American Journal of Respiratory and Critical Care Medicine

Rationale: Traditionally, Mycobacterium avium complex (MAC) has been composed of M. avium and M. intracellulare; however, advances in genetic sequencing have allowed discovery of several novel species. With these discoveries, investigation of differences in risk factors, virulence, and clinical outcomes have emerged.

Objectives: We conducted a retrospective cohort study evaluating all MAC isolates obtained from pulmonary specimens at our institution from 2000 to 2012 and investigated the clinical courses associated with distinct MAC species.

Methods: To classify isolates into distinct species, a multilocus sequence analysis using rpoB and internal transcribed spacer (ITS) as targets was performed. We reviewed patient medical records to analyze clinical characteristics and outcomes for the cohort.

Measurements and Main Results: Of the isolates from the 448 included patients, 54% were M. avium, 18% were M. intracellulare, and 28% were M. chimaera. Using American Thoracic Society/Infectious Diseases Society of America criteria, patients whose isolates were identified as M. avium (adjusted odds ratio [AOR], 2.14; 95% confidence interval [CI], 1.33–3.44) or M. intracellulare (AOR, 3.12; 95% CI, 1.62–5.99) were more likely to meet criteria for infection than patients with M. chimaera. Patients infected with M. chimaera were more likely to be prescribed an immunosuppressant compared with all other patients (AOR, 2.75; 95% CI, 1.17–6.40). Patients treated for infections with M. avium (AOR, 5.64; 95% CI, 1.51–21.10) and M. chimaera (AOR, 4.47; 95% CI, 1.08–18.53) were more likely to have a clinical relapse/reinfection than those with M. intracellulare.

Conclusions: Our findings suggest that specific MAC species have varying degrees of virulence and classifying MAC isolates into distinct species aids in identifying which patients are at higher risk of clinical relapse/reinfection.

Scientific Knowledge on the Subject

The current American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines on the management of Mycobacterium avium complex (MAC) pulmonary disease do not recommend categorizing MAC isolates to the species level as there is no prognostic or therapeutic advantage in performing such identification.

What This Study Adds to the Field

We found clinical differences among the three most commonly encountered MAC species at our institution. Patients with M. chimaera isolated in culture were less likely to meet ATS/IDSA criteria for infection, suggesting a lower virulence than M. avium and M. intracellulare. Patients infected with M. chimaera were more likely to be immunosuppressed. Of patients who completed treatment for a MAC pulmonary infection, those infected with M. intracellulare were less likely to suffer clinical relapse/reinfection. Our findings propose that classifying MAC isolates into distinct species offers a potential prognostic benefit.

Traditionally, Mycobacterium avium complex (MAC) was thought to be composed primarily of M. avium and M. intracellulare, two species that are indistinguishable by standard physical and biochemical testing. Through the use of DNA probes, these organisms can be easily differentiated, but there is no current evidence that further classification into these distinct species offers a clinical advantage (1). Advances in genetic sequencing of MAC isolates have allowed for numerous new species to be added to this complex (28). With the identification of these new species, the potential for different risk factors for infection, virulence, and therapeutic strategies has emerged (2, 912). Of the limited number of studies that have compared the pathogenicity of distinct MAC species, results have been mixed. Some studies claim M. intracellulare is a more virulent species then M. avium (9, 10, 13), and conflicting reports exist on the virulence of M. chimaera (2, 12). The remainder of the MAC species are rarely recovered from humans and do not seem to play a major role in MAC pulmonary disease (1417).

Although widely accepted criteria exist to define MAC pulmonary infections (1), decisions concerning patient monitoring and treatment are often quite complicated. It is understood that not every patient who meets these criteria requires antimicrobial therapy. Conversely, some patients who do not meet the requirements for infection warrant therapy, so risks and benefits of antimicrobial treatment must be considered in patients on an individual basis (18). Once a clinician decides to begin therapy, up to 50% of patients are unable to tolerate the initial antibiotic regimen (19), and up to 45% of patients who complete the recommended treatment suffer a clinical relapse or failure of therapy (20). As the prevalence of MAC pulmonary disease continues to rise in the United States and numerous other countries (2126), clinicians are faced with a growing number of difficult decisions regarding the management of these infections.

In an effort to better understand the pathogenicity of the distinct MAC species and to aid clinicians in the management of MAC pulmonary disease, we investigated the different clinical courses associated with distinct MAC species recovered from pulmonary specimens. To accomplish this, we identified all MAC isolates grown from pulmonary mycobacterial cultures from 2000 to 2012 and subjected these samples to multilocus sequence analysis to taxonomically classify them into distinct species. We then reviewed the demographics, risk factors, clinical symptoms, treatment courses, and clinical relapses/reinfections in the patients from whom these isolates were obtained to evaluate the differences between the three most commonly encountered species: M. avium, M. intracellulare, and M. chimaera.

Patient Selection and Data Collection

From January 1, 2000, through December 31, 2012, at our institution, we performed a retrospective cohort study evaluating all patients who provided a pulmonary specimen (sputum, bronchoalveolar lavage, biopsy) that subsequently grew MAC. We reviewed each patient’s electronic medical record (EMR) and recorded patient demographics, laboratory values, comorbidities, radiographic findings, treatment courses, and episodes of clinical relapse/reinfection in a standardized data collection sheet. The majority of the variables were obtained directly from the patient medical records; however, the following variables did require interpretation. To define those with true infection, we used the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria for nontuberculous mycobacterial (NTM) pulmonary infections (1). Patients defined as undergoing a transplantation included solid organ and stem cell transplant recipients. Patients defined as experiencing a clinical relapse/reinfection (1) had to be diagnosed with MAC pulmonary disease on the basis of the ATS/IDSA criteria, (2) had to have completed the recommended antibiotic regimen for that infection (at least 12 mo of therapy), (3) had to have been labeled as clinically cured by the managing physician, based on cessation of anti-MAC therapy and symptomatic improvement, and then (4) had to have a new MAC isolate of the same species cultured from a pulmonary specimen that met ATS/IDSA criteria for infection. We chose to use the term “clinical relapse/reinfection” because of the inability to distinguish between them solely on the basis of culture results (1). All radiographic findings were taken directly from radiology reports. Patients who provided multiple positive cultures were included only once in our statistical analysis. This study was conducted at Northwestern Memorial Hospital (Chicago, IL), an 894-bed tertiary referral hospital for the greater Chicago area, and included samples obtained from hospitalized patients and those obtained from an outpatient setting. Before initiation, the study was approved by the Northwestern University Institutional Review Board.

MAC Isolate Storage and Growth

Five hundred and eighty-five continuously frozen isolates (–70°C) previously identified as MAC, using an AccuProbe MAC culture identification test (Gen-Probe, San Diego, CA), were cultured on Middlebrook 7H11 agar by incubation at 35°C for 14–21 days. Isolated colonies were subjected to PCR analysis.

PCR and Sequence Analysis

To prepare a DNA template for PCR, several bacterial colonies were suspended in 50 μl of water, boiled for 5 minutes, and centrifuged. One microliter of the template DNA was used in a 50-μl PCR. PCR amplification was performed with a GeneAmp rTth PCR kit (Applied Biosystems, Foster City, CA). Primers 5′-GGCAAGGTCACCCCGAAGGG-3′ and 5′-AGCGGCTGCTGGGTGATCATC-3′ and primers 5′-TTGTACACACCGCCCGTCA-3′ and 5′-TCTCGATGCCAAGGCATCCACC-3′ were used to amplify and sequence the β subunit of the bacterial RNA polymerase gene (rpoB) and the entire 16S–23S ribosomal DNA internal transcribed spacer (ITS) region, respectively, under previously described conditions (27, 28). Sequence comparisons of rpoB were performed by BLAST (Basic Local Alignment Search Tool) analysis, using sequences in the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/) database. Identification of M. intracellulare and M. chimaera was further confirmed by amplification and sequencing of the ITS.

Statistical Analysis

Because the vast majority of MAC isolates were M. avium, M. intracellulare, and M. chimaera, only patients with pulmonary specimens with these three species were included in the statistical analysis. Analysis of imputed data sets was performed with SPSS Statistics version 22 (IBM, Armonk, NY). As this was a retrospective study, there were instances when we could not locate certain information on a patient’s clinical course from the EMR. When a patient’s EMR did not provide information for a variable being evaluated in this study, the patient was excluded from that analysis. Baseline differences between groups were evaluated, using χ2 tests for categorical variables; continuous variables were expressed as means and compared by means of a univariate general linear model. Initial analysis of the association of individual variables and the outcomes of interest was performed with a univariate logistic regression model. Variables with a univariate analysis P < 0.25 were included in the multivariate logistic regression analysis to calculate an adjusted odds ratio.

Increasing Prevalence and PCR Identification of Distinct MAC Species

After completion of EMR review, 69 isolates (40 M. avium, 8 M. intracellulare, and 21 M. chimaera) were excluded because they were a duplicate sample from a patient included in the study. An additional 15 samples had multiple species in a single culture and were excluded. Five samples yielded MAC species that are rare causes of infection in humans (M. colombiense [two], M. marseillense, M. timonense, and M. yongonense) and were not included in the statistical analysis. After removal of these samples, we were left with 448 unique patients, 48 of whom suffered an episode of clinical relapse/reinfection. Of these samples from unique patients, 241 (54%) were M. avium, 81 (18%) were M. intracellulare, and 126 (28%) were M. chimaera. The number of patients who had MAC grown from pulmonary culture in 2012 was 4.3 times greater than the number in 2000. Each year, M. avium was the species with the highest prevalence, and since 2005, the yearly prevalence of M. chimaera has been greater than that of M. intracellulare. A yearly breakdown of these MAC isolates and the increasing prevalence at our institution are shown in Figure 1.

Overall Patient Characteristics and Interspecies Differences

The patient population had a mean age of 63.0 years, 62.3% were female, and the mean body mass index (BMI) was 23.3 kg/m2. Twenty-three percent of the samples were smear positive on initial evaluation, 15% of patients had radiographic evidence of cavitary disease, 9.4% had HIV, 4.2% were transplant patients, and 15.6% were taking an immunosuppressive medication. Of the patients for whom information was available, 58% (251 of 436) met ATS/IDSA criteria for MAC pulmonary infection, and 43% (168 of 392) were eventually started on antimicrobial therapy for MAC. Of the patients labeled as being cured by their physicians, only 35% (49 of 142) had a documented negative mycobacterial culture after initiation of antimicrobial therapy.

When patients were grouped by species, numerous differences were seen in patient characteristics including female sex (P < 0.001), smear positivity (P = 0.009), immunosuppressant use (P = 0.03), hypoxia (P = 0.02), bilateral radiographic changes (P = 0.002), and meeting ATS/IDSA criteria for pulmonary infection (P < 0.001) (Table 1). The M. intracellulare group had a higher percentage of females and more patients with bilateral radiographic changes than the other two groups. To further investigate the differences in smear positivity, immunosuppressant use, and ATS/IDSA criteria for pulmonary infections, we combined the patients in the M. avium and M. intracellulare groups and compared them with the M. chimaera group. Patients in the M. chimaera group were significantly less likely to provide a smear-positive specimen (14 vs. 26%; P = 0.006) or meet criteria for infection (43 vs. 63%; P < 0.001) and significantly more likely to be prescribed immunosuppressants (23 vs. 13%; P = 0.007).

Table 1. Characteristics of Patients with Mycobacterium avium Complex Isolated in Pulmonary Mycobacterial Culture from 2000 to 2012, Compared by Species

CharacteristicsM. avium (n = 241)M. intracellulare (n = 81)M. chimaera (n = 126)P Value*
Demographic variables (n = 448)    
 n24181126
 Female, n (%)140 (58)66 (82)73 (58)<0.001
 Age, yr, mean ± SD62.7 ± 15.965.1 ± 12.762.1 ± 16.60.35
 BMI, kg/m2, mean ± SD23.2 ± 4.822.3 ± 3.824.1 ± 7.30.09
 Current smoker, n (%)32 (13)15 (19)22 (18)0.40
 Former smoker, n (%)109 (45)38 (47)59 (47)0.94
Laboratory evaluation (n = 448)    
 n24181126 
 Smear positive, n (%)59 (25)26 (32)18 (14)0.009
 No. of positive cultures, mean ± SD1.37 ± 0.71.50 ± 0.81.30 ± 0.60.15
Comorbidities (n = 423)    
 n22379121 
 COPD, n (%)42 (19)9 (11)26 (22)0.18
 Prior TB, n (%)14 (6)4 (5)11 (9)0.48
 CAD, n (%)50 (22)12 (15)34 (28)0.10
 Malignancy, n (%)60 (27)24 (30)40 (33)0.48
 Transplantation, n (%)9 (4)1 (1)8 (7)0.18
 Immunosuppressants, n (%)28 (13)10 (13)28 (23)0.03
 HIV, n (%)26 (12)2 (3)12 (10)0.06
 DM, n (%)18 (8)6 (8)5 (4)0.37
Clinical symptoms (n = 376)    
 n19868110 
 Weight loss, n (%)37 (19)11 (16)26 (24)0.41
 Hemoptysis, n (%)30 (15)7 (10)12 (11)0.43
 Cough, n (%)148 (75)48 (71)87 (79)0.43
 Hypoxia, n (%)28 (14)3 (4)22 (20)0.02
Radiographic findings (n = 439)    
 n23680123 
 Cavitary disease, n (%)33 (14)10 (13)24 (20)0.29
 Bilateral lung disease, n (%)169 (72)71 (89)82 (67)0.002
ATS/IDSA criteria for diagnosis of pulmonary infection (n = 436)    
 n23280124
 Meets criteria, n (%)142 (61)56 (70)53 (43)<0.001
Started on treatment (n = 392)    
 n20976107 
 Yes, n (%)95 (46)36 (47)37 (35)0.12

Definition of abbreviations: ATS = American Thoracic Society; BMI = body mass index; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; DM = diabetes mellitus; IDSA = Infectious Diseases Society of America; TB = tuberculosis.

*Calculated by χ2 testing for categorical variables and general linear model univariate analysis for continuous variables.

Number of patients for whom information on group of variables was available.

Patients who were prescribed an immunosuppressive medication at the time of culture.

Univariate and Multivariate Analysis for Meeting ATS/IDSA Criteria for Pulmonary Infection

To evaluate which patients were most likely to meet ATS/IDSA criteria for MAC pulmonary infection, we performed univariate and multivariate analyses for numerous variables (Table 2). In our patient population, an individual was more likely to meet criteria for infection if that patient was female (adjusted odds ratio [AOR], 1.83; 95% confidence interval [CI], 1.15–2.91), had a lower BMI (AOR, 0.96; 95% CI, 0.92–0.99), provided a smear-positive sample (AOR, 2.46; 95% CI, 1.41–4.30), or had cavitary disease (AOR, 1.79; 95% CI, 1.04–3.23) or bilateral lung disease (AOR, 1.65; 95% CI, 1.05–2.82) on radiographic examination. Patients in the M. avium (AOR, 2.14; 95% CI, 1.33–3.44) and M. intracellulare (AOR, 3.12; 95% CI, 1.62–5.99) groups were significantly more likely to meet criteria for infection than patients in the M. chimaera group.

Table 2. Univariate and Multivariate Analyses for Meeting American Thoracic Society/Infectious Diseases Society of America Criteria for Mycobacterium avium Complex Pulmonary Infection

VariablesUnivariate AnalysisMultivariate Analysis
OR (95% CI)P ValueAOR (95% CI)*P Value
Species compared with M. chimaera    
M. avium2.11 (1.36–3.30)0.0012.14 (1.33–3.44)0.002
M. intracellulare3.13 (1.72–5.67)<0.0013.12 (1.62–5.99)0.001
Demographics    
 Age1.01 (0.99–1.02)0.201.00 (0.99–1.02)0.58
 Female2.04 (1.37–3.03)<0.0011.83 (1.15–2.91)0.01
 BMI0.95 (0.92–0.99)0.0090.96 (0.92–0.99)0.04
 Ever-smoker0.66 (0.45–0.97)0.040.69 (0.45–1.05)0.08
Laboratory values    
 Smear positive2.97 (1.79–4.92)<0.0012.46 (1.41–4.30)0.002
Comorbidities    
 COPD0.62 (0.38–1.03)0.060.66 (0.37–1.17)0.15
 Malignancy1.26 (0.81–1.93)0.30  
 Transplant0.71 (0.28–1.82)0.47  
 HIV0.69 (0.36–1.33)0.27  
 Immunosuppressants0.84 (0.49–1.42)0.51  
Radiographic findings    
 Cavitary disease1.69 (0.97–2.95)0.071.79 (1.04–3.23)0.04
 Bilateral lung disease2.22 (1.44–3.43)<0.0011.65 (1.05–2.82)0.02

Definition of abbreviations: AOR = adjusted odds ratio; BMI = body mass index; CI = confidence interval; COPD = chronic obstructive pulmonary disease; OR = odds ratio.

*Species, age, sex, BMI, smoking status, transplantation status, HIV status, immunosuppressant use, and malignancy included in multivariate analysis.

Patients who were prescribed an immunosuppressive medication at the time of culture.

Interspecies Differences in Patients with MAC Pulmonary Infections

We had a total of 251 patients who were diagnosed with MAC pulmonary infections when using ATS/IDSA criteria for NTM pulmonary infections. We grouped these patients by species and performed a univariate analysis for numerous variables (Table 3). Significant differences were noted in sex (P = 0.001), immunosuppressants (P = 0.02), bilateral lung disease (P = 0.02), and clinical relapse/reinfection (P = 0.05). Compared with those infected with M. avium or M. intracellulare, patients infected with M. chimaera were more likely to have at least one of the following underlying risk factors: immunosuppressant use, malignancy, or transplant (34 vs. 53%; χ2 P = 0.02). To further investigate the difference seen in those taking immunosuppressants, we calculated an adjusted odds ratio for this variable, comparing the patients infected with M. chimaera with those infected with M. avium or M. intracellulare. Variables included in the multivariate analysis were age, sex, BMI, smoking status, underlying malignancy, history of transplantation, and HIV. We found that patients infected with M. chimaera were more likely to be prescribed an immunosuppressive medication (AOR, 2.75; 95% CI, 1.17–6.40).

Table 3. Characteristics of Patients Meeting American Thoracic Society/Infectious Diseases Society of America Criteria for a Mycobacterium avium Complex Pulmonary Infection, Grouped by Species

CharacteristicsM. avium (n = 142)M. intracellulare (n = 56)M. chimaera (n = 53)P Value*
Demographic variables (n = 251)    
 n1425653 
 Female, n (%)89 (63)50 (89)37 (70)0.001
 Age (yr), mean ± SD64.3 ± 14.765.1 ± 12.865.9 ± 15.50.69
 BMI (kg/m2), mean ± SD22.8 ± 4.721.9 ± 3.322.5 ± 5.00.32
 Current smoker, n (%)15 (11)8 (14)5 (9)0.68
 Former smoker, n (%)65 (46)22 (39)19 (36)0.40
Laboratory evaluation (n = 251)    
 n1425653 
 Smear positive, n (%)44 (31)21 (38)12 (23)0.24
 No. of positive cultures, mean ± SD1.47 ± 0.81.64 ± 0.91.47 ± 0.70.26
Comorbidities (n = 244)    
 n1365652 
 COPD, n (%)23 (17)5 (9)9 (17)0.33
 Prior TB, n (%)8 (6)2 (4)3 (6)0.80
 CAD, n (%)29 (21)7 (13)13 (25)0.23
 Malignancy, n (%)42 (31)17 (30)18 (34)0.87
 Transplant, n (%)6 (4)0 (0)3 (6)0.23
 Immunosuppressants, n (%)14 (10)8 (14)14 (27)0.02
 HIV, n (%)16 (12)1 (2)3 (6)0.06
 DM, n (%)12 (9)6 (11)0 (0)0.07
Clinical symptoms (n = 220)    
 n1245046 
 Weight loss, n (%)24 (19)8 (16)11 (24)0.61
 Hemoptysis, n (%)19 (15)7 (14)2 (4)0.16
 Cough, n (%)88 (71)36 (72)34 (74)0.93
 Hypoxia, n (%)12 (10)3 (6)2 (4)0.45
Radiographic findings (n = 248)    
 n1405652 
 Cavitary disease, n (%)27 (19)7 (13)11 (21)0.44
 Bilateral lung disease, n (%)108 (77)52 (93)38 (73)0.02
Started on treatment (n = 222)    
 n1285440 
 Yes, n (%)71 (55)28 (52)19 (48)0.66
Clinical relapse/reinfection (n = 190)    
 n1193437 
 Yes, n (%)34 (29)3 (9)11 (29)0.05

Definition of abbreviations: BMI = body mass index; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; DM = diabetes mellitus; TB = tuberculosis.

*Calculated by χ2 testing for categorical variables and general linear model univariate analysis for continuous variables.

Number of patients for whom information on group of variables was available.

Patients who were prescribed an immunosuppressive medication at the time of culture.

Risk Factors Associated with Clinical Relapse/Reinfection

Of the 190 patients who completed a course of antimicrobial therapy, we had a total of 48 (25%) episodes of clinical relapse/reinfection. To identify risk factors for clinical relapse/reinfection, we conducted a univariate and multivariate logistic regression comparing patients who experienced clinical relapse/reinfection with those who did not (Table 4). We found that older age (AOR, 1.04; 95% CI, 1.01–1.07), lower BMI (AOR, 0.87; 95% CI, 0.78–0.96), and cavitary disease (AOR, 3.73; 95% CI, 1.38–10.09) were significantly associated with clinical relapse/reinfection. Patients infected with M. intracellulare were significantly less likely to experience clinical relapse/reinfection than patients infected with M. avium (AOR, 5.64; 95% CI, 1.51–21.10) or M. chimaera (AOR, 4.47; 95% CI, 1.08–18.53).

Table 4. Univariate and Multivariate Analyses of Variables as Predictors for Clinical Relapse/Reinfection

 Univariate AnalysisMultivariate Analysis
 OR (95% CI)P ValueAOR (95% CI)*P Value
Demographics    
 Age1.04 (1.01–1.07)0.0031.04 (1.01–1.07)0.006
 Sex (female)1.77 (0.81–3.84)0.151.75 (0.69–1.79)0.24
 BMI0.87 (0.80–0.96)0.0050.87 (0.78–0.96)0.008
 Ever-smoker0.48 (0.24–0.97)0.040.49 (0.22–1.10)0.08
Laboratory evaluation    
 Smear positive1.48 (0.77–2.84)0.241.92 (0.88–4.18)0.10
Species compared with Mycobacterium intracellulare    
M. avium4.13 (1.18–14.43)0.035.64 (1.51–21.10)0.01
M. chimaera4.37 (1.10–17.35)0.034.47 (1.08–18.53)0.04
Comorbidities    
 COPD1.99 (0.98–4.05)0.061.78 (0.70–4.51)0.23
 Prior TB0.94 (0.29–3.11)0.93  
 Malignancy0.70 (0.34–1.47)0.35  
 Immunosuppressants1.23 (0.56–2.71)0.60  
Clinical symptoms    
 Hemoptysis2.82 (0.99–8.00)0.051.84 (0.51–6.60)0.35
Radiographic findings    
 Cavitary disease2.22 (1.07–4.63)0.033.73 (1.38–10.09)0.01
 Bilateral lung disease2.55 (0.72–8.97)0.141.66 (0.42–6.61)0.40

Definition of abbreviations: AOR = adjusted odds ratio; BMI = body mass index; CI = confidence interval; COPD = chronic obstructive pulmonary disease; OR = odds ratio; TB = tuberculosis.

*Multivariate analysis includes species, age, sex, BMI, smoking status, malignancy, immunosuppressant use, and cavitary disease. Multivariate analysis was performed only if initial OR had P < 0.25.

Of the 8 transplant patients and 12 HIV-infected patients who underwent treatment for Mycobacterium avium complex, there were no relapses/reinfections, and thus we were unable to calculate an OR.

Patients who were prescribed an immunosuppressive medication at the time of culture.

From our cohort, we were able to identify numerous differences in the patient characteristics, clinical courses, and clinical relapse rates associated with distinct MAC species. On the basis of our data, M. chimaera is a less virulent species than M. avium and M. intracellulare. When M. chimaera does cause true infection, these patients are often immunosuppressed. Also, patients with M. intracellulare pulmonary disease were less likely to suffer a clinical relapse/reinfection after antibiotic therapy than patients infected with the other MAC species.

The characteristics of the patients included in our study (i.e., older population, higher number of females, lower BMI) are consistent with past studies evaluating patients with MAC pulmonary disease (9, 29, 30). In our cohort, M. avium was the most commonly identified species, and the prevalence of M. chimaera was greater than that of M. intracellulare. The prevalence of M. chimaera has been addressed in only two prior studies. In a study assessing whether the reservoir for M. intracellulare pulmonary disease was a patient’s household water supply, Wallace and colleagues performed genetic sequencing on 54 respiratory isolates previously identified as M. intracellulare. Only 4 (7.4%) of the respiratory isolates were identified as M. chimaera, whereas 49 (90.7%) were identified as M. intracellulare (31). In a German cohort, Schweickert and colleagues performed ITS identification on 166 isolates that had been previously classified as M. intracellulare, and after genetic sequencing found 143 (86%) of these samples to be M. chimaera (12). These observed differences suggest a geographic variation of distinct MAC species, as has been observed with overall NTM prevalence rates (1, 26, 3235). Our cohort improves on these prior estimates as it is larger, spanned a longer period of time, and includes an additional MAC species, M. avium, in its analysis. To our knowledge, this is the first U.S. collection of patients with M. chimaera pulmonary disease to be studied.

Overall, our patients in the M. chimaera group were less likely to be infected and more likely to be colonized with MAC than patients in the M. avium and M. intracellulare groups, suggesting M. chimaera is a less virulent species. Two prior publications have commented on M. chimaera as a pulmonary pathogen, and they disagree on the virulence of this organism. Tortoli and colleagues are responsible for defining M. chimaera as a distinct species in 2004, and based on the outcomes of the 12 patients identified from five Italian hospitals over 5 years, they concluded that M. chimaera had an unusually high virulence (2). This discrepancy may be the result of a sampling bias of patients with more severe disease, as all of their patients were hospitalized. This difference in patient population and their small sample size complicates comparison with our population. Schweickert and colleagues were able to obtain clinical data on 90 of the patients who provided an M. chimaera isolate, and concluded that only 3 (3.3%) of these patients had clinically significant pulmonary disease, suggesting that M. chimaera has low virulence (12). This rate is lower than that found in our study, but this group used different criteria for pulmonary disease (36), may have provided care for a lower number of immunosuppressed patients, and was unable to investigate the clinical courses of at least 53 patients with M. chimaera isolated in culture.

Because we believed that M. chimaera was a less virulent organism than the other MAC species, we evaluated the subset of individuals who had true pulmonary infections caused by M. chimaera. More than half of these patients had an underlying malignancy, received a stem cell or solid-organ transplant, or were taking an immunosuppressive medication, suggesting an abnormal host immune system. These findings suggest that whereas M. chimaera may have a low level of virulence, it may be more of an opportunistic pathogen than the other MAC species.

On the basis of similar rates of hemoptysis, cavitary disease, clinically relevant pulmonary disease, and need for antimicrobial therapy, our findings suggest that M. intracellulare and M. avium have similar levels of virulence, a result observed in past studies (37, 38). Alternatively, two prior clinical studies have suggested that M. intracellulare is a more virulent organism than M. avium (9, 10). Koh and colleagues evaluated a South Korean cohort and may have arrived at different conclusions because of the baseline differences in our study populations, as 50% of their patients with M. intracellulare pulmonary disease had a history of tuberculosis, 50% were male, and 26% had cavitary disease (10). Han and colleagues also suggested that M. intracellulare results in more severe pulmonary disease than M. avium; however, this study was conducted in a population of patients with underlying malignancies (9), a different population than our cohort. Our cohort is likely more similar to patient populations being evaluated in many U.S.-based tertiary care centers, perhaps lending stronger external validity in this setting than prior studies.

We found that patients with M. intracellulare pulmonary disease were less likely to experience clinical relapse/reinfection than patients infected with the other species. To our knowledge, no prior publications have commented on the rates of relapse/reinfection with respect to individual MAC species. Numerous studies have commented on environmental exposures to water supplies (household and environmental) as a risk factor for MAC pulmonary infections (31, 3942). It should be noted that such exposure could have influenced the rates of clinical relapse/reinfection reported in our cohort, but quantification of the influence of this type of exposure was beyond the scope of the current study.

One limitation of our study is its retrospective nature; all data had to be collected from EMRs, which were not widely used at our institution until 2004. This resulted in a small number of patients for whom we were unable to obtain information on all variables. However, the amount of missing data was small compared with the number of patients in our study; this helped reduce this limitation. Second, the decision on whether a patient met the ATS/IDSA criteria for infection was obtained from EMR review. It is possible that a patient could have radiographs or cultures at other hospitals that could affect this decision. Third, we wanted to assess cure in our patient population but were unable to do so because the majority of patients labeled as clinically cured, based on symptomatic improvement and cessation of anti-MAC therapy, did not have documented sputum clearance. Fourth, the use of the term clinical relapse/reinfection is not based on microbiological cure in these patients, but on the judgment of the physician managing the patient. It is possible that patients labeled clinical relapse/reinfection could represent inadequate therapy, relapse, reinfection, or a patient who never cleared his or her sputum.

In conclusion, our retrospective evaluation of a large, diverse patient population suggests that the various specific MAC species have various degrees of virulence. As physicians are evaluating a growing number of patients for MAC pulmonary disease, classification of MAC into distinct species offers a potential prognostic benefit regarding disease severity and recurrence.

The authors acknowledge the Clinical Microbiology Laboratory personnel at Northwestern Memorial Hospital for expert assistance in the initial identification and preservation of Mycobacterium avium complex isolates.

1. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, et al.; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367416.
2. Tortoli E, Rindi L, Garcia MJ, Chiaradonna P, Dei R, Garzelli C, Kroppenstedt RM, Lari N, Mattei R, Mariottini A, et al. Proposal to elevate the genetic variant MAC-A, included in the Mycobacterium avium complex, to species rank as Mycobacterium chimaera sp. nov. Int J Syst Evol Microbiol 2004;54:12771285.
3. Murcia MI, Tortoli E, Menendez MC, Palenque E, Garcia MJ. Mycobacterium colombiense sp. nov., a novel member of the Mycobacterium avium complex and description of MAC-X as a new ITS genetic variant. Int J Syst Evol Microbiol 2006;56:20492054.
4. Ben Salah I, Cayrou C, Raoult D, Drancourt M. Mycobacterium marseillense sp. nov., Mycobacterium timonense sp. nov. and Mycobacterium bouchedurhonense sp. nov., members of the Mycobacterium avium complex. Int J Syst Evol Microbiol 2009;59:28032808.
5. Bang D, Herlin T, Stegger M, Andersen AB, Torkko P, Tortoli E, Thomsen VO. Mycobacterium arosiense sp. nov., a slowly growing, scotochromogenic species causing osteomyelitis in an immunocompromised child. Int J Syst Evol Microbiol 2008;58:23982402.
6. van Ingen J, Boeree MJ, Kösters K, Wieland A, Tortoli E, Dekhuijzen PN, van Soolingen D. Proposal to elevate Mycobacterium avium complex ITS sequevar MAC-Q to Mycobacterium vulneris sp. nov. Int J Syst Evol Microbiol 2009;59:22772282.
7. van Ingen J, Lindeboom JA, Hartwig NG, de Zwaan R, Tortoli E, Dekhuijzen PN, Boeree MJ, van Soolingen D. Mycobacterium mantenii sp. nov., a pathogenic, slowly growing, scotochromogenic species. Int J Syst Evol Microbiol 2009;59:27822787.
8. Kim BJ, Math RK, Jeon CO, Yu HK, Park YG, Kook YH, Kim BJ. Mycobacterium yongonense sp. nov., a slow-growing non-chromogenic species closely related to Mycobacterium intracellulare. Int J Syst Evol Microbiol 2013;63:192199.
9. Han XY, Tarrand JJ, Infante R, Jacobson KL, Truong M. Clinical significance and epidemiologic analyses of Mycobacterium avium and Mycobacterium intracellulare among patients without AIDS. J Clin Microbiol 2005;43:44074412.
10. Koh WJ, Jeong BH, Jeon K, Lee NY, Lee KS, Woo SY, Shin SJ, Kwon OJ. Clinical significance of the differentiation between Mycobacterium avium and Mycobacterium intracellulare in M avium complex lung disease. Chest 2012;142:14821488.
11. Maekura R, Okuda Y, Hirotani A, Kitada S, Hiraga T, Yoshimura K, Yano I, Kobayashi K, Ito M. Clinical and prognostic importance of serotyping Mycobacterium avium-Mycobacterium intracellulare complex isolates in human immunodeficiency virus-negative patients. J Clin Microbiol 2005;43:31503158.
12. Schweickert B, Goldenberg O, Richter E, Göbel UB, Petrich A, Buchholz P, Moter A. Occurrence and clinical relevance of Mycobacterium chimaera sp. nov., Germany. Emerg Infect Dis 2008;14:14431446.
13. Tateishi Y, Hirayama Y, Ozeki Y, Nishiuchi Y, Yoshimura M, Kang J, Shibata A, Hirata K, Kitada S, Maekura R, et al. Virulence of Mycobacterium avium complex strains isolated from immunocompetent patients. Microb Pathog 2009;46:612.
14. Zurita J, Ortega-Paredes D, Mora M, Espinel N, Parra H, Febres L, Zurita-Salinas C. Characterization of the first report of Mycobacterium timonense infecting an HIV patient in an Ecuadorian hospital. Clin Microbiol Infect 2014;20:O1113O1116.
15. Tortoli E, Adriani B, Baruzzo S, Degl’Innocenti R, Galanti I, Lauria S, Mariottini A, Pascarella M. Pulmonary disease due to Mycobacterium arosiense, an easily misidentified pathogenic novel mycobacterium. J Clin Microbiol 2009;47:19471949.
16. Esparcia O, Navarro F, Quer M, Coll P. Lymphadenopathy caused by Mycobacterium colombiense. J Clin Microbiol 2008;46:18851887.
17. Tortoli E, Mariottini A, Pierotti P, Simonetti TM, Rossolini GM. Mycobacterium yongonense in pulmonary disease, Italy. Emerg Infect Dis 2013;19:19021904.
18. Daley CL, Griffith DE. Pulmonary non-tuberculous mycobacterial infections. Int J Tuberc Lung Dis 2010;14:665671.
19. Huang JH, Kao PN, Adi V, Ruoss SJ. Mycobacterium avium-intracellulare pulmonary infection in HIV-negative patients without preexisting lung disease: diagnostic and management limitations. Chest 1999;115:10331040.
20. Field SK, Fisher D, Cowie RL. Mycobacterium avium complex pulmonary disease in patients without HIV infection. Chest 2004;126:566581.
21. 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;185:881886.
22. Cassidy PM, Hedberg K, Saulson A, McNelly E, Winthrop KL. Nontuberculous mycobacterial disease prevalence and risk factors: a changing epidemiology. Clin Infect Dis 2009;49:e124e129.
23. Prevots DR, Shaw PA, Strickland D, Jackson LA, Raebel MA, Blosky MA, Montes de Oca R, Shea YR, Seitz AE, Holland SM, et al. Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems. Am J Respir Crit Care Med 2010;182:970976.
24. Koh WJ, Chang B, Jeong BH, Jeon K, Kim SY, Lee NY, Ki CS, Kwon OJ. Increasing recovery of nontuberculous mycobacteria from respiratory specimens over a 10-year period in a tertiary referral hospital in South Korea. Tuberc Respir Dis (Seoul) 2013;75:199204.
25. Lai CC, Tan CK, Chou CH, Hsu HL, Liao CH, Huang YT, Yang PC, Luh KT, Hsueh PR. Increasing incidence of nontuberculous mycobacteria, Taiwan, 2000-2008. Emerg Infect Dis 2010;16:294296.
26. Marras TK, Mendelson D, Marchand-Austin A, May K, Jamieson FB. Pulmonary nontuberculous mycobacterial disease, Ontario, Canada, 1998-2010. Emerg Infect Dis 2013;19:18891891.
27. Ben Salah I, Adékambi T, Raoult D, Drancourt M. rpoB sequence-based identification of Mycobacterium avium complex species. Microbiology 2008;154:37153723.
28. Frothingham R, Wilson KH. Sequence-based differentiation of strains in the Mycobacterium avium complex. J Bacteriol 1993;175:28182825.
29. Chan ED, Iseman MD. Slender, older women appear to be more susceptible to nontuberculous mycobacterial lung disease. Gend Med 2010;7:518.
30. Kim RD, Greenberg DE, Ehrmantraut ME, Guide SV, Ding L, Shea Y, Brown MR, Chernick M, Steagall WK, Glasgow CG, et al. Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome. Am J Respir Crit Care Med 2008;178:10661074.
31. Wallace RJ Jr, Iakhiaeva E, Williams MD, Brown-Elliott BA, Vasireddy S, Vasireddy R, Lande L, Peterson DD, Sawicki J, Kwait R, et al. Absence of Mycobacterium intracellulare and presence of Mycobacterium chimaera in household water and biofilm samples of patients in the United States with Mycobacterium avium complex respiratory disease. J Clin Microbiol 2013;51:17471752.
32. Aliyu G, El-Kamary SS, Abimiku A, Brown C, Tracy K, Hungerford L, Blattner W. Prevalence of non-tuberculous mycobacterial infections among tuberculosis suspects in Nigeria. PLoS ONE 2013;8:e63170.
33. Simons S, van Ingen J, Hsueh PR, Van Hung N, Dekhuijzen PN, Boeree MJ, van Soolingen D. Nontuberculous mycobacteria in respiratory tract infections, eastern Asia. Emerg Infect Dis 2011;17:343349.
34. van der Werf MJ, Ködmön C, Katalinić-Janković V, Kummik T, Soini H, Richter E, Papaventsis D, Tortoli E, Perrin M, van Soolingen D, et al. Inventory study of non-tuberculous mycobacteria in the European Union. BMC Infect Dis 2014;14:62.
35. Thomson RM; NTM working group at Queensland TB Control Centre and Queensland Mycobacterial Reference Laboratory. Changing epidemiology of pulmonary nontuberculous mycobacteria infections. Emerg Infect Dis 2010;16:15761583.
36. Medical Section of the American Lung Association. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med 1997;156:S1S25.
37. Yamori S, Tsukamura M. Comparison of prognosis of pulmonary diseases caused by Mycobacterium avium and by Mycobacterium intracellulare. Chest 1992;102:8990.
38. Maesaki S, Kohno S, Koga H, Miyazaki Y, Kaku M. A clinical comparison between Mycobacterium avium and Mycobacterium intracellulare infections. Chest 1993;104:14081411.
39. Falkinham JO III. Nontuberculous mycobacteria from household plumbing of patients with nontuberculous mycobacteria disease. Emerg Infect Dis 2011;17:419424.
40. Tichenor WS, Thurlow J, McNulty S, Brown-Elliott BA, Wallace RJ Jr, Falkinham JO III. Nontuberculous Mycobacteria in household plumbing as possible cause of chronic rhinosinusitis. Emerg Infect Dis 2012;18:16121617.
41. Nishiuchi Y, Maekura R, Kitada S, Tamaru A, Taguri T, Kira Y, Hiraga T, Hirotani A, Yoshimura K, Miki M, et al. The recovery of Mycobacterium avium-intracellulare complex (MAC) from the residential bathrooms of patients with pulmonary MAC. Clin Infect Dis 2007;45:347351.
42. Falkinham JO III, Iseman MD, de Haas P, van Soolingen D. Mycobacterium avium in a shower linked to pulmonary disease. J Water Health 2008;6:209213.
Correspondence and requests for reprints should be addressed to Daniel P. Boyle, M.D., Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, 645 N. Michigan Avenue, Suite 900, Chicago, IL 60611. E-mail:

Author Contributions: All authors were involved in the conception, hypothesis formation, and design of the study; the acquisition and analysis of the presented data; and the drafting and revision of the manuscript.

Originally Published in Press as DOI: 10.1164/rccm.201501-0067OC on April 2, 2015

Author disclosures are available with the text of this article at www.atsjournals.org.

Comments Post a Comment




New User Registration

Not Yet Registered?
Benefits of Registration Include:
 •  A Unique User Profile that will allow you to manage your current subscriptions (including online access)
 •  The ability to create favorites lists down to the article level
 •  The ability to customize email alerts to receive specific notifications about the topics you care most about and special offers
American Journal of Respiratory and Critical Care Medicine
191
11

Click to see any corrections or updates and to confirm this is the authentic version of record