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18 Cases of pulmonary Mycobacterium abscessus: Clinical difference depending on the presence or absence of Mycobacterium avium complex
J Infect Chemother 22 (2016) 622e628
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Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Original article
18 Cases of pulmonary Mycobacterium abscessus: Clinical difference depending on the presence or absence of Mycobacterium avium complex Kenjiro Furuta a, b, *, Akihiro Ito b, Tadashi Ishida b, Yuhei Ito b, Naoyuki Sone b, Takuya Takaiwa b, c, Toshihide Yokoyama b, Hiromasa Tachibana b, d, Machiko Arita b, Toru Hashimoto b a
Department of Respiratory Medicine, Kobe City Hospital Organization Kobe City Medical Center West Hospital, 2-4 Ichibancho, Nagata-ku, Kobe, Hyogo 653-0013, Japan b Department of Respiratory Medicine, Ohara Memorial Kurashiki Healthcare Foundation, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, Okayama 710-8602, Japan c Department of Respiratory Medicine, Sakai City Medical Center, 1-1-1 Ebarajicho, Nishi-ku, Sakai, Osaka 593-8304, Japan d Department of Respiratory Medicine, National Hospital Organization Minami Kyoto Hospital, 11 Ashihara, Joyo, Kyoto 610-0113, Japan
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Article history: Received 2 February 2016 Received in revised form 6 May 2016 Accepted 16 June 2016 Available online 16 July 2016
Background and objectives: It can be difficult to treat respiratory tract infections caused by Mycobacterium abscessus (M. abscessus) as there is no established treatment strategy. Complications involving other nontuberculous mycobacterial infections such as Mycobacterium avium complex (MAC) are also commonly observed. Methods: We investigated the clinical background and course of 18 cases of pulmonary M. abscessus infection treated over 8 years at Kurashiki Central Hospital. Radiological evaluation was performed using NICE scoring system, a method of semi-quantitative evaluation of imaging findings of pulmonary MAC infection. Results: The mean age of the 18 patients (males, 6; females, 12) was 74.7 years. The median follow-up period was 1316 days (95% confidence interval; 720e1675 days), and 11 patients were concomitantly infected with pulmonary MAC. Among the patients that underwent antibacterial treatment for M. abscessus, there was one MAC-complication case and one non-MAC-complication case. All MACcomplication cases underwent antibacterial treatment including clarithromycin. Chest X-ray NICE scores for all cases were 8.50 ± 5.45 and 10.94 ± 6.03 at baseline and follow-up, respectively (p ¼ 0.0063). For MAC-complication cases, scores were 8.36 ± 4.74 and 12.00 ± 6.02 at baseline and follow-up, respectively (p ¼ 0.00818), and for non-MAC-complication cases, scores were 8.71 ± 6.82 and 9.29 ± 6.13 at baseline and follow-up, respectively (p ¼ 0.356). MAC-complication cases were significantly further exacerbated than non-MAC-complication cases (p ¼ 0.027). Conclusions: Some cases of pulmonary M. abscessus infection progressed well without undergoing antibacterial treatment. In particular, results suggested that the clinical course of MAC-complication and non-MAC-complication cases differs. © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Coinfection Japan Mycobacterium abscessus Mycobacterium avium complex Nontuberculous mycobacteria
1. Introduction
* Corresponding author. Department of Respiratory Medicine, Kobe City Hospital Organization Kobe City Medical Center West Hospital, 2-4 Ichibancho, Nagata-ku, Kobe, Hyogo 653-0013, Japan. Tel.: þ81 78 576 5251; fax: þ81 78 576 5358. E-mail address: [email protected] (K. Furuta).
Mycobacterium abscessus (M. abscessus) is a rapidly growing nontuberculous mycobacterium (NTM) that belongs to the Runyon classification group IV [1] [2]. It is indigenous to environments such as soil and water and is known to cause skin and soft tissue infections in addition to respiratory tract infections [3] [4]. In Japan, it
http://dx.doi.org/10.1016/j.jiac.2016.06.009 1341-321X/© 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
K. Furuta et al. / J Infect Chemother 22 (2016) 622e628
has been reported that in pulmonary NTM infections, M. abscessus is second most common pathogen following Mycobafcterium Mycobacterium avium complex (MAC) [5] Mycobacterium kansasii. Furthermore, complications with other NTM infections may also be observed. Although skin and soft tissue infections often respond well to antibacterial treatment, it is frequently difficult to treat respiratory tract infections as there is no established protocol for the timing of treatment initiation, selection of the appropriate antibacterial agent, or treatment duration [3]. In recent years, M. abscessus using whole genome sequencing of clinically isolated strains, M. abscessus is classified into three subspecies; M. abscessus, Mycobacterium massiliense (M. massiliense), and Mycobacterium bolletii (M. bolletii) [6], which are together known as the M. abscessus complex [7]. We retrospectively investigated the clinical course and findings, including the diagnostic imaging results, of 18 cases of pulmonary M. abscessus complex infection that occurred over 8 years at Kurashiki Central Hospital. We have discussed our results based on the presence or absence of a complicating MAC infection. 2. Patients and methods Subjects comprised 18 patients diagnosed with pulmonary M. abscessus infection over 8 years between January 1, 2005 and December 31, 2012 at Kurashiki Central Hospital (Kurashiki, Japan). Subsequent progress of the patients was followed-up until March 2015. All cases met the diagnostic criteria for NTM infection, as determined by the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) [3]. We retrospectively investigated various background factors such as underlying disease, laboratory findings, diagnostic imaging findings, treatment details, and clinical course, based on the medical records of these cases. For imaging findings in particular, two pulmonologists (K.F. and A.I.) evaluated the chest X-ray findings obtained at a date closest to when M. abscessus was first detected in respiratory tract specimens and the most recently available chest-ray at Kurashiki Central Hospital. The evaluation method used was the NICE scoring system (N; nodule, I; infiltration, C; cavity, E; bronchiectasis), which was recently proposed by Kurashima et al. for the semi-quantitative evaluation of MAC [8]. In the NICE scoring system, the lungs are divided into six zones (zone 1: area on the upper right above the level of the carina, zone 2: area on the upper left above the level of the carina, zone 3: area on the right between the level of the carina and the lower pulmonary vein, zone 4: area on the left between the level of the carina and the lower pulmonary vein, zone 5: area on the right below the lower pulmonary vein, and zone 6: area on the left below the lower pulmonary vein). Then, imaging findings for each zone are scored from 0 to 4 points based on four factors (N, I, C, E), according to the proportion of each zone that the lesion comprises. For 0%, 0 points are awarded; for 0% to <25%, 1 point; for 25% to <50%, 2 points; for 50% to <75%, 3 points; and for 75%, 4 points. The follow-up period in this study was set as the number of days between the two X-ray imaging sessions evaluated with the NICE scoring system. Cases were divided for analysis into those diagnosed as MAC-complication cases diagnosed according to the NTM infection diagnostic criteria of the ATS/IDSA [3] or non-MACcomplication cases. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Kanda, 2012), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria, version 2.13.0) [9]. Follow-up periods were reported as median and 95% confidence interval (CI), and compared using logrank test. Other absolute data were reported as mean ± standard deviation. Categorical variables were compared using Fisher's exact test. Continuous variables were compared
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using t test. All p values were two-sided, and p values of 0.05 were considered statistically significant. This study was approved by the Ethics Committee of Kurashiki Central Hospital, Approved Number 1941. 3. Results A total of 19 patients were diagnosed with pulmonary M. abscessus infections over the 8-year observation period. Of these, the underlying disease in one patient was a chest wall tumor (solitary fibrous tumor). This case was excluded from our analysis due to the influence of the tumor on chest contrast images. The backgrounds and bacteriological basis for making a diagnosis of pulmonary M. abscessus infection in the remaining 18 cases that were subject to analysis are shown in Table 1. Subjects included six males and 12 females, with a mean age of 74.7 years. There were 11 cases (cases 1e11) that were complicated by pulmonary MAC infection either before diagnosed or during the course of pulmonary M. abscessus infection. Of the seven cases that were not complicated by pulmonary MAC infection (cases 12e18), one was complicated by pulmonary M. kansasii infection (case 17). Underlying diseases included diabetes in three patients and active, malignant tumors in three patients (one lung cancer, one prostate cancer, and one gastric cancer). Furthermore, two patients were being administered corticosteroids (prednisolone (PSL) 12 mg/day for one case of vasculitis, and PSL 5 mg/day for one case of interstitial pneumonia). Data indicated that none of the patients had problems related to room air oxygenation except for one (case 13) who had originally undergone long-term oxygen therapy for pulmonary thromboembolism. The bacteriological basis for making a diagnosis of pulmonary M. abscessus infection included two consecutive positive results for sputum culture (14 cases), a positive result for bronchoalveolar lavage fluid culture (two cases), a positive result from the tissue culture of the surgical specimen of a simultaneously diagnosed lung cancer (one case), and two positive results for sputum culture together with a positive result from he bronchoalveolar lavage fluid culture (one case). Table 2 shows the treatment details, follow-up periods and outcomes for each case. All of the MAC-complication cases (cases 1e11) except for case 7, received antibacterial treatment for MAC, which mainly included clarithromycin (CAM), rifampicin (RFP), and ethambutol (EB). Only case 2 was treated with imipenem/cilastatin (IPM/CS), amikacin (AMK), and CAM for M. abscessus, but the treatment was discontinued due to fatigue approximately one month after starting treatment. Thus, no MAC-complication cases received sufficient treatment for M. abscessus. Only one case (case 9) died during the observation period due to disseminated infection of MAC. With regard to the non-MAC-complication cases (cases 12e18), only case 17 received two rounds of treatment with IPM/CS, AMK, and CAM for M. abscessus, and the treatment periods were 5 and 4 months, respectively. Although the sputum culture turned negative after the first round of treatment, a subsequent repeat sputum culture indicated growth of M. abscessus again. Therefore, a second round of treatment was performed, after which the sputum culture turned negative again. However, M. kansasii was also later detected in the sputum. During the observation period, only one case (case 17) died, but the cause of death was unclear. The median follow-up period for all cases was 1316 days (95% CI; 720e1675 days). The median follow-up periods for MAC-complication cases and nonMAC-complication cases were 1468.5 days (95% CI; 644e1820 days) and 995.0 days (95% CI; 417e1638 days), respectively (p ¼ 0.245). Total NICE score results were 8.50 ± 5.45 at baseline (the time when M. abscessus was firstly detected in culture results) and
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Table 1 Patient characteristics: case1-11 MAC-complication cases, case12-18 non-MAC-complication cases. Case
Age/sex
Smoking history
Symptom
Major past history/comorbidity
Co-existence of other NTM
Basis of diagnosis
1 2 3 4 5 6 7 8 9
71 72 68 69 81 70 76 77 77
F F F F F F M F F
Unknown Never Unknown Never Never Unknown Past Never Never
None Cough Sputum None Fatigue, DOE Cough Hemoptysis Cough, sputum None
MAC MAC MAC MAC MAC MAC MAC MAC MAC
Sputum culture over two times Sputum culture over two times Sputum culture over two times Sputum culture over two times Sputum culture over two times Sputum culture over two times Surgical specimen culture Sputum culture over two times BLF culture
10 11 12 13 14 15 16 17 18
70 80 80 82 77 85 78 72 60
F F M F M M M M F
Never Never Never Never Past Past Past Past Never
None Hemoptysis Cough DOE Fatigue Cough, sputum Sputum, DOE Cough, sputum Fever, hemoptysis
Renal cancer, thyroid cancer RPGN, cerebral infarction None Thymoma Diabetes mellitus None Lung cancer, DM Hypertension Vasculitis (PSL 12 mg/day), sarcoma None Old tuberculosis Hypertension, sinusitis Pulmonary thromboembolism AP, SSS, prostate cancer IP(PSL 5 mg/day), DM AP, cerebral infarction Silicosis, COPD, gastric cancer Adult T-cell leukemia
MAC MAC None None None None None M. kansasii None
Sputum culture Sputum culture Sputum culture BLF culture Sputum culture Sputum culture Sputum culture Sputum culture Sputum culture
over two times over two times over two times over two times over two times over two times over two times and BLF culture
Abbreviation: RPGN; rapidly progressive glomerulonephritis, DOE; dyspnea on effort, DM; diabetes mellitus, BLF; bronchial lavage fluid, AP; angina pectoris, IP; interstitial pneumonia, COPD; chronic obstructive pulmonary disease.
Table 2 Treatment for NTM, follow up period and patient outcome. Case
Treatment for M. abscessus
Treatment for MAC
Duration of follow up (days)
Outcome
1 2
CAM þ RFP þ EB CAM þ RFP þ EB
2861 936
Alive Alive
3 4 5 6 7 8 9
e IPM/CS þ AMK þ CAM (1 month, cessation due to fatigue) e e e e e e e
2338 1596 1341 1820 644 967 83
10 11
e e
Alive Alive Alive Alive Alive Alive Died (due to MAC) Alive Alive
12 13 14 15 16 17
e e e e e IPM/CS þ AMK þ CAM (2 times; 5 months, 4 months) e
18
CAM CAM CAM CAM e CAM CAM
þ þ þ þ
RFP þ EB RFP þ EB RFP þ EB þ LVFX RFP
þ RFP þ EB þ RFP þ EB þ SM
CAM þ RFP þ EB CAM þ RFP þ EB þ SM / CAM þ RFP þ EB e e e e e e
1675 1316
e
417
998 629 995 1638 720 1773
Alive Alive Alive Alive Alive Died (unknown cause) Alive
Abbreviation: AMK; amikacin, LVFX; levofloxacin, SM; streptomycin.
10.94 ± 6.03 at follow-up (the time when the most recent chest Xray images taken at our hospital), indicating statistically significant changes (p ¼ 0.0063). For MAC-complication cases, the score results at follow-up (12.00 ± 6.02) significantly worsened than those at baseline (8.36 ± 4.74) (p ¼ 0.00818). On the other hand, for nonMAC-complication cases, no statistically significant differences were noted between the score results at baseline (8.71 ± 6.82) and follow-up (9.29 ± 6.13) (p ¼ 0.356). Compared with MACcomplication cases and non-MAC-complication cases (comparison of the difference between the score of baseline and that of followup), MAC-complication cases were significantly further exacerbated than non-MAC-complication cases (p ¼ 0.027) (Fig. 1). Although nine of eleven MAC-complication cases (82%) rose by one or more points from baseline to follow-up, there were only three of seven among non-MAC-complication cases (43%; p ¼ 0.141).
Fig. 2 shows a comparison of MAC-complication and non-MACcomplication case scores at baseline and follow-up when divided according to each NICE factor. N factor of MAC-complication cases and I and E factors of non-MAC-complication cases at follow-up were significantly further exacerbated than those at baseline. Compared with MAC-complication cases and non-MACcomplication cases, I factor was significantly further exacerbated (p ¼ 0.024). Next, specific cases are presented. For Case 3, M. abscessus was detected from a sputum culture during the treatment with CAM, RFP, and EB for pulmonary MAC infection. As the sputum culture subsequently turned negative for MAC, the treatment for MAC was concluded. Sometime after the treatment, only the growth of M. abscessus was noted in the sputum; however later, the growth of MAC alone was noted in the sputum. The NICE score worsened from
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Fig. 1. Total NICE score (N; nodule, I; infiltration, C; cavity, E; bronchiectasis) of baseline and follow-up period (mean ± standard deviation). For MAC-complication cases, there was a significant difference between the scores at baseline and follow-up, and MAC-complication cases were significantly further exacerbated than non-MAC-complication cases.
Fig. 2. The score of every factor (upper left: N, upper right: I, lower left: C, lower right: E) (mean ± standard deviation). In I factor the score more worsened for MAC-complication cases than for non-MAC-complication cases.
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Fig. 3. Chest X-ray and NICE score of case 3 (left: baseline, right: follow up). In zone 3 (right middle field) the I score worsened from 0 to 2 in X-ray, but in fact the shadow of zone 3 represented the cavity in computed tomography.
Fig. 4. Chest X-ray and NICE score of case 15 (left: baseline, right: follow up). There was a slightly deterioration of reticular shadow of bilateral lower field due to interstitial pneumonia, but there was no change of NICE score.
K. Furuta et al. / J Infect Chemother 22 (2016) 622e628
9 at baseline to 15 at follow-up, and in particular increase of I score in the upper and middle lung zones was noted (Fig. 3). However, the increase of I score in zone 3 exhibited no increased infiltration on computed tomography (CT), but did exhibit an increased cavitation. Thus, a discrepancy was noted between chest X-ray images and CT images. Case 15 was already being administered PSL for interstitial pneumonia. The exacerbation of an inexplicable shadow was noted while being treated for interstitial pneumonia and the sputum culture indicated growth of M. abscessus. However, no treatment was performed for M. abscessus. The NICE score indicated no change from 8 at baseline to 8 at follow-up and there were almost no changes noted for any factors (Fig. 4). 4. Discussion According to the 2007 ATS/IDSA statement [3], there is no established treatment regimen for pulmonary M. abscessus infection. Therefore, it is considered to be more difficult to completely cure pulmonary M. abscessus infection than pulmonary MAC infection. Our results suggested that pulmonary M. abscessus infection cases complicated by MAC infection may differ clinically from those not complicated by MAC infection. Furthermore, it appears that particular caution is required when observing the clinical course and treating cases complicated by MAC infection. Until 1992, M. abscessus had been classified as a subspecies called Mycobacterium chelonae subsp. abscessus, rather than an independent bacterial strain. Subsequently, Tsukamura et al. indicated the strong possibility that M. abscessus was an independent bacterial strain [10], and Kusunoki et al. proposed the concept of M. abscessus as an independent bacterial strain based on DNA homology [11]. Moreover, in 2009, Zelazny et al. reported that sequence analysis of rpoB, hsp65, and secA revealed that M. abscessus could be subtyped into three types (M. abscessus, M. massiliense, and M. bolletii) [6]. There are opinions that M. massiliense and M. bolletii should be combined and treated as M. abscessus subsp. bolletii comb [12]. However, differences in response to treatment and in sensitivity to drugs, particularly between the subtyped M. abscessus and M. massiliense have been reported. Koh et al. investigated 145 cases of pulmonary M. abscessus complex infection (equivalent to M. abscessus infection before the subtypes were identified) and reported on the treatment course and drug sensitivity of 57 cases that underwent sensitivity testing and combination chemotherapy including CAM [7]. They found that improvement of clinical symptoms and initial sputum culture negativity rates for pulmonary M. abscessus infection and pulmonary M. massiliense infection cases were 75% vs. 97% and 42% vs. 97%, respectively, indicating better results for cases of pulmonary M. massiliense infection. The results for 47 cases that could be investigated over time for sensitivity to CAM showed that sensitivity to CAM was maintained until 14 days after starting treatment for all M. massiliense cases. In contrast, although sensitivity to CAM was maintained until 3 days after starting treatment for all M. abscessus cases, resistance to CAM was noted in all of these cases at 14 days after starting treatment. The ATS/IDSA statement [3] suggests that it may be possible to control pulmonary M. abscessus infection with CAM monotherapy, but this treatment may be successful in treating M. massiliense infection, whereas the buildup of resistance to CAM in cases of M. abscessus infection may make treatment difficult in such cases. Griffith et al. investigated 154 cases of rapidly growing mycobacteria in North America [13] and reported that approximately 15% of M. abscessus infection cases exhibited germ discharge of MAC during the course of treatment, suggesting a close relationship between the two. In contrast, another report by Griffith et al. [14]
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indicated that out of 180 patients treated for MAC pulmonary infection, M. abscessus was detected in the respiratory specimens of 53 cases (29%), of which 21 of these cases (12%) appeared to be clinically significant M. abscessus pulmonary infection. According to Simons et al., an epidemiological study of NTM in Eastern Asia [15] revealed that MAC accounted for 56% of pulmonary NTM infection cases in Eastern Asia and for 81% of pulmonary NTM infection cases in Japan. M. abscessus complex accounted for 35% of pulmonary NTM infection cases in Eastern Asia. Thus, in contrast to the results of the report by Griffith et al., it appears that in Eastern Asia, there may be more cases of M. abscessus complex infection and MAC complications. Nagano et al. reported that of 11 cases of pulmonary M. abscessus infection in Osaka, Japan, five cases (45.4%) were complicated by pulmonary MAC infection [16]. In the present study, we also found that in 11 of 18 cases (61%) pulmonary M. abscessus infection was accompanied by pulmonary MAC infection. Although our results suggest that cases with concomitant MAC infection may exhibit more shadow exacerbation than cases with no such complications, significant issues still remain regarding treatment. Although treatment for pulmonary MAC infection is based on CAM or azithromycin (AZM) with combination of EB and RFP, M. abscessus is resistant to EB and RFP [3]; therefore, performing treatment with CAM, EB, and RFP for MAC in cases complicated by M. abscessus complex infection is essentially performing CAM monotherapy for M. abscessus complex. If the case is complicated by M. massiliense infection, the report by Koh et al. [7] has suggested that the condition may be controlled with CAM monotherapy. However, the presence of M. abscessus infection may induce resistance to CAM, which acts as a dilemma for treatment. Kurashima et al. [17] reported that for pulmonary M. abscessus infection, even if there were very few lesions, it is recommended to implement aggressive antibacterial chemotherapy. The ATS/IDSA statement [3] also indicates that although there is no established treatment regimen, as stated above, it is recommended to perform combination therapy involving surgical resection and multidrug chemotherapy if the lesion is localized. The recommended drugs include the usage of macrolides with amikacin, cefoxitin, or imipenem. In the present study, 10 of the 11 cases with both MAC and M. abscessus infection were not treated for M. abscessus infection but underwent multidrug treatment using CAM for MAC infection. Our results suggested that according to imaging evaluation, more shadow exacerbations were noted in cases complicated by MAC infection than those not complicated by MAC infection. Although most of the cases in this study did not receive treatment for M. abscessus infection, no clear exacerbation of the shadows observed on imaging were noted in cases not complicated by MAC infection. This suggests that the natural course of M. abscessus is possibly slow. It is also possible that the exacerbation in imaging findings for MAC-complication cases was reflecting MAC exacerbation rather than M. abscessus exacerbation. This study had several limitations. First, the bacterial strain was not classified in more detail than M. abscessus, so the results could not be differentiated as M. abscessus, M. massiliense or M. bolletii. The results suggested a further exacerbation in cases complicated by MAC infection, but because we were unable to divide the results according to bacterial strain, non-MAC-complication cases may have included many cases of M. massiliense and M. bolletii infection. However, in clinical practice, it is impossible to identify subspecies of the M. abscessus complex, and we must needs treat empirically. With regard to MAC infections, M. avium and Mycobacterium intracellulare have not been considered separately. In recent years, Koh et al. reported that M. intracellulare infection exhibited a more severe presentation and worse prognosis than M. avium infection [18]. Thus, the course of cases complicated by MAC infection may
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have differed, according to whether the infection was caused by M. avium or M. intracellulare. Second, the NICE scoring system used for imaging evaluation in this study was originally proposed for the semi-quantitative evaluation of imaging findings for MAC. Therefore, although M. abscessus is a type of NTM, it is unclear as to whether the NICE scoring system can be used to evaluate M. abscessus. Kurashima et al. [8] reported that although chest Xray images and CT images exhibited a significant correlation with the NICE scoring system, it is unclear whether the same is true for M. abscessus. In case 3 of this study, an instance of what appeared to be increased infiltration was actually shown to be an increased cavitation on CT imaging. The usefulness of the NICE scoring system for serial assessment is also unclear. Third, this study had no negative control cases. We didn't compare the cases of only MAC infection, without M. abscessus infection. Thus, we can't evaluate the influence of M. abscessus infection strictly. This is a subject of future investigation. In conclusion, although it appears that some cases of pulmonary M. abscessus infections follow slowly progressive courses even without treatment, the results suggested that cases complicated by MAC infections exhibit further exacerbation than those not complicated by MAC infections. In Eastern Asia, where pulmonary MAC infections are more common than in Western countries, it is expected that the number of cases of M. abscessus infections complicated by MAC infection will increase. Therefore, it is important to conduct long-term follow-up of the cases in this study and gather data on additional cases to formulate an effective treatment strategy. Conflict of interest None declared. References [1] Runyon EH. Anonymous mycobacteria in pulmonary disease. Med Clin North Am 1959;43:273e90. [2] Saito H. Symposium/Mycobacterial tests. Kekkaku 2008;83:50 [Article in Japanese]. [3] Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of
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Original article
18 Cases of pulmonary Mycobacterium abscessus: Clinical difference depending on the presence or absence of Mycobacterium avium complex Kenjiro Furuta a, b, *, Akihiro Ito b, Tadashi Ishida b, Yuhei Ito b, Naoyuki Sone b, Takuya Takaiwa b, c, Toshihide Yokoyama b, Hiromasa Tachibana b, d, Machiko Arita b, Toru Hashimoto b a
Department of Respiratory Medicine, Kobe City Hospital Organization Kobe City Medical Center West Hospital, 2-4 Ichibancho, Nagata-ku, Kobe, Hyogo 653-0013, Japan b Department of Respiratory Medicine, Ohara Memorial Kurashiki Healthcare Foundation, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, Okayama 710-8602, Japan c Department of Respiratory Medicine, Sakai City Medical Center, 1-1-1 Ebarajicho, Nishi-ku, Sakai, Osaka 593-8304, Japan d Department of Respiratory Medicine, National Hospital Organization Minami Kyoto Hospital, 11 Ashihara, Joyo, Kyoto 610-0113, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 February 2016 Received in revised form 6 May 2016 Accepted 16 June 2016 Available online 16 July 2016
Background and objectives: It can be difficult to treat respiratory tract infections caused by Mycobacterium abscessus (M. abscessus) as there is no established treatment strategy. Complications involving other nontuberculous mycobacterial infections such as Mycobacterium avium complex (MAC) are also commonly observed. Methods: We investigated the clinical background and course of 18 cases of pulmonary M. abscessus infection treated over 8 years at Kurashiki Central Hospital. Radiological evaluation was performed using NICE scoring system, a method of semi-quantitative evaluation of imaging findings of pulmonary MAC infection. Results: The mean age of the 18 patients (males, 6; females, 12) was 74.7 years. The median follow-up period was 1316 days (95% confidence interval; 720e1675 days), and 11 patients were concomitantly infected with pulmonary MAC. Among the patients that underwent antibacterial treatment for M. abscessus, there was one MAC-complication case and one non-MAC-complication case. All MACcomplication cases underwent antibacterial treatment including clarithromycin. Chest X-ray NICE scores for all cases were 8.50 ± 5.45 and 10.94 ± 6.03 at baseline and follow-up, respectively (p ¼ 0.0063). For MAC-complication cases, scores were 8.36 ± 4.74 and 12.00 ± 6.02 at baseline and follow-up, respectively (p ¼ 0.00818), and for non-MAC-complication cases, scores were 8.71 ± 6.82 and 9.29 ± 6.13 at baseline and follow-up, respectively (p ¼ 0.356). MAC-complication cases were significantly further exacerbated than non-MAC-complication cases (p ¼ 0.027). Conclusions: Some cases of pulmonary M. abscessus infection progressed well without undergoing antibacterial treatment. In particular, results suggested that the clinical course of MAC-complication and non-MAC-complication cases differs. © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Coinfection Japan Mycobacterium abscessus Mycobacterium avium complex Nontuberculous mycobacteria
1. Introduction
* Corresponding author. Department of Respiratory Medicine, Kobe City Hospital Organization Kobe City Medical Center West Hospital, 2-4 Ichibancho, Nagata-ku, Kobe, Hyogo 653-0013, Japan. Tel.: þ81 78 576 5251; fax: þ81 78 576 5358. E-mail address: [email protected] (K. Furuta).
Mycobacterium abscessus (M. abscessus) is a rapidly growing nontuberculous mycobacterium (NTM) that belongs to the Runyon classification group IV [1] [2]. It is indigenous to environments such as soil and water and is known to cause skin and soft tissue infections in addition to respiratory tract infections [3] [4]. In Japan, it
http://dx.doi.org/10.1016/j.jiac.2016.06.009 1341-321X/© 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
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has been reported that in pulmonary NTM infections, M. abscessus is second most common pathogen following Mycobafcterium Mycobacterium avium complex (MAC) [5] Mycobacterium kansasii. Furthermore, complications with other NTM infections may also be observed. Although skin and soft tissue infections often respond well to antibacterial treatment, it is frequently difficult to treat respiratory tract infections as there is no established protocol for the timing of treatment initiation, selection of the appropriate antibacterial agent, or treatment duration [3]. In recent years, M. abscessus using whole genome sequencing of clinically isolated strains, M. abscessus is classified into three subspecies; M. abscessus, Mycobacterium massiliense (M. massiliense), and Mycobacterium bolletii (M. bolletii) [6], which are together known as the M. abscessus complex [7]. We retrospectively investigated the clinical course and findings, including the diagnostic imaging results, of 18 cases of pulmonary M. abscessus complex infection that occurred over 8 years at Kurashiki Central Hospital. We have discussed our results based on the presence or absence of a complicating MAC infection. 2. Patients and methods Subjects comprised 18 patients diagnosed with pulmonary M. abscessus infection over 8 years between January 1, 2005 and December 31, 2012 at Kurashiki Central Hospital (Kurashiki, Japan). Subsequent progress of the patients was followed-up until March 2015. All cases met the diagnostic criteria for NTM infection, as determined by the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) [3]. We retrospectively investigated various background factors such as underlying disease, laboratory findings, diagnostic imaging findings, treatment details, and clinical course, based on the medical records of these cases. For imaging findings in particular, two pulmonologists (K.F. and A.I.) evaluated the chest X-ray findings obtained at a date closest to when M. abscessus was first detected in respiratory tract specimens and the most recently available chest-ray at Kurashiki Central Hospital. The evaluation method used was the NICE scoring system (N; nodule, I; infiltration, C; cavity, E; bronchiectasis), which was recently proposed by Kurashima et al. for the semi-quantitative evaluation of MAC [8]. In the NICE scoring system, the lungs are divided into six zones (zone 1: area on the upper right above the level of the carina, zone 2: area on the upper left above the level of the carina, zone 3: area on the right between the level of the carina and the lower pulmonary vein, zone 4: area on the left between the level of the carina and the lower pulmonary vein, zone 5: area on the right below the lower pulmonary vein, and zone 6: area on the left below the lower pulmonary vein). Then, imaging findings for each zone are scored from 0 to 4 points based on four factors (N, I, C, E), according to the proportion of each zone that the lesion comprises. For 0%, 0 points are awarded; for 0% to <25%, 1 point; for 25% to <50%, 2 points; for 50% to <75%, 3 points; and for 75%, 4 points. The follow-up period in this study was set as the number of days between the two X-ray imaging sessions evaluated with the NICE scoring system. Cases were divided for analysis into those diagnosed as MAC-complication cases diagnosed according to the NTM infection diagnostic criteria of the ATS/IDSA [3] or non-MACcomplication cases. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Kanda, 2012), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria, version 2.13.0) [9]. Follow-up periods were reported as median and 95% confidence interval (CI), and compared using logrank test. Other absolute data were reported as mean ± standard deviation. Categorical variables were compared using Fisher's exact test. Continuous variables were compared
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using t test. All p values were two-sided, and p values of 0.05 were considered statistically significant. This study was approved by the Ethics Committee of Kurashiki Central Hospital, Approved Number 1941. 3. Results A total of 19 patients were diagnosed with pulmonary M. abscessus infections over the 8-year observation period. Of these, the underlying disease in one patient was a chest wall tumor (solitary fibrous tumor). This case was excluded from our analysis due to the influence of the tumor on chest contrast images. The backgrounds and bacteriological basis for making a diagnosis of pulmonary M. abscessus infection in the remaining 18 cases that were subject to analysis are shown in Table 1. Subjects included six males and 12 females, with a mean age of 74.7 years. There were 11 cases (cases 1e11) that were complicated by pulmonary MAC infection either before diagnosed or during the course of pulmonary M. abscessus infection. Of the seven cases that were not complicated by pulmonary MAC infection (cases 12e18), one was complicated by pulmonary M. kansasii infection (case 17). Underlying diseases included diabetes in three patients and active, malignant tumors in three patients (one lung cancer, one prostate cancer, and one gastric cancer). Furthermore, two patients were being administered corticosteroids (prednisolone (PSL) 12 mg/day for one case of vasculitis, and PSL 5 mg/day for one case of interstitial pneumonia). Data indicated that none of the patients had problems related to room air oxygenation except for one (case 13) who had originally undergone long-term oxygen therapy for pulmonary thromboembolism. The bacteriological basis for making a diagnosis of pulmonary M. abscessus infection included two consecutive positive results for sputum culture (14 cases), a positive result for bronchoalveolar lavage fluid culture (two cases), a positive result from the tissue culture of the surgical specimen of a simultaneously diagnosed lung cancer (one case), and two positive results for sputum culture together with a positive result from he bronchoalveolar lavage fluid culture (one case). Table 2 shows the treatment details, follow-up periods and outcomes for each case. All of the MAC-complication cases (cases 1e11) except for case 7, received antibacterial treatment for MAC, which mainly included clarithromycin (CAM), rifampicin (RFP), and ethambutol (EB). Only case 2 was treated with imipenem/cilastatin (IPM/CS), amikacin (AMK), and CAM for M. abscessus, but the treatment was discontinued due to fatigue approximately one month after starting treatment. Thus, no MAC-complication cases received sufficient treatment for M. abscessus. Only one case (case 9) died during the observation period due to disseminated infection of MAC. With regard to the non-MAC-complication cases (cases 12e18), only case 17 received two rounds of treatment with IPM/CS, AMK, and CAM for M. abscessus, and the treatment periods were 5 and 4 months, respectively. Although the sputum culture turned negative after the first round of treatment, a subsequent repeat sputum culture indicated growth of M. abscessus again. Therefore, a second round of treatment was performed, after which the sputum culture turned negative again. However, M. kansasii was also later detected in the sputum. During the observation period, only one case (case 17) died, but the cause of death was unclear. The median follow-up period for all cases was 1316 days (95% CI; 720e1675 days). The median follow-up periods for MAC-complication cases and nonMAC-complication cases were 1468.5 days (95% CI; 644e1820 days) and 995.0 days (95% CI; 417e1638 days), respectively (p ¼ 0.245). Total NICE score results were 8.50 ± 5.45 at baseline (the time when M. abscessus was firstly detected in culture results) and
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Table 1 Patient characteristics: case1-11 MAC-complication cases, case12-18 non-MAC-complication cases. Case
Age/sex
Smoking history
Symptom
Major past history/comorbidity
Co-existence of other NTM
Basis of diagnosis
1 2 3 4 5 6 7 8 9
71 72 68 69 81 70 76 77 77
F F F F F F M F F
Unknown Never Unknown Never Never Unknown Past Never Never
None Cough Sputum None Fatigue, DOE Cough Hemoptysis Cough, sputum None
MAC MAC MAC MAC MAC MAC MAC MAC MAC
Sputum culture over two times Sputum culture over two times Sputum culture over two times Sputum culture over two times Sputum culture over two times Sputum culture over two times Surgical specimen culture Sputum culture over two times BLF culture
10 11 12 13 14 15 16 17 18
70 80 80 82 77 85 78 72 60
F F M F M M M M F
Never Never Never Never Past Past Past Past Never
None Hemoptysis Cough DOE Fatigue Cough, sputum Sputum, DOE Cough, sputum Fever, hemoptysis
Renal cancer, thyroid cancer RPGN, cerebral infarction None Thymoma Diabetes mellitus None Lung cancer, DM Hypertension Vasculitis (PSL 12 mg/day), sarcoma None Old tuberculosis Hypertension, sinusitis Pulmonary thromboembolism AP, SSS, prostate cancer IP(PSL 5 mg/day), DM AP, cerebral infarction Silicosis, COPD, gastric cancer Adult T-cell leukemia
MAC MAC None None None None None M. kansasii None
Sputum culture Sputum culture Sputum culture BLF culture Sputum culture Sputum culture Sputum culture Sputum culture Sputum culture
over two times over two times over two times over two times over two times over two times over two times and BLF culture
Abbreviation: RPGN; rapidly progressive glomerulonephritis, DOE; dyspnea on effort, DM; diabetes mellitus, BLF; bronchial lavage fluid, AP; angina pectoris, IP; interstitial pneumonia, COPD; chronic obstructive pulmonary disease.
Table 2 Treatment for NTM, follow up period and patient outcome. Case
Treatment for M. abscessus
Treatment for MAC
Duration of follow up (days)
Outcome
1 2
CAM þ RFP þ EB CAM þ RFP þ EB
2861 936
Alive Alive
3 4 5 6 7 8 9
e IPM/CS þ AMK þ CAM (1 month, cessation due to fatigue) e e e e e e e
2338 1596 1341 1820 644 967 83
10 11
e e
Alive Alive Alive Alive Alive Alive Died (due to MAC) Alive Alive
12 13 14 15 16 17
e e e e e IPM/CS þ AMK þ CAM (2 times; 5 months, 4 months) e
18
CAM CAM CAM CAM e CAM CAM
þ þ þ þ
RFP þ EB RFP þ EB RFP þ EB þ LVFX RFP
þ RFP þ EB þ RFP þ EB þ SM
CAM þ RFP þ EB CAM þ RFP þ EB þ SM / CAM þ RFP þ EB e e e e e e
1675 1316
e
417
998 629 995 1638 720 1773
Alive Alive Alive Alive Alive Died (unknown cause) Alive
Abbreviation: AMK; amikacin, LVFX; levofloxacin, SM; streptomycin.
10.94 ± 6.03 at follow-up (the time when the most recent chest Xray images taken at our hospital), indicating statistically significant changes (p ¼ 0.0063). For MAC-complication cases, the score results at follow-up (12.00 ± 6.02) significantly worsened than those at baseline (8.36 ± 4.74) (p ¼ 0.00818). On the other hand, for nonMAC-complication cases, no statistically significant differences were noted between the score results at baseline (8.71 ± 6.82) and follow-up (9.29 ± 6.13) (p ¼ 0.356). Compared with MACcomplication cases and non-MAC-complication cases (comparison of the difference between the score of baseline and that of followup), MAC-complication cases were significantly further exacerbated than non-MAC-complication cases (p ¼ 0.027) (Fig. 1). Although nine of eleven MAC-complication cases (82%) rose by one or more points from baseline to follow-up, there were only three of seven among non-MAC-complication cases (43%; p ¼ 0.141).
Fig. 2 shows a comparison of MAC-complication and non-MACcomplication case scores at baseline and follow-up when divided according to each NICE factor. N factor of MAC-complication cases and I and E factors of non-MAC-complication cases at follow-up were significantly further exacerbated than those at baseline. Compared with MAC-complication cases and non-MACcomplication cases, I factor was significantly further exacerbated (p ¼ 0.024). Next, specific cases are presented. For Case 3, M. abscessus was detected from a sputum culture during the treatment with CAM, RFP, and EB for pulmonary MAC infection. As the sputum culture subsequently turned negative for MAC, the treatment for MAC was concluded. Sometime after the treatment, only the growth of M. abscessus was noted in the sputum; however later, the growth of MAC alone was noted in the sputum. The NICE score worsened from
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Fig. 1. Total NICE score (N; nodule, I; infiltration, C; cavity, E; bronchiectasis) of baseline and follow-up period (mean ± standard deviation). For MAC-complication cases, there was a significant difference between the scores at baseline and follow-up, and MAC-complication cases were significantly further exacerbated than non-MAC-complication cases.
Fig. 2. The score of every factor (upper left: N, upper right: I, lower left: C, lower right: E) (mean ± standard deviation). In I factor the score more worsened for MAC-complication cases than for non-MAC-complication cases.
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Fig. 3. Chest X-ray and NICE score of case 3 (left: baseline, right: follow up). In zone 3 (right middle field) the I score worsened from 0 to 2 in X-ray, but in fact the shadow of zone 3 represented the cavity in computed tomography.
Fig. 4. Chest X-ray and NICE score of case 15 (left: baseline, right: follow up). There was a slightly deterioration of reticular shadow of bilateral lower field due to interstitial pneumonia, but there was no change of NICE score.
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9 at baseline to 15 at follow-up, and in particular increase of I score in the upper and middle lung zones was noted (Fig. 3). However, the increase of I score in zone 3 exhibited no increased infiltration on computed tomography (CT), but did exhibit an increased cavitation. Thus, a discrepancy was noted between chest X-ray images and CT images. Case 15 was already being administered PSL for interstitial pneumonia. The exacerbation of an inexplicable shadow was noted while being treated for interstitial pneumonia and the sputum culture indicated growth of M. abscessus. However, no treatment was performed for M. abscessus. The NICE score indicated no change from 8 at baseline to 8 at follow-up and there were almost no changes noted for any factors (Fig. 4). 4. Discussion According to the 2007 ATS/IDSA statement [3], there is no established treatment regimen for pulmonary M. abscessus infection. Therefore, it is considered to be more difficult to completely cure pulmonary M. abscessus infection than pulmonary MAC infection. Our results suggested that pulmonary M. abscessus infection cases complicated by MAC infection may differ clinically from those not complicated by MAC infection. Furthermore, it appears that particular caution is required when observing the clinical course and treating cases complicated by MAC infection. Until 1992, M. abscessus had been classified as a subspecies called Mycobacterium chelonae subsp. abscessus, rather than an independent bacterial strain. Subsequently, Tsukamura et al. indicated the strong possibility that M. abscessus was an independent bacterial strain [10], and Kusunoki et al. proposed the concept of M. abscessus as an independent bacterial strain based on DNA homology [11]. Moreover, in 2009, Zelazny et al. reported that sequence analysis of rpoB, hsp65, and secA revealed that M. abscessus could be subtyped into three types (M. abscessus, M. massiliense, and M. bolletii) [6]. There are opinions that M. massiliense and M. bolletii should be combined and treated as M. abscessus subsp. bolletii comb [12]. However, differences in response to treatment and in sensitivity to drugs, particularly between the subtyped M. abscessus and M. massiliense have been reported. Koh et al. investigated 145 cases of pulmonary M. abscessus complex infection (equivalent to M. abscessus infection before the subtypes were identified) and reported on the treatment course and drug sensitivity of 57 cases that underwent sensitivity testing and combination chemotherapy including CAM [7]. They found that improvement of clinical symptoms and initial sputum culture negativity rates for pulmonary M. abscessus infection and pulmonary M. massiliense infection cases were 75% vs. 97% and 42% vs. 97%, respectively, indicating better results for cases of pulmonary M. massiliense infection. The results for 47 cases that could be investigated over time for sensitivity to CAM showed that sensitivity to CAM was maintained until 14 days after starting treatment for all M. massiliense cases. In contrast, although sensitivity to CAM was maintained until 3 days after starting treatment for all M. abscessus cases, resistance to CAM was noted in all of these cases at 14 days after starting treatment. The ATS/IDSA statement [3] suggests that it may be possible to control pulmonary M. abscessus infection with CAM monotherapy, but this treatment may be successful in treating M. massiliense infection, whereas the buildup of resistance to CAM in cases of M. abscessus infection may make treatment difficult in such cases. Griffith et al. investigated 154 cases of rapidly growing mycobacteria in North America [13] and reported that approximately 15% of M. abscessus infection cases exhibited germ discharge of MAC during the course of treatment, suggesting a close relationship between the two. In contrast, another report by Griffith et al. [14]
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indicated that out of 180 patients treated for MAC pulmonary infection, M. abscessus was detected in the respiratory specimens of 53 cases (29%), of which 21 of these cases (12%) appeared to be clinically significant M. abscessus pulmonary infection. According to Simons et al., an epidemiological study of NTM in Eastern Asia [15] revealed that MAC accounted for 56% of pulmonary NTM infection cases in Eastern Asia and for 81% of pulmonary NTM infection cases in Japan. M. abscessus complex accounted for 35% of pulmonary NTM infection cases in Eastern Asia. Thus, in contrast to the results of the report by Griffith et al., it appears that in Eastern Asia, there may be more cases of M. abscessus complex infection and MAC complications. Nagano et al. reported that of 11 cases of pulmonary M. abscessus infection in Osaka, Japan, five cases (45.4%) were complicated by pulmonary MAC infection [16]. In the present study, we also found that in 11 of 18 cases (61%) pulmonary M. abscessus infection was accompanied by pulmonary MAC infection. Although our results suggest that cases with concomitant MAC infection may exhibit more shadow exacerbation than cases with no such complications, significant issues still remain regarding treatment. Although treatment for pulmonary MAC infection is based on CAM or azithromycin (AZM) with combination of EB and RFP, M. abscessus is resistant to EB and RFP [3]; therefore, performing treatment with CAM, EB, and RFP for MAC in cases complicated by M. abscessus complex infection is essentially performing CAM monotherapy for M. abscessus complex. If the case is complicated by M. massiliense infection, the report by Koh et al. [7] has suggested that the condition may be controlled with CAM monotherapy. However, the presence of M. abscessus infection may induce resistance to CAM, which acts as a dilemma for treatment. Kurashima et al. [17] reported that for pulmonary M. abscessus infection, even if there were very few lesions, it is recommended to implement aggressive antibacterial chemotherapy. The ATS/IDSA statement [3] also indicates that although there is no established treatment regimen, as stated above, it is recommended to perform combination therapy involving surgical resection and multidrug chemotherapy if the lesion is localized. The recommended drugs include the usage of macrolides with amikacin, cefoxitin, or imipenem. In the present study, 10 of the 11 cases with both MAC and M. abscessus infection were not treated for M. abscessus infection but underwent multidrug treatment using CAM for MAC infection. Our results suggested that according to imaging evaluation, more shadow exacerbations were noted in cases complicated by MAC infection than those not complicated by MAC infection. Although most of the cases in this study did not receive treatment for M. abscessus infection, no clear exacerbation of the shadows observed on imaging were noted in cases not complicated by MAC infection. This suggests that the natural course of M. abscessus is possibly slow. It is also possible that the exacerbation in imaging findings for MAC-complication cases was reflecting MAC exacerbation rather than M. abscessus exacerbation. This study had several limitations. First, the bacterial strain was not classified in more detail than M. abscessus, so the results could not be differentiated as M. abscessus, M. massiliense or M. bolletii. The results suggested a further exacerbation in cases complicated by MAC infection, but because we were unable to divide the results according to bacterial strain, non-MAC-complication cases may have included many cases of M. massiliense and M. bolletii infection. However, in clinical practice, it is impossible to identify subspecies of the M. abscessus complex, and we must needs treat empirically. With regard to MAC infections, M. avium and Mycobacterium intracellulare have not been considered separately. In recent years, Koh et al. reported that M. intracellulare infection exhibited a more severe presentation and worse prognosis than M. avium infection [18]. Thus, the course of cases complicated by MAC infection may
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have differed, according to whether the infection was caused by M. avium or M. intracellulare. Second, the NICE scoring system used for imaging evaluation in this study was originally proposed for the semi-quantitative evaluation of imaging findings for MAC. Therefore, although M. abscessus is a type of NTM, it is unclear as to whether the NICE scoring system can be used to evaluate M. abscessus. Kurashima et al. [8] reported that although chest Xray images and CT images exhibited a significant correlation with the NICE scoring system, it is unclear whether the same is true for M. abscessus. In case 3 of this study, an instance of what appeared to be increased infiltration was actually shown to be an increased cavitation on CT imaging. The usefulness of the NICE scoring system for serial assessment is also unclear. Third, this study had no negative control cases. We didn't compare the cases of only MAC infection, without M. abscessus infection. Thus, we can't evaluate the influence of M. abscessus infection strictly. This is a subject of future investigation. In conclusion, although it appears that some cases of pulmonary M. abscessus infections follow slowly progressive courses even without treatment, the results suggested that cases complicated by MAC infections exhibit further exacerbation than those not complicated by MAC infections. In Eastern Asia, where pulmonary MAC infections are more common than in Western countries, it is expected that the number of cases of M. abscessus infections complicated by MAC infection will increase. Therefore, it is important to conduct long-term follow-up of the cases in this study and gather data on additional cases to formulate an effective treatment strategy. Conflict of interest None declared. References [1] Runyon EH. Anonymous mycobacteria in pulmonary disease. Med Clin North Am 1959;43:273e90. [2] Saito H. Symposium/Mycobacterial tests. Kekkaku 2008;83:50 [Article in Japanese]. [3] Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of
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