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Environmental Risk Factors for Pulmonary Mycobacterium avium-intracellulare Complex Disease
CHEST
Original Research CHEST INFECTIONS
Environmental Risk Factors for Pulmonary Mycobacterium avium-intracellulare Complex Disease Koichi Maekawa, MD; Yutaka Ito, MD, PhD; Toyohiro Hirai, MD, PhD; Takeshi Kubo, MD, PhD; Seiichiro Imai, MD; Shuji Tatsumi, MD; Kohei Fujita, MD; Shunji Takakura, MD, PhD; Akio Niimi, MD, PhD; Yoshitsugu Iinuma, MD, PhD; Satoshi Ichiyama, MD, PhD; Kaori Togashi, MD, PhD; and Michiaki Mishima, MD, PhD
Background: Mycobacterium avium-intracellulare complex (MAC) is a ubiquitous pathogen found in soil and water. Environmental exposure is the primary route for MAC infection. However, specific environmental risk factors have been poorly determined in immunocompetent patients with pulmonary MAC disease. Methods: A case-control study was performed with 106 patients with pulmonary MAC disease (men [women], 23 [83]; age, 64.3 ⫾ 9.2 years) and 53 age-matched control patients with bronchiectasis but not pulmonary MAC infection (men [women], 7[46]; age, 63.0 ⫾ 11.0 years). All participants completed a standardized questionnaire that included questions about medical history, smoking history, alcohol usage, age at menopause, and environment exposures. Environment exposures included soil exposure from farming or gardening; water exposure from bathing, showering, hot tub use, dishwashing, swimming, and drinking water; and pet exposure. Results: No differences were identified in the patient characteristics and underlying diseases. More case patients experienced high soil exposure (ⱖ 2 per week) than control patients (23.6% vs 9.4%, P 5 .032); this remained significant after multivariate analysis (OR, 5.9; 95% CI, 1.4-24.7; P 5 .015). There were no significant differences in other environmental exposures. Case patients with high soil exposure were significantly older than those with low soil exposure (67.3 ⫾ 7.3 years vs 64.3 ⫾ 9.5 years, P 5 .037). Other characteristics, underlying diseases, and mycobacterial species did not differ between the two groups. Conclusions: Patients with pulmonary MAC disease had significantly more soil exposure than noninfected control patients, which suggests that environmental soil exposure is a likely risk factor for the development of pulmonary MAC disease. CHEST 2011; 140(3):723–729 Abbreviations: GERD 5 gastroesophageal reflux disease; MAC 5 Mycobacterium avium-intracellulare complex; MVP 5 mitral valve prolapse; NTM 5 nontuberculous mycobacterial
avium-intracellulare complex (MAC) Mycobacterium is a ubiquitous pathogen that causes infections in both immunocompromised and immunocompetent patients. Two types of pulmonary MAC disease exist that can be differentiated by chest radiograph and CT scan. The apical fibrocavitary type is characterized as a large cavitary disease that is evident in male smokers and is often associated with preexisting emphysematous and fibrocavitary lung disease. The nodular bronchiectatic type is characterized by multiple small nodules with bronchiectasis and frequently involves the right middle lobe and lingula. This type occurs predominately in nonsmoking, postmenopausal women
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and is termed “Lady Windermere Syndrome.”1,2 Pulmonary MAC disease has been found in patients with various preexisting lung diseases and other conditions. Kim et al3 reported that female patients with pulmonary nontuberculous mycobacterial (NTM) disease had a thinner body habitus and more scoliosis, pectus excavatum, and mitral valve prolapse (MVP) than control populations. Thomson et al4 reported that gastroesophageal reflux disease (GERD), acid suppression, and clinically suspected aspiration were more common in patients with pulmonary MAC disease. MAC organisms have been isolated from various environmental sources, including soil, water, and CHEST / 140 / 3 / SEPTEMBER, 2011
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animals (eg, birds, pigs, and cattle).5-14 Several epidemiologic studies have shown that potting soils, soil samples at patients’ homes, and hospital or patients’ bathrooms, including shower water, were all potential sources of pulmonary MAC infection after detection of identical MAC isolates from patients and these environmental sources.5,11-14 Furthermore, case-control studies have shown that occupational exposure to soil was associated with MAC infection using M avium sensitin skin testing.15 Another study demonstrated that consumption of hard cheese was a risk factor for MAC disease in patients with HIV-1 infection.16 Although Kim et al3 reported that no distinct behavioral activities or exposures were found in immunocompetent patients with pulmonary NTM disease, these observational results were limited to patients with pulmonary NTM disease. Therefore, a casecontrol study was performed to determine the environmental risk factors for pulmonary MAC disease after adjustments for the potential confounding diseases and conditions in pulmonary NTM disease.
period. Age was matched between each case and control group (10-year groupings). The protocol was approved by the ethics review board of Kyoto University Hospital, and written informed consent was obtained from all patients. Data Collection All participants completed a standardized questionnaire that included questions about underlying diseases and conditions, age at menopause, smoking status, alcohol usage, and environmental exposures, such as soil exposure from farming or gardening, use of fertilizer manure or chemical matter, water exposure from taking baths, showering, hot tub use, washing dishes, or swimming in a pool, and pet exposure (eg, dog, cat, bird, or fish) (e-Figure 1). Additionally, patients were asked to complete the Frequency Scale for the Symptoms of GERD17 and the questionnaire for the diagnosis of reflux disease.18 Both the Frequency Scale for the Symptoms of GERD and Questionnaire for the Diagnosis of Reflux Disease were self-reported questionnaires, and cutoff values were set at eight points and four points, respectively. Data were also collected about the history of regular proton pump inhibitors or histamine type-2 receptor antagonists. Furthermore, chest radiographs and CT scans were retrospectively reviewed by one radiologist and two pulmonary clinicians, and the presence of scoliosis and pectus excavatum was recorded for each patient.19 Statistical Analysis
Materials and Methods Study Subjects Both case and control patients were prospectively recruited between January 2007 and January 2010 at Kyoto University Hospital. Eight patients who had a history of corticosteroid or immunosuppressive drug use and seven patients who had active malignancy were excluded. Patients either had negative results of serologic HIV testing or no obvious risk factors for HIV infection. All 106 patients with pulmonary MAC had two or more positive cultures from sputum specimens consistent with MAC infection based on American Thoracic Society guidelines.1 All 53 control patients had bronchiectatic findings on their radiographic examinations. They had either negative or a single positive MAC culture from sputum specimens (49 patients and four patients, respectively). All control patients were followed for at least 1 year and provided sputum cultures on at least three separate occasions. We isolated organisms other than MAC during the observational Manuscript received September 7, 2010; revision accepted February 9, 2011. Affiliations: From the Department of Respiratory Medicine (Drs Maekawa, Ito, Hirai, Imai, Tatsumi, Fujita, Niimi, and Mishima), the Department of Nuclear Medicine and Diagnostic Imaging (Drs Kubo and Togashi), and the Department of Clinical Laboratory Medicine (Drs Takakura and Ichiyama), Graduate School of Medicine, Kyoto University, Kyoto; and the Department of Infectious Diseases (Dr Iinuma), Kanazawa Medical University, Kanazawa, Japan. Funding/Support: The authors have reported to CHEST that no funding was received for this study. Correspondence to: Yutaka Ito, MD, PhD, Department of Respiratory Medicine, Kyoto University, 54, Kawahara, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan; e-mail: [email protected]. ac.jp © 2011 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.10-2315
A software package (JMP, version 9.0; SAS Institute; Cary, North Carolina) was used for statistical analysis. Associations for each categorical and continuous variable between the case and control groups were tested using the x2 or Wilcoxon test, respectively. Variables were included in conditional logistic regression analysis if the P values were , .1 by univariate analysis. ORs and respective 95% CIs were computed as estimates of relative risk. A P value , .05 was considered statistically significant.
Results Patient Characteristics, Mycobacterial Species, and Radiologic Findings Characteristics of case and control patients are shown in Table 1. The mean age of case patients with pulmonary MAC disease was 64.3 ⫾ 9.2 years. Women and nonsmokers comprised the majority of patients (78.3% and 81.2%, respectively). Fortyfive case patients (42.5%) had underlying diseases, and 25 case patients (23.6%) had underlying lung diseases. Case patients were lean (BMI, 19.4 ⫾ 2.2 kg/m2). Scoliosis and pectus excavatum were observed in 17.0% and 13.6% of case patients, respectively. GERD symptoms were demonstrated in 33.7% of patients, and acid-suppressive drugs were used in 18.1% of patients. No significant differences were found in the prevalence of female gender; mean age at menopause; underlying disease; body morphologic type, including BMI, scoliosis, and pectus excavatum; GERD symptoms; the use of acid-suppressive drugs; smoking status; alcohol use; or symptoms. Of 106 case patients, 75 patients (70.8%) had infection with M avium, and 19 patients had infection with
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M intracellulare. Both M avium and M intracellulare strains were isolated in 12 patients. Other NTM species were not isolated. In seven of 53 control patients, mycobacteria were cultured from sputum once only (one patient with M avium, three patients with M intracellulare, and three patients with unidentified Mycobacterium species). Pseudomonas aeruginosa was isolated in two case patients, whereas Klebsiella pneumoniae, Haemophilus influenzae, and methicillinresistant Staphylococcus aureus were isolated in each of three control patients. Seventy case patients (66.6%) and four control patients (7.7%) had received antimicrobial treatment of the isolated organisms. One hundred four case patients underwent CT scans (two were lost to follow up), and the CT scan findings are summarized in Table 2. Bronchiectasis was detected in 93 patients (89.4%) and cavities in 28 patients (26.9%). Radiographic abnormalities were more prevalent in the right middle lobe (84.6%) and lingula (77.9%). All 53 control patients demonstrated bronchiectatic findings on CT scan. Right middle lobe (44 patients, 83.0%) and lingula (36 patients, 67.9%) were also predominantly involved in the control patients. Environmental Risk Factors Table 3 shows environmental risk factors, including exposure to soil, water, and animals, in each patient group. More case patients experienced high soil exposure (ⱖ 2 per week) than control patients (23.6% vs 9.4%, P 5 .032), but there was no significant difference in the source of soil exposure and the use of fertilizers. Water exposures and caring for pets also did not significantly differ between case and control patients. Case patients tended to use hot tubs with jetted or agitated water more frequently than control patients (11.4% vs 2.4%, P 5 .09). In the multivariate analysis, high soil exposure remained significant in patients with pulmonary MAC disease (OR, 5.9; 95% CI, 1.4-24.7; P 5 .015). Next, case patients with high soil exposure (25 patients) were compared with those with low soil exposure (81 patients) to evaluate confounding factors for the frequency of soil exposure. The high soil exposure group was significantly older than the low soil exposure group (67.3 ⫾ 7.3 years vs 64.3 ⫾ 9.5 years, P 5 .037). Gender, underlying disease, morphologic features, presence of GERD, smoking status, alcohol use, and mycobacterial species did not confound the frequency of soil exposure (Table 4). Discussion This is the first case-control study, to our knowledge, showing that immunocompetent patients with pulmonary MAC disease had significantly more soil expowww.chestpubs.org
sure than bronchiectatic control patients who shared similar predisposing diseases to pulmonary NTM disease. Patients with pulmonary MAC disease in this study were predominantly postmenopausal, nonsmoking women who presented with the nodular bronchiectatic form of MAC that involved the right middle lobe and lingula. Bronchiectatic control patients in this study shared these characteristics and demonstrated radiographic findings notable for idiopathic bronchiectasis.20,21 Because estrogen deficiency was shown to increase susceptibility to MAC infection in a murine study, age at menopause and frequency of postmenopausal women were assessed and found not to differ in our study.22 The control patients in this study were distinct from the control patients in a previous case-control study that showed that specific body morphologic features, such as low BMI, scoliosis, pectus excavatum, and MVP, were noted in patients with pulmonary NTM disease.3 However, a high prevalence (10%) of pectus excavatum was also identified in adult patients with primary ciliary dyskinesia.23 Furthermore, either scoliosis or truncal asymmetry was associated with adolescent girls with lower BMI.24 Although echocardiography was not performed in our study, patients with MVP were generally associated with lower BMI.25 Thomson et al4 showed that GERD and acid suppression were more common in patients with pulmonary MAC disease than control patients matched according to preexisting lung disease. Although patients with preexisting lung disease were also matched in this study, all control patients had bronchiectasis in this study, whereas 19% of control subjects had bronchiectasis in the study by Thomson et al.4 Li et al26 reported that a 24-h esophageal pH study was positive for acid reflux in 45% of patients with non-cystic fibrosis bronchiectasis. Therefore, these reported morphologic features and high prevalence of GERD in patients with pulmonary NTM disease may also include patients with bronchiectasis and slender, older women. NTM species are ubiquitous in soil and water and have been identified around patients’ homes. Yajko et al5 reported that MAC organisms were detected in 55% of soil samples from the home environment of 290 patients with HIV infection, and some of the soil isolates were the same serotype and related genotype as the respective clinical isolates. De Groote et al11 found that one M avium isolate and two M intracellulare isolates from potting soil samples provided by patients with pulmonary MAC disease were closely related to isolates from those patients when analyzed by pulsed field gel electrophoresis. Therefore, soil exposure has been considered a possible risk factor for the development of pulmonary MAC disease. We found that soil exposure was independently associated in patients with pulmonary MAC disease. CHEST / 140 / 3 / SEPTEMBER, 2011
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Table 1—Characteristics of Patients With and Without Pulmonary MAC Disease Variables Age, y Gender, M (F) Age at menopause, y Premenopause women BMI, kg/m2 Underlying diseases Lung disease COPD Bronchial asthma Previous TB Other Malignant disease Diabetes mellitus Liver disease Renal disease Autoimmune disease Scoliosis Pectus excavatum GERD symptoms Acid-suppressive drug usea Smoking status Current Past Never Alcohol drinking habitb Symptoms Cough Sputum Hemoptysis Fever
Case Patients (MAC) (n 5 106)
Control Patients (Non-MAC) (n 5 53)
P Value
64.3 ⫾ 9.2 (34-85) 23 (83) 49.6 ⫾ 4.3 (36-58) 6 (7.5) 19.4 ⫾ 2.2 (16.7-25.0) 45 (42.5) 25 (23.6) 3 (2.8) 2 (1.9) 16 (15.1) 6 (5.7) 18 (17.0) 8 (7.6) 4 (3.8) 1 (0.9) 3 (2.8) 18 (17.0) 14 (13.6) 30 (32.6) 17 (18.1)
63.0 ⫾ 11.0 (32-84) 7 (46) 48.9 ⫾ 4.9 (35-55) 4 (9.1) 19.8 ⫾ 2.7 (15.1-27.3) 25 (47.2) 11 (20.8) 1 (1.9) 1 (1.9) 7 (13.2) 2 (3.8) 9 (17.0) 3 (5.7) 3 (5.7) 2 (3.8) 3 (5.7) 15 (28.9) 5 (10.4) 15 (37.5) 8 (18.6)
.56 .20 .71 .76 .41 .57 .69 .72 . .99 .75 .61 . .99 .66 .59 .22 .38 .09 .58 .59 .94
1 (0.9) 19 (17.9) 88 (81.2) 36 (34.0)
2 (3.8) 4 (7.5) 47 (88.7) 12 (26.4)
.11
.33
30 (28.4) 26 (24.5) 26 (24.5) 7 (6.6)
20 (37.7) 12 (22.7) 12 (22.7) 2 (3.8)
.23 .79 .61 .47
Data show No. (%) or mean ⫾ SD (range). P values were calculated by x2 test or Wilcoxon test. F 5 female; GERD 5 gastroesophageal reflux disease; M 5 male; MAC 5 Mycobacterium avium-intracellulare complex. aProton pump inhibitor and histamine type-2 receptor antagonists are included. bDrinking alcohol at least one time per week.
Exposure of aerosolized water (eg, in a hot tub) is possibly related to a hypersensitivity-like pneumonitis (hot tub lung).27 Nishiuchi et al13 found that MAC isolates were recovered from 15 of 29 bathrooms (52%) of patients with pulmonary MAC disease in Japan, and nearly one-half (seven of 15) of these bathrooms contained MAC strains that were identical or Table 2—CT Scan Findings of Case Patients Findings
No. (%)
CT scan findings Nodules Air-space disease Bronchiectasis Cavities Location Right upper lobe Right middle lobe Right lower lobe Left upper division Lingula Left lower lobe
98 (94.4) 67 (64.4) 93 (89.4) 28 (26.9) 75 (72.1) 88 (84.6) 68 (65.4) 45 (43.3) 81 (77.9) 63 (60.6)
similar to their respective clinical isolates. However, there was no association between a high frequency of water exposure, such as taking a bath, showering, hot tub use, washing dishes, or swimming in a pool, and patients with pulmonary MAC disease (Table 3). This study has some limitations. First, environmental exposures were not directly quantified, nor were MAC strains isolated from patients’ homes. Instead, patients were questioned about the frequency of environmental exposures. Therefore, it is not possible to know whether the high frequency of environmental exposure actually increased exposure to MAC organisms, and why soil (and not water) exposure was a risk for pulmonary MAC disease. Second, GERD symptoms were evaluated without a 24-h esophageal pH study, and thus asymptomatic patients may have been missed. Furthermore, no echocardiograms for the detection of MVP were performed, and MVP has been reported as a predisposing factor for pulmonary NTM disease.3 Therefore, not all of the known predisposing factors between the case and control patients could be adjusted. Furthermore, our study
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Table 3—Environmental Exposure in Patients With and Without Pulmonary MAC Disease Living Habits Soil exposure High (ⱖ 2 per week) Low Farming Gardening Use of fertilizer/manure Use of chemicals Bath High (ⱖ 1 per day) Low Showering Hot tub usea Dishwashing High (. 1 per day) Low Swimming in pool Use of natural water Caring for pets
Case Patients (MAC) (n 5 106)
Control Patients (Non-MAC) (n 5 53)
25 (23.6) 81 (76.4) 3 (3.4) 33 (37.5) 25 (28.4) 20 (22.7)
5 (9.4) 48 (90.6) 1 (2.4) 13 (31.7) 7 (17.1) 8 (19.5)
.032
78 (73.6) 28 (26.4) 76 (86.4) 10 (11.4)
47 (79.2) 11 (20.8) 38 (92.7) 1 (2.4)
.43
75 (70.8) 31 (29.2) 4 (3.8) 4 (3.8) 25 (23.6)
41 (77.4) 12 (22.6) 2 (3.8) 2 (3.8) 10 (18.9)
.38
P Value
.77 .52 .17 .68
.30 .09
. .99 . .99 .50
Data show No. (%). P values were calculated by x2 test. See Table 1 for expansion of abbreviation. aHot tub with jetted or agitated water.
population was insufficient to exclude b error in such presumed risks. Because this was a cross-sectional study, the timing of the pulmonary MAC disease diagnoses and the collection of questionnaires regarding behavioral habits and GERD symptoms were not simultaneous. Some patients were given questionnaires after their diagnoses, and the relationship of environ-
mental exposure and presence of GERD with the development of pulmonary MAC disease was unclear. However, patients with pulmonary MAC can have long periods between the time of initial infection and diagnosis. Even if data were collected at the time of diagnosis, this information may not be helpful. Last, four control patients with positive cultures for MAC
Table 4—Confounding Factors for the Frequency of Soil Exposure Variables Age, y Gender, M (F) BMI, kg/m2 Underlying diseases Lung disease Malignant disease Diabetes mellitus Liver disease Renal disease Autoimmune disease Scoliosis Pectus excavatum GERD symptoms Acid-suppressive drug usea Smoking status Current Past Never Alcohol drinking habitb Mycobacterial species Mycobacterium avium Mycobacterium intracellulare M avium and M intracellulare
High Soil Exposure (n 5 25)
Low Soil Exposure (n 5 81)
P Value
67.3 ⫾ 7.3 (51-81) 5 (20) 19.8 ⫾ 2.2 (14.5-23.2) 10 (40.0) 6 (24.0) 5 (20.0) 1 (4.0) 0 (0.0) 0 (0.0) 0 (0.0) 5 (20.0) 1 (4.2) 4 (18.2) 2 (9.1)
64.3 ⫾ 9.5 (34-85) 18 (63) 19.2 ⫾ 2.2 (13.8-25.0) 35 (43.2) 19 (23.5) 13 (16.1) 7 (8.6) 4 (4.9) 1 (1.2) 3 (3.7) 13 (16.1) 13 (16.5) 26 (37.1) 15 (20.8)
.037 .81 .17 .78 .96 .65 .44 .26 .58 .33 .65 .12 .10 .21
0 (0.0) 3 (12.0) 22 (88.0) 8 (32.0)
1 (1.2) 16 (19.8) 64 (79.0) 28 (34.6)
.57 … … .81
13 (52.0) 7 (28.0) 5 (20.0)
62 (76.5) 12 (14.8) 7 (8.6)
.059 … …
Data show No. (%) or mean ⫾ SD (range). P values were calculated by x2 test or Wilcoxon test. See Table 1 for expansion of abbreviations. aProton pump inhibitor and histamine type-2 receptor antagonists are included. bDrinking alcohol at least one time per week. www.chestpubs.org
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strains in a single sputum specimen may have met the American Thoracic Society criteria for MAC disease.1 However, the MAC strain was not isolated in more than 10 sputum samples except for the single positive sample from these patients, and bronchial washing specimens did not yield the MAC strain in two patients. Therefore, a single positive MAC culture was considered contamination. Even when those four patients were excluded from the control group, the association of high soil exposure with pulmonary MAC disease remained significant (P 5 .022). In conclusion, this study showed that patients with pulmonary MAC disease had significantly more soil exposure than bronchiectatic control patients with specific morphologic features and predisposing conditions similar to patients with pulmonary NTM disease. These findings suggest that environmental soil exposure is likely a risk factor for the development of pulmonary MAC disease. A prospective cohort study assessing environmental exposures among patients without pulmonary MAC disease is necessary to confirm this hypothesis. Acknowledgments Author contributions: Dr Maekawa: contributed to collecting and interpreting the data and drafting the manuscript. Dr Ito: contributed to the study design, recruiting patients, collecting and interpreting the data, and revising the manuscript. Dr Hirai: contributed to recruiting patients, collecting and interpreting the data, and revising the manuscript. Dr Kubo: contributed to reviewing chest radiographs and CT scans and revising the manuscript. Dr Imai: contributed to collecting the data and revising the manuscript. Dr Tatsumi: contributed to collecting the data and revising the manuscript. Dr Fujita: contributed to collecting the data and revising the manuscript. Dr Takakura: contributed to interpretation of the data and revising the manuscript. Dr Niimi: contributed to interpretation of the data and revising the manuscript. Dr Iinuma: contributed to interpretation of the data and revising the manuscript. Dr Ichiyama: contributed to interpretation of the data and revising the manuscript. Dr Togashi: contributed to interpretation of the data and revising the manuscript. Dr Mishima: contributed to supervising the study and revising the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Additional information: The e-Figure can be found in the Online Supplement at http://chestjournal.chestpubs.org/content/140/3/ 723/suppl/DC1.
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Original Research CHEST INFECTIONS
Environmental Risk Factors for Pulmonary Mycobacterium avium-intracellulare Complex Disease Koichi Maekawa, MD; Yutaka Ito, MD, PhD; Toyohiro Hirai, MD, PhD; Takeshi Kubo, MD, PhD; Seiichiro Imai, MD; Shuji Tatsumi, MD; Kohei Fujita, MD; Shunji Takakura, MD, PhD; Akio Niimi, MD, PhD; Yoshitsugu Iinuma, MD, PhD; Satoshi Ichiyama, MD, PhD; Kaori Togashi, MD, PhD; and Michiaki Mishima, MD, PhD
Background: Mycobacterium avium-intracellulare complex (MAC) is a ubiquitous pathogen found in soil and water. Environmental exposure is the primary route for MAC infection. However, specific environmental risk factors have been poorly determined in immunocompetent patients with pulmonary MAC disease. Methods: A case-control study was performed with 106 patients with pulmonary MAC disease (men [women], 23 [83]; age, 64.3 ⫾ 9.2 years) and 53 age-matched control patients with bronchiectasis but not pulmonary MAC infection (men [women], 7[46]; age, 63.0 ⫾ 11.0 years). All participants completed a standardized questionnaire that included questions about medical history, smoking history, alcohol usage, age at menopause, and environment exposures. Environment exposures included soil exposure from farming or gardening; water exposure from bathing, showering, hot tub use, dishwashing, swimming, and drinking water; and pet exposure. Results: No differences were identified in the patient characteristics and underlying diseases. More case patients experienced high soil exposure (ⱖ 2 per week) than control patients (23.6% vs 9.4%, P 5 .032); this remained significant after multivariate analysis (OR, 5.9; 95% CI, 1.4-24.7; P 5 .015). There were no significant differences in other environmental exposures. Case patients with high soil exposure were significantly older than those with low soil exposure (67.3 ⫾ 7.3 years vs 64.3 ⫾ 9.5 years, P 5 .037). Other characteristics, underlying diseases, and mycobacterial species did not differ between the two groups. Conclusions: Patients with pulmonary MAC disease had significantly more soil exposure than noninfected control patients, which suggests that environmental soil exposure is a likely risk factor for the development of pulmonary MAC disease. CHEST 2011; 140(3):723–729 Abbreviations: GERD 5 gastroesophageal reflux disease; MAC 5 Mycobacterium avium-intracellulare complex; MVP 5 mitral valve prolapse; NTM 5 nontuberculous mycobacterial
avium-intracellulare complex (MAC) Mycobacterium is a ubiquitous pathogen that causes infections in both immunocompromised and immunocompetent patients. Two types of pulmonary MAC disease exist that can be differentiated by chest radiograph and CT scan. The apical fibrocavitary type is characterized as a large cavitary disease that is evident in male smokers and is often associated with preexisting emphysematous and fibrocavitary lung disease. The nodular bronchiectatic type is characterized by multiple small nodules with bronchiectasis and frequently involves the right middle lobe and lingula. This type occurs predominately in nonsmoking, postmenopausal women
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and is termed “Lady Windermere Syndrome.”1,2 Pulmonary MAC disease has been found in patients with various preexisting lung diseases and other conditions. Kim et al3 reported that female patients with pulmonary nontuberculous mycobacterial (NTM) disease had a thinner body habitus and more scoliosis, pectus excavatum, and mitral valve prolapse (MVP) than control populations. Thomson et al4 reported that gastroesophageal reflux disease (GERD), acid suppression, and clinically suspected aspiration were more common in patients with pulmonary MAC disease. MAC organisms have been isolated from various environmental sources, including soil, water, and CHEST / 140 / 3 / SEPTEMBER, 2011
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animals (eg, birds, pigs, and cattle).5-14 Several epidemiologic studies have shown that potting soils, soil samples at patients’ homes, and hospital or patients’ bathrooms, including shower water, were all potential sources of pulmonary MAC infection after detection of identical MAC isolates from patients and these environmental sources.5,11-14 Furthermore, case-control studies have shown that occupational exposure to soil was associated with MAC infection using M avium sensitin skin testing.15 Another study demonstrated that consumption of hard cheese was a risk factor for MAC disease in patients with HIV-1 infection.16 Although Kim et al3 reported that no distinct behavioral activities or exposures were found in immunocompetent patients with pulmonary NTM disease, these observational results were limited to patients with pulmonary NTM disease. Therefore, a casecontrol study was performed to determine the environmental risk factors for pulmonary MAC disease after adjustments for the potential confounding diseases and conditions in pulmonary NTM disease.
period. Age was matched between each case and control group (10-year groupings). The protocol was approved by the ethics review board of Kyoto University Hospital, and written informed consent was obtained from all patients. Data Collection All participants completed a standardized questionnaire that included questions about underlying diseases and conditions, age at menopause, smoking status, alcohol usage, and environmental exposures, such as soil exposure from farming or gardening, use of fertilizer manure or chemical matter, water exposure from taking baths, showering, hot tub use, washing dishes, or swimming in a pool, and pet exposure (eg, dog, cat, bird, or fish) (e-Figure 1). Additionally, patients were asked to complete the Frequency Scale for the Symptoms of GERD17 and the questionnaire for the diagnosis of reflux disease.18 Both the Frequency Scale for the Symptoms of GERD and Questionnaire for the Diagnosis of Reflux Disease were self-reported questionnaires, and cutoff values were set at eight points and four points, respectively. Data were also collected about the history of regular proton pump inhibitors or histamine type-2 receptor antagonists. Furthermore, chest radiographs and CT scans were retrospectively reviewed by one radiologist and two pulmonary clinicians, and the presence of scoliosis and pectus excavatum was recorded for each patient.19 Statistical Analysis
Materials and Methods Study Subjects Both case and control patients were prospectively recruited between January 2007 and January 2010 at Kyoto University Hospital. Eight patients who had a history of corticosteroid or immunosuppressive drug use and seven patients who had active malignancy were excluded. Patients either had negative results of serologic HIV testing or no obvious risk factors for HIV infection. All 106 patients with pulmonary MAC had two or more positive cultures from sputum specimens consistent with MAC infection based on American Thoracic Society guidelines.1 All 53 control patients had bronchiectatic findings on their radiographic examinations. They had either negative or a single positive MAC culture from sputum specimens (49 patients and four patients, respectively). All control patients were followed for at least 1 year and provided sputum cultures on at least three separate occasions. We isolated organisms other than MAC during the observational Manuscript received September 7, 2010; revision accepted February 9, 2011. Affiliations: From the Department of Respiratory Medicine (Drs Maekawa, Ito, Hirai, Imai, Tatsumi, Fujita, Niimi, and Mishima), the Department of Nuclear Medicine and Diagnostic Imaging (Drs Kubo and Togashi), and the Department of Clinical Laboratory Medicine (Drs Takakura and Ichiyama), Graduate School of Medicine, Kyoto University, Kyoto; and the Department of Infectious Diseases (Dr Iinuma), Kanazawa Medical University, Kanazawa, Japan. Funding/Support: The authors have reported to CHEST that no funding was received for this study. Correspondence to: Yutaka Ito, MD, PhD, Department of Respiratory Medicine, Kyoto University, 54, Kawahara, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan; e-mail: [email protected]. ac.jp © 2011 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.10-2315
A software package (JMP, version 9.0; SAS Institute; Cary, North Carolina) was used for statistical analysis. Associations for each categorical and continuous variable between the case and control groups were tested using the x2 or Wilcoxon test, respectively. Variables were included in conditional logistic regression analysis if the P values were , .1 by univariate analysis. ORs and respective 95% CIs were computed as estimates of relative risk. A P value , .05 was considered statistically significant.
Results Patient Characteristics, Mycobacterial Species, and Radiologic Findings Characteristics of case and control patients are shown in Table 1. The mean age of case patients with pulmonary MAC disease was 64.3 ⫾ 9.2 years. Women and nonsmokers comprised the majority of patients (78.3% and 81.2%, respectively). Fortyfive case patients (42.5%) had underlying diseases, and 25 case patients (23.6%) had underlying lung diseases. Case patients were lean (BMI, 19.4 ⫾ 2.2 kg/m2). Scoliosis and pectus excavatum were observed in 17.0% and 13.6% of case patients, respectively. GERD symptoms were demonstrated in 33.7% of patients, and acid-suppressive drugs were used in 18.1% of patients. No significant differences were found in the prevalence of female gender; mean age at menopause; underlying disease; body morphologic type, including BMI, scoliosis, and pectus excavatum; GERD symptoms; the use of acid-suppressive drugs; smoking status; alcohol use; or symptoms. Of 106 case patients, 75 patients (70.8%) had infection with M avium, and 19 patients had infection with
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M intracellulare. Both M avium and M intracellulare strains were isolated in 12 patients. Other NTM species were not isolated. In seven of 53 control patients, mycobacteria were cultured from sputum once only (one patient with M avium, three patients with M intracellulare, and three patients with unidentified Mycobacterium species). Pseudomonas aeruginosa was isolated in two case patients, whereas Klebsiella pneumoniae, Haemophilus influenzae, and methicillinresistant Staphylococcus aureus were isolated in each of three control patients. Seventy case patients (66.6%) and four control patients (7.7%) had received antimicrobial treatment of the isolated organisms. One hundred four case patients underwent CT scans (two were lost to follow up), and the CT scan findings are summarized in Table 2. Bronchiectasis was detected in 93 patients (89.4%) and cavities in 28 patients (26.9%). Radiographic abnormalities were more prevalent in the right middle lobe (84.6%) and lingula (77.9%). All 53 control patients demonstrated bronchiectatic findings on CT scan. Right middle lobe (44 patients, 83.0%) and lingula (36 patients, 67.9%) were also predominantly involved in the control patients. Environmental Risk Factors Table 3 shows environmental risk factors, including exposure to soil, water, and animals, in each patient group. More case patients experienced high soil exposure (ⱖ 2 per week) than control patients (23.6% vs 9.4%, P 5 .032), but there was no significant difference in the source of soil exposure and the use of fertilizers. Water exposures and caring for pets also did not significantly differ between case and control patients. Case patients tended to use hot tubs with jetted or agitated water more frequently than control patients (11.4% vs 2.4%, P 5 .09). In the multivariate analysis, high soil exposure remained significant in patients with pulmonary MAC disease (OR, 5.9; 95% CI, 1.4-24.7; P 5 .015). Next, case patients with high soil exposure (25 patients) were compared with those with low soil exposure (81 patients) to evaluate confounding factors for the frequency of soil exposure. The high soil exposure group was significantly older than the low soil exposure group (67.3 ⫾ 7.3 years vs 64.3 ⫾ 9.5 years, P 5 .037). Gender, underlying disease, morphologic features, presence of GERD, smoking status, alcohol use, and mycobacterial species did not confound the frequency of soil exposure (Table 4). Discussion This is the first case-control study, to our knowledge, showing that immunocompetent patients with pulmonary MAC disease had significantly more soil expowww.chestpubs.org
sure than bronchiectatic control patients who shared similar predisposing diseases to pulmonary NTM disease. Patients with pulmonary MAC disease in this study were predominantly postmenopausal, nonsmoking women who presented with the nodular bronchiectatic form of MAC that involved the right middle lobe and lingula. Bronchiectatic control patients in this study shared these characteristics and demonstrated radiographic findings notable for idiopathic bronchiectasis.20,21 Because estrogen deficiency was shown to increase susceptibility to MAC infection in a murine study, age at menopause and frequency of postmenopausal women were assessed and found not to differ in our study.22 The control patients in this study were distinct from the control patients in a previous case-control study that showed that specific body morphologic features, such as low BMI, scoliosis, pectus excavatum, and MVP, were noted in patients with pulmonary NTM disease.3 However, a high prevalence (10%) of pectus excavatum was also identified in adult patients with primary ciliary dyskinesia.23 Furthermore, either scoliosis or truncal asymmetry was associated with adolescent girls with lower BMI.24 Although echocardiography was not performed in our study, patients with MVP were generally associated with lower BMI.25 Thomson et al4 showed that GERD and acid suppression were more common in patients with pulmonary MAC disease than control patients matched according to preexisting lung disease. Although patients with preexisting lung disease were also matched in this study, all control patients had bronchiectasis in this study, whereas 19% of control subjects had bronchiectasis in the study by Thomson et al.4 Li et al26 reported that a 24-h esophageal pH study was positive for acid reflux in 45% of patients with non-cystic fibrosis bronchiectasis. Therefore, these reported morphologic features and high prevalence of GERD in patients with pulmonary NTM disease may also include patients with bronchiectasis and slender, older women. NTM species are ubiquitous in soil and water and have been identified around patients’ homes. Yajko et al5 reported that MAC organisms were detected in 55% of soil samples from the home environment of 290 patients with HIV infection, and some of the soil isolates were the same serotype and related genotype as the respective clinical isolates. De Groote et al11 found that one M avium isolate and two M intracellulare isolates from potting soil samples provided by patients with pulmonary MAC disease were closely related to isolates from those patients when analyzed by pulsed field gel electrophoresis. Therefore, soil exposure has been considered a possible risk factor for the development of pulmonary MAC disease. We found that soil exposure was independently associated in patients with pulmonary MAC disease. CHEST / 140 / 3 / SEPTEMBER, 2011
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Table 1—Characteristics of Patients With and Without Pulmonary MAC Disease Variables Age, y Gender, M (F) Age at menopause, y Premenopause women BMI, kg/m2 Underlying diseases Lung disease COPD Bronchial asthma Previous TB Other Malignant disease Diabetes mellitus Liver disease Renal disease Autoimmune disease Scoliosis Pectus excavatum GERD symptoms Acid-suppressive drug usea Smoking status Current Past Never Alcohol drinking habitb Symptoms Cough Sputum Hemoptysis Fever
Case Patients (MAC) (n 5 106)
Control Patients (Non-MAC) (n 5 53)
P Value
64.3 ⫾ 9.2 (34-85) 23 (83) 49.6 ⫾ 4.3 (36-58) 6 (7.5) 19.4 ⫾ 2.2 (16.7-25.0) 45 (42.5) 25 (23.6) 3 (2.8) 2 (1.9) 16 (15.1) 6 (5.7) 18 (17.0) 8 (7.6) 4 (3.8) 1 (0.9) 3 (2.8) 18 (17.0) 14 (13.6) 30 (32.6) 17 (18.1)
63.0 ⫾ 11.0 (32-84) 7 (46) 48.9 ⫾ 4.9 (35-55) 4 (9.1) 19.8 ⫾ 2.7 (15.1-27.3) 25 (47.2) 11 (20.8) 1 (1.9) 1 (1.9) 7 (13.2) 2 (3.8) 9 (17.0) 3 (5.7) 3 (5.7) 2 (3.8) 3 (5.7) 15 (28.9) 5 (10.4) 15 (37.5) 8 (18.6)
.56 .20 .71 .76 .41 .57 .69 .72 . .99 .75 .61 . .99 .66 .59 .22 .38 .09 .58 .59 .94
1 (0.9) 19 (17.9) 88 (81.2) 36 (34.0)
2 (3.8) 4 (7.5) 47 (88.7) 12 (26.4)
.11
.33
30 (28.4) 26 (24.5) 26 (24.5) 7 (6.6)
20 (37.7) 12 (22.7) 12 (22.7) 2 (3.8)
.23 .79 .61 .47
Data show No. (%) or mean ⫾ SD (range). P values were calculated by x2 test or Wilcoxon test. F 5 female; GERD 5 gastroesophageal reflux disease; M 5 male; MAC 5 Mycobacterium avium-intracellulare complex. aProton pump inhibitor and histamine type-2 receptor antagonists are included. bDrinking alcohol at least one time per week.
Exposure of aerosolized water (eg, in a hot tub) is possibly related to a hypersensitivity-like pneumonitis (hot tub lung).27 Nishiuchi et al13 found that MAC isolates were recovered from 15 of 29 bathrooms (52%) of patients with pulmonary MAC disease in Japan, and nearly one-half (seven of 15) of these bathrooms contained MAC strains that were identical or Table 2—CT Scan Findings of Case Patients Findings
No. (%)
CT scan findings Nodules Air-space disease Bronchiectasis Cavities Location Right upper lobe Right middle lobe Right lower lobe Left upper division Lingula Left lower lobe
98 (94.4) 67 (64.4) 93 (89.4) 28 (26.9) 75 (72.1) 88 (84.6) 68 (65.4) 45 (43.3) 81 (77.9) 63 (60.6)
similar to their respective clinical isolates. However, there was no association between a high frequency of water exposure, such as taking a bath, showering, hot tub use, washing dishes, or swimming in a pool, and patients with pulmonary MAC disease (Table 3). This study has some limitations. First, environmental exposures were not directly quantified, nor were MAC strains isolated from patients’ homes. Instead, patients were questioned about the frequency of environmental exposures. Therefore, it is not possible to know whether the high frequency of environmental exposure actually increased exposure to MAC organisms, and why soil (and not water) exposure was a risk for pulmonary MAC disease. Second, GERD symptoms were evaluated without a 24-h esophageal pH study, and thus asymptomatic patients may have been missed. Furthermore, no echocardiograms for the detection of MVP were performed, and MVP has been reported as a predisposing factor for pulmonary NTM disease.3 Therefore, not all of the known predisposing factors between the case and control patients could be adjusted. Furthermore, our study
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Table 3—Environmental Exposure in Patients With and Without Pulmonary MAC Disease Living Habits Soil exposure High (ⱖ 2 per week) Low Farming Gardening Use of fertilizer/manure Use of chemicals Bath High (ⱖ 1 per day) Low Showering Hot tub usea Dishwashing High (. 1 per day) Low Swimming in pool Use of natural water Caring for pets
Case Patients (MAC) (n 5 106)
Control Patients (Non-MAC) (n 5 53)
25 (23.6) 81 (76.4) 3 (3.4) 33 (37.5) 25 (28.4) 20 (22.7)
5 (9.4) 48 (90.6) 1 (2.4) 13 (31.7) 7 (17.1) 8 (19.5)
.032
78 (73.6) 28 (26.4) 76 (86.4) 10 (11.4)
47 (79.2) 11 (20.8) 38 (92.7) 1 (2.4)
.43
75 (70.8) 31 (29.2) 4 (3.8) 4 (3.8) 25 (23.6)
41 (77.4) 12 (22.6) 2 (3.8) 2 (3.8) 10 (18.9)
.38
P Value
.77 .52 .17 .68
.30 .09
. .99 . .99 .50
Data show No. (%). P values were calculated by x2 test. See Table 1 for expansion of abbreviation. aHot tub with jetted or agitated water.
population was insufficient to exclude b error in such presumed risks. Because this was a cross-sectional study, the timing of the pulmonary MAC disease diagnoses and the collection of questionnaires regarding behavioral habits and GERD symptoms were not simultaneous. Some patients were given questionnaires after their diagnoses, and the relationship of environ-
mental exposure and presence of GERD with the development of pulmonary MAC disease was unclear. However, patients with pulmonary MAC can have long periods between the time of initial infection and diagnosis. Even if data were collected at the time of diagnosis, this information may not be helpful. Last, four control patients with positive cultures for MAC
Table 4—Confounding Factors for the Frequency of Soil Exposure Variables Age, y Gender, M (F) BMI, kg/m2 Underlying diseases Lung disease Malignant disease Diabetes mellitus Liver disease Renal disease Autoimmune disease Scoliosis Pectus excavatum GERD symptoms Acid-suppressive drug usea Smoking status Current Past Never Alcohol drinking habitb Mycobacterial species Mycobacterium avium Mycobacterium intracellulare M avium and M intracellulare
High Soil Exposure (n 5 25)
Low Soil Exposure (n 5 81)
P Value
67.3 ⫾ 7.3 (51-81) 5 (20) 19.8 ⫾ 2.2 (14.5-23.2) 10 (40.0) 6 (24.0) 5 (20.0) 1 (4.0) 0 (0.0) 0 (0.0) 0 (0.0) 5 (20.0) 1 (4.2) 4 (18.2) 2 (9.1)
64.3 ⫾ 9.5 (34-85) 18 (63) 19.2 ⫾ 2.2 (13.8-25.0) 35 (43.2) 19 (23.5) 13 (16.1) 7 (8.6) 4 (4.9) 1 (1.2) 3 (3.7) 13 (16.1) 13 (16.5) 26 (37.1) 15 (20.8)
.037 .81 .17 .78 .96 .65 .44 .26 .58 .33 .65 .12 .10 .21
0 (0.0) 3 (12.0) 22 (88.0) 8 (32.0)
1 (1.2) 16 (19.8) 64 (79.0) 28 (34.6)
.57 … … .81
13 (52.0) 7 (28.0) 5 (20.0)
62 (76.5) 12 (14.8) 7 (8.6)
.059 … …
Data show No. (%) or mean ⫾ SD (range). P values were calculated by x2 test or Wilcoxon test. See Table 1 for expansion of abbreviations. aProton pump inhibitor and histamine type-2 receptor antagonists are included. bDrinking alcohol at least one time per week. www.chestpubs.org
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strains in a single sputum specimen may have met the American Thoracic Society criteria for MAC disease.1 However, the MAC strain was not isolated in more than 10 sputum samples except for the single positive sample from these patients, and bronchial washing specimens did not yield the MAC strain in two patients. Therefore, a single positive MAC culture was considered contamination. Even when those four patients were excluded from the control group, the association of high soil exposure with pulmonary MAC disease remained significant (P 5 .022). In conclusion, this study showed that patients with pulmonary MAC disease had significantly more soil exposure than bronchiectatic control patients with specific morphologic features and predisposing conditions similar to patients with pulmonary NTM disease. These findings suggest that environmental soil exposure is likely a risk factor for the development of pulmonary MAC disease. A prospective cohort study assessing environmental exposures among patients without pulmonary MAC disease is necessary to confirm this hypothesis. Acknowledgments Author contributions: Dr Maekawa: contributed to collecting and interpreting the data and drafting the manuscript. Dr Ito: contributed to the study design, recruiting patients, collecting and interpreting the data, and revising the manuscript. Dr Hirai: contributed to recruiting patients, collecting and interpreting the data, and revising the manuscript. Dr Kubo: contributed to reviewing chest radiographs and CT scans and revising the manuscript. Dr Imai: contributed to collecting the data and revising the manuscript. Dr Tatsumi: contributed to collecting the data and revising the manuscript. Dr Fujita: contributed to collecting the data and revising the manuscript. Dr Takakura: contributed to interpretation of the data and revising the manuscript. Dr Niimi: contributed to interpretation of the data and revising the manuscript. Dr Iinuma: contributed to interpretation of the data and revising the manuscript. Dr Ichiyama: contributed to interpretation of the data and revising the manuscript. Dr Togashi: contributed to interpretation of the data and revising the manuscript. Dr Mishima: contributed to supervising the study and revising the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Additional information: The e-Figure can be found in the Online Supplement at http://chestjournal.chestpubs.org/content/140/3/ 723/suppl/DC1.
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