The TBRU Epidemiology component is headed by Christopher Whalen, M.D.,MS. There are two research phases which are based on the TBRU contract periods: The first phase was from 1994 - 2000 and was called the Household Contact (HHC) study; the second from 2000 - 2006 and is now called the Kawempe Community Health (KCH) study. The first phase focused on the epidemiology of tuberculosis in households of infectious index cases; the second phase evolved into a population-based study of TB risk factors and transmission.

Description of Study Aims

This study is a systematic approach to study TB using a household contact design comprising a hybrid of a cross-sectional and cohort study designs towards furthering the scientific understanding of the epidemiology of tuberculosis In populations with a high prevalence of disease.

Work Statement

The overarching goal of the Epidemiology Component of the TBRU is to develop and implement a systematic approach towards furthering scientific understanding of the epidemiology of tuberculosis in populations with a high prevalence of disease. The specific aims are:

1. To implement studies for the assessment of critical host factors associated with primary infection, re-infection, reactivation, and progression of clinical disease.
2. Implement the capability to identify and track individual strains of M. tuberculosis.
3. Implement incidence and prevalence surveys in the population proposed to provide the background information for phase II/III vaccine or therapeutic clinical trials
   

Study Rationale

The initial TBRU contract (1994 -1999) period established that the household contact design is an excellent model, or systematic approach, for the study of tuberculosis epidemiology, transmission dynamics, genetics, and immunology. Evaluation of household contacts allows for efficient identification of individuals with different stages of tuberculosis infection: exposed and uninfected, exposed and infected without disease, recent infection (skin test converters), and active tuberculosis. These groups can form the basis for comparing behavioral, clinical and epidemiologic characteristics, genetic and host immune responses.

HHC Study (1994-2000)

Objectives:

• To evaluate the value of contact tracing in an area of high prevalence of tuberculosis
• To determine factors relating to the index case and the household contact, and the organism that are associated with tuberculosis infection and active disease
• To estimate the rate of household transmission with disease progression in the households of index cases.
  to describe the spectrum of tuberculosis in children exposed to the index case and determine sensitivity and specificity of new diagnostic strategies
• To conduct preliminary immunogenetic studies on the susceptibility of tuberculous infection and active tuberculosis
• Determine feasibility of studying incident cases in household contacts

Component Projects:

• Spectrum of tuberculosis in household contacts
• Impact of HIV on MTB transmission and disease
• Effect of BCG Vaccination onTB skin test reactivity in household contacts
• Transmission dynamics of tuberculosis transmission in households versus the community
• TB diagnostics in children
• Immunology of household contacts
• Genetic analysis of intermediate phenotype
• Assessment of M. tuberculosis virulence

Major Findings:

• One in 20 contacts of smear-positive index cases has active TB
• Household acts as system of risk for disease, not as a collection of individual risk factors
• BCG vaccination does not interfere with the interpretation of theTST in household investigations
• HIV infection in the index case does not alter risk of infection or disease in household contacts
• HIV infection in the household contact increases the risk for disease but not infection
• Attack rate for tuberculous infection is between 30-40% in these households
• Tnfα expression has a high degree of heritability
• Ifng expression is highly variable among patients with a reactive TST
• Compared with adults, children with tb have high levels of both tnfα and ifnγ
  
• Molecular diagnosis of TB in children has good sensitivity and fair specificity
  
• 35% of TB cases is contacts is caused by a strain different from the index case strain
  
• Young age and low body mass were predictors of a chain of transmission where as HIV status was a predictor of transmission outside the household

Overall Conclusions:

• Excellent model for studying:
  
• Transmission dynamics of M. tuberculosis
  
• Immunological correlates of infection and disease
  
• Genetic factors associated with infection and disease
  
• Virulence of M. tuberculosis strains
  

KCH Study (2000-2006)

Goals and Objectives

To address the contract goals, we have organized the study around four themes:

• General epidemiology
  
• immunology of household Contacts
  
• Genetic susceptibility to tuberculosis
  
• Transmission dynamics of M. tuberculosis in households

Study Site

The Kawempe is a division of Kampala City and has a population density of 5,081 persons/km². The total population of Kawempe and Kampala is approximately 153,900 and 774, 241 respectively. Kawempe was selected as study site because it is a has a high incidence of tuberculosis (500 cases/100,000 population) that reports to the NTLP. The division is also conveniently located adjacent to the TBRU clinical offices.

Study Design

To address the specific aims of the proposal, we are using the household contact design and embedded cross-sectional and cohort hybrid designs to study the epidemiology of tuberculosis. During the study (4/2002-4/2005), 100 index cases will be enrolled per year for a total of 300 over three years. With an average family size of 5, approximately 400 household contacts will be enrolled each year for a total of 1200 over three years. Once enrolled index cases will be started on a standard regimen of antituberculous therapy, followed monthly during therapy, and then quarterly thereafter for a minimum of one year after completion of treatment. The outcomes of interest in the index cases include cure, treatment failure, relapse and death. Systematic evaluation of culture-positive relapse cases will determine whether the cases result from reactivation or reinfection. Household contacts of index cases will be identified and evaluated through a standard household investigation that will include tuberculin skin testing (with antigens from M. tuberculosis and M. avium), chest radiography, sputum microscopy and culture (when indicated), HIV testing, nutritional assessment, and a risk assessment questionnaire. The outcomes of interest in the household contacts include skin test conversion, persistent negative PPD skin test, skin test reversion with isoniazid treatment, incident TB and co-prevalent TB. First-degree relatives, not living in the house of the index case will be identified, traced and similarly evaluated by tuberculin skin testing, chest radiography, sputum microscopy and culture (when indicated), HIV testing, nutritional assessment. The outcomes of interest in the first-degree relatives include skin test reactivity and active TB.

To determine host risk factors for disease progression, all household contacts will be followed for a minimum of two years with standard evaluations at 3 and 12 months for tuberculin conversion or reversion or active tuberculosis. Household contacts considered to be infected with M. tuberculosis will be offered isoniazid prevention therapy.

General Epidemiology:

Basic parameters of TB infection and disease will be estimated in Kawempe households or community.

Immunology of Household Contacts:

The immunology component of this study focuses on recent skin test convertors, contacts with persistent negative skin tests, and children. A panel of immune assays is used to characterize host immunity to M. tuberculosis.

Genetics:

The genetic component will use quantitative methods using intermediate phenotypes to evaluate host susceptibility to tuberculosis.

Transmission Dynamics:

This component tracks the transmission of MTB in Ugandan households using restriction fragment length polymorphism (RFLP). Strains are mapped onto a geographic information system (GIS) digital map.

Selected Papers And Manuscripts

“Tuberculosis in household contacts of infectious tuberculosis cases in Kampala”, Uganda” Guwatudde D, Nakakeeto M, Jones-Lopez EC, Maganda A, Chiunda A, Okwera A, Mugerwa RD, Ellner JJ, Bukenya G, Whalen CC (Accepted Am J. Epi.).

“Heritability of an intermediate immunologic trait for tuberculosis susceptibility”, Catherine Stein and D. Guwatudde for the TBRU (Accepted to Journal Infectious Diseases).

“The impact of HIV iInfection on transmission of tuberculosis in sub-Saharan Africa”, Guwatudde D, Kamya RM, Nakakeeto MK, Nakandi L, Musoke P, Kintu F, Bukenya GB, Okwera A, Mugerwa RD, Ellner JJ, Whalen CC (Submitted to AIDS).

“Transmission dynamics of MTB in Uganda households” Whalen C for the TBRU (In final internal review).

“Tuberculous infection in Uganda households”, Guwatudde D. for the TBRU (In preparation).

“Immunology of tuberculosis and TB infection in Uganda”, Whalen C. for the TBRU (In preparation).

“Tuberculosis in Ugandan children”, Nakakeeto M. for the TBRU (In preparation).

“Geographic distribution of TB cases according to population density in the Kawempe Division, Uganda. Chiunda A for the TBRU (In preparation).