Abstract
To predict the natural history of pulmonary Mycobacterium avium-intracellulare (MAI) infection with nodular bronchiectasis, we retrospectively evaluated clinical manifestations, laboratory data, and bronchoalveolar lavage fluid (BALF) findings in 57 patients. The patients received follow-up chest computed tomographic scans and testing for sputum bacteriology between intervals of at least 12 mo. They were divided into two groups after observation for 28 ± 13 mo: deteriorated (n = 34) and not-deteriorated (n = 23). There were no patients with spontaneous improvement. At the start of observation, the mean age was greater in the deteriorated group (69 ± 9 yr) than in the not-deteriorated group (57 ± 9 yr). The mean body-mass index was lower in the deteriorated group (19.2 ± 3.1 kg/m2) than in the not-deteriorated group (21.5 ± 1.5 kg/m2). C-reactive protein, erythrocyte sedimentation rate, and carbohydrate antigen 19-9 were significantly elevated in the deteriorated group. The BALF findings of the deteriorated group showed that the neutrophil cell counts were significantly increased. Thirty-four of 57 patients with pulmonary MAI infection with nodular bronchiectasis had progressive clinical and/or radiographic disease. The older and thinner patients tended to become worse. Neutrophil-related inflammation associated with a decrease in CD4 + lymphocyte might reflect the progression of pulmonary MAI infection with nodular bronchiectasis. Yamazaki Y, Kubo K, Takamizawa A, Yamamoto H, Honda T, Sone S. Markers indicating deterioration of pulmonary Mycobacterium avium-intracellulare infection.
Pulmonary Mycobacterium avium-intracellulare (MAI) infection usually occurs in patients with damaged lungs, including those with chronic obstructive lung disease (COPD), pulmonary tuberculosis, bronchiectasis, or pneumonoconiosis (1-3). However, MAI infection may also occur in patients without predisposing lung disease or demonstrable immunodeficiency, and the number of patients with this disorder has been increasing in the United States (4-6) and Japan (7, 8). Patients with MAI infection without predisposing lung disease were predominantly thin, elderly women. Chest computed tomographic (CT) scans revealed characteristic findings of multiple small nodules and bronchiectasis distributed mainly in the upper, middle, and lingular lobes (7-12). Recently, we have clarified that the disorder mainly affects the small airways (12) and that neutrophils and CD4+ lymphocyte cell counts in bronchoalveolar lavage (BAL) fluid (BALF) are significantly increased (13).
Thus, the clinical features of pulmonary MAI infection with nodular bronchiectasis are gradually becoming clear. One unanswered question is which factors determine deterioration. Furthermore, there are few studies in which certain types of patients show true progressive deterioration of MAI infection. In the present study, we retrospectively analyzed the clinical features, laboratory data, and BALF findings of patients with MAI to investigate ways to predict the short-term natural history of pulmonary MAI infection with nodular bronchiectasis.
We diagnosed MAI infection in 57 (51 women) patients who visited Shinshu University Hospital between April 1994 and March 1997 for evaluation of respiratory disease. In no patient had MAI infection been previously diagnosed before visiting our University Hospital. As we reported previously (8, 12, 13), we used American Thoracic Society diagnostic criteria (14) when making a diagnosis of pulmonary MAI infection with nodular bronchiectasis. All patients had abnormal findings on chest radiographs and/or CT scans, suggesting MAI infection such as multiple small nodules and bronchiectasis. MAI was cultured in sputum on at least two separate occasions and/or in samples obtained from the radiographically affected region using a sterilized fiberoptic bronchoscope when patients had no sputum and/or negative-sputum culture. The patients were free from other distinct lung diseases, as judged by medical history and previous chest radiographs and/or CT findings, which in most cases, had been performed as part of a complete examination. The patients were free from HIV infection. They had received no treatment for MAI.
We checked the duration of symptoms until the start of observation when the diagnosis of MAI infection was made. To localize the extent of disease on chest CT, and regions affected by MAI infection were divided into 18 segments (S) as depicted in Tables 3 and 4.
| Patient No. | Age (yr) | Sex | Symptom (duration) | Tabacco (pack-year) | Sputum | Bronchoscopy | Chest CT Segmental Analysis | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gaffky | Culture | Gaffky | Culture | |||||||||||||||
| 1 | 76 | F | None | 0 | ND | ND | 0 | ++ | rt.S2,4,5,6 | |||||||||
| 2 | 72 | F | C,S,B (7 yr) | 0 | 0 | ++ | 0 | +++ | rt.S2,3,5; lt.S4,5 | |||||||||
| 3 | 57 | F | C,S (3 yr) | 0 | 0 | − | 0 | ++ | rt.S2,3,4,5; lt.S4,5 | |||||||||
| 4 | 61 | F | C,S,B (7 mo) | 0 | ND | ND | 0 | ++ | rt.S2,3,4,5,6,10; lt.S4,10 | |||||||||
| 5 | 68 | F | C,S,B (5 yr) | 0 | ND | ND | 0 | +++ | rt.S2,3,4,5; lt.S1 + 2 | |||||||||
| 6 | 76 | M | C,S (10 mo) | 40 | 5 | ++++ | 0 | ++ | rt.S3,4,5,6; lt.S4 | |||||||||
| 7 | 76 | F | C,S,B (2 yr) | 0 | 0 | ++ | ND | ND | rt.S2,3 | |||||||||
| 8 | 80 | F | None | 0 | 4 | ++ | ND | ND | rt.S3,4,5 | |||||||||
| 9 | 71 | F | C,S (3 mo) | 0 | 0 | ++ | ND | ND | rt.S2,3,4,8; lt.S3,5 | |||||||||
| 10 | 59 | F | C (18 mo) | 0 | 0 | − | 0 | + | rt.S2,3,4,5,8; lt.S3,4,5 | |||||||||
| 11 | 49 | F | C,S (2 mo) | 0 | 0 | ++ | 5 | +++ | rt.S3,4,5; lt.S4,5 | |||||||||
| 12 | 63 | F | C,S (10 mo) | 0 | 2 | +++ | 5 | +++ | rt.S4,5; lt.S4,5 | |||||||||
| 13 | 70 | F | B (5 yr) | 0 | ND | ND | 0 | ++ | rt.S2,3,4,5,9,10; lt.S4,5 | |||||||||
| 14 | 86 | F | C,S (8 mo) | 0 | 0 | − | 0 | +++ | rt.S2,3,4,5; lt.S4,5 | |||||||||
| 15 | 64 | F | C,S (4 mo) | 0 | ND | ND | 0 | ++ | rt.S2,6,8; lt.S6 | |||||||||
| 16 | 72 | F | C (12 mo) | 0 | ND | ND | 0 | ++ | rt.S2,3,4,5; lt.S3,4,5 | |||||||||
| 17 | 75 | F | B (1 mo) | 0 | ND | ND | 5 | ++ | rt.S3,4,5; lt.S5 | |||||||||
| 18 | 69 | M | Ch (2 yr) | 35 | 2 | ++ | ND | ND | rt.S4,5; lt.S4,5 | |||||||||
| 19 | 65 | F | Ch (3 yr) | 0 | 4 | ++ | 2 | ++++ | rt.S2,3,4,5,8; lt.S3,4,5 | |||||||||
| 20 | 77 | F | C,S (7 mo) | 0 | 0 | − | 0 | ++ | rt.S4,5; lt.S4,5 | |||||||||
| 21 | 76 | F | C (4 mo) | 0 | ND | ND | 0 | ++ | rt.S2,3,4,5; lt.S4,5,8 | |||||||||
| 22 | 52 | F | B (2 mo) | 0 | ND | ND | 0 | ++ | rt.S4 | |||||||||
| 23 | 47 | F | None | 0 | 0 | − | 0 | +++ | rt.S2,3,4,5,8; lt.S4,5 | |||||||||
| 24 | 57 | F | None | 0 | 0 | − | 0 | + | rt.S2,3,4,5,6; lt.S4,5 | |||||||||
| 25 | 46 | F | None | 0 | 0 | − | 0 | + | rt.S2,3,4,5; lt.S4,5 | |||||||||
| 26 | 82 | F | C (5 yr) | 0 | 3 | ++ | 0 | ++ | rt.S2,3,4,5,6; lt.S5 | |||||||||
| 27 | 81 | M | C,S (2 yr) | 50(f) | 2 | + | 0 | ++ | rt.S2,3,4,5 | |||||||||
| 28 | 70 | F | C,S (6 mo) | 0 | 3 | ++ | 1 | +++ | rt.S2,3,4,5; lt.S3,4,5,6 | |||||||||
| 29 | 75 | F | C,S (2 yr) | 0 | 1 | ++ | ND | ND | rt.S2,3,4,5,8,9,10; lt.S5 | |||||||||
| 30 | 72 | F | C,S,B (2 mo) | 0 | 0 | − | 1 | ++ | rt.S2,3,4,5; lt.S4,5 | |||||||||
| 31 | 75 | F | None | 0 | 0 | − | 0 | ++ | rt.S3,8; lt.S1 + 2,4,5 | |||||||||
| 32 | 76 | F | C,S (5 yr) | 0 | 3 | ++ | 3 | ++ | rt.S2,3,4,5,6,8; lt.S4,5 | |||||||||
| 33 | 61 | F | C,S (12 mo) | 0 | 0 | ++ | 0 | +++ | rt.S2,3,4,5,8,9; lt.S4,5 | |||||||||
| 34 | 77 | F | C (3 mo) | 0 | 0 | ++ | 0 | ++ | rt.S2,3,4,5,8 | |||||||||
| Patient No. | Age (yr) | Sex | Symptom (duration) | Tabacco (pack-year) | Sputum | Bronchoscopy | Chest CT Segmental Analysis | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gaffky | Culture | Gaffky | Culture | |||||||||||||||
| 1 | 60 | F | None | 0 | ND | ND | 2 | ++ | rt.S2,3,4,5; lt.S5 | |||||||||
| 2 | 53 | F | None | 0 | ND | ND | 0 | ++ | rt.S2,3,5,6; lt.S4,5 | |||||||||
| 3 | 44 | F | None | 0 | ND | ND | 0 | ++ | rt.S2,3,4,5 | |||||||||
| 4 | 59 | F | None | 0 | ND | ND | 2 | ++ | rt.S2,3,4,5; lt.S4,5 | |||||||||
| 5 | 56 | F | None | 0 | ND | ND | 0 | ++ | rt.S2,3,4,5,6; lt.S4,5 | |||||||||
| 6 | 45 | F | C,B (2 yr) | 0 | ND | ND | 0 | + | rt.S3,5,8; lt.S4,5,6 | |||||||||
| 7 | 59 | M | None | 0 | 0 | ++ | 0 | ++ | rt.S2,3,4,5,8; lt.S3,4,5,6 | |||||||||
| 8 | 68 | M | C,S,B (3 yr) | 40 | 0 | + | ND | ND | rt.S2,3,4,5,6; lt.S1 + 2,4,5 | |||||||||
| 9 | 65 | F | C,S,B (3 yr) | 0 | 0 | ++ | ND | ND | rt.S2,3,4,5,8,9; lt.S4,5 | |||||||||
| 10 | 62 | F | C,S (4 mo) | 0 | 0 | + | 0 | ++ | rt.S2,3,4,5,8; lt.S4,5 | |||||||||
| 11 | 66 | F | S,B (12 mo) | 0 | 0 | ++ | 2 | ++ | rt.S3,8; lt.S1 + 2,4,5 | |||||||||
| 12 | 57 | F | None | 0 | ND | ND | 0 | ++ | rt.S2,3,4,5,6; lt.S4,5 | |||||||||
| 13 | 55 | F | None | 0 | ND | ND | 0 | ++ | rt.S2,3,4,5; lt.S4,5 | |||||||||
| 14 | 56 | F | B (10 mo) | 0 | ND | ND | 0 | ++ | rt.S2,3,4,5,8,9,10; lt.S5 | |||||||||
| 15 | 48 | F | None | 0 | ND | ND | 0 | + | rt.S2,3,4 | |||||||||
| 16 | 57 | F | C,S (2 mo) | 0 | 2 | ++ | 1 | ++ | rt.S2,3,4,5; lt.S1 + 2 | |||||||||
| 17 | 55 | F | None | 0 | 0 | − | 0 | ++ | rt.S2,3,4,8; lt.S3,5 | |||||||||
| 18 | 55 | M | C,S (3 mo) | 26 | 0 | ++ | ND | ND | rt.S3,4,5; lt.S4,5 | |||||||||
| 19 | 63 | F | None | 0 | 0 | − | 0 | ++ | rt.S2,3,4,5,9,10; lt.S4,5 | |||||||||
| 20 | 45 | F | None | 12 | 0 | ++ | 2 | +++ | rt.S2,6,8; lt.S6 | |||||||||
| 21 | 72 | F | None | 0 | 0 | − | 0 | ++ | rt.S2,3,4,5,8; lt.S3,4,5 | |||||||||
| 22 | 41 | F | None | 5 | ND | ND | 0 | ++ | rt.S2,3,4,5; lt.S4,5,8 | |||||||||
| 23 | 75 | F | None | 0 | ND | ND | 0 | ++ | rt.S2,3,4,5 | |||||||||
We explained to all patients in whom MAI had been diagnosed that this disorder is not always progressive. Some patients need no treatment, whereas some need antituberculosis drugs and/or clarithromycin because of deterioration of pulmonary MAI. Therefore, we need at least a 12-mo observation period without treatment. When the disease is clearly recognized as being progressive, the patients start therapy immediately.
Clinical data were collected on each patient, including age, height, body weight, body-mass index (BMI), respiratory symptoms, and routine laboratory tests. Circulating blood cell counts, erythrocyte sedimentation rate (ESR), blood chemistry, C-reactive protein (CRP), and carbohydrate antigen 19-9 (CA19-9) were evaluated. CA19-9 was assayed by enzyme-linked immunosorbent assay.
BAL was performed from relevant segments identified by chest CT scans, as we reported previously (13). Three 50-ml aliquots of sterile normal saline at 37° C were instilled, and each was removed by gentle suction. We identified cell populations and differential cell counts, and BALF pallets for lymphocyte subsets were analyzed by flow cytometry using CD4, CD8, and HLA-Dr monoclonal antibodies (Becton Dickinson Co., Mountain View, CA). One milliliter of recovered lavage fluid was processed for bacterial and fungal culture by routine methods (15).
Expectorated sputum and samples obtained by bronchoscopy were examined by Ziehl-Neelsen stain and cultured for mycobacteria using 3% Ogawa egg medium. Cultures were quantitated from zero to 4+ using published standards (15). These semiquantiative culture groups were: exact number of colonies = zero to 49 colonies; 1+ = 50 to 99 colonies; 2+ = 100 to 199 colonies; 3+ = 200 to 499 colonies, and 4+ = ⩾ 500 colonies. Mycobacteria were identified and differentiated by growth characteristics and conventional biochemical tests. The materials were cultured for other bacteria and fungi by routine methods (15).
Natural history was estimated mainly using chest CT and sputum bacteriology. Chest CT was performed at intervals of at least 12 mo. Chest CT scans were evaluated by two chest radiologists who were blinded to the patients' clinical course and a prechest and postchest CT reading. When patients complained of expectoration, we performed MAI bacteriology of sputum for three consecutive days every 3 mo. Fifty-seven patients were divided into two groups, a deteriorated group and a not-deteriorated group, after a mean observation interval of 28 ± 13 mo (12 to 42 mo). The former group showed progressive nodules and/or consolidation in chest CT scans, and/or a change of MAI culture in sputum from negative to positive. The latter showed no change in chest CT findings or sputum bacteriology.
Values are expressed as mean ± SD in the text and in the Tables. For statistical evaluation of difference between the two groups, we used the Mann-Whitney U test for nonparametric data. For comparison between the groups, the estimated median difference and a 95% confidence interval for the difference were used. A p value of < 0.05 was considered significant.
All data in the Tables were those at the start of observation, when MAI infection with nodular bronchiectasis was diagnosed.
Among the 57 patients, 34 (31 female) were in the deteriorated group, 23 patients (20 female) were in the not-deteriorated group. The clinical manifestations of the two groups are shown in Table 1. The number of patients with respiratory symptoms such as cough, sputum, and bloody sputum, was frequently higher in the deteriorated group. There were no alcohol abusers in either group. The mean age of the deteriorated group (69 ± 9 yr) was significantly higher than that of the not-deteriorated group (57 ± 9 yr). The mean BMI of the deteriorated group (19.2 ± 3.1 kg/m2) was significantly lower than that of the not-deteriorated group (21.5 ± 1.5 kg/m2). After the observation period, 32 of the 34 deteriorated patients were begun on clarithromycin and several antituberculosis drugs.
| Not-deteriorated Group (n = 23) | Deteriorated Group (n = 34 ) | |||
|---|---|---|---|---|
| Age, yr | 57 ± 9* | 69 ± 9* | ||
| Sex, female/male | 20/3 | 31/3 | ||
| Symptom | ||||
| Cough | 4 | 22 | ||
| Sputum | 6 | 17 | ||
| Bloody sputum | 4 | 7 | ||
| Chest pain | 0 | 2 | ||
| Chronic sinusitis | 4 | 2 | ||
| Previous diseases | ||||
| Tuberculosis | 2 | 1 | ||
| Pleuritis | 0 | 3 | ||
| Pneumonia | 0 | 1 | ||
| Gastrectomy | 2 | 3 | ||
| Cigarette smoking | 3 | 4 | ||
| Alcohol drinking | 2 | 1 | ||
| Body height, cm | 156 ± 4*,† | 152 ± 3*,‡ | ||
| Body weight, kg | 53 ± 5*,† | 44 ± 6*,§ | ||
| BMI, kg/m2 | 21.5 ± 1.5*,† | 19.2 ± 3.1*,† |
The data from the two groups are shown in Table 2. Serum CRP and ESR in the deteriorated group (0.26 ± 0.39 mg/dl and 28 ± 23 mm/h) were significantly increased compared with those of the not-deteriorated group (0.10 ± 0.08 mg/dl and 7 ± mm/h). The CA19-9 level of the deteriorated group (96.1 ± 121.1 U/ml)was higher than that of the not-deteriorated group (19.2 ± 31.8 U/ml).
| Not-deteriorated Group (n = 23) | Deteriorated Group (n = 34 ) | |||
|---|---|---|---|---|
| White blood cell, μl | 5,528 ± 1,224 | 5,905 ± 1,983 | ||
| Red blood cell, × 104/μl | 447 ± 56 | 425 ± 30 | ||
| Hemoglobin, g/dl | 14.4 ± 1.5 | 12.8 ± 1.2† | ||
| Platelet, × 104/μl | 21.9 ± 3.2 | 27.3 ± 7.0‡ | ||
| Erythrocyte sedimentation rate, mm/h | 7 ± 7 | 28 ± 23† | ||
| Total protein, g/dl | 7.7 ± 0.5 | 7.4 ± 0.5 | ||
| Albumin, g/dl | 4.6 ± 0.2 | 4.4 ± 0.3† | ||
| Asparate aminotransferase, U/l | 24 ± 7 | 23 ± 7 | ||
| Alanin aminotransferase, U/l | 20 ± 9 | 16 ± 8 | ||
| Total cholesterol, mg/dl | 230 ± 41 | 206 ± 60 | ||
| Glucose, mg/dl | 102 ± 10 | 97 ± 10 | ||
| Hemoglobin A1c, % | 5.5 ± 0.8 | 5.6 ± 0.4 | ||
| C/reactive protein, mg/dl | 0.10 ± 0.08 | 0.26 ± 0.39† | ||
| Alpha-1-antitrypsin, mg/dl | 187 ± 56 | 169 ± 84 | ||
| Carbohydrate antigen 19-9, U/ml | 19.2 ± 31.8 | 96.9 ± 121.1† |
The sputum acid-fast smears were positive in 10 patients (40%) and in one patient (9%) in the deteriorated (n = 34) and the not-deteriorated (n = 23) groups, respectively. Sputum MAI culture was positive in 15 patients (43%) in the deteriorated group, and in six (26%)in the not-deteriorated group. Fiberoptic bronchoscopy showed cultures positive for MAI in 29 patients (83%) in the deteriorated group and in 20 (87%) in the not-deteriorated group (Tables 3 and 4). Three patients in the deteriorated group showed an increased amount of MAI culture, and three patients in the deteriorated group had MAI cultures that changed from negative to positive.
BALF data from the two groups are shown in Tables 5 and 6. BALF was performed in 13 and in eight patients in the deteriorated and not-deteriorated groups, respectively. The neutrophils in the deteriorated group (130 ± 115 × 103/ml) were increased significantly compared with those of the not-deteriorated group (42 ± 59 × 103/ml). Also, the percentages of CD4+ and HLA-Dr lymphocytes were significantly decreased in the deteriorated group compared with those in the not- deteriorated group. However, CD8 levels showed no significant differences between the two groups. Bacterial cultures produced positive results in two of 13 patients in the deteriorated group (H. parainfluenzae 1+, Serratia marcescens 1+), and in one of eight in the not-deteriorated group (S. aureus 1+).
| Total Cells (%) | Macrophages (%) | Lymphocytes (%) | Neutrophils (%) | Eosinophils (%) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Not-deteriorated | 53.6 ± 26.7 | 32.6 ± 22.1 | 13.7 ± 15.4 | 0.2 ± 0.4 | ||||||
| × 103/ml, n = 8 | 197 ± 123 | 85 ± 45 | 69 ± 62 | 42 ± 59 | 0.4 ± 0.9 | |||||
| Deteriorated | 36.1 ± 14.7 | 25.4 ± 17.4 | 37.9 ± 21.8† | 0.7 ± 1.3 | ||||||
| × 103/ml, n = 13 | 297 ± 191 | 111 ± 93 | 68 ± 58 | 130 ± 115† | 2 ± 5 |
| CD4+ (%) | CD8+ (%) | CD4+/CD8+ (%) | HLA-Dr (%) | |||||
|---|---|---|---|---|---|---|---|---|
| Not-deteriorated | 73.4 ± 7.7 | 12.8 ± 4.9 | 6.6 ± 3.1 | 66.3 ± 7.3 | ||||
| × 103/ml, n = 8 | 61.7 ± 56.0 | 12.0 ± 12.8 | 65.2 ± 44.1 | |||||
| Deteriorated | 55.7 ± 17.8† | 21.1 ± 14.7 | 5.3 ± 5.1 | 53.1 ± 10.7† | ||||
| × 103/ml, n = 13 | 30.9 ± 40.2† | 7.8 ± 6.2 | 25.8 ± 30.0 |
In the present study, we investigated the short-term natural history of patients with MAI infection with nodular bronchiectasis. One of the main results of the present study was that the deteriorated group of patients with pulmonary MAI infection showed significantly higher levels of ESR and serum CRP and a significant increase in BALF neutrophils compared with those of the not-deteriorated group. Because positive bacterial culture results in BALF were few in the present study, these changes suggested the existence of maintained inflammation in the small airways mainly caused by MAI infection. It seems likely that chronic inflammation led to lower BMI and anemia in the deteriorated group. We recently reported that pulmonary MAI infection with neither predisposing lung disease nor immunodeficiency resulted in air trapping distal to the small airways using inspiratory-expiratory high-resolution CT scans (12). Further study is necessary to clarify the relationship between inflammation and the degree of air trapping.
The results of this study also indicated that serum CA19-9 levels might be a marker for deterioration of MAI infection. Serum CA19-9, a tumor-associated carbohydrate antigen, is known to be a useful marker for gastrointestinal malignancies, particularly pancreas adenocarcinoma (16). The elevated serum CA19-9 levels occur in patients with lung cancer (17). CA19-9 is also elevated in patients with nonmalignant lung diseases such as idiopathic pulmonary fibrosis (IPF), bronchiectasis, and cystic fibrosis (18). This inicates that the higher serum CA19-9 was probably due to hypersecretion of mucus glycoprotein secreted from hypertrophic glands and/or epithelial cells in the bronchioles. The extravagation into the circulatory system was caused by pathogenic change accompanying chronic inflammation of the small airways. Furthermore, CA19-9 could be a measure of the severity of the bronchiectasis, which may have antedated the MAI, although there have been no studies on CA19-9 and bronchiectasis.
Increased neutrophils in the BALF are another factor in the estimation of the deterioration of MAI infection. We recently reported that elevated neutrophils and lymphocytes were the main cellular constituents in pulmonary MAI infection (13). An elevated number of neutrophils and a concentration of proinflammatory cytokines and neutrophil elastase may lead to chronic inflammation in this disorder. Increased numbers of activated T-cells, including CD4+ cells, may be related to granuloma formation in MAI infection. It seems that neutrophils might play an important role in the progress of MAI infection to the formation of multiple nodules caused by inflammatory changes in bronchioles and ectasis of small bronchi. Recently, it was found that in pulmonary tuberculosis, neutrophils reflected the presentation and outcome of pulmonary tuberculosis (19). The investigators reported that in patients with positive smears and/or cavitary disease, macrophages and neutrophils were the predominant BAL cell types. Further studies are needed to clarify the role of neutrophil in MAI infection.
CD4+ lymphocytes may play a role in MAI infection (13). In the present study, the %CD4+ lymphocyte was significantly decreased in the deteriorated group when compared with the not-deteriorated group. However, the %CD8 lymphocytes did not change between the groups. Therefore, the total percentage of lymphocytes was depleted. It is probable that depletion of CD4+ lymphocytes deteriorates host defense against the pathogen. Although there is evidence of involvement of CD4+ lymphocytes, CD8+ lymphocytes, natural killer cells, and γδ T-cells in the immune response against mycobacteria (20), there is little information about the cellular immune response to MAI infection. Further studies are also needed to analyze the role of CD4+ lymphocytes, including Th1-Th2 interaction, in pulmonary MAI infection, using cells in BALF.
In summary, we have estimated the clinical and laboratory markers indicating a high risk of progression of pulmonary MAI infection with nodular bronchiectasis. Thirty-four of 57 patients had progressive clinical and/or radiographic features during observation periods with a mean of 28 mo. The older, thinner patients tended to become worse. Serum CA19-9, as well as ESR and CRP, represent the activity of this pulmonary infection. Chronic neutrophil-related inflammation associated with a decrease in CD4+ lymphocytes in bronchioles and/or peripheral small airways is probably related to the deterioration of this disorder.
The writers would like to thank Y. Kawakami, Y. Okimura, I. Ueno, and E. Hidaka in the Central Clinical Laboratory for their generous assistance in this study. They are also grateful to the staff of the Department of Radiology, Shinshu University School of Medicine, for their suggestions and reviews of chest radiographs and CT images.
Supported in part by Grant-in-Aid for Scientific Research (B) No. 09470539 from the Ministry of Education, Science, Sports and Culture of Japan.
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