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A comparative study of transfusion-acquired human immunodeficiency virus-infected children with and without disseminated Mycobacterium avium complex.

For identification of the features of disseminated Mycobacterium avium complex (DMAC) in human immunodeficiency virus (HIV)-infected children, a retrospective medical record review of 31 long-term survivors with transfusion-acquired HIV was conducted. Nine patients developed DMAC defined as positive isolation of M. avium complex from peripheral blood. DMAC was diagnosed in patients 51 to 132 months of age (mean, 101). The time from HIV-infecting transfusion to DMAC diagnosis ranged from 37 to 132 months (mean, 92) and survival from the time of DMAC diagnosis ranged from 4 to 21 months (mean, 10). Selected laboratory and clinical measures in DMAC-positive and DMAC-negative subjects were compared. DMAC-positive patients had significantly lower CD4+ T cell counts and higher HIV p24 antigen concentrations than DMAC-negative patients at comparable times. Increased percentages of circulating leukocyte band forms and increased aspartate aminotransferase values were seen more often in DMAC-positive patients. Fever and abdominal pain were the only clinical features seen more often in DMAC-positive than in DMAC-negative patients. At the end of the study period overall survival of DMAC-positive patients was less than that of DMAC-negative children, at 33% vs. 73%. DMAC occurs in profoundly immunocompromised children with advanced HIV disease and significantly affects survival. The clinical and laboratory features of DMAC are relatively nonspecific and a high index of suspicion in patients with markedly reduced CD4+ T cells is essential.

AIDS-Related Opportunistic Infections↗

Estimating the frequency of tap-water exposures to Mycobacterium avium complex in the U.S. population with advanced AIDS.

Mycobacterium avium complex (MAC) is a group of ubiquitous and opportunistic bacterial pathogens included on the U.S. Environmental Protection Agency Drinking Water Contaminant Candidate List. The risk of contracting a disseminated MAC infection is primarily limited to the immunocompromised, including those with advanced acquired immunodeficiency syndrome (AIDS). These infections likely result from exposures to MAC-contaminated tap water, food, or soil, although the epidemiologic evidence is insufficient to implicate a specific medium. The objective of this study was to assess tap water exposure to MAC in the U.S. population with advanced AIDS, defined here as having fewer than 100 CD4(+) cells/mm(3) of blood. Using limited data on the detection of MAC and self-reported post-tap treatment practices, two exposure models were developed to simulate the likelihood of exposure to MAC via tap water consumption in this sensitive population. The first model integrated data from studies that described sources of water for consumption and post-tap treatment rates in cohorts infected with human immunodeficiency virus (HIV(+)). The second model used data from a study that categorized the fraction of water intake consisting of tap water that was not further treated. Approximately 1500 individuals with advanced AIDS were estimated to ingest tap water with detectable concentrations of MAC organisms daily. Additional studies on tap-water use in U.S. HIV(+) populations are needed to confirm these findings. Longitudinal and cross-sectional studies on the occurrence of MAC in tap water, particularly in regions with large HIV(+)/AIDS populations, would help address some of the uncertainty in these exposure estimates.

AIDS-Related Opportunistic Infections↗

Mycobacterial infections in AIDS patients, with an emphasis on the Mycobacterium avium complex.

Serious infections caused by the Mycobacterium avium complex (MAC) have been increasingly recognized over the last three decades. However, the epidemic of the acquired immunodeficiency syndrome (AIDS) has increased interest in these infections. Disseminated mycobacterial disease is common in patients with AIDS, and MAC is the predominant bacterial isolate. Indeed, at UCLA Medical Center, MAC organisms are now the predominant isolates in both AIDS- and non-AIDS-associated mycobacterial disease. MAC lung infections have been difficult to treat. Complex regimens employing four to six drugs are not clearly effective and are usually associated with considerable toxicity. Treatment of MAC infections in patients with AIDS has been particularly frustrating, and evidence that treatment can either eradicate disease or prolong life is limited. MAC organisms are invariably resistant to traditional antituberculosis medications. We have examined a variety of other compounds, and our findings, based on both in vitro and animal-model studies, have identified drugs which, when used in combination, are potentially of therapeutic utility.

Acquired Immunodeficiency Syndrome↗

Mycobacterium avium complex develop resistance to synergistically active drug combinations during infection.

Isolates of Mycobacterium avium complex from five patients on longterm (3-5 yrs) anti-mycobacterial drug treatment were collected during the early and late phase of disease, and studied in vitro for their susceptibility to anti-mycobacterial drugs and drug-combinations. All isolates were resistant or moderately resistant to ethambutol, rifampicin and streptomycin when given singly; however, all strains isolated early in the disease were susceptible to the combination of ethambutol with either rifampicin or streptomycin. All late isolates had developed resistance to one or both of these combinations. Three of the patients died within a year after the last isolation of M. avium complex, and the two remaining patients still have severe chronic disease. It is concluded that the susceptibility of M. avium strains to combinations of drugs should be monitored during the course of treatment, in order to guide the selection of effective drug-combinations throughout the infection.

Aged↗

Acid-fast smear and culture of respiratory secretions, bone marrow, and stools as predictors of disseminated Mycobacterium avium complex infection.

Disseminated infection caused by Mycobacterium avium complex (MAC) is common in patients with acquired immune deficiency syndrome and is difficult to treat because of the high degree of resistance to antimycobacterial agents. Early diagnosis and treatment may prolong survival of patients with acquired immune deficiency syndrome and MAC infection. Twenty patients with disseminated MAC infection were evaluated for recovery of the organism from bone marrow, bronchial washings or sputum, and stools before the organism was isolated in blood culture. For 40 to 67% of patients, MAC was recovered from these specimens before it was isolated in blood culture.

Acquired Immunodeficiency Syndrome↗

[Value of the stool bacteriological test in Mycobacterium avium complex infections in AIDS].

Incidence of Mycobacterium avium complex (MAC) infection has increased in HIV infected patients. We report a retrospective study of 25 cases of MAC infection occurring in HIV patients. Stools examination was performed in 5 (31%) of the patients without digestive symptoms and in the 9 (100%) patients presenting with diarrhoea. The stools culture are positive in 79% of cases (11/14). In all the patients with diarrhoea, direct examination of the stools gave the diagnosis of MAC infection. All the patients had profound immunodepression with CD4+ cell count < 5/mm3. The mean survival time from mycobacteriosis diagnosis was 122 +/- 90 days despite antimycobacteriosis therapy.

AIDS-Related Opportunistic Infections↗

Endogenous interleukin-12 is involved in resistance of mice to Mycobacterium avium complex infection.

Acquired cellular resistance against Mycobacterium avium complex (MAC) infections involves the induction of Th1 type gamma interferon (IFN-gamma)-producing T cells. Interleukin-12 (IL-12) is a cytokine involved in the control of IFN-gamma production by T cells and NK cells. The role of IL-12 in the response to MAC infection was investigated. Depletion of endogenous IL-12 by injection of monoclonal antibody prior to and during intranasal infection with MAC resulted in an 150- to 550-fold increase in bacterial load in lung, spleen, and liver homogenates by 10 weeks postinfection. Depletion of IL-12 abrogated the ability of spleen cell cultures to produce IFN-gamma in response to stimulus with live MAC. IL-12-depleted mice showed a 75% decrease in the number of inflammatory cells entering the lungs following intranasal infection with MAC, with significant reductions in cytotoxic activity and nitric oxide production by lung cells. This work suggests that IL-12 plays a major role in the activation of IFN-gamma-producing cells during MAC infection.

Animals↗

[Effects of various steroidal and non-steroidal anti-inflammatory drugs on in-vitro IL-10 production of murine peritoneal macrophages infected with Mycobacterium avium complex].

In murine infections due to Mycobacterium avium complex (MAC), bacterial regrowth of the pathogens is frequently encountered in the relatively late phase of infection even in mice receiving daily treatments with antimicrobial agents including rifamycins and macrolides. In this case, the bacterial regrowth is usually accompanied by concomitant increase in the tissue levels of IL-10 and transforming growth factor-beta (TGF-beta), well known immunosuppressive cytokines. In this context, it is of interest to note recent findings that steroidal anti-inflammatory drugs up-regulate TGF-beta production from T lymphocytes, thereby suggesting participation of immunosuppressive cytokines in the expression of their anti-inflammatory activity. In this study, we examined the effects of various anti-inflammatory drugs including glucocorticoids and non-steroidal anti-inflammatory drugs (NSAID) on in-vitro IL-10 production of murine peritoneal macrophages (M phi s) infected with MAC organisms. When the IL-10 production by MAC-infected M phi s was measured in terms of protein and mRNA expression of the cytokine using ELISA and RT-PCR assays, the following results were obtained. First, the IL-10 production into M phi culture fluids was temporarily increased around days 1 to 3, thereafter gradually declined, and returned to normal by day 14. Secondly, IL-10 mRNA expression of M phi s was rapidly induced after MAC-infection and the maximum level of the mRNA expression was achieved at 2 hr. Thereafter, IL-10 mRNA expression ceased rapidly and returned to normal by 24 hr. Thirdly, the majority of test anti-inflammatory drugs, not only glucocorticoids but also NSAID, were found to up-regulate the IL-10 production of MAC-infected M phi s, suggesting some possible roles of IL-10 in the expression of the anti-inflammatory activities of these agents.

Animals↗

Investigation of spa pools associated with lung disorders caused by Mycobacterium avium complex in immunocompetent adults.

Three cases of Mycobacterium avium complex-related lung disorders were associated with two poorly maintained spa pools by genotypic investigations. Inadequate disinfection of the two spas had reduced the load of environmental bacteria to less than 1 CFU/ml but allowed levels of M. avium complex of 4.3 x 10(4) and 4.5 x 10(3) CFU/ml. Persistence of the disease-associated genotype was demonstrated in one spa pool for over 5 months until repeated treatments with greater than 10 mg of chlorine per liter for 1-h intervals eliminated M. avium complex from the spa pool. A fourth case of Mycobacterium avium complex-related lung disease was associated epidemiologically but not genotypically with another spa pool that had had no maintenance undertaken. This spa pool contained low numbers of mycobacteria by smear and was culture positive for M. avium complex, and the nonmycobacterial organism count was 5.2 x 10(6) CFU/ml. Public awareness about the proper maintenance of private (residential) spa pools must be promoted by health departments in partnership with spa pool retailers.

Adult↗

Plasmid profiles of Mycobacterium avium complex isolated from swine.

Twenty strains of Mycobacterium avium complex (MAC) isolated from swine and five strains from humans were examined for drug susceptibility and plasmid content. Four strains of swine origin and two strains of human origin harbored plasmid DNAs differing in molecular weights. No relationship between plasmid contents and drug resistance was observed. Southern DNA-DNA hybridization showed that small plasmids from swine MAC strains were homologous to those from human origin at the nucleotide level.

Animals↗

Oxidative and non-oxidative intracellular killing of Mycobacterium avium complex.

Among mycobacteria, those belonging to the Mycobacterium avium complex (MAC) are the most common cause of bacteremia in AIDS patients. To understand better the mechanisms by which human macrophages kill intracellular MAC, we studied in an in vitro test system transparent morphotypes of the three most common bacteremic serotypes from AIDS patients and an opaque variant, obtained in vitro from the most mouse-virulent strain (MAC 101). The three serotypes differed in susceptibility to oxidative bactericidal mechanisms of macrophages. The transparent morphotype of strain 101 (serotype 1) was completely resistant to the intracellular killing effects of a phagocyte's reactive oxygen radicals and hydrogen peroxide, whereas strains 109 (serotype 4), 100 (serotype 8), and the opaque variant from strain 101 were killed by oxidative bactericidal mechanisms. However, even for these bacteria, non-oxidative mechanisms appear to have a role in intracellular killing.

Acquired Immunodeficiency Syndrome↗

Multilocus enzyme electrophoresis analysis of the Mycobacterium avium complex and other mycobacteria.

Multilocus enzyme electrophoresis analysis was used to evaluate the Mycobacterium avium complex (MAC), M. paratuberculosis, and nine other mycobacterial species. The average number of alleles per locus was 2.8 for the 35 MAC and 2 M. paratuberculosis strains which represented 24 electrophoretic types (ETs) and two distinct groups. The M. avium group was resolved into 17 ETs and contained the M. paratuberculosis ET. The M. intracellulare group consisted of six ETs. There was complete agreement between Gen-Probe identification and group placement by multilocus enzyme electrophoresis. The mean genetic diversity per locus for the 24 MAC ETs was 0.38. This procedure subdivided some serovars and, if implemented, should prove to be a powerful epidemiologic tool for the MAC. Eleven additional ETs were formed after the data for the other mycobacterial species were pooled with those for the MAC.

Alleles↗

Genetic diversity in clinical isolates of Mycobacterium avium complex from Guinea-Bissau, West Africa.

Isolates of Mycobacterium avium complex (MAC) were cultured from sputum samples obtained from patients in Guinea-Bissau, West Africa. Twenty-eight isolates hybridising with MAC probe (AccuProbe) were further characterised by different molecular techniques: hybridisation with species-specific probes (AccuProbe) for M. avium and M. intracellulare, partial sequencing of 16S rRNA gene and PCR detection of the DT1-DT6 sequences and the macrophage-induced gene (mig). Only one of the 28 isolates reacted with the M. avium probe and four with the M. intracellulare probe. Two isolates expressed the DT1 sequence, and three the DT6. The mig was detected in 18 (64%) of the isolates. Sequencing of 16S rRNA had the greatest discriminative power of the typing methods applied, without strong correlation with any other technique. Clinical MAC isolates from Guinea-Bissau demonstrated a wide genetic diversity among the members of M. avium complex that might reflect on biotope variation.

DNA, Bacterial↗

Isolation of Mycobacterium avium complex from bone marrow aspirates of AIDS patients in Brazil.

Mycobacterium avium complex (MAC) infection has not been reported as a major opportunistic infection among patients with AIDS in Latin America or Africa. In this study, 125 AIDS patients who had persistent fever, anemia, and leukopenia were examined among 2628 AIDS patients admitted to Instituto de Infectologia Emilio Ribas between May 1990 and April 1992. From the bone marrow aspirates of the 125 patients, MAC was isolated from 23 (18.4%) and Mycobacterium tuberculosis was isolated from 9 (7.2%). Between 1985 and 1990, only 11 MAC isolations among 60,000 cultures obtained from human immunodeficiency virus-seronegative patients were documented in São Paulo. Hence, the minimal estimated rate of MAC infection in AIDS patients in this city was 23/2628, or 0.88%. These findings suggest that MAC infection is an important opportunistic infection, especially among a subset of patients with AIDS in Brazil who have clinical characteristics and risk activities similar to those associated with MAC infections in North America and Europe.

AIDS-Related Opportunistic Infections↗

Interpretive criteria for use of AccuProbe for identification of Mycobacterium avium complex directly from 7H9 broth cultures.

Rapid identification of Mycobacterium avium complex (MAC) is possible by use of AccuProbe (Gen-Probe, San Diego, Calif.). To evaluate the reliability of the MAC AccuProbe for testing 7H9 cultures inoculated with broth from MGIT cultures positive for acid-fast bacilli or growth on a solid medium, we compared probe results to results obtained by sequencing a portion of the 16S rRNA gene. Isolates were sequenced if the MAC probe result was <100,000 relative light units (RLU) or if it was > or =100,000 RLU and the colony morphology was not classic or there were two colony types. For the 1,389 cultures tested in phase 1, conducted to evaluate cutoff values for the MAC probe in testing of 7H9 cultures inoculated with broth from MGIT cultures, the sensitivity and specificity of the MAC AccuProbe were 97.7% and 88.8%, respectively, according to the manufacturer's interpretive criteria (> or =30,000 RLU is positive). If the cutoff for a positive result were 80,000 RLU, the specificity would be 100% and the sensitivity 92.3%. Of the 344 isolates in phase 2, which was conducted to confirm the 80,000-RLU cutoff for a positive result and therefore included only isolates with a MAC probe result of < or =100,000 RLU, 13 of 16 with results of > or =30,000 but <80,000 RLU were identified as mycobacteria other than MAC, including five Mycobacterium tuberculosis complex isolates. These data support the use of 80,000 RLU as the cutoff for a positive result in testing of 7H9 broth cultures with the MAC AccuProbe.

Bacterial Typing Techniques↗

A case of "hot tub lung" due to Mycobacterium avium complex in an immunocompetent host.

Pulmonary disease due to Mycobacterium avium complex (MAC) typically occurs in patients with impaired cellular immunity or chronic lung disease. Recently, there has been an increase in the number of reports of pulmonary disease caused by MAC occurring in otherwise healthy individuals, including those reporting recent hot tub use. It is not clear if this respiratory illness represents a true infectious process or a hypersensitivity pneumonitis. We report a case of diffuse pulmonary disease caused by MAC in an immunocompetent individual after hot tub use. The patient's clinical course, transbronchial lung biopsy results, and microbiologic examination findings all pointed to a hypersensitivity reaction due to MAC. With avoidance of the hot tub, and no pharmacological treatment, the patient had complete resolution within 2 months. In light of the number of new cases of "hot tub lung" in otherwise healthy individuals, clinicians should advise their patients of the potential risk associated with hot tub use.

Diagnosis, Differential↗

Comparative antigenic analysis of Mycobacterium avium complex (MAC) isolates from AIDS patients.

Sonicates of several Mycobacterium avium complex (MAC) strains isolated from acquired immunodeficiency syndrome (AIDS) patients were characterized in order to study the prominent antigens of these strains. Sonicates of 6-week-old cultures were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. A major 12 kDa glycoprotein antigen was observed in all the sonicates along with other proteins ranging up to 100 kDa. Western blotting, using the 12 kDa M. leprae 'specific' murine monoclonal antibody (MAb) MLO6, indicated the presence of a determinant in the 12 kDa antigen (in all the MAC isolates studied) which was immunologically cross-reactive with the 12 kDa antigen of M. leprae. The transparent variant of MAC 101 also demonstrated MLO6 reactivity while the opaque variant did not. Polyclonal antiserum raised against MAC 101 sonicate reacted with all the MAC isolates in immunodiffusion. These observations point to the cross-reactivity between these strains and suggest that they possess a M. leprae 'specific' determinant on a cross-reacting component which could be involved in virulence.

AIDS-Related Opportunistic Infections↗