Effect of vaccination on transmission of COVID-19: an observational study in healthcare workers and their households (preprint)

Background: The effect of vaccination for COVID-19 on onward transmission is unknown. Methods: A national record linkage study determined documented COVID-19 cases and hospitalizations in unvaccinated household members of vaccinated and unvaccinated healthcare workers from 8th December 2020 to 3rd March 2021. The primary endpoint was COVID-19 >= 14 days following the first dose. Results: The cohort comprised of 194,362 household members (mean age 31.1 years) and 144,525 healthcare workers (mean age 44.4 years). 113,253 (78.3%) of healthcare workers received at least one dose of the BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccine and 36,227 (25.1%) received a second dose. Household members of vaccinated healthcare workers had a lower risk of COVID-19 case compared to household members of unvaccinated healthcare worker (rate per 100 person-years 9.40 versus 5.93; HR 0.70, 95% confidence interval [CI] 0.63-0.78). The effect size for COVID-19 hospitalization was similar, with the confidence interval crossing the null (HR 0.77 [0.53-1.10]). The rate per 100 person years was lower in vaccinated compared to unvaccinated healthcare workers for documented (20.13 versus 8.51; HR 0.45 [0.42-0.49]) and hospitalized COVID-19 (0.97 versus 0.14; HR 0.16 [0.09-0.27]). Compared to the period before the first dose, the risk of documented COVID-19 case was lower at >= 14 days after the second dose for household members (HR 0.46 [0.30-0.70]) and healthcare workers (HR 0.08 [0.04-0.17]). Conclusion: Vaccination of health care workers was associated with a substantial reduction in COVID-19 cases in household contacts consistent with an effect of vaccination on transmission.

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

* Objectives - To investigate:(1) the risk of severe COVID-19 in those eligible for shielding, and (2) the relation of severe COVID-19 to transmission-related factors in those in shielding and the general population. * Design - Matched case-control study (REACT-SCOT). * Setting - Population of Scotland from 1 March 2020 to 28 January 2021. * Participants - All 160307 diagnosed cases of COVID-19 and 1564782 controls matched for age, sex and primary care practice, linked with all 204913 individuals identified as eligible for shielding by Public Health Scotland. * Main outcome measure - Severe COVID-19, defined as cases that entered critical care or were fatal. * Results - With those without risk conditions as reference category, the univariate rate ratio for severe COVID-19 was 5.3 (95% CI 5.0 to 5.7, p=4 x 10-527) in those with moderate risk conditions and 7.6 (95% CI 7.1 to 8.3, p=1 x 10-527) in those eligible for shielding. The highest rate was in solid organ transplant recipients: rate ratio 13.6 (95% CI 9.6 to 19.2, p=8 x 10-50). In both the shielded and the general population, the 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 12.6 (95% CI 11.7 to 13.6, p=2 x 10-989) overall. In a case-crossover analysis with less recent exposure only (15 to 24 days before first testing positive) as reference category, the rate ratio associated with recent exposure only was 6.3 (95% CI 3.6 to 11.1, p=2 x 10-10). Among those eligible for shielding, the population attributable risk fraction (PARF) of severe cases for recent exposure to hospital was 36%. In the general population the PARF for recent exposure to hospital peaked at 46% in May 2020 and again at 64% 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. For solid organ transplant recipients, in whom the efficacy of vaccines is uncertain, these results support a policy of offering vaccination to household contacts. Mitigating the impact of the epidemic requires control of nosocomial transmission.

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

ObjectiveChildren are relatively protected from COVID-19, possibly due to cross-protective immunity. We investigated if contact with children also affords adults a degree of protection from COVID-19. DesignCohort study based on linked administrative data. SettingScotland Study populationAll NHS Scotland healthcare workers and their household contacts as of March 2020. Main exposureNumber of young children (0-11 years) living in the participants household. Main outcomesCOVID-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. Results241,266, 41,198, 23,783 and 3,850 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 hazard ratio (aHR) 0.93 per child (95% CI 0.79-1.10). The risk of any COVID-19 was similarly reduced, with the association being statistically significant (aHR per child 0.93; 95% CI 0.88-0.98). 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 0.92-1.14). ConclusionBetween 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 re-opened.

Risk of hospitalisation with coronavirus disease 2019 in healthcare workers and their households:a nationwide linkage cohort study (preprint)

ObjectiveMany healthcare staff work in high-risk settings for contracting and transmitting Severe Acute Respiratory Syndrome Coronavirus 2. Their risk of hospitalisation for coronavirus disease 2019 (COVID-19), and that of their households, is poorly understood. Design and settings and participantsDuring the peak period for COVID-19 infection in Scotland (1st March 2020 to 6th June 2020) we conducted a national record linkage study to compare the risk of COVID-19 hospitalisation among healthcare workers (age: 18-65 years), their households and other members of the general population. Main outcomeHospitalisation with COVID-19 ResultsThe cohort comprised 158,445 healthcare workers, the majority being patient facing (90,733 / 158,445; 57.3%), and 229,905 household members. Of all COVID-19 hospitalisations in the working age population (18-65-year-old), 17.2% (360 / 2,097) were in healthcare workers or their households. Adjusting for age, sex, ethnicity, socio-economic deprivation and comorbidity, the risk of COVID-19 hospitalisation in non-patient facing healthcare workers and their households was similar to the risk in the general population (hazards ratio [HR] 0.81; 95%CI 0.52-1.26 and 0.86; 95%CI 0.49-1.51 respectively). In models adjusting for the same covariates however, patient facing healthcare workers, compared to non-patient facing healthcare workers, were at higher risk (HR 3.30; 95%CI 2.13-5.13); so too were household members of patient facing healthcare workers (HR 1.79; 95%CI 1.10-2.91). On sub-dividing 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 (HR 2.09; 95%CI 1.49-2.94). For most patient facing healthcare workers and their households, the estimated absolute risk of COVID-19 hospitalisation was less than 0.5% but was 1% and above in older men with comorbidity. ConclusionsHealthcare workers and their households contribute a sixth of hospitalised COVID-19 cases. Whilst the absolute risk of hospitalisation was low overall, patient facing healthcare workers and their households had 3- and 2-fold increased risks of COVID-19 hospitalisation.

Associations of severe COVID-19 with polypharmacy in the REACT-SCOT case-control study (preprint)

Objectives -- To investigate the relation of severe COVID-19 to prior drug prescribing. Design -- Matched case-control study (REACT-SCOT) based on record linkage to hospital discharges since June 2015 and dispensed prescriptions issued in primary care during the last 240 days. Setting -- Scottish population. Main outcome measure -- Severe COVID-19, defined by entry to critical care or fatal outcome. Participants -- All 4272 cases of severe COVID-19 in Scotland since the start of the epidemic, with 36948 controls matched for age, sex and primary care practice. 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 care homes, in whom the rate ratio (95% CI) associated with dispensing of 12 or more drug classes versus none was 10.8 (8.7, 13.2), and was not accounted for by treatment of conditions designated as conferring increased risk. 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. The largest effect was for antipsychotic agents: rate ratio 4.14 (3.39, 5.07). Other drug classes with large effects included proton pump inhibitors (rate rato 2.19 (1.70, 2.80) for >= 2 defined daily doses/day), opioids (3.62 (2.65, 4.94) 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. Although the evidence for causality is not conclusive, these results support existing guidance on reducing overprescribing of these drug classes and limiting inappropriate polypharmacy as a potential means of reducing COVID-19 risk. Registration -- ENCEPP number EUPAS35558

COVID-19 Disease in People with Diabetes in Scotland: Incidence, Severity and Risk Stratification Using Matched Case-Control and Prospective Cohort Studies (preprint)

Background: The risks of, and risk factors for, COVID-19 disease associated with diabetes are poorly quantified. Methods: We identified as cases all those in Scotland with a positive SARS-CoV-2 nucleic acid test in the national laboratory database and anyone else with a death certificate mentioning COVID-19. Seven controls matched for age, sex and general practice were selected per case. Data were linked to the national diabetes register, hospitalisation and critical care unit (CCU) databases. Analyses focused on those with COVID-19 requiring critical care or dying. Analyses were by conditional and unconditional logistic regression. Findings: 0.3% (n=845) of those with diabetes had developed severe or fatal COVID-19, representing rate ratios of 3.86 (2.74, 5.45) in type 1 and 1.69 (1.56, 1.84) in type 2 diabetes. Rates were almost threefold in the most versus least socioeconomically deprived quintiles of the population. Most (77%) cases had another recognised co-morbidity such as heart or lung disease (OR 2.6). Diabetes specific factors associated with increased risk included; HbA1c odds ratio (OR) >85 mmol/mol versus <53: 1.96(1.55,2.48);p-value <0.001, prior diabetic ketoacidosis: OR 2.44(1.41,4.20);p-value 0.001 and hypoglycaemia hospitalisations: OR 3.28(2.41,4.46);p-value <0.001. Chronic retinal and renal complications were also associated with increased risk. A cross-validated predictive model of severe or fatal disease had a C-statistic of 0.83. Interpretations: Relative risks of severe or fatal COVID-19 are substantially elevated in both types of diabetes. Risk scores based on prior clinical history should be useful for identifying those with diabetes needing tailored protective measures.Funding Statement: There was no specific funder for this study.Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: This research was conducted with approval from the Public Benefit Privacy Protection Panel (PBPP ref. 1617- 0147), originally set up under PAC 33/11, with approval from the Scotland A Research Ethics Committee (ref. 11/AL/0225). All datasets were de-identified before analysis.

Rapid Epidemiological Analysis of Comorbidities andTreatments as risk factors for COVID-19 in Scotland(REACT-SCOT): a population-based case-control study (preprint)

BackgroundThe objectives of this study were to identify risk factors for severe COVID-19 and to lay the basis for risk stratification based on demographic data and health records. Methods and FindingsThe design was a matched case-control study. Severe COVID-19 was defined as either a positive nucleic acid test for 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 ten controls per case matched for sex, age and primary care practice were selected from the population register. All diagnostic codes from the past five years of hospitalisation records and all drug codes from prescriptions dispensed during the past nine months were extracted. Rate ratios for severe COVID-19 were estimated by conditional logistic regression. There were 4272 severe cases. 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 (95% CI) 21.4 (19.1, 23.9). Univariate rate ratios (95% CIs) for conditions listed by public health agencies as conferring high risk were 2.75 (1.96, 3.88) for Type 1 diabetes, 1.60 (1.48, 1.74) for Type 2 diabetes, 1.49 (1.37, 1.61) for ischemic heart disease, 2.23 (2.08, 2.39) for other heart disease, 1.96 (1.83, 2.10) for chronic lower respiratory tract disease, 4.06 (3.15, 5.23) for chronic kidney disease, 5.4 (4.9, 5.8) for neurological disease, 3.61 (2.60, 5.00) for chronic liver disease and 2.66 (1.86, 3.79) for immune deficiency or suppression. 78% of cases and 52% of controls had at least one listed condition (NA of cases and NA of controls under age 40). Severe disease was associated with encashment of at least one prescription in the past nine months and with at least one hospital admission in the past five years [rate ratios 3.10 (2.59, 3.71)] and 2.75 (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 1.25 bits (C-statistic 0.825). A limitation of this study is that records from primary care were not available. ConclusionsAlong 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. Author summaryMost people infected with the SARS-CoV-2 coronavirus do not become seriously ill. It is The risk of severe or fatal illness is higher in older than in younger people, and is higher in people with conditions such as asthma and diabetes than in people without these conditions. Using Scotlands capability for linking electronic health records, we report the first systematic study of the relation of severe or fatal COVID-19 to pre-existing health conditions and other risk factors. We show that the strongest risk factor, apart from age, is residence in a care home. The conditions associated with increased risk include not only those already designated by public health agencies - asthma, diabetes, heart disease, disabling neurological disease, kidney disease - but many other diagnoses, associated with frailty and poor health. This lays a basis for constructing risk scores based on electronic health records that can be used to advise people at high risk of severe disease to shield themselves when there cases in their neighbourhood.