Published date: Jul 29 2020

Journal Title: Journal of Ophthalmic and Vision Research

Issue title: July–September 2020, Volume 15, Issue 3

Pages: 372–395

DOI: 10.18502/jovr.v15i3.7456

Amir A. Azariamirazarimd@gmail.comOphthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Amir ArabiOphthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Conjunctivitis is a commonly encountered condition in ophthalmology clinics throughout the world. In the management of suspected cases of conjunctivitis, alarming signs for more serious intraocular conditions, such as severe pain, decreased vision, and painful pupillary reaction, must be considered. Additionally, a thorough medical and ophthalmic history should be obtained and a thorough physical examination should be done in patients with atypical findings and chronic course. Concurrent physical exam findings with relevant history may reveal the presence of a systemic condition with involvement of the conjunctiva. Viral conjunctivitis remains to be the most common overall cause of conjunctivitis. Bacterial conjunctivitis is encountered less frequently and it is the second most common cause of infectious conjunctivitis. Allergic conjunctivitis is encountered in nearly half of the population and the findings include itching, mucoid discharge, chemosis, and eyelid edema. Long-term usage of eye drops with preservatives in a patient with conjunctival irritation and discharge points to the toxic conjunctivitis as the underlying etiology. Effective management of conjunctivitis includes timely diagnosis, appropriate differentiation of the various etiologies, and appropriate treatment.

1. Shekhawat NS, Shtein RM, Blachley TS, Stein JD. Antibiotic prescription fills for acute conjunctivitis among enrollees in a large United States managed care network. Ophthalmology 2017;124:1099–1107.

2. Smith AF, Waycaster C. Estimate of the direct and indirect annual cost of bacterial conjunctivitis in the United States. BMC Ophthalmol 2009;9:13.

3. Ryder EC, Benson S. Conjunctivitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing LLC; 2020.

4. de Laet C, Dionisi-Vici C, Leonard JV, McKiernan P, Mitchell G, Monti L, et al. Recommendations for the management of tyrosinaemia type 1. Orphanet J Rare Dis 2013;8:8–8.

5. Sati A, Sangwan VS, Basu S. Porphyria: varied ocular manifestations and management. BMJ Case Rep 2013;2013:bcr2013009496.

6. Narayana S, McGee S. Bedside diagnosis of the ’Red Eye’: a systematic review. Am J Med 2015;128:1220–1224.e1221.

7. Everitt H, Little P. How do GPs diagnose and manage acute infective conjunctivitis? A GP survey. Fam Pract 2002;19:658–660.

8. La Rosa M, Lionetti E, Reibaldi M, et al. Allergic conjunctivitis: a comprehensive review of the literature. Ital J Pediatr 2013;39:18.

9. Friedlaender MH. Ocular allergy. Curr Opin Allergy Clin Immunol 2011;11:477–482.

10. Bielory L, Frohman LP. Allergic and immunologic disorders of the eye. J Allergy Clin Immunol 1992;89:1–15.

11. Bielory B, Bielory L. Atopic dermatitis and keratoconjunctivitis. Immunol Allergy Clin North Am 2010;30:323–336.

12. Wilson-Holt N, Dart JK. Thiomersal keratoconjunctivitis, frequency, clinical spectrum and diagnosis. Eye 1989;3:581–587.

13. Soparkar CN, Wilhelmus KR, Koch DD, Wallace GW, Jones DB. Acute and chronic conjunctivitis due to overthe- counter ophthalmic decongestants. Arch Ophthalmol 1997;115:34–38.

14. van Ketel WG, Melzer-van Riemsdijk FA. Conjunctivitis due to soft lens solutions. Contact Dermatitis 1980;6:321–324.

15. Woodland RM, Darougar S, Thaker U, Cornell L, Siddique M, Wania J, et al. Causes of conjunctivitis and keratoconjunctivitis in Karachi, Pakistan. Trans Royal Soc Trop Med Hygiene 1992;86:317–320.

16. Bielory BP, O’Brien TP, Bielory L. Management of seasonal allergic conjunctivitis: guide to therapy. Acta Ophthalmologica 2012;90:399–407.

17. Rietveld RP, van Weert HC, ter Riet G, Bindels PJ. Diagnostic impact of signs and symptoms in acute infectious conjunctivitis: systematic literature search. BMJ 2003;327:789.

18. Rietveld RP, ter Riet G, Bindels PJ, Sloos JH, van Weert HC. Predicting bacterial cause in infectious conjunctivitis: cohort study on informativeness of combinations of signs and symptoms. BMJ 2004;329:206–210.

19. Jefferis J, Perera R, Everitt H, van Weert H, Rietveld R, Glasziou P, et al. Acute infective conjunctivitis in primary care: who needs antibiotics? An individual patient data meta-analysis. Br J Gen Pract 2011;61:e542–548.

20. van Weert HC, Tellegen E, Ter Riet G. A new diagnostic index for bacterial conjunctivitis in primary care. A rederivation study. Eur J Gen Pract 2014;20:202–208.

21. Azari AA, Barney NP. Conjunctivitis: a systematic review of diagnosis and treatment. JAMA 2013;310:1721–1729.

22. Drew RJ, Cole TS, Newman W. How to use… eye swabs. Arch Dis Child Educ Pract Ed 2015;100:155–161.

23. Wong VW, Lai TY, Chi SC, Lam DS. Pediatric ocular surface infections: a 5-year review of demographics, clinical features, risk factors, microbiological results, and treatment. Cornea 2011;30:995–1002.

24. Kam KY, Ong HS, Bunce C, Ogunbowale L, Verma S. Sensitivity and specificity of the AdenoPlus point-of-care system in detecting adenovirus in conjunctivitis patients at an ophthalmic emergency department: a diagnostic accuracy study. Br J Ophthalmol 2015;99:1186–1189.

25. Stenson S, Newman R, Fedukowicz H. Laboratory studies in acute conjunctivitis. Arch Ophthalmology 1982;100:1275–1277.

26. Fitch CP, Rapoza PA, Owens S, Murillo-Lopez F, Johnson RA, Quinn TC, et al. Epidemiology and diagnosis of acute conjunctivitis at an inner-city hospital. Ophthalmology 1989;96:1215–1220.

27. Newman H, Gooding C. Viral ocular manifestations: a broad overview. Rev Med Virol 2013;23:281–294.

28. O’Brien TP, Jeng BH, McDonald M, Raizman MB. Acute conjunctivitis: truth and misconceptions. Curr Med Res Opin 2009;25:1953–1961.

29. Singh G, Zhou X, Lee JY, Yousuf MA, Ramke M, Ismail AM, et al. Recombination of the epsilon determinant and corneal tropism: human adenovirus species D types 15, 29, 56, and 69. Virology 2015;485:452–459.

30. Kuo IC. Adenoviral keratoconjunctivitis: diagnosis, management, and prevention. Curr Ophthalmol Rep 2019;7:118–127. 31. Li J, Lu X, Sun Y, Lin C, Li F, Yang Y, et al. A swimming pool-associated outbreak of pharyngoconjunctival fever caused by human adenovirus type 4 in Beijing, China. Int J Infect Dis 2018;75:89–91. 32. Harley D, Harrower B, Lyon M, Dick A. A primary school outbreak of pharyngoconjunctival fever caused by adenovirus type 3. Comm Dis Intell 2001;25:9–12. 33. Sinclair RG, Jones EL, Gerba CP. Viruses in recreational water-borne disease outbreaks: a review. J Appl Microbiol 2009;107:1769–1780. 34. Darougar S, Grey RH, Thaker U, McSwiggan DA. Clinical and epidemiological features of adenovirus keratoconjunctivitis in London. Br J Ophthalmol 1983;67:1– 7. 35. Jhanji V, Chan TC, Li EY, Agarwal K, Vajpayee RB. Adenoviral keratoconjunctivitis. Surv Ophthalmol 2015;60:435–443. 36. Chintakuntlawar AV, Chodosh J. Cellular and tissue architecture of conjunctival membranes in epidemic keratoconjunctivitis. Ocul Immunol Inflamm 2010;18:341– 345. 37. Chigbu DI, Labib BA. Pathogenesis and management of adenoviral keratoconjunctivitis. Infect Drug Resist 2018;11:981–993. 38. Richmond S, Burman R, Crosdale E, et al. A large outbreak of keratoconjunctivitis due to adenovirus type 8. The Journal of hygiene 1984;93:285-291. 39. Okumus S, Coskun E, Tatar MG, Kaydu E, Yayuspayi R, Comez A, et al. Cyclosporine a 0.05% eye drops for the treatment of subepithelial infiltrates after epidemic keratoconjunctivitis. BMC Ophthalmol 2012;12:42.

40. Ghanem RC, Vargas JF, Ghanem VC. Tacrolimus for the treatment of subepithelial infiltrates resistant to topical steroids after adenoviral keratoconjunctivitis. Cornea 2014;33:1210–1213.

41. Gallenga PE, Lobefalo L, Colangelo L, Della Loggia G, Orzalesi N, Velati P, et al. Topical lomefloxacin 0.3% twice daily versus tobramycin 0.3% in acute bacterial conjunctivitis: a multicenter double-blind phase III study. Ophthalmologica 1999;213:250–257.

42. Udeh BL, Schneider JE, Ohsfeldt RL. Cost effectiveness of a point-of-care test for adenoviral conjunctivitis. Am J Med Sci 2008;336:254–264.

43. Jackson WB, Low DE, Dattani D, Whitsitt PF, Leeder RG, MacDougall R. Treatment of acute bacterial conjunctivitis: 1% fusidic acid viscous drops vs. 0.3% tobramycin drops. Can J Ophthalmol 2002;37:228–237; discussion 237.

44. Gordon YJ, Gordon RY, Romanowski E, Araullo-Cruz TP. Prolonged recovery of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. Ophthalmology 1993;100:1835–1839; discussion 1839–1840.

45. Junk AK, Chen PP, Lin SC, Nouri-Mahdavi K, Radhakrishnan S, Singh K, et al. Disinfection of Tonometers: a report by the American Academy of Ophthalmology. Ophthalmology 2017;124:1867–1875.

46. Bremond-Gignac D, Mariani-Kurkdjian P, Beresniak A, El Fekih L, Bhagat Y, Pouliquen P, et al. Efficacy and safety of azithromycin 1.5% eye drops for purulent bacterial conjunctivitis in pediatric patients. Pediatr Infect Dis J 2010;29:222–226.

47. Varu DM, Rhee MK, Akpek EK, Amescua G, Farid M, Garcia-Ferrer FJ, et al. Conjunctivitis preferred practice pattern®. Ophthalmology 2019;126:P94–P169.

48. Leibowitz HM. Antibacterial effectiveness of ciprofloxacin 0.3% ophthalmic solution in the treatment of bacterial conjunctivitis. Am J Ophthalmol 1991;112:29s–33s.

49. Trinavarat A, Atchaneeyasakul LO. Treatment of epidemic keratoconjunctivitis with 2% povidone-iodine: a pilot study. J Ocul Pharmacol Ther 2012;28:53–58.

50. Kovalyuk N, Kaiserman I, Mimouni M, Cohen O, Levartovsky S, Sherbany H, et al. Treatment of adenoviral keratoconjunctivitis with a combination of povidone-iodine 1.0% and dexamethasone 0.1% drops: a clinical prospective controlled randomized study. Acta Ophthalmol 2017;95:e686–e692.

51. Holland EJ, Bartlett JD, Paterno MR, Usner DW, Comstock TL. Effects of loteprednol/tobramycin versus dexamethasone/tobramycin on intraocular pressure in healthy volunteers. Cornea 2008;27:50–55.

52. Belfort R, Jr., Gabriel L, Martins Bispo PJ, Muccioli C, Zacharias Serapicos PC, Clark L, et al. Safety and efficacy of moxifloxacin-dexamethasone eyedrops as treatment for bacterial ocular infection associated with bacterial blepharitis. Adv Ther 2012;29:416–426.

53. Clement C, Capriotti JA, Kumar M, et al. Clinical and antiviral efficacy of an ophthalmic formulation of dexamethasone povidone-iodine in a rabbit model of adenoviral keratoconjunctivitis. Investigative ophthalmology & visual science 2011;52:339-344.

54. Pinto RD, Lira RP, Abe RY, Fernandes Felix JP, Fernandes Pereira AV, Leite Arieta CE, et al. Dexamethasone/povidone eye drops versus artificial tears for treatment of presumed viral conjunctivitis: a randomized clinical trial. Curr Eye Res 2015;40:870–877.

55. Pepose JS, Ahuja A, Liu W, Narvekar A, Haque R. Randomized, controlled, phase 2 trial of povidoneiodine/ dexamethasone ophthalmic suspension for treatment of adenoviral conjunctivitis. Am J Ophthalmol 2019;205:197.

56. Levinger E, Slomovic A, Sansanayudh W, Bahar I, Slomovic AR. Topical treatment with 1% cyclosporine for subepithelial infiltrates secondary to adenoviral keratoconjunctivitis. Cornea 2010;29:638–640.

57. Jeng BH, Holsclaw DS. Cyclosporine A 1% eye drops for the treatment of subepithelial infiltrates after adenoviral keratoconjunctivitis. Cornea 2011;30:958–961.

58. Reinhard T, Godehardt E, Pfahl HG, Sundmacher R. [Local cyclosporin A in nummuli after keratoconjunctivitis epidemica. a pilot study]. Ophthalmologe 2000;97:764– 768.

59. Hillenkamp J, Reinhard T, Ross RS, Böhringer D, Cartsburg O, Roggendorf M, et al. Topical treatment of acute adenoviral keratoconjunctivitis with 0.2% cidofovir and 1% cyclosporine: a controlled clinical pilot study. Arch Ophthal 2001;119:1487–1491.

60. Berisa Prado S, Riestra Ayora AC, Lisa Fernandez C, Chacon Rodriguez M, Merayo-Lloves J, Alfonso Sanchez JF. Topical tacrolimus for corneal subepithelial infiltrates secondary to adenoviral keratoconjunctivitis. Cornea 2017;36:1102–1105.

61. Cronau H, Kankanala RR, Mauger T. Diagnosis and management of red eye in primary care. Am Fam Phys 2010;81:137–144.

62. Sheikh A, Hurwitz B, van Schayck CP, McLean S, Nurmatov U. Antibiotics versus placebo for acute bacterial conjunctivitis. Cochrane Database Syst Rev 2012;19:Cd001211.

63. Papa V, Aragona P, Scuderi AC, Blanco AR, Zola P, Alessandro Di B, et al. Treatment of acute bacterial conjunctivitis with topical netilmicin. Cornea 2002;21:43– 47.

64. Puri LR, Shrestha GB, Shah DN, Chaudhary M, Thakur A. Ocular manifestations in herpes zoster ophthalmicus. Nepal J Ophthalmol 2011;3:165–171.

65. Sy A, McLeod SD, Cohen EJ, Margolis TP, Mannis MJ, Lietman TM, et al. Practice patterns and opinions in the management of recurrent or chronic herpes zoster ophthalmicus. Cornea 2012;31:786–790.

66. Lim KH, Yin-Murphy M. Epidemic conjunctivitis in Singapore in 1970 and 1971. Singapore Med J 1973;14:86– 89.

67. Kono R, Sasagawa A, Miyamura K, Tajiri E. Serologic characterization and sero-epidemiologic studies on acute hemorrhagic conjunctivitis (AHC) virus. Am J Epidemiol 1975;101:444–457.

68. Zhang L, Zhao N, Huang X, Jin X, Geng X, Chan TC, et al. Molecular epidemiology of acute hemorrhagic conjunctivitis caused by coxsackie a type 24 variant in China, 2004-2014. Sci Rep 2017;7:45202.

69. Langford MP, Anders EA, Burch MA. Acute hemorrhagic conjunctivitis: anti-coxsackievirus A24 variant secretory immunoglobulin A in acute and convalescent tear. Clin Ophthalmol 2015;9:1665–1673.

70. Serin S, Bozkurt Oflaz A, Karabagli P, Gedik S, Bozkurt B. Eyelid molluscum contagiosum lesions in two patients with unilateral chronic conjunctivitis. Turk J Ophthalmol 2017;47:226–230.

71. Breman JG, Heymann DL, Lloyd G, McCormick JB, Miatudila M, Murphy FA, et al. Discovery and description of ebola zaire virus in 1976 and relevance to the West African epidemic during 2013-2016. J Infect Dis 2016;214:S93– S101.

72. Moshirfar M, Fenzl CR, Li Z. What we know about ocular manifestations of Ebola. Clin Ophthalmol 2014;8:2355– 2357.

73. Bausch DG, Schwarz L. Outbreak of ebola virus disease in Guinea: where ecology meets economy. PLoS Negl Trop Dis 2014;8:e3056–e3056.

74. Peiris JS, Lai ST, Poon LL, Guan Y, Yam LYC, Lim W, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 2003;361:1319-1325.

75. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:P497–P506.

76. Karimi S, Arabi A, Shahraki T, Safi S. Detection of severe acute respiratory syndrome Coronavirus-2 in the tears of patients with Coronavirus disease 2019. Eye. Retrieved from: https://doi.org/10.1038/s41433-020-0965-2.

77. Epling J. Bacterial conjunctivitis. BMJ Clin Evid 2012;2012:0704.

78. Shields T, Sloane PD. A comparison of eye problems in primary care and ophthalmology practices. Fam Med 1991;23:544–546.

79. Karpecki P, Depaolis M, Hunter JA, White EM, Rigel L, Brunner LS, et al. Besifloxacin ophthalmic suspension 0.6% in patients with bacterial conjunctivitis: A multicenter, prospective, randomized, double-masked, vehiclecontrolled, 5-day efficacy and safety study. Clin Ther 2009;31:514–526.

80. Hovding G. Acute bacterial conjunctivitis. Acta Ophthalmol 2008;86:5–17.

81. Horven I. Acute conjunctivitis. A comparison of fusidic acid viscous eye drops and chloramphenicol. Acta Ophthalmol 1993;71:165–168.

82. Wall AR, Sinclair N, Adenis JP. Comparison of fucithalmic (fusidic acid viscous eyedrops 1%) and noroxin (norfloxacin ophthalmic solution 0.3%) in the treatment of acute bacterial conjunctivitis. J Drug Assess 1998;1:549–558.

83. Rose PW, Harnden A, Brueggemann AB, Perera R, Sheikh A, Crook D, et al. Chloramphenicol treatment for acute infective conjunctivitis in children in primary care: a randomised double-blind placebo-controlled trial. Lancet 2005;366:37–43.

84. Schiebel NE. Evidence-based emergency medicine/systematic review abstract. Use of antibiotics in patients with acute bacterial conjunctivitis. Ann Emer Med 2003;41:407–409.

85. Gong L, Sun XH, Qiu XD, Zhang Y-Q, Qu J, Yuan Zl, et al. [Comparative research of the efficacy of the gatifloxacin and levofloxacin for bacterial conjunctivitis in human eyes]. [Zhonghua yan ke za zhi] Chinese J Ophthalmol 2010;46:525–531.

86. Tepedino ME, Heller WH, Usner DW, Brunner LS, Morris TW, Haas W, et al. Phase III efficacy and safety study of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis. Curr Med Res Opin 2009;25:1159–1169.

87. Hwang DG, Schanzlin DJ, Rotberg MH, Foulks G, Raizman MB. A phase III, placebo controlled clinical trial of 0.5% levofloxacin ophthalmic solution for the treatment of bacterial conjunctivitis. Br J Ophthalmol 2003;87:1004– 1009.

88. Shanmuganathan VA, Armstrong M, Buller A, Tullo AB. External ocular infections due to methicillin-resistant Staphylococcus aureus (MRSA). Eye 2005;19:284–291.

89. Zhang M, Hu Y, Chen F. [Clinical investigation of 0.3% levofloxacin eyedrops on the treatment of cases with acute bacterial conjunctivitis and bacterial keratitis]. Yan Ke Xue Bao [Eye Sci] 2000;16:146–148.

90. Gross RD, Lichtenstein S, Schlech BA, Gower LA, Potts SL. Early clinical and microbiological responses in the treatment of bacterial conjunctivitis with moxifloxacin ophthalmic solution 0.5% (VigamoxTM ) using B.I.D. dosing. Today Ther Trends 2003;21:227–237.

91. Thareja T, Kowalski R, Jhanji V, Kamyar R, Dhaliwal D. MRSA keratitis and conjunctivitis: what does it mean practically? Curr Ophthalmol Rep 2019;7:110–117.

92. Burton MJ. Trachoma: an overview. Br Med Bull 2007;84:99–116.

93. Granet DB, Dorfman M, Stroman D, Cockrum P. A multicenter comparison of polymyxin B sulfate/trimethoprim ophthalmic solution and moxifloxacin in the speed of clinical efficacy for the treatment of bacterial conjunctivitis. J Pediatr Ophthalmol Strabismus 2008;45:340–349.

94. Leibowitz HM. The red eye. New Engl J Med 2000;343:345–351.

95. Tabbara KF, El-Sheikh HF, Islam SM, Hammouda E. Treatment of acute bacterial conjunctivitis with topical lomefloxacin 0.3% compared to topical ofloxacin 0.3%. Eur J Ophthalmol 1999;9:269–275.

96. Abelson MB, Heller W, Shapiro AM, Si E, Hsu P, Bowman LM. Clinical cure of bacterial conjunctivitis with azithromycin 1%: vehicle-controlled, double-masked clinical trial. Am J Ophthalmol 2008;145:959–965.

97. Cochereau I, Meddeb-Ouertani A, Khairallah M, Amraoui A, Zaghloul K, Pop M, et al. 3-day treatment with azithromycin 1.5% eye drops versus 7-day treatment with tobramycin 0.3% for purulent bacterial conjunctivitis: multicentre, randomised and controlled trial in adults and children. Br J Ophthalmol 2007;91:465–469.

98. Darville T. Chlamydia trachomatis infections in neonates and young children. Semin Pediatr Infect Dis 2005;16:235–244.

99. Mallika P, Asok T, Faisal H, Aziz S, Tan A, Intan G. Neonatal conjunctivitis - a review. Malays Fam Phys 2008;3:77–81.

100. Castro Ochoa KJ, Mendez MD. Ophthalmia Neonatorum. In: StatPearls. Treasure Island (FL): StatPearls Publishing LLC; 2020.

101. Forster RK, Dawson CR, Schachter J. Late follow-up of patients with neonatal inclusion conjunctivitis. Am J Ophthalmol 1970;69:467–472.

102. Tipple MA, Beem MO, Saxon EM. Clinical characteristics of the afebrile pneumonia associated with Chlamydia trachomatis infection in infants less than 6 months of age. Pediatrics 1979;63:192–197.

103. Zikic A, Schunemann H, Wi T, Lincetto O, Broutet N, Santesso N. Treatment of neonatal chlamydial conjunctivitis: a systematic review and meta-analysis. J Pediatr Infect Dis Soc 2018;7:e107–e115.

104. Hammerschlag MR, Gelling M, Roblin PM, Kutlin A, Jule JE. Treatment of neonatal chlamydial conjunctivitis with azithromycin. Pediatr Infect Dis J 1998;17:1049–1050.

105. Srivastava K, Arora A, Kataria A, Cappelleri JC, Sadosky A, Peterson AM. Impact of reducing dosing frequency on adherence to oral therapies: a literature review and metaanalysis. Patient Prefer Adherence 2013;7:419–434.

106. Costumbrado J, Ng DK, Ghassemzadeh S. Gonococcal conjunctivitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.

107. Hammerschlag MR, Smith-Norowitz T, Kohlhoff SA. Keeping an eye on Chlamydia and gonorrhea conjunctivitis in infants in the United States, 2010-2015. Sex Transm Dis 2017;44:577.

108. Pak KY, Kim SI, Lee JS. Neonatal bacterial conjunctivitis in Korea in the 21st century. Cornea 2017;36:415–418.

109. Leonardi A, De Dominicis C, Motterle L. Immunopathogenesis of ocular allergy: a schematic approach to different clinical entities. Curr Opin Allergy Clin Immunol 2007;7:429–435.

110. Wong AH, Barg SS, Leung AK. Seasonal and perennial allergic conjunctivitis. Recent Pat Inflamm Allergy Drug Discov 2014;8:139–153.

111. Bonini S. Atopic keratoconjunctivitis. Allergy 2004;59:71–73.

112. Rathi VM, Murthy SI. Allergic conjunctivitis. Commun Eye Health 2017;30:S7–S10.

113. Sofi RA, Mufti A. Vernal keratoconjunctivitis in Kashmir: a temperate zone. Int Ophthalmol 2016;36:875–879.

114. Katelaris CH. Ocular allergy in the Asia Pacific region. Asia Pac Allergy 2011;1:108–114.

115. De Smedt S, Wildner G, Kestelyn P. Vernal keratoconjunctivitis: an update. Br J Ophthalmol 2013;97:9–14.

116. Jun J, Bielory L, Raizman MB. Vernal conjunctivitis. Immunol Allergy Clin North Am 2008;28:59–82, vi.

117. Zicari AM, Capata G, Nebbioso M, De Castro G, Midulla F, Leonardi L, et al. Vernal keratoconjunctivitis: an update focused on clinical grading system. Ital J Pediatr 2019;45:64.

118. Zicari AM, Nebbioso M, Zicari A, Mari E, Celani C, Occasi F, et al. Serum levels of IL-17 in patients with vernal keratoconjunctivitis: a preliminary report. Eur Rev Med Pharmacol Sci 2013;17:1242–1244.

119. Validad MH, Khazaei HA, Pishjoo M, Safdari Z. The study of Interleukin-17 level in vernal keratoconjunctivitis disease and its relationship between symptom and sign severity. Sem Ophthalmol 2017;32:721–724.

120. Occasi F, Zicari AM, Petrarca L, Nebbioso M, Salvatori G, Duse M. Vernal keratoconjunctivitis and immunemediated diseases: one unique way to symptom control? Pediatr Allergy Immunol 2015;26:289–291.

121. Zicari AM, Nebbioso M, Lollobrigida V, Bardanzellu F, Celani C, Occasi F, et al. Vernal keratoconjunctivitis: atopy and autoimmunity. Eur Rev Med Pharmacol Sci 2013;17:1419–1423.

122. Singhal D, Sahay P, Maharana PK, Raj N, Sharma N, Titiyal JS. Vernal keratoconjunctivitis. Surv Ophthalmol 2019;64:289–311.

123. Pucci N, Novembre E, Lombardi E, Cianferoni A, Bernardini R, Massai C, et al. Atopy and serum eosinophil cationic protein in 110 white children with vernal keratoconjunctivitis: differences between tarsal and limbal forms. Clin Exp Allergy 2003;33:325–330.

124. Kumagai N, Fukuda K, Fujitsu Y, Yamamoto K, Nishida T. Role of structural cells of the cornea and conjunctiva in the pathogenesis of vernal keratoconjunctivitis. Prog Retin Eye Res 2006;25:165–187.

125. Leonardi A, Bogacka E, Fauquert JL, Kowalski ML, Groblewska A, Jedrzejczak-Czechowicz M, et al. Ocular allergy: recognizing and diagnosing hypersensitivity disorders of the ocular surface. Allergy 2012;67:1327– 1337.

126. Solomon A. Corneal complications of vernal keratoconjunctivitis. Curr Opin Allergy Clin Immunol 2015;15:489–494.

127. Cameron JA, Mullaney PB. Amblyopia resulting from shield ulcers and plaques of the cornea in vernal keratoconjunctivitis. J Pediatr Ophthalmol Strabismus 1997;34:261–262.

128. Cameron JA. Shield ulcers and plaques of the cornea in vernal keratoconjunctivitis. Ophthalmology 1995;102:985–993.

129. Totan Y, Hepsen IF, Cekic O, Gunduz A, Aydin E. Incidence of keratoconus in subjects with vernal keratoconjunctivitis: a videokeratographic study. Ophthalmology 2001;108:824–827.

130. Guglielmetti S, Dart JK, Calder V. Atopic keratoconjunctivitis and atopic dermatitis. Curr Opin Allergy Clin Immunol 2010;10:478–485.

131. Offiah I, Calder VL. Immune mechanisms in allergic eye diseases: what is new? Curr Opin Allergy Clin Immunol 2009;9:477–481.

132. Chen JJ, Applebaum DS, Sun GS, Pflugfelder SC. Atopic keratoconjunctivitis: a review. J Am Acad Dermatol 2014;70:569–575.

133. Li A, Li S, Ruan F, Jie Y. Atopic keratoconjunctivitis: a diagnostic dilemma-a case report. Medicine 2018;97:e0372.

134. Elhers WH, Donshik PC. Giant papillary conjunctivitis. Curr Opin Allergy Clin Immunol 2008;8:445–449.

135. Forister JF, Forister EF, Yeung KK, Ye P, Chung MY, Tsui A, et al. Prevalence of contact lens-related complications: UCLA contact lens study. Eye Contact Lens 2009;35:176– 180.

136. Vengayil S, Vanathi M, Dada T, Kai S, Panda A. Filtering bleb-induced giant papillary conjunctivitis. Cont Lens Anterior Eye 2008;31:41–43.

137. Elhers W, Donshik P. Giant papillary conjunctivitis. Curr Opin Allergy Clin Immunol 2008;8:445–449.

138. Donshik PC, Ehlers WH, Ballow M. Giant papillary conjunctivitis. Immunol Allergy Clin North Am 2008;28:83–103, vi.

139. Niederkorn JY. Immune regulatory mechanisms in allergic conjunctivitis: insights from mouse models. Curr Opin Allergy Clin Immunol 2008;8:472–476.

140. Oboki K, Ohno T, Saito H, Nakae S. Th17 and allergy. Allergol Int 2008;57:121–134.

141. Dart J. Corneal toxicity: the epithelium and stroma in iatrogenic and factitious disease. Eye 2003;17:886–892.

142. Schmid KL, Schmid LM. Ocular allergy: causes and therapeutic options. Clin Exp Optom 2000;83:257–270.

143. Gokhale NS. Systematic approach to managing vernal keratoconjunctivitis in clinical practice: Severity grading system and a treatment algorithm. Indian J Ophthalmol 2016;64:145–148.

144. Owen CG, Shah A, Henshaw K, Smeeth L, Sheikh A. Topical treatments for seasonal allergic conjunctivitis: systematic review and meta-analysis of efficacy and effectiveness. Br J Gen Pract 2004;54:451–456.

145. Mishra GP, Tamboli V, Jwala J, Mitra AK. Recent patents and emerging therapeutics in the treatment of allergic conjunctivitis. Recent Pat Inflamm Allergy Drug Discov 2011;5:26–36.

146. Maziak W, Behrens T, Brasky TM, Duhme H, Rzehak P, Weiland SK, et al. Are asthma and allergies in children and adolescents increasing? Results from ISAAC phase I and phase III surveys in Munster, Germany. Allergy 2003;58:572–579.

147. Welch D, Ousler GW, 3rd, Nally LA, Abelson MB, Wilcox KA. Ocular drying associated with oral antihistamines (loratadine) in the normal population-an evaluation of exaggerated dose effect. Adv Exp Med Biol 2002;506:1051–1055.

148. Broide DH. Immunomodulation of allergic disease. Ann Rev Med 2009;60:279–291.

149. Szamocki S, Martyn-Hemphill C, Green J. Reactive arthritis: can’t see, can’t pee, can’t climb a tree…. Trends Urol Men Health 2016;7:17–20.

150. Keat A. Reiter’s syndrome and reactive arthritis in perspective. New Engl J Med 1983;309:1606–1615.

151. Hamdulay SS, Glynne SJ, Keat A. When is arthritis reactive? Postgrad Med J 2006;82:446–453.