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    1. Disease
    2. Infectious Disease

    Benefits of molecular test-and-treat for Group A Streptococcus pharyngitis

    June 24, 2024
    66609c9dbdbc1be37391f05b Cover Illustration

    Group A streptococcal (GAS) infections have been on the rise since late 2022 and 2023 after an overall low incidence during the years of the COVID-19 pandemic.1  GAS infections are common among children and may be asymptomatic or produce mild infections such as pharyngitis, impetigo, and scarlet fever.1 Symptoms of GAS pharyngitis, also known as strep throat, include fever, pain when swallowing, sudden onset sore throat, red and swollen tonsils, white patches or pus on tonsils, tiny red spots on the roof of mouth, and swollen lymph nodes in the front of the neck.2  GAS pharyngitis typically occurs in winter and early spring in temperate climates.

    Invasive GAS (iGAS) infections are potentially life threatening and clinical presentation of iGAS infections include sepsis, necrotizing fasciitis, streptococcal toxic shock syndrome, and other severe infections. Presently, iGAS infections affect 1.8 million persons worldwide, both young and old, with a mortality rate approaching 20%.1  iGAS infections may have non-specific symptoms such as fever, which makes clinical diagnosis problematic. Preliminary 2023 data from the U.S. Centers for Disease Control and Prevention (CDC) indicate that the number of severe infections caused by GAS reached a 20-year high.2 Similarly, non-invasive GAS, including GAS pharyngitis, has returned to similar or higher levels than those seen in the pre-COVID-19 pandemic years.2 The recent increase in GAS infections may be due to a number of factors, including increased circulation of more virulent strains, increased susceptibility in children due to reduced incidence during the COVID-19 pandemic, and/or increased susceptibility due to high rates of respiratory viral coinfection in the pediatric population.3

    Pharyngitis diagnostic tests

    While acute pharyngitis is common, a minority of sore throats are caused by GAS infections. Because symptoms caused by the different agents of pharyngitis can overlap, clinical assessment alone may be insufficient for the differentiation of viral versus bacterial pharyngitis.4 Specific identification GAS as a causative agent of illness, especially in children, is integral to appropriate medical management of patients. Early and effective antibiotic treatment for GAS infections is essential to prevention of post-infectious sequelae, including iGAS infections and rheumatic fever, decrease of transmission to close contacts, and improvement of clinical symptoms.4 In the 2012 guidelines, the Infectious Diseases Society of America (IDSA) recommended rapid antigen detection tests (RADTs) for diagnosis of GAS in patients presenting with symptoms consistent with GAS pharyngitis; then backed-up by throat culture if the RADT is negative, due to the low sensitivity of the antigen test.4  In recent years, GAS identification using newly available molecular methods such as polymerase chain reaction (PCR) or other nucleic acid amplification tests (NAATs) conducted at point-of-care (POC) or ‘near patient’ locations is increasingly implemented due the relative simplicity, rapidity, and increased diagnostic sensitivity of this approach (Table 1). Rapid result availability allows for diagnosis while the patient is still in the clinic, increasing the likelihood of appropriate antibiotic use. POC NAATs for GAS can take between 15–25 minutes for results, slightly longer than the typical result time of RADTs (5–15 minutes).5 Conversely, culture of throat swabs requires 18 – 48 hours for results and may be performed in a laboratory that is remotely located.5

    Table 1. Available GAS molecular tests.
    Table 1. Available GAS molecular tests.

    Antimicrobial stewardship

    The ability to appropriately prescribe antibiotics during the initial patient visit is an important benefit of POC RADT or NAAT testing compared to diagnosis by throat culture. In a meta-analysis of 15 primary care medical records in the United States. from 2018 to 2019, 99% of antibiotics were prescribed during the initial patient visit regardless of the diagnostic method used.6 A retrospective analysis using data from 2011–2015 found that during this time, 66% of the pharyngitis cases diagnosed by RADT plus culture began antibiotic therapy on the day of the patient’s initial visit.7 The implication of both analyses is that antibiotics were given before culture results were available and that treatment may have been unnecessary and ineffective. Inappropriate antibiotic use is associated with increased risk of adverse reactions in the patient as well as population-level increases in antibiotic resistance. Rapid molecular POC tests with field-verified high sensitivities and specificities have the potential to reduce inappropriate antibiotic prescriptions. Several U.S. studies compared PCR POC with RADT plus culture methods for appropriate antibiotic use and demonstrated that use of POC NAATs resulted in higher rates of appropriate antibiotic use when compared to the dual methodology due to the superior diagnostic accuracy of NAATs.5,6,8

    Near-patient testing

    Near-patient testing is defined as “an investigation taken at the time of the [clinical] consultation with instant availability of results to make immediate and informed decisions about patient care.”9 Near-patient testing has been used interchangeably with POC testing (POCT). Streamlined healthcare, relying on near-patient testing at community-based and one-stop clinics, has the potential to reduce healthcare disparities by providing earlier diagnosis, immediate patient counseling, and appropriate therapies.9  ‘One and done’ clinic visits may improve disease management, patient outcomes, patient satisfaction, and increase cost-effectiveness per visit.9 Studies in both clinical and pharmacy settings have shown that incorporating pharyngitis POCT improves both patient access and workflow. Results from near-patient pharyngitis NAATs improved the clinician’s confidence in the diagnosis compared to RADT and reduced the number of confirmatory cultures ordered.6 In the pharmacy setting, GAS near-patient testing improved patient access to care especially among the uninsured and patients without a primary care provider; 38% of the pharmacy visits were outside normal clinic hours and 54% did not have a primary care provider.10

    A POC testing approach may improve testing workflows in the clinical laboratory. Laboratories certified by the College of American Pathologists (CAP) are required to perform confirmatory testing for all negative GAS antigen tests performed on pediatric patients.11 In addition to ensuring clinicians collect and send specimens for confirmation, laboratories may need to demonstrate compliance to CAP inspectors by tracking rates of completed confirmatory testing for all associated clinics performing RADTs. Due to superior sensitivity, GAS NAATs do not require confirmatory testing, and use of CLIA-waived POC NAATs in near-patient locations confers workflow benefits to both the clinical and microbiology laboratory.

    “Test-and-treat” workflow

    Near-patient testing has the potential to eliminate unnecessary tests, waits, and return clinical visits. In a study where clinicians were discouraged from ordering throat cultures after a negative GAS NAAT result, follow-up throat cultures were ordered on 7% of patients with a negative GAS NAAT compared to 52% of patients with a negative RADT.6  An observational study of GAS near-patient testing found that implementation of this service in a community pharmacy could be achieved with minimal disruptions to the workflow and staff.12  Rates of additional patient follow-up visits for pharyngitis were not significantly different between near-patient GAS NAAT and RADT plus culture test according to a 2019 report (data not shown).5 Further studies are needed to examine and optimize workflow with near-patient tests.

    Healthcare costs versus patient outcomes

    Implementation of POC NAATs is associated with increased test costs compared to RADTs, but these costs may be offset by increased test performance resulting in fewer throat cultures, increased clinician confidence, and decreased inappropriate antibiotic use. Calculating healthcare costs is complicated due to the many difficult-to-quantify factors involved, including quality of life days, patient satisfaction, treatment complications, staff time, access to treatment, and other healthcare resources. Many studies and meta-analyses recognize the potential for cost savings using POC NAATs but fail to quantify them in a meaningful way.

    In a U.S. study which examined the cost-effectiveness and budget impact of POC NAAT for GAS, costs and outcomes were calculated using a decision tree model that compared POC NAAT with RADT plus culture methods.8 Outputs included quality-adjusted life-days lost, GAS morbidity, antibiotic complications, number of patients appropriately treated, and antibiotic utilization.8 The final analysis projected that a POC NAAT strategy would cost $44 per patient compared to $78 for RADT plus culture.8 Additionally, compared with RADT plus culture, POC NAAT would increase the number of appropriately treated patients, avert unnecessary use of antibiotics, and potentially yield cost savings to U.S. third-party payers.8

    One cost-analysis study leaned more heavily on patient welfare and outcomes. Savings from POCT for respiratory infections (otitis media, sinusitis, pharyngitis and bronchitis) resulted from reductions in antibiotic use and reduction in complications from untreated infections and antibiotic side effects.13  Finally, a study evaluating near-patient GAS testing and treatment in community pharmacies suggested potential savings by reducing the patient burden on primary care.14 Further studies of near-patient GAS molecular tests in settings are needed to understand their full impact and potential benefits, especially concerning healthcare disparities in treatment.

    Conclusion

    Although more costly, POC or near-patient NAATs offer superior performance and a more streamlined workflow compared to traditionally used RADTs. Implementation of POC GAS NAAT use may lead to increased diagnostic accuracy and reduction of inappropriate antibiotic use in patients with acute pharyngitis. 

    References

    1. Massese M, La Sorda M, De Maio F, et al. Epidemiology of group A streptococcal infection: are we ready for a new scenario? Lancet Microbe. 2024;22:S2666-5247(24)00071-5. doi:10.1016/S2666-5247(24)00071-5.
    2. CDC. Current group A strep activity facts. Group A Strep Infection. Published May 22, 2024. Accessed May 30, 2024. https://www.cdc.gov/group-a-strep/data-research/facts-stats/?CDC_AAref_Val=https://www.cdc.gov/groupastrep/current-activity.html.
    3. Lassoued Y, Assad Z, Ouldali N, et al. Unexpected Increase in Invasive Group A Streptococcal Infections in Children After Respiratory Viruses Outbreak in France: A 15-Year Time-Series Analysis. Open Forum Infect Dis. 2023;6;10(5):ofad188. doi:10.1093/ofid/ofad188.
    4. Shulman ST, Bisno AL, Clegg HW, 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;15;55(10):1279-82. doi:10.1093/cid/cis847.
    5. Rao A, Berg B, Quezada T, et al. Diagnosis and antibiotic treatment of group a streptococcal pharyngitis in children in a primary care setting: impact of point-of-care polymerase chain reaction. BMC Pediatr. 2019;16;19(1):24. doi:10.1186/s12887-019-1393-y.
    6. May L, Sickler J, Robbins EM, et al. The Impact of Point-of-Care Polymerase Chain Reaction Testing on Prescribing Practices in Primary Care for Management of Strep A: A Retrospective Before-After Study. Open Forum Infect Dis. 2022;24;9(5):ofac147. doi:10.1093/ofid/ofac147.
    7. Luo R, Sickler J, Vahidnia F, et al. Diagnosis and Management of Group a Streptococcal Pharyngitis in the United States, 2011-2015. BMC Infect Dis. 2019;26;19(1):193. doi:10.1186/s12879-019-3835-4.
    8. Bilir SP, Kruger E, Faller M, et al. US cost-effectiveness and budget impact of point-of-care NAAT for streptococcus. Am J Manag Care. 2021;1;27(5):e157-e163. doi:10.37765/ajmc.2021.88638.
    9. Khunti K. Near-patient testing in primary care. Br J Gen Pract. 2010;60(572):157-8. doi:10.3399/bjgp10X483454.
    10. Klepser DG, Klepser ME, Smith JK, et al. Utilization of influenza and streptococcal pharyngitis point-of-care testing in the community pharmacy practice setting. Res Social Adm Pharm. 2018;14(4):356-359. doi:10.1016/j.sapharm.2017.04.012.
    11. Cap.org. Accessed May 30, 2024. https://documents-cloud.cap.org/appsuite/learning/LAP/TLTM/resources/checklists/2020/cl-mic.pdf.
    12. Corn CE, Klepser DG, Dering-Anderson AM, et al. Observation of a Pharmacist-Conducted Group A Streptococcal Pharyngitis Point-of-Care Test: A Time and Motion Study. J Pharm Pract. 2018;31(3):284-291. doi:10.1177/0897190017710518.
    13. Schneider JE, Boehme C, Borisch B, Dittrich S. Application of a simple point-of-care test to reduce UK healthcare costs and adverse events in outpatient acute respiratory infections. J Med Econ. 2020;23(7):673-682. doi:10.1080/13696998.2020.1736872.
    14. Thornley T, Marshall G, Howard P, Wilson AP. A feasibility service evaluation of screening and treatment of group A streptococcal pharyngitis in community pharmacies. J Antimicrob Chemother. 2016;71(11):3293-3299. doi:10.1093/jac/dkw264.