The Writing On The Wall Intravitreal Injection Compliance During The COVID-19 Pandemic and Its Foreseeable Consequences

Background: Intravitreal injections (IVI) of anti-vascular endothelial growth factor (anti-VEGF) agents have become the most prevalent intraocular procedure as they represent the major therapeutic modality for prevalent retinal conditions such as age-related macular degeneration (AMD) and diabetic retinopathy. Effective therapy requires adherence to a schedule of iterative IVI as well as routine clinic appointments. The ongoing Coronavirus disease 2019 (COVID-19) pandemic has resulted in the reduction of attendance at scheduled clinics visits and IVI. In this study we attempted to analyze the effect of COVID-19 on compliance with anti-VEGF therapy. Methods: A total of 636 eyes received injections during a four-week period of the COVID-19 outbreak in the Retina Clinic. The number of clinic visits for IVI during one month from March 15 to April 14 of 2020 was compared to the similar time period in each of the last four years. Results: The study demonstrates a decrease in clinic visits for IVI when compared with the same four-week interval in the four previous years. Based on the trend of the previous four years, 10.2% of the year’s total was expected for this time period. Using this model, the 636 reported number of injections for the March-April, 2020 period was ~ 5%. This represents a decrease of ~50% of the expected IVI for this time period. Conclusion: The COVID-19 outbreak in Israel severely impacted compliance with anti-VEGF treatments.


Background
Intravitreal injections (IVI) are a prevalent intraocular procedure in the ophthalmology clinic and have been described to treat various retinal pathologies (1). Individuals often receive serial injections and require these treatments on a regular basis (2). Compliance with the treatment prescription is crucial (3)(4)(5)(6)(7)(8).
Even slight deviations may be associated with decreased vision (9). The Coronavirus (COVID-19) outbreak in Israel resulted in a curtailment of ophthalmologic clinic appointments. This began in mid-March 2020 by order of the Ministry of Health of the State of Israel in order for hospitals and healthcare facilities to accommodate the onslaught of COVID-19 patients. To assess the risk of potential visual loss, we compared IVI clinic attendance during the pandemic to clinic attendance in previous years.

Data Collection
Initially, the number of intravitreal injections performed at the Shaare Zedek Medical Center retina clinic during four weeks of the COVID-19 pandemic March 15 to April 14 2020 was analyzed. Injections with anti-vascular endothelial growth factor (anti-VEGF) agents bevacizumab (Avastin), ranibizumab (Lucentis) and a ibercept (Eylea) were analyzed jointly and individually. These results were compared to the same time period in the previous four years, March 15 to April 14 2016, 2019. The Shaare Zedek Medical Center Institutional Ethics Committee approved the study and did not require an individual informed consent from the subjects. All indications for anti-VEGF were included, regardless of diagnosis, duration of treatment or previous compliance to the injection schedule. Individual injections were tabulated and patients who received treatment for both eyes were counted twice.

Statistical Analysis
All data collected in this study were analyzed using SPSS software (SPSS 24.0, SPSS Science, Chicago, IL, USA). Linear regression was performed for the present analysis.

Results
A total of 636 injections were performed during the period of the COVID-19 outbreak in Israel, from March 15 2020 to April 14 2020 (Table 1) Based on this model, it was expected that the injections would increase to 12,672 in 2020. As a proportion of what is expected for the entire year, the 636 reported number of injections for the March-April, 2020 period was about 5%, less than half the actual proportion observed in previous years. Figure 2 represents the downward trend IVI over the time associated with the COVID-19 outbreak milestones in Israel. From the week of February 20th 2020 to the week of April 1st 2020, there was a 58% decrease of total IVI: 60% for bevacizumab, 61% for ranibizumab and 50% for a ibercept.

Discussion
This analysis demonstrates a marked decrease in IVI of anti-VEGF agents delivered during a four-week period of the COVID-19 outbreak. The decrease in IVI correlated with the advancing coronavirus outbreak in Israel, namely increasing numbers of individuals testing positive for the virus, hospitalizations and deaths. The outbreak resulted in an increase in governmental restriction on local and foreign travel and quarantine of Jerusalem neighborhoods. Hospital services including elective surgeries and clinics were curtailed. Although IVI were considered essential clinic visits and this service was not curtailed, this study indicates that many individuals requiring IVI chose not to attend previously scheduled appointments.
Compliance in individuals obtaining IVI has been previously described to vary based on the treated condition (10,11). There is currently no data on the effect of a pandemic on IVI clinic visit. The risk for mortality from COVID-19 rises substantially in individuals older than 65 years of age (12), those living in skilled nursing facilities (13) and individuals with co-morbidities such as diabetes (14) and obesity (15). As the two major indications for iterative IVI are neovascular AMD and diabetic ocular complications (16)(17)(18), these individuals are precisely those at highest risk for COVID-19 associated mortality. Furthermore, since viral transmission has been documented in asymptomatic individuals, it is understandable that an ophthalmologic patient may be fearful regarding exposure to coronavirus at a crowded outpatient hospital (19)(20)(21).
As ophthalmologic specialists, we are necessarily concentrating our efforts on the ophthalmologic care of our patients and are concerned about resultant potential vision loss from missing IVI (22). However, in this circumstance, it is our duty to balance the desire to treat their ophthalmic disease while protecting them from being harmed from inadvertent viral transmission (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Several ways may be considered to improve delivery of retinal care (32). One option is to provide home injections with appropriate protection of the healthcare workers (33). A second option may be to concentrate IVI in skilled nursing facilities and day care centers. Thirdly, albeit a more distant goal, is accelerating development of long acting anti-VEGF therapeutics which would reduce the frequency of clinic visits.
Limitations include the relatively brief period and the single center nature of the study.

Conclusions
During the four-week period of the COVID-19 outbreak in Israel, we observed a greater than 50% drop in attendance at the IVI in our Retina Clinic. It became evident that many of our patients were being lost to follow-up. This marked decrease in attendance is understandable taking into consideration that many of these individuals exhibit co-morbidities that place them at increased risk for mortality should they contract COVID-19 infection. It is imperative, however, that we recognize the "writing on the wall" and begin to plan for the consequences of this missed therapy. We therefore reached out to patients and their families to demonstrate our concern. We wished to make every effort to better understand how they were coping with the outbreak, and to remind them that should they experience any visual changes that we, their ophthalmologists, are here for them ( Figure 2).

Declarations
Ethics Approval: . The Shaare Zedek Medical Center Institutional Ethics Committee approved the study and did not require an individual informed consent from the subjects.

Consent for Publication: Not applicable
Availability of Data and Materials: The datasets analyzed during the current study are not publicly available due the concern for patient safety and con dentiality but are available from the corresponding author upon reasonable request.
Competing Interests: All authors declare no competing interests.
Funding: No funding was received for this study.

Acknowledgements: Not applicable
As compared to the same period in 2019, there is a decrease for all intravitreally injected anti-VEGF compounds. Throughout the ve years presented, bevacizumab reached a low point during the COVID-19 crisis. Figure 1 As governmental measures became more stringent, the number of delivered injections dropped.