Immunopathogenesis of Progressive Scarring Trachoma: Results of a 4-Year Longitudinal Study in Tanzanian Children.

Trachoma is initiated during childhood following repeated conjunctival infection with Chlamydia trachomatis, which causes a chronic inflammatory response in some individuals that leads to scarring and in-turning of the eyelids in later life. There is currently no treatment to halt the progression of scarring trachoma due to an incomplete understanding of disease pathogenesis. A cohort study was performed in northern Tanzania in 616 children aged 6 to 10 years at enrollment. Every 3 months for 4 years, children were examined for clinical signs of trachoma, and conjunctival swabs were collected for C. trachomatis detection and to analyze the expression of 46 immunofibrogenic genes. Data were analyzed in relation to progressive scarring status between baseline and the final time point. Genes that were significantly associated with scarring progression included those encoding proinflammatory chemokines (CXCL5, CCL20, CXCL13, and CCL18), cytokines (IL23A, IL19, and IL1B), matrix modifiers (MMP12 and SPARCL1), immune regulators (IDO1, SOCS3, and IL10), and a proinflammatory antimicrobial peptide (S100A7). In response to C. trachomatis infection, IL23A and PDGF were significantly upregulated in scarring progressors relative to in nonprogressors. Our findings highlight the importance of innate proinflammatory signals from the epithelium and implicate interleukin 23A (IL-23A)-responsive cells in driving trachomatous scarring, with potential key mechanistic roles for PDGFB, MMP12, and SPARCL1 in orchestrating fibrosis.

Ocular immune responses, Chlamydia trachomatis infection and clinical signs of trachoma before and after azithromycin mass drug administration in a treatment naïve trachoma-endemic Tanzanian community.

BACKGROUND: Trachoma, caused by Chlamydia trachomatis, remains the leading infectious cause of blindness worldwide. Persistence and progression of the resulting clinical disease appears to be an immunologically mediated process. Azithromycin, which is distributed at the community level for trachoma control, has immunomodulatory properties. We investigated the impact of one round of oral azithromycin on conjunctival immune responses, C. trachomatis infection and clinical signs three- and six- months post treatment relative to three pre-treatment time-points. METHODOLOGY: A cohort of children aged 6 to 10 years were recruited from a trachoma endemic region of northern Tanzania and were visited five times in a 12-month period. They were examined for clinical signs of trachoma and conjunctival swabs were collected for laboratory analysis. C. trachomatis infection was detected and the expression of 46 host genes was quantified using quantitative PCR. All community members were offered azithromycin treatment immediately after the six-month timepoint according to international guidelines. FINDINGS: The prevalence of C. trachomatis infection and inflammatory disease signs were significantly reduced three- and six- months post-mass drug administration (MDA). C. trachomatis infection was strongly associated with clinical signs at all five time-points. A profound anti-inflammatory effect on conjunctival gene expression was observed 3 months post-MDA, however, gene expression had largely returned to pre-treatment levels of variation by 6 months. This effect was less marked, but still observed, after adjusting for C. trachomatis infection and when the analysis was restricted to individuals who were free from both infection and clinical disease at all five time-points. Interestingly, a modest effect was also observed in individuals who did not receive treatment. CONCLUSION: Conjunctival inflammation is the major clinical risk factor for progressive scarring trachoma, therefore, the reduction in inflammation associated with azithromycin treatment may be beneficial in limiting the development of potentially blinding disease sequelae. Future work should seek to determine whether this effect is mediated directly through inhibition of pro-inflammatory intracellular signalling molecules, through reductions in concurrent, sub-clinical infections, and/or through reduction of infection exposure.

Fluorometholone 0.1% as Ancillary Therapy for Trachomatous Trichiasis Surgery: Randomized Clinical Trial.

PURPOSE: To assess the hypothesis that fluorometholone 0.1% eye drops are safe and effective as adjunctive therapy for trachomatous trichiasis (TT) surgery; determining the most promising dose. DESIGN: Randomized, placebo-controlled, double-masked parallel dose-ranging clinical trial. METHODS: Patients undergoing upper lid TT surgery at a rural Ethiopian hospital were randomized to fluorometholone 0.1% twice daily for 4 weeks, 4 times daily for 4 weeks, 4 times daily for 8 weeks, or matching frequency placebo in a 3:1:3:1:3:1 ratio for 1 eye. Randomization was stratified by TT severity (1-4 vs ≥5 lashes touching the globe). Safety outcomes (intraocular pressure [IOP] elevation, cataract, and other dose-limiting toxicities) and postoperative TT incidence were assessed over 1 year. RESULTS: Subjects randomized were 39:13:39:13:38:13 in the respective groups, and 1 subject in the 8-weeks fluorometholone group was withdrawn. Of 154 subjects, 148 (96.1%) completed 1 year's follow-up. Among 76 eyes receiving fluorometholone 4 times daily, 1 developed IOP elevation ≥ 30 mm Hg (to 37 mm Hg) and 1 had an allergic reaction attributed to the study drug; each resolved upon drug cessation without sequelae. No cataract or other dose-limiting toxicity events occurred. Postoperative TT within 1 year occurred in 29.3% of placebo eyes vs 17.7%, 19.6%, and 23.2% among the respective fluorometholone groups (P = .29 comparing placebo vs all active treatments combined). CONCLUSIONS: The results suggest fluorometholone 0.1% is likely to be safe and efficacious to reduce postoperative TT following TT surgery, and 1 drop twice daily for 4 weeks is the most promising dose. Confirmation in a full-scale clinical trial is needed before programmatic implementation.

The burden of and risk factors for active trachoma in the North and South Wollo Zones of Amhara Region, Ethiopia: a cross-sectional study.

BACKGROUND: Trachoma is a disease of the eye, caused by the bacteria Chlamydia trachomatis, which can lead to blindness if left untreated. Ethiopia is one of the most trachoma-affected countries in the world. The objective of this study was to determine the prevalence of and associated risk factors for active trachoma among children in selected woredas of North and South Wollo Zones in Amhara Region, Ethiopia. METHODS: This study was a community-based, cross-sectional study, which was conducted from October to December 2014 among children aged 1-8. A four-stage random cluster sampling technique was employed to select the study areas and participants. From each selected household, one child was clinically assessed for active trachoma. A structured questionnaire was used to collect sociodemographic, behavioral, and clinical data. Multivariate logistic regression analysis was used to analyze the association between predictor variables and active trachoma. RESULTS: The overall prevalence of active trachoma among 1358 children was found to be 21.6% (95% CI: 19.4-23.8%). When analyzed by the presence or absence of individual WHO simplified system signs of active trachoma, trachomatous inflammation-follicular cases constituted18% (95% CI: 15.9-20.2%), while 4.7% (95% CI: 3.6-5.8%) were trachomatous inflammation-intense cases. Ocular discharge (aOR = 5.2; 95% CI: 3.3-8.2), nasal discharge (aOR = 1.8; 95% CI: 1.2-2.7), time taken to fetch water (aOR = 0.02; 95% CI: 0.01-0.05), frequency of hand and face washing (aOR = 4.4; 95% CI: 1.1-17.8), and access to a latrine (aOR = 0.006; 95% CI: 0.001-0.030) were found to be independently associated with the presence of active trachoma. CONCLUSIONS: There is a high burden of active trachoma among children in the study areas. Lack of personal hygiene and limited access to a safe water supply and latrines were associated with increased prevalence of active trachoma. In order to reduce the burden of active trachoma, facial cleanliness and environmental improvement components of the SAFE strategy should be upgraded in the study areas.

Predictors of Trachomatous Trichiasis Surgery Outcome.

PURPOSE: Unfavorable outcomes after trachomatous trichiasis (TT) surgery are undermining the global trachoma elimination effort. This analysis investigates predictors of postoperative TT (PTT), eyelid contour abnormalities (ECAs), and granuloma in the 2 most common TT surgery procedures: posterior lamellar tarsal rotation (PLTR) and bilamellar tarsal rotation (BLTR). DESIGN: Secondary data analysis from a randomized, controlled, single-masked clinical trial. PARTICIPANTS: A total of 1000 patients with TT, with lashes touching the eye or evidence of epilation, in association with tarsal conjunctival scarring. METHODS: Participants were randomly allocated and received BLTR (n = 501) or PLTR (n = 499) surgery. Disease severity at baseline, surgical incisions, sutures, and corrections were graded during and immediately after surgery. Participants were examined at 6 and 12 months by assessors masked to allocation. MAIN OUTCOME MEASURES: Predictors of PTT, ECA, and granuloma. RESULTS: Data were available for 992 (99.2%) trial participants (496 in each arm). There was strong evidence that performing more peripheral dissection with scissors in PLTR (odd ratio [OR], 0.70; 95% confidence interval [CI], 0.54-0.91; P = 0.008) and BLTR (OR, 0.83; 95% CI, 0.72-0.96; P = 0.01) independently protected against PTT. Baseline major trichiasis and mixed location lashes and immediate postoperative central undercorrection independently predicted PTT in both surgical procedures. Peripheral lashes in PLTR (OR, 5.91; 95% CI, 1.48-23.5; P = 0.01) and external central incision height ≥4 mm in BLTR (OR, 2.89; 95% CI, 1.55-5.41; P = 0.001) were independently associated with PTT. Suture interval asymmetry of >2 mm (OR, 3.18; 95% CI, 1.31-7.70; P = 0.01) in PLTR and baseline conjunctival scarring in BLTR (OR, 1.72; 95% CI, 1.06-2.81; P = 0.03) were independently associated with ECA. Older age was independently associated with ECA in both PLTR (P value for trend < 0.0001) and BLTR (P value for trend = 0.03). There was substantial intersurgeon variability in ECA rates for both PLTR (range, 19.0%-36.2%) and BLTR (range, 6.1%-28.7%) procedures. In PLTR surgery, irregular posterior lamellar incision at the center of the eyelid (OR, 6.72; 95% CI, 1.55-29.04; P = 0.01) and ECA (OR, 3.08; 95% CI, 1.37-6.94; P = 0.007) resulted in granuloma formation. CONCLUSIONS: Poor postoperative outcomes in TT surgery were associated with inadequate peripheral dissection, irregular incision, asymmetric suture position and tension, inadequate correction, and lash location. Addressing these will improve TT surgical outcomes.

Corneal Sensitivity and Presence of Pathogenic Organisms Among Participants Who Have Undergone Trichiasis Surgery Differ by Surgical Outcome.

PURPOSE: To explore the potential association between reduced corneal sensation and/or conjunctival bacterial colonization and postoperative trichiasis and eyelid contour abnormalities after corrective eyelid surgery among participants with a history of trachomatous trichiasis. METHODS: As an ancillary study to the Partnership for Rapid Elimination of Trachoma (PRET) Surgery Trial in southern Tanzania, we collected data on 580 PRET participants who had undergone trichiasis surgery 1 year earlier and 200 age-group-matched individuals without trichiasis. Assessments included eyelid status evaluation (presence and severity of postoperative trichiasis and/or eyelid contour abnormality), corneal sensitivity by Cochet-Bonnet aesthesiometer, a questionnaire on symptoms of ocular irritation, and conjunctival microbiology. We divided PRET participants based on their eyelid status and compared results across PRET groups and versus normals. RESULTS: PRET participants had reduced corneal sensitivity compared with age-matched normals (mean sensitivity ranged from 2.8 to 3.8 cm in PRET participants vs. 5.9 cm in normals), and increasing severity of postoperative trichiasis was associated in a stepwise fashion with reduced corneal sensitivity (mean = 3.5 cm for mild and 2.6 cm for severe postoperative trichiasis). Conjunctival colonization with pathogenic bacteria was also associated with more severe postoperative trichiasis (Cochran-Armitage trend test P = 0.001) and with reduced corneal sensitivity (trend test P < 0.0001). Symptoms of ocular irritation were not associated with previous trichiasis surgery, postoperative trichiasis, or eyelid contour abnormality. CONCLUSIONS: These findings indicate that reduced corneal sensitivity accompanies trachomatous trichiasis and suggest that reduced corneal sensitivity may play an important role in the harboring of pathogenic bacteria on the ocular surface.

The Versatile Lid Crease Approach to Upper Eyelid Margin Rotation.

Lid margin rotational procedures have been used to correct cicatricial trachomatous entropion since the 19(th) century. There are two basic types of surgeries used for lid margin rotation. The first type is based on through-and-through approach combining tarsotomy and the use of sutures on the anterior lamella. The second type of surgery was suggested by Trabut, who proposed a tarsal advancement by posterior approach. We demonstrate that using a lid crease incision combines the basic mechanisms of the anterior and posterior approaches and in addition, addresses a variety of lid problems commonly found in the aged population with cicatricial entropion. After tarsal plate exposure, a tarsotomy through conjunctiva is performed as described by Trabut. Then, instead of using external sutures secured by bolsters, internal absorbable sutures can be used to simultaneously advance the distal tarsal fragment and exert strong tension on the marginal orbicularis muscle. Sixty lids of 40 patients underwent surgery with a lid crease incision. The follow-up ranged from 1 to 12 months (mean 3.0 months ± 2.71). Forty percent of the patients (24 lids) had more than 3 months of follow-up. Adequate margin rotation was achieved in all lids but one that showed a medial eyelash touching the cornea.

Management of trachomatous keratopathy by automated lamellar therapeutic keratoplasty.

PURPOSE: To evaluate the efficacy of automated lamellar therapeutic keratoplasty (ALTK) for the management of anterior corneal stromal scarring caused by trachoma. METHODS: Seventeen cases of trachomatous keratopathy that were treated by ALTK were retrospectively evaluated. The main outcome measures were uncorrected visual acuity, best-corrected visual acuity (BCVA), keratometry, pachymetry, time to epithelialization, graft clarity, and complications, if any. RESULTS: The mean age of the patients was 50.3 ± 14.1 years. Five of the 17 cases had Salzmann nodular degeneration. The mean decimal BCVA was 0.06 ± 0.05 preoperatively, which improved to 0.41 ± 0.16 at 12 months, and 12 eyes (70.6%) had a postoperative BCVA of 6/18 or better. The median epithelialization time was 6 days (range, 1-38 days). Persistent epithelial defect developed in 6 eyes, and 1 eye developed graft infection. CONCLUSIONS: Anterior stromal corneal scarring caused by trachoma can be effectively treated with ALTK. However, occurrence of persistent epithelial defects may complicate the success of this surgery.

Bacterial infection in scarring trachoma.

PURPOSE: To assess whether non-chlamydial bacterial infection is associated with trachomatous scarring in adults. METHODS: This was a case-control study of 360 cases with trachomatous scarring but without trichiasis, and 360 controls without scarring. All participants underwent clinical examination, and a swab was taken from the inferior conjunctival fornix. Samples were inoculated onto blood and chocolate agar later that day. RESULTS: Bacterial isolates were identified in 54.0% of cases compared with 34.6% of controls (P < 0.001). A multivariate logistic regression model adjusted for age and lack of education showed that scarring was associated with the presence of commensal organisms (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.01-2.09) and was strongly associated with the presence of pathogenic organisms (OR, 4.08; 95% CI, 1.59-10.45). There was an increasing prevalence of all bacterial isolates with increasing severity of scarring (P(trend) < 0.001). CONCLUSIONS: Trachomatous scarring is strongly associated with non-chlamydial bacterial infection compared with controls. The role of such infection with regard to scarring progression should be investigated and may have important implications for trachoma control strategies and prevention of blindness.

The effect of topical cyclosporine A treatment on corneal thickness in patients with trachomatous dry eye.

PURPOSE: The purpose of the present study was to evaluate the effect of topical cyclosporine A (CsA) treatment on corneal thickness (CT) in patients with trachomatous dry eye. METHODS: Sixty-four patients with trachomatous dry eye with a Schirmer test showing 5 mm or less and a tear film break-up time (TFBUT) of five seconds or less were included. Thirty-two patients were treated with twice daily application of CsA (0.05% ophthalmic emulsion) plus non-preserved artificial tears, while the remaining 32 patients serving as controls received only non-preserved artificial tears. CT was measured using ultrasonic pachymetry at five locations of the central (CCT) and mid-peripheral cornea, at baseline and after one, three and six months of treatment. RESULTS: At the sixth month of treatment, CT measurements were significantly changed in both groups, compared to baseline. In the CsA treatment group, the mean CCT before and after six months of treatment were 517.4 +/- 36.2 and 546.5 +/- 32.4 microm, respectively (p < 0.001); yielding an average CCT increase of 29.1 +/- 8.0 microm (5.62 per cent) from baseline. In the control group, corresponding figures were 520.2 +/- 34.2 and 526.0 +/- 35.4 microm, respectively (p < 0.01), with an average increase of 5.8 +/- 3.1 microm (1.11 per cent). CONCLUSIONS: In the present study, the CsA treatment group exhibited significantly greater increases in CT compared to controls. Such an increase may indicate an improvement in the integrity of the ocular surface and resolution of the underlying inflammation as a consequence of topical CsA treatment.

The natural history of trachoma infection and disease in a Gambian cohort with frequent follow-up.

BACKGROUND: The natural history of ocular Chlamydia trachomatis infections in endemic communities has not been well characterised and is an important determinant of the effectiveness of different mass treatment strategies to prevent blindness due to trachoma. METHODOLOGY/PRINCIPAL FINDINGS: A multistate hidden Markov model was fitted to data on infection and active disease from 256 untreated villagers in The Gambia who were examined every 2 weeks over a 6-month period. Parameters defining the natural history of trachoma were estimated, and associations between these parameters, demographic and baseline immune measurements examined. The median incubation period following infection was estimated at 17 days (95% confidence interval: 11-28). Disease persisted for longer than infection (median 21 (15-32) weeks) versus 17 (12-24) weeks), with an estimated median duration of post-infection inflammation of 5 (3-8) weeks. The duration of active disease showed a significant decline with age even after accounting for lower rates of re-infection and disease at older ages (p = 0.004). Measurements of levels of baseline IgA to epitopes in the major outer membrane protein of Chlamydia trachomatis were not significantly correlated with protection or more rapid clearance of infection. CONCLUSIONS: The average duration of infection with Chlamydia trachomatis especially at younger ages is long. This contributes to the persistence and gradual return of trachoma after community-wide treatment with antibiotics.

Trachoma.

Trachoma is a keratoconjunctivitis caused by ocular infection with Chlamydia trachomatis. Repeated or persistent episodes lead to increasingly severe inflammation that can progress to scarring of the upper tarsal conjunctiva. Trichiasis develops when scarring distorts the upper eyelid sufficiently to cause one or more lashes to abrade the cornea, scarring it in turn and causing blindness. Active trachoma affects an estimated 84 million people; another 7.6 million have end-stage disease, of which about 1.3 million are blind. Trachoma should stand on the brink of extinction thanks to a 1998 initiative launched by WHO--the Global Elimination of Trachoma by 2020. This programme advocates control of trachoma at the community level with four inter-related population-health initiatives that form the SAFE strategy: surgery for trichiasis, antibiotics for active trachoma, facial cleanliness, and environmental improvement. Evidence supports the effectiveness of this approach, and if current world efforts continue, blinding trachoma will indeed be eliminated by 2020.

Penetrating keratoplasty for trachomatous corneal scarring.

PURPOSE: To evaluate graft survival and visual outcome after penetrating keratoplasty (PKP) for trachomatous corneal scarring. METHODS: A retrospective review was conducted on all cases of PKP performed at King Khaled Eye Specialist Hospital between January 1, 1997, and December 31, 2001, for trachomatous corneal scarring. RESULTS: This study included 127 eyes. The mean age at the time of surgery was 64.7 years (range, 40-90 years). The mean follow-up was 1266 days (range, 91-3423 days). At the most recent visit, 102 (80.2%) grafts were clear, and 25 (19.7%) had failed. Kaplan-Meier graft survival was 98.3% at 1 year, 85.9% at 2 years, 83.2% at 3 years, 80.2% at 4 years, and 76.6% at 5 years. Major postoperative complications included worsening of glaucoma (27.6%), endothelial rejection (17.3%), and bacterial keratitis (8.7%). Visual acuity improved in 107 (84.3%) eyes, remained the same in 12 (9.5%) eyes, and worsened in 8 (6.3%) eyes. Final visual acuity of 20/160 or better was obtained in 67 (56.7%) eyes. CONCLUSIONS: Treating trachomatous corneal scarring with PKP can be associated with a good prognosis for graft survival and improved vision in carefully selected cases with mild or well-controlled ocular surface disease and absent or previously surgically corrected eyelid abnormalities.

Clinical evaluation of changes in cornea and tear film after surgery for trachomatous upper lid entropion.

PURPOSE: To determine the effect of entropion surgery on corneal health in terms of surface epithelium, tear film stability, change in curvature and vision. METHODS: Prospective study; included consecutive patients with trachomatous upper lid entropion undergoing corrective surgery. Corneal opacity and other conditions that reduced vision were recorded. Best-corrected visual acuity, corneal fluorescein staining, tear film break-up time, Schirmer I test, and keratometry were performed before and after surgery. Data were analysed using Student's t-test, chi(2) test, one-way ANOVA, one-sample t-test, and logistic and multiple regression. RESULTS: Thirty-six female and 15 male patients with an average age of 59.1+/-10.65 years were included. Lenticular and retinal causes resulted in blindness (P=0.008), and low vision (P=0.02), more often than entropion. At 90 days after surgery, vision improved by 0.55+/-1.48 lines (P=0.01). Superficial punctate staining of the cornea reduced by half over 1-15 days (average 6.96+/-4.99) after surgery, and completely in 1-90 days (average 26.15+/-17.49). Tear film break-up time (range: 3-20 s preoperatively) improved significantly after surgery (P=0.005) whereas Schirmer I (range: 10-35 mm preoperatively) and keratometry values showed insignificant change. CONCLUSIONS: Surgery for entropion results in healing of superficial keratopathy, improves tear film stability, and the realigned lid margin spreads tears evenly and efficiently, thus contributing to improved vision. These changes, taking place over 1-90 days, should be kept in mind when planning intraocular surgery, keratoplasty, or keratorefractive procedures after entropion correction.

Bacterial infection and trachoma in the gambia: a case control study.

PURPOSE: Trachoma is the leading infectious cause of blindness worldwide. Conjunctival scarring is initiated by recurrent Chlamydia trachomatis infection. However, disease progression to trichiasis occurs even in regions where chlamydial prevalence is currently low, which suggests that other factors, for example other bacterial infection, may also drive inflammation and scarring, particularly in the late stages of trachoma. This study was undertaken to investigate whether trachomatous trichiasis or conjunctival scarring are associated with increased prevalence of bacterial infection. METHODS: Within a case-control study design, individuals with trichiasis or conjunctival scarring (without trichiasis) were compared with normal matched control subjects. Subjects were examined for signs of trachoma. Conjunctival swab samples were collected for bacteriologic culture and C. trachomatis PCR. RESULTS: Recruited for the study were 121 trichiasis case-control pairs and 117 conjunctival scarring case-control pairs. Eyes with trichiasis were more frequently infected with bacteria (37%) than were normal control eyes (7%) (OR: 8.2; P < 0.001; 95% CI: 3.24-20.8). Bacterial infection was more common with increased trichiasis severity. In the conjunctival scarring case-control group, scarred eyes had slightly more bacterial infection (11%) than did normal control eyes (6%), although this was not significantly different (OR: 2.2; P = 0.144; 95% CI: 0.79-6.33). CONCLUSIONS: Trichiasis is associated with increased risk of bacterial infection, and there may be a similar trend in eyes with conjunctival scarring. Bacterial infection of the conjunctiva is associated with inflammation, which may result in progressive scarring. Prospective studies are needed to determine the contribution of bacterial infection to disease progression. Bacterial infection probably also contributes to the development of corneal opacification.