Risk of myocarditis and pericarditis following COVID-19 vaccination in England and Wales (preprint)

We describe our analyses of data from over 52 million people in England and Wales, representing near-complete coverage of the relevant population, to assess the risk of myocarditis and pericarditis following COVID-19 vaccination. A self-controlled case series (SCCS) design has previously reported increased risk of myocarditis after first doses of ChAdOx1, BNT162b2, and mRNA-1273 vaccinations and after second doses of the mRNA COVID-19 vaccinations in England. Here, we use a cohort design to estimate hazard ratios for hospitalised or fatal myocarditis/pericarditis and excess events after first and second doses of BNT162b2 and ChAdOx1 vaccinations. SCCS and cohort designs are subject to different assumptions and biases and therefore provide the opportunity for triangulation of evidence. In contrast to the findings from the SCCS approach previously reported for England, we found evidence of lower incidence of hospitalised or fatal myocarditis/pericarditis after first dose ChAdOx1 and BNT162b2 vaccination.

Association of COVID-19 with arterial and venous vascular diseases: a population-wide cohort study of 48 million adults in England and Wales (preprint)

Importance: The long-term effects of COVID-19 on the incidence of vascular diseases are unclear. Objective: To quantify the association between time since diagnosis of COVID-19 and vascular disease, overall and by age, sex, ethnicity, and pre-existing disease. Design: Cohort study based on population-wide linked electronic health records, with follow up from January 1st to December 7th 2020. Setting and participants: Adults registered with an NHS general practice in England or Wales and alive on January 1st 2020. Exposures: Time since diagnosis of COVID-19 (categorised as 0-6 days, 1-2 weeks, 3-4, 5-8, 9-12, 13-26 and 27-49 weeks since diagnosis), with and without hospitalisation within 28 days of diagnosis. Main outcomes and measures: Primary outcomes were arterial thromboses (mainly acute myocardial infarction and ischaemic stroke) and venous thromboembolic events (VTE, mainly pulmonary embolism and lower limb deep vein thrombosis). We also studied other vascular events (transient ischaemic attack, haemorrhagic stroke, heart failure and angina). Hazard ratios were adjusted for demographic characteristics, previous disease diagnoses, comorbidities and medications. Results: Among 48 million adults, 130,930 were and 1,315,471 were not hospitalised within 28 days of COVID-19. In England, there were 259,742 first arterial thromboses and 60,066 first VTE during 41.6 million person-years follow-up. Adjusted hazard ratios (aHRs) for first arterial thrombosis compared with no COVID-19 declined rapidly from 21.7 (95% CI 21.0-22.4) to 3.87 (3.58-4.19) in weeks 1 and 2 after COVID-19, 2.80 (2.61-3.01) during weeks 3-4 then to 1.34 (1.21-1.48) during weeks 27-49. aHRs for first VTE declined from 33.2 (31.3-35.2) and 8.52 (7.59-9.58) in weeks 1 and 2 to 7.95 (7.28-8.68) and 4.26 (3.86-4.69) during weeks 3-4 and 5-8, then 2.20 (1.99-2.44) and 1.80 (1.50-2.17) during weeks 13-26 and 27-49 respectively. aHRs were higher, for longer after diagnosis, after hospitalised than non-hospitalised COVID-19. aHRs were also higher among people of Black and Asian than White ethnicity and among people without than with a previous event. Across the whole population estimated increases in risk of arterial thromboses and VTEs were 2.5% and 0.6% respectively 49 weeks after COVID-19, corresponding to 7,197 and 3,517 additional events respectively after 1.4 million COVID-19 diagnoses. Conclusions and Relevance: High rates of vascular disease early after COVID-19 diagnosis decline more rapidly for arterial thromboses than VTEs but rates remain elevated up to 49 weeks after COVID-19. These results support continued policies to avoid COVID-19 infection with effective COVID-19 vaccines and use of secondary preventive agents in high-risk patients.

Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, and thrombocytopenic events: whole population cohort study in 46 million adults in England (preprint)

BackgroundThromboses in unusual locations after the COVID-19 vaccine ChAdOx1-S have been reported. Better understanding of population-level thrombotic risks after COVID-19 vaccination is needed. MethodsWe analysed linked electronic health records from adults living in England, from 8th December 2020 to 18th March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous and thrombocytopenic outcomes 1-28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and [≥]70 years, and adjusted for age, sex, comorbidities, and social and demographic factors. ResultsOf 46,162,942 adults, 21,193,814 (46%) had their first vaccination during follow-up. Adjusted HRs 1-28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and [≥]70 respectively, were 0.97 (95% CI: 0.90-1.05) and 0.58 (0.53-0.63) for venous thromboses, and 0.90 (0.86-0.95) and 0.76 (0.73-0.79) for arterial thromboses. Corresponding HRs for BNT162b2 were 0.81 (0.74-0.88) and 0.57 (0.53-0.62) for venous thromboses, and 0.94 (0.90-0.99) and 0.72 (0.70-0.75) for arterial thromboses. HRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines. Rates of intracranial venous thrombosis (ICVT) and thrombocytopenia in adults aged <70 years were higher 1-28 days after ChAdOx1-S (adjusted HRs 2.27, 95% CI:1.33- 3.88 and 1.71, 1.35-2.16 respectively), but not after BNT162b2 (0.59, 0.24-1.45 and 1.00, 0.75-1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1-28 days after ChAdOx1-S were 0.9-3 per million, varying by age and sex. ConclusionsIncreases in ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults <40 years are needed. For people aged [≥]70 years, rates of arterial or venous thrombotic, events were generally lower after either vaccine.

Older biological age is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank (preprint)

Background: Older chronological age is the most powerful risk factor for adverse coronavirus disease-19 (COVID-19) outcomes. It is uncertain, however, whether older biological age, as assessed by leucocyte telomere length (LTL), is also associated with COVID-19 outcomes. Methods: We associated LTL values obtained from participants recruited into UK Biobank (UKB) during 2006-2010 with adverse COVID-19 outcomes recorded by 30 November 2020, defined as a composite of any of the following: hospital admission, need for critical care, respiratory support, or mortality. Using information on 131 LTL-associated genetic variants, we conducted exploratory Mendelian randomisation (MR) analyses in UKB to evaluate whether observational associations might reflect cause-and-effect relationships. Findings: Of 6,775 participants in UKB who had tested positive for infection with SARS-CoV-2 in the community, there were 914 (13.5%) with adverse COVID-19 outcomes. The odds ratio (OR) for adverse COVID-19 outcomes was 1.17 (95% CI 1.05-1.31; P=0.004) per 1-SD shorter usual LTL, after adjustment for chronological age, sex and ethnicity. Similar ORs were observed in analyses that: adjusted for additional risk factors; disaggregated the composite outcome and reduced the scope for selection or collider bias. In MR analyses, the OR for adverse COVID-19 outcomes was directionally concordant but non-significant. Interpretation: Shorter LTL, indicative of older biological age, is associated with higher risk of adverse COVID-19 outcomes, independent of several major risk factors for COVID-19 including chronological age. Further data are needed to determine whether this association reflects causality.

Accuracy of four lateral flow immunoassays for anti SARS-CoV-2 antibodies: a head-to-head comparative study (preprint)

BackgroundSARS-CoV-2 antibody tests are used for population surveillance and might have a future role in individual risk assessment. Lateral flow immunoassays (LFIAs) can deliver results rapidly and at scale, but have widely varying accuracy. MethodsIn a laboratory setting, we performed head-to-head comparisons of four LFIAs: the Rapid Test Consortiums AbC-19 Rapid Test, OrientGene COVID IgG/IgM Rapid Test Cassette, SureScreen COVID-19 Rapid Test Cassette, and Biomerica COVID-19 IgG/IgM Rapid Test. We analysed blood samples from 2,847 key workers and 1,995 pre-pandemic blood donors with all four devices. FindingsWe observed a clear trade-off between sensitivity and specificity: the IgG band of the SureScreen device and the AbC-19 device had higher specificities but OrientGene and Biomerica higher sensitivities. Based on analysis of pre-pandemic samples, SureScreen IgG band had the highest specificity (98.9%, 95% confidence interval 98.3 to 99.3%), which translated to the highest positive predictive value across any pre-test probability: for example, 95.1% (95%CI 92.6, 96.8%) at 20% pre-test probability. All four devices showed higher sensitivity at higher antibody concentrations ("spectrum effects"), but the extent of this varied by device. InterpretationThe estimates of sensitivity and specificity can be used to adjust for test error rates when using these devices to estimate the prevalence of antibody. If tests were used to determine whether an individual has SARS-CoV-2 antibodies, in an example scenario in which 20% of individuals have antibodies we estimate around 5% of positive results on the most specific device would be false positives. FundingPublic Health England. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched for evidence on the accuracy of the four devices compared in this study: OrientGene COVID IgG/IgM Rapid Test Cassette, SureScreen COVID-19 Rapid Test Cassette, Biomerica COVID-19 IgG/IgM Rapid Test and the UK Rapid Test Consortiums AbC-19 Rapid Test. We searched Ovid MEDLINE (In-Process & Other Non-Indexed Citations and Daily), PubMed, MedRxiv/BioRxiv and Google Scholar from January 2020 to 16th January 2021. Search terms included device names AND ((SARS-CoV-2) OR (covid)). Of 303 records assessed, data were extracted from 24 studies: 18 reporting on the accuracy of the OrientGene device, 7 SureScreen, 2 AbC-19 and 1 Biomerica. Only three studies compared the accuracy of two or more of the four devices. With the exception of our previous report on the accuracy of the AbC-19 device, which the current manuscript builds upon, sample size ranged from 7 to 684. For details, see Supplementary Materials. The largest study compared OrientGene, SureScreen and Biomerica. SureScreen was estimated to have the highest specificity (99.8%, 95% CI 98.9 to 100%) and OrientGene the highest sensitivity (92.6%), but with uncertainty about the latter result due to small sample sizes. The other two comparative studies were small (n = 65, n = 67) and therefore provide very uncertain results. We previously observed spectrum effects for the AbC-19 device, such that sensitivity is upwardly biased if estimated only from PCR-confirmed cases. The vast majority of previous studies estimated sensitivity in this way. Added value of this studyWe performed a large scale (n = 4,842), head-to-head laboratory-based evaluation and comparison of four lateral flow devices, which were selected for evaluation by the UK Department of Health and Social Cares New Tests Advisory Group, on the basis of a survey of test and performance data available. We evaluated the performance of diagnosis based on both IgG and IgM bands, and the IgG band alone. We found a clear trade-off between sensitivity and specificity across devices, with the SureScreen and AbC-19 devices being more specific and OrientGene and Biomerica more sensitive. Based on analysis of 1,995 pre-pandemic blood samples, we are 99% confident that SureScreen (IgG band reading) has the highest specificity of the four devices (98.9%, 95% CI 98.3, 99.3%). We found evidence that all four devices have reduced sensitivity at lower antibody indices, i.e. spectrum effects. However, the extent of this varies by device and appears to be less for other devices than for AbC-19. Our estimates of sensitivity and specificity are likely to be higher than would be observed in real use of these devices, as they were based on majority readings of three trained laboratory personnel. Implications of all the available evidenceWhen used in epidemiological studies of antibody prevalence, the estimates of sensitivity and specificity provided in this study can be used to adjust for test errors. Increased precision in error rates will translate to increased precision in seroprevalence estimates. If lateral flow devices were used for individual risk assessment, devices with maximum specificity would be preferable. However, if, for an example, 20% of the tested population had antibodies, we estimate that around 1 in 20 positive results on the most specific device would be incorrect.