bs_bs_banner
ORIGINAL ARTICLE
Nontuberculous mycobacteria in diffuse panbronchiolitis TAKAHIRO TSUJI, EISAKU TANAKA, IKKOH YASUDA, YOSHINARI NAKATSUKA, YUSUKE KAJI, TAKEHIRO YASUDA, SEISHU HASHIMOTO, MOON HEE HWANG, TAKASHI HAJIRO AND YOSHIO TAGUCHI Department of Respiratory Medicine, Tenri Hospital, Nara, Japan
ABSTRACT Background and objective: Nontuberculous mycobacterial (NTM) lung disease secondary to cystic fibrosis (CF) has been reported, but there is limited data about NTM prevalence in non-CF bronchiectasis. We retrospectively investigated the prevalence of NTM associated with diffuse panbronchiolitis (DPB), a disorder also characterized by reduced mucociliary clearance with bronchiectasis. Methods: We reviewed mycobacterial cultures, patient characteristics and computed tomography findings of 33 patients with DPB between January 2000 and December 2012. Prevalence was based on at least one positive NTM culture. Results: Mean patient age was 51.5 years. During a mean 162.8-month follow-up, the prevalence of NTM in sputum was 21.2% (seven patients). Of the seven positive patients, six had Mycobacterium avium complex, one had M. kansasii and M. chelonae co-cultured with M. avium complex. Three patients were positive twice, and two had positive smears. The mean time from DPB diagnosis to the first positive result was 194.6 months. NTM-positive patients tended to have lower forced expiratory volume in 1 s (% predicted) than NTM-negative patients (50.0% vs 77.3%, P = 0.03), but there were no radiological or clinical differences between the two groups. Conclusions: Our observations suggest that NTM is found more often in DPB. Defects of mucociliary clearance may predispose individuals to NTM infection. Keywords: bronchiectasis, Japan, mucociliary clearance, prevalence.
Abbreviations: AFB, acid-fast bacteria; ATS/IDSA, American Thoracic Society/Infectious Diseases Society of America; AZM, azithromycin; BMI, body mass index; CAM, clarithromycin; CF, cystic fibrosis; CT, computed tomography; DPB, diffuse panbronchiolitis; EM, erythromycin; FEV1, forced expiratory volume in 1 s; MAC, Mycobacterium avium complex; NTM, nontuberculous mycobacterial; PCD, primary ciliary dyskinesia; PFT, pulmonary function test; SEM, standard error of the mean. Correspondence: Takahiro Tsuji, Department of Respiratory Medicine, Tenri Hospital, 200 Mishima-cho, Tenri City, Nara 6328552, Japan. Email: [email protected] Received 10 March 2014; invited to revise 5 May 2014; revised 2 August 2014; accepted 11 August 2014 (Associate Editor: Yuanlin Song). © 2014 Asian Pacific Society of Respirology
SUMMARY AT A GLANCE Defects in the mucociliary transport system are assumed to be a predisposing factor to nontuberculous mycobacterial (NTM) infection. We retrospectively investigated the prevalence of NTM associated with diffuse panbronchiolitis (DPB), which is characterized by mucociliary dysfunction. We detected a high prevalence comparable to rates in cystic fibrosis.
INTRODUCTION Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can often induce respiratory diseases in patients with pre-existing lung damage.1,2 In the past two decades, bronchiectatic diseases, such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD), have been identified as predisposing factors of NTM infection.3,4 With regard to CF, some previous reports and a prospective multi-centre study showed that NTM was isolated from 13% to 23% respiratory specimens.3,5–8 In PCD, a high prevalence of NTM (10%) was also reported.4 Although many studies have stated the prevalence of NTM in CF, there is little data about non-CF bronchiectasis (2–10.3%).9–13 Although the reasons for the high prevalence of NTM in patients with CF and PCD remain unclear, underlying structural airway disease and altered mucociliary clearance are assumed to be predisposing factors.1 Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory disease with an incidence rate of 11.1 per 100 000 individuals in Japan according to a population-based survey conducted in 1980.14 In the 1990s, long-term macrolide therapy for DPB exhibited marked efficacy.15 Recently, the incidence and prevalence of DPB appear to have decreased.16 In DPB, morphological and functional abnormalities of the mucociliary transport system have been documented,17 and the clinical characteristics of DPB are similar to those of CF, including bronchiectasis, chronic respiratory tract infection (often associated with P. aeruginosa infection) and recurrent sinusitis. Respirology (2015) 20, 80–86 doi: 10.1111/resp.12412
81
NTM in DPB
We hypothesized that DPB would be a predisposing factor for NTM infection similar to CF, and retrospectively investigated the prevalence of NTM in DPB.
METHODS Retrospective study population A total of 33 patients with ‘definite’ DPB who visited our hospital (local central 815 beds hospital in Nara Prefecture, Japan) from January 2000 to December 2012 were recruited, based on the diagnostic criteria established by the Ministry of Health and Welfare of Japan.18,19 All patients who continued to regularly visit the hospital provided written informed consent according to hospital guidelines. For patients who had discontinued regular hospital visits, the requirement for written informed consent was waived by the hospital ethics committee due to the retrospective nature of the research. This study was approved by the institutional ethical committee of Tenri Hospital. Patient characteristics and symptoms Patient characteristics and respiratory symptoms were determined by reviewing medical records (Appendix S1). Treatment for DPB was defined as long-term antibiotic therapy,15 which had been administered following the collection of mycobacteria culture samples. Biological analysis We retrospectively collected all the results of acid-fast bacteria (AFB) tests of sputum conducted during the follow-up period, which included smears, culture tests, polymerase chain reaction tests and antibiotic susceptibility. Prevalence of NTM was assessed by at least one positive NTM culture during the follow-up period, and these subjects were defined as ‘NTMpositive’. Patients who had only negative AFB cultures were defined as ‘NTM-negative’, and those who received no AFB tests were referred to as ‘NTMundetermined’. The prevalence rate was defined as the proportion of NTM-positive subjects to all DPB subjects, including NTM-undetermined subjects. AFB tests had been carefully performed with standard methods (Appendix S1). The results of routine bacteriological examination in sputum specimens were also investigated. Lung function and body mass index We collected forced expiratory volume in 1 s (FEV1) and body mass index (BMI) during the follow-up period. The reports of pulmonary function test (PFT) were available for 31 of 33 patients. Radiology Two respiratory physicians separately checked computed tomography (CT) findings for the following signs: the extent and existence of bronchiectasis, multiple small centrilobular nodules, cavitation, © 2014 Asian Pacific Society of Respirology
nodular shadows, and consolidation (Appendix S1).20–22 Clinical information was blinded and inter-observer disagreement was resolved by consensus. Changes in CT and/or chest X-ray findings were also investigated, and classified into three categories: ‘deteriorated’, ‘stable’ or ‘improved’.
Statistical analysis NTM-positive and NTM-negative subjects were compared using the Fisher’s exact test for categorical data. BMI and %FEV1 predicted were homoscedastic and compared using the unpaired t-test. Ages were not homoscedastic and were compared using Welch’s test. SPSS Statistics (version 15.0; SPSS Inc., Chicago, IL, USA) was used for data analysis.
RESULTS Mean age was 51.5 ± 2.6 years (mean ± standard error of the mean) at the first visit with 162.8 ± 22.5 months of follow-up time. Cultures for AFB were performed in 29 patients, and the mean number of AFB tests per patient was 2.8 ± 0.5. All the patients were Japanese and received long-term antibiotic therapy with macrolides. Mean BMI was 20.7 ± 0.7, and FEV1 was 70.8% ± 4.9% predicted. One NTM-positive patient and one NTM-negative patient died of DPB progression. Another NTM-negative patient died due to an iliopsoas muscle abscess caused by Escherichia coli. Characteristics of all DPB patients are shown in Table 1. Of the 33 DPB patients, seven (21.2%) were positive for NTM at least once during the follow-up period. Characteristics of NTM-positive cases are shown in Table 2. Three patients (9.1%) had positive cultures more than twice (American Thoracic Society/ Infectious Diseases Society of America (ATS/IDSA) diagnostic criteria). Mycobacterium avium complex (MAC) was isolated in six patients, M. kansasii in one and M. chelonae was co-cultured with MAC in one patient. Four of the seven positive samples subsequently underwent susceptibility tests, and all four were susceptible to clarithromycin (CAM). None received treatment for NTM. One patient had few symptoms (case 5 in Table 2), and one patient decided to avoid multiple drug therapy because of advanced age (case 1). One patient was under close observation (case 2), but the patient would not receive multi-drug therapy for NTM in the future because of advanced age (76 years old) and mild symptoms with slow progression. As shown in Table S1, Pseudomonas aeruginosa was isolated most frequently in DPB patients (14/33 patients: 42.4%) during their clinical course, and there was no significant difference in the frequency of isolation between NTM-positive and NTMnegative subjects (total rate of isolated subjects 42.9% vs 50.0%, P = 1.00; multiple isolation 28.6% vs 36.4%, P = 1.00). There was no difference in the frequency of Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus between the two groups. Respirology (2015) 20, 80–86
82
T Tsuji et al.
Table 1
Patient characteristics in DPB patients with or without NTM isolation
Patients Male
All DPB patients
NTM-positive
33 15
7 5
100%
±SEM
Mean Age at first visit (years) Follow-up time (months) Number of AFB samples per patient Pulmonary function test (n) % pred FEV1 BMI Smoking status Never Former/current Unknown Immunocompromised state Diabetes Cancer chemotherapy CS/IS HIV Treatment for DPB EM CAM RXM
NTM-negative
21.2%
±SEM
Mean
22 6
Mean
66.7% 0.07
±SEM
51.5 162.8
±2.6 ±22.5
47.1 227.2
±8.9 ±43.9
51.5 164.2
±2.7 ±28.0
2.8 31 70.5 20.7
±0.5
3.1 7 50.0 20.0
±1.4
3.2 20 77.3 20.7
±0.6
±4.9 ±0.66
±9.5 ±1.55
21 4/1 7 8 5 1 2 0
3 0/0 4 1 1 0 0 0
16 3/0 3 6 3 1 2 0
17 15 1
5 1 1
9 13 0
P
±5.9 ±0.86
0.52 0.27
0.03 0.65 1.00
0.65
0.16*
Data are presented as the number of patients or the mean ± standard error of the mean (SEM). * P value was calculated using Fisher’s exact test as 2 × 2 contingency table, categorized into EM and CAM. % pred FEV1, percentage of predicted forced expiratory volume in 1 s; AFB, acid-fast bacteria; BMI, body mass index; CAM, clarithromycin; CS/IS, corticosteroid and/or immunosuppressor; DPB, diffuse panbronchiolitis; EM, erythromycin; HIV, human immunodeficiency virus; NTM, nontuberculous mycobacterium; RXM, roxithromycin.
Table 2
Clinical characteristics in NTM-positive subjects Age†/ Sex
Smear
1
88/F
++
2 3
52/M 17/M
+ −
4
36/M
−
5
45/F
−
6 7
56/M 29/M
− −
Mean
48.3
Case
Culture for Mycobacteria M. avium (×2) Negative (×1) M. intracellulare (×2) M. avium complex (×1) M. chelonae (×1) M. avium complex (×1) Negative (×10) M. intracellulare (×2) M. kansasii (×1) M. avium (×1) Negative (×3)
MIC for CAM (μg/mL)
Time from Dx‡
Therapy for DPB
Other microorganisms
57.9
EM
P. aeruginosa
23.1 16.4
78.4 27.9
EM EM
H. influenzae S. pneumoniae
232.4
15.2
28.5
CAM
P. aeruginosa
0.125
278.1
22.0
59.2
EM
ND 2
254.4 164.8
26.3 20.3
79.8 26.9
EM RXM
P. aeruginosa H. influenzae normal flora H. influenzae S. pneumoniae
194.6
20.0
50.0
BMI§
%FEV1§
5.1
16.5
0.125 ND
292.1 135.1
ND
1
† Age when diagnosed with DPB. Data are shown as years. In case 1, the age at first hospital visit was used instead of the age at diagnosis. ‡ The time from DPB diagnosis to the first positive result of NTM culture. Data are shown in months. § The latest data before the first positive NTM culture result is shown. %FEV1, percentage of predicted forced expiratory volume in 1 s; BMI, body mass index; CAM, clarithromycin; DPB, diffuse panbronchiolitis; Dx, diagnosis; EM, erythromycin; H. influenzae, Haemophilus influenzae; M. avium, Mycobacterium avium; M. chelonae, Mycobacterium chelonae; M. intracellulare, Mycobacterium intracellulare; M. kansasii, Mycobacterium kansasii; MIC, minimal inhibitory concentration; ND, no data; NTM, nontuberculous mycobacterial; P. aeruginosa, Pseudomonas aeruginosa; RXM, roxithromycin; S. pneumoniae, Streptococcus pneumoniae.
Respirology (2015) 20, 80–86
© 2014 Asian Pacific Society of Respirology
83
NTM in DPB Table 3 HRCT findings in DPB patients with or without NTM NTM-positive n Bronchiectasis RSL RML RIL LSS LLS LIL Nodular shadows Centrilobular micronodules Cavity Consolidation
7 7 5 7 6 4 7 6 5 4 1 5
(100%) (71.4%) (100%) (85.7%) (57.1%) (100%) (85.7%) (71.4%) (57.1%) (14.3%) (71.4%)
NTM-negative 22 22 20 22 22 17 20 21 9 17 1 6
(100%) (90.9%) (100%) (100%) (77.3%) (90.9%) (95.5%) (40.9%) (77.3%) (4.5%) (27.3%)
NTM-undetermined 4 4 2 3 3 1 3 3 2 1 0 0
(100%) (50.0%) (13.6%) (13.6%) (4.5%) (13.6%) (13.6%) (9.1%) (4.5%) (0%) (0%)
P*
1.00
0.21 0.36 0.43 0.07
Data are presented as the number of patients. * P value was calculated with Fisher’s test by comparing NTM-positive and NTM-negative subjects. DPB, diffuse panbronchiolitis; HRCT, high-resolution computed tomography; LIL, left inferior lobe; LLS, left lingular segment; LSS, left superior segment; NTM, nontuberculous mycobacteria; RIL, right inferior lobe; RML, right middle lobe; RSL, right superior lobe.
Figure 1 Computed tomography (CT) findings of nontuberculous mycobacteriapositive patients: (a) CT images of case 3. Centrilobular small nodules are diffusely presented. Some clusters showed ‘tree-inbud’ appearance (black arrow). (b and c) CT images of case 4 (b) and case 1 (c). Nodular shadow (white arrow), bronchiectasis (white arrowhead) and clusters of centrilobular small nodules (black arrowhead) are also present.
Compared with NTM-negative subjects, NTMpositive subjects had significantly lower % predicted FEV1 (positive vs negative; 50.0% vs 77.3%, P = 0.03). There was no significant difference in other clinical characteristics or symptoms (Table 1, Table S2). The trend of %FEV1 in the NTM-positive group is presented in Figure S1. Three patients underwent PFT both before and after testing positive for NTM. FEV1 was improved in two patients, but deteriorated in one patient. On CT, there was no significant difference between NTM-positive and NTM-negative subjects (Table 3). All NTM-positive and NTM-negative subjects had bronchiectasis with no difference in the extent of disease. Multiple small centrilobular nodules (positive vs negative; 57.1% vs 77.3%, P = 0.36), consolidation (71.4% vs 27.3%, P = 0.07) and nodular shadows (71.4% vs 40.9%, P = 0.21) were also common findings. Typical CT findings of NTM-positive subjects are shown in Figure 1. Radiological deterioration was observed in four patients in the NTM-positive group, including three patients who met the ATS/IDSA criteria, and in six patients in the NTM-negative group. © 2014 Asian Pacific Society of Respirology
The signs of deterioration were similar between the two groups, and included an increase in multiple centrilobular nodules and progression of bronchiectasis (Table S3, Fig. 2).
DISCUSSION This is the first retrospective study of NTM in DPB, a disorder of mucociliary clearance with bronchiectasis. The overall prevalence of NTM in DPB was 21.2%, which is comparable with that associated with CF (13.0% in >10-year-old patients) and PCD (10% in >30year-old patients).3,4 In the NTM-positive patients, it is possible that some had colonization rather than infection. However, at least three (9.1%) were assumed to have NTM infection because they met the ATS/IDSA criteria and showed deterioration on radiological examination. The prevalence of NTM in DPB was higher than that reported in other studies of non-CF bronchiectasis9–13 and the previous surveillance of NTM in the general Japanese population (5.7/100 000 in 2007).23 As institutional biological information, we Respirology (2015) 20, 80–86
84
T Tsuji et al.
Figure 2 Computed tomography (CT) findings in nontuberculous mycobacteria (NTM)-positive and NTMnegative patients: (a) Progression of CT findings in an NTM-positive patient. CT images before testing positive for NTM (left) and 27 months after testing positive (right) are shown. An increase in centrilobular small nodules was observed in right middle lobe, right inferior lobe, left lingular segment and left inferior lobe. (b) CT findings in an NTM-negative patient. CT images taken at an interval of 4 years are shown. An increase in centrilobular small nodules was also observed in the right middle lobe, right inferior lobe, left lingular segment and left inferior lobe.
investigated the prevalence of NTM in 482 patients with chronic obstructive pulmonary disease who regularly visited our hospital for more than 5 years from January 2000 to December 2012. Among them, 41 patients (8.6%) were positive for NTM and 12 (2.5%) met the ATS/IDSA criteria (Table S4, Fig. S2). Personto-person transmission would not have contributed because the regular visits of the seven patients were independent. Impairment of the mucociliary transport system, which plays an important role in host defence17,24,25 and bronchiectatic change per se, may affect local respiratory tract defences and NTM predisposition. In addition, a recent study in mice suggested a possible link between macrolide use and increased risk of NTM infection.26 In DPB patients, the prevalence of NTM tended to be higher in males than in females. Similar to fibrocavitary lung disease, pre-existing lung damage would predispose individuals to NTM infection, and the effect of female gender would be relatively less important.1 NTM-positive subjects had significantly lower % predicted FEV1 than NTM-negative subjects. NTM would be positive in advanced DPB patients. In contrast, Olivier et al.3 showed in their multi-centre study that higher % predicted FEV1 was associated with NTM in CF patients. In CF, the prevalence of NTM is highly correlated with age, which was explained in Olivier’s report by the fact that CF patients with more severe disease would die earlier, and mild cases would have longer available NTM exposure times. With DPB, long-term macrolide therapy enables severely affected patients to survive over decades (13.6 year follow-up period on average) and thus have longer exposure to NTM.15 We could not detect a trend in pulmonary function in NTM-positive patients. Respirology (2015) 20, 80–86
Other than % predicted FEV1, our results showed similar characteristics between NTM-positive and NTM-negative patients, including patient background, symptoms, CT findings, radiological progression and other microorganisms cultured. Our results suggest that NTM infection could not be ruled out in DPB patients based on only clinical and radiological information. When DPB is found to be deteriorating clinically and/or radiologically, mycobacterial screening tests should be considered. In addition, the characteristics of NTM-positive DPB patients are similar to the well-known characteristics of primary NTM lung disease, particularly the nodular/bronchiectatic type.20,22,27 We should consider that patients diagnosed with nodular/bronchiectatic NTM lung disease may have secondary infections predisposed by hidden bronchiectatic diseases, such as DPB. The high prevalence of NTM associated with DPB raises concerns for the development of macrolideresistant NTM infections because CAM is a key drug in NTM treatment and its monotherapy for NTM carries a significant risk of developing resistant NTM.1,28,29 In our four cases, long-term erythromycin (EM) therapy did not lead to CAM-resistant NTM. Recently, Binder et al. showed that in CF, NTM cases were less likely to have undergone prior long-term azithromycin (AZM) use.30 In our limited data, there was no statistical difference in the regimen of macrolide therapy between the NTM-positive and NTM-negative group. However, it should be noted that only one patient was NTMpositive among 15 receiving long-time CAM therapy and that patient had only one positive culture following 10 successive negative cultures. Two factors may have contributed to these results. First, long-term CAM administration, not EM, may haveprevented © 2014 Asian Pacific Society of Respirology
85
NTM in DPB
NTM colonization or infection, similar to AZM in CF. Second, CAM in sputum samples may just suppress NTM growth when testing and yield some falsenegative results. Kikuchi et al.31 showed that oral CAM produces higher concentrations in bronchial and alveolar epithelial lining fluid than in serum. The risk of inducing CAM resistance is still unclear, and AFB test should be carefully monitored when administering long-term macrolide monotherapy. Our study has several limitations. First, the study design was retrospective, and indications of AFB tests were not standardized. However, standardized indications of mycobacterial screening could only increase the prevalence rate because NTM-positive patients would be picked out without omission.We believe that the unstandardized nature of the tests does not impair our finding of high prevalence. Second, we selected ‘definite’ DPB patients receiving long-term macrolide therapy. Subsequently, comparatively severe patients were likely to be selected because macrolide therapy is greatly effective, and patients with mild symptoms had stopped visiting hospital before diagnosis. If the speculation that more severe DPB is associated with NTM infection is accurate, the prevalence rate observed may be overestimated. Third, this was a singlecentre investigation and the analyzed population was small; hence, we cannot account for the variation in the prevalence of NTM in different medical centres, the community and the country. Prospective multicentre studies are needed to address these issues. Fourth, we were unable to investigate CFTR genes of the subjects because the CFTR test is not included in routine clinical practice. CF is rare in Japanese population, and previous reports showed that DPB develops with no relevance to CFTR genes.32 In addition, our study population was older at the first visit than typical CF patients. Fifth, we could not perfectly demonstrate that bronchiectasis preceded NTM infection in each patient.33 In this study, however, definitely diagnosed DPB patients with pure primary non-CF bronchiectasis were evaluated. The study population would be less likely to include patients with primary NTM infection preceding bronchiectasis. In summary, this retrospective study showed that the long-term prevalence of NTM in DPB was high and that NTM-positive DPB patients tend to have lower FEV1 compared with NTM-negative patients. The high prevalence of NTM in DPB is compatible with the hypothesis that defects of mucociliary clearance and/or bronchiectasis predispose individuals to NTM infection and colonization similar to that in CF.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Acknowledgements The authors would like to thank H Obayashi (Tenri Hospital, Nara, Japan) for statistical advice, H Kohno (Tenri Hospital, Nara, Japan) for analyzing biological data and Enago (www.enago.jp) for the English language review.
17
18
REFERENCES 1 Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF © 2014 Asian Pacific Society of Respirology
19
et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am. J. Respir. Crit. Care Med. 2007; 175: 367–416. Aksamit TR. Mycobacterium avium complex pulmonary disease in patients with pre-existing lung disease. Clin. Chest Med. 2002; 23: 643–53. Olivier KN, Weber DJ, Wallace RJ Jr, Faiz AR, Lee JH, Zhang Y, Brown-Elliot BA, Handler A, Wilson RW, Schechter MS et al. Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis. Am. J. Respir. Crit. Care Med. 2003; 167: 828–34. Noone PG, Leigh MW, Sannuti A, Minnix SL, Carson JL, Hazucha M, Zariwala MA, Knowles MR. Primary ciliary dyskinesia: diagnostic and phenotypic features. Am. J. Respir. Crit. Care Med. 2004; 169: 459–67. Kilby JM, Gilligan PH, Yankaskas JR, Highsmith WE Jr, Edwards LJ, Knowles MR. Nontuberculous mycobacteria in adult patients with cystic fibrosis. Chest 1992; 102: 70–5. Aitken ML, Burke W, McDonald G, Wallis C, Ramsey B, Nolan C. Nontuberculous mycobacterial disease in adult cystic fibrosis patients. Chest 1993; 103: 1096–9. Levy I, Grisaru-Soen G, Lerner-Geva L, Kerem E, Blau H, Bentur L, Aviram M, Rivlin J, Picard E, Lavy A et al. Multicenter crosssectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Israel. Emerg. Infect. Dis. 2008; 14: 378–84. Roux AL, Catherinot E, Ripoll F, Soismier N, Macheras E, Ravilly S, Bellis G, Vibet MA, Le Roux E, Lemonnier L et al. Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis in France. J. Clin. Microbiol. 2009; 47: 4124–8. Chan CH, Ho AK, Chan RC, Cheung H, Cheng AF. Mycobacteria as a cause of infective exacerbation in bronchiectasis. Postgrad. Med. J. 1992; 68: 896–9. Fowler SJ, French J, Screaton NJ, Foweraker J, Condliffe A, Haworth CS, Exley AR, Bilton D. Nontuberculous mycobacteria in bronchiectasis: prevalence and patient characteristics. Eur. Respir. J. 2006; 28: 1204–10. Wickremasinghe M, Ozerovitch LJ, Davies G, Wodehouse T, Chadwick MV, Abdallah S, Shah P, Wilson R. Non-tuberculous mycobacteria in patients with bronchiectasis. Thorax 2005; 60: 1045–51. Martinez-Ceron E, Prados C, Gomez-Carrera L, Cabanillas JJ, Lopez-Lopez G, Alvarez-Sala R. Non-tuberculous mycobacterial infection in patients with non-cystic fibrosis bronchiectasias. Rev. Clin. Esp. 2012; 212: 127–30. Palwatwichai A, Chaoprasong C, Vattanathum A, Wongsa A, Jatakanon A. Clinical, laboratory findings and microbiologic characterization of bronchiectasis in Thai patients. Respirology 2002; 7: 63–6. Odaka M. An epidemiological study of DPB in a large company. In: Homma H (ed) Annual Report on the Study of Interstitial Lung Disease in 1980. Ministry of Health and Welfare of Japan, Tokyo, 1981; 25–8. Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am. J. Respir. Crit. Care Med. 1998; 157: 1829–32. Kono C, Yamaguchi T, Yamada Y, Uchiyama H, Kono M, Takeuchi M, Sugiyamas Y, Azuma A, Kudoh S, Sakurai T et al. Historical changes in epidemiology of diffuse panbronchiolitis. Sarcoidosis Vasc. Diffuse Lung Dis. 2012; 29: 19–25. Imai T, Sasaki Y, Ohishi H, Uchida H, Ito S, Mikasa K, Sawaki M, Narita N. Clinical aerosol inhalation cine-scintigraphy to evaluate mucociliary transport system in diffuse panbronchiolitis. J. Nucl. Med. 1995; 36: 1355–62. Poletti V, Casoni G, Chilosi M, Zompatori M. Diffuse panbronchiolitis. Eur. Respir. J. 2006; 28: 862–71. Nakata K. Revision of clinical guidelines for diffuse panbronchiolitis. In: Kudoh S (ed) Annual Report on the Study of Diffuse Lung Disease in 1998. Grant-in Aid from the Ministry of Health and Welfare of Japan, Tokyo, 1999; 109–11. Respirology (2015) 20, 80–86
86 20 Tanaka E, Amitani R, Niimi A, Suzuki K, Murayama T, Kuze F. Yield of computed tomography and bronchoscopy for the diagnosis of Mycobacterium avium complex pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 155: 2041–6. 21 Grenier P, Cordeau MP, Beigelman C. High-resolution computed tomography of the airways. J. Thorac. Imaging 1993; 8: 213–29. 22 Koh WJ, Lee KS, Kwon OJ, Jeong YJ, Kwak SH, Kim TS. Bilateral bronchiectasis and bronchiolitis at thin-section CT: diagnostic implications in nontuberculous mycobacterial pulmonary infection. Radiology 2005; 235: 282–8. 23 Morimoto K, Iwai K, Ohmori M, Okumura M, Yoshiyama T, Yoshimori K, Ogata H, Kurashima A, Kudoh S. Nontuberculous mycobacteriosis mortality in Japan. Kekkaku 2011; 86: 547–52. 24 Kollberg H, Mossberg B, Afzelius BA, Philipson K, Camner P. Cystic fibrosis compared with the immotile-cilia syndrome. A study of mucociliary clearance, ciliary ultrastructure, clinical picture and ventilatory function. Scand. J. Respir. Dis. 1978; 59: 297–306. 25 Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Invest. 2002; 109: 571–7. 26 Renna M, Schaffner C, Brown K, Shang S, Tamayo MH, Hegyi K, Grimsey NJ, Cusens D, Coulter S, Cooper J et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J. Clin. Invest. 2011; 121: 3554–63. 27 Park HY, Suh GY, Chung MP, Kim H, Kwon OJ, Chung MJ, Kim TS, Lee KS, Koh WJ. Comparison of clinical and radiographic characteristics between nodular bronchiectatic form of nontuberculous mycobacterial lung disease and diffuse panbronchiolitis. J. Korean Med. Sci. 2009; 24: 427–32. 28 Wallace RJ Jr, Brown BA, Griffith DE, Girard WM, Murphy DT, Onyi GO, Steingrube VA, Mazurek GH. Initial clarithromycin monotherapy for Mycobacterium avium-intracellulare complex lung disease. Am. J. Respir. Crit. Care Med. 1994; 149: 1335–41. 29 Dautzenberg B, Saint Marc T, Meyohas MC, Eliaszewitch M, Haniez F, Rogues AM, De Wit S, Cotte L, Chauvin JP, Grosset J. Clarithromycin and other antimicrobial agents in the treatment of disseminated Mycobacterium avium infections in patients with acquired immunodeficiency syndrome. Arch. Intern. Med. 1993; 153: 368–72. 30 Binder AM, Adjemian J, Olivier KN, Prevots DR. Epidemiology of nontuberculous mycobacterial infections and associated chronic macrolide use among persons with cystic fibrosis. Am. J. Respir. Crit. Care Med. 2013; 188: 807–12.
Respirology (2015) 20, 80–86
T Tsuji et al. 31 Kikuchi E, Yamazaki K, Kikuchi J, Hasegawa N, Hashimoto S, Ishizaka A, Nishimura M. Pharmacokinetics of clarithromycin in bronchial epithelial lining fluid. Respirology 2008; 13: 221–6. 32 Akai S, Okayama H, Shimura S, Tanno Y, Sasaki H, Takishima T. Delta F508 mutation of cystic fibrosis gene is not found in chronic bronchitis with severe obstruction in Japan. Am. Rev. Respir. Dis. 1992; 146: 781–3. 33 Levin DL. Radiology of pulmonary Mycobacterium avium-intracellulare complex. Clin. Chest Med. 2002; 23: 603–12.
Supporting Information Additional Supporting Information may be found at the publisher’s web-site: Figure S1 Trends in forced expiratory volume in 1 s (FEV1) % predicted in the nontuberculous mycobacteria (NTM)-positive patients. Six of seven NTM-positive patients were presented. One patient had received pulmonary function test once (data not shown). Three patients received pulmonary function test both before and after NTM-positive result. FEV1 was improved in two patients, but deteriorated in one patient. Figure S2 Comparison of nontuberculous mycobacteria (NTM) prevalence between patients with diffuse panbronchiolitis (DPB) and chronic obstructive pulmonary disease (COPD). (a) NTM prevalence of total patients who regularly visit the institute. (b) NTM prevalence of patient who received acid fast bacterium (AFB) culture test. P value was calculated using Fisher’s exact test as 2 × 2 contingency table. Definition of abbreviations: ATS: American Thoracic Society; IDSA: Infectious Diseases Society of America. Table S1 Microbiological characteristics in DPB patients with or without NTM. Table S2 Respiratory symptoms in DPB patients with or without NTM. Table S3 Radiological progression in DPB patients with or without NTM. Table S4 NTM prevalence in COPD patients. Appendix S1 Methods.
© 2014 Asian Pacific Society of Respirology
Copyright of Respirology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
ORIGINAL ARTICLE
Nontuberculous mycobacteria in diffuse panbronchiolitis TAKAHIRO TSUJI, EISAKU TANAKA, IKKOH YASUDA, YOSHINARI NAKATSUKA, YUSUKE KAJI, TAKEHIRO YASUDA, SEISHU HASHIMOTO, MOON HEE HWANG, TAKASHI HAJIRO AND YOSHIO TAGUCHI Department of Respiratory Medicine, Tenri Hospital, Nara, Japan
ABSTRACT Background and objective: Nontuberculous mycobacterial (NTM) lung disease secondary to cystic fibrosis (CF) has been reported, but there is limited data about NTM prevalence in non-CF bronchiectasis. We retrospectively investigated the prevalence of NTM associated with diffuse panbronchiolitis (DPB), a disorder also characterized by reduced mucociliary clearance with bronchiectasis. Methods: We reviewed mycobacterial cultures, patient characteristics and computed tomography findings of 33 patients with DPB between January 2000 and December 2012. Prevalence was based on at least one positive NTM culture. Results: Mean patient age was 51.5 years. During a mean 162.8-month follow-up, the prevalence of NTM in sputum was 21.2% (seven patients). Of the seven positive patients, six had Mycobacterium avium complex, one had M. kansasii and M. chelonae co-cultured with M. avium complex. Three patients were positive twice, and two had positive smears. The mean time from DPB diagnosis to the first positive result was 194.6 months. NTM-positive patients tended to have lower forced expiratory volume in 1 s (% predicted) than NTM-negative patients (50.0% vs 77.3%, P = 0.03), but there were no radiological or clinical differences between the two groups. Conclusions: Our observations suggest that NTM is found more often in DPB. Defects of mucociliary clearance may predispose individuals to NTM infection. Keywords: bronchiectasis, Japan, mucociliary clearance, prevalence.
Abbreviations: AFB, acid-fast bacteria; ATS/IDSA, American Thoracic Society/Infectious Diseases Society of America; AZM, azithromycin; BMI, body mass index; CAM, clarithromycin; CF, cystic fibrosis; CT, computed tomography; DPB, diffuse panbronchiolitis; EM, erythromycin; FEV1, forced expiratory volume in 1 s; MAC, Mycobacterium avium complex; NTM, nontuberculous mycobacterial; PCD, primary ciliary dyskinesia; PFT, pulmonary function test; SEM, standard error of the mean. Correspondence: Takahiro Tsuji, Department of Respiratory Medicine, Tenri Hospital, 200 Mishima-cho, Tenri City, Nara 6328552, Japan. Email: [email protected] Received 10 March 2014; invited to revise 5 May 2014; revised 2 August 2014; accepted 11 August 2014 (Associate Editor: Yuanlin Song). © 2014 Asian Pacific Society of Respirology
SUMMARY AT A GLANCE Defects in the mucociliary transport system are assumed to be a predisposing factor to nontuberculous mycobacterial (NTM) infection. We retrospectively investigated the prevalence of NTM associated with diffuse panbronchiolitis (DPB), which is characterized by mucociliary dysfunction. We detected a high prevalence comparable to rates in cystic fibrosis.
INTRODUCTION Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can often induce respiratory diseases in patients with pre-existing lung damage.1,2 In the past two decades, bronchiectatic diseases, such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD), have been identified as predisposing factors of NTM infection.3,4 With regard to CF, some previous reports and a prospective multi-centre study showed that NTM was isolated from 13% to 23% respiratory specimens.3,5–8 In PCD, a high prevalence of NTM (10%) was also reported.4 Although many studies have stated the prevalence of NTM in CF, there is little data about non-CF bronchiectasis (2–10.3%).9–13 Although the reasons for the high prevalence of NTM in patients with CF and PCD remain unclear, underlying structural airway disease and altered mucociliary clearance are assumed to be predisposing factors.1 Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory disease with an incidence rate of 11.1 per 100 000 individuals in Japan according to a population-based survey conducted in 1980.14 In the 1990s, long-term macrolide therapy for DPB exhibited marked efficacy.15 Recently, the incidence and prevalence of DPB appear to have decreased.16 In DPB, morphological and functional abnormalities of the mucociliary transport system have been documented,17 and the clinical characteristics of DPB are similar to those of CF, including bronchiectasis, chronic respiratory tract infection (often associated with P. aeruginosa infection) and recurrent sinusitis. Respirology (2015) 20, 80–86 doi: 10.1111/resp.12412
81
NTM in DPB
We hypothesized that DPB would be a predisposing factor for NTM infection similar to CF, and retrospectively investigated the prevalence of NTM in DPB.
METHODS Retrospective study population A total of 33 patients with ‘definite’ DPB who visited our hospital (local central 815 beds hospital in Nara Prefecture, Japan) from January 2000 to December 2012 were recruited, based on the diagnostic criteria established by the Ministry of Health and Welfare of Japan.18,19 All patients who continued to regularly visit the hospital provided written informed consent according to hospital guidelines. For patients who had discontinued regular hospital visits, the requirement for written informed consent was waived by the hospital ethics committee due to the retrospective nature of the research. This study was approved by the institutional ethical committee of Tenri Hospital. Patient characteristics and symptoms Patient characteristics and respiratory symptoms were determined by reviewing medical records (Appendix S1). Treatment for DPB was defined as long-term antibiotic therapy,15 which had been administered following the collection of mycobacteria culture samples. Biological analysis We retrospectively collected all the results of acid-fast bacteria (AFB) tests of sputum conducted during the follow-up period, which included smears, culture tests, polymerase chain reaction tests and antibiotic susceptibility. Prevalence of NTM was assessed by at least one positive NTM culture during the follow-up period, and these subjects were defined as ‘NTMpositive’. Patients who had only negative AFB cultures were defined as ‘NTM-negative’, and those who received no AFB tests were referred to as ‘NTMundetermined’. The prevalence rate was defined as the proportion of NTM-positive subjects to all DPB subjects, including NTM-undetermined subjects. AFB tests had been carefully performed with standard methods (Appendix S1). The results of routine bacteriological examination in sputum specimens were also investigated. Lung function and body mass index We collected forced expiratory volume in 1 s (FEV1) and body mass index (BMI) during the follow-up period. The reports of pulmonary function test (PFT) were available for 31 of 33 patients. Radiology Two respiratory physicians separately checked computed tomography (CT) findings for the following signs: the extent and existence of bronchiectasis, multiple small centrilobular nodules, cavitation, © 2014 Asian Pacific Society of Respirology
nodular shadows, and consolidation (Appendix S1).20–22 Clinical information was blinded and inter-observer disagreement was resolved by consensus. Changes in CT and/or chest X-ray findings were also investigated, and classified into three categories: ‘deteriorated’, ‘stable’ or ‘improved’.
Statistical analysis NTM-positive and NTM-negative subjects were compared using the Fisher’s exact test for categorical data. BMI and %FEV1 predicted were homoscedastic and compared using the unpaired t-test. Ages were not homoscedastic and were compared using Welch’s test. SPSS Statistics (version 15.0; SPSS Inc., Chicago, IL, USA) was used for data analysis.
RESULTS Mean age was 51.5 ± 2.6 years (mean ± standard error of the mean) at the first visit with 162.8 ± 22.5 months of follow-up time. Cultures for AFB were performed in 29 patients, and the mean number of AFB tests per patient was 2.8 ± 0.5. All the patients were Japanese and received long-term antibiotic therapy with macrolides. Mean BMI was 20.7 ± 0.7, and FEV1 was 70.8% ± 4.9% predicted. One NTM-positive patient and one NTM-negative patient died of DPB progression. Another NTM-negative patient died due to an iliopsoas muscle abscess caused by Escherichia coli. Characteristics of all DPB patients are shown in Table 1. Of the 33 DPB patients, seven (21.2%) were positive for NTM at least once during the follow-up period. Characteristics of NTM-positive cases are shown in Table 2. Three patients (9.1%) had positive cultures more than twice (American Thoracic Society/ Infectious Diseases Society of America (ATS/IDSA) diagnostic criteria). Mycobacterium avium complex (MAC) was isolated in six patients, M. kansasii in one and M. chelonae was co-cultured with MAC in one patient. Four of the seven positive samples subsequently underwent susceptibility tests, and all four were susceptible to clarithromycin (CAM). None received treatment for NTM. One patient had few symptoms (case 5 in Table 2), and one patient decided to avoid multiple drug therapy because of advanced age (case 1). One patient was under close observation (case 2), but the patient would not receive multi-drug therapy for NTM in the future because of advanced age (76 years old) and mild symptoms with slow progression. As shown in Table S1, Pseudomonas aeruginosa was isolated most frequently in DPB patients (14/33 patients: 42.4%) during their clinical course, and there was no significant difference in the frequency of isolation between NTM-positive and NTMnegative subjects (total rate of isolated subjects 42.9% vs 50.0%, P = 1.00; multiple isolation 28.6% vs 36.4%, P = 1.00). There was no difference in the frequency of Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus between the two groups. Respirology (2015) 20, 80–86
82
T Tsuji et al.
Table 1
Patient characteristics in DPB patients with or without NTM isolation
Patients Male
All DPB patients
NTM-positive
33 15
7 5
100%
±SEM
Mean Age at first visit (years) Follow-up time (months) Number of AFB samples per patient Pulmonary function test (n) % pred FEV1 BMI Smoking status Never Former/current Unknown Immunocompromised state Diabetes Cancer chemotherapy CS/IS HIV Treatment for DPB EM CAM RXM
NTM-negative
21.2%
±SEM
Mean
22 6
Mean
66.7% 0.07
±SEM
51.5 162.8
±2.6 ±22.5
47.1 227.2
±8.9 ±43.9
51.5 164.2
±2.7 ±28.0
2.8 31 70.5 20.7
±0.5
3.1 7 50.0 20.0
±1.4
3.2 20 77.3 20.7
±0.6
±4.9 ±0.66
±9.5 ±1.55
21 4/1 7 8 5 1 2 0
3 0/0 4 1 1 0 0 0
16 3/0 3 6 3 1 2 0
17 15 1
5 1 1
9 13 0
P
±5.9 ±0.86
0.52 0.27
0.03 0.65 1.00
0.65
0.16*
Data are presented as the number of patients or the mean ± standard error of the mean (SEM). * P value was calculated using Fisher’s exact test as 2 × 2 contingency table, categorized into EM and CAM. % pred FEV1, percentage of predicted forced expiratory volume in 1 s; AFB, acid-fast bacteria; BMI, body mass index; CAM, clarithromycin; CS/IS, corticosteroid and/or immunosuppressor; DPB, diffuse panbronchiolitis; EM, erythromycin; HIV, human immunodeficiency virus; NTM, nontuberculous mycobacterium; RXM, roxithromycin.
Table 2
Clinical characteristics in NTM-positive subjects Age†/ Sex
Smear
1
88/F
++
2 3
52/M 17/M
+ −
4
36/M
−
5
45/F
−
6 7
56/M 29/M
− −
Mean
48.3
Case
Culture for Mycobacteria M. avium (×2) Negative (×1) M. intracellulare (×2) M. avium complex (×1) M. chelonae (×1) M. avium complex (×1) Negative (×10) M. intracellulare (×2) M. kansasii (×1) M. avium (×1) Negative (×3)
MIC for CAM (μg/mL)
Time from Dx‡
Therapy for DPB
Other microorganisms
57.9
EM
P. aeruginosa
23.1 16.4
78.4 27.9
EM EM
H. influenzae S. pneumoniae
232.4
15.2
28.5
CAM
P. aeruginosa
0.125
278.1
22.0
59.2
EM
ND 2
254.4 164.8
26.3 20.3
79.8 26.9
EM RXM
P. aeruginosa H. influenzae normal flora H. influenzae S. pneumoniae
194.6
20.0
50.0
BMI§
%FEV1§
5.1
16.5
0.125 ND
292.1 135.1
ND
1
† Age when diagnosed with DPB. Data are shown as years. In case 1, the age at first hospital visit was used instead of the age at diagnosis. ‡ The time from DPB diagnosis to the first positive result of NTM culture. Data are shown in months. § The latest data before the first positive NTM culture result is shown. %FEV1, percentage of predicted forced expiratory volume in 1 s; BMI, body mass index; CAM, clarithromycin; DPB, diffuse panbronchiolitis; Dx, diagnosis; EM, erythromycin; H. influenzae, Haemophilus influenzae; M. avium, Mycobacterium avium; M. chelonae, Mycobacterium chelonae; M. intracellulare, Mycobacterium intracellulare; M. kansasii, Mycobacterium kansasii; MIC, minimal inhibitory concentration; ND, no data; NTM, nontuberculous mycobacterial; P. aeruginosa, Pseudomonas aeruginosa; RXM, roxithromycin; S. pneumoniae, Streptococcus pneumoniae.
Respirology (2015) 20, 80–86
© 2014 Asian Pacific Society of Respirology
83
NTM in DPB Table 3 HRCT findings in DPB patients with or without NTM NTM-positive n Bronchiectasis RSL RML RIL LSS LLS LIL Nodular shadows Centrilobular micronodules Cavity Consolidation
7 7 5 7 6 4 7 6 5 4 1 5
(100%) (71.4%) (100%) (85.7%) (57.1%) (100%) (85.7%) (71.4%) (57.1%) (14.3%) (71.4%)
NTM-negative 22 22 20 22 22 17 20 21 9 17 1 6
(100%) (90.9%) (100%) (100%) (77.3%) (90.9%) (95.5%) (40.9%) (77.3%) (4.5%) (27.3%)
NTM-undetermined 4 4 2 3 3 1 3 3 2 1 0 0
(100%) (50.0%) (13.6%) (13.6%) (4.5%) (13.6%) (13.6%) (9.1%) (4.5%) (0%) (0%)
P*
1.00
0.21 0.36 0.43 0.07
Data are presented as the number of patients. * P value was calculated with Fisher’s test by comparing NTM-positive and NTM-negative subjects. DPB, diffuse panbronchiolitis; HRCT, high-resolution computed tomography; LIL, left inferior lobe; LLS, left lingular segment; LSS, left superior segment; NTM, nontuberculous mycobacteria; RIL, right inferior lobe; RML, right middle lobe; RSL, right superior lobe.
Figure 1 Computed tomography (CT) findings of nontuberculous mycobacteriapositive patients: (a) CT images of case 3. Centrilobular small nodules are diffusely presented. Some clusters showed ‘tree-inbud’ appearance (black arrow). (b and c) CT images of case 4 (b) and case 1 (c). Nodular shadow (white arrow), bronchiectasis (white arrowhead) and clusters of centrilobular small nodules (black arrowhead) are also present.
Compared with NTM-negative subjects, NTMpositive subjects had significantly lower % predicted FEV1 (positive vs negative; 50.0% vs 77.3%, P = 0.03). There was no significant difference in other clinical characteristics or symptoms (Table 1, Table S2). The trend of %FEV1 in the NTM-positive group is presented in Figure S1. Three patients underwent PFT both before and after testing positive for NTM. FEV1 was improved in two patients, but deteriorated in one patient. On CT, there was no significant difference between NTM-positive and NTM-negative subjects (Table 3). All NTM-positive and NTM-negative subjects had bronchiectasis with no difference in the extent of disease. Multiple small centrilobular nodules (positive vs negative; 57.1% vs 77.3%, P = 0.36), consolidation (71.4% vs 27.3%, P = 0.07) and nodular shadows (71.4% vs 40.9%, P = 0.21) were also common findings. Typical CT findings of NTM-positive subjects are shown in Figure 1. Radiological deterioration was observed in four patients in the NTM-positive group, including three patients who met the ATS/IDSA criteria, and in six patients in the NTM-negative group. © 2014 Asian Pacific Society of Respirology
The signs of deterioration were similar between the two groups, and included an increase in multiple centrilobular nodules and progression of bronchiectasis (Table S3, Fig. 2).
DISCUSSION This is the first retrospective study of NTM in DPB, a disorder of mucociliary clearance with bronchiectasis. The overall prevalence of NTM in DPB was 21.2%, which is comparable with that associated with CF (13.0% in >10-year-old patients) and PCD (10% in >30year-old patients).3,4 In the NTM-positive patients, it is possible that some had colonization rather than infection. However, at least three (9.1%) were assumed to have NTM infection because they met the ATS/IDSA criteria and showed deterioration on radiological examination. The prevalence of NTM in DPB was higher than that reported in other studies of non-CF bronchiectasis9–13 and the previous surveillance of NTM in the general Japanese population (5.7/100 000 in 2007).23 As institutional biological information, we Respirology (2015) 20, 80–86
84
T Tsuji et al.
Figure 2 Computed tomography (CT) findings in nontuberculous mycobacteria (NTM)-positive and NTMnegative patients: (a) Progression of CT findings in an NTM-positive patient. CT images before testing positive for NTM (left) and 27 months after testing positive (right) are shown. An increase in centrilobular small nodules was observed in right middle lobe, right inferior lobe, left lingular segment and left inferior lobe. (b) CT findings in an NTM-negative patient. CT images taken at an interval of 4 years are shown. An increase in centrilobular small nodules was also observed in the right middle lobe, right inferior lobe, left lingular segment and left inferior lobe.
investigated the prevalence of NTM in 482 patients with chronic obstructive pulmonary disease who regularly visited our hospital for more than 5 years from January 2000 to December 2012. Among them, 41 patients (8.6%) were positive for NTM and 12 (2.5%) met the ATS/IDSA criteria (Table S4, Fig. S2). Personto-person transmission would not have contributed because the regular visits of the seven patients were independent. Impairment of the mucociliary transport system, which plays an important role in host defence17,24,25 and bronchiectatic change per se, may affect local respiratory tract defences and NTM predisposition. In addition, a recent study in mice suggested a possible link between macrolide use and increased risk of NTM infection.26 In DPB patients, the prevalence of NTM tended to be higher in males than in females. Similar to fibrocavitary lung disease, pre-existing lung damage would predispose individuals to NTM infection, and the effect of female gender would be relatively less important.1 NTM-positive subjects had significantly lower % predicted FEV1 than NTM-negative subjects. NTM would be positive in advanced DPB patients. In contrast, Olivier et al.3 showed in their multi-centre study that higher % predicted FEV1 was associated with NTM in CF patients. In CF, the prevalence of NTM is highly correlated with age, which was explained in Olivier’s report by the fact that CF patients with more severe disease would die earlier, and mild cases would have longer available NTM exposure times. With DPB, long-term macrolide therapy enables severely affected patients to survive over decades (13.6 year follow-up period on average) and thus have longer exposure to NTM.15 We could not detect a trend in pulmonary function in NTM-positive patients. Respirology (2015) 20, 80–86
Other than % predicted FEV1, our results showed similar characteristics between NTM-positive and NTM-negative patients, including patient background, symptoms, CT findings, radiological progression and other microorganisms cultured. Our results suggest that NTM infection could not be ruled out in DPB patients based on only clinical and radiological information. When DPB is found to be deteriorating clinically and/or radiologically, mycobacterial screening tests should be considered. In addition, the characteristics of NTM-positive DPB patients are similar to the well-known characteristics of primary NTM lung disease, particularly the nodular/bronchiectatic type.20,22,27 We should consider that patients diagnosed with nodular/bronchiectatic NTM lung disease may have secondary infections predisposed by hidden bronchiectatic diseases, such as DPB. The high prevalence of NTM associated with DPB raises concerns for the development of macrolideresistant NTM infections because CAM is a key drug in NTM treatment and its monotherapy for NTM carries a significant risk of developing resistant NTM.1,28,29 In our four cases, long-term erythromycin (EM) therapy did not lead to CAM-resistant NTM. Recently, Binder et al. showed that in CF, NTM cases were less likely to have undergone prior long-term azithromycin (AZM) use.30 In our limited data, there was no statistical difference in the regimen of macrolide therapy between the NTM-positive and NTM-negative group. However, it should be noted that only one patient was NTMpositive among 15 receiving long-time CAM therapy and that patient had only one positive culture following 10 successive negative cultures. Two factors may have contributed to these results. First, long-term CAM administration, not EM, may haveprevented © 2014 Asian Pacific Society of Respirology
85
NTM in DPB
NTM colonization or infection, similar to AZM in CF. Second, CAM in sputum samples may just suppress NTM growth when testing and yield some falsenegative results. Kikuchi et al.31 showed that oral CAM produces higher concentrations in bronchial and alveolar epithelial lining fluid than in serum. The risk of inducing CAM resistance is still unclear, and AFB test should be carefully monitored when administering long-term macrolide monotherapy. Our study has several limitations. First, the study design was retrospective, and indications of AFB tests were not standardized. However, standardized indications of mycobacterial screening could only increase the prevalence rate because NTM-positive patients would be picked out without omission.We believe that the unstandardized nature of the tests does not impair our finding of high prevalence. Second, we selected ‘definite’ DPB patients receiving long-term macrolide therapy. Subsequently, comparatively severe patients were likely to be selected because macrolide therapy is greatly effective, and patients with mild symptoms had stopped visiting hospital before diagnosis. If the speculation that more severe DPB is associated with NTM infection is accurate, the prevalence rate observed may be overestimated. Third, this was a singlecentre investigation and the analyzed population was small; hence, we cannot account for the variation in the prevalence of NTM in different medical centres, the community and the country. Prospective multicentre studies are needed to address these issues. Fourth, we were unable to investigate CFTR genes of the subjects because the CFTR test is not included in routine clinical practice. CF is rare in Japanese population, and previous reports showed that DPB develops with no relevance to CFTR genes.32 In addition, our study population was older at the first visit than typical CF patients. Fifth, we could not perfectly demonstrate that bronchiectasis preceded NTM infection in each patient.33 In this study, however, definitely diagnosed DPB patients with pure primary non-CF bronchiectasis were evaluated. The study population would be less likely to include patients with primary NTM infection preceding bronchiectasis. In summary, this retrospective study showed that the long-term prevalence of NTM in DPB was high and that NTM-positive DPB patients tend to have lower FEV1 compared with NTM-negative patients. The high prevalence of NTM in DPB is compatible with the hypothesis that defects of mucociliary clearance and/or bronchiectasis predispose individuals to NTM infection and colonization similar to that in CF.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Acknowledgements The authors would like to thank H Obayashi (Tenri Hospital, Nara, Japan) for statistical advice, H Kohno (Tenri Hospital, Nara, Japan) for analyzing biological data and Enago (www.enago.jp) for the English language review.
17
18
REFERENCES 1 Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF © 2014 Asian Pacific Society of Respirology
19
et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am. J. Respir. Crit. Care Med. 2007; 175: 367–416. Aksamit TR. Mycobacterium avium complex pulmonary disease in patients with pre-existing lung disease. Clin. Chest Med. 2002; 23: 643–53. Olivier KN, Weber DJ, Wallace RJ Jr, Faiz AR, Lee JH, Zhang Y, Brown-Elliot BA, Handler A, Wilson RW, Schechter MS et al. Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis. Am. J. Respir. Crit. Care Med. 2003; 167: 828–34. Noone PG, Leigh MW, Sannuti A, Minnix SL, Carson JL, Hazucha M, Zariwala MA, Knowles MR. Primary ciliary dyskinesia: diagnostic and phenotypic features. Am. J. Respir. Crit. Care Med. 2004; 169: 459–67. Kilby JM, Gilligan PH, Yankaskas JR, Highsmith WE Jr, Edwards LJ, Knowles MR. Nontuberculous mycobacteria in adult patients with cystic fibrosis. Chest 1992; 102: 70–5. Aitken ML, Burke W, McDonald G, Wallis C, Ramsey B, Nolan C. Nontuberculous mycobacterial disease in adult cystic fibrosis patients. Chest 1993; 103: 1096–9. Levy I, Grisaru-Soen G, Lerner-Geva L, Kerem E, Blau H, Bentur L, Aviram M, Rivlin J, Picard E, Lavy A et al. Multicenter crosssectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Israel. Emerg. Infect. Dis. 2008; 14: 378–84. Roux AL, Catherinot E, Ripoll F, Soismier N, Macheras E, Ravilly S, Bellis G, Vibet MA, Le Roux E, Lemonnier L et al. Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis in France. J. Clin. Microbiol. 2009; 47: 4124–8. Chan CH, Ho AK, Chan RC, Cheung H, Cheng AF. Mycobacteria as a cause of infective exacerbation in bronchiectasis. Postgrad. Med. J. 1992; 68: 896–9. Fowler SJ, French J, Screaton NJ, Foweraker J, Condliffe A, Haworth CS, Exley AR, Bilton D. Nontuberculous mycobacteria in bronchiectasis: prevalence and patient characteristics. Eur. Respir. J. 2006; 28: 1204–10. Wickremasinghe M, Ozerovitch LJ, Davies G, Wodehouse T, Chadwick MV, Abdallah S, Shah P, Wilson R. Non-tuberculous mycobacteria in patients with bronchiectasis. Thorax 2005; 60: 1045–51. Martinez-Ceron E, Prados C, Gomez-Carrera L, Cabanillas JJ, Lopez-Lopez G, Alvarez-Sala R. Non-tuberculous mycobacterial infection in patients with non-cystic fibrosis bronchiectasias. Rev. Clin. Esp. 2012; 212: 127–30. Palwatwichai A, Chaoprasong C, Vattanathum A, Wongsa A, Jatakanon A. Clinical, laboratory findings and microbiologic characterization of bronchiectasis in Thai patients. Respirology 2002; 7: 63–6. Odaka M. An epidemiological study of DPB in a large company. In: Homma H (ed) Annual Report on the Study of Interstitial Lung Disease in 1980. Ministry of Health and Welfare of Japan, Tokyo, 1981; 25–8. Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am. J. Respir. Crit. Care Med. 1998; 157: 1829–32. Kono C, Yamaguchi T, Yamada Y, Uchiyama H, Kono M, Takeuchi M, Sugiyamas Y, Azuma A, Kudoh S, Sakurai T et al. Historical changes in epidemiology of diffuse panbronchiolitis. Sarcoidosis Vasc. Diffuse Lung Dis. 2012; 29: 19–25. Imai T, Sasaki Y, Ohishi H, Uchida H, Ito S, Mikasa K, Sawaki M, Narita N. Clinical aerosol inhalation cine-scintigraphy to evaluate mucociliary transport system in diffuse panbronchiolitis. J. Nucl. Med. 1995; 36: 1355–62. Poletti V, Casoni G, Chilosi M, Zompatori M. Diffuse panbronchiolitis. Eur. Respir. J. 2006; 28: 862–71. Nakata K. Revision of clinical guidelines for diffuse panbronchiolitis. In: Kudoh S (ed) Annual Report on the Study of Diffuse Lung Disease in 1998. Grant-in Aid from the Ministry of Health and Welfare of Japan, Tokyo, 1999; 109–11. Respirology (2015) 20, 80–86
86 20 Tanaka E, Amitani R, Niimi A, Suzuki K, Murayama T, Kuze F. Yield of computed tomography and bronchoscopy for the diagnosis of Mycobacterium avium complex pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 155: 2041–6. 21 Grenier P, Cordeau MP, Beigelman C. High-resolution computed tomography of the airways. J. Thorac. Imaging 1993; 8: 213–29. 22 Koh WJ, Lee KS, Kwon OJ, Jeong YJ, Kwak SH, Kim TS. Bilateral bronchiectasis and bronchiolitis at thin-section CT: diagnostic implications in nontuberculous mycobacterial pulmonary infection. Radiology 2005; 235: 282–8. 23 Morimoto K, Iwai K, Ohmori M, Okumura M, Yoshiyama T, Yoshimori K, Ogata H, Kurashima A, Kudoh S. Nontuberculous mycobacteriosis mortality in Japan. Kekkaku 2011; 86: 547–52. 24 Kollberg H, Mossberg B, Afzelius BA, Philipson K, Camner P. Cystic fibrosis compared with the immotile-cilia syndrome. A study of mucociliary clearance, ciliary ultrastructure, clinical picture and ventilatory function. Scand. J. Respir. Dis. 1978; 59: 297–306. 25 Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Invest. 2002; 109: 571–7. 26 Renna M, Schaffner C, Brown K, Shang S, Tamayo MH, Hegyi K, Grimsey NJ, Cusens D, Coulter S, Cooper J et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J. Clin. Invest. 2011; 121: 3554–63. 27 Park HY, Suh GY, Chung MP, Kim H, Kwon OJ, Chung MJ, Kim TS, Lee KS, Koh WJ. Comparison of clinical and radiographic characteristics between nodular bronchiectatic form of nontuberculous mycobacterial lung disease and diffuse panbronchiolitis. J. Korean Med. Sci. 2009; 24: 427–32. 28 Wallace RJ Jr, Brown BA, Griffith DE, Girard WM, Murphy DT, Onyi GO, Steingrube VA, Mazurek GH. Initial clarithromycin monotherapy for Mycobacterium avium-intracellulare complex lung disease. Am. J. Respir. Crit. Care Med. 1994; 149: 1335–41. 29 Dautzenberg B, Saint Marc T, Meyohas MC, Eliaszewitch M, Haniez F, Rogues AM, De Wit S, Cotte L, Chauvin JP, Grosset J. Clarithromycin and other antimicrobial agents in the treatment of disseminated Mycobacterium avium infections in patients with acquired immunodeficiency syndrome. Arch. Intern. Med. 1993; 153: 368–72. 30 Binder AM, Adjemian J, Olivier KN, Prevots DR. Epidemiology of nontuberculous mycobacterial infections and associated chronic macrolide use among persons with cystic fibrosis. Am. J. Respir. Crit. Care Med. 2013; 188: 807–12.
Respirology (2015) 20, 80–86
T Tsuji et al. 31 Kikuchi E, Yamazaki K, Kikuchi J, Hasegawa N, Hashimoto S, Ishizaka A, Nishimura M. Pharmacokinetics of clarithromycin in bronchial epithelial lining fluid. Respirology 2008; 13: 221–6. 32 Akai S, Okayama H, Shimura S, Tanno Y, Sasaki H, Takishima T. Delta F508 mutation of cystic fibrosis gene is not found in chronic bronchitis with severe obstruction in Japan. Am. Rev. Respir. Dis. 1992; 146: 781–3. 33 Levin DL. Radiology of pulmonary Mycobacterium avium-intracellulare complex. Clin. Chest Med. 2002; 23: 603–12.
Supporting Information Additional Supporting Information may be found at the publisher’s web-site: Figure S1 Trends in forced expiratory volume in 1 s (FEV1) % predicted in the nontuberculous mycobacteria (NTM)-positive patients. Six of seven NTM-positive patients were presented. One patient had received pulmonary function test once (data not shown). Three patients received pulmonary function test both before and after NTM-positive result. FEV1 was improved in two patients, but deteriorated in one patient. Figure S2 Comparison of nontuberculous mycobacteria (NTM) prevalence between patients with diffuse panbronchiolitis (DPB) and chronic obstructive pulmonary disease (COPD). (a) NTM prevalence of total patients who regularly visit the institute. (b) NTM prevalence of patient who received acid fast bacterium (AFB) culture test. P value was calculated using Fisher’s exact test as 2 × 2 contingency table. Definition of abbreviations: ATS: American Thoracic Society; IDSA: Infectious Diseases Society of America. Table S1 Microbiological characteristics in DPB patients with or without NTM. Table S2 Respiratory symptoms in DPB patients with or without NTM. Table S3 Radiological progression in DPB patients with or without NTM. Table S4 NTM prevalence in COPD patients. Appendix S1 Methods.
© 2014 Asian Pacific Society of Respirology
Copyright of Respirology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
