Clusters of post-acute COVID-19 symptoms: a latent class analysis across 9 databases and 7 countries (preprint)

Prior evidence has suggested the multisystem symptomatic manifestations of post-acute COVID-19 condition (PCC). Here we conducted a network cluster analysis of 24 WHO proposed symptoms to identify potential latent subclasses of PCC. Individuals with a positive test of or diagnosed with SARS-CoV-2 after 09/2020 and with at least one symptom within ≥ 90 to 365 days following infection were included. Sub-analyses were conducted among people with ≥ 3 different symptoms. Summary characteristics were provided for each cluster. All analyses were conducted separately in 9 databases from 7 countries, including data from primary care, hospitals, national health claims and national health registries, allowing to validate clusters across the different healthcare settings. 787,078 persons with PCC were included. Single-symptom clusters were common across all databases, particularly for joint pain, anxiety, depression and allergy. Complex clusters included anxiety-depression and abdominal-gastrointestinal symptoms. Substantial heterogeneity within and between PCC clusters was seen across healthcare settings. Current definitions of PCC should be critically reviewed to reflect this variety in clinical presentation.

Collateral effects of the COVID-19 pandemic on endocrine treatments for breast and prostate cancer in the UK: implications for bone health (preprint)

BackgroundThe COVID-19 pandemic affected cancer screening, diagnosis and treatment pathways. This study examined the impact of the pandemic on incidence and trends of endocrine treatments in patients with breast or prostate cancer; and endocrine treatment-related side-effects. MethodsPopulation-based cohort study using UK primary care Clinical Practice Research Datalink (CPRD) GOLD database. There were 13,701 newly diagnosed breast cancer patients and 12,221 prostate cancer patients with [≥]1-year data availability since diagnosis between January 2017-June 2022. Incidence rates (IR) and incidence rate ratios (IRR) were calculated across multiple time periods before and after lockdown to examine the impact of changing social restrictions on endocrine treatments and treatment-related outcomes, including osteopenia, osteoporosis and bisphosphonate prescriptions. ResultsIn patients with breast cancer, aromatase inhibitor prescriptions increased during lockdown compared to pre-pandemic (IRR: 1.22 [95% Confidence Interval: 1.11-1.34]), followed by a decrease post-first lockdown (IRR: 0.79 [95%CI: 0.69-0.89]). In patients with prostate cancer, first-generation antiandrogen prescriptions increased compared to pre-pandemic (IRR: 1.23 [95% CI: 1.08-1.4]). For breast cancer patients on aromatase inhibitors, diagnoses of osteopenia, osteoporosis and bisphosphonate prescriptions were reduced across all lockdown periods compared to pre-pandemic (IRR range: 0.31-0.62). ConclusionDuring the first two years of the pandemic, newly diagnosed breast and prostate cancer patients were prescribed more endocrine treatments compared to pre-pandemic, due to restrictions on hospital procedures replacing surgeries with bridging therapies. But breast cancer patients had fewer diagnoses of osteopenia and osteoporosis, and bisphosphonate prescriptions. These patients should be followed up in the coming years for signs of bone thinning. Evidence of poorer management of treatment-related side-effects will allow us to determine whether there is a need to better allocate resources to patients at high risk for bone-related complications.

The impact of the COVID-19 pandemic on short-term cancer survival in the United Kingdom: a cohort analysis (preprint)

Objectives: The COVID-19 pandemic profoundly affected healthcare systems and patients. There is a pressing need to comprehend the collateral effects of the pandemic on non-communicable diseases. Here we examined the impact of the COVID-19 pandemic on short-term cancer survival in the United Kingdom (UK). We hypothesised that short-term survival from nine cancers would be reduced during the pandemic, particularly cancers that benefit from screening and early detection (e.g., breast and colorectal cancer). Design: Population-based cohort study. Setting: Electronic health records from UK primary care Clinical Practice Research Datalink (CPRD) GOLD database. Participants: There were 12,259,744 eligible patients aged [≥]18 years with [≥]one year of prior history identified from January 2000 to December 2021. Main outcome measures: We estimated age-standardised incidence rates (IR) and short-term (one- and two-year) survival of several common cancers (breast, colorectal, head and neck, liver, lung, oesophagus, pancreatic, prostate, and stomach cancer) from 2000 to 2019 (in five-year strata) compared to 2020 to 2021 using the Kaplan-Meier method. Results: Apart from pancreatic cancer, IRs decreased for all cancers in 2020 and recovered to different extents in 2021. Short-term survival improved for most cancers between 2000 to 2019, but then declined for those diagnosed in 2020 to 2021.This was most pronounced for colorectal cancer, with one-year survival falling from 79.3% [95% confidence interval: 78.5%-80.1%] in 2015 to 2019 to 76.3% [74.6%-78.1%] for those diagnosed in 2020 to 2021. Conclusion: Short-term survival for many cancers was impacted by the management of the COVID-19 pandemic in the UK. This decline was most prominent for colorectal cancer, with reductions in survivorship equivalent to returning to mortality seen in the first decade of the 2000s. These results illustrate the need for an immediate and well-funded investment in resolving the current backlog in cancer screening and diagnostic procedures in the UK National Health Service to improve patient outcomes.

The Impact of the UK COVID-19 Lockdown on the Screening, Diagnostics and Incidence of Breast, Colorectal, Lung and Prostate Cancer in the UK: a Population-Based Cohort Study (preprint)

Objectives: This study aimed to assess the impact of the COVID-19 lockdown on the screening and diagnosis of breast, colorectal, lung, and prostate cancer. The study also investigated whether the rates returned to pre-pandemic levels by December 2021. Design: Cohort study. Setting: Electronic health records from UK primary care Clinical Practice Research Datalink (CPRD) GOLD database. Participants: The study included individuals registered with CPRD GOLD between January 2017 and December 2021, with at least 365 days of prior observation. Main outcome measures: The study focused on screening, diagnostic tests, referrals and diagnoses of first-ever breast, colorectal, lung, and prostate cancer. Incidence rates (IR) were stratified by age, sex and region, and incidence rate ratios (IRR) were calculated to compare rates during and after lockdown with the reference period before lockdown. Forecasted rates were estimated using negative binomial regression models. Results: Among 5,191,650 eligible participants, the initial lockdown resulted in reduced screening and diagnostic tests for all cancers, which remained dramatically reduced across the whole observation period for almost all tests investigated. For cancer incidence rates, there were significant IRR reductions in breast (0.69), colorectal (0.74), and prostate (0.71) cancers. However, the reduction in lung cancer incidence (0.92) was non-significant. Extrapolating to the entire UK population, an estimated 18,000 breast, 13,000 colorectal, 10,000 lung, and 21,000 prostate cancer diagnoses were missed from March 2020 to December 2021. Conclusion: The national COVID-19 lockdown in the UK had a substantial impact on cancer screening, diagnostic tests, referrals and diagnoses. Although incidence rates started to recover after the lockdown, they remained significantly lower than pre-pandemic levels for breast and prostate cancers and associated tests. Delays in diagnosis are likely to have adverse consequences on cancer stage, treatment initiation, mortality rates, and years of life lost. Urgent strategies are needed to identify undiagnosed cases and address the long-term implications of delayed diagnoses.

The role of COVID-19 vaccines in preventing post COVID-19 thromboembolic and cardiovascular complications: a multinational cohort study (preprint)

ImportanceThe overall effects of vaccination on the risk of cardiac, and venous and arterial thromboembolic complications following COVID-19 remain unclear. ObjectiveWe studied the association between COVID-19 vaccination and the risk of acute and subacute COVID-19 cardiac and thromboembolic complications. DesignMultinational staggered cohort study, based on national vaccination campaign rollouts. SettingNetwork study using electronic health records from primary care records from the UK, primary care data linked to hospital data from Spain, and national insurance claims from Estonia. ParticipantsAll adults with a prior medical history of [≥]180 days, with no history of COVID-19 or previous COVID-19 vaccination at the beginning of vaccine rollout were eligible. ExposureVaccination status was used as a time-varying exposure. Vaccinated individuals were classified by vaccine brand according to the first dose received. Main OutcomesPost COVID-19 complications including myocarditis, pericarditis, arrhythmia, heart failure (HF), venous (VTE) and arterial thromboembolism (ATE) up to 1 year after SARS-CoV-2 infection. MeasuresPropensity Score overlap weighting and empirical calibration based on negative control outcomes were used to minimise bias due to observed and unobserved confounding, respectively. Fine-Gray models were fitted to estimate sub-distribution Hazard Ratios (sHR) for each outcome according to vaccination status. Random effect meta-analyses were conducted across staggered cohorts and databases. ResultsOverall, 10.17 million vaccinated and 10.39 million unvaccinated people were included. Vaccination was consistently associated with reduced risks of acute (30-day) and subacute post COVID-19 VTE and HF: e.g., meta-analytic sHR 0.34 (95%CI, 0.27-0.44) and 0.59 (0.50-0.70) respectively for 0-30 days, sHR 0.58 (0.48 - 0.69) and 0.71 (0.59 - 0.85) respectively for 90-180 days post COVID-19. Additionally, reduced risks of ATE, myocarditis/pericarditis and arrhythmia were seen, but mostly in the acute phase (0-30 days post COVID-19). ConclusionsCOVID-19 vaccination reduced the risk of post COVID-19 complications, including cardiac and thromboembolic outcomes. These effects were more pronounced for acute (1-month) post COVID-19 outcomes, consistent with known reductions in disease severity following breakthrough vs unvaccinated SARS-CoV-2 infection. RelevanceThese findings highlight the importance of COVID-19 vaccination to prevent cardiovascular outcomes after COVID-19, beyond respiratory disease. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the impact of COVID-19 vaccination to prevent cardiac complications and thromboembolic events following a SARS-CoV-2 infection? FindingsResults from this multinational cohort study showed that COVID-19 vaccination reduced risk for acute and subacute COVID-19 heart failure, as well as venous and arterial thromboembolic events following SARS-CoV-2 infection. MeaningThese findings highlight yet another benefit of vaccination against COVID-19, and support the recommendations for COVID-19 vaccination even in people at high cardiovascular risk.

The burden of long COVID: a multinational cohort analysis of Spanish and UK data including SARS-CoV-2 infections, reinfections, and matched contemporaneous test negative controls (preprint)

As limited data was available on the effect of persisting COVID-19 symptoms, we characterised long COVID and identified key symptoms associated with persistent disease. Using primary care data from Spain and UK, we estimated incidence rates of long COVID in the population and among COVID-19 patients over time. Subsequently, we investigated which WHO-listed symptoms were particularly differential for long COVID by comparing their frequency in COVID-19 patients vs matched test-negative controls. Lastly, we compared persistent symptoms after first infections vs. reinfections. Fortunately, the proportion of COVID-19 cases resulting in long COVID declined over the study period.  Risk for altered smell/taste, dyspnoea, and fatigue were consistently higher in long COVID patient vs controls [RR between 5.97-1.09]. All persistent symptoms were less common after reinfection than first infection. More research is needed into the definition of long COVID, and the effect of interventions to minimise the risk and impact of persistent symptoms.

Observational methods for COVID-19 vaccine effectiveness research: a trial emulation and empirical evaluation (preprint)

Despite much research on the topic, little work has been done comparing the use of methods to control for confounding in the estimation of COVID-19 vaccine effectiveness in routinely collected medical record data. We conducted a trial emulation study to replicate the ChAdOx1 (Oxford/AstraZeneca) and BNT162b2 (BioNTech/Pfizer) COVID-19 phase 3 efficacy studies. We conducted a cohort study including individuals aged 75+ from UK CPRD AURUM (N = 916,128) in early 2021. Three different methods were assessed: Overlap weighting, inverse probability treatment weighting, and propensity score matching. All three methods successfully replicated the findings from both phase 3 trials, and overlap weighting performed best in terms of confounding, systematic error, and precision. Despite lack of trial data beyond 3 weeks, we found that even 1 dose of BNT162b2 was effective against SARS-CoV-2 infection for up to 12 weeks before a second dose was administered. These results support the UK Joint Committee on Vaccination and Immunisation modelling and related UK vaccination strategies implemented in early 2021.

Digital ethnicity data in population-wide electronic health records in England: a description of completeness, coverage, and granularity of diversity (preprint)

Background The link between ethnicity and healthcare inequity, and the urgency for better data is well-recognised. This study describes ethnicity data in nation-wide electronic health records in England, UK. Methods We conducted a retrospective cohort study using de-identified person-level records for the England population available in the National Health Service (NHS) Digital trusted research environment. Primary care records (GDPPR) were linked to hospital and national mortality records. We assessed completeness, consistency, and granularity of ethnicity records using all available SNOMED-CT concepts for ethnicity and NHS ethnicity categories. Findings From 61.8 million individuals registered with a primary care practice in England, 51.5 (83.3%) had at least one ethnicity record in GDPPR, increasing to 93·9% when linked with hospital records. Approximately 12·0% had at least two conflicting ethnicity codes in primary care records. Women were more likely to have ethnicity recorded than men. Ethnicity was missing most frequently in individuals from 18 to 39 years old and in the southern regions of England. Individuals with an ethnicity record had more comorbidities recorded than those without. Of 489 SNOMED-CT ethnicity concepts available, 255 were used in primary care records. Discrepancies between SNOMED-CT and NHS ethnicity categories were observed, specifically within “Other-” ethnicity groups. Interpretation More than 250 ethnicity sub-groups may be found in health records for the English population, although commonly categorised into “White”, “Black”, “Asian”, “Mixed”, and “Other”. One in ten individuals do not have ethnicity information recorded in primary care or hospital records. SNOMED-CT codes represent more diversity in ethnicity groups than the NHS ethnicity classification. Improved recording of self-reported ethnicity at first point-of-care and consistency in ethnicity classification across healthcare settings can potentially improve the accuracy of ethnicity in research and ultimately care for all ethnicities. Funding British Heart Foundation Data Science Centre led by Health Data Research UK. Research in context Evidence before this study Ethnicity has been highlighted as a significant factor in the disproportionate impact of SARS-CoV-2 infection and mortality. Better knowledge of ethnicity data recorded in real clinical practice is required to improve health research and ultimately healthcare. We searched PubMed from database inception to 14 th July 2022 for publications using the search terms “ethnicity” and “electronic health records” or “EHR,” without language restrictions. 228 publications in 2019, before the COVID-19 pandemic, and 304 publications between 2020 and 2022 were identified. However, none of these publications used or reported any of over 400 available SNOMED-CT concepts for ethnicity to account for more granularity and diversity than captured by traditional high-level classification limited to 5 to 9 ethnicity groups. Added value of this study We provide a comprehensive study of the largest collection of ethnicity records from a national-level electronic health records trusted research environment, exploring completeness, consistency, and granularity. This work can serve as a data resource profile of ethnicity from routinely-collected EHR in England. Implications of all the available evidence To achieve equity in healthcare, we need to understand the differences between individuals, as well as the influence of ethnicity both on health status and on health interventions, including variation in the behaviour of tests and therapies. Thus, there is a need for measurements, thresholds, and risk estimates to be tailored to different ethnic groups. This study presents the different medical concepts describing ethnicity in routinely collected data that are readily available to researchers and highlights key elements for improving their accuracy in research. We aim to encourage researchers to use more granular ethnicity than the than typical approaches which aggregate ethnicity into a limited number of categories, failing to reflect the diversity of underlying populations. Accurate ethnicity data will lead to a better understanding of individual diversity, which will help to address disparities and influence policy recommendations that can translate into better, fairer health for all.

“Association between COVID-19 vaccination, infection, and risk of Guillain-Barre syndrome, Bell’s palsy, encephalomyelitis and transverse myelitis: a population-based cohort and self-controlled case series analysis” (preprint)

ABSTRACT OBJECTIVE We aimed to study the association between COVID-19 vaccines, SARS-CoV-2 infection, and the risk of immune-mediated neurological events. METHODS Design Population-based historical rate comparison study and self-controlled case series (SCCS) analysis. Setting Primary care records from the United Kingdom. Participants Individuals who received the first dose of ChAdOx1 or BNT162b2 between 8 December 2020 and 6 March 2021. A cohort with a first positive RT-PCR test for SARS-CoV-2 between 1 September 2020 and 28 February 2021 was used for comparison. Main outcome measures Outcomes included Guillain-Barre syndrome (GBS), Bell’s palsy, encephalomyelitis, and transverse myelitis. Incidence rates were estimated in the 28 days post first-dose vaccine, 90 days post-COVID-19, and between 2017 to 2019 for the general population cohort for background rates. Indirectly standardised incidence ratios (SIRs) were estimated. Adjusted incidence rate ratios (IRR) were estimated from the SCCS when sufficient statistical power was reached. Results We included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees; 299,311 people infected with COVID-19; and 2,290,537 from the general population. SIRs for GBS were 1.91 [95% CI: 0.86 to 4.26] after ChAdOx1, 1.29 [0.49 to 3.45] after BNT162b2, and 5.20 [1.95 to 13.85] after COVID-19. In the same cohorts, SIRs for Bell’s palsy were 1.34 [1.05 to 1.72], 1.15 [0.88 to 1.50], and 1.23 [0.80 to 1.89], and for encephalomyelitis 1.62 [0.61 to 4.31], 0.86 [0.22 to 3.46], and 11.05 [5.27 to 23.17], respectively. Transverse myelitis was too rare to analyse (n<5 in all cohorts). SCCS analysis was only conducted for Bell’s palsy due to limited statistical power. We found no association between either vaccine and Bell’s palsy, with an IRR of 1.10 [0.81 to 1.46] and 1.15 [0.87 to 1.49] for BNT162b2 and ChAdOx1, respectively. Conclusions We found no consistent association between either vaccine and any of the studied neuroimmune adverse events studied. Conversely, we found a 5-fold increase in risk of GBS and an 11-fold of encephalomyelitis following COVID-19.

Thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2: a population-based cohort analysis (preprint)

Objectives To calculate the observed rates of thrombosis and thrombocytopenia following vaccination against SARS-CoV-2, infection with SARS-CoV-2, and to compare them to background (expected) rates in the general population. Design Cohort study using routinely collected primary care records. Setting Routine practice in the United Kingdom. Participants Two mutually exclusive vaccinated cohorts included people vaccinated with either ChAdOx1 or BNT162b2 between 8 December 2020 and 6 March 2021. A third cohort consisted of people newly infected with SARS-Cov-2 identified by a first positive RT-PCR test between 1 September 2020 and 28 February 2021. The fourth general population cohort for background rates included those people with a visit between 1 January 2017 and 31 December 2019. In total, we included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees, 299,311 people infected with SARS-CoV-2, and 2,290,537 people from the general population. Interventions First-dose of either ChAdOx1 or BNT162b2 Main outcome measures Outcomes included venous thrombosis, arterial thrombosis, thrombocytopenia, and thrombosis with thrombocytopenia. Outcome rates were estimated for recipients of the ChAdOx1 or BNT162b2 vaccines, for people infected with SARS-CoV-2, and background rates in the general population. Indirectly standardized incidence ratios (SIR) were estimated. Results We included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees, 299,311 people infected with SARS-CoV-2, and 2,290,537 people from the general population for background rates. The SIRs for pulmonary embolism were 1.23 [95% CI, 1.09-1.39] after vaccination with ChAdOx1, 1.21 [1.07-1.36] after vaccination with BNT162b2, and 15.31 [14.08 to 16.65] for infection with SARS-CoV-2. The SIRs for thrombocytopenia after vaccination were 1.25 [1.19 to 1.31] for ChAdOx1 and 0.99 (0.94 to 1.04) for BNT162b2. Rates of deep vein thrombosis and arterial thrombosis were similar among those vaccinated and the general population. Conclusions ChAdOx1 and BNT162b2 had broadly similar safety profiles. Thrombosis rates after either vaccine were mostly similar to those of the general population. Rates of pulmonary embolism increased 1.2-fold after either vaccine and 15-fold with SARS-CoV-2 infection. Thrombocytopenia was more common among recipients of ChAdOx1 but not of BNT162b2.

Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 25.4 million people in six European countries (preprint)

Background Thrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of TTS in 6 European countries. Methods Electronic medical records from France, Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke, all with concurrent thrombocytopenia, were estimated among the general population between 2017 to 2019. A range of additional adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner. Findings A total of 25,432,658 individuals were included. Background rates ranged from 1.0 (0.7 to 1.4) to 8.5 (7.4 to 9.9) per 100,000 person-years for DVT with thrombocytopenia, from 0.5 (0.3 to 0.6) to 20.8 (18.9 to 22.8) for PE with thrombocytopenia, from 0.1 (0.0 to 0.1) to 2.5 (2.2 to 2.7) for SVT with thrombocytopenia, and from 0.2 (0.0 to 0.4) to 30.9 (28.6 to 33.3) for stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.1 to 0.2) per 100,000 person-years. The incidence of TTS increased with age, with those affected typically having more comorbidities and greater medication use than the general population. TTS was also more often seen in men than women. A sizeable proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their TTS event. Interpretation Although rates vary across databases, TTS has consistently been seen to be a very rare event among the general population. While still very rare, rates of TTS are typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population. Funding This study was funded by the European Medicines Agency (EMA/2017/09/PE Lot 3).

Characterizing the incidence of adverse events of special interest for COVID-19 vaccines across eight countries: a multinational network cohort study (preprint)

BackgroundAs large-scale immunization programs against COVID-19 proceed around the world, safety signals will emerge that need rapid evaluation. We report population-based, age- and sex- specific background incidence rates of potential adverse events of special interest (AESI) in eight countries using thirteen databases. MethodsThis multi-national network cohort study included eight electronic medical record and five administrative claims databases from Australia, France, Germany, Japan, Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model. People observed for at least 365 days before 1 January 2017, 2018, or 2019 were included. We based study outcomes on lists published by regulators: acute myocardial infarction, anaphylaxis, appendicitis, Bells palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain-Barre syndrome, hemorrhagic and non-hemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, and transverse myelitis. We calculated incidence rates stratified by age, sex, and database. We pooled rates across databases using random effects meta-analyses. We classified meta-analytic estimates into Council of International Organizations of Medical Sciences categories: very common, common, uncommon, rare, or very rare. FindingsWe analysed 126,661,070 people. Rates varied greatly between databases and by age and sex. Some AESI (e.g., myocardial infarction, Guillain-Barre syndrome) increased with age, while others (e.g., anaphylaxis, appendicitis) were more common in young people. As a result, AESI were classified differently according to age. For example, myocardial infarction was very rare in children, rare in women aged 35-54 years, uncommon in men and women aged 55-84 years, and common in those aged [≥]85 years. InterpretationWe report robust baseline rates of prioritised AESI across 13 databases. Age, sex, and variation between databases should be considered if background AESI rates are compared to event rates observed with COVID-19 vaccines.