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.

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.

Impact of COVID-19 on care-home mortality and life expectancy in Scotland.

BACKGROUND: COVID-19 deaths are commoner among care-home residents, but the mortality burden has not been quantified. METHODS: Care-home residency was identified via a national primary care registration database linked to mortality data. Life expectancy was estimated using Makeham-Gompertz models to (i) describe yearly life expectancy from November 2015 to October 2020 (ii) compare life expectancy (during 2016-18) between care-home residents and the wider population and (iii) apply care-home life expectancy estimates to COVID-19 death counts to estimate years of life lost (YLL). RESULTS: Among care-home residents, life expectancy in 2015/16 to 2019/20 ranged from 2.7 to 2.3 years for women and 2.3 to 1.8 years for men. Age-sex-specific life expectancy in 2016-18 in care-home residents was lower than in the Scottish population (10 and 2.5 years in those aged 70 and 90, respectively). Applying care home-specific life expectancies to COVID-19 deaths yield mean YLLs for care-home residents of 2.6 and 2.2 for women and men, respectively. In total YLL care-home residents have lost 3,560 years in women and 2,046 years in men. Approximately half of deaths and a quarter of YLL attributed to COVID-19 were accounted for by the 5% of over-70s who were care-home residents. CONCLUSION: COVID-19 infection has led to the loss of substantial years of life in care-home residents aged 70 years and over in Scotland. Prioritising the 5% of older adults who are care-home residents for vaccination is justified not only in terms of total deaths, but also in terms of YLL.

COVID-19 - exploring the implications of long-term condition type and extent of multimorbidity on years of life lost: a modelling study.

Background: COVID-19 is responsible for increasing deaths globally. As most people dying with COVID-19 are older with underlying long-term conditions (LTCs), some speculate that YLL are low. We aim to estimate YLL attributable to COVID-19, before and after adjustment for number/type of LTCs, using the limited data available early in the pandemic. Methods: We first estimated YLL from COVID-19 using WHO life tables, based on published age/sex data from COVID-19 deaths in Italy. We then used aggregate data on number/type of LTCs in a Bayesian model to estimate likely combinations of LTCs among people dying with COVID-19. We used routine UK healthcare data from Scotland and Wales to estimate life expectancy based on age/sex/these combinations of LTCs using Gompertz models from which we then estimate YLL. Results: Using the standard WHO life tables, YLL per COVID-19 death was 14 for men and 12 for women. After adjustment for number and type of LTCs, the mean YLL was slightly lower, but remained high (11.6 and 9.4 years for men and women, respectively). The number and type of LTCs led to wide variability in the estimated YLL at a given age (e.g. at ≥80 years, YLL was >10 years for people with 0 LTCs, and <3 years for people with ≥6). Conclusions: Deaths from COVID-19 represent a substantial burden in terms of per-person YLL, more than a decade, even after adjusting for the typical number and type of LTCs found in people dying of COVID-19. The extent of multimorbidity heavily influences the estimated YLL at a given age. More comprehensive and standardised collection of data (including LTC type, severity, and potential confounders such as socioeconomic-deprivation and care-home status) is needed to optimise YLL estimates for specific populations, and to understand the global burden of COVID-19, and guide policy-making and interventions.

Genomic epidemiology reveals multiple introductions of SARS-CoV-2 from mainland Europe into Scotland.

Coronavirus disease 2019 (COVID-19) was first diagnosed in Scotland on 1 March 2020. During the first month of the outbreak, 2,641 cases of COVID-19 led to 1,832 hospital admissions, 207 intensive care admissions and 126 deaths. We aimed to identify the source and number of introductions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into Scotland using a combined phylogenetic and epidemiological approach. Sequencing of 1,314 SARS-CoV-2 viral genomes from available patient samples enabled us to estimate that SARS-CoV-2 was introduced to Scotland on at least 283 occasions during February and March 2020. Epidemiological analysis confirmed that early introductions of SARS-CoV-2 originated from mainland Europe (the majority from Italy and Spain). We identified subsequent early outbreaks in the community, within healthcare facilities and at an international conference. Community transmission occurred after 2 March, 3 weeks before control measures were introduced. Earlier travel restrictions or quarantine measures, both locally and internationally, would have reduced the number of COVID-19 cases in Scotland. The risk of multiple reintroduction events in future waves of infection remains high in the absence of population immunity.

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.

Risk of hospital admission with coronavirus disease 2019 in healthcare workers and their households: nationwide linkage cohort study.

OBJECTIVE: To assess the risk of hospital admission for coronavirus disease 2019 (covid-19) among patient facing and non-patient facing healthcare workers and their household members. DESIGN: Nationwide linkage cohort study. SETTING: Scotland, UK, 1 March to 6 June 2020. PARTICIPANTS: Healthcare workers aged 18-65 years, their households, and other members of the general population. MAIN OUTCOME MEASURE: Admission to hospital with covid-19. RESULTS: The cohort comprised 158 445 healthcare workers, most of them (90 733; 57.3%) being patient facing, and 229 905 household members. Of all hospital admissions for covid-19 in the working age population (18-65 year olds), 17.2% (360/2097) were in healthcare workers or their households. After adjustment for age, sex, ethnicity, socioeconomic deprivation, and comorbidity, the risk of admission due to covid-19 in non-patient facing healthcare workers and their households was similar to the risk in the general population (hazard ratio 0.81 (95% confidence interval 0.52 to 1.26) and 0.86 (0.49 to 1.51), respectively). In models adjusting for the same covariates, however, patient facing healthcare workers, compared with non-patient facing healthcare workers, were at higher risk (hazard ratio 3.30, 2.13 to 5.13), as were household members of patient facing healthcare workers (1.79, 1.10 to 2.91). After sub-division of patient facing healthcare workers into those who worked in "front door," intensive care, and non-intensive care aerosol generating settings and other, those in front door roles were at higher risk (hazard ratio 2.09, 1.49 to 2.94). For most patient facing healthcare workers and their households, the estimated absolute risk of hospital admission with covid-19 was less than 0.5%, but it was 1% and above in older men with comorbidity. CONCLUSIONS: Healthcare workers and their households contributed a sixth of covid-19 cases admitted to hospital. Although the absolute risk of admission was low overall, patient facing healthcare workers and their household members had threefold and twofold increased risks of admission with covid-19.

COVID-19 – exploring the implications of long-term condition type and extent of multimorbidity on years of life lost: a modelling study [version 1;peer review: awaiting peer review]

Background: The COVID-19 pandemic is responsible for increasing deaths globally. Most estimates have focused on numbers of deaths, with little direct quantification of years of life lost (YLL) through COVID-19. As most people dying with COVID-19 are older with underlying long-term conditions (LTCs), some have speculated that YLL are low. We aim to estimate YLL attributable to COVID-19, before and after adjustment for number/type of LTCs. Methods: We first estimated YLL from COVID-19 using standard WHO life tables, based on published age/sex data from COVID-19 deaths in Italy. We then used aggregate data on number/type of LTCs to model likely combinations of LTCs among people dying with COVID-19. From these, we used routine UK healthcare data to estimate life expectancy based on age/sex/different combinations of LTCs. We then calculated YLL based on age, sex and type of LTCs and multimorbidity count. Results: Using the standard WHO life tables, YLL per COVID-19 death was 14 for men and 12 for women. After adjustment for number and type of LTCs, the mean YLL was slightly lower, but remained high (13 and 11 years for men and women, respectively). The number and type of LTCs led to wide variability in the estimated YLL at a given age (e.g. at ≥80 years, YLL was 10 years for people with 0 LTCs, and 3 years for people with ≥6). Conclusions: Deaths from COVID-19 represent a substantial burden in terms of per-person YLL, more than a decade, even after adjusting for the typical number and type of LTCs found in people dying of COVID-19. The extent of multimorbidity heavily influences the estimated YLL at a given age. More comprehensive and standardised collection of data on LTCs is needed to better understand and quantify the global burden of COVID-19 and to guide policy-making and interventions.