Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Management and Visual Outcomes of Acute Bacterial Endophthalmitis Following Intravitreal Injection of Contaminated Bevacizumab in a Single Day

Kunyong Xu, MD, MHSc; Raed Mousa, MD; Anat Loewenstein, MD; Adiel Barak, MD; Eric K. Chin, MD; David R.P. Almeida, MD, MBA, PhD

Abstract

BACKGROUND AND OBJECTIVE:

Bevacizumab requires compounding for off-label intravitreal injection, thus creating a risk of possible contamination during preparation.

PATIENTS AND METHODS:

This retrospective, consecutive case series from a single site included patients who developed culture-proven acute endophthalmitis after intravitreal injection with contaminated bevacizumab. All patients suspected of endophthalmitis had vitreous biopsy and microbial cultures prior to initiation of treatment and were managed with immediate tap and injection of antibiotics followed early by pars plana vitrectomy. Main outcome measures included best-corrected visual acuity (BCVA) at 3-month follow-up after treatment.

RESULTS:

Twenty-four patients developed acute bacterial endophthalmitis following intravitreal injection of contaminated bevacizumab single-dose syringes in a single day. Twenty-three cases (95.8%) grew Streptococcus species and one (4.2%) grew Enterococcus species. Six cases (25.0%) had optic nerve atrophy, three (12.5%) developed retinal detachment, one (4.2%) had vitreous hemorrhage, and one (4.2%) had band keratopathy. At 3-month follow-up, compared to BCVA at the time of initial presentation, 11 patients (45.8%) had improved vision, eight (33.3%) had unchanged BCVA, and five (20.8%) had worse BCVA. However, when compared to BCVA prior to endophthalmitis (baseline), 22 cases (91.7%) had significantly worse BCVA at 3-month follow-up.

CONCLUSIONS:

Contamination of off-label bevacizumab poses devastating risk of endophthalmitis following intravitreal injection. Vigilance is needed to ensure all possible safeguards are in place to prevent contamination.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:346–352.]

Abstract

BACKGROUND AND OBJECTIVE:

Bevacizumab requires compounding for off-label intravitreal injection, thus creating a risk of possible contamination during preparation.

PATIENTS AND METHODS:

This retrospective, consecutive case series from a single site included patients who developed culture-proven acute endophthalmitis after intravitreal injection with contaminated bevacizumab. All patients suspected of endophthalmitis had vitreous biopsy and microbial cultures prior to initiation of treatment and were managed with immediate tap and injection of antibiotics followed early by pars plana vitrectomy. Main outcome measures included best-corrected visual acuity (BCVA) at 3-month follow-up after treatment.

RESULTS:

Twenty-four patients developed acute bacterial endophthalmitis following intravitreal injection of contaminated bevacizumab single-dose syringes in a single day. Twenty-three cases (95.8%) grew Streptococcus species and one (4.2%) grew Enterococcus species. Six cases (25.0%) had optic nerve atrophy, three (12.5%) developed retinal detachment, one (4.2%) had vitreous hemorrhage, and one (4.2%) had band keratopathy. At 3-month follow-up, compared to BCVA at the time of initial presentation, 11 patients (45.8%) had improved vision, eight (33.3%) had unchanged BCVA, and five (20.8%) had worse BCVA. However, when compared to BCVA prior to endophthalmitis (baseline), 22 cases (91.7%) had significantly worse BCVA at 3-month follow-up.

CONCLUSIONS:

Contamination of off-label bevacizumab poses devastating risk of endophthalmitis following intravitreal injection. Vigilance is needed to ensure all possible safeguards are in place to prevent contamination.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:346–352.]

Introduction

Biologic vascular endothelial growth factor (VEGF) antagonists, such as bevacizumab (Avastin; Genentech, South San Francisco, CA), ranibizumab (Lucentis; Genentech, South San Francisco, CA), and aflibercept (Eylea; Regeneron, Tarrytown, NY), are mainstays in the treatment for common vitreoretinal disorders such as diabetic macular edema, exudative age- related macular degeneration and cystoid macular edema secondary to retinal vein occlusion. Although the incidence of endophthalmitis following anti-VEGF injections is low, this is still the most devastating and challenging complication of intravitreal injections.1–5

Worldwide, bevacizumab is used off-label and is provided as either a 100-mg or 400-mg vial from which it must be compounded into multiple individual 1.25-mg syringes via a compounding pharmacy. There is risk for contamination and loss of sterility, which can produce unfortunate clusters of complications such as endophthalmitis.

Our case series is an unfortunate example of a cohort of patients who were affected by a contaminated batch of bevacizumab vials that resulted in severe endophthalmitis. Although we routinely extrapolate management of endophthalmitis following cataract surgery as suggested in the Endophthalmitis Vitrectomy Study (EVS),6 this study is both dated and inadequate when faced with atypical occurrences such as contamination from compounding. The purpose of our case series is to evaluate the microbiology results, management, and visual outcomes of endophthalmitis following intravitreal injection secondary to contaminated bevacizumab to mitigate the knowledge gap present in these inherently rare circumstances.

Patients and Methods

Study Design

This case series was conducted adhering to the tenets of the Declaration of Helsinki with Institutional Ethics Review Board approval. This study is HIPAA- compliant. The study sample is composed of all patients with culture-proven acute bacterial endophthalmitis following intravitreal injection of bevacizumab injections at the International Eye Centre (Palestinian Authority, Gaza). All patients received intravitreal injection on June 13, 2019. All patients injected developed endophthamitis (100% rate of endophthalmitis). Once risk of possible contamination was identified, no other patients were treated with the same bevacizumab lot. No other cases of endophthalmitis occurred during the study period.

Data were retrospectively collected from clinical records included: age, sex, clinical diagnosis, number of days from inciting event to presentation, number of days from presentation to undergoing tap and injections of antibiotics (TAI), number of days from TAI to pars plana vitrectomy (PPV), and number of days from presentation to undergoing PPV. Snellen best-corrected visual acuity (BCVA) at the time of receiving bevacizumab injections, at presentation of infection, and 3 months post-management of the endophthalmitis were collected. In addition, microbiology culture results and complications were also recorded.

Anti-VEGF Agent and Injection Technique

All of the eyes with acute endophthalmitis were previously injected with bevacizumab 1.25 mg/0.05 mL in an outpatient clinic setting. The single dose syringes of bevacizumab were provided by Concept Pharmacy (Tel Aviv), a compounding company located in Gaza. After identifying the cluster of endophthalmitis cases, it was discovered that sterility had not been ensured during transportation of single dose bevacizumab syringes likely resulting in contaminated anti-VEGF agent.

Facemasks were utilized during intravitreal injections and talking was minimized during injection by physician and patient. Topical anesthetic drops (proparacaine 0.5%) and gel anesthetic (tetracaine 0.5%) were used to anesthetize the eye prior to intravitreal injection. Topical 5% povidone-iodine (Betadine; Aviro Health, Stamford, CT) was used to prep the eye by swabbing the eyelashes, caruncle, and upper and lower eyelid followed by the instillation of two to three drops of this solution into the conjunctival cul-de-sac prior to injection. The lids were held open with a sterile eyelid speculum to keep the eyelids and eyelashes out of the field. Bevacizumab was injected into the vitreous cavity via the pars plana (3 to 4 mm from the limbus) using a short 30-gauge needle for all patients by two different retina specialists. All injections were performed in the inferotemporal location. No postoperative eye drops (eg, antibiotics) were prescribed to the patient after the injection.

Endophthalmitis Management

Once the clinical diagnosis of endophthalmitis was made, all eyes received immediate diagnostic vitreous biopsy followed by injection of intravitreal antibiotics on the same day. Diagnostic vitreous tap was performed through the pars plana. The vitreous biopsy was performed with insertion of a short 25-gauge needle into the vitreous cavity to aspirate a vitreous sample. A 0.1- to 0.3-mL vitreous sample was taken for microbiological assessment. All collected specimens were sent for gram stain, cultures, and sensitivities. Patients were then given intravitreal injections of vancomycin (1 mg/0.1 mL), ceftazidime (2.25 mg/0.1 ml), and dexamethasone (0.4 mg/0.1 ml). Topical steroid (1% prednisolone acetate) and fortified antibiotic drops (vancomycin and ceftazidime) were also prescribed and the patients were followed daily.

Following initial TAI, all 24 patients underwent PPV within 72 hours of presentation. The benefit of early vitrectomy is to remove infectious material and vitreous debris as well as to get a vitreous sample for assisting diagnosis. A retrobulbar block was placed in the periorbital space for anesthesia. The eye was then prepped and draped in usual sterile fashion and a lid speculum was inserted. PPV (20-gauge) was performed and all opacified vitreous were removed with the vitreous cutter. Limited core vitrectomies were performed, and peripheral shaving was not performed. When required, the corneal epithelium was debrided and pars plana lensectomy was performed. Inspection was performed and any retinal breaks (if present) were demarcated with laser retinopexy. A partial or complete air-fluid exchange was performed. All sclerotomy sites were sutured. Silicone oil was used for severe cases. At the conclusion of the case, intravitreal injection of 0.1 mL of vancomycin (1.0 mg/0.1 mL) and 0.1 mL of ceftazidime (2.25 mg/0.1 mL) were performed through the pars plana with a short 30-gauge needle.

Statistical Analysis

Descriptive analysis was used to describe the sample characteristics. Continuous variables were described by using means and standard deviations (SD). Categorical variables were described by using frequencies and percentages (%). All statistical analyses were performed using the SAS, Version 9.3 (SAS, Institute, Cary, NC).

Results

Twenty-four patients with culture-proven acute bacterial endophthalmitis following bevacizumab intravitreal injection related to contaminated lots were identified. Patients' mean age was 59.3 (standard deviation [SD] = 8.7) years, and 58.3% of the patients were male. Majority of patients received bevacizumab for proliferative diabetic retinopathy (PDR) (66.7%) and diabetic macular edema (DME) (58.3%) (Table 1). Before developing endophthalmitis, six patients (25.0%) had a baseline vision better than 20/40, four (16.7%) had 20/40 to 20/80 vision, 11 (45.8%) had 20/100 to 20/400 vision, two (8.3%) had counting figures (CF) vision, and one (4.2%) had hand motion (HM) vision (Table 2).

Study Sample (n = 24)

Table 1:

Study Sample (n = 24)

Visual Acuity Prior to Endophthalmitis, at Presentation, and at 3-Month Follow-Up After Treatments (n = 24)

Table 2:

Visual Acuity Prior to Endophthalmitis, at Presentation, and at 3-Month Follow-Up After Treatments (n = 24)

The mean time between bevacizumab injection and the initial presentation was 2.3 days (SD = 0.7). All patients received TAI on the same day of initial presentation. At presentation, two patients (8.3%) had a BCVA of 20/100 to 20/400, four patients (16.7%) had a vision of CF, 17 (70.8%) had HM vision, and one (4.2%) had LP vision. On presentation, 19 patients (79.1%) had severe inflammation, four (16.7%) had moderate inflammation, and one (4.2%) had mild inflammation. The mean BCVA at presentation was significantly worse compared to the mean BCVA at the time receiving bevacizumab injection (logMAR 2.7 vs. 0.8; P < .0001).

All patients had a culture-positive vitreous biopsy result. Out of 24 patients, 23 (95.8%) grew Streptococcus species and one (4.2%) grew Enterococcus species. Following initial TAI, all patients underwent PPV and the mean time between TAI and PPV was 2.0 days (SD = 0.81). During PPV, one patient (4.2%) had pars plana lensectomy and two patients (8.3%) had SO tamponade. One patient needed repeat PPV with intravitreal injection of antibiotics for persistent vitreous opacities.

During the 3-month follow-up period after PPV, six patients (25.0%) developed optic nerve atrophy, three (12.5%) developed retinal detachment (RD), one (4.2%) had vitreous hemorrhage, and one (4.2%) had band keratopathy (Table 3).

Complications Following Endophthalmitis and Treatments (n = 24)

Table 3:

Complications Following Endophthalmitis and Treatments (n = 24)

At 3-month follow-up, six patients (25.0%) had a BCVA of 20/100 to 20/400, eight (33.3%) had a vision of CF, five (20.8%) had HM vision, four (16.7%) had LP vision, and one (4.2%) had no light perception vision. Additionally, compared to the BCVA before patients developed endophthalmitis, one patient (4.2%) had improved BCVA, one (4.2%) had same BCVA but 22 (91. 7%) had worse BCVA. The mean BCVA at 3-month follow-up was significantly worse compared to the mean BCVA at the time receiving bevacizumab injection (logMAR 2.4 vs. 0.8; P < .0001). There was no statistical difference in mean BCVA between 3-month follow-up and at presentation (logMAR 2.4 vs. 2.7; P = .2229). When comparing BCVA at 3-month follow-up to the BCVA at the initial endophthalmitis presentation, 11 (45.8%) patients had improved BCVA, eight patients (33.3%) had unchanged BCVA, and five (20.8%) had worse BCVA (Figure 1).

Best-corrected visual acuity (BCVA) at the time receiving bevacizumab injection, at presentation with endophthalmitis, and at 3-month follow-up after treatments.

Figure 1.

Best-corrected visual acuity (BCVA) at the time receiving bevacizumab injection, at presentation with endophthalmitis, and at 3-month follow-up after treatments.

Discussion

Although rare, acute bacterial endophthalmitis following intravitreal injection of contaminated bevacizumab has been reported worldwide.7,8 In the literature, cases of cluster infectious endophthalmitis following intravitreal injection using an U.S. Food and Drug Administration-approved product are not well reported.9 Previously, a cluster of four patients and a cluster of 12 patients of infectious endophthalmitis following intravitreal injection of bevacizumab were reported.7,8 Our case series is one of the largest cluster of acute endophthalmitis following intravitreal injection of bevacizumab, which consists of predominantly Streptococcus species. Previously, it was suggested that the positive culture of Streptococcus in postinjection endophthalmitis might reflect on the possibility of aerosol contamination of the surgical field by respiratory flora.10 In our case series, the cluster feature of the affected cases was a result from contamination occurring by loss of sterility during transportation of single use bevacizumab syringes (facemask was used by treating physician in all cases).

Previously, we have shown that there is no significant difference in BCVA at 6-month follow-up between TAI and PPV with intravitreal injection of antibiotics as the initial management for patients with endophthalmitis following anti-VEGF injections.5 Although we know visual outcomes are guarded for patients with Streptococcus species, when approaching atypical and rare occurrences such as contamination, no suitable evidence-based literature exists. Our case series demonstrates that when the causative pathogen is Streptococcus species, aggressive management with prompt TAI followed by early PPV may be essential to improve or preserve any meaningful vision. In our current analysis, earlier vitrectomy done within 72 hours of endophthalmitis diagnosis might be beneficial as it not only allows for removal of bacteria, inflammatory cells or membranes, and toxic debris from the vitreous cavity but also promotes better diffusion of antibiotics.

Retinal detachment (RD) is a known complication of endophthalmitis, TAI and PPV. In 1983, Olson et al., reported an overall rate of 10% for RD following treatment of postsurgical endophthalmitis (14% for eyes with PPV).11 In 1985, Nelsen et al. reported an overall rate of 16% for RD after endophthalmitis (21% for eyes treated with PPV and 9% for eyes not treated with PPV).12 In 2000, based on the data collected for the EVS, Doft et al. reported an incidence of 8.3% for RD after treatment of post-cataract endophthalmitis, and there was no difference in incidence based on whether initial management was PPV (7.8%) or TAI (9.0%).13 In the same study, the authors also reported that the rates were relatively low among eyes with no growth (5%) or Gram-positive coagulase-negative growth (5%).13 Higher rates were reported for more virulent organisms, at 12% for Gram-negative organisms and 23% for “other” Gram-positive organisms (the term used in the EVS to describe all Gram-positive organisms that were not coagulase-negative micrococci).13 In our case series, three patients (12.5%) developed RD after TAI plus PPV for the treatment for endophthalmitis following bevacizumab injections. Compared to the rates of RD following PPV previously reported,11,12 a lower rate was reported in our study, which might suggest the significant advancements in vitreoretinal surgery technology and this might have allowed surgeons to perform a more thorough vitrectomy while reducing the risk of inducing iatrogenic retinal injury and subsequent RD. Compared to the rate of RD following treatment for endophthalmitis reported in Doft's study, our case series reported a higher rate of RD. One of the explanations for this might be associated with less virulent organisms in the EVS. For example, the rate of Streptococcus associated post- operative endophthalmitis was 9.0% among culture-positive endophthalmitis cases in the EVS,6 whereas 95.8% patients in our case series had a positive culture of Streptococcus species.

In a previous study, we found that the mean time between last anti-VEGF injection and the symptoms of endophthalmitis was 3.6 (SD = 1.7) for patients with a positive culture (66.7% grew coagulase-negative Staphylococcus, followed by Streptococcus species (16.7%), Haemophilus influenzae (4.2%), Erisypelothrix rusiopathiae (4.2%), Serratia marcescens (4.2%), and Enterococcus faecalis (4.2%).14 In our current case series, the time between bevacizumab injection and start of symptoms could not accurately be determined; nonetheless, mean time between bevacizumab injection and presentation was 2.29 days (SD = 0.69). This suggests a long-held belief that virulent pathogens, like Streptococcus, which are capable of producing severe endophthalmitis, have earlier presentation times. Similar to previous studies, we see very poor visual outcomes after Streptoccocus endophthalmitis and 91.6% of patients had worse BCVA at 3-month follow-up compared to baseline vision prior to developing endophthalmitis.

There are several limitations in this case series. Firstly, the data were collected retrospectively; therefore, there might be biases inherent in the data collection. Secondly, we compared the BCVA at 3-month follow-up with the BCVA when the patient received the bevacizumab injection, as well as the BCVA at the presentation. This could be problematic since many patients had worsening cataract after vitrectomy which will undoubtedly adversely affect BCVA. Thirdly, although our collection of 24 cases is one of the largest in the literature for a series of endophthalmitis due to contamination, the sample size is still relatively small.

In conclusion, we describe culture results, management, complications, and visual outcomes for patients with acute endophthalmitis after intravitreal injection secondary to contaminated bevacizumab. Although rare, contamination of off- label bevacizumab poses a devastating risk of endophthalmitis following intravitreal injection, and remains a risk whenever handling of medication is performed by multiple sites as is typical for compounding pharmacies. The likelihood of virulent pathogens like Streptococcus species is associated with very poor visual prognosis and immediate aggressive management is necessary in the hopes of minimizes vision loss.

References

  1. Mason JO III, White MF, Feist RM, et al. Incidence of acute onset endophthalmitis following intravitreal bevacizumab (Avastin) injection. Retina. 2008;28(4):564–567. doi:10.1097/IAE.0b013e3181633fee [CrossRef] PMID:18398358
  2. Fintak DR, Shah GK, Blinder KJ, et al. Incidence of endophthalmitis related to intravitreal injection of bevacizumab and ranibizumab. Retina. 2008;28(10):1395–1399. doi:10.1097/IAE.0b013e3181884fd2 [CrossRef] PMID:18827737
  3. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJCATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–1908. doi:10.1056/NEJMoa1102673 [CrossRef] PMID:21526923
  4. Fileta JB, Scott IU, Flynn HW Jr, . Meta-analysis of infectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmic Surg Lasers Imaging Retina. 2014;45(2):143–149. doi:10.3928/23258160-20140306-08 [CrossRef] PMID:24635156
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  6. Endophthalmitis Vitrectomy Study Group. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol. 1995;113(12):1479–1496. doi:10.1001/archopht.1995.01100120009001 [CrossRef] PMID:7487614
  7. Edison LS, Dishman HO, Tobin-D'Angelo MJ, Allen CR, Guh AY, Drenzek CL. Endophthalmitis outbreak associated with repackaged bevacizumab. Emerg Infect Dis. 2015;21(1):171–173. doi:10.3201/eid2101.141040 [CrossRef] PMID:25531168
  8. Goldberg RA, Flynn HW Jr, Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012;153(2):204–208.e1. doi:10.1016/j.ajo.2011.11.035 [CrossRef] PMID:22264943
  9. Moshfeghi DM. Whither (or Wither) Adherence to Retina Trial Protocols in Clinical Practice?Ophthalmic Surg Lasers Imaging Retina. 2017;48(9):692–698. doi:10.3928/23258160-20170829-02 [CrossRef] PMID:28902328
  10. McCannel CA. Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: causative organisms and possible prevention strategies. Retina. 2011;31(4):654–661. doi:10.1097/IAE.0b013e31820a67e4 [CrossRef] PMID:21330939
  11. Olson JC, Flynn HW Jr, Forster RK, Culbertson WW. Results in the treatment of postoperative endophthalmitis. Ophthalmology. 1983;90(6):692–699. doi:10.1016/S0161-6420(83)34511-5 [CrossRef] PMID:6604248
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  14. Xu K, Chin EK, Almeida DRP. Variables associated with culture positive endophthalmitis after intravitreal injection of vascular endothelial growth factor inhibitors. J Vitreoretin Dis. 2019;3(5):317–323. doi:10.1177/2474126419875652 [CrossRef]

Study Sample (n = 24)

VariablesMeans(SD)Frequency(%)

Age59.38.7

Sex
  Male1458.3
  Female1041.7

Diagnosis (Treatment Indications)
  PDR with DME937.5
  PDR without DME729.2
  NPDR with DME520.8
  Exudative AMD28.3
  CSCR14.2

Time from bevacizumab injection to presentation (days)2.30.7

Time from bevacizumab injection to TAI (days)2.30.7

Time from TAI to PPV (days)2.00.8

Culture
   Streptococcus species2395.8
   Enterococcus species14.2

Visual Acuity Prior to Endophthalmitis, at Presentation, and at 3-Month Follow-Up After Treatments (n = 24)

VariablesMeans(SD)Frequency(%)

BCVA at the time of receiving bevacizumab injection (logMAR)0.80.7
  Better than 20/40625.0
  20/40 to 20/80416.7
  20/100 to 20/4001145.8
  CF28.3
  HM14.2
  LP00.0
  NLP00.0

BCVA at presentation (logMAR)2.70.7
  Better than 20/4000.0
  20/40 to 20/8000.0
  20/100 to 20/40028.3
  CF416.7
  HM1770.8
  LP14.2
  NLP00.0

BCVA at 3-month follow-up (logMAR)2.41.2
  Better than 20/4000.0
  20/40 to 20/8000.0
  20/100 to 20/400625.0
  CF833.3
  HM520.8
  LP416.7
  NLP14.2

Complications Following Endophthalmitis and Treatments (n = 24)

ComplicationsFrequency(%)
Optic nerve atrophy625.0
Retinal detachment312.5
Vitreous hemorrhage14.2
Band keratopathy14.2
Authors

From the Department of Ophthalmology and Visual Sciences, University of Arizona, Tucson, Arizona (KX); International Eye Centre, Palestinian Authority, Gaza (RM); Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (AL, AB); Retina Consultants of Southern California, Redlands, California (EKC); and Erie Retinal Surgery, Erie, Pennsylvania (DRPA).

Dr. Loewenstein has received grants, personal, and other support (advisory board) from Alergan, Bayer, and Novartis; grants and other support (advisory board) from Notal-Vision; personal fees from Syneos Health, Pres-By, Xbran, WebMD, KHB, and Oxurion; personal fees and other support (advisory board) from Beyeonics and Roche; grants from Sensor; and is on the advisory board for Oculis outside the submitted work. Dr. Barak has received grants from Novartis and Cellcure, personal fees from Nanoretina, and grants and personal fees from Byeonics. Dr. Chin is a research investigator for Alcon, Genentech, Novartis, Senju Pharmaceutical Co., and Chendgu Kanghong Biotechnology outside the submitted work. The remaining authors report no relevant financial disclosures.

Address correspondence to Kunyong Xu, MD, MHSc, Department of Ophthalmology and Visual Science University of Arizona, 655 N. Alvernon Way, Suite 204, Tucson, AZ 85711; email: kunyong.xu@medportal.ca.

Received: March 08, 2020
Accepted: April 28, 2020

10.3928/23258160-20200603-05

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