key: cord-0930933-2ba66rkv authors: Julin, C. H.; Robertson, A. H.; Hungnes, O.; Tunheim, G.; Bekkevold, T.; Laake, I.; Aune, I. F.; Rykkvin, R.; Dorenberg, D. H.; Stene-Johansen, K.; Berg, E. S.; Steens, A.; Naess, L. M. title: Household transmission of SARS-CoV-2 in Norway; a prospective, longitudinal study showing increased transmissibility of the Alpha variant (B.1.1.7) compared with other variants date: 2021-08-18 journal: nan DOI: 10.1101/2021.08.15.21261478 sha: ad0c75ad0a486ed58fddf9a4596054aa37607d40 doc_id: 930933 cord_uid: 2ba66rkv ABSTRACT Background We studied the secondary attack rate (SAR), risk factors, and precautionary practices of household transmission in a prospective longitudinal study. Moreover, we compared household transmission between the Alpha (B.1.1.7) variant and non-variants of concern (non-VOCs). Methods We recruited households of confirmed COVID-19 cases from May 2020 to May 2021. Households received 8 home visits over 6 weeks. Biological samples and questionnaire data were collected. Results We recruited 70 confirmed COVID-19 cases and 146 household contacts. Transmission occurred in 60% of the households; the overall SAR for household contacts was 49.6%. The SAR was significantly higher for the Alpha variant (77.8%) compared with non-VOC variants (42.5%) and was associated with a higher viral load. SAR was higher in household contacts aged [≥]40 years (64%) than in younger contacts (40-47%), and for contacts of cases with loss of taste/smell. Close contact prior to confirmation of infection tended to give a higher SAR. A significantly lower SAR was found for sleeping separately from the primary case after confirmation of infection. Conclusion We found substantial household transmission, particularly for the Alpha variant. Precautionary practices seem to reduce SAR; however, prevention of transmission within households may become difficult with more transmissible variants. BACKGROUND SARS-CoV-2, the virus that causes the respiratory disease COVID-19, was first detected in China in 2019 and spread rapidly throughout the world. In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic. Households appear to be one of the most important sites of transmission in Norway [1] , as well as in other countries [2] . It is therefore important to identify risk factors for household transmission and precautionary practices to contain the epidemic. Moreover, secondary attack rate (SAR) calculated from household studies provides an important measure of the transmissibility of SARS-CoV-2. Initial household transmission studies have mainly described transmission of the SARS-CoV-2 variants dominating in the early phase of the pandemic or have not described the genetic variant(s). The Alpha variant/variant of concern (VOC) 202012/01 (Pango lineage B.1.1.7) rapidly outcompeted other SARS-CoV-2 lineages in the UK after its emergence in November 2020 [3, 4] . The first confirmed case of the Alpha variant in Norway was reported in December 2020, and from mid-February 2021 it has been the dominant variant [1] . Even though increased transmissibility of the Alpha variant has been shown [5] [6] [7] , knowledge is still sparse regarding how it affects the SAR in households. We conducted a prospective longitudinal household study to investigate the household SAR in Norway, and to identify risk factors for transmission within these households, using frequent testing and biological sampling, together with questionnaire data. Close follow-up and systematic data collection allowed for determination of the role of viral load in transmission. Moreover, we compared the SAR for the Alpha variant with the SAR for other circulating variants in Norway during the study period. This prospective longitudinal study was designed based on the WHO Household Transmission Investigation protocol [8] . From May to June 2020, and from September 2020 to May 2021, we recruited households of confirmed COVID-19 cases in the capital Oslo and the surrounding county Viken. The course of the pandemic in Oslo/Viken, and of recruitment in this period, are shown in Figure 1A and Figure 1B , respectively. All households with a PCR-confirmed SARS-CoV-2 case aged ≥ 12 years, living with at least one other person aged ≥ 2 years, were eligible for participation. To avoid recruitment of households with co-primary cases, households with more than two members who tested positive on the same date were not eligible, unless the transmission dynamics were known. A further exclusion criterion was added when COVID-19 vaccines became available, whereby households with vaccinated individuals were not eligible. Primary cases and their household contacts were identified by the municipalities' infection control teams following a positive PCR test and were subsequently contacted by the study team. Households willing to participate were visited at home, and written informed consent was obtained from the participants and/or their guardians before study inclusion. The study was approved by the Regional Ethics Committee in Norway (#118354). According to the Norwegian COVID-19 regulations, isolation was mandatory for persons with confirmed COVID-19. The isolation should be implemented at home or similar for at least 8-10 days after symptom debut (recommendations varied throughout the study period), lasting at least three days after symptom relief. Asymptomatic cases had to isolate for 10 days after their initial PCR confirmation. In isolation, positive cases were instructed to stay ≥ 2 meters from other household members, use separate bathrooms, towels, and bedrooms if possible. Household contacts were instructed to quarantine in their homes, maintaining an increased distance to other adults in the household. The first home visit for inclusion and sampling was termed Day0, and seven further home visits for sampling were performed during the following 6 weeks (i.e. Day3, Day7, Day10, Day14, Day21, Day28, and Day42) (Supplementary Figure 1) . Oropharyngeal (OP) samples and neat saliva samples were gathered from eligible participants on each visit to test for SARS-CoV-2 by RT-PCR. Health care workers collected OP samples using OP flocked swabs (FLOQSwabs™Copan, Italy), in 3 ml UTM (Universal Transport Medium, Copan Italy). Whole blood (Vacuette®EDTA-k2) was collected once for each participant aged ≥ 18 years for blood typing. Saliva and blood for immunological analyses were also collected at Day0, Day7, Day14, Day28, Day42 and Day180 (results not presented in this paper). All participants were asked to answer a questionnaire on Day0 (Q-D0), to obtain information about the household in general, transmission risk factors, clinical symptoms, and general health status. This questionnaire was adapted from the WHO protocol. The questions on behavioral risk factors in the Q-D0 related to the period up to 10 days prior to SARS-CoV-2 confirmation of the primary case, and precautionary practices after confirmation. An additional questionnaire (Q-DX) asking about the suspected source of transmission, adherence to isolation/quarantine regulations and self-report of the severity of disease, was answered by participants at the home visit on Day28/Day42 or collected through phone interviews. In addition, a symptom diary adapted from the WHO protocol was completed daily from Day0 to Day28 by all participants. All OP and saliva samples were tested for the presence of SARS-CoV-2 at the National Reference Laboratory for influenza and coronaviruses with outbreak potential at the Department of Virology at the NIPH, Oslo. Reverse transcriptase-based droplet digital PCR (ddPCR) testing was performed for absolute quantification of viral load on the first SARS-CoV-2 positive saliva sample for all participants, if sufficient material was available. Amplicon-based next-generation sequencing (NGS) of SARS-CoV-2 was performed at the Norwegian Sequencing Centre (NSC). See Supplementary Methods for details about laboratory procedures. Household contacts were defined as individuals aged ≥ 2 years who resided with the primary case. A household contact was considered a secondary case if they had a positive PCR test, and their symptom onset/PCR positive test (which ever came first; defined as T0) was within 14 days after T0 of the primary case. If a household contact had a T0 ≥ 2 days prior to T0 of the original primary case, the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 18, 2021. ; https://doi.org/10.1101/2021.08.15.21261478 doi: medRxiv preprint household contact was defined as alternative primary case. If household members had the same T0, or +/-1 day, they were re-defined as co-primary cases, unless the original primary case had a known source of infection outside of the household. For the main overall SAR analysis, households containing co-primary cases were excluded. Households with alternative primary cases were included in the overall SAR analysis but excluded from the analysis on behavioral factors and preventive measures due to lacking data from the Q-D0 questionnaire ( Figure 2 ). For comparisons between genetic variants, households with the Alpha VOC lineages were compared with non-VOC variants [9] , while households with other VOCs were excluded from the analyses (one household with the Beta variant). One household contact lacked variant data and was assigned the same variant as the primary case. The SAR was estimated as the proportion (%) of household contacts that were defined as confirmed cases [8] . Cluster robust standard errors were used to calculate 95% confidence intervals. The proportion of households with secondary transmission was also estimated. To test for differences in proportions, the Pearson chi-square test statistics was corrected with the second-order correction of Rao and Scott and converted into an F statistic [10] . To account for dependencies within households, a mixed-effect logistic regression model with a household-level random intercept was used to study the associations between potential risk factors for transmission and of infection among the household contacts. The multivariable models were adjusted for age and sex of the household contacts and of the primary cases, and household size. Analysis on associations between ddPCR (log10-values) and symptoms was limited to the confirmed cases using a mixed-effect logistic regression adjusted for age and sex, and logistic regression for primary cases only. To study the association between genetic variant and ddPCR (log10-values) viral load, a mixedeffect linear regression adjusted for age and sex was used. All analyses were performed in STATA/SE 15.0 (StataCorp. College Station, Texas USA). A p-value of <0.05 was considered statistically significant (shown in bold in the tables). We recruited 70 households, including 216 participants ( Figure 2 ). Ninety eight percent of eligible household members agreed to participate in the study. A total of 65 primary cases/households and their 135 household contacts (200 participants) were eligible for the evaluation of secondary transmission. Among the 65 households, 18 of the primary cases were infected with the Alpha variant, one with the Beta variant and 40 with other circulating non-VOC variants (Supplementary Table S1 ). Households with the Alpha variant were recruited between March and May 2021, while households with non-VOC variants were mainly recruited before February 2021, reflecting the viral circulation in the study area during the recruitment period (Supplementary Figure 2) . Sequence data showed the same genetic lineage for all sequenced members within individual households. Demographic and clinical characteristics of the participants in the SAR analyses are shown in Table 1 . The median age of the participants was 31 years, and primary cases were generally older than household contacts (38 and 24 years, respectively). About 1/3 rd of the participants were children aged <18 years, while only All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 18, 2021. ; https://doi.org/10.1101/2021.08.15.21261478 doi: medRxiv preprint six were older than 65. The proportion of males and females was equal, and 51% were of Nordic ethnicity (but there was considerable missing data for this variable). The median household size was four, ranging from two to six people, and families with young children constituted about 45% of the households. The household size was slightly smaller in households where participants were infected with the Alpha genetic variant (median = 3), compared with households infected with non-VOC variants (median = 4). The remaining characteristics were broadly similar between these two groups. Of the 200 participants 132 (66%) were infected. Fourteen percent of the confirmed cases were asymptomatic, while 43% had mild disease and 42% had a moderate disease, based on their reported symptoms within 14 days of their first positive PCR sample. Few study participants were hospitalized (discharged the following day). There were slightly more asymptomatic cases (22%) among the Alpha variant participants compared with participants with non-VOC variants (9%) (p=0.09) (Supplementary Table S2 ). Severity also varied with age, with 36% of children (<18 years) being asymptomatic compared to 8% of adults (p<0.01) Secondary transmission occurred in 60% of the households in the study (95% CI, 47.4-71.4; Table 2 ). The secondary attack rate (SAR) among all household contacts was 49.6% (95% CI, 37.8-61.5). Secondary transmission was significantly higher in households with the Alpha variant (83.3%, 95%CI, 55.9%-95.2%) compared with non-VOC variants (55.0%, 95% CI 39.8%-70.1%), (p=0.04). For household contacts, SAR was 77.8% (95% CI 49.4-92.6) in households with the Alpha variant, compared with 42.5% (95% CI 28.7-57.7) in households with non-VOC variants, resulting in a significantly higher adjusted odds ratio (OR) for secondary transmission in households with the Alpha variant (p=0.03) ( Table 2) . Neither age nor sex of the primary case appeared to have an impact on SAR (Table 3) . Household contacts aged ≥ 40 years were more likely to be infected (SAR 69%), compared with those aged 2-17 (47%) or 18-39 (40%) ( Table 3 ). The sex and blood type of the household contacts did not impact the infection risk. Household contacts living in overcrowded houses had a higher infection risk than those not living in overcrowded houses (SAR 90%, and 52%, respectively) but the difference was not significant when adjusted for age, sex and household size (note that the exposed group was small). Secondary transmission did not differ with household size, type of dwelling or number of bathrooms in the household. Both fever and loss of taste/smell were significantly more common in primary cases with the Alpha variant compared to others (Supplementary Table S3 ). Hence the SAR was higher if these symptoms were present (Table 4 ). If the primary case reported loss of taste/smell, the SAR was 60% versus 27%, and there was a similar trend for fever (61% versus 39%), and a weak trend for cough. Dyspnea in the primary case did not appear to influence the SAR, nor clinical severity. Viral RNA copy number determined by ddPCR was significantly correlated with the RT-PCR CTvalues (r = -0.659, p < 0.001). There was a trend that viral load was associated with secondary infection risk (adjusted OR 2.84 (95% CI 0.81-9.93), p=0.10). Higher viral load was also associated with increased risk of loss of taste/smell (adjusted OR = 1.39 (95% CI 1.05-1.83), p=0.02), and possibly dyspnea (OR = 1.15 (95%CI 0.99-1.34, p=0.07) and cough (adjusted OR = 1.15 (95%CI 0.97-1.37), p=0.11) (Supplementary Table S4 ). However, despite an OR larger than 1, this association All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not significant when looking at only the primary cases, possibly because of the lower sample size. The viral load was higher for the alpha variant than for non-VOC variants (mean 3.18 log 10 RNA copies/µl and 2.47 log 10 RNA copies/µl respectively), also when stratified according to age group (Supplementary Table S5 ). The association between viral load and the alpha variant was also significant when adjusting for age and sex in a mixed-effect linear regression model (adjusted regression coefficient of 0.82 (95% 0.30-1.34), p= 0.002). The median interval from the date of the first positive SARS-CoV-2 test (collected by the municipality for the primary case) and the Day0 visit in the study was 3 days (IQR; 2-4 days). A large proportion of the secondary cases (38.5%) were already infected at Day0, while 61.5% of the secondary cases were detected during study follow-up. The overall serial interval (the number of days between symptom onset of the primary case and a household contact) was estimated to 4 days (range 1-11, n=50). The median serial interval was similar for the Alpha variant (4 days, range 2-11, n=17) and non-VOC variants (4 days, range 1-9 days, n=31). The overall median interval between symptom onset of the primary case and the first RT-PCR-positive test of a household contact was 3 days (range 1-12, n=60), and this interval was the same for Alpha (3 days, range 1-11, n=25) and non-VOC variants (4 days, range 1-9 days, n=33). None of the contact behaviors between the primary case and the household contacts prior to confirmation of infection of the primary case were significantly associated with SAR (Table 5) . Nevertheless, there was a trend that the SAR was higher for contacts who shared a toilet, hugged, kissed, shook/ held hands, slept in the same room and shared a bed with the primary case before infection was confirmed. After confirmation of the infection of the primary case, the only precautionary practice to significantly prevent household transmission was sleeping separately from the primary case, with a SAR of 67%, compared to 38% for those who slept separately (adjusted OR, p=0.048) ( Table 5 ). All other precautionary practices seemed to lower the SAR to a certain degree, particularly isolation of the primary case, but associations were not statistically significant. This prospective longitudinal household study with close follow-up and systematic sampling shows a high overall SAR (49.6%), confirming that households are an important site of transmission. The SAR of the Alpha variant (B.1.1.7 VOC) was significantly higher, at 77.8%, compared with 42.5% for the other non-VOCs dominating in Norway until Feb/March 2021. A significantly higher viral load was found in participants with the Alpha variant, which may partly contribute to the increased transmissibility. Close contact behavior prior to confirmation of infection of the primary case tended to give a higher SAR, though not statistically significant. However, we showed that SAR was reduced if the primary case was isolated from the rest of the household after confirmation of infection, including sleeping in a separate room. Our SAR estimate for non-VOC variants was higher than previous estimates of 16.6% [2] and 17.1% [11] reported in two reviews based on studies from the first months of the epidemic. However, our estimate is in accordance with the 37% found in a prospective study performed in the UK in the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 18, 2021. ; https://doi.org/10.1101/2021.08.15.21261478 doi: medRxiv preprint beginning of 2020 [12] , even though they also included probable secondary cases not confirmed by RT-PCR. A household study from Norway in the spring of 2020 reported a SAR of 47% based on RT-PCR and seroconversion [13] . Similar high SARs were found in the US (53%) and the Netherlands (51% in adults, 35% in children) [14, 15] . A recent Norwegian national register based study found a considerably lower household SAR of only 21% [16] . The discrepancy with our SAR might be due to register-based studies being sensitive to underreporting of cases, as it is not mandatory to test all household members. In particular, parents may hesitate to test children because of discomfort with nasopharyngeal swabbing. Indeed, Fung et al. [11] showed that studies that tested household members more frequently observed higher SARs. None of the aforementioned studies performed sequencing of positive virus samples or viral quantitation, and most were performed before the Alpha strain appeared. The Alpha variant has been shown to be generally more transmissible than non-VOC variants [6, 17] and the current study demonstrate this in a household setting. Our finding of a significantly higher SAR for the Alpha variant compared with previous non-VOC variants, is in agreement with a Canadian household study by Buchan et al. [18] . This study found a lower SAR than our study for both Alpha variant and wildtype (25.1% and 20.2%, respectively); probably due to their retrospective study design. A case-control study from Oslo, Norway, conducted in March 2021 during the period of Alpha variant dominance found that approximately 40% of SARS-CoV-2 infections among adults aged 18-70 years occurred within their households. Other household studies where variant-specific SARs have been determined [19, 20] , have been based on register data; which, as described, may generate smaller SARs. In our study, extensive testing over several weeks, including testing of small children probably enabled identification of most infected cases in the households, and thus contributed to our higher SAR estimates both overall and for the Alpha variant. We found no difference between the median serial interval for the Alpha variant and the non-VOC variants, which is in accordance with other studies [21] . Household contacts aged ≥ 40 years had increased risk of secondary infection. This is in accordance with previous findings [11] . The SAR has generally been reported to be lower in children than adults [2, 15] , but we did not observe such a difference. This could be due to the repeated testing of children regardless of symptoms in our study. We found that primary cases experiencing loss of taste/smell, a distinctive feature of COVID-19 [22] was associated with a significant increase in SAR, possibly due to the observed increase in viral load in participants reporting loss of taste/smell. The association between taste/smell impairment and higher viral load has also been found by others [23, 24] . This may be dependent on variant, as we found that loss of taste/smell was more common amongst primary cases with the alpha variant. None of the contact behaviors between the primary case and the household contacts prior to confirmed infection significantly increased the chance of being infected, however most contact behavior such as kissing, slightly increased the odds of secondary transmission. We found that not sleeping in the same room as the primary case after confirmation of infection prevented secondary infection, as shown previously [25] . Other measures reducing contact with the primary case, especially isolation, also seemed to lower secondary transmission. Although we observed that a high fraction of the transmission had already occurred quite early, our findings thus confirm the importance of starting precautionary practices after infection. The present study has several limitations. First, we did not design the study to evaluate differences in SAR between the Alpha variant and other non-VOC variants. Thus, the data presented regarding this All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 18, 2021. ; https://doi.org/10.1101/2021.08.15.21261478 doi: medRxiv preprint difference is observational, as the dominance of the variants differed during the study period. We can therefore not exclude that climate, people's behavior, or other factors, could have influenced our results. Quarantine and isolation guidelines were similar throughout the whole study period, thus we assume that this has not significantly influenced our results. Second, our sample size was small, which complicated the comparison between factors associated with the Alpha variant and other variants. Third, the age span of participants was limited, with few elderly individuals and mostly adult primary cases, although this may reflect the demographics in the study area. In conclusion, in this prospective longitudinal household study, we found an overall secondary attack rate for household contacts of 49.6%. The SAR was even higher for the Alpha variant, indicating a very high level of household transmission for this VOC. Implementation of precautionary measures in households after SARS-CoV-2 has been detected seem to reduce household transmission, but with more transmissible variants emerging, preventing transmission within a household will become increasingly difficult. Our results emphasize the role of households in the transmission of SARS-CoV-2 in the Norwegian population and the importance of strict adherence to the isolation and quarantine regulations in all households with a confirmed case. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 18, 2021. ; https://doi.org/10.1101/2021.08.15.21261478 doi: medRxiv preprint All authors declare no conflict of interest This research was solely funded by the Norwegian Institute of Public Health (NIPH) and received no specific grant from any funding agency, commercial or not-for-profit sectors. The results have not been presented at any scientific meetings. Lisbeth Meyer Naess, MSc, PhD (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Abbreviations: HH contact, household contact a recruited participants were tested for SARS-CoV-2 (PCR) and provided information on symptom onset (Q-D0 questionnaire) b includes household contacts that were SARS-CoV-2 negative c non-VOC: non-variant of concern COVID-19 Ukesrapport -uke 14 Household Transmission of SARS-CoV-2: A Systematic Review and Meta-analysis Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations Investigation of novel SARS-COV-2 variant Variant of Concern 202012/01. Public Health England Estimating the elevated transmissibility of the B.1.1.7 strain over previously circulating strains in England using GISAID sequence frequencies Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: Insights from linking epidemiological and genetic data Household transmission investigation protocol for 2019-novel coronavirus (COVID-19) infection European Centre for Disease Prevention and Control (ECDC) On Chi-Squared Tests for Multiway Contingency Tables with Cell Proportions Estimated from Survey Data The household secondary attack rate of SARS-CoV-2: A rapid review Transmission dynamics of COVID-19 in household and community settings in the United Kingdom Attack rates amongst household members of outpatients with confirmed COVID-19 in Bergen, Norway: A case-ascertained study Transmission of SARS-COV-2 Infections in Households -Tennessee and Wisconsin High infection secondary attack rates of SARS-CoV-2 in Dutch households revealed by dense sampling Secondary attack rates of COVID-19 in Norwegian families: a nation-wide register-based study Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England Increased household secondary attacks rates with Variant of Concern SARS-CoV-2 index cases Comparative Household Secondary Attack Rates associated with B.1.1.7, B.1.351, and P.1 SARS-CoV-2 Variants Increased Transmissibility of SARS-CoV-2 Lineage B.1.1.7 by Age and Viral Load: Evidence from Danish Households Serial interval of COVID-19 and the effect of Variant B.1.1.7: analyses from a prospective community cohort study (Virus Watch) The Prevalence of Olfactory and Gustatory Dysfunction in COVID-19 Patients: A Systematic Review and Meta-analysis Is there a correlation between viral load and olfactory & taste dysfunction in COVID-19 patients? Acute onset olfactory/taste disorders are associated with a high viral burden in mild or asymptomatic SARS-CoV-2 infections SARS-CoV-2 seroprevalence and transmission risk factors among high-risk close contacts: a retrospective cohort study We want to thank all the participants who willingly let us into their homes and provided frequent samples over a long period of time. We also want to acknowledge the following; our health care workers who visited and sampled all the participants (Marit F. Killengren, Torunn R. Strand, Hena Anawar, Christina Nitschke, Kristina Maudal); the head of Section for Influenza, Karoline Bragstad, as well as the coordinators, technicians and bioinformaticians at the Department of Virology, the Department of Bacteriology, the Reception of Biological Samples, the engineers at the Department of Method Development and Analytics; the municipalities' infection control teams in Oslo/Viken for their contribution to recruitment of participants; WHO for developing the protocol which formed the basis for the study. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.