American Journal of Ophthalmology

COVID-19 and Chloroquine/Hydroxychloroquine: is there Ophthalmological Concern?

Michael F. Marmor∗

Chloroquine (CQ) and hydroxychloroquine (HCQ) are generic antiviral agents that have shown effectiveness against SARS virus, and in this time of pandemic, physicians are trying any plausible approach to therapy.۱ News reports have appeared recently about China starting trials with a variety of medications to treat coronavirus (COVID-19), including both of these agents.۲ In fact, at least 10 trials have started now in different countries.۳ The Chinese are giving typically up to a 10-day course of 500 mg CQ twice daily, or 400 mg HCQ four 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 (SLE) and other rheumatoid diseases. Retinopathy is infrequently seen before 10 or more years of usage at American Academy of Ophthalmology (AAO) recommended dosage of <5 mg/kg real weight.۴ 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 short-term treatments. Do we need to be worry, 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 had been giving 1200 mg/day for 6 weeks as a loading dose when starting HCQ for SLE, and no visual loss was reported although detailed ophthalmologic exams were not performed.۵ , ۶ Two trials on treatment of myeloma and solid tumors used 1200 mg/day for 4-8 weeks, and again no visual loss was reported.۷ , ۸ The only high-dose ophthalmologic study by Leung et al followed 7 patients at 3-month intervals for 7-25 months while using 1000 mg/day of HCQ for small-cell lung cancer.۹ By patient weight these doses were 3-5 times greater than the AAO recommendation. Two patients developed subtle and suggestive OCT changes in the parafoveal ellipsoid zone after 11 and 17 months, and definitive toxicity after 15 and 25 months. None of the others 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 will show up by the time this is published. For example, a pre-publication just appeared on a small French trial of 22 COVID-19 positive patients using 600 mg/day of HCQ for 10 days to reduce the viral load.۱۰ The number of PCR-positive cases fell nearly 50% relative to controls, and it dropped to nearly zero if azithromycin was added. This dose is only about 2 times AAO recommended levels on average and should have no risk of retinopathy in this time frame. News media are now also citing interest in using 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 retinopathy risk.۱۱ Older literature used to cite 1000 g/day as a “toxic” dose of HCQ, but measures of absolute usage are misleading with respect to retinopathy, since toxicity relates to dose by weight.۴ , ۱۱ People come in all sizes, and 400 mg means something very different risk-wise to a small woman than to a large man. Short-term trials (under 2 weeks) will have negligible risk even with doses 5-6 times the usual 5 mg/kg/day maximum recommendation. Usage for a few months will still have very low risk with doses under 3-4 times the usual level. However, if physicians suggest using these drugs for a year or more, I would strongly advise staying within the AAO recommendation, and screening annually.

Bottom line: I do not believe ophthalmic screening is necessary for COVID-19 patients who take CQ or HCQ for less than 2 weeks as anti-viral therapy, since the likelihood of retinal damage is exceedingly low even with high doses. In a time of pandemic with world-wide shortages of medical personnel, funds, hospital beds, equipment, screening tests, and proven therapy, it would be counter-productive (and raise inappropriate fears) to suggest the addition of labor-intensive and expensive eye exams that are of low yield. However, as new protocols arise these will have to 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.

Investigate Oral Zinc as a Prophylactic Treatment for Those at Risk for COVID-19

 Scott W. McPherson,a Jan E. Keunen,b Alan C. Bird,c Emily Y. Chew,d and Frederik J. van Kuijka,∗

The novel coronavirus disease of 2019 (COVID-19), which can cause a severe respiratory syndrome in humans, results from infection by the SARS-CoV-2 virus. A very recent report identified the interaction between the receptor-binding domain of the spike glycoprotein (S protein) of SARS-CoV-2 and the peptidase domain of angiotensin-converting enzyme 2 (ACE2) as critical for viral entry into host cells.۱ Because of the strong link between ACE2 and SARS-CoV-2 infection, inhibitors of ACE2 have been discussed as potential therapeutic agents against COVID-19.۲ , ۳ We believe there already might be a safe, potential inhibitor of ACE2 function that could constrain the ability of SARS-CoV-2 to infect cells—and that is the trace mineral zinc. Given that zinc supplements are widely used, proven safe in moderate doses, and available without prescription, we propose that there is an urgent need to determine if zinc can be an effective prophylactic treatment against COVID-19.

SARS-CoV-2 is an enveloped, positive strand RNA virus that is about 80% identical to the SARS-CoV virus that was responsible for the severe acute respiratory syndrome (SARS) outbreak of 2002-2003. Research at that time identified interaction between the S protein of SARS-CoV and ACE2 as a mechanism of viral infection.۴ ACE2 is a type I integral membrane protein characterized by the HEXXH + E zinc-binding domain and is found on the surface of epithelial cells of the heart, lung, kidney, and intestine. ACE2 has also been found to be expressed in cells of the upper respiratory tract and in oral epithelial cells.۵ , ۶ This could explain why the SARS-CoV-2 virus can be highly infectious and COVID-19 symptoms can include pneumonia and diarrhea. Despite being a zinc metallopeptidase, very little research has been done on the effect of exogenous zinc on ACE2 function. One report showed that zinc blocked the ability of ACE2 to metabolize substrate in a dose-dependent manner starting at concentrations as small as 10 μM,۷ indicating that zinc could possibly inhibit the interaction between SARS-CoV-2 S protein and ACE2.

Although limited, there are research findings concerning the antiviral effects of zinc.۸ It was first shown that zinc lozenges, which coat the oral cavity with zinc, were somewhat effective with short-term use at mitigating the duration of rhinovirus infections especially at doses greater than 75 mg zinc daily.۹ , ۱۰ It has also been suggested zinc can limit influenza virus infections.۱۱ , ۱۲ The antiviral effects of zinc against rhinoviruses and influenza are thought to be due to enhanced immune cell function,۸ , ۱۱ , ۱۲ although the ability of zinc to interfere with the binding of these viruses to cells remains a possibility. It has also been suggested that zinc can inhibit coronavirus replication by the inhibition of RNA synthesis.۱۳ Clearly, there is an urgent need to further study the antiviral mechanisms of zinc, particularly as they relate to coronaviruses. It should be noted that SARS-CoV-2, influenza, and rhinoviruses all use different cellular receptors, but the presence of ACE2 on the epithelium of the oral cavity and upper airway offers an excellent rationale for oral zinc therapy.

Based on the Age-Related Eye Disease Study (AREDS) and the AREDS 2 studies۱۴ many, primarily elderly, are already taking zinc-containing supplements in order to limit the progression of their age-related macular degeneration. Normal serum levels of zinc are around 12 μM, and the AREDS formula, which provides 80 mg of zinc daily, was able to increase serum zinc by 17% within 1 year.۱۵ It should be studied to determine if this increase in zinc can prevent or limit disease duration for those particularly vulnerable to COVID-19.

We realize the scientific and clinical evidence to fully support the use of an oral zinc supplement as a prophylactic agent remains incomplete. Given that a vaccine is at least a year away, any safe, natural compound with antiviral potential should be given serious consideration as a prophylactic agent. Double-blind, placebo-controlled studies will ultimately need to be done to prove the efficacy of zinc supplements against SARS-CoV-2. However, because of their availability, safety, and potential benefits, they merit strong consideration for immediate studies (analyzing possible differences in progression of respiratory disease patients between AREDS 2 users and abstainers) by health researchers at this time to identify a possible tool that can work against COVID-19. In view of the serious, life-threatening circumstances of this pandemic, we believe there is potential benefit in taking oral zinc for those at risk of developing COVID-19. Therefore, shorter open-label retrospective studies should be quickly completed.

Whether or not any benefit from oral zinc can be demonstrated, we warn users strongly against taking more zinc than provided by the AREDS 2 formula and developing a false sense of security by using oral zinc. Social distancing and meticulous hand hygiene remain of the utmost importance in limiting the spread of COVID-19 and should continue to be the primary strategy against the SARS-CoV-2 pandemic.

In summary, investigating oral zinc supplementation for the prevention of COVID-19 should commence immediately.

Corneal Epithelial Thickness Measured Using Anterior Segment Optical Coherence Tomography as a Diagnostic Parameter for Limbal Stem Cell Deficiency.

Liang Q, Le Q, Cordova DW, Tseng CH, Deng SX.

Objective

Using anterior segment optical coherence tomography (AS-OCT), we investigated the epithelial thickness (ET) of the central cornea and limbal regions in patients with limbal stem cell deficiency (LSCD) as a diagnostic and staging parameter.

Design

Prospective, cross-sectional study.

Methods

The central corneal epithelium thickness (CET) and maximum limbal epithelium thickness (mLET) were measured in the superior, inferior, nasal, and temporal limbus on AS-OCT images of the normal and eyes with LSCD. CET was obtained by 1-point (OCT-CET1) and 3-point measurement (OCT-CET3). The values of OCT-CET1 and OCT-CET3 were compared to the CET obtained with in vivo confocal microscopy (IVCM-CET).

Results

Sixty-eight eyes of 50 patients with LSCD and 52 eyes of 34 normal subjects were included. The mean (±standard deviation) OCT-CET3 was 55.0 ± ۳.۰ μm (range, 50.6-62.0 μm) in the control group and 41.6 ± ۱۰.۸ μm (range, 0-56.3 μm) in the LSCD group ( P < .001). OCT-CET3 had a better correlation with IVCM-CET (r = ۰.۹۱) than did OCT-CET1 (r = ۰.۸۷, P = .۰۰۱). The degree of reduction in OCT-CET3 increased in more advanced clinical stages of LSCD (all P < .001). The OCT-CET3 cutoff value that suggests LSCD was 46.6 μm. Compared with the control group, the LSCD group had decreases in mLET in all 4 limbal regions (all P < .001). The sensitivity and specificity of OCT-CET3 is the highest among all mLET in detecting LSCD.

Conclusions

Both CET and mLET were thinner in patients with LSCD than in normal subjects. OCT-CET3 appears to be a reliable parameter to confirm LSCD when there is clinical suspicion.

Efficacy for Differentiating Nonglaucomatous Versus Glaucomatous Optic Neuropathy Using Deep Learning Systems

 Hee Kyung Yang, Young Jae Kim, Jae Yun Sung, Dong Hyun Kim, Kwang Gi Kim, and Jeong-

Min Hwan

Purpose

We sought to assess the performance of deep learning approaches for differentiating nonglaucomatous optic neuropathy with disc pallor (NGON) vs glaucomatous optic neuropathy (GON) on color fundus photographs by the use of image recognition.

Design

Development of an Artificial Intelligence Classification algorithm.

Methods

This single-institution analysis included 3815 fundus images from the picture archiving and communication system of Seoul National University Bundang Hospital consisting of 2883 normal optic disc images, 446 NGON images, and 486 GON images. The presence of NGON and GON was interpreted by 2 expert neuro-ophthalmologists and had corroborated evidence on visual field testing and optical coherence tomography. Images were preprocessed in size and color enhancement before input. We applied the convolutional neural network (CNN) of ResNet-50 architecture. The area under the precision-recall curve (average precision) was evaluated for the efficacy of deep learning algorithms to assess the performance of classifying NGON and GON.

Results

The diagnostic accuracy of the ResNet-50 model to detect GON among NGON images showed a sensitivity of 93.4% and specificity of 81.8%. The area under the precision-recall curve for differentiating NGON vs GON showed an average precision value of 0.874. False positive cases were found with extensive areas of peripapillary atrophy and tilted optic discs.

Conclusion

Artificial intelligence–based deep learning algorithms for detecting optic disc diseases showed excellent performance in differentiating NGON and GON on color fundus photographs, necessitating further research for clinical application.