Risk Factors for Trachoma: 6-Year Follow-up of Children Aged 1 and 2 Years
Yu-Hsiang Hsieh1,2,
Linda D. Bobo1,
Thomas C. Quinn3,4 and
Sheila K. West5
1 Division of Pediatric Infectious Diseases, Department of Pediatrics, School of Medicine, The Johns Hopkins University, Baltimore, MD.
2 Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD.
3 Division of Infectious Diseases, Department of Medicine, School of Medicine, The Johns Hopkins University, Baltimore, MD.
4 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
5 Dana Center for Investigative Ophthalmology, The Johns Hopkins University, Baltimore, MD.
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ABSTRACT
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The authors investigated the long-term stability of risk factors in predicting the presence of active trachoma and severe inflammatory trachoma in 176 children in Kongwa, Tanzania, who were aged 1 and 2 years in 1989 and were available for follow-up in 1995. Familial cattle ownership, living more than 2 hours away from a water source, and facial cleanliness at both time points were associated with the presence of active trachoma at both time points (odds ratio (OR) = 2.58, 95% confidence interval (CI): 1.15, 5.79; OR = 3.07, 95% CI: 1.23, 7.64; and OR = 0.52, 95% CI: 0.26, 1.03, respectively). An association of familial cattle ownership with facial cleanliness and water accessibility was observed. Having a clean face at both time points was associated with lower odds of active trachoma at both time points for children in non-cattle-herding families (OR = 0.40, 95% CI: 0.18, 0.87). Living more than 2 hours away from a water source at both time points increased the odds of active trachoma at both time points in children of cattle-herding families (OR = 8.00, 95% CI: 1.99, 32.10). Noticeably, severe inflammatory trachoma at baseline predicted mortality in children from villages in which trachoma was less common (OR = 3.75, 95% CI: 1.09, 12.98). The results suggest that risk factor reduction could diminish persistent disease. Am J Epidemiol 2000;152:20411.
child; Chlamydia trachomatis; hygiene; mortality; risk factors; trachoma
Abbreviations:
CI, confidence interval; DFA, direct fluorescent antibody; OR, odds ratio; PCR, polymerase chain reaction; EIA, enzyme immunoassay.
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INTRODUCTION
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Trachoma is still one of the leading causes of blindness worldwide, especially in many developing countries of Africa, Asia, Latin America, and Oceania (1
, 2
). It is believed that repeated ocular Chlamydia trachomatis infections result in a broad spectrum of clinical signs of trachoma, from follicular trachoma or intense inflammatory trachoma in children to conjunctival scarring in young adults and trichiasis/entropion in older adults (3
). The latter sign can lead to blindness in later adulthood. Studies have identified a subgroup of children in trachoma-hyperendemic communities with chronic, severe disease and some with persistent infection (4
, 5
). It is suspected that this group of children is at high risk of developing severe sequelae later in life. However, a significant proportion of people with chlamydial infection do not have any clinical signs, and, cross-sectionally, a significant proportion of people with clinical trachoma have no laboratory evidence of C. trachomatis infection (6
, 7
). It is likely that multifactorial interactions between the host and chlamydia determine the clinical presentation and duration of trachoma in the face of infection (5
).
Epidemiologic factors, including demographic, socioeconomic, environmental, biologic, and genetic, have been associated with clinical trachoma and with ocular chlamydial infection in cross-sectional studies and in longitudinal studies with intermittent 1-year follow-up (4
, 5
, 8

11
). However, the strength of the relation of these epidemiologic factors to subsequent disease after a longer follow-up period remains to be elucidated. Moreover, to our knowledge, the association of trachoma severity with subsequent mortality in children has not been explored.
High mortality among very young children in sub-Saharan countries is still a tremendously devastating health issue for the underserved populations. Infectious diseases such as malaria, measles, and acquired immunodeficiency syndrome, as well as malnutrition and poverty, have been linked to mortality of young children (12
). Factors associated with childhood mortality, such as socioeconomic status and poor water sources, are also related to the presence of trachoma (13
). In addition, host haplotypes of human lymphocyte antigen that might affect a person's survival from other infections may contribute to differential immune and clinical responses to chlamydial infection and disease presentation (14
,
). It is possible that severe clinical manifestations of trachoma are linked to mortality of young children through other infectious processes or that severe inflammatory trachoma could be an indicator for poor socioeconomic status in association with a specific host genetic makeup that predisposes to mortality.
The purposes of this study were threefold. We aimed to 1) identify epidemiologic factors as predictive indicators for the presence of active trachoma and severe inflammatory trachoma 6 years later in a cohort of children in a trachoma-hyperendemic region, 2) predict trachoma at a later time point according to previous trachoma status, and 3) examine the association between trachoma severity and childhood mortality.
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MATERIALS AND METHODS
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Subjects
Kongwa, Tanzania, is a trachoma-hyperendemic area in which 60 percent of preschool children suffer from this disease (10
). In 1989, a face-washing intervention was carried out at the village level. Six villages were randomized into two arms: the first to receive mass topical tetracycline treatment followed by an intense 1-month health education campaign about face washing, the second to receive mass topical tetracycline treatment alone (16
). The community-based clinical trial reported that the intervention had a modest effect on improving facial cleanliness and that children with clean faces postintervention, in either arm, were less likely to have severe trachoma at 1 year. In each village that participated in this trial, 250 households with at least one child aged 17 years were randomly selected after a complete census was taken. In each household, one child (aged 17 years) was randomly selected to serve as an index child (16
). All 289 children aged 1 and 2 years from the five villages that were part of the trial in 1989 were identified from the files of the Kongwa Trachoma Project (one village was excluded because it was enrolled in another project). These children were traced, and 176 children were found in 1995 for this follow-up study. Because children aged 37 years in 1989 would be aged 913 years in 1995, and trachoma rates decline dramatically after age 7 years (10
), we chose to study only the children aged 1 and 2 years from the original trial.
In 1989, data were collected on age, gender, residential village and neighborhood, and familial socioeconomic status as represented by the presence of a tin roof on the house and cattle ownership (16
). Maternal educational level was categorized as "some" if the child's mother had received any school education or "none" is she had never received any education. The time required to walk from the house to the nearest water source during the dry season was also determined as more than or less than 2 hours. In addition, the facial hygiene status of children was evaluated by trained local interviewers who looked for the presence of ocular or nasal discharge (16
). A clean face was defined as having none or only one facial sign present. Additional data collected in 1995 included tribal affiliation (being Mkaguru). The reasons for loss to follow-up were collected and were coded as refusal, death, or migration.
Two photographs of the right tarsal conjunctivum of each child were taken before a sample was collected for C. trachomatis at each time point. In 1989, the tarsal conjunctivum of the right eye of each child was sampled by using a cotton-tipped Dacron swab (Baxter Health Corporation, McGaw Park, Illinois), which was then rolled on direct fluorescent antibody (DFA) slides. In 1995, the ocular sample was placed in polymerase chain reaction (PCR) transport buffer (6
). Verbal informed consent was obtained from participants' parents. Children with active trachoma identified clinically were treated with topical tetracycline after samples were collected. All study procedures were approved by the Joint Committee on Clinical Investigation of The Johns Hopkins Hospital, Baltimore, Maryland, in accordance with the Declaration of Helsinki.
Clinical grading of trachoma
Trachoma was graded by using the photographs of the right tarsal conjunctiva and the simplified grading scheme of the World Health Organization (17
): follicular trachoma if at least five follicles of >0.5 mm were observed, severe inflammatory trachoma with or without follicles if 50 percent or more of the deep tarsal vessels were occluded, and scarring if any scarring was evident. Active trachoma was defined as the presence of severe inflammatory or follicular trachoma. The photographs were graded by a trained reader who was masked regarding village, child's name, and laboratory results.
Laboratory procedures
Each DFA slide was scraped with an individual razor blade; the scrapings were then suspended in 100 µl of water and were boiled for 10 minutes (18
). A diagnostic PCR/enzyme immunoassay (PCR-EIA) for a conserved omp1 280 base-pairs gene fragment was performed (19
). Processing controls for DNA contamination consisted of known DFA sample slides that were both DFA and PCR negative from a previous study and were included in every 10th sample slide. The samples collected in 1995, which were in transport buffer, were processed as described previously (6
). The diagnostic PCR-EIA was performed on all samples by using methods described previously (6
, 19
). Taq DNA polymerase (2.5 units) (Boehringer-Mannheim, Indianapolis, Indiana) was used in all PCRs.
Data analysis
Characteristics of availability for follow-up were compared by conducting contingency table analyses. McNemar's test was used to examine the trend in trachoma for the children who were followed up during the 6-year period. To investigate the odds of trachoma, logistic regression models were used to predict either active trachoma as a function of previous active trachoma status or severe inflammatory trachoma as a function of previous severe inflammatory trachoma after adjusting for age and gender.
Multivariate logistic regression was used to examine the association between trachoma and explanatory variables in the following analyses. To determine long-term predictive ability, risk factors at baseline were used to predict trachoma and infection status in 1995. In addition, the associations between risk factors in 1989 and a measure of "persistent trachoma" were studied by using active trachoma or severe inflammatory trachoma at both time points. Finally, the effects on "persistent" active trachoma and severe inflammatory trachoma were evaluated by using risk factors present at both time points and risk factors that changed over time.
The risk of "persistent" active trachoma was modeled further by exploring the potential effect modification of familial cattle ownership on facial cleanliness and water accessibility. Multivariate logistic regression analysis was used to assess effect modification after adjusting for age, gender, and maternal education.
The association between childhood mortality, trachoma, and C. trachomatis infection at baseline was examined after adjusting for age, gender, familial cattle ownership, and mother's educational level. The potential effect modification of trachoma prevalence in the village was assessed further by using multivariate logistic regression analysis. Villages were stratified into two groups based on the prevalence of active trachoma in 1989: 1) trachoma "high-prevalence villages," with a 77 percent prevalence of active trachoma; and 2) trachoma "low-prevalence villages," with prevalences of 45, 59, and 65 percent (figure 1).

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FIGURE 1. Subdistricts of the Kongwa district, Dodoma Region of Tanzania. , study villages; *, study administrative site. Prevalence rates of active trachoma for each village in 1989 are shown in parentheses; 1 mile = 0.62 km.
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RESULTS
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Characteristics of children followed versus lost to follow-up
Sixty-one percent (176/289) of the children aged 1 and 2 years who were identified from Kongwa Trachoma Project files in 1989 were available in 1995. Except for disease status, the baseline characteristics of the children who could not be located for follow-up were similar to those for the children who were followed up (table 1). Compared with children who were followed up, children lost to follow-up tended not to have severe inflammatory trachoma or C. trachomatis infection and to live in families that did not own cattle. None of the other epidemiologic characteristics of children who were followed up in 1995 and children who were not was significantly different. In the subset of 28 (10 percent) children lost to follow-up because of death, 61 percent were aged 1 year in 1989 compared with 38 percent who were aged 1 year and available for follow-up in 1995 (table 1). Death rates were higher for younger children, so this finding was expected. Two (0.7 percent) children did not participate in 1995 because their parents refused permission.
Change in prevalence of trachoma and infection during 6-year follow-up
Among the 176 children who were followed up, the prevalence of active trachoma dropped significantly from 70 to 55 percent (p < 0.05, McNemar's test), while the prevalence of severe inflammatory trachoma dropped slightly from 33 to 25 percent. Such a decline parallels the age-specific declines in prevalence found in other epidemiologic studies (9
, 10
, 20
). The prevalence of ocular chlamydial infection in 1995 was 40 percent. We did not compare infection rates from baseline to follow-up because different techniques were used at each time point.
Stability of risk factors in 1989 and 1995
The presence or absence of trachoma and four epidemiologic factors for the same children in 1989 and 1995 are illustrated in table 2. At both time points for the 176 children available for follow-up, 44 percent had active trachoma, 19 percent were free of active trachoma, and a significant proportion (14 percent) had severe inflammatory trachoma. The status of over 80 percent of the children did not change regarding familial ownership of cattle or the presence of a tin roof on the house, indicating stability for this risk factor. However, there was a 36 percent improvement in facial cleanliness, and 25 percent of the children had better access to water in 1995 (table 2). The improvement in cleanliness could not be linked to the 1989 intervention, as the degree of improvement was similar for children in intervention and control villages (data not shown).
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TABLE 2. Comparison of characteristics in 1989 with those in 1995 for 176 children* available for follow-up for trachoma, Kongwa, Tanzania
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Prediction of disease 6 years later by baseline disease status
Disease status in 1989 was used to predict disease status in 1995. Children with active trachoma in 1989 were more likely to have the same outcome in 1995 after adjustment for age and gender (odds ratio (OR) = 3.10, 95 percent confidence interval (CI): 1.58, 6.11). Similarly, severe trachoma in 1989 predicted severe trachoma 6 years later (OR = 3.96, 95 percent CI: 1.93, 8.16).
Risk factors in 1995
Children who lived more than 2 hours away from a water source in 1989 were more likely to have severe inflammatory trachoma (OR = 2.15, 95 percent CI: 1.01, 4.58). In addition, familial cattle ownership at baseline was marginally associated with the presence of trachoma (OR = 1.82, 95 percent CI: 0.91, 3.62). No other variables except disease status (as described above) at baseline were associated with trachoma 6 years later.
Risk factors for persistent trachoma
The results of further analyses of risk factors for the presence of "persistent" trachoma (trachoma at both time points) are shown in table 3. Familial cattle ownership in 1989 was significantly associated with the presence of active trachoma at both time points, while facial cleanliness in 1989 was marginally protective against disease at both time points. In addition, living more than 2 hours away from a water source in the dry season and familial cattle ownership in 1989 were predictors for severe inflammatory trachoma at both time points.
The risk of persistent trachoma may be more likely if the risk factors are consistently present and less likely if the risk factors improve over time. Some factors in our study, such as distance to water, changed over time. Therefore, familial cattle ownership, having a tin roof on the house, facial cleanliness, and living more than 2 hours away from a water source in the dry season at both time points were evaluated for their effect on persistent trachoma (table 4). In fact, familial cattle ownership and living more than 2 hours away from a water source in the dry season at both time points were associated with the presence of persistent active trachoma. In addition, familial cattle ownership at both time points was a predictor for the presence of persistent severe inflammatory trachoma, although the confidence interval overlapped 1.00. Thus, a sustained distance to water was important regarding the presence of persistent trachoma.
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TABLE 4. Presence of disease in both 1989 and 1995 in association with categorical variables present at both time points for 176 children, Kongwa, Tanzania
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Reduction in disease prevalence by a change in risk factors
To determine whether a modification of risk factors (other than age and gender) would change the risk of trachoma, we investigated factors that could change over time (table 5). Children who had an unclean face at baseline but a clean face at follow-up had a reduced risk of severe inflammatory trachoma when compared with those whose faces were unclean at both time points (table 5). A change in status regarding cattle herding or distance to a water source also was related to disease reduction in 1995, but the associations were not statistically significant after adjustment for age, gender, maternal education, and active trachoma status at baseline.
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TABLE 5. Reduction in active trachoma or severe inflammatory trachoma in children in 1995 associated with change in the status of risk factors at the subsequent time point, Kongwa, Tanzania
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We hypothesized that the risk associated with familial cattle ownership might overwhelm a protective effect of facial cleanliness and interact with water accessibility to increase the odds of trachoma. We observed effect modification by familial cattle ownership on facial cleanliness and distance to a water source after adjusting for age, gender, and maternal education (table 6). For children in families without cattle, sustained facial cleanliness at both time points was associated with significant protection against "persistent" active trachoma. This protective effect did not occur for children in families with cattle. Compared with children whose families did not own cattle and lived less than 2 hours from a water source at both time points, children who lived more than 2 hours from a water source at both time points were eight times more likely to have "persistent" active trachoma if their families also owned cattle.
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TABLE 6. Effects of facial cleanliness and water availability on a child's risk for active trachoma at both time points 6 years apart, by familial cattle ownership status, Kongwa, Tanzania, 19891995
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Child mortality and severe inflammatory trachoma
Ten percent of the study children aged 1 and 2 years in 1989 were known to have died by 1995. After adjustment for age, gender, familial cattle ownership, and maternal education, there was a tendency for active trachoma, severe inflammatory trachoma, and C. trachomatis infection to predict the death of children (table 7). Severe inflammatory trachoma was the strongest predictor of mortality and was most marked in villages in which the prevalence of trachoma was 65 percent or less.
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TABLE 7. Six-year child mortality predicted by disease and infection in 1989 in high- and low-prevalence villages, Kongwa, Tanzania
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DISCUSSION
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In probably the longest prospective study of children with active disease yet reported, we found that children who had active trachoma, severe inflammatory trachoma, or C. trachomatis infection early in life were more likely to have trachoma and infection 6 or 7 years later in this trachoma-endemic area. Prevalence and duration of trachoma in children appear to decrease with age (10
, 20
). Reasons for this decline are not well understood. Some evidence exists that the immune system in older children may generate some degree of protective immunity to chlamydial reinfection (21
). There may be less exposure to C. trachomatis with increasing age because of improved hygiene and less exposure to young children.
In this study, we expected to find a decline in active trachoma 6 years later in children aged 1 and 2 years at baseline. However, a significant proportion of children (44 percent) tended to have trachoma at both time points. In one longitudinal study in Gambia with three time points over 20 months, persons who previously had moderate or severe trachoma were more likely to have active disease at subsequent examinations during the 20-month period compared with those who had mild trachoma (22
). We demonstrated previously that subsets of children in this region tended to have persistent, severe disease within 1 year and, in another study, to be infected for up to 3 months (4
, 5
). In this study, the presence of active trachoma and severe inflammatory trachoma at baseline was predictive of trachoma and severe inflammatory trachoma 6 years later, confirming our previous findings.
One possible explanation for "persistent" disease is that the child is at high risk for constant reinfection. This explanation assumes that by reducing chlamydial reinfection through modification of behavioral, hygiene, and environmental factors or administration of antibiotic treatment, "persistent" disease also will be reduced (4
, 16
, 23
25
). Our data suggested that the risk of having severe trachoma at the second time point was reduced by changing the status of facial hygiene during a 6-year period. In addition, we also demonstrated that maintaining risk factors at both time points, including a long distance to a water source and an unclean face, at least among children in the non-cattle-herding families, was associated with "persisting" disease.
Public health interventions for trachoma endemicity should consider different approaches. The majority of children's families in this study did not own cattle; for them, it is likely that interventions to improve water availability and increase facial hygiene could reduce the number of repeated episodes of active trachoma. Further research is warranted on why such factors are not as protective for children in families with cattle.
An additional explanation for "persistent" disease is that it represents persistent C. trachomatis infection and not exogenous reinfection. It has been demonstrated that persistent ocular C. trachomatis infection is associated with high chlamydial loads versus sporadic infection being associated with a low chlamydial burden (5
). In addition, interferon-
can induce persistent chlamydial infection in tissue-cultured cells (
). Genotyping on the major outer membrane protein gene (omp1) in 22 children with "persisting" infection in our study demonstrated that almost half of the children had the same omp1 genotype at both time points. Thus, a subgroup of children may never clear infection. The data suggest that host-associated factors may interact with socioenvironmental risk factors to maintain disease in this cohort.
In this study, 10 percent of the children aged 1 and 2 years in 1989 were not available for follow-up in 1995 because they had died. The overall number of children who died during the 6-year period could be higher, since mortality information was unknown for those lost to follow-up. However, the similar distributions of age, gender, socioeconomic status (living in a house with a tin roof), and maternal education for children who migrated out of the study area and children who survived suggest that for the children who migrated, mortality is probably low. In addition, the prevalence of severe trachoma and chlamydial infection was much lower at baseline for this group of children. Therefore, the likely lower death rate for the group lost to follow-up also would be associated with lower trachoma rates, which is compatible with our observations.
To our knowledge, the association of child mortality with severe trachoma has not been reported previously, and it was unexpected. In our study, severe inflammatory trachoma was predictive of the death of children only in low-prevalence villages, after adjustment for age, gender, and socioeconomic factors (familial cattle herding and maternal education), but not in high-prevalence villages. Since the mortality rate was similar for both groups of villages, it is unlikely that severe inflammatory trachoma per se caused the death of young children. In addition, there was no difference in loss to follow-up according to type of "prevalence village." One possible explanation is that severe inflammatory trachoma in low-prevalence villages is a marker for children at high risk of death. In high-prevalence villages, where trachoma is endemic, infection is more common and severe trachoma loses its predictive power. Nevertheless, further work is needed to explore the relation between severe inflammatory trachoma and increased risk of death in children aged 1 and 2 years in trachoma-endemic countries.
In summary, this study demonstrated that familial cattle ownership and distance to a water source can be associated with the presence of active trachoma and severe inflammatory trachoma, even for as long as 6 years. Evidence that changes in risk factors over time are associated with a decline in subsequent disease, accounting for declines with age, suggests that public health approaches to reduce risk are appropriate.
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ACKNOWLEDGMENTS
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This work was supported by The Edna McConnell Clark Foundation. Dr. West is a Research to Prevent Blindness Senior Scientific Investigator.
The authors thank the Kongwa Trachoma Project Team, especially Zefania Chilangwa and Sidney Katala, for their assistance with field work; Fan-Chi Hsu, Beatriz Muñoz, Dr. Nathaniel Briggs, and Dr. Kung-yee Liang for their suggestions about the statistical analyses; and Dr. Robert Blount for his superior photography and first-class input in the field.
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NOTES
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Reprint requests to Dr. Yu-Hsiang Hsieh, Division of Infectious Diseases, School of Medicine, The Johns Hopkins University, Ross 1155B, 720 Rutland Avenue, Baltimore, MD 21205 (e-mail: yhhsieh{at}welchlink.welch.jhu.edu).
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Received for publication December 23, 1998.
Accepted for publication July 29, 1999.