- Email: [email protected]
Azithromycin in non-cystic-fibrosis bronchiectasis
Correspondence
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Mosley H, Chen LC. Analytical framework for the study of child survival in developing countries. Popul Dev Rev 1984; 10 (suppl): 25–45. Sanda S. Niger’s success in child survival. Lancet 2012; 380: 1127–28. Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ 2011; 343: d5094. Imdad A, Yakoob MY, Sudfeld C, Haider BA, Black RE, Bhutta ZA. Impact of vitamin A supplementation on infant and childhood mortality. BMC Public Health 2011; 11 (suppl 3): S20.
Azithromycin in non-cystic-fibrosis bronchiectasis Although we appreciate the paper by Conroy Wong and colleagues (Aug 18, p 660),1 which suggests that thrice weekly azithromycin might be a new intervention to prevent exacerbations in patients with noncystic-fibrosis bronchiectasis, we welcome the cautionary Comment2 by Robert Wilson and Athol Wells about patient selection. We wonder whether the patients in this trial were adequately screened for infection with non-tuberculous mycobacteria (NTM). No NTM seem to have been isolated during screening of 179 patients, and only one NTM was cultivated from one sputum specimen during follow-up. This number seems low, since a conservative estimate of the expected number of NTM infections in patients with non-cysticfibrosis bronchiectasis is 2%.3 We expect this number to be substantially higher in our settings in the southern USA—an expectation supported by the recent recognition of the geographic variability of NTM disease in the USA.4 How frequently sputa were cultivated during follow-up in Wong and colleagues’ study was not clear. Additionally, although Wong and colleagues warn of the risk of macrolide resistance in Streptococcus pneumoniae, we and others have shown that macrolide monotherapy is the most important risk factor for www.thelancet.com Vol 381 January 5, 2013
infection with macrolide-resistant Mycobacterium avium complex.5 We wholeheartedly agree with the suggestion to screen candidates for NTM before starting azithromycin monotherapy, but we also recommend that physicians be vigilant in monitoring for symptoms and signs of NTM lung disease and for having a low threshold for repeating sputum microbiology tests for acid-fast bacilli. The risk of inducing macrolide resistance might vary geographically; research is needed to address this concern. We declare that we have no conflicts of interest.
*Kevin P Fennelly, David E Griffith [email protected]fl.edu NTM Disease Program, University of Florida, Gainesville, FL 32610, USA (KPF); and Pulmonary and Critical Care Division, University of Texas Health Sciences Center at Tyler, Tyler, TX, USA (DEG) 1
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Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380: 660–67. Wilson R, Wells AU. Azithromycin in bronchiectasis: when should it be used? Lancet 2012; 380: 627–29. Pasteur MC, Helliwell SM, Houghton SJ, et al. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med 2000; 162: 1277–84. Adjemian J, Olivier KN, Seitz AE, Holland SM, Prevots DR. Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries. Am J Respir Crit Care Med 2012; 185: 881–86. Griffith DE, Brown-Elliott BA, Langsjoen B, et al. Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2006; 174: 928–34.
Authors’ reply Kevin Fennelly and David Griffith draw attention to the low rate of detection of non-tuberculous mycobacteria during screening in our patients with non-cystic-fibrosis bronchiectasis.1 There are several factors that might explain this finding. Patients were prescreened and excluded from the study if any nontuberculous mycobacteria were cultured in the 2 years before screening. Hence, at screening, our rate of positive cultures would be expected to be low, and proved to be lower than the
2% rate described in a study of highly selected patients with bronchiectasis in the UK.2 Our patients also had CT scans before inclusion in the study. These were reviewed for evidence of nontuberculous mycobacterial disease to ensure that we did not enrol patients with mycobacterial infection. We did not routinely culture sputum for mycobacteria during follow-up. However, none of the patients has been diagnosed with non-tuberculous mycobacterial disease since the completion of the study. We agree that physicians should be vigilant in monitoring for the clinical features of non-tuberculous mycobacterial disease and have a low threshold for repeating sputum mycobacterial cultures.
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2
We declare that we have no conflicts of interest.
*Conroy Wong, Lata Jayaram, Noel Karalus, David Milne, Cecilia Tong [email protected] Middlemore Hospital, Counties Manukau District Health Board, Otahuhu, Auckland 2025, New Zealand (CW, CT); Monash Medical Centre, Clayton, VIC, Australia (LJ); Waikato Hospital, Waikato District Health Board, Hamilton, New Zealand (NK); and Auckland City Hospital, Auckland District Health Board, Auckland, New Zealand (DM) 1
2
Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380: 660–67. Wickremasinghe M, Ozerovitch LJ, Davies G, et al. Non-tuberculous mycobacteria in patients with bronchiectasis. Thorax 2005; 60: 1045–51.
Understanding surgical interventions in RCTs: the need for better methodology The response to the trial of minimally invasive versus open oesophagectomy1 shows how surgeons often react to trials and don’t believe randomised data. The letters identify individual preoperative,2 perioperative,3,4 and postoperative4,5 components of surgery and argue that had components been different or more tightly controlled, 27
3 4
5
Mosley H, Chen LC. Analytical framework for the study of child survival in developing countries. Popul Dev Rev 1984; 10 (suppl): 25–45. Sanda S. Niger’s success in child survival. Lancet 2012; 380: 1127–28. Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ 2011; 343: d5094. Imdad A, Yakoob MY, Sudfeld C, Haider BA, Black RE, Bhutta ZA. Impact of vitamin A supplementation on infant and childhood mortality. BMC Public Health 2011; 11 (suppl 3): S20.
Azithromycin in non-cystic-fibrosis bronchiectasis Although we appreciate the paper by Conroy Wong and colleagues (Aug 18, p 660),1 which suggests that thrice weekly azithromycin might be a new intervention to prevent exacerbations in patients with noncystic-fibrosis bronchiectasis, we welcome the cautionary Comment2 by Robert Wilson and Athol Wells about patient selection. We wonder whether the patients in this trial were adequately screened for infection with non-tuberculous mycobacteria (NTM). No NTM seem to have been isolated during screening of 179 patients, and only one NTM was cultivated from one sputum specimen during follow-up. This number seems low, since a conservative estimate of the expected number of NTM infections in patients with non-cysticfibrosis bronchiectasis is 2%.3 We expect this number to be substantially higher in our settings in the southern USA—an expectation supported by the recent recognition of the geographic variability of NTM disease in the USA.4 How frequently sputa were cultivated during follow-up in Wong and colleagues’ study was not clear. Additionally, although Wong and colleagues warn of the risk of macrolide resistance in Streptococcus pneumoniae, we and others have shown that macrolide monotherapy is the most important risk factor for www.thelancet.com Vol 381 January 5, 2013
infection with macrolide-resistant Mycobacterium avium complex.5 We wholeheartedly agree with the suggestion to screen candidates for NTM before starting azithromycin monotherapy, but we also recommend that physicians be vigilant in monitoring for symptoms and signs of NTM lung disease and for having a low threshold for repeating sputum microbiology tests for acid-fast bacilli. The risk of inducing macrolide resistance might vary geographically; research is needed to address this concern. We declare that we have no conflicts of interest.
*Kevin P Fennelly, David E Griffith [email protected]fl.edu NTM Disease Program, University of Florida, Gainesville, FL 32610, USA (KPF); and Pulmonary and Critical Care Division, University of Texas Health Sciences Center at Tyler, Tyler, TX, USA (DEG) 1
2
3
4
5
Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380: 660–67. Wilson R, Wells AU. Azithromycin in bronchiectasis: when should it be used? Lancet 2012; 380: 627–29. Pasteur MC, Helliwell SM, Houghton SJ, et al. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med 2000; 162: 1277–84. Adjemian J, Olivier KN, Seitz AE, Holland SM, Prevots DR. Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries. Am J Respir Crit Care Med 2012; 185: 881–86. Griffith DE, Brown-Elliott BA, Langsjoen B, et al. Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2006; 174: 928–34.
Authors’ reply Kevin Fennelly and David Griffith draw attention to the low rate of detection of non-tuberculous mycobacteria during screening in our patients with non-cystic-fibrosis bronchiectasis.1 There are several factors that might explain this finding. Patients were prescreened and excluded from the study if any nontuberculous mycobacteria were cultured in the 2 years before screening. Hence, at screening, our rate of positive cultures would be expected to be low, and proved to be lower than the
2% rate described in a study of highly selected patients with bronchiectasis in the UK.2 Our patients also had CT scans before inclusion in the study. These were reviewed for evidence of nontuberculous mycobacterial disease to ensure that we did not enrol patients with mycobacterial infection. We did not routinely culture sputum for mycobacteria during follow-up. However, none of the patients has been diagnosed with non-tuberculous mycobacterial disease since the completion of the study. We agree that physicians should be vigilant in monitoring for the clinical features of non-tuberculous mycobacterial disease and have a low threshold for repeating sputum mycobacterial cultures.
Science Photo Library
2
We declare that we have no conflicts of interest.
*Conroy Wong, Lata Jayaram, Noel Karalus, David Milne, Cecilia Tong [email protected] Middlemore Hospital, Counties Manukau District Health Board, Otahuhu, Auckland 2025, New Zealand (CW, CT); Monash Medical Centre, Clayton, VIC, Australia (LJ); Waikato Hospital, Waikato District Health Board, Hamilton, New Zealand (NK); and Auckland City Hospital, Auckland District Health Board, Auckland, New Zealand (DM) 1
2
Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380: 660–67. Wickremasinghe M, Ozerovitch LJ, Davies G, et al. Non-tuberculous mycobacteria in patients with bronchiectasis. Thorax 2005; 60: 1045–51.
Understanding surgical interventions in RCTs: the need for better methodology The response to the trial of minimally invasive versus open oesophagectomy1 shows how surgeons often react to trials and don’t believe randomised data. The letters identify individual preoperative,2 perioperative,3,4 and postoperative4,5 components of surgery and argue that had components been different or more tightly controlled, 27