Familial pulmonary Mycobacterium avium complex disease

We report two Japanese families affected by pulmonary Mycobacterium avium complex (MAC) disease, involving an older brother and younger sister in one family and two brothers in the second family. We investigated whether defects in the natural resistance-associated macrophage protein gene (NRAMP1) underlay susceptibility to MAC in these cases. All of the patients had computed tomographic findings of peripheral nodules and bronchiectasis. Pulse-field gel electrophoresis patterns of mycobacterial genomic DNA restriction fragments revealed that none of the MAC strains isolated from the patients was epidemiologically related to any of the others. Direct sequencing of the complementary DNA of the patients' NRAMP1 revealed a nonconservative missense mutation at codon 419 in one patient, which was heterozygous and was not seen in his affected sibling. No variations similar to those found in mice that show susceptibility to MAC were found. The results suggest an underlying genetic defect in host defense rather than exposure to an unusually virulent strain of MAC as the pathogenetic factor in MAC disease; however, alterations in the coding region of NRAMP1 do not appear to explain the susceptibility to MAC.     

Sentinel-site surveillance of Mycobacterium avium complex pulmonary disease.

The incidence of Mycobacterium avium complex (MAC) pulmonary disease in HIV-negative patients was studied prospectively from January 1, 2000 to December 31, 2002 through 32 sentinel sites distributed all over France. Among the 275 patients who yielded MAC isolates from respiratory clinical specimens, 101 (36.7%) met the bacteriological, radiographical and clinical criteria established by the American Thoracic Society for nontuberculous mycobacterial respiratory disease. Of these 101 patients, 81 had underlying lung disease, mainly previous tuberculosis, bronchectasis or chronic obstructive pulmonary disease. Among the 20 patients with no underlying lung disease, 12 had a predisposing factor such as leukaemia or immunosuppressive treatment and eight had no predisposing factor. All patients with MAC respiratory disease had clinical symptoms, commonly cough and fatigue, and 52 (51.5%) were sputum smear positive for acid-fast bacillus. The ratio of patients with Mycobacterium avium complex pulmonary disease to patients with pulmonary tuberculosis in France was estimated to be 3% and the incidence of Mycobacterium avium complex pulmonary disease in France was 0.2 per 100,000 inhabitants.     

Results of surgery in Mycobacterium avium complex pulmonary disease]

Recently, several studies have revealed the usefulness of surgical therapy for nontuberculous mycobacterial (NTM) disease. We have encountered and taken many opportunities for surgical therapy in Mycobacterium avium complex (MAC) disease. From April 1995 through March 1999, 14 patients with MAC disease underwent 16 pulmonary resections. NTM was diagnosed at our hospital in all subjects according to the criteria of the American Thoracic Society. There were 8 women and 6 men, with a mean age of 54 years. The most common indications for surgery were localized lesion (7 cases), severe symptoms (5 cases) and progressive disease (2 cases). Twelve patients were receiving multidrug chemotherapy, 10 of whom were also receiving clarithromycin. The mean period of preoperative chemotherapy was 17 months. Ten patients had a variety of symptoms, with some combination of cough, sputum, hemosputum, dyspnea, fever and anorexia. About 30% of the symptoms were improved after preoperative chemotherapy. The symptoms disappeared in all except one patient, who underwent pneumonectomy. After surgery, all patients attained a sputum-negative status. Nine patients underwent 11 partial resections, comprising 3 thoracotomies and 8 video-assisted thoracic surgeries (VATS). There was no operative mortality. Re-operation was performed in a patient with bronchopleural fistula after initial surgery. Currently, 2 months after the last operation, we have encountered no other severe complication and no relapse. Surgery may play an important role in treatment of MAC disease. We recommend partial resection with VATS for localized MAC disease.     

Mycobacterium avium complex pulmonary disease in patients with pre-existing lung disease

Patients with MAC-PD and pre-existing lung disease are a distinct group from the more common and recently recognized group of predominantly middle- to older-aged women without pre-existing lung disease. Those with pre-existing disease are expected to have more sputum positivity and slower conversion of sputum with treatment, and they may require combined medical treatment with surgical resection for optimal results. Attention to bronchial hygiene, avoidance of unnecessary use of macrolides, and treatment of underlying esophageal and lung disease can result in marked symptomatic improvement in many cases. Appropriate consideration must be given to mycobacterial antibiotic treatment, and awareness must be maintained for other processes such as bronchogenic cancer in select groups of high-risk patients.     

Medical management of pulmonary disease caused by Mycobacterium avium complex

The current medical therapy for Mycobacterium avium complex is controversial. American Thoracic Society recommendations advocate empiric therapy with drug susceptibility testing only for clarithromycin. At National Jewish, where we mainly see cases complicated by treatment failure and drug intolerance, we use in vitro susceptibility testing and therapeutic drug monitoring to optimize efficacy and reduce toxicity.     

Mycobacterium avium complex pulmonary disease in patients without HIV infection

Mycobacterium avium complex (MAC) is ubiquitous. It is found in various freshwater and saltwater sources around the world, including hot water pipes. Although the organism was identified in the 1890s, its potential to cause human disease was only recognized 50 years later. Only a minority of people exposed to the organism will acquire MAC lung disease, usually those with underlying lung disease or immunosuppression. MAC may, however, cause progressive parenchymal lung disease and bronchiectasis in patients without underlying lung disease, particularly in middle-aged and elderly women. Preliminary data suggest that the interferon-gamma pathways may be deficient in elderly women with MAC lung disease. Other groups of patients who are more likely to harbor MAC in their lungs include patients with a cystic fibrosis or an abnormal alpha(1)-antiproteinase gene and patients with certain chest wall abnormalities. Treatment results continue to be disappointing, and the mortality of patients with MAC lung disease remains high. A PubMed search identified 38 reports of the treatment of MAC lung disease. Apart from the British Thoracic Society study, the only published controlled investigation, the studies published since 1994 have included a macrolide, either clarithromycin or azithromycin, usually in combination with ethambutol and a rifamycin. If success is defined as eradication of the organism without relapse over a period of several years after treatment has been discontinued, the reported treatment success rate with the macrolide containing regimens is approximately 55%. The prolonged treatment period, side effects, and possibly reinfection rather than relapse are responsible for the high failure rate.     

Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease.

We have investigated the efficacy of a clarithromycin-containing four-drug regimen for Mycobacterium avium complex (MAC) pulmonary disease in 46 patients without acquired immunodeficiency syndrome (AIDS). The patients were 14 males and 32 females with a mean age of 60.9 +/- 11.5 yr. Patients received 10 mg/kg/d of clarithromycin plus ethambutol, rifampin, and initial kanamycin and subsequent quinolone for 24 mo. Seven patients (15.2%) were dropped in the first 6 mo. Among 39 patients who received more than 6 mo of therapy, 28 patients (71.8%) converted their sputa to negative: 26 of 31 patients (83.9%) infected with clarithromycin-susceptible strains and two of eight patients (25.0%) with resistant or intermediate strains. The timing of sputum conversion was 3.6 +/- 1.9 mo, with a range of 2 to 9 mo. The conversion rate was significantly lower in patients who were infected with clarithromycin-resistant or intermediate strains, who had had prior therapy (55.0% versus 89.5%), or who were acid-fast bacilli (AFB) smear-positive at entry (60.7% versus 100%). The age and sex of patients, the species of pathogen (M. avium or M. intracellulare), type and extent of the disease, and the use of kanamycin did not significantly affect the conversion rate. Although the regimen was efficacious for newly treated patients, frequent adverse reactions and a low conversion rate of sputum in retreated patients are problems that remain to be solved.     

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

OBJECTIVE AND BACKGROUND: To investigate the characteristic clinical features of chronic necrotizing pulmonary aspergillosis (CNPA) as a complication of pulmonary Mycobacterium avium complex (MAC) disease. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Gastroesophageal reflux disease, acid suppression, and Mycobacterium avium complex pulmonary disease

BACKGROUND: Weekly symptoms of gastroesophageal reflux disease (GERD) occur in 20% of the population, and GERD has been implicated in the pathophysiology of many respiratory diseases. Microaspiration of contaminated water is a potential portal of entry for Mycobacterium avium complex (MAC) organisms into the respiratory tract, and acid-suppression therapy may enhance the survival of mycobacteria in the stomach. This study aimed to assess the prevalence of GERD, swallowing disorders, reflux symptoms, and acid-suppression therapy in patients with MAC lung disease (MAC positive [MAC+]), and to compare these patients to control subjects without MAC lung disease (MAC negative [MAC-]). METHODS: Clinical information was collected on 58 MAC+ patients and 58 age- and sex-matched MAC- patients who were asked to complete a DeMeester questionnaire of reflux symptoms and to identify any acid-suppressive medication consumed. RESULTS: A clinical diagnosis of GERD was documented in 23 of 52 MAC+ patients (44.2%), compared to 16 MAC- patients (27.6%) [p = 0.019]. MAC+ patients consumed significantly more histamine type 2 receptor antagonists and prokinetic agents, and MAC- patients consumed more antacids. The mean DeMeester questionnaire score (+/- SD) for MAC+ patients was 1.39 +/- 1.8, and for MAC- patients was 0.88 +/- 1.4. (p = 0.098). Aspiration was suspected in nine MAC+ patients (15.5%), compared to three MAC- patients (5.2%) [p = 0.032]. There was no association between GERD and radiologic presentation of MAC disease. Consolidation and nodules > 5 mm were more common in those receiving acid suppression than those who were not. CONCLUSIONS: GERD, acid suppression, and clinically suspected aspiration are more common in patients with MAC lung disease than in similar patients without MAC disease.     

Analysis of chest CT in patients with Mycobacterium avium complex pulmonary disease

BACKGROUND: The radiographic changes of Mycobacterium avium complex (MAC) pulmonary disease during therapy have not been studied well. OBJECTIVE: To assess the efficacy of antituberculous drug therapy against MAC pulmonary disease using computed tomography (CT). METHOD: We analyzed chest CT scans before and after antituberculous therapy in 30 patients (21 women, 9 men) with MAC pulmonary disease. To evaluate radiographic changes during therapy, we defined a 'degree of improvement' (DI) that is calculated according to the CT appearance. RESULTS: DI was better (1.35 +/- 0.21) in patients who had converted sputum culture than in those who had not (0.44 +/- 0.25) (p < 0.05). In patients who were diagnosed by bronchial washing, DI was better (1.60 +/- 0.22) than in patients who were diagnosed by sputum (0.67 +/- 0.20) (p < 0.01). We categorized the CT appearance into 6 types: small nodules, cavities, bronchial wall thickening, infiltration, pleural thickening and atelectasis. Patients who showed pleural thickening had a significantly worse DI (0.12 +/- 0.40) than those who did not (1.23 +/- 0.18) (p < 0.01). Most of the lesions that disappeared after therapy were small nodules. CONCLUSION: These results indicate that chest CT might be a useful tool for the prediction or assessment of drug therapy for MAC pulmonary disease.     

Diagnosis of disease caused by Mycobacterium avium complex

Isolation of Mycobacterium avium complex from sputum specimens in association with the appearance of a new cavitary (or infiltrative) lesion was studied in 299 patients from whom the organism was isolated one or more times. Of the patients studied, 114 showed only single isolation. Of these 114, only two patients (2 percent) had association with appearance of a cavitary lesion. Of 29 patients who showed two isolations, 26 (90 percent) had the association. Of 40 patients who showed three isolations, 39 (98 percent) had the association. All 116 patients who showed four or more isolations had the association with appearance of a cavitary lesion. Accordingly, of a total of 185 patients who showed two or more isolations, 181 (98 percent) had the association. Of these 181, 176 (97 percent) showed two or more isolations in the sputum examinations made in the initial three days. Therefore, the sputum examination in the first three days after onset of disease is most important for the diagnosis of disease caused by Mycobacterium avium complex. Since the probability that casual isolation of the organism occurs twice is extremely low, we can make the diagnosis of pulmonary infection caused by this organism by evidence of two or more isolations of the organism in the first few days after the onset of disease, which is associated with appearance of a new cavitary (or infiltrative) lesion. Moreover, theoretical consideration made in this study has led us to conclude that patients who have had a single isolation of the organism together with a new cavitary lesion should be regarded as having an infection.     

A study on the effect of combined chemotherapy on Mycobacterium avium complex pulmonary disease

Annual incidence of Mycobacterium avium complex (MAC) pulmonary disease has been gradually increasing in the last 10 years in Japan, however, the optimal therapeutic regimen for the disease has not yet established. We investigated the effect of our new regimen in twenty seven cases of pulmonary MAC infection without HIV infection, diagnosed according to the American Thoracic Society criteria during the period from January 1996 to October 1997 at our hospital. These patients were treated with rifampicin (RFP), ethambutol (EB) and clarithromycin (CAM) for more than 12 months, together with streptomycin (SM) initially (first 2-3 months), except one patient who was treated for 11 months only. Twenty-four months after the therapy, sputum cultures converted from positive to negative in 13 patients and the amount of bacilli in sputum reduced in two patients. The radiological findings improved in 10 patients, showed no significant changes in 11 patients, while worsened in the remaining 6 patients. As to adverse reactions 1 case of liver damage, 3 cases of skin disorders, 4 cases of gastrointestinal malfunctions, and 1 case of optic neuritis were observed. This regimen was safe and tolerable even in the elderly outpatients, but not so effective against MAC pulmonary disease compared with the results of recent reports from the U.S. and Europe. Size of pulmonary lesions was closely associated with the effectiveness in this study. However, five bacteriologically converted cases did not show radiological improvement, and the reasons behind this fact remain to be investigated.     

A case of pulmonary Mycobacterium avium complex disease, mimicking hot tub lung]

A 56-year-old man in whom reticulonodular shadows had been noted on a previous chest radiography study was admitted to our hospital with complaint of exertional dyspnea in March 2004. His thoracic computed tomography (CT) showed diffuse ground-glass opacities and multiple centrilobular small nodules in both lung fields. Lymphocytes occupied a high proportion in the cells recovered from the bronchoalveolar lavage fluid. These findings were compatible with those for hypersensitivity pneumonitis. Histopathological findings observed in the video-assisted thoracoscopic surgical biopsy specimens included necrotizing granulomas, organizing pneumonia associated with collective epithelioid cell granulomas without necrosis, and alveolar septal thickening with lymphocyte infiltration that showed a centrilobular distribution. These findings were also compatible with those for hot tub lung. Further information that supported the diagnosis were the identifications of Mycobacterium avium complex in his sputum by acid-fast bacteriological culture as well as positive for Mycobacterium avium polymerase chain reaction in lung specimen. He responded well to corticosteroid therapy, resulting in improvement in his clinical condition as well as in his chest radiographs. He was later put on an antituberculosis therapy, and the corticosteroid therapy was discontinued. This led to an exacerbation of his disease and corticosteroid therapy was restarted. It is not long time since the disease was first recognized, and thus few cases have been reported in Japan. Our report may provide valuable information on the disease in this country.     

A case of pulmonary Mycobacterium avium complex disease complicated by interstitial pneumonia with collagen vascular disease

A 45-year-old woman with scleroderma for 15 years duration, rheumatoid arthritis in the past five years, and interstitial pneumonia in the past two years had been followed at OPD. Although sputum had appeared and cough had increased since January 2002, there was no obvious abnormal findings on chest X-ray. Later, as a chest X-ray revealed an infiltrative shadow with cavity in the right lower lung field, we suspected pulmonary tuberculosis and performed the direct smear examination of sputum immediately. As acid-fast bacilli were positive (Gaffky 10) and the polymerase chain reaction (PCR) test was positive for only Mycobacterium avium, we diagnosed the case as pulmonary nontuberculous mycobacterial disease. This case was thought to be pulmonary nontuberculous mycobacterial disease complicated with interstitial pneumonia with collagen vascular disease as a secondary infectious type, and as the cause of the disease, the decrease of the local pulmonary defence mechanism due to pre-existing pulmonary lesions was suspected.     

Treatment strategies with alternative treatment options for patients with Mycobacterium avium complex pulmonary disease

Diseases caused by Mycobacterium avium complex (MAC) infection in the lungs are increasing worldwide. The recurrence rate of MAC-pulmonary disease (PD) has been reported to be as high as 25–45%. A significant percentage of recurrences occurs because of reinfection with a new genotype from the environment. A focus on reducing exposure to MAC organisms from the environment is therefore an essential component of the management of this disease as well as standard MAC-PD treatment. A macrolide-containing three-drug regimen is recommended over a two-drug regimen as a standard treatment, and azithromycin is recommended rather than clarithromycin. Both the 2007 and 2020 guidelines recommend a treatment duration of MAC-PD of at least one year after the culture conversion. Previous clinical studies have reported that ethambutol could prevent macrolide resistance. Furthermore, the concomitant use of aminoglycoside, amikacin liposomal inhalation, clofazimine, linezolid, bedaquiline, and fluoroquinolone with modification of guideline-based therapy has been studied.Long-term management of MAC-PD remains challenging because of the discontinuation of multi-drug regimens and the acquisition of macrolide resistance. Moreover, the poor compliance of guideline-based therapy for MAC-PD treatment worldwide is concerning since it causes macrolide resistance.Therefore, in this review, we focus on MAC-PD treatment and summarize various treatment options when standard treatment cannot be maintained, with reference to the latest ATS/ERS/ESCMID/IDSA clinical practice guidelines revised in 2020.     

Mycobacterium avium complex pleuritis

Non-tuberculous mycobacterium infection is rarely accompanied by pleural involvement. We report a very rare case of Mycobacterium avium-intracellurare complex (MAC) pleuritis with massive pleural effusion. The patient was a non-compromised 67-year-old female and had been treated for pulmonary non-tuberculous mycobacterium infection. She was admitted to hospital because of general malaise, low-grade fever and right pleural effusion. Cytological examination of the effusion did not show malignant cells. MAC was only identified by culture and PCR. No other bacteria were detected. Complete resolution of the pleural effusion occurred after administration of anti-tubercular agents (isoniazid, rifampin, ethambutol) and clarithromycin.