Brownsville Regional Campus 

Overview of the Tuberculosis Research Program
University of Texas Health Science Center Houston- School of Public Health
Brownsville Regional Campus
University of Texas Brownsville, SPH Bldg
80 Fort Brown
Brownsville, Texas 78520 

Index

I.                     Background: Tuberculosis in South Texas and northeastern Mexico

II.                   Description of the University of Texas School of Public Health Brownsville Campus (UT-SPH-B)

III.                  Summary of ongoing (funded) tuberculosis research projects

IV.               Summary of key investigators

I.  Background: Tuberculosis (TB) in the South Texas and Northeastern Mexico border

 The threat of importation of TB to the United States:  Mexico is the country of origin for the largest proportion of foreign-born US TB patients (23%), and the Mexican border is therefore the major gateway for importation of TB This is also a route for spread of drug resistant strains, with Mexico being the country from which drug-resistant (DR) and multi-drug resistant (MDR) strains are most frequently introduced into the US.

MDR-TB along the US-Mexico border:  Texas has one of the highest incidence rates of TB in the US, with the highest rates in Texas present in the counties bordering Mexico (3) (Table 1) (2; 4-9). This is the busiest and most porous border in the world, with frequent migration, relocation of families, travelers and migrant workers. Reports of TB in different areas of the US have been traced back to the Mexico-US border(6). A substantial population of newly arrived immigrants settle in semi-rural communities called “colonias” in south Texas. The rate of TB in the colonias is at least 4.4 times higher compared with the US rate (Table 1) Reactivation and spread of TB is facilitated in a population made vulnerable by health disparity, poverty, stress of migration, crowding and concomitant disease, lack of medical insurance, poor access to medical healthcare, and illegal immigrant status(10). The high incidence of diabetes in this Hispanic population further elevates the risk for TB  Furthermore there is a 70% higher rate of isoniazid (INH) resistance and 100% higher rate of rifampin (RIF) resistance along the Texas-Mexico border(14). In 1991 the Texas Department of Health (TDH) Laboratory in Harlingen-Texas reported the highest percentage (14.1%) of DR resistant isolates in the US  In the year 2001, 2213 specimens were processed in this program, 26% were positive, of which 33% were DR or MDR, some resistant to as many as 9 different antimicrobials. Mexican data depend solely on passive reporting, indicating that a patient is recorded only when sick enough to seek medical care. The data from Chiapas (Southern Mexico)  shown in table 1 reveal that actual prevalence with active case finding may be as much as 8 times the reported rate (10).  In the social conditions of South Texas it is likely that actual rates are similarly higher than reported rates in the absence of effective active case finding.

Definition of our study area for TB research. The UTSPH Brownsville campus is located 0.5 miles from the Mexico border, and therefore, our common interest with Mexico is to study issues dealing with TB control along the border of both countries, particularly multi-drug resistant disease. We are currently conducting studies on both sides of the border. In Texas the sites include the populations from the counties of Cameron, Hidalgo, Zapata, Starr and Webb counties, where the major cities of Brownsville, McAllen and Laredo are located (Fig. 1). The Mexican sites comprise defined regions within two states which border the opposite bank of the Rio Grande river.  In the state of Tamaulipas we are working with the “Jurisdicciones sanitarias” (equivalent to public health regions) III (Matamoros), IV (Reynosa) and V (Nuevo Laredo), located on the northern part of the state (Fig. 1).  In the state of Nuevo León we have collaborators from the Universidad Autónoma de Nuevo León, who operate a pulmonary clinic that covers a major portion of the TB cases from the metropolitan area of our nearest industrial city, Monterrey (Fig. 1). The population for these sites and estimated passive incidence rates are indicated in Table 2.

Organization of the South Texas TB elimination program:  All US sites within this project (Hidalgo, Cameron, Starr, Willacy, Zapata and Webb counties) are under the direction of the TDH TB Elimination program. TDH Region 11 coordinates the local county and city health departments providing the guidelines to identify, treat and follow all cases through directly observed therapy (DOT) to completion. TB is a reportable disease, and the patient’s sociodemographic information and medical/social risk factors for TB are recorded on the standard TB400A and B forms. Each health department handles their own detailed database with patient information, but in addition, TDH unifies data from the TB400A and B forms in a single database. The statistical findings are published in regular reports by TDH(9).  Each new case undergoes a contact investigation using standard 340 forms with interview of all named contacts, with tuberculin skin testing, X-ray, physical examination and chemoprophylactic treatment.  Specimens from Hidalgo and Cameron Counties and some from Starr County are processed at the TDH laboratory located in the South Texas Healthcare System (STHCS) in Harlingen. Specimens from Zapata and Webb Counties (City of Laredo) are processed at the TDH State laboratory in Austin. Both laboratories perform drug-sensitivity on all isolates.  TDH participates in a number of local and national programs, including the binational TB program “Ten against TB”, which comprises ten US and Mexico border states. In this program, patients from Mexico who are not responding to treatment are enrolled in the binational program. Culture and drug-sensitivity testing is performed in Texas and DR and MDR patients are administered DOT. Possible contacts are referred to appropriate Mexican authorities.

 Organization of the northeast Mexico TB elimination program:  TB is a reportable disease in Mexico, and most patients are managed through Jurisdicciones sanitarias, which provide free treatment, coordination and follow-up of patients. (Jurisdicciones sanitarias in Tamaulipas are analogous to the TDH regional offices, and work with local government and non-government health institutions to coordinate regional health.  They are directed out of the central office for the Secretaría de Salud de Tamaulipas in Ciudad Victoria.  Patient information is recorded using a standard EPI-TB questionnaire (see Appendix I) and database format, and information is sent regularly to the central office in Mexico City. The system lacks resources for routine culture and drug-sensitivity, and diagnosis is usually dependent on direct smears. Patients with DR strains are only promptly identified when they fail to respond to treatment, at which point, depending on their location, they may be incorporated in the binational TB program.  This program provides isolation and drug senstivities performed at the STHCS laboratory at Harlingen. In practice STHCS receives specimens from Matamoros and Valle Hermoso. Though the same facility is available to Reynosa, until recently not many specimens were actually received.  In Monterrey, Neuvo León, Dr. Rendon is in the process of upgrading isolation facilities in a collaborative effort between the Universidad Autónoma de Nuevo León  (UNAL) and the Instituto Mexicano del Seguro Social (IMSS) in Monterrey. However, culture in Monterrey depends on the vagaries of funding in Mexico. In 2001, funding was available and isolation was performed, in 2002 funding terminated, and isolation discontinued. There are no isolation rooms, routine contact investigations or targeted TB testing programs. Reporting in both states depends on the patient being sick enough to consult a physician. DOT is officially executed in Mexico, but field observation is that implementation is patchy.  Thus treatment is often inadequate and development and dissemination of MDR-TB is a major, underreported threat. 

II.  Description of our campus in Brownsville
The UT SPH Brownsville campus occupies a purpose built building completed in January 2002, situated on the UT Brownsville campus. This building has 28,000 square feet of teaching, office and laboratory space. This new school of public health was established as part of the Regional Academic Health Center (RAHC), mandated by the Texas State Legislature to serve the Lower Rio Grande Valley (counties of Hidalgo, Cameron, Willacy and Starr). This initiative is designed to address the serious health disparities of this predominantly Hispanic region of South Texas by locating medical education, medical research and public health in the LRGV where the local population can become closely involved and educated in their own health research. The SPH component of the RAHC is the first to be completed and operational, and now has a faculty of nine with four support staff, one of whom is an experienced research assistant. Students have been enrolled for MPH degrees since January 2001, and several are now actively engaged in research projects as part of their training both in the field and in the laboratory.

 Laboratory:
The laboratory will have nearly 3000 square feet of wet lab space, projected to be completed in Phase II in 2005.  In the meantime we are occupying 700 square feet of laboratory space in an adjacent building where the Department of Biology of UTB is located, and additional laboratory space is shared with UTB research laboratories. Core facilities and major equipment are shared by both faculties, and we have joint committees for Biosafety, Radiation Safety and Animal Care and Use. The UTSPH-B laboratory is under the direction of Drs. Susan P. Fisher-Hoch, MD, PhD (Professor, Biological Sciences), and two experienced molecular biology scientists, Dr. Blanca I. Restrepo (Ph.D. Microbiology), and Boris Ermolinsky (Ph.D. Chemistry). They supervise a full time technician, a graduate and two undergraduate students. The strategy for development of the laboratory component of this exciting new public health laboratory facility is provision of high technology, high throughput assays for screening large numbers of specimens, actively supported by expert researchers in Houston. This core laboratory is supported by NIH grant Number MD000170 P20 (EXPORT), five years from February 2003. 

Laboratory equipment:
The UTSPH-B laboratory has an ABI Sequence Detector, (Model 7900) for qPCR assays with 96-well format. We anticipate purchase a plate adaptor and robotics for 385 well format in the next couple of years to allow faster screening of large numbers of specimens. Also available are class IIA laminar flow cabinets, spectrophotometers, a Kodak EDAS 290 w/epi-illumination, electrophoresis apparatus, standard thermocylers, a bead-beater, computers, -70 ^oC and -20^oC freezers, water baths, high temperature hybridization water bath, and a full range of other equipment for molecuar studies. Additional major equipment is shared with UTB researchers allowing UTSPH-B access to tissue culture facilties, Class IIA laminar flow hoods, fume hoods, additional electrophoresis facilities, microscopy, HPLC, gel drying apparatus, centrifuges, pH meters, balances, CO₂ incubators, liquid nitrogen etc.  Microarray readers and other equipment is projected for purchase in the next 12 to 24 months, at which time we will also have completed facilities for handling of radionucleotides.  Flow cytometers and other major equipment is meanwhile available to us at our Houston core facilities.  Computers are available in the laboratory. 

Clinical:
For the purposes of the TB studies we access patients at the health departments from each of the study sites in Texas and Mexico.  The School of Public Health is developing a satellite of the Houston Health Sciences center Clinical Research Center in Brownsville at the Brownsville Medical Center (submitted June 1, 2003) where non-active cases and uninfected study subjects may be seen.  We also have trained interviewers, phlebotomists and other staff who can pay patients visits in their homes to gather data and specimens.

 Animal:  N/A.

 Computer:
UT-SPH at Brownsville provides a computational resource department, including a computer specialist who supports all networks, ITV, teaching technology, etc. Online services to E-mail and internet are standard. Extensive access to Medline, full text journals etc. are available electronically via the UT Health Sciences Center Library facilities in Houston. Programs for word processing, graphics, data analysis (SAS and Sudaan), geocoding (ArcGIS), genebank searches, etc. are routinely available.

Office space and communication facilities:
Private office space is provided for each faculty member. There is additional desk space and computers for the students and support staff. Fax, and color printers and photocopiers are available. Secretarial support is provided. The classrooms and meeting rooms equipped with state-of-the-art projection and communication equipment, including Smartboards for computer projection and ITV facilities. There is a large computer laboratory for teaching. The support staff including a computer and communications specialist, a specialist in web based teaching and student support. The campus has its own support budget for these facilities.

 Research programs- UTSPH-B has a faculty that covers expertise in epidemiology, biological sciences, infectious diseases, nutrition, behavioral science, health economics, biometry and environmental sciences. The strategy for development of the laboratory component of the exciting new UTSPH-B facility is provision of high technology, high throughput assays that can be applied to population studies. We are setting up research programs along these lines in the laboratory, and have begun generating data in studies related to human papillomavirus and its association with cervical cancer, HIV vaccine development, and tuberculosis (described below in more detail). Additional ongoing research in the School of Public Health includes a study of the genetics of diabetes, prevention of obesity and cardiovascular disease, studies of breast, prostate and cervical cancer.  There are several behavioral and environmental research projects in hand.

III.        Summary of the ongoing (funded) research programs in tuberculosis

We have now established a comprehensive TB research program in the UT-SPH Brownsville campus. The program is led by Dr. Restrepo and also involves Drs. Fisher-Hoch, Reininger, Perez and McCormick.  Studies range from basic science particularly pathogenesis of early tuberculosis,  to field studies aimed at early detection and understanding of TB transmission along the US-Mexico border using modern molecular, social network and GIS techniques. We have access to tuberculosis study sites and specimens and data from clinics both sides of the border, under several protocols.  We collaborate closely with the Texas Department of Health (TDH), and have a full time nurse with a small clinic and laboratory space within the Hidalgo County Health Department Tuberculosis Clinic, specifically to identify TB patients and collect data and specimens.  We also have good relationships with the TDH South Texas Hospital laboratory where all the TB specimens from both sides of the border are processed, and we have access to all cultures, and data..  Members of our consortium in San Antonio and Houston are responsible for genotyping strains isolated both sides of the border, and we have access to those data.

A.  EMERGING MDR TUBERCULOSIS ACROSS THE US/MEXICO BORDER (NIAID R21, $400,000)

Principal Investigator: Joseph McCormick

Co-investigators UT-SPH-B: Susan P. Fisher-Hoch
Blanca I. Restrepo
Adriana Perez
Belinda Reininger

Other Texas sites:
Edward Graviss (Baylor College of Medicine, Houston),
Teresa Quitugua (UTSCA, San Antonio), and Brian Smith and Ken Jost, (TDH Austin and Region 11)

            Mexican sites: Francisco López-Leal, Gonzalo Crespo, (Ciudad Victoria, Tamaulipas) Adrian Rendón (Monterrey, Nuevo León)

Given our strategic location in the Texas-Mexico border, and the magnitude of TB in this area, we sought and recently obtained pilot funds from NIH to consolidate a working consortium of public health workers and researchers from this region. The list of consortium members is shown in Table 3. The study area is shown in Fig. 1.  In aims 1 and 2 we are locating, sharing, cleaning and merging existing demographic, epidemiologic and molecular MDR-TB data, geocoding these data, and performing spatial analysis.  We expect this to create a preliminary comprehensive regional picture of the distribution of MDR-TB across the border. We will be able to link individual cases over the past 3-5 years over the whole area with molecular fingerprints, drug susceptibility patterns, geocoding information and sociodemographic characteristics. Results will be compared with data from Houston, Monterrey and elsewhere, to determine the patterns and consequence of MDR-TB transmission across the border and within the United States. The third aim is to standardize laboratory protocols and develop expertise in the LRGV and northeastern Mexico for MDR-TB molecular studies, specifically MIRU and spoligotyping. In aim 4 we are evaluating a social network analysis strategy.  This extends the classical “TB contact investigations” focused on persons, to a more thorough investigation of dynamics of social behavior in time and space associated with TB transmission. The preliminary data from all these studies will be used to apply for further funding in epidemiologic and translational research studies.

B.  DESIGN OF A qPCR ASSAY FOR EARLY TB DIAGNOSIS (NIH PILOT STUDY UNDER EXPORT PROGRAM, $55,000)

Principal investigator: Blanca I Restrepo
Co-investigators: Susan P. Fisher-Hoch and Joseph McCormick
The goal of this pilot project is to design a battery of real-time, quantitative PCR assays (Q-PCR) to study the dynamics of early Mycobacterium tuberculosis (MTB) infection, by detection of bacterial DNA in peripheral blood mononuclear cells (PBMCs). We have already developed taqman assays for detection of the single-copy gene encoding the 16S ribosomal RNA (rRNA) to enable MTB genome quantification, and the multi-copy insertion sequence element IS6110 for improved sensitivity. In the present pilot study we will continue the development of tools to study early TB bacillemia by refining our previously-established DNA extraction technique from MTB in PBMCs.  The developed protocols will be tested and further refined using blood from infected guinea pigs.  These animals are highly susceptible to MTB infection and provide a highly-reproducible animal model of primary tuberculosis.  Specimens will be taken between 3-5 weeks of infection when bacillemia is known to occur.  Finally, preliminary study in human specimens will be done to establish the feasibility of identifying individuals with active TB disease through Q-PCR testing in peripheral blood. The results from this pilot study should set the stage for further, in-depth understanding of the kinetics of “silent” bacillemia in early tuberculosis, and may result in a rapid and effective molecular screening tool for early tuberculosis in the community.  Future studies will be extended to explore DNA expression through RNA quantification, expanding even further the possibilities to study the host-parasite relations at a critical stage of infection where scanty information is available.

C.  DIABETES AND TUBERCULOSIS:  THE STRENGTH OF THEIR ASSOCIATION AND THE ECONOMIC IMPACT IN THE LOWER RIO GRANDE VALLEY (NIH PILOT STUDY UNDER EXPORT PROGRAM, $48,814)

Principal investigator: Adriana Perez
Co-investigators: Blanca I Restrepo and Shelton Brown
Screening for Mycobacterium tuberculosis infection in those at high risk for developing clinical tuberculosis (TB) is a key strategy of the Centers for Disease Control and Prevention (CDC) to control the spread of TB in the US. This is particularly important at the US/Mexico border, where converging socioeconomic and demographic factors contribute to the higher burden of TB when compared to the US national average.  This region also has high prevalence of type II diabetes (DB), which has long been known to predispose to active tuberculosis.  Based on this information, we hypothesize that DB contributes to the burden of TB in the Hispanic population from four Texan counties along the Mexican-American border. Four counties in the Lower Rio Grande Valley (LRGV) are being analyzed in this pilot project: Hidalgo, Cameron, Willacy and Starr, and compared to the data from the 15 border counties with Mexico, and with the entire state of Texas. A secondary analysis of the Texas hospital discharges during 2001 is being implemented using ICD 9 codes for case and control selection. Unconditional multiple logistic regression analysis is being used to evaluate the relationship between tuberculosis and tentative associated factors. Aim 1 is to determine the degree of association of DB and TB among Hispanics in the LRGV. Our preliminary analysis indicated that the most susceptible population for TB in the LRGV are Hispanic males with 45 years or older (p≤ 0.005). In the border counties similar sociodemographic risk factors were found, but the age group was 18 years or older.  For the entire state of Texas the risk was extended to Black individuals. DB was a risk factor for TB (odds ratio= 1.7, 1.5 and 1 for the LRGV, 15 counties or all Texas, respectively). For aim 2 we are examining the strength of the association between TB and its associated risk factors (besides DB), with emphasis on underlying medical conditions. Data indicates that HIV is the major risk factor (OR= 203.5, 102.2 and 80.3 for LRGV, 15 counties and all Texas, respectively), followed by nutrition deficit (OR=8.5, 28.3 and 5.9 for LRGV, 15 counties and all Texas, respectively). Other risk factors in order of importance included septicemia, lung disease, alcohol abuse and cancer. For Aim 3 we will estimate health production function that will identify relevant socio-economic indicators of TB and DB.

IV.   Summary of key investigators
 Dr. Joseph McCormick and Dr. Susan Fisher-Hoch have extensive experience working in clinical studies in developing countires (see biosketches), including urban Karachi and rural Africa.  Their studies include comprehensive clinical trials of intravenous ribavirin to treat viral hemorrhagic fevers, and Phase IV studies of polio in Pakistan.  Dr. McCormick has further experience in that he established and developed the epidemiology division of Aventis Pasteur in France, and thereby gained extensive experience in pre and post licensure vaccine studies, vaccine development, marketing and the implementation of vaccine programs.  He also has extensive experience in outbreak control using vaccines.  Drs. McCormick and Fisher-Hoch have experience of the massive problems facing TB control in South Asia, and have contributed to several studies looking at these difficult public health situations.  On their return to the United States they sought out a location which would allow them to apply this experience to serious public health problems, and on their arrival to establish a research program on the US/Mexico border it was clear that TB led the field in candidates for public health, basic science and intervention studies.  It was also clear that given the close proximity of high technology in Texas and high rates of endemicity in Mexico, that the opportunity was there to perform unique studies with good quality control of all aspects of data, and at reasonable cost in a community that is eager to participate in well conducted research.  Dr. Restrepo was recruited to lead and develop this program (see biosketch), and has already made considerable progress in gaining funds and establishing several studies.  She is supported by Dr. Belinda Reininger (see biosketch) who provides behavioral science expertise, and Dr. Adriana Perez (see biosketch) who leads the biometrics support program on site.  The site has developed collaboration with experts in TB, namely Dr. David McMurray of Texas A&M, and Dr. Edward Graviss of Baylor College of Medicine (see biosketches).  This new program will continue to develop by incorporating other experts who can make specific needed contributions and by seeking further funds for more in depth studies.  The program receives enthusiastic support from the Texas Department of Health both locally and in Austin, where Dr. Eduardo Sanchez, the Director of TDH is taking particular interest in our progress and providing us with whatever support he can.

Reference List

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   11.    Bastida E, Cuellar I, Villas P. Prevalence of diabetes mellitus and related conditions in a south Texas Mexican American sample. J Community Health Nurs 2001;18(2):75-84.

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   13.    Hanis CL, Chu HH, Lawson K, Hewett-Emmett D, Barton SA, Schull WJ et al. Mortality of Mexican Americans with NIDDM. Retinopathy and other predictors in Starr County, Texas. Diabetes Care 1993;16(1):82-9.

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