Relation of Incident Type 1 Diabetes to Recent COVID-19 Infection: Cohort Study Using e-Health Record Linkage in Scotland.

OBJECTIVE: Studies using claims databases reported that SARS-CoV-2 infection >30 days earlier was associated with an increase in the incidence of type 1 diabetes. Using exact dates of diabetes diagnosis from the national register in Scotland linked to virology laboratory data, we sought to replicate this finding. RESEARCH DESIGN AND METHODS: A cohort of 1,849,411 individuals aged <35 years without diabetes, including all those in Scotland who subsequently tested positive for SARS-CoV-2, was followed from 1 March 2020 to 22 November 2021. Incident type 1 diabetes was ascertained from the national registry. Using Cox regression, we tested the association of time-updated infection with incident diabetes. Trends in incidence of type 1 diabetes in the population from 2015 through 2021 were also estimated in a generalized additive model. RESULTS: There were 365,080 individuals who had at least one detected SARS-CoV-2 infection during follow-up and 1074 who developed type 1 diabetes. The rate ratio for incident type 1 diabetes associated with first positive test for SARS-CoV-2 (reference category: no previous infection) was 0.86 (95% CI 0.62, 1.21) for infection >30 days earlier and 2.62 (95% CI 1.81, 3.78) for infection in the previous 30 days. However, negative and positive SARS-CoV-2 tests were more frequent in the days surrounding diabetes presentation. In those aged 0-14 years, incidence of type 1 diabetes during 2020-2021 was 20% higher than the 7-year average. CONCLUSIONS: Type 1 diabetes incidence in children increased during the pandemic. However, the cohort analysis suggests that SARS-CoV-2 infection itself was not the cause of this increase.

Vaccine efficacy against severe COVID-19 in relation to delta variant (B.1.617.2) and time since second dose in patients in Scotland (REACT-SCOT): a case-control study.

BACKGROUND: Reports have suggested that the efficacy of vaccines against COVID-19 might have fallen since the delta (B.1.617.2) SARS-CoV-2 variant replaced the alpha (B.1.1.7) variant as the predominant variant. We aimed to investigate, for the two main classes of vaccine, whether efficacy against severe COVID-19 has decreased since delta became the predominant variant and whether the efficacy of two doses of vaccine against severe COVID-19 wanes with time since second dose. METHODS: In the REACT-SCOT case-control study, vaccine efficacy was estimated using a matched case-control design that includes all diagnosed cases of COVID-19 in Scotland up to Sept 8, 2021. For every incident case of COVID-19 in the Scottish population, ten controls matched for age rounded to the nearest year, sex, and primary care practice, and alive on the day of presentation of the case that they were matched to were selected using the Community Health Index database. To minimise ascertainment bias we prespecified the primary outcome measure to assess vaccine efficacy as severe COVID-19, defined as diagnosed patients with entry to critical care within 21 days of first positive test, death within 28 days of first positive test, or any death for which COVID-19 was coded as underlying cause. Although the data extracted for this study included cases presenting up to Sept 22, 2021, the analyses reported here are restricted to cases and controls presenting from Dec 1, 2020, to Sept 8, 2021, ensuring follow-up for at least 14 days after presentation date to allow classification of hospitalisation and (for most cases) severity based on entry to critical care or fatal outcome. FINDINGS: During the study period, a total of 5645 severe cases of COVID-19 were recorded; these were matched to 50 096 controls. Of the severe cases, 4495 (80%) were not vaccinated, and of the controls, 36 879 (74%) were not vaccinated. Of the severe cases of COVID-19 who had been vaccinated, 389 had received an mRNA vaccine and 759 had received the ChAdOx1 vaccine. The efficacy of vaccination against severe COVID-19 decreased in May, 2021, coinciding with the replacement of the alpha SARS-CoV-2 variant by the delta variant in Scotland, but this decrease was reversed over the following month. In the most recent time window centred on July 29, 2021, the efficacy of two doses was 91% (95% CI 87-94) for the ChAdOx1 vaccine and 92% (88-95) for mRNA (Pfizer or Moderna) vaccines. The efficacy of the ChAdOx1 vaccine against severe COVID-19 declined with time since second dose to 69% (95% CI 52-80) at 20 weeks from second dose. The efficacy of mRNA vaccines declined in the first ten weeks from second dose but more slowly thereafter to 93% (88-96) at 20 weeks from second dose. INTERPRETATION: Our results are reassuring with respect to concerns that vaccine efficacy against severe COVID-19 might have fallen since the delta variant became predominant, or that efficacy of mRNA vaccines wanes within the first 5-6 months after second dose. However, the efficacy of the ChAdOx1 vaccine against severe COVID-19 wanes substantially by 20 weeks from second dose. Efficacy of mRNA vaccines after 20 weeks and against newer variants remains to be established. Our findings support the case for additional protective measures for those at risk of severe disease, including, but not limited to, booster doses, at times when transmission rates are high or expected to rise. FUNDING: None.

Cohort profile: the Scottish Diabetes Research Network national diabetes cohort - a population-based cohort of people with diabetes in Scotland.

PURPOSE: The Scottish Diabetes Research Network (SDRN)-diabetes research platform was established to combine disparate electronic health record data into research-ready linked datasets for diabetes research in Scotland. The resultant cohort, 'The SDRN-National Diabetes Dataset (SDRN-NDS)', has many uses, for example, understanding healthcare burden and socioeconomic trends in disease incidence and prevalence, observational pharmacoepidemiology studies and building prediction tools to support clinical decision making. PARTICIPANTS: We estimate that >99% of those diagnosed with diabetes nationwide are captured into the research platform. Between 2006 and mid-2020, the cohort comprised 472 648 people alive with diabetes at any point in whom there were 4 million person-years of follow-up. Of the cohort, 88.1% had type 2 diabetes, 8.8% type 1 diabetes and 3.1% had other types (eg, secondary diabetes). Data are captured from all key clinical encounters for diabetes-related care, including diabetes clinic, primary care and podiatry and comprise clinical history and measurements with linkage to blood results, microbiology, prescribed and dispensed drug and devices, retinopathy screening, outpatient, day case and inpatient episodes, birth outcomes, cancer registry, renal registry and causes of death. FINDINGS TO DATE: There have been >50 publications using the SDRN-NDS. Examples of recent key findings include analysis of the incidence and relative risks for COVID-19 infection, drug safety of insulin glargine and SGLT2 inhibitors, life expectancy estimates, evaluation of the impact of flash monitors on glycaemic control and diabetic ketoacidosis and time trend analysis showing that diabetic ketoacidosis (DKA) remains a major cause of death under age 50 years. The findings have been used to guide national diabetes strategy and influence national and international guidelines. FUTURE PLANS: The comprehensive SDRN-NDS will continue to be used in future studies of diabetes epidemiology in the Scottish population. It will continue to be updated at least annually, with new data sources linked as they become available.

Association of cerebral venous thrombosis with recent COVID-19 vaccination: case-crossover study using ascertainment through neuroimaging in Scotland.

BACKGROUND: To investigate the association of primary acute cerebral venous thrombosis (CVT) with COVID-19 vaccination through complete ascertainment of all diagnosed CVT in the population of Scotland. METHODS: Case-crossover study comparing cases of CVT recently exposed to vaccination (1-14 days after vaccination) with cases less recently exposed. Cases in Scotland from 1 December 2020 were ascertained through neuroimaging studies up to 17 May 2021 and diagnostic coding of hospital discharges up to 28 April 2021, linked to national vaccination records. The main outcome measure was primary acute CVT. RESULTS: Of 50 primary acute CVT cases, 29 were ascertained only from neuroimaging studies, 2 were ascertained only from hospital discharges, and 19 were ascertained from both sources. Of these 50 cases, 14 had received the Astra-Zeneca ChAdOx1 vaccine and 3 the Pfizer BNT162b2 vaccine. The incidence of CVT per million doses in the first 14 days after vaccination was 2.2 (95% credible interval 0.9 to 4.1) for ChAdOx1 and 1 (95% credible interval 0.1 to 2.9) for BNT162b2. The rate ratio for CVT associated with exposure to ChAdOx1 in the first 14 days compared with exposure 15-84 days after vaccination was 3.2 (95% credible interval 1.1 to 9.5). CONCLUSIONS: These findings support a causal association between CVT and the AstraZeneca vaccine. The absolute risk of post-vaccination CVT in this population-wide study in Scotland was lower than has been reported for populations in Scandinavia and Germany; the explanation for this is not clear.

Sharing a household with children and risk of COVID-19: a study of over 300 000 adults living in healthcare worker households in Scotland.

OBJECTIVE: Children are relatively protected from COVID-19, due to a range of potential mechanisms. We investigated if contact with children also affords adults a degree of protection from COVID-19. DESIGN: Cohort study based on linked administrative data. SETTING: Scotland. STUDY POPULATION: All National Health Service Scotland healthcare workers and their household contacts as of March 2020. MAIN EXPOSURE: Number of young children (0-11 years) living in the participant's household. MAIN OUTCOMES: COVID-19 requiring hospitalisation, and any COVID-19 (any positive test for SARS-CoV-2) in adults aged ≥18 years between 1 March and 12 October 2020. RESULTS: 241 266, 41 198, 23 783 and 3850 adults shared a household with 0, 1, 2 and 3 or more young children, respectively. Over the study period, the risk of COVID-19 requiring hospitalisation was reduced progressively with increasing numbers of household children-fully adjusted HR (aHR) 0.93 per child (95% CI 0.79 to 1.10). The risk of any COVID-19 was similarly reduced, with the association being statistically significant (aHR per child 0.93; 95% CI 0.88 to 0.98). After schools reopened to all children in August 2020, no association was seen between exposure to young children and risk of any COVID-19 (aHR per child 1.03; 95% CI 0.92 to 1.14). CONCLUSION: Between March and October 2020, living with young children was associated with an attenuated risk of any COVID-19 and COVID-19 requiring hospitalisation among adults living in healthcare worker households. There was no evidence that living with young children increased adults' risk of COVID-19, including during the period after schools reopened.

Risk of hospital admission with covid-19 among teachers compared with healthcare workers and other adults of working age in Scotland, March 2020 to July 2021: population based case-control study.

OBJECTIVE: To determine the risk of hospital admission with covid-19 and severe covid-19 among teachers and their household members, overall and compared with healthcare workers and adults of working age in the general population. DESIGN: Population based nested case-control study. SETTING: Scotland, March 2020 to July 2021, during defined periods of school closures and full openings in response to covid-19. PARTICIPANTS: All cases of covid-19 in adults aged 21 to 65 (n=132 420) and a random sample of controls matched on age, sex, and general practice (n=1 306 566). Adults were identified as actively teaching in a Scottish school by the General Teaching Council for Scotland, and their household members were identified through the unique property reference number. The comparator groups were adults identified as healthcare workers in Scotland, their household members, and the remaining general population of working age. MAIN OUTCOME MEASURES: The primary outcome was hospital admission with covid-19, defined as having a positive test result for SARS-CoV-2 during hospital admission, being admitted to hospital within 28 days of a positive test result, or receiving a diagnosis of covid-19 on discharge from hospital. Severe covid-19 was defined as being admitted to intensive care or dying within 28 days of a positive test result or assigned covid-19 as a cause of death. RESULTS: Most teachers were young (mean age 42), were women (80%), and had no comorbidities (84%). The risk (cumulative incidence) of hospital admission with covid-19 was <1% for all adults of working age in the general population. Over the study period, in conditional logistic regression models adjusted for age, sex, general practice, race/ethnicity, deprivation, number of comorbidities, and number of adults in the household, teachers showed a lower risk of hospital admission with covid-19 (rate ratio 0.77, 95% confidence interval 0.64 to 0.92) and of severe covid-19 (0.56, 0.33 to 0.97) than the general population. In the first period when schools in Scotland reopened, in autumn 2020, the rate ratio for hospital admission in teachers was 1.20 (0.89 to 1.61) and for severe covid-19 was 0.45 (0.13 to 1.55). The corresponding findings for household members of teachers were 0.91 (0.67 to 1.23) and 0.73 (0.37 to 1.44), and for patient facing healthcare workers were 2.08 (1.73 to 2.50) and 2.26 (1.43 to 3.59). Similar risks were seen for teachers in the second period, when schools reopened in summer 2021. These values were higher than those seen in spring/summer 2020, when schools were mostly closed. CONCLUSION: Compared with adults of working age who are otherwise similar, teachers and their household members were not found to be at increased risk of hospital admission with covid-19 and were found to be at lower risk of severe covid-19. These findings should reassure those who are engaged in face-to-face teaching.

Relation of severe COVID-19 in Scotland to transmission-related factors and risk conditions eligible for shielding support: REACT-SCOT case-control study.

BACKGROUND: Clinically vulnerable individuals have been advised to shield themselves during the COVID-19 epidemic. The objectives of this study were to investigate (1) the rate ratio of severe COVID-19 associated with eligibility for the shielding programme in Scotland across the first and second waves of the epidemic and (2) the relation of severe COVID-19 to transmission-related factors in those in shielding and the general population. METHODS: In a matched case-control design, all 178,578 diagnosed cases of COVID-19 in Scotland from 1 March 2020 to 18 February 2021 were matched for age, sex and primary care practice to 1,744,283 controls from the general population. This dataset (REACT-SCOT) was linked to the list of 212,702 individuals identified as eligible for shielding. Severe COVID-19 was defined as cases that entered critical care or were fatal. Rate ratios were estimated by conditional logistic regression. RESULTS: With those without risk conditions as reference category, the univariate rate ratio for severe COVID-19 was 3.21 (95% CI 3.01 to 3.41) in those with moderate risk conditions and 6.3 (95% CI 5.8 to 6.8) in those eligible for shielding. The highest rate was in solid organ transplant recipients: rate ratio 13.4 (95% CI 9.6 to 18.8). Risk of severe COVID-19 increased with the number of adults but decreased with the number of school-age children in the household. Severe COVID-19 was strongly associated with recent exposure to hospital (defined as 5 to 14 days before presentation date): rate ratio 12.3 (95% CI 11.5 to 13.2) overall. The population attributable risk fraction for recent exposure to hospital peaked at 50% in May 2020 and again at 65% in December 2020. CONCLUSIONS: The effectiveness of shielding vulnerable individuals was limited by the inability to control transmission in hospital and from other adults in the household. Mitigating the impact of the epidemic requires control of nosocomial transmission.

Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.

BACKGROUND: The objective of this study was to investigate the relation of severe COVID-19 to prior drug prescribing. METHODS: Severe cases were defined by entry to critical care or fatal outcome. For this matched case-control study (REACT-SCOT), all 4251 cases of severe COVID-19 in Scotland since the start of the epidemic were matched for age, sex and primary care practice to 36,738 controls from the population register. Records were linked to hospital discharges since June 2015 and dispensed prescriptions issued in primary care during the last 240 days. RESULTS: Severe COVID-19 was strongly associated with the number of non-cardiovascular drug classes dispensed. This association was strongest in those not resident in a care home, in whom the rate ratio (95% CI) associated with dispensing of 12 or more drug classes versus none was 10.8 (8.8, 13.3), and in those without any of the conditions designated as conferring increased risk of COVID-19. Of 17 drug classes postulated at the start of the epidemic to be "medications compromising COVID", all were associated with increased risk of severe COVID-19 and these associations were present in those without any of the designated risk conditions. The fraction of cases in the population attributable to exposure to these drug classes was 38%. The largest effect was for antipsychotic agents: rate ratio 4.18 (3.42, 5.11). Other drug classes with large effects included proton pump inhibitors (rate ratio 2.20 (1.72, 2.83) for = 2 defined daily doses/day), opioids (3.66 (2.68, 5.01) for = 50 mg morphine equivalent/day) and gabapentinoids. These associations persisted after adjusting for covariates and were stronger with recent than with non-recent exposure. CONCLUSIONS: Severe COVID-19 is associated with polypharmacy and with drugs that cause sedation, respiratory depression, or dyskinesia; have anticholinergic effects; or affect the gastrointestinal system. These associations are not easily explained by co-morbidity. Measures to reduce the burden of mortality and morbidity from COVID-19 should include reinforcing existing guidance on reducing overprescribing of these drug classes and limiting inappropriate polypharmacy. REGISTRATION: ENCEPP number EUPAS35558.

Risks of and risk factors for COVID-19 disease in people with diabetes: a cohort study of the total population of Scotland.

BACKGROUND: We aimed to ascertain the cumulative risk of fatal or critical care unit-treated COVID-19 in people with diabetes and compare it with that of people without diabetes, and to investigate risk factors for and build a cross-validated predictive model of fatal or critical care unit-treated COVID-19 among people with diabetes. METHODS: In this cohort study, we captured the data encompassing the first wave of the pandemic in Scotland, from March 1, 2020, when the first case was identified, to July 31, 2020, when infection rates had dropped sufficiently that shielding measures were officially terminated. The participants were the total population of Scotland, including all people with diabetes who were alive 3 weeks before the start of the pandemic in Scotland (estimated Feb 7, 2020). We ascertained how many people developed fatal or critical care unit-treated COVID-19 in this period from the Electronic Communication of Surveillance in Scotland database (on virology), the RAPID database of daily hospitalisations, the Scottish Morbidity Records-01 of hospital discharges, the National Records of Scotland death registrations data, and the Scottish Intensive Care Society and Audit Group database (on critical care). Among people with fatal or critical care unit-treated COVID-19, diabetes status was ascertained by linkage to the national diabetes register, Scottish Care Information Diabetes. We compared the cumulative incidence of fatal or critical care unit-treated COVID-19 in people with and without diabetes using logistic regression. For people with diabetes, we obtained data on potential risk factors for fatal or critical care unit-treated COVID-19 from the national diabetes register and other linked health administrative databases. We tested the association of these factors with fatal or critical care unit-treated COVID-19 in people with diabetes, and constructed a prediction model using stepwise regression and 20-fold cross-validation. FINDINGS: Of the total Scottish population on March 1, 2020 (n=5 463 300), the population with diabetes was 319 349 (5·8%), 1082 (0·3%) of whom developed fatal or critical care unit-treated COVID-19 by July 31, 2020, of whom 972 (89·8%) were aged 60 years or older. In the population without diabetes, 4081 (0·1%) of 5 143 951 people developed fatal or critical care unit-treated COVID-19. As of July 31, the overall odds ratio (OR) for diabetes, adjusted for age and sex, was 1·395 (95% CI 1·304-1·494; p<0·0001, compared with the risk in those without diabetes. The OR was 2·396 (1·815-3·163; p<0·0001) in type 1 diabetes and 1·369 (1·276-1·468; p<0·0001) in type 2 diabetes. Among people with diabetes, adjusted for age, sex, and diabetes duration and type, those who developed fatal or critical care unit-treated COVID-19 were more likely to be male, live in residential care or a more deprived area, have a COVID-19 risk condition, retinopathy, reduced renal function, or worse glycaemic control, have had a diabetic ketoacidosis or hypoglycaemia hospitalisation in the past 5 years, be on more anti-diabetic and other medication (all p<0·0001), and have been a smoker (p=0·0011). The cross-validated predictive model of fatal or critical care unit-treated COVID-19 in people with diabetes had a C-statistic of 0·85 (0·83-0·86). INTERPRETATION: Overall risks of fatal or critical care unit-treated COVID-19 were substantially elevated in those with type 1 and type 2 diabetes compared with the background population. The risk of fatal or critical care unit-treated COVID-19, and therefore the need for special protective measures, varies widely among those with diabetes but can be predicted reasonably well using previous clinical history. FUNDING: None.

Rapid Epidemiological Analysis of Comorbidities and Treatments as risk factors for COVID-19 in Scotland (REACT-SCOT): A population-based case-control study.

BACKGROUND: The objectives of this study were to identify risk factors for severe coronavirus disease 2019 (COVID-19) and to lay the basis for risk stratification based on demographic data and health records. METHODS AND FINDINGS: The design was a matched case-control study. Severe COVID-19 was defined as either a positive nucleic acid test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the national database followed by entry to a critical care unit or death within 28 days or a death certificate with COVID-19 as underlying cause. Up to 10 controls per case matched for sex, age, and primary care practice were selected from the national population register. For this analysis-based on ascertainment of positive test results up to 6 June 2020, entry to critical care up to 14 June 2020, and deaths registered up to 14 June 2020-there were 36,948 controls and 4,272 cases, of which 1,894 (44%) were care home residents. All diagnostic codes from the past 5 years of hospitalisation records and all drug codes from prescriptions dispensed during the past 240 days were extracted. Rate ratios for severe COVID-19 were estimated by conditional logistic regression. In a logistic regression using the age-sex distribution of the national population, the odds ratios for severe disease were 2.87 for a 10-year increase in age and 1.63 for male sex. In the case-control analysis, the strongest risk factor was residence in a care home, with rate ratio 21.4 (95% CI 19.1-23.9, p = 8 × 10-644). Univariate rate ratios for conditions listed by public health agencies as conferring high risk were 2.75 (95% CI 1.96-3.88, p = 6 × 10-9) for type 1 diabetes, 1.60 (95% CI 1.48-1.74, p = 8 × 10-30) for type 2 diabetes, 1.49 (95% CI 1.37-1.61, p = 3 × 10-21) for ischemic heart disease, 2.23 (95% CI 2.08-2.39, p = 4 × 10-109) for other heart disease, 1.96 (95% CI 1.83-2.10, p = 2 × 10-78) for chronic lower respiratory tract disease, 4.06 (95% CI 3.15-5.23, p = 3 × 10-27) for chronic kidney disease, 5.4 (95% CI 4.9-5.8, p = 1 × 10-354) for neurological disease, 3.61 (95% CI 2.60-5.00, p = 2 × 10-14) for chronic liver disease, and 2.66 (95% CI 1.86-3.79, p = 7 × 10-8) for immune deficiency or suppression. Seventy-eight percent of cases and 52% of controls had at least one listed condition (51% of cases and 11% of controls under age 40). Severe disease was associated with encashment of at least one prescription in the past 9 months and with at least one hospital admission in the past 5 years (rate ratios 3.10 [95% CI 2.59-3.71] and 2.75 [95% CI 2.53-2.99], respectively) even after adjusting for the listed conditions. In those without listed conditions, significant associations with severe disease were seen across many hospital diagnoses and drug categories. Age and sex provided 2.58 bits of information for discrimination. A model based on demographic variables, listed conditions, hospital diagnoses, and prescriptions provided an additional 1.07 bits (C-statistic 0.804). A limitation of this study is that records from primary care were not available. CONCLUSIONS: We have shown that, along with older age and male sex, severe COVID-19 is strongly associated with past medical history across all age groups. Many comorbidities beyond the risk conditions designated by public health agencies contribute to this. A risk classifier that uses all the information available in health records, rather than only a limited set of conditions, will more accurately discriminate between low-risk and high-risk individuals who may require shielding until the epidemic is over.