Tuberculosis case detection revisited: better testing might not improve outcomes
Authors: Frauke Rudolf, Christian Wejse
Journal: The Lancet Global Health (2015)

Tuberculosis case-finding and diagnostics are far from perfect. The worldwide case detection rate of tuberculosis has stagnated at around 60%, not reaching the target of 70% originally set for 2000 but postponed to 2005, and then judged to be unreachable.1Lawn SD Zumla AI Tuberculosis.Lancet. 2011; 378: 57-72Summary Full Text Full Text PDF PubMed Scopus (625) Google Scholar In sub-Saharan Africa, case detection rates are as low as 52%.2WHOGlobal tuberculosis control: WHO report 2014. WHO/HTM/TB/2014.8. Geneva.http://www.who.int/tb/publications/global_report/en/Date: 2014Google Scholar Diagnosis of tuberculosis in high-endemic low-income areas has been, and still is, a challenge. Although the gold standard for tuberculosis diagnosis is sputum culture, which takes time and relies on a consistent power supply, many settings are still reliant on sputum smear microscopy, a 125-year-old method that fails to detect up to 50% of cases––even more if laboratory capacity is exceeded, as is often the case in low-resource settings. Since WHO has recommended Xpert MTB/RIF, it has been used by 108 of the 145 countries that were eligible for concessional pricing.2WHOGlobal tuberculosis control: WHO report 2014. WHO/HTM/TB/2014.8. Geneva.http://www.who.int/tb/publications/global_report/en/Date: 2014Google Scholar From the initially recommended use in people at risk of multidrug-resistant tuberculosis and HIV-infected patients, current guidelines encourage use of Xpert MTB/RIF for all people with suspected tuberculosis.3WHOXpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children: policy update. World Health Organization, Geneva2013http://apps.who.int/iris/bitstream/10665/112472/1/9789241506335_eng.pdf?ua=1Google Scholar In The Lancet Global Health, Gavin Churchyard and colleagues4Churchyard GJ Stevens WS Mametja LD et al.Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF.Lancet Glob Health. 2015; 3: e450-e457Summary Full Text Full Text PDF PubMed Scopus (168) Google Scholar report the results of XTEND, a cluster-randomised trial testing the effect of Xpert MTB/RIF on patient-relevant outcomes in the context of routine implementation. The XTEND trial was embedded in the national South African rollout of Xpert MTB/RIF and compared the effect of XPERT MTB/RIF with fluorescence microscopy on outcomes such as mortality at 6 months, proportion of positive cases, and the proportion of patients investigated for tuberculosis who started treatment. Churchyard and colleagues enrolled 4712 participants with suspicion of tuberculosis and observed no difference between the study groups in mortality, proportion starting tuberculosis treatment, or initial loss to follow-up. They did, however, note a 50% higher rate of people with bacteriological confirmation of tuberculosis in the Xpert group, thus allowing a reduced time to treatment initiation. The effect of routine implementation of Xpert MTB/RIF was also recently assessed in the TB-NEAT trial;5Theron G Zijenah L Chanda D et al.Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial.Lancet. 2014; 383: 424-435Summary Full Text Full Text PDF PubMed Scopus (332) Google Scholar however, compared with the TB-NEAT trial, which used morbidity as an outcome as assessed by the Bandim TBscore,6Rudolf F Joaquim LC Vieira C et al.The Bandim tuberculosis score: reliability and comparison with the Karnofsky performance score.Scand J Infect Dis. 2013; 45: 256-264Crossref PubMed Scopus (23) Google Scholar XTEND was a more robust evaluation in more real-life settings. The XTEND trial, therefore, adds important insights and confirms the somewhat disappointing findings of the TB-NEAT trial in a setting even closer to reality, in that the decision to refer to tuberculosis diagnostics was left to health-care staff, and existing diagnostic pathways were not altered. The XTEND trial could, therefore, inform those who make decisions for country programmes about when and how to invest in new diagnostic tests for tuberculosis. Importantly, the XTEND trial draws attention to the importance of simultaneously strengthening health systems alongside introduction of new diagnostic methods to reduce initial loss to follow-up. So, why did rollout of Xpert MTB/RIF not have an effect on mortality at 6 months? Most deaths were HIV related, and many patients were unaware of their HIV status or were not taking antiretroviral therapy if they were known to be HIV positive. Furthermore, the effect of averting tuberculosis deaths through earlier diagnosis and treatment might be difficult to show in such a setting and with a relatively short 6 month follow-up period. Churchyard and colleagues' findings are an important lesson that no new diagnostics can overcome gaps in weak health-care systems, so roll-out of prompt linkage to HIV care or immediate tuberculosis treatment for all at the time and place of diagnosis might be more important than the introduction of new technological solutions. Another observation from the XTEND trial is that all enrolled participants were adults seeking health care and who had sputum smear tests requested by clinic staff. Thus, the authors were reliant on the health-care providers' initial suspicions of tuberculosis and referral for testing. Referral rates are often low because of very broad case definitions for tuberculosis7Storla DG Yimer S Bjune GA A systematic review of delay in the diagnosis and treatment of tuberculosis.BMC Public Health. 2008; 8: 15Crossref PubMed Scopus (659) Google Scholar and high thresholds for referral,8Rudolf F Haraldsdottir TL Mendes MS et al.Can case-finding among pulmonary tuberculosis suspects be improved? Oberservations from Bissau.Int J Tuberc Lung Dis. 2014; 18: 277-285Crossref PubMed Scopus (23) Google Scholar and many patients who are later diagnosed with tuberculosis are initially missed.9Porskrog A Bjerregaard-Andersen M Oliveira I Rabna P Andersen PL Wejse C Enhanced identification of TB cases through a 1 month follow-up visit of smear negative TB suspects in Guinea-Bissau.Int J Tuberc Lung Dis. 2011; 15: 459-464Crossref PubMed Scopus (25) Google Scholar Improvements in the rates of relevant patients with suspected tuberculosis being referred for these new diagnostics are, therefore, urgently needed, and implementation of trials of relevant algorithms8Rudolf F Haraldsdottir TL Mendes MS et al.Can case-finding among pulmonary tuberculosis suspects be improved? Oberservations from Bissau.Int J Tuberc Lung Dis. 2014; 18: 277-285Crossref PubMed Scopus (23) Google Scholar should be a priority. Staff at clinics who had received training during the implementation of Xpert MTB/RIF did refer slightly healthier patients than did clinics where training had not yet been given, which indicates that training of staff in how to detect the more insidious tuberculosis cases is needed to tackle the global tuberculosis burden. The implementation of Xpert MTB/RIF will not be possible in all high-endemic settings because it requires a stable power supply and a constant supply of cartridges. The current implementation is mainly donor funded, largely dependent on testing in centralised laboratories, and mostly involves patients with presumed drug-resistant tuberculosis or HIV infection.10Pai M Schito M Tuberculosis Diagnostics in 2015: Landscape, Priorities, Needs, and Prospects.J Infect Dis. 2015; 211: S21-S28Crossref PubMed Scopus (133) Google Scholar Nevertheless, Xpert MTB/RIF is now being rolled out in many settings, and it is important to remember, could increase detection rates if implementation is done strategically and well. Yet, every diagnostic assessment depends on clinical suspicion and referral for testing by a health worker. The challenge in providing better case-finding is, therefore, to ensure that overwhelmed and undertrained health staff at the front line have: first, good algorithms for referral in order to improve triage of those seeking health care for symptoms of tuberculosis; second, good point-of-care diagnostics; and, third, health systems with linkage between diagnostics and treatment for not only tuberculosis but also HIV. We declare no competing interests. Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIFXpert did not reduce mortality at 6 months compared with sputum microscopy. Improving outcomes in drug-sensitive tuberculosis programmes might require not only better diagnostic tests but also better linkage to care. Full-Text PDF Open Access