Comment
the investigators, which might have resulted in selective reporting bias: stent deformation is easier to detect with platinum stents because of their higher radiopacity. In support of this possibility, data from both industry-initiated7 and investigator-initiated8 studies that incorporated systematic quantitative analysis did not confirm higher frequencies of deformation with platinum-chromium-based stents. Finally, a broader issue arises in relation to the conduct of contemporary trials with drug-eluting stents. Obviously, any well-conducted comparison of approved drug-eluting stents, such as DUTCH PEERS, eases the stent selection process in everyday practice. However, the past decade has seen substantial development and testing of new devices (table), the cost of which is ultimately borne by society in terms of economic burden and the opportunity costs of alternative research foregone. The fact that most such trials have a non-inferiority design gives cause for reflection. From an industry perspective, although non-inferiority trials might be of interest in terms of competition for market share, the study of me-too devices in trials with a non-inferiority design does not best serve iterative advancement. Non-inferiority trials are best justified for assessing a new device against standard of care on the premise that it has some other potential advantage—eg, a new class of drug, improved or absent polymer, or a bioresorbable backbone. Otherwise, a model based on superiority testing should attract more resources so that findings can provide a rationale for
adoption of new devices. As a community, perhaps it is time that we reassessed the focus of clinical trials of drug-eluting stents to promote progress.
*Robert A Byrne, Adnan Kastrati Deutsches Herzzentrum, Technische Universität, Munich 80636, Germany; and DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany [email protected] AK has received speaker’s fees from Abbott Laboratories, Biosensors International, and Biotronik. RAB declares that he has no conflicts of interest. 1
2 3
4
5 6
7
8
Byrne RA, Sarafoff N, Kastrati A, Schomig A. Drug-eluting stents in percutaneous coronary intervention: a benefit-risk assessment. Drug Saf 2009; 32: 749–70. Stefanini GG, Holmes DR Jr. Drug-eluting coronary-artery stents. N Engl J Med 2013; 368: 254–65. von Birgelen C, Sen H, Lam MK, et al. Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single-blind, multicentre, non-inferiority trial. Lancet 2013; published online Oct 31. http://dx.doi.org/10.1016/S0140-6736(13)62037-1. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c332. Joner M, Byrne RA. The importance of preclinical research in contemporary interventional cardiology. EuroIntervention 2010; 6: 19–23. Hanratty CG, Walsh SJ. Longitudinal compression: a “new” complication with modern coronary stent platforms—time to think beyond deliverability? EuroIntervention 2011; 7: 872–77. Kereiakes DJ, Popma JJ, Cannon LA, et al. Longitudinal stent deformation: quantitative coronary angiographic analysis from the PERSEUS and PLATINUM randomised controlled clinical trials. EuroIntervention 2012; 8: 187–95. Kim H. Randomized comparison of PtCr-EES versus CoCr-ZES in all-comers receiving PCI: the HOST-ASSURE randomized trial. American College of Cardiology Scientific Sessions; San Francisco, CA, USA; March 9–11, 2013. Session 2667.
Point-of-care diagnostics for tuberculosis elimination? Published Online October 28, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62003-6 See Articles page 424
388
In recent years the development of diagnostics for tuberculosis has progressed rapidly.1 The major advance has been the GeneXpert MTB/RIF automated molecular assay for rapid diagnosis of tuberculosis and detection of rifampicin resistance, which has been endorsed by WHO.2 This has led to new optimism, particularly with respect to the use of this assay in low-resource settings with high tuberculosis burden, where diagnostic facilities are often limited to sputum smear microscopy and chest radiograph. Feasibility tests have shown promising results,3 but concerns have been raised that the assay might not be appropriate for use at scale in peripheral health-care facilities.4 So studies that assess the clinical effect of this assay have been greatly needed. In The Lancet, Grant Theron and colleagues5 report the outcome of a randomised trial comparing point-
of-care Xpert MTB/RIF with smear microscopy in the management of tuberculosis. This study assesses the new molecular tuberculosis diagnostics from a public health perspective by measuring the clinical effect in several real-life situations, comparing nurse-managed Xpert MTB/RIF with a standard set-up of diagnostics with smear microscopy and radiography in well managed settings in four countries. The findings are not unexpected: Xpert MTB/RIF improved same-day treatment initiation (23% in the Xpert group vs 15% in the microscopy group). Furthermore, fewer culture-positive patients in the Xpert MTB/RIF group who had a positive MTB/RIF test result did not receive treatment (8% vs 15%), halving drop-out, and by day 56 fewer patients in the Xpert MTB/RIF group without a positive test had been given treatment on www.thelancet.com Vol 383 February 1, 2014
the basis of empirical evidence (17% vs 26%). However, surprisingly, the proportion of patients given treatment was not higher in the Xpert MTB/RIF group: 43% of people with suspected tuberculosis were given treatment by day 56 in the Xpert MTB/RIF group compared with 42% in the microscopy group. Yet significantly more culture-positive patients in the Xpert MTB/RIF group were given treatment by day 56 (91% vs 84%)—so a higher number of patients with true positive tests were treated— and more culture-positive patients in the Xpert MTB/RIF group were diagnosed on the day of presentation (81% vs 43%). Importantly, despite a longer delay to treatment in the microscopy group, there was no effect on the primary outcome, which was difference in morbidity according to the TBscore6 and Karnofsky performance score in culturepositive patients who had begun treatment; 2 months and 6 months after randomisation the scores were the same in the two groups. Likewise, mortality was 8% in both groups of the study; the study was not powered to detect mortality differences. These findings will be of major interest to policy makers, because the costs of rolling out Xpert MTB/ RIF are very high. Cost-effectiveness studies in low incidence areas have been promising for Xpert MTB/ RIF,7 and mathematical modelling has suggested that implementation of Xpert MTB/RIF could substantially reduce tuberculosis morbidity and mortality in southern Africa.8 But considering the findings of Theron and colleagues,5 the substantial financial burden of Xpert MTB/RIF rollout needs to be reassessed to see if it provides value for the cost. Placing very expensive equipment in health-care facilities in rural Africa that might have no electricity and poorly trained, underpaid staff is going to be a difficult undertaking. Are the incremental gains in same-day diagnosis and treatment initiation, as well as reduced loss to follow-up, enough to justify this investment? Theron and colleagues5 report from the context of a well managed tuberculosis programme in which sputum smear fluorescence microscopy and good quality radiography were available, and from a highHIV-prevalence setting where one in four people with suspected tuberculosis were culture-positive and nearly every second patient was given treatment according to WHO criteria. In many other high-burden areas the number needed to test would be much higher, and in some studies from areas with high HIV prevalence only www.thelancet.com Vol 383 February 1, 2014
Stephane De Sakutin/AFP/Getty Images
Comment
one in six people with suspected tuberculosis ended up receiving tuberculosis treatment.9,10 In Guinea Bissau, an algorithm based on WHO definitions and TBscore has been used, and only one in ten people received treatment according to WHO guidelines (Rudolf F, Bandim Health Project, personal communication). At a cassette cost of US$10 (reduced price for low-resource settings), testing large numbers of people with suspected tuberculosis will put substantial pressure on already resource-limited tuberculosis programmes in which the drugs for treatment might not always be available. Hence, the provocative question raised by this study is whether tuberculosis elimination is most likely to be advanced by distributing GeneXpert machines to all peripheral health facilities in the world, or by investing the same amount in ensuring that health facilities have the set-up available in this study—ie, well trained and paid staff, electricity, and reagents. I would support the latter, because that approach is likely to promote the necessary shift towards building health care in general—what has been called the diagonal approach to global health11—instead of the vertical approach that large-scale implementation of Xpert MTB/RIF entails. Xpert MTB/RIF is highly appreciated, but, considering the knowledge now available, the benefit of large rollout might be highly context specific. An important use of Xpert MTB/RIF might be mainly in regional facilities in areas where multidrug-resistant tuberculosis is highly prevalent, rather than for large-scale diagnosis of drug-susceptible tuberculosis. Xpert MTB/RIF could have a role in the clinic in better-resourced countries 389
Comment
such as South Africa, with high prevalence of multidrugresistant tuberculosis and drop-out. Until less costly and user-friendly follow-on technologies become available, Xpert MTB/RIF might have a role in tuberculosis hotspots in such settings. Yet caution is needed, because many patients are wrongly identified as having rifampicin-resistant tuberculosis, and might risk being sent to isolated facilities far from home for unnecessary multidrugresistant tuberculosis treatment.12 As the investigators state, the projected epidemiological effect of Xpert MTB/RIF might be overestimated, so this fascinating and promising new tool is unlikely to be the magic bullet that paves the way towards tuberculosis elimination. To reach that goal, better methods for case identification are needed, but the overwhelming number of latently infected individuals should also be targeted.
2
3
4
5
6
7
8
9
Christian Wejse GloHAU, Center for Global Health, Department of Public Health, Aarhus University, 8000 Aarhus C, Denmark; Bandim Health Project, INDEPTH Network, Guinea Bissau; and Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark [email protected] I declare that I have no conflicts of interest. 1
10
11 12
WHO. Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system: policy statement. Geneva: World Health Organization, 2011. Boehme CC, Nicol MP, Nabeta P, et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet 2011; 377: 1495–505. Trébucq A, Enarson DA, Harries AD, et al. Xpert MTB/RIF for national tuberculosis programmes in low-income countries: when, where and how? Int J Tuberc Lung Dis 2011; 15: 1567–72. Theron G, Zijenah L, Chanda D, et al, for the TB-NEAT team. 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 2013; published online Oct 28. http://dx.doi.org/ 10.1016/S0140-6736(13)62073-5. Rudolf 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: 256–64. Choi HW, Miele K, Dowdy D, Shah M. Cost-effectiveness of Xpert MTB/RIF for diagnosing pulmonary tuberculosis in the United States. Int J Tuberc Lung Dis 2013; 17: 1328–35. Menzies NA, Cohen T, Lin HH, et al. Population health impact and cost-effectiveness of tuberculosis diagnosis with Xpert MTB/RIF: a dynamic simulation and economic evaluation. PLoS Med 2012; 9: e1001347. Hanrahan CF, Selibas K, Deery CB, et al. Time to treatment and patient outcomes among TB suspects screened by a single point-of-care Xpert MTB/RIF at a primary care clinic in Johannesburg, South Africa. PLoS One 2013; 8: e65421. Botha E, den Boon S, Lawrence KA, et al. From suspect to patient: tuberculosis diagnosis and treatment initiation in health facilities in South Africa. Int J Tuberc Lung Dis 2008; 12: 936–41. Kim JY, Farmer P, Porter ME. Redefining global health-care delivery. Lancet 2013; 382: 1060–69. Steingart KR, Sohn H, Schiller I, et al. Xpert MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 2013; 1: CD009593.
Lawn SD, Mwaba P, Bates M, et al. Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect Dis 2013; 13: 349–61.
Science Photo Library
Stem-cell transplantation for chronic granulomatous disease
Published Online October 23, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62144-3 See Articles page 436
390
Every effort to improve access to and outcomes of haemopoietic stem-cell transplantation (HSCT)— the only curative option—for patients with chronic granulomatous disease is commendable. This disease is a rare but devastating primary immunodeficiency disorder that leads to infections, progressive organ problems, immune-mediated cellular destruction, poor quality of life, and early death.1 HSCT usually involves high (myeloablative) doses of conditioning chemotherapy to destroy the host haemopoietic system and replace defective immune machinery with normal donorderived cells from bone marrow, peripheral blood stem cells (PBSC), or umbilical cord blood. Although HSCT is conceptually elegant, the process itself is fraught with limitations of donor availability, risks associated with conditioning chemotherapy, and complications arising from interactions between the host and donor immune
systems.2 Not every patient is able to find a suitable donor or withstand high doses of chemotherapy because of pre-existing organ and infection problems, and not every patient will survive despite engraftment of donor cells.3 Reports4,5 of excellent survival after myeloablative HSCT for chronic granulomatous disease have increased acceptance of HSCT among doctors, and generated greater interest in this therapeutic option in patients and their families. However, in addition to the risks of myeloablative conditioning, survivors of myeloablative transplants are prone to long-term problems such as infertility.6 In The Lancet, Tayfun Güngör and colleagues7 present the results of an international prospective study of reducedintensity conditioning and HSCT in a large cohort of patients with chronic granulomatous disease (n=56) who were transplanted between June, 2003, and December, www.thelancet.com Vol 383 February 1, 2014
the investigators, which might have resulted in selective reporting bias: stent deformation is easier to detect with platinum stents because of their higher radiopacity. In support of this possibility, data from both industry-initiated7 and investigator-initiated8 studies that incorporated systematic quantitative analysis did not confirm higher frequencies of deformation with platinum-chromium-based stents. Finally, a broader issue arises in relation to the conduct of contemporary trials with drug-eluting stents. Obviously, any well-conducted comparison of approved drug-eluting stents, such as DUTCH PEERS, eases the stent selection process in everyday practice. However, the past decade has seen substantial development and testing of new devices (table), the cost of which is ultimately borne by society in terms of economic burden and the opportunity costs of alternative research foregone. The fact that most such trials have a non-inferiority design gives cause for reflection. From an industry perspective, although non-inferiority trials might be of interest in terms of competition for market share, the study of me-too devices in trials with a non-inferiority design does not best serve iterative advancement. Non-inferiority trials are best justified for assessing a new device against standard of care on the premise that it has some other potential advantage—eg, a new class of drug, improved or absent polymer, or a bioresorbable backbone. Otherwise, a model based on superiority testing should attract more resources so that findings can provide a rationale for
adoption of new devices. As a community, perhaps it is time that we reassessed the focus of clinical trials of drug-eluting stents to promote progress.
*Robert A Byrne, Adnan Kastrati Deutsches Herzzentrum, Technische Universität, Munich 80636, Germany; and DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany [email protected] AK has received speaker’s fees from Abbott Laboratories, Biosensors International, and Biotronik. RAB declares that he has no conflicts of interest. 1
2 3
4
5 6
7
8
Byrne RA, Sarafoff N, Kastrati A, Schomig A. Drug-eluting stents in percutaneous coronary intervention: a benefit-risk assessment. Drug Saf 2009; 32: 749–70. Stefanini GG, Holmes DR Jr. Drug-eluting coronary-artery stents. N Engl J Med 2013; 368: 254–65. von Birgelen C, Sen H, Lam MK, et al. Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single-blind, multicentre, non-inferiority trial. Lancet 2013; published online Oct 31. http://dx.doi.org/10.1016/S0140-6736(13)62037-1. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c332. Joner M, Byrne RA. The importance of preclinical research in contemporary interventional cardiology. EuroIntervention 2010; 6: 19–23. Hanratty CG, Walsh SJ. Longitudinal compression: a “new” complication with modern coronary stent platforms—time to think beyond deliverability? EuroIntervention 2011; 7: 872–77. Kereiakes DJ, Popma JJ, Cannon LA, et al. Longitudinal stent deformation: quantitative coronary angiographic analysis from the PERSEUS and PLATINUM randomised controlled clinical trials. EuroIntervention 2012; 8: 187–95. Kim H. Randomized comparison of PtCr-EES versus CoCr-ZES in all-comers receiving PCI: the HOST-ASSURE randomized trial. American College of Cardiology Scientific Sessions; San Francisco, CA, USA; March 9–11, 2013. Session 2667.
Point-of-care diagnostics for tuberculosis elimination? Published Online October 28, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62003-6 See Articles page 424
388
In recent years the development of diagnostics for tuberculosis has progressed rapidly.1 The major advance has been the GeneXpert MTB/RIF automated molecular assay for rapid diagnosis of tuberculosis and detection of rifampicin resistance, which has been endorsed by WHO.2 This has led to new optimism, particularly with respect to the use of this assay in low-resource settings with high tuberculosis burden, where diagnostic facilities are often limited to sputum smear microscopy and chest radiograph. Feasibility tests have shown promising results,3 but concerns have been raised that the assay might not be appropriate for use at scale in peripheral health-care facilities.4 So studies that assess the clinical effect of this assay have been greatly needed. In The Lancet, Grant Theron and colleagues5 report the outcome of a randomised trial comparing point-
of-care Xpert MTB/RIF with smear microscopy in the management of tuberculosis. This study assesses the new molecular tuberculosis diagnostics from a public health perspective by measuring the clinical effect in several real-life situations, comparing nurse-managed Xpert MTB/RIF with a standard set-up of diagnostics with smear microscopy and radiography in well managed settings in four countries. The findings are not unexpected: Xpert MTB/RIF improved same-day treatment initiation (23% in the Xpert group vs 15% in the microscopy group). Furthermore, fewer culture-positive patients in the Xpert MTB/RIF group who had a positive MTB/RIF test result did not receive treatment (8% vs 15%), halving drop-out, and by day 56 fewer patients in the Xpert MTB/RIF group without a positive test had been given treatment on www.thelancet.com Vol 383 February 1, 2014
the basis of empirical evidence (17% vs 26%). However, surprisingly, the proportion of patients given treatment was not higher in the Xpert MTB/RIF group: 43% of people with suspected tuberculosis were given treatment by day 56 in the Xpert MTB/RIF group compared with 42% in the microscopy group. Yet significantly more culture-positive patients in the Xpert MTB/RIF group were given treatment by day 56 (91% vs 84%)—so a higher number of patients with true positive tests were treated— and more culture-positive patients in the Xpert MTB/RIF group were diagnosed on the day of presentation (81% vs 43%). Importantly, despite a longer delay to treatment in the microscopy group, there was no effect on the primary outcome, which was difference in morbidity according to the TBscore6 and Karnofsky performance score in culturepositive patients who had begun treatment; 2 months and 6 months after randomisation the scores were the same in the two groups. Likewise, mortality was 8% in both groups of the study; the study was not powered to detect mortality differences. These findings will be of major interest to policy makers, because the costs of rolling out Xpert MTB/ RIF are very high. Cost-effectiveness studies in low incidence areas have been promising for Xpert MTB/ RIF,7 and mathematical modelling has suggested that implementation of Xpert MTB/RIF could substantially reduce tuberculosis morbidity and mortality in southern Africa.8 But considering the findings of Theron and colleagues,5 the substantial financial burden of Xpert MTB/RIF rollout needs to be reassessed to see if it provides value for the cost. Placing very expensive equipment in health-care facilities in rural Africa that might have no electricity and poorly trained, underpaid staff is going to be a difficult undertaking. Are the incremental gains in same-day diagnosis and treatment initiation, as well as reduced loss to follow-up, enough to justify this investment? Theron and colleagues5 report from the context of a well managed tuberculosis programme in which sputum smear fluorescence microscopy and good quality radiography were available, and from a highHIV-prevalence setting where one in four people with suspected tuberculosis were culture-positive and nearly every second patient was given treatment according to WHO criteria. In many other high-burden areas the number needed to test would be much higher, and in some studies from areas with high HIV prevalence only www.thelancet.com Vol 383 February 1, 2014
Stephane De Sakutin/AFP/Getty Images
Comment
one in six people with suspected tuberculosis ended up receiving tuberculosis treatment.9,10 In Guinea Bissau, an algorithm based on WHO definitions and TBscore has been used, and only one in ten people received treatment according to WHO guidelines (Rudolf F, Bandim Health Project, personal communication). At a cassette cost of US$10 (reduced price for low-resource settings), testing large numbers of people with suspected tuberculosis will put substantial pressure on already resource-limited tuberculosis programmes in which the drugs for treatment might not always be available. Hence, the provocative question raised by this study is whether tuberculosis elimination is most likely to be advanced by distributing GeneXpert machines to all peripheral health facilities in the world, or by investing the same amount in ensuring that health facilities have the set-up available in this study—ie, well trained and paid staff, electricity, and reagents. I would support the latter, because that approach is likely to promote the necessary shift towards building health care in general—what has been called the diagonal approach to global health11—instead of the vertical approach that large-scale implementation of Xpert MTB/RIF entails. Xpert MTB/RIF is highly appreciated, but, considering the knowledge now available, the benefit of large rollout might be highly context specific. An important use of Xpert MTB/RIF might be mainly in regional facilities in areas where multidrug-resistant tuberculosis is highly prevalent, rather than for large-scale diagnosis of drug-susceptible tuberculosis. Xpert MTB/RIF could have a role in the clinic in better-resourced countries 389
Comment
such as South Africa, with high prevalence of multidrugresistant tuberculosis and drop-out. Until less costly and user-friendly follow-on technologies become available, Xpert MTB/RIF might have a role in tuberculosis hotspots in such settings. Yet caution is needed, because many patients are wrongly identified as having rifampicin-resistant tuberculosis, and might risk being sent to isolated facilities far from home for unnecessary multidrugresistant tuberculosis treatment.12 As the investigators state, the projected epidemiological effect of Xpert MTB/RIF might be overestimated, so this fascinating and promising new tool is unlikely to be the magic bullet that paves the way towards tuberculosis elimination. To reach that goal, better methods for case identification are needed, but the overwhelming number of latently infected individuals should also be targeted.
2
3
4
5
6
7
8
9
Christian Wejse GloHAU, Center for Global Health, Department of Public Health, Aarhus University, 8000 Aarhus C, Denmark; Bandim Health Project, INDEPTH Network, Guinea Bissau; and Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark [email protected] I declare that I have no conflicts of interest. 1
10
11 12
WHO. Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system: policy statement. Geneva: World Health Organization, 2011. Boehme CC, Nicol MP, Nabeta P, et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet 2011; 377: 1495–505. Trébucq A, Enarson DA, Harries AD, et al. Xpert MTB/RIF for national tuberculosis programmes in low-income countries: when, where and how? Int J Tuberc Lung Dis 2011; 15: 1567–72. Theron G, Zijenah L, Chanda D, et al, for the TB-NEAT team. 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 2013; published online Oct 28. http://dx.doi.org/ 10.1016/S0140-6736(13)62073-5. Rudolf 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: 256–64. Choi HW, Miele K, Dowdy D, Shah M. Cost-effectiveness of Xpert MTB/RIF for diagnosing pulmonary tuberculosis in the United States. Int J Tuberc Lung Dis 2013; 17: 1328–35. Menzies NA, Cohen T, Lin HH, et al. Population health impact and cost-effectiveness of tuberculosis diagnosis with Xpert MTB/RIF: a dynamic simulation and economic evaluation. PLoS Med 2012; 9: e1001347. Hanrahan CF, Selibas K, Deery CB, et al. Time to treatment and patient outcomes among TB suspects screened by a single point-of-care Xpert MTB/RIF at a primary care clinic in Johannesburg, South Africa. PLoS One 2013; 8: e65421. Botha E, den Boon S, Lawrence KA, et al. From suspect to patient: tuberculosis diagnosis and treatment initiation in health facilities in South Africa. Int J Tuberc Lung Dis 2008; 12: 936–41. Kim JY, Farmer P, Porter ME. Redefining global health-care delivery. Lancet 2013; 382: 1060–69. Steingart KR, Sohn H, Schiller I, et al. Xpert MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 2013; 1: CD009593.
Lawn SD, Mwaba P, Bates M, et al. Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect Dis 2013; 13: 349–61.
Science Photo Library
Stem-cell transplantation for chronic granulomatous disease
Published Online October 23, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62144-3 See Articles page 436
390
Every effort to improve access to and outcomes of haemopoietic stem-cell transplantation (HSCT)— the only curative option—for patients with chronic granulomatous disease is commendable. This disease is a rare but devastating primary immunodeficiency disorder that leads to infections, progressive organ problems, immune-mediated cellular destruction, poor quality of life, and early death.1 HSCT usually involves high (myeloablative) doses of conditioning chemotherapy to destroy the host haemopoietic system and replace defective immune machinery with normal donorderived cells from bone marrow, peripheral blood stem cells (PBSC), or umbilical cord blood. Although HSCT is conceptually elegant, the process itself is fraught with limitations of donor availability, risks associated with conditioning chemotherapy, and complications arising from interactions between the host and donor immune
systems.2 Not every patient is able to find a suitable donor or withstand high doses of chemotherapy because of pre-existing organ and infection problems, and not every patient will survive despite engraftment of donor cells.3 Reports4,5 of excellent survival after myeloablative HSCT for chronic granulomatous disease have increased acceptance of HSCT among doctors, and generated greater interest in this therapeutic option in patients and their families. However, in addition to the risks of myeloablative conditioning, survivors of myeloablative transplants are prone to long-term problems such as infertility.6 In The Lancet, Tayfun Güngör and colleagues7 present the results of an international prospective study of reducedintensity conditioning and HSCT in a large cohort of patients with chronic granulomatous disease (n=56) who were transplanted between June, 2003, and December, www.thelancet.com Vol 383 February 1, 2014
