NEW YORK (360Dx) – A team of scientists at Imperial College London has developed a new interferon-gamma release-assay (IGRA) for detecting active tuberculosis in patients that they claim could be used in routine clinical practice.
In a recent study, the researchers also confirmed that the two most widely used IGRAs used for diagnosing the disease in developed countries are not accurate for active TB. The same study, published last month in The Lancet Infectious Diseases, also showed that their next-generation test might be sensitive enough to rule out TB in patients presenting with symptoms.
As such, the investigators believe their findings might redirect the way IGRAs are applied in the diagnosis of TB, and also support the introduction a test to market that might become a new clinical standard.
Currently two tests are used widely to rule out active TB in patients in the UK: Oxford Immunotec's T-Spot.TB and Qiagen's QuantiFeron-TB Gold. Both tests measure levels of interferon gamma (IFN-γ) released by patient T cells in response to exposure with TB antigens.
These assays have been cleared for clinical use in both the US and Europe for more than a decade, however, they are intended for diagnosing patients with latent TB — those who are infected with the bacteria but are asymptomatic — versus those presenting symptoms who may have progressed to active TB.
Despite this, both IGRAs are use widely within the UK's National Health Service to rule out TB in patients presenting with symptoms, though the evidence that these tests work for active TB is scant, and they are not actually intended for that purpose.
"The need for a [rapid] test is so high that even though these IGRAs, which are recommended for latent TB, are not recommended for active TB, doctors use them widely," said Avit Lalvani, chair of infectious diseases at the National Heart and Lung Institute in Imperial College London and a corresponding author on the study.
"In the case of active TB we have an inadequate toolkit for diagnosis," he said. "In particular, what we need is a rapid test to tell us within the first day or so if that person could have TB or whether we could rule it out."
Lalvani noted that currently patients often undergo testing via IGRA, come up as positive, and under further monitoring turn out to not have TB at all. Though there are about 5,000 cases of TB diagnosed in the UK each year, the number of people tested is many times higher, he said.
"Those who may have it are worked up in more detail, admitted to hospitals, put in isolation, et cetera," Lalvani noted. "All of that takes a lot of time, effort, and money," he said. "If we had a test that said a negative result means the patient doesn't have TB, that would really help."
Lalvani has long had an interest in developing tests for the diagnosis of TB. He led the development of an IGRA for latent TB while at the University of Oxford, technology that was later licensed to Oxford Immunotec and marketed as a replacement for the then standard of care, the Mantoux tuberculin skin test, which has been used for over 100 years to diagnose latent TB.
In 2011, Lalvani and fellow researchers at ICL published a paper describing the study of a new antigen for TB — Rv3615c — that could be used together with the antigens ESAT-6 and CFP-10 that are used to diagnose TB in patients in current IGRAs. It is the combination of these three antigens or Rv3615c with CFP-10 and Rv3879c that comprise the second-generation IGRA assessed in the most recent study.
For the study, Lalvani and colleagues had two goals: to determine the clinical utility of commercial IGRAs for diagnosis of active TB, given their widespread use in countries with a low incidence of the disease, and to observe the second-generation assay in a clinical context.
They carried out a prospective study of adults with suspected TB in routine secondary care in the UK. Patients were tested for TB with T-Spot.TB and QuantiFeron-TB Gold In-Tube tests, as well as the newly developed test. They were then tracked for up to a year to establish a definitive diagnosis. The researchers gathered data on test sensitivity, specificity, positive and negative likelihood ratios, and predictive values of the tests as part of their research.
Of the 1,060 adults enrolled, 845 were tested using the IGRAs, and 363 were ultimately diagnosed with TB. The researchers found that the sensitivity of Oxford Immunotec's T-Spot.TB in all cases was about 81 percent, while the sensitivity of the QuantiFeron test was about 67 percent. The second-generation test meantime had a sensitivity of 94 percent.
"The first goal of this study was to see if they were useful or not" for diagnosing active TB, Lalvani said. "The answer is, they are absolutely not useful," he said. "You cannot use them as a triage, because they lack the diagnostic sensitivity and lack the negative predictivity," he said. "That result shows that we shouldn't be using the tests in this setting and could save quite a lot of money if we cease doing that."
He said the performance of the second-generation study in the test meantime showcased its use for detecting active TB. "The second-generation assay can be used as a triage test to screen for suspected active TB and clinically be able to rule it out in patients within 24 hours of presentation," he said. "That's really the bottom line."
But will the test become commercially available? Lalvani said that he plans to bring the test to market, not via Oxford Immunotec, but through a new company. He said that a development path for the assay exists and that "there is a lot of work ongoing and in process," but declined to further elaborate. A new company has been founded, though, to commercialize the test and bring to through the regulatory clearance so that it can be used in routine clinical care, he confirmed.
As for the results of the study, Lalvani said he expects clinicians to alter their behavior based on the findings, and to cease using IGRAs for active TB. "The quality of the evidence is clear for all to see and the recognition that the existing tests are not reliable has gotten home," he said.
In the weeks since the paper was published, Lalvani said he has already received interest in the second-generation test. "The interest to start using the test is palpably there," he said. He reiterated a point made in the paper that the test is applicable as a triage only in low-incidence settings, such as Europe, North America, or Japan, but not in the developing world. Despite its low incidence in these regions, though, he said that test volumes are actually high.
"For every patient diagnosed with TB, there are about 10 in whom it is suspected," Lalvani said. "The amount of final diagnoses is not the number of tests done."
A representatives for Qiagen noted its test is not marketed for diagnosing active TB, something the authors made clear in the paper.
Masae Kawamura, senior director of TB medical and scientific affairs at Qiagen, noted that neither QuantiFeron-TB Gold nor T-Spot.TB are cleared by US or European regulatory authorities for diagnosing active TB.
Kawamura said the study's findings therefore were "not surprising, as these tests were not developed for or intended to diagnose active TB infection." She added that the use of such tests in sick patients with TB or other conditions "should be used with caution as they are often immunosuppressive and a negative result does not rule out TB infection." A chest x-ray, Kawamura said, "remains the gold-standard test method to support the diagnosis of active TB infection."
Kawamura also noted that Qiagen has introduced a fourth generation of its test called QuantiFeron-TB Gold Plus. Based on some recent studies, she said that the newer version of the test "may show improved performance in certain populations and provide additional clinical information that can help predict progression from latent to active TB infection."
However, she noted that QuantiFeron-TB Gold Plus remains a test for latent, not active, TB.
Qiagen is also unaware to what extent its test has been used for active TB. "As they are not indicated for this purpose we neither advise nor track if this is done," a spokesperson said.
Oxford Immunotec CEO Peter Wrighton-Smith expressed satisfaction with the new study, noting that T-Spot.TB was shown to be the "best performing diagnostic" available. He also said the firm was "pleased" that the second-generation test described in the paper could be used in the future to rule out a diagnosis of tuberculosis in clinical settings with a low-to-moderate prevalence of tuberculosis.
"We believe continued focus on innovation and the advancement of IGRAs will greatly assist in the control of TB, which remains a massive public health problem," said Wrighton-Smith. "Our ongoing R&D programs support this aim," he added.