Increasing patients with pulmonary Mycobacterium avium complex disease and associated underlying diseases in Japan

doi:10.1016/j.jiac.2015.01.004

Journal of Infection and Chemotherapy

Volume 21, Issue 5, May 2015, Pages 352-356

https://doi.org/10.1016/j.jiac.2015.01.004 Get rights and content

Abstract

This study was conducted to evaluate trends in the isolation of strains of nontuberculous mycobacteria (NTM) and trends in the number of patients with pulmonary Mycobacterium avium complex (MAC) disease. We retrospectively reviewed microbiological results and clinical data to identify patients who were diagnosed with pulmonary MAC disease at Kyoto University Hospital in Japan between 2000 and 2013. NTM were isolated from 6327 of 80,285 samples (7.9%) for mycobacterial culture. The proportion of NTM isolates among all mycobacterial isolates increased from 355 of 792 samples (44.8%) in 2000 to 688 of 847 samples (81.2%) in 2013. MAC was most frequently observed (5436 isolates, 85.9%), followed by Mycobacterium abscessus (175 isolates, 2.8%) and Mycobacterium kansasii (74 isolates, 1.2%). A total of 592 patients with pulmonary MAC disease were identified (age, 66.0 ± 11.5 years; females, 61.1%). Compared with the early cohort (2000–2006, 236 patients), more patients in the late cohort (2007–2013, 356 patients) had an underlying disease (157 [66.5%] vs. 284 [79.8%], P = 0.0003), a Charlson comorbidity index score ≥1 (115 [48.7%] vs. 213 [59.8%], P = 0.008), collagen vascular disease (18 [7.6%] vs. 60 [16.9%], P = 0.001), rheumatoid arthritis (11 [4.7%] vs. 41 [11.5%], P = 0.004), and used immunosuppressive drugs (22 [9.3%] vs. 63 [17.7%], P = 0.004). The numbers of patients with lung disease, malignant disease and diabetes mellitus increased; however, their frequencies did not differ. The recovery rate of NTM and patients with pulmonary MAC disease increased, especially in patients with collagen vascular disease or rheumatoid arthritis or who used immunosuppressive drugs.

Introduction

The prevalence of nontuberculous mycobacteria (NTM) disease has increased in several countries. Previous population-based studies have demonstrated a 1.5- to 3-fold increase in the isolation of NTM and the prevalence of pulmonary NTM disease in Canada, the USA, England and Australia [1], [2], [3], [4], [5]. The annual incidence of pulmonary NTM disease increased 4-fold from 2000 to 2008 at a tertiary care center in Taiwan [6]. The rate of NTM recovery from respiratory specimens increased approximately 6-fold from 2000 to 2011 at a tertiary referral hospital in South Korea [7].

Mycobacterium avium complex (MAC) disease is the most frequently observed NTM disease [8], [9], [10]. Although pulmonary MAC disease had predominantly presented in a fibrocavitary form in elderly males with chronic lung disease and cavitary disease, the prevalence of a nodular bronchiectatic form that occurs mostly in elderly female patients with no apparent preexisting lung disease has increased [10]. Among the various underlying diseases in patients with pulmonary MAC disease, chronic obstructive pulmonary disease (COPD) was more common in the USA, Denmark and Germany [8], [11], [12], whereas previous tuberculosis (TB) is more common in Japan and Korea [13], [14]. COPD and asthma patients treated with inhaled corticosteroid (ICS) therapy and patients using immunosuppressive agents and tumor necrosis factor (TNF)-α antagonists have an increased risk of pulmonary NTM disease [15], [16], [17]. However, Al-Houqani et al. reported that COPD and use of a TNF-α antagonist resulted in a smaller increase in pulmonary MAC disease [18].

In Japan, the prevalence of NTM disease was estimated to be 33–65/100,000 [19]. Although more than half of patients with pulmonary MAC disease were male in the 1980s, the number of female patients increased after 1996 and accounted for 70% of patients [20]. Although the annual incidence of pulmonary MAC disease was nearly stable in one hospital in Japan between 1996 and 2002 [20], the trend after 2003 has not been previously reported.

The aim of this study was to evaluate trends in the isolation of NTM strains, trends in the number of patients with pulmonary MAC disease and trends in their underlying diseases over a 14-year period in a university hospital in Japan.

Section snippets

Materials and methods

We retrospectively reviewed microbiological results from the electronic laboratory record system at Kyoto University Hospital (1121 beds) between January 2000 and December 2013 and identified patients who met the 2007 American Thoracic Society microbiological criteria for pulmonary NTM disease [10]. Culture was performed using the BACTEC Mycobacteria Growth Indicator Tube 960 system (BD, Franklin Lakes, NJ, USA). Identification of Mycobacterium tuberculosis, M. avium and Mycobacterium

Annual incidence of mycobacterial isolates

From 2000 to 2013, the laboratory at Kyoto University Hospital received 80,285 clinical samples for mycobacterial culture. M. tuberculosis and NTM were isolated from 3777 samples (4.7%) and 6327 samples (7.9%), respectively. M. tuberculosis and NTM, respectively, were isolated from 2143 samples (5.3%) and 2473 samples (6.2%) of 40,205 samples in the early cohort and 1634 samples (4.1%) and 3854 samples (9.6%) of 40,080 samples in the late cohort. The proportion of NTM isolates among all

Discussion

In our hospital, MAC accounted for 85% of NTM species, which is consistent with a previous report in Japan [19]. The annual recovery of NTM isolates, the proportion of NTM compared with TB and the number of patients with pulmonary MAC disease increased 2-fold from 2000 to 2013. Although a trend in the incidence of NTM disease has not been reported in Japan, Morimoto et al. reported that the annual mortality rate due to NTM disease in Japan nearly doubled from 2000 to 2010, from approximately

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research by the Japanese Society for the Promotion of Science (24591479).

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Amikacin liposome inhalation suspension for Mycobacterium avium complex pulmonary disease: A subgroup analysis of Japanese patients in the randomized, phase 3, CONVERT study
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CONVERT, a randomized, active-controlled, global, Phase 3 trial demonstrated that patients with treatment-refractory Mycobacterium avium complex (MAC) pulmonary disease were more likely to achieve culture conversion with amikacin liposome inhalation suspension (ALIS) plus guideline-based therapy (GBT) versus those continuing on GBT alone. This subgroup analysis reports the efficacy and safety of ALIS in Japanese patients enrolled in CONVERT.
Japanese patients aged ≥20 years with treatment-refractory MAC pulmonary disease from Japanese sites were included. Patients were randomized to receive once-daily 590 mg ALIS + GBT or GBT alone; patients converting by Month 6 remained in the study to complete 12-month treatment followed by a 12-month off-treatment period. Nonconverters exited the study at Month 8. The primary endpoint was the proportion of patients achieving culture conversion by Month 6.
Of the 59 Japanese patients screened, 48 were randomized to receive ALIS + GBT (n = 34) or GBT alone (n = 14), and 41/48 (85.4 %) were women. The mean (standard deviation) age of patients was 64.5 (8.6) years, and 83.3 % of patients had bronchiectasis at baseline. By Month 6, sputum culture conversion was cumulatively achieved in 9/34 (26.5 %) patients receiving ALIS + GBT versus none receiving GBT alone. Treatment-emergent adverse events were reported in 94.1 % and 100.0 % of patients receiving ALIS + GBT and GBT alone, respectively. No deaths were reported.
The efficacy observed in the Japanese subpopulation was largely consistent with that in the overall CONVERT study population, with more patients achieving culture conversion with ALIS + GBT versus GBT alone. Safety profiles were similar between the overall population and the Japanese subpopulation.
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Global Epidemiology of Nontuberculous Mycobacterial Pulmonary Disease: A Review
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Global trends of pulmonary infections with nontuberculous mycobacteria: a systematic review
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MAC trend data were available for 30 studies, with a majority reporting an increasing trend for infection (n = 15/19, 78.9%) and disease (n = 10/12, 83.3%) (Supplementary F1, F3). Eight of the 30 studies of MAC had trend data for subspecies M. avium and Mycobacterium intracellulare (Boyle et al., 2015; Dakić et al., 2018; Ito et al., 2015; Pedro et al., 2008; Ryoo et al., 2008; Thomson et al., 2020; van Ingen et al., 2010; Wu et al., 2014). One of these studies reported increasing MAC isolates mainly driven by M. avium, whereas the number of M. intracellulare was stable (van Ingen et al., 2009).
To describe the global trends of pulmonary nontuberculous mycobacteria (NTM) infection and disease.
A systematic review of studies including culture-based NTM data over time. Studies reporting on pulmonary NTM infection and/or disease were included. Information on the use of guideline-based criteria for disease were collected, in which, infection is defined as the absence of symptoms and radiological findings compatible with NTM pulmonary disease. The trends of change for incidence/prevalence were evaluated using linear regressions, and the corresponding pooled estimates were calculated.
Most studies reported increasing pulmonary NTM infection (82.1%) and disease (66.7%) trends. The overall annual rate of change for NTM infection and disease per 100,000 persons/year was 4.0% (95% confidence interval [CI]: 3.2-4.8) and 4.1% (95% CI: 3.2-5.0), respectively. For absolute numbers of NTM infection and disease, the overall annual change was 2.0 (95% CI: 1.6-2.3) and 0.5 (95% CI: 0.3-0.7), respectively. An increasing trend was also seen for Mycobacterium avium complex infection (n = 15/19, 78.9%) and disease (n = 10/12, 83.9%) and for Mycobacterium abscessus complex (n = 15/23, 65.2%) infection (n = 11/17, 64.7%) but less so for disease (n = 2/8, 25.0%).
Our data indicate an overall increase in NTM worldwide for both infection and disease. The explanation to this phenomenon warrants further investigation.
Tolerability, adverse events, and efficacy of treatment for Mycobacterium avium complex pulmonary disease in elderly patients
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Mycobacterium avium complex (MAC) pulmonary disease is the most prevalent of NTM pulmonary disease, with an estimated incidence rate of 13.1 cases per 100,000 person-years in 2014 [3]. Population aging is a major risk factor for the increasing rates of MAC pulmonary disease [4,5]. The median age of all individuals with MAC disease was 73.6 years, and 86.6% was aged over 70 years old in a laboratory-based study of NTM lung disease in Japan [6].
Although the number of patients with Mycobacterium avium complex (MAC) pulmonary disease has been increasing among the elderly individuals due to population aging in Japan, few studies have reported treatment in elderly patients with MAC pulmonary disease. We conducted a retrospective cohort study to evaluate differences in the tolerability of, adverse events associated with and efficacy of treatment for MAC pulmonary disease in elderly and nonelderly patients.
The medical records of 96 newly diagnosed MAC pulmonary disease patients at Nagoya City University Hospital between April 2014 and March 2019 were reviewed.
Elderly patients ≥75 years old started multidrug treatment less frequently than nonelderly patients <75 years old (17 of 41 patients, 41.5% vs. 41 of 55 patients, 74.5%, P = 0.001). The treated elderly patients had more symptoms, more extensive radiological disease and a higher rate of positivity on sputum smear than the treated nonelderly patients. Eleven elderly patients and 19 nonelderly patients continued the initial multidrug regimen (64.7% vs. 46.3%, P = 0.26). Adverse events occurred in 6 elderly patients and 25 nonelderly patients (35.3% vs. 61.0%, P = 0.074). The rates of achievement of sputum conversion and radiological improvement after treatment for over 1 year were similar between the elderly and nonelderly patients (61.5% vs. 75.0%, P = 0.37; 76.9% vs. 78.1%, P = 1).
The tolerability, adverse events, and efficacy of treatment in elderly patients with MAC pulmonary disease were not noticeably different from those in nonelderly patients.
Recent increase in non-tuberculous mycobacterial infection in patients with connective tissue diseases in Japan
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Few reports have investigated changes in NTM incidence in all connective tissue diseases. In a study of trends in NTM isolation between 2000 and 2013, the proportion of patients with RA who had NTM infection increased significantly from 2000 to 2006 to 2007–2013 [5]. In that study, 9.0% of patients had RA, 76% of RA patients were female, 60.8% were ≥60 years old, and the number of cases of RA receiving methotrexate or biological agent had increased.
Non-tuberculous mycobacterial (NTM) infection is currently a growing health concern due to the increasing incidence and the need for prolonged therapy. In patients with connective tissue diseases, use of immunosuppressants may lead to an increased risk of NTM infection. However, few studies have examined the recent incidence of NTM infection among connective tissue diseases patients. This study investigated recent trends in NTM infection among connective tissue diseases patients.
We included adult patients from whose cultures NTM were isolated between January 2009 and October 2017 in our hospital. By reviewing their medical records, connective tissue diseases patients were identified. Types of connective tissue disease, NTM species, and treatment of NTM infection were extracted.
NTM was isolated from 657 patients during the period. Among these, 24 patients had connective tissue diseases. The number and rate of NTM isolates from connective tissue diseases patients increased during the period, with 4 patients 2009 to 2012 (1.9%), and 20 patients from 2013 to 2017 (3.3%; P = 0.04). The proportion of Mycobacterium avium complex (MAC) to total NTM tended to be lower among connective tissue diseases patients (58.3%) than among non-connective tissue disease-patients (72.8%), but the difference was not significant (P = 0.20). Mycobacterium xenopi was significantly more frequent in connective tissue disease patients than in non-connective tissue diseases patients (P < 0.01).
The recent increase in the incidence of NTM infections in connective tissue diseases patients was larger than that in the total population. NTM species other than MAC were isolated from connective tissue diseases patients.
Mycobacterium avium complex infection in a patient with systemic sclerosis- associated interstitial lung disease: A case report
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However, he has a condition (Systemic sclerosis) in which several humoral and cellular immunological abnormalities occur, an associated pulmonary interstitial disease with bronchiectasis and an esophageal compromise [13]. Collagen vascular diseases have been identified in up to 16.9% of Japanese patients with pulmonary MAC disease [14]. However, it is unclear if the infection was related to the disease immunological abnormalities or to the use of immunosuppressive drugs such as methotrexate, corticosteroids and TNF-α antagonists [15].
We describe a case of a 65-year-old male with recently diagnosed diffuse cutaneous systemic sclerosis associated with usual interstitial pneumonia and pulmonary hypertension. Patient presented to the emergency department complaining of low-grade fever, increased sputum production, progressive dyspnea and weight loss. High-resolution computed tomography scan showed multifocal bronchiectasis with multiple small nodules. Bronchoalveolar lavage culture was positive for Mycobacterium intracellulare. Antimicrobial treatment was started which improved respiratory symptoms. One month after the initiation of antibiotics, cyclophosphamide therapy was started with adequate tolerance.

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Original articleIncreasing patients with pulmonary Mycobacterium avium complex disease and associated underlying diseases in Japan

Abstract

Introduction

Section snippets

Materials and methods

Annual incidence of mycobacterial isolates

Discussion

Conflict of interest

Acknowledgments

Chest

Chest

Chest

J Chronic Dis

Diagn Microbiol Infect Dis

Isolation prevalence of pulmonary non-tuberculous mycobacteria in Ontario, 1997–2003

Thorax

Pulmonary nontuberculous mycobacterial disease, Ontario, Canada, 1998–2010

Emerg Infect Dis

Prevalence of nontuberculous mycobacterial lung disease in U.S. medicare beneficiaries

Am J Respir Crit Care Med

Increasing reports of non-tuberculous mycobacteria in England, Wales and Northern Ireland, 1995–2006

BMC Public Health

NTM working group at Queensland TB Control Centre and Queensland Mycobacterial Reference Laboratory. Changing epidemiology of pulmonary nontuberculous mycobacteria infections

Emerg Infect Dis

Increasing incidence of nontuberculous mycobacteria, Taiwan, 2000–2008

Emerg Infect Dis

Increasing recovery of nontuberculous mycobacteria from respiratory specimens over a 10-year period in a tertiary referral hospital in South Korea

Tuberc Respir Dis – Seoul

Pulmonary nontuberculous mycobacterial disease prevalence and clinical features: an emerging public health disease

Am J Respir Crit Care Med

Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems

Am J Respir Crit Care Med

Original article
Increasing patients with pulmonary Mycobacterium avium complex disease and associated underlying diseases in Japan