Revisiting the timetable of tuberculosisBMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k2738 (Published 23 August 2018) Cite this as: BMJ 2018;362:k2738
All rapid responses
We congratulate Behr MA et al (1) for their re-analysis of the timeline of tuberculosis (TB) and urging us to focus on persons with active tuberculosis disease and their newly infected contacts. The undersigned are in agreement and stress the importance of attending promptly to persons presenting with symptoms and signs suggestive of tuberculosis, for example, in the courses and technical support missions by the International Union Against Tuberculosis and Lung Disease (The Union).
In 2017, four million of the 10 million persons estimated to have new tuberculosis were missed globally (2). They may have been diagnosed and treated but there is no record and we do not know whether they were cured. They could have remained undetected and died from a preventable cause or continued to transmit Mycobacterium tuberculosis (M. tb) to their contacts. In the same year, it was estimated that only one out of four persons with multidrug-resistant tuberculosis was initiated on second line treatment and a modest proportion was cured (2).
Gaps in case-finding are found at all levels of the health systems (3). A study in South Africa reported a tuberculosis prevalence that was not statistically different among persons attending primary health care services for TB-related symptoms and those attending for other complaints. It described how persons belonging to both groups were missed at every step from symptom screening, collection of sputum specimens to capturing the laboratory test results. It was estimated that 63-79% of those attending the clinics for TB symptoms were missed and 90-100% of those who attended for other reasons (4). A fifth of persons with bacteriologically confirmed tuberculosis recorded in the laboratory registers in Kenya could not be found in the electronic treatment register (5). Findings in both urban and rural Zimbabwe were suggestive of delays and significant pre-diagnosis and pre-treatment loss-to-follow-up: up to one out of three to five persons with tuberculosis may not have been started on treatment (6, 7). In India, a study that analysed care cascades revealed that only 45% of persons with tuberculosis completed treatment (8).
Through household contact management a significant proportion of persons with active tuberculosis, especially infants and children, can be found and preventive therapy offered to those without tuberculosis. A recent mathematical modelling study estimated that every year over 100,000 tuberculosis deaths and 160,000 cases among children could be prevented through ‘full’ household contact management (9). The second group of persons that will benefit from preventive therapy is people living with HIV (PLHIV) as long as active tuberculosis has been ruled out and holistic approach to support tuberculosis prevention is available (10). There is ample room for improvement in both aspects of preventive therapy: in 2017, it was provided to only approximately 23% of under-fives who were contacts of persons with bacteriologically confirmed pulmonary tuberculosis and 36% of eligible HIV-positive persons in 59 countries that provided necessary data for calculations (2).
How can national tuberculosis programmes in low-income countries master provision of both passive and active tuberculosis case finding, particularly management of household contacts and PLHIV, and quality treatment for both disease and infection? Tuberculosis programmes function frequently in challenging circumstances within fragile health systems. Human resources are often inadequate and may be drawn to respond to other health calamities (11). Tuberculosis diagnosis is marred by weak laboratory services, including limited access to drug susceptibility testing and logistical support for specimen transportation and communication of results. Even first-line tuberculosis medicines may be out-of-stock in selected situations (12).
Both types of tuberculosis case finding should be made robust by rebuilding from ‘bottom up’. In high burden settings, health professionals in all service entry points need to be re-engaged to provide tuberculosis services. Focal staff need to be trained to tabulate, analyse and use routinely available tuberculosis data for local decision making. It is not enough to produce quarterly case notification and treatment outcome reports (13) that are submitted mechanically from one level to another finally reaching the central level without meaningful attention to the data in these reports.
Rather, these real data must be arranged in such a way that staff can see the gaps in the cascades of care for persons with presumptive and diagnosed tuberculosis, including those with co-morbidities, and identify where they do not transition to the next step. By assessing the data staff who know the local situation are able to prioritise the most appropriate actions within available resources. Through repeated cycles of review of quarterly data on care cascades, the results of the local interventions can be monitored and performance strengthened. Promising results of a pilot on systematic use of tuberculosis data for practical ways to find and treat missing tuberculosis patients have been reported by the national programme in Zimbabwe (14). By nurturing facility staff ownership, improvement in access and quality of services may be more sustainable than in interventions that are not placed at the local level (15). Tuberculosis coordinators at the sub-national levels can play a pivotal role in integrating review of these real data into supervision that can improve data quality and reduce the dependence on estimates. Operational research has an important role to further examine policies and practices that enhance the quality, effectiveness or performance of programmes (16).
Organisations providing technical support to national programmes in high tuberculosis transmission countries should consider non-fragmented assistance that takes into consideration all prerequisites that the programmes need to carry out their core functions: stopping transmission by early detection and effective treatment of persons with tuberculosis and managing their contacts wherever they live.
(1) Behr MA, Edelstein PH, Ramakrishnan L. Revisiting the timetable of tuberculosis. BMJ 2018; 362. doi:10.1136/bmj.k2738
(2) World Health Organization. Global Tuberculosis Report 2018; WHO/CDS/TB/2018.25
(3) Wells WA. Onions and prevalence surveys: how to analyze and quantify tuberculosis case-finding gaps. Int J Tuberc Lung Dis 2017; 21: 1101–1113
(4) Kweza PF, Van Schalkwyk C, Abraham N et al. Estimating the magnitude of pulmonary tuberculosis patients missed by primary health care clinics in South Africa. Int J Tuberc Lung Dis 2018; 22(3): 264-272
(5) Tollefson D, Ngari F, Mwakala M et al. Under-reporting of sputum-smear positive tuberculosis cases in Kenya. Int J Tuberc Lung Dis 2016; 20(10):1334-1341
(6) Mugauri H, Shewade HD, Dlodlo RA et al. Bacteriologically confirmed pulmonary tuberculosis patients: Loss to follow-up, death and delay before treatment initiation in Bulawayo, Zimbabwe from 2012-2016. IJID 2018; https://doi.org/10.1016/ij.ijid.2018.07.012
(7) Murongazvombo A, Dlodlo RA, Shewade HD et al. Where, when, and how many tuberculosis patients are lost from presumption until treatment initiation? A step by step assessment in a rural district in Zimbabwe. IJID 2018; https://doi.org/10.1016/ij.ijid.2018.10.013
(8) Subbaraman R, Nathavitharana RR, Satyanarayana S et al. The tuberculosis cascade of care in India’s public sector: a systematic review and meta-analysis. PLOS Medicine 2016; DOI:10.1371/journal.pmed.1002149
(9) Dodd PJ, Yuen CM, Becerra MC et al. Potential effect of household contact management on childhood tuberculosis: a mathematical modelling study. Lancet Glob Health 2018; 6(12):e1329-e1338
(10) Harries AD, Schwoebel V, Monedero I et al. Challenges and opportunities to prevent tuberculosis in people living with HIV in low income countries. Int J Tuberc Lung Dis (accepted for publication)
(11) Makoni M. Inside Zimbabwe’s efforts to tame cholera. Lancet 2018; Vol 392, Sept 29, 2018
(12) Rusen ID, Harries AD, Heldal E et al. Drug supply shortages in 2010: the inexcusable failure of global tuberculosis control. Int J Tuberc Lung Dis 2010; 14 (3): 253-254
(13) Cazabon D, Alsdruf H, Satyanarayana S et al. Quality of tuberculosis care in high burden countries: the urgent need to address gaps in the care cascade. IJID 2016; http://dx.doi.org/10.1016/j.ijid2016.10.016
(14) Heldal E, Dlodlo RA, Mlilo N et al. Local staff making sense of their tuberculosis data: key to quality care and ending tuberculosis. Int J Tuberc Lung Dis (accepted for publication)
(15) Davis JL, Katamba A, Vasquez J et al. Evaluation of tuberculosis case detection via real-time monitoring of tuberculosis diagnosis services. Am J Respir Crit Care Med 2011; Vol 184: 362-274
(16) Zachariah R, Harries AD, Ishikawa N et al. Operational research in low-income countries: what, why and how? Lancet Infect Dis 2009; 9: 711-717
Competing interests: No competing interests
Dr. Emery suggests that we have underemphasized the contribution of long incubation tuberculosis to TB incidence in low TB burden countries. This was not our intention, as we emphasized in our review that this is a significant issue in low burden countries.
As the incidence of tuberculosis declines the relative proportion of TB due to long incubation period (“reactivation”) disease becomes more common. We believe that the data we reviewed prior to and after the publication of the review support the limited duration of TB infection in the majority of persons, and that focusing on the entire population of people with tuberculin reactivity is misplaced. Finding a method that determines which of those who are infected will develop disease more than several years after infection is a worthy goal, and could be important for TB elimination, although as pointed out recently by Schulger the logistics and cost of this would be daunting(1). In high burden countries long incubation period disease is of less public health importance. We agree that Emery that there can be a long delay in TB diagnosis and treatment, but do not think that this has an impact on the incubation periods that were determined for multiple studies, based on the methodologies used for the studies.
1. Schluger NW. Tuberculosis Elimination, Research, and Respect for Persons. Am J Respir Crit Care Med. 2018;epub ahead of print.
Competing interests: No competing interests
Dr. Basu questions whether tuberculosis elimination in India and other high burden countries can be achieved without a vigorous effort to give preventive drug treatment to those with latent TB. He also questions the equity of different approaches to latent TB treatment in high income, low burden countries versus lower income, higher burden countries.
Public health authorities think that in high burden countries the bulk of the effort to control TB should be devoted to active case finding, rapid diagnosis and treatment of TB disease and interruption of transmission by tracing contacts and finding and treating all cases of TB in those contacts. Offering preventive treatment to recent contacts and other high risk persons per WHO guidelines also forms the core of the control efforts (1). With at least 20% of TB cases being undiagnosed world-wide, available public health care resources should be devoted mainly to active case finding and treatment (2). At such time that TB prevalence drops dramatically in high burden countries then a more vigorous approach to disease elimination by targeting latent TB in low risk populations has its advocates. However, since the current assays for TB infection have low positive predictive values (1 to 10%) for the development of TB disease in low risk contacts, and since testing the entire population for TB infection is a huge financial and logistic burden, TB elimination would not come without a substantial cost and adverse-drug reactions for those with TB infection who will never develop TB disease (3).
1. World Health Organization. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva: World Health Organization; 2018. p. i-64.
2. World Health Organization. Global tuberculosis report 2018. Geneva: World Health Organization; 2018. Report No.: 978-92-4-156564-6.
3. Schluger NW. Tuberculosis Elimination, Research, and Respect for Persons. Am J Respir Crit Care Med. 2018;epub ahead of print.
Competing interests: No competing interests
Menzies et al. assert that we have not provided evidence regarding clearance of latent TB infection. This assertion overlooks the literature we reviewed on autopsy studies from the pre-antibiotic era (1). Furthermore, they provide no evidence for the alternative hypothesis, namely that most infected individuals harbor viable Mycobacterium tuberculosis for the remainder of their lives. We agree that medical and pharmacologic immunosuppression is associated with an increased risk of developing active TB, as noted in our article. However, this increased risk would be seen if only a fraction of infected individuals developed a persistent decades-long infection. Supporting this, in the era prior to screening for TB and providing INH prophylaxis, over 95% of TST positive individuals who received infliximab did not develop TB (2-5). While this finding is consistent with the possibility that all of these individuals had a live M. tuberculosis infection that they were able to control through TNF-independent mechanisms, it seems more plausible that a large fraction of these individuals had already cleared their infection despite remaining TST-positive. Studies from US and UK find that individuals who were TST positive for long periods prior to receiving isoniazid treatment remain TST positive after treatment. These studies, discussed in our paper, suggest that TST-positivity is not a good indicator of being currently infected. It is merely a measure of immunoreactivity to persistent or past (cleared) infection. Unfortunately, there is no current assay to distinguish persistent versus cleared infection in individuals. Until such an assay is available, we submit that everyone with a positive TST who undergoes immunosuppressive treatment should be assumed to be infected, and treated accordingly. This does not however mean that we should assume that one-quarter to one-third of humanity is infected with live Mycobacterium tuberculosis. Efforts to identify those truly at risk are in keeping with a human-rights/equity perspective as personalizing the decision to treat will maximize individual benefit and minimize harms of unnecessary treatment.
Menzies et al. challenge the conclusion from our narrative review that the long-term efficacy of preventive treatment is limited in high-transmission settings due to reinfection. Yet, the systematic reviews they cite reached the same conclusion. Ayieko et al. (6) stated: "The results also suggest that the efficacy of INH was greater in TB non-endemic regions (RR = 0.40, 95% CI 0.27, 0.57 p < 0.001) compared to TB endemic regions (RR = 0.78, 95% CI 0.55, 1.11 p = 0.08)." Zenner et al. (7) stated: "Inclusion of high versus low TB incidence in the country of study as a covariate reduced between-study variability; treatment was generally less efficacious in high-incidence populations (ROR, 1.58 [CrI, 1.01 to 2.48])." Menzies and colleagues suggest that we wish to diminish access to treatment in high-transmission settings. We made no such recommendation. Rather, we wished to make the point that the greatest benefits of preventive therapy will be realized when transmission is halted. This point was noted in 1975 by George Comstock, who wrote: “Available evidence indicates that the reduction in tuberculosis risk caused by prophylactic treatment with INH is lifelong when the risk of exogenous reinfection is virtually negligible“ (8). Regarding their recommendation to offer preventive treatment to newly infected contacts, where ever they live, on this matter we are in complete agreement. To reiterate our concluding sentence: “If focused attention was given to those with active TB disease and their newly infected contacts, TB elimination might be achieved sooner than projected.”
1. Canetti G, Sutherland I, Svandova E. Endogenous reactivation and exogenous reinfection: their relative importance with regard to the development of non-primary tuberculosis. Bull Int Union Tuberc. 1972;47:116-34.
2. Baldin B, Dozol A, Spreux A, Chichmanian RM. Tuberculoses lors de traitements par l’infliximab. Suivi national du 1er janvier 2000 au 30 juin 2003. Presse Med. 2005;34(5):353-7.
3. Gomez-Reino JJ, Carmona L, Angel Descalzo M, Biobadaser G. Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection. Arthritis Rheum. 2007;57(5):756-61.
4. Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD, Group B. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 2003;48(8):2122-7.
5. Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum. 2004;50(2):372-9.
6. Ayieko J, Abuogi L, Simchowitz B, Bukusi EA, Smith AH, Reingold A. Efficacy of isoniazid prophylactic therapy in prevention of tuberculosis in children: a meta-analysis. BMC Infect Dis. 2014;14:91.
7. Zenner D, Beer N, Harris RJ, Lipman MC, Stagg HR, van der Werf MJ. Treatment of Latent Tuberculosis Infection: An Updated Network Meta-analysis. Ann Intern Med. 2017;167(4):248-55.
8. Comstock GW, Edwards PQ. The competing risks of tuberculosis and hepatitis for adult tuberculin reactors. Am Rev Respir Dis. 1975;111(5):573-7.
Competing interests: No competing interests
To the Editor,
We read with interest the recent paper published in the BMJ by Behr and colleagues “Revisiting the timetable of tuberculosis” 1. While we found the paper a valuable challenge to traditional dogma, based on a re-examination of new and old studies, we have several concerns with the methods and conclusions of this review.
While we appreciate the expert opinion of the three authors, it is unfortunate that the article was not a systematic review, without which the conclusions can not be based on a systematic and reproducible assessment of all available evidence. Although a systematic review of the natural history of tuberculosis (TB) is more challenging, since many of the relevant publications are from the pre-antibiotic era, we think the authors could have considered the systematic methodology described in the elegant review of the “Natural History of Tuberculosis” by Tiemersma and colleagues2.
The authors have provided a useful reminder that the risk of TB is highest in the first few years after infection, highlighting the need for timely initiation of latent TB infection (LTBI) treatment. However, the authors have not provided evidence on which to base their conclusion that LTBI is cleared or cured, which, if correct, would result in over-estimation of the prevalence of TB infection using available diagnostic tests. There is a large body of published evidence on reactivation of active TB among individuals with evidence of long-standing latent infection presenting with new vulnerability such as medical co-morbidity. The most extreme examples of this are reports describing individuals who developed active TB soon after starting anti-TNF-alpha therapy3,4 or organ transplantation5,6, or renal failure7, without evidence of new TB exposure. Active TB developed within a few months of starting TNF-alpha therapy in one report4, or an average of 1.5 years after developing renal failure in a cohort of foreign-born in British Colombia (BC)8, who had arrived in Canada eleven years earlier, supporting the idea that long-standing latent infection developed only after developing greater vulnerability. While we agree that studies have consistently shown that the annual rate of TB disease among immigrants declines after the first two to three years, in long term cohort studies, risk remains elevated beyond 10 years8,9, or even 20 years10, with the result that the lifetime cumulative risk is not low, and more than half of all cases occur after the first two years8-11.
The authors also contend that the observation of declining TB incidence rates over several decades in older adults in Norway12 supports their hypothesis of spontaneously cured latent TB infection. Another interpretation of the same data, that we support, is that the higher rates in the oldest cohorts - also seen in a similar study in Ontario13 –is most likely due to long-standing latent infection, acquired when they were young, at a time of greater exposure. In a recent long term cohort study of immigrants to BC, incidence initially declined after arrival, but then increased in the older age cohorts after 10 years or more in Canada10. The idea that these higher and increasing rates could result from recent exposure and infection in the most elderly seems implausible; molecular epidemiologic studies suggest that recent exposure accounts for a very small fraction of all cases among the elderly14. The apparently contradictory findings of declining incidence among the cohorts described in Norway, but increasing rates when individuals were followed, suggests a “healthy cohort” effect – the cohorts surviving successive decades may have had lower TB risk because of better general health, and possibly lower TB exposure when they were young. However, when individuals are followed (as in BC), then it is apparent that individual risk does increase in the elderly.
While we agree that treatment of long-standing latent TB infection, particularly in elderly without comorbidities, may be of questionable benefit, we disagree strongly with the authors’ conclusions that “in high transmission countries, preventive therapy for contacts is of limited value”. This conclusion ignores numerous randomized trials among close contacts and other high risk individuals in low- and high-incidence settings15-17 which have demonstrated important individual benefits in prevention of TB. Behr et al argue that “the high continuous chance of re-infection from known and unknown contacts” in high-incidence settings may obviate the benefit of preventive therapy. However, the evidence cited to support this statement comes from a study with limited generalizability as it was conducted amongst South African gold-miners whose occupational environment resulted in very high exposure and co-morbidities resulted in limited protection from prior infection18. In contrast, trials of LTBI therapy in multiple settings have demonstrated sustained benefits of LTBI treatment with long term follow-up – for over 5 years in Hong Kong19, 7 years in Brazil20, 10 years in France21 and 19 years among Alaska natives22.
Finally, in contrast to the authors statements, our reading of the most recent recommendations from WHO is that treatment of LTBI among close contacts is recommended in all settings (see page 2 of the 2018 publication23). Given these guidelines, plus the clear and consistent individual benefits, from a human rights perspective, we ask: why should recently infected contacts in high-transmission settings not receive care that is considered appropriate in low-transmission settings? It may be difficult to eliminate an individual’s future risk, but we can lower their current risk - with treatments we know to be safe and effective. Hence, we feel that access to latent TB therapy should be expanded in high-incidence settings, not diminished as the authors suggest. We recognize there are major barriers, but all of the undersigned are committed to meeting that challenge.
Yours very truly,
Dick Menzies, McGill Intl TB Centre, Canada, and
Menonli Adjobimey, National TB program, Benin;
Faiz Ahmad Khan, McGill Intl TB Centre, Canada;
Leila Barss, University of Calgary, Canada;
Warwick Britton, Centenary Institute, The University of Sydney, Australia;
Jonathon Campbell, McGill Intl TB Centre, Canada;
Victoria J Cook, University of British Columbia & Provincial TB Services, BC Centre for Disease Control, Canada;
Justin Denholm, Victorian Tuberculosis Program, Melbourne, Australia;
Dina Fisher, U Calgary, Canada;
Greg Fox, University of Sydney, Australia;
Federica Fregonese, McGill Intl TB Centre, Canada;
Panji Hadisoemarto, UNPAD, Indonesia;
Philip Hill, U Otago, New Zealand;
James Johnston, University of British Columbia & Provincial TB Services, BC Centre for Disease Control, Canada;;
Richard Long, University of Alberta, Canada;
Guy Marks, University of New South Wales, and Woolcock Institute, Australia;
Thu Anh Nguyen, Woolcock institute, Hanoi, Vietnam;
Joseph Obeng, Komofi Anyoke Teaching Hospital, Ghana;
Olivia Oxlade, McGill Intl TB Centre, Canada;
Rovina Ruslami, UNPAD, Indonesia;
Kevin Schwartzman, McGill Intl TB Centre, Canada ;
Anete Trajman; Federal University of Rio de Janeiro, Brazil and McGill Intl TB Centre.
1. Behr MA, Edelstein PH, Ramakrishnan L. Revisiting the timetable of tuberculosis. BMJ 2018; 362: k2738.
2. Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ. Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One 2011; 6(4): e17601.
3. Ai JW, Zhang S, Ruan QL, et al. The Risk of Tuberculosis in Patients with Rheumatoid Arthritis Treated with Tumor Necrosis Factor-alpha Antagonist: A Metaanalysis of Both Randomized Controlled Trials and Registry/Cohort Studies. J Rheumatol 2015; 42(12): 2229-37.
4. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345(15): 1098-104.
5. Adamu B, Abdu A, Abba AA, Borodo MM, Tleyjeh IM. Antibiotic prophylaxis for preventing post solid organ transplant tuberculosis. Cochrane Database Syst Rev 2014; (3): CD008597.
6. Holty JE, Gould MK, Meinke L, Keeffe EB, Ruoss SJ. Tuberculosis in liver transplant recipients: a systematic review and meta-analysis of individual patient data. Liver Transpl 2009; 15(8): 894-906.
7. Al-Efraij K, Mota L, Lunny C, Schachter M, Cook V, Johnston J. Risk of active tuberculosis in chronic kidney disease: a systematic review and meta-analysis. Int J Tuberc Lung Dis 2015; 19(12): 1493-9.
8. Campbell JR, Johnston JC, Ronald LA, et al. Screening for Latent Tuberculosis Infection in Migrants With CKD: A Cost-effectiveness Analysis. Am J Kidney Dis 2018.
9. Marks GB, Bai J, Simpson SE, Sullivan EA, Stewart GJ. Incidence of tuberculosis among a cohort of tuberculin-positive refugees in Australia: reappraising the estimates of risk. Am J Respir Crit Care Med 2000; 162(5): 1851-4.
10. Ronald LA, Campbell JR, Balshaw RF, et al. Demographic predictors of active tuberculosis in people migrating to British Columbia, Canada: a retrospective cohort study. CMAJ 2018; 190(8): E209-E16.
11. Zuber PL, McKenna MT, Binkin NJ, Onorato IM, Castro KG. Long-term risk of tuberculosis among foreign-born persons in the United States. JAMA 1997; 278(4): 304-7.
12. Wiker HG, Mustafa T, Bjune GA, Harboe M. Evidence for waning of latency in a cohort study of tuberculosis. BMC Infect Dis 2010; 10: 37.
13. Grzybowski S, Allen EA. The Challenge of Tuberculosis in Decline. A Study Based on the Epidemiology of Tuberculosis in Ontario, Canada. Am Rev Respir Dis 1964; 90: 707-20.
14. Shea KM, Kammerer JS, Winston CA, Navin TR, Horsburgh CR, Jr. Estimated rate of reactivation of latent tuberculosis infection in the United States, overall and by population subgroup. Am J Epidemiol 2014; 179(2): 216-25.
15. Ayele HT, Mourik MS, Debray TP, Bonten MJ. Isoniazid Prophylactic Therapy for the Prevention of Tuberculosis in HIV Infected Adults: A Systematic Review and Meta-Analysis of Randomized Trials. PLoS One 2015; 10(11): e0142290.
16. Ayieko J, Abuogi L, Simchowitz B, Bukusi EA, Smith AH, Reingold A. Efficacy of isoniazid prophylactic therapy in prevention of tuberculosis in children: a meta-analysis. BMC Infect Dis 2014; 14: 91.
17. Zenner D, Beer N, Harris RJ, Lipman MC, Stagg HR, van der Werf MJ. Treatment of Latent Tuberculosis Infection: An Updated Network Meta-analysis. Ann Intern Med 2017; 167(4): 248-55.
18. Churchyard GJ, Fielding KL, Lewis JJ, et al. A trial of mass isoniazid preventive therapy for tuberculosis control. N Engl J Med 2014; 370(4): 301-10.
19. BMRC HKCS. A double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. Am Rev Respir Dis 1992; 145(1): 36-41.
20. Golub JE, Cohn S, Saraceni V, et al. Long-term protection from isoniazid preventive therapy for tuberculosis in HIV-infected patients in a medium-burden tuberculosis setting: the TB/HIV in Rio (THRio) study. Clin Infect Dis 2015; 60(4): 639-45.
21. Debre R, Perdrizet S, Lotte A, Naveau M, Lert F. Isoniazid chemoprophylaxis of latent primary tuberculosis: in five trial centres in France from 1959 to 1969. Int J Epidemiol 1973; 2(2): 153-60.
22. Comstock GW, Baum C, Snider DEJ. Isoniazid prophylaxis among Alaskan eskimos: A Final Report of the Bethel Isoniazid Studies. Am Rev Respir Dis 1979; 119: 827-30.
23. World Health Organization. Latent TB Infection : Updated and consolidated guidelines for programmatic management. https://www.who.int/tb/publications/2018/latent-tuberculosis-infection/en/, 2018.
Competing interests: No competing interests
Reactivation disease: a minor component of the TB epidemic
The elegantly argued paper by Behr et al (1) parallels our thinking of many years. The 5% plus 5% estimate for active TB (recent transmission, RT) and reactivation TB after infection does not appear to generate acceptable data. If we accept that according to WHO estimates there are 1.7 billion people infected by TB and that 5% will reactivate over a lifetime (we use 40 years as a conservative approximation of a lifetime) we would expect 2.13 million cases per annum. This is substantially less than the WHO estimate of 10 million cases. Therefore we can assume that the balance of just under 80% of cases represents those from recent transmission.
This estimate is surprisingly close to estimates for transmission followed by active disease development within 2 years in a high burden country such as South Africa. Our own estimates using genotyping techniques range between 70-95% in a high incidence community (2). Other studies provide estimates that consistently range around 72-77% (3). We acknowledge that these estimates have limitations (4): for example, biases such as incomplete sampling, sampling only from a defined area and not outside that area, not taking into account a pre-existing epidemic, and the use of RT estimates which remove “point sources” which will have the effect of reducing the estimate.
Furthermore, we acknowledge other limitations, such as the breaking down of large clusters into smaller clusters with higher discrimination technology such as whole genome sequencing. However, that merely increases the number of clusters and does not negate that transmission has occurred. The estimates given above are also perfectly aligned with estimates for recent transmission progressing to active disease for drug resistant cases ( viz 72-81%) (5,6). In most regions of the world, it has been shown that even antibiotic resistant TB is now predominantly driven by transmission rather than acquisition of resistance, with an estimated 95.9% of MDR-TB in new TB cases and 61.3% in previously treated cases being due to transmission (7). It is also clear that reinfection is common (ref reinfection and mixed infection), especially in high burden settings, and it has been shown that the reinfection rate (and therefore infection rate) is linked to the incidence (8).
It is clear from the literature and various TB reports, as well as active funding for research into latent TB, that there is concern that we will not be able to eliminate TB unless “Latent TB” or reactivation disease is eliminated. Although that is strictly correct, we are of the opinion that too much attention is given to this problem (latent TB) in view of the high global burden of actively transmitted TB. Whilst low burden countries such as the Netherlands report that about half of their cases in the native Dutch people are attributed to latent TB, the total burden of such cases in low burden countries is a very small fraction of the total TB burden globally. In many developed countries such as the UK, the Netherlands or Switzerland, which are low burden countries, approximately 60-75% of TB cases 74% were among non-native born people and attributed to recently acquired infection in their country of origin and subsequent progression to disease.
Thus the balance of cases in native-born inhabitants is divided between recently transmitted disease and reactivation disease. Clearly then, reactivation disease caused by so-called latency is a relatively minor component of the total TB burden in such countries. Therefore looking at low burden countries such as those in Western Europe, the USA, Canada, New Zealand, Australia and others, the number of potential reactivation cases is a tiny fraction of the global burden. We venture to say that this hardly constitutes a major problem for eliminating TB at this stage of the epidemic. We prefer to use the term controlling TB or reducing the TB burden at this stage.
Therefore we suggest that for low burden countries some attention to reactivation disease is arguably justified and different preferred outcomes and action plans may be justified compared to high incidence countries. However, if we really wish to reduce the global burden of active TB meaningfully, a concentrated focus on recent transmission leading to active disease in high burden countries is needed.
Robin M Warren
Paul D Van Helden
DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town.
The authors are funded by the South African Medical Research Council and National Research Foundation.
1. Behr MA, Edelstein PH, Ramakrishnan L. Revisiting the timetable of tuberculosis. BMJ 2018;362. doi:10.1136/bmj.k2738
2. Van der Spuy GD, Warren RM, Richardson M, Beyers N, Behr MA, Van Helden PD. (2003) Use of genetic distance as a measure of ongoing transmission of Mycobacterium tuberculosis. J. Clin. Micro. 41(12): 5640-5644
3. Verver S, Warren RM, Munch Z, Vynnycky E, van Helden PD, Richardson M, van der Spuy GD, Enarson DA, Borgdorff MW, Behr MA, Beyers N.(2004) Transmission of tuberculosis in a high incidence urban community in South Africa. Int J Epidemiol.33(2):351-7.
4. Van Schalkwyk C, Cule M, Welte A, van Helden P, van der Spuy G, Uys P. (2012) Towards eliminating bias in cluster analysis of TB genotyped data. PloS One. 7(3): e34109
5. Helen S. Cox , Cheryl McDermid, Virginia Azevedo, Odelia Muller, David Coetzee, John Simpson, Marinus Barnard, Gerrit Coetzee, Gilles van Cutsem, Eric Goemaere (2010 Epidemic Levels of Drug Resistant Tuberculosis (MDR and XDR-TB) in a High HIV Prevalence Setting in Khayelitsha, South Africa. ) PLoS One https://doi.org/10.1371/journal.pone.0013901
6. Auld SC, Sarita Shah N, Mathema B, Brown TS, Ismail N, Omar SV, Brust JCM, Nelson KN, Allana S, Campbell A, Mlisana K, Moodley P, Gandhi NR. (2018) XDR tuberculosis in South Africa: genomic evidence supporting transmission in communities. Eur Respir J. doi: 10.1183/13993003.00246-2018 epub ahead of print
7. Kendall EA, Fofana MO, Dowdy DW.(2015) Burden of transmitted multidrug resistance in epidemics of tuberculosis: a transmission modelling analysis. The Lancet Respiratory medicine; 3(12): 963-72
8. Uys PW, van Helden PD, Hargrove JW. (2009) Tuberculosis reinfection rate as a proportion of total infection rate correlates with the logarithm of the incidence rate: a mathematical model. J R Soc Interface. 8. doi: 10.1098/rsif.2008.0184
Competing interests: No competing interests
Behr et al make a case for reconsidering current Tuberculosis control strategies advocating intensive latent TB treatment by listing evidence that most TB disease cases occur within 18-24 months of infection.1 The researchers have argued that persisting with existing approaches could divert public health research focus and resources away from the newly infected people who are at highest risk of disease progression.
India accounts for one-fourth of the global TB burden has set an ambitious target for TB elimination by 2025. Similarly, several developing TB endemic countries are experiencing this dual burden of active and latent TB. Furthermore, well-established risk factors for TB disease progression in infected (latent) TB cases like pediatric TB contacts especially those with protein-energy malnutrition, PLHIV, underweight adults, diabetes and CKD patients and workers in the silica industry are also concentrated in the low and middle-income countries.2 Current latent TB treatment strategies in the endemic countries are largely restricted to children below 6 years and the PLHIV since there exist concerns regarding development of INH resistance, side effects, doubtful efficacy of treatment and high rates of re-infection.3
In this regard, there are certain pertinent queries which need further assessment by the global scientific community. First, how feasible are realization of end-TB targets in high-burden countries in absence of improvement and expansion of latent TB detection and treatment strategies that could interrupt the chain of transmission. Second, are current approaches for latent TB management which provide intensive treatment in developed, low-burden countries but restrict it elsewhere just and equitable or is there an apparent paradox? Should all close contacts of TB patients at higher risk of disease progression not be provided an informed choice for accepting or rejecting a latent TB regimen which is comparatively safer than a full 4 drug DOTS anti-tubercular therapy which is associated with more adverse effects? Third, the focus on screening for active TB cases may be particularly challenging in resource-constrained settings with high rate of migration among close contacts of TB cases.
1. BMJ 2018;362:k2738
2. Fox GJ, Dobler CC, Marais BJ, Denholm JT. Preventive therapy for latent tuberculosis infection-the promise and the challenges. Int J Infect Dis. 2017;56:68-76.
3. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva: World Health Organization; 2018.
Competing interests: No competing interests
We read with interest the recent publication by Behr et al.  re-evaluating the incubation period for tuberculosis (TB). The authors make the case for widespread self-sterilisation amongst TST/IGRA reactive individuals and we agree that this is an important possibility, with significant consequences for our understanding of TB epidemiology and control. We do however note some further considerations that we think are pertinent to any re-examination of the current research priorities to End TB.
Whilst the authors concede the relevance of individuals with long incubation periods (what is commonly referred to as reactivation) in low-incidence settings, we believe they understate the importance of such individuals. Indeed, in the three-part Canetti paper cited by the authors , Sutherland and Svandova use statistical modelling to estimate that 45-68% of cases amongst males aged between 40-59 in the Netherlands in 1967 occurred through reactivation. These are in keeping with the proportions found through careful transmission modelling by Vynnycky and Fine  using TB incidence in the UK between 1953-1988. More recent molecular epidemiological studies from the Netherlands  also found that just under half of TB episodes in the native population were likely due to reactivation.
As part of the End TB Strategy  to eradicate TB by 2035, countries will have to rapidly transition from high to low incidence settings through interrupting transmission. If the global TB community is successful in this aim, we will therefore transition to a world where a significant proportion of remaining TB cases will develop through reactivation, as in those settings discussed above. To End TB, it is therefore vital we proactively research the tools necessary to discern and prevent those who may still progress to TB disease from the estimated 1.7-billion people who have been exposed, aside from the estimated 55-million recently infected individuals . As such, we are wary of understating the relevance of reactivation in strategies to End TB in case such research efforts are neglected as a result.
Finally, a key issue in determining our success or failure in interrupting transmission is how we reduce the infectious period between disease onset and diagnosis. Whilst the title of the article refers to a timetable of TB, the authors only consider the incubation period which we assume to mean the time between infection and disease onset. Indeed, the closely observed historical cohort studies cited by the authors neglect such real-world delays in diagnosis, a timeframe that modelling studies have estimated in terms of years, rather than months . We believe that discussion of the timetable of TB and interrupting transmission needs to carefully consider both the incubation period and, importantly, the lag in diagnosis during which transmission occurs.
To eradicate TB, we must understand its natural history. A healthy debate on the (re)interpretation of historical and contemporary data is essential, and we congratulate Behr and colleagues on stimulating such discussions with their article.
Correspondence to: firstname.lastname@example.org
 Behr MA, Edelstein PH, Ramakrishnan L. Revisiting the timetable of tuberculosis. BMJ 2018;362. doi:10.1136/bmj.k2738
 Canetti G, Sutherland I, Svandova E. Endogenous reactivation and exogenous reinfection: their relative importance with regard to the development of non-primary tuberculosis. Bull Int Union Tuberc 1972;47:116–34.
 Vynnycky E, Fine PE. The natural history of tuberculosis: the implications of age-dependent risks of disease and the role of reinfection. Epidemiol Infect 1997;119:183–201.
 Borgdorff MW, van den Hof S, Kremer K, et al. Progress towards tuberculosis elimination: secular trend, immigration and transmission. Eur Respir J 2010;36:339–47. doi:10.1183/09031936.00155409
 World Health Organisation. End TB Strategy. http://www.who.int/tb/strategy/end-tb/en/
 Houben RMGJ, Dodd PJ. The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Med 2016;13:e1002152. doi:10.1371/journal.pmed.1002152
 Horton KC, Sumner T, Houben RMGJ, et al. A Bayesian approach to understanding gender differences in tuberculosis disease burden. Am J Epidemiol Published Online First: 27 June 2018. doi:10.1093/aje/kwy131
Competing interests: No competing interests