Comment
forks and the separation of transmission for subsequent sources in a chain of transmission in time. Unfortunately, the current WGS is also not a perfect method.
4 5
6
Dick van Soolingen National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, Netherlands; and Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands [email protected]
7
8
I declare that I have no competing interests. Copyright © van Soolingen. Open Access article distributed under the terms of CC BY. 1 2
3
Borgdorff MW, van Soolingen D. The re-emergence of tuberculosis: what have we learnt from molecular epidemiology? Clin Microbiol Infect 2013; 19: 889–901. de Vries G, Baars HW, Sebek MM, van Hest NA, Richardus JH. Transmission classification model to determine place and time of infection of tuberculosis cases in an urban area. J Clin Microbiol 2008; 46: 3924–30. de Boer AS, Borgdorff MW, de Haas PE, Nagelkerke NJ, van Embden JD, van Soolingen D. Analysis of rate of change of IS6110 RFLP patterns of Mycobacterium tuberculosis based on serial patient isolates. J Infect Dis 1999; 180: 1238–44.
9
10
Gardy JL, Johnston JC, Ho Sui SJ, et al. Whole-genome sequencing and socialnetwork analysis of a tuberculosis outbreak. N Engl J Med 2011; 364: 730–39. Schurch AC, Kremer K, Daviena O, et al. High-resolution typing by integration of genome sequencing data in a large tuberculosis cluster. J Clin Microbiol 2010; 48: 3403–06. Walker TM, Lalor MK, Broda A, et al. Assessment of Mycobacterium tuberculosis transmission in Oxfordshire, UK, 2007–12, with whole pathogen genome sequences: an observational study. Lancet Respir Med 2014; published online March 4. http://dx.doi.org/10.1016/S2213-2600(14)70027-X. Sloot R, Borgdorff MW, de Beer JL, van Ingen J, Supply P, van Soolingen D. Clustering of tuberculosis cases based on variable-number tandem-repeat typing in relation to the population structure of Mycobacterium tuberculosis in the Netherlands. J Clin Microbiol 2013; 51: 2427–31. Bryant JM, Schurch AC, van Deutekom H, et al. Inferring patient to patient transmission of Mycobacterium tuberculosis from whole genome sequencing data. BMC Infect Dis 2013; 13: 110. Walker TM, Ip CL, Harrell RH, et al. Whole-genome sequencing to delineate Mycobacterium tuberculosis outbreaks: a retrospective observational study. Lancet Infectious Dis 2013; 13: 137–46. Schurch AC, Kremer K, Kiers A, et al. The tempo and mode of molecular evolution of Mycobacterium tuberculosis at patient-to-patient scale. Infect Genet Evol 2010; 10: 108–14.
Pixologicstudio/Science Photo Library
Should we pursue pulmonary vasodilation in patients with COPD?
Published Online March 5, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70036-0 See Articles page 293
252
Pulmonary hypertension is a pathophysiological disorder defined as an increase in pulmonary arterial pressure, as assessed by right heart catheterisation (mean pressure ≥25 mm Hg at rest). Pulmonary hypertension can arise in various clinical disorders, which have been classified by WHO into five clinical groups, on the basis of mechanisms, with different pathogenic, prognostic, and therapeutic features.1 The first group is defined as pulmonary arterial hypertension, whereas the third group encompasses pulmonary hypertension due to lung diseases or hypoxaemia, including hypertension due to chronic obstructive pulmonary disease (COPD), interstitial lung disease, and sleep-disordered breathing. In patients with COPD, the presence of COPD-associated pulmonary hypertension has been linked with reduced exercise capacity, impaired quality of life, and increased risk of mortality.2,3 Therefore, interventions that alleviate COPD-associated pulmonary hypertension are needed to improve symptoms, prevent right heart failure, and prolong survival. Prostanoids, endothelin receptor antagonists, and phosphodiesterase type-5 (PDE5) inhibitors are the main treatment options for patients with pulmonary arterial hypertension.1 PDE5 inhibitors increase cyclic guanosine
monophosphate (GMP), the final mediator in the nitric oxide pathway, in smooth muscle cells of the pulmonary artery, causing pulmonary arterial vasodilation. PDE5 inhibitors have proven effectiveness in pulmonary arterial hypertension, enhancing exercise capacity and quality of life. However, in patients with COPD-associated pulmonary hypertension, treatment with the short-acting PDE5 inhibitor sildenafil did not improve exercise capacity or quality of life.4 In The Lancet Respiratory Medicine, Andrew Goudie and colleagues investigate whether the long-acting PDE5 inhibitor tadalafil is beneficial in patients with severe COPD and mild pulmonary hypertension.5 Findings from this randomised, double-blind, parallel-group, placebocontrolled trial show that, compared with placebo, tadalafil did not improve exercise capacity after 12 weeks, as measured by the primary endpoint of 6 minute walking distance (between-group difference 0·5 m, 95% CI –11·6 to 12·5; p=0·937). Additionally, tadalafil did not improve quality of life, lung function (spirometry and diffusion of lung carbon monoxide [DLCO]), or serum B-natriuretic peptide, a biomarker associated with worse prognosis in patients with pulmonary hypertension. Why was tadalafil ineffective in patients with COPDassociated pulmonary hypertension in this trial? www.thelancet.com/respiratory Vol 2 April 2014
Comment
Several reasons that are not mutually exclusive could be envisaged: the wrong patient population, the wrong (primary) outcome, the wrong dose, or the wrong target (ie, the nitric oxide–cyclic GMP pathway, including PDE5). First, the target population consisted of patients with severe COPD and emphysema who had borderline to mild pulmonary hypertension as estimated by Doppler echocardiography. However, for logistical and ethical reasons, the presence of pulmonary hypertension was not confirmed by right heart catheterisation, implicating that several patients with COPD with false-positive echo-defined pulmonary hypertension might have been enrolled. Would the trial have produced positive results if patients with mild-to-moderate COPD with rightheart-catheterisation-confirmed severe pulmonary hypertension, disproportionate to the degree of airflow limitation, had been selected? Second, the primary endpoint was the 6 minute walking distance, a valid and reliable measure of exercise capacity in patients with pulmonary arterial hypertension and in those with COPD. The main determinant of exercise intolerance in patients with pulmonary arterial hypertension (which arises most frequently in young patients) is right ventricular dysfunction due to pulmonary arterial vasoconstriction and obliteration. By contrast, the impaired exercise capacity in older patients with COPD is caused by a combination of airflow limitation, dynamic hyperinflation, cardiovascular comorbidities, anaemia, muscle weakness and deconditioning, in addition to the increased pulmonary arterial pressure.6–8 Moreover, exercise intolerance in patients with COPD is further increased during exacerbations. Therefore, that part alleviation of one component of the multifactorial impairment of the exercise capacity did not improve 6 minute walking distance is unsurprising. Because most secondary outcomes, including quality of life, lung function, and B-natriuretic peptide were also not improved, the study is probably truly negative. Tadalafil had positive effects only on some echocardiographic parameters (pulmonary acceleration time and right ventricular systolic pressure), but the clinical relevance of these small but statistically significant differences in intermediate outcomes is unclear. Third, for safety reasons and on the basis of pharmacokinetic assumptions in an elderly population with COPD, the investigators chose to adjust the dose of tadalafil to 10 mg once daily.5 However, the licensed www.thelancet.com/respiratory Vol 2 April 2014
dosage for tadalafil for treatment of pulmonary arterial hypertension is 40 mg daily (as starting dose). A randomised trial in patients with pulmonary arterial hypertension comparing four different doses of tadalafil (2·5 mg, 10 mg, 20 mg, and 40 mg) has shown that only the 40 mg dose significantly improved 6 minute walking distance and quality of life.9 Would the present trial have been positive if tadalafil had been given at a higher dose? Finally, should we pursue pulmonary vasodilation in patients with COPD-associated pulmonary hypertension? Should we target the nitric oxide–cyclic GMP pathway with PDE5 inhibitors in patients with COPD-associated pulmonary hypertension? Careful assessment of the risk–benefit ratio of PDE5 inhibitors in patients with COPD-associated pulmonary hypertension is essential to answer this question. Pulmonary vasodilator drugs can cause systemic hypotension and decrease oxygen saturation in these patients. COPD and emphysema are characterised by inhomogeneous ventilation and perfusion of the lungs, leading to ventilation perfusion (V/Q) mismatch. By antagonisation of hypoxic pulmonary vasoconstriction, PDE5 inhibitors can increase blood flow to poorly ventilated areas of the lung in patients with COPD, aggravating V/Q mismatch and decreasing oxygen saturation (SpO2).10 Because of these safety concerns, Goudie and colleagues did a single dose test with 50 mg sildenafil during the run-in period, and excluded participants who had clinically significant symptoms or systemic hypotension. Importantly, even in the 120 patients with COPD-associated pulmonary hypertension who passed the sildenafil test, a significant decrease was shown in SpO2 (mean maximum fall of 2%, from 95% to 93%, 60 min after sildenafil). Moreover, during the 12 week treatment period, two patients died in the tadalafil group, whereas no patients died in the placebo group. Scrutiny is thus warranted with study of PDE5 inhibitors in patients with COPD-associated pulmonary hypertension. In conclusion, Goudie and colleagues’ study5 clearly showed that tadalafil does not improve exercise capacity or quality of life in patients with COPD-associated pulmonary hypertension, despite exerting pulmonary vasodilation. These important findings emphasise that the clinical classification of pulmonary hypertension has important therapeutic implications, and that use of drug therapy specific to pulmonary arterial hypertension is not recommended in patients with COPD-associated pulmonary hypertension.1 253
Comment
Guy Brusselle Department of Respiratory Medicine, Ghent University Hospital, Ghent B-9000, Belgium; and Departments of Epidemiology and Respiratory Medicine, Erasmus Medical Centre Rotterdam, Rotterdam 3000 CA, Netherlands [email protected] I declare that I have no competing interests. 1
2
3 4
Galié N, Hoeper MM, Humbert M, et al. ESC/ERS Guidelines. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34: 1219–63. Sims MW, Margolis DJ, Localio AR, Panetierri RA, Kawut SM, Christie JD. Impact of pulmonary artery pressure on exercise function in severe COPD. Chest 2009; 136: 412–19. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J 2008; 32: 1371–85. Blanco I, Gimeno E, Munoz PA, Pizarro S, et al. Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Am J Respir Crit Care Med 2010; 181: 270–78.
5
6
7 8
9 10
Goudie AR, Lipworth BJ, Hopkinson PJ, Wei L, Struthers AD. Tadalafil in patients with chronic obstructive pulmonary disease: a randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med 2014; published online Feb 27. http:// http://dx.doi.org/10.1016/ S2213-2600(14)70013-X. O’Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164: 770–77. Naeije R and Boerrigter BG. Pulmonary hypertension at exercise in COPD: does it matter? Eur Respir J 2013; 41: 1002–04. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/ European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med 2013; 188: 1011–27. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119: 2894–903. Lederer DJ, Bartels MN, Schluger NW, Brogan F, Jellen P, Thomashow BM, Kawut SM. Sildenafil for chronic obstructive pulmonary disease: a randomized crossover trial. COPD 2012; 9: 268–75.
Andy Crump, TDR, Who/Science Photo Library
Child health and tuberculosis
Published Online March 24, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70009-8 See Editorial Lancet Respir Med 2013: 1: 755
254
Historically, children were excluded from programmes for tuberculosis control that focused exclusively on the identification and treatment of infectious adult cases. Tuberculosis was included in the sixth Millennium Development Goal (MDG). This goal focused on major global epidemics, which reinforced the emphasis on epidemic control with little appreciation of the importance of tuberculosis in the context of child survival. This situation is changing. World Tuberculosis Day 2012 was devoted to childhood tuberculosis and there is growing awareness that tuberculosis is a major cause of illness and death in young children in tuberculosis-endemic areas. A recent Save the Children report about preventable deaths in childhood celebrated some impressive achievements, but emphasised that rising inequities will jeopardise the gains.1 Globally, the deaths in children are increasingly concentrated in the poorest and most disadvantaged groups in society.1 Tuberculosis is strongly associated with social deprivation, and poverty stricken areas are often pockets of frequent and sustained transmission of Mycobacterium tuberculosis. The contribution of tuberculosis to child mortality requires careful scrutiny in these areas, but accurate data are hard to obtain because of difficulties in confirmation of the diagnosis and frequent overlap of clinical presentation with other common causes of child mortality in these settings. Pooled analysis of autopsy studies identified tuberculosis in about 10% of 811 children (with and without HIV infection) who died from respiratory disease in five
African countries.2 Of the estimated 1·3 million deaths in children attributed to pneumonia in 2011, most occurred in young children living in tuberculosis-endemic areas, almost half in Africa.3 Apart from its contribution to pneumonia deaths, tuberculosis can also be the underlying cause in children dying from meningitis, presumed sepsis, HIV/AIDS, or severe malnutrition.4 The WHO Global Tuberculosis Report 2013 estimates that 530 000 children developed tuberculosis during 2012, resulting in 74 000 deaths in HIV-uninfected children.5 Estimates are limited by poor case ascertainment and incomplete recording and reporting practices. Increasing the visibility of the tuberculosis burden in children requires improved diagnostic methods combined with enhanced surveillance and reporting systems. Until then, mathematical modelling with setting-specific epidemiological and demographic data and known agerelated risks of infection and disease might improve the estimation of disease burden. The table summarises recent progress and key challenges in childhood tuberculosis. Vertical national tuberculosis control programmes (NTPs) can provide improved focus and oversight, but the entry point to diagnosis and care for young children with tuberculosis is usually in the child healthcare sector. There is a need for stronger links and collaboration between the child health-care sector and NTPs to provide improved case-detection and management (including at the primary and secondary levels of care), to provide more robust national data www.thelancet.com/respiratory Vol 2 April 2014
forks and the separation of transmission for subsequent sources in a chain of transmission in time. Unfortunately, the current WGS is also not a perfect method.
4 5
6
Dick van Soolingen National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, Netherlands; and Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands [email protected]
7
8
I declare that I have no competing interests. Copyright © van Soolingen. Open Access article distributed under the terms of CC BY. 1 2
3
Borgdorff MW, van Soolingen D. The re-emergence of tuberculosis: what have we learnt from molecular epidemiology? Clin Microbiol Infect 2013; 19: 889–901. de Vries G, Baars HW, Sebek MM, van Hest NA, Richardus JH. Transmission classification model to determine place and time of infection of tuberculosis cases in an urban area. J Clin Microbiol 2008; 46: 3924–30. de Boer AS, Borgdorff MW, de Haas PE, Nagelkerke NJ, van Embden JD, van Soolingen D. Analysis of rate of change of IS6110 RFLP patterns of Mycobacterium tuberculosis based on serial patient isolates. J Infect Dis 1999; 180: 1238–44.
9
10
Gardy JL, Johnston JC, Ho Sui SJ, et al. Whole-genome sequencing and socialnetwork analysis of a tuberculosis outbreak. N Engl J Med 2011; 364: 730–39. Schurch AC, Kremer K, Daviena O, et al. High-resolution typing by integration of genome sequencing data in a large tuberculosis cluster. J Clin Microbiol 2010; 48: 3403–06. Walker TM, Lalor MK, Broda A, et al. Assessment of Mycobacterium tuberculosis transmission in Oxfordshire, UK, 2007–12, with whole pathogen genome sequences: an observational study. Lancet Respir Med 2014; published online March 4. http://dx.doi.org/10.1016/S2213-2600(14)70027-X. Sloot R, Borgdorff MW, de Beer JL, van Ingen J, Supply P, van Soolingen D. Clustering of tuberculosis cases based on variable-number tandem-repeat typing in relation to the population structure of Mycobacterium tuberculosis in the Netherlands. J Clin Microbiol 2013; 51: 2427–31. Bryant JM, Schurch AC, van Deutekom H, et al. Inferring patient to patient transmission of Mycobacterium tuberculosis from whole genome sequencing data. BMC Infect Dis 2013; 13: 110. Walker TM, Ip CL, Harrell RH, et al. Whole-genome sequencing to delineate Mycobacterium tuberculosis outbreaks: a retrospective observational study. Lancet Infectious Dis 2013; 13: 137–46. Schurch AC, Kremer K, Kiers A, et al. The tempo and mode of molecular evolution of Mycobacterium tuberculosis at patient-to-patient scale. Infect Genet Evol 2010; 10: 108–14.
Pixologicstudio/Science Photo Library
Should we pursue pulmonary vasodilation in patients with COPD?
Published Online March 5, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70036-0 See Articles page 293
252
Pulmonary hypertension is a pathophysiological disorder defined as an increase in pulmonary arterial pressure, as assessed by right heart catheterisation (mean pressure ≥25 mm Hg at rest). Pulmonary hypertension can arise in various clinical disorders, which have been classified by WHO into five clinical groups, on the basis of mechanisms, with different pathogenic, prognostic, and therapeutic features.1 The first group is defined as pulmonary arterial hypertension, whereas the third group encompasses pulmonary hypertension due to lung diseases or hypoxaemia, including hypertension due to chronic obstructive pulmonary disease (COPD), interstitial lung disease, and sleep-disordered breathing. In patients with COPD, the presence of COPD-associated pulmonary hypertension has been linked with reduced exercise capacity, impaired quality of life, and increased risk of mortality.2,3 Therefore, interventions that alleviate COPD-associated pulmonary hypertension are needed to improve symptoms, prevent right heart failure, and prolong survival. Prostanoids, endothelin receptor antagonists, and phosphodiesterase type-5 (PDE5) inhibitors are the main treatment options for patients with pulmonary arterial hypertension.1 PDE5 inhibitors increase cyclic guanosine
monophosphate (GMP), the final mediator in the nitric oxide pathway, in smooth muscle cells of the pulmonary artery, causing pulmonary arterial vasodilation. PDE5 inhibitors have proven effectiveness in pulmonary arterial hypertension, enhancing exercise capacity and quality of life. However, in patients with COPD-associated pulmonary hypertension, treatment with the short-acting PDE5 inhibitor sildenafil did not improve exercise capacity or quality of life.4 In The Lancet Respiratory Medicine, Andrew Goudie and colleagues investigate whether the long-acting PDE5 inhibitor tadalafil is beneficial in patients with severe COPD and mild pulmonary hypertension.5 Findings from this randomised, double-blind, parallel-group, placebocontrolled trial show that, compared with placebo, tadalafil did not improve exercise capacity after 12 weeks, as measured by the primary endpoint of 6 minute walking distance (between-group difference 0·5 m, 95% CI –11·6 to 12·5; p=0·937). Additionally, tadalafil did not improve quality of life, lung function (spirometry and diffusion of lung carbon monoxide [DLCO]), or serum B-natriuretic peptide, a biomarker associated with worse prognosis in patients with pulmonary hypertension. Why was tadalafil ineffective in patients with COPDassociated pulmonary hypertension in this trial? www.thelancet.com/respiratory Vol 2 April 2014
Comment
Several reasons that are not mutually exclusive could be envisaged: the wrong patient population, the wrong (primary) outcome, the wrong dose, or the wrong target (ie, the nitric oxide–cyclic GMP pathway, including PDE5). First, the target population consisted of patients with severe COPD and emphysema who had borderline to mild pulmonary hypertension as estimated by Doppler echocardiography. However, for logistical and ethical reasons, the presence of pulmonary hypertension was not confirmed by right heart catheterisation, implicating that several patients with COPD with false-positive echo-defined pulmonary hypertension might have been enrolled. Would the trial have produced positive results if patients with mild-to-moderate COPD with rightheart-catheterisation-confirmed severe pulmonary hypertension, disproportionate to the degree of airflow limitation, had been selected? Second, the primary endpoint was the 6 minute walking distance, a valid and reliable measure of exercise capacity in patients with pulmonary arterial hypertension and in those with COPD. The main determinant of exercise intolerance in patients with pulmonary arterial hypertension (which arises most frequently in young patients) is right ventricular dysfunction due to pulmonary arterial vasoconstriction and obliteration. By contrast, the impaired exercise capacity in older patients with COPD is caused by a combination of airflow limitation, dynamic hyperinflation, cardiovascular comorbidities, anaemia, muscle weakness and deconditioning, in addition to the increased pulmonary arterial pressure.6–8 Moreover, exercise intolerance in patients with COPD is further increased during exacerbations. Therefore, that part alleviation of one component of the multifactorial impairment of the exercise capacity did not improve 6 minute walking distance is unsurprising. Because most secondary outcomes, including quality of life, lung function, and B-natriuretic peptide were also not improved, the study is probably truly negative. Tadalafil had positive effects only on some echocardiographic parameters (pulmonary acceleration time and right ventricular systolic pressure), but the clinical relevance of these small but statistically significant differences in intermediate outcomes is unclear. Third, for safety reasons and on the basis of pharmacokinetic assumptions in an elderly population with COPD, the investigators chose to adjust the dose of tadalafil to 10 mg once daily.5 However, the licensed www.thelancet.com/respiratory Vol 2 April 2014
dosage for tadalafil for treatment of pulmonary arterial hypertension is 40 mg daily (as starting dose). A randomised trial in patients with pulmonary arterial hypertension comparing four different doses of tadalafil (2·5 mg, 10 mg, 20 mg, and 40 mg) has shown that only the 40 mg dose significantly improved 6 minute walking distance and quality of life.9 Would the present trial have been positive if tadalafil had been given at a higher dose? Finally, should we pursue pulmonary vasodilation in patients with COPD-associated pulmonary hypertension? Should we target the nitric oxide–cyclic GMP pathway with PDE5 inhibitors in patients with COPD-associated pulmonary hypertension? Careful assessment of the risk–benefit ratio of PDE5 inhibitors in patients with COPD-associated pulmonary hypertension is essential to answer this question. Pulmonary vasodilator drugs can cause systemic hypotension and decrease oxygen saturation in these patients. COPD and emphysema are characterised by inhomogeneous ventilation and perfusion of the lungs, leading to ventilation perfusion (V/Q) mismatch. By antagonisation of hypoxic pulmonary vasoconstriction, PDE5 inhibitors can increase blood flow to poorly ventilated areas of the lung in patients with COPD, aggravating V/Q mismatch and decreasing oxygen saturation (SpO2).10 Because of these safety concerns, Goudie and colleagues did a single dose test with 50 mg sildenafil during the run-in period, and excluded participants who had clinically significant symptoms or systemic hypotension. Importantly, even in the 120 patients with COPD-associated pulmonary hypertension who passed the sildenafil test, a significant decrease was shown in SpO2 (mean maximum fall of 2%, from 95% to 93%, 60 min after sildenafil). Moreover, during the 12 week treatment period, two patients died in the tadalafil group, whereas no patients died in the placebo group. Scrutiny is thus warranted with study of PDE5 inhibitors in patients with COPD-associated pulmonary hypertension. In conclusion, Goudie and colleagues’ study5 clearly showed that tadalafil does not improve exercise capacity or quality of life in patients with COPD-associated pulmonary hypertension, despite exerting pulmonary vasodilation. These important findings emphasise that the clinical classification of pulmonary hypertension has important therapeutic implications, and that use of drug therapy specific to pulmonary arterial hypertension is not recommended in patients with COPD-associated pulmonary hypertension.1 253
Comment
Guy Brusselle Department of Respiratory Medicine, Ghent University Hospital, Ghent B-9000, Belgium; and Departments of Epidemiology and Respiratory Medicine, Erasmus Medical Centre Rotterdam, Rotterdam 3000 CA, Netherlands [email protected] I declare that I have no competing interests. 1
2
3 4
Galié N, Hoeper MM, Humbert M, et al. ESC/ERS Guidelines. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34: 1219–63. Sims MW, Margolis DJ, Localio AR, Panetierri RA, Kawut SM, Christie JD. Impact of pulmonary artery pressure on exercise function in severe COPD. Chest 2009; 136: 412–19. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J 2008; 32: 1371–85. Blanco I, Gimeno E, Munoz PA, Pizarro S, et al. Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Am J Respir Crit Care Med 2010; 181: 270–78.
5
6
7 8
9 10
Goudie AR, Lipworth BJ, Hopkinson PJ, Wei L, Struthers AD. Tadalafil in patients with chronic obstructive pulmonary disease: a randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med 2014; published online Feb 27. http:// http://dx.doi.org/10.1016/ S2213-2600(14)70013-X. O’Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164: 770–77. Naeije R and Boerrigter BG. Pulmonary hypertension at exercise in COPD: does it matter? Eur Respir J 2013; 41: 1002–04. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/ European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med 2013; 188: 1011–27. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119: 2894–903. Lederer DJ, Bartels MN, Schluger NW, Brogan F, Jellen P, Thomashow BM, Kawut SM. Sildenafil for chronic obstructive pulmonary disease: a randomized crossover trial. COPD 2012; 9: 268–75.
Andy Crump, TDR, Who/Science Photo Library
Child health and tuberculosis
Published Online March 24, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70009-8 See Editorial Lancet Respir Med 2013: 1: 755
254
Historically, children were excluded from programmes for tuberculosis control that focused exclusively on the identification and treatment of infectious adult cases. Tuberculosis was included in the sixth Millennium Development Goal (MDG). This goal focused on major global epidemics, which reinforced the emphasis on epidemic control with little appreciation of the importance of tuberculosis in the context of child survival. This situation is changing. World Tuberculosis Day 2012 was devoted to childhood tuberculosis and there is growing awareness that tuberculosis is a major cause of illness and death in young children in tuberculosis-endemic areas. A recent Save the Children report about preventable deaths in childhood celebrated some impressive achievements, but emphasised that rising inequities will jeopardise the gains.1 Globally, the deaths in children are increasingly concentrated in the poorest and most disadvantaged groups in society.1 Tuberculosis is strongly associated with social deprivation, and poverty stricken areas are often pockets of frequent and sustained transmission of Mycobacterium tuberculosis. The contribution of tuberculosis to child mortality requires careful scrutiny in these areas, but accurate data are hard to obtain because of difficulties in confirmation of the diagnosis and frequent overlap of clinical presentation with other common causes of child mortality in these settings. Pooled analysis of autopsy studies identified tuberculosis in about 10% of 811 children (with and without HIV infection) who died from respiratory disease in five
African countries.2 Of the estimated 1·3 million deaths in children attributed to pneumonia in 2011, most occurred in young children living in tuberculosis-endemic areas, almost half in Africa.3 Apart from its contribution to pneumonia deaths, tuberculosis can also be the underlying cause in children dying from meningitis, presumed sepsis, HIV/AIDS, or severe malnutrition.4 The WHO Global Tuberculosis Report 2013 estimates that 530 000 children developed tuberculosis during 2012, resulting in 74 000 deaths in HIV-uninfected children.5 Estimates are limited by poor case ascertainment and incomplete recording and reporting practices. Increasing the visibility of the tuberculosis burden in children requires improved diagnostic methods combined with enhanced surveillance and reporting systems. Until then, mathematical modelling with setting-specific epidemiological and demographic data and known agerelated risks of infection and disease might improve the estimation of disease burden. The table summarises recent progress and key challenges in childhood tuberculosis. Vertical national tuberculosis control programmes (NTPs) can provide improved focus and oversight, but the entry point to diagnosis and care for young children with tuberculosis is usually in the child healthcare sector. There is a need for stronger links and collaboration between the child health-care sector and NTPs to provide improved case-detection and management (including at the primary and secondary levels of care), to provide more robust national data www.thelancet.com/respiratory Vol 2 April 2014
