Studies on the Development of Scarring Trachoma in Tanzania

Trachoma is an ancient blinding disease which remains a public health and socio-economic threat to many communities, mainly in sub-Saharan Africa. Repeated conjunctival infection with Chlamydia trachomatis is thought to cause prolonged inflammation which leads to scarring and blindness, however, the disease is often found to progress in the absence of detected infection. Furthermore, despite apparently similar infection exposure, only some individuals progress to scarring. The relationship between infection and scarring progression and the immunopathological mechanisms underlying it are not clearly understood. A four-year longitudinal study was conducted in northern Tanzania in order to identify associations between C. trachomatis infection, conjunctival inflammation and immuno-fibrogenic gene expression with disease and scarring progression. Children aged 6-10 years at baseline were eligible for inclusion and 666 children were enrolled in the study. Participants were visited every three months for four years. Clinical signs and conjunctival swabs for C. trachomatis detection and immuno-fibrogenic gene expression by qPCR were collected at each time-point. Conjunctival photographs from baseline and final timepoints were graded and compared side-by-side to determine scarring incidence and progression. All community members were offered mass drug administration (MDA) with azithromycin for trachoma control annually for three years during the study. Host immuno-fibrogenic gene expression was profiled at the first five time-points. At baseline, host immune responses were analysed in relation to C. trachomatis infection, trachomatous inflammation – follicular (TF), papillary inflammation (TP) and scarring. Th1 and NK cell associated pathways were strongly associated with infection, suggesting their importance in the clearance of infection. Growth and matrix factors (MMPs) were strongly associated with the inflammation that persisted after infection was cleared (TF/TP), suggesting they might contribute to scarring development. Th17 pathway-associated cytokines were associated with infection and inflammation, therefore their contribution to protection versus pathology is unclear. The effect of azithromycin on inflammatory gene expression was investigated due to the reported immunomodulatory role of this antibiotic. Azithromycin treatment was found to have an anti-inflammatory effect on conjunctival gene expression, detectable three months posttreatment, suggesting that it may protect against pathological inflammation and therefore scarring development. The effect was gone by 6 months post treatment. Of the 448 children with outcome data, 103 (23.0%) had trachomatous scarring progression over the four-year study period. In 48 (10.7%) children this was incident scarring, whereas 55 (12.3%) had progression of pre-existing scarring. Scarring progression was strongly associated with papillary inflammation. Weaker associations between TF and C. trachomatis infection with scarring in univariate models were absent in a multivariable model adjusting for TP. These data suggest that the effect of infection and TF is mediated through TP, and that other factors contributing to the development of TP are important in driving scarring progression. Female sex was also associated with scarring progression. These findings suggest that the use of TP by trachoma control programs might be a more discriminating clinical marker to predict future scarring disease and requirements for trichiasis surgery than TF. In addition to clearing C. trachomatis infection, MDA might have an additional independent mechanism for reducing conjunctival inflammation, which may reduce subsequent risk of scarring progression.