TB or not TB? Newer assays settle in

Dr. Wilson agrees with the need to know the demographics of patients and employees before it can be known which meth­od is better. “We just participated in a five-year multicenter screening study with CDC in a very low-risk population. It turns out that skin testing and IGRAs have different roles, not that one is always better than the other,” he says. “For high-risk patients in a TB clinic, IGRAs are better. If you are in a high-incidence area you would probably screen employees with an IGRA. But in Denver, where the incidence of TB is so low in the general population, you would end up getting more false-positive results.” At Denver Health Medical Center, TST is used for employee screening, whereas IGRAs are used in the Metro TB Clinic, in the HIV clinic, and in high-risk obstetric patients and foreign-born patients from high-incidence countries.

Dr. Lindquist says the real value of IGRAs is in foreign-born individuals who have had BCG vaccination. “So we use them pretty universally [in that population] even if someone doesn’t have the ability to pay.” The Kitsap Public Health District does not use IGRAs in all groups, however. Interferon-gamma-release assays are not approved in the under-five population, for instance. Dr. Lindquist also has questions about using IGRAs in those who are HIV-positive. “So there is still a role for skin testing,” he says, “as long as you understand its limitations.”

In San Francisco, Dr. Higashi sees the entire spectrum of TB. “We serve the whole city and county,” she says. “We cover active and latent TB. We see all patients who are TB suspects.” Those with latent TB are generally referred in from community health clinics. Some clinics do skin testing, Dr. Higashi says. A smaller group has the ability to do IGRAs. “We get referrals for people with a positive skin test or a positive blood test.”

The advantage of the latter for San Francisco’s Department of Public Health is that the city and county have a large population of people born in a country with endemic TB who had the BCG vaccination. “In this era, where we are looking for ways to become more efficient, to concentrate services as much as possible in the populations that need them the most, the blood test allows us to eliminate people who would have a positive skin test due to vaccination,” Dr. Higashi explains. “In the foreign-born population, we see one-half to two-thirds fewer positive tests with interferon-gamma-release assays.”

San Francisco also has a large urban population that is marginally housed or homeless. “We have a shelter program for TB testing,” Dr. Higashi says. “It is difficult for some shelters and other service providers to ensure that clients and patients come back for reading of their skin test.” While the cost-effectiveness of IGRAs, for which only one encounter is needed, has not been rigorously studied in these settings, Dr. Higashi says, she believes they are somewhat cost-effective in some populations. “We have had a huge number of staffing cuts over the last few years,” she says. “To some extent we have been able to maintain clinic services because [IGRAs] allow us to triage and reduce the number of chest x-rays and the number of patients we put on isoniazid.”

Dr. Higashi’s clinic also gets referrals from primary testing of HIV-positive persons. “Community clinics do both skin testing and/or a blood test in that population. We need to maximize sensitivity in those with HIV,” she says. Studies of those who are immunocompromised, including individuals with HIV, have been confined to relatively small samples. Immunocompromised persons include those scheduled for organ transplantation or for cancer chemotherapy. If a patient is about to be immunosuppressed, the clinician has to know whether the patient has latent TB so he or she can treat the infection during immunosuppressive therapy.

It may happen that a person has both a TST and an IGRA and the results are discordant. “A lot of our work in the last five years has been learning how to manage discordant results,” Dr. Higashi says. “For someone with a normal immune system who has received BCG and who has a positive skin test and a negative IGRA, we are confident and comfortable to let the IGRA finding drive our diagnosis. For any patient with an immunocompromised condition, we have to be careful what we do with discordant results.”

Puzzling results can arise with IGRAs during serial testing, especially in low-risk populations. For instance, in health care workers tested annually, TST has a less than one percent conversion rate. A far higher apparent conversion rate, five percent to six percent, has been seen with IGRAs. “That is a repeatability issue with blood tests,” Dr. Higashi says. “We now understand that better in the context of screening and are developing better guidance on how to handle these apparent conversions. A lot of that five percent is probably not true conversion.”

Dr. Daley calls this variability “wobble.”

“This is still an issue in low-risk populations,” he says. “Whether it is short term—six weeks, or six months or one year—we still see this problem. They appear to be false conversions. When we re-test they are negative. And if we re-test again, they are still negative. Most of these people have no risk or history of exposure.” A high rate of reversion from positive to negative with IGRAs was seen in a multicenter study, coordinated by Dr. Daley, of more than 2,500 health care workers. None developed TB regardless of the test result, even though very few were treated.

An institution that chooses to use an IGRA has two commercial choices: QuantiFeron-TB Gold and its newer In-Tube version (Cellestis, a Qiagen company, Valencia, Calif.) and T-Spot.TB (Oxford Immunotec Limited, United Kingdom). T-Spot requires isolated WBCs rather than whole blood, which can be more technically demanding. On the other hand, T-Spot may be more sensitive in those who are immunocompromised. Says Dr. Mase, “Between QuantiFeron Gold In-Tube and T-Spot, which assay a program adopts depends on variables such as cost and ease of implementation.”

Whether it is TST or IGRA that is used for TB testing, an important challenge remains: identifying individuals who will progress from latent TB to active infection. “Our current consensus is that IGRAs are as predictive as skin testing,” Dr. Daley says. “The problem is that neither one is very good.” Fewer than five percent of persons who are positive on TST or IGRA will progress to active disease. “We need a test that is 80 percent to 90 percent predictive,” Dr. Daley says. “The whole point is to treat and prevent progression while avoiding inappropriate therapy.”

Dr. Lindquist agrees. “What we really need for TB care,” he says, “is a rapid diagnostic that is accurate and that identifies those patients who will go on to active disease.” 

William Check is a writer in Ft. Lauderdale, Fla.