Avium Complex Disease Research Articles

Distinguishing tuberculosis from <I>Mycobacterium avium</I> complex disease using an interferon-gamma release assay

The QuantiFERON-TB Gold (QFT-G) test can be used to distinguish between tuberculosis (TB) and non-tuberculous mycobacterial disease, but a high background TB infection rate may pose a problem. Although the QuantiFERON-TB (QFT) test, the first-generation QFT-G test, employs a non-specific PPD antigen, avium sensitin is also used as a stimulating antigen. To evaluate the utility of these two interferon gamma release assays (IGRAs), QFT-G and QFT, and the tuberculin skin test (TST), to differentiate TB from Mycobacterium avium complex (MAC) disease in an intermediate TB burden country. We compared the diagnostic performance of these three tests in 38 prospectively enrolled patients with TB and 40 with MAC lung disease. The TST yielded positive results in 70.6% of TB and 47.5% of MAC patients; the proportions were respectively 89.5% and 34.3% for QFT-G and 86.8% and 35.3% for QFT. The three tests were of similar accuracy, sensitivity and specificity in diagnosing TB. Our findings indicate that the TST and IGRAs could not discriminate between active TB and MAC disease or latent TB infection in a TB-endemic area.

Serodiagnosis of Mycobacterium avium-complex pulmonary disease with an enzyme immunoassay kit that detects anti-glycopeptidolipid core antigen IgA antibodies in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) has many pulmonary manifestations, including bronchial abnormalities that can develop into Mycobacterium avium-complex (MAC) pulmonary disease (PD). MAC-PD can be lethal in patients receiving tumor necrosis factor-alpha blockers despite administration of antibiotics. Diagnosis of MAC-PD is often difficult, because MAC is an environmental organism. In this study, we investigated the usefulness of serodiagnosis of MAC-PD in RA patients by using an enzyme immunoassay (EIA) kit that detects anti-glycopeptidolipid (GPL) core antigen IgA antibodies. Antibody levels were measured in 63 patients with RA: 14 with MAC-PD plus 3 cultured nontuberculous mycobacteria (NTM) other than MAC, 16 with pulmonary abnormalities characterizing NTM but undetected in sputum culture, and 30 control subjects. RA patients with MAC-PD showed significantly higher antibody levels than controls (p = 0.02). The cutoff point was set at 0.7 IU/l, making the sensitivity and specificity of the antibody in MAC-PD and control patients 43% and 100%, respectively. The EIA kit is useful for diagnosis of MAC-PD in RA patients because of its high specificity. This test is an easier and less invasive form of examination and could therefore replace bronchoscopy as the main diagnostic procedure for RA patients with MAC-PD.

Evaluation of a rapid detection method of clarithromycin resistance genes in Mycobacterium avium complex isolates

Clarithromycin is the key drug in the various treatment regimens of Mycobacterium avium complex (MAC) diseases, and is the only drug for which drug susceptibility has been shown to correlate with clinical response in these diseases. A point mutation at either positions 2058 or 2059 of the 23S rRNA gene has been reported to occur in high-level clarithromycin-resistant isolates. In this study, we examined the correlation between the results from a drug susceptibility test and the mutation of the 23S rRNA gene involved in drug resistance in MAC. Furthermore, we adapted a rapid detection method using amplification refractory mutation system (ARMS)-PCR to identify mutations in the 23S rRNA gene in MAC isolates. Using a microdilution method based on the NCCLS/CLSI recommendation, the MIC of clarithromycin was determined for 245 clinical MAC isolates. Of these, 219 clarithromycin-susceptible and 26 clarithromycin-resistant strains were analysed by sequencing of the 23S rRNA gene and ARMS-PCR. The drug susceptibility test revealed a bimodal distribution of MICs for both the susceptible and resistant strains. Sequence analysis of the 23S rRNA gene revealed that all of the clarithromycin-susceptible strains were wild-type whereas 24 of the clarithromycin-resistant strains were mutant type. The sensitivity of the sequence and ARMS-PCR analyses was 92.3% and 84.6%, respectively, and the specificity of both was 100%. We found a correlation between MICs of clarithromycin and 23S rRNA gene mutations. ARMS-PCR for 23S rRNA mutations of MAC isolates is useful for rapid detection of clarithromycin resistance.

慢性肺アスペルギルス症に対するイトラコナゾール注射薬と 高用量カプセル薬による維持療法の検討

Itraconazole (ITCZ) is a novel triazole antifungal with a broad spectrum including Aspergillus species. We conducted a three-month open, noncomparative multicenter study of the efficacy and safety of ITCZ injections and high dose capsules in chronic pulmonary aspergillosis. Patients with chronic pulmonary aspergillosis received intravenous injection of ITCZ (200mg) (twice a day for the first two days, then once a day for the following 3-12 days) prior to the oral administration of ITCZ capsules (200mg) twice a day. Radiologic findings by chest CT and clinical symptoms were evaluated at baseline and 12 weeks later. We also measured ITCZ plasma trough concentrations after two weeks and four weeks of the study. Twenty patients were included in the study, among which 14 patients presented with chronic necrotizing pulmonary aspergillosis (CNPA) and 6 presented with pulmonary aspergilloma. The efficacy evaluation was available in 17 patients (CNPA, 12 patients; aspergilloma, 5 patients). Radiological improvement was observed in nine (52.9%, 95%CI: 31.0%-73.8%) patients (CNPA, 7 patients; aspergilloma, 2 patients). One patient with aspergilloma showed deterioration. The clinical symptoms showed significant improvement on expectoration, bloody sputum, and pyrexia. Two patients had to stop treatment with ITCZ because of congestive heart failure. Other adverse effects were reported but did not lead to the discontinuation of treatment, as follows: hepatic dysfunction, two patients; hypokalemia, nine patients. In two patients who combined pulmonary Mycobacterium avium complex disease coadministration of ITCZ and rifampicin was done. Their ITCZ plasma concentrations were extremely low, and one of them was the only deterioration case in the primarily radiologic evaluation. Itraconazole injections and high dose capsules maintenance therapy is effective in treating chronic pulmonary aspergillosis.

Clinical usefulness of combination chemotherapy for pulmonary Mycobacterium avium complex disease

BACKGROUND: This study compared the clinical usefulness of combination chemotherapy including various doses of clarithromycin (CAM) for pulmonary Mycobacterium avium complex (MAC) disease. METHODS: The subjects were divided into three groups receiving combination chemotherapy at various dose levels of CAM. The analysis of microbiological effects was based on the sputum conversion rate and sputum relapsing rate and that of clinical effects was performed by clinical symptoms and radiological findings for patients with pulmonary MAC disease. RESULTS: There were no significant differences among the three groups with regard to patient characteristics. The sputum conversion rate significantly increased with the dose of CAM (CAM 400mg: 43%, CAM 600mg: 69%, CAM 800mg: 88%). The sputum relapsing rate did not significantly differ among the three groups (CAM 400mg: 47%, CAM 600mg: 35%, CAM 800mg: 33%). Along with the sputum conversion rate, the rate of clinical improvement was significantly increased with the dose of CAM (CAM 400mg: 27%, CAM 600mg: 40%, CAM 800mg: 54%). Adverse reactions, such as gastrointestinal symptoms, were most frequently recognized in the group receiving CAM 800mg (38%) compared to those in the other two groups (CAM 400mg: 23% and CAM 600mg: 25%). CONCLUSIONS: Although both the sputum conversion rate and clinical improvement significantly increased with the dose of CAM, the rate of adverse reactions, such as gastrointestinal symptoms, also increased. It is important to continue close monitoring of patients with pulmonary MAC disease treated with a regimen that includes CAM 800mg.

Comparative study for the virulence of Mycobacterium avium isolates from patients with nodular-bronchiectasis- and cavitary-type diseases

Mycobacterium avium (Mav) lung infections, called nodular-bronchiectasis (NB)-type M. avium complex (MAC) disease, are globally increasing. To elucidate whether there are unusual populations of Mav, causing NB-type disease rather than cavitary (CA)-type disease, we compared the virulence of Mav isolates from patients with NB-type (NB-Mav) and those from CA-type (CA-Mav) diseases, based on intracellular growth in various types of human cells. Five strains each of NB-Mav and CA-Mav were compared with each other for their invasiveness and ability to intracellularly replicate in various types of cultured cells of human origin. The two types of Mav isolates showed a similar ability, on average, to replicate in macrophages and lung epithelial cells. Moreover, they showed a similar ability to induce the production of reactive nitrogen intermediates and reactive oxygen intermediates by macrophages and susceptibility to antimicrobial molecules. Therefore, it appears that there is no essential difference in virulence in terms of infectivity to human macrophages and lung cells between Mav strains isolated from NB-MAC disease and those from CA-MAC disease. These findings indicate the importance of further studies to elucidate the mechanism for the establishment of NB-type MAC diseases based on host immunological conditions rather than the pathogenic nature of MAC organisms themselves.

Identification ofMICAas a Susceptibility Gene for PulmonaryMycobacterium aviumComplex Infection

Host genetic susceptibility to adult pulmonary Mycobacterium avium complex disease remains unknown. To identify genetic loci for the disease, we prepared 3 sets of pooled DNA samples from 300 patients and 300 sex-matched control subjects and genotyped 19,651 microsatellite markers in a case-control manner. D6S0009i-located in the MICA (major histocompatibility complex class I chain-related A) gene, which encodes a ligand of the NKG2D receptor-had the lowest P value in pooled and individual DNA typing. The A6 allele of the microsatellite was significantly associated with female patients (P <. 001), whereas the classical HLA-B and HLA-DRB1 alleles did not show significant association. Functional analysis of allelic expression imbalance revealed that A6-derived messenger RNA was more highly expressed than non-A6-derived messenger RNA in human bronchial epithelial cells. MICA was expressed in bronchiolar epithelium, alveolar macrophages, and granulomatous lesions. These findings suggest that MICA might be one of the immune molecules affecting the pathogenesis of the disease.

&lt;i&gt;Mycobacterium avium&lt;/i&gt; Complex Organisms Predominantly Colonize in the Bathtub Inlets of Patients’ Bathrooms

Medical treatment of pulmonary Mycobacterium avium complex (MAC) disease does not always provide curative effects and is frequently hampered by recurrence. This suggests the presence of a reservoir for MAC in the environment surrounding patients. We previously reported the recovery of MAC isolates from the residential bathrooms of outpatients. In the present study, to ascertain the colonizing sites and the possibility of an MAC reservoir in the bathrooms of patients, we tested the recovery and the genetic diversity of MAC isolates from 6 sites of specimens, including 2 additional sampling sites, inside the showerhead and the bathtub inlet, in the residential bathrooms of patients with pulmonary MAC disease. MAC isolates were recovered from 15 out of the 29 bathrooms (52%), including specimens from 14 bathtub inlets and 3 showerheads. Nearly half of these bathrooms (7/15) contained MAC strains that were identical or similar to their respective clinical isolates Additionally, in 5 out of 15 bathrooms, polyclonal colonization was revealed by pulsed-field gel electrophoresis. The results imply that colonization of MAC organisms in the bathrooms of MAC patients occurs predominantly in the bathtub inlets, and there is thus a risk of infection and/or reinfection for patients via use of the bathtub and other sites in the bathroom.

Long-term observation of pulmonary Mycobacterium avium complex disease treated with chemotherapy-- following the guidelines for treatment

OBJECTIVE We performed a long-term retrospective investigation of pulmonary Mycobacterium avium complex (MAC) disease treated with combined chemotherapy following the ATS guideline or the Japanese Society for Tuberculosis guideline. We also studied when to terminate the combined chemotherapy. MATERIALS AND METHODS The subjects of this study consisted of 90 patients who underwent combined chemotherapy according to these guidelines for minimum one-year period and followed up for at least one year since April, 1998. RESULTS The mean patients' age was 64.8 years old and the gender distribution consisted of 34 males and 56 females. While the sputum negative conversion was observed in 54 of 90 patients (60%), clinical improvement was recognized in 35 patients (39%) following combined chemotherapy administered according to the guidelines. Out of 54 patients with sputum conversion, 30 cases were followed up after the discontinuation of treatment, and sputum relapse later was seen in 18 patients. Out of 24 patients who continued the same treatment, sputum relapse was seen in 10 patients. Out of 35 patients with clinical improvement, 17 cases have been followed up after the discontinuation of treatment, clinical worsening was later recognized in 9 patients. Out of 18 patients who continued the same treatment, clinical worsening was recognized in 6 patients. CONCLUSIONS As the probability of sputum relapse after discontinuation of treatment was high even among patients whose sputum converted to negative by combined treatment according to the guidelines, we think that it is better to continue treatment according to the guidelines as long as possible.

Clinical Presentation and Mortality of Mycobacterium avium Complex Disease in a Public Sector Hospital, South Africa

Clinical Presentation and Mortality of Mycobacterium avium Complex Disease in a Public Sector Hospital, South Africa

Virulence of Mycobacterium avium complex strains isolated from immunocompetent patients

Mycobacterium avium complex (MAC) disease has been increasing worldwide not only in immunocompromised but also in immunocompetent humans. However, the relationship between mycobacterial strain virulence and disease progression in immunocompetent humans is unclear. In this study, we isolated 6 strains from patients with pulmonary MAC disease. To explore the virulence, we examined the growth in human THP-1 macrophages and pathogenicity in C57BL/6 mice. We found that one strain, designated 198, which was isolated from a patient showing the most progressive disease, persisted in THP-1 cells. In addition, strain 198 grew to a high bacterial load with strong inflammation in mouse lungs and spleens 16 weeks after infection. To our knowledge, strain 198 is the first isolated MAC strain that exhibits hypervirulence consistently for the human patient, human macrophages in vitro, and even for immunocompetent mice. Other strains showed limited survival and weak virulence both in macrophages and in mice, uncorrelated to disease progression in human patients. We demonstrated that there is a hypervirulent clinical MAC strain whose experimental virulence corresponds to the serious disease progression in the patients. The existence of such strain suggests the involvement of bacterial virulence in the pathogenesis of pulmonary MAC disease in immunocompetent status.

Bronchoscopic Microsampling to Analyze the Epithelial Lining Fluid of Patients with Pulmonary Mycobacterium avium Complex Disease

Background: A new bronchoscopic microsampling (BMS) probe has recently been developed, which allows the minimally invasivecollection of epithelial lining fluid (ELF) simultaneously from multiple sites. While the number of immunocompetent patients with pulmonary Mycobacterium avium complex(MAC) disease is growing, the precise pathogenesis of the disease remains to be clarified. Objectives: This study aimed to measure biochemical markers in the ELF of patients with pulmonary MAC disease using BMS. Methods: We studied 8 healthy volunteers (controls) and 8 patients with pulmonary MAC disease. In the patients, ELF was collected from visibly abnormal (involved) and normal (uninvolved) sites using high-resolution computed tomography (HRCT). Results: The concentration of IFN-γ (means ± SEM) was significantly higher in patient ELF sampled from involved (26.62 ± 9.66 pg/ml) than from uninvolved sites (5.33 ± 1.44 pg/ml; p < 0.05) or from normal controls (<1.56 pg/ml; p < 0.05). In most patients, there was no difference in IFN-γ concentrations between the involved and uninvolved sites. The concentration of KL-6 in ELF was significantly higher in the involved (793 ± 108 U/ml) than in the uninvolved sites (192 ± 43 U/ml;p < 0.05) or in normal controls (186 ± 38 U/ml;p < 0.05). Conclusions: The specific inflammatory reaction caused by MAC infection might not be limited to sites that were visibly abnormal on HRCT. Although further improvement has to be considered, BMS may help to increase the understanding of the pathogenesis of various respiratory disorders.

High-resolution computed tomography inMycobacterium aviumcomplex disease: one step forward, two steps back

To the Editors: We read with interest the article by Kuroishi et al. 1, in which the group pleasantly documented the prognostic implications of high-resolution computed tomography (HRCT) findings in Mycobacterium avium complex (MAC) disease. Kuroishi et al. 1, found that the presence of atelectasis, cavities, pleural thickening or bronchiectasis on a computed tomography (CT) scan indicated poor prognosis and concluded that CT findings are good predictors of the response to treatment in MAC disease patients. However, there are a few practical issues regarding the topic that need …

Anatomic Lung Resection for Nontuberculous Mycobacterial Disease

Chronic lung infections involving nontuberculous mycobacteria are often inadequately treated owing to concomitant lung parenchymal damage, leading to persistence of the offending organisms. Little is known about the results of surgical therapy as part of a multimodality approach to these infections. A retrospective review was conducted of 236 consecutive patients who underwent anatomic lung resection for nontuberculous mycobacteria disease at our institution as part of a multimodality treatment program. In all, 236 patients underwent 265 operations. The average age was 54 years (range, 23 to 77). Fifty-three patients had prior thoracic procedures. All patients had in-vitro sensitivity testing of cultured organisms, and had several months of guided antibiotic therapy. Special emphasis was placed on nutritional status. Eighty percent of patients had Mycobacterium avium complex disease. Anatomic lung resection was performed in all patients, with 126 lobectomies, 55 segmentectomies, 44 pneumonectomies, and 40 mixed procedures. Sixty-seven patients had either muscle or omental transposition. Mortality rate was 2.6%. The major morbidity rate was 11.7%. Average length of stay was 6.5 days. Presence on postoperative bronchopleural fistula was associated with positive sputum at operation and right pneumonectomy, particularly right completion pneumonectomy. This series represents the largest cohort of patients in the literature to date who underwent operation for nontuberculous mycobacteria infection. Surgery for nontuberculous mycobacteria disease may be accomplished with minimal morbidity and mortality. A multidisciplinary approach including targeted antimicrobial therapy and complete anatomic resection is the key to success.

Mycobacterium avium complex disease: prognostic implication of high-resolution computed tomography findings

To evaluate the prognostic implications of computed tomography (CT) findings in assessing responses to treatment in Mycobacterium avium complex (MAC) pulmonary disease without underlying lung disease, high-resolution (HR)CT findings were correlated based on the results of sputum conversion after anti-MAC therapy. A total of 59 patients underwent HRCT before treatment and the therapeutic efficacy was evaluated by the results of sputum conversion. Atelectasis, cavities and pleural thickening on HRCT were significantly more frequent and extensive among patients in the sputum nonconverted group than among those in the converted group. Furthermore, bronchiectasis was also significantly more extensive among patients in the nonconverted group, even though there was no significant difference in frequency between these two groups. These results suggest that high-resolution computed tomography findings are good predictors of response to treatment in Mycobacterium avium complex pulmonary disease.

The Clinical Efficacy of Kanamycin for &lt;i&gt;Mycobacterium avium&lt;/i&gt; Complex Disease

No previous reports have compared clarithromycin (CAM), rifampicin (RFP) and ethambutol (EB) containing regimens with and without an aminoglycoside antibiotic kanamycin (KM) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease. We conducted a retrospective study to investigate the clinical efficacy of KM using data from 40 patients who received combined chemotherapy for MAC disease with or without KM in the National Hospital Organization Tokyo Hospital from July, 1999 to December, 2005. All patients were administered CAM, RFP and EB for 6 to 12 months, and 20 of the 40 simultaneously received combined chemotherapy with KM. The difference in the backgrounds of the groups was not statistically significant. The improvement rates of clinical symptoms and radiological findings were significantly higher in the KM-treated group than in the KM-untreated group (75% versus 35% and 80% versus 25%). Moreover, the sputum relapse rate was significantly lower in the KM-treated group (18% versus 75%). However, there were no significant differences in the sputum conversion rate (55% with KM versus 40% without KM). As for adverse reactions, there were no significant differences between the groups. Furthermore, we examined time-kill kinetics of KM and streptomycin (SM) against a clinical isolate of M. avium. Most M. avium was killed by KM and SM at concentrations higher than MIC (8 microg/ml), and concentration- and time-dependent killing by KM and SM were almost identical. These observations indicate that KM is effective for treatment of patients with MAC disease.

Clinical Factors on Cavitary and Nodular Bronchiectatic Types in Pulmonary Mycobacterium avium Complex Disease

Pulmonary Mycobacterium avium complex (MAC) disease is the most common pulmonary non-tuberculous mycobacteriosis (NTM). The clinical and radiological findings were similar to those of pulmonary tuberculosis, both of which are characterized by upper lobe cavities. On the other hand, the presence of middle and lower field lesions with centrilobular nodules and bronchiectasis has been noted. We analyzed the clinical feature of these two radiologically different types and identified their prognostic factors. The clinical, laboratory and radiological findings of 273 cases of MAC disease, newly diagnosed during the recent 7 years periods, were investigated. They were radiologically classified into cavitary (Cav) and nodular bronchiectasis (NB) types at the time of diagnosis. The findings of 44 fatal cases were compared with those of the newly diagnosed cases. A prominent increase in the number of cases was recently found only in females. Low body mass index (BMI) and moderately reduced serum albumin were found at the time of first hospital visit in both newly diagnosed and fatal cases. In the latter, peripheral blood lymphocyte count was slightly decreased, and tuberculin skin test was negative in 57.7% of the cases. Radiologically, Cav type was prevalent in males and NB type in females in the newly diagnosed cases, while in the fatal cases Cav type was frequently found in both males and females. The two radiological patterns did not change during the entire disease course. Cav type in females was one of the pathogenetic factors. Deterioration of cell-mediated immunity may underlie MAC disease.

The mycobacterial mystery

Before the advent of HIV, which led to an increased awareness of Mycobacterium avium complex disease, followed by the first prospective comparison studies on treatment regimens 1, 2, the topic of nontuberculous mycobacterial disease was a true example of Aristotelian science. Previously, only a few experts worldwide had compiled empirical data and disseminated knowledge on the subject, which was based upon meticulous observations in small series or case studies from the 1950s onwards 3. These studies demonstrated the manifold particularities of M. avium complex disease and others as compared with tuberculosis, and also showed how even nontuberculous mycobacterial lung diseases alone, quite apart from manifestations in other organs, appear in widely varying forms. To this day, an ever increasing number of reports on uncommon or recently detected and potentially pathogenic species with strange names deepen the impression that we are dealing with an intricate matter. In 1979, Wolinsky 4 published his legendary review on nontuberculous mycobacteria (NTM) and associated diseases, which is still worth reading and citing: “The pathogenesis of adult pulmonary disease is obscure. Does it represent primary infection after inhalation of aerosolized infected droplet nuclei that then localize and proliferate in specific areas of damaged lung? Or is it a reactivation of dormant bacilli that had been acquired previously?” 4. Meanwhile, the history of HIV especially, and the growing number of patients with transplants, have helped in understanding the role, and some mechanisms, of systemic immunosuppression as an important factor in the development of both disseminated and pulmonary disease. Have we, however, deepened our understanding of the pathophysiology of localised lung disease in non-HIV patients, this being a key issue? Focusing on treatment, in 1985 another pioneer in the field of tuberculosis and nontuberculous mycobacterial diseases, Karl Ludwig Radenbach (1918–1986), wrote: “Clinically, treatment cannot …

Clinical Reevaluation of the QuantiFERON TB-2G Test as a Diagnostic Method for Differentiating Active Tuberculosis from Nontuberculous Mycobacteriosis

We reevaluated the usefulness of a whole-blood interferon-gamma enzyme-linked immunosorbent assay (QuantiFERON TB-2G [QFT-TB]; Cellestis) in obtaining a differential diagnosis between active tuberculosis (TB) and nontuberculous mycobacteriosis (NTM). The subjects were 50 healthy volunteers, 50 patients with active TB, and 100 patients with NTM who satisfied the diagnostic guidelines of the American Thoracic Society from April 2005 through June 2006. The tuberculin skin test (TST) and the QFT-TB test were performed for all subjects. The QFT-TB test was performed every 2 months. Of the healthy volunteers, 64% had a negative TST result and 94% had a negative QFT-TB test result. Of the patients with active TB, 64% had a positive TST result and 4% had a negative QFT-TB test result. Of the patients with pulmonary Mycobacterium avium complex disease, 60% had a positive TST result and 7% had a positive QFT-TB test result. The QFT-TB test had a mean sensitivity of 86% and a mean specificity of 94%. The QFT-TB test results for patients with active TB transiently decreased during treatment involving antituberculous drugs. The rate of positive QFT-TB test results was 86% at the initiation of treatment, 48% 6 months later, and 33% 12 months later. We confirmed that the QFT-TB test is a useful diagnostic method for differentiating active pulmonary TB from NTM, compared with the TST. However, because it is possible that the effect of the QFT-TB test may be long lasting after treatment and may not be resolved over time, even with treatment, as in this study, it may not provide any level of certainty regarding cure of infection.

Chronic necrotizing pulmonary aspergillosis as a complication of pulmonary Mycobacterium avium complex disease

To investigate the characteristic clinical features of chronic necrotizing pulmonary aspergillosis (CNPA) as a complication of pulmonary Mycobacterium avium complex (MAC) disease. Clinical analysis of nine cases without a history of old pulmonary tuberculosis in whom CNPA was found to be a complication during the follow-up period for MAC disease. The average duration from the diagnosis of pulmonary MAC disease to the diagnosis of CNPA was 36.0 months. Five patients received antituberculous therapy including clarithromycin for pulmonary MAC disease, but this treatment was ineffective in most. A positive culture for Aspergillus spp. from sputum and a bronchoscopic specimen and clinical evidence of a chronic infective process were recognized in all cases at the time of detection of CNPA. Serological fungal examinations for anti-Aspergillus IgG antibody were initially negative and became positive in all cases during the follow-up period of pulmonary MAC disease. The presence of CNPA surrounding the cavity previously caused by MAC was characterized by local thickening of the cavity with a fungus ball and the appearance of an infiltration shadow surrounding the cavity. In most of the cases, CNPA was at first treated with oral itriconazole and then with i.v. infusion of micafungin, but the clinical efficacy was generally poor. The results of this study showed that during the long follow-up period of patients with pulmonary MAC disease it is important to not only carry out serological examinations, but also perform radiological examinations using chest CT.