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EDITORIAL 55
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3 COVID-19 and Chloroquine/Hydroxychloroquine: is 58
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there Ophthalmological Concern? 60
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8 Q3 MICHAEL F. MARMOR 64
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12 HLOROQUINE (CQ) AND HYDROXYCHLOROQUINE Two patients developed subtle and suggestive OCT
(HCQ) are generic antiviral agents that have changes in the parafoveal ellipsoid zone after 11 and 68
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shown effectiveness against SARS virus, and in 17 months, and definitive toxicity after 15 and 25 months. 69
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this time of pandemic, physicians are trying any plausible None of the others showed damage. Thus, evidence to date 70
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approach to therapy.1 News reports have appeared recently indicates that extreme doses do accelerate retinal toxicity, 71
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about China starting trials with a variety of medications to but with a probable time course of many months rather 72
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treat coronavirus (COVID-19), including both of these than days. 73
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agents.2 In fact, at least 10 trials have started now in As this is being written other reports are coming out that 74
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different countries.3 The Chinese are giving typically up may alter the landscape of CQ and HCQ usage, and more 75
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to a 10-day course of 500 mg CQ twice daily, or 400 mg will show up by the time this is published. For example, a 76
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HCQ four times daily and these extreme doses have raised pre-publication just appeared on a small French trial of 77
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concerns about retinal damage. 22 COVID-19 positive patients using 600 mg/day of 78
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CQ and HCQ are well known to ophthalmologists HCQ for 10 days to reduce the viral load.10 The number 79
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because of retinal toxicity after long-term usage for sys- of PCR-positive cases fell nearly 50% relative to controls, 80
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temic lupus erythematosus (SLE) and other rheumatoid and it dropped to nearly zero if azithromycin was added. 81
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diseases. Retinopathy is infrequently seen before 10 or This dose is only about 2 times AAO recommended levels 82
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more years of usage at American Academy of Ophthal- on average and should have no risk of retinopathy in this 83
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mology (AAO) recommended dosage of <5 mg/kg real time frame. News media are now also citing interest in us- 84
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weight.4 However, the doses proposed to treat COVID- ing CQ or HCQ intermittently as prophylaxis, much like 85
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19 are 4-5 times higher, and it is important that our spe- the use for malaria, although doses have not been 86
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cialty be informed whether there is ocular risk from these mentioned. 87
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short-term treatments. Do we need to be worry, and what Ophthalmologists should judge all of this evolving infor- 88
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if anything should ophthalmology be doing? mation in light of well-established knowledge about dose/ 89
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Even though the Chinese COVID-19 doses are weight and duration as the primary determinants of retinop- 90
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extremely high, they are used for a very brief period of athy risk.11 Older literature used to cite 1000 g/day as a 91
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time. High-dose HCQ has been used for other medical ‘‘toxic’’ dose of HCQ, but measures of absolute usage are 92
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treatments. Some rheumatologists had been giving misleading with respect to retinopathy, since toxicity relates 93
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1200 mg/day for 6 weeks as a loading dose when starting to dose by weight.4,11 People come in all sizes, and 400 mg 94
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HCQ for SLE, and no visual loss was reported although means something very different risk-wise to a small woman 95
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detailed ophthalmologic exams were not performed.5,6 than to a large man. Short-term trials (under 2 weeks) will 96
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Two trials on treatment of myeloma and solid tumors have negligible risk even with doses 5-6 times the usual 97
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used 1200 mg/day for 4-8 weeks, and again no visual loss 5 mg/kg/day maximum recommendation. Usage for a few 98
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was reported.7,8 The only high-dose ophthalmologic study months will still have very low risk with doses under 3-4 99
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by Leung et al followed 7 patients at 3-month intervals times the usual level. However, if physicians suggest using 100
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for 7-25 months while using 1000 mg/day of HCQ for these drugs for a year or more, I would strongly advise staying 101
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small-cell lung cancer.9 By patient weight these doses within the AAO recommendation, and screening annually. 102
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were 3-5 times greater than the AAO recommendation. Bottom line: I do not believe ophthalmic screening is 103
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necessary for COVID-19 patients who take CQ or HCQ 104
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for less than 2 weeks as anti-viral therapy, since the likeli- 105
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hood of retinal damage is exceedingly low even with high 106
51 Department of Ophthalmology and Byers Eye Institute, Stanford
doses. In a time of pandemic with world-wide shortages 107
52 University School of Medicine, Palo Alto, CA, USA.
Inquiries to Michael F. Marmor, Department of Ophthalmology and of medical personnel, funds, hospital beds, equipment, 108
53 Byers Eye Institute, Stanford University School of Medicine, 649
screening tests, and proven therapy, it would be counter- 109
54 Mirada Avenue, Stanford, CA 94305, USA; e-mail: marmor@stanford.
edu productive (and raise inappropriate fears) to suggest the 110

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111 addition of labor-intensive and expensive eye exams that Ophthalmologists will be most effective in this time of 178
112 are of low yield. However, as new protocols arise these crisis by reassuring physicians and the public where reti- 179
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will have to evaluated relative to the risk of retinopathy nopathy is not a serious concern with respect to CQ or
114 181
115 that their particular doses and durations of use may pose. HCQ usage for coronavirus. 182
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118 FINANCIAL DISCLOSURES: NONE. 185
Financial Support: None.
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123 REFERENCES 6. Munster T, Gibbs JP, Shen D, et al. Hydroxychloroquine 190
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