Abstract
Rationale: The prognostic factors of Mycobacterium avium complex lung disease (MAC-LD) are not clearly defined.
Objectives: To assess the prognostic factors of all-cause and MAC-specific mortality in patients with MAC-LD, especially in accordance with radiographic features, first-line treatment, and host predisposition.
Methods: Medical records of 634 HIV-negative patients with MAC-LD treated at our institution in Saitama, Japan were retrospectively analyzed.
Measurements and Main Results: Patients’ mean age was 68.9 years, and median follow-up period was 4.7 years. Radiographic features included nodular/bronchiectatic (NB) disease: 482 patients (76.0%); fibrocavitary (FC) disease: 105 patients (16.6%); FC+NB disease: 30 patients (4.7%); and other types: 17 patients (3.0%). First-line treatments were observation or one drug: 479 patients (75.6%); 2 to 5 drugs: 131 patients (20.7%); and unknown: 24 patients (3.8%). A multivariate Cox proportional hazard model showed male sex, older age, presence of systemic and/or respiratory comorbidity, non-NB radiographic features, body mass index (BMI) less than 18.5 kg/m2, anemia, hypoalbuminemia, and erythrocyte sedimentation rate greater than or equal to 50 mm/h to be negative prognostic factors for all-cause mortality, and FC or FC+NB radiographic features, BMI less than 18.5 kg/m2, anemia, and C-reactive protein greater than or equal to 1.0 mg/dl to be negative prognostic factors for MAC-specific mortality.
Conclusions: The first-line treatment regimen was not associated with all-cause mortality. FC or FC+NB disease, BMI less than 18.5 kg/m2, and anemia were negative prognostic factors for both all-cause and MAC-specific mortality.
Mortality after nontuberculous mycobacterial (NTM) lung disease is influenced by the particular species. The species most frequently involved in NTM lung disease in most parts of the world is Mycobacterium avium complex (MAC). Prognostic factors of MAC lung disease have not been studied on a large scale.
Negative prognostic factors of all-cause mortality include male sex, older age, presence of comorbidity, nonnodular/bronchiectatic disease, BMI less than 18.5 kg/m2, anemia, hypoalbuminemia, and erythrocyte sedimentation rate greater than or equal to 50 mm/h. The choice of first-line treatment was not associated with all-cause mortality. Prognostic factors should be considered in the design of clinical trials for patients with MAC lung disease.
Nontuberculous mycobacteria (NTM) are ubiquitous organisms. Mycobacterium avium complex (MAC) includes the mycobacteria M. avium and Mycobacterium intracellulare, the species most frequently associated with NTM lung disease in most of the world (1–10). MAC lung disease (MAC-LD) comprises five clinical diseases: nodular/bronchiectatic (NB) disease, fibrocavitary (FC) disease, solitary pulmonary nodule, disseminated disease, and hypersensitivity-like disease (1). NB disease frequently involves the right middle lobe or lingula, occurs in predominantly postmenopausal, nonsmoking women (1, 11), and generally progresses much more slowly than FC disease. However, death may still be related to disease progression (1, 12). FC disease is characterized radiographically by apical FC change. Left untreated, FC disease generally progresses relatively quickly and can result in extensive cavitary lung destruction and respiratory failure (1). Disseminated disease is among the most common and severe infection in people with advanced HIV infections. Hypersensitivity-like disease was previously termed “hot tub lung” (1).
Sputum culture conversion rate, symptom relief, radiological improvement, relapse rate, and mortality have been used to evaluate treatment effectiveness in patients with MAC-LD (13). Drugs primarily used between 1957 and 1978 were isoniazid (INH), paraaminosalicylic acid, and streptomycin (SM) (13). Rifampin (RIF) and ethambutol (EB) were used in most treatment studies published between 1974 and 1993 (13–19). Clarithromycin (CAM) or azithromycin was included in most studies published after 1993 (20–30). Sputum culture conversion rates gradually improved over these three periods. However, the Research Committee of the British Thoracic Society (RC-BTS) reported that the 5-year mortality rate of patients with MAC-LD treated with either RIF+EB or RIF+EB+INH was 31% (31). The Committee conducted a further trial of RIF+EB+CAM versus RIF+EB+ciprofloxacin (CPFX) for 2 years and monitored results for 3 years thereafter, for which mortality rates were 48 and 29%, respectively (32). Andréjak and coworkers reported a 5-year mortality rate for patients with MAC-LD during 1997 to 2008 of 39.7% (2). Because MAC-LD mortality rates even now are not so low, treatment effectiveness might be evaluated by mortality.
The American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) guidelines state that “making the diagnosis of NTM lung disease does not necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients” (1). If evaluating treatment effectiveness on the basis of mortality, the negative prognostic factors of MAC-LD should be elucidated first; however, data on prognostic factors are very limited (2). Three different disease types in patients with Mycobacterium xenopi pulmonary infections each had a different prognosis (33). Mortality after MAC-LD may be influenced by disease type, treatment regimen, and host predisposition. Therefore, we assessed the prognostic factors of all-cause and MAC-LD progression mortality, especially in accordance with the radiographic features seen and first-line treatment undergone, in patients with MAC-LD. Some of the results of this study were previously reported in the form of an abstract (34).
We studied 634 patients with MAC-LD aged greater than 18 years of age who fulfilled the 2007 ATS/IDSA diagnostic criteria and were newly diagnosed from 1999 through 2005 and treated at Saitama Cardiovascular and Respiratory Center (a tertiary referral center with 155 beds for respiratory disease) in Saitama, Japan. We excluded patients with solitary nodule MAC-LD or patients who previously received MAC-LD treatment elsewhere.
This was a retrospective cohort study. Clinical data were collected from medical records. Baseline clinical parameters were obtained within 1 month of the initial diagnosis. Radiographic abnormalities were classified according to the following five disease patterns on the basis of chest high-resolution computed tomography (HRCT) scanning: NB, FC, FC+NB, disseminated, and unclassifiable. NB disease was defined if HRCT scans showed multiple nodules and bronchiectasis. FC disease was defined if HRCT scans showed apical fibrocavitary lesions. If a patient had coexisting NB and FC disease, the disease type was defined as FC+NB disease. If radiographic abnormalities could not be determined to fit any specific pattern because of underling pulmonary disease or in case of several nodules with consolidation, we considered them to have unclassifiable disease. No patients had hypersensitivity-like disease. Because bronchiectasis and MAC-LD often coexist, making causality difficult to determine (1), bronchiectasis was not counted as an underlying pulmonary disease. If drug administration was initiated within 6 months after diagnosis and continued for more than 3 months, this was considered the first-line treatment. If no treatment was initiated within 6 months after diagnosis, the first-line treatment was considered observation. Patients were followed through March 2010 or until death before March 2010. Survival status was obtained from medical records and/or telephone interviews. This study was approved by the institutional review board of Saitama Cardiovascular and Respiratory Center.
Categorical baseline characteristics are summarized by frequency and percent, and continuous characteristics are reported as the mean ± SD. To investigate potential risk factors of mortality, we compared baseline characteristics for each radiographic feature and the number of first-line treatment drug regimens by Fisher exact test or Kruskal-Wallis test in accordance with nominal and continuous variables, respectively. We chose the variables from these results that showed significant effector that had previously recognized clinical significance (35) for entry into univariate Cox regression analysis: sex, age, smoking history, systemic comorbidity, respiratory comorbidity, radiographic feature, body weight loss (based on patient's complaint or description in the medical record), body temperature, body mass index (BMI), lymphocyte count, hemoglobin, serum albumin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and the number of first-line treatment drugs. We then performed multivariate Cox regression analysis with backward variable selection.
Survival in each patient group was estimated by Kaplan-Meier analysis. Mortality rates of all-cause and MAC-specific mortality rates for each radiographic feature were compared with a log-rank test. A P value of less than 0.05 was considered to be statistically significant in all analyses. Missing data were categorized as “unknown” and were entered into each statistical analysis model. All data were analyzed with SAS version 9.1.3 (SAS Institute Inc., Cary, NC).
Of the 634 patients, 371 patients were female. Mean patient age was 68.9 years. No patients were infected with HIV. Comorbidities were found in 421 (66.4%) patients. Symptoms included sputum production in 311 (49.1%) patients, cough in 302 (47.6%), bloody sputum in 98 (15.5%), breathlessness in 87 (13.7%), and fever in 87 (13.7%).
Radiographic features included NB disease in 482 (76.0%) patients, FC disease in 105 (16.6%), FC+NB disease in 30 (4.7%), and other types in 17 (2.7%) (Table 1). In comparison with patients with FC or FC+NB disease, patients with NB disease were significantly more frequently female, younger, and nonsmokers, and had higher lymphocyte counts. Associated comorbidity, body weight loss, low BMI, anemia, hypoalbuminemia, and elevation of inflammatory markers occurred significantly more frequently in patients with FC or FC+NB disease than in patients with NB disease.
| Radiographic Features | ||||||
| Characteristic | Total | NB | FC | FC+NB | Others* | P Value† |
| No. of patients | 634 (100) | 482 (100) | 105 (100) | 30 (100) | 17 (100) | |
| Women | 371 (58.5) | 323 (67.0) | 29 (27.6) | 17 (56.7) | 2 (11.8) | <0.001 |
| Age, yr | 68.9 ± 11.4 | 68.1 ± 11.2 | 70.8 ± 11.8 | 75.7 ± 8.8 | 66.2 ± 13.6 | <0.001 |
| Smoker | 200 (31.5) | 127 (26.3) | 53 (50.5) | 6 (20.0) | 14 (82.4) | <0.001 |
| Comorbidity | 421 (66.4) | 301 (62.4) | 85 (81.0) | 20 (66.7) | 15 (88.2) | 0.003 |
| Respiratory disease | 243 (38.3) | 174 (36.1) | 48 (45.7) | 10 (33.3) | 11 (64.7) | 0.161 |
| Old pulmonary tuberculosis | 117 (18.2) | 73 (15.1) | 33 (31.4) | 9 (30.0) | 2 (11.8) | |
| Pulmonary emphysema | 37 (5.8) | 24 (5.0) | 9 (8.6) | 2 (6.7) | 2 (11.8) | |
| Idiopathic pulmonary fibrosis | 28 (4.4) | 17 (3.5) | 5 (4.8) | 1 (3.3) | 5 (29.4) | |
| Other interstitial pneumonia | 12 (1.9) | 12 (2.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| Lung cancer | 27 (4.2) | 20 (4.1) | 3 (2.9) | 1 (3.3) | 3 (17.6) | |
| Asthma | 11 (1.7) | 11 (2.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| Pneumoconiosis | 10 (1.6) | 5 (1.0) | 4 (3.8) | 0 (0.0) | 1 (5.9) | |
| Pulmonary tuberculosis | 5 (0.8) | 3 (0.6) | 2 (1.9) | 0 (0.0) | 0 (0.0) | |
| Others | 44 (6.9) | 39 (8.1) | 2 (1.9) | 1 (3.3) | 2 (11.8) | |
| Systemic disease | 256 (40.4) | 187 (38.8) | 51 (48.6) | 11 (36.7) | 7 (41.2) | 0.173 |
| Ischemic heart disease | 63 (9.8) | 50 (10.4) | 10 (9.5) | 0 (0.0) | 3 (17.6) | |
| Diabetes mellitus | 62 (9.7) | 38 (7.9) | 19 (18.1) | 4 (13.3) | 1 (5.9) | |
| Collagen vascular disease | 36 (5.7) | 29 (6.0) | 7 (6.7) | 0 (0.0) | 0 (0.0) | |
| Malignancy (nonpulmonary) | 41 (6.4) | 27 (5.6) | 7 (6.7) | 4 (13.3) | 3 (17.6) | |
| Chronic liver disease | 33 (5.1) | 22 (4.6) | 10 (9.5) | 1 (3.3) | 0 (0.0) | |
| Chronic renal disease | 6 (0.9) | 5 (1.0) | 1 (1.0) | 0 (0.0) | 0 (0.0) | |
| Old cerebral infarction | 2 (0.3) | 2 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| Others | 70 (10.9) | 60 (12.4) | 7 (6.7) | 2 (6.7) | 1 (5.9) | |
| Steroid use | 22 (3.5) | 12 (2.5) | 8 (7.6) | 0 (0.0) | 2 (11.8) | 0.142 |
| Methotrexate use | 6 (0.9) | 4 (0.8) | 2 (1.9) | 0 (0.0) | 0 (0.0) | 0.142 |
| Use of another antirheumatic drug | 17 (2.7) | 13 (2.7) | 4 (3.8) | 0 (0.0) | 0 (0.0) | 0.849 |
| Body weight loss | 92 (14.5) | 63 (13.1) | 19 (18.1) | 6 (20.0) | 4 (23.5) | 0.046 |
| Body temperature | 36.6 ± 0.6 | 36.6 ± 0.5 | 36.8 ± 0.7 | 36.6 ± 0.5 | 36.7 ± 0.8 | 0.053 |
| BMI, kg/m2 | 19.8 ± 3.1 | 20.0 ± 3.1 | 18.6 ± 2.7 | 17.6 ± 2.7 | 22.1 ± 3.5 | <0.001 |
| Lymphocytes, /μl | 1,492 ± 567 | 1,512 ± 518 | 1,296 ± 527 | 1,452 ± 749 | 1,960 ± 1155 | 0.002 |
| Hb, g/dl | 12.8 ± 1.6 | 12.9 ± 1.6 | 12.5 ± 1.7 | 11.9 ± 1.4 | 12.8 ± 2.3 | 0.009 |
| Albumin, g/dl | 3.9 ± 0.5 | 4.0 ± 0.4 | 3.7 ± 0.5 | 3.4 ± 0.6 | 4.0 ± 0.6 | <0.001 |
| ESR, mm/h | 42.3 ± 30.6 | 38.6 ± 28.2 | 52.5 ± 34.0 | 72.2 ± 39.4 | 42.1 ± 24.4 | <0.001 |
| CRP, mg/dl | 1.7 ± 3.8 | 1.3 ± 3.1 | 3.1 ± 5.4 | 3.2 ± 4.8 | 3.0 ± 4.9 | <0.001 |
Treatments undergone are shown in Table 2. First-line treatment regimens included observation in 438 (69.1%). Of the 172 patients who received first-line therapy, 41 (24%) were treated with a single antibacterial drug, 33 (19%) were treated with two drugs, and 98 (57%) were treated with at least three drugs. Of the 438 patients whose first-line treatment was observation, 374 (59.0%) ultimately underwent observation only.
| First-Line Treatment Regimen | No. of Patients (%) | After First-Line Therapy, No. of Patients (%) |
| Observation | 438 (69.1) | Observation only: 374 (59.0) |
| Some drug therapy: 63 (9.9) | ||
| Unknown: 1 (0.2) | ||
| One drug | 41 (6.5) | First-line drug continued: 19 (3.0) |
| CAM | 37 (5.8) | Observation: 15 (2.4) |
| FQ | 3 (0.5) | Some other drug therapy: 7 (1.1) |
| INH | 1 (0.2) | |
| Two drugs | 33 (5.2) | First-line drugs continued: 12 (1.9) |
| CAM+FQ | 26 (4.1) | Observation: 10 (1.6) |
| EB+RIF | 5 (0.8) | Some other drug therapy: 11 (1.7) |
| RIP+INH | 2 (0.3) | |
| Three drugs | 49 (7.7) | First-line drugs continued: 12 (1.9) |
| RIF+INH+EB | 31 (4.9) | Observation: 15 (2.4) |
| CAM+RIF+EB | 13 (2.1) | Some other drug therapy: 22 (3.3) |
| Other combination | 5 (0.8) | |
| Four drugs | 47 (7.4) | First-line drugs continued: 13 (2.0) |
| CAM+EB+RIF+SM | 20 (3.1) | Observation: 5 (0.8) |
| CAM+EB+RIF+FQ | 19 (3.0) | Some other drug therapy: 29 (4.6) |
| Other combination | 8 (1.3) | |
| Five drugs | 2 (0.3) | Observation: 1 (0.2) |
| CAM+EB+RIF+FQ+SM | 2 (0.3) | Some other drug therapy: 1 (0.2) |
| Unknown | 24 (3.8) | Unknown: 24 (3.8) |
Patients whose first-line treatment regimens included treatment with two to five drugs were more frequently men and had comorbidities, FC disease, body weight loss, high body temperature, low BMI, low lymphocyte count, hypoalbuminemia, and elevation of inflammatory markers (Table 3).
| Number of First-Line Treatment Drugs | ||||
| Characteristic | 0 or 1 | 2–5 | Unknown | P Value* |
| No. of patients | 479 (100.0) | 131 (100.0) | 24 (100.0) | |
| Women | 298 (62.2) | 61 (46.6) | 12 (50.0) | 0.002 |
| Age, yr | 69.0 ± 11.3 | 68.4 ± 10.6 | 69.9 ± 17.0 | 0.500 |
| Smoker | 150 (31.3) | 43 (32.8) | 7 (29.2) | 0.063 |
| Comorbidity | 307 (64.1) | 99 (75.6) | 15 (62.5) | 0.023 |
| Respiratory disease | 182 (38.0) | 56 (42.7) | 5 (20.8) | 0.363 |
| Systemic disease | 181 (37.8) | 64 (48.9) | 11 (45.8) | 0.027 |
| Radiographic features | <0.001 | |||
| NB | 397 (82.9) | 71 (54.2) | 14 (58.3) | |
| FC | 55 (11.5) | 43 (32.8) | 7 (29.2) | |
| FC+NB | 16 (3.3) | 12 (9.2) | 2 (8.3) | |
| Disseminated | 0 (0.0) | 0 (0.0) | 1 (4.2) | |
| Unclassifiable | 11 (2.3) | 5 (3.8) | 0 (0.0) | |
| Body weight loss | 56 (11.7) | 24 (18.3) | 4 (16.7) | <0.001 |
| Body temperature | 36.6 ± 0.5 | 36.8 ± 0.7 | 36.7 ± 0.4 | <0.001 |
| BMI, kg/m2 | 20.1 ± 3.0 | 19.0 ± 3.3 | 17.3 ± 2.9 | 0.008 |
| Lymphocyte, /μl | 1,555 ± 563 | 1,338 ± 528 | 1,000 ± 473 | <0.001 |
| Hb, g/dl | 12.9 ± 1.6 | 12.5 ± 1.6 | 11.9 ± 2.0 | 0.060 |
| Albumin, g/dl | 4.0 ± 0.4 | 3.7 ± 0.6 | 3.7 ± 0.3 | 0.002 |
| ESR, mm/h | 38.6 ± 28.2 | 54.2 ± 35.2 | 52.8 ± 35.0 | <0.001 |
| CRP, mg/dl | 1.2 ± 2.9 | 3.4 ± 5.4 | 3.0 ± 5.5 | <0.001 |
Death from any cause occurred in 160 (25.2%) patients over a median follow-up period of 4.7 years (range, 0–11.1 yr), and overall cumulative 5- and 10-year mortality rates were 23.9 and 46.5%, respectively (Table 4). Patients died from progression of the MAC-LD (MAC-specific) (21.9%), pneumonia (21.3%), lung cancer (10.6%), other pulmonary diseases (11.3%), nonpulmonary diseases (21.9%), and unknown causes (13.1%). Five-year and 10-year MAC-specific mortality rates were 5.4 and 15.7%, respectively.
| All-Cause Mortality | MAC-LD Mortality | |||
| Variable | 5 yr | 10 yr | 5 yr | 10 yr |
| Total | 23.9 | 46.5 | 5.4 | 15.7 |
| Radiographic features | ||||
| NB | 18.4 | 34.8 | 2.8 | 9.0 |
| FC/FC+NB | 41.1 | 74.8 | 17.1 | 38.9 |
| Others* | 50.1 | 58.4 | 0.0 | 0.0 |
| No. of treatment regimens | ||||
| 0 | 21.5 | 44.0 | 2.5 | 9.2 |
| 1 | 20.2 | 25.2 | 8.6 | 8.6 |
| 2 | 41.0 | 52.8 | 25.7 | 40.6 |
| 3 | 27.2 | 40.4 | 5.9 | 5.9 |
| 4 or 5 | 26.5 | 61.6 | 14.7 | 47.8 |
| 0 or 1 | 21.4 | 41.8 | 3.1 | 8.9 |
| 2–5 | 30.3 | 52.8 | 14.0 | 33.0 |
| Unknown | 39.8 | 70.7 | 5.9 | 5.9 |
All-cause mortality for each radiographic feature was estimated (Figure 1). The log-rank test showed a significant difference between survival curves in patients with NB disease and FC disease or FC+NB disease (P < 0.001) and that between NB disease and other disease types (P < 0.001). In a multivariate Cox proportional hazard model, male sex; older age; presence of systemic and/or respiratory comorbidity; radiographic features of FC, FC+NB, or other disease; BMI less than 18.5 kg/m2; anemia; hypoalbuminemia; and ESR greater than or equal to 50 mm/h were found to be negative prognostic factors (Table 5).
Figure 1. Kaplan-Meier survival curves of all-cause mortality according to the radiographic features of patients with Mycobacterium avium complex lung disease. The log-rank test indicated that the difference between survival curves in patients with nodular/bronchiectatic (NB) disease and fibrocavitary (FC) disease or FC+NB disease (P < 0.001) and that between patients with NB disease and the other disease types, including disseminated and unclassifiable disease, was significant (P < 0.001).
[More] [Minimize]| Univariate Cox Regression | Multivariate Cox Regression Final Model | |||||
| Variable | Crude HR | 95% CI | P Value | Adjusted HR | 95% CI | P Value |
| Sex | ||||||
| Female | Reference | — | — | Reference | — | — |
| Male | 2.585 | 1.875–3.562 | <0.001 | 1.839 | 1.292–2.618 | <0.001 |
| Age | ||||||
| <70 yr | Reference | — | — | Reference | — | — |
| ≥70 yr | 4.594 | 3.172–6.655 | <0.001 | 2.601 | 1.755–3.855 | <0.001 |
| Smoking status | ||||||
| Ex/current smoker | Reference | — | — | |||
| Never smoker | 0.505 | 0.359–0.710 | <0.001 | |||
| Unknown | 1.321 | 0.837–2.085 | 0.232 | |||
| Systemic comorbidity | ||||||
| None | Reference | — | — | Reference | — | — |
| Some | 1.931 | 1.414–2.638 | <0.001 | 1.608 | 1.161–2.228 | 0.004 |
| Respiratory comorbidity | ||||||
| None | Reference | — | — | Reference | — | — |
| Some | 2.122 | 1.553–2.900 | <0.001 | 1.454 | 1.043–2.027 | 0.027 |
| Radiographic features | ||||||
| NB | Reference | — | — | Reference | — | — |
| FC/FC+NB | 3.019 | 2.176–4.188 | <0.001 | 1.695 | 1.184–2.425 | 0.004 |
| Others* | 4.226 | 2.125–8.404 | <0.001 | 3.870 | 1.82–8.228 | <0.001 |
| Body weight loss | ||||||
| None | Reference | — | — | |||
| Some | 2.777 | 1.873–4.118 | <0.001 | |||
| Unknown | 2.897 | 2.016–4.163 | <0.001 | |||
| Body temperature | ||||||
| <37°C | Reference | — | — | |||
| ≥37°C | 1.924 | 1.294–2.861 | 0.001 | |||
| Unknown | 1.758 | 1.228–2.515 | 0.002 | |||
| BMI | ||||||
| ≥18.5 kg/m2 | Reference | — | — | Reference | — | — |
| <18.5 kg/m2 | 2.634 | 1.758–3.946 | <0.001 | 1.881 | 1.238–2.858 | 0.003 |
| Unknown | 2.981 | 2.026–4.384 | <0.001 | 1.990 | 1.329–2.979 | <0.001 |
| Lymphocytes | ||||||
| <1,000/μl | Reference | — | — | |||
| ≥1,000/μl | 0.324 | 0.211–0.496 | <0.001 | |||
| Unknown | 0.873 | 0.546–1.396 | 0.571 | |||
| Hb | ||||||
| ≥10.0 g/dl | Reference | — | — | Reference | — | — |
| <10.0 g/dl | 8.919 | 4.474–17.782 | <0.001 | 2.832 | 1.36–5.898 | 0.005 |
| Unknown | 2.722 | 1.875–3.949 | <0.001 | 1.824 | 1.068–3.113 | 0.028 |
| Albumin | ||||||
| ≥3.5 g/dl | Reference | — | — | Reference | — | — |
| <3.5 g/dl | 6.162 | 3.694–10.278 | <0.001 | 2.497 | 1.454–4.286 | <0.001 |
| Unknown | 1.994 | 1.358–2.929 | <0.001 | 1.838 | 1.182–2.857 | 0.007 |
| ESR | ||||||
| <50 mm/h | Reference | — | — | Reference | — | — |
| ≥50 mm/h | 4.046 | 2.691–6.082 | <0.001 | 2.397 | 1.509–3.808 | <0.001 |
| Unknown | 3.452 | 2.31–5.159 | <0.001 | 1.470 | 0.872–2.478 | 0.148 |
| CRP | ||||||
| <1.0 mg/dl | Reference | — | — | |||
| ≥1.0 mg/dl | 4.210 | 2.902–6.107 | <0.001 | |||
| Unknown | 2.865 | 1.907–4.304 | <0.001 | |||
| No. of drugs in first-line treatment | ||||||
| 0 or 1 | Reference | — | — | |||
| ≥2 | 1.435 | 1.006–2.047 | 0.046 | |||
| Unknown | 1.983 | 1.035–3.799 | 0.039 | |||
MAC-specific mortality for each radiographic feature was also estimated (Figure 2). The log-rank test showed significant difference between survival curves in patients with NB disease and FC disease or FC+NB disease (P < 0.001), but the difference between NB disease and other disease types was not significant (P = 0.608). In a multivariate Cox proportional hazard model, radiologic features of FC or FC+NB disease, BMI less than 18.5 kg/m2, anemia, and CRP greater than or equal to 1.0 mg/dl were all found to be negative prognostic factors (Table 6).
Figure 2. Kaplan-Meier survival curves of Mycobacterium avium complex–specific mortality according to the radiographic features. The log-rank test indicated that the difference between survival curves in patients with nodular/bronchiectatic (NB) disease and fibrocavitary (FC) disease or FC+NB disease was significant (P < 0.001), but the difference between patients with NB disease and the other disease types, including disseminated and unclassifiable disease, was not significant (P = 0.608).
[More] [Minimize]| Univariate Cox Regression | Multivariate Cox Regression Final Model | |||||
| Variable | Crude HR | 95% CI | P Value | Adjusted HR | 95% CI | P Value |
| Sex | ||||||
| Female | Reference | — | — | |||
| Male | 2.886 | 1.444–5.768 | 0.003 | |||
| Age | ||||||
| <70 yr | Reference | — | — | |||
| ≥70 yr | 3.583 | 1.703–7.539 | 0.001 | |||
| Smoking status | ||||||
| Ex/current smoker | Reference | — | — | |||
| Never smoker | 0.504 | 0.242–1.048 | 0.067 | |||
| Unknown | 1.438 | 0.552–3.746 | 0.457 | |||
| Systemic comorbidity | ||||||
| None | Reference | — | — | |||
| Some | 1.863 | 0.958–3.621 | 0.067 | |||
| Respiratory comorbidity | ||||||
| None | Reference | — | — | |||
| Some | 2.023 | 1.039–3.940 | 0.038 | |||
| Radiographic features | ||||||
| NB | Reference | — | — | Reference | — | — |
| FC/FC+NB | 7.614 | 3.83–15.139 | <0.001 | 5.325 | 2.634–10.763 | <0.001 |
| Others* | 0.000 | 0.000 | 0.989 | 0.000 | 0.000 | 0.988 |
| Body weight loss | ||||||
| None | Reference | — | — | |||
| Some | 3.981 | 1.802–8.793 | <0.001 | |||
| Unknown | 2.903 | 1.278–6.593 | 0.011 | |||
| Body temperature | ||||||
| <37°C | Reference | — | — | |||
| ≥37°C | 1.570 | 0.682–3.613 | 0.289 | |||
| Unknown | 1.163 | 0.522–2.588 | 0.712 | |||
| BMI | ||||||
| ≥18.5 kg/m2 | Reference | — | — | Reference | — | — |
| <18.5 kg/m2 | 5.796 | 2.267–14.819 | <0.001 | 4.319 | 1.655–11.270 | 0.003 |
| Unknown | 4.365 | 1.657–11.496 | 0.003 | 3.529 | 1.302–9.563 | 0.013 |
| Lymphocytes | ||||||
| <1,000/μl | Reference | — | — | |||
| ≥1,000/μl | 0.451 | 0.17–1.197 | 0.11 | |||
| Unknown | 0.953 | 0.319–2.845 | 0.931 | |||
| Hb | ||||||
| ≥10.0 g/dl | Reference | — | — | Reference | — | — |
| <10.0 g/dl | 13.908 | 4.082–47.384 | 0.001 | 5.814 | 1.677–20.161 | 0.006 |
| Unknown | 2.391 | 1.031–5.544 | 0.042 | 4.911 | 0.79–30.547 | 0.088 |
| Albumin | ||||||
| ≥3.5 g/dl | Reference | — | — | |||
| <3.5 g/dl | 6.300 | 2.341–16.955 | <0.001 | |||
| Unknown | 1.374 | 0.629–3.000 | 0.425 | |||
| ESR | ||||||
| <50 mm/h | Reference | — | — | |||
| ≥50 mm/h | 5.281 | 2.34–11.919 | <0.001 | |||
| Unknown | 2.187 | 0.863–5.542 | 0.099 | |||
| CRP | ||||||
| <1.0 mg/dl | Reference | — | — | Reference | — | — |
| ≥1.0 mg/dl | 7.381 | 3.217–16.939 | <0.001 | 4.484 | 1.923–10.455 | <0.001 |
| Unknown | 3.109 | 1.166–8.291 | 0.023 | 0.873 | 0.14–5.444 | 0.884 |
| No. of drugs in first-line treatment | ||||||
| 0 or 1 | Reference | — | — | |||
| ≥2 | 3.913 | 1.986–7.713 | <0.001 | |||
| Unknown | 1.276 | 0.169–9.647 | 0.814 | |||
Five-year and 10-year MAC-specific mortality rates for the patients treated by observation were 2.5 and 9.2%, respectively (Table 4). Of the patients treated by observation who died from MAC itself, all but one were 75 to 88 years old and had severe comorbidities.
We investigated MAC-LD to assess the prognostic factors of all-cause and MAC-specific mortality, especially in accordance with the radiographic features seen, the first-line treatment undergone, and host predisposition. Of the three HRCT disease patterns, the survival rate of patients with NB disease was the longest compared with that of patients with FC/FC+NB disease or other disease types.
The traditionally recognized presentation of FC disease has been in men in their 40s and early 50s with a history of cigarette smoking (1, 36). In the present study, male patients and smokers predominated in the FC disease group, but their mean age was 70.8 years. Findings in the present study that the patients with NB disease were predominantly women and nonsmokers with a mean age of 68.1 years were similar to those of previous studies (1, 3, 13, 37). Associated comorbidity, body weight loss, low BMI, anemia, hypoalbuminemia, and elevation of inflammatory markers occurred significantly more frequently in patients with FC or FC+NB disease than in patients with NB disease.
Some nodules present in NB disease might have a cavity (7). In the present study, such patients were categorized as having NB disease. However, some patients simultaneously had many upper lobe cavities, multiple nodules, and bronchiectasis, and we categorized such patients as having FC+NB disease. Aksamit was of the opinion that “left untreated, the disease in patients with nodular infiltrates and cylindrical bronchiectasis can progress to more diffuse disease and, in some instances, to FC disease that is essentially indistinguishable from pre-existing bronchiectatic lung disease” (38). In the present statistical analysis, because FC+NB disease had a prognosis similar to that of the FC disease, FC disease and FC+NB disease were combined into the FC/FC+NB disease group.
One of the most important and unresolved questions in MAC-LD is whether treatment must begin immediately or can be delayed. The ATS/IDSA guidelines stated that “some experts believe that because of frequent and severe adverse drug events that microbiologic cure may not be possible, especially for older, frail individuals with comorbid conditions who have difficulty tolerating multidrug MAC treatment regimens. For these patients, MAC infection can be viewed as a chronic, usually indolent, incurable disease, and less aggressive, or even suppressive, treatment strategies may be appropriate” (1). In the present study, the treatment of more than half of the patients was by observation only. The respective 5- and 10-year MAC-specific mortality rates in these patients were 2.5 and 9.2%. Most patients treated by observation who died from MAC itself were 75- to 88-year-old patients with severe comorbidities.
The 2007 ATS/IDSA guidelines recommend a three- or four-drug regimen for the treatment of MAC-LD: CAM or azithromycin, RIF, EB, ± SM or amikacin. However, randomized clinical trials demonstrated the efficacy of macrolide therapy for MAC in HIV-positive patients (32), so the RC-BTS conducted a further trial to assess the values of CAM and CPFX in the treatment of opportunist mycobacterial pulmonary disease in patients not known to be HIV positive by comparing 2-year therapy with RIF+EB+CAM versus 2-year therapy with RIF+EB+CPFX. Among the patients with MAC, mortality was higher in the CAM arm than in the CPFX arm (48 vs. 29%) (32). The RC-BTS stated that perhaps the “best buy” initial regimen could be RIF+EB, with the addition of INH or CPFX if the patient is not doing well at 12 months (32).
Of the two- to five-drug treatment regimens used in the present study, the most frequently used regimen was the ATS/IDSA-recommended regimen (CAM+RIF+EB ± SM) in 33 patients, and the second most frequently used regimen was RIF+INH+EB in 31 patients. Because our institution has 51 beds for tuberculosis, many patients who had smears positive for acid-fast bacilli and who were suspected of having tuberculosis were referred to our hospital. Among these patients, especially those with FC-type disease were treated with a three-drug regimen (RIF+INH+EB) from the first day of admission due to a suspected diagnosis of tuberculosis. After identification of the species as MAC, some patients were changed to the ATS/IDSA-recommended regimen. However, if clinical improvement was observed with the original RIF+INH+EB regimen, this regimen was not changed in some patients in the present study. This is why the RIF+INH+EB regimen was the second most frequently used regimen.
In the present study, the 5-year mortality rate of patients with MAC-LD who were treated with many regimens, including that of observation only, was 23.9%. The RC-BTS reported the 5-year mortality of the patients with MAC-LD who were treated with RIF+EB or RIF+EB+INH to be 31% (31). Andréjak and coworkers reported that the 5-year mortality rate of patients with MAC-LD during 1997 to 2008 was 39.7% (2). They reviewed the medical charts of 1,282 patients and found that the vast majority were treated appropriately according to the consensus guidelines.
Little is known about the prognostic factors of MAC-LD. It is assumed, but not proven, that mycobacterial virulence and/or host predisposition influence the prognosis (1, 3, 37). For mycobacterial virulence, progressive lung disease due to MAC infection is associated with specific variable numbers of tandem repeat genotypes of MAC (39). Another study showed that patients with serotype 4 MAC-LD had a poorer prognosis than did patients with MAC of other serotypes (40). Because patients with NB disease experience multiple and/or repeated infections due to MAC (41), the genotype or serotype of MAC isolates from culture-persistent or relapsed patients might need to be examined repeatedly. Of the NTM species, M. xenopi is associated with a worse prognosis than that of MAC (2, 31, 42). For host predisposition, negative prognostic factors of NTM lung disease included advanced age, a high level of comorbidity, and male sex (2). These factors were consistent with those of our study. Andréjak and coworkers investigated the prognostic factors of M. xenopi pulmonary infections (33). That study found two independent prognostic factors: presence of a radiological pattern of acute infiltrate was associated with a bad prognosis, whereas combination therapy with a rifamycin-containing regimen was found to be a protective factor. In the present study, FC or FC+NB disease, BMI less than 18.5 kg/m2, and anemia were negative prognostic factors for both all-cause and MAC-specific mortality. Other radiographic features, which included disseminated and unclassifiable disease, were negative prognostic factors only of all-cause mortality. Many patients with unclassifiable disease had severe respiratory comorbidities. Because the causes of death in these patients were underlying diseases, patients with other radiographic features had negative prognostic factors of all-cause mortality but did not have those of MAC-specific mortality. The first-line treatment regimen was not associated with all-cause or MAC-specific mortality. One reason might be that the patients treated with two to five drugs more frequently had negative prognostic factors than those treated with no drugs or one drug. The trial conducted by the RC-BTS showed that 2 years of treatment with RIF+EB or with RIF+EB+INH achieved results comparable with those reported with previous regimens, which often contained five or six antimycobacterial drugs, but the patients experienced considerably fewer problems from drug intolerance (31, 43). Further accumulation of data is required to assess the relation between treatment regimens and outcome.
Davidson and coworkers reported that the specific causes of death of 52 patients who died of MAC-LD included progression of MAC-LD (25%), pneumonia (9.6%), lung cancer (11.5%), other pulmonary disease (13.5%), nonpulmonary disease (25%), and unknown reason (15.4%) (15). Distributions of these causes of death are similar to those of the present study. Although Maekura and coworkers reported that 61.8% of their patients with MAC-LD died from the progression of MAC-LD (40), the MAC-specific mortality rates of the two trials by the RC-BTS were only 13 and 7.6% (31, 32, 43). Many patients in the trials conducted by the RC-BTS died of respiratory failure (32, 43). The Committee stated that “the outlook for patients with pulmonary disease due to MAC, M. malmoense or M. xenopi treated with currently available drugs continues to be poor. As these diseases appear to be markers of poor health, studies of various methods of optimising general health and of managing co-morbidity in this population are needed, just as much as research into better antimycobacterial drugs with which to devise new regimens for testing in clinical trials” (32).
One limitation of this study is that it was retrospective, so some clinical and laboratory findings were not available. Patients suspected of having MAC-LD but who did not meet the diagnostic criteria were followed with examination of three sputum specimens for acid-fast bacilli smears and culture every 3 months. Because BMI and/or blood samples were not always measured every 3 months, when the diagnosis was firmly established, some of these data were not available. Second, if patients suspected of having MAC-LD but who could not expectorate sputum were examined by bronchoscope, the day of diagnosis would be earlier, and thus the 5-year mortality rate might be lower. It is reported that bronchial washings are more sensitive for MAC isolation than are routine expectorated sputum samples (44). Finally, although routine susceptibility testing of MAC isolates is recommended for CAM (1), we did not perform it. Macrolide-resistant MAC-LD requires aggressive drug and surgical therapy for a cure (20). We could not assess the association of CAM resistance with outcome.
Despite these limitations, the present study clarified the following points. Male sex, older age, presence of systemic and/or respiratory comorbidity, non-NB radiographic features, BMI less than 18.5 kg/m2, anemia, hypoalbuminemia, and ESR greater than or equal to 50 mm/h were negative prognostic factors for all-cause mortality, whereas FC or FC+NB radiographic features, BMI less than 18.5 kg/m2, anemia, and CRP greater than or equal to 1.0 mg/dl were negative prognostic factors for MAC-specific mortality. The first-line treatment regimen was not associated with all-cause or MAC-LD progression mortality. In conclusion, as clinical trials testing the effectiveness of drug therapy in patients with MAC-LD are being designed and implemented, the trial patients need to be stratified according to these prognostic factors before randomization.
The authors thank Drs. Takashi Ishiguro, Naho Kagiyama, Koichiro Yoneda, Kazuyoshi Kurashima, and Daido Tokunaga of the Department of Respiratory Medicine at the Saitama Cardiovascular and Respiratory Center for their handling of the diagnosis and treatment of the patients with MAC-LD. They also thank Professor Manabu Iwasaki of Seikei University and Yukinori Nakajima of Medical Toukei Co., Ltd. for his advice on statistical analysis.
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Author Contributions: M.H. performed the primary data analysis. N.T. had the idea for the study. N.T. and T.K. reviewed the chest radiographs and HRCT scans. M.H. and N.T. wrote the manuscript. Y.M., T.Y., and Y.S. contributed to study design, interpreted the data, and reviewed the manuscript. All authors approved the final version of the manuscript.
Originally Published in Press as DOI: 10.1164/rccm.201107-1203OC on December 23, 2011
Author disclosures
