1 Makerere University Medical School, Kampala, Uganda.
2 Mulago Hospital, Kampala, Uganda.
3 Tuberculosis Research Unit, Case Western Reserve University School of Medicine, Cleveland, OH.
4 Department of Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ.
5 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH.
Received for publication May 21, 2002; accepted for publication May 7, 2003.
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ABSTRACT |
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cohort studies; disease transmission; risk; risk factors; tuberculosis
Abbreviations: Abbreviations: BCG, Bacillus Calmette-Guérin; CI, confidence interval; HIV, human immunodeficiency virus; OR, odds ratio.
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INTRODUCTION |
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Previous studies of tuberculosis have shown that comorbidities such as HIV infection, lymphoma, and malnutrition increase the risk for active tuberculosis, yet except for HIV disease these conditions do not account for the burden of tuberculosis worldwide. Other studies have shown that environmental characteristics such as crowding and social factors (16, 17), including poverty, are associated with tuberculosis, but a causal link between environment and host factors for susceptibility has not been explicitly made. Finally, little is known about the virulence of different M. tuberculosis strains and whether it affects transmission or disease. These issues are rendered more complex where transmission of M. tuberculosis is high and recurrent exposure and reinfection may occur.
The current study was performed to examine the relative contribution of host and environmental factors to the risk of tuberculosis in African households. The household is a natural setting in which to study tuberculosis because the epidemiology of infection and disease can be characterized. In this article, we describe in detail the epidemiology of tuberculosis disease and factors associated with it in Ugandan households.
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MATERIALS AND METHODS |
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A household was defined as a group of people living within one residence who share meals together and identified a head of family who made decisions for the household. An index case was defined as the first tuberculosis case identified in the household. A household contact was defined as an individual who had resided in the household for at least 7 consecutive days during the 3 months prior to the diagnosis of tuberculosis in the index case. Secondary cases were defined as tuberculosis cases among household contacts of the index case. Secondary cases were classified as "coprevalent" if active tuberculosis was present at the time of the baseline household investigation or as "incident" if active tuberculosis was absent at the time of the baseline household investigation and developed during follow-up.
Measurements
Index cases were evaluated with a medical history and physical examination performed by Ugandan medical officers. Sputum samples were collected for microscopic examination and mycobacterial culture. Chest radiographs were taken, and HIV serology and tuberculin skin testing were performed. Index cases were treated with standard self-administered, short-course tuberculosis chemotherapy (18). Home visitors evaluated eligible household contacts at baseline with standardized questionnaires, a limited physical examination including height and weight (19), and tuberculin skin testing.
Children aged 5 years or less, HIV-seropositive contacts older than 5 years, and contacts with signs or symptoms of tuberculosis were considered tuberculosis suspects. These suspects were evaluated for active tuberculosis with a medical examination, specimen microscopy, mycobacterial culture, and chest radiograph. Children aged 5 years or less and HIV-seropositive adults without active tuberculosis were offered a 6-month course of isoniazid treatment. All confirmed secondary tuberculosis cases were treated with short-course therapy (18).
After the baseline evaluation, contacts were evaluated at 3, 12, and 24 months for active tuberculosis. Study participants were instructed to attend the study clinic at any time in case of illness. Patients not attending scheduled appointments were traced by home visitors to enhance follow-up and to determine their vital status.
Tuberculin skin testing was performed on all study subjects by placing 0.1 ml of 5 tuberculin units of purified protein derivative (Tubersol; Connaught Laboratories, Limited, Toronto, Canada) on the left forearm using the Mantoux method. After 4872 hours, the diameter of palpable induration was recorded by home visitors using standardized procedures (20). A tuberculin skin test was considered positive if it was 5 mm or greater (21).
A posteroanterior chest radiograph was taken on all study subjects at baseline and on tuberculosis suspects. The extent of disease on these radiographs was graded on a four-category ordinal scale by experienced physicians (22).
Three sputum samples were collected from index cases and tuberculosis suspects. A sputum smear grade of acid-fast bacilli was recorded on a four-point ordinal scale (23). In children and patients unable to produce a sputum sample, gastric lavage was performed. Specimens were cultured on Lowenstein-Jensen slants at 37°C and examined weekly for 8 weeks.
HIV testing by enzyme-linked immunosorbent assay (Cambridge BiosScience, Worcester, Massachusetts) was performed with counseling on all consenting study subjects. For children 5 years of age or younger, HIV testing was done when the mother was seropositive or when the child was diagnosed with active tuberculosis; otherwise, a child was considered HIV seronegative if the mother tested negative.
The household environment was assessed for dwelling type, number of people in the household, number of habitable rooms, and number of windows in the house. A house was classified as a "muzigo" if it was a multifamily housing unit on the same building block, usually with one or two rooms per family.
Tuberculosis was classified as definite, probable, and possible tuberculosis (24) by investigators using clinical, radiographic, and microbiologic findings in tuberculosis suspects. Response to therapy was defined by improvement of radiographic abnormalities and weight gain with treatment. For this analysis, active tuberculosis was defined as definite or probable tuberculosis. In three incident cases, review of baseline chest radiographs indicated subtle abnormalities in the area of subsequent disease; these cases were reclassified as coprevalent instead of incident cases in this analysis.
Analytical strategy
The goal of the analysis was to determine whether characteristics of the index case, household contact, and environment were associated with active tuberculosis in household contacts. The main outcome was active tuberculosis in a household contact; separate analyses were performed for coprevalent and incident tuberculosis. To determine factors associated with active tuberculosis in contacts, we performed a univariate analysis with secondary tuberculosis as the outcome. Predictor variables included clinical and epidemiologic characteristics of the index case and household contacts, as well as environmental factors. Variables associated with tuberculosis in the univariate analysis (p < 0.15) were retained for the multivariable analysis. A series of logistic regression models were fit using the generalized estimation equation method (SAS version 8.0, PROC GENMOD; SAS Institute, Inc., Cary, North Carolina) to adjust for household correlations (25). No two-way interaction effects were found. Crude and adjusted odds ratios and 95 percent confidence intervals are reported.
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RESULTS |
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Tuberculosis patients
As shown in table 3, among the 302 index cases, there was a 1:1 male:female ratio, only 54 percent had BCG scars, and 49 percent were HIV seropositive. Cough was present in all the cases, and it had lasted more than 90 days in half of the patients. The chest radiograph at diagnosis indicated either moderately advanced or far advanced disease in 86 percent of the index cases. All index cases were smear positive, most with high smear grades and positive mycobacterial cultures.
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Coprevalent cases aged more than 5 years were more likely to be female or HIV infected when compared with index cases. Like children with coprevalent disease, older coprevalent cases had a shorter duration of symptoms and less advanced disease on chest radiograph than did index cases. Unlike children, 13 of 17 coprevalent cases aged more than 5 years (77 percent) were confirmed through culture.
Children aged 5 years or less and HIV-seropositive contacts carried the highest risk for active tuberculosis (table 4). In this logistic regression model, age was the only confounder of the association between HIV infection and tuberculosis. In stratified analyses, the proportion of tuberculosis cases was lower in BCG-vaccinated versus nonvaccinated contacts, among not only children (8 percent vs. 19 percent; odds ratio (OR) = 0.41, 95 percent confidence interval (CI): 0.19, 0.89) but also older contacts (3.5 percent vs. 7.2 percent; OR = 0.46, 95 percent CI: 0.25, 0.86). A similar association between BCG vaccination and disease was seen in HIV-seropositive (17 percent vs. 34 percent; OR = 0.45, 95 percent CI: 0.18, 1.09) and HIV-seronegative (9 percent vs. 12 percent; OR = 0.62, 95 percent CI: 0.33, 1.15) contacts. Cavitary disease in the index case, prolonged contact with an index case (>18 hours/day), and muzigo residence were independently associated with coprevalent disease (table 4). Other host factors were not significantly associated with active tuberculosis in the contacts.
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At the time of baseline household investigation, HIV infection and the presence of chronic cough in the contact were associated with the development of incident tuberculosis (table 5). The rate of tuberculosis tended to be lower in 236 contacts treated with isoniazid compared with 925 contacts not treated (1.7 percent vs. 2.2 percent; OR = 0.75, 95 percent CI: 0.26, 2.24). Of the 236 contacts that received isoniazid treatment, 185 contacts completed 56 months of treatment, and tuberculosis occurred in three of these contacts.
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DISCUSSION |
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The presentation of the secondary tuberculosis cases differed from that of the index cases and posed challenges to the diagnosis of tuberculosis in the household contacts. These challenges were imposed partly by the young age of the contacts and the inherent difficulty in making the diagnosis of active disease in children (26, 27). The diagnostic criteria for pediatric tuberculosis used in the study were conservative, requiring either culture or smear evidence of disease and weight gain or improvement in chest radiograph appearance with treatment. Children with minimal extent of disease on chest radiograph were not often considered to have disease unless additional signs or symptoms of tuberculosis were present.
The challenge of diagnosis was also imposed by the early stage of tuberculosis at presentation. Although no formal staging system for active tuberculosis exists, many of the secondary cases presented with pauci-bacillary, minimal disease. This presentation differed markedly from that of the index cases, who often had advanced signs and symptoms, moderate or advanced disease on chest radiograph, and positive sputum microscopy or mycobacterial culture. Further, many incident cases had a chronic cough at the time of the baseline household evaluation but no other evidence of active tuberculosis despite a detailed clinical evaluation, sputum examination and culture, and chest radiography. If these persons with cough at baseline had subclinical, active disease and were misclassified, then conventional methods for diagnosis were inadequate. Finally, the presentation of secondary cases may have been affected by the prevalence of HIV infection in the population (approximately 10 percent) and the atypical presentation of tuberculosis seen in HIV-infected persons. The methods for diagnosis of tuberculosis in advanced disease are, for the most part, satisfactory, but the findings from our study emphasize the need for diagnostic tools that identify tuberculosis in its early stages.
Because secondary cases often present with subtle manifestations of disease, one may ask how best to identify these cases in the context of household investigation. The risk of transmission of M. tuberculosis has been correlated with the clinical characteristics of the index case (4, 28, 29) and behaviors that promote contact with infectious cases (16, 29). Once infection has occurred, the risk for disease is attributed to the duration of infection (30) and intrinsic characteristics such as age (31), body build (32), BCG vaccination (33), HIV infection (34), and host genetic susceptibility (35, 36).
In the current study, we found that young age and HIV infection were associated with increased risk for active tuberculosis at the time of contact evaluation, whereas BCG vaccination reduced the risk. Ten percent of children aged less than 5 years had active tuberculosis at the time of the contact investigation. The findings in children must be interpreted with caution because culture-confirmed cases were few (26 percent), giving rise to the possibility of misclassification and overestimation of disease status in the young children. Of the 123 HIV-seropositive contacts, 23 percent had or developed active tuberculosis, indicating the high risk for tuberculosis faced by these individuals, as seen in other studies (12, 13, 37, 38).
BCG vaccination was the only factor that reduced the risk for tuberculosis among contacts of all ages, even in this setting of acute transmission. For contact cases, the magnitude of protection based on the adjusted logistic regression model was 49 percent and is consonant with published studies (33, 39). These findings support the continued use of BCG vaccination in Uganda where transmission of M. tuberculosis is high and where HIV infection is endemic. Isoniazid treatment of latent tuberculosis infection reduced the risk of incident tuberculosis, but the magnitude of protective effect, 25 percent, was less than the protective effect of 77 percent seen in clinical trials (11). This attenuated effect may result from incomplete adherence with treatment, as it was self-administered, or from the short duration of treatment. Revised guidelines for the treatment of tuberculosis infection recommend 9 instead of 6 months of treatment (40). The moderate effect observed with the shorter regimen provides support for longer periods of isoniazid treatment in this setting.
In this study, host characteristics were not the only factors associated with secondary tuberculosis in households. Cavitary disease in the index case, duration of daily contact with the index case, and type of housing were also associated with the risk for disease. In previous household contact studies, the presence of acid-fast bacilli in the sputum of the index case was a consistent predictor of active disease in household contacts (3, 4, 6, 28). Because we enrolled only patients with smear-positive tuberculosis, it was not possible to examine the effect of smear-negative disease on tuberculosis in the household. Among smear-positive patients, the presence of cavitary disease in the index case was found to be important. Cavitary disease has been associated with a greater burden of organisms and greater grade of acid-fast bacilli (41). These two clinical measures were highly correlated in our study, suggesting that patients with cavitary disease had a high burden of organisms and were highly infectious.
Among the many environmental factors explored, only the duration of contact with the index case and the muzigo type of housing were associated with disease. These factors likely measured the nature of contact with the index case. Of the variables included to assess the intensity of contact with the index case, contact of more than 18 hours per day was associated with the presence of active tuberculosis. In many instances, prolonged contact occurred when the caregiver of a dependent child had active tuberculosis, most often the mother. A muzigo is a building with multiple rooms that often share air space. These dwellings have limited ventilation, usually with only one door or window, and are often crowded, so they are an efficient type of setting for transmission of tuberculosis.
Why would these environmental factors, usually associated with transmission of M. tuberculosis and tuberculous infection, be associated with development of disease? The results of the study are consistent with at least two possible explanations. First, recent infection with M. tuberculosis confers a high risk for developing progressive primary tuberculosis (30). Second, environmental features could be markers for or determinants of risk for tuberculosis (16, 29). This explanation is likely because the environmental factors and host characteristics were correlated in this study. Indeed, there was a web of connectedness among the many factors associated with tuberculosis (figure 3), consistent with a multicausal model for tuberculosis (4244). In this web, young children appear most vulnerable. For example, although young children were more often vaccinated with BCG, they more often lived in crowded muzigos and had more contact-hours with infectious cases. The only factor not linked with the other risk factors was cavitary disease in the index case. Although each factor was independently associated with the risk of tuberculosis, thereby conferring unique information about the risk for disease, the web of connections between these host and environmental factors suggests that the household may function more like a complex system of risk than a collection of individuals at risk.
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In conclusion, tuberculosis is common among household contacts of index cases in Africa, especially among young children and HIV-infected contacts. Host risk factors cannot, however, be completely distinguished from the effects of environmental risk factors, suggesting that a household may represent a complex system of interacting risks for disease. Household evaluation of contacts is hindered by shortcomings of current diagnostic methods for early or minimal disease. New approaches to household contact tracing will require improved diagnostic methods and assessment of household environmental risks. Further efforts to improve living conditions and to control HIV infection are essential in reducing household risk for tuberculosis in Africa.
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ACKNOWLEDGMENTS |
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The authors would like to acknowledge the invaluable contribution made by the study medical officers, health visitors, and data clerk: Dr. Sarah Zalwango, Dr. Love Nakende, Barbara Kyeyune, Margaret Nansumba, Faith Kintu, Gladys Mpalanyi, and Philo Nassozi. They would like to acknowledge and thank Dr. Francis Adatu Engwau, Head of the Uganda National Tuberculosis and Leprosy Program, for his expert advice and support of this project. They would like to acknowledge Dr. Alphonse Okwera and the staff of the National Tuberculosis Treatment Centre, Mulago Hospital, the Ugandan National Tuberculosis and Leprosy Program, and the Uganda Tuberculosis Investigation Bacteriological Unit, Wandegeya, and thank them for their contributions to this study.
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NOTES |
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REFERENCES |
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