Comment
11
12
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239–46. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368: 2385–94.
13
14
Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 2009; 373: 1097–104. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol 2013; 31: 3320–26.
Giacomo Pirozzi/Panos
Quantifying the tuberculosis disease burden in children
Published Online March 24, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60489-X See Articles page 1572 See Viewpoint page 1605
1530
Awareness is growing that tuberculosis is a major cause of disease and death in children from areas endemic with tuberculosis, but its contribution is poorly quantified because of diagnostic difficulties in resource-limited settings.1 Globally, in 2011, an estimated 1·3 million deaths in children were attributed to pneumonia.2 Most of these deaths occurred in areas endemic with tuberculosis, where the actual cause of death was rarely verified. Autopsy studies identified tuberculosis in 11% of children infected with HIV, and 8% of children not infected with HIV who died from respiratory disease in five African countries.3 Tuberculosis might also be an underlying cause of death in children dying from meningitis, sepsis, HIV/AIDS, or severe malnutrition, and its relative contribution to child morbidity and mortality is likely to increase if widespread rollout of Haemophilus influenza type B, pneumococcal, and rotavirus vaccines reduces the effect of these diseases.4 An emerging threat is the rise of drug-resistant tuberculosis, which poses a major challenge to global tuberculosis control efforts.5 WHO estimates that 450 000 (range 300 000–600 000) cases of multidrugresistant tuberculosis (resistant to isoniazid and rifampicin) occurred in 2012, with less than 20% (77 000) of cases receiving appropriate treatment.6 Failure to treat infectious multidrug-resistant tuberculosis cases facilitates ongoing transmission of drug-resistant strains and exposes vulnerable young children to infection.7 Crude projections estimate that roughly 10% of the global tuberculosis disease burden occurs in children,8 suggesting that around 45 000 paediatric multidrug-resistant tuberculosis cases occurred in 2012. However, such estimates are difficult to verify and fail to account for variability in the paediatric tuberculosis burden, which depends on the level of epidemic control achieved, the use of preventive therapy, and the population demographics in particular
areas.9 In the absence of reliably reported data, accurate assessment of the paediatric disease burden requires evidence-based extrapolation from existing data and consideration of regional variation. A study by Helen Jenkins and colleagues10 in The Lancet creatively combines three elements to estimate the number of incident tuberculosis and multidrug-resistant tuberculosis cases in children by WHO region. First, the authors did a systematic literature review to describe the relation between multidrug-resistant tuberculosis in children and treatment-naive adults, excluding studies in which children with drug-resistant tuberculosis were more likely to be included, such as outbreak and contact investigations. The proportions of multidrugresistant tuberculosis cases were similar (estimated slope of regression line 1·0691) in treatment-naive adults and in children with tuberculosis, showing that both groups represent local transmission of multidrug-resistant tuberculosis, consistent with previous observations.11 Country-level estimates of multidrug-resistant tuberculosis in treatment-naive adults then guided estimates of the proportion of child tuberculosis cases with multidrug-resistant tuberculosis, providing a neat solution to the absence of reliable data for multidrug-resistant tuberculosis in children. Second, the authors adjusted sputum smear-positive cases reported to WHO by a factor that accounts for the expected age-specific proportions of sputum smear-positive disease. Because some countries failed to report age-disaggregated data to WHO, Jenkins and colleagues fitted a logistic regression model with the estimated proportion of paediatric tuberculosis cases as the dependent variable and the log10 of the estimated tuberculosis incidence as the explanatory variable. The estimated percentage of tuberculosis cases in children aged younger than 15 years varied from 8% to 12%, www.thelancet.com Vol 383 May 3, 2014
Comment
depending on the adult tuberculosis incidence rate. This value correlates well with previous global estimates, but seems conservative in high incidence settings where paediatric proportions in excess of 30% of new tuberculosis cases have been reported.9 However, the proportion of children among new tuberculosis cases provides an overestimate in settings where many adult cases present with a second tuberculosis episode. The fact that the authors included both new and previously treated cases in the denominator provides more conservative, but likely more realistic, areaspecific estimates. Last, to estimate the incidence of multidrugresistant tuberculosis in children, the authors multiplied country-specific multidrug-resistant tuberculosis proportions (deduced from multidrugresistant tuberculosis rates in treatment-naive adults) and incident paediatric tuberculosis case numbers (deduced from adult incidence estimates) to calculate regional and global multidrug-resistant tuberculosis incidence rates. Using these approaches, they estimate that 999 792 (95% CI 937 877–1 055 414) children developed tuberculosis in 2010, of whom 31 948 (25 594–38 663) had multidrug-resistant tuberculosis. This value is nearly double the 530 000 (range 510 000–550 000) paediatric cases estimated by WHO to have occurred in 2012.6 Jenkins and colleagues’ study is the most rigorous effort to date to provide contextualised estimates of both tuberculosis and multidrug-resistant tuberculosis incidence in children, and is likely to provide a benchmark for future studies in the area. As the authors point out, it is sobering to consider that all the cases ever reported in the literature represent only 2% of new multidrug-resistant tuberculosis cases estimated to occur each year.10 Given that treatment outcomes for children with multidrugresistant tuberculosis are excellent (clinical cure rates in excess of 80%),12 every effort should be made to reduce the massive case-detection gap and address the vast unmet need for diagnosis and treatment. Awaiting better diagnostic instruments in children, a
www.thelancet.com Vol 383 May 3, 2014
key strategy to consider is the provision of appropriate preventive therapy to vulnerable young children in close contact with an infectious multidrug-resistant tuberculosis case.7,13 Evidence from a pragmatic cohort study in South Africa showed clear benefit with this approach,14 but more rigorous evidence is required to guide policy change. Ben J Marais Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia; and Clinical School, The Children’s Hospital at Westmead, Sydney Medical School, University of Sydney, Sydney, 2145 NSW, Australia [email protected] I declare that I have no competing interests. 1 2
3
4
5
6
7
8 9 10
11 12
13
14
Marais BJ, Graham SM, Maeurer M, Zumla A. Progress and challenges in childhood tuberculosis. Lancet Infect Dis 2013; 13: 287–89. Liu L, Johnson HL, Cousens S, et al. Global, regional and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 2012; 379: 2151–61. Bates M, Mudenda V, Mwaba P, Zumla A. Deaths due to respiratory tract infections in Africa: a review of autopsy studies. Curr Opin Pulm Med 2013; 19: 229–37. Graham SM, Sismanidis C, Menzies HJ, Marais BJ, Detjen AK, Black RE. Importance of tuberculosis control to address child survival. Lancet 2014; published online March 24. http://dx.doi.org/10.1016/S01406736(14)60420-7. Abubakar I, Ford N, Cox H, et al. The rising tide of drug-resistant tuberculosis—time for visionary leadership. Lancet Infect Dis 2013; 13: 529–39. WHO. Global tuberculosis report 2013. Geneva: World Health Organization, 2013. http://www.who.int/iris/bitstream/10665/91355/1/ 9789241564656_eng.pdf?ua=1 (accessed March 12, 2014). Shah NS, Yuen CM, Heo M, Tolman AW, Becerra MC. Yield of contact investigations in households of patients with drug-resistant tuberculosis: systematic review and meta-analysis. Clin Infect Dis 2014; 58: 381–91. Perez-Velez CM, Marais BJ. Tuberculosis in children. N Engl J Med 2012; 367: 348–61. Donald PR. Childhood tuberculosis: out of control? Curr Opin Pulm Med 2002; 8: 178–82. Jenkins HE, Tolman AW, Yuen CM, et al. Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates. Lancet 2014; published online March 24. http://dx.doi.org/10.1016/S01406736(14)60195-1. Zignol M, Sismanidis C, Falzon D, et al. Multidrug-resistant tuberculosis in children: evidence from global surveillance. Eur Respir J 2013; 42: 701–07. Ettehad D, Schaaf HS, Seddon J, et al. Treatment outcomes for children with multi-drug resistant tuberculosis: a systematic review and metaanalysis. Lancet Infect Dis 2012; 12: 449–56. Schaaf HS, Marais BJ. Management of multidrug-resistant tuberculosis in children: a survival guide for paediatricians. Paediatr Respir Rev 2011; 12: 31–38. Seddon JA, Hesseling AC, Finlayson H, et al. Preventive therapy for child contacts of multidrug-resistant tuberculosis: a prospective cohort study. Clin Infect Dis 2013; 57: 1676–84.
1531
11
12
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239–46. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368: 2385–94.
13
14
Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 2009; 373: 1097–104. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol 2013; 31: 3320–26.
Giacomo Pirozzi/Panos
Quantifying the tuberculosis disease burden in children
Published Online March 24, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60489-X See Articles page 1572 See Viewpoint page 1605
1530
Awareness is growing that tuberculosis is a major cause of disease and death in children from areas endemic with tuberculosis, but its contribution is poorly quantified because of diagnostic difficulties in resource-limited settings.1 Globally, in 2011, an estimated 1·3 million deaths in children were attributed to pneumonia.2 Most of these deaths occurred in areas endemic with tuberculosis, where the actual cause of death was rarely verified. Autopsy studies identified tuberculosis in 11% of children infected with HIV, and 8% of children not infected with HIV who died from respiratory disease in five African countries.3 Tuberculosis might also be an underlying cause of death in children dying from meningitis, sepsis, HIV/AIDS, or severe malnutrition, and its relative contribution to child morbidity and mortality is likely to increase if widespread rollout of Haemophilus influenza type B, pneumococcal, and rotavirus vaccines reduces the effect of these diseases.4 An emerging threat is the rise of drug-resistant tuberculosis, which poses a major challenge to global tuberculosis control efforts.5 WHO estimates that 450 000 (range 300 000–600 000) cases of multidrugresistant tuberculosis (resistant to isoniazid and rifampicin) occurred in 2012, with less than 20% (77 000) of cases receiving appropriate treatment.6 Failure to treat infectious multidrug-resistant tuberculosis cases facilitates ongoing transmission of drug-resistant strains and exposes vulnerable young children to infection.7 Crude projections estimate that roughly 10% of the global tuberculosis disease burden occurs in children,8 suggesting that around 45 000 paediatric multidrug-resistant tuberculosis cases occurred in 2012. However, such estimates are difficult to verify and fail to account for variability in the paediatric tuberculosis burden, which depends on the level of epidemic control achieved, the use of preventive therapy, and the population demographics in particular
areas.9 In the absence of reliably reported data, accurate assessment of the paediatric disease burden requires evidence-based extrapolation from existing data and consideration of regional variation. A study by Helen Jenkins and colleagues10 in The Lancet creatively combines three elements to estimate the number of incident tuberculosis and multidrug-resistant tuberculosis cases in children by WHO region. First, the authors did a systematic literature review to describe the relation between multidrug-resistant tuberculosis in children and treatment-naive adults, excluding studies in which children with drug-resistant tuberculosis were more likely to be included, such as outbreak and contact investigations. The proportions of multidrugresistant tuberculosis cases were similar (estimated slope of regression line 1·0691) in treatment-naive adults and in children with tuberculosis, showing that both groups represent local transmission of multidrug-resistant tuberculosis, consistent with previous observations.11 Country-level estimates of multidrug-resistant tuberculosis in treatment-naive adults then guided estimates of the proportion of child tuberculosis cases with multidrug-resistant tuberculosis, providing a neat solution to the absence of reliable data for multidrug-resistant tuberculosis in children. Second, the authors adjusted sputum smear-positive cases reported to WHO by a factor that accounts for the expected age-specific proportions of sputum smear-positive disease. Because some countries failed to report age-disaggregated data to WHO, Jenkins and colleagues fitted a logistic regression model with the estimated proportion of paediatric tuberculosis cases as the dependent variable and the log10 of the estimated tuberculosis incidence as the explanatory variable. The estimated percentage of tuberculosis cases in children aged younger than 15 years varied from 8% to 12%, www.thelancet.com Vol 383 May 3, 2014
Comment
depending on the adult tuberculosis incidence rate. This value correlates well with previous global estimates, but seems conservative in high incidence settings where paediatric proportions in excess of 30% of new tuberculosis cases have been reported.9 However, the proportion of children among new tuberculosis cases provides an overestimate in settings where many adult cases present with a second tuberculosis episode. The fact that the authors included both new and previously treated cases in the denominator provides more conservative, but likely more realistic, areaspecific estimates. Last, to estimate the incidence of multidrugresistant tuberculosis in children, the authors multiplied country-specific multidrug-resistant tuberculosis proportions (deduced from multidrugresistant tuberculosis rates in treatment-naive adults) and incident paediatric tuberculosis case numbers (deduced from adult incidence estimates) to calculate regional and global multidrug-resistant tuberculosis incidence rates. Using these approaches, they estimate that 999 792 (95% CI 937 877–1 055 414) children developed tuberculosis in 2010, of whom 31 948 (25 594–38 663) had multidrug-resistant tuberculosis. This value is nearly double the 530 000 (range 510 000–550 000) paediatric cases estimated by WHO to have occurred in 2012.6 Jenkins and colleagues’ study is the most rigorous effort to date to provide contextualised estimates of both tuberculosis and multidrug-resistant tuberculosis incidence in children, and is likely to provide a benchmark for future studies in the area. As the authors point out, it is sobering to consider that all the cases ever reported in the literature represent only 2% of new multidrug-resistant tuberculosis cases estimated to occur each year.10 Given that treatment outcomes for children with multidrugresistant tuberculosis are excellent (clinical cure rates in excess of 80%),12 every effort should be made to reduce the massive case-detection gap and address the vast unmet need for diagnosis and treatment. Awaiting better diagnostic instruments in children, a
www.thelancet.com Vol 383 May 3, 2014
key strategy to consider is the provision of appropriate preventive therapy to vulnerable young children in close contact with an infectious multidrug-resistant tuberculosis case.7,13 Evidence from a pragmatic cohort study in South Africa showed clear benefit with this approach,14 but more rigorous evidence is required to guide policy change. Ben J Marais Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia; and Clinical School, The Children’s Hospital at Westmead, Sydney Medical School, University of Sydney, Sydney, 2145 NSW, Australia [email protected] I declare that I have no competing interests. 1 2
3
4
5
6
7
8 9 10
11 12
13
14
Marais BJ, Graham SM, Maeurer M, Zumla A. Progress and challenges in childhood tuberculosis. Lancet Infect Dis 2013; 13: 287–89. Liu L, Johnson HL, Cousens S, et al. Global, regional and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 2012; 379: 2151–61. Bates M, Mudenda V, Mwaba P, Zumla A. Deaths due to respiratory tract infections in Africa: a review of autopsy studies. Curr Opin Pulm Med 2013; 19: 229–37. Graham SM, Sismanidis C, Menzies HJ, Marais BJ, Detjen AK, Black RE. Importance of tuberculosis control to address child survival. Lancet 2014; published online March 24. http://dx.doi.org/10.1016/S01406736(14)60420-7. Abubakar I, Ford N, Cox H, et al. The rising tide of drug-resistant tuberculosis—time for visionary leadership. Lancet Infect Dis 2013; 13: 529–39. WHO. Global tuberculosis report 2013. Geneva: World Health Organization, 2013. http://www.who.int/iris/bitstream/10665/91355/1/ 9789241564656_eng.pdf?ua=1 (accessed March 12, 2014). Shah NS, Yuen CM, Heo M, Tolman AW, Becerra MC. Yield of contact investigations in households of patients with drug-resistant tuberculosis: systematic review and meta-analysis. Clin Infect Dis 2014; 58: 381–91. Perez-Velez CM, Marais BJ. Tuberculosis in children. N Engl J Med 2012; 367: 348–61. Donald PR. Childhood tuberculosis: out of control? Curr Opin Pulm Med 2002; 8: 178–82. Jenkins HE, Tolman AW, Yuen CM, et al. Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates. Lancet 2014; published online March 24. http://dx.doi.org/10.1016/S01406736(14)60195-1. Zignol M, Sismanidis C, Falzon D, et al. Multidrug-resistant tuberculosis in children: evidence from global surveillance. Eur Respir J 2013; 42: 701–07. Ettehad D, Schaaf HS, Seddon J, et al. Treatment outcomes for children with multi-drug resistant tuberculosis: a systematic review and metaanalysis. Lancet Infect Dis 2012; 12: 449–56. Schaaf HS, Marais BJ. Management of multidrug-resistant tuberculosis in children: a survival guide for paediatricians. Paediatr Respir Rev 2011; 12: 31–38. Seddon JA, Hesseling AC, Finlayson H, et al. Preventive therapy for child contacts of multidrug-resistant tuberculosis: a prospective cohort study. Clin Infect Dis 2013; 57: 1676–84.
1531
