Kekkaku Vol.85, No.1:17-31, 2010
The 84th Annual Meeting Symposium
NOVEL DIAGNOSTIC TESTS FOR TUBERCULOSIS INFECTION : THEIR PROBLEMS AND PERSPECTIVES
Chairpersons : 1Tadayuki AHIKO and 2Kiminori SUZUKI
Abstract
Since 2000, the incidence of tuberculosis (TB) has decreased gradually in Japan. However, more than 24 thousand TB patients were newly notified in 2008, and Japan is still classified as an “intermediate burden country.”
Early identification and treatment of those with latent tuberculosis infection (LTBI), having a high risk to progress to active TB, will decline TB incidence effectively and result in elimination of TB.
The only method for identifying LTBI has been the tuberculin skin test (TST), but TST may give false positive results in BCG-vaccinated people and in those exposed to nontuberculous mycobacteria. New diagnostic tests, called Interferon-Gamma Release Assays (IGRAs), have been recently introduced,in order to improve the specificity of TST.
These include the QuantiFERON-TB (QFT) and the T-SPOT.TB tests. The former is available in two formats : QuantiFERON TB-Gold (QFT-G) and a newer version of QFT assay, so-called QuantiFERON-TB Gold In-Tube
The Japanese Society for Tuberculosis recommends that QFT tests should be used in all circumstances in which TST is used, including contact investigations and TB screening of healthcare workers. Although the QFT tests are widely utilized, the QFT tests have shown some limitations and problems :
- limited sensitivity of QFT-G,
- difficulty in interpretation of data in immunosuppressed subjects and in children,
- lack of predictive value for future development of active TB,
- the inter-laboratory variability and quality assurance.
In this symposium, we’ll discuss the above mentioned issues and
their search for solutions.
1. Quality assurance of QFT and research on improvement of its sensitivity :
Nobuyuki HARADA (Immunology Division, Department Mycobacterium Research and Reference, The Research Institute of Tuberculosis)
Since there were some discrepancies of QFT-G results of the same subjects among different laboratories, the quality assurance of QFT-G is thought to be important.
We have carried out the quality assurances of QFT-G in 2007 and 2008.
Although, approximately half of participants were categorized to be non-acceptable in the first quality assurance, many of those categorized to be non-acceptable became acceptable in the second one.
From their results it is conceivable that the introduction of the quality assurance would be effective to improve the test skills. IGRAs including QFT-G are relatively new methods to diagnose TB infection, and the efforts to improve the performance of IGRAs are still under way.
A new version of QFT-G (QFT-GIT) is more convenient in the first step of QFT (i.e. blood culture), and we have shown that QFTGIT has the higher sensitivity than QFT-G. Another method, T-SPOT.TB based on ELISPOT method, has been shown to be more sensitive than QFT assays. A recent study has demonstrated that measurement of monokines, such as IP-10, along with interferon-gamma (IFN-y), could improve the sensitivity of QFT to diagnose TB infection.
More promising diagnostic methods could be developed in the near future.
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2. Application of IGRAs to pediatric TB practice ; its usefulness and limitation : Osamu TOKUNAGA, Takeshi MIYANOMAE (Department of Pediatrics, National Hospital Organization Minami-Kyoto National Hospital)
Our study group, named “The Research Group on the Performance of QuantiFERON-TB in Children”, has collected data on the performance of QFT in pediatric patients with active TB diseases and TB contact examination cases, and also investigated the usefulness and limitation of QFT in the diagnosis of tuberculosis infection in children.
Although the sensitivity of QFT for pediatric patients with active TB diseases was about 90%, as high as for adult active TB cases, the sensitivity for the diagnosis of latent TB infection in children, especially both in infants and toddlers, was quite low.
Positive QFT results may be useful to confirm TB infection and diagnose active TB disease in children whose radiological findings are compatible with TB disease, but have no bacteriological evidence.
On the other hand, negative QFT results should not be used to rule out TB infection in children who had a contact history with contagious TB patients.
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3. Performance of QFT for diagnosis of latent TB infection in immunocompromised patients : Haruyuki ARIGA (National Hospital Organization Tokyo National Hospital)
The detection of LTBI in compromised hosts is essential for TB control, but T cell assay might be influenced by the degree of cell-mediated immunosuppression.
However, the relationship between immunocompetence and specific IFN-y response in QFT-G is uncertain. Our data indicated that the proportion of positive QFT assay results was found to be positively associated with lymphocyte count. Conversely, indeterminate assay results showed a negative relationship with lymphocyte count.
Indeterminate result rates significantly increased in the categories with less than 700 lymphocyte cells/mm3.
Most markedly, in severe lymphocytopenia with less than 300 cells/mm3, the
fraction of test with indeterminate result was 37.8%.
In patients with impaired cell-mediated immunity or Symposium / Novel Diagnostics for TB Infection 31 lymphocytopenia, QFT-G results should be interpreted carefully since false-negative proportion could be increased.
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4. QFT-G as a tool for the detection of TB infection among contacts of TB cases : Takashi YOSHIYAMA (Fukujuji Hospital,JATA)
QFT-G has become available for the detection of TB infection among contacts of TB cases in Japan.
We would like to discuss the limitations and problems of QFT-G and their solutions.
1) Sensitivity of QFT-G
The meta-analysis has shown the sensitivity of QFT-G to be approximately 80%. However, the reports on the sensitivity of QFT-G for the contacts of TB cases are limited in number, and we reviewed TB cases detected during a follow-up period after contact investigations by the classification of QFT-G results at the time of contact examinations. Among 39 cases detected during a follow-up period, 19 cases were negative with QFT-G at the time of contact examinations.
All these cases with negative QFT-G at the time of contact examination were contacts of highly infectious (with high QFT-G positivity among contacts)
TB cases.
2) Timing of application of QFT-G
I previously reported that among 8 contacts who became QFT-G positive during a follow-up period, all contacts became positive within 3 months of last contacts before diagnosis, except one pregnant woman, who became QFT-G positive 6 months after the last contacts with TB cases (QFT-G results at 2 months and 5 months were negative).
A certain immunological status must be taken into consideration in the timing of its application.
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5. Introduction of QFT-G for the nosocomial infection control for health care workers : Hidetoshi IGARI (Division of Control and Treatment of Infecious Diseases, Chiba University Hospital)
At Chiba University Hospital we have met some patients with active TB every year, partly due to their immunocompromised status. I presented a case of contact screening.
QFT-G is a useful tool to detect a condition of LTBI in the health care workers. However there is scant evidence to support that the QFT current cut-off value is appropriate for the diagnosis of LTBI. Further study is needed to estimate its efficacy of QFT as an administrative tool for the infection control in health care facilities.
