TITLE: Point of Care Testing for Streptococcal Sore Throat: A Review of Diagnostic Accuracy, Cost-Effectiveness, and Guidelines

Transcription

1 TITLE: Point of Care Testing for Streptococcal Sore Throat: A Review of Diagnostic Accuracy, Cost-Effectiveness, and Guidelines DATE: 24 April 2009 CONTEXT AND POLICY ISSUES: Group A β-hemolytic streptococcus (GABHS) [also known as streptococcus pyogenes or hemolytic streptococcal (GAS)] is a gram-positive coccus that produces small colonies with surrounding β-hemolysis on sheep blood agar and is the most common cause of acute pharyngitis. 1 It is a common cause of throat infection globally and most frequent cause of respiratory infections among children. 2 GAS pharyngitis occurs in approximately 10-20% of the pediatric population, specifically among children between five and nine years old. 3 Symptoms may include sore throat, pain on swallowing, fever, headaches, nausea or vomiting, and abdominal pain. Physicians are generally unable to accurately diagnose GABHS pharyngitis according to clinical presentation alone since many patients do not present with the classic symptoms. Clinical scoring systems by Centor 4 or by McIsaac 5 were developed to improve the accuracy of clinical diagnosis of GABHS pharyngitis in order to reduce the risk of inappropriate use of antibiotics. The scoring system is based on the following criteria: tonsillar exudates, swollen tender anterior cervical adenopathy, lack of cough, and history of fever. The criteria defined by McIssac also accounted for the patient s age. The optimal management strategy for the patient is then based on the clinical score. Patients who consistently display signs or symptoms of GABHS pharyngitis may warrant diagnostic testing. 1 Throat culture or a rapid antigen detection test (RADT) are conducted for confirmation of GABHS pharyngitis. 6 Throat culture on a sheep blood agar is currently accepted as the gold standard for GABHS diagnosis. 6 The sensitivity of a throat swab is approximately 90-95%, if the test is performed according to accepted protocols. 1,6 The published literature suggests that negative test results be re-examined after an additional 24 hours. If the test results remain negative, they should be examined for a third time after 24 hours to ensure the maximum sensitivity of the test. 6 Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information on available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 RADTs for the rapid identification of GABHS became available in the 1980s. 7 In addition to routine laboratory testing, these tests allow for diagnosis in the physician s office, also known as point-of-care testing (POCT). Leung et al. describe RADTs as follows, all RADTs involve an extraction step for releasing the group-specific carbohydrate antigen from the GABHS cell wall and identification of the antigen by an immunological reaction. Nitrous acid is often used in the extraction process. 6 The first-generation RADTs use latex agglutination, where latex particles are covered with an antibody that reacts to the group A streptococcal antigen extracted from throat specimens. The main limitation of these diagnostic tests is their low sensitivity and unclear test results. 6 The second-generation RADTs use enzyme immunoassay techniques that have greater sensitivity and are easier to interpret. Optical immunoassay technology is a third type of point-of-care test that uses an anti-gabhs polyclonal rabbit antibody bound to an optical film to detect the presence of GABHS antigen. 6 Newer RADTs use chemiluminescent DNA probes and rapid-cycle real-time polymerase chain reaction methods, but given the numerous steps involved, these tests are not considered to be POCTs. 6 In Canada, there are several RADTs available for the detection of GABHS pharyngitis which can be found by searching Health Canada s Medical Devices Active Licence Listing. 8 One disadvantage of culture tests is the delay in results (1-2 days). The delay may postpone the start of antibiotic therapy or prompt the physician to prescribe antibiotics according to clinical symptoms prior to receiving the test results. This may result in indiscriminate use of antibiotics that may cause patient adverse events, antibiotic resistance and increased healthcare costs. 6 RADTs generally have a high specificity (i.e., over 95%), therefore positive results do not normally require throat cultures for confirmation. RADTs may be administered by a physician, nurse, or a nurse s aide, and the average turnaround time for results is approximately 15 minutes. 1 The published literature indicates a high variability in the sensitivity of RADT, depending on the commercial kits used and disease severity. As a result, a throat confirmation for negative RADTs may be necessary in some cases. 6 Clinical presentation alone is insufficient to diagnose GABHS pharyngitis and may lead to improper use of antibiotics. Patients may be diagnosed with throat cultures or RADTs. Throat culture is considered to be the gold standard when properly administered but requires several days for the results. RADTs quickly identify patients with GABHS pharyngitis; however, the sensitivity of the test varies and is more expensive than culture-based methods. This report reviews the available evidence with regards to the clinical and cost-effectiveness and Canadian and US recommendations on POCT for streptococcal sore throat. RESEARCH QUESTIONS: 1. What is the diagnostic accuracy of POCT for streptococcal sore throat? 2. What is the cost-effectiveness of POCT for streptococcal sore throat? 3. What are the guidelines or recommendations for POCT for streptococcal sore throat? METHODS: A limited literature search was conducted on key health technology assessment resources, including PubMed, EBSCOhost CINAHL, The Cochrane Library (Issue 1, 2009), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English Point of Care Testing for Streptococcal Sore Throat 2

3 language articles published between 2004 and March No filters were applied to limit the retrieval by study type. HTIS reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessment reports, systematic reviews and meta-analyses are presented first. These are followed by RCTs, observational studies, economic evaluations, and evidencebased guidelines. SUMMARY OF FINDINGS: The literature search identified eight observational studies, one economic evaluation, and four guidelines published in Canada and in the US. No systematic reviews, health technology assessments or randomized controlled trials (RCTs) were identified. Observational studies Tanz et al. 9 evaluated the performance characteristics of RADTs [Quidel QuickVue dipstick (Quidel, San Diego, California)] versus blood agar plates (BAPs) (Becton Dickinson, Sparks, Maryland) for the diagnosis of group A streptococcus pharyngitis. McIsaac scores were also calculated for each patient to categorize them according to their clinical presentation, a proxy for the likelihood of having GABHS pharyngitis. Two throat swabs were collected from 1,848 children between 3 and 18 years old from November 2004 to May 2005 in six community pediatric clinics. 9 The first swab was used to streak BAP culture plates that were processed and interpreted in each clinic. The same swab was also used for the RADT, also interpreted by a staff member in the clinic. The second swab was refrigerated in the office for one to three days and then transported to the hospital laboratory in a shipment that did not include matching data forms. Data forms were sent separately to the laboratory only after the culture results were recorded. RADTs were performed for 1,843 patients, office BAP cultures were performed for 1,842 patients, and both office tests were performed for 1,839 patients. GABHS was isolated from 30% of laboratory BAP cultures (553 of 1,848 cultures; range among clinics: 21 to 36%). 9 For the overall study population, the sensitivity of BAP cultures was significantly greater than that of RADTs (80.8% versus 69.6%; P<0.001). The sensitivity of BAP cultures in the individual offices ranged from 70.6% to 90.5% and that of RADTs ranged from 60.5% to 80.2%. 9 McIsaac scores were greater than 2 for 56% of patients, and 38% of them had positive predictive value (PPV). The negative predictive value (NPV) for patients with a score less than or equal to 2 was 81%. 9 The authors concluded that sensitivity of office BAPs was significantly greater than the sensitivity of RADTs, but neither test was very sensitive. Streaking the BAP with swab A before the RADT may have decreased the sensitivity of the RADT. One cross-sectional study conducted in Brazil evaluated the diagnostic test accuracy of RADTs versus culture for acute pharyngitis diagnosis among the pediatric population attending primary care services. 10 The study took place from January 1997 to January 2001 in a public emergency and private clinic in pediatric patients with a clinical presentation of acute pharyngitis. The study investigators performed latex particle agglutination testing with one swab (Patho Dx, DPC, Los Angeles) and the second swab was used to streak an agar and 5% lamb s blood plate that was incubated for 18 to 24 hours in microarophilic conditions at 37 o C. The sample size for the analysis was 229 children. More than half were female (56.8%) and 74.9% of patients age ranged from 4 to 10 years. 10 Patients may have displayed at least one of the following symptoms: fever (88%), swollen tonsils (73.8%), pain when swallowing (73.4%), and prostration (73.4%). The sensitivity and 95% confidence interval (CI) was 90.7% (95% CI: 85.1 to 96.4%), specificity was 89.1% (95% CI: 83.0 to 95.2%), PPV was 72.1% (95% CI: 63.3 to 80.9%), and NPV was 96.9% (95% CI: 93.5 to 100.3%). 10 The specificity (89.1%) was lower than the Point of Care Testing for Streptococcal Sore Throat 3

4 sensitivity in past studies. It is possible that there was a high prevalence of healthy GAHBS carriers and the test does not distinguish between colonized and infected patients, so the number of false positives increased. It is also possible that different test kits were used in past studies. The authors concluded that the rapid tests had a positive correlation with culture tests and would be useful in clinical practice for detection of GABHS. In 2007, Al-Najjar and Uduman 11 conducted a prospective study to assess the clinical utility of RADTs by Diaquick Strep A Test (SAT) (Dialab GmbH, Vienna, Austria) among children in two outpatient clinics, and its impact of antibiotic use in the pediatric population. Based on the authors description, SAT is a one-step think-layer chromatography sandwich type immunoassay for rapid, qualitative detection of GAS antigen directly from the throat. SAT was compared with a culture-based method (diagnostic test description not provided). 11 Children included in the study sample displayed symptoms such as fever, acute catarrh and acutely inflamed throat or tonsils with or without exudates, and children with clear viral infections and those who already received antibiotics in the previous week. The study sample comprised 278 boys (55%) and 227 girls (45%). Four-hundred and nine children (81%) were less than five years old and 96 (19%) were greater than five years old. 11 For the whole study sample, SAT and culture-based test were negative in 422 cases (84%) and positive in 68 cases (13%), and test results were inconsistent in 15 cases (3%). The PPV with SAT was 95.8% (68/71) and the NPV was 99% (422/425). 11 Potential study limitations were not discussed. RADTs were found to be simple, quick and extremely reliable tests and may help to reduce the use of antibiotics in children with fever, catarrh and acute pharyngotonsillitis. 11 Van Limbergen et al. (2006) 12 evaluated the introduction of rapid streptococcal tests (RSTs) for GABHS diagnosis in a tertiary pediatric accident and emergency department. The second objective was to assess through a questionnaire, the clinical diagnosis of GABHS and the relative contribution of various symptoms. 12 This HTIS report focuses results pertaining to the the primary objective. Nursing staff members administered and analyzed samples for the QuickVie+ Strep A test (Quidel Inc., San Diego, CA). Negative RST results were followed-up with throat culture tests and specimens were reviewed by the laboratory staff. The sample size included 213 children [boys=110 and girls=103; mean [standard deviation (SD)] age=3.85 (3.15) years old]. Since 12 patients did not have follow-up throat culture sent, a total of 201 patients were included the analysis. The diagnostic test results indicate 33 patients with positive results using either RST or throat culture and 21 patients with positive results with RST only. 12 Eleven samples were negative with RST but positive with throat culture. The sensitivity of RST was 65.6% (21/32; 95% CI: 46.8 to 81.4%) and specificity was 99.4% (168/169; 95% CI: 96.7 to 99.9%) with disease prevalence of 15.9% (32/201). Positive likelihood ratio was 1.96 (minimal increase in the likelihood of disease) and negative likelihood ratio was 0.60 (minimal decrease in the likelihood of disease). 12 The authors did not describe potential study limitations. The research found RST to be highly specific, which may facilitate early diagnosis of GABHS, but has a low sensitivity. The sensitivity in the current study was significantly different from the sensitivity reported by the manufacturer. As a result, the authors do not recommend that RST be used as single diagnostic tool and recommend that the performance characteristics of the new diagnostic tests be audited. 12 Forward et al. (2006) 13 compared the performance characteristics of the Strep A Rapid Test Device (SARTD) (Nova Century Scientific Inc, Canada) with culture-based tests in the pediatric and adult population. Pharyngeal swabs were collected from children 16 years or younger (n=490) and adults (n=328) at the Queen Elizabeth II Health Sciences Clinical Microbiology in Halifax, Nova Scotia. The SARTD was used as per the manufacturer s instructions. Plates for the culture were incubated anaerobically at 35 o C and were read at 24 hours and 48 hours. 13 The sensitivity and specificity were 67.8% and 93.8% for children and 81.1% and 94.9% for adults. Point of Care Testing for Streptococcal Sore Throat 4

5 Moreover, the PPVs and NPVs were 77.7% and 90.2% for children and 75.4% and 96.3% adults. 13 The authors did not perform a broth enrichment step for the throat culture, so the true proportion of throat swabs containing S pyogenes may have been underestimated. The study findings report that the overall sensitivity for STARD (72%) was less than the sensitivity indicated by the product monograph (90%). 13 Camurdan et al. 14 evaluated the validity of the RADT INTEX Strep A Test II (INTEX Diagnostica Pharmazeutische Produkte AG, Muttenz, Schweiz) for the diagnosis of streptococcal pharyngitis in an outpatient clinic within the pediatric population to measure the prevalence of streptolococcal pharyngitis between 1998 and RADT results were compared with those of throat culture. The study population consisted of 1,248 patients [males=646 (51.8%) and females=602 (48.2%); mean age=6.3±3.6 years]. The patients were subdivided in three age categories: group 1, 0 to 6 years (n=655); group 2, 7 to12 years (n=518); and group 3, 13 years and older (n=75). 14 The prevalence of GABHS for the entire study sample was 35.9% (448/1248) with RADTs and 38.1% with throat cultures (475/1248) (P>0.05). Compared with throat cultures, RADTs demonstrated a sensitivity of 89.7%, a specificity of 97.2%, a PPV of 95.0%, and NPV of 93.8% for the whole sample. 14 Among the age categories, there was little variation in the sensitivity (87.1% to 90.0% ) and specificity (96.9% to 97.7%) (P>0.05). 14 The authors concluded that the diagnostic value of RADT was high and can be used among populations susceptible to streptococcal pharyngitis and related clinical symptoms. 14 A prospective cohort study was conducted by Humair et al. in a walk-in clinic of a universitybased primary care center in Switzerland from March 1, 1999 to September 20, The primary objective was to measure the performance of rapid streptococcal antigen tests (RSATs) in patients with a range of clinical scores and to compare antibiotic prescription with direct costs for different recommended strategies using the clinical scores by Centor et al. and McIsaac et al., RSAT and culture test results to manage acute pharyngitic in adult patients. 15 This HTIS report focuses on the results of the performance characteristics of the diagnostic tests. RSATs, an optical enzyme-linked immunosorbent assays (TestPack Plus Strep A w/on-board Controls ii; Abbott Laboratories, Abbott Park, Illinois) were performed by physicians, and throat cultures were incubated on two blood agar plates in anaerobic conditions without inhibitor (not-specified) in the university hospital laboratory and results were reported after 48 hours. The study sample comprised 372 consecutive ambulatory patients with pharyngitis. Over 75% of the study population were 35 years or younger (283/372), 55.1% were female (205/372), and approximately 80% had a clinical score of 2 or 3 (304/372). 15 The prevalence of GABHS pharyngitis based on throat culture was 37.6% and increased with the clinical score (score 2=3.6%, score 3=41.0%, and score 4=60.3%). The RSAT compared with throat culture had a sensitivity and specificity of 91.4% (95% CI: 85.6 to 95.0%) and 95.3% (95% CI: 91.7 to 97.3%), respectively. 15 The PPV and NPV were 92% and 95% and the likelihood ratio equaled 19.3 (suggests a large and often conclusive increase in the likelihood of GABHS pharyngitis). The test results indicated a positive correlation between the clinical scores and sensitivity and PPVs, whereas the specificity and NPVs did not vary much between test scores. 15 The sample population may have included a greater proportion of patients with a high disease severity compared with patients normally seen in a community primary care practice and diagnostic tests cannot differentiate between colonization and infection. The prevalence of GABHS may have therefore been overestimated. The authors conclude that RSAT combined with a clinical score is the most effective approach for the diagnosis and treatment of GABHS in the adult population. 15 McIsaac et al. 16 evaluated the impact of the Infectious Diseases Society of America (IDSA)/American College of Physicians-American Society of Internal Medicine/American Academy of Family Physicians/US Centers for Disease Control and Prevention (ASIM) guideline Point of Care Testing for Streptococcal Sore Throat 5

6 recommendation and alternative strategies on identification and treatment of GABHS pharyngitis in the pediatric and adult population. The study was conducted in a family practice clinic that serves approximately 11,500 patients in Calgary, Alberta. Six strategies were assessed. They are as follows: 1) Strategy 1 (Standard Approach): Obtain a throat culture in all children and adults with sore throat and treat only those having a positive culture result. 2) Strategy 2 (IDSA/ASIM 1 ): Perform rapid test on all children and treat those having positive test results; perform throat culture on those with negative rapid test results and treat those having positive culture results, perform rapid test on all adults and treat those having positive rapid test results without culture confirmation of negative results. 3) Strategy 3 (ASIM 2 ): Treat children per IDSA recommendations. Perform rapid test on all adults having a Centor score of 2 or 3 and treat those with positive rapid test results; treat all adults having a score of 4 or more empirically. 4) Strategy 4 (ASIM 3 ): Treat children per IDSA recommendations. Test no adults and treat those having a Centor score of 3 or 4 or more empirically. 5) Strategy 5 (Modified Centor Score and Culture Approach): Perform throat culture on all children and adults having a Centor score of 2 or 3 and treat those having positive culture results. Treat those having a score of 4 or more empirically. 6) Strategy 6 (Rapid Test Approach): Perform rapid test on all children and adults and treat those having positive results without culture confirmation of negative results. (p1589) 16 A rapid enzyme-linked immunosorbent assay kit, Abbott TestPack Plus Strep A with On Board Controls II (Abbott Laboratories, Montreal, Quebec), was used for the study, and throat cultures were performed in a central microbiology laboratory using standard methods (i.e. streaking and stabbing sheep blood agar plates incubated anaerobically at 35 o C with confirmation of β- hemolytic colonies as GABHS using latex agglutination) [PathoDx Strep A Typing, Diagnostic Products Corp, Los Angeles, California] in a microbiology laboratory in Calgary, Alberta. 16 Nine-hundred and eighteen patients were screened from September 1999 to August 2002 and 787 (86%) completed the study. The median age of the patient population was 16 years (range from 3 to 69 years), with 454 persons (57.7%) aged 3 to 17 years and 333 persons (42.3%) aged 18 to 69 years. 16 The prevalence of positive throat culture for the study sample was 29.0% (228/787) and 194 patients had a positive rapid test result. 16 The sensitivity was 82.9%, specificity was 99.1%, and the NPV was 93.4%. 16 Strategy 6 (rapid test only) had the lowest sensitivity of 82.9% (189/229) compared with the other strategies with a sensitivity of greater than 90% for GABHS diagnosis for the study sample. Sensitivities were lower among adults for strategies excluding throat cultures (strategies 2, 3, 4, and 6) versus strategies with throat cultures (strategies 1 and 5). The specificities for all strategies were greater than 90%, except for strategy 4 (ASIM 3 ) which had a specificity of 73.4% (410/559) for the sample population. 16 One study limitation relates to the inclusion of children and adults with a Centor score of 2 or greater; however, this patient population selection is supported by the IDSA and ASIM guidelines. The authors were unable to determine the impact of low or high prevalence of GABHS on the performance characteristics of the test since the outcomes for each strategy came from individual children or adults and not the population as a whole. 16 Edmonson and Farwell 17 conducted a retrospective, cross-sectional study to measure the sensitivity of a second-generation RADT for GABHS pharyngitis in pediatric clinic patients. Laboratory records and clinical chart data of patients who were less than 24 years old, who visited the clinical between January 2000 and May 2002, and who had a diagnostic test for pharyngeal GABHS, were reviewed. The McIsaac clinical scores were calculated in a blinded chart review to estimate the pretest positive and negative likelihood of GABHS pharyngitis. 17 The throat-swabbing technique used was not standardized; however, the providers were aware Point of Care Testing for Streptococcal Sore Throat 6

7 the recommended locations for swabbing sites (e.g., each tonsil/tonsillar bed and posterior pharynx, avoiding the tongue/soft palate). The RADT was carried out with CARDS QS Strep A (Quidel Corp, San Diego, California), a lateral-flow immunoassay that uses chemochromographic indicators to detect GABHS. 17 The test was conducted by medical assistants and phlebotomists at the on-site clinic. Throat swab cultures were plated on 5% sheep blood agar, incubated anaerobically overnight at 35 to 37 o C. The plates were read each morning for the two following days. Subculture plates were inoculated with selected β-hemolytic colonies and were confirmed as GABHS by latex agglutination (PATHoDx, Remel, Lenexa, KS) or disk detection of pyrrolidonyl peptidase (PYR Disk, Remel). 17 The RADT sensitivity for the sample population was 86% (384/449 [95% CI: 83 to 89%]) and GABHS prevalence among patients test with a RADT was 38% (449/1,184 [95% CI: 35 to 41%]). Statistical analyses indicated that test sensitivity increased (P<0.05) as the patient s age decreased in 5-year increments, when the patient had a sore throat, no cough was reported, when a patient had recently completed treatment for GABHS pharyngitis or when tonsillar exudate or swelling were present on physical examination. 17 The authors did not report any statistically significant differences in RADT sensitivity based on patient gender, year of visit, season of year, history of runny nose, fever, tender anterior cervical nodes, or history of recent household or school exposure to a reported case of GABHS pharyngitis. 17 One major limitation is the retrospective study design. It was a challenge to determine if the providers recorded the patient history or physical finding before reviewing the RADT results. Also, singles throat cultures were used as a reference standard instead of double cultures, a more sensitive diagnostic test. Subsequently, the sensitivity of RADTs may have been lower. Economic evaluations Van Howe et al. 3 conducted a cost-utility analysis on the diagnosis and management of pharyngitis in the pediatric population. A decision tree was developed for six strategies to pharyngitis among children. The six strategies are as follows: 1) treat all patients suspected to have pharyngitis with antibiotics with no testing; 2) observe all patients without testing or treatments; 3) test all patients with pharyngitis using a rapid antigen test and treat patients with a positive test result with antibiotics; 4) test all patients with pharyngitis using a throat culture and treat those with a positive test result with antibiotics; 5) test all patients with pharyngitis using a rapid antigen test and treat patients with a positive test result with antibiotics and perform a culture for patients with a negative test result; and 6) use a modified Centor clinical scoring system to triage the diagnostics approach. For example, patients with a low score would not be tested, those with a medium score would be tested and treated if they had positive test results, and patients with a high score would be treated without having to be tested. 3 The decision tree model measured the total costs and quality-adjusted life-days (QALDs) for each of the six approaches from a societal perspective. The total costs and QALDs were also measured from an insurance payer perspective. The marginal differences in costs and QALDs for calculated for each strategy. 3 Cost items include testing, treatment, expected sequelae, and parental time lost from work. All costs are presented in 2003 US dollars. The utility variables used were incidence of peritonsillar abscess (PTA), the incidence of acute rheumatic fever (ARF), costs of throat culture and of death, utility of treatment of hemolytic streptococcal (GAS) pharyngitis, and cephalosporin compared with penicillin in the treatment of GAS pharyngitis. 3 Sensitivity analyses were conducted for each of the variables. The CIs for the costs and utility for each of six strategies were estimated using Monte Carlo simulations with 10,000 repetitions. 3 The co-authors defined Monte Carlo simulations as, [using] random sampling techniques to assign values from within a specified range and distribution for each of the variables in the model. The utility measures and their CIs used to estimate the QALDs and Quality-Adjusted Point of Care Testing for Streptococcal Sore Throat 7

8 Life-Years (QALYs) were calculated with the General Health Policy Model and the Quality of Well-being Scale and previously published values listed in the study. 3 Table 1 outlines the cost per QALY reported for the strategies from a societal perspective. The co-authors determined that the test using throat culture strategy provided the best cost-utility from a societal perspective with the current Medicaid reimbursement for testing (data not reported). 3 Rapid antigen testing had the best cost-utility from a private insurance reimbursement perspective ($32, per QALY). From an insurance payer perspective, the strategy to do no testing resulted in the lowest cost and lowest mortality rate (data not reported). This strategy also incurred the highest cost and lowest mortality rate from a societal perspective (data not reported). 3 Table 1: Cost per QALY 3 Strategy Description Cost per QALY (2003 US$) 1 Treat all 1,135,609 2 Treat none NR 3 Rapid testing 315,000 4 Culture all NR 5 Rapid testing then culture 291,000 6 Clinical scoring 632,000 NR=not reported; QALY=quality-adjusted life-year The Monte Carlo simulation suggests that the no-treatment strategy was significantly more costly compared with the clinical scoring, rapid test, culture test, rapid test followed by culture and treat all strategies (101.15$ [95% CI: to $])(P>0.05) but had significantly lower rates of morbidity compared with the other strategies ( [95% CI: to ]. 3 The authors concluded that observing all patients with pharyngitis had the lowest mortality rate and costs. 3 Costs of the observation strategy were related to parental time lost from work. Futhermore, risks of developing acute rheumatic fever and peritonsillar absess must be measured accurately prior to recommending the observation instead of the treatment of GAS pharyngitis. 3 Guidelines The Alberta Medical Association published an update of clinical practice guidelines for the diagnosis and management of acute pharyngitis in The guidelines were developed by a Clinical Practice Guideline working group with the intention to reduce the use of antibiotics to treat pharyngitis. 18 The methods, such as data sources used to develop the recommendations, were not described. The guidelines do not recommend rapid strep tests for the diagnosis of acute pharyngitis since they lack sensitivity and evidence of improved clinical outcome. Instead, they recommend a throat culture done according to standard practices. 18 In 2008, the Institute for Clinical Systems Improvement (ICSI) published guidelines on the diagnosis and treatment of respiratory illness in children and adults. 19 A multidisciplinary working group developed the evidence-based guidelines. The guidelines undergo a critical review process by clinicians and are approved by an ICSI steering committee. The current guidelines recommend that rapid strep test be followed by strep culture since its sensitivity is not Point of Care Testing for Streptococcal Sore Throat 8

9 high enough to be used alone and also indicate that strep culture is the most sensitive for group A beta streptococcal. 19 The Michigan Quality Improvement Consortium Guideline developed guidelines for acute pharyngitis in children in The guidelines were developed through a literature search of computer databases including MEDLINE to identify published studies, protocols, and clinical practice guidelines on acute pharyngitis in children. The target population for guideline recommendations is patients between two and 18 years of age with a low or high risk of developing GABHS, and the intended users are clinicians in family practice, internal medicine, otolaryngology, and pediatrics. 20 A list of the items considered to assess the likelihood of GABHS is provided in the appendix. The guidelines recommend no testing for patients with a low risk of GABHS and symptomatic treatment only. Among patients in the intermediate risk categories, rapid screening should be followed by throat culture, and antibiotics should be administered if either the throat culture or rapid screen tests positive. 20 Patients in the high-risk category (i.e., history of rheumatic fever or household contact with rheumatic fever or confirmed strep) should start antibiotics immediately but stop the treatment if throat culture test results are negative. 21 The University of Michigan Health System published guidelines in October 2006 for pharyngitis for patients three years old through adulthood. 22 The development process of the guidelines was not described by the pharyngitis guideline team. The strength of each recommendation was measured with the GRADE scoring system. The guidelines for clinical care recommend laboratory diagnostic test for the adult population when GABHS is suspected and the patient displays at least two clinical symptoms and when a patient between three to 15 years of age display at least one clinical symptom. The clinical symptoms include recent fever, tender anterior cervical lymphadenopathy, red pharynx (with or without tonsillar swelling or exudates), and no cough. 22 The guidelines recommend the use of rapid strep tests for patients who are likely to have GABHS, and negative test results should be confirmed by culture for patients less than 16 years old since this patient population has a greater probability of developing acute rheumatic fever. 22 Throat culture is consider the gold standard for GABHS screening and may be sufficient for GABHS screening among patients in the low-risk category. The GRADE recommendation for the above recommendations is C (lacking direct evidence). Limitations Eight observational studies, but no systematic reviews, meta-analyses, or RCTs that compared RADTs with throat culture for GABHS pharyngitis were identified. Subjects in observational studies are assigned to an intervention group by a participating physician rather than via a randomized process, thereby increasing the chance of confounding. Observational studies are also limited by their lacking of blinding which may influence the interpretation of test results. Only one economic evaluation on the diagnosis and management of pharyngitis among children was found in the literature. The selected studies compared POCT using RADTs versus culture-methods in hospital laboratory, which are rarely available to physicians in the medical office or outpatient clinics. Test methods used should reflect the availability of tools in the physician s general practice for a more accurate comparison. The evaluation of performance characteristics of RADTs is affected by several factors such as the study setting, patient population, disease severity, and test administration. For example, a few studies exhibited spectrum bias as a potential limitation, where the RADT and culture-test sensitivities among patients with a clinical score greater than 2 were significantly higher Point of Care Testing for Streptococcal Sore Throat 9

10 compared with patients with a clinical score less than 2. Patients with a higher clinical score will have greater likelihood of GABHS pharyngitis compared with patients with a lower clinical score. The literature search timeframe was limited to the last five years. It is possible that some systematic reviews, RCTs, observational studies, or economic evaluations were not retrieved since they did not meet the date criterion. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: The current evidence indicates that RADTs generally have a lower sensitivity compared with throat cultures for GABHS diagnosis. This is more evident in the pediatric population. Only one economic evaluation that compared the cost-utility of RADTs compared with throat cultures and other approaches (e.g., no testing, clinical score) was identified for GABHS diagnosis among children. The decision model concluded that throat cultures had the best cost-utility from a societal perspective. The Canadian guidelines by the Alberta Medical Association do not recommend the RADTs for the diagnosis of acute pharyngitis due to the low sensitivity, and the US guidelines recommend that RADTs be followed by throat cultures since the culture method is the most sensitive for GABHS. Since throat culture is the gold standard for testing, it may be sufficient for patients with a low risk for GABHS. Advantages of RADTs are the ease of use and convenience since they can be conducted by a nurse or medical assistant in a physician s office and the low turnaround time for test results. Future research should include RCTs and more economic evaluations that measure the clinical and cost-effectiveness of POCT using RADTs compared with throat cultures for GABHS diagnosis in pediatric and adult populations. Additional studies should also measure the impact of POCT on the antibiotic therapy for GABHS. Higher quality research will, in turn, support policy-makers in making informed decisions. PREPARED BY: Julie Polisena, MSc, Research Officer Carolyn Spry, MLIS, Information Specialist Health Technology Inquiry Service htis@cadth.ca Tel: Point of Care Testing for Streptococcal Sore Throat 10

11 REFERENCES 1. Armengol CE, Hendley JO, Schalager TA. An office-based guide to diagnosing streptococcal pharyngitis. Contemp Pediatr 2006;23(5):64, 65-6, Dean L, Perry K. Group A streptococcus rapid antigen detection test kits: a review of evaluation literature [MHRA 04123]. London: Medicines and Healthcare Products Regulatory Agency; Van Howe RS, Kusnier LP. Diagnosis and management of pharyngitis in a pediatric population based on cost-effectiveness and projected health outcomes. Pediatrics 2006;117(3): Available: (accessed 2009 Apr 2). 4. Centor RM, Witherspoon JM, Dalton HP, Brody CE, Link K. The diagnosis of strep throat in adults in the emergency room. Med Decis Making 1981;1(3): McIsaac WJ, White D, Tannenbaum D, Low DE. A clinical score to reduce unnecessary antibiotic use in patients with sore throat. CMAJ 1998;158(1): Available: (accessed 2009 Apr 20). 6. Leung AK, Newman R, Kumar A, Davies HD. Rapid antigen detection testing in diagnosing group A beta-hemolytic streptococcal pharyngitis. Expert Rev Mol Diagn 2006;6(5): Gerber MA, Shulman ST. Rapid diagnosis of pharyngitis caused by group A streptococci. Clin Microbiol Rev 2004;17(3): Medical devices active license listing [database online]. Ottawa: Medical Devices Bureau, Therapeutic Products Directorate, Health Canada; Available: (accessed 2009 Apr 24). 9. 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 offices: implications for management of pharyngitis. Pediatrics 2009;123(2): Fontes MJ, Bottrel FB, Fonseca MT, Lasmar LB, Diamante R, Camargos PA. Early diagnosis of streptococcal pharyngotonsillitis: assessment by latex particle agglutination test. J Pediatr (Rio J) 2007;83(5): Al-Najjar FY, Uduman SA. Clinical utility of a new rapid test for the detection of group A Streptococcus and discriminate use of antibiotics for bacterial pharyngitis in an outpatient setting. Int J Infect Dis 2008;12(3): Van Limbergen J, Kalima P, Taheri S, Beattie TF. Streptococcus A in paediatric accident and emergency: are rapid streptococcal tests and clinical examination of any help? Emerg Med J 2006;23(1): Forward KR, Haldane D, Webster D, Mills C, Brine C, Aylward D. A comparison between the Strep A Rapid Test Device and conventional culture for the diagnosis of streptococcal pharyngitis. Can J Infect Dis Med Microbiol 2006;17(4): Available: Point of Care Testing for Streptococcal Sore Throat 11

12 (accessed 2009 Apr 2). 14. Camurdan AD, Camurdan OM, Ok I, Sahin F, Ilhan MN, Beyazova U. Diagnostic value of rapid antigen detection test for streptococcal pharyngitis in a pediatric population. Int J Pediatr Otorhinolaryngol 2008;72(8): Humair JP, Revaz SA, Bovier P, Stalder H. Management of acute pharyngitis in adults: reliability of rapid streptococcal tests and clinical findings. Arch Intern Med 2006;166(6): Available: (accessed 2009 Apr 2). 16. McIsaac WJ, Kellner JD, Aufricht P, Vanjaka A, Low DE. Empirical validation of guidelines for the management of pharyngitis in children and adults. JAMA 2004;291(13): Available: (accessed 2009 Apr 2). 17. Edmonson MB, Farwell KR. Relationship between the clinical likelihood of group a streptococcal pharyngitis and the sensitivity of a rapid antigen-detection test in a pediatric practice. Pediatrics 2005;115(2): Available: (accessed 2009 Apr 2). 18. Guideline for the diagnosis and management of acute pharyngitis. In: Toward Optimized Practice: clinical practice guidelines. Edmonton: Toward Optimized Practice (TOP); Available: ngitis_guideline.pdf (accessed 2009 Apr 20). 19. Diagnosis and treatment of respiratory illness in children and adults. 2nd ed. Bloomington (MN): Institute for Clinical Systems Improvement (ICSI); Available: guideline_/respiratory_illn ess_in_children_and_adults guideline html (accessed 2009 Apr 20). 20. Acute pharyngitis in children [summary]. In: National Guideline Clearinghouse [database online]. Rockville (MD): NGC; Available: ute+and+pharyngitis+and+children (accessed 2009 Apr 20). 21. Acute pharyngitis in children. In: MQIC guidelines. Southfield (MI): Michigan Quality Improvement Consortium (MQIC); Available: (accessed 2009 Apr 23). 22. Pharyngitis. In: University of Michigan Health System: clinical care guidelines. Ann Arbor (MI): University of Michigan; Available: (accessed 2009 Apr 20). Point of Care Testing for Streptococcal Sore Throat 12

13 Appendix: Items Used to Assess the Likelihood of GABHS 21 Sudden onset Sore throat Fever Patchy discrete exudates Headache Nausea, vomiting, and abdominal pain Inflammation of pharynx and tonsils Tender, enlarged anterior cervical nodes Patient aged 5-15 years Presentation of winter or early spring History of exposure No cough Point of Care Testing for Streptococcal Sore Throat 13