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Objectives: Patients with rheumatoid arthritis (RA) are at an increased risk of Mycobacterium avium complex pulmonary disease (MAC-PD). We aimed to identify factors associated with MAC-PD in RA patients, and investigate their clinical significance for diagnosis of this disease., Methods: We examined 396 patients with RA for the presence of MAC-PD, using the criteria of the American Thoracic Society and conducted three years of follow-up on these patients. Multivariate logistic analyses were employed for selecting factors associated with MAC-PD. We developed a point system based on these factors which we call MAC-PD score to improve diagnosis of MAC-PD., Results: During this study, 14 out of 396 patients were newly diagnosed with MAC-PD. Multivariate analyses revealed body mass index (BMI) <18.0 kg/m 2 and lymphocyte count <1500/μl were associated with MAC-PD in RA patients. Points were assigned to them and totalled to provide the MAC-PD score. Among 20 patients with high-resolution computer tomography images consistent with MAC-PD, the scores were significantly higher in 14 patients with MAC-PD than those in six patients without MAC-PD., Conclusion: Using these data, in the forms of the MAC-PD score, could help to identify patients who should be considered for bronchoscopy more selectively.

The role that colonization with Mycobacterium avium plays in the development of disseminated disease is unclear. In this study, we determined whether all M. avium strains isolated from the portals of M. avium infection are capable of crossing the mucosal border and causing infection. The patients in this study were enrolled in AIDS Clinical Trial Group protocol 341. The patients were divided into 3 groups; 2 groups differed in their immunological and clinical risk for M. avium disease. A third group (n=22 patients) had culture-documented disseminated M. avium complex disease at the time of entry in the study. Eight of 22 patients had M. avium isolated from both a colonized site and blood or bone marrow specimens. All 8 patients had distinct M. avium strains; 2 patients had a polyclonal infection. The virulence properties of 13 strains were determined, including invasion of gastrointestinal cells and replication in macrophages. There were significant differences in the virulence properties, and these differences may provide insight into the interplay between microbial pathogenesis and host defense.

Mycobacterium avium complex (MAC) infection is the most common disseminated bacterial infection in untreated patients with acquired immunodeficiency syndrome (AIDS). We investigated the potential role of monocyte chemotactic protein-1 (MCP-1) in the pathogenesis of disseminated MAC, using the simian immunodeficiency virus (SIV)/macaque model of AIDS. Macaques were inoculated with SIV, followed by challenge with a pathogenic AIDS isolate of M. avium 14 days later. After challenge with M. avium, marked increases in serum MCP-1 levels were detected in SIV-infected macaques, a finding that was duplicated in coinoculated bronchoalveolar macrophages. MCP-1 levels were significantly higher in SIV-infected macaques than in non-SIV-infected controls (327.1 vs. 151.5 pg/mL, respectively; P=.04), suggesting that up-regulation of MCP-1 contributes to the development of progressive mycobacterial disease. Similarly, morphometric analysis revealed increased expression of MCP-1 in hepatic microgranulomas from SIV-infected macaques. We conclude that the pronounced increases in MCP-1 levels demonstrated in tissue and serum samples after M. avium inoculation may play a role in the development of disseminated mycobacterial disease.

Whether infection with Mycobacterium avium complex (MAC) among patients with acquired immune deficiency syndrome results from recent exposure to virulent strains or reactivation of latent infection acquired years earlier is unknown. To address this question, tissue samples from 47 simian immunodeficiency virus (SIV)-infected and 63 SIV-uninfected rhesus macaques were cultured. MAC was cultured from 14 SIV-uninfected macaques (22.2%) and 32 SIV-infected macaques (68.1%); median bacterial burdens were 33.3 and 998.7 cfu/g, respectively. Genetically distinct strains of MAC were identified for 13 SIV-uninfected macaques (20.6%) and 15 SIV-infected macaques (31.9%). A genetically identical MAC strain (K128A) was identified for 25 SIV-infected macaques (53.2%) and 1 SIV-uninfected macaque (1.6%). Multivariate analysis identified infection with SIV/Delta(B670), diagnosis of an SIV-related tumor or opportunistic infection, and birth on site as risks for MAC infection. SIV-uninfected and SIV-infected macaques yielding unique strains of MAC were considered to have latent and reactivation infection, respectively, whereas animals infected with strain K128A were considered to have recent infection, demonstrating that both mechanisms occur among rhesus macaques.

Previously, we have found that immunosuppressive macrophages (M(phi)s) induced by Mycobacterium intracellulare-infection (MI-M(phi)s) required cell contact with target T cells to express their suppressor activity against concanavalin A (Con A)-induced T cell mitogenesis. In this study, we examined the profiles of cell-to-cell interaction of MI-M(phi)s with target T cells. First, MI-M(phi)s displayed suppressor activity in an H-2 allele-unrestricted manner, indicating that MHC molecules are not required for cell contact. The suppressor activity of MI-M(phi)s was reduced markedly by paraformaldehyde fixation or treatment with cytochalasin B or colchicine, indicating that vital membrane functions are required for their suppressor activity. Secondly, the suppressor activity of MI-M(phi)s was independent of cell-to-cell interaction via CD40 ligand/CD40 and M(phi)-derived indoleamine 2,3-dioxygenase, which causes rapid degradation of tryptophan in T cells. Thirdly, precultivation of splenocytes with MI-M(phi)s, allowing cell-to-cell contact, reduced Con A- or anti-CD3 antibody-induced mitogenesis but not phorbol myristate acetate/calcium ionophore A23187-elicited proliferation of T cells. In addition, co-cultivation of T cells with MI-M(phi)s caused marked changes in profiles of the tyrosine phosphorylation of 33 kDa, 34 kDa and 35-kDa proteins and, moreover, the activation of protein kinase C and its translocation to the cell membrane. It thus appears that suppressor signals of MI-M(phi)s, which are transmitted to the target T cells via cell contact, principally cross-talk with the early signalling events before the activation of PKC and/or intracellular calcium mobilization.

Isolates of Mycobacterium avium-intracellulare (MAI) form multiple colony types named red-opaque, white-opaque, red-transparent (RT), and white-transparent (WT). The newly discovered WT morphotype is multidrug resistant relative to other variants in vitro. To determine whether the WT morphotype occurs in humans, 32 MAI-positive clinical samples from 2 sites were plated directly onto indicator agar without prior passage in vitro. WT was the predominant morphotype in 26 (81%) of these samples and was absent in only 2 samples. WT variants grew better than isogenic RT variants in mouse and human macrophage models of infection, and RT clones that passed through such systems underwent rapid shifts to the WT morphotype. The RT morphotype was heterogeneous with regard to infectivity. In summary, the white morphotype was common in humans and was favored in disease models. It may play an important role in the establishment and persistence of MAI infection.

Systemic human disease caused by organisms of the Mycobacterium avium-Mycobacterium intracellulare complex (MAC) represent a chronic intracellular infection in human hosts who are usually immunocompromised. To develop improved treatment and prophylaxis, and to obtain a better understanding of pathogenesis, we studied the beige mouse (C57 beige(+)/beige(+)) challenged orally or intravenously with a human isolate that causes lethal disease in patients with AIDS (MAC 101, serovar 1). Encouraging anti-MAC studies in animals, as reviewed here, should provide the basis for considering human trials with a promising agent. The ability of an antimicrobial agent to achieve high intracellular concentrations has correlated with the in vivo activity of several specific compounds.

The clinicopathologic spectrum of infections due to nontuberculous mycobacteria (NTM) includes cavitary disease, opportunistic infection, and nodular disease associated with bronchiectasis. We report a less well-described manifestation of NTM infection: 10 immunocompetent patients without preexisting bronchiectasis had radiographic evidence of diffuse infiltrative lung disease. The most common symptoms were dyspnea, cough, hypoxia, and fever. All 10 patients had used a hot tub. Histologic examination revealed exuberant nonnecrotizing, frequently bronchiolocentric, granulomatous inflammation in all cases. In 1 case, necrotizing granulomas were also noted. The inflammation often was associated with patchy chronic interstitial pneumonia and organization. Cultures revealed NTM in all cases (Mycobacterium avium complex in all but 1 case), but staining for acid-fast bacilli was positive in only 1 case. Four patients received corticosteroids alone for presumed hypersensitivity pneumonia, 4 were treated with antimycobacterial therapy, and 2 received both. All patients demonstrated significant improvement at the time of follow-up. These findings suggest that disease due to NTM may manifest as diffuse infiltrates in immunocompetent adults and that hot tub use may be an important risk factor for this disease pattern.

Eight-day-old embryonated hen's eggs were used as a model to study Mycobacterium avium virulence. Strains isolated from human patients caused 20-90% mortality when eggs were infected by injection of bacterial suspensions into the amniotic sac. Virulence of examined strains subsequently decreased with passage through eggs to between 0 and 40% mortality in four passages. Virulence of the egg-attenuated strains could be restored by passage through human peripheral blood mononuclear cells. The site of infection in the egg was usually the mesodermal layer of the chorioallantoic membrane. A few small granulomas containing acid-fast bacteria were seen in the liver, but not in other organs. Death of chicken embryos may have resulted from destruction of the mesodermal layer of the chorioallantoic membrane with consequent respiratory failure. PBMCs infected with less virulent egg-passaged strains of M. avium produced higher levels of tumor necrosis factor-alpha than did peripheral blood mononuclear cells infected with more virulent nonpassaged strains.

Sequence analysis of the ribosomal internal transcribed spacer of 56 Mycobacterium avium complex isolates from pediatric patients with AIDS or lymphadenitis revealed (similar to the situation in adults) that the closely related Mav-B and Mav-A sequevars caused the vast majority of disease. IS1245 restriction fragment-polymorphism analysis and pulsed-field gel electrophoresis revealed sets of isolates with closely related patterns among strains from patients in the Boston area and among isolates from Los Angeles and Miami patients. The finding of related strains that cause disease in epidemiologically unrelated patients is most consistent with one of two hypotheses: (1) a limited subset of M. avium strains is more virulent and therefore more likely to cause disease in humans, or (2) pathogenic strains are more prevalent in the environment.

The virulence of different isolates of MAC was studied in naturally susceptible BALB/c mice. In preliminary experiments, MAC bacteria forming smooth transparent colonies on solid media (SmT variants) were found to be virulent for BALB/c mice, causing progressive infection; smooth opaque (SmOp) were generally avirulent, being slowly eliminated from the infected organs; and rough (Rg) variants were either avirulent or as virulent as SmT variants. We chose to compare the virulence of different isolates of MAC of different origins, studying only the SmT morphotype. Strains of MAC isolated from naturally infected animals were those that most consistently caused progressive infections. AIDS patients-derived isolates were of intermediate virulence or devoid of virulence in mice. The environmental strains were eliminated from mice or did not proliferate. Strains of MAC isolated from individuals who were not infected by HIV varied in virulence from completely avirulent to highly virulent. There was no close correlation between virulence and restriction fragment length polymorphism (RFLP) type, although all highly virulent strains were of the A/I type. There was also no correlation between virulence analysed in vivo and the ability to grow in cultured macrophages.

Mycobacterium avium complex (MAC) is frequently isolated from the respiratory or gastrointestinal tract of patients with advanced human immunodeficiency virus (HIV) infection. Whether they are at increased risk of MAC bacteremia and whether culture of respiratory tract or stool specimens is useful for predicting bacteremia are unclear. HIV-infected patients with < or = 50 CD4+ cells/microL were prospectively studied. The risk of MAC bacteremia was approximately 60% within 1 year for patients with MAC in either the respiratory or gastrointestinal tract and was greater than for those without MAC in these sites (relative hazards for respiratory and gastrointestinal tract, 2.3 and 6.0; 95% confidence intervals, 1.1-4.6 and 2.5-14.6, respectively). Both respiratory tract specimen and stool culture had poor sensitivities (22% and 20%, respectively) but good positive predictive values (approximately 60%) for bacteremia. Symptomatic HIV-infected patients with MAC in the respiratory or gastrointestinal tract are at a substantial risk for developing MAC bacteremia; culture of these sites has limited usefulness as a screening test.

Mycobacterium avium complex (MAC) organisms are the most common bacterial cause of disseminated infection in patients with AIDS. MAC, facultative intracellular bacteria, invade and multiply within macrophages. Treatment of MAC-infected macrophages with ethanol (10-100 micrograms/dL) is associated with increased intracellular multiplication of MAC. To investigate whether this enhanced growth is due to a stress-related response induced by nonlethal concentrations of ethanol, strain 101 (serovar 1) was exposed to ethanol, and the regulation of the expression of proteins was examined. Exposure of MAC to ethanol (range, 10-100 micrograms/dL) was associated with up-regulation of the expression of a number of bacterial proteins, some of which (65 and 33 kDa) interfered with macrophage functions, such as production of superoxide anion and killing of Staphylococcus aureus. Thus, exposure of MAC to small concentrations of ethanol may induce a stress-related response with consequent increase in the synthesis of proteins possibly associated with its ability to survive within macrophages.

Members of the Mycobacterium avium-intracellulare complex (MAC) can exist in a transparent or opaque colonial morphology when cultured on synthetic medium. An opaque variant was developed from a transparent strain of a clinical MAC isolate. Comparison of the two variants showed a greater ability of the transparent colonial variant to infect normal human monocytes as measured by growth in monocyte-bacteria cocultures. Further analyses indicated diminished ability of the transparent variant to induce extracellular secretion of interleukin (IL)-1 and IL-6, as well as membrane-associated IL-1 when compared with the opaque isotype. At the molecular level, induction of specific IL-1 alpha, IL-1 beta, and IL-6 mRNAs was consistent with the protein results. These results suggest that the virulent transparent MAC, as opposed to the avirulent opaque type, may escape host defenses by failing to induce IL-1 and IL-6, key factors in the initiation of a normal immune response.

Mycobacterium avium is a cause of disseminated infection in AIDS patients. The pathogenicity of M. avium for human monocytes was examined in an in vitro model. Peripheral blood monocytes obtained from 13 healthy donors were precultured for 2 days before infection. Monocytes were infected with six AIDS-associated and three non-AIDS-associated strains and four strains of M. avium selected on the basis of colonial morphology. Uptake of M. avium detected by counting intracellular acid-fast bacilli differed according to colonial morphology: Bacteria with round and opaque colony forms were phagocytosed more readily than those with flat colonies. Virulence as defined by intracellular growth was also partly associated with colonial morphology. Some but not all bacilli with flat colony forms multiplied in human monocytes; strains of the round opaque colonial form did not. The effects of recombinant human interferon-gamma on M. avium infection also were examined. Pretreatment of monocytes suppressed phagocytosis. After infection, coculturing usually augmented mycobacterial growth inhibition by human monocytes, but these effects were variable from strain to strain. Overall, interferon-gamma produced a small but statistically significant inhibition of intracellular growth in three of four strains tested.

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.