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Thoracic Imaging |
1 From the Division of Pulmonary and Critical Care Medicine, Department of Medicine (W.J.K., O.J.K.) and Department of Radiology and Center for Imaging Science (K.S.L., Y.J.J., S.H.K., T.S.K.), Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135–710, Korea. From the 2003 RSNA Annual Meeting. Received February 28, 2004; revision requested May 5; revision received May 10; accepted June 15. Supported in part by Samsung Biomedical Research Institute grant SBRI C-A4–113-1. Address correspondence to K.S.L. (e-mail: kslee@smc.samsung.co.kr).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Institutional review board approved this research study; patient informed consent (not required) was obtained from all patients to perform CT. From July 2000 to December 2002, 126 consecutive patients, who were suspected of having NTM pulmonary infection at helical CT (120 kVp, 70 mA, 2.5-mm collimation, pitch of 6) with findings of bilateral bronchiectasis and bronchiolitis, were included. Of these, 105 patients underwent study for diagnosis of NTM disease. Medical records and CT scans were reviewed for final diagnoses. Clinical and chest CT findings in patients with NTM disease and those with other airway diseases were compared (unpaired t test, 
2 test, or Fisher exact test).
RESULTS: NTM pulmonary infection was seen in 36 (34%) of 105 patients; NTM was definite in 32 (30%) and probable in four (4%). In decreasing order of frequency, organisms involved were MAC in 18 patients (50%), with M avium in 10 and M intracellulare in eight, Mycobacterium abscessus in 14 (39%), Mycobacterium kansasii in one (3%), and Mycobacterium fortuitum in one (3%); organisms were unidentifiable in two (6%). Female (P = .031) nonsmokers (P = .037) with history of treatment for Mycobacterium tuberculosis (P = .002), sputum smear positive for acid-fast bacilli (P < .001), and thin-section CT findings of bronchiolitis in more than five lobes with bronchiectasis (P = .011), lobular consolidation (P = .010), and a cavity (P < .001) were related to diagnosis of NTM pulmonary infection.
CONCLUSION: About one-third of patients with thin-section CT findings of bilateral bronchiectasis and bronchiolitis have NTM pulmonary infection; in these situations, MAC and M abscessus are two most frequent causative organisms. Thin-section CT findings of bronchiectasis and bronchiolitis involving more than five lobes, especially when associated with lobular consolidation or a cavity, are highly suggestive of NTM pulmonary infection.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MAC pulmonary infection recently has been differentiated into two distinct subtypes: cavitary disease of the upper lobe and nodular bronchiectatic disease (1). Nodular bronchiectatic disease, a new clinical manifestation of MAC pulmonary infection, had been reported predominantly in elderly women and nonsmokers with no underlying disease other than bronchiectasis (the so-called Lady Windermere syndrome) (5,6).
In several studies with chest computed tomography (CT), researchers have demonstrated that the presence of bilateral multifocal bronchiolitis (well-defined small nodules and branching centrilobular nodules, or tree-in-bud pattern) and bronchiectasis distributed mainly in the right middle lobe and lingular segment are indicative of MAC pulmonary infection (7–11). Accordingly, it is believed that radiologic findings of bilateral bronchiolitis and bronchiectasis on chest CT scans specifically suggest MAC pulmonary infection (1).
These CT findings, however, may not be specific for MAC pulmonary infection. CT patterns of bronchiectasis and bronchiolitis in the pulmonary infections caused by various NTM organisms have been reported, and these organisms include Mycobacterium kansasii, Mycobacterium xenopi, and rapidly growing mycobacteria such as Mycobacterium abscessus, Mycobacterium fortuitum, and Mycobacterium chelonae (12–14). In addition, not all patients with bronchiectasis and bronchiolitis have NTM pulmonary infection. Two recent studies showed that only about 50% of patients with such CT features have MAC pulmonary infection (9,15). To the best of our knowledge, however, in no report have the clinical or CT characteristics that are associated with NTM pulmonary infection in patients with bronchiectasis and bronchiolitis at CT been described. Thus, the purpose of our study was to determine the frequency of NTM pulmonary infection in patients with bilateral bronchiectasis and bronchiolitis at chest CT and to investigate whether these CT findings are specifically indicative of MAC infection.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Of these 126 patients, 105 patients (67 female and 38 male patients; age range, 17–88 years; mean age, 56.3 years) subsequently underwent a sufficient diagnostic work-up for NTM pulmonary infection and were included in this study. The remaining 21 of 126 patients were excluded from this study because they underwent fewer than three sputum examinations with staining for acid-fast bacilli (AFB) and because culture or bronchoscopy was not performed. Tests for human immunodeficiency virus were negative in all 105 patients. For a diagnosis of NTM infection, sputum AFB (Ziehl-Neelsen method) staining and culture examinations for mycobacteria were performed at least three times in 102 patients. Bronchoscopy also was performed for bronchial washing or transbronchial lung biopsy in 40 of these 102 patients. In the remaining three of 105 patients, sputum examinations were performed only once or twice, but bronchial washing or transbronchial lung biopsy was performed, and these patients were included in the study population.
Chest CT Scans
CT examinations were performed by using a scanner (LightSpeed QX/i, HiSpeed Advantage; GE Medical Systems, Milwaukee, Wis) in all 126 patients. All CT data were reconstructed by using a high-spatial-frequency algorithm. A thin-section CT technique (2.5-mm collimation, 120 kVp, 70 mA, and pitch of 6 [total active detector length pitch of 1.5]) was used. Data were reformatted with a thickness of 2.5 mm for transverse images. Scans were obtained from the level of the lung apices to the lung bases. The scan data were displayed directly on monitors of a picture archiving and communication system (Centricity 1.0; GE Medical Systems Integrated Imaging Solutions, Mt Prospect, Ill). The monitors displayed both mediastinal (window width, 400 HU; window level, 20 HU) and lung (window width, 1500 HU; window level, –700 HU) window images.
Isolation and Identification of Mycobacteria
Expectorated sputum and samples obtained with bronchoscopy were examined after AFB staining and were cultured for mycobacteria by using 3% Ogawa egg medium (Korean Institute of Tuberculosis, Seoul, South Korea). Colony numbers were counted after incubation for as long as 8 weeks. Mycobacterium tuberculosis isolates were identified (Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test; Gen-Probe, San Diego, Calif), and NTM species identification was confirmed by using a polymerase chain reaction–restriction fragment length polymorphism method based on the rpoB gene (16). In all cases, sputum examinations were performed (range, 0–171 days; mean, 17.2 days) and bronchoscopic samples were obtained (range, 0–27 days; mean, 4.7 days) within 6 months after CT.
Diagnostic Criteria
The diagnosis of definite NTM pulmonary infection was determined when patients fulfilled the 1997 American Thoracic Society diagnostic criteria, which include clinical, radiologic, and microbiologic criteria (1). Probable NTM pulmonary infection was diagnosed if the patients satisfied the clinical and radiologic criteria of the 1997 American Thoracic Society diagnostic criteria but did not fully satisfy the microbiologic criteria. Namely, the patients either had only one or two cultures positive for organisms specifically identified as NTM with smear results negative for AFB or had more than three cultures positive for NTM without precise species identification; in addition, the patients had symptoms and radiologic evidence of disease, which consisted of bilateral bronchiectasis and bronchiolitis. A diagnosis of pulmonary tuberculosis was made when patients had a culture positive for M tuberculosis.
The clinical diagnostic criteria for diffuse panbronchiolitis were as follows (17): (a) symptoms—chronic cough, sputum, and dyspnea on exertion; (b) physical signs—crackles and rhonchi; (c) chest radiographs—diffusely disseminated fine nodular opacities, mainly in the lower zones of the lung, with hyperinflation of the lungs; (d) lung function studies, with at least three of the following four abnormalities—forced expiratory volume in 1 second of less than 70%, vital capacity of less than 80% of the predicted value, residual volume of more than 150% of the predicted value, and partial pressure of oxygen (arterial) of less than 80 mm Hg. When no definite cause was identified after evaluation of the causative factors, patients received a diagnosis of bronchiectasis or nonspecific bronchiolitis.
Chart Review
The medical records of all patients were reviewed by one of the authors (W.J.K.) for the following information, if available: height, body weight, history of tobacco use, history of previous antituberculous treatment, results of AFB staining, isolation and identification of mycobacteria, and the number of NTM-positive isolates.
Imaging Evaluation
Two chest radiologists (K.S.L., Y.J.J.) retrospectively evaluated the chest CT scans. The observers were unaware of the microbiologic test results and final diagnoses; conclusions were reached in consensus.
A total of six lung lobes in each patient (the lingular segment was considered a separate lobe) were assessed for the presence of lung lesions and other abnormal findings. Each lobe in the lungs was evaluated with regard to the presence or absence of bronchiectasis, well-defined small nodules (<10 mm in diameter), and branching centrilobular nodules (ie, tree-in-bud pattern). Bronchiolitis was defined as the presence of well-defined small nodules and branching centrilobular nodules on chest CT scans. The extents of involvement of bronchiectasis and bronchiolitis were estimated by counting the number of involved lobes. The presence of other abnormalities, including nodules (10–30 mm in diameter), lobular consolidation (consolidation of 10–20 mm in diameter with a polygonal shape), segmental consolidation, cavities, and volume reduction, was also recorded.
Comparison between Patients with NTM Disease and Patients with Non-NTM Disease
After classification of patients according to the previously mentioned diagnostic criteria, the 105 patients were categorized into two groups: the NTM pulmonary infection group, including the patients with definite or probable NTM pulmonary infection, and the non-NTM pulmonary infection group. Comparisons of the clinical and chest CT findings in patients with NTM diseases with those in patients with other airway diseases were determined.
Statistical Analysis
Values are expressed as the mean ± standard deviation. By stratifying the age distribution of included patients according to birth sex and decades of patients’ ages, we tested whether there were statistically significant differences between the distributions by using the 2 test. All continuous variables were tested for normality with the Kolmogorov-Smirnov test, and all had a Gaussian distribution. To statistically evaluate differences in continuous variables between the two groups, we used the unpaired t test. Frequencies were analyzed by using the 2 test or the Fisher exact test, as appropriate. A difference with a P value of less than .05 was considered statistically significant. Statistical software (SPSS 11.0; SPSS, Chicago, Ill) was used throughout.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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A summary of final diagnoses is shown in Table 1. The specific cause of bilateral bronchiectasis and bronchiolitis was identified in 52 (50%) patients, whereas no definite cause was established in 53 (50%). NTM pulmonary infection (Figs 1, 2) was diagnosed in 36 (34%) patients; diffuse panbronchiolitis (Fig 3), in eight (8%); pulmonary tuberculosis, in six (6%); primary ciliary dyskinesia, in one (1%); and bronchiectasis associated with X-linked agammaglobulinemia, in one (1%). Primary ciliary dyskinesia was diagnosed on the basis of electron microscopic findings in nasal mucosal biopsy specimens (18), and X-linked agammaglobulinemia was diagnosed with identification of BTK gene mutations (19).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The second and less dramatic clinical manifestation, so-called nodular bronchiectatic disease, only recently has been recognized (1,5,6) and occurs predominantly in nonsmoking middle-aged or elderly women who also have chronic cough and sputum production. Interestingly, previous or underlying lung disease has not been noted in these patients (5,6). In addition, the radiographic findings are quite distinct from those of classic cavitary disease of the upper lobe; the characteristic findings are bilateral nodular or reticulonodular change, predominantly in the lower zones of the lung, and particularly in the middle lobe of the right lung and the lingular segment of the upper lobe of the left lung (5–11). This type of disease represents about 50% of clinical cases nowadays in the United States, Japan, and Korea (22–24). The typical thin-section CT findings are multiple small nodules (<5 mm) and branching centrilobular nodular structures combined with bronchiectasis in the same lobe of the lung. These structures are usually confined to, or most severe in, the middle lobe of the right lung and the lingular segment of the upper lobe of the left lung (8–10,24). Not all patients with bilateral bronchiectasis and bronchiolitis on chest CT scans, however, have NTM pulmonary infection. Swensen et al (9) reported that of 15 patients with bronchiectasis and small nodules on CT scans in whom sputum or bronchial washings for mycobacterial cultures were performed, eight (53%) had cultures positive for MAC. Tanaka et al (15) reported that MAC was isolated in the expectorated sputum in six (23%) of 26 patients and in the bronchial washings in 13 (50%) of those patients with bronchiectasis and bronchiolitis on CT scans.
Several important observations were apparent during the present study. First, about one-third of patients with findings of bilateral bronchiectasis and bronchiolitis at CT had NTM pulmonary infection. Our study included more than 100 patients, a relatively large study population compared with that in previous studies (9,15). Bronchiectasis, in general, can manifest in either of two forms: as a local or focal obstructive process of a lobe or segment of a lung or as a diffuse process involving much of the lungs (25). In patients with diffuse bronchiectasis, the disease is more likely to be associated with specific causes, such as infection (NTM infection, Aspergillus infection), congenital conditions (primary ciliary dyskinesia, cystic fibrosis), or immunodeficiency (25). The present study demonstrates that NTM infection is the most important cause of, or condition associated with, bilateral bronchiectasis, especially when combined with multiple small nodules and branching centrilobular nodular structures (tree-in-bud pattern of bronchiolitis). Interestingly, eight (8%) patients had diffuse panbronchiolitis, which is a chronic inflammatory lung disease of unknown cause and which is prevalent in the Far East, including Japan and Korea (17,26). The CT findings in patients with diffuse panbronchiolitis are diffuse small round and linear opacities, dilatation of the small bronchi and bronchioles, and bronchial wall thickening (27). These CT findings are very similar to those reported for patients with NTM pulmonary infection (8–11). Further studies may be needed to identify those clinical or radiologic characteristics helpful for differentiation of NTM lung disease from diffuse panbronchiolitis.
We also found that the CT findings in patients with bilateral bronchiectasis and bronchiolitis are not specific for MAC pulmonary infection. In 36 patients with NTM pulmonary infection, the cause was MAC in 18 (50%) patients and M abscessus in 14 (39%). Apart from MAC, researchers in few radiologic studies have described pulmonary parenchymal changes in terms of individual causative NTM species. Some investigators in recently published studies, however, showed that the CT patterns of bronchiectasis and bronchiolitis are produced by pulmonary infections of various NTM organisms, including M kansasii (12), M xenopi (12), and rapidly growing mycobacteria such as M abscessus (14) and M chelonae (12,13). In Korea, the pathogen most frequently responsible for NTM lung disease is MAC, followed by M abscessus (4,28). We recently reported that the most common CT findings in lung disease caused by M abscessus are bronchiectasis and bronchiolitis, which were found in 90% of patients (14). Therefore, it may be justified that the radiologic findings of bilateral bronchiectasis and bronchiolitis on CT scans suggest NTM pulmonary infection rather than, specifically, MAC pulmonary infection.
Finally, our study findings show that some clinical and radiologic characteristics are more likely to be associated with NTM pulmonary infection in patients with bilateral bronchiectasis and bronchiolitis. To our knowledge, this is the first study to show that some clinical characteristics, such as female sex, nonsmoker status, prior antituberculous treatment, a sputum smear positive for AFB, and CT findings, such as bronchiolitis in more than five lobes, lobular consolidation, and the presence of a cavity, are helpful for differentiation of patients with NTM pulmonary infection from patients with non-NTM pulmonary infection.
In patients with the nodular bronchiectatic form of NTM pulmonary infection without a cavity, expectorated sputum cultures had a high false-negative rate, and many patients required bronchoscopy or lung biopsy for diagnosis. Therefore, in situations where there is a significant clinical suspicion of NTM pulmonary infection, and multiple sputum cultures are negative for organisms, bronchoscopy should be performed to adequately exclude or diagnose the disease (29). Considering, however, that only one-third or one-half of patients with bilateral bronchiectasis and bronchiolitis actually have NTM pulmonary infection and that bronchial washing or transbronchial lung biopsy by using bronchoscopy is invasive and expensive, clinical and radiologic characteristics suggestive of NTM infection would be useful during clinical decision making.
It is well known that the nodular bronchiectatic form of MAC pulmonary infection occurs predominantly in elderly nonsmoking female patients (5,6,8–11). According to one study (30), a history of previous tuberculosis treatment was reported to be closely associated with NTM disease. Interestingly, we found that a sputum smear considered positive for AFB was common (81%) in patients with NTM pulmonary infection, compared with previous results. Investigators in a previous study reported that sputum smears were positive for AFB in only approximately 20% of patients with the nodular bronchiectatic form, and these results are unlike those for patients with the cavitary form in the upper lobe in which sputum smears are positive for AFB in more than 70% of patients with the disease (22,31). In our previous study of radiographic findings in patients with lung disease caused by M abscessus, the nodular bronchiectatic form was observed in 58% of patients and the cavitary form of the upper lobe was observed in 42%; surprisingly, all patients had sputum smears positive for AFB (14). These findings suggested that the present study might have been biased toward more advanced lung disease and that the clinical and radiologic characteristics reported here may differ substantially from those found in the community, because our institution is a tertiary referral center for advanced mycobacterial disease.
In the current study, extensive bronchiolitis of small nodules and branching centrilobular nodules (tree-in-bud pattern) in more than five lobes associated with bronchiectasis at CT were suggestive of NTM pulmonary infection. In an initial report on the nodular bronchiectatic form of NTM pulmonary infection, bronchiectasis and bronchiolitis were confined to the middle lobe of the right lung and the lingular segment of the upper lobe of the left lung (6). Findings in subsequent reports, especially those about NTM pulmonary infection caused by rapidly growing species, however, suggested more extensive involvement of bronchiectasis and bronchiolitis in both lungs (8,10,11,13,14).
Our study had limitations. Specific causative diagnoses including NTM pulmonary infection were determined in only 52 (50%) of the 105 patients with bilateral bronchiectasis and bronchiolitis at CT. Moreover, bronchoscopic washing or transbronchial lung biopsies were performed in only 43 (41%) of 105 patients, and had we routinely performed bronchoscopic examinations, a more specific diagnosis would have been established in patients with nonspecific bronchiectasis and bronchiolitis.
In summary, about one-third of patients with bilateral bronchiectasis and bronchiolitis at CT have NTM pulmonary infection, and in these situations, MAC and M abscessus are the two most frequent causative organisms. Therefore, the nodular bronchiectatic form of NTM pulmonary infection is not specific for MAC organisms. More specifically, female sex, nonsmoker status, history of tuberculosis treatment, sputum smear positive for AFB, and thin-section CT findings of bronchiolitis in more than five lobes with bronchiectasis, lobular consolidation, and the presence of a cavity are believed to be related to the diagnosis of NTM pulmonary infection.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, W.J.K., K.S.L.; study concepts, W.J.K., K.S.L., O.J.K.; study design, W.J.K., K.S.L.; literature research, all authors; clinical studies, W.J.K., K.S.L., O.J.K.; data acquisition, W.J.K., O.J.K., Y.J.J., S.H.K.; data analysis/interpretation, W.J.K., K.S.L., Y.J.J.; statistical analysis, W.J.K., K.S.L.; manuscript preparation, W.J.K.; manuscript definition of intellectual content and editing, W.J.K., K.S.L.; manuscript revision/review and final version approval, all authors
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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