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Oral doxycycline for the prevention of postoperative trachomatous trichiasis in Ethiopia: a randomised, double-blind, placebo-controlled trial


Trachoma is a leading infectious cause of blindness worldwide. The neglected tropical disease is caused by Chlamydia trachomatis. Recurrent C trachomatis infections cause chronic inflammation and conjunctival scarring. The eyelids turn inwards and eyelashes scratch the surface of the eye (trachomatous trichiasis), leading to sight loss due to corneal opacification. Globally, an estimated 1·9 million people are visually impaired, of whom 0·45 million have irreversible blindness caused by trachoma.1x1WHO and Department of Control of Neglected Tropical Diseases. WHO Alliance for the Global Elimination of Trachoma by 2020: progress report on elimination of trachoma. http://www.who.int/trachoma/resources/who_wer9226/en; 2014–2016. ()
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Unfavourable outcomes after trichiasis surgery are a considerable concern for trachoma control programmes, and are reported to occur in around a third of patients. The most common adverse postoperative outcomes include postoperative trichiasis (about 20% of patients), eyelid contour abnormalities (around 10% of patients), and conjunctival granulomas (about 5% of patients).5x5Rajak, SN, Collin, JR, and Burton, MJ. Trachomatous trichiasis and its management in endemic countries. Surv Ophthalmol. 2012; 57: 105–135
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| Google ScholarSee all References
,6x6Burton, MJ, Habtamu, E, Ho, D, and Gower, EW. Interventions for trachoma trichiasis. Cochrane Database Syst Rev. 2015; 11 ()
Google ScholarSee all References
,7x7Habtamu, E, Wondie, T, Aweke, S et al. Posterior lamellar versus bilamellar tarsal rotation surgery for trachomatous trichiasis in Ethiopia: a randomised controlled trial. Lancet Glob Health. 2016; 4: e175–e184
Summary | Full Text | Full Text PDF | PubMed
| Google ScholarSee all References
,8x8West, SK, West, ES, Alemayehu, W et al. Single-dose azithromycin prevents trichiasis recurrence following surgery: Randomized trial in ethiopia. Arch Ophthalmol. 2006; 124: 309–314
Crossref | PubMed | Scopus (52)
| Google ScholarSee all References
,9x9Gower, EW, West, SK, Harding, JC et al. Trachomatous trichiasis clamp vs standard bilamellar tarsal rotation instrumentation for trichiasis surgery: results of a randomized clinical trial. JAMA Ophthalmol. 2013; 131: 294–301
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
Postoperative trichiasis can lead to vision loss and pain and has the potential to undermine elimination efforts. On the basis of current clinical practice more than 54 000 patients who have surgery for trichiasis develop trachomatous trichiasis annually.1x1WHO and Department of Control of Neglected Tropical Diseases. WHO Alliance for the Global Elimination of Trachoma by 2020: progress report on elimination of trachoma. http://www.who.int/trachoma/resources/who_wer9226/en; 2014–2016. ()
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Evidence before this study

Doxycycline has been widely used in various clinical situations for its putative anti-inflammatory and anti-scarring properties. In the first weeks after trachomatous trichiasis surgery, progressive conjunctival inflammation and contractile scarring mediated by matrix metalloproteinase and inflammatory cytokine activity might lead to unfavourable outcomes. On Sept 13, 2017, we updated a search done for a published Cochrane Collaboration systematic review of the management of trachomatous trichiasis (Burton and colleagues, 2015). We searched CENTRAL, Ovid MEDLINE, Embase, the International Clinical Trials Registry Platform, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform using the search terms “trachoma” and “trichiasis”. Full search methods for each database are available in the Cochrane review’s appendix. We found no studies examining the effect of doxycycline on trichiasis surgery outcomes.

Added value of this study

To the best of our knowledge this is the first trial investigating the use of doxycycline to improve outcomes following trichiasis surgery. Our trial was done to investigate whether oral doxycycline might improve trachomatous trichiasis surgery outcomes by suppressing progressive inflammation and contractile scarring during the surgical wound healing process. The results show that oral doxycycline does not improve surgical outcomes following trichiasis surgery, and does not affect the extent of postoperative conjunctival scarring or conjunctival inflammation, whether this is related to the initial wound healing process or longer-term chronic progression.

Implications of all the available evidence

This study provides evidence that oral doxycycline does not improve outcomes in trachomatous trichiasis surgery, and therefore should not be indicated for this purpose. Consistent with previous studies, our study showed that other factors, such as preoperative disease severity, surgeon skill, and patient age are important determinants of outcome, suggesting that trachoma control programmes should focus on addressing these factors and continue to make efforts to improve surgical training and supervision. Further studies are required to investigate the association between postoperative scarring and trichiasis surgery outcomes.

Conjunctival inflammation is frequently observed in people with trichiasis.10x10West, ES, Mkocha, H, Munoz, B et al. Risk factors for postsurgical trichiasis recurrence in a trachoma-endemic area. Invest Ophthalmol Vis Sci. 2005; 46: 447–453
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,12x12Burton, MJ, Kinteh, F, Jallow, O et al. A randomised controlled trial of azithromycin following surgery for trachomatous trichiasis in the Gambia. Br J Ophthalmol. 2005; 89: 1282–1288
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,13x13Burton, MJ, Bowman, RJC, Faal, H et al. Long term outcome of trichiasis surgery in the Gambia. Br J Ophthalmol. 2005; 89: 575–579
Crossref | PubMed | Scopus (42)
| Google ScholarSee all References
,14x14Burton, MJ, Bowman, RJ, Faal, H et al. The long-term natural history of trachomatous trichiasis in the Gambia. Invest Ophthalmol Vis Sci. 2006; 47: 847–852
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,15x15Bowman, RJC, Faal, H, Myatt, M et al. Longitudinal study of trachomatous trichiasis in the Gambia. Br J Ophthalmol. 2002; 86: 339–343
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,16x16Burton, MJ, Rajak, SN, Hu, VH et al. Pathogenesis of progressive scarring trachoma in Ethiopia and Tanzania and its implications for disease control: two cohort studies. PLoS Negl Trop Dis. 2015; 9: e0003763
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,17x17Rajak, SN, Habtamu, E, Weiss, HA et al. Absorbable versus silk sutures for surgical treatment of trachomatous trichiasis in Ethiopia: a randomised controlled trial. PLoS Med. 2011; 8: e1001137
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,18x18Rajak, SN, Habtamu, E, Weiss, HA et al. Surgery versus epilation for the treatment of minor trichiasis in Ethiopia: a randomised controlled noninferiority trial. PLoS Med. 2011; 8: e1001136
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
The drivers of this persistent inflammation in individuals with scarring and trichiasis have not been fully elucidated; however, it is rarely associated with C trachomatis infection.16x16Burton, MJ, Rajak, SN, Hu, VH et al. Pathogenesis of progressive scarring trachoma in Ethiopia and Tanzania and its implications for disease control: two cohort studies. PLoS Negl Trop Dis. 2015; 9: e0003763
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,19x19Muñoz, B, Bobo, L, Mkocha, H, Lynch, M, Hsieh, YH, and West, S. Incidence of trichiasis in a cohort of women with and without scarring. Int J Epidemiol. 1999; 28: 1167–1171
Crossref | PubMed
| Google ScholarSee all References
Chronic conjunctival inflammation is associated with progressive conjunctival scarring.20x20Ramadhani, AM, Derrick, T, Holland, MJ, and Burton, MJ. Blinding trachoma: systematic review of rates and risk factors for progressive disease. PLoS Negl Trop Dis. 2016; 10: e0004859
Crossref | PubMed | Scopus (4)
| Google ScholarSee all References

To reduce early postoperative trachomatous trichiasis due to contractile scarring it might be beneficial to inhibit MMP and inflammatory cytokine activity. However, at present, interventions used in other types of ophthalmic surgery (ie, mitomycin and fluorouracil) would not be suitable for patients who have surgery for trachomatous trichiasis because of their toxicity, specific handling requirements, and high cost. Doxycycline is a widely available, broad-spectrum, tetracycline-based antibiotic that is effective against C trachomatis, and also has anti-inflammatory and anti-MMP properties.24x24Golub, LM, Lee, HM, Ryan, ME, Giannobile, WV, Payne, J, and Sorsa, T. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res. 1998; 12: 12–26
Crossref | PubMed
| Google ScholarSee all References

Doxycycline has been widely used in various clinical situations because of its putative anti-inflammatory and anti-scarring properties, mediated via the inhibition of MMPs and inflammatory cytokines, including periodontitis, pulmonary fibrosis, and vascular disorders, and in ophthalmology for treating ocular surface disorders, such as ocular rosacea, severe microbial keratitis, alkali injuries, and recurrent corneal erosion syndrome.27x27van Zuuren, EJ, Fedorowicz, Z, Carter, B, van der Linden, MM, and Charland, L. Interventions for rosacea. Cochrane Database Syst Rev. 2015; 4 ()
Crossref | Scopus (53)
| Google ScholarSee all References
,28x28Wang, L, Tsang, H, and Coroneo, M. Treatment of recurrent corneal erosion syndrome using the combination of oral doxycycline and topical corticosteroid. Clin Exp Opthamol. 2008; 36: 8–12
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,29x29McElvanney, AM. Doxycycline in the management of pseudomonas corneal melting: two case reports and a review of the literature. Eye Contact Lens. 2003; 29: 258–261
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,30x30Ralph, RA. Tetracyclines and the treatment of corneal stromal ulceration: a review. Cornea. 2000; 19: 274–277
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,31x31Del Rosso, JQ, Webster, GF, Jackson, M et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007; 56: 791–802
Summary | Full Text | Full Text PDF | PubMed | Scopus (141)
| Google ScholarSee all References
,32x32Mishra, A, Bhattacharya, P, Paul, S, Paul, R, and Swarnakar, S. An alternative therapy for idiopathic pulmonary fibrosis by doxycycline through matrix metalloproteinase inhibition. Lung India. 2011; 28: 174
Crossref | PubMed | Scopus (10)
| Google ScholarSee all References
,33x33Kurosawa, K, Matsumura, JS, and Yamanouchi, D. Current status of medical treatment for abdominal aortic aneurysm. Circ J. 2013; 77: 2860–2866
Crossref | PubMed | Scopus (33)
| Google ScholarSee all References
,34x34Minagar, A, Alexander, JS, Schwendimann, RN et al. Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: an open-label trial. Arch Neurol. 2008; 65: 199–204
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
Doxycycline is considered a safe drug, and has been tested in a community-wide treatment study of onchocerciasis,35x35Wanji, S, Tendongfor, N, Nji, T et al. Community-directed delivery of doxycycline for the treatment of onchocerciasis in areas of co-endemicity with loiasis in Cameroon. Parasit Vectors. 2009; 2: 39
Crossref | PubMed | Scopus (0)
| Google ScholarSee all References
,36x36Tamarozzi, F, Tendongfor, N, Enyong, PA et al. Long term impact of large scale community-directed delivery of doxycycline for the treatment of onchocerciasis. Parasit Vectors. 2012; 5: 53
Crossref | PubMed | Scopus (25)
| Google ScholarSee all References
in which patient adherence was high (97%) and no serious side-effects were reported.

In view of the unfavourable outcomes following surgery in patients with trachomatous trichiasis and the anti-MMP and anti-inflammatory properties of doxycyline, we hypothesised that doxycycline might improve surgical outcomes. The aim of our trial was to determine whether oral doxycycline can reduce the risk of postoperative trichiasis and eyelid contour abnormalities following surgery in patients with trachomatous trichiasis.



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