ICT gathered a small panel of experts to share their perspectives on issues relating to rapid diagnostic testing for influenza. Panel participants are:
• Elliot Rank, PhD, director of scientific affairs/medical affairs for BD Diagnostics - Diagnostic Systems
• Catherine Lathem, marketing development manager for Medical Diagnostics for 3M Health Care
• Drew Hoffman, senior marketing manager, Quidel Corp.
ICT: How important is early screening for influenza in the acute-care environment?
Rank: An influenza infection can lead to severe complications and even death. The ability to rapidly detect influenza, as well as differentiate the strain type, enables a clinician to confirm the infection and make a guided decision with regard to treatment, such as antiviral vs. antimicrobial therapy. Effective and timely antiviral therapy may potentially reduce the severity of symptoms or shorten the duration of an influenza infection. For example, patients with influenza A are more likely to respond to an antiviral regimen such as those recommended by the FDA. Alternatively, patients presenting with flu-like symptoms may, in fact, have actually contracted an entirely different infection, such as bacterial pneumonia, which would indicate a different treatment. The early time to result of rapid tests enables clinicians to make earlier, more guided therapeutic decisions. In an acute care environment, screening for influenza may be additionally effective as antiviral therapy is most effective early in the progression of the disease.
Hoffman: We’ve seen six reasons to adopt a point-of-care rapid influenza test. These include:
- Aid in the diagnosis, prognosis and treatment.
- Manage bed assignment.
- Help avoid the use of unnecessary antibiotics.
- Determine local epidemiology.
- Report to surveillance insight to the CDC.
- Reduce downstream diagnostic costs.
Lathem: Early detection is needed for both the management of influenza and to reduce the spread. Early screening helps to identify which patients to isolate or cohort and determine who would be appropriate for antiviral therapy. It also helps to more effectively use antibiotics for non viral respiratory illnesses because signs and symptoms of influenza overlap with signs and symptoms of other respiratory illnesses.
ICT: What specifically are clinicians looking for in rapid diagnostic testing?
Rank: Physicians look for a rapid test that is accurate, easy to use and easy to read. The busy laboratory also benefits from a rapid test that is easy to perform without need for complicated, expensive and time intensive laboratory equipment and resources.
Lathem: Clinicians are primarily concerned with rapid, reliable results using a simple test that is easy to perform and interpret. Rapid, reliable tests help prevent misdiagnosis, direct appropriate treatment, help prevent transmission, help minimize severity and length of illness, and maximize limited isolation resources. When tests are easy to perform, they minimize error which helps increase confidence of results. In addition, if they are easy to interpret, they help to eliminate the subjectivity of reading the test results which improves overall consistency in reading of the results.
Hoffman: High sensitivity and specificity, limited number of preparation steps and high quality manufacturing which produces lot-to-lot consistency. Training is key to getting the expected results so the simpler the test, the better.
ICT: What are the imperatives for clinicians to remember about sensitivity, specificity, positive predictive value and negative predictive value of rapid influenza tests?
Rank: The most important aspect in reviewing the statistical performance characteristics related to rapid diagnostic tests for influenza is that the prevalence rate of influenza in the population has a direct impact on the positive predictive value of the test. The co-demonstration of high statistical sensitivity and specificity is very desirable. Yet, if the prevalence rate for influenza is unseasonably low, the positive predictive value for the test is also low. For example, a diagnostic test with a sensitivity of 99 percent and a specificity of 99 percent, tested during a time when the prevalence of influenza is only 1 percent (i.e., only one person out of 100 is actually positive for the disease) has only a 50 percent positive predictive value. However, as the seasonal prevalence of influenza increases during the late autumn-winter-early spring months of the year, the positive predictive value will increase correspondingly. So, even the most exquisitely sensitive test will not perform adequately during seasonal low-points of the year or in populations not susceptible to the ravages of influenza. The sample type can also impact on the test result. Nasopharyngeal (NP) aspirates are generally recognized as the premier specimen type, probably followed closely by nasopharyngeal washes and swabs. NP samples are mandated in some countries such as Australia and New Zealand. In the US, common nasal swabs are used the most often. However, the nasal swab sample is taken from the front (anterior) nares and may not extend deep enough into the pharynges where the influenza virus resides. While other methods, such as culture, offer better sensitivity than rapid tests, rapid tests require no special training, equipment, space, or storage facilities and the results are known and available in 15 minutes.
Lathem: According to the Centers for Disease Control and Prevention, accuracy depends upon prevalence.Unfortunately, the positive and negative predictive values vary considerably depending upon the prevalence of influenza in the community. For instance, false-positive influenza test results are more likely to occur when disease prevalence is low, which is generally at the beginning and end of the influenza season. False-negative influenza test results are more likely to occur when disease prevalence is high, which is typically at the height of the influenza season. Sample type, patient age, quality of the specimen all impact the sensitivity and specificity of a rapid influenza test. It is important to follow manufacturer's instructions to ensure the correct result.
Hoffman: It’s important for clinicians to remember that all tests are not created equal. Many clinicians adopted flu tests many years ago and haven’t conducted product correlations recently.
ICT: Are false positives/negatives a significant concern with rapid diagnostics tests in general/flu tests in specific?
Rank: False-positive and false-negative test results are important, regardless of the test, the method, or the approach. False-positive results can be caused by cross-contamination of specimens, incorrect specimen labeling, or nonobjective, manual, or misreading by the technologist. A false-positive result may cause a clinician to treat empirically with the incorrect regimen, thereby potentially leading to a worsening of the patient’s condition because the true ailment has been misidentified and/or the condition misdiagnosed. False-negative results can be caused by improper, inadequate, or incorrect specimen collection, or incorrect performance of the procedure. A false-negative result may cause a physician not to treat at all, thereby possibly worsening the patient’s condition because the true ailment has been missed entirely! The intended use instructions on flu tests recommend that negative flu test results be confirmed by culture.
Lathem: Yes, in general, accuracy and confidence in tests results are important for all rapid diagnostic tests. 3M has combined science and technology to create the 3M™ Rapid Detection Flu A+B Test that is very reliable to help minimize issues associated with false positives and false negatives. Since rapid diagnostics tests are considered screening tests, it is understood that the clinician uses the information along with other assessments such as patient history and risk factors to make a diagnosis. Currently, the FDA recommends that, during the influenza season, all negative results be confirmed using culture. This is because false negatives are more likely during high prevalence times.
ICT: Besides the increased length of time that methods such as fluorescent antibody staining and rapid cell culture take, are there additional drawbacks to these methods, and how else does your company’s test differentiate itself?
Rank: Fluorescent antibody (FAB) staining and rapid cell culture are highly complex methods requiring:
- highly trained personnel to perform the test, specialized equipment and space for test performance, laborious and rigid adherence to protocol instructions for the correct performance of the test, laboratory licensure, demonstrated personnel proficiency, and
a lengthier time to obtain the test result.
- FAB staining requires a minimum of four hours to perform in the most ideal conditions. Rapid cell culture takes a minimum of two days to perform for a positive result, and up to one week for a negative result.
The BD DirectigenTM EZ Flu A+B test detects the presence of the influenza A and B viral antigens on a two-channel, immunochromogenic platform cassette. It requires no special training, equipment, space, or storage facilities and the results are known and available in 15 minutes.
Lathem: Technical expertise is required to perform and interpret these tests. They require expensive instrumentation (fluorescent microscope) and if the respiratory specimen does not contain cells, they are unable to perform the test. The 3M Rapid Detection Flu A+B Test provides superior performance to the number one leading hospital competitor and requires less technical expertise.
Hoffman: These methods require a substantial amount of training to prepare and read the results. Quickvue tests are easy to use and require minimal training. This said, speed is crucial to helping to determine care pathways during a busy flu season.
ICT: What studies currently support the merits of your company’s test?
Rank: Two recent studies have highlighted the utility and outstanding performance of the BD rapid diagnostic test for influenza, the BD Directigen EZ Flu A+B. Dr. Martyn Tilse, Mater Hospital, Brisbane, Austrialia, compared the BD Directigen EZ Flu A+B test to the Quidel QuickVue A+B RDT and an indirect immunofluorescence antibody staining technique1. Discrepant results were retested with polymerase chain reaction (PCR) testing. There was relative equivalence in the findings, with the BD Directigen EZ Flu A+B test having greater sensitivity and a far greater reading clarity. The Quidel QuickVue A+B RDT had a slightly better specificity. The BD product was adopted as the standard of rapid diagnostic testing for the hospital. Dr. Alexandra Valsamakis compared the BD EZ Flu A+B to the BinaxNow Influenza A+B rapid diagnostic test using several references to detect flu positives2. Although there was a slight decrease in overall expected sensitivity rates of the products due to the large number of reference methods, the two tests performed comparably well. The study concluded that rapid diagnostic tests can be most useful during periods of high prevalence for influenza.
1. Martin Tilse, Theo Molle, Suzanne Hinds, David Siebert, Michelle Baker, and Elliot Rank. Abstract TP-22. “Rapid Diagnosis of Influenza A and B from Nasopharyngeal Aspirates (NPA): Comparison of Two Rapid Chromatographic Immunoassays (RCI) to an Indirect Immunofluorescent Assay (IFA).” 23rd Annual Clinical Virology Symposium. Clearwater, Fla. 2007.
2. S.H. Clemens, R.C. Alcabasa, D.Z. Aird, J.A. Wehrlin, and A. Valsamakis. Abstract M-17. “Rapid Detection of Influenza Viruses: Performance Characteristics of Directigen EZ Flu A+B and BinaxNow Influenza A&B Tests.” 24th Annual Clinical Virology Symposium. Daytona Beach, Fla. 2008.
Lathem: C.C. Ginnochio et al. Clinical Evaluation of the 3MTM Rapid Detection Flu A+B Test. Abstract/Poster. Clinical Virology Sympsium. Daytona, Fla., April 2008.
Suzanne E. Dale, PhD., Christine Mayer, BS, Marie C. Mayer, BS, and Marilyn Menegus PhD. The Analytical Sensitivity of the 3M(tm) Rapid Detection of Flu A+B Assay. Oral Presentation. Infectious Disease Society of America. San Diego, CA, Oct 2007.
Clinical data to support 510k submission-see package insert.
Hoffman: The University of Rochester did a comparison of four influenza antigen assays. The Quidel QuickVue Influenza A+B assay was analytically more sensitive in 38/40 instances and equivalent in 2/40. Sensitivity is a critical component when selecting a rapid test.