By Paul Nicolaus
March 7, 2018 While the severity of any given flu season can vary widely, the burden is always substantial—lost time, lost productivity, and lost lives. In the U.S. alone, direct medical costs average $10.4 billion annually, for example, and the Centers for Disease Control and Prevention (CDC) estimates between 12,000 and 56,000 lives lost every year.
And this year’s flu season has been particularly active. “Most people with influenza are being infected with the H3N2 influenza virus,” Dan Jernigan, director of the CDC’s Influenza Division, said during a briefing held on Jan. 26, 2018. “And in seasons where H3N2 is the main cause of influenza, we see more cases, more visits to the doctor, more hospitalizations, and more deaths, especially among older people.”
The most recent flu pandemic took place nearly a decade ago, but in some ways this year’s season has been just as bad. During a Feb. 9, 2018, update, Anne Schuchat, acting director of the CDC, indicated the levels of influenza-like-illness across the country were as high as those noted at the peak of 2009.
The viruses are elusive, evolving from one year to the next and even changing over the course of an individual season. When the H1N1 flu virus emerged back in 2009 after the seasonal vaccine had already been developed, the strain spread and caused a global outbreak. But diagnostics also played a role.
The performance of some flu tests available at the time of that crisis raised concerns about the accuracy of detecting influenza, Amy Krafft, influenza drug development and diagnostic development program officer with the National Institute of Allergy and Infectious Diseases (NIAID) told Diagnostics World. “That’s when we were able to recognize that a lot of these tests could use improvement.”
Role of Flu Diagnostics
There are several reasons why flu diagnostics are put to use in the realm of public health. One big need is the monitoring of the seasonal level of incidence every year, Krafft said. A voluntary public health surveillance network made up of doctors’ offices and clinics reports how many people come in with flu every week, and the CDC reports this flu activity and surveillance to help determine where it is occurring.
In public health labs, many of the viruses are cultured and sometimes sequenced to determine what strains are circulating. CDC uses next-generation gene sequencing tools to analyze flu viruses as part of its Advanced Molecular Detection (AMD) initiative. The technology enables researchers to study more viruses at faster speeds and in greater detail than ever before, which the agency says improves disease detection.
Diagnostics are also used to look for drug resistance that could compromise treatment and to initiate infection control measures, Krafft said, noting the example of school closings intended to prevent additional spread of the flu. In addition, detection tools are used to monitor for novel flu strains, such as avian flu, which could emerge and become a severe pandemic threat.
In clinical settings, testing takes on an interesting role with this illness, said Joseph Ladapo, associate professor of medicine at UCLA. With some conditions, like heart disease, there’s a clear action plan when a diagnosis is made. It can lead to new medications, recommendations for lifestyle changes, or even procedures.
“With influenza, for most people, it doesn’t change anything in terms of management,” he said. For most people, the recommendation is rest, fluids, and over-the-counter medication for comfort. A diagnosis does, however, give patients some reassurance when they wonder why they’re feeling sick. And in some cases, it can change management.
When patients arrive at the Ronald Reagan UCLA Medical Center with flu, Tamiflu is commonly prescribed even though the evidence for the medication is not what Ladapo would call a “slam dunk,” so to speak. “We think it helps, on average,” Ladapo said, but believes it is also valuable because some patients develop other issues. “We think it may reduce the risk of complications or improve the outcomes of patients who do have complications.”
There are a variety of testing options available in the clinical setting, all of which require a nasal swab or similar sample to run the analysis. In doctors’ offices, rapid influenza diagnostic tests (RIDTs) that detect proteins associated with the virus are commonly used.
“These tests are very specific but they’re not very sensitive,” Ladapo said, and they detect proteins that are associated with the virus. RIDTs are inexpensive, easy to use, and fast—they offer up an answer in less than 20 minutes—but there is a higher chance of missing positives or producing false negative results.
Molecular diagnostic tests, on the other hand, are highly sensitive and very specific. “PCR tests tend to require more equipment, so the upfront costs are more expensive,” he said, which is why they are more commonly found in hospitals and major medical centers. They also tend to take a few hours to produce a result, he said, although rapid molecular assays that come back in 15 or 20 minutes have begun to emerge in recent years.
Diagnostic Landscape
The emergence of these faster point-of-care molecular tests is the most notable development that has taken place in recent years within this realm of flu diagnostics, said Amesh Adalja, senior scholar with the Johns Hopkins Center for Health Security.
In the past, these molecular tests were handled in a centralized laboratory, there was a long turnaround time, and they weren’t something that could be used practically up front. Now, though, a number of these highly sensitive, highly specific products can be used in a doctor’s office or in an emergency department.
As she considers the diagnostic landscape at large and the various improvements underway, NIAID’s Krafft pointed out that some tests are attempting to distinguish a viral infection from a bacterial infection while others are attempting to more rapidly subtype the flu. (Flu has 18 different subtypes, she explained, and a handful of these subtypes have caused pandemics.)
In addition, some rapid tests are being used in the field within remote areas. “Now we’re also encouraging integrating smart phone capabilities,” she said, so that information can be transferred from a field test to a pharmacy, public health center, or hospital. Beyond that, there are also very early efforts underway to develop home-based flu detection kits.
Part of NIAID’s role is to conduct and support research to come up with faster, more accurate, more cost-effective, and more portable ways to detect the flu. To date, the agency has backed several diagnostics that have been approved by the FDA.
Among those tests is the FilmArray diagnostic system (BioFire), which uses PCR to detect viruses, bacteria, yeast, and parasites in about an hour. Other examples include the Xpert Flu A/B diagnostic (Cepheid), the Lab-in-a-Tube (Liat) influenza A/B assay (Roche), and the QuickVue Influenza Test (Quidel), all of which can detect and differentiate between flu type A and flu type B.
“What we’re trying to encourage are tests that are not PCR-based because those are the ones that tend to require complicated instruments,” Krafft noted, “So we’re trying to encourage simplification.” She pointed to several NIAID grantees to highlight examples of the type of development that is currently underway.
Texas-based Paratus Diagnostics is working on a low-cost, high-speed diagnostic device that can meet various needs by switching out a cartridge, for example. Meanwhile, both Boulder, Colorado-based InDevR and Micronics, based in the Seattle area, are working on subtyping the flu.
Peering into the Future
Today, the use of the less sensitive rapid antigen tests is still prevalent, which can be problematic. “We see people with misdiagnosed flu because they are overly reliant on these rapid diagnostic tests,” Adalja said, “which can be dangerous in those settings when people don’t know the limitations of the test.”
“I think in the future, what we’re going to see, hopefully, is the rollout of these molecular tests that will test not only for flu but test for a whole host of respiratory viruses at the point of care,” he continued, “and I think that’s the big opportunity is to get very specific with these diagnoses in emergency departments, urgent care centers, and doctors’ offices so we have less inappropriate antibiotic use for what are viral infections.”
This would improve the treatment of influenza because positive test results would likely increase the uptake of antiviral medications, he added, and it will also improve epidemiology because more will be known about which viruses are circulating.
Krafft highlighted the impact of pricing dynamics, noting that the higher cost of molecular tests creates a bias toward using the less expensive, less accurate testing. If pricing can come down over time, she said this could very well lead to increased use of more accurate tests.
She also noted the importance of a fully informed diagnosis. All of these tests can aid in diagnosis, but there’s still a need to understand the whole patient. The thought was echoed by Ladapo, who said it’s important to remember that even the best tests are not flawless.
The PCR testing is pretty close to perfect, he said, and the precision of molecular diagnostics is high enough that there can be confidence in a positive or negative result. But that test is still just one piece of information—albeit an important one.
Paul Nicolaus is a freelance writer specializing in science, technology, and health. Learn more at www.nicolauswriting.com.