Rapid point-of-care assays for influenza testing

The estimated overall vaccine effectiveness rate for the 2015-2016 flu vaccine was below 50 percent,¹ underscoring the importance of accurate and timely diagnosis for improving patient outcomes and reducing the public health impact of this potentially deadly illness.

Clinical guidelines from the U.S. Centers for Disease Control and Prevention (CDC) and other expert groups recommend initiating antiviral treatment within 48 hours of onset.¹ Yet many of the influenza assays widely used today do not realize the full potential of diagnosis because they do not provide highly accurate results quickly enough for clinicians to make informed treatment decisions while the patient is still under their care.

The combination of suboptimal diagnosis, the highly transmissible nature of the virus, and the wide overlap of symptoms with more urgent conditions such as pneumonia has led to widespread empirical treatment of patients who present with influenza-like illness. Empirical treatment based on symptoms alone not only is inaccurate² but through overtreatment can lead to drug resistance.³

This article will discuss currently available influenza diagnostic methods with a focus on new advances in screening technology, and will provide guidance for selecting and utilizing influenza diagnostic tests.

The goal: fast, accurate, and cost-effective diagnosis

The primary imperative for a lab is accurate reporting for doctors. Sensitive and specific diagnostic tests help healthcare providers make therapeutically optimal and cost-effective decisions on hospital admission, antibiotic therapy, further diagnostic testing, and direct influenza therapies. Accurate and timely diagnosis may help reduce hospitalizations, length of inpatient stays, ancillary tests, and complications, thereby optimizing outcomes and reducing transmission of the virus.^4-6

The problem is that performance and price don’t always correlate with the timing necessary to impact patient treatment decisions. Influenza assays widely used today reflect trade-offs between accuracy and speed, in particular:

• Culture tests: results in four to five days, or 48 to 72 hours for newer “shell viral” platforms;
• Direct fluorescent antibody (DFA) tests: results in one to two hours, but relatively complex to administer and require additional reagents and equipment;
• First-generation rapid influenza diagnostic tests: results within 30 minutes with generally high specificity, but often with poor to moderate sensitivity;
• Polymerase chain reaction (PCR) and other amplified molecular tests: improved sensitivity but require repeated, time-consuming thermocycling and complex instrumentation, which limits their utility for direct testing at the time of presentation.

New molecular technologies are starting to bridge the gap between accuracy and speed. Point-of-care assays are becoming available that can provide accurate results quickly enough for clinicians to make informed treatment decisions in an actionable timeframe.

There are 28 molecular flu assays cleared for marketing by the U.S. Food and Drug Administration (FDA) as of this writing, including two assays with test times of 15 to 20 minutes that have been granted waived status under the terms of the Clinical Laboratory Improvement Amendments of 1988 (CLIA).⁷ These tests are beginning to be used by healthcare providers to test for influenza in a wide range of settings, potentially improving the utility and cost-effectiveness of screening.

Quantifying the cost-effectiveness of influenza screening is complicated by the wide range of variables at play, such as the inherently seasonal nature of flu testing, the duration and severity of a given flu season, the volume and multiple testing target capacity of tests, and utilization of antivirals. Even a large-scale study evaluating the cost-effectiveness of using rapid PCR flu tests among high-risk emergency department patients concluded only that the local prevalence of influenza at a given time had an enormous impact on cost-effectiveness. Similarly, parsing the cost of testing is difficult, and it requires accounting not only for the test itself, but also for the reagent, instrumentation for sample extraction, and labor.⁸

Best practices

The emergence of accurate, rapid, and easy-to-use molecular tests may eventually shift the cost-utility balance of flu testing. In the meantime, healthcare providers should adopt best practices to maximize the utility and cost-effectiveness of flu testing, regardless of the setting or the type of test deployed.

Limit testing to high-risk patients and time periods. Testing should be offered only during flu season, or once influenza has been reported in your area. Administering flu tests off-season can affect their positive predictive value, which is based on prevalence. Office and hospital staff can use tools such as the CDC flu map (http://www.cdc.gov/flu/weekly/usmap.htm) to track the spread of viral activity. Exceptions to the general testing limitations may be made for occasional patients who have traveled to the southern hemisphere or the tropics, where influenza activity is different from that in the temperate northern hemisphere.

Whenever possible, test early in illness. Flu tests are most sensitive early in illness, when patients are most infectious. Antiviral therapy for infected patients is most effective when initiated early.

Train staff on correct specimen collection. Collecting nasopharyngeal and nasal samples is not difficult, but care must be taken to obtain them properly. A good collection may be uncomfortable for the patient, but it is essential for optimal testing.

Select testing platforms that correspond to the needs and capabilities of the testing laboratory or setting. Platforms that also detect other illnesses, such as respiratory syncytial virus (RSV) and Strep A, will have utility throughout the year. Economies of scale can make higher complexity tests have less labor per sample if done in high volume. No “one-size-fits-all” solution is available; each facility should investigate the options and choose testing solutions to fit their situation.

Finally, despite recent advances in testing, prevention remains the cornerstone of influenza management. Healthcare professionals, including laboratory personnel, should take steps to prevent nosocomial infection, such as paying attention to hand hygiene and limiting contact with others when sick. The CDC, the Advisory Committee on Immunization Practices, and the Healthcare Infection Control Practices Advisory Committee also recommend that all healthcare workers, with rare exceptions, get vaccinated annually.⁹

REFERENCES

1. U.S. Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: summary for clinicians. http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm.
2. Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and symptoms predicting influenza infection. Arch Intern Med. 2000;27;160(21):3243-3247.
3. Dharan NJ, Gubareva LJ, Meyer JJ, et al. Infections with oseltamivir-resistant influenza A (H1N1) virus in the United States. JAMA. 2009;301(10):1034-1041.
4. Blaschke AJ, Shapiro DJ, Pavia AT, et al. A national study of the impact of rapid influenza testing on clinical care in the emergency department. J Pediatric Infect Dis Soc. 2014;3(2):112-118.
5. Williams KM, Jackson MA, Hamilton M. Rapid diagnostic testing for URIs in children: impact on physician decision making and cost. Infect Med. 2002;19(3):109-111.
6. Bonner AB, Monroe KW, Talley LI, et al. Impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency department: results of a randomized, prospective, controlled trial. Pediatrics. 2003;112(2):363-367.
7. U.S. Centers for Disease Control and Prevention. Guidance for clinicians on the use of RT-PCR and other molecular assays for diagnosis of influenza virus
   infection. http://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm.
8. Dugas AF, Coleman S, Gaydos CA, et al. Cost-utility of rapid polymerase chain reaction-based influenza testing for high-risk emergency department patients. Ann Emerg Med. 2013; 62(1):80-88.
9. CDC. Influenza Vaccination Information for Health Care Workers. http://www.cdc.gov/flu/healthcareworkers.htm.

Norman Moore, PhD, is a microbiologist and director of scientific affairs for Alere. Moore has six patents in the diagnostic field and is the inventor of such tests as the rapid urinary antigen for Legionella and S. pneumoniae. He works on multiple medical committees and gives educational lectures around the globe.