Clinical characteristics and treatment outcomes of cytomegalovirus anterior uveitis and endotheliitis: A systematic review and meta-analysis

      Abstract

      Cytomegalovirus (CMV) anterior uveitis is the most common form of ocular manifestation of CMV in immunocompetent individuals. The difficulty in diagnosing CMV anterior uveitis may delay adequate treatment and affect outcomes. We sought to review systemically the overall clinical characteristics and compare treatment outcomes in CMV anterior uveitis and endotheliitis. A literature search was performed, and studies describing clinical characteristics, treatment regimens, and outcomes that included more than 5 treated eyes were included. In these 23 studies, acute CMV anterior uveitis commonly presented with high intraocular pressure (95.31%, 95% CI 90.45–98.60) and mild anterior chamber inflammation (cells >2+ = 3.18%, 95% CI 0.21–0.54). About two-thirds of CMV endotheliitis cases presented with high intraocular pressure and coin-shaped corneal lesions. Acute CMV anterior uveitis showed good clinical response to topical 0.15% ganciclovir (GCV) gel or oral valganciclovir (VGCV) (90%, 95% CI 74–100% and 95%, 95% CI 88–100%, respectively). For chronic CMV anterior uveitis, both topical GCV and oral VGCV yielded comparable results. Topical 0.5–2% GCV or a combination of topical and oral VGCV for CMV endotheliitis both resulted in good clinical response. Recurrence of inflammation was common after cessation of maintenance therapy. Overall, topical GCV resulted in an optimal outcome for CMV anterior uveitis. Escalated concentration and frequency of usage are needed for chronic CMV anterior uveitis and endotheliitis. Adequate induction and maintenance phases of anti-CMV treatment seem necessary to prevent recurrences.

      Keywords

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      References

        • Accorinti M
        • Gilardi M
        • Pirraglia MP
        • et al.
        Cytomegalovirus anterior uveitis: long-term follow-up of immunocompetent patients.
        Graefe's Arch Clin Exp Ophthalmol. 2014; 252: 1817-1824https://doi.org/10.1007/s00417-014-2782-4
        • Antoun J
        • Willermain F
        • Makhoul D
        • Motulsky E
        • Caspers L
        • Relvas LJ.
        Topical ganciclovir in cytomegalovirus anterior uveitis.
        J Ocul Pharmacol Ther. 2017; 33: 313-318https://doi.org/10.1089/jop.2016.0138
        • Bhoopat T
        • Takhar JS
        • Oldenburg CE
        • Keenan JD
        • Gonzales JA
        • Margolis TP.
        Treatment of cytomegalovirus anterior uveitis at a North American Tertiary Center with oral valganciclovir.
        Cornea. 2020; 39: 584-589https://doi.org/10.1097/ICO.0000000000002251
        • van Boxtel LAA
        • van der Lelij A
        • van der Meer J
        • Los LI.
        Cytomegalovirus as a cause of anterior uveitis in immunocompetent patients.
        Ophthalmology. 2007; 114: 1358-1362https://doi.org/10.1016/j.ophtha.2006.09.035
        • Brown F
        • Banken L
        • Saywell K
        • Arum I.
        Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers.
        Clin Pharmacokinet. 1999; 37: 167-176https://doi.org/10.2165/00003088-199937020-00005
        • Carmichael A.
        Cytomegalovirus and the eye.
        Eye (Lond). 2012; 26: 237-240https://doi.org/10.1038/eye.2011.327
        • Chan NSW
        • Chee SP.
        Demystifying viral anterior uveitis: A review.
        Clin Exp Ophthalmol. 2019; 47: 320-333https://doi.org/10.1111/ceo.13417
        • Chan NSW
        • Chee SP
        • Caspers L
        • Bodaghi B.
        Clinical features of CMV-associated anterior uveitis.
        Ocul Immunol Inflamm. 2018; 26: 107-115https://doi.org/10.1080/09273948.2017.1394471
        • Chee S-P
        • Jap A
        • Ling ECW
        • Ti S-E.
        Cytomegalovirus-positive corneal stromal edema with keratic precipitates after penetrating keratoplasty: A case-control study.
        Cornea. 2013; 32: 1094-1098https://doi.org/10.1097/ICO.0b013e318283c887
        • Chee SP
        • Bacsal K
        • Jap A
        • Se-Thoe SY
        • Cheng CL
        • Tan BH.
        Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients.
        Am J Ophthalmol. 2008; 145: 834-840https://doi.org/10.1016/j.ajo.2007.12.015
        • Chee SP
        • Jap A.
        Cytomegalovirus anterior uveitis: Outcome of treatment.
        Br J Ophthalmol. 2010; 94: 1648-1652https://doi.org/10.1136/bjo.2009.167767
        • Chee SP
        • Jap A.
        Treatment outcome and risk factors for visual loss in cytomegalovirus endotheliitis.
        Graefe's Arch Clin Exp Ophthalmol. 2012; 250: 383-389https://doi.org/10.1007/s00417-011-1813-7
        • Chew MC
        • Tan DT
        • Chee S-P
        • Li L.
        Optimising graft survival in endothelial keratoplasty for endothelial failure secondary to cytomegalovirus endotheliitis.
        J Ophthalmic Inflamm Infect. 2019; 9: 15https://doi.org/10.1186/s12348-019-0180-0
        • Choi JA
        • Kim KS
        • Jung Y
        • Park HYL
        • Park CK.
        Cytomegalovirus as a cause of hypertensive anterior uveitis in immunocompetent patients.
        J Ophthalmic Inflamm Infect. 2016; 6: 1245-1249https://doi.org/10.1186/s12348-016-0100-5
        • Chou TY
        • Hong BY.
        Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: Background, effectiveness, tolerability, safety, and future applications.
        Ther Clin Risk Manag. 2014; 10: 665-681https://doi.org/10.2147/TCRM.S58242
        • Fan NW
        • Chung YC
        • Liu YC
        • Liu CJL
        • Kuo YS
        • Lin PY.
        Long-term topical ganciclovir and corticosteroids preserve corneal endothelial function in cytomegalovirus corneal endotheliitis.
        Cornea. 2016; 35: 596-601https://doi.org/10.1097/ICO.0000000000000791
        • De Groot-Mijnes JDF
        • Chan ASY
        • Chee SP
        • Verjans GMGM.
        Immunopathology of virus-induced anterior uveitis.
        Ocul Immunol Inflamm. 2018; 26: 338-346https://doi.org/10.1080/09273948.2018.1439069
        • Harada Y
        • Fukuda K
        • Nakahira A
        • Tada K
        • Sumi T
        • Fukushima A.
        Requirement of longer term antiviral therapy in patients with cytomegalovirus anterior uveitis with corneal endothelial cell damage.
        Clin Ophthalmol. 2018; 12: 1311-1316https://doi.org/10.2147/OPTH.S164184
        • Hsiao YT
        • Kuo MT
        • Chiang WY
        • Chao TL
        • Kuo HK.
        Epidemiology and clinical features of viral anterior uveitis in southern Taiwan–Diagnosis with polymerase chain reaction.
        BMC Ophthalmol. 2019; 19: 87https://doi.org/10.1186/s12886-019-1093-2
        • Hwang JH
        • Ha M
        • Park Y
        • Chung SH.
        The effect of topical ganciclovir and corticosteroid on cytomegalovirus corneal endotheliitis in Korean patients.
        Ocul Immunol Inflamm. 2019; 27: 338-344https://doi.org/10.1080/09273948.2018.1486436
        • Hwang Y-S
        • Lin K-K
        • Lee J-S
        • et al.
        Intravitreal loading injection of ganciclovir with or without adjunctive oral valganciclovir for cytomegalovirus anterior uveitis.
        Graefe's Arch Clin Exp Ophthalmol. 2010; 248: 263-269https://doi.org/10.1007/s00417-009-1195-2
        • Hwang YS
        • Shen CR
        • Chang SHL
        • et al.
        The validity of clinical feature profiles for cytomegaloviral anterior segment infection.
        Graefe's Arch Clin Exp Ophthalmol. 2011; 249: 103-110https://doi.org/10.1007/s00417-010-1510-y
        • Jap A
        • Chee SP.
        Cytomegalovirus-associated anterior segment infection.
        Expert Rev Ophthalmol. 2011; (Published online): 517-528https://doi.org/10.1586/eop.11.49
        • Kam KW
        • Leung KS
        • Kwok RPW
        • et al.
        Clinical features, diagnosis and treatment outcomes of cytomegalovirus endotheliitis in Hong Kong.
        Acta Ophthalmol. 2018; 96: e541-e542https://doi.org/10.1111/aos.13109
        • Kandori M
        • Inoue T
        • Takamatsu F
        • et al.
        Prevalence and features of keratitis with quantitative polymerase chain reaction positive for cytomegalovirus.
        Ophthalmology. 2010; 117: 216-222https://doi.org/10.1016/j.ophtha.2009.06.059
        • Keorochana N
        • Choontanom R.
        Efficacy and safety of an extemporaneous preparation of 2% ganciclovir eye drops in CMV anterior uveitis.
        BMJ Open Ophthalmol. 2017; 2e000061https://doi.org/10.1136/bmjophth-2016-000061
        • Keorochana N
        • Treesit I
        • Funarunart P.
        Characteristics and clinical outcomes of hypertensive anterior uveitis.
        Ocul Immunol Inflamm. 2020; 28: 538-548https://doi.org/10.1080/09273948.2019.1587471
        • Kitazawa K
        • Jongkhajornpong P
        • Inatomi T
        • et al.
        Topical ganciclovir treatment post-Descemet's stripping automated endothelial keratoplasty for patients with bullous keratopathy induced by cytomegalovirus.
        Br J Ophthalmol. 2018; 102: 1293-1297https://doi.org/10.1136/bjophthalmol-2017-311145
        • Kobayashi R
        • Hashida N
        • Soma T
        • et al.
        Clinical findings of anterior segment spectral domain optical coherence tomography images in cytomegalovirus corneal endotheliitis.
        Cornea. 2016; 36: 411-414
        • Koizumi N
        • Inatomi T
        • Suzuki T
        • et al.
        Clinical features and management of cytomegalovirus corneal endotheliitis: Analysis of 106 cases from the Japan corneal endotheliitis study.
        Br J Ophthalmol. 2015; 99: 54-58https://doi.org/10.1136/bjophthalmol-2013-304625
        • Koizumi N
        • Miyazaki D
        • Inoue T
        • et al.
        The effect of topical application of 0.15% ganciclovir gel on cytomegalovirus corneal endotheliitis.
        Br J Ophthalmol. 2017; 101: 114-119https://doi.org/10.1136/bjophthalmol-2015-308238
        • Koizumi N
        • Suzuki T
        • Uno T
        • et al.
        Cytomegalovirus as an etiologic factor in corneal endotheliitis.
        Ophthalmology. 2008; 115 (e3.): 292-297https://doi.org/10.1016/j.ophtha.2007.04.053
        • Kongyai N
        • Sirirungsi W
        • Pathanapitoon K
        • et al.
        Viral causes of unexplained anterior uveitis in Thailand.
        Eye. 2012; 26: 529-534https://doi.org/10.1038/eye.2011.363
        • Miyanaga M
        • Sugita S
        • Shimizu N
        • et al.
        A significant association of viral loads with corneal endothelial cell damage in cytomegalovirus anterior uveitis.
        Br J Ophthalmol. 2010; 94: 336-340https://doi.org/10.1136/bjo.2008.156422
        • Miyazaki D
        • Shimizu D
        • Shimizu Y
        • et al.
        Diagnostic efficacy of real-time PCR for ocular cytomegalovirus infections.
        Graefe's Arch Clin Exp Ophthalmol. 2018; 256: 2413-2420https://doi.org/10.1007/s00417-018-4111-9
        • Morlet N
        • Young S
        • Naidoo D
        • Graham G
        • Coroneo MT.
        High dose intravitreal ganciclovir injection provides a prolonged therapeutic intraocular concentration.
        Br J Ophthalmol. 1996; 80: 214-216https://doi.org/10.1136/bjo.80.3.214
        • Murad MH
        • Sultan S
        • Haffar S
        • Bazerbachi F.
        Methodological quality and synthesis of case series and case reports.
        BMJ Evidence-Based Med. 2018; 23: 60-63https://doi.org/10.1136/bmjebm-2017-110853
        • Okumura N
        • Tanaka T
        • Fukui Y
        • Koizumi N.
        Stability, safety, and pharmacokinetics of ganciclovir eye drops prepared from ganciclovir for intravenous infusion.
        Jpn J Ophthalmol. 2019; 63: 289-296https://doi.org/10.1007/s10384-019-00665-8
        • Perrottet N
        • Decosterd LA
        • Meylan P
        • Pascual M
        • Biollaz J
        • Buclin T
        Valganciclovir in adult solid organ transplant recipients: pharmacokinetic and pharmacodynamic characteristics and clinical interpretation of plasma concentration measurements.
        Clin Pharmacokinet. 2009; 48: 399-418https://doi.org/10.2165/00003088-200948060-00006
        • Pleyer U
        • Chee S-P
        Current aspects on the management of viral uveitis in immunocompetent individuals.
        Clin Ophthalmol. 2015; 9: 1017-1028https://doi.org/10.2147/OPTH.S60394
        • Qian Z
        • Li H
        • Tao Y
        • Li W
        Initial intravitreal injection of high-dose ganciclovir for cytomegalovirus retinitis in HIV-negative patients.
        BMC Ophthalmol. 2018; 18: 314https://doi.org/10.1186/s12886-018-0983-z
        • Sakai J-I
        • Usui Y
        • Suzuki J
        • Kezuka T
        • Goto H
        Clinical features of anterior uveitis caused by three different herpes viruses.
        Int Ophthalmol. 2019; 39: 2785-2795https://doi.org/10.1007/s10792-019-01125-5
        • Sobolewska B
        • Deuter C
        • Doycheva D
        • Zierhut M.
        Long-term oral therapy with valganciclovir in patients with Posner-Schlossman syndrome.
        Graefe's Arch Clin Exp Ophthalmol. 2014; 252: 117-124https://doi.org/10.1007/s00417-013-2535-9
        • Standardization of Uveitis Nomenclature (SUN) Working Group
        Classification criteria for cytomegalovirus anterior uveitis.
        Am J Ophthalmol. 2021; 228: 89-95https://doi.org/10.1016/j.ajo.2021.03.060
        • Su CC
        • Wang IJ
        • Chen WL
        • Lin CP
        • His B
        • Hu FR
        Topical ganciclovir treatment in patients with cytomegalovirus endotheliitis receiving penetrating keratoplasty.
        Clin Exp Ophthalmol. 2013; 41: 339-347https://doi.org/10.1111/j.1442-9071.2012.02888.x
        • Sun B-J
        • Peng R-M
        • Lu Q
        • Hong J.
        Retinal and corneal toxicity and pharmacokinetic analysis of intraocular injection of ganciclovir in rabbit eyes.
        J Ophthalmol. 2019; 20193054758https://doi.org/10.1155/2019/3054758
        • Takase H
        • Kubono R
        • Terada Y
        • et al.
        Comparison of the ocular characteristics of anterior uveitis caused by herpes simplex virus, varicella-zoster virus, and cytomegalovirus.
        Jpn J Ophthalmol. 2014; 58: 473-482https://doi.org/10.1007/s10384-014-0340-6
        • Terada Y
        • Kaburaki T
        • Takase H
        • et al.
        Distinguishing features of anterior uveitis caused by herpes simplex virus, varicella-zoster virus and cytomegalovirus.
        Am J Ophthalmol. 2021; https://doi.org/10.1016/j.ajo.2021.03.020
        • Touhami S
        • Qu L
        • Angi M
        • et al.
        Cytomegalovirus anterior uveitis: Clinical characteristics and long-term outcomes in a French series.
        Am J Ophthalmol. 2018; 194: 134-142https://doi.org/10.1016/j.ajo.2018.07.021
        • Voigt V
        • Andoniou CE
        • Schuster IS
        • et al.
        Cytomegalovirus establishes a latent reservoir and triggers long-lasting inflammation in the eye.
        PLoS Pathog. 2018; 14e1007040https://doi.org/10.1371/journal.ppat.1007040
        • Waduthantri S
        • Zhou L
        • Chee SP
        Intra-cameral level of ganciclovir gel, 0.15% following topical application for cytomegalovirus anterior segment infection: A pilot study.
        PLoS One. 2018; 13e0191850https://doi.org/10.1371/journal.pone.0191850
        • Wensing B
        • Mochizuki M
        • De Boer JH
        Clinical characteristics of herpes simplex virus associated anterior uveitis.
        Ocul Immunol Inflamm. 2018; 26: 333-337https://doi.org/10.1080/09273948.2017.1420806
        • Wong JXH
        • Agrawal R
        • Wong EPY
        • Teoh SC
        Efficacy and safety of topical ganciclovir in the management of cytomegalovirus (CMV)-related anterior uveitis.
        J Ophthalmic Inflamm Infect. 2016; 6: 10https://doi.org/10.1186/s12348-016-0078-z
        • Wong MOM
        • Yu AHY
        • Chan CKM
        Efficacy and safety of oral valganciclovir in cytomegalovirus anterior uveitis with uncontrolled intraocular pressure.
        Br J Ophthalmol. 2020; https://doi.org/10.1136/bjophthalmol-2020-317044
        • Wong VWY
        • Chan CKM
        • Leung DYL
        • Lai TYY
        Long-term results of oral valganciclovir for treatment of anterior segment inflammation secondary to cytomegalovirus infection.
        Clin Ophthalmol. 2012; 6: 595-600https://doi.org/10.2147/OPTH.S30476
        • Yu T
        • Peng R-M
        • Xiao G-G
        • Feng L-N
        • Hong J.
        Clinical evaluation of intravitreal injection of ganciclovir in refractory corneal endotheliitis.
        Ocul Immunol Inflamm. 2020; 28: 270-280https://doi.org/10.1080/09273948.2019.1573261