Risk factors for SARS-CoV-2 infection: A test-negative case-control study with additional population controls
Authors: Sarjomaa Marjut , Zhang Chi , Tveten Yngvar , Kersten Hege , Reiso Harald , Eikeland Randi , Kongerud Johny , Berg Kristine Karlsrud , Thilesen Carina , Nordbø Svein Arne , Aaberge Ingeborg S. , Vandenbroucke Jan Paul , Pearce Neil , Møller Fell Anne Kristin 
Published: March 2023

ABSTRACTObjectivesTo assess risk factors for SARS-CoV-2 infection by first comparing positive cases with negative controls as determined by polymerase chain reaction (PCR) testing and then comparing these two groups with an additional population control group.Design and settingTest-negative design (TND), multicentre case-control study with additional population controls in South Eastern Norway.ParticipantsAdults who underwent SARS-CoV-2 PCR testing between February and December 2020. PCR-positive cases, PCR-negative controls, and additional age-matched population controls.Primary outcome measuresThe associations between various risk factors based on self-reported questionnaire and SARS-CoV-2 infection comparing PCR positive cases and PCR-negative controls. Using subgroup analysis, the risk factors were then compared with a population control group. Univariate and multivariate regression analyses were performed.ResultsIn total, 400 SARS-CoV-2 PCR-positive cases, 719 PCR-negative controls, and 14,509 population controls were included. Male sex was associated with the risk of SARS-CoV-2 infection when PCR-positive cases were compared with PCR-negative controls (OR 1.9, 95% CI 1.4 to 2.6). Age, education level, comorbidities (asthma, diabetes, hypertension), an exercise were not associated with the risk of SARS-CoV-2 infection when PCR-positive cases were compared with PCR-negative controls. In the subgroup analysis comparing PCR-positive cases with age-matched population controls, asthma was associated with the risk of SARS-CoV-2 infection (OR 1.6, 95% CI 1.1 to 2.1). Daily or occasional smoking was negatively associated with the risk of SARS-CoV-2 infection in both analyses (OR 0.5, 95% CI 0.3 to 0.8 and OR 0.55, 95% CI 0.35, to 0.82, respectively).ConclusionsMale sex was a possible risk factor, whereas smoking was negatively associated with the risk of SARS-CoV-2 infection, when comparing PCR-positive cases and PCR-negative controls. Asthma was associated with the risk of SARS-CoV-2 infection when PCR-positive cases were compared with population controls.ARTICLE SUMMARYStrengths and limitations of this studyThe test-negative design (TND) was an important strength of this study. The design can reduce confounding from healthcare-seeking bias because PCR-controls are likely to have similar healthcare-seeking attitudes as PCR+ cases.This study mostly included non-hospitalised patients, which can improve the generalisability of the findings to the general public.The use of an additional control group from the general public for comparison with the findings from the test-negative controls provides further information on the similarities and differences in risk factors for COVID-19 and other respiratory tract infections.In the subgroup analyses, PCR+ cases and PCR- controls were compared with the population controls to assess the risk factors for those aged 18–55 years. Hence, the results may not be generalisable to patients older than 55 years.PCR test results, rather than symptoms, were used to categorise the participants into cases or controls, and therefore risk factors for SARS-CoV-2 infection and not COVID-19 disease were assessed.