wide analysis. Further, we determined associations between the ABO/RhD blood groups and the age at the first diagnosis. Estimates were adjusted for multiple testing. Results: The retrospective cohort included 482,914 Danish patients (60.4% females). The incidence rate ratios (IRRs) of 101 phecodes were found statistically significant between the ABO blood groups, while the IRRs of 28 phecodes were found statistically significant for the RhD blood group. The associations included cancers and musculoskeletal-, genitourinary-, endocrinal-, infectious-, cardiovascular-, and gastrointestinal diseases. Conclusions: We found associations of disease-wide susceptibility differences between the blood groups of the ABO and RhD systems, including cancer of the tongue, monocytic leukemia, cervical cancer, osteoarthrosis, asthma, and HIV- and hepatitis B infection. We found marginal evidence of associations between the blood groups and the age at first diagnosis. Funding: Novo Nordisk Foundation and the Innovation Fund Denmark.

The effect of prostacyclin (Iloprost) infusion at a dose of 1 ng/kg/min for 72 hours compared to placebo in mechanically ventilated patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: To investigate the effect of continuous infusion of the potential endothelial cytoprotective agent prostacyclin (Iloprost) 1 ng/kg/min vs. placebo for 72 hours on pulmonary endotheliopathy in mechanically ventilated COVID-19 patients. TRIAL DESIGN: A multicenter, randomized (1:1, active: placebo), blinded, parallel group exploratory trial PARTICIPANTS: Inclusion criteria are: Adult patients (>18 years); Confirmed COVID-19 infection; Need for mechanical interventions; Endothelial biomarker soluble thrombomodulin >4ng/ml. EXCLUSION CRITERIA: Withdrawal from active therapy; Pregnancy (non-pregnancy confirmed by patient being postmenopausal (age 60 or above) or having a negative urine- or plasma-hCG); Known hypersensitivity to iloprost or to any of the other ingredients; Previously included in this trial or a prostacyclin trial within 30 days; Consent cannot be obtained; Life-threatening bleeding defined by the treating physician; Known severe heart failure (NYHA class IV); Suspected acute coronary syndrome The study is conducted at five intensive care units in the Capital Region of Denmark at Rigshospitalet, Herlev Hospital, Hvidovre Hospital, Bispebjerg Hospital, Nordsjællands Hospital. INTERVENTION AND COMPARATOR: The patients are randomized to 72-hours continuous infusion of either prostacyclin (Iloprost/Ilomedin) at a dose of 1 ng/kg/min or Placebo (normal saline). MAIN OUTCOMES: Primary endpoint: Days alive without mechanical ventilation in the intensive care units within 28 days RANDOMISATION: The randomisation sequence is performed in permuted blocks of variable sizes stratified for trial site using centralised, concealed allocation. The randomisation sequence is generated 1:1 (active/placebo) using the online randomisation software 'Sealed Envelope' ( https://www.sealedenvelope.com/ ). Once generated the randomisation sequence is formatted and uploaded into Research Electronic Data Capture system (REDCap) to facilitate centralised, web-based allocation according to local written instruction. BLINDING (MASKING): The following are blinded: all clinicians, patients, investigators, and those assessing the outcomes including the statisticians. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Forty patients are planned to be randomized to each group, with a total sample size of 80 patients. TRIAL STATUS: Protocol version 1.4 dated May 25, 2020. Recruitment is ongoing. The recruitment was started June 15, 2020 and the anticipated finish of recruitment is February 28, 2021 with 90 days follow up hereafter. TRIAL REGISTRATION: Trial registration at clinicaltrialregisters.eu; EudraCT no. 2020-001296-33 on 3 April 2020 and at ClinicalTrials.gov Identifier: NCT04420741 on 9 June 2020 FULL PROTOCOL: The full protocol is attached as an additional file, 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.