[
Editorials
]
The Growing Challenge of Nontuberculous Mycobacteria Neil W. Schluger, MD, FCCP New York, NY
Over the past several years, there has been an increasing appreciation of the burden of pulmonary disease caused by nontuberculous mycobacteria (NTM) in both the general population1-3 and in patients receiving immunosuppressive drugs. Soon after the first tumor necrosis factor-a antagonist was introduced into clinical use, the increased risk of mycobacterial infections, TB especially, in patients receiving these agents was recognized.4 Physicians are by now well sensitized to the importance of screening patients with various rheumatic and other systemic inflammatory conditions for TB prior to initiation of treatment with tumor necrosis factor-a blockers. Nearly every practicing pulmonologist by now is aware of the challenges of treating patients with Mycobacterium avium, Mycobacterium xenopi, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium fortuitum, and others. It is well appreciated, through both large epidemiologic studies and individual experience, that in economically developed countries that generally have low incidence rates of TB, the burden of NTM infections far outstrips that of TB. Much less well understood, however, are the particular risk factors for developing infections with NTM, the natural history of these infections, and the best approaches to treatment. In this issue of CHEST (see page 563), Brode and colleagues5 make an important AFFILIATIONS: From the Department of Medicine, the Department of Epidemiology, and the Department of Environmental Health Science, Columbia University, College of Physicians and Surgeons, Mailman School of Public Health. FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. CORRESPONDENCE TO: Neil W. Schluger, MD, FCCP, Columbia University Medical Center, PH-8 E, Room 101, 622 W 168th St, New York, NY 10032; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0279
journal.publications.chestnet.org
contribution to our understanding of the epidemiology of NTM infections and they point the way to important avenues of future research. Brode and colleagues5 examined the incidence of and risk factors for mycobacterial infections overall in patients with rheumatoid arthritis (RA) in Ontario, Canada, in a large cohort followed for a 10-year period beginning in 2001. (That they were able to do this at all is a benefit of the Canadian health-care system, in which all Canadians are enrolled, thus, allowing fairly comprehensive and complete population-based datasets to be assembled and analyzed.). Their study has three major findings: The risk of both TB and NTM disease was significantly higher in patients with RA than in patients without RA; NTM infections were much more common than TB; and the risk of death in patients with RA and NTM was higher than in patients with RA without NTM. It is important to note that the relative risk of developing TB or NTM in patients with RA as compared with those without RA was about the same: roughly twofold. However, because Canada is a low-burden country for TB, the absolute number of patients with NTM infections was far greater than the number with TB. Similar findings would likely be seen in the United States and much of Western Europe. The most immediate implications of the study by Brode and colleagues5 are related to the striking finding of a 1.8 times increased odds of death in patients with RA who also have NTM. Although the study was not able to determine the exact cause of death, this finding should alert physicians to be very concerned when these two conditions coexist. A limitation of the study, of course, is that it could not determine causal relationships among RA, NTM, and death. Did patients with NTM and RA die of NTM, or was the presence of NTM just a marker of more severe RA? Could the course of NTM, including the risk of mortality, be affected by treatment? These questions will be important to address in future studies. The relationship between RA and mycobacterial infections is clear, although the cause is not. The most obvious link would be in immunosuppressive medications that are often used to treat RA and which would increase susceptibility to TB and NTM. Unfortunately, the use of specific medications and the risk of mycobacterial infections
529
could not be explored in this study. Within the group of patients with RA, further risk factors for developing mycobacterial infections included chronic kidney disease, asthma, and COPD. A relationship between end-stage renal disease and TB has long been known but has not been described previously in NTM. The link between COPD and NTM has been described previously,6-8 but a relationship with asthma is more novel, if confirmed in future studies. Some patients with COPD may have a component of bronchiectasis that predisposes to NTM infection, or the additional steroids used to treat COPD and asthma may contribute to increased susceptibility to infection. In this study, diabetes and HIV infection did not further amplify the risk accorded by RA. In the case of HIV, there may simply have been too few patients to detect an effect. Diabetes has been clearly shown to be a risk factor for TB, but the effect on NTM here may have been swamped by the immunosuppression associated with RA or its treatment. The current study does not address issues of treatment or the effect of treatment on outcomes. Given the increased risk of mortality the authors detected in patients with RA and NTM, this should be a subject of considerable concern and focus in the future. In general, treatment of NTM is often a complex and frustrating endeavor. Physicians often elect not to treat elderly patients with NTM (usually M avium complex) if their symptoms are limited to cough, which is commonly the case. If treatment is initiated, a three-drug regimen of a macrolide, a rifamycin (rifampin or rifabutin), and ethambutol is preferred, and in many patients this regimen can be given thrice weekly.9,10 No randomized trials have been done to evaluate this regimen, although observational studies have indicated clinical and microbiologic improvement with this regimen in a considerable number of patients. Conducting trials in patients with complex conditions such as those in this study should be a particular priority. The group, led by Dr Marras, the senior author on the current study,5 should be commended for their focus on NTM disease and for their many important insights. We anticipate further elucidation on this complex subject from them in the future.
References 1. Bodle EE, Cunningham JA, Della-Latta P, Schluger NW, Saiman L. Epidemiology of nontuberculous mycobacteria in patients without HIV infection, New York City. Emerg Infect Dis. 2008;14(3):390-396. 2. Kendall BA, Winthrop KL. Update on the epidemiology of pulmonary nontuberculous mycobacterial infections. Semin Respir Crit Care Med. 2013;34(1):87-94.
530 Editorials
3. Marras TK, Mendelson D, Marchand-Austin A, May K, Jamieson FB. Pulmonary nontuberculous mycobacterial disease, Ontario, Canada, 1998-2010. Emerg Infect Dis. 2013;19(11):1889-1891. 4. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345(15):1098-1104. 5. Brode SK, Jamieson FB, Ng R, et al. Risk of mycobacterial infections associated with rheumatoid arthritis in Ontario, Canada. Chest. 2014;146(3):563-572. 6. Huang CT, Tsai YJ, Wu HD, et al. Impact of non-tuberculous mycobacteria on pulmonary function decline in chronic obstructive pulmonary disease. Int J Tuberc Lung Dis. 2012;16(4):539-545. 7. Chan ED, Iseman MD. Underlying host risk factors for nontuberculous mycobacterial lung disease. Semin Respir Crit Care Med. 2013;34(1): 110-123. 8. de Mello KG, Mello FC, Borga L, et al. Clinical and therapeutic features of pulmonary nontuberculous mycobacterial disease, Brazil, 1993-2011. Emerg Infect Dis. 2013;19(3):393-399. 9. Wallace RJ Jr, Brown-Elliott BA, McNulty S, et al. Macrolide/azalide therapy for nodular/bronchiectatic: Mycobacterium avium complex lung disease. Chest. 2014;146(2):276-282. 10. Lam PK, Griffith DE, Aksamit TR, et al. Factors related to response to intermittent treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2006;173(11):1283-1289.
Choose Wisely Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Sarcoidosis Atul C. Mehta, MBBS, FCCP Francisco A. Almeida, MD, FCCP Cleveland, OH
You must choose. But choose wisely. Indiana Jones and the Last Crusade1
Confirming the diagnosis of sarcoidosis presents a plethora of options to the pulmonologist, ranging from a close follow-up to an open lung biopsy. Flexible bronchoscopy and conventional transbronchial needle aspiration (cTBNA) have empowered bronchoscopists in the confirmation of sarcoidosis since their introduction in the late 1960s and 1980s, respectively.2 The last decade has witnessed the addition of endobronchial AFFILIATIONS:
From the Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic. FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. CORRESPONDENCE TO: Atul C. Mehta, MBBS, FCCP, Respiratory Institute, Cleveland Clinic, 9500 Euclid Ave, A-90, Cleveland, OH 44195; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0374
[
146#3 CHEST SEPTEMBER 2014
]
Editorials
]
The Growing Challenge of Nontuberculous Mycobacteria Neil W. Schluger, MD, FCCP New York, NY
Over the past several years, there has been an increasing appreciation of the burden of pulmonary disease caused by nontuberculous mycobacteria (NTM) in both the general population1-3 and in patients receiving immunosuppressive drugs. Soon after the first tumor necrosis factor-a antagonist was introduced into clinical use, the increased risk of mycobacterial infections, TB especially, in patients receiving these agents was recognized.4 Physicians are by now well sensitized to the importance of screening patients with various rheumatic and other systemic inflammatory conditions for TB prior to initiation of treatment with tumor necrosis factor-a blockers. Nearly every practicing pulmonologist by now is aware of the challenges of treating patients with Mycobacterium avium, Mycobacterium xenopi, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium fortuitum, and others. It is well appreciated, through both large epidemiologic studies and individual experience, that in economically developed countries that generally have low incidence rates of TB, the burden of NTM infections far outstrips that of TB. Much less well understood, however, are the particular risk factors for developing infections with NTM, the natural history of these infections, and the best approaches to treatment. In this issue of CHEST (see page 563), Brode and colleagues5 make an important AFFILIATIONS: From the Department of Medicine, the Department of Epidemiology, and the Department of Environmental Health Science, Columbia University, College of Physicians and Surgeons, Mailman School of Public Health. FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. CORRESPONDENCE TO: Neil W. Schluger, MD, FCCP, Columbia University Medical Center, PH-8 E, Room 101, 622 W 168th St, New York, NY 10032; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0279
journal.publications.chestnet.org
contribution to our understanding of the epidemiology of NTM infections and they point the way to important avenues of future research. Brode and colleagues5 examined the incidence of and risk factors for mycobacterial infections overall in patients with rheumatoid arthritis (RA) in Ontario, Canada, in a large cohort followed for a 10-year period beginning in 2001. (That they were able to do this at all is a benefit of the Canadian health-care system, in which all Canadians are enrolled, thus, allowing fairly comprehensive and complete population-based datasets to be assembled and analyzed.). Their study has three major findings: The risk of both TB and NTM disease was significantly higher in patients with RA than in patients without RA; NTM infections were much more common than TB; and the risk of death in patients with RA and NTM was higher than in patients with RA without NTM. It is important to note that the relative risk of developing TB or NTM in patients with RA as compared with those without RA was about the same: roughly twofold. However, because Canada is a low-burden country for TB, the absolute number of patients with NTM infections was far greater than the number with TB. Similar findings would likely be seen in the United States and much of Western Europe. The most immediate implications of the study by Brode and colleagues5 are related to the striking finding of a 1.8 times increased odds of death in patients with RA who also have NTM. Although the study was not able to determine the exact cause of death, this finding should alert physicians to be very concerned when these two conditions coexist. A limitation of the study, of course, is that it could not determine causal relationships among RA, NTM, and death. Did patients with NTM and RA die of NTM, or was the presence of NTM just a marker of more severe RA? Could the course of NTM, including the risk of mortality, be affected by treatment? These questions will be important to address in future studies. The relationship between RA and mycobacterial infections is clear, although the cause is not. The most obvious link would be in immunosuppressive medications that are often used to treat RA and which would increase susceptibility to TB and NTM. Unfortunately, the use of specific medications and the risk of mycobacterial infections
529
could not be explored in this study. Within the group of patients with RA, further risk factors for developing mycobacterial infections included chronic kidney disease, asthma, and COPD. A relationship between end-stage renal disease and TB has long been known but has not been described previously in NTM. The link between COPD and NTM has been described previously,6-8 but a relationship with asthma is more novel, if confirmed in future studies. Some patients with COPD may have a component of bronchiectasis that predisposes to NTM infection, or the additional steroids used to treat COPD and asthma may contribute to increased susceptibility to infection. In this study, diabetes and HIV infection did not further amplify the risk accorded by RA. In the case of HIV, there may simply have been too few patients to detect an effect. Diabetes has been clearly shown to be a risk factor for TB, but the effect on NTM here may have been swamped by the immunosuppression associated with RA or its treatment. The current study does not address issues of treatment or the effect of treatment on outcomes. Given the increased risk of mortality the authors detected in patients with RA and NTM, this should be a subject of considerable concern and focus in the future. In general, treatment of NTM is often a complex and frustrating endeavor. Physicians often elect not to treat elderly patients with NTM (usually M avium complex) if their symptoms are limited to cough, which is commonly the case. If treatment is initiated, a three-drug regimen of a macrolide, a rifamycin (rifampin or rifabutin), and ethambutol is preferred, and in many patients this regimen can be given thrice weekly.9,10 No randomized trials have been done to evaluate this regimen, although observational studies have indicated clinical and microbiologic improvement with this regimen in a considerable number of patients. Conducting trials in patients with complex conditions such as those in this study should be a particular priority. The group, led by Dr Marras, the senior author on the current study,5 should be commended for their focus on NTM disease and for their many important insights. We anticipate further elucidation on this complex subject from them in the future.
References 1. Bodle EE, Cunningham JA, Della-Latta P, Schluger NW, Saiman L. Epidemiology of nontuberculous mycobacteria in patients without HIV infection, New York City. Emerg Infect Dis. 2008;14(3):390-396. 2. Kendall BA, Winthrop KL. Update on the epidemiology of pulmonary nontuberculous mycobacterial infections. Semin Respir Crit Care Med. 2013;34(1):87-94.
530 Editorials
3. Marras TK, Mendelson D, Marchand-Austin A, May K, Jamieson FB. Pulmonary nontuberculous mycobacterial disease, Ontario, Canada, 1998-2010. Emerg Infect Dis. 2013;19(11):1889-1891. 4. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345(15):1098-1104. 5. Brode SK, Jamieson FB, Ng R, et al. Risk of mycobacterial infections associated with rheumatoid arthritis in Ontario, Canada. Chest. 2014;146(3):563-572. 6. Huang CT, Tsai YJ, Wu HD, et al. Impact of non-tuberculous mycobacteria on pulmonary function decline in chronic obstructive pulmonary disease. Int J Tuberc Lung Dis. 2012;16(4):539-545. 7. Chan ED, Iseman MD. Underlying host risk factors for nontuberculous mycobacterial lung disease. Semin Respir Crit Care Med. 2013;34(1): 110-123. 8. de Mello KG, Mello FC, Borga L, et al. Clinical and therapeutic features of pulmonary nontuberculous mycobacterial disease, Brazil, 1993-2011. Emerg Infect Dis. 2013;19(3):393-399. 9. Wallace RJ Jr, Brown-Elliott BA, McNulty S, et al. Macrolide/azalide therapy for nodular/bronchiectatic: Mycobacterium avium complex lung disease. Chest. 2014;146(2):276-282. 10. Lam PK, Griffith DE, Aksamit TR, et al. Factors related to response to intermittent treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2006;173(11):1283-1289.
Choose Wisely Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Sarcoidosis Atul C. Mehta, MBBS, FCCP Francisco A. Almeida, MD, FCCP Cleveland, OH
You must choose. But choose wisely. Indiana Jones and the Last Crusade1
Confirming the diagnosis of sarcoidosis presents a plethora of options to the pulmonologist, ranging from a close follow-up to an open lung biopsy. Flexible bronchoscopy and conventional transbronchial needle aspiration (cTBNA) have empowered bronchoscopists in the confirmation of sarcoidosis since their introduction in the late 1960s and 1980s, respectively.2 The last decade has witnessed the addition of endobronchial AFFILIATIONS:
From the Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic. FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. CORRESPONDENCE TO: Atul C. Mehta, MBBS, FCCP, Respiratory Institute, Cleveland Clinic, 9500 Euclid Ave, A-90, Cleveland, OH 44195; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0374
[
146#3 CHEST SEPTEMBER 2014
]
