While Ebola was the infectious disease grabbing most of the headlines in the last year, experts say it is actually the flu that should have us most worried domestically. In the closing days of 2014, the U.S. Centers for Disease Control and Prevention (CDC) officially declared that the flu has reached epidemic status in the United States, with 6.8 percent of all deaths observed through the agency's 122 Cities Mortality Reporting System attributed to pneumonia and flu. Widespread activity was found in 36 states. While epidemic status is reached every year, what infectious disease experts find troubling is the trend toward earlier reports of flu intensity each of the past few years.
The high flu activity seen this season is the result of a confluence of factors: an early start to the flu season (the peak has typically occurred in February); relatively low vaccination rates (less than 50 percent of the population, despite recommendations for universal vaccination in everyone over six months of age); and a mismatch between this year's flu vaccine and the most prevalent circulating virus, influenza A (H3N2). This strain also tends to cause more severe illness than other variants. The last influenza A (H3N2)-predominant season in the United States was in 2012-2013.
Key to stopping the spread of any infectious disease outbreak is accurate diagnosis. Flu testing volumes can vary dramatically year to year and testing this flu season is expected to be in high demand. Driving the increased volume is, of course, high flu activity, but experts say that increased awareness of flu-like symptoms in light of the Ebola threat will further drive sick patients to seek care and testing.
Even before the beginning of the current flu season, experts began to reexamine the adequacy of current flu testing methods, raising concerns over the low sensitivity of rapid flu tests. In light of the bad flu outlook for the current season, DTET examined trends in flu testing and emerging tests that will shape testing in future seasons.
Differentiating Flu
Early symptoms of the flu are often clinically indistinguishable from other viral and bacterial causes of upper respiratory infections. However, differentiating the cause of the infection (bacterial or viral) can impact treatment decisions - whether ensuring appropriate antibiotic stewardship or providing the option of using antiviral therapy. While the majority of patients recover from the flu without any treatment, the growing number of antibiotic resistant pathogens is causing alarm and efforts are underway internationally to rein in inappropriate antibiotic use.
Acute respiratory infections are by far the most common reason for prescribing an antibiotic in primary care, even though the majority of these infections are caused by viruses, which will not respond to antibiotic treatment. Researchers recently found, though, that use of a point-of-care biomarker test in the primary care setting can cut inappropriate antibiotic use. In a meta-analysis, published Nov. 6, 2014 in the Cochrane Library, Danish researchers assessed six randomized trials (involving 3,284 predominantly adult patients) of a point-of-care test for C-reactive protein (CRP). Although, CRP is a non-specific test of inflammation, it can indicate a serious bacterial infection.
The researchers found that 631 out of the 1,685 people tested were prescribed antibiotics, compared to 785 out of the 1,599 people not tested. The authors caution that differences in study design precluded a precise effect estimate in the reduction of antibiotic use, but they did find that cuts in antibiotic use did not affect patient-reported outcomes, including recovery from and duration of illness, or patient satisfaction with their care.
While the results do show that rapid, point-of-care tests can positively guide the appropriate use of therapies, there has been increasing concern in the United States regarding the accuracy of rapid influenza diagnostic tests (RIDTs).
Rapid Flu Tests
The use of commercial RIDTs has increased substantially in recent years, with a dozen products currently on the market, according to the U.S. Food and Drug Administration (FDA). These tests can be performed in a doctor's office or clinic and conveniently provide results within 15 minutes. They rely on enzyme immunoassay technology to detect antigens to the seasonal flu virus in the patient sample, but RIDTs vary in terms of sensitivity and specificity. According to data collected by the CDC, when compared with reference standards for flu testing (viral culture or reverse transcriptase polymerase chain reaction (RT-PCR)), RIDT sensitivities range from 50 percent to 70 percent, while specificities are greater than 90 percent, yielding more false negative results than false positive results, especially during peak influenza activity. Experts say though, that there can be serious consequences in some individuals whose cases of flu are missed by these tests.
To address these sensitivity concerns, the FDA is proposing to reclassify RIDTs from class I devices to class II with special controls. The flu viruses' ability to frequently mutate and the new strains, the FDA says, "potentially affect the performance of these devices." By reclassifying the tests, the FDA can require additional ongoing regulation. The FDA's Microbiology Advisory Panel made four recommendations, laid out in the proposed rule published in the Federal Register in May 2014. These recommendations include: setting minimum sensitivity criteria; identifying the best "comparator" test to determine RIDT accuracy of RIDTs (would likely include newer molecular-based assays); annual reassessments of device accuracy based on the latest influenza viruses in circulation; and subject the device immediately to novel flu strains in emergency situations (i.e., the 2009 H1N1 pandemic).
| Flu Testing Methods |
| Method |
Test Time |
CLIA-Waived |
| Viral cell culture* |
Conventional - 3 days to 10 days
Rapid - 1 day to 3 day |
No |
| Immunofluorescence |
1 hour to 4 hour |
No |
| antibody staining
(not recommended) |
|
|
| Molecular assays*
(including RT-PCR) |
1 hour to 6 hour |
No |
| Rapid diagnostic tests
(antigen testing) |
15 minutes or le |
Ye |
| *Reference standard for laboratory confirmation
ource: Adapted from the CDC |
Emerging Technologies
Back in June, Alere (Waltham, Mass.) received the FDA's first clearance of a rapid molecular flu test, delivering results within 15 minutes. The Alere i Influenza A & B test uses isothermal nucleic acid amplification for viral detection, eliminating the need for thermal cycling and sample purification steps, enabling highly accurate, molecular results in less than 15 minutes. In trials, the test delivered PCR-comparable results. The company is awaiting a CLIA-waiver for the toaster-sized device, which will enable broader testing at the point of care. The company's Strep A test for the Alere i platform is under FDA review, while a respiratory syncytial virus (RSV) assay is in development.
Alere feels very well positioned to capitalize on shifting flu testing needs. "Knowing now matters," the company's vision to provide reliable, actionable results when and where they are needed most, encapsulates many of the driving forces reshaping flu testing, Keith Stauffer, vice president of marketing for rapid diagnostics at Alere, tells DTET. Rapid molecular flu testing addresses many of the factors reshaping flu testing, including the FDA's potential reclassification of rapid tests, the need to initiate antiviral therapy within 48 hours of symptom onset, and calls for better antibiotic stewardship. But, Stauffer cautions that "the shift towards molecular will be an evolution, not a revolution."
The need for rapid results closer to the patient is also driving development of a novel, low-cost POC testing platform at OJ Bio (United Kingdom). While the immunochemistry platform is capable of detecting a broad range of pathogen targets, the company is initially focusing on flu and respiratory virus detection.
The wireless diagnostic system is a joint venture between Japan Radio Company and Orla Protein Technologies. The biosensor at the core of the device combines a surface acoustic wave (SAW) electronic chip coated with disease-specific biocapture surface coating. The biochip is held in a disposable cartridge and used in conjunction with a low-cost, handheld reader. The company says that the presence of a disease antigen causes a shift in the phase angle of the SAW passing across the chip surface and this is translated into an electronic signal. Bluetooth connection of the reading device to special diagnostic software enables the test results to be displayed within seconds.
The three-channel chip is capable of assessing multiple analytes on one cartridge. The company has validated the chip for Flu A/B and RSV, which delivered performance characteristics comparable to PCR, in a study of retrospectively collected samples. Dale Athey, Ph.D., managing director at OJ Bio, tells DTET that the device brings better performance than lateral flow devices (as well the value-added capability of providing quantitative results). Given the electronics component, it will not be as low of a cost test as lateral flow, but the company is aiming for a $30 device with per test costs ranging from $2 to $10 depending on the application. OJ Bio is now in final product development of a single cassette and plans to commence prospective clinical trials in 2015 and bring the device to market within the next two years.
"In the United States the whole mix of telephone, electronics, and life science companies is exploding right now from the testing view," says Athey. "There is strong interest on the consumer-side and those on the clinical-side to wake up to this idea that people want to understand their own health and desire the technology to do this themselves."
Takeaway: Companies are developing innovative solutions to address evolving flu testing needs, with the goal of improving sensitivity and bringing quick results to care providers closer to the point of care.
| 2014 FDA Approved Flu Tests |
| Company |
Test Name |
Date |
| Focus Diagnostics (Quest) |
implexa Flu A/B & RSV Direct |
12/5 |
| Cepheid |
XPERT FLU/RSV XC Assay |
11/22 |
| Quidel |
Parainfluenza Multiplex
Nucleic Acid Assay |
10/9 |
| CDC |
Influenza Virus Real-Time RT-PCR
Diagnostic Panel
Influenza A/H5 Subtyping |
8/1 |
| Alere |
ALERE I Influenza A & B |
6/13 |
| Meridian Bioscience |
TRU FLU, a rapid, qualitative,
lateral flow immunochromatographic
assay for detecting both influenza A and influenza B |
1/3 |
