key: cord-0043094-i1kyymdt authors: Marmor, Michael F. title: COVID-19 and Chloroquine/Hydroxychloroquine: Is There Ophthalmological Concern? date: 2020-05-08 journal: Am J Ophthalmol DOI: 10.1016/j.ajo.2020.03.029 sha: 06945b23826751b3a63447ce96ffb329ef6050c8 doc_id: 43094 cord_uid: i1kyymdt nan (HCQ) are generic antiviral agents that have shown effectiveness against severe acute respiratory syndrome (SARS) virus infection, and in this time of pandemic, physicians are trying any plausible approach to therapy. 1 News reports have appeared recently about China starting trials with a variety of medications to treat coronavirus 2019 (COVID-19) infection, including both of those agents. 2 In fact, at least 10 trials have started now in different countries. 3 The Chinese are giving a course of CQ, 500 mg twice daily, for up to 10 days, or 400 mg of HCQ 4 times daily, and these extreme doses have raised concerns about retinal damage. CQ and HCQ are well known to ophthalmologists because of retinal toxicity after long-term usage for systemic lupus erythematosus and other rheumatoid diseases. Retinopathy Q3 is seen infrequently before 10 or more years of usage at the American Academy of Ophthalmology (AAO) recommended dosage of <5 mg/kg real weight. 4 However, the doses proposed to treat COVID-19 are 4-5 times higher, and it is important that our specialty be informed whether there is ocular risk from these shortterm treatments. Do we need to be worried, and what, if anything, should ophthalmology be doing? Even though the Chinese COVID-19 doses are extremely high, they are used for a very brief period of time. High-dose HCQ has been used for other medical treatments. Some rheumatologists have been giving 1,200 mg/day for 6 weeks as a loading dose when starting HCQ therapy for systemic lupus erythematosus, and no visual losses have been reported, although detailed ophthalmologic examinations were not performed. 5, 6 Two trials of treatment of myeloma and solid tumors used 1,200 mg/day for 4-8 weeks, and again no visual loss was reported. 7, 8 The only high-dose ophthalmologic study by Leung and associates 9 followed 7 patients at 3-month intervals for 7-25 months while using 1,000 mg/day HCQ therapy for small-cell lung cancer. By patient weight, these doses were 3-5 times greater than that recommended by the AAO. Two patients developed subtle and suggestive changes on optical coherence tomography in the parafoveal ellipsoid zone after 11 and 17 months and definitive toxicity after 15 and 25 months. None of the other patients showed damage. Thus, evidence to date indicates that extreme doses do accelerate retinal toxicity but with a probable time course of many months rather than days. As this is being written, other reports are coming out that may alter the landscape of CQ and HCQ usage, and more reports will show up by the time this one is published. For example, a prepublication just appeared of a small French trial of 22 COVID-19-positive patients using 600 mg/day HCQ for 10 days to reduce the viral load. 10 The number of polymerase chain reaction-positive cases fell nearly 50% relative to those of controls and dropped to nearly zero if azithromycin was added. The HCQ dosage of 600 mg/day is only approximately twice that recommended by the AAO, on average, and should present no risk of retinopathy in this time frame. News media are now also citing interest in the use of CQ or HCQ intermittently as prophylaxis, much like the use for malaria, although doses have not been mentioned. Ophthalmologists should judge all of this evolving information in light of well-established knowledge about dose, weight, and duration as the primary determinants of risk of retinopathy. 11 Older studies used to cite 1,000 g/day as a ''toxic'' dose of HCQ, but measurements of absolute usage are misleading with respect to retinopathy because toxicity relates to dose by weight. 4, 11 People come in all sizes, and medical personnel, funds, hospital beds, equipment, screening tests, and proven therapy, it would be counterproductive (and raise inappropriate fears) to suggest the addition of labor-intensive and expensive eye examinations that are of low yield. However, as new protocols arise, these steps will need to be evaluated relative to the risk of retinopathy that their particular doses and durations of use may pose. Ophthalmologists will be most effective in this time of crisis by reassuring physicians and the public where retinopathy is not a serious concern with respect to CQ or HCQ usage for coronavirus. ---2020 AMERICAN JOURNAL OF OPHTHALMOLOGY 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Coronavirus puts drug repurposing on the fast track Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision) Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double-blind sixweek trial with eighteen-week extension Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/ refractory myeloma Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma Rapid onset of retinal toxicity from high-dose hydroxychloroquine given for cancer therapy Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy