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Artemis Koukounari,
Irini Moustaki,
Nicholas C Grassly,
Isobel M Blake,
María-Gloria Basáñez,
Manoj Gambhir, David C W Mabey,
Robin L Bailey,
Matthew J Burton,
Anthony W Solomon,
Christl A Donnelly
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ABSTRACT: In disease control or elimination programs, diagnostics are essential for assessing the impact of interventions, refining treatment strategies, and minimizing the waste of scarce resources. Although high-performance tests are desirable, increased accuracy is frequently accompanied by a requirement for more elaborate infrastructure, which is often not feasible in the developing world. These challenges are pertinent to mapping, impact monitoring, and surveillance in trachoma elimination programs. To help inform rational design of diagnostics for trachoma elimination, we outline a nonparametric multilevel latent Markov modeling approach and apply it to 2 longitudinal cohort studies of trachoma-endemic communities in Tanzania (2000-2002) and The Gambia (2001-2002) to provide simultaneous inferences about the true population prevalence of Chlamydia trachomatis infection and disease and the sensitivity, specificity, and predictive values of 3 diagnostic tests for C. trachomatis infection. Estimates were obtained by using data collected before and after mass azithromycin administration. Such estimates are particularly important for trachoma because of the absence of a true "gold standard" diagnostic test for C. trachomatis. Estimated transition probabilities provide useful insights into key epidemiologic questions about the persistence of disease and the clearance of infection as well as the required frequency of surveillance in the postelimination setting.
American journal of epidemiology 04/2013; · 5.59 Impact Factor
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ABSTRACT: Trachoma is a fibrotic disease of the conjunctiva initiated by Chlamydia trachomatis infection. This blinding disease affects over 40 million people worldwide yet the mechanisms underlying its pathogenesis remain poorly understood. We have investigated host microRNA (miR) expression in health (N) and disease (conjunctival scarring with (TSI) and without (TS) inflammation) to determine if these epigenetic differences are associated with pathology.
We collected two independent samples of human conjunctival swab specimens from individuals living in The Gambia (n = 63 & 194). miR was extracted, and we investigated the expression of 754 miR in the first sample of 63 specimens (23 N, 17 TS, 23 TSI) using Taqman qPCR array human miRNA genecards. Network and pathway analysis was performed on this dataset. Seven miR that were significantly differentially expressed between different phenotypic groups were then selected for validation by qPCR in the second sample of 194 specimens (93 N, 74 TS, 22 TSI).
Array screening revealed differential expression of 82 miR between N, TS and TSI phenotypes (fold change >3, p<0.05). Predicted mRNA targets of these miR were enriched in pathways involved in fibrosis and epithelial cell differentiation. Two miR were confirmed as being differentially expressed upon validation by qPCR. miR-147b is significantly up-regulated in TSI versus N (fold change = 2.3, p = 0.03) and miR-1285 is up-regulated in TSI versus TS (fold change = 4.6, p = 0.005), which was consistent with the results of the qPCR array.
miR-147b and miR-1285 are up-regulated in inflammatory trachomatous scarring. Further investigation of the function of these miR will aid our understanding of the pathogenesis of trachoma.
PLoS Neglected Tropical Diseases 03/2013; 7(3):e2117. · 4.69 Impact Factor
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Matthew J Burton,
Saul N Rajak,
Athumani Ramadhani,
Helen A Weiss,
Esmael Habtamu,
Baye Abera,
Paul M Emerson,
Peng T Khaw, David C W Mabey,
Martin J Holland,
Robin L Bailey
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ABSTRACT: Surgery for trachomatous trichiasis (TT) is a key component of the SAFE Strategy for trachoma control. Unfortunately, recurrent TT following surgery is common, probably due to various surgical and disease factors. To develop strategies to reduce recurrence rates it is necessary to understand its pathological basis. In this study we investigated the relationship between recurrent trichiasis and the expression of various cytokines and fibrogenic genes during a two-year follow-up period.
Individuals undergoing surgery for TT were examined at baseline (pre-operative), 6, 12, 18 and 24 months. Conjunctival swab samples were collected from the tarsal conjunctiva for RNA isolation on each occasion. Individuals who developed recurrent TT with at least 3 lashes touching the eye on one or more occasion were designated "cases" and an equal number of "controls" were randomly selected from those without recurrent TT, frequency matched for age and baseline TT severity. The expression of the following genes was measured by quantitative RT-PCR: S100A7, IL1B, CXCL5, TNFA, NOS2A, CTGF, MMP7, MMP9 and MMP12. Thirteen hundred individuals were enrolled and underwent surgery. By two years 122 had developed recurrent TT with at least 3 lashes touching the eye. Recurrent TT was consistently associated across multiple time points with about a 2-fold increase in S100A7 expression (p = 0.008). Clinically visible conjunctival inflammation was associated with increased S100A7, IL1B, CXCL5, MMP9 and MMP12 expression.
Increased S100A7 expression was associated with trachomatous conjunctival scarring and may be linked to the pathophysiology of recurrent TT. S100A7 expression could be a potential biomarker for this disease process. As part of the epithelial innate immune response S100A7 has multiple actions, potentially contributing to a chronic pro-inflammatory response, which may lead to ongoing tissue damage and increased scarring.
PLoS Neglected Tropical Diseases 12/2012; 6(12):e1985. · 4.69 Impact Factor
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Anthony W Solomon, David C W Mabey,
Clare Gilbert,
Ulla Griffiths,
Anne Mills,
Allen Foster,
Sheila K West,
Paul Courtright,
Joseph Feczko,
Wondu Alemayehu,
Catherine Cross,
Thomas M Lietman,
Danny Haddad,
Caroline Harper,
Paul Emerson,
Richard Le Mesurier,
Dirk Engels,
Silvio P Mariotti
BMJ (Clinical research ed.). 01/2012; 344:e2579; author reply e2588.
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Saul N Rajak,
Esmael Habtamu,
Helen A Weiss,
Amir Bedri,
Teshome Gebre,
Asrat Genet,
Peng T Khaw,
Robin L Bailey, David C W Mabey,
Clare E Gilbert,
Paul M Emerson,
Matthew J Burton
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ABSTRACT: Eight million people have trachomatous trichiasis (TT). The World Health Organization (WHO) recommends entropion surgery for TT regardless of severity. However, epilation is widely practiced for treating minor TT (1-5 lashes touching the globe). We report the frequency and effectiveness of patient-initiated epilation and its relationship to corneal opacity.
Cross-sectional baseline data of individuals recruited to 2 randomized, clinical trials.
We included 2556 individuals (4310 eyes) with previously unoperated TT in ≥ 1 eye.
A single ophthalmologist examined all participants for signs of trachoma using WHO grading systems with additional assessment of entropion grading, location and number of trichiatic lashes, and evidence of epilation. A questionnaire enquired about epilation practices.
The association between epilation and degree of corneal opacity. Epilation practices of TT patients.
Central corneal scarring was present in 1436 (33%) eyes. Entropion was absent/mild in 2328 (54%) eyes, moderate in 1259 (29.2%), and severe in 723 (16.8%). The median number of lashes touching the eye was 2 (interquartile range, 1-5; range, 0-133). There was clinical evidence of epilation in 3018 (70%) eyes, of which 738 (24%) were successfully epilated (no lashes touching globe). Epilation was performed frequently (at least monthly in 3311 [76.8%] eyes), by someone other than the patient (92.8%), and using locally made forceps (88.9%). Controlling for age and degree of entropion, successful epilation was associated with less corneal opacity (odds ratio [OR], 0.61; 95% confidence interval [CI]. 0.43-0.88; P = 0.007). The association was only significant in patients with severe entropion (OR, 0.07; 95% CI, 0.02-0.25; P<0.005).
We found an association between successful epilation and less central corneal opacity. This indicates the importance of preventing eyelashes from touching the cornea, particularly in individuals with severe entropion. This is a cross-sectional study; therefore, a causative relationship cannot be concluded. However, the results suggest that among patients who decline or are unable to access surgery, and perhaps in minor TT where the management remains controversial, the provision of high-quality forceps and epilation training may be beneficial.
The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Ophthalmology 01/2012; 119(1):84-9. · 5.45 Impact Factor
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ABSTRACT: Trachoma is the most common infectious cause of blindness and a major public health problem in many developing countries. It is caused by recurrent ocular infection with Chlamydia trachomatis in childhood, with conjunctival scarring seen later in life. The pathogenesis of trachomatous scarring, however, is poorly understood, and this study was carried out to investigate the immunofibrogenic correlates of trachomatous conjunctival scarring. A case-control study of 363 cases with conjunctival scarring and 363 control participants was conducted. Investigations included in vivo confocal microscopy (IVCM) assessment, quantitative real-time PCR gene expression, C. trachomatis detection, and nonchlamydial bacterial culture. Trachomatous scarring was found to be strongly associated with a proinflammatory, innate immune response with increased expression of psoriasin, interleukin-1β, tumor necrosis factor alpha, defensin-β4A, chemokine ligand 5, and serum amyloid A1. There was also differential expression of various modifiers of the extracellular matrix, including metalloproteinases 7, 9, 10, and 12, tissue inhibitor of matrix metalloproteinase 1, and secreted protein acidic cystein-rich-like 1. The expression of many of these genes was also significantly associated with the presence of nonchlamydial bacterial infection. These infections had a marked effect on conjunctival immune processes, including an increased inflammatory infiltrate and edema seen with IVCM. This study supports the possibility that the immunofibrogenic response in scarring trachoma is partly stimulated by nonchlamydial bacterial infection, which is characterized by the expression of innate factors.
Infection and immunity 01/2012; 80(1):121-30. · 4.21 Impact Factor
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Saul N Rajak,
Esmael Habtamu,
Helen A Weiss,
Amir Bedri Kello,
Teshome Gebre,
Asrat Genet,
Robin L Bailey, David C W Mabey,
Peng T Khaw,
Clare E Gilbert,
Paul M Emerson,
Matthew J Burton
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ABSTRACT: Trachomatous trichiasis can cause corneal damage and visual impairment. WHO recommends surgery for all cases. However, in many regions surgical provision is inadequate and patients frequently decline. Self-epilation is common and was associated with comparable outcomes to surgery in nonrandomised studies for minor trichiasis (<six lashes touching eye). This trial investigated whether epilation is noninferior to surgery for managing minor trichiasis.
1,300 individuals with minor trichiasis from Amhara Regional State, Ethiopia were recruited and randomly assigned (1:1) to receive trichiasis surgery or epilation. The epilation group were given new forceps and epilation training. The surgical group received trichiasis surgery. Participants were examined every 6 months for 2 years by clinicians masked to allocation, with 93.5% follow-up at 24 months. The primary outcome measure ("failure") was ≥five lashes touching the eye or receiving trichiasis surgery during 24 months of follow-up, and was assessed for noninferiority with a 10% prespecified noninferiority margin. Secondary outcomes included number of lashes touching, time to failure, and changes in visual acuity and corneal opacity. Cumulative risk of failure over 24 months was 13.2% in the epilation group and 2.2% in the surgical group (risk difference = 11%). The 95% confidence interval (8.1%-13.9%) includes the 10% noninferiority margin. Mean number of lashes touching the eye was greater in the epilation group than the surgery group (at 24 months 0.95 versus 0.09, respectively; p<0.001); there was no difference in change in visual acuity or corneal opacity between the two groups.
This trial was inconclusive regarding inferiority of epilation to surgery for the treatment of minor trichiasis, relative to the prespecified margin. Epilation had a comparable effect to surgery on visual acuity and corneal outcomes. We suggest that surgery be performed whenever possible but epilation be used for treatment of minor trichiasis patients without access to or declining surgery.
ClinicalTrials.gov NCT00522912.
PLoS Medicine 12/2011; 8(12):e1001136. · 16.27 Impact Factor
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Saul N Rajak,
Esmael Habtamu,
Helen A Weiss,
Amir Bedri Kello,
Teshome Gebre,
Asrat Genet,
Robin L Bailey, David C W Mabey,
Peng T Khaw,
Clare E Gilbert,
Paul M Emerson,
Matthew J Burton
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ABSTRACT: Trachoma causes blindness through an anatomical abnormality called trichiasis (lashes touching the eye). Trichiasis can recur after corrective surgery. We tested the hypothesis that using absorbable sutures instead of silk sutures might reduce the risk of recurrent disease among patients with major trichiasis in a randomised trial.
1,300 individuals with major trichiasis from rural villages in the Amhara Region of Ethiopia were recruited and assigned (1:1) by computer-generated randomisation sequence to receive trichiasis surgery using either an absorbable suture (polyglactin-910) or silk sutures (removed at 7-10 days) in an otherwise identical surgical technique. Participants were examined every 6 months for 2 years by clinicians masked to allocation. The primary outcome measure was recurrent trichiasis (≥one lash touching the eye) at 1 year. There was no difference in prevalence of recurrent trichiasis at 1 year (114 [18.2%] in the absorbable suture group versus 120 [19.7%] in the silk suture group; odds ratio = 0.90, 95% CI 0.68-1.20). The two groups also did not differ in terms of corneal opacification, visual acuity, conjunctival inflammation, and surgical complications.
There was no evidence that use of absorbable polyglactin-910 sutures was associated with a lower prevalence of trichiasis recurrence at 1 year postsurgery than silk sutures. However, from a programmatic perspective, polyglactin-910 offers the major advantage that patients do not have to be seen soon after surgery for suture removal. The postoperative review after surgery using absorbable polyglactin-910 sutures can be delayed for 3-6 months, which might allow us to better determine whether a patient needs additional surgery.
ClinicalTrials.gov NCT00522860.
PLoS Medicine 12/2011; 8(12):e1001137. · 16.27 Impact Factor
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ABSTRACT: To characterize the tissue and cellular changes found in trachomatous scarring (TS) and inflammation using in vivo confocal microscopy (IVCM).
Two complimentary case-control studies.
The first study included 363 cases with TS (without trichiasis), of whom 328 had IVCM assessment, and 363 control subjects, of whom 319 had IVCM assessment. The second study included 34 cases with trachomatous trichiasis (TT), of whom 28 had IVCM assessment, and 33 control subjects, of whom 26 had IVCM assessment.
All participants were examined with ×2.5 loupes. The IVCM examination of the upper tarsal conjunctiva was carried out with a Heidelberg Retina Tomograph 3 with the Rostock Cornea Module (Heidelberg Engineering GmbH, Dossenheim, Germany).
The IVCM images were graded in a masked manner using a previously published grading system evaluating the inflammatory infiltrate density; the presence or absence of dendritiform cells (DCs), tissue edema, and papillae; and the level of subepithelial connective tissue organization.
Subjects with clinical scarring had a characteristic appearance on IVCM of well-defined bands and sheets of scar tissue visible. Similar changes were also seen in some clinically normal subjects consistent with subclinical scarring. Scarred subjects had more DCs and an elevated inflammatory infiltrate, even after adjusting for other factors, including the level of clinical inflammation. Cellular activity was usually seen only in or just below the epithelium, rarely being seen deeper than 30 μm from the surface. The presence of tissue edema was strongly associated with the level of clinical inflammation.
In vivo confocal microscopy can be quantitatively used to study inflammatory and scarring changes in the conjunctiva. Dendritic cells seem to be closely associated with the scarring process in trachoma and are likely to be an important target in antifibrotic therapies or the development of a chlamydial vaccine. The increased number of inflammatory cells seen in scarred subjects is consistent with the immunopathologic nature of the disease. The localization of cellular activity close to the conjunctival surface supports the view that the epithelium plays a central role in the pathogenesis of trachoma.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Ophthalmology 09/2011; 118(11):2138-46. · 5.45 Impact Factor
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ABSTRACT: The immunological basis of scarring trachoma is not well understood. It is unclear whether it is driven primarily through cell-mediated adaptive or epithelial-cell-derived innate responses. The purpose of this study was to investigate the expression of the inflammatory and fibrogenic mediators which may be involved. We conducted a cross-sectional survey of children living in an untreated trachoma-endemic community in Tanzania. The children were examined for signs of trachoma, and swabs were collected for bacteriological culture and RNA and DNA isolation. Chlamydia trachomatis was detected by the Amplicor PCR test. The expression of the following genes was measured by quantitative reverse transcription-PCR (RT-PCR): S100A7, IL1B, IL17A, IL23A, CXCL5, CCL18, TLR2, NLRP3, KLRD1, CTGF, and MMP9. Four hundred seventy children under the age of 10 years were included. Follicular trachoma (TF) was detected in 65 children (14%), C. trachomatis was detected in 25 (5%), and bacterial pathogens were cultured in 161 (34%). TF was associated with significantly increased expression of S100A7, IL17A, CCL18, CXCL5, and CTGF. Expression was increased further in the presence of papillary inflammation. Nonchlamydial bacterial infection was associated with increased expression of IL17A, CXCL5, CCL18, and KLRD1. IL17A expression was associated with increased expression of S100A7, CXCL5, CCL18, KLRD1, and CTGF. These data are consistent with a role for IL-17A in orchestrating the proinflammatory response in trachoma. Its activity may be promoted either as part of the cell-mediated response or through innate pathways. It may drive a range of proinflammatory factors leading to excessive tissue damage and repair involving fibrosis.
Infection and immunity 09/2011; 79(12):4977-83. · 4.21 Impact Factor
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Saul N Rajak,
Esmael Habtamu,
Helen A Weiss,
Amir Bedri,
Teshome Gebre,
Robin L Bailey, David C W Mabey,
Peng T Khaw,
Clare E Gilbert,
Paul M Emerson,
Matthew J Burton
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ABSTRACT: Trachomatous trichiasis (TT) is usually described as a cicatricial entropion of the upper lid; however, other forms of trichiasis have been reported. This variation in clinical phenotype is potentially important for treatment guidelines. Therefore, this study was conducted to investigate the range of disease type and severity encompassed by TT.
Individuals presenting with TT to surgical treatment campaigns were examined by a single ophthalmologist using the Detailed WHO Trachoma Grading System. Additional features were graded, including type of trichiatic lashes (metaplastic, misdirected, and entropic), lower lid trichiasis, entropion severity, and lid margin mucocutaneous junction (MCJ) position.
Recruited were 2556 individuals with previously unoperated TT in at least one eye (4310 eyes). The median number of lashes touching the eye was 2 (range, 0 [epilating]-133). Entropion was absent or mild in 2328 (54.0%) eyes, moderate in 1259 (29.2%) eyes, and severe in 723 (16.8%) eyes. Trichiatic lashes were predominantly metaplastic or misdirected (80.2%), rather than secondary to entropion; 4204 (97.7%) had anteroplacement of the MCJ; and lower lid trichiasis was present in 494 (11.5%). Entropion was more severe among those with a low BMI, those who were female, those aged less than 50 years, and those with moderate to severe conjunctival inflammation, central corneal opacity, and severe conjunctival scarring.
Many patients with TT have minimal or no entropion. The trichiasis is frequently attributable to metaplastic or misdirected eyelashes. The results of tarsal rotation surgery in TT patients without manifest entropion should be investigated and potentially alternative treatment strategies evaluated.
Investigative ophthalmology & visual science 09/2011; 52(11):7974-80. · 3.43 Impact Factor
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Emma M Harding-Esch,
Martin J Holland,
Jean-François Schémann,
Sandra Molina,
Isatou Sarr,
Aura A Andreasen,
Chrissy h Roberts,
Ansumana Sillah,
Boubacar Sarr,
Edward F Harding,
Tansy Edwards,
Robin L Bailey, David C W Mabey
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ABSTRACT: The clinical signs of active trachoma are often present in the absence of ocular Chlamydia trachomatis infection in low prevalence and mass treated settings. Treatment decisions are currently based on the prevalence of clinical signs, and this may result in the unnecessary distribution of mass antibiotic treatment. We aimed to evaluate the diagnostic accuracy of a prototype point-of-care (POC) test, developed for field diagnosis of ocular C. trachomatis, in low prevalence settings of The Gambia and Senegal.
Three studies were conducted, two in The Gambia and one in Senegal. Children under the age of 10 years were screened for the clinical signs of trachoma. Two ocular swabs were taken from the right eye. The first swab was tested by the POC test in the field and the result independently graded by two readers. The second swab was tested for the presence of C. trachomatis by Amplicor Polymerase Chain Reaction. In Senegal, measurements of humidity and temperature in the field were taken. A total of 3734 children were screened, 950 in the first and 1171 in the second Gambian study, and 1613 in Senegal. The sensitivity of the prototype POC test ranged between 33.3-67.9%, the specificity between 92.4-99.0%, the positive predictive value between 4.3-21.0%, and the negative predictive value between 98.0-99.8%. The rate of false-positives increased markedly at temperatures above 31.4°C and relative humidities below 11.4%.
In its present format, this prototype POC test is not suitable for field diagnosis of ocular C. trachomatis as its specificity decreases in hot and dry conditions: the environment in which trachoma is predominantly found. In the absence of a suitable test for infection, trachoma diagnosis remains dependent on clinical signs. Under current WHO recommendations, this is likely resulting in the continued mass treatment of non-infected communities.
PLoS Neglected Tropical Diseases 08/2011; 5(8):e1234. · 4.69 Impact Factor
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ABSTRACT: In low prevalence settings, clinically active follicular trachoma (TF) is often found in the absence of detectable Chlamydia trachomatis. The reasons for this persistent follicular phenotype are not well understood; one possible explanation is that other bacterial species are provoking the inflammatory response. This study investigated the relationship between TF, C. trachomatis, and nonchlamydial bacterial infection.
A cross-sectional survey was conducted in a trachoma endemic village in Tanzania. All available children were examined for trachoma and swabs were collected for microbiologic culture (blood and chocolate agar) and C. trachomatis PCR (Amplicor).
Four hundred seventy-three children under 10 years of age were recruited for this study. The prevalences of TF and C. trachomatis were 13.7% and 5.3%, respectively, and were not associated. Bacteria were cultured from 305 (64.5%) swab samples; 162 (34.3%) grew a pathogen (with or without a commensal organism) and 143 (30.2%) grew commensal bacteria only. The most common pathogens were Streptococcus pneumoniae and Haemophilus influenzae (type B and non-type B). The presence of bacterial pathogens was associated with TF (odds ratio, 4.68; 95% confidence interval, 2.31-9.50; P < 0.001).
In regions with low levels of endemic trachoma, it is possible that much of the TF that is observed is attributable to nonchlamydial bacterial pathogens. It is plausible that individuals who have previously developed a follicular conjunctivitis in response to C. trachomatis may more readily reform conjunctival follicles when challenged with certain other bacterial species.
Investigative ophthalmology & visual science 06/2011; 52(8):6012-7. · 3.43 Impact Factor
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ABSTRACT: Trachomatous trichiasis (TT) caused by repeated or chronic ocular infection with Chlamydia trachomatis is the result of a pro-fibrotic ocular immune response. At the conjunctiva, the increased expression of both inflammatory (IL1B, TNF) and regulatory cytokines (IL10) have been associated with adverse clinical outcomes. We measured in vitro immune responses of peripheral blood to a number of chlamydial antigens. Peripheral blood effector cells (CD4, CD69, IFNγ, IL-10) and regulatory cells (CD4, CD25, FOXP3, CTLA4/GITR) were readily stimulated by C. trachomatis antigens but neither the magnitude (frequency or stimulation index) or the breadth and amount of cytokines produced in vitro [IL-5, IL-10, IL-12 (p70), IL-13, IFNγ, and TNFα] were significantly different between TT cases and their non-diseased controls. Interestingly we observed that CD4+ T cells account for <50% of the IFNγ positive cells induced following stimulation. Further investigation in individuals selected from communities where exposure to ocular infection with C. trachomatis is endemic indicated that CD3-CD56+ (classical natural killer cells) were a major early source of IFNγ production in response to C. trachomatis elementary body stimulation and that the magnitude of this response increased with age. Future efforts to unravel the contribution of the adaptive immune response to conjunctival fibrosis should focus on the early events following infection and the interaction with innate immune mediated mechanisms of inflammation in the conjunctiva.
Frontiers in microbiology. 01/2011; 2:10.
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ABSTRACT: To assess whether non-chlamydial bacterial infection is associated with trachomatous scarring in adults.
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.
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).
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.
Investigative ophthalmology & visual science 12/2010; 52(5):2181-6. · 3.43 Impact Factor
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ABSTRACT: Trachoma is the leading infectious cause of blindness and is endemic in 52 countries. There is a critical need to further our understanding of the host response during disease and infection, as millions of individuals are still at risk of developing blinding sequelae. Infection of the conjunctival epithelial cells by the causative bacterium, Chlamydia trachomatis, stimulates an acute host response. The main clinical feature is a follicular conjunctivitis that is incompletely defined at the tissue-specific gene expression and molecular levels. To explore the features of disease and the response to infection, we measured host gene expression in conjunctival samples from Gambian children with active trachoma and healthy controls. Genome-wide expression and transcription network analysis identified signatures characteristic of the expected infiltrating immune cell populations, such as neutrophils and T/B lymphocytes. The expression signatures were also significantly enriched for genes in pathways which regulate NK cell activation and cytotoxicity, antigen processing and presentation, chemokines, cytokines, and cytokine receptors. The data suggest that in addition to polymorph and adaptive cellular responses, NK cells may contribute to a significant component of the conjunctival inflammatory response to chlamydial infection.
Infection and immunity 11/2010; 78(11):4895-911. · 4.21 Impact Factor
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ABSTRACT: To describe the in vivo confocal microscopy (IVCM) appearances of the tarsal conjunctiva in trachoma compared with the appearance of healthy conjunctiva and to develop grading systems for IVCM examination of the tarsal conjunctiva for use in future studies on trachoma and other conjunctival diseases.
Prospective observational study.
In vivo confocal microscopy examination was performed on 302 clinically normal adults, 16 clinically normal children, 750 adults with trachomatous conjunctival scarring, and 25 children with active trachoma.
Clinical evaluation was performed with ×2.5 loupes, and IVCM examination of the upper tarsal conjunctiva was carried out with a Heidelberg Retina Tomograph 3 with the Rostock Cornea Module (Heidelberg Engineering GmbH, Dossenheim, Germany).
In vivo confocal microscopy images were analyzed for cellular and tissue changes associated with trachomatous inflammation and scarring compared with healthy subjects.
Trachomatous subjects with follicular and papillary inflammation had an increased inflammatory cellular infiltrate, including dendritiform cells, discrete follicular and papillary structures, and cystic lacunae suggestive of tissue edema. Trachomatous conjunctival scarring was seen with IVCM as organization of the subepithelial connective tissue into bands/sheets. Grading systems for inflammatory changes and scarring were developed, with the system for scarring showing good interobserver agreement with an intraclass coefficient of 0.88.
In vivo confocal microscopy provides a powerful tool for examining the ocular surface. Numerous cellular and tissue changes were observed in subjects with trachoma, the first time IVCM has been applied to this disease. These changes both complement and add to previous histologic analyses. In vivo confocal microscopy promises to provide new insights into the pathogenesis of trachoma and other conjunctival diseases.
Ophthalmology 11/2010; 118(4):747-54. · 5.45 Impact Factor
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ABSTRACT: Trachoma is the leading infectious cause of blindness. Conjunctival Chlamydia trachomatis infection causes scarring, entropion, trichiasis, and blinding corneal opacification. Worldwide, there are 8 million people with trichiasis. Although trichiasis surgery can reduce the risk of blindness, retrospective data suggest that long-term recurrence rates may be high. A 4-year prospective investigation of recurrent trichiasis was conducted in The Gambia.
Patients with trichiasis were examined at baseline, 6 months, 1 year, and 4 years after posterior lamellar tarsal rotation surgery. Conjunctival swabs for bacteriology and PCR for C. trachomatis were collected at baseline, 6 months, and 1 year.
Three hundred fifty-six Gambian patients were enrolled at baseline and 266 were reassessed at 4 years (94% of surviving patients). The recurrence rates were 32%, 40%, and 41% at 6 months, 1 year, and 4 years, respectively. At 4 years, 30% of patients had bilateral trichiasis and 21% had bilateral corneal opacity. Recurrence was associated with severe conjunctival inflammation and severe trichiasis (>10 lashes) at baseline.
Trichiasis recurrence rates were high, and most cases recurred within 6 months of surgery. The results suggest that there are important aspects of surgical technique and quality that should to be addressed. Persistent inflammation is strongly associated with recurrence at 4 years.
Investigative ophthalmology & visual science 10/2010; 51(10):4996-5001. · 3.43 Impact Factor
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Matthew J Burton,
Saul N Rajak,
Julien Bauer,
Helen A Weiss,
Sonda B Tolbert,
Alice Shoo,
Esmail Habtamu,
Alphaxard Manjurano,
Paul M Emerson, David C W Mabey,
Martin J Holland,
Robin L Bailey
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ABSTRACT: Trachoma is a poorly understood immunofibrogenic disease process, initiated by Chlamydia trachomatis. Differences in conjunctival gene expression profiles between Ethiopians with trachomatous trichiasis (with [TTI] or without [TT] inflammation) and controls (C) were investigated to identify relevant host responses. Tarsal conjunctival swab samples were collected for RNA isolation and C. trachomatis PCR. Transcriptome-wide microarray experiments were conducted on 42 samples (TTI, n = 13; TT, n = 15; C, n =14). Specific results were confirmed by using multiplex quantitative reverse transcription-PCR for 16 mRNA targets in an independent collection of case-control samples: 386 case-control pairs (TTI, n = 244; TT, n = 142; C, n = 386). The gene expression profiles of cases were consistent with squamous metaplasia (keratins, SPRR), proinflammatory cytokine production (IL1β, CXCL5, and S100A7), and tissue remodeling (MMP7, MMP9, MMP12, and HAS3). There was no difference in the level of IFNγ between cases and controls. However, cases had increased INDO, NOS2A, and IL13RA2 and reduced IL13. C. trachomatis was detected in 1/772. Cases show evidence of ongoing inflammation and tissue remodeling, which were more marked where clinical inflammation was also present. Significantly, these processes appear to be active in the absence of current C. trachomatis infection. There was limited evidence of a T(H)1 response (INDO and NOS2A) and no association between a T(H)2 response and cases. The epithelium appears to be actively involved in late cicatricial stages of trachoma through the production of proinflammatory factors (IL1β, CXCL5, and S100A7). Longitudinal studies are needed to investigate which etiological factors and pathways are associated with progressive scarring and whether simply controlling chlamydial infection will halt progression in people with established cicatricial disease.
Infection and immunity 10/2010; 79(1):499-511. · 4.21 Impact Factor
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ABSTRACT: Trachoma is the commonest infectious cause of blindness. Recurrent episodes of infection with serovars A-C of Chlamydia trachomatis cause conjunctival inflammation in children who go on to develop scarring and blindness as adults. It was estimated that in 2002 at least 1.3 million people were blind from trachoma, and currently 40 million people are thought to have active disease and 8.2 million to have trichiasis. The disease is largely found in poor, rural communities in developing countries, particularly in sub-Saharan Africa. The WHO promotes trachoma control through a multifaceted approach involving surgery, mass antibiotic distribution, encouraging facial cleanliness and environmental improvements. This has been associated with significant reductions in the prevalence of active disease over the past 20 years, but there remain a large number of people with trichiasis who are at risk of blindness.
Tropical Medicine & International Health 04/2010; 15(6):673-91. · 2.80 Impact Factor
