To the Editor:
A recent review by Ruamviboonsuk et al discusses the retinal safety considerations for the use of chloroquine/hydroxychloroquine in the treatment of COVID-19.1 The authors draw attention to the risk associated with a short-term, high-dose regimen for these agents, especially when treating the high-risk elderly patients likely to have a significant preexisting ocular disease. They emphasize the importance of an ophthalmologic examination before initiation of treatment and recommend avoiding these agents in patients who have significant ocular abnormalities. They further suggest that, in most instances, the higher risk could be determined by reviewing patients’ previous ocular disease history. Although we believe that the authors’ assertions are clinically accurate, a lack of objective data either in previous studies or in their review that supports or refutes authors’ opinion engenders concerns.
We are currently enrolling patients to examine the effects of hydroxychloroquine therapy on cardiovascular disease in patients with chronic kidney disease in a phase 2b randomized controlled trial (NCT03636152). The study is being conducted in the US Veterans population and as such, largely enrolls older male patients with high comorbidity index, which would be classified as high-risk in the context of COVID-19. As a part of the protocol, we evaluate patients for their ophthalmologic eligibility to receive hydroxychloroquine therapy by a 2-step process: a prescreen comprised of ophthalmic history with electronic medical record review, followed by a detailed eye examination comprising of visual fields, autofluorescence, spectral-domain ocular coherence tomography, and dilated fundus examination. To date, we have prescreened 413 high cardiovascular-risk chronic kidney disease patients (mean age 71.5 ± 6.3 years). Based on the review of preexisting ophthalmic history, we found 14 individuals (3.4%) as ineligible. Of the 57 without significant ophthalmologic diagnosis on history and enrolled to undergo detailed eye examination, only 2 patients (3.5%) were found to have severe ophthalmologic pathology. The limiting diagnoses for these individuals were: advanced macular degeneration (n = 2), advanced glaucoma (n = 4), severe ischemic retinopathy (n = 3), central chorioretinal scar (n = 3), monocular status (n = 3), and inherited retinal degeneration (n = 1). Pathology was bilateral in half the patients. Overall, the drug-limiting ophthalmologic pathology was present in 16 patients (3.8% of the total), and a majority (87.5%) of these pathologies were preexisting diagnosis, identifiable on review of their ophthalmic history.
The safety of high-dose hydroxychloroquine, even when used for short duration therapy, is not known, especially for elderly populations who may have a preexisting severe ophthalmic disease. In vitro experiments have shown impairment of retinal metabolism with acute high doses.2,3 For these reasons, we fully agree with the authors that the prescribing physicians must ensure that the patients do not have preexisting severe ocular pathology, especially when considering high doses. Many professional ophthalmology organizations across the world also concur and recommend prescreening and avoidance of hydroxychloroquine in patients who have a significant preexisting central outer retinal loss or have significant ocular pathology that might prevent surveillance for drug-induced toxicity.1,2 Despite these, to our knowledge, few studies have reported the prevalence of severe ophthalmic disease as an important limitation to initiating hydroxychloroquine therapy. Liu et al in a study of IgA nephropathy reported only 1 of 100 screened to have ophthalmologic contraindications, whereas in a randomized trial involving rheumatoid arthritis, 10 of 170 patients (5.8%) were found as ineligible. 4,5
Our data combined with these studies indicate that the preexisting ophthalmic pathologies could potentially preclude the use of hydroxychloroquine in 3% to 5% of patients. An encouraging aspect of our data that validates the authors’ clinical opinion is that the vast majority of high-retinal risk patients in these elderly populations are easily identified either by obtaining a comprehensive history or with a thorough electronic medical review and do not require a detailed eye examination. This allows a quick medical decision-making in COVID-19. Although hydroxychloroquine is gaining recognition in many institutions worldwide as a standard of care for COVID-19,6 these safety considerations are important as elderly patients with multiple comorbidities are more likely to contract a severe infection.
1. Ruamviboonsuk P, Lai TYY, Chang A, et al. for Asia-Pacific Vitreo-Retina Society. Chloroquine and hydroxychloroquine retinal toxicity consideration in the treatment of COVID-19. Asia Pac J Ophthalmol (Phila)
2. Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF. American Academy of Opthalomology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 Revision). Ophthalmology
3. Korthagen NM, Bastiaans J, van Meurs JC, van Bilsen K, van Hagen PM, Dik WA. Chloroquine and hydroxychloroquine increase retinal pigment epithelial layer permeability. J Biochem Mol Toxicol
4. Liu LJ, Yang YZ, Shi SF, et al. Effects of hydroxychloroquine on proteinuria in IgA nephropathy: a randomized controlled trial. Am J Kidney Dis
5. A randomized trial of hydroxychloroquine in early rheumatoid arthritis: The HERA study. Am J Med
6. Shukla AM, Archibald LK, Shukla AW, Mehta HJ, Cherabuddi K. Chloroquine and hydroxychloroquine in the context of COVID-19. Drugs Context