Predicting tuberculosis: the blood, the skin, or the Sibyl?
Authors: Jean-Pierre Zellweger
Journal: The Lancet Infectious Diseases (2018)

In The Lancet Infectious Diseases, Ibrahim Abubakar and colleagues1Abubakar I Drobniewski F Southern J et al.Prognostic value of interferon-γ gamma release assays and tuberculin skin test in predicting the development of active tuberculosis: the UK PREDICT tuberculosis cohort study.Lancet Infect Dis. 2018; (published online Aug 30.)http://dx.doi.org/10.1016/S1473-3099(18)30355-4Summary Full Text Full Text PDF Scopus (96) Google Scholar report the results of the UK PREDICT tuberculosis cohort study, which compared the prognostic value of two interferon-γ release assays (IGRAs) and a tuberculin skin test (TST) in predicting the development of active tuberculosis among high-risk individuals who were not undergoing preventive treatment. The study's large prospective cohort of 9610 eligible participants, recruited from 54 UK National Health Service (NHS) centres and community settings, comprised recent contacts of active tuberculosis (4861 [50·6%]) and migrants who entered the UK within the past 5 years from countries with a high incidence of tuberculosis (4749 [49·4%]). Participants were tested for latent tuberculosis infection by use of three screening procedures—namely, T-SPOT.TB, QuantiFERON-TB Gold In-Tube, and TST with three thresholds for a positive result dependent on the size of skin induration: TST-5 at 5 mm, TST-10 at 10 mm, and TST-15, which was a BCG vaccination status dependent measure, at 5 mm for BCG-naive and at 15 mm for BCG-vaccinated participants. After a median follow-up of 2·9 years (range 21 days to 5·9 years), the annual incidence of active tuberculosis varied between 6·8 per 1000 people (95% CI 5·2–8·7) and 13·2 per 1000 people (9·9–17·4) depending on which test was used, while the annual incidence was very low among participants who had negative results (1·2 per 1000 people [95% CI 0·6–2·0] to 1·9 per 1000 people [1·3–2·7]). A low threshold for TST (5 mm) identified more participants who progressed to active tuberculosis than a high threshold (10 or 15 mm), but classified large groups of individuals as infected who then did not progress. T-SPOT.TB, QuantiFERON-TB Gold In-Tube, and the BCG-stratified TST-15 were significantly better predictors of progression than the lower TST thresholds of 5 and 10 mm. The work supports other studies that have shown that the rate of progression to active tuberculosis and the predictive value of positive TST and IGRA results among recent contacts of active tuberculosis and migrants is globally low, but that the negative predictive value of the tests is high (with almost no risk of active tuberculosis in contacts or migrants with a negative test result).2Altet N Dominguez J Souza-Galvão ML et al.Predicting the development of tuberculosis with the tuberculin skin test and QuantiFERON testing.Ann Am Thorac Soc. 2015; 12: 680-688Crossref PubMed Scopus (32) Google Scholar, 3Zellweger JP Sotgiu G Block M Dore S Altet N Blunschi R et al.Risk assessment of tuberculosis in contacts by IFN-γ release assays. A Tuberculosis Network European Trials Group study.Am J Respir Crit Care Med. 2015; 191: 1176-1184Crossref PubMed Scopus (90) Google Scholar Abubakar and colleagues' study also supports the observation that most contacts of individuals with tuberculosis and migrants from countries with a high incidence of tuberculosis will not develop the disease and that, when considering preventive treatment, the exclusion of individuals who have been exposed to tuberculosis and who have no significant risk of disease is probably more important in practice than the inclusion of large groups of individuals who might not be at risk. This study should be interpreted within the framework of the ongoing discussion about the role of screening and preventive treatment for latent tuberculosis infection, as shown by the updated recommendations from WHO4WHOGuidelines on the management of latent tuberculosis infection. World Health Organization, Geneva2015http://www.who.int/tb/publications/latent-tuberculosis-infection/en/Date accessed: July 4, 2018Google Scholar, 5WHOLatent TB infection: updated and consolidated guidelines for programmatic management. World Health Organization, Geneva2018http://www.who.int/tb/publications/2018/latent-tuberculosis-infection/en/Date accessed: July 4, 2018Google Scholar that try to integrate the management of latent tuberculosis infection within the global vision of tuberculosis elimination in low-incidence settings.6WHOTowards TBs elimination: an action framework for low-incidence countries. World Health Organization, Geneva2014http://apps.who.int/iris/bitstream/handle/10665/132231/9789241507707_eng.pdf;jsessionid=5FBC4A3B20E05C314029DDC58274E9AE?sequence=1Date accessed: July 4, 2019Google Scholar The idea is that better attention to the pool of future tuberculosis cases could contribute to a decrease in the number of cases globally. Even if the risk of progression to active tuberculosis in contacts who have a positive test result for latent infection is low, the prevalence of disease in this group is much higher (an estimated 25 times higher5WHOLatent TB infection: updated and consolidated guidelines for programmatic management. World Health Organization, Geneva2018http://www.who.int/tb/publications/2018/latent-tuberculosis-infection/en/Date accessed: July 4, 2018Google Scholar) than in the local population and, in absolute numbers, contacts and migrants from high-incidence regions are a source of a lot of potentially preventable cases. Therefore, the key issue in practice is to select among the individuals who are latently infected with tuberculosis in these two populations those who have the highest risk of disease progression and who will benefit most from a preventive treatment. This selection should be on the basis of not only the result of a blood or skin test, but also individual factors like age, intensity of exposure, and general state of health and immunological defences. Combining these data could help decrease the number of people who need to be treated to prevent a single future case of tuberculosis from 373Zellweger JP Sotgiu G Block M Dore S Altet N Blunschi R et al.Risk assessment of tuberculosis in contacts by IFN-γ release assays. A Tuberculosis Network European Trials Group study.Am J Respir Crit Care Med. 2015; 191: 1176-1184Crossref PubMed Scopus (90) Google Scholar, 7Sester M van Crevel R Leth F Lange C Numbers needed to treat to prevent tuberculosis.Eur Respir J. 2015; 46: 1836-1838Crossref PubMed Scopus (27) Google Scholar to six,8Saunders MJ Wingfield T Tovar MA et al.A score to predict and stratify risk of tuberculosis in adult contacts of tuberculosis index cases: a prospective derivation and external validation cohort study.Lancet Infect Dis. 2017; 17: 1190-1199Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar thus reducing the unnecessary prescription of drugs. Additionally, if a short, efficient, and well tolerated preventive treatment is selected and given under controlled conditions (thus increasing adherence), the benefit for the population could largely exceed the costs. Furthermore, taking into consideration the level of the test response could add a useful indication about the risk of future tuberculosis, as already known for TSTs,9Morán-Mendoza O Marion SA Elwood K Patrick DM FitzGerald JM Tuberculin skin test size and risk of tuberculosis development: a large population-based study in contacts.Int J Tuberc Lung Dis. 2007; 11: 1014-1020PubMed Google Scholar and suggested for the QuantiFERON-TB Gold In-Tube assay by a recent study from Norway.10Winje BA White R Syre H Skutlaberg DH Oftung F Mengshoel AT et al.Stratification by interferon-γ release assay level predicts risk of incident TB.Thorax. 2018; (published online April 5.)DOI:10.1136/thoraxjnl-2017-211147Crossref PubMed Scopus (37) Google Scholar The tests currently used are far from ideal, but they help to filter the vast majority of individuals who have been exposed to tuberculosis who can be confidently reassured that they will not develop the disease, from the small subgroup who might benefit from further examination, care, and surveillance. Depriving individuals at risk of the potential benefit of a preventive treatment just because the screening tools are not perfect and the preventive treatment is not satisfactorily adhered to (but could be if well prescribed and managed) is clinically and ethically disputable.11MacIntyre CR Plant AJ Yung A Streeton JA Missed opportunities for prevention of tuberculosis in Victoria, Australia.Int J Tuberc Lung Dis. 1997; 1: 135-141PubMed Google Scholar This is like asking the Sibyl the future, dismissing the answer that we do not understand, and just hoping that nothing will go wrong in the future. I have received speaker fees from Qiagen. Prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort studyIGRA-based or BCG-stratified TST strategies appear most suited to screening for potential disease progression among high-risk groups. Further work will be needed to assess country-specific cost-effectiveness of each screening test, and in the absence of highly specific diagnostic tests, cheap non-toxic treatments need to be developed that could be given to larger groups of people at potential risk. Full-Text PDF Open Access