title: Pathogenesis of progressive scarring trachoma in Ethiopia and Tanzania and its implications for disease control: two cohort studies.
abstract: BACKGROUND
  Trachoma causes blindness through a conjunctival scarring process initiated by ocular Chlamydia trachomatis infection; however, the rates, drivers and pathophysiological determinants are poorly understood. We investigated progressive scarring and its relationship to conjunctival infection, inflammation and transcript levels of cytokines and fibrogenic factors.
  
  
  RESULTS
  We recruited two cohorts, one each in Ethiopia and Tanzania, of individuals with established trachomatous conjunctival scarring. They were followed six-monthly for two years, with clinical examinations and conjunctival swab sample collection. Progressive scarring cases were identified by comparing baseline and two-year photographs, and compared to individuals without progression. Samples were tested for C. trachomatis by PCR and transcript levels of S100A7, IL1B, IL13, IL17A, CXCL5, CTGF, SPARCL1, CEACAM5, MMP7, MMP9 and CD83 were estimated by quantitative RT-PCR. Progressive scarring was found in 135/585 (23.1%) of Ethiopian participants and 173/577 (30.0%) of Tanzanian participants. There was a strong relationship between progressive scarring and increasing inflammatory episodes (Ethiopia: OR 5.93, 95%CI 3.31-10.6, p<0.0001. Tanzania: OR 5.76, 95%CI 2.60-12.7, p<0.0001). No episodes of C. trachomatis infection were detected in the Ethiopian cohort and only 5 episodes in the Tanzanian cohort. Clinical inflammation, but not scarring progression, was associated with increased expression of S100A7, IL1B, IL17A, CXCL5, CTGF, CEACAM5, MMP7, CD83 and reduced SPARCL1.
  
  
  CONCLUSIONS
  Scarring progressed in the absence of detectable C. trachomatis, which raises uncertainty about the primary drivers of late-stage trachoma. Chronic conjunctival inflammation appears to be central and is associated with enriched expression of pro-inflammatory factors and altered expression of extracellular matrix regulators. Host determinants of scarring progression appear more complex and subtle than the features of inflammation. Overall this indicates a potential role for anti-inflammatory interventions to interrupt progression and the need for trichiasis disease surveillance and surgery long after chlamydial infection has been controlled at community level.
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom; National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London (UCL) Institute of Ophthalmology, London, United Kingdom; Department of Ophthalmology, Kilimanjaro Christian Medical Centre, Moshi, Tanzania.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Burton
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Saul N
authors.initials: SN
authors.lastname: Rajak
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom; Department of Ophthalmology, Kilimanjaro Christian Medical Centre, Moshi, Tanzania.
authors.forename: Victor H
authors.initials: VH
authors.lastname: Hu
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom; Department of Ophthalmology, Kilimanjaro Christian Medical Centre, Moshi, Tanzania.
authors.forename: Athumani
authors.initials: A
authors.lastname: Ramadhani
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom; The Carter Center, Addis Ababa, Ethiopia.
authors.forename: Esmael
authors.initials: E
authors.lastname: Habtamu
authors.affiliation: Department of Ophthalmology, Kilimanjaro Christian Medical Centre, Moshi, Tanzania.
authors.forename: Patrick
authors.initials: P
authors.lastname: Massae
authors.affiliation: The Carter Center, Addis Ababa, Ethiopia.
authors.forename: Zerihun
authors.initials: Z
authors.lastname: Tadesse
authors.affiliation: The Carter Center, Atlanta, Georgia, United States of America.
authors.forename: Kelly
authors.initials: K
authors.lastname: Callahan
authors.affiliation: International Trachoma Initiative, Atlanta, Georgia, United States of America.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Emerson
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London (UCL) Institute of Ophthalmology, London, United Kingdom.
authors.forename: Peng T
authors.initials: PT
authors.lastname: Khaw
authors.affiliation: Medical Research Council (MRC) Laboratories, Fajara, The Gambia.
authors.forename: David
authors.initials: D
authors.lastname: Jeffries
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: David C W
authors.initials: DC
authors.lastname: Mabey
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Bailey
authors.affiliation: Medical Research Council (MRC) Tropical Epidemiology Group, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Weiss
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Holland
mesh_terms: D000328:Adult; D001766:Blindness / Q000382:microbiology / Q000473:pathology*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism; D002692:Chlamydia trachomatis / Q000235:genetics / Q000472:pathogenicity; D002921:Cicatrix / Q000473:pathology*; D015331:Cohort Studies; D003228:Conjunctiva / Q000382:microbiology / Q000473:pathology*; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005002:Ethiopia / Q000453:epidemiology; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D013636:Tanzania / Q000453:epidemiology; D014141:Trachoma / Q000453:epidemiology / Q000382:microbiology / Q000473:pathology*; D058457:Trichiasis / Q000175:diagnosis / Q000382:microbiology / Q000473:pathology
chemical_list: C526317:CCN2 protein, human; C527875:CEACAM5 protein, human; D002272:Carcinoembryonic Antigen; D016207:Cytokines; D058851:GPI-Linked Proteins; C508717:IL17A protein, human; D020381:Interleukin-17; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D055513:Connective Tissue Growth Factor; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7