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Indication - Streptococcal pharyngitis
Group A Streptococcus antigen
Facility level:
1. No laboratory
Assay formats
RDT
Status history
First added in 2020
Purpose type
Aid to diagnosis
Purpose
To aid in the diagnosis of Group A streptococcal pharyngitis
Specimen types
Throat Swab
WHO prequalified or recommended products
N/A
WHO supporting documents
N/A
Codes
ICD11 code: 1B51

Summary of evidence evaluation

The evidence of the diagnostic accuracy of GAS RADT to aid in the diagnosis of GAS pharyngitis has been summarized in three comprehensive systematic reviews, all with similar findings. The evidence base is substantial, and average sensitivity and specificity of the RADTs is 85% and 95%, respectively; this has not been found to vary systematically with test technology – LFIAs, EIAs and OIAs (optical immunoassays) – or age group (adults and children). Although the reviews have revealed methodological weaknesses in the primary studies, these do not appear to influence the observed accuracy. Unexplained heterogeneity in accuracy has been noted, and there may be variations between test brands or versions; but no clear explanations have been given. Use in patients where the prevalence of GAS is 30% yields positive predictive values of 88% and negative predictive values of 94%. Guidelines suggest that the positive predictive value is high enough to recommend antibiotics. But guidelines also judge that the risk of missing infection in children is high and recommend that those testing negative also have culture to confirm diagnosis within 24–48 h. The negative RADT result is seen as adequate to withhold antibiotics in adults. Evidence of the impact of RADTs is mixed, and likely to depend on current local practice, although it has been shown to reduce antibiotic use. The full evidence review for this test category is available online at: https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/new-prod-categories_3

Summary of SAGE IVD deliberations

GAS pharyngitis is a common and severe condition, especially among children, for which there is no test currently listed in the EDL. Because prompt and adequate treatment improves the prognosis of GAS pharyngitis, rapid diagnosis is a requisite of children’s primary care worldwide. The proposed IVDs have enough potential for adequate diagnosis and are both convenient and cost-effective. The current gold standard (throat culture) takes too long to deliver results and is often unavailable in facilities in LMICs. Importantly, a POC test for GAS pharyngitis could help avoid unnecessary use of antibiotics, thereby contributing to lower health care costs, fewer adverse events and reduced risk of antibiotic resistance. SAGE IVD noted the very recent publication of a systematic review on the impact of GAS RADTs which shows that they reduce antibiotic use by 8% and antibiotic prescription by 25% (14).

SAGE IVD recommendation

SAGE IVD recommended including the Group A Streptococcus antigen test category in the third EDL: • as a disease-specific IVD for use in community settings and health facilities without laboratories and as a disease-specific IVD for use in clinical laboratories (EDL 3, Sections I.b and II.b); • using an RDT or immunoassay format; • to aid in the diagnosis of Group A Streptococcal pharyngitis. The group clarified the need for the dual listing in Sections I.b and II.b of the EDL, saying that while the RADT can be used in primary care settings, most guidelines require culture confirmation of a negative test (because rapid tests have lower specificities than immunoassays). SAGE IVD also highlighted the potential for this test to be grossly overused, and it emphasized the value of adding a note on rational use to this entry in the EDL. To this end, while acknowledging that the EDL is designed to be a policy support document rather than a guide to medical use, SAGE IVD recommended considering the inclusion of an additional column in future editions of the EDL, where comments or qualifications of importance can be made.

Details of submission from 2020

Background

Disease condition and impact on patients Streptococcal pharyngitis, also known as strep throat, is an infection of the back of the throat, including the tonsils, caused by GAS (Streptococcus pyogenes). Common symptoms include fever, sore throat, red tonsils and enlarged lymph nodes in the neck. A headache, abdominal pain, and nausea or vomiting may also occur. Symptoms typically begin 1–3 days after exposure and last 7–10 days. Complications that may arise if strep throat is not correctly diagnosed and managed include rheumatic fever with potential long-term heart damage or death, kidney inflammation and peri-tonsillar abscess, sepsis and necrotizing fasciitis. Does the test meet a medical need? A rapid antigen detection test (RADT) for GAS pharyngitis enables rapid administration of antibiotics to patients (mostly children between the ages of 5 and 15) to prevent progression to suppurative and non-suppurative complications. Antibiotic treatment does not affect the incidence or outcomes related to some non-suppurative complications such as post-streptococcal glomerulonephritis and arthritis. The test could also potentially reduce antibiotic prescription in children and adults presenting with signs and symptoms of pharyngitis, by offering selective treatment to those testing positive and those at higher risk of complications. How the test is used The GAS RADT comes in two formats: a lateral flow immunoassay rapid test and an instrument-based digital immunoassay. Both have high specificity and relatively low sensitivity. Guidelines state that a positive result is diagnostic of GAS pharyngitis. In children, a negative result must be confirmed with culture to prevent the risk of infection progressing from strep throat to more serious conditions such as rheumatic fever.

Public health relevance

Prevalence and socioeconomic impact Strep throat is a common bacterial infection in children 5–15 years of age and a rare one in children under 3 years of age. It causes 15–40% of sore throats among children and 5–15% among adults. Cases are more common in late winter and early spring. A lack of reliable data makes accurately estimating global disease burden difficult. A 2005 review estimated that at least 18.1 million people suffered from invasive GAS diseases, with another 1.78 million incident cases occurring each year (1). These estimates did not include the more than 111 million cases of streptococcal pyoderma and 616 million cases of GAS pharyngitis each year. The health, economic and social burden of GAS pharyngitis (and skin infections) can be significant despite the fact that these diseases are relatively benign. Direct health costs come from antibiotic use, as well as missed schooldays for children and workdays for their parents; but their causal association with invasive infection also has clinical and public health implications. A small 2008 study in Boston, USA, estimated that the total cost of GAS pharyngitis among children in the USA ranges from US$ 224 to US$ 539 million per year, half of which is non-medical costs related to school- and workdays missed (2). By far the heaviest burden of GAS infections falls on low- and middle-income countries (LMICs), because children living in crowded or unsanitary conditions are at much higher risk not only of contracting the infections but also of these not being diagnosed correctly and progressing to invasive disease (3).

WHO or other clinical guidelines relevant to the test

The Infectious Diseases Society of America (IDSA) in its 2012 guidelines recommends the GAS RADT or culture of throat swabs to diagnose GAS pharyngitis in children older than 3 years of age with a suspicion of bacterial pharyngitis. The recommendations reiterate that a positive test result does not require culture; but that a negative RADT result should be backed up with a throat swab culture, especially in children and adolescents (4).

Evidence for diagnostic accuracy

In 2018, the Canadian Agency for Drugs and Technologies in Health (CADTH) compiled a report to assess the clinical accuracy and utility and economic benefit of RADTs and molecular tests (5). The report examined three systematic reviews, one UK randomized clinical trial (RCT) that included an economic analysis, and 23 primary studies across 11 countries and a broad range of income levels. It found that the sensitivity and specificity of immunoassay-based tests was 55–94% and 81–100%, respectively, for children and mixed populations of children and adults tested using immunoassays with culture assays as reference tests. Lean et al. (6) evaluated LFIAs and reported sensitivity and specificity at 84% (95% CI: 80–88) and 96% (95% CI: 94–97), respectively. A 2014 meta-analysis by Stewart et al. (7) evaluated both LFIAs and enzyme immunoassays (EIAs) and found these to be accurate in adults but not in children. It reported pooled sensitivity of LFIAs among children ranging from less than 80% (6 of 28 studies) to 90%, and pooled specificity ranging from less than 80% to more than 95%. For EIA-based methods in children, there was less heterogeneity: pooled sensitivity was 86% (95% CI: 79–92) and pooled specificity was 92% (95% CI: 88–95). In adults, pooled sensitivity for LFIAs was 91% (95% CI: 87–94) with pooled specificity of 93% (95% CI: 92–95); and pooled sensitivity for EIAs was 86% (95% CI: 81–91) with pooled specificity of 97% (95% CI: 96–99). A 2016 systematic review by Cohen et al. (8) compared EIAs and OIAs among children with throat culture standard and found a summary sensitivity of 85.6% (95% CI: 83.3–87.6) and summary specificity of 95.4% (95% CI: 94.5–96.2).

Evidence for clinical usefulness and impact

Reduction in antibiotic use GAS RADTs have a low sensitivity, and thus a low negative predictive value for diagnosing GAS pharyngitis in children. The sensitivity is acceptable for adults. Recent studies have shown that use of GAS RADTs in emergency departments along with clinical scoring reduced antibiotic use in children (9) and in hospital settings (10). In adult populations, primary studies recently published show that the test has potential for application in pharmacies and family health clinics to reduce antibiotic prescription and subsequent nucleic acid testing (11, 12). Prevention of suppurative complications: No evidence provided or available, although suppurative complications are thought to result from untreated GAS tonsillitis. Prevention of acute rheumatic fever: The evidence on GAS pharyngitis diagnosis and treatment preventing acute rheumatic fever has recently been called into question. Developed countries that withhold antibiotics have not seen a resurgence of acute rheumatic fever. And it has been suggested that acute rheumatic fever results from specific M types of GAS rather than all types, so diagnosis with RADT may not directly prevent this burden. But incidence may vary widely among populations, and data from LMICs are lacking, with the sample size of existing studies called too small.

Evidence for economic impact and/or cost–effectiveness

The Primary Care Streptococcal Management (PRISM) study in the United Kingdom was an RCT done in primary care practices to study the effect of RADT on antibiotic use, compared with clinical scoring (13). It found no difference in the two arms and favoured clinical scoring over RADT. The cost/quality-adjusted life-years (QALYs) and cost/change in symptom severity analyses showed clinical scoring alone to be more cost-effective. Cost impact was not the primary outcome in this study. A study done by Kose et al. in Turkey (10) investigated the effect of an RADT on the diagnosis of streptococcal pharyngitis. Performing RADT in children with pharyngitis has an important impact on treatment decisions of clinicians, reduction of unnecessary antibiotic prescriptions and antibiotic costs.

Ethical issues, equity and human rights issues

The Primary Care Streptococcal Management (PRISM) study in the United Kingdom was an RCT done in primary care practices to study the effect of RADT on antibiotic use, compared with clinical scoring (13). It found no difference in the two arms and favoured clinical scoring over RADT. The cost/quality-adjusted life-years (QALYs) and cost/change in symptom severity analyses showed clinical scoring alone to be more cost-effective. Cost impact was not the primary outcome in this study. A study done by Kose et al. in Turkey (10) investigated the effect of an RADT on the diagnosis of streptococcal pharyngitis. Performing RADT in children with pharyngitis has an important impact on treatment decisions of clinicians, reduction of unnecessary antibiotic prescriptions and antibiotic costs.
1. The current evidence for the burden of group A streptococcal diseases. Geneva: World Health Organization; 2005 (WHO/FCH/CAH/05.07). 2. Pfoh E, Wessels MR, Goldmann D, Lee GM. Burden and economic cost of group A streptococcal pharyngitis. Pediatrics. 2008;121(2):229–234. doi:10.1542/peds.2007-0484. 3. Sanyahumbi AS, Colquhoun S, Wyber R, Carapetis JR. Global disease burden of group A streptococcus. In: Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes: basic biology to clinical manifestations. Oklahoma City: University of Oklahoma Health Sciences Center; 2016. 4. Shulman ST, Bisno AL, Clegg HW, Gerber MA, Kaplan EL, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55(10):e86–e102. doi:10.1093/cid/cis629. 5. Banerjee S, Ford C. Rapid tests for the diagnosis of group A streptococcal infection: a review of diagnostic test accuracy, clinical utility, safety, and cost effectiveness. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2018. 6. Lean WL, Arnup S, Danchin M, Steer AC. Rapid diagnostic tests for group A streptococcal pharyngitis: a meta-analysis. Pediatrics. 2014;134(4):771–781. doi:10.1542/peds.2014-1094. 7. Stewart EH, Davis B, Clemans-Taylor BL, Littenberg B, Estrada CA, et al. Rapid antigen group A streptococcus test to diagnose pharyngitis: a systematic review and meta-analysis. PLoS One. 2014;9(11):e111727. doi:10.1371/journal.pone.0111727. 8. Cohen JF, Bertille N, Cohen R, Chalumeau M. Rapid antigen detection test for group A streptococcus in children with pharyngitis. Cochrane Database Syst Rev. 2016;7:CD010502. doi:10.1002/14651858.CD010502.pub2. 9. Bird C, Winzor G, Lemon K, Moffat A, Newton T, et al. A pragmatic study to evaluate the use of a rapid diagnostic test to detect group A streptococcal pharyngitis in children with the aim of reducing antibiotic use in a UK emergency department. Pediatr Emerg Care. 2018 Jul 24. doi:10.1097/PEC.0000000000001560. 10. Kose E, Kose SS, Akca D, Yildiz K, Elmas C, et al. The effect of rapid antigen detection test on antibiotic prescription decision of clinicians and reducing antibiotic costs in children with acute pharyngitis. J Trop Pediatr. 2016;62(4):308–315. doi:10.1093/tropej/fmw014. 11. Dodd M, Adolphe A, Parada A, Brett M, Culbreath K, et al. Clinical impact of a rapid streptococcal antigen test on antibiotic use in adult patients. Diagn Microbiol Infect Dis. 2018;91(4):339–344. doi:10.1016/j.diagmicrobio.2018.03.018. 12. Demoré B, Tebano G, Gravoulet J, Wilcke C, Ruspini E, et al. Rapid antigen test use for the management of group A streptococcal pharyngitis in community pharmacies. Eur J Clin Microbiol Infect Dis. 2018;37(9):1637–1645. doi:10.1007/s10096-018-3293-8. 13. Little P, Hobbs FDR, Moore M, Mant D, Williamson I, et al. Primary care Streptococcal Management (PRISM) study: in vitro study, diagnostic cohorts and a pragmatic adaptive randomised controlled trial with nested qualitative study and cost-effectiveness study. Health Technol Assess. 2014;18(6):vii–xxv. doi:10.3310/hta18060. 14. Cohen JF, Pauchard JY, Hjelm N, Cohen R, Chalumeau M. Efficacy and safety of rapid tests to guide antibiotic prescriptions for sore throat. Cochrane Database Syst Rev. 2020;6(6):CD012431. doi:10.1002/14651858.CD012431.pub2.