Tuberculosis—making predictions, especially about the future
Authors: Anna M Mandalakas, Frank Cobelens
Journal: The Lancet Infectious Diseases (2017)

The End TB Strategy aims to reduce the burden of tuberculosis worldwide until global prevalence reaches that already attained by many developed countries. The goal amounts to 90% reduction in the incidence of tuberculosis and 95% reduction in tuberculosis deaths.1Uplekar M Weil D Lonnroth K et al.WHO's new end TB strategy, on behalf of WHO's Global TB Program.Lancet. 2015; 385: 1799-1801Summary Full Text Full Text PDF PubMed Scopus (627) Google Scholar The strategy focuses on early detection and treatment and preventive therapy. In 2015, 4·3 million patients with tuberculosis are estimated to have gone undetected and untreated globally,2WHOGlobal tuberculosis report, 2016. World Health Organization, Geneva2016Google Scholar which highlights the need for expanding case finding among those most at risk. Evidence shows consistently that preventive therapy effectively reduces individual risk of tuberculosis.3Comstock GW Baum C Snider Jr, DE Isoniazid prophylaxis among Alaskan Eskimos: a final report of the bethel isoniazid studies.Am Rev Respir Dis. 1979; 119: 827-830PubMed Google Scholar, 4International Union Against Tuberculosis Committee on ProphylaxisEfficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial.Bull World Health Organ. 1982; 60: 555-564PubMed Google Scholar, 5Sharma SK Sharma A Kadhiravan T Tharyan P Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB.Cochrane Database Syst Rev. 2013; 7 (CD007545)PubMed Google Scholar Expansion of preventive treatment beyond children, however, is hampered by poor ability to predict who will develop tuberculosis after exposure. Even among people with positive tuberculin skin test or interferon-γ-release assay results, no more than 2·7% will develop tuberculosis within 2 years. Thus, at least 37 individuals will need to be treated to prevent one case, which, clearly, is too many.6Diel R Loddenkemper R Nienhaus A Predictive value of interferon-gamma release assays and tuberculin skin testing for progression from latent TB infection to disease state: a meta-analysis.Chest. 2012; 142: 63-75Summary Full Text Full Text PDF PubMed Scopus (212) Google Scholar Improved prediction, therefore, is essential for reaching the End TB Strategy targets. In The Lancet Infectious Diseases, Matthew J Saunders and colleagues7Saunders 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; (published online Aug 18.)http://dx.doi.org/10.1016/S1473-3099(17)30447-4PubMed Google Scholar present a derivation and external validation cohort study of a risk score that effectively identified adult tuberculosis contacts at risk of developing the disease in two Peruvian communities. The score is based on nine established and readily collectable clinical and demographic risk factors for the disease that need no testing. Capitalising on 10 years of observational data for prevalence of tuberculosis and repeated fitting of 200 bootstrap samples from the original cohort to their risk model, the score stratified individuals by risk of tuberculosis in the derivation cohort. The 10-year risks were low 2·8% (95% CI 1·7–4·4), medium 6·2% (4·8–8·1), and high 21% (17–24). Assuming 75% effectiveness of preventive therapy, these data suggest that the number of contacts who would need to be treated to prevent one case of tuberculosis would be 48 in the low-risk group, 22 in the medium-risk group, and six in the high-risk group. In the validation cohort, information from patients with tuberculosis was used to calculate and stratify 2·5-year risks among contacts, which were 1·4% (95% CI 0·70–2·8) for low risk, 3·9% (2·5–5·9) for medium risk, and 8·6% (5·9–12·6) for high risk. These findings indicate the potential of this risk score as a practical tool to use in the field. Saunders and colleagues eloquently demonstrate the usefulness of well recognised risk factors to identify contacts at risk in a region with medium tuberculosis incidence and low HIV prevalence. They further show the feasibility of using their risk score to target screening, surveillance, and preventive treatment among adult contacts, complementing the evidence supporting simple approaches to stratify risk among child contacts.8Mandalakas AM Kirchner HL Lombard C et al.Well-quantified tuberculosis exposure is a reliable surrogate measure of tuberculosis infection.Int J Tuberc Lung Dis. 2012; 16: 1033-1039Crossref PubMed Scopus (68) Google Scholar, 9Mandalakas AM Hesseling AC Gie RP Schaaf HS Marais BJ Sinanovic E Modelling the cost-effectiveness of strategies to prevent tuberculosis in child contacts in a high-burden setting.Thorax. 2013; 68: 247-255Crossref PubMed Scopus (65) Google Scholar However, although the study potentially represents a major step forward, there are some points of caution to consider. Based on data from the derivation cohort only, the authors surmise that their score predicts increased risk of tuberculosis for at least 10 years. Since the validation cohort had only 2·5 years of follow-up, this conclusion might have been made post hoc. Moreover, with an annual tuberculosis case notification rate of 199 per 100 000 people in the derivation cohort study area, 20% of tuberculosis cases occurring in a 10-year period might be due to reinfection, which a contact risk score is unlikely to predict. The cumulative risk of up to 8·6% seen in the validation cohort might, therefore, be more realistic than 21% in the derivation cohort. Nonetheless, Saunders and colleagues' findings still suggest an important advance over existing approaches for risk stratification among adult contacts. The risk score captures a combination of factors related to transmission and disease progression, which reflects the complex relation between characteristics of the community, the host, and the infecting Mycobacterium tuberculosis strain. These relations are setting specific, and, therefore, the predictive power of the risk score will be also. This issue seems exemplified by the weaker prediction in the external than in the internal validation. Recognised risk factors for tuberculosis, such as drug resistance, HIV, and diabetes, were not included in the risk score, but might need to be considered in populations with high prevalence. The risk score focused on household transmission, but exposure outside households is also suggested to contribute substantially to transmission in some communities.10Yates TA Khan PY Knight GM et al.The transmission of Mycobacterium tuberculosis in high burden settings.Lancet Infect Dis. 2016; 16: 227-238Summary Full Text Full Text PDF PubMed Scopus (116) Google Scholar Scores that include community transmission would, therefore, also be useful. Additionally, scores that include housing characteristics and socioeconomic status might yield varying results in different populations.11Morris SS Carletto C Hoddinott J Christiaensen LJ Validity of rapid estimates of household wealth and income for health surveys in rural Africa.J Epidemiol Community Health. 2000; 54: 381-387Crossref PubMed Scopus (186) Google Scholar Saunders and colleagues' risk score needs to be validated in a variety of populations and then adaptated to local conditions based on the findings. Finally, evaluation of preventive strategies for tuberculosis that target adults will be crucial to show cost-effectiveness and equal benefit across socioeconomic groups.12Squire SB Ramsay AR van den Hof S et al.Making innovations accessible to the poor through implementation research.Int J Tuberc Lung Dis. 2011; 15: 862-870Crossref PubMed Scopus (33) Google Scholar Elimination of tuberculosis worldwide will need a global commitment to narrow the extensive case-detection gap and expand preventive efforts. Evidence-based and risk-based approaches to deliver preventive therapy can help to pave the path towards this goal. We declare no competing interests. A score to predict and stratify risk of tuberculosis in adult contacts of tuberculosis index cases: a prospective derivation and external validation cohort studyOur externally validated risk score could predict and stratify 10-year risk of developing tuberculosis in adult contacts, and could be used to prioritise tuberculosis control interventions for people most likely to benefit. Full-Text PDF Open Access