Can self-testing be enhanced to hasten safe return of healthcare workers in pandemics? Random order, open label trial using two manufacturers' SARS-CoV-2 lateral flow devices concurrently (preprint)

ObjectivesTo inform management of competing risks from Covid-19 and key-worker absence, we evaluated whether using two manufacturers lateral flow tests (LFTs) concurrently improved SARS-CoV-2 Omicron detection and was acceptable to hospital staff. In a nested study, to understand the risks of return to work after a fixed number of days of isolation or quarantine, we examined virus culture at Days 5-7 after positive test or significant exposure. Methods and Analysis1419 fully-vaccinated Liverpool (UK) University Hospitals staff participated in a random-order, open-label trial testing whether dual LFTs improved SARS-CoV2 detection, and whether dual swabbing was acceptable to users. Main outcome was self-reported LFT result. Staff enrolled via routine testing sites for symptomatic staff and close contacts. Recruitment took place between 7th February and 8th May 2022. Participants employed nose-throat swab Innova and nose-only swab Orient Gene LFTs for 10 days, with daily LFTs taken in random order. A swab for polymerase chain reaction (PCR) analysis was taken at Day-5 and, if positive, Day-10. A questionnaire on acceptability was administered on exit. Selected participants gave swabs for viral culture on Days 5-7; swabs were delivered and returned by courier. Cultures were considered positive if cytopathic effect was apparent or the SARs-COV2 N gene sub-genomic RNA was detected by sequencing. Results226 individuals reported 1466 pairs of LFT results. Tests disagreed in 127 cases (8.7%). Orient Gene was more likely (78 cf. 49, P=0.03) to be positive. Orient Gene positive Innova negative result-pairs became more frequent over time (P<0.001). If Innova was swabbed second, it was less likely to agree with a positive Orient Gene result (P=0.005); swabbing first with Innova made no significant difference (P=0.85). Of 311 individuals completing the exit questionnaire, 90.7% reported dual swabbing was easy, 57.1% said it was no barrier to their daily routine and 65.6% preferred dual testing. Respondents had more confidence in dual c.f. single test results (median 9 cf. 8 on 10-point scale, P<0.001). Viral cultures from swabs taken at Days 5-7 were positive for 6/31 (19.4%, 7.5%-37.5%) and indeterminate for 11/31 (35.5%, 19.2%-54.6%) LFT-positive participants, indicating they were likely still infectious. ConclusionsDual brand testing increased LFT detection of SARS-CoV-2 antigen by a small but meaningful margin and was acceptable to hospital workers. Viral cultures demonstrated that policies recommending safe return to work [~]5 days after Omicron infection/exposure were flawed. Key-workers should be prepared for dynamic self-testing protocols in future pandemics. Trial registrationhttps://www.isrctn.com/ISRCTN47058442 (IRAS Project ID:311842) Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIOmicron BA.1 and BA.2 waves caused large-scale healthcare worker absence in late 2021 - early 2022, risking patient safety from both Covid-19 and reduced care capacity C_LIO_LILateral flow tests (LFTs) reliably detected SARS-CoV-2 antigen, more so with Omicron than prior variants, identifying the most infectious individuals C_LIO_LISelf-testing with LFT SARS-CoV-2 rapid antigen tests reduced Covid-19 transmission, mitigating risks of return to work, including healthcare settings C_LI What this study addsO_LIDual c.f. single brand LFT testing increased SARS-CoV-2 antigen detection marginally, but more than can be explained by extending swabbing from nose-only to nose-throat C_LIO_LINHS deployment of nose-only LFTs in response to compound pressures from Omicron, winter and pandemic burnout was safe and acceptable to most participating hospital staff C_LIO_LICulturable virus was detected confidently in a fifth (and potentially in a further third) of LFT-positive hospital workers 5-7 days after their self-referral for testing, indicating substantial protracted infectiousness C_LI How this study might affect research, practice or policyO_LIThis study shows international Covid-19 policies for return to work after fixed periods (e.g. 5 days after positive test) were flawed: too little emphasis was placed on variation in infectivity between individuals C_LIO_LIFuture pandemic preparedness needs to plan testing quality assurance unified across healthcare and community self-testing contexts, including continuous study of serial daily antigen, nucleic acid and culturable virus test results C_LI

Comparison of the performance of SARS-CoV-2 RNA qRT-PCR testing based on expectorated and drooled saliva samples (preprint)

Purpose Saliva has been considered a suitable sample material for SARS-CoV-2 testing but uncertainty remained regarding the sensitivity and reliability of different saliva collection methods for community mass testing. This study aimed to investigate the potential utility of expectorated saliva (ES) and drooled saliva (DS) through a large cohort study. Methods ES and DS samples were collected in a two-stage non-randomized prospective cohort study. Their utility for SARS-CoV-2 RNA qRT-PCR testing was assessed by comparison with results for combined throat and nose (CTN) swabs. A total of 2,878 subjects were recruited, from which 2,747 were evaluable for statistical analyses. Results Using CTN swab-based results as reference,DS- and ES-based tests showed the same high level of concordance (98% vs 98%) or specificity (99% vs 99%). Sensitivity seemed to be higher for DS than for ES (93% vs 80%) but not significantly once viral concentration was taken into account. Multivariable analysis indicated however an inferior sensitivity of saliva-based testing for female compared to male subjects with low viral burden. Assuming no false positive qRT-PCR results, an unbiased comparison showed no significant difference in sensitivity between saliva- and swab-based testing. Conclusion SARS-CoV-2 RNA testing based on saliva showed high diagnostic accuracy and can be considered an alternative where swabbing may not be tolerated or operationally feasible. Drooled saliva yielded the same diagnostic performance compared to expectorated saliva and may present a preferred option with reduced aerosol risk and increased compliance. Observed sex-specific difference in detection performance however warrant further investigations.

Performance of antigen lateral flow devices in the United Kingdom during the Alpha, Delta, and Omicron waves of the SARS-CoV-2 pandemic (preprint)

Background Antigen lateral flow devices (LFDs) have been widely used to control SARS-CoV-2. Changes in LFD sensitivity and detection of infectious individuals during the pandemic with successive variants, vaccination, and changes in LFD use are incompletely understood. Methods Paired LFD and PCR tests were collected from asymptomatic and symptomatic participants, across multiple settings in the UK between 04-November-2020 and 21-March-2022. Multivariable logistic regression was used to analyse LFD sensitivity and specificity, adjusting for viral load, LFD manufacturer, setting, age, sex, assistance, symptoms, vaccination, and variant. National contact tracing data were used to estimate the proportion of transmitting index cases (with [≥]1 PCR/LFD-positive contact) potentially detectable by LFDs over time, accounting for viral load, variant, and symptom status. Findings 4131/75,382 (5.5%) participants were PCR-positive. Sensitivity vs. PCR was 63.2% (95%CI 61.7-64.6%) and specificity 99.71% (99.66-99.74%). Increased viral load was independently associated with being LFD-positive. There was no evidence LFD sensitivity differed between Delta vs. Alpha/pre-Alpha infections, but Omicron infections were more likely to be LFD positive. Sensitivity was higher in symptomatic participants, 68.7% (66.9-70.4%) than in asymptomatic participants, 52.8% (50.1-55.4%). 79.4% (68.6-81.3%) of index cases resulting in probable onward transmission with were estimated to have been detectable using LFDs, this proportion was relatively stable over time/variants, but lower in asymptomatic vs. symptomatic cases. Interpretation LFDs remained able to detect most SARS-CoV-2 infections throughout vaccine roll-out and different variants. LFDs can potentially detect most infections that transmit to others and reduce risks. However, performance is lower in asymptomatic compared to symptomatic individuals. Funding UK Government.

A cluster randomised trial of the impact of a policy of daily testing for contacts of COVID-19 cases on attendance and COVID-19 transmission in English secondary schools and colleges (preprint)

Summary Background School-based COVID-19 contacts in England are asked to self-isolate at home. However, this has led to large numbers of missed school days. Therefore, we trialled daily testing of contacts as an alternative, to investigate if it would affect transmission in schools. Methods We performed an open-label cluster randomised controlled trial in students and staff from secondary schools and further education colleges in England ( ISRCTN18100261 ). Schools were randomised to self-isolation of COVID-19 contacts for 10 days (control) or to voluntary daily lateral flow device (LFD) testing for school contacts with LFD-negative contacts remaining at school (intervention). Household contacts were excluded from participation. Co-primary outcomes in all students and staff were symptomatic COVID-19, adjusted for community case rates, to estimate within-school transmission (non-inferiority margin: <50% relative increase), and COVID-19-related school absence. Analyses were performed on an intention to treat (ITT) basis using quasi-Poisson regression, also estimating complier average causal effects (CACE). Secondary outcomes included participation rates, PCR results in contacts and performance characteristics of LFDs vs. PCR. Findings Of 99 control and 102 intervention schools, 76 and 86 actively participated (19-April-2021 to 27-June-2021); additional national data allowed most non-participating schools to be included in the co-primary outcomes. 2432/5763(42.4%) intervention arm contacts participated. There were 657 symptomatic PCR-confirmed infections during 7,782,537 days-at-risk (59.1/100k/week) and 740 during 8,379,749 days-at-risk (61.8/100k/week) in the control and intervention arms respectively (ITT adjusted incidence rate ratio, aIRR=0.96 [95%CI 0.75-1.22;p=0.72]) (CACE-aIRR=0.86 [0.55-1.34]). There were 55,718 COVID-related absences during 3,092,515 person-school-days (1.8%) and 48,609 during 3,305,403 person-school-days(1.5%) in the control and intervention arms (ITT-aIRR=0.80 [95%CI 0.53-1.21;p=0.29]) (CACE-aIRR 0.61 [0.30-1.23]). 14/886(1.6%) control contacts providing an asymptomatic PCR sample tested positive compared to 44/2981(1.5%) intervention contacts (adjusted odds ratio, aOR=0.73 [95%CI 0.33-1.61;p=0.44]). Rates of symptomatic infection in contacts were 44/4665(0.9%) and 79/5955(1.3%), respectively (aOR=1.21 [0.82-1.79;p=0.34]). Interpretation Daily contact testing of school-based contacts was non-inferior to self-isolation for control of COVID-19 transmission. COVID-19 rates in school-based contacts in both intervention and control groups were <2%. Daily contact testing is a safe alternative to home isolation following school-based exposures.