LISBON — Better diagnostic tests are seen as essential in the campaign to control the global tuberculosis epidemic—and help is on the way.
The archaic, nearly 100-year-old tuberculin skin test was until recently the sole tool available for diagnosis of latent TB infection. The skin test has several limitations, chiefly its low specificity due to cross-reactivity with the BCG vaccine and false-positives in persons infected with non-TB mycobacteria, Dr. Karin Weldingh said at the 12th International Congress on Infectious Diseases.
Major international aid organizations including the Foundation for Innovative New Diagnostics, the Stop TB Partnership, and the World Health Organization have declared development of faster, simpler, more convenient, and more accurate TB diagnostic tests to be a high priority.
Recently, two novel cell-mediated immune response-based assays have become widely commercially available as alternatives to the skin test for detection of latent TB. The in vitro assays—the QuantiFERON-TB Gold and T-SPOT.TB assay—measure interferon-γ released by sensitized T cells following stimulation by antigens specific to Mycobacterium tuberculosis, including culture filtrate protein-10 (CFP-10) and early secreted antigenic target-6 (ESAT-6).
Studies show these assay kits have better specificity for detection of latent TB and are at least as sensitive as the skin test for active TB; plus, they're interpreted more objectively, with results available in a day, said Dr. Weldingh of the Statens Serum Institute, Copenhagen.
The QuantiFERON-TB Gold assay was first to win approval by the Food and Drug Administration. Late in 2005, the Centers for Disease Control and Prevention recommended its use in all situations where the skin test has been used, including serial evaluation of health care workers.
The downsides of using these assays in the developing world are that they require living cells and ready access to a lab for enzyme-linked immunosorbent assay.
“This means you have to process blood samples within 12 hours. You have to be careful with the blood. It's sensitive to temperature. You can't put it in the fridge and leave it for the weekend. You cannot leave it out in the car. You cannot mail the blood sample to a lab,” she explained at the congress sponsored by the International Society for Infectious Diseases.
For these reasons, Dr. Weldingh sees the assays ultimately being most useful for latent TB case-finding via contact tracing and screening of high-risk groups in low-endemic, highly developed areas such as Western Europe and the United States. The tests should also prove useful in areas with an intermediate TB incidence and good infrastructure, such as parts of Brazil.
In places where TB rates are high, roads poor, and laboratories hard to come by, these tests aren't practical. The ultimate solution in such places is probably an improved skin test that utilizes M. tuberculosis-specific antigens rather than the traditional purified protein derivative; such tests, which are simple, low-tech, and low-cost, are now under evaluation in field studies.
Another approach involves serologic antibody tests. These offer several potential advantages. They're much less temperature-sensitive and fragile than the interferon-γ tests, they don't require living cells or access to a laboratory, and they yield results in 15–30 minutes.
The newer ones, which utilize M. tuberculosis-specific antigens, perform best. They'll never serve as a stand-alone test for diagnosis of active TB—there are too many false-positives in highly endemic areas where uninfected people are often re-exposed to TB—but they could have a role as rule-in point-of-care screening tests that trigger a visit to a clinic for definitive testing, she said.
That sounded good to Dr. Peter Godfrey-Faussett.
“I was very heartened by the work on rapid diagnostic tests with serologic agents, because I think eventually—maybe with antigen detection for screening people—that might be the way to go. We've got to be thinking about tests that can be used out in the field at the point of care, because you won't get people to come in to the health center to have a fancy test or x-ray; they can't afford the bus fare,” said Dr. Godfrey-Faussett, professor of infectious diseases and international health at the London School of Hygiene and Tropical Medicine.
'I was very heartened by the work on rapid diagnostic tests with serologic agents.' DR. GODFREY-FAUSSETT
This patient had a positive reaction to the 48-hour Mantoux test, in which tuberculin is injected between the layers of the skin. CDC