Performance of a Rapid Antigen-Detection Test and Throat Culture in Community Pediatric Offices: Implications for Management of Pharyngitis Robert

R. Tanz, Michael A. Gerber, William Kabat, Jason Rippe, Roopa Seshadri and Stanford T. Shulman Pediatrics 2009;123;437 DOI: 10.1542/peds.2008-0488

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/123/2/437.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2009 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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ARTICLE

Performance of a Rapid Antigen-Detection Test and Throat Culture in Community Pediatric Ofces: Implications for Management of Pharyngitis
Robert R. Tanz, MDa, Michael A. Gerber, MDb, William Kabat, BSc, Jason Rippe, JDc, Roopa Seshadri, PhDd, Stanford T. Shulman, MDa
aDepartment of Pediatrics, Childrens Memorial Hospital and Northwestern University Feinberg School of Medicine, Chicago, Illinois; bCincinnati Childrens Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; cInfectious Diseases Laboratory, Childrens Memorial Hospital, Chicago, Illinois; dMary Ann and J. Milburn Smith Child Health Research Program, Childrens Memorial Research Center, Chicago, Illinois

Financial Disclosure: Dr Shulman is on the medical advisory board of Quidel Corp; the other authors have no nancial relationships relevant to this article to disclose.

Whats Known on This Subject

RADTs for GAS are considered insufciently sensitive to be used alone. Therefore, throat culture is recommended to conrm negative RADT results. Previous studies have demonstrated that RADT results are affected by the pretest likelihood of GAS pharyngitis.

What This Study Adds

The sensitivity of the RADT is fairly low, as is the sensitivity of the ofce BAP culture. Both tests perform better among patients with greater pretest likelihood of strep throat. The results support selective testing of patients with pharyngitis.

ABSTRACT
OBJECTIVES. The goals were to establish performance characteristics of a rapid antigendetection test and blood agar plate culture performed and interpreted in community pediatric ofces and to assess the effect of the pretest likelihood of group A streptococcus pharyngitis on test performance (spectrum bias). METHODS. Two throat swabs were collected from 1848 children 3 to 18 years of age who

www.pediatrics.org/cgi/doi/10.1542/ peds.2008-0488 doi:10.1542/peds.2008-0488

This work was presented in part at the 4th World Congress of the World Society for Pediatric Infectious Diseases, September 6, 2005, Warsaw, Poland; the XVIth Lanceeld International Symposium on Streptococci and Streptococcal Diseases, September 26, 2005, Cairns, Queensland, Australia; and the annual meeting of the Pediatric Academic Societies, April 29, 2006, San Francisco, CA. Key Words pharyngitis, rapid diagnostic tests, throat culture, group A Streptococcus Abbreviations BAP blood agar plate GAS group A streptococcus RADTrapid antigen-detection test POLphysician ofce laboratory ARFacute rheumatic fever CLIAClinical Laboratory Improvement Act CI condence interval
Accepted for publication May 19, 2008 Address correspondence to Robert R. Tanz, MD, Childrens Memorial Hospital, Division of General Academic Pediatrics, 2300 Childrens Plaza, Box 16, Chicago, IL 60614. E-mail: rtanz@northwestern.edu PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2009 by the American Academy of Pediatrics

were evaluated for acute pharyngitis between November 15, 2004, and May 15, 2005, in 6 community pediatric ofces. One swab was used to perform the rapid antigen-detection test and a blood agar plate culture in the ofce and the other was sent to our laboratory for blood agar plate culture. Clinical ndings were used to calculate the McIsaac score for each patient. The sensitivities of the ofce tests were calculated, with the hospital laboratory culture results as the criterion standard.
RESULTS. Thirty percent of laboratory blood agar plate cultures yielded group A strep-

tococcus (range among sites: 21%36%). Rapid antigen-detection test sensitivity was 70% (range: 61% 80%). Ofce culture sensitivity was signicantly greater, 81% (range: 71%91%). Rapid antigen-detection test specicity was 98% (range: 98% 99.5%), and ofce culture specicity was 97% (range: 94%99%), a difference that was not statistically signicant. The sensitivity of a combined approach using the rapid antigen-detection test and back-up ofce culture was 85%. Among patients with McIsaac scores of 2, rapid antigen-detection test sensitivity was 78%, ofce culture sensitivity was 87%, and combined approach sensitivity was 91%. Positive diagnostic test results were signicantly associated with McIsaac scores of 2.
CONCLUSIONS. The sensitivity of the ofce culture was signicantly greater than the sensitivity of the rapid antigen-detection test, but neither test was highly sensitive. The sensitivities of each diagnostic modality and the recommended combined approach were best among patients with greater pretest likelihood of group A streptococcus pharyngitis. Pediatrics 2009;123:437444

HROAT CULTURE WITH a blood agar plate (BAP) is the standard method for establishing the diagnosis of pharyngitis caused by group A streptococcus (GAS) in children.14 Rapid diagnostic tests became available for ofce-based physicians in the 1980s. Compared with BAP cultures, the specicity of these rapid antigen-detection tests (RADTs) was considered excellent (at least 90%95%), but the sensitivity was lower (often 75% 85%).1 Although RADT technology has evolved since these tests were rst introduced,1 the American Academy of Pediatrics, the Infectious Diseases Society of America, and the American Heart Association continue to recommend conrmation of negative RADT results with a BAP culture.24 There is no consensus regarding BAP culture methods. BAP culture performance is affected by swab techniques,5 the skill of the personnel who process and interpret BAP cultures,6 whether the cultures are processed in physician ofce laboratories (POLs) or more-centralized laboratories,6 and the specic materials and conditions used for plating

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and incubation of the cultures.1,7 Discordance between the results of simultaneous cultures is well described.810 Assessment of RADT performance is affected by all aspects of BAP culture methods that affect culture results. The impact of culture methods and interpretation on RADT sensitivity was clearly demonstrated in a study of the optical immunoassay RADT.11 Moreover, GAS RADTs are more likely to yield positive results when a concurrent BAP culture has heavier growth of GAS12,13 or when a larger inoculum is used to perform the RADT.14 The sensitivity of RADTs also may be affected by the pretest likelihood of GAS pharyngitis.13,1517 This phenomenon is called spectrum effect or spectrum bias and occurs when test performance is affected by variations in disease presentation or population subgroups.18,19 For example, a test may have low sensitivity for young children and much higher sensitivity for teenagers (eg, heterophil test for infectious mononucleosis), or sensitivity may vary during the course of a disease (eg, chest radiographs early or later in the course of pneumonia). In the case of pharyngitis, RADT results may be affected by clinical disease severity or presentation.13,1517 The Clinical Laboratory Improvement Act (CLIA) of 1988 has affected the availability of BAP cultures in POLs.2022 The CLIA requires that POLs meet standards for test performance and quality control based on test complexity. BAP cultures and some RADTs are considered moderately complex tests, and POLs must be certied to perform them; some RADTs that are easier to perform are classied as CLIA-waived and can be performed without certication. RADTs were performed in the ofce by 90% of surveyed physicians who cared for children, but only 13% of family practice physicians and 32% of pediatricians performed BAP cultures in the ofce.22 Although physicians may send throat swabs for BAP cultures to a hospital or commercial laboratory, some do not test for GAS at all or rely on RADTs alone.20,22,23 Failure to test for GAS was associated with a high rate of antibiotic prescribing for pharyngitis in the Kentucky Medicaid program,23 whereas testing was associated with lower rates of antibiotic prescribing for pharyngitis in national surveys.24 RADTs may have higher sensitivity than BAP cultures, when both are performed and interpreted in POLs and then compared with simultaneous cultures performed in a research laboratory.11,25 If RADT sensitivity approximates or exceeds the sensitivity of BAP cultures, then the need to conrm negative RADT results with BAP cultures would be eliminated. We evaluated a CLIA-waived RADT for GAS pharyngitis in 6 community pediatric ofces that perform and interpret routinely both RADTs and BAP cultures in the ofce. Our 2 main hypotheses were that RADTs performed in POLs are more sensitive than BAP cultures performed and interpreted in POLs, when each test is compared with a simultaneous BAP culture processed and interpreted in a hospital laboratory, and RADT sensitivity is subject to spectrum bias.13,1517 Specically, RADT sensitivity is greater when the pretest probability of GAS pharyngitis is greater.
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METHODS Patients and Community-Based Practices Eligible patients were 3 to 18 years of age and evaluated for pharyngitis by their physicians between November 15, 2004, and May 15, 2005. Six pediatric ofces participated, 3 in the Chicago, Illinois, area and 3 in the Cincinnati, Ohio, area. Each practice participates in 1 ofce-based research network. The POLs were CLIAcertied for moderately complex tests, used a RADT for GAS pharyngitis, processed BAP cultures by using CLIAapproved methods, and were monitored through CLIA prociency testing. The BAP culture procedures used in the ofces were not reviewed or modied for this study, and we did not provide training in performance or interpretation of BAP cultures. Staff members in each ofce were trained in performance of the RADT used in this study, by representatives of the RADT manufacturer, before initiation of the study. Throat Swabs Patients deemed by their physicians to need evaluation for GAS pharyngitis had throat swabs obtained with 2 round-tipped rayon swabs. The swabs were rubbed together, and swab A was used to streak the BAP used by the ofce (ofce BAP culture) and then was used to perform the RADT (Quidel QuickVue dipstick [Quidel, San Diego, CA]). The result of the RADT was recorded on the top portion of a data collection form developed for this study, which was then separated from the bottom portion. Ofce BAP cultures were processed and interpreted by designated personnel in each ofce, following the ofce protocol that conformed to CLIA standards. The ofce BAP culture results were recorded on the bottom portion of the data form. Swab B was labeled and refrigerated in the ofce for 1 to 3 days, in the transport medium contained in the culture tube. It was then sent to the hospital laboratory in a shipment that did not include the matching data forms. The swab was streaked on a plate containing trypticase soy agar with 5% sheep blood (Becton Dickinson, Sparks, MD), and the plate was incubated in room air at 35C (laboratory BAP culture) and checked for growth of -hemolytic colonies at 24 and 48 hours. -Hemolytic colonies were conrmed as GAS with PathoDX (Los Angeles, CA) grouping reagents. Data forms were sent to the laboratory after the laboratory BAP culture results were recorded; laboratory personnel did not have knowledge of the ofce results before completion of the laboratory BAP culture. Clinical Information and Clinical Scores Patient gender and age (in years) were recorded. By using a checklist on the data form, limited clinical information (temperature of 38C [100.4F] by history or in the ofce, tender anterior cervical lymphadenopathy, enlarged tonsils, tonsillar or pharyngeal exudates, and cough) was collected for all patients whose throat swabs were included in the study. McIsaac scores were calculated to stratify patients according to their clinical presentation, a proxy for the likelihood that they had GAS pharyngitis.26 The scoring

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TABLE 1 Study Population

n (%) Total Age (N 1848)b 34 y 59 y 1014 y 1518 y All Gender (N 1834)c Female Male
a b

TABLE 2 Distribution of McIsaac Scores (N 1848)

GAS-Positive 68 (27) 304 (40) 148 (26) 33 (13) 553 (30)
a

McIsaac Score 0 1 2 3 4 5

n (%) Total 42 (2) 200 (11) 576 (31) 552 (30) 365 (20) 113 (6) GAS-Positivea 3 (7) 37 (19) 118 (20) 162 (29) 163 (45) 70 (62)

249 (13) 766 (41) 579 (31) 254 (14) 1848 (100) 969 (53) 865 (47)

Hospital laboratory BAP culture-positive for GAS.

278 (29) 267 (31)

Hospital laboratory BAP culture-positive for GAS. The sum of age group proportions equals 99% because of rounding. The mean age was 9.28 years (median: 9.00 years). c Gender was not recorded for 14 patients.

system was validated in a general medical practice that included children and adults.2628 The 5 McIsaac score criteria are history of temperature of 38C, absence of cough, tender anterior cervical adenopathy, tonsillar swelling or exudates, and age of 15 years.26 Although 1 point is awarded for each factor present, the maximal score is sometimes considered 4.26,27 A maximal score of 5 was used more recently by McIsaac et al,28 and we chose to conform to that approach. We dened patients with increased pretest likelihood of GAS pharyngitis as those with McIsaac scores of 2.2628 Sample size was estimated by using a contingency table that varied the sensitivity of one test from 80% to 95% and the other from 75% to 90%. A 10% difference between the tests would be statistically signicant at P .001 across this range of sensitivities if there were 500 patients with GAS pharyngitis. Assuming the prevalence of GAS pharyngitis to be 25%, we sought a total sample of 2000 patients, and we asked each ofce to collect swabs from 325 to 350 patients. Neither hospital laboratory personnel nor the investigators could trace laboratory results to individual patients. The results of the studies performed in the hospital laboratory were not available for clinical care of patients. The institutional review boards at both Childrens Memorial Hospital and Cincinnati Childrens Medical Center considered the study exempt from review under US 45CFR46.101(b)4. Data Analysis Patient demographic features, results of all tests for GAS, and clinical information were entered into a computer database. The laboratory BAP culture was considered the criterion standard for diagnosis of GAS pharyngitis. The McIsaac score was calculated for each patient. The sensitivity, specicity, and accuracy (proportion of patients categorized correctly as being GAS-positive or GAS-negative) of the RADT and the ofce BAP culture were determined for the entire cohort of eligible patients and stratied according to clinical scores (0 2 or 2). The 95% condence intervals (CIs) were calculated for sensitivity, specicity, and accuracy. The sensitivities of RADT and ofce BAP culture were

compared by using McNemars test for paired categorical data. Receiver operating characteristic analyses were conducted to identify a clinical score value that was associated with good sensitivity and specicity for each diagnostic test (RADT, ofce BAP culture, and laboratory BAP culture). Logistic regression analyses were used to determine the odds (with 95% CIs) of positive test results when the McIsaac score was 2. RESULTS Swabs were collected from 2008 patients with pharyngitis, 1848 of whom were 3 to 18 years of age, with an average of 308 eligible patients with swabs per ofce (range: 288 348 patients per ofce). Clinical scores could be calculated for all eligible patients. RADTs were performed for 1843 patients, ofce BAP cultures were performed for 1842 patients, and both ofce tests were performed for 1839 patients; therefore, there are minor variations in the denominators in the tables. Data on the patient population are presented in Table 1. GAS was isolated from 30% of laboratory BAP cultures (553 of 1848 cultures; range among sites: 21%36%). Table 2 presents the rates of recovery of GAS from laboratory BAP cultures according to calculated McIsaac scores. McIsaac scores were 2 for 56% of patients, and 38% of them had GAS-positive laboratory BAP culture results (positive predictive value), accounting for 71% of true-positive culture ndings (395 of 553 cultures) (sensitivity). The negative predictive value of a score of 2 was 81%. The performance of RADTs and ofce BAP cultures differed little in specicity and accuracy in the individual ofces and overall (Table 3). For all ofce sites combined, the sensitivity of ofce BAP cultures was signicantly higher than that of RADTs (80.8% vs 69.6%; P .001). In individual ofces, the sensitivity of ofce BAP cultures ranged from 70.6% to 90.5% and that of RADTs ranged from 60.5% to 80.2%. BAP culture sensitivity was higher than RADT sensitivity in 5 of 6 ofces, and the difference was statistically signicant in 4 cases. In 5 of 6 ofces, however, the sensitivity of ofce BAP cultures was 90%; in 4 ofces, the sensitivity was 85%. Forty-one patients had positive ofce BAP culture results and negative laboratory culture results, whereas 105 had negative ofce BAP culture results and positive laboratory BAP culture results. Both ofce diagnostic tests exhibited spectrum bias (Table 4). RADT and ofce BAP culture sensitivities were signicantly higher among patients with McIsaac scores of 2, compared with patients with McIsaac scores of
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TABLE 3 Performance of RADT and Ofce BAP Culture in POLs

Category Sensitivity All patients (30% criterion-positive) RADT (n 1843) Ofce BAP culture (n 1842) Ofce A (29% criterion-positive) RADT (n 347) Ofce BAP culture (n 348) Ofce B (27% criterion-positive) RADT (n 279) Ofce BAP culture (n 279) Ofce C (21% criterion-positive) RADT (n 303) Ofce BAP culture (n 304) Ofce D (31% criterion-positive) RADT (n 326) Ofce BAP culture (n 324) Ofce E (36% criterion-positive) RADT (n 289) Ofce BAP culture (n 288) Ofce F (35% criterion-positive) RADT (n 299) Ofce BAP culture (n 299) 69.6 (65.673.4) 80.8 (77.384.1) 65.7 (55.674.8) 70.6 (60.879.2) 60.5 (48.771.6) 80.3 (69.588.5) 74.6 (62.184.7) 90.5 (80.496.4) 80.2 (71.187.5) 79.6 (70.387.1) 69.5 (59.878.1) 87.4 (79.493.1) 67.0 (57.275.8) 80.2 (71.387.3) Estimate (95% CI), % Specicity 97.8 (96.898.5) 96.8 (95.797.7) 98.4 (95.999.6) 98.8 (96.599.8) 99.0 (96.599.9) 94.1 (89.996.9) 97.1 (94.198.8) 95.0 (91.597.4) 97.3 (94.399) 98.7 (96.299.7) 99.5 (97.099.9) 96.2 (92.498.5) 95.3 (91.397.9) 97.9 (94.899.4) Accuracy 89.3 (87.990.7) 92.1 (90.993.3) 88.8 (85.592.1) 90.5 (87.493.6) 88.5 (84.892.2) 90.3 (86.893.8) 92.4 (89.495.4) 94.1 (91.596.7) 92.0 (89.194.9) 92.9 (90.195.7) 88.6 (84.992.3) 93.1 (90.296.0) 85.3 (81.389.3) 91.6 (88.594.7) P Comparing Sensitivitiesa .001

.25

.001

.002

.74

.001

.004

The concurrent hospital laboratory BAP culture was used as the criterion standard. a McNemars test was used. Specicities of the RADT and ofce BAP culture also were compared but did not differ statistically overall or in any ofce.

2, but the sensitivities of these ofce tests remained signicantly different (P .001). Table 5 shows that McIsaac scores of 2 were significantly associated with positive results for each diagnostic test. However, the receiver operating characteristic analyses demonstrated that there was not a clinical score that discriminated between positive and negative results for any of the tests well enough to be used alone (area under the curve: 0.65 0.70). Therefore, McIsaac scores cannot be used in place of laboratory test results for diagnosis of GAS pharyngitis. The strategy of conrming negative RADT results

with ofce BAP cultures improved diagnostic sensitivity to 85.1% (95% CI: 81.8% 87.9%). Marked spectrum bias was evident with this combination strategy; sensitivity was 70.5% for patients with McIsaac scores of 2 and 90.9% for patients with scores of 2 (Table 4). DISCUSSION No ofce-based diagnostic modality (clinical score, ofce BAP culture, or RADT), when used alone in this study, was both highly sensitive and signicantly superior to the others, with laboratory BAP culture being used as the criterion standard. The sensitivity of the ofce BAP

TABLE 4 Spectrum Bias of RADT and Ofce BAP Culture

Category Sensitivity All patients (30% criterion-positive) RADT (n 1843) Ofce BAP culture (n 1842) Combined (n 1839)a McIsaac scores of 02 (19% criterion-positive) RADT (n 817) Ofce BAP culture (n 815) Combined (n 814)a McIsaac scores of 35 (38% criterion-positive) RADT (n 1026) Ofce BAP culture (n 1027) Combined (n 1025)a Estimate (95% CI), % Specicity Accuracy P Comparing Sensitivitiesb .001 n/a .001 n/a .001 n/a

69.6 (65.673.4) 97.8 (96.898.5) 89.3 (87.990.7) 80.8 (77.384.1) 96.8 (95.797.7) 92.1 (90.993.3) 85.1 (81.887.9) 94.7 (93.495.8) 91.8 (90.593.1) 49.4 (41.357.4) 97.8 (97.699.5) 89.2 (87.191.3) 64.7 (56.772.2) 97.3 (95.798.4) 91.0 (84.897.2) 70.5 (62.777.5) 96.2 (94.497.5) 91.3 (89.193.1) 77.7 (73.381.7) 96.7 (95.097.9) 89.4 (87.591.3) 87.2 (83.590.4) 96.4 (94.697.7) 92.9 (91.394.5) 90.9 (87.693.5) 93.2 (90.995) 92.3 (90.593.9)

The concurrent hospital laboratory BAP culture was used as the criterion standard, and results for the 6 pediatric ofces were combined. a Combined indicates the use of current guidelines that consider positive RADT results as diagnostic of GAS pharyngitis and recommend conrming negative RADT results with a BAP culture. b McNemars test was used. Specicities and accuracies of the RADT and ofce BAP culture also were compared but did not differ statistically.

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TABLE 5 Odds Ratios for Positive Diagnostic Test Results With McIsaac Scores of >2
Test RADT Ofce BAP Laboratory BAP
The baseline score level was 0 to 2.

Odds Ratio (95% CI) 3.99 (3.085.18) 3.23 (2.564.07) 2.60 (2.103.22)

P .001 .001 .001

culture was signicantly greater than the sensitivity of the RADT when the 2 tests were compared with a simultaneously collected swab that was plated and processed in the hospital laboratory. Both ofce-based tests performed better among patients with symptoms characteristic of acute GAS pharyngitis (ie, those with McIsaac scores of 2). Spectrum bias of RADTs was noted previously.13,1517 Pretest likelihood of GAS pharyngitis should now be added to the list of factors that affect ofce BAP culture sensitivity. American Academy of Pediatrics, Infectious Diseases Society of America, and American Heart Association guidelines recommend that negative RADT results be conrmed with throat cultures, whereas ofce BAP cultures are considered adequate as the only test for diagnosis of GAS pharyngitis even when results are negative.24 The ofces that participated in this study were all CLIA-certied to perform BAP cultures, and all belonged to 1 pediatric ofce-based research network. Their performance of BAP cultures in the ofce would be expected to be excellent; however, the sensitivity of ofce BAP cultures, although higher than the sensitivity of RADTs, was only 81% overall. RADT sensitivity in some published studies was within the 95% CI for ofce BAP culture sensitivity found in the present study (77% 84%) or higher.1 The sensitivity of ofce BAP cultures in this study is not unprecedented; it is higher than the value of 50% reported by Mondzac29 and similar to values reported by Wegner et al,30 Battle and Glasgow,31 and Rosenstein et al,32 that is, 72%, 80%, and 85%, respectively. In an earlier study, we found the overall sensitivity of ofce BAP culture to be 89% (95% CI: 87%91%) when laboratory BAP culture alone was the criterion standard and 78% (95% CI: 75% 80%) when a more-rigorous research laboratory method (laboratory BAP culture plus broth culture) was used,11 which illustrates the impact of culture methods on assessment of sensitivity. If the diagnostic goal is to maximize identication of patients infected with GAS, then our data indicate that negative ofce test results, including throat culture results, should be conrmed with BAP cultures processed in a hospital or commercial laboratory. We do not advocate this, because use of the ofce BAP culture as the denitive diagnostic test for GAS pharyngitis has not been implicated in missed treatment opportunities and subsequent outbreaks of acute rheumatic fever (ARF), invasive GAS disease, or increased prevalence of GAS pharyngitis and its suppurative complications. Moreover, it would increase costs, and the subsequent delay in receiving nal results might result in increased pre-

scribing of antibiotics for patients who ultimately have negative culture results,24 many of whom would complete a full course of antibiotic therapy.22 With the application of published guidelines to our data, the sensitivity of RADTs plus back-up ofce BAP cultures was 85.1% overall and 90% for patients with McIsaac scores of 2, which is another demonstration of spectrum bias. These results support current recommendations,24 including advice to avoid testing patients with symptoms more typical of viral illnesses.2,3 Inappropriate or unnecessary use of antibiotics is common and contributes to the development of resistance to antimicrobial agents by many species of bacteria.3335 Rates of antibiotic prescribing for pharyngitis, that is, 53% to 69% among children24 and 62% among patients of all ages seen by primary care physicians,34 are much higher than would be expected if only laboratoryconrmed GAS pharyngitis were treated with antibiotics by US physicians. McCaig et al36 reported that the rate of antibiotic prescribing for pharyngitis in 1999 2000 was 738 prescriptions per 1000 physician visits. At best, 68% of surveyed physicians reported using an appropriate strategy for evaluation of children with pharyngitis, but 27% reported often or always treating before they had test results.22 Mangione-Smith et al37 found that clinical guidelines for evaluation were not followed for 25% of children treated with antibiotics for pharyngitis in 5 health plans. A study of adults with pharyngitis found that no established strategy was followed in 66% of visits; 80% of patients had a test performed and 17% had positive test results, but 47% received antibiotics.38 These studies indicate that many physicians are unable or unwilling to follow current pharyngitis management guidelines and apparently favor antibiotic treatment over diagnostic testing. The currently recommended diagnostic approach is intended to identify accurately patients with GAS pharyngitis, so that they can be treated with antibiotics. Diagnosis of GAS pharyngitis has been driven for 6 decades by the desire to prevent ARF, which is still considered by expert panels and 95% of clinicians as an important reason to identify and to treat children.24,22 Prevention of suppurative complications, symptom relief, and reduction of contagiousness were each chosen as reasons by 70% of pediatricians and family practitioners.22 Physicians clearly have incorporated prevention of ARF and other sequelae into their thinking about pharyngitis management. However, rates of ARF, suppurative complications of GAS pharyngitis, and invasive disease are quite low in the United States.39,40 In fact, the decrease in ARF in the United States began before effective antibiotics were available,39 and GAS serotypes responsible for ARF outbreaks in past decades either are rare or have vanished from North America.39,41 Modication of the management paradigm in the United States and other countries with low rates of ARF and suppurative complications may be warranted. A signicant conceptual change would be to shift the clinical goal from preventing rare GAS complications to minimizing unnecessary or inappropriate use of antibiotics by recognizing patients unlikely to have a GAS
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infection and not testing them. Data from adults indicate that more-selective testing alone may reduce inappropriate use of antibiotics.38 Our data indicated that McIsaac scores of 2 were associated with decreased likelihood of GAS pharyngitis (determined on the basis of isolation of GAS in the laboratory BAP culture). Limiting throat swabs to patients with scores of 2 would eliminate testing for the large proportion of patients with viral pharyngitis and some patients more likely to be GAS carriers; these patient groups do not benet from antibiotics commonly used for GAS pharyngitis42 but often receive them.22,24,34,3638 Our data indicated that selective testing using an ofce-based RADT, with ofcebased BAP culture conrmation of negative test results, would increase diagnostic sensitivity to 90%, but we think that the emphasis should be on limiting antibiotic exposure, rather than maximizing GAS identication. Selective testing is currently suggested by expert bodies2,3 and has been emphasized by Linder et al38 and Centor and Cohen.43 It could be incorporated into community-based interventions aimed at decreasing inappropriate antibiotic prescribing,44 and we think that it should be a focus of physician education. An additional dramatic (and likely controversial) change in management could be reliance on the result of the initial ofce test (whether RADT or BAP culture) even if it is negative, ignoring the relatively low sensitivity of both ofce-based diagnostic tests. In this paradigm, no back-up testing would be performed routinely and antibiotics would be prescribed only for patients with positive test results. Because 90% of US pediatricians and family physicians have access to RADTs and 93% perform them on site,22 the vast majority of patients tested would receive a diagnosis immediately. This approach would be a major departure from 20 years of recommended practice, and additional studies are needed before it can be endorsed. The risk that either of these approaches would be associated with increased rates of ARF is likely low. The risk for an increase in invasive infections also seems to be low, because most cases of invasive disease in developed countries are not associated with pharyngitis.32,45 The effect on rates of suppurative complications is not known. In developing countries or areas with high rates of ARF and other GAS complications, the enormous burden of GAS disease alters diagnostic and treatment considerations.46 Our results may have been affected by several factors. The physicians in the participating pediatric practices were instructed to evaluate patients with pharyngitis in their ordinary manner. We did not attempt to alter their management strategies, swab techniques, or ofce laboratory procedures, except that the same CLIA-waived study RADT was used in all ofces. We did not review or modify the specic BAP culture methods used in each ofce, because each was approved and monitored according to the provisions of the CLIA; the results reect the real world of pediatric POL performance. Our results might have been different if another RADT had been used. There are few data that address the possibility
442 TANZ et al

that waived and nonwaived RADTs perform differently in POLs.1 Although the RADT manufacturer indicated that the RADT should not be affected, it is possible that streaking the BAP with swab A before the RADT was performed decreased the sensitivity of the RADT. Discordant BAP culture results can affect the apparent sensitivity of the ofce BAP culture. Random swab discordance, favoring neither swab A nor swab B, should have resulted in similar frequencies of ofce-negative/laboratory-positive and ofce-positive/laboratory-negative cases. Our ndings do not seem to be attributable to random swab discordance. The ofce RADT results were separated from the ofce BAP culture results to minimize the possibility of the ofce BAP culture readings being inuenced by knowledge of the RADT results. We are not certain of the effectiveness of this effort. During the course of this investigation, we discovered notations on some data collection forms that indicated that the RADT was used to evaluate suspected colonies on the ofce BAP culture. Personnel from 5 ofces later acknowledged that they sometimes used the RADT for this purpose, but usually they did not document this procedure. We do not know how often this was done, but it might have affected the number of ofce BAP cultures reported as positive. Such off-label use of the RADT has not been evaluated. The assessment of spectrum bias is not straightforward. We used the McIsaac score to stratify our patients, but other clinical scores or other means of determining the pretest likelihood of GAS pharyngitis might have altered the results. A threshold McIsaac score of 2 identied 71% of our patients with true-positive results and might not be optimal. Decreasing the threshold score to 1 in this study would increase sensitivity to 93% by including 87% of patients (1606 of 1848 patients), without greatly improving the negative predictive value (83% for McIsaac scores of 1; data not shown). A laboratory test is required to diagnose GAS pharyngitis reliably. CONCLUSIONS This large prospective study found that the sensitivity of throat cultures performed in the ofce was signicantly greater than the sensitivity of ofce RADTs. However, both the ofce RADT and the ofce BAP culture demonstrated relatively low sensitivity overall. The RADT, ofce BAP culture, and ofce BAP culture conrmation of negative RADT results all exhibited spectrum bias, which supports selective testing of patients with pharyngitis. In areas with low rates of GAS complications, such as North America and Western Europe, the diagnostic paradigm for pharyngitis should emphasize selective swabbing to avoid testing of patients who are unlikely to have GAS pharyngitis and avoidance of antimicrobial overuse through treatment only of patients with positive test results. ACKNOWLEDGMENTS This work was supported by a grant from Quidel (San Diego, CA). Quidel did not design this study, collect or

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analyze the data, or participate in any way in manuscript preparation or review. We thank the ofce staff members and pediatricians of the 6 participating pediatric practices: North Shore Pediatrics (Chicago, IL), Town and Country Pediatrics (Chicago, IL), DuPage Pediatrics (Darien, IL), Anderson Hills Pediatrics (Cincinnati, OH), Landen Lake Pediatrics (Mason, OH), and West Side Pediatrics (Cincinnati, OH). REFERENCES
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37. Mangione-Smith R, Elliott MN, Wong L, McDonald L, Roski J. Measuring the quality of care for group A streptococcal pharyngitis in 5 US health plans. Arch Pediatr Adolesc Med. 2005; 159(5):491 497 38. Linder JA, Chan JC, Bates DW. Evaluation and treatment of pharyngitis in primary care practice: the difference between guidelines is largely academic. Arch Intern Med. 2006;166(13): 1374 1379 39. Shulman ST, Stollerman G, Beall B, Dale JB, Tanz RR. Temporal changes in streptococcal M protein types and the neardisappearance of acute rheumatic fever in the US. Clin Infect Dis. 2006;42(4):441 447 40. Stevens DL. Life-threatening streptococcal infections: scarlet fever, necrotizing fasciitis, myositis, bacteremia, and streptococcal toxic shock syndrome. In: Stevens DL, Kaplan EL, eds. Streptococcal Infections: Clinical Aspects, Microbiology, and Molecular Pathogenesis. New York, NY: Oxford University Press; 2000:163179

41. Shulman ST, Tanz RR, Kabat W, et al. North American group A streptococcal pharyngitis serotype surveillance. Clin Infect Dis. 2004;39(3):325332 42. Gerber MA, Tanz RR, Kabat W, et al. Potential mechanisms for failure to eradicate Group A streptococci from the pharynx. Pediatrics. 1999;104(4):911917 43. Centor RM, Cohen SJ. Pharyngitis management: focusing on where we agree. Arch Intern Med. 2006;166(13):13451346 44. Perz JF, Craig AS, Coffey CS, et al. Changes in antibiotic prescribing for children after a community-wide campaign. JAMA. 2002;287(23):31033109 45. Darenberg J, Luca-Harari B, Jasir A, et al. Molecular and clinical characteristics of invasive group A streptococcal infection in Sweden. Clin Infect Dis. 2007;45(4):450 458 46. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5(11):685 694

GUIDELINES SET FOR PREVENTING HOSPITAL INFECTIONS Hoping to improve infection control in hospitals, the nations top epidemiological societies joined Wednesday with the American Hospital Association and the Joint Commission, which accredits hospitals, to issue a compendium of guidelines for preventing 6 lethal conditions. The unied backing of the hospital association and the accrediting agency should give the recommendations some teeth. The Joint Commissions vice president, Dr Robert A. Wise, said his agency would spend the next year studying which guidelines it would add to its accrediting standards in 2010. The recommended practices, like vigorous hand-washing before the insertion of catheters and warnings against using razors to remove hair before surgery, do not vary in signicant ways from the encyclopedic guidelines issued and revised over the last 2 decades by a government advisory panel. Epidemiologists contend that the challenge in reducing hospital infections, which are said to attack 1 of every 22 patients, has not been a dearth of guidelines but a lack of adherence. A survey of hospitals last year by The Leapfrog Group, which advocates for health-care quality, found that 87% did not consistently follow infectioncontrol guidelines. One of the reasons hospitals are having difculty now is that when they look at guidelines they are drinking from a re hose, Dr Wise said. There are thousands of these things, and they dont quite know what to do with them. The 6 conditions covered in the guidelines, which run 6 to 16 pages, are central-line-associated bloodstream infections, ventilator-associated pneumonia, catheter-associated urinary tract infections, Methicillinresistant Staphylococcus aureus, or MRSA, and Clostridium difcile, an intestinal bacteria.
Sack K. New York Times. October 9, 2008 Noted by JFL, MD

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ERRATA

Perella D, Fiks AG, Jumaan A, et al. Validity of Reported Varicella History as a Marker for Varicella Zoster Virus Immunity Among Unvaccinated Children, Adolescents, and Young Adults in the PostVaccine Licensure Era. Pediatrics. 2009;123(5): e820 e828

An error occurred in this article by Perella et al, published in the May 2009 issue of Pediatrics (doi: 10.1542/peds.2008-3310). On page e823, under Table 2, Sensitivity, Specicity, PPV, and Negative Predictive Value of Reported Varicella History According to Age Group, the last column header reads: (N 344). This should have read: 20-29 y (N 344).
doi:10.1542/peds.2009-1156

Tanz RR, Gerber MA, Kabat W, Rippe J, Seshadri R, Shulman ST. Performance of a Rapid Antigen-Detection Test and Throat Culture in Community Pediatric Ofces: Implications for Management of Pharyngitis. Pediatrics. 2009;123(2): 437 444

An error occurred in this article by Tanz et al published in the February 2009 issue of Pediatrics (doi:10.1542/peds.2008-0488). On page 441, the body of Table 5 reads:

Test RADT Ofce BAP Laboratory

Odd Ratio (95% CI) 3.44 (2.66, 4.44) 2.75 (2.15, 5.34) 2.81 (3.20, 3.60)

P .001 .001 .001 P .001 .001 .001

All of the odds ratios and 95% condence intervals were incorrect. Table 5 should have read: Test RADT Ofce BAP Laboratory Odd Ratio (95% CI) 3.99 (3.08, 5.18) 3.23 (2.56, 4.07) 2.60 (2.10, 3.22)

doi:10.1542/peds.2009-1300

Marks K, Hix-Small H, Clark K, Newman J. Lowering Developmental Screening Thresholds and Raising Quality Improvement for Preterm Children. Pediatrics. 2009;123(6): 1516 1523

Three errors occurred in this article by Marks et al, published in the June 2009 issue of Pediatrics (doi:10.1542/peds.2008-2051). On page 1518, under the heading, EI/ECSE Agency and Developmental-Behavioral Outcomes, 1st paragraph, 1st sentence, the authors wrote: Of the EI/ECSE-eligible children, 18.8% were preterm (n 12) and 8.8% were term (n 120). This should have read: 18.8% (12 of 64) of preterm and 8.8% (120 of 1363) of term children were made EI/ECSEeligible. On page 1522, Fig 3 (4th box from the top), reads, EI/ECSE agency (n 32) 12 PDI (with or without ASQ) 15 ASQ-only referrals. This should have read: EI/ECSE agency (n 32) 17 PDI (surveillance) 15 ASQ-only referrals. Figure 3 (6th box from the top) reads Parents accepted EI/ECSE services [23/24, 96%]. This should have read Parents ultimately accepted EI/ECSE services [17/18, 94%]. Please refer to the corrected Fig 3 online.
doi:10.1542/peds.2009-1535

846

ERRATA

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Performance of a Rapid Antigen-Detection Test and Throat Culture in Community Pediatric Offices: Implications for Management of Pharyngitis Robert R. Tanz, Michael A. Gerber, William Kabat, Jason Rippe, Roopa Seshadri and Stanford T. Shulman Pediatrics 2009;123;437 DOI: 10.1542/peds.2008-0488
Updated Information & Services including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/123/2/437.full.ht ml This article cites 41 articles, 16 of which can be accessed free at: http://pediatrics.aappublications.org/content/123/2/437.full.ht ml#ref-list-1 This article has been cited by 6 HighWire-hosted articles: http://pediatrics.aappublications.org/content/123/2/437.full.ht ml#related-urls 2 P3Rs have been posted to this article http://pediatrics.aappublications.org/cgi/eletters/123/2/437 This article, along with others on similar topics, appears in the following collection(s): Infectious Disease & Immunity http://pediatrics.aappublications.org/cgi/collection/infectious_ disease An erratum has been published regarding this article. Please see: http://pediatrics.aappublications.org/content/124/2/846.2.full. html Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2009 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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