Evaluation of diagnostic test procedures for SARS-CoV-2 using latent class models: comparison of antigen test kits and sampling for PCR testing based on Danish national data registries (preprint)

Antigen test kits have been used extensively as a screening tool during the worldwide pandemic of coronavirus (SARS-CoV-2). While it is generally expected that taking samples for analysis with PCR testing gives more reliable results than using antigen test kits, the overall sensitivity and specificity of the two protocols in the field have not yet been estimated without assuming that the PCR test constitutes a gold standard. We use latent class models to estimate the in situ performance of both PCR and antigen testing, using data from the Danish national registries. The results are based on 240,000 paired tests results sub-selected from the 55 million test results that were obtained in Denmark during the period from February 2021 until June 2021. We found that the specificity of both tests is very high in our data sample (>99.7%), while the sensitivity of PCR sampling was estimated to be 95.7% (95% CI: 92.8-98.4%) and that of the antigen test kits used in Denmark over the study period was estimated at 53.8% (95% CI: 49.8-57.9%). Our findings can be used as supplementary information for consideration when implementing serial testing strategies that employ a confirmatory PCR sample following a positive result from an antigen test kit, such as the policy used in Denmark. We note that while this strategy reduces the number of false positives associated with antigen test screening, it also increases the false negatives. We demonstrate that the balance of trading false positives for false negatives only favours the use of serial testing when the expected true prevalence is low. Our results contain substantial uncertainty in the estimates for sensitivity due to the relatively small number of positive test results over this period: validation of our findings in a population with higher prevalence would therefore be highly relevant for future work.

A nationwide study of Chlamydia trachomatis infections in Denmark during the COVID-19 pandemic (preprint)

Objectives: COVID-19 policies have been employed in Denmark since March 2020. We examined whether COVID-19 restrictions had an impact on Chlamydia trachomatis infections compared with 2018 and 2019. Methods: This retrospective nation-wide Danish observational study was performed using monthly incidences of laboratory confirmed chlamydia cases and number of tests, obtained from nation-wide surveillance data. Additionally, Oxford COVID-19 Government Response Tracker data, and Google COVID-19 Community Mobility Reports were used to contextualise the behavioural adaptions seen as a result of COVID-19 policies. Testing rates were compared using Poisson regression and test positivity rates were compared using logistic regression. Results: The crude incidence rate (IR) of laboratory confirmed chlamydia infections was reduced to 66.5 per 105 during the first (March-April 2020) lockdown period as compared to 88.3 per 105 in March-April 2018-2019, but the testing rate was also reduced (Rate ratio 0.72 95% CI 0.71-0.73), whereas the odds ratio for a positive test between the two periods was 0.98 (95% CI 0.96-1.00). The period of eased COVID 19 restrictions (May-December 2020) and the second lockdown period (December 2020-March 2021) were characterised by marginally increased crude IRs, while the number of tests performed, and test positivity rates returned very close to the levels seen in 2018-2019. These results were independent of sex, age group, and geographical location. Conclusion: The first Danish COVID-19 lockdown resulted in a reduction in the number of chlamydia tests performed and a consequent reduction in the number of laboratory-identified cases. This period was followed by a return of testing and test positivity close to the level seen in 2018-2019. Altogether the Danish COVID-19 restrictions have had negligible effects on laboratory confirmed C. trachomatis transmission.

Increased Transmissibility of SARS-CoV-2 Lineage B.1.1.7 by Age and Viral Load: Evidence from Danish Households (preprint)

Aim The aim of this study was to estimate the household transmissibility of SARSCoV-2 for lineage B.1.1.7 compared with other lineages, by age and viral load. Furthermore, we wanted to estimate whether there is a multiplicative or additive effect of the increased transmissibility of B.1.1.7 compared with other lineages. Background New lineages of SARS-CoV-2 are of potential concern due to higher transmissibility, risk of severe outcomes, and/or escape from neutralizing antibodies. Lineage B.1.1.7 has been estimated to be more transmissible than other previously known lineages, but the association between transmissibility and risk factors, such as age of primary case and viral load is still unknown. Methods We used comprehensive administrative data from Denmark, comprising the full population, all SARS-CoV-2 RT-PCR tests, and all WGS lineage data (January 11 to February 7, 2021), to estimate household transmissibility stratified by lineage B.1.1.7 and other lineages. Results We included 5,241 households with primary cases; 808 were infected with SARS-CoV-2 lineage B.1.1.7 and 4,433 were infected with other lineages. The attack rate was 38% in households with a primary case infected with B.1.1.7 and 27% in households with a primary case infected with other lineages. Primary cases infected with B.1.1.7 had an increased transmissibility of 1.5-1.7 times that of primary cases infected with other lineages. The increased transmissibility of B.1.1.7 was multiplicative across age and viral load. Conclusions The results found in this study add new knowledge that can be used to mitigate the further spread of SARS-CoV-2 lineage B.1.1.7, which is becoming increasingly widespread in numerous countries. Our results clarify that the transmissibility of B.1.1.7 should be included as a multiplicative effect in mathematical models used as a tool for decision makers. The results may have important public health implications, as household transmission may serve as a bridge between otherwise separate transmission domains, such as schools and physical workplaces, despite implemented non-pharmaceutical interventions.

Increased Risk of Hospitalisation Associated with Infection with SARS-CoV-2 Lineage B.1.1.7 in Denmark (preprint)

Background: The more infectious SARS-CoV-2 virus lineage B.1.1.7, rapidly spread in Europe after December 2020, and a concern of B.1.1.7 causing more severe disease has been raised. Denmark has one of Europe´s highest capacities per capita of SARS-CoV-2 reverse transcription polymerase chain reaction (RT PCR) test and whole genome sequencing (WGS). We used national health register-data to explore whether B.1.1.7 increases the risk of COVID-19 hospitalisation. Methods and Findings: In an observational cohort study we included all SARS-CoV-2 RT PCR test-positive individuals in Denmark sampled between the 1st January and until the 9th February, 2021, identified in the national COVID-19 surveillance system. The surveillance system includes national individual RT PCR test results and viral WGS analyses and data from national health registers including COVID-19 related hospital admissions defined as first admission within 14 days of the test-positive swab. The odds ratio (OR) of admission according to infection with B.1.1.7, vs other co-existing lineages, was calculated in a logistic regression model adjusted for sex, age, period, follow-up time less than 14 days, region, and comorbidities. A total of 35,887 test-positive individuals were identified, 23,057 (64%) had WGS performed, of whom 18,499 (80%) resulted in a viral genome and a total of 2,155 of these were lineage B.1.1.7. The proportion of individuals with B.1.1.7 increased from 4% in early January to 45% in early February. Among the individuals with viral genome data, B.1.1.7 was associated with a crude OR of admission of 0.87 (95%CI, 0.72-1.05) and an adjusted OR of 1.64 (95%CI, 1.32-2.04) based on 128 admissions after B.1.1.7 infection and 1,107 admissions after infection with other lineages. The adjusted OR was increased in all strata of age and calendar time - the two most important confounders of the crude OR. Conclusions: Infection with lineage B.1.1.7 was associated with an increased risk of hospitalisation compared with other lineages. This finding may have serious public health impact in countries with spread of B.1.1.7 and can support hospital preparedness and modelling of projected impact of the epidemic.Funding Statement: The authors received no specific funding for this work.Declaration of Interests: The authors declare that they have no competing interest.Ethics Approval Statement: This study was conducted on administrative register data. According to Danish law, ethics approval is not needed for such research.

Characteristics and predictors of hospitalization and death in the first 9,519 cases with a positive RT-PCR test for SARS-CoV-2 in Denmark: A nationwide cohort (preprint)

ObjectiveTo provide population-level knowledge on individuals at high risk of severe and fatal coronavirus disease 2019 (COVID-19) in order to inform targeted protection strategies in the general population and appropriate triage of hospital contacts. Design, Setting, and ParticipantsNationwide population-based cohort of all 228.677 consecutive Danish individuals tested (positive or negative) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA from the identification of the first COVID-19 case on February 27th, 2020 until April 30th, 2020. Main Outcomes and MeasuresWe examined characteristics and predictors of inpatient hospitalization versus community-management, and death versus survival, adjusted for age-, sex- and number of comorbidities. ResultsWe identified 9,519 SARS-CoV-2 PCR-positive cases of whom 78% were community-managed, 22% were hospitalized (3.2% at an intensive care unit) and 5.5% had died within 30 days. Median age varied from 45 years (interquartile range (IQR) 31-57) among community-managed cases to 82 years (IQR 7589) among those who died. Age was a strong predictor of fatal disease (odds ratio (OR) 14 for 70-79-year old, OR 26 for 80-89-year old, and OR 82 for cases older than 90 years, when compared to 50-59-year old and adjusted for sex and number of comorbidities). Similarly, the number of comorbidities was strongly associated with fatal disease (OR 5.2, for cases with [≥]4 comorbidities versus no comorbidities), and 82% of fatal cases had at least 2 comorbidities. A wide range of major chronic diseases were associated with hospitalization with ORs ranging from 1.3-1.4 (e.g. stroke, ischemic heart disease) to 2.2-2.7 (e.g. heart failure, hospital-diagnosed kidney disease, chronic liver disease). Similarly, chronic diseases were associated with mortality with ORs ranging from 1.2-1.3 (e.g. ischemic heart disease, hypertension) to 2.4-2.7 (e.g. major psychiatric disorder, organ transplantation). In the absence of comorbidities, mortality was relatively low (5% or less) in persons aged up to 80 years. Conclusions and RelevanceIn this first nationwide population-based study, increasing age and number of comorbidities were strongly associated with hospitalization requirement and death in COVID-19. In the absence of comorbidities, the mortality was, however, lowest until the age of 80 years. These results may help in accurate identification, triage and protection of high-risk groups in general populations, i.e. when reopening societies.