Improved Diagnostic Performance of an Immunofluorescence-Based Rapid

Antigen Detection Test for Group A Streptococci in Children with Pharyngitis

Laurence Lacroix1, MD, Abdessalam Cherkaoui2, PHD, Diane Schaller3, MD, Sergio
Manzano1, MD, Annick Galetto-Lacour1, MD, Ulrich Pfeifer3, MD, René Tabin3, MD, and
Alain Gervaix1, MD
1
Pediatric Emergency Department, Geneva University Hospitals, Geneva, Switzerland
2
Bacteriology Laboratory, Division of Laboratory Medicine, Geneva University Hospitals,
Geneva, Switzerland
3
Valais Hospital, Sion, Switzerland

Abstract
Background: Accurate diagnosis and appropriate treatment of Group A streptococcal
(GAS) pharyngitis are important to prevent complications. Most available rapid
antigen detection tests (RADTs) have shown excellent specificity but often lack
sensitivity. Our objective was to compare the diagnostic performances of a new
fluorescence-based immunoassay and a classic immunochromatographic RADT using
standard throat culture or PCR as references.
Materials/Methods: Prospective observational study in 2 pediatric emergency
departments in children aged 3 to 15 years old presenting with pharyngitis and a
McIsaac score ≥ 2. Three throat swabs were obtained simultaneously: one for culture
and one for each of both RADTs. PCR assay of the DNaseB sequence was performed
in case of discordant results (culture negative and either RADTs positive).
Results: A total of 1002 patient were analyzed, with an overall 37.1% prevalence of
GAS pharyngitis. Sensitivity, specificity, positive and negative predictive values were
respectively 84.9%*, 96.8%, 94.0% and 91.6% for the new fluorescence-based
immunoassay, and 75.3%*, 98.1%, 95.9%, 87.0% for the immunochromatographic
test (* p< 0.05).
Conclusion: The immunofluorescence-based assay demonstrated improved
diagnostic performances over the standard immunochromatographic RADT.
Similarly specific for GAS detection, it demonstrates significantly higher sensitivity
in children with McIsaac scores 2 or more. A negative result rules out a risk of GAS
pharyngitis in 91.6 % of children, making it an appropriate tool in pediatric
emergency settings. Combined to the low incidence of rheumatic strains, critical
appraisal of current practice to routinely perform a back-up throat culture from
children with pharyngitis and with negative GAS RADT could be reconsidered.
Key words: Streptococcal, GAS, Pharyngitis, Children, RADT
Introduction

Sore throat is one of the most frequent complaints in children presenting to primary
care providers. Although the causative agent is most commonly viral (adenovirus,
enterovirus, herpes viruses such as Epstein Barr virus (EBV) or herpes simplex virus
(HSV), respiratory syncytial virus (RSV), para-influenza or influenza virus)1 and will
require only symptomatic treatment, group A Streptococcus (GAS) is still the most
common cause of bacterial pharyngitis affecting over 600 million cases annually
among people aged over 4 years 2. In a recent meta- analysis, the pooled prevalence
of GAS from studies involving symptomatic children of all ages with sore throat was
37% and the pooled prevalence of GAS carriage among asymptomatic children of all
ages was 12% 3. A prospective, population-based study of the incidence of GAS
pharyngitis in a nonindigenous population in an industrialized country (Australia),
has recently demonstrated an incidence of 13 per 100 child-years of GAS culture–
positive sore throat in children aged 5 to 12 years, almost unchanged since the 1950’s
4
.
Although GAS pharyngitis is typically a self-limited disease, antibiotic
treatment is still recommended for individuals with symptomatic pharyngitis once
GAS has been confirmed5. The goal of antimicrobial therapy is to improve clinical
symptoms, to decrease transmission to close contacts, to prevent suppurative
complications (otitis media, sinusitis, peritonsillar or retropharyngeal abscesses,
suppurative cervical adenitis) and nonsuppurative streptococcal sequelae, particularly
acute rheumatic fever 6. However, whereas the latter is still a leading cause of
cardiovascular morbidity and mortality in many developing parts of the world, the
role of antibiotics in the treatment of acute pharyngitis is a continuing source of
controversy in developed countries where the incidence of acute rheumatic fever is
low.
Prescription of antibiotics should be reserved to GAS infected patients in
order not to increase the potential for bacterial resistance occurrence. Isolated clinical
features are not sufficiently accurate to reliably discriminate between GAS and viral
pharyngitis 7. Clinical prediction rules such as Mc Isaac and Centor scores integrate
symptoms and signs in order to better identify GAS infected patients8, 9. While
Centor score was elaborated for the adult population, Mc Isaac score was designed
for both adults and children. In a large scale validation study of the McIsaac score,
the risk for GAS pharyngitis in patients aged 3 years up to 14 years old showing a
score ≥ 2 was 44%10. Although a clinically important reduction in unnecessary
antibiotic use would be encountered when applying clinical prediction rules, too
many GAS infections would still be missed5, 7. On the other hand, performing throat
cultures, which is the gold standard test to confirm the presence of GAS in any
patient presenting with pharyngitis is not cost-effective and implies a 24 until 48-
hours delay before the result is available11. Return visits for follow-up and
prescription of the appropriate treatment can therefore be problematic.
Easy-to-perform rapid antigen detection tests (RADTs) have been developed
in order to better discriminate between GAS and non-GAS, mainly viral pharyngeal
infections. These tests show many advantages: availability for bed-side testing, rapid
GAS identification, prompt treatment, and reduction of unnecessary antibiotic
12
prescription . Current recommendations include symptomatic treatment without
further need for testing in children with McIsaac score <3. In children with Mc Isaac
score ≥3, it is recommended that RADT should be performed to detect GAS.
Antibiotic treatment should be prescribed in case RADT is positive, but any negative
result should be confirmed by throat culture according to American recommendations
5
.
Therefore, international recommendations mainly support positive RADTs as
true positive results, because they are highly specific (>95%), whereas negative
results are recommended to be confirmed by back-up throat cultures because of a
13-15
relative lack of sensitivity for some of them, which can be as low as 70% .A
RADT showing better sensitivity could make useless the need for throat culture
confirmation, hence simplifying the procedure for the patient, parents or caregivers.
 Recently, a new immunoassay using the optical immunoassay technology, the
Sofia® Strep A Fluorescent immunoassay (FIA) (Quidel Corporation, San Diego,
CA, USA) has shown excellent in vitro performances with up to 100% GAS detection
(manufacturer’s package insert, data not published). In vitro data suggest that this
fluorescent based immunoassay may be more sensitive than other RADTs and
perhaps may even be as sensitive as standard throat cultures.
However, diagnostic performances of the test and routine use still need to be tested in
the pediatric population, since children are more prone to GAS infections than adults.
Our primary objective was to compare the diagnostic characteristics of a
fluorescent based immunoassay (Sofia® StrepA FIA) with those of a standard
immunochromatographic RADT (Alere® TestPack Strep A, Alere Inc., Waltham,
MA, USA) in real-life conditions, in children with pharyngitis using standard throat
culture and PCR as references to detect GAS presence. The secondary objective of
the present study was to determine the performances of both tests in relationship to
the pretest-probability of GAS infection measured by the McIsaac score.

Material and Methods

Study design
We conducted a prospective observational multicenter hospital-based study. The
study was approved by the Institutional Ethics Committee in accordance with Good
Clinical Practic guidelines and provisions of the Declaration of Helsinki, and is
registered on ClinicalTrials.gov (NCT 03099018).

Setting and selection of participants

The study was conducted in a tertiary care urban pediatric center with 28’300 annual
visits and a regional district hospital with 5’500 annual visits. Patients aged between
3 and 15 years showing a clinical diagnosis of pharyngitis (defined as inflammation
of the pharyngeal mucosa in the context of acute sore throat, with or without
exudates) with a McIsaac score ≥2 were asked to participate to the study. Exclusion
criteria included antibiotic treatment received in the two weeks preceding the
consultation and any missing obligatory data (any missing or invalid RATDs, culture
or PCR for discrepant results). After parental written informed consent was obtained,
three throat swab specimens were simultaneously collected from eligible patients who
presented to the Pediatric Emergency Department (PED) at both participating centers.
One swab was used for the new FIA (Sofia® StrepA FIA), the second one for a
standard RADT (Alere® TestPack Strep A), and the third swab was sent for routine
culture. All diagnostic tests were performed in each patient, and PCR was secondarily
performed on the culture swab in case of discordant results (i.e. either RADT positive
with negative throat culture). RADTs’ performance results were compared,
considering positive throat culture or positive PCR as gold standard tests for GAS
detection. Clinical presentation assessed with McIsaac score was recorded for each
patient.

Swabbing method
Three throat swabs were performed simultaneously and not sequentially in order not
to harm the patient more than would represent a unique standard GAS testing. In
order to test the accuracy of the swabbing technique, a preliminary study was
performed on 11 patients (10 patients with positive RADT, and 1 negative control) to
ascertain that the number of colonies was concordant between the three swabs.
Cohen’s ĸ was run to determine if the colony counts (cfu/mL) showed agreement
between the three swabs performed at once. Each sample showed perfect agreement
between the three swabs. (ĸ=1.000, p<.0005, data not shown).

RADT workup
Concerning RADT, both the Sofia® StrepA FIA and the Alere® TestPack Strep A
assays were performed according to the manufacturer’s protocol. The new Sofia®
StrepA FIA employs immunofluorescence technology in combination with an
analyzer to detect GAS antigen, after extraction of the antigenic components of GAS
from a throat swab of a symptomatic patient.
After migration of the sample through a test strip, GAS antigens will be bound by
antibodies coupled to fluorescent microparticles that migrate through a test strip
where they are detected by the analyzer.

Culture method
Throat swab specimens were sent to the bacteriology lab in ESwab™ tubes,
permitting technicians to run multiple tests from the same specimen resuspended in
1mL of liquid suspension. An inoculum of 10 µl of liquid sample suspension was
seeded in duplicate on the surface of a 5% sheep blood agar and incubated
anaerobically for 18–24 hours. Negative plates at 24 hours were re-incubated
anaerobically for another 24 hours. For positive cultures, the media was examined for
the quantity and morphological type of organisms present. With a 10 µl loop, one
colony equals 100 CFU/ml. All β-hemolytic colonies isolated were identified by
standard microbiological techniques and Matrix-assisted desorption ionization-time
of flight mass spectrometry (MALDI-TOF MS, Maldi Biotyper 2.0, Bruker
Daltonics, Bremen, Germany). 900 µl of liquid sample suspension were stored at -
20°C.

Discrepant results
Discrepant results between the culture and the corresponding RADT (i.e. any positive
RADT in case of a negative throat culture for GAS) were resolved after thawing of
the remaining culture sample using additional PCR assay as a reference (Quidel
AmpliVue® GAS Assay kit) according to the manufacturer's instructions.

Outcome measures
The primary objective was to compare sensitivity and specificity of two rapid tests
(Sofia® StrepA FIA and Alere® TestPack Strep A) using standard throat culture or
PCR as a reference. Secondary objectives were to determine the sensitivity and
specificity of the two tests in relationship to the pretest-probability of GAS infection
measured by the McIsaac score.

Statistical analysis
The sample size of 1000 patients was dictated by the number of patients satisfying a
5% difference in sensitivity between both RATDs. Indeed, based on the recent
literature, the sensitivity of current commercially available RADTs for GAS detection
is between 70 and 90%. In-vitro sensitivity of the Sofia® StrepA FIA is 100%
(manufacturer’s package insert). In vivo, a sensitivity of 95% for the Sofia® StrepA
FIA would be a clinically significant difference compared to a sensitivity approaching
90% of most currently available RADT13, 15
. In order to show such a difference
between the two tests (paired data) with throat culture as the gold- standard and PCR
for discrepant results, 345 patients would be necessary, assuming a GAS prevalence
of 100% among the included subjects (α 0.05, 1-β 0.80). Since the expected GAS
prevalence in the study population (McIsaac ≥2) is 44% according to previously
10
published data, the total number of patients to be recruited was 785 . For more
security regarding missing data, we have decided to enroll 1000 patients.

We used t test if data were normally distributed and the Mann-Whitney test if they
were not. Quantitative variables were expressed as mean and standard deviation (SD)
if data were normally distributed and as median and interquartile range if they were
not. Sensitivity, specificity, and predictive values were calculated using culture or
PCR results as diagnostic gold standards. As both RADTs were performed on each
patient, paired data result and methods that account for the correlated binary
outcomes were necessary (McNemar's test). Anonymized data were recorded using
Microsoft Excel Database and then computed under PASW 22.0.
Results
Demographic characteristics
A total of 74’814 patients presented to the PED in both centers during the study
period between June 2014 and October 2016 and a total of 1’109 patients meeting
inclusion criteria were enrolled. 107 of them were excluded (Sofia® StrepA FIA
assay result invalid or missing: 52 patients, no culture: 23 patients, missing case
report form or consent: 32 patients). After exclusion of missing obligatory data, a
total of 1002 patients with pharyngitis and McIsaac score
≥2 were finally included in the study, of which 808 in the tertiary care hospital and
194 in the regional hospital.
In our population, the overall prevalence of GAS pharyngitis rate based on the culture
or PCR for discrepant results was 37.1%. Ages were normally distributed, with a
mean age of 6.1 years (SD 3.3 years) and an age range of 3.0 16.0 years.
Demographic and clinical characteristics are shown in Table 1.

Evaluation of GAS detection methods

Table 2 summarizes diagnostic performance results of the standard RADT and the
fluorescent immunoassay versus routine culture or versus routine culture plus
associated PCR testing for
discrepant results. Whereas both assays show similar specificity results, the Sofia®
StrepA FIA showed an overall 84.9% sensitivity (95% CI 82.6-86.7%) and 91.6%
negative predictive value (95% CI 90.3 – 92.6), which are better than those of the
standard immunochromatographic Alere® TestPack Strep A assay. Both diagnostic
tests were performed on each patient.
McNemar's test showed significant difference in the detection of GAS infected
patients between both tests (p < 0.00001).
Discrepant results
False negative cases
53 patients showed a negative Sofia® StrepA FIA assay but a positive throat culture.
Three additional patients with a negative Sofia® StrepA FIA, a negative culture but a
positive Alere® TestPack Strep A assay showed a positive PCR assay for GAS. Of
the 56 false positive cases, a total of 16 had a positive Alere® TestPack Strep A test.
GAS colonies were quantified in 44 of the 53 culture-positive specimens. Of these,
no relationship was found between the assay result and colony counts (Figure 1).
Moreover, no correlation was found between the number of discrepant results and
clinical presentation scores according to McIsaac scores.
92 patients showed a negative Alere® TestPack Strep A assay but either a positive
culture or a positive PCR assay for GAS. 5 patients out of 5 with a negative Alere®
TestPack Strep A assay and a negative culture but a positive GAS PCR assay showed
a positive Sofia® StrepA FIA.

False positive cases

31 patients showed a positive Sofia® StrepA FIA assay with a negative culture, of
which 11 positive PCR (true positive), 9 negative PCR (false positive).
Unfortunately, 11 additional PCR assays could not be performed because of missing
samples. We considered these cases as false positive results by default, based on the
sole result of the culture. The same proportions were found for the 21 patients
presenting a positive Alere® TestPack Strep A assay with a negative culture: 9
positive PCR (true positive), 8 negative PCR (false positive), and 4 PCR that could
not be performed because of missing samples, considered as false positive results by
default.

Influence of McIsaac scores on diagnostic performance of the tests

Table 3 shows diagnostic performances of both the standard RADT and the Sofia®
StrepA FIA test stratified on various McIsaac score categories (Mc Isaac scores =2,
≥3, ≥4 or =5). For each of these, specificity was comparable for both tests, but
sensitivity was always significantly higher for the Sofia® StrepA FIA than for the
standard RADT.

Discussion
GAS pharyngitis recognition still represents a common challenge in primary
care settings. Although a majority of presentations are linked to common viral throat
infections and will only need supportive treatments, it is still recommended that GAS
pharyngeal infections are adequately recognized in order to benefit from an
appropriate antibiotic treatment.
Diagnostic accuracy of RADTs for the detection of GAS pharyngitis in
children shows a summary sensitivity of 85.6% (95% CI 83.3-87.6) and a summary
specificity of 95.4% (95% CI 94.5-96.2)16. Our results showed that in real-life
conditions, diagnostic performances of the Sofia® StrepA FIA assay for GAS
detection were better than that of the standard comparative immunochromatographic
RADT but consistent with most recent findings, with 84.9 % sensitivity13, 14, 16.
There are many different types of RADTs for GAS detection. The first
generation of tests (latex agglutination, then followed by enzyme-linked
immunosorbent assays (ELISAs) showed relatively poor sensitivity, limiting their
clinical implication. A recent meta-analysis of RADTs performances for GAS
pharyngitis also showed an overall 0.86 sensitivity (95% CI 0.83 to 0.88), with the
best performing tests being those using the newer molecular techniques15. Although
some molecular RADTs among the most recent ones show a rapid turnaround time
with few preanalytical manipulations17, 18
, most of them still require a long
turnaround time (1 to 3 hours) before the result is obtainable, limiting their
practicality in emergency and primary care settings. A few non molecular tests
performed well, but sampling techniques showed great variability between the studies
(number and type of throat swabs)15.
Several breakthroughs have occurred over the past few years that have
enabled the implementation of fluorescent based immunoassay systems at the point of
care. Advantages of a fluorescent detection system are numerous. They include
higher sensitivity in detection of the analyte, simplified reagents and simpler assay
designs, opportunity for walk away mode testing along with the elimination of
misinterpretation often associated with visually-read point-of-care assays, and finally
host connectivity for transfer of results.
Both American and European guidelines recommend the use of RADTs in
clinical practice, somewhat slightly differently regarding their use and implications.
Whereas European recommendations are based on the results of RADTs without
backup culture of negative tests19, American recommendations take into account
clinical factors to decide whether the patient should undergo throat swabbing and
specify that any negative RADT result should be confirmed by throat culture if the
clinical suspicion is high enough5, 20.
Although consistent, this strategy is not efficient enough. Indeed, it implies
higher costs than the use of RADT alone as well as several disadvantages: the need
for 2 serial tests for the patient (RADT followed by throat culture), 24 to 48-hours
delay before diagnostic confirmation, the need for parents or caregivers to get the
prescription secondarily, thereby implying a potential risk for missing the patient
once the child discharged from hospital, as well as additional costs to handle the
backup throat culture.
Moreover, only few new cases are detected secondarily. It is therefore not
surprising that adherence rates to these recommendations are low among primary care
pediatricians21.
Besides sensitivity analysis, negative predictive value is even more relevant in
clinical practice since it takes into account prevalence rates of the infection in the
corresponding population. In our pediatric population of children presenting with a
McIsaac score ≥2, the prevalence of GAS pharyngitis was 37.1%, which is consistent
with many previously published studies10.
Consequently, in children showing a McIsaac score ≥2, a negative Sofia®
StrepA FIA result ruled out a risk of GAS pharyngitis in ≥ 91.6 % of cases. After
stratification on different McIsaac score categories, sensitivity of the Sofia® StrepA
FIA was always statistically significantly better than that of the standard RADT, as
well as the even more clinically relevant corresponding negative predictive values.
The Sofia® StrepA FIA also showed a high specificity, as for the great majority of
most available RADTs (i.e., 95% or greater) when compared to throat cultures. In our
cohort, only 20 false positive Sofia® StrepA FIA results were detected. Hence,
because of only few false positive tests, the positive predictive value of the test is
high, and the decision to treat the patient can be based on a positive test with a great
degree of confidence, with no need for further culture confirmation.
Positive culture results were considered the gold standard method for
streptococcal detection. However, optimal sampling of both tonsils and the posterior
pharyngeal wall is sometimes difficult in young children, with culture sensitivity as
low as 20% in case of suboptimal sampling techniques22. For this reason, negative
culture results in children with any of both RADTs showing positive results were
confirmed by PCR testing.

False positive RADT results are unusual. They can result from presence in the
pharynx of commensal Streptococcus milleri strains that express the group A
carbohydrate antigen, or from nutritional variants of Group A streptococci or non-
hemolytic Group A streptococci, which are difficult to identify on standard blood
agar plates culture. In our study, no serological confirmation was performed to
differentiate true infection from carrier state. It is hence likely that sensitivity might
have been underestimated whereas specificity may even show higher results once
patients with carrier status have been taken into account in the performance analysis.
In most developed countries the prevalence of rheumatic heart disease is low, the
accessibility to medical care is high, and the diagnostic accuracy of most RADT is
constantly improving.
Critical evaluation of current practice to routinely perform a back-up throat
culture from children with pharyngitis showing a sufficient clinical suspicion of GAS
infection (i.e. McIsaac score greater than 2 in the present study) and with negative
GAS RADT should therefore be re- considered.
Surprisingly, false negative results of the Sofia® StrepA FIA test did not show any
correlation with the amount of colony-forming units/mL found on the corresponding
culture samples.
However, it has been previously described that RADTs sensitivity may vary
according to the severity of the disease, with greater sensitivity in patients with more
severe symptoms (spectrum effect)23, 24. In our setting, this could be explained by the
fact that sensitivity may also be influenced by the sampling method itself, with
greater sensitivity in children showing a greater number of colonies in the inoculum
from the throat swab. Moreover, it has also been described that physicians who had
previously received a specific training on the sampling method showed greater
sensitivity in the test they perform25. In our study, although appropriate training in the
swabbing method has been provided to physicians in charge of the study, rotating
residents may not have had access to the full training provided once only at the
beginning.
Our study has some limitations. First, we chose using PCR testing as a backup
for negative throat culture together with any positive RADTs only. The culture
method is not 100% sensitive nor is it discriminating between active infection and
GAS carrier status. The latter could have been determined through antistreptolysin O
(ASLO) blood titer determination, but this would have implied venous puncture. We
had intentionally chosen to avoid this strategy, as determination of GAS presence is
not associated with any type of blood test nowadays in case there is no complication.
Our methodology assumes that all culture-positive patients are true positives, and that
there is no false-positive culture results; as a result, specificity of the culture itself is
assumed to be 100% and sensitivity can therefore be underestimated. However, to
date, there is no RADT that differs between carrier status and active infection.
Secondly, sensitivity varies not only with the performance of the test itself but also
with the quality of the sampling method.
Third, for practical reasons, control of the quality of the swab samples has not
been performed. However, with such a high sensitivity and specificity, the Sofia®
StrepA FIA assay can adequately identify patients with GAS pharyngitis who should
benefit from early antimicrobial therapy. Consequently, they should rapidly be able to
return to school, limiting the risk for spreading GAS through secretions and droplets.
Moreover, this also allows parents or caregivers to go back to work quickly. Since in
developed countries many untreated patients will finally become asymptomatic
without any sequelae, the opportunity to change both GAS testing and treatment
recommendations could be evaluated.
In summary, pharyngitis in children is a frequent diagnostic challenge in the
PED. Although some RADTs show a sensitivity that is not optimal, improved
sensitivity for GAS detection has been found for the immunofluorescence-based
lateral flow Sofia® StrepA FIA which demonstrated improved diagnostic
performances over a standard immunochromatographic RADT in children with
pharyngitis. The Sofia® StrepA FIA is therefore an appropriate tool for the detection
of GAS infections in pediatric emergency settings. Combined to the low incidence of
rheumatical strains, critical appraisal of current practice to routinely perform a
backup throat culture in children with pharyngitis and with negative GAS RADT
could be reconsidered.
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