Commentary

Abstract

[Ann Emerg Med. 2013;61:574-575.] Seasonal and pandemic influenza outbreaks continually challenge emergency departments (EDs) with regard to optimal strategies for timely and accurate treatment for individual patients and to management of associated surges in ED patient volumes. Optimization of treatment decisions for patients with respiratory-related illness when influenza is suspected has been complicated by the lack of highly sensitive rapid influenza diagnostic assays for clinical use. Conceptually, such assays could assist with more accurate antiviral, antibiotic, and infection control decisions. Notably, multiple previous pilot studies, several in the ED literature, suggest that integration of routine RIDTs—even those with imperfect sensitivity—may yield important positive outcomes. These include reduction of unnecessary ED evaluation for other diagnoses, decreased rates of unnecessary antibiotic use, improved timeliness of infection control measures, and decreased ED door-to-discharge times.1Bonner A.B. Monroe K.W. Talley L.I. 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: 363-367Crossref PubMed Scopus (310) Google Scholar, 2Jennings L.C. Skopnik H. Burckhardt I. et al.Effect of rapid influenza testing on the clinical management of paediatric influenza.Influenza Other Respi Viruses. 2009; 3: 91-98Crossref PubMed Scopus (43) Google Scholar, 3Falsey A.R. Murata Y. Walsh E.E. Impact of rapid diagnosis on management of adults hospitalized with influenza.Arch Intern Med. 2007; 167: 354-360Crossref PubMed Scopus (132) Google Scholar, 4Petrozzino J.J. Smith C. Atkinson M.J. Rapid diagnostic testing for seasonal influenza: an evidence-based review and comparison with unaided clinical diagnosis.J Emerg Med. 2010; 39: 476-490Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Influenza is also a well-known cause of ED crowding, as exemplified by the 2009 H1N1 outbreak when ED volumes increased at an alarming rate, with one large academic medical center reporting a 74% increase in pediatric ED visits and a more than 10% increase in adult ED visits. Although compelling, the promise of RIDTs has been tempered by reports of increased variability in sensitivity observed during the past several years, particularly for evolving strains of influenza. Before 2009, performance of RIDTs was approximately 80% to 83% for seasonal A (H3N2) and 60% to 80% for seasonal A (H1N1).5Centers for Disease Control and PreventionEvaluation of rapid influenza diagnostic tests for detection of novel influenza A (H1N1) Virus—United States, 2009.MMWR Morb Mortal Wkly Rep. 2009; 58: 826-829PubMed Google Scholar Emergence of the novel H1N1 strain in 2009 yielded a dramatic decline in RIDTs performance, with some studies showing sensitivity of the commonly used RIDTs to be as low as 11%.6Dexler J.F. Helmer A. Kirberg H. et al.Poor clinical sensitivity of rapid antigen test for influenza A pandemic (H1N1) 2009 virus.Emerg Infect Dis. October 2009; (Accessed January 4, 2013)http://wwwnc.cdc.gov/eid/article/15/10/09-1186.htmGoogle Scholar This led many medical centers to completely abandon rapid testing; conceptually (based on the above-cited work), this could result in less-than-ideal decisionmaking with regard to antiviral or antibiotic use, as well as delays in infection control and ED throughput.7Petrozzino J.J. Smith C. Atkinson M.J. Rapid diagnostic testing for seasonal influenza: an evidence-based review and comparison with unaided clinical diagnosis.J Emerg Med. 2010; 39: 476-490Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Since 2009, commercial development of the antigen-based RIDTs has continued, with 11 RIDTs now approved by the FDA and available for use during the 2012 to 2013 influenza season. This Morbidity and Mortality Weekly Report article provides a comprehensive overview of those platforms offering the first direct, head-to-head comparison of currently available tests over a range of viral concentrations and a baseline methodology for future comparison as new tests evolve. The 11 RIDTs were analytically tested in vitro with the 23 distinct influenza viruses (16 influenza A strains and 7 influenza B strains) known to be circulating in the United States since 2006, each at 5 separate dilutions. Dilutions were carefully chosen to represent the range of viral concentrations found in clinical specimens.8Calfee D.P. Peng A.W. Cass L.M. et al.Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection.Antimicrob Agents Chemother. 1999; 43: 1616-1620PubMed Google Scholar This study provides several essential points for ED clinicians about the performance of current RIDTs, as well as how this may affect their clinical use. Overall, the antigen-based RIDTs had the highest sensitivity for influenza B, followed by influenza A H3N2, and finally influenza A H1N1. At the highest concentrations, nearly all the RIDTs performed well, with the exception of SAS FluAlert Influenza A, which did not uniformly detect influenza A viruses at the highest concentrations.9Centers for Disease Control and PreventionEvaluation of 11 commercially available rapid influenza diagnostic tests—United States 2011-2012.MMWR Morb Mortal Wkly Rep. 2012; 61: 873-876PubMed Google Scholar However, the investigators pointed out that the highest viral concentration used in this study may not reflect the viral levels present in most clinical samples and that nearly all the commercially available tests could not detect viruses at the 2 lowest concentrations.10Döller G. Schuy W. Tjhen K.Y. et al.Direct detection of influenza virus antigen in nasopharyngeal specimens by direct enzyme immunoassay in comparison with quantitating virus shedding.J Clin Microbiol. 1992; 30: 866-869PubMed Google Scholar, 11Kaiser L. Briones M.S. Hayden F.G. Performance of virus isolation and Directigen Flu A to detect influenza A virus in experimental human infection.J Clin Virol. 1999; 14: 191-197Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Only 1 of the rapid tests, BD Directigen EZ Flu A+B, consistently detected influenza A strains in third-level dilution samples. Test performance decreased precipitously as viral concentration decreased, meaning that both timing and collection technique are vital to maximizing sensitivity of the test in clinical practice. Sensitivity is improved when samples are collected at the highest viral concentrations, 24 to 72 hours after symptom onset. This is based on the fact that viral concentration in the nasopharynx may be relatively low less than 24 hours and greater than 72 hours after symptom onset.12Watanabe M. Nakagawa N. Ito M. et al.Sensitivity of rapid immunoassay for influenza A and B in the early phase of the disease.Pediatr Int. 2009; 51: 211-215Crossref PubMed Scopus (28) Google Scholar Appropriate sample collection includes both selection of the appropriate swab (some swab materials can interfere with the results for some RIDTs) and use of the proper collection technique of inserting the swab until resistance is met and then turning the swab for 10 to 15 seconds. (A simple 1-minute video such as the one available in the referenced New England Journal of Medicine article can be helpful in this regard.13Baden L.R. Drazen J.M. Kritek P.A. et al.H1N1 Influenza A disease—information for heath professionals.N Engl J Med. 2009; 360: 2666-2667Crossref PubMed Scopus (50) Google Scholar) In practice, some patients may have difficulty tolerating specimen collection, which will compromise assay performance. Because variation in sensitivity according to test characteristics, time since symptom onset, and sample collection have serious implications for assay performance, a negative RIDT result in a patient with symptoms suggestive of influenza does not exclude infection. Thus, according to current CDC algorithms, patients should receive antiviral treatment (even if they test negative) if they meet criteria for treatment (eg, age <2 or >65 years, hospitalized, comorbidities).14Fiore A.E. Fry A. Shay D. et al.Centers for Disease Control and PreventionAntiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Surveill Summ. 2011; 60: 1-24Google Scholar The RIDT tests described in this Morbidity and Mortality Weekly Report article are thus most relevant for affecting care for patients with positive test results but do not yet fulfill their potential with regard to broadly guiding antiviral and antibiotic treatment and maximally assisting infection control measures. There are important recent advances in the development of genetic-based rapid diagnostics for influenza, not discussed in this Morbidity and Mortality Weekly Report article, which is focused on antigen-based tests. Several of these have already been approved by the FDA, including PCR-based GeneXpert by Cepheid and FilmArray by Idaho Technologies, each with reported sensitivities of above 90%.15Jenny S.L. Hu Y. Overduin et al.Evaluation of the Xpert Flu A Panel nucleic acid amplification based point-of-care test for influenza A virus detection and pandemic H1 subtyping.J Clin Virol. 2010; 49: 85-89Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 16Caliendo A. Multiplex PCR and emerging technologies for the detection of respiratory pathogens.Clin Infect Dis. 2011; 52: 326-330Crossref Scopus (157) Google Scholar With a turnaround time of approximately 1 hour, these rapid direct detection assays take longer than the estimated 15 minutes typical for antigen-based RIDT but are much faster than traditional criterion standard PCR or viral culture, which takes 8 hours or longer. Most important, these PCR-based assays have excellent sensitivity, which is consistent across multiple strains, compared with the antigen-based RIDTs, in which sensitivity varies substantially by strain. Although further study is required, PCR-based rapid influenza tests offer the potential to fulfill several of the benefits of rapid influenza testing, including more directed antiviral treatment, less overall diagnostic testing, improved ED throughput, and improved isolation decisions. Although promising, these rapid PCR-based platforms are not yet widely available in most episodic care settings because of several practical concerns, including increased turnaround time and cost. Comparative cost benefit analysis will be helpful to determine whether the benefits of the improved sensitivity outweigh the increased financial costs. Ultimately, emergency medicine would benefit from an RIDT with high sensitivity to allow more accurate treatment decisions, infection control measures, and facilitation of ED throughput. The currently available antigen-based tests aid in more expedited and appropriate care for patients who test positive; however, given the high rate of false-negative results, the index of suspicion must remain high for patients who test negative, limiting the full potential benefits that might be realized with a more sensitive rapid test. Evaluation of 11 Commercially Available Rapid Influenza Diagnostic Tests—United States, 2011-2012Annals of Emergency MedicineVol. 61Issue 5Preview[Centers for Disease Control and Prevention. Evaluation of 11 commercially available rapid influenza diagnostic tests—United States 2011-2012. MMWR Morb Mortal Wkly Rep. 2012;61:873-876.] Full-Text PDF