© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case–control study S.A. Longworth, C. Vinnard, I. Lee, K.D. Sims, T.D. Barton, E.A. Blumberg. Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case–control study. Transpl Infect Dis 2014: 16: 76–83. All rights reserved Abstract: Background. The epidemiology of nontuberculous mycobacteria (NTM) disease in solid organ transplant recipients is poorly defined. Methods. We identified all solid organ transplant recipients with NTM disease at a single center over a 7.5-year period, and collected data on patient demographics, co-morbidities, immunosuppressive medications, and rejection. We conducted a case–control study to identify risk factors for disease, matching 3 control patients to each case patient by date of transplantation. Results. A total of 34 cases of NTM disease occurred during the study period, involving 6 single lung, 13 bilateral lung, 8 heart, 4 liver, 2 kidney, and 1 pancreas-kidney recipients. Cases were predominantly male (24/34), with a median age of 55 years (interquartile range [IQR]: 46–61 years), and developed after a median of 8 months post transplantation (IQR: 2–87 months). Mycobacterium abscessus and Mycobacterium avium complex were the most common pathogens, and the lung (including pleura) was the most common site of disease. In the adjusted case–control analysis, lung transplant recipients had the highest risk of NTM disease. Conclusions. Additional studies are needed to evaluate the role of targeted surveillance measures for NTM disease in high-risk patients, particularly lung transplant recipients, and to characterize the mechanisms of disease acquisition.
S.A. Longworth1, C. Vinnard2, I. Lee3, K.D. Sims4, T.D. Barton5, E.A. Blumberg5 1
Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA, 2Department of Medicine, Division of Infectious Diseases & HIV Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA, 3 Merck Sharp & Dohme, Corp., North Wales, Pennsylvania, USA, 4Bristol-Myers Squibb, Princeton, New Jersey, USA, 5Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA Key words: mycobacteria; nontuberculous; NTM; epidemiology; risk factors; solid organ transplant Correspondence to: Emily Blumberg, MD, Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine of the University of Pennsylvania, Suite E, 3 Silverstein, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA Tel: (215) 662 7066 Fax: (215) 662 7611 E-mail: [email protected]
Received 7 December 2012, revised 10 April 2013, accepted for publication 27 May 2013 DOI: 10.1111/tid.12170 Transpl Infect Dis 2014: 16: 76–83
The nontuberculous mycobacteria (NTM) are a diverse group of organisms that are commonly found in the environment, including soil and water, and include >65 different species (1). Although NTM organisms are generally regarded as uncommon causes of human disease, few estimates have been made of disease incidence in populations. Risk factors for NTM disease include patients with acquired immunodeficiency syndrome (particularly with CD4+ T cell counts 3 years after transplantation. The longest time interval between transplantation and development of NTM disease was 13 years, observed in a kidney transplant recipient. Of note, 14 patients were transplanted before 2002; however, there was no evidence of NTM disease before their enrollment in this study. Between January 1, 2002 and July 1, 2009 at our institution, the numbers of incident episodes of NTM disease per 100 transplant recipients per year of follow-up time were 0.8 (lung recipients), 0.3 (heart recipients), 0.1 (liver recipients), and 0.02 (kidney recipients).
single case patient. Two patients (1 liver and 1 bilateral lung transplant recipient) had mixed infections, both of whom developed pleuropulmonary infections with MAC and M. abscessus. Considerable diversity was also seen in the sites of infection of case patients. Pleuropulmonary disease was the most common site of disease, accounting for 21 of 34 case patients (62%) overall, including 15 of 19 lung transplant recipients (79%). Disseminated disease was the next most common presentation, observed in 6 of 34 patients (18%). Bloodstream infection was documented in all but 1 of the case patients with disseminated disease. Heart transplant recipients had the greatest diversity with regards to sites of disease, which included disseminated disease in 3 patients, and 1 patient each with cutaneous, deep tissue, osteoarticular, pleuropulmonary, and intra-abdominal infections. Surgical site infections developed in 5 of the 34 case patients (15%), consisting of 2 heart transplant recipients, 2 lung transplant recipients, and 1 renal transplant recipient. The time that elapsed between transplanta-
Indications for transplantation among 34 solid organ transplant recipients with nontuberculous mycobacterial infections Organ (N)
Indications for transplantation (N)
Single lung (6)
Chronic obstructive pulmonary disease (2) Idiopathic pulmonary fibrosis (4)
Bilateral lung (13)
Chronic obstructive pulmonary disease (7) Idiopathic pulmonary fibrosis (2) Cystic fibrosis (2) Sarcoidosis (1) Alpha-1 antitrypsin deficiency (1)
Heart (8)
Ischemic cardiomyopathy (5) Idiopathic cardiomyopathy (2) Unknown (1)
Liver (4)
Hepatitis B-associated hepatocellular carcinoma (1)
Microbiology and sites of infection
Hepatitis C-associated hepatocellular carcinoma (1)
Sites of disease, and the organisms isolated from each site, are shown in Table 3. We found significant diversity with regard to the species of NTM organism isolated from case patients, with 6 different NTM species contributing to clinical disease. The most common isolate was M. abscessus, isolated in 15 of 34 NTM infections (44%), followed by MAC in 14 of 34 infections (41%). Mycobacterium fortuitum, M. kansasii, and Mycobacterium marinum were each responsible for infection in 2 patients, and M. chelonae was isolated in a
Budd–Chiari syndrome (1) Biliary cirrhosis (1) Kidney (2)
IgA nephropathy (1) Focal segmental glomerulosclerosis (1)
Pancreas-kidney (1)
Type 1 diabetes mellitus (1)
N, number; IgA, immunoglobulin A.
Table 2
Transplant Infectious Disease 2014: 16: 76–83
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Longworth et al: NTM infections in SOT recipients
tion and infection in these patients ranged from 1.5 to 10 months. Four of the 5 infections were due to M. abscessus, and the fifth was with M. fortuitum (another rapidly growing NTM species). In no instance did these patients grow NTM from a culture preoperatively, as such an occurrence would have excluded them from the study. The renal transplant recipient who grew M. fortuitum from his abdomen post transplant had undergone peritoneal dialysis pre-transplant; the dialysis catheter was removed 1.5 months
Sites and infection and species of organisms in solid organ transplant recipients with nontuberculous mycobacterial infections
Type of organ transplantation
Site of infection for each type of transplant recipient (N)
Organisms isolated from each site (N)
Single lung
Pleuropulmonary (6)
MAC (4) Mycobacterium abscessus (2)
Bilateral lung
Pleuropulmonary (9)
M. abscessus (4) MAC (3) Mycobacterium fortuitum (1) Mixed infection (1): MAC and M. abscessus
Heart
Disseminated (3)
M. abscessus (3)
Cutaneous (1)
Mycobacterium marinum (1)
Disseminated (3)
M. abscessus (2) Mycobacterium kansasii (1)
Liver
Pleuropulmonary (1)
MAC (1)
Cutaneous (1)
Mycobacterium chelonae (1)
Osteoarticular (1)
M. marinum (1)
Intra-abdominal (1)
MAC(1)
Deep tissue (1)
MAC (1)
Pleuropulmonary (4)
MAC (3) Mixed infection (1): MAC and M. abscessus
Kidney
Intra-abdominal (2)
Pleuropulmonary
M. kansasii (1)
N, number; MAC, Mycobacterium avium complex.
Table 3
80
Association of LuTx and NTM infection For the case–control study, 34 case patients (median age at transplantation 53.7 years) with NTM disease post transplantation were matched to 102 control patients (median age at transplantation 53.9 years) according to date of transplantation, for a total of 136 study patients. In unadjusted analysis, LuTx was strongly associated with the development of NTM disease. Nineteen of 34 case patients were lung transplant recipients (56%), as compared with 10 of 102 control patients (10%), corresponding to a Mantel– Haenszel OR of 11.49 (95% CI: 3.86, 34.18). Among the other factors examined in the unadjusted analysis, only a history of biopsy-proven acute rejection was associated with NTM disease at the level P < 0.05, with a Mantel–Haenszel OR of 4.00 (95% CI: 1.07, 14.90). Based on unadjusted associations with NTM disease (Table 4), the variables that were evaluated in the adjusted model included age, malnutrition, CMV disease, chronic renal insufficiency, acute rejection, receipt of tacrolimus, and receipt of azathioprine. In the adjusted analysis, we found that age and malnutrition were significant confounders of the association between LuTx and NTM disease. When age was included in the adjusted model, the OR for NTM disease and LuTx increased to 13.58 (95% CI: 4.21, 43.78). No other variables that were evaluated in the adjusted model were found to be confounders of the association between NTM disease and LuTx. In a secondary analysis, we examined the relationship between LuTx and NTM disease by characterizing the strength of association separately for single and bilateral lung transplant recipients, repeating the steps of the primary analysis. As before, only age was a significant confounding variable. In the adjusted model that accounted for matching, the OR for NTM disease among single lung transplant recipients was 9.45 (95% CI: 1.82, 48.96), and among bilateral lung transplant recipients the OR was 16.22 (95% CI: 4.24, 62.08).
M. abscessus (1) M. fortuitum (1)
Pancreaskidney
post transplant and may have served as the portal of entry.
Transplant Infectious Disease 2014: 16: 76–83
Discussion In this single-center, retrospective study, LuTx was significantly associated with the development of NTM disease, even after adjusting for potential confounding factors. Several mechanisms may explain the associa-
Longworth et al: NTM infections in SOT recipients
Unadjusted associations of clinical and demographic factors with the development of nontuberculous mycobacterial infection, with control patients matched 3:1 by date of transplantation Cases (%)
Controls (%)
N = 34
N = 102
Mantel–Haenszel OR (95% CI)
Non-lung
15 (44)
92 (90)
Reference
Lung
19 (56)
10 (10)
11.49 (3.86, 34.18)
White
26 (76)
82 (80)
Reference
Black
4 (12)
13 (13)
Variable
P-value
Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case–control study S.A. Longworth, C. Vinnard, I. Lee, K.D. Sims, T.D. Barton, E.A. Blumberg. Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case–control study. Transpl Infect Dis 2014: 16: 76–83. All rights reserved Abstract: Background. The epidemiology of nontuberculous mycobacteria (NTM) disease in solid organ transplant recipients is poorly defined. Methods. We identified all solid organ transplant recipients with NTM disease at a single center over a 7.5-year period, and collected data on patient demographics, co-morbidities, immunosuppressive medications, and rejection. We conducted a case–control study to identify risk factors for disease, matching 3 control patients to each case patient by date of transplantation. Results. A total of 34 cases of NTM disease occurred during the study period, involving 6 single lung, 13 bilateral lung, 8 heart, 4 liver, 2 kidney, and 1 pancreas-kidney recipients. Cases were predominantly male (24/34), with a median age of 55 years (interquartile range [IQR]: 46–61 years), and developed after a median of 8 months post transplantation (IQR: 2–87 months). Mycobacterium abscessus and Mycobacterium avium complex were the most common pathogens, and the lung (including pleura) was the most common site of disease. In the adjusted case–control analysis, lung transplant recipients had the highest risk of NTM disease. Conclusions. Additional studies are needed to evaluate the role of targeted surveillance measures for NTM disease in high-risk patients, particularly lung transplant recipients, and to characterize the mechanisms of disease acquisition.
S.A. Longworth1, C. Vinnard2, I. Lee3, K.D. Sims4, T.D. Barton5, E.A. Blumberg5 1
Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA, 2Department of Medicine, Division of Infectious Diseases & HIV Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA, 3 Merck Sharp & Dohme, Corp., North Wales, Pennsylvania, USA, 4Bristol-Myers Squibb, Princeton, New Jersey, USA, 5Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA Key words: mycobacteria; nontuberculous; NTM; epidemiology; risk factors; solid organ transplant Correspondence to: Emily Blumberg, MD, Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine of the University of Pennsylvania, Suite E, 3 Silverstein, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA Tel: (215) 662 7066 Fax: (215) 662 7611 E-mail: [email protected]
Received 7 December 2012, revised 10 April 2013, accepted for publication 27 May 2013 DOI: 10.1111/tid.12170 Transpl Infect Dis 2014: 16: 76–83
The nontuberculous mycobacteria (NTM) are a diverse group of organisms that are commonly found in the environment, including soil and water, and include >65 different species (1). Although NTM organisms are generally regarded as uncommon causes of human disease, few estimates have been made of disease incidence in populations. Risk factors for NTM disease include patients with acquired immunodeficiency syndrome (particularly with CD4+ T cell counts 3 years after transplantation. The longest time interval between transplantation and development of NTM disease was 13 years, observed in a kidney transplant recipient. Of note, 14 patients were transplanted before 2002; however, there was no evidence of NTM disease before their enrollment in this study. Between January 1, 2002 and July 1, 2009 at our institution, the numbers of incident episodes of NTM disease per 100 transplant recipients per year of follow-up time were 0.8 (lung recipients), 0.3 (heart recipients), 0.1 (liver recipients), and 0.02 (kidney recipients).
single case patient. Two patients (1 liver and 1 bilateral lung transplant recipient) had mixed infections, both of whom developed pleuropulmonary infections with MAC and M. abscessus. Considerable diversity was also seen in the sites of infection of case patients. Pleuropulmonary disease was the most common site of disease, accounting for 21 of 34 case patients (62%) overall, including 15 of 19 lung transplant recipients (79%). Disseminated disease was the next most common presentation, observed in 6 of 34 patients (18%). Bloodstream infection was documented in all but 1 of the case patients with disseminated disease. Heart transplant recipients had the greatest diversity with regards to sites of disease, which included disseminated disease in 3 patients, and 1 patient each with cutaneous, deep tissue, osteoarticular, pleuropulmonary, and intra-abdominal infections. Surgical site infections developed in 5 of the 34 case patients (15%), consisting of 2 heart transplant recipients, 2 lung transplant recipients, and 1 renal transplant recipient. The time that elapsed between transplanta-
Indications for transplantation among 34 solid organ transplant recipients with nontuberculous mycobacterial infections Organ (N)
Indications for transplantation (N)
Single lung (6)
Chronic obstructive pulmonary disease (2) Idiopathic pulmonary fibrosis (4)
Bilateral lung (13)
Chronic obstructive pulmonary disease (7) Idiopathic pulmonary fibrosis (2) Cystic fibrosis (2) Sarcoidosis (1) Alpha-1 antitrypsin deficiency (1)
Heart (8)
Ischemic cardiomyopathy (5) Idiopathic cardiomyopathy (2) Unknown (1)
Liver (4)
Hepatitis B-associated hepatocellular carcinoma (1)
Microbiology and sites of infection
Hepatitis C-associated hepatocellular carcinoma (1)
Sites of disease, and the organisms isolated from each site, are shown in Table 3. We found significant diversity with regard to the species of NTM organism isolated from case patients, with 6 different NTM species contributing to clinical disease. The most common isolate was M. abscessus, isolated in 15 of 34 NTM infections (44%), followed by MAC in 14 of 34 infections (41%). Mycobacterium fortuitum, M. kansasii, and Mycobacterium marinum were each responsible for infection in 2 patients, and M. chelonae was isolated in a
Budd–Chiari syndrome (1) Biliary cirrhosis (1) Kidney (2)
IgA nephropathy (1) Focal segmental glomerulosclerosis (1)
Pancreas-kidney (1)
Type 1 diabetes mellitus (1)
N, number; IgA, immunoglobulin A.
Table 2
Transplant Infectious Disease 2014: 16: 76–83
79
Longworth et al: NTM infections in SOT recipients
tion and infection in these patients ranged from 1.5 to 10 months. Four of the 5 infections were due to M. abscessus, and the fifth was with M. fortuitum (another rapidly growing NTM species). In no instance did these patients grow NTM from a culture preoperatively, as such an occurrence would have excluded them from the study. The renal transplant recipient who grew M. fortuitum from his abdomen post transplant had undergone peritoneal dialysis pre-transplant; the dialysis catheter was removed 1.5 months
Sites and infection and species of organisms in solid organ transplant recipients with nontuberculous mycobacterial infections
Type of organ transplantation
Site of infection for each type of transplant recipient (N)
Organisms isolated from each site (N)
Single lung
Pleuropulmonary (6)
MAC (4) Mycobacterium abscessus (2)
Bilateral lung
Pleuropulmonary (9)
M. abscessus (4) MAC (3) Mycobacterium fortuitum (1) Mixed infection (1): MAC and M. abscessus
Heart
Disseminated (3)
M. abscessus (3)
Cutaneous (1)
Mycobacterium marinum (1)
Disseminated (3)
M. abscessus (2) Mycobacterium kansasii (1)
Liver
Pleuropulmonary (1)
MAC (1)
Cutaneous (1)
Mycobacterium chelonae (1)
Osteoarticular (1)
M. marinum (1)
Intra-abdominal (1)
MAC(1)
Deep tissue (1)
MAC (1)
Pleuropulmonary (4)
MAC (3) Mixed infection (1): MAC and M. abscessus
Kidney
Intra-abdominal (2)
Pleuropulmonary
M. kansasii (1)
N, number; MAC, Mycobacterium avium complex.
Table 3
80
Association of LuTx and NTM infection For the case–control study, 34 case patients (median age at transplantation 53.7 years) with NTM disease post transplantation were matched to 102 control patients (median age at transplantation 53.9 years) according to date of transplantation, for a total of 136 study patients. In unadjusted analysis, LuTx was strongly associated with the development of NTM disease. Nineteen of 34 case patients were lung transplant recipients (56%), as compared with 10 of 102 control patients (10%), corresponding to a Mantel– Haenszel OR of 11.49 (95% CI: 3.86, 34.18). Among the other factors examined in the unadjusted analysis, only a history of biopsy-proven acute rejection was associated with NTM disease at the level P < 0.05, with a Mantel–Haenszel OR of 4.00 (95% CI: 1.07, 14.90). Based on unadjusted associations with NTM disease (Table 4), the variables that were evaluated in the adjusted model included age, malnutrition, CMV disease, chronic renal insufficiency, acute rejection, receipt of tacrolimus, and receipt of azathioprine. In the adjusted analysis, we found that age and malnutrition were significant confounders of the association between LuTx and NTM disease. When age was included in the adjusted model, the OR for NTM disease and LuTx increased to 13.58 (95% CI: 4.21, 43.78). No other variables that were evaluated in the adjusted model were found to be confounders of the association between NTM disease and LuTx. In a secondary analysis, we examined the relationship between LuTx and NTM disease by characterizing the strength of association separately for single and bilateral lung transplant recipients, repeating the steps of the primary analysis. As before, only age was a significant confounding variable. In the adjusted model that accounted for matching, the OR for NTM disease among single lung transplant recipients was 9.45 (95% CI: 1.82, 48.96), and among bilateral lung transplant recipients the OR was 16.22 (95% CI: 4.24, 62.08).
M. abscessus (1) M. fortuitum (1)
Pancreaskidney
post transplant and may have served as the portal of entry.
Transplant Infectious Disease 2014: 16: 76–83
Discussion In this single-center, retrospective study, LuTx was significantly associated with the development of NTM disease, even after adjusting for potential confounding factors. Several mechanisms may explain the associa-
Longworth et al: NTM infections in SOT recipients
Unadjusted associations of clinical and demographic factors with the development of nontuberculous mycobacterial infection, with control patients matched 3:1 by date of transplantation Cases (%)
Controls (%)
N = 34
N = 102
Mantel–Haenszel OR (95% CI)
Non-lung
15 (44)
92 (90)
Reference
Lung
19 (56)
10 (10)
11.49 (3.86, 34.18)
White
26 (76)
82 (80)
Reference
Black
4 (12)
13 (13)
Variable
P-value
