Does misclassification of former tobacco smokers explain the 'smoker's paradox' in the risk of COVID-19? Insights from the Stockholm Public Health Cohort.

BACKGROUND: The association between tobacco smoking and the risk of COVID-19 and its adverse outcomes is controversial, as studies reported contrasting findings. Bias due to misclassification of the exposure in the analyses of current versus non-current smoking could be a possible explanation because former smokers may have higher background risks of the disease due to co-morbidity. The aim of the study was to investigate the extent of this potential bias by separating non-, former, and current smokers when assessing the risk or prognosis of diseases. METHODS: We analysed data from 43,400 participants in the Stockholm Public Health Cohort, Sweden, with information on smoking obtained prior to the pandemic. We estimated the risk of COVID-19, hospital admissions and death for (a) former and current smokers relative to non-smokers, (b) current smokers relative to non-current smokers, that is, including former smokers; adjusting for potential confounders (aRR). RESULTS: The aRR of a COVID-19 diagnosis was elevated for former smokers compared with non-smokers (1.07; 95% confidence interval (CI) =1.00-1.15); including hospital admission with any COVID-19 diagnosis (aRR= 1.23; 95% CI = 1.03-1.48); or with COVID-19 as the main diagnosis (aRR=1.23, 95% CI= 1.01-1.49); and death within 30 days with COVID-19 as the main or a contributory cause (aRR=1.40; 95% CI=1.00-1.95). Current smoking was negatively associated with risk of COVID-19 (aRR=0.79; 95% CI=0.68-0.91). CONCLUSIONS: Separating non-smokers from former smokers when assessing the disease risk or prognosis is essential to avoid bias. However, the negative association between current smoking and the risk of COVID-19 could not be entirely explained by misclassification.

A population-based cohort study of sex and risk of severe outcomes in covid-19.

There is a male sex disadvantage in morbidity and mortality due to COVID-19. Proposed explanations to this disparity include gender-related health behaviors, differential distribution of comorbidities and biological sex differences. In this study, we investigated the association between sex and risk of severe COVID-19 while adjusting for comorbidities, socioeconomic factors, as well as unmeasured factors shared by cohabitants which are often left unadjusted. We conducted a total-population-based cohort study (n = 1,854,661) based on individual-level register data. Cox models was used to estimate the associations between sex and risk for severe COVID-19. We additionally used a within-household design and conditional Cox models aiming to account for unmeasured factors shared by cohabitants. A secondary aim was to compare the risk of COVID-19 related secondary outcomes between men and women hospitalized due to COVID-19 using logistic regression. Men were at higher risk for hospitalization (HR = 1.63;95%CI = 1.57-1.68), ICU admission (HR = 2.63;95%CI = 2.38-2.91) and death (HR = 1.81;95%CI = 1.68-1.95) due to COVID-19, based on fully adjusted models. However, the effect of sex varied significantly across age groups: Among people in their 50s, men had > four times higher risk of COVID-19 death. The within-household design did not provide any further explanation to the sex disparity. Among patients hospitalized due to COVID-19, men had an increased risk for viral pneumonia, acute respiratory distress syndrome, acute respiratory insufficiency, acute kidney injury, and sepsis which persisted in fully adjusted models. Recognition of the combined effect of sex and age on COVID-19 outcomes has implications for policy strategies to reduce the adverse effects of the disease.

HMG-CoA reductase inhibitors and COVID-19 mortality in Stockholm, Sweden: A registry-based cohort study.

BACKGROUND: The relationship between statin treatment and Coronavirus Disease 2019 (COVID-19) mortality has been discussed due to the pleiotropic effects of statins on coagulation and immune mechanisms. However, available observational studies are hampered by study design flaws, resulting in substantial heterogeneity and ambiguities. Here, we aim to determine the relationship between statin treatment and COVID-19 mortality. METHODS AND FINDINGS: This cohort study included all Stockholm residents aged 45 or older (N = 963,876), followed up from 1 March 2020 until 11 November 2020. The exposure was statin treatment initiated before the COVID-19-pandemic, defined as recorded statin dispensation in the Swedish Prescribed Drug Register between 1 March 2019 and 29 February 2020. COVID-19-specific mortality was ascertained from the Swedish Cause of Death Registry. Hazard ratios (HRs) were calculated using multivariable Cox regression models. We further performed a target trial emulation restricted to initiators of statins. In the cohort (51.6% female), 169,642 individuals (17.6%) were statin users. Statin users were older (71.0 versus 58.0 years), more likely to be male (53.3% versus 46.7%), more often diagnosed with comorbidities (for example, ischemic heart disease 23.3% versus 1.6%), more frequently on anticoagulant and antihypertensive treatments, less likely to have a university-level education (34.5% versus 45.4%), and more likely to have a low disposable income (20.6% versus 25.2%), but less likely to reside in crowded housing (6.1% versus 10.3%). A total of 2,545 individuals died from COVID-19 during follow-up, including 765 (0.5%) of the statin users and 1,780 (0.2%) of the nonusers. Statin treatment was associated with a lowered COVID-19 mortality (adjusted HR, 0.88; 95% CI, 0.79 to 0.97, P = 0.01), and this association did not vary appreciably across age groups, sexes, or COVID-19 risk groups. The confounder adjusted HR for statin treatment initiators was 0.78 (95% CI, 0.59 to 1.05, P = 0.10) in the emulated target trial. Limitations of this study include the observational design, reliance on dispensation data, and the inability to study specific drug regimens. CONCLUSIONS: Statin treatment had a modest negative association with COVID-19 mortality. While this finding needs confirmation from randomized clinical trials, it supports the continued use of statin treatment for medical prevention according to current recommendations also during the COVID-19 pandemic.