This is the tale of two entities—the clinical laboratory and the platelet. The clinical laboratory has been an essential tool in the detection, diagnosis, and management of disease for most of a century. As we move into the era of personalized or precision medicine, the role of the clinical laboratory is becoming ever more closely linked to the care of patients. Platelets and their functions can no longer be considered exclusively tied to hemostasis, or limited to a day shift specialty lab. The number and manner of ways platelets behave has yet to be finalized.
With its seasonal variability, multiple strains, and symptoms that overlap with other respiratory viruses, testing for influenza is fraught with uncertainty. It has not helped that the latest guidelines for flu testing and treatment were issued in 2009—a virtual lifetime ago in the rapidly changing diagnostic world. Recently, the Infectious Diseases Society of America (IDSA) addressed this situation by issuing a much-needed update to its influenza guidelines.
By volume, flu testing contributes significantly to clinical lab workload. According to the Centers for Disease Control and Prevention (CDC), clinical labs in the United States tested more than 1.2 million specimens for flu during the 2017-2018 season alone.1
In recent years, rapid antigen flu tests have been used widely, often in outpatient settings where results generated in 15 minutes can have a positive impact on patient care. Unfortunately, several studies have now demonstrated that the low sensitivity of these tests yields too many false negatives.2,3 As a result, rapid antigen tests are no longer recommended for clinical use in the new IDSA guidelines, due to the unacceptably high risk of false-negative results.
The alternative the IDSA now recommends is rapid molecular testing. While these diagnostics take slightly longer than rapid antigen tests—generally a couple of hours—they have much higher sensitivity. This allows physicians, pharmacists, and other medical professionals to get reliable answers in a clinically relevant time frame, making it possible to tailor care to each patient’s specific needs. Several types of molecular diagnostics (MDx) can be used for flu testing; in this article, we’ll consider how and when each option would be most appropriate and discuss the changes made in the latest guidelines.
Updates to the IDSA recommendations
Prior IDSA guidelines for flu testing were issued back when rapid MDx testing for influenza was still relatively new to the field. In the decade since, the types of flu tests available to clinical labs have changed considerably. The new IDSA guidelines not only recommend molecular diagnostics over other kinds of tests, but they hone the specific use cases for when these tests are the best option.3 They also build on a wealth of recent flu studies, as well as information about the H1N1 flu strain, which caused a pandemic shortly after the last guidelines were released in 2009.4
The most significant change in the new guidelines comes from the shift away from rapid antigen tests. As the guideline publication reports, “an updated meta-analysis of observational studies of rapid influenza antigen tests reported pooled sensitivities of 54 percent and 53 percent to detect influenza A and influenza B virus antigens, respectively.”5 Sensitivity appeared lower for adults than for children. Still, these numbers were worrisome enough that the performance of rapid antigen tests needed to be addressed. As the paper notes, one study pegs the global death toll from influenza at more than 600,000 per year.6
Considering the high stakes, the IDSA opted to recommend rapid molecular diagnostic tests instead. The authors reported that “a meta-analysis of rapid molecular assays reported pooled sensitivities of 92 percent and 95 percent for detection of influenza A and B viruses, respectively, and pooled specificities of 99 percent.”7
In general, the new guidelines recommend rapid molecular diagnostics over rapid antigen tests, immunofluorescence tests, serologic testing, and viral culture. Among molecular assays, there is a specific suggestion for tests based on reverse-transcription polymerase chain reaction (RT-PCR).
The guidelines also consider specific patient populations and infection situations. For example, immunocompromised patients who have been admitted to the hospital should be tested with a multiplex RT-PCR assay that targets a broad panel of respiratory pathogens, according to the IDSA guidelines. Other hospitalized patients may require such panel-based testing even if they are not immunocompromised; the guidelines note if the multiplex panel results would be useful for making decisions on whether to prescribe antibiotics.
Panel-based testing may also be prudent for cases in which bacterial coinfection is suspected. When influenza has already been confirmed, clinical testing for bacterial infection is recommended when patients do not improve from antiviral treatment, deteriorate after a brief period of improvement, or present with severe disease that appears to go beyond influenza symptoms.
Evaluating molecular assay options
Many types of molecular assays are now available to clinical lab teams for flu testing. Diagnostics may test just for influenza A and B strains, or they may feature larger panels of pathogens associated with a range of respiratory infections. Targeted tests tend to cost less per sample, but if the initial results are negative, performing many of them to broaden the clinical hypothesis adds significant time and expense. Syndromic testing typically costs more per assay, though it can provide the answers for about a dozen or more pathogens in a single instrument run. In some cases, flexible testing options allow clinical lab staff to run the full syndromic panel, but only pay for the results they unmask. This makes it possible to begin with a single hypothesis—influenza A, for example—and then consider alternative options only when that result is negative. Because the results are all available from the syndromic panel, unmasking additional results takes no extra testing time.
A few scenarios can illustrate how each of these tests could be used for optimal patient care while also managing costs.
In the first scenario, an otherwise healthy patient reports to the emergency room with typical respiratory symptoms at the height of flu season. For this patient, a targeted flu A/B test would be sufficient to address the obvious hypothesis and would also be the most economical option.
In the second scenario, a hospitalized, elderly patient with a compromised immune system presents with severe respiratory symptoms toward the end of flu season. Because of the likelihood that something other than influenza may be at play, in this case, the best option could be a full syndromic panel, delivering many results as quickly as possible to help guide treatment selection.
In the third scenario, a relatively healthy adult presents with symptoms consistent with influenza during the summer months, but the patient has recently traveled to a country where other respiratory infections are in full swing. For this situation, a flexible syndromic test likely offers the best balance of information and cost-effectiveness. The lab team can unmask results for the first suspect, influenza, and then unmask results for other possible culprits if the flu results turn out to be negative. This saves the patient the full cost of running a syndromic panel, but also saves critical time by avoiding the need to run serial, targeted tests.
Flexible testing also allows clinical labs to expand their testing menu without adding new targeted tests and extra instrumentation. For example, lab technicians might start with a flexible syndromic test for respiratory infection featuring 10 or 15 pathogens. Then, based on the needs of their physicians and trends among their specific patient population, they could select the most common pathogens and offer that subset of the broader test as a mini-panel. This controls costs effectively while generating necessary clinical information for relevant patient cases.
Looking ahead
Each year, influenza represents a familiar yet ever-evolving health threat. Clinical labs have to make important and difficult decisions well in advance, such as how many assays and reagents to purchase leading into flu season. This year, for instance, data from Australia suggests that flu season may begin early and could be fairly severe.8 Clinical lab managers may need to stock up on supplies earlier than usual, which can be a challenge for some facilities.
Given the built-in uncertainties of influenza testing, having additional ambiguity due to outdated clinical guidelines has put unnecessary stress on lab experts. The new IDSA guidelines provide welcome clarity for this type of clinical testing and reinforce the decision many labs have already made to step away from less sensitive rapid antigen tests.
The new emphasis on MDx, along with the specific recommendations for when to use which type of assay, should be quite helpful to clinical lab teams and the medical professionals they support. Going forward, this will allow the lab community to coalesce around rapid MDx as a best practice. As lower-sensitivity options are retired, physicians will have higher confidence in the flu results from lab tests.
REFERENCES
- Garten R, Blanton L, Elal A, et al. Update: Influenza Activity in the United States During the 2017–18 Season and Composition of the 2018–19 Influenza Vaccine. CDC (online). Available from: https://www.cdc.gov/mmwr/volumes/67/wr/mm6722a4.htm?s_cid=mm6722a4_w.
- Evaluation of rapid influenza diagnostic tests for influenza A (H3N2)v virus and updated case count—United States, 2012. CDC. MMWR Morb Mortal Wkly Rep. 2012 Aug 17; 61(32):619-21.
- Trombetta V, Chan Y, Bankowski M. Are Rapid Influenza Antigen Tests Still Clinically Useful in Today’s Molecular Diagnostics World? Hawaii J Med Public Health. 2018;77(9):226–230.
- 2009 H1N1 Pandemic (H1N1pdm09 Virus). CDC (online). Available from: https://www.cdc.gov/flu/pandemic-resources/2009-h1n1-pandemic.html.
- Uyeki T, Bernstein H, Bradley J, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza. Clin Infect Dis. 2019 Mar 5;68(6):e1-e47. doi: 10.1093/cid/ciy866.
- Iuliano A, Roguski K, Chang H, et al. Global Seasonal Influenza-Associated Mortality Collaborator Network. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. Lancet. 2018 Mar;391(10127):1285-1300. doi: 10.1016/S0140-6736(17)33293-2.
- Merckx J, Wali R, Schiller I, et al. Diagnostic accuracy of novel and traditional rapid tests for influenza infection compared with reverse transcriptase polymerase chain reaction: a systematic review and meta-analysis. Ann Intern Med 2017; 167:394–409.
- Australian Government Department of Health: Australian Influenza Surveillance Report No. 5 – 17 June to 30 June 2019. Figures 2 and 6. Accessed July 15, 2019.
