key: cord-0308685-qh58y1m7
authors: Fujita-Rohwerder, N.; Beckmann, L.; Zens, Y.; Verma, A.
title: Diagnostic accuracy of rapid point-of-care tests for diagnosis of current SARS-CoV-2 infections in children: A systematic review and meta-analysis
date: 2021-08-13
journal: nan
DOI: 10.1101/2021.08.11.21261830
sha: 7e850e267a86ead12f78c2958a69c2240208cd8f
doc_id: 308685
cord_uid: qh58y1m7

Objective: To systematically assess the diagnostic accuracy of rapid point-of-care tests for diagnosis of current SARS-CoV-2 infections in children under real-life conditions. Study design: Multiple bibliographic databases including MEDLINE and Embase, clinical trial registries and further information sources were systematically searched for literature (last bibliographic search: May 7, 2021). Diagnostic cross-sectional or cohort studies that included paediatric study participants and evaluated rapid point-of care tests for diagnosing current SARS-CoV-2 infections against RT-PCR as the reference standard were eligible for inclusion. QUADAS-2 was used to assess the risk of bias and the applicability of the included studies. Bivariate meta-analyses with random effects were performed. Variability was assessed by subgroup analyses. Results: We included 17 studies with a total of 6355 paediatric study participants. All included studies compared antigen tests against RT-PCR. Only one study was at low risk of bias. The pooled overall diagnostic sensitivity and specificity in paediatric populations was 64.2% (95% CI: 57.4%-70.5%) and 99.1% (95% CI: 98.2%-99.5%), respectively. In symptomatic children, the pooled diagnostic sensitivity was 71.8% (95% CI: 63.6%-78.8%) and the pooled diagnostic specificity was 98.7% (95% CI: 96.6%-99.5%). The pooled diagnostic sensitivity in asymptomatic children was 56.2% (95% CI: 47.6%-64.4%) and the pooled diagnostic specificity was 98.6% (95% CI: 97.3%-99.3%). Conclusions: Performance of current antigen tests under real-life conditions varies broadly. Policymakers should especially be aware of the low diagnostic sensitivity of current antigen tests. Results should be interpreted with caution since risk of bias was predominantly judged as unclear due to poor reporting. Study Registration: CRD42021236313 (PROSPERO).

we required reporting of data that allowed constructing a complete 2x2 contingency table.

The full set of eligibility criteria is shown in Table 1 . For studies that did not fully meet the inclusion criteria for the population, index test and/or reference standard, we required that at least 80% of the pediatric (sub-)population matched the population we defined for this systematic review. Studies were excluded, if the index test and the reference standard were performed in less than 80% of the pediatric study population. Besides journal articles, reports (including clinical study reports) that adhered to reporting standards such as STARD [18] or recommendations given by government agencies [10, 19] were considered eligible for inclusion. Studies that mentioned the inclusion of pediatric study participants without reporting any corresponding outcome data but otherwise met the eligibility criteria were preliminary included, and study authors were contacted and asked to provide such data.

Further, if the study population's baseline characteristics included information on age, we estimated the proportion of pediatric study participants assuming ages of study participants following a normal distribution and the proportion of PCR-positive pediatric assuming no changes in the PCR positivity rate among age groups. We contacted authors if we estimated at least 10 PCR-positive pediatric study participants in the study population.

We performed a comprehensive search for primary studies and secondary publications (systematic reviews and Health Technology Assessment (HTA) reports) in the following electronic bibliographic databases: MEDLINE (Ovid), Embase (Ovid), the Cochrane Library (Wiley), and preprint servers (Europe PMC) including medRxiv and bioRxiv (see [20] for full Evidence Search and Guidance websites of Britain's National Institute for Health and Care Excellence (NICE).

In accordance with the Cochrane Handbook for DTA Reviews [21] , the search strategy included concepts addressing the index test and the target condition. The development of the search strategy followed an objective approach that involved text-analytic procedures to identify candidate search terms based on the method described by Hausner et al. [22] . One researcher performed analyses of simple word frequencies and keywords-in-contexts in R using the Quanteda package [23] . Because of substantial differences between types of tests, separate test sets were used to identify candidate search terms for antigen tests and molecular tests, respectively. Test sets included potentially relevant studies (irrespective of pediatric study participants) from the Cochrane Review by Dinnes et al. [8] and from a frequently updated website that lists DTA studies on antigen tests [24] . Due to a limited number of potentially relevant references addressing rapid molecular tests for point-of-care usage, the draft search strategy was supplemented by search terms derived from a conceptual approach. Furthermore, brand names of tests included in the Cochrane Review were added to increase sensitivity. The final search strategy was tested for completeness against the validation sets and relevant references of studies that included pediatric participants identified via exploratory searches beforehand. Prior to execution, the search strategy was peer-reviewed by a senior information specialist following the Peer Review of 1 1 queries led to the inclusion of 8 further studies [48, 50, 51, 54, 61, 63, 64, 67] resulting in a total of 17 relevant studies for this review (12 peer-reviewed journal articles and 5 preprints). The full list of included studies is reported in Table 3 .

Furthermore, we screened 113 records identified from study registries and 323 records identified from other information sources. The search for studies in study registries allowed to identify 4 planned or ongoing and 4 completed studies with no results posted, see Table 4 for further details. Information retrieval from other information sources included screening 18 records retrieved from the FIND website, 78 records from NICE Evidence Search, 28 records from NICE, and 23 records from reference lists of 6 systematic reviews [8, [68] [69] [70] [71] [72] identified via searching bibliographic databases. As a result, no additional study that met the inclusion criteria was identified.

All 17 included studies (6355 pediatric study participants) evaluated the performance of antigen tests against the reference standard RT-PCR. The main study characteristics for each individual study are summarized in Table 5 , further details are reported in Table 6 and Table 7 . While 14 studies evaluated the test performance in mixed-age populations, including 24 to 928 pediatric study participants, 3 studies with a sample size between 440 and 1620 individuals exclusively recruited children. In 8 studies, the purpose of testing included diagnostic testing of symptomatic individuals suggestive of SARS-CoV-2 infection.

nasopharyngeal samples were collected for the index test. 6 test evaluations used anterior nasal specimens for the index test. In all studies, the reference standard was RT-PCR performed in a laboratory setting.

The results of the quality assessment are summarized in Table 8 and Figure 2 . Quality among studies varied. Only 1 study was at low risk of bias in all four domains of the QUADAS-2 tool. For patient selection, more than half of the studies were at high (n=1) or unclear (n=12) risk of bias because inadequate exclusion of participants occurred, or it was not clear whether a consecutive or random sample was enrolled into the study. All but 1 study was judged as having an unclear risk of bias for the reference standard due to insufficient reporting of blinding. Risk of bias in the flow and timing domain was high in 3 studies due to more than 5% of missing outcome data.

Overall applicability concerns were high in 3 studies due to high concerns in either the patient selection or index test domain. 3 studies were of low concern and the remaining 11 were rated unclear due to insufficient reporting in at least 1 domain.

RT-PCR positivity rate, diagnostic sensitivity, diagnostic specificity as well as PPV and NPV (and their 95% CIs) of individual studies based on data from 2x2 contingency tables for pediatric populations are reported in Table 9 and Figure 3 . The RT-PCR positivity rate, which corresponds to the SARS-CoV-2 prevalence in the sample population, varied between 4.1% and 50%, with a median of 14,5% over n=17 studies. The sensitivity and specificity ranged from 33.3% to 85.7% and 91.7% to 100%, respectively. PPV and NPV ranged from 60.0% to 98.7% and 73.3% to 98.9%, respectively.

For individual studies, separate analyses for subgroups based on symptom status are reported in Tables 10-12 Figure 4 . Here, populations were defined as symptomatic or asymptomatic if at least 80% of pediatric study participants were reported as being . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 3 symptomatic or asymptomatic, respectively. Mixed populations refer to populations with no predominant symptom status. RT-PCR positivity rates of the primary analysis population and the different subgroups based on symptom status are presented in Figure 5 . 2 studies [51, 54] were performed in high-prevalence populations with RT-PCR positivity rates of 38.7% and 50.0%, respectively. The median RT-PCR positivity rate was 13.2% (n=10 test evaluations) in asymptomatic populations, 13.8% in mixed populations (n=3 test evaluations), and 25.7% in symptomatic populations (n=13 test evaluations). Thus, we observed a slight trend in the RT-PCR positivity rate with respect to the proportion of symptomatic subjects. Although the bivariate meta-analysis might be influenced by the difference in the prevalence [73] , we did not directly analyze the impact of the prevalence within the bivariate model. Instead, we performed a subgroup analysis with respect to symptom status (see below).

In our primary meta-analyses, we used data from 17 studies evaluating the diagnostic accuracy of antigen tests in pediatric participants. Estimated pooled sensitivity and specificity were 64.2% (95% CI: 57.4%-70.5%) and 99.1% (95% CI: 98.2%-99.5%), respectively. While the estimates for the sensitivity revealed high heterogeneity and thus justified the application of the bivariate model with random effects, the estimates for the specificity were limited to a small range, as shown in Figure 6 . As a consequence, the estimated summary receiver operating characteristic (SROC) curve cannot be meaningfully interpreted. As pre-specified in the protocol, we performed subgroup analysis evaluating the diagnostic accuracy according to symptom status. Estimated pooled sensitivity and specificity in asymptomatic children was 56.2% (95% CI: 47.6%-64.4%) and 98.6% (95% CI: 97.3%-99.3%), respectively, based on data from 2439 asymptomatic children in 10 studies. Estimated pooled sensitivity and specificity in symptomatic children was 71.8% (95% CI: 63.6%-78.8%) and 98.7% (95% CI: 96.6%-99.5%), respectively, based on data from 3413 symptomatic children in 13 studies. Estimated pooled sensitivity and specificity in the mixed population of . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 4 symptomatic and asymptomatic children from 3 studies including 419 children was 63.4% (95% CI: 37.3%-83.5%) and 98.7% (95% CI: 90.8%-99.8%), respectively. The corresponding SROC curves are shown in Figure 7 . The likelihood ratio test (LRT) for differences between the three groups revealed a p-value of p LRT =0.066. Results for the other subgroup analyses did not show relevant differences in the pooled estimates (setting p LRT =0.400; index test sample type p LRT =0.303; reference standard sample type p LRT =0.723;

RT-PCR Ct cutoff value p LRT =0.105; publication status p LRT =0.551; test type (most used) p LRT =0.146). Due to insufficient data, we did not perform subgroup analysis with respect to test type (antigen vs. molecular) and end-user (layperson (self-testing) vs. trained staff/health care worker). Except for 1 study [61, 74] where the testing procedure involved (supervised) self-collection of samples by study participants, in all other studies, testing was conducted with trained staff and/or health care workers (if reported). Univariate metaanalysis with random effects for sensitivity and specificity in cases where only a few studies were included (mixed population of symptomatic and asymptomatic children) did not show remarkable differences to the bivariate analysis. The results of all bivariate meta-analyses are summarized in Table 15 .

To our knowledge, this is the first systematic review that focused on evaluating the diagnostic accuracy of rapid point-of-care tests for current SARS-CoV-2 infections in pediatric populations. Our current review comprises 17 studies with 18 evaluations of 7 different antigen tests in children, whereas comprehensive author queries allowed us to include 8 studies that did not provide sufficient data on pediatric study participants in their original study publication. We did not identify any evaluations of molecular-based tests that met our inclusion criteria confirming the current dominant role of antigen tests for rapid pointof-care usage.

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 The better performance in symptomatic populations might be explained by changes in the viral load over the course of infection and the timing of the test: most symptomatic individuals were tested within 7 days of symptom onset in contrast to asymptomatic individuals with more variable disease onset, including individuals in the early (presymptomatic) or late stages of infection when viral loads are relatively low [77] . Further, since test performance can also be influenced by prevalence, one should note that median prevalence in symptomatic study populations was about 12 percentage points higher than in asymptomatic study populations.

As expected, the sensitivity increased when the positivity threshold of the reference standard was set to a lower Ct cutoff value of 30 or 25. However, such analyses should not be overinterpreted since Ct values are not standardized across systems or laboratories, making it difficult to directly compare results between different studies. Furthermore, while the Ct value . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 6 from RT-PCR is a strong indicator of viral load, there is no specific cutoff viral load which allows distinguishing individuals as being infectious or not. As shown in Table 13 and Table   14 , an increase in sensitivity comes at the cost of a decrease in specificity as antigen tests also identify individuals with moderate or low viral loads, who would then be considered as false positives.

Despite some methodological differences (such as the stringency of inclusion criteria) and

neglecting differences between included studies (e.g. settings), the findings of our review are similar to those in the recent Cochrane Review by Dinnes et al. [8] . These similarities between pediatric and adult populations might be explained by the findings by Jones et al. [78] , who only identified minor differences in viral loads across age groups in a comprehensive analysis of more than 25,000 individuals who tested positive for SARS-CoV-2 by RT-PCR.

For the current version of our review, publication bias is not considered as relevant due to the novelty of the topic. Non-publication of studies, in particular underreporting of studies with unfavorable outcomes, may introduce bias and threaten the validity of systematic reviews. It is now commonly expected to publish results of clinical studies within 12 months of completion [79] [80] [81] . No study included in our review was published before November 2020. All 4 completed studies that were identified through searching study registries were completed within the last 9 months. Of note is that for all but 1 study [39] included in our review no entry in a study registry was reported.

Despite the roll-out of vaccines, testing continues to be a key to pandemic control. As experts predict new surges of infections in fall, early identification of outbreaks will remain vital for controlling the spread of SARS-CoV-2, particularly in populations with low vaccination rates. Consequently, multi-layered mitigation strategies will continue involving screening testing of children in schools and kindergarten to avoid further closures. The high specificity of antigen tests and the corresponding PPVs calculated for the pediatric study populations suggest that antigen testing might be a valuable tool to rapidly identify children . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 7 with SARS-CoV-2 infection in moderate to high prevalence settings. However, at the same time, it is important to raise awareness that antigen tests should not be used to rule out SARS-CoV-2 infection (or infectiousness) due to their limited sensitivity. Whether increasing the frequency of antigen-based testing leads to an improved overall diagnostic accuracy that allows to effectively reduce transmission of SARS-CoV-2, has yet to be demonstrated in practice [82] . The latter two aspects and the urgent need for high quality screening tests likely led to the recent publication of a new target product profile by the MHRA in the UK

[83], which includes increased performance requirements for self-tests to be used in national testing programs that aim at detecting current SARS-CoV-2 infections in individuals without symptoms. Here, the minimum acceptable sensitivity for tests to "rule out" a current infection is ≥ 97% with two-sided 95% CI entirely above 95%. The minimum acceptable specificity is ≥ 99.5% with two-sided 95% CI entirely above 97%. Further, it is stated that performance claims of repeated testing strategies require adequate clinical evidence rather than evidence from modelling studies only.

Other screening testing methods such as molecular-based pool testing, which involves RT- Screening testing programs of children in schools and kindergarten using antigen tests have been implemented in many countries. Specific aspects that define these use cases, such as sample collection in toddlers by laypersons or self-testing in schools performed by children, are likely to influence the real-life test performance but were not addressed in any of the studies included in our review. Furthermore, one should keep in mind that diagnostic accuracy is only one factor affecting the effectiveness of testing programs [88]. 4) Only 7 different antigen tests were included in our review, and 4 of these were only evaluated in 1 study each. Thus, the performance of most antigen tests under real-life conditions remains unknown. While the number of antigen tests is still small in the US due to more rigorous approval processes, the situation in Europe is different, since the current regulatory replied to our author queries and who provided us with separate data on the pediatric study participants included in their studies. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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The copyright holder for this preprint this version posted August 13, 2021. In Vitro Diagnostic (IVD) self-tests for the detection of SARS-CoV-2 in people without symptoms. Target Prod Profile Vitro Diagn IVD Self-Tests Detect SARS-CoV-2 People Symptoms n.d. https://www.gov.uk/government/publications/how-tests-and-testing-kits-

the-detection-of-sars-cov-2-in-people-without-symptoms (accessed July 10, 2021). . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted August 13, 2021. ; 3 2 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08.11.21261830 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a 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 13, 2021. ; https://doi.org/10.1101/2021.08.11.21261830 doi: medRxiv preprint and 500 participants, large circle: >500 participants). The pooled estimate (black dot) of the pair of sensitivity (Se) and specificity (Sp) is surrounded by its 95% confidence region (closed curve with short dashes) and prediction region (closed curve with long dashes). The estimation of the SROC curve is based on the bivariate approach by Rutter and Gatsonis [29] .

. CC-BY 4.0 International license It is made available under a 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 13, 2021. ;

populations. Each circle represents the point estimate of an individual study, whereas the size of the circle correlates with the number of paediatric study participants (small circle: <100 participants, medium circle: between 100 and 500 participants, large circle: >500 participants). The pooled estimate (black dot) of the pair of sensitivity (Se) and specificity (Sp) is surrounded by its 95% confidence region (closed curve with short dashes) and prediction region (closed curve with long dashes). The estimation of the SROC curve is based on the bivariate approach by Rutter and Gatsonis [29] .

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It is made available under a 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 13, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08.11.21261830 doi: medRxiv preprint 1 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted August 13, 2021. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

D S o u t h A f r i c a ( N o v 2 0 ) P a n b i o C O V I D - 1 9 A g R a p i d T

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The copyright holder for this preprint this version posted August 13, 2021. ; 5 1 Table 9 : Calculated RT-PCR positivity rate, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) with 95% confidence interval (CI) for each included study based on the 2x2 contingency tables extracted for the entire pediatric study populations irrespective of symptom status. :  t  r  u  e  p  o  s  i  t  i  v  e  ,  F  P  :  f  a  l  s  e  p  o  s  i  t  i  v  e  ,  T  N  :  t  r  u  e  n  e  g  a  t  i  v  e  ,  F  N  :  f  a  l  s  e  n  e  g  a  t  i  v  e   I  T  1  :  I  n  d  e  x  t  e  s  t  1  ;  I  T  2  :  I  n  d  e  x  t  e  s  t  2 .

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The copyright holder for this preprint this version posted August 13, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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; https://doi.org/10.1101/2021.08.11.21261830 doi: medRxiv preprint 5 5 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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