It used to take days for laboratories to return test results for infectious diseases. Thanks to new knowledge and technology, it's increasingly possible to get the answer in minutes.
Rapid diagnostic tests are faster, more reliable, and more widely available than ever. At the same time, however, the tests remain expensive and may not unilaterally lead to better care.
“Internal medicine and hospitalists are at the threshold of going from the technology of the days of Pasteur to a new era of rapid genotyping and phenotyping tests,” said Robert A. Bonomo, MD, a professor of medicine at Case Western Reserve University in Cleveland and chief of medical service at Louis Stokes Cleveland Department of Veteran Affairs Medical Center. “It's going to change for us soon.”
Also known as point-of-care testing, rapid diagnostics are increasingly being developed for a range of infectious diseases, from influenza to Clostridium difficile.
At the core of the recent boom is rapid molecular diagnostics (RMD), a technique that identifies telltale biological markers in a given tissue or fluid sample, as opposed to, for instance, waiting for bacteria to grow in a culture before its presence can be detected. More specifically, polymerase chain reaction (PCR) allows laboratory technicians to detect specific genes that indicate the presence of infectious agents.
The tests are much faster, and in many cases can test for multiple organisms at one time. According to data from the Centers for Disease Control and Prevention, reported sensitivity of rapid molecular testing ranges from 70% to 100%.
Drug and device manufacturers are getting on board, marketing rapid tests designed for common diseases and everyday hospital practice. In January, test manufacturer Alere announced it was the first to receive a Clinical Laboratory Improvement Amendments (CLIA) waiver from the U.S. Food and Drug Administration for an influenza A and B rapid molecular test with a technology called isothermal nucleic acid amplification that it says can return results in about 15 minutes.
In September, Roche's PCR flu test also received a CLIA waiver, which effectively establishes the test as one that (with proper training) can be conducted with little to no risk or difficulty.
“This is a whole new game for us,” said Angela Caliendo, MD, PhD, FACP, vice chair of medicine at Alpert Medical School of Brown University in Providence, R.I. “We should see these tests start to be used pretty widely… They're so simple that a non-laboratory person like a medical assistant or a nurse can do it.”
New technology has transformed not only the speed of testing but also accuracy and ease of use. Though PCR testing has existed since the 1980s, shaky technology meant results often had to be confirmed or refuted by slower traditional methods. That, too, is changing.
“These are no longer second-best methods,” said David Peaper, MD, PhD, assistant professor of laboratory medicine at Yale School of Medicine and director of the clinical microbiology laboratory at Yale-New Haven Hospital in Connecticut. “Historically, [rapid tests] were better than nothing, but you would rely on more sensitive tests to back it up. But now the relative simplicity is such that that is no longer the case, and [testing] can be done 24/7 by almost anyone.”
The expedited results mean clinicians can potentially use the tests to avoid the unnecessary use of antibiotics, a key benefit at a time when more microbes are drug-resistant.
“It means having a test back in a timeframe short enough to influence a clinical decision,” Dr. Caliendo said. “Either the diagnosis is influenza and you use oseltamivir, or it's not and you don't. This helps the patient understand that antibiotics are not going to help… If we can identify a virus, that helps us justify not using antibiotics.”
Body of evidence
The new generation of rapid diagnostics is so new that many of the tests have not yet been widely studied. Some research has emerged suggesting that the tests are efficacious and can improve clinical outcomes, while other data paint a less favorable picture.
Earlier this year, a study published in Infection Control and Hospital Epidemiology found that the availability of rapid molecular tests for Staphylococcus aureus after incision and drainage of cutaneous abscesses in adults was associated with more targeted antibiotic selection.
In the summer, a report in Clinical Infectious Diseases revealed that rapid multiplex PCR testing for bacteria, fungi, and resistance genes in blood cultures “reduced treatment of contaminants and use of broad-spectrum antimicrobials.”
Another report in Clinical Infectious Diseases, published in November, found that “[Rapid molecular diagnostic] platforms can assist with informing empiric β-lactam therapy.”
These and other studies appear to suggest that new rapid tests are accurate and fast enough to affect physician behavior.
“If you were to have a patient in front of you and you have results from the lab, how confident are you in picking the best therapy?” said Dr. Bonomo, a co-author of the study published in November. “We tried to crystallize a real clinical situation.”
However, other data show that the opposite can occur. A September study in JAMA Internal Medicine found that molecular diagnosis led to overtreatment and overdiagnosis of Clostridium difficile.
“Patients with a positive molecular test result and a negative toxin immunoassay test result had outcomes that were comparable to patients without C difficile by either method,” the study authors concluded. “Exclusive reliance on molecular tests for [Clostridium difficile] diagnosis without tests for toxins or host response is likely to result in overdiagnosis, overtreatment, and increased health care costs.”
In addition to concerns about overdiagnosis, the rapid tests face other obstacles. The largest single barrier to wider adoption is the simplest: The tests remain expensive. New equipment must be acquired and reagents for molecular tests are typically more expensive than those for conventional methods such as enzyme immunoassays and antigen tests.
“We all know health care costs too much in the United States, so making sure there's good downstream savings is important,” said Sandra Richter, MD, section head of microbiology at the Cleveland Clinic. “Make sure clinicians really want the rapid result and will act on it.”
Without appropriate infrastructure—or clinical need—it can be difficult to realize a full return on such an investment or justify the initial outlay. That is why clinical leaders and microbiologists recommended assessing local prevalence rates to determine whether specific rapid tests are necessary.
If a need exists, a hospital should institute staff training and a system (potentially including information technology changes) for transmitting samples to ensure that rapid testing is actually rapid and does not bog down in communication choke points.
“The lab does not exist in a vacuum,” Dr. Peaper said. “Get everyone on board. You may need IT support. Do you need to communicate with the infection control team or other providers? Can you use electronic communication to better alert people to these results?… There needs to be a good relationship between the results and alerting antibiotic stewardship, pulmonologists, GI docs, pharmacy, infectious diseases staff. That's established for blood cultures, now it needs to be done for rapid testing.”
Quality assurance can be challenging when testing is performed outside of the laboratory. Some of the testing platforms that received waivers incorporate software that will prevent the instrument from being used if quality control has not been performed or the operator has not completed required training, Dr. Richter said.
“Competent staff must be available who will perform the test according to the package insert in order to ensure accurate results and comply with regulatory standards,” she added.
Government regulators, including the FDA, have generally fostered a friendly environment for rapid testing in recent years, thanks in part to a push for greater pandemic preparedness. That could change, however, experts said. As part of the Protecting Access to Medicare Act, passed in 2014, regulators are examining all tests as a potential source for cuts.
Cuts to the reimbursement for testing could slow the spread of rapid testing. “Laboratories or office practices can't adopt technologies that change clinical practice if reimbursement is below the cost of doing it,” said Dr. Caliendo, who also noted that ideally the health care system should also consider potential savings from a new test, such as reductions in antibiotic use, when judging its cost.
In the meantime, physicians called for more research on the issue, noting that the flu seasons may offer good opportunities for further study. The effect of rapid diagnostics on length of stay and other metrics could be particularly important, according to Dr. Bonomo. If those studies return favorable results, rapid testing could continue to spread into regular hospital protocol.
“One of the real challenges here is using rapid molecular diagnostics to make better treatment decisions,” Dr. Bonomo said, noting that clinicians will determine how the new tests are applied to care.
“Are you actually going to change your protocols and your practices?…[Or] are you still going to prescribe oseltamivir no matter what?” Dr. Caliendo asked.