REVIEW ARTICLE

Rapid Diagnostic Tests for Group A Streptococcal

Pharyngitis: A Meta-analysis
AUTHORS: Wei Ling Lean, MBBS, BMedSc,a Sarah Arnup,
BSc(Hons), MPhil, MBiostat,b Margie Danchin, MBBS, abstract
FRACP, PhD,a,c,d and Andrew C. Steer, MBBS, BMedSc, MPH,
BACKGROUND AND OBJECTIVE: Effective management of group A strep-
FRACP, PhDa,c,e
aDepartment
tococcal (GAS) pharyngitis is hindered by impracticality of the gold stan-
of General Medicine, Royal Children’s Hospital,
Melbourne, Australia; bClinical Epidemiology and Biostatistics dard diagnostic test: throat culture. Rapid antigen diagnostic tests
Unit, cGroup A Streptococcal Research Group, and dVaccine and (RADTs) are a promising alternative, although concerns about their sen-
Immunisation Research Group, Murdoch Children’s Research sitivity and specificity, and variation between test methodologies, have
Institute, Melbourne, Australia; and eCentre for International
Child Health, Department of Paediatrics, University of Melbourne,
limited their clinical use. The objective of this study was to perform a sys-
Melbourne, Australia tematic review with meta-analysis of the diagnostic accuracy of RADTs for
KEY WORDS GAS pharyngitis.
group A streptococcus, pharyngitis, rapid test, sensitivity, METHODS: Medline and Embase from 1996 to 2013 were used as data
specificity
sources. Of 159 identified studies, 48 studies of diagnostic accuracy of
ABBREVIATIONS
CI—confidence interval
GAS RADTs using throat culture on blood agar as a reference standard
ELISA—enzyme-linked immunosorbent assay were selected. Bivariate random-effects regression was used to estimate
FISH—fluorescence in situ hybridization sensitivity and specificity with 95% confidence intervals (CIs). Additional
GAS—group A b-hemolytic streptococcus
meta-analyses were performed for pediatric data.
OIA—optical immunoassay
PCR—polymerase chain reaction RESULTS: A total of 60 pairs of sensitivity and specificity from 48 stud-
QUADAS—Quality Assessment of Diagnostic Accuracy Studies ies were included. Overall summary estimates for sensitivity and spec-
RADT—rapid antigen diagnostic test
ROC—receiver operating characteristics ificity of RADTs were 0.86 (95% CI 0.83 to 0.88) and 0.96 (95% CI 0.94 to
S-ROC—summary receiver operating characteristics 0.97), respectively, and estimates for pediatric data were similar.
Dr. Lean collected data for the study and drafted the initial Molecular-based RADTs had the best diagnostic accuracy. Considerable
manuscript; Dr Arnup carried out the statistical analyses and variability exists in methodology between studies. There were insuffi-
reviewed and revised the manuscript; Drs Danchin and Steer
cient studies to allow meta-regression/subgroup analysis within each
conceptualized the study, supervised data collection, and
critically reviewed and revised the manuscript; and all authors test type.
approved the final manuscript as submitted. CONCLUSIONS: RADTs can be used for accurate diagnosis of GAS phar-
www.pediatrics.org/cgi/doi/10.1542/peds.2014-1094 yngitis to streamline management of sore throat in primary care. RADTs
doi:10.1542/peds.2014-1094 may not require culture backup for negative tests in most low-incidence
Accepted for publication Jul 21, 2014 rheumatic fever settings. Newer molecular tests have the highest sen-
Address correspondence to A/Prof Andrew Steer, Centre for sitivity, but are not true point-of-care tests. Pediatrics 2014;134:771–
International Child Health, Department of Paediatrics, University 781
of Melbourne, Royal Children’s Hospital, Flemington Road,
Parkville, Vic 3052, Australia. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2014 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: Drs Danchin and Steer received
funding for a clinical study conducted in 2012 of a Quidel
Corporation rapid antigen diagnostic test product; the other
authors have no financial relationships relevant to this article to
disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated
they have no potential conflicts of interest to disclose.

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Sore throat is a common presentation culture of a throat swab. However, ef- because the incidence of GAS pharyngitis
to primary health care and emergency fective management is hindered by the is generally lower than in children and
departments, especially in the pediatric impracticality of throat culture because because the risk of rheumatic fever is
population. The most common bacterial of the relatively long lag time between low. However, most RADTs have high
cause of acute sore throat is the group the collection of the specimen and final specificity, meaning that a positive RADT
A b-hemolytic Streptococcus (GAS). In microbiological diagnosis.5 This delay is result does not require a backup culture
a cohort study done in Australia, the in- especially problematic in low-resource and that the rate of overdiagnosis is low.9
cidence of pharyngitis caused by GAS in settings, as it may not be feasible for We conducted a systematic review with
children aged 5 to 12 years was 13 cases patients to return for further follow-up meta-analysis to determine the diag-
per 100 person-years.1 GAS pharyngitis visits and appropriate treatment.6 nostic accuracy of each class of RADTs in
causes a considerable cost to society; in Rapid antigen diagnostic tests (RADTs) children and adults combined and chil-
the United States it is estimated that GAS are a potentially more feasible alterna- dren only with GAS pharyngitis, and to
pharyngitis in children alone costs be- tive because of their quick turnaround explore the heterogeneity among stud-
tween $224 and $539 million per year.2 In time, so that the clinician can make ies by analyzing subgroups classified
addition to the acute symptoms of sore a decision regarding treatment at the according to type of test in both children
throat, GAS can lead to suppurative se- point of care.7 Since their inception in and adults combined and restricted to
quelae, including peri-tonsillar abscess, the early 1980s, there have been several children.
and nonsuppurative sequelae, including generations of RADTs that have used
rheumatic fever, although this compli- different methodologies.8 The first-
cation is rare today in most industri- METHODS
generation tests used latex agglutination,
alized countries. followed by enzyme-linked immuno- Data Collection
However, there are challenges in the di- sorbent assays (ELISAs), lateral flow We systematically searched Medline and
agnosis of GAS pharyngitis. First, the and immunochromatographic assays, Embase via OvidSP for articles published
signs and symptoms of GAS pharyngitis and optical immunoassays (OIAs). More between 1996 and 2013. We used the
are often indistinguishable from viral and recently, molecular-based techniques, following search terms: Streptococcus
other causes of sore throat. No symptom such as DNA probes, polymerase chain pyogenes, streptococcal infections, group
or sign in isolation has been shown to reaction (PCR), and fluorescence in situ A streptococcal infection, pharyngitis,
have a sufficiently high likelihood ratio to hybridization (FISH) methods, have been rapid test, diagnostic reagent kits, im-
permit an accurate diagnosis of GAS developed.8 RADTs have been incorpo- munoassay, immunoenzyme technique,
pharyngitis.3 Combinations of symptoms rated into both the Infectious Diseases enzyme immunoassay, latex fixation test,
and signs have been developed into Society of America and the European latex agglutination test, diagnostic test,
clinical prediction rules to help identify Society for Clinical Microbiology and molecular biology. The search was sup-
patients who have a higher likelihood of Infectious Diseases clinical practice plemented by a manual review of bib-
GAS infection. One of the most commonly guidelines,4,9 but are not used routinely liographies of articles meeting inclusion
used prediction rules validated in both in all countries, including Australia.10 criteria and the bibliographies of pre-
adults and children are the Centor cri- Widespread use of RADTs has been vious reviews. The search was limited to
teria, which use up to 4 clinical features hindered by low sensitivity for most English-language articles only.
(tonsillar exudates, swollen tender an- commonly used RADTs (immunoassays). The abstract of all identified articles
terior cervical nodes, fever, and the lack Previous reviews of RADT performance was reviewed. We included articles in
of cough). However, this rule identifies have identified considerable variability our review if they contained data on the
only 53% of patients with GAS culture– in the diagnostic accuracy, especially accuracy of GAS RADTs. Review articles,
positive sore throat even when all 4 sensitivity, between different test meth- letters, comments, and study protocols
criteria are present.4,5 Therefore, if the odologies.4,11 The American guidelines with incomplete data were excluded
clinician intends to treat GAS pharyngitis, recommend that negative RADTs in (Fig 1). After this, full articles were re-
it is generally recommended that labo- children and adolescents should be trieved and reviewed.
ratory confirmation of the presence of backed up by a throat culture to reduce Each study was assessed for quality and
GAS be sought to limit unnecessary an- the number of missed GAS pharyngitis risk of bias by 2 investigators (WLL, ACS)
tibiotic prescription. cases.9 These guidelines, along with using the Quality Assessment of Di-
The gold standard laboratory inves- European guidelines,4 suggest that a agnostic Accuracy Studies (QUADAS)
tigation of GAS pharyngitis is bacterial backup culture in adults is not necessary tool for inclusion within a meta-analysis

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 REVIEW ARTICLE

of studies.12 The Cochrane version of 11 specificity, and sample characteristics. sensitivity, specificity, and their 95%
QUADAS criteria was used in the quality Where sensitivity and specificity were confidence intervals (CIs), for each RADT
assessment of each study (Supplemental not presented in the article, we inde- category with more than 3 pairs of
Table 2).12 All the analyzed studies used pendently calculated sensitivity and sensitivity and specificity and all cate-
culture on a blood agar plate as a mini- specificity from published raw data or gories combined.13–15 Because a corre-
mum reference standard; data within from data submitted by authors at our lation may exist between sensitivity and
individual studies that were not com- request. Studies were categorized on the specificity across studies, each study
pared with blood agar culture were ex- basis of the type of test, setting (emer- measurement of sensitivity and speci-
cluded from analysis. Studies that used gency department, outpatient clinic, ficity was analyzed together as a pair.
only throat culture as a backup for neg- inpatient), and a subgroup of studies To explore heterogeneity between stud-
ative RADTs were excluded from the meta- performed in children (aged ,18 years) ies, we prepared forest plots of the in-
analysis because this methodology was defined. For type of test, we included dividual pairs of sensitivity and specificity
assumes that all test-positives are true- studies that reported on lateral flow as- with 95% confidence intervals; and plot-
positives, and there are no false-positives; say and immunochromatographic assay ted each pair in receiver operating
as a result, specificity is assumed to be in a single category, and DNA probe, PCR characteristic (ROC) space, along with
100% and sensitivity can be over- assay, and FISH in a single category a summary ROC (S-ROC) curve, summary
estimated. Only studies that used throat (molecular technique), in addition to 4 estimates of sensitivity and specificity,
swabs, not mouth swabs, were included. other categories: latex agglutination, li- and a 95% confidence ellipse around the
posomal technology, ELISA, and OIA. summary estimates. The S-ROC curve
Data Extraction and Categorization illustrates the estimated relationship
Multiple variables were extracted from Statistical Analysis between sensitivity and specificity across
the studies, including sample size, prev- A bivariate random-effects model was studies; where there is a correlation
alence of GAS culture positivity, sensitivity, used to estimate summary values of between sensitivity and specificity across

FIGURE 1
Study flow diagram. This flow diagram follows the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA)76 with modifications.

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studies, the individual pairs of sen- The range of values for each RADT type is We continued to observe a large
sitivity and specificity are expected to summarized in Supplemental Table 3. amount of variability in the sensitivity
lie along the S-ROC curve.16 Hetero- found in studies within each cate-
geneity was further investigated by Sensitivity and Specificity Analysis: gory, particularly in the lateral-flow/
performing separate analyses in the Summary Estimates immunochromatographic assay cate-
following clinical subgroups: RADT The summary estimate of sensitivity of gory where sensitivity ranged from 0.59
types with more than 3 studies (lateral RADTs among all studies included was to 0.96. Of the test types not included in
flow/immunochromatographic assay, 0.86 (95% CI 0.83 to 0.88), whereas the the meta-analyses described previously,
ELISA, OIA, molecular technique), and summary estimate for specificity was both test types (latex agglutination and
RADT types with more than 3 studies 0.96 (95% CI 0.94 to 0.97, Supplemental liposomal technology) had relatively
including children only. Fig 4). We observed considerable vari- poor sensitivity (Supplemental Fig 4,
Many (19/48) studies reported more ability across studies in sensitivity, but Supplemental Table 3).
than 1 pair of sensitivity and speci- little variability in specificity. Despite There was less variability in specificity,
ficity. Where the multiple sensitivity this variability, we consider it appro- although there were 2 clear outliers in
and specificity pairs were estimated priate to estimate diagnostic accuracy the OIA category in our meta-analysis.42,43
from different samples of patients, with a summary measure for sensitivity The study by Hart et al42 compared
each pair is treated in our analysis as and specificity, rather than with an BioStar Strep A OIA RADT with a Selec-
if it came from a separate study.6,17–20 S-ROC curve, because there was no evi- tive Strep Agar with 5% sheep blood
Where a different RADT was tested in dence of a correlation between sensi- that was incubated anaerobically. The
the same sample of patients, we in- tivity and specificity when the RADTs prevalence of GAS pharyngitis in this
cluded each sensitivity and specificity were pooled (correlation coefficient study was 12%, which is much lower
pair in the subgroup analysis for the 0.06, 95% CI –0.26 to 0.37). Furthermore, than the other studies of OIA included.
respective RADT.21–25 the forest plot for all studies showed no This study found that weakly positive
Where multiple sensitivity and speci- systematic decrease in specificity with test results were frequently associated
ficity pairs were estimated from the increasing sensitivity, illustrating that with false-positive results; reclassifi-
same patients in a study, only 1 pair of a threshold effect, such as variation in cation of these weakly positive test
sensitivity and specificity was included cutoff value for a positive test result results as negative results would in-
in our analysis.22,23,25–34 We selected the between studies, does not account for crease the specificity of the OIA. Possi-
pairs that were the focus of primary the observed variability in diagnostic ble cross-reactivity with groups B and C
analysis of the selected studies. accuracy between studies. streptococci also were observed in
some of the false-positive cases.42 Sim-
Statistical analysis was performed in Sensitivity and Specificity Analysis:
ilarly, false-positive results were fre-
Stata 12 (Stata Corp, College Station, TX) Test Types
quent in the study by Filho et al43 in
using the Metandi package.35 Results from 4 of the 6 categories of RADT Brazil, contributing to low specificity.
were pooled (Fig 2). Overall, specificity This was a small study with a sample
RESULTS was higher than sensitivity for all 4 test size of 81, comparing the Strep A OIA
A total of 60 pairs of sensitivity and categories. There was no evidence for Max RADT to the reference standard of
specificity, comprising 23 934 patients a correlation between sensitivity and 5% goat blood agar culture medium in
from 48 studies were included in the specificity within the test categories. an aerobic environment. The high rate
final analysis (Table 1). Of note, 7 studies Test performance appeared best for the of false-positives (32.6%) was attributed
were excluded after application of the molecular technique category with a to failure of the RADT method, detecting
modified QUADAS tool; 6 of these studies pooled sensitivity and specificity of 0.92 nonspecific bacterial antigens or cross-
were excluded because of an inade- (95% CI 0.89 to 0.95) and 0.99 (95% CI reaction with other nongroup A strep-
quate reference standard (Fig 1 and 0.97 to 0.99), respectively. The sensitivity tococci.43
Supplemental Table 2).36–41 All studies and specificity of the other 3 test cate-
included used culture as the reference gories were comparable with pooled Sensitivity and Specificity Analysis:
standard to compare the RADT perfor- sensitivity ranging from 0.84 to 0.86, and Pediatric Population
mance. Thirty-six of the 48 studies were pooled specificity ranging from 0.94 to Thirty-three paired sensitivity and speci-
carried out in a developed country and 0.96. The S-ROC curves for each RADT ficity results from 25 studies evaluated
12 in a developing country. Eight types of type compared with the other test cat- RADTs in children only, and meta-analysis
RADTs were found among these articles. egories are shown in Fig 3. was performed for 3 categories of test

774 LEAN et al
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 REVIEW ARTICLE

TABLE 1 Characteristics of Studies With Data on Performance of RADTs

Author, Year Trade Name Age Range, y No. of Patients Setting Country
Latex agglutination
Bar-Dayan et al,53 1997 Detect A Strep Mean 24 32 Clinic Israel
Fontes et al,54 2007 Patho Dx, DPC 1–18 229 ED, clinic Brazil
Liposomal technology
Dagnelie et al,27 1998 Directigen 1,2,3 Strep A; Becton Dickinson 4–69 558 Clinic Netherlands
Lateral flow/immunochromatographic assays
Finger et al,28 1999 Quickvue Flex Strep A 3–16 777 ED, clinic Vietnam
Nerbrand et al,25 2002 Quickvue In-Line Strep A test All ages 536 Clinic Sweden
Gieseker et al,22 2002 OSOM Ultra Strep A Children 302 ED, clinic US
Gieseker et al,30 2003 OSOM Ultra Strep A Children 887 Clinic US
Atlas et al,55 2005 Acceava $18 148 Clinic US
Fox et al,23 2006 Signify Rapid Strep A Test 3–18 53 Hospital US
Forward et al,33 2006 Strep A Rapid Test Device, Nova Centuty Scientific Inc. All ages 818 Clinic Canada
Abu-Sabaah et al,32 2006 Immunostics Strep A Direct All ages 355 Hospital, clinic Saudi Arabia
Van Limbergen et al,56 2006 Quickvue+ Strep A Test Mean 3.85 201 ED Scotland
Wright et al,57 2007 Quickvue In-Line Strep A test & OSOM Ultra 0–18 338 Clinic US
Maltezou et al,58 2008 Link2 Strep A 2–14 451 Clinic Greece
Camurdan et al,59 2008 INTEX Strep A II #17 1248 Clinic Turkey
Al-Najjar et al,44 2008 Diaquick Strep A Test Children 496 Clinic UAE
Tanz et al,60 2009 Quickvue 3–18 1848 Clinic US
Kim,45 2009 SD Bioline Strep A Children 193 Clinic Korea
Llor et al,34 2009 OSOM Strep A $14 222 Clinic Spain
Gurol et al,20 2010 Quickvue 0–90 1048 Clinic Turkey
Sarikaya et al,61 2010 Quickvue 18–64 100 ED US
Ding et al,24 2011 Clearview Exact Strep A #14 630 Clinic China
Cohen et al,62 2012 StreptAtest, Dectrapharm 3–15 785 Clinic France
ELISA
Kurtz et al,29 2000 Abbott TestPack Plus 4–15 537 Clinic US
Rosenberg et al,63 2001 Abbott TestPack Plus .3 126 ED Canada
Roosevelt et al,64 2001 Abbott Signify Strep A 3–16 322 Hospital US
Sheeler et al,18 2002 Abbott TestPack Plus All ages 443 Clinic US
Nerbrand et al,25 2002 Abbott TestPack Plus All ages 536 Clinic Sweden
Santos et al,65 2003 Abbott TestPack Strep A 1–12 49 Clinic Brazil
Johansson et al,66 2003 Abbott TestPack Strep A Plus $4 169 Clinic Sweden
Lindbaek et al,31 2004 Abbott TestPack Strep A Plus Mean 23.9 306 Clinic Norway
McIsaac et al,5 2004 Abbott TestPack Strep A Plus 3–69 787 Clinic Canada
Humair et al,67 2006 Abbott TestPack Plus Strep A .15 372 Clinic Switzerland
OIA
Schlager et al,68 1996 Biostar Strep A OIA All ages 262 Clinic US
Seaberg et al,69 1997 Biostar Strep A OIA All ages 86 ED US
Kaltwasser et al,26 1997 Biostar Strep A OIA Children 200 ED US
Gerber et al,17 1997 Biostar Strep A OIA 1–51 2113 Clinic US
Hart et al,42 1997 Biostar Strep A OIA All ages 263 Clinic US
Needham et al,70 1998 Biostar Strep A OIA All ages 465 Clinic US
Supon et al,71 1998 Biostar Strep A OIA MAX All ages 413 ED, clinic US
Pitetti et al,72 1998 Biostar Strep A OIA 1–18 233 ED, clinic US
Kuhn et al,73 1999 Biostar Strep A OIA 2–18 363 ED, clinic US
Chapin et al,21 2002 Thermo Biostar Strep A OIA Children 520 Clinic US
Gieseker et al,22 2002 Strep A OIA MAX Children 302 ED, clinic US
Ezike et al,19 2005 Strep A OIA MAX 5–18 363 ED US
Filho et al,43 2006 Strep A OIA MAX $18 81 ED Brazil
Rimoin et al,6 2010 Strep A OIA MAX 2–12 2472 Clinic Brazil, Croatia,
Egypt, Latvia
DNA probe
Heelen et al,74 1996 Gen-Probe All ages 318 ED, clinic US
Chapin et al,21 2002 Gen-Probe Children 520 Clinic US
Fox et al,23 2006 Gen-Probe 3–18 53 Hospital US
PCR assay
Slinger et al,46 2011 Laboratory developed Children 306 ED Canada
FISH
Tajbakhsh et al,75 2011 Not available All ages 110 Unknown Iran
Ding et al,24 2011 Not available #14 630 Clinic China
ED, emergency department.

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FIGURE 2
Forest plots of summary estimates of sensitivity and specificity stratified by RADT category. The black boxes indicate the sensitivity and specificity, and the
horizontal black lines indicate the corresponding 95% CIs for each result in each RADT category. For each RADT category with more than 3 results, a diamond is
centered on the summary estimate for sensitivity and specificity, with points on the corresponding 95% CI, as estimated jointly by bivariate random-effects
regression. FN, false-negative; FP, false-positive; IC, immunochromatographic assay; TN, true-negative; TP, true-positive.

776 LEAN et al
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 REVIEW ARTICLE

Strep A test (Dialab GmbH, Vienna, Aus-

tria) and culture. With a GAS prevalence
of 14%, the positive predictive value was
very high (0.96) with a negative predic-
tive value of more than 0.99.44 In the
OIA group, the study by Ezike et al,19
which used the OIA MAX test, found the
highest sensitivity and specificity. This was
achieved by using a single throat swab for
both the OIA and for culture in children
aged 5 to 18 years who presented with
symptoms of acute pharyngitis.19 It is
noteworthy that when investigators in
this study collected throat swab speci-
mens by rubbing 2 swabs simultaneously
on the posterior pharynx and both ton-
sils, rather than a single swab, they ob-
served a lower sensitivity (0.92) and
specificity (0.96).19 In the molecular
technique group, the GAS direct probe
test (Gen-Probe, San Diego, CA) was one
of the RADTs evaluated in 520 patients in
the study by Chapin et al21; its perfor-
FIGURE 3
S-ROC curve and sensitivity and specificity stratified by RADT category. In each panel, all pairs of sensitivity mance parameters were reported to be
and specificity from RADT categories with more than 3 results are represented as a cross (+). A black comparable to those of culture when
cross indicates the pair is from the indicated RADT category, whereas a gray cross shows pairs from all both were compared with Todd-Hewitt
other RADT categories with more than 3 results. Each panel also shows for the indicated RADT category
the summary estimate (black closed circle) and corresponding 95% confidence ellipse (thick black line), broth culture. Similarly, a retrospective
and the S-ROC curve (thin black line), which were derived from bivariate random-effects regression. In clinical study on a laboratory-developed
addition, each panel shows in gray the summary estimate and 95% confidence ellipse, and S-ROC curve, and internally controlled rapid GAS PCR
for all other RADT categories with more than 3 results. IC, immunochromatographic assay.
assay using the dnaseB gene as the tar-
get gene reported a sensitivity and
type(lateralflow/immunochromatographic a sensitivity of 0.85 (95% CI 0.80 to specificity of 0.96 and 0.99, respectively.
assay, OIA, and molecular technique). We 0.89), and the specificity of lateral flow/ An equally high sensitivity and specificity
did not find evidence for a correlation immunochromatographic assay was was observed when the test was carried
between sensitivity and specificitywithin slightly higher (0.97, 95% CI 0.95 to 0.98) out using either flocked swabs or con-
the test categories. The summary esti- than OIA (0.95, 95% CI 0.93 to 0.97). ventional swabs.46 These 2 more recently
mates of sensitivity and specificity among developed RADTs have a turnaround time
studies in children were 0.87 (95% CI 0.84 Best-Performing Tests of 1 to 2 hours and require special labo-
to 0.89) and 0.96 (95% CI 0.95 to 0.97), There were 6 studies that had a sensi- ratory setups, which may necessitate
respectively, which is similar to the overall tivity of 0.95 or above. These included follow-up with patients for relaying re-
summary estimates (Supplemental Figs 2 studies from the lateral flow/ sults, as compared with other techniques
5 and 6). Molecular techniques per- immunochromatographic assay cate- that are true point-of-care tests.8
formed better than OIA and lateral flow/ gory, 1 of OIA, 1 of ELISA, and 2 from the
immunochromatographic assay in the molecular technique group.19,21,31,44–46
pediatric population, with a pooled sen- Of these, 4 also had a specificity over DISCUSSION
sitivity of 0.93 (95% CI 0.89 to 0.96) and 0.95.19,21,44,46 In the lateral flow/ Our study is the most comprehensive
a pooled specificity of 0.99 (95% CI 0.98 to immunochromatographic assay group, meta-analysis of RADTs for GAS phar-
1.0). The performance of OIA and lateral the study by Al-Najjar et al44 in the United yngitis to date. We made an objective
flow/immunochromatographic assay Arab Emirates collected paired throat assessment of study quality by using the
was similar, OIA and lateral flow/ swabs from 505 children with prede- modified QUADAS tool and were able to
immunochromatographic assay had fined symptoms for testing with Diaquick evaluate 4 categories of test type with

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pooled results. Overall, the sensitivity of RADTs in either adults or children.9 The compared with AUD$30 per test for
included RADTs in our study was 0.86 reasons for these differences in recom- culture, whereas costs in the United
(95% CI 0.83 to 0.88) and specificity 0.96 mendations are not immediately clear, States and Europe are more difficult to
(95% CI 0.94 to 0.97), although with but may relate to differing opinions be- compare because of the wide range of
noticeable variability among individual tween the expert groups as to the pricing by individual commercial com-
tests. These results indicate that RADTs perceived necessity of treating GAS panies . The practice of using confir-
in general have high diagnostic accu- pharyngitis to prevent suppurative and matory cultures to back up RADTs has
racy. The sensitivity and specificity of nonsuppurative complications, particu- been shown to cost .$8 million per
these tests when analyzed in pediatric larly acute rheumatic fever.47 We con- additional case of rheumatic heart dis-
studies alone were similar to the overall sider that our data show that the overall ease prevented,52 and should be ques-
estimates. Overall, the newer molecular sensitivity of RADTs is sufficiently high tioned as a cost-effective approach to
techniques were the best-performing that a backup culture is generally not management.
tests, particularly in terms of their necessary, with the possibility of missing There are several limitations to our
sensitivity, although a minority of non- 14% of potential GAS pharyngitis cases study. Despite our best efforts to ex-
molecular tests also performed ex- being an acceptable level of risk given clude low-quality studies, particularly
tremely well. There was less variability the low risk of acute rheumatic fever in those with an inadequate reference
in sensitivity observed for the more most industrialized settings, but this standard, there was considerable var-
recently developed RADTs compared decision is likely to be at the treating iability in methodology among studies.
with the older tests. physician’s discretion. The high overall This included number and type of throat
The 2 recently published major US and specificity of RADTs means that these swabs used, as well as techniques used
European guidelines both recommend tests can prevent unnecessary antibiotic to obtain these throat swabs.19,23,29,46
the use of RADTs in routine clinical prescription due to minimal overdiag- Methods of sample collection were not
practice,4,9 although with differences in nosis of GAS pharyngitis in the vast ma- clearly reported in all studies and
the indications for their use and in- jority of cases. there is no way to control the quality of
terpretation of their results. There is Although rheumatic fever is uncommon the swab samples. Studies included
also considerable variability in recom- in Europe and the United States, with an also differed in their settings and the
mendations for use of RADTs when other incidence of ,1 per 100 000, the dis- clinical severity of included patients.
guidelines are considered, and some ease remains an important cause of For example, we included studies that
countries, including Australia, do not cardiac morbidity and mortality in assessed diagnostic accuracy of RADTs
currently recommend the use of RADTs.47 many tropical developing countries among patients both before receiving,
The recent US guidelines recommend where the incidence is frequently .50 and after receiving, antibiotic treat-
RADTs for the diagnosis of GAS pharyn- per 100 000.48 In these countries, there ment.18,28 These factors are potential
gitis in adults and children at least 3 is a clear indication for treatment of confounders in the estimation of di-
years of age with acute sore throat who GAS pharyngitis to prevent rheumatic agnostic accuracy and may explain
do not have clinical features suggestive fever and its chronic and disabling some of the observed heterogeneity
of a viral etiology (cough, rhinorrhea, sequelae, rheumatic heart disease.49 A across each type of RADT. However, be-
hoarseness, and oral ulcers).9 These highly sensitive ($95%) and inexpensive cause of insufficient numbers of studies
guidelines recommend the use of RADT with a very rapid turnaround time within each test type, we were unable to
backup culture for negative RADTs in could make a major contribution to con- perform either a meta-regression or
children (but not in adults) because of trol efforts for rheumatic fever. Based on a subgroup analysis to determine the
concern regarding low sensitivity. The our data, however, no single test cur- importance of these factors. In terms of
recent European guidelines recommend rently fulfills all 3 of these criteria. quality of included studies, blinding of
using the Centor criteria to guide the use When cost is considered in the man- reference standard results was not well
of RADTs in the diagnosis of GAS phar- agement of pharyngitis, RADTs have reported in most of the included studies.
yngitis; physicians can consider the use been shown to be the more cost-effective Information on uninterpretable results
of RADTs in patients with 3 to 4 Centor option when compared directly with was also poorly reported. It was not
criteria, whereas there is no need to culture (as treating all and none have possible to determine if uninterpretable
routinely use RADTs in patients with 0 to unacceptable costs).50,51 In terms of di- results occurred in 24 of the included
2 criteria.4 These guidelines do not rec- rect costs, in Australia, RADTs cost ap- studies. In addition, withdrawals were
ommend a backup culture for negative proximately AUD$5 to AUD$10 per test unclear or not explained in 16 of the

778 LEAN et al
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 REVIEW ARTICLE

included studies (Supplemental Table 2). truly “point-of-care” tests with a turn- with culture and antibiotic treatment,
Finally, we included studies published in around time between 1 and 3 hours, especially in the pediatric population,
the English language only, which may whereas the immune-based tests have would be beneficial for policy makers
have reduced the numbers of studies a turnaround time as fast as 30 sec- and clinicians with regard to choice of
included in our meta-analysis. onds. Other factors that may have an RADT and treatment decisions.
The diagnostic accuracy of the more impact on sensitivity and specificity of Our meta-analysis shows that RADTs can
recently developed RADTs (molecular the RADTs, such as the type of throat be used as accurate, rapid tests for the
techniques) is encouraging. However, swab and sampling techniques, also diagnosis of GAS pharyngitis and that
further research could focus on im- need to be further investigated in well- generally backup culture for negative
proving the practicality of these tests, designed studies, to further improve the tests are not necessary in most low-
especially when they are used in the diagnostic accuracy of RADTs. Finally, incidence rheumatic fever settings, par-
primary care settings. A considerable studies to examine cost-effective analy- ticularly if tests with a high sensitivity are
drawback of these tests is that none are sis of each class of RADTs compared used,includingthenewermolecular tests.

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Rapid Diagnostic Tests for Group A Streptococcal Pharyngitis: A Meta-analysis
Wei Ling Lean, Sarah Arnup, Margie Danchin and Andrew C. Steer
Pediatrics 2014;134;771
DOI: 10.1542/peds.2014-1094 originally published online September 8, 2014;

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
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Rapid Diagnostic Tests for Group A Streptococcal Pharyngitis: A Meta-analysis
Wei Ling Lean, Sarah Arnup, Margie Danchin and Andrew C. Steer
Pediatrics 2014;134;771
DOI: 10.1542/peds.2014-1094 originally published online September 8, 2014;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/134/4/771

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: .

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