A new blood test called the T SPOT-TB is a more trustworthy measure of tuberculosis (TB) infection in children than the standard TB test according to the results of a prospective clinical study published recently in The Lancet (Liebeschuetz). The study, conducted at a district hospital in Kwa-Zulu Natal South Africa, also demonstrated that the test can be performed in settings without highly trained lab personnel and with only limited laboratory facilities.
Need for a better test
TB control programmes have long been hampered by the lack of a diagnostic aid that can reliably detect TB infection in people with HIV and in children.
The widely used tuberculin skin test (TST) hasn’t changed much since it was developed over a hundred years ago (by Robert Koch who also discovered M. tuberculosis). TST works by looking injecting a small amount of tuberculin protein into the skin — if a person has been exposed to TB, a “memory” immune response should cause a welt to form at the site of the injection within a few days. However, this type of immune reaction is frequently absent or weakened in people with advanced HIV disease and in young children.
The sensitivity of TST in children with active TB is also low, and is even lower in children with disseminated TB, malnutrition, or HIV infection, which are all common in regions with a high prevalence of TB
Even when there is a positive TST result in children, it cannot always be relied upon because the TST cannot differentiate between a response to TB and a response to the BCG vaccine. In many settings, the BCG vaccine is given to children in an effort to protect them from tuberculosis (with mixed results at best). It contains the tuberculin protein since the vaccine is made out of a non-disease causing organism closely related to the TB mycobacteria. Thus any child who has been inoculated recently could also have a positive response to the TST.
Diagnosis of childhood tuberculosis is extremely challenging. The disease can occur quite early in life (it can be transmitted in the womb – especially if the mother is also HIV-infected) but it frequently bears little resemblance to the pulmonary disease usually seen in adults. Extrapulmonary TB is particularly hard to diagnose and is far more common in children with active disease. Even when there are clinical symptoms or x-ray findings suggestive of TB, they can be impossible to differentiate from other common conditions — particularly in children with HIV.
Both under and over diagnosis and treatment are therefore common.
Finding a faster and more reliable tool for TB diagnosis could save lives, save time and money spent on improper treatment and should improve TB control.
T-SPOT TB test
The T-SPOT-TB, which was approved last August for use in the European Union, is a new blood test designed to replace the TST. The test was originally developed at Oxford University and research versions have been tested in over 3,000 patients worldwide. Some of these studies have been reviewed on this site (see here and here for further details).
The test works by looking for a type of immune response in a patient’s blood sample that is specific to TB — BCG vaccination will not cause a false positive with this test. Results are available next day and their measurement is much less subjective than with the TST.
T-SPOT TB in patients with HIV
T-SPOT may also be more likely to work in people with HIV. In one study in Zambia (Chapman) that compared an early version of the T-SPOT to TST or PPD (PPD is a variation on the TST) in HIV negative and positive patients, with active TB or without, HIV status had less of an impact on the T-Spot TB test than on the skin test.
In patients with active TB, (confirmed by clinical and x-ray findings and one TB positive smear result) the T-SPOT test was a little less accurate in patients with HIV but it was still more sensitive than skin testing. While the T-SPOT test detected TB infection in eleven out of eleven HIV negative patients, 4 out of 39 (10%) of the HIV-positive patients with active TB had negative results on the T-SPOT test — probably because of very advanced immune dysfunction in these patients.
However, skin testing only detecting TB infection in 28 out of the 39 HIV positive patients with active disease.
In another group of 75 adult subjects without active TB, the T-SPOT test detected latent TB in 69% of the HIV-negative patients, and in 43% of those who were HIV positive (p=0.064). The TST however was positive in 80% of the patients without HIV and in only 36% of those with HIV.
TB SPOT test in children, with and without HIV
Similar findings were observed in the South African study in children with suspected TB.
The study was conducted at a district hospital in Kwa-Zulu Natal South Africa, a region with a high prevalence of both TB and HIV. The study enrolled 293 children presenting with suspected active tuberculosis in routine clinical practice. The T-SPOT and TST tests were performed at the initial assessment, and test results were compared with the final clinical and microbiological (by culture) diagnoses.
The T-SPOT TB test detected 83% of the cases in children with confirmed or highly probable tuberculosis (95% CI 75–89, n=133), significantly more (p<0.001) than the 63% (95% CI 54–72) recognized by the TST (n=116).
The TST was significantly less sensitive in children younger than 3 years (51%), with HIV co-infection (36%), or with malnutrition (44%). Age had no affect on the sensitivity of the T-SPOT test, while HIV status and malnutrition only slightly reduced the T-SPOT’s sensitivity 73%, and 78% (respectively). According to the study authors, the low sensitivity of TST in children with any one of these features — common in this setting — “made it diagnostically useless.”
Negative TST, positive T-SPOT accounted for 53% of children with confirmed disease. Negative TST, positive T-SPOT accounted for 14% of children with highly probable disease.
Cases of TB infection missed by one test were often caught by the other test. Combined, the two tests were able to detect 91.4% (95% CI 85–95, n=116) of the active TB cases.
Clinical implications
The full clinical ramifications of the study findings are somewhat unclear. The cases of confirmed TB were destined to receive treatment anyway but using the T-SPOT test rather than the TST test should increase the number of treated cases considered “highly probable TB” — particularly in younger children, malnourished children and those with HIV disease.
According to the investigators “using the tests together could provide a clinically useful diagnostic sensitivity in children with a moderate or low index of suspicion for active tuberculosis; if both tests were negative, the child would be unlikely to have tuberculosis.
In suspected cases in which TB is a little harder to diagnose, a positive TST is generally used as the basis for empiric treatment. In this study, the T-SPOT test was also more likely to be positive for TB exposure in cases with “possible TB.” But it is not yet clear if T-SPOT should be used as a basis for offering empiric treatment since a positive result does not necessarily indicate active TB (infection may be latent). Long-term-follow-up of these patients could have suggested whether they were in fact in need of TB treatment.
However, this trial was not really designed to answer that question. And according to the study investigators “no firm conclusion could be drawn, since 69” [out of 80] “children from the “possible tuberculosis” group were lost to follow-up, including 22 who were treated, so that it was not possible to assess response to antituberculosis treatment, or absence of it.”
Longitudinal studies to determine the risk for subsequent active tuberculosis in T-SPOT-positive children have been started. If T-SPOT is to be used to guide treatment in possible cases of TB, treatment would become more widely used — not less. And as promising as the new test is, it is unlikely to reduce over-treatment since a negative result cannot exclude active TB with 100% certainty.
Finally, the T-SPOT TB test was performed in a district hospital laboratory by a paediatrician with no laboratory experience who received only one week of training, suggesting that the assay could be adopted by any laboratory with a microscope, centrifuge, and incubator.
However, if the test “is to have a substantial effect on management of paediatric tuberculosis in the developing world,” said the investigators “it will need to be very cheap—and further simplification of the technique would also be helpful.”
More information on the TB-SPOT TB test can be found on the manufacturer’s website: www.oxfordimmunotec.com
Chapman A et al. Rapid detection of active and latent tuberculosis infection in HIV-positive individuals by enumeration of Mycobacterium Tuberculosis-specific T cells. AIDS 16:2285-2293, 2002.
Elzinga G et al. Scale up: meeting targets in global tuberculosis control. Lancet 363: 814-19, 2004.
Lalvani A. Counting antigen-specific T-cells: a new approach for monitoring response to tuberculosis treatment? Clinical Infectious Diseases 38: 757-9, 2004.
Liebeschuetz S et al. Diagnosis of tuberculosis in South African children with a T-cell-based assay: a prospective cohort study. Lancet 364: 2196–203, 2004.