The requirement of ongoing treatment and involvement of both eyes has led to increased use of anti-VEGF agents for diseases that cause pathological neovascularization. After the coronavirus outbreak, an increase in the number of Covid-19 positive individuals resulted in serious restrictions by the Ministry of Health of the State of Turkey. Unfortunately, ophthalmologic patients requiring IVI chose not to attend pre-scheduled appointments, as they were at the highest risk for COVID-19-related mortality, depending on their age and comorbidities. Following a strict 3–4-month period of the outbreak, we encountered an accumulative and worsened patient group. This has put an increasing burden on both patients and practices. After restrictions eased, when able to come to the clinic, most of the patients with bilateral disease demanded injections in both eyes in one visit. We also preferred concomitant bilateral injection in these patients with the condition of providing detailed information to the patient.
Although the safety profile is major concern, according to previous study reports the applicability of bilateral injection in the same session is encouraging.[10–21] At this point there are adverse events and ocular complications that are feared or reasonably anticipated; like, endophthalmitis and the amount of anti-VEGF agent passed into the systemic circulation. Studies with large sample sizes evaluating the rates of endophthalmitis after conventional unilateral intravitreal anti-VEGF injections reported very low rates, ranging 0.027%- 0.0075%.[23–25] A meta-analysis by McCannel reported that 52 out of 105536 injections (0.049%) had endophthalmitis. They also suggested avoiding talking, coughing, and sneezing and wearing surgical mask during IVIs. Casparis et al, reported that risk of endophthalmitis was very low (0.0075% ) with the performing IVI under the sterile conditions of the operating room.. A study by Rayess et al, with a large sample size (503890 anti-VEGF injections), analyzed all three anti-VEGF agents in terms of occurrence of endophthalmitis, and found that the rate of endophthalmitis was independent of the agent used. Similar to these reports; we observed that adverse events were independent of the agent used, and we performed IVIs in the operating room by wearing a surgical mask with taking care not to speak.
Previous studies of bilateral same-day IVIs, reinforce that concomitant bilateral intravitreal anti-VEGF injections are safe and well tolerated by patients. Thus, the popularity of this application is increasing among clinicians, studies are conducted to evaluate this application through different factors. When we analyze the purposes of these studies, it was seen that the most frequently investigated outcomes were endophthalmitis and adverse events. Although our study is in this direction too, unlike other studies, the safety and preferability of concomitant bilateral IVI application during the covid 19 outbreak were investigated in this study. The number of bilateral injections in previous similar studies ranged from 208 to 101932. The largest retrospective cohort was reported by Borkar et al, they have encountered 28 ( 0.027%) endophthalmitis cases out of 101932 concomitant bilateral injections, none of the endophthalmitis were bilateral. In another study with a large sample size of approximately 5000 bilateral injections, it was reported that unilateral endophthalmitis developed in only one patient who had undergone 7 unproblematic bilateral ranibizumab injections before, and systemic side effects were not observed in any patient. Jang et al who experienced higher numbers of bevacizumab than the others, stated that bevacizumab was relatively more prone to infections than aflibercept or ranibizumab due to the preparation phase, dispensing process and storage. Considering the literature reporting the association of previous endophthalmitis outbreaks with multiple dose contamination and preparation by the compound pharmacy, we did not prefer prepackaged bevacizumab syringes in our study, instead we received bevacizumab from a 4 mL vial as much as needed just before injection, and we never used the remaining bevacizumab again. Injections of the recent studies mentioned above had been done in an office-based environment.[19–21] As an important difference, we performed the injections in the operating rooms where we performed our intraocular surgeries. In a study reporting a total of 1 (0.012%) culture-proven endophthalmitis and 19 (0.233%) acute intraocular inflammation in 6,560 unilateral and 1,612 bilateral injections, injections were performed in cabins with sterile laminar flow equipment. They claimed that these cabins had lower particle and microorganism levels, due to this sterile laminar flow equipment compared to normal office environments. In addition, in this study by Ruão et al, endophthalmitis was not observed in patients who underwent concomitant bilateral injection, whereas endophthalmitis developed in 1 patient who received unilateral injection. Interestingly, Ruão et al, also reported that the patient who was diagnosed with acute intraocular inflammation in the bilateral injection group did not have any signs of inflammation in the other eye. As can be understood from here, vision-threatening complications are actually associated with a wide range of unpredictable variables. When the IVI application methods of different studies are analyzed, the common point that is emphasized in almost all of them is that none of the instruments used in the previous eye is reused in the fellow eye while making concomitant bilateral injection. Likewise, in our study, we treated the second eye of the same patient as if we were injecting it into a different patient using a new sterile set of equipment. There are many ocular complications and adverse events reported in previous studies such as floaters, painless subconjunctival hemorrhage, elevated IOP, ocular inflammation, uveitis, retinal epithelial tear, retinal detachment, subretinal hemorrhage and endophthalmitis. None of the patients included in this current study experienced serious vision-threatening complications or adverse events such as endophthalmitis, retinal detachment. The degrees of non-infectious anterior inflammation observed in our study were trace amounts (†0.5+: 1–5 cells in anterior chamber, †1+: 6–15 cells in anterior chamber) similar to recent reports [20, 21] and vitritis was not seen. Although this is not mentioned in the literature; we encountered considerable number of punctate epitheliopathy with or without sensitive painful eye complaint at first day after IVI. This may be happened due to the povidone iodine instillation and keeping it for 3 minutes on each eye or remnants of povidone iodine on conjunctival fornix or the underlying untreated dry eye disease. However, most of patient complaints resolved after 3 days. Albeit it has been reported that there may be permanent IOP elevation secondary to the cumulative effect of recurrent IVI, we did not encounter severe permanent IOP elevation in most of our patients. We observed subconjunctival hemorrhage in some patients due to conjunctival capillary injury at the injector insertion site, which regressed spontaneously in a short time. In studies evaluating subconjunctival hemorrhage, the relationship between this condition and any vision threatening outcome was not mentioned.[15, 20, 21] In this study population, there was no significant difference between bilateral and unilateral IVI application or anti-VEGF agent used in terms of adverse event ; however, among three anti-VEGF agents which we used, the least anterior chamber reaction was observed in patients who were administered ranibizumab. Similarly, previous studies reported fewer acute inflammations and also systemic exposure with ranibizumab.[28, 29] This has mostly been attributed to the absence of the Fc segment on ranibizumab, as known this segment was found associated with intraocular inflammatory reactions. Souied et al, compared severe ocular inflammation rates in patients treated with ranibizumab versus aflibercept, and showed more frequent severe ocular inflammation following IVI with aflibercept than with ranibizumab during routine clinical use in patients with nAMD. Although the analyzes of almost all studies conducted are not statistically strong enough because the incidence of a rare complication such as endophthalmitis is evaluated; few studies comparing unilateral application with bilateral application indicated that there was no difference between the two applications in the means of non-ocular adverse events and ocular complications.[14, 16, 18] Likewise to these published reports we did not observe any significant difference between unilateral and concomitant bilateral injections. Data regarding the amount of released anti-VEGF from eye to systemic circulation is still insufficient. In a prospective study by Wang et al., the amount of anti-VEGF (bevacizumab) entering the systemic circulation after concomitant bilateral administration was compared with unilateral administration by using the enzyme-linked immunosorbent test method, and as a result, no difference was found in serum levels. In a similar study by Wang et al., serum and plasma VEGF concentrations were evaluated in nAMD patients treated bimonthly with an IVI of aflibercept or ranibizumab, and concluding that serum and plasma VEGF concentrations were not significantly affected by ranibizumab. In our study, in which we administered more ranibizumab than aflibercept and bevacizumab, none of the patients experienced non-ocular systemic emergencies suggesting systemic exposure. Due to the uncertainty of systemic exposure, we also avoided intravitreal anti-VEGF injection if the patient had a history of significant systemic events such as stroke, cardiac arrest, or uncontrolled hypertension within the last three months. Another important logical expectation that should be considered is the increase in the risk of developing immune sensitization against the anti-VEGF agent used with the number of injections made. However, our study and recent reports in the literature, showed no significant correlation between the occurrence of inflammation and the number of injections the patient received.[10, 12, 21] Bakri et al., observed a sterile ocular inflammation in one eye of a patient in whom both eyes had previously received intravitreal bevacizumab, however, they also stated that if the expected immunization was to occur, there would have to be inflammation in both eyes. When we evaluate the studies stating that concomitant bilateral injection, or in other words, same-session bilateral injection, can be tolerated by patients and preferred to conventional unilateral injection method, it is seen that the number of patients returning to unilateral injection after bilateral application is low or none.[10, 13–15, 17, 19] Despite the irritation of both eyes with povidone iodine residues, our patients tolerated concomitant bilateral injection well. Only a few of them (3 patients-2.6%) requested alternating unilateral injections after receiving the second concomitant bilateral injections. Studies that did not report any endophthalmitis after concomitant bilateral injection had relatively small sample sizes, such as ours, and acknowledged the need for larger studies.[10, 12–15, 17, 21] However, since there are multiple variables apart from sample size in each study that may alter the complication outcome, no firm conclusion could be drawn about the safety of concomitant bilateral injection. If we evaluate our results in our own conditions, without making a comparison with published studies with many different variables; we can attribute the absence of sight-threatening complications in our patients to the following measures: administration of IVI in operating rooms, keeping povidone iodine on the conjunctiva for three minutes, wearing a mask, using a new set of sterile equipment for both eyes, and avoiding the use of prepackaged bevacizumab syringes.