Pulmonary Mycobacterium avium complex infection associated with the IVS8-T5 allele of the CFTR gene.

BACKGROUND: The T5 allele in intron 8 (IVS8) on specific haplotype backgrounds (e.g., long TG repeats) causes abnormal splicing in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and is also known to be associated with chronic airway diseases. OBJECTIVE: To investigate the role of CFTR variations for susceptibility to pulmonary Mycobacterium avium complex (MAC) infection. PARTICIPANTS: Three hundred patients with pulmonary MAC infection (72 males, 228 females; mean age at onset 61.6 +/- 12.4 years) took part in this study. Diagnosis of MAC infection was based on American Thoracic Society criteria. Clinical profiles were collected and blood samples were genotyped for TG repeats, poly-T and M470V polymorphisms. RESULTS: We found significantly higher T5 frequency in MAC patients than in healthy controls from our own study (0.035 and 0.005, respectively, P = 0.023) and other reports. Homozygote for the T5 allele was found in two MAC patients. All T5 alleles were associated with longer TG repeats, the TG12 or TG13 allele. Seventeen of the 21 T5 alleles appeared to be associated with the V470 allele. Other polymorphisms did not show any significant differences in frequency. CONCLUSIONS: These findings suggest that the IVS8 5T allele might be involved in susceptibility to pulmonary MAC infection.     

Disseminated Mycobacterium avium complex infection: clinical identification and epidemiologic trends.

To evaluate the incidence of disseminated Mycobacterium avium complex infection (DMAC) and to define the association between signs and symptoms and development of DMAC in patients with human immunodeficiency virus (HIV) infection, all cases of DMAC at Grady Memorial Hospital Infectious Disease Clinic (Atlanta) between 1985 and 1990 were reviewed, and a prospective study of the association of symptoms with DMAC was done. Between 1985 and 1990, DMAC occurred in 16% of patients with AIDS. Incidence increased from 5.7% in 1985-1988 to 23.3% in 1989-1990 (P less than .001). Median time from AIDS diagnosis to diagnosis of DMAC increased from 4.5 months in 1985-1988 to 8 months in 1989-1990 (P less than .02). In the prospective study, DMAC was seen only in persons with a CD4+ count less than 100 cells/mm3 and was associated with fever (P less than .03), anemia (P less than .001), weight loss (P less than .01), diarrhea (P less than .01), and elevated alkaline phosphatase (P less than .01). It is recommended that all such HIV-infected persons have mycobacterial blood cultures done.     

Mycobacterium avium complex infection in kidney transplant patients

Mycobacterium avium complex (MAC) infections have been reported rarely in renal transplant patients. Consequently the clinical course and optimal treatment of these patients are not well understood. We present 3 patients with MAC infections after receiving a renal transplant (2 with generalized and 1 with localized infection). All patients were treated with combination antibiotic therapy and reduction of immunosuppression. One patient experienced clinical control of disease but a mild cellular rejection that was successfully treated with high-dose corticosteroids. One patient died of disseminated MAC infection. The patient with localized infection died of unrelated causes. In summary, MAC infection, although rare in renal transplant patients, may respond to combination antimicrobial therapy and reduction of immunosuppression.     

Natural history of disseminated Mycobacterium avium complex infection in AIDS.

This study sought to better characterize the natural history of AIDS-associated disseminated Mycobacterium avium complex (MAC) infection. Towards that end two retrospective studies were done: a case-control survival study and a MAC respiratory colonization study. Among 137 consecutive patients who had a sterile body site cultured for mycobacteria within 3 months of their first AIDS-defining episode of Pneumocystis carinii pneumonia, median survival was significantly shorter in those with disseminated MAC infection (107 days; 95% confidence interval [CI] 55-179) than those with negative cultures (275 days; 95% CI 230-318; P less than .01), even after controlling for age, absolute lymphocyte count, and hemoglobin concentration. Among 34 patients with AIDS and respiratory MAC colonization, 22 later developed disseminated infection (65% predictive value for subsequent MAC dissemination). Disseminated MAC infection was associated with significantly shorter survival for patients with AIDS, and the presence of MAC in respiratory specimens has substantial predictive value for subsequent disseminated infection.     

The hamster model of chronic Mycobacterium avium complex infection

Male golden Syrian hamsters were evaluated as a model for the pathogenesis of human infection with Mycobacterium avium complex. Intratracheal inoculation produced a chronic, nonfatal, pulmonary and disseminated infection (overall rate, 86%). The frequency of infection in hamsters that received 5 x 10(8) versus 1 x 10(8) colony forming units (cfu) was not significantly different (87% and 92%, respectively), but 1 x 10(7) cfu produced infection in only 78% of inoculated animals (P = .034). The percentage of animals developing pulmonary infection with M. avium complex did not differ between inoculum groups (77%-80%). Disseminated infection occurred significantly less frequently in the 1 x 10(7) group (46%) compared with the 5 x 10(8) (79%) and 1 x 10(8) (68%) groups (P = .001 and .056, respectively). After seven weeks, partial clearance of M. avium complex from the lungs coincided with an increased number of animals with splenic involvement. The hamster may be a useful model for human infection with M. avium complex.     

Diagnostic pitfall: Mycobacterium avium complex pulmonary infection and positive ANCA

We report the case of a 58-year-old female who presented with productive cough, weight loss, pulmonary nodular infiltrates and cavitations. She had a positive anti-neutrophil cytoplasmic antibodies (ANCA) test. A diagnosis of vasculitis was considered and a video-assisted thoracoscopic biopsy of the lung nodules was organised. However, prior to the biopsy, the sputum results revealed the presence of acid-fast bacilli, which were identified as Mycobacterium avium complex. A repeat ANCA assay was positive for atypical ANCA with negative proteinase-3 and myeloperoxidase titres. The patient was treated with rifampicin, ethambutol and clarithromycin with clinical and radiological improvement. The objective of this report is to highlight a rare association between positive ANCA titres and a non-tuberculous mycobacterial infection as a misdiagnosis and treatment of this patient with immunosuppressive therapy might have led to serious consequences.     

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.     

Mycobacterium avium complex and other nontuberculous mycobacteria in patients with HIV infection

Nontuberculous mycobacteria (NTM) have been frequently identified as opportunistic pathogens in individuals with advanced human immunodeficiency virus (HIV) infection. The majority of these infections have been caused by members of the Mycobacterium avium-intracellulare complex (MAC). Disseminated MAC infection has generally been diagnosed late in the course of HIV infection, and it is often associated with persistent nonspecific symptoms of fever, generalized weakness, and weight loss. Abdominal pain and/or diarrhea with malabsorption may also occur in some patients. Despite frequent isolation of MAC organisms from respiratory secretions in these patients, significant pulmonary involvement has not been seen commonly with disseminated MAC infection. While MAC can be isolated from a variety of clinical specimens in infected individuals, culturing of blood is the single most useful diagnostic procedure to evaluate for MAC infection. The prognosis for disseminated MAC infection in HIV-infected patients has been poor, with a reported median survival of 7.4 months after diagnosis. The overall contribution of MAC infection to mortality in these patients has not been clearly delineated. Treatment of MAC infection in HIV-infected individuals using a variety of drug regimens has not been effective in clearing mycobacteremia or improving overall survival in the majority of patients. However, initiation of drug therapy for MAC may decrease the severity of disease symptoms in some patients. Several NTM other than MAC have also been reported as causing infection in HIV-infected patients. Many of these organisms are ubiquitous in the environment and are frequent colonizers of biologic specimens. Although many NTM are regarded as relatively avirulent, these organisms need to be recognized as potentially important pathogens in HIV-infected patients with significant immunosuppression.     

Disseminated Mycobacterium avium complex infection in a patient with autoantibody to interferon-gamma

A 54-year-old man was admitted to our hospital because of intermittent high fever, general malaise, cough and body weight loss after he had been examined and treated at the former hospital for 3 years without a definitive diagnosis and effective therapy. Bacterial examination on admission revealed Streptococcus pyogenes in peripheral blood, bone marrow aspirates and pleural effusion. Furthermore, Mycobacterium avium complex (MAC) was detected in sputum, gastric juice, bone marrow liquid, pleural effusion by acid-fast bacillus culture or polymerase chain reaction (PCR). Biopsy of the neck lymph node showed multiple granulomas and the presence of acid-fast bacilli. Administration of ABPC/SBT and later CLDM resulted in disappearance of Streptococcus pyrogenes after 2 weeks. We suspected of generalized immunodeficiency that might underlie the severe bacteremia/osteomyelitis and disseminated MAC infection. We tested interferon (IFN)-gamma production of peripheral blood mononuclear cells (PBMC) of the patient after phytohemagglutinin (PHA)-stimulation and found that these cells produced no or undetectable levels of IFN-gamma in the presence of autologous plasma while produced almost normal levels of IFN-gamma in the presence of healthy donor's plasma. Since this neutralizing activity was co-purified in the IgG fraction, the immunodeficient state of the patient seemed to be caused by autoantibody to IFN-gamma. As far as we know, this is the first report of a Japanese case of disseminated MAC infection presumably due to autoantibody to IFN-gamma.     

Mycobacterium avium complex infection in patients with the acquired immunodeficiency syndrome. A clinicopathologic study

Despite the recognition of Mycobacterium avium complex (MAC) infection as a common complication of AIDS, the specific clinical features, significance, and need for treatment have been difficult to assess. We reviewed the clinical records and autopsy material of 68 patients dying with AIDS, 32 (47 percent) of whom had MAC isolated from autopsy tissue. All had postmortem evidence of systemic infection. Eleven (34 percent) had MAC isolated from lung tissue. Little, if any, local tissue inflammation and destruction were associated with MAC infection. Patients with autopsy evidence of MAC infection had a longer time interval from diagnosis of AIDS to death. The infection was detected antemortem in 14 (44 percent), blood culture being the most sensitive means (86 percent yield). Although recurrent fever was noted among both MAC infected and uninfected patients, weight loss greater than 20 lb, weakness, anorexia, abdominal pain, and diarrhea were more frequent among infected patients. Severe anemia, thrombocytopenia, lymphopenia, and reduced mean CD-4 percentages and CD-4/CD-8 ratios were associated with MAC infection. Of eight patients who had MAC cultured antemortem and received multidrug antituberculosis therapy, none responded clinically, and all but one had MAC isolated at autopsy. Because MAC is associated with significant discomfort and disability, development of more effective treatment regimens could be beneficial for some affected AIDS patients.     

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.     

Chemoprophylaxis against Mycobacterium avium complex infection induced in mice]

M. avium complex (MAC) is one of the important causative agents of opportunistic infections among AIDS patients. Recent evidence showed that the entry of infection is through the gastrointestinal tract. In the present study, we compared the prophylactic effect of some antimicrobials against MAC infection induced in mice. Different groups of beige mice were fed with pellets containing 0.0067% (10 mg/kg) of KRM-1648, rifabutin (RFB) and clarithromycin (CAM). Seven days after the administration of drugs, the mice were infected with M. intracellular N-241 (5 x 10(8) CFU) orally, five times, every other day and killed one and 126 days after the last infection. The effect of drug was evaluated using the frequency and severity of gross lung lesions in the mice and by the total CFU recovered from the lungs and spleen. MAC infection was not likely to be established since there was no macroscopic evidence of lesion in organs and the recovery of cultures from lungs and spleen tested was negative, in 3 of 10 mice in the control group, 2 of 9 in the CAM group, 4 of 9 in the RFB group and 4 of 10 in the KRM group. These mice were excluded from the analysis of the study results. Thus, we examined 7 mice in the control group, 7 in the CAM group, 5 in the RFB group, and 6 in the KRM group. Tubercle-like lesions were observed in the lungs of all 7 mice in the control group (severity: 3+ in 5 mice; 4+ in 2 mice), in 5 of 7 mice (71%) in the CAM group (severity: 2+ in 1 mouse; 3+ in 4 mice), and in 4 of 5 mice (80%) in the RFB group (severity: 1+ in 1 mouse; 2+ in 1 mouse; 4+ in 2 mice), while only slight lesions (severity: 1+) were observed in 4 of 6 mice (67%) in the KRM group. There was no macroscopic evidence of lesion in spleen, liver and kidneys. The log CFU was determined at the next day of the completion of the last infection. The log CFU of the lungs was 2.49 and 2.28 in the control group and the CAM group, respectively. The bacteria were not recovered either from the lungs in the RFB and KRM groups, nor from the spleen in all the groups. The order of efficacy of the drugs on the basis of the CFUs recovered from the lungs and spleen in each group determined 126 days after the completion of the last infection was as follows; KRM > CAM > RFB in the lungs and KRM > CAM [symbol: see text] RFB in the spleen, although there was no significant difference among the three drugs (P < 0.05). However, the significantly preferable effect was obtained in the three drug groups as compared with the control group.