Frontline testing with multiplex respiratory panels

Acute respiratory tract infections (RTIs) have a high burden of disease and can be caused by a variety of pathogens that include viral and bacterial agents.¹ The clinical presentation of a patient with an RTI is often nonspecific and could mimic other non-infectious etiologies (i.e., chronic obstructive pulmonary disease exacerbation). Further complicating accurate diagnosis are the changes in influenza and other respiratory virus activity during the ongoing COVID-19 pandemic. Rates of co-infection with SARS-CoV-2 and other common respiratory viruses ranges from 3-21%; the large gap is potentially due to differences in sample size between studies and variations in quarantine measures between countries.^2,3 More recently, U.S. surveillance summary data showed an atypical seasonal circulation pattern of respiratory viruses.⁴ Given this information, the Centers for Disease Control and Prevention (CDC) recently advised that clinicians should be aware of increased circulation, sometimes offseason, of some respiratory viruses and consider multi-pathogen testing.⁴

Rapid identification of causative pathogen(s) with a molecular multiplex respiratory panel (RP) is important to provide a level of diagnostic certainty as well as appropriate clinical management, effective initiation of isolation precautions, and patient cohorting. Furthermore, given the growing concern of antibiotic resistance, the Infectious Diseases Society of America (IDSA) guideline for implementing an antibiotic stewardship program (ASP) recommends the use of rapid testing for respiratory pathogens to reduce the inappropriate use of antibiotics.⁵ The use of a multiplex RP as a frontline testing option may offer favorable benefits to overall stewardship efforts, such as decreasing unnecessary antibiotic use and length of hospital stay, while increasing appropriate use of antivirals and patient satisfaction.^6,7

Impact of respiratory illness testing on antibiotic stewardship

In order to meet SARS-CoV-2 testing demands, institutions found it vital to adopt at least one, but often multiple, respiratory testing platforms, and these institutions varied widely in their respiratory illness testing algorithms. For instance, some laboratories have instituted an algorithm that involves automatic reflex testing to a broader panel if a limited panel (e.g., influenza A/B) does not yield a positive result. Alternatively, some labs chose to be more restrictive and only perform a multiplex RP upon written request by the clinician after the results of the initial limited test(s) have been made available. Yet, another approach includes a combination of both algorithms with automatic reflex testing to a multiplex RP only for specific patient populations (e.g., immunocompromised patients, critically ill, or those admitted with respiratory symptoms).

It is imperative that an institution’s respiratory testing algorithm be established with interdepartmental collaboration, and patient care is at the forefront of these decisions.

Antibiotic overuse in patients with viral respiratory tract infections has only been exacerbated by the COVID-19 pandemic. Empiric antibiotic regimens are often initiated while waiting for additional clinical evaluation, and antibiotic continuation may be associated more with concerns of concomitant bacterial pneumonia despite detection of a virus. A recent meta-analysis of 24 studies showed that bacterial co-infection in patients diagnosed with COVID-19 was identified in 3.5% of patients, and despite this, nearly 72% received antibiotics.⁸

However, is there enough clinical value to test all patients who present to the hospital with acute respiratory symptoms with a multiplex RP? A study by Semret et al. evaluated the impact of multiplex RP on changes in antibiotic therapy among hospitalized adults.9 Notably, patients who tested positive for influenza were nine times more likely to be initiated on oseltamivir if they were not empirically started. Conversely, among patients who were empirically started on antibiotic therapy prior to RP results, antibiotics were discontinued in 39% of patients who tested positive for influenza and 20% of those who tested positive for non-influenza viruses.

In a randomized controlled trial evaluating the routine use of a multiplex RP in adults presenting to the hospital with an acute respiratory illness, Brendish et al. found that patients who were tested with a rapid multiplex RP experienced a reduced length of stay (5.7 days vs. 6.8 days), and more specifically, patients that tested positive for a viral pathogen received shorter courses of antibiotics (6.2 days vs. 8.0 days) compared to the control group.¹ Similarly, Weiss et al. noted an 8.4% drop in admissions for patients with a positive multiplex RP test result from the emergency department, likely due to an increase in provider comfort in discharging a patient with a confirmed viral pathogen.¹⁰

A study in a pediatric setting showed a rapid multiplex RP was associated with a trend towards decreased antibiotic usage but was unable to demonstrate similar length of stay or admission outcomes in the adult population.¹¹ Importantly, these studies highlight the need for stewardship tactics involving testing with multiplex RPs including, but not limited to, development of testing algorithms, clinician education and clinical decision support tools.

Aside from the challenge of differentiating between viral and bacterial respiratory infections, another problem is that ASPs face barriers in terms of adequate resources and stewardship personnel, especially during the COVID-19 pandemic. This now prompts the question: how can multiplex panels best be utilized to maximize efficiency for overburdened stewardship programs and to improve patient care and resource utilization?

How to approach testing with multiplex panels

One such approach may be to enact what could be considered passive interventions via clinical decision support software (CDSS) using targeted comments or alerts to clinicians. This strategy would allow ASPs to focus resources on what one might consider higher impact interventions (e.g., prospective review of positive blood culture results) while also guiding physicians with more than a lone multiplex result. This concept has proven useful in several studies when utilized for respiratory and bloodstream infections in varying ways. Banerjee et al. implemented a comment for clinicians providing guidance for resistance marker interpretation and therapy selection for bloodstream infections that led to near identical time to appropriate antibiotic escalation as real-time stewardship intervention.¹²

Two additional studies, which focused on multiplex RP testing, implemented alerts to identify patients in which antibiotic de-escalation or discontinuation may be feasible.^13,14 The first study utilized positive RP results plus a negative procalcitonin (PCT) result as a prompt for clinicians to reassess the necessity of ongoing antibiotic therapy.¹³ This specific strategy resulted in a reduction in antibiotic days of therapy by 2.2 days and is unique in that it directs the provider’s attention to not only the positive RP result (which alone does not necessarily rule out the presence of bacterial co-infection), but also to other factors, suggesting the absence of a bacterial infection, such as a negative PCT.¹³ In the second study, a CDSS alert was created to alert ASP personnel when patients receiving antibiotic therapy had a positive multiplex RP result.¹⁴ Improvements were made in time to initiation of oseltamivir for influenza-positive patients (11.3 hours vs 3.6 hours), and a slight change in time to discontinuation of antibiotic therapy, albeit nonsignificant, was also observed.¹⁴

For ASPs with limited resources and other areas of major focus, using rapid multiplex RPs to the fullest extent may seem daunting. SARS-CoV-2 has created an environment where antibiotic overuse may be difficult for prescribers to avoid, given their understandable concerns about patients’ risk for concomitant infections and severe illness. Now, more than ever, strategies requiring minimal use of direct stewardship resources are needed to reduce unnecessary antibiotic use for viral respiratory tract infections.

Financial impact of broad multiplex testing

Lastly, it is important to consider the downstream financial effects associated with the broader implementation of a multiplex respiratory panel. While patient outcomes should be at the forefront of these decisions, financial implications cannot be ignored. Reimbursement for RPs can be limited and, in some cases, with patients potentially receiving a bill anywhere from hundreds to thousands of dollars for these tests.^15,16 Physicians are aware of the perceived high cost to patients and appropriately may limit the use of these panels for financial reasons alone.

Interestingly, the IDSA and five other governing bodies drafted a letter to the Centers for Medicare & Medicaid Services (CMS) in the early days of the pandemic, requesting immediate national coverage of multiplex RP tests, highlighting the benefits of routine use of RP when SARS-CoV-2 testing supplies are limited and to aid in diagnosing co-infections.¹⁷ Given that the average cost per test of a multiplex RP panel (varying by manufacturer) is about $120 and likely to continue to decrease, we hypothesize that if the reimbursement were decreased to a figure that still covered the laboratories cost, but minimized the billing implications to the patient, we would use a multiplex RP test more often on patients.

Benefits to patient care and hospital cost savings related to more rapid decision-making about the appropriate course of treatment are important factors to justify broader use of these panels, especially as the pandemic shows no signs of slowing.

References:

1. Brendish NJ, Malachira AK, Armstrong L, et al. Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial. Lancet Respir Med. 2017;5(5):401-411. doi:10.1016/S2213-2600(17)30120-0.
2. Marshall NC, Kariyawasam RM, Zelyas N, et al. Broad respiratory testing to identify SARS-CoV-2 viral co-circulation and inform diagnostic stewardship in the COVID-19 pandemic. Virol J. 18, 93 (2021). https://doi.org/10.1186/s12985-021-01545-9.
3. Kim D, Quinn J, Pinsky B, et al. Rates of co-infection between SARS-CoV-2 and other respiratory pathogens. JAMA. 2020;323(20):2085-2086. doi:10.1001/jama.2020.6266.
4. Olsen SJ, Winn AK, Budd AP, et al. Changes in influenza and other respiratory virus activity during the COVID-19 pandemic – United States, 2020–2021. MMWR Morb Mortal Wkly Rep 2021;70(29):1013–1019. doi: 10.15585/mmwr.mm7029a1.
5. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):e51-e77. doi:10.1093/cid/ciw118.
6. Covert K, Bashore E, Edds M, Lewis PO. Utility of the respiratory viral panel as an antimicrobial stewardship tool. J Clin Pharm Ther. 2021;46(2):277-285. doi:10.1111/jcpt.13326.
7. Schreckenberger PC, McAdam AJ. Point-counterpoint: Large multiplex PCR panels should be first-line tests for detection of respiratory and intestinal pathogens. J Clin Microbiol. 2015;53(10):3110-3115. doi:10.1128/JCM.00382-15.
8. Langford BJ, So M, Raybardhan S, et al. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect. 2020;26(12):1622-1629. doi:10.1016/j.cmi.2020.07.016.
9. Semret M, Schiller I, Jardin BA, et al. Multiplex respiratory virus testing for antimicrobial stewardship: A prospective assessment of antimicrobial use and clinical outcomes among hospitalized adults. J Infect Dis. 2017;216(8):936-944. doi:10.1093/infdis/jix288.
10. Weiss ZF, Cunha CB, Chambers AB, et al. Opportunities revealed for antimicrobial stewardship and clinical practice with implementation of a rapid respiratory multiplex assay. J Clin Microbiol. 2019;57(10):e00861-19. doi:10.1128/JCM.00861-19.
11. May L, Tatro G, Poltavskiy E, et al. Rapid multiplex testing for upper respiratory pathogens in the emergency department: A randomized controlled trial. Open Forum Infect Dis. 2019;6(12):ofz481. doi:10.1093/ofid/ofz481.
12. Banerjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. Clin Infect Dis. 2015;61(7):1071-1080. doi:10.1093/cid/civ447.
13. Moradi T, Bennett N, Shemanski S, et al. Use of procalcitonin and a respiratory polymerase chain reaction panel to reduce antibiotic use via an electronic medical record alert. Clin Infect Dis. 2020;71(7):1684-1689. doi:10.1093/cid/ciz1042.
14. Srinivas P, Rivard KR, Pallotta AM, et al. Implementation of a stewardship initiative on respiratory viral PCR-based antibiotic deescalation. Pharmacotherapy. 2019;39(6):709-717. doi:10.1002/phar.2268.
15. Cedars-Sinai Finance Decision Support Cash Package Quote. Sep 2020. Available at: https://www.cedars-sinai.org/content/dam/cedars-sinai/billing-insurance/financial-assistance/documents/oon-insured-patient-charges-covid-19-related-services-revised-9-23-20.pdf.
16. Atrium Health Coronavirus (COVID-19) Test Price/Cost (PDF). Jan 2021. Available at: https://cdn.atriumhealth.org/-/media/chs/files/for-patients-visitors/covid-19/coronavirus-covid-19-test-price-cost.pdf?rev=3c6195fba7f74916a22de78dc3ee9aa1&_ga=2.137585334.764388801.1632838302-1545425194.1632838302.
17. AMP-CAP Sign-on Letter Requesting Immediate National Coverage for Multiplex PCR Respiratory Panel (RVP) Tests. April 2020. Available at: https://www.amp.org/AMP/assets/File/advocacy/FINAL_Sign-On%20Letter%20to%20CMS_Coverage%20for%20RVP%20Tests_042820.pdf.