EPIDEMIOLOGIC TRENDS OF LUNG DISEASE DUE TO MYCOBACTERIA KANSASII AND AVIUM-INTRACELLULARE IN TEXAS, 1977-1983

This study compared the reported isolations of Mycobacterium kansasii (MK) and Myobacterium avium-intracellulare (MAI) with Mycobacterium tuberculosis (MTB) between 1977-1983 in Texas. A total of 15,395 mycobacterial cases were identified of which 1,352 (8.8%) were MK or MAI. The incidence of MK was higher in urban areas than nonurban areas (p < .005). The incidence of MAI has increased in the Dallas metroplex from 34 cases to 251 for the same time period. Although the number of MK cases previously reported has always exceeded those of MAI, the numbers were equal in the last year (1983) of the study.^ More than 75% of patients with MK or MAI were Caucasians compared to only 18% of patients with MTB. Male to female ratios for MK and MAI are 3:1 and 3:2, respectively. The age distribution of MK patients were an average of 5 years younger than patients with MAI, a finding which concurs with previous studies. MK and MAI pulmonary infections continue to be absent among children and relatively absent among Hispanics.^ MK appears to be associated with occupations in construction, whereas MAI is more often associated with farm work. ^

Role of FbpA and FbpB in the pathogenesis and mycolyltransferase activity of Mycobacterium tuberculosis

Mycobacterium tuberculosis infects more people worldwide each year than any other single organism. The Antigen 85 Complex, a family of fibronectin-binding proteins (Fbps) found in several species of mycobacteria and possibly involved in host interaction, is considered among the putative virulence factors of M. tuberculosis. These proteins are implicated in the production of trehalose dimycolate (TDM) and arabinogalactan-mycolate (AG-M), two prominent components of the mycobacterium cell wall and potent modulators of the immune system during infection. For these reasons, the principal members of the complex, FbpA and FbpB, were the focus of these studies. The genes encoding these proteins, fbpA and fbpB, were each disrupted by insertion of a kanamycin resistance cassette in a pathogenic strain of M. tuberculosis, H37Rv. Neither mutation affected growth in routine broth culture. Thin layer chromatography analysis of TDM and AG-M showed no difference in content between the parent strain H37Rv and the FbpA- and FbpB-deficient mutants grown under two different culture conditions. However, metabolic radiolabeling of the strains showed that the production of TDM (but not its precursor TMM) was delayed in the FbpA- and FbpB-deficient mutants compared to the parent H37Rv. During this same labeling period, FbpA-deficient mutant LAa1 failed to produce AG-M and in the FpbB-deficient mutant LAb1 production was decreased. In macrophage tissue culture assay, LAa1 failed to multiply when bacteria in early log phase were used to infect monolayers while LAb1 grew like the parent strain. The growth deficiency of LAa1 as well as the deficiencies in TDM and AG-M production were restored by complementing LAa1 with a functional fbpA gene. These results suggest that the FbpA and FbpB proteins are involved in synthesis of TDM (but not its precursor TMM) as well as AG-M. Other members of the complex appear to compensate for defects in synthesis caused by mutation of single genes in the complex over time. Mutation of the FbpA gene causes greater in vivo effect than mutation of the FbpB gene despite very similar deficiencies in the rate of production of mycolate containing molecules on the cell surface. ^

Evaluation of Mycobacterium avium complex lung disease in women

Mycobacterium avium complex (MAC) is a ubiquitous organism responsible for most pulmonary and disseminated disease caused by non-tuberculosis (NTM) mycobacteria. Though MAC lung disease without predisposing factors is uncommon, in recent years it has been increasingly described in middle-aged and elderly women. Recognition and correct diagnosis, is often delayed due to the indolent nature of the disease. It is unclear if these women have significant clinical disease as or if their airways are simply colonized by the bacterium. This study describes the clinical presentation, identifies risk factors, and describes the clinical significance of MAC lung disease in HIV-negative women aged 50 or greater. ^ A hybrid study design utilizing both cross-sectional and case-control methodologies was used. A comparison population was selected from previously identified tuberculosis suspects found throughout Harris County. The study population had at least one acid fast bacillus pulmonary culture performed between 1/1/1998 and 12/31/2000 from a pulmonary source. Clinical presentation and symptoms were analyzed using a cross-sectional design. Past medical history and other risk factors were evaluated using a traditional case-control study design. Differences in categorical variables were estimated with the Chi Square or Fisher's Exact test as appropriate. Odds ratios and 95% confidence intervals were utilized to evaluate associations. Multivariate logistic regression was used to identify predictive factors for MAC. All statistical tests were two-sided and P-values <0.05 were considered statistically significant. ^ Culture confirmed MAC pulmonary cases were more likely to be white, have bronchiectasis, scoliosis, evidence of cavitation and pleural changes on chest radiography and granulomas on histopathologic examination than women whose pulmonary cultures were AFB negative. After controlling for selected risk factors, white race continued to be significantly associated with MAC lung disease (OR = 4.6, 95% CI = 2.3, 9.2). In addition, asthma history, smoking history and alcohol use were less likely to be evident among MAC cases in a multivariate analysis. Right upper and right middle lobe disease was further noted among clinically significant cases. Based on population data, MAC lung disease appears to represent a significant clinical syndrome in HIV-negative women thus supporting the theory of the Lady Windermere Syndrome. ^

Regulation of T cell function by complement C5A in mice during mycobacterial infection

Tuberculosis is the leading cause of death in the world due to a single infectious agent, making it critical to investigate all aspects of the immune response mounted against the causative agent, Mycobacterium tuberculosis , in order to better treat and prevent disease. Previous observations show a disparity in the ability to control mycobacterial growth between mouse strains sufficient in C5, such as C57BL/6 and B10.D2/nSnJ, and those naturally deficient in C5, such as A/J and B10.D2/nSnJ, with C5 deficient mice being more susceptible. It has been shown that during M. tuberculosis infection, C5 deficient macrophages have a defect in production of interleukin (IL)-12, a cytokine involved in the cyclical activation between infected macrophages and effector T cells. T cells stimulated by IL-12 produce interferon (IFN)-γ, the signature cytokine of T helper type 1 (Th1) cells. It is known that a cell-mediated Th1 response is crucial for control of M. tuberculosis in the lungs of humans and mice. This study demonstrates that murine T cells express detectable levels of CD88, a receptor for C5a (C5aR), following antigen presentation by macrophages infected with mycobacteria. T cells from C5 deficient mice infected with M. tuberculosis were found to secrete less IFN-γ and had a reduced Th1 phenotype associated with fewer cells expressing the transcription factor, T-box expressed in T cells (T-bet). The altered Th1 phenotype in M. tuberculosis infected C5 deficient mice coincided with a rise in IL-4 and IL-10 secretion from Th2 cells and inducible regulatory T cells, respectively. It was found that the ineffective T cell response to mycobacteria in C5 deficient mice was due indirectly to a lack of C5a via poor priming by infected macrophages and possibly by a direct interaction between T cells and C5a peptide. Therefore, these studies show a link between the cells of the innate and adaptive arms of the immune system, macrophages and T cells respectively, that was mediated by C5a using a mouse model of M. tuberculosis infection. ^

Role of T cell response during vaccine immunity to tuberculosis

Tuberculosis remains one of the leading causes of death in man due to a single infectious agent. An estimated one-third of the world's population is infected with the causative agent, Mycobacterium tuberculosis (Mtb), despite the availability of the widely used vaccine, BCG. BCG has significantly varying protection rates with the lowest level of protection seen with the most common form of TB, adult pulmonary TB. Thus, numerous studies are being conducted to develop a more efficient vaccine. The ideal candidate vaccine would possess the ability to induce a solid and strong Th1 response, as this is the subset of T cells primarily involved in clearance of the infection. A novel vaccine should also induce such a response that may be recalled and expanded upon subsequent infection. Our group has introduced a mutant of a virulent strain of Mtb which lacks a component of the immunogenic antigen 85 complex (Ag85). Our vaccine, ΔfbpA, does not secrete the fibronectin binding protein Ag85A, and this has shown to lead to its attenuation in both murine macrophages and mice. Previous studies have also proven that ΔfbpA is more protective in mice than BCG against virulent aerosol challenge with Mtb. This study addresses the mechanisms of protection observed with ΔfbpA by phenotyping responding T cells. We first evaluated the ability of dendritic cells to present the mycobacteria to naïve T cells, an in vitro mock of primary immunization. We also measured the response of primed T cells to macrophage-presented mycobacteria to interpret the possible response of a vaccinated host to a boost. We concluded that ΔfbpA can elicit a stronger Th1 response compared to BCG in vitro, and further observed that this enhanced response is at least partly due to the presence of proteins encoded by a region of the genome absent in all strains of BCG. Finally, we observed this heightened Th1 response in the mouse model after primary vaccination and a virulent aerosol challenge. The cytolytic T cell response was also measured after virulent challenge and was found to be superior in the ΔfbpA-treated group when compared to the BCG group. ^

Epidemiology of tuberculosis and nontuberculous mycobacterial infections in Houston children

Background. Nontuberculous mycobacteria (NTM) are environmentally ubiquitous organisms whose epidemiology is poorly understood. Species differ with respect to disease presentation, prognosis, and antimicrobial susceptibility. We reviewed one Texas pediatric hospital's experience with NTM and tuberculosis (TB) disease.^ Methods. This was a retrospective case series of children with culture-confirmed mycobacterial infections seen at a children's hospital from 2003-2008.^ Results. One hundred sixty-two isolates were identified from 150 children; 132 (81.5%) had NTM species isolated, and 30 (18.5%) had M. tuberculosis isolated; 2 children had both NTM and M. tuberculosis isolated. The most common species were Mycobacterium avium complex (MAC) (29%), M. tuberculosis (18.5%), M. abscessus (13%), M. fortuitum (11.7%), and M. chelonae-abscessus (9.9%). TB was the most common organism isolated from respiratory specimens. MAC and M. simiae were significantly more likely to be associated with lymphadenopathy than other NTM species (p < 0.001). Mycobacterium fortuitum was significantly more likely to be associated with soft tissue infections than other NTM species (p < 0.001). Seventy-five children met criteria for NTM disease (30 lymphadenopathy, 17 pulmonary, 17 soft tissue infections, 11 bacteremia). Children with NTM lymphadenopathy were more likely to be Hispanic (OR 24, CI 2.8-1063), younger (3.3 years vs. 10.6 years, p < 0.001), and previously healthy (OR 0.004, CI 0-0.06) than children with NTM pulmonary disease. Children with NTM disease were less likely to be previously healthy (OR 0.30, 95% CI 0.09-0.88) and foreign-born (OR 0.09, CI 0.03-0.29) than children with TB.^ Conclusions. Children with NTM lymphadenopathy were younger and more likely to be healthy than children with NTM pulmonary disease. Tuberculosis comprised a large proportion of mycobacterial disease in this series. Children with NTM pulmonary disease were less likely to be previously healthy and born abroad when compared to children with TB. There was wide variation in antimicrobial susceptibility patterns among NTM species. This, together with the large percentage of disease caused by TB, emphasizes the importance of securing a specific microbiologic diagnosis in children with pulmonary or lymph node disease caused by mycobacteria.^

Non-staphylococcal infections of cardiac implantable electronic devices

Background. The number of infections of cardiac implantable electronic devices (CIED) continues to escalate out of proportion to the increase rate of device implantation. Staphylococcal organisms account for 70% to 90% of all CIED infections. However, little is known about non-staphylococcal infections, which have been described only in case reports, small case series or combined in larger studies with staphylococcal CIED infections, thereby diluting their individual impact. ^ Methods. A retrospective review of hospital records of patients admitted with a CIED-related infections were identified within four academic hospitals in Houston, Texas between 2002 and 2009. ^ Results. Of the 504 identified patients with CIED-related infection, 80 (16%) had a non-staphylococcal infection and were the focus of this study. Although the demographics and comorbities of subjects were comparable to other reports, our study illustrates many key points: (a) the microbiologic diversity of non-staphylococcal infections was rather extensive, as it included other Gram-positive bacteria like streptococci and enterococci, a variety of Gram-negative bacteria, atypical bacteria including Nocardia and Mycobacteria, and fungi like Candida and Aspergillus; (b) the duration of CIED insertion prior to non-staphylococcal infection was relatively prolong (mean, 109 ± 27 weeks), of these 44% had their device previously manipulated within a mean of 29.5 ± 6 weeks; (c) non-staphylococcal organisms appear to be less virulent, cause prolonged clinical symptoms prior to admission (mean, 48 ± 12.8 days), and are associated with a lower mortality (4%) than staphylococcal organisms; (d) thirteen patients (16%) presented with CIED-related endocarditis; (e) although not described in prior reports, we identified 3 definite and 2 suspected cases of secondary Gram-negative bacteremia seeding of the CIED; and (f) inappropriate antimicrobial coverage was provided in approximately 50% of patients with non-staphylococcal infections for a mean period of 2.1 days. ^ Conclusions. Non-staphylococcal CIED-related infections are prevalent and diverse with a relatively low virulence and mortality rate. Since non-staphylococcal organisms are capable of secondarily seeding the CIED, a high suspicion for CIED-related infection is warranted in patients with bloodstream infection. Additionally, in patients with suspected CIED infection, adequate Gram positive and -negative antibacterial coverage should be administered until microbiologic data become available.^