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Biomedical subjects

Stephen E Weis

Publications and source records attributed to Stephen E Weis.

17 recordsLinked to original sources

What are the costs of suspected but not reported tuberculosis?

PURPOSE: Little is known regarding patients suspected, but not proven, to have tuberculosis before meeting reporting requirements. These patients generate unmeasured tuberculosis costs to the health care system. Elimination efforts are undervalued without fully quantifying the burden of tuberculosis. This may lead to decreased support and resurgence of this disease. This report provides a preliminary quantification of these costs. METHODS: We used acid-fast bacillus (AFB) cultures completed as a proxy to estimate the number of patients with suspected tuberculosis who are never reported. We collected data on the number of AFB tests conducted in Tarrant County, TX, for calendar year 2002. We excluded all tests positive for Mycobacterium tuberculosis or secondary to growth of mycobacteria not M tuberculosis. We considered all AFBs conducted on an individual within 90 days to be single diagnostic episodes. We measured the number of diagnostic episodes, number of AFBs, number of AFBs meeting inclusion criteria, estimated cost incurred by testing, and individuals affected. RESULTS: The Tarrant County hospitals sampled completed 6935 AFB cultures on an inpatient volume of 142,356 patients. One hundred ninety-three cultures confirmed tuberculosis or other mycobacteria, and 6742 AFBs were collected on persons suspected, but not proved, to have tuberculosis at an estimated $114.06 per culture. The total cost of eliminating tuberculosis as a cause of illness was $768,993. Laboratory costs for each patient with suspected, but not confirmed, tuberculosis averaged $364.11. One hundred forty-eight AFB cultures costing $16,830 were needed to confirm one case of tuberculosis. CONCLUSIONS: The suspicion of tuberculosis incurs significant burdens and cost in the US health care system. More fully valuing tuberculosis elimination is important for tuberculosis management and will help maintain support for tuberculosis elimination.

Costs and Cost Analysis↗

What is the outcome of targeted tuberculosis screening based on universal genotyping and location?

RATIONALE AND OBJECTIVES: Identifying and treating persons with latent tuberculosis (TB) infection (LTBI) at high risk for developing TB is part of the current TB elimination strategy. There are no specific criteria, other than medical risks, to designate groups as high risk for developing TB. We hypothesized that, if location-based screenings were done in communities where persons with genotypically clustered Mycobacterium tuberculosis resided, then persons with LTBI from recent transmission and with undiagnosed TB could be identified. METHODS: Location-based TB screenings were done in partnership with multiple community-based organizations using resources previously used for other types of screening. MAIN RESULTS: Location-based screenings identified one person with TB for every 83 screened, and one person with LTBI for every five screened. The yield of this targeted screening program for discovering persons with TB and LTBI exceeded what would be expected from nontargeted screening in a county with a TB incidence of 5.7 per 100,000 population. CONCLUSIONS: Genotyping combined with geographic information systems analysis can potentially be used to define high-risk status and to define areas for location-based TB screenings.

Adolescent↗

Using cost and health impacts to prioritize the targeted testing of tuberculosis in the United States.

PURPOSE: Evaluation improves efficiency and effectiveness. Current U.S. tuberculosis (TB) control policies emphasize the treatment of latent TB infection (LTBI). However, this policy, if not targeted, may be inefficient. We determined the efficiency of a state-law mandated TB screening program and a non state-law mandated one in terms of cost, morbidity, treatment, and disease averted. METHODS: We evaluated two publicly funded metropolitan TB prevention and control programs through retrospective analyses and modeling. Main outcomes measured were TB incidence and prevalence, TB cases averted, and cost. RESULTS: A non state-law mandated TB program for homeless persons in Tarrant County screened 4.5 persons to identify one with LTBI and 82 persons to identify one with TB. A state-law mandated TB program for jail inmates screened 109 persons to identify one with LTBI and 3274 persons to identify one with TB. The number of patients with LTBI treated to prevent one TB case was 12.1 and 15.3 for the homeless and jail inmate TB programs, respectively. Treatment of LTBI by the homeless and jail inmate TB screening programs will avert 11.9 and 7.9 TB cases at a cost of 14,350 US dollars and 34,761 US dollars per TB case, respectively. CONCLUSIONS: Mandated TB screening programs should be risk-based, not population-based. Non mandated targeted testing for TB in congregate settings for the homeless was more efficient than state-law mandated targeted testing for TB among jailed inmates.

Costs and Cost Analysis↗

Enzyme-linked immunospot and tuberculin skin testing to detect latent tuberculosis infection.

RATIONALE: Diagnosis of latent tuberculosis infection (LTBI) is currently based on the tuberculin skin test. The enzyme-linked immunospot assay (ELISPOT) is a new blood test to diagnose LTBI. OBJECTIVE: To compare the ELISPOT and the tuberculin skin test for detecting LTBI in contacts of patients with tuberculosis. METHODS: Prospective study of 413 contacts of patients with tuberculosis. MEASUREMENTS AND MAIN RESULTS: Because there is no gold standard for LTBI, the sensitivity and specificity of the ELISPOT and tuberculin skin test cannot be directly measured. For each contact, we therefore estimated the likelihood of having LTBI by calculating a contact score that quantified exposure to and infectiousness of the index case. We analyzed the relationship of contact score to ELISPOT and tuberculin skin test results. The likelihood of a positive ELISPOT (p = 0.0005) and a tuberculin skin test (p = 0.01) increased significantly with rising contact scores. The contact score was more strongly related to the ELISPOT than to the tuberculin skin test results, although this difference was not statistically significant. Among U.S.-born persons and those who were not vaccinated with bacille Calmette-Guérin, approximately 30% had positive ELISPOT or tuberculin skin test results. Foreign-born, bacille Calmette-Guérin-vaccinated persons were significantly more likely to have a positive tuberculin skin test than a positive ELISPOT result (p < 0.0001). CONCLUSIONS: Compared with the tuberculin skin test, the ELISPOT appears to be at least as sensitive for diagnosis of LTBI in contacts of patients with tuberculosis.

Adolescent↗

Treatment of active tuberculosis: challenges and prospects.

This article reviews the basic principles of drug treatment of tuberculosis, individual pharmacologic agents, current treatment recommendations, and several special situations that clinicians are likely to encounter in medical practice.

Antitubercular Agents↗

Using GIS technology to identify areas of tuberculosis transmission and incidence.

BACKGROUND: Currently in the U.S. it is recommended that tuberculosis screening and treatment programs be targeted at high-risk populations. While a strategy of targeted testing and treatment of persons most likely to develop tuberculosis is attractive, it is uncertain how best to accomplish this goal. In this study we seek to identify geographical areas where on-going tuberculosis transmission is occurring by linking Geographic Information Systems (GIS) technology with molecular surveillance. METHODS: This cross-sectional analysis was performed on data collected on persons newly diagnosed with culture positive tuberculosis at the Tarrant County Health Department (TCHD) between January 1, 1993 and December 31, 2000. Clinical isolates were molecularly characterized using IS6110-based RFLP analysis and spoligotyping methods to identify patients infected with the same strain. Residential addresses at the time of diagnosis of tuberculosis were geocoded and mapped according to strain characterization. Generalized estimating equations (GEE) analysis models were used to identify risk factors involved in clustering. RESULTS: Evaluation of the spatial distribution of cases within zip-code boundaries identified distinct areas of geographical distribution of same strain disease. We identified these geographical areas as having increased likelihood of on-going transmission. Based on this evidence we plan to perform geographically based screening and treatment programs. CONCLUSION: Using GIS analysis combined with molecular epidemiological surveillance may be an effective method for identifying instances of local transmission. These methods can be used to enhance targeted screening and control efforts, with the goal of interruption of disease transmission and ultimately incidence reduction.

Journal Article↗

NK cells regulate CD8+ T cell effector function in response to an intracellular pathogen.

We studied the role of NK cells in regulating human CD8+ T cell effector function against mononuclear phagocytes infected with the intracellular pathogen Mycobacterium tuberculosis. Depletion of NK cells from PBMC of healthy tuberculin reactors reduced the frequency of M. tuberculosis-responsive CD8+IFN-gamma+ cells and decreased their capacity to lyse M. tuberculosis-infected monocytes. The frequency of CD8+ IFN-gamma+ cells was restored by soluble factors produced by activated NK cells and was dependent on IFN-gamma, IL-15, and IL-18. M. tuberculosis-activated NK cells produced IFN-gamma, activated NK cells stimulated infected monocytes to produce IL-15 and IL-18, and production of IL-15 and IL-18 were inhibited by anti-IFN-gamma. These findings suggest that NK cells maintain the frequency of M. tuberculosis-responsive CD8+IFN-gamma+ T cells by producing IFN-gamma, which elicits secretion of IL-15 and IL-18 by monocytes. These monokines in turn favor expansion of Tc1 CD8+ T cells. The capacity of NK cells to prime CD8+ T cells to lyse M. tuberculosis-infected target cells required cell-cell contact between NK cells and infected monocytes and depended on interactions between the CD40 ligand on NK cells and CD40 on infected monocytes. NK cells link the innate and the adaptive immune responses by optimizing the capacity of CD8+ T cells to produce IFN-gamma and to lyse infected cells, functions that are critical for protective immunity against M. tuberculosis and other intracellular pathogens.

Antibodies, Blocking↗

Human CD8+ T cells recognize epitopes of the 28-kDa hemolysin and the 38-kDa antigen of Mycobacterium tuberculosis.

Mycobacterium tuberculosis antigens that are recognized by human CD8+ T cells are potentially important vaccine target molecules. We used a motif-based strategy to screen selected proteins of M. tuberculosis for peptides predicted to bind to human leukocyte antigen (HLA)-A*0201. We identified two 10 amino acid peptides that elicited cytolytic T lymphocyte activity and interferon-gamma production by CD8+ T cells from HLA-A*0201+ healthy tuberculin reactors. These peptides were derived from the 38-kDa antigen and the 28-kDa hemolysin, the latter being a novel target for CD8+ T cells. We speculate that hemolysins may alter the phagosomal membrane surrounding intracellular M. tuberculosis, allowing themselves and other antigens to gain access to the major histocompatibility complex class I processing pathway.

Adult↗

CD40 ligand trimer enhances the response of CD8+ T cells to Mycobacterium tuberculosis.

We investigated the effect of recombinant CD40 ligand trimer (CD40LT) on the functional capacity of peripheral blood CD8(+) T cells from healthy tuberculin reactors that were cultured with Mycobacterium tuberculosis-infected autologous monocytes. CD40LT enhanced the capacity of M. tuberculosis-responsive CD8(+) T cells to produce IFN-gamma by increasing the number of IFN-gamma-producing CD8(+) T cells and the amount of IFN-gamma produced per cell. CD40LT-induced IFN-gamma production was dependent on production of IL-12 and IL-18, but did not require IL-15. CD40LT up-regulated expression of the transcription factors phosphorylated CREB and c-Jun, both of which have been previously shown to stimulate IFN-gamma mRNA transcription by binding to the IFN-gamma promoter. CD40LT also enhanced the capacity of CD8(+) T cells to lyse M. tuberculosis-infected monocytes, and increased CTL activity was associated with higher expression of perforin and granulysin, but not of Fas ligand. We conclude that CD40LT can enhance CD8(+) T cell effector function in response to M. tuberculosis.

Adjuvants, Immunologic↗

Serum cytokine concentrations do not parallel Mycobacterium tuberculosis-induced cytokine production in patients with tuberculosis.

We measured serum cytokine concentrations and Mycobacterium tuberculosis-stimulated cytokine production by peripheral blood mononuclear cells (PBMCs) obtained from persons infected with M. tuberculosis. Serum interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) concentrations were elevated in patients with tuberculosis compared with healthy persons who had reactions to tuberculin skin tests, but IL-18 concentrations were not. In contrast, M. tuberculosis-stimulated PBMCs from patients with tuberculosis produced less IFN-gamma and IL-18 but similar amounts of IL-10, compared with PBMCs from healthy subjects who had reactions to tuberculin skin tests. Pretreatment of PBMCs from healthy subjects with reaction to tuberculin with serum from patients with tuberculosis inhibited IFN-gamma production in response to M. tuberculosis, and inhibition was blocked by anti-IL-10. Thus, serum concentrations of IFN-gamma, IL-18, and IL-10 do not parallel M. tuberculosis-induced cytokine levels, and increased IL-10 serum levels in patients with tuberculosis inhibit IFN-gamma production in response to mycobacterial antigens.

Cell Culture Techniques↗

Transmission dynamics of tuberculosis in Tarrant county, Texas.

To understand the transmission dynamics of tuberculosis in Tarrant County, Texas, we performed a population-based study of 159 patients with culture-proven tuberculosis, combining restriction fragment length polymorphism (RFLP) analysis of Mycobacterium tuberculosis isolates with prospective interviewing to identify epidemiologic links between patients. Patients whose isolates had identical or closely related RFLP patterns were considered a cluster. Seventy-six (48%) of 159 patients were in 19 clusters, suggesting that recent transmission accounted for 36% of tuberculosis morbidity. Unconditional logistic regression showed that birth in the United States, continuous residence in Tarrant County, a history of homelessness, and a history of visiting or working in bars were independent predictors of clustering. Four homeless shelters and five bars were associated with specific clusters, suggesting that they were sites of tuberculosis transmission. Patients in some clusters recognized more photographs of patients in their cluster than did patients outside their cluster. We conclude that (1) homeless shelters and bars are important sites of tuberculosis transmission in Tarrant County, and (2) the use of photograph recognition of patients with tuberculosis, in combination with RFLP analysis, has the potential to enhance tuberculosis control by facilitating identification of epidemiologic links between patients.

Adult↗

The NKp46 receptor contributes to NK cell lysis of mononuclear phagocytes infected with an intracellular bacterium.

We used human tuberculosis as a model to investigate the role of NK cytotoxic mechanisms in the immune response to intracellular infection. Freshly isolated NK cells and NK cell lines from healthy donors lysed Mycobacterium tuberculosis-infected monocytes to a greater extent than uninfected monocytes. Lysis of infected monocytes was associated with increased expression of mRNA for the NKp46 receptor, but not the NKp44 receptor. Antisera to NKp46 markedly inhibited lysis of infected monocytes. NK cell-mediated lysis was not due to reduced expression of MHC class I molecules on the surface of infected monocytes or to enhanced production of IL-18 or IFN-gamma. NK cell lytic activity against M. tuberculosis-infected monocytes and NKp46 mRNA expression were reduced in tuberculosis patients with ineffective immunity to M. tuberculosis compared with findings in healthy donors. These observations suggest that 1) the NKp46 receptor participates in NK cell-mediated lysis of cells infected with an intracellular pathogen, and 2) the reduced functional capacity of NK cells is associated with severe manifestations of infectious disease.

Cell Line↗

Reduced expression of nuclear cyclic adenosine 5'-monophosphate response element-binding proteins and IFN-gamma promoter function in disease due to an intracellular pathogen.

Mycobacterium tuberculosis-induced IFN-gamma protein and mRNA expression have been shown to be reduced in tuberculosis patients, compared with healthy tuberculin reactors. To determine whether this decrease was associated with reduced activity of the IFN-gamma promoter, we first studied binding of nuclear proteins to the radiolabeled proximal IFN-gamma promoter (-71 to -40 bp), using EMSAs with nuclear extracts of freshly isolated peripheral blood T cells. Nuclear extracts of T cells from most tuberculosis patients showed markedly reduced expression of proteins that bind to the proximal IFN-gamma promoter, compared with findings in nuclear extracts of T cells from healthy tuberculin reactors. These DNA-binding complexes contained CREB proteins, based on competitive EMSAs, supershift assays, and Western blotting with an anti-CREB Ab. Transient transfection of PBLs with a luciferase reporter construct under the control of the IFN-gamma promoter revealed reduced IFN-gamma promoter activity in tuberculosis patients. Transient transfection of Jurkat cells with a dominant-negative CREB repressor plasmid reduced IFN-gamma promoter activity. These data suggest that reduced expression of CREB nuclear proteins in tuberculosis patients results in decreased IFN-gamma promoter activity and reduced IFN-gamma production.

Consensus Sequence↗

Transmission of drug-resistant tuberculosis in Texas and Mexico.

To examine the transmission of drug-resistant (DR) tuberculosis between Texas and Mexico, Mycobacterium tuberculosis isolates resistant to one or more of the first-line antimycobacterial drugs were obtained from 606 patients who resided in Texas and 313 patients who resided in Mexico, primarily within the state of Tamaulipas. The isolates were genotyped by IS6110-based restriction fragment length polymorphism (RFLP) analysis and spoligotyping. Of the 919 isolates genotyped, 413 (45%) grouped into 105 clusters containing 2 or more isolates with identical genotypes. In addition to having identical genotypes, identical drug resistance patterns were identified in 250 isolates in 78 clusters (DR clusters). Twenty DR clusters, containing isolates from 32% of the total number of patients infected with DR strains, were geographically distributed across Mexico and Texas. Within this population of 919 patients infected with DR isolates, the probability of being in a DR cluster was the same for residents of Mexico and Texas. In Texas, the significant independent predictors of clustering within DR clusters as opposed to genotype clusters were found to be race, age, country of birth, human immunodeficiency virus (HIV) infection status, and resistance to more than one drug. Specifically, isolates from African Americans, individuals under age 65, individuals born in the United States, and HIV-positive individuals were each more likely to be associated with a DR cluster. By contrast, no significant independent predictors of clustering in a DR cluster were identified in Mexico. Although some DR M. tuberculosis strains are geographically restricted, this study suggests that a number of strains are transmitted between Mexico and the United States.

Adolescent↗

Lability of serum low-density lipoprotein cholesterol levels during screening in subgroup of Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) cohort.

In the enrollment phase of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a number of heart disease-free potential subjects did not qualify to participate in the study because their low-density lipoprotein cholesterol (LDL-C) levels fluctuated. This report looks at the incidence of lability of LDL-C levels and premature coronary heart disease (CHD) in the nuclear family based on data collected on a group excluded primarily based on lipid levels during the enrollment phase at the TexCAPS site. Lipid inclusion criteria were total cholesterol (TC), 180 mg/dL to 264 mg/dL; low-density lipoprotein cholesterol (LDL-C), 130 mg/dL to 190 mg/dL; high-density lipoprotein cholesterol (HDL-C), less than or equal to 45 mg/dL for men and less than or equal to 47 mg/dL for women; and triglyceride (TG) concentrations, less than or equal to 400 mg/dL. After participants had been on the American Heart Association (AHA) step 1 diet for 8 to 10 weeks, lipid parameters were again tested in a total of 4257 individuals. Both lipid screening measurements at 8 and 10 weeks were required to be within 15% of each other for inclusion in subsequent study. A total of 2868 individuals met the study criteria and were randomly assigned to groups; 1389 failed to qualify for a variety of reasons. Of these, 1070 (25.1% of those who initially qualified based on lipid levels) were excluded because of unacceptable lipid levels on the evaluations repeated at 8 and 10 weeks. This excluded subpopulation (n = 1070) was stratified into three groups based on changes of LDL-C between 8 and 10 weeks on the AHA step 1 diet. One group had a less than 15% fluctuation in LDL-C (LN group, n = 637, 15.0% of cohort, n = 4257). Of those with LDL-C variability, 177 had a greater than 15% increase in LDL-C (LI group, n = 177, 4.2% of cohort); and 256 had a greater than 15% decrease in LDL-C (LD, n = 256, 6.0% of cohort). At week 8, TC and LDL-C levels were lower and the HDL-C level was higher in the LN group compared with both groups having labile lipid levels (LI and LD groups). Changes by gender showed similar trends; however, HDL-C was 5 mg/dL lower at 8 weeks in both groups of women with labile LDL-C levels (groups LI and LD) when compared with the women in the LN group (P < .01). The frequency of TG concentrations greater than 150 mg/dL was greater in men having labile LDL-C level when compared with the control group. The trend was similar for women. In assessing the incidence of CHD in the nuclear family, parents of probands with labile LDL-C levels (LI and LD groups) had a higher frequency (P = .0044) of premature CHD than parents of probands with stable LDL-C (LN). The following conclusions can be drawn: (1) within the general population, there is a substantial number (10%, 433 of 4257) of individuals with labile LDL-C levels; (2) labile LDL-C levels in the probands were found to be associated with an increased familial frequency of premature CHD in their parents. Definition of the molecular basis for this lability of LDL-C could reveal new opportunities to regulate plasma cholesterol levels and thus have an impact on CHD-associated morbidity and mortality in a substantial portion of the general population.

Aged↗

Associate investigations: detection of tuberculosis infections in children resulting in discovery of undiagnosed tuberculosis in adults.

The authors present the design and implementation of associate investigations of young children with positive tuberculin skin test results. Case study analysis of an associate investigation was done using epidemiologic surveillance techniques, medical interviewing, sociogram mapping, tuberculin skin testing, radiographic evidence, and bacteriologic analysis. Deoxyribonucleic acid fingerprinting of the Mycobacterium tuberculosis isolates using a standardized IS6110-based restriction fragment length polymorphism analysis and IS6110-independent DNA spoligotyping methods was done to track and identify specific bacterial strains. Deoxyribonucleic acid fingerprinting and spoligotyping done on isolates obtained from family members demonstrated same-strain transmission of M. tuberculosis. Three adults with active pulmonary disease and six individuals with latent tuberculosis (TB) were discovered during this investigation. The arrival of a family member from Mexico who had the same strain suggests that the source case lives in Mexico. A child with positive tuberculin skin test results indicates recent and potentially ongoing transmission of TB in the community. Targeted tuberculin skin testing performed on high-risk groups by primary care physicians allows for detection of TB infections. When TB infections are discovered in children, associate investigations can result in the discovery of undiagnosed adult cases and prevent further transmission within the community.

Adult↗