Differential diagnosis of endophthalmitis after intravitreal drug injection for age related macular degeneration: sterile vs. infectious | Archivos de la Sociedad Española de Oftalmología (English Edition)

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Montolío-Marzo, L. Vidal-Oliver, E. Montolío-Marzo, R. Dolz-Marco, R. Gallego-Pinazo" "autores" => array:5 [ 0 => array:4 [ "nombre" => "S." "apellidos" => "Montolío-Marzo" "email" => array:1 [ 0 => "s.montoliomarzo@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "L." "apellidos" => "Vidal-Oliver" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "E." "apellidos" => "Montolío-Marzo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "R." "apellidos" => "Dolz-Marco" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "R." "apellidos" => "Gallego-Pinazo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Clínica Oftalvist, Valencia, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "FISABIO Oftalmología Médica, Valencia, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Hospital Clínico Universitario San Carlos, Madrid, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Diagnóstico diferencial de las reacciones inflamatorias tras uso de medicación intravítrea en degeneración macular asociada a la edad: estéril vs. infeccioso" ] ] "textoCompleto" => "IntroductionThe term endophthalmitis refers to inflammation of the vitreous and/or aqueous humour, usually secondary to infectious or exogenous etiologies. The first reports of endophthalmitis in the scientific literature date back to 1916, but initially the increase in the number of cataract surgeries and subsequently the rise of intravitreal drug treatment have been responsible for its increased prevalence.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>The most commonly used anti-vascular endothelial growth factor (VEGF) drugs have been bevacizumab (Avastin®, Genentech, San Francisco, CA, USA), ranibizumab (Lucentis®, Genentech, South San Francisco, CA, USA) and aflibercept (Eylea®, Regeneron, Tarrytown, New York, USA). With the increase in intravitreal injections after entering the market, most of the published literature has been aimed at optimising the injection protocol for the prevention of infectious complications arising from the surgical procedure itself.In recent years, the introduction of new active ingredients has responded to the market's need to optimise results, space out treatments and seek new therapeutic targets to broaden current indications. Along with these new active ingredients, new challenges have also arisen in terms of the complications derived from their application.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>Both brolucizumab (Beovu®; Novartis, East Hanover, New Jersey, USA) and abicipar pegol (Abicipar®, Allergan, Dublin, Ireland) have been developed to achieve better anatomical and functional outcomes, as well as to space out injections in patients with age-related macular degeneration (AMD) to alleviate the high rates of non-adherence to treatment, and to minimise the incidence of complications arising from surgery.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> In addition, the application of these drugs is being extended to other diseases that are also susceptible to treatment with antiangiogenic drugs, such as diabetic macular edema, among others. These new treatments have been accompanied by an increase in reported inflammatory complications following their application. As a result of this trend, interest has grown in the inflammatory adverse effects associated with intravitreal medication and the need to adapt our clinical practice to the new circumstances.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>The first cases of severe uveitis and occlusive retinal vasculitis in association with brolucizumab were reported in early 2020.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> However, despite these adverse effects, brolucizumab has continued to be marketed despite several recommendations regarding its use for the prevention of serious adverse effects.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>In case of abicipar pegol, the rate of inflammatory adverse events in the clinical trials were higher than in the ranibizumab-treated group during the first year of follow-up.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> This trend appears to be reduced after the first year of treatment in these same patients and also after modification of the drug manufacturing process in a parallel study.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a>In this context, it is essential to differentiate between infectious and inflammatory etiology in endophthalmitis following intravitreal injection.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> We must bear in mind that depending on the etiology of the inflammation, both the treatment and the prognosis of the process differ. Until now, the report of sterile endophthalmitis was more frequent with the use of intravitreal triamcinolone than antiangiogenic medication, but the use of new molecules is changing this trend.The aim is to find the key points for the differential diagnosis between processes of sterile inflammatory and infectious etiology after intravitreal injection of anti-angiogenic drugs, in addition to establishing the clinical picture of both entities, their incidence and the variations in the clinical pattern introduced by the new anti-angiogenic drugs.Material and methodsA narrative literature review was conducted following a literature search in the Pubmed database using "intravitreal injection", "uveitis", "inflammation" and "endophthalmitis" as keywords.ReviewThe reported incidence of sterile intraocular inflammation following intravitreal injection is 0.005–4.4% and that of infectious endophthalmitis between 0.027 and 0.15%.<a class="elsevierStyleCrossRefs" href="#bib0020">4,10–12</a>Sterile inflammatory reactions following intravitreal antiangiogenic medication vary from a mild and transient inflammatory reaction to more severe processes that may compromise the long-term visual prognosis. While sterile processes may resolve without major sequelae with appropriate treatment, infectious processes tend to be more severe and are associated with a worse prognosis.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>There is much heterogeneity in diagnostic criteria and nomenclature regarding the reporting of sterile inflammatory and infectious complications in the literature. Cases are reported of severe inflammatory processes that are considered infectious based on the clinical condition, without having been able to demonstrate the presence of any microorganism.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Considering that only 30–60% of cultures are positive after sampling, this is not an uncommon situation.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> It should also be taken into account that there are infectious cases caused by bacterial toxins that will not produce any growth on culture media either and cannot be considered purely sterile processes.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>In the case of sterile inflammatory reactions, many go unnoticed because they are mild processes with a tendency to self-resolve, thus underestimating their prevalence.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> To this we add the heterogeneity of the terms used to describe and classify them, grouping them under a common generic term or dividing them according to the location of the ocular involvement.Incidence of sterile intraocular inflammation in different drugsThe incidence of infectious endophthalmitis does not vary significantly according to the anti-angiogenic agent used, which explains its probable relationship with the surgical procedure rather than the mechanism of the drug itself.<a class="elsevierStyleCrossRefs" href="#bib0060">12,17</a> However, looking at endophthalmitis of a sterile nature, there are significant differences in the incidence rate of sterile inflammation depending on the drug used.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Sigford et al. reviewed prospective studies reporting complications after injection of classical antiangiogenic drugs and found a higher rate of sterile inflammatory complications in patients treated with bevacizumab versus ranibizumab.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> These differences in the rate of sterile inflammatory reactions have increased with the introduction of new anti-angiogenic drugs.A) Classical antiangiogenics: bevacizumab, ranibizumab, afliberceptThe incidence of sterile endophthalmitis associated with bevacizumab injection has been reported to be between 0.09 and 1.1% depending on the series consulted.<a class="elsevierStyleCrossRefs" href="#bib0020">4,12</a>The reported incidence associated with ranibizumab injection is lower compared to other anti-VEGFs according to some studies, although these differences have been questioned.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> The MARINA and ANCHOR trials reported an incidence of sterile endophthalmitis for ranibizumab of 0.05%. The incidence in the VIEW trial for ranibizumab was 1.5%<a class="elsevierStyleCrossRef" href="#bib0090">18</a> and in the CATT trial it was 0.7%.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Reports of higher incidence rates of sterile endophthalmitis for this drug are as high as 2% of cases with post-injection inflammatory phenomena.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>In the case of aflibercept 2 mg, the HAWK and HARRIER trials reported a sterile intraocular inflammation rate of 0.3 and 0%, respectively.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> The incidence in the VIEW trial was 1.1%.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> In the various series reported in the literature, the rate of aflibercept-associated sterile ocular inflammation ranges from 0.3% to 14.3%.<a class="elsevierStyleCrossRefs" href="#bib0020">4,18</a>The first results of aflibercept 8 mg are currently being presented at various scientific meetings. The drug has not yet been approved by the FDA for use in our environment. The PULSAR trial appears to have met its objective of demonstrating non-inferiority of aflibercept 8 mg to standard aflibercept 2 mg treatment regimens. Intraocular inflammation rates for aflibercept 8 mg versus aflibercept 2 mg were 0.7% versus 0.6% in PULSAR. This rate of sterile inflammatory complications should be re-evaluated in post-marketing studies involving patients in routine clinical practice in our practices.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>B) New anti-angiogenic drugsFollowing brolucizumab injection in patients with AMD, the incidence of intraocular inflammation in the HAWK and HARRIER trials was 2.2 and 0.8 respectively for 6 mg doses, and 1.4% for 3 mg doses. Most of these events were mild and transient forms.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> In a subsequent analysis of the same patients included in these trials, the rate of intraocular inflammation found was 4.6%.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> In the MERLIN trial with a maintained 4-weekly injection schedule (not recommended in the drug label after marketing), the rate of ocular inflammation was 9.3%, which is why the trial was stopped.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> The incidence of intraocular inflammation has been reported as high as 14.6% outside these clinical trials.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> In the phase III trials KESTREL and KITE for the extension of indications of brolucizumab also to diabetic macular edema, intraocular inflammation rates of 3.7% and 1.7% respectively for 6 mg and 4.7% for 3 mg doses were reported.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> The results for inflammatory complications were only slightly superior in the treatment of diabetic macular edema. It is possible that the pro-inflammatory status of diabetic patients may influence these differences.The CEDAR/SEQUOIA trials report inflammation rates of 15.4% and 15.3% with treatment extensions of Q8 and Q12, respectively after abicipar pegol injection.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> Of these cases, 1.8% of patients developed retinal vasculitis. In the MAPLE trial after modification of drug manufacturing, they reported intraocular inflammation rates of 8.9%.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Other recently marketed molecules such as faricimab aim to achieve a longer period between treatments, without decreasing the efficacy achieved or increasing the rate of associated inflammatory complications.<a class="elsevierStyleCrossRefs" href="#bib0120">24,25</a> In the TENAYA and LUCERNE clinical trials comparing it with aflibercept 2 mg for the treatment of AMD, an inflammatory event rate of 2% was reported in both cases.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> Similar results have been obtained in the YOSEMITE and RHINE trials comparing aflibercept 2 mg with faricimab for the control of diabetic macular edema, finding an inflammatory event rate of 2 and 1%, respectively.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> In summary, in case of faricimab we found a rate of sterile inflammatory complications similar to that found with classical antiangiogenics.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> No differential clinical pattern has been reported so far in these inflammatory episodes associated with faricimab injection compared to those found with classical antiangiogenics.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>C) Biosimilars approved by the European Medicines AgencyIn addition to new molecules, we must take into account the entry of biosimilars into the European market. Some biosimilars have been approved and widely used in other parts of the world.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> In our setting, the European Medicines Agency has approved the use of Ximluci® (STADA Arzneimittel AG; Hessen, Germany), Byooviz® (Samsung Bioepis; Delft, The Netherlands) and Ranivisio® (Midas Pharma GmbH; Ingelheim, Germany) as biosimilars of ranibizumab for the treatment of AMD.<a class="elsevierStyleCrossRefs" href="#bib0135">27–29</a> Byoviiz® in its phase 3 clinical trial showed an endophthalmitis rate of 0.7%, with 0.15% being sterile phenomena (no cases of retinal vasculitis associated with its use were reported).<a class="elsevierStyleCrossRef" href="#bib0150">30</a> In any case, active pharmacovigilance of these new drugs should be maintained to determine their characteristics in clinical practice in our environment.Characteristics of the early sterile inflammatory reactionThis reaction comprises episodes of inflammation and acute onset without infectious cause that resolve without antibiotic treatment.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> These early acute reactions have been reported after injection of "classical" antiangiogenic drugs. An acute inflammatory reaction following injection of brolucizumab<a class="elsevierStyleCrossRef" href="#bib0155">31</a> is also possible, and cross-sensitisation to other antiangiogenics following injection of this drug has been proposed.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>These episodes usually occur in the days following the injection, between 24 h and one week after the intervention.<a class="elsevierStyleCrossRefs" href="#bib0080">16,32</a> Several series report all their cases within the first 3 days, but the time criterion does not allow a certainty diagnosis.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>Usually, said episodes comprise a mild inflammatory reaction with cellularity and/or discrete flare in the anterior chamber.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The process usually tends to self-resolve, so that in a pattern of monthly check-ups a low-grade inflammation will go unnoticed and no treatment will be necessary.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>Sometimes this inflammation is more severe and clinically significant. The most frequent clinical manifestations are decreased visual acuity (93%) and myodesopsia (60%) accompanied by vitreous cellularity (81%) and/or anterior chamber cellularity (74%).<a class="elsevierStyleCrossRefs" href="#bib0020">4,33</a> Less frequently, we find other symptoms such as corneal edema, conjunctival hyperemia, ocular pain (46% of patients, <10% severe pain), photophobia (19%), hypopyon, keratic precipitates, trabeculitis, retinal infiltrates or hemorrhages.<a class="elsevierStyleCrossRefs" href="#bib0080">16,34</a> Some symptoms are associated, as most patients with pain also have hyperemia, and without it the presence of pain is rare.<a class="elsevierStyleCrossRefs" href="#bib0080">16,33</a>Most patients showing acute inflammatory reactions have been previously treated with antiangiogenic drugs, even the same type of drug, without any adverse effects.<a class="elsevierStyleCrossRefs" href="#bib0080">16,33</a> In the series published by Hahn et al. all patients who were studied for acute sterile inflammatory reaction after injection had been previously treated with another antiangiogenic drug, 33% with the same active substance (in this case aflibercept), with no previous inflammatory complications.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> Similarly, retreatment after an inflammatory episode does not necessarily involve complications.<a class="elsevierStyleCrossRefs" href="#bib0175">35,36</a> In the series published by Chong et al. 48% of patients received bevacizumab injection after a previous episode of inflammation and only 6.8% showed a new inflammatory episode, although in these patients the virulence of the process was much higher than in the initial episode.<a class="elsevierStyleCrossRef" href="#bib0180">36</a>We found cases of sterile etiology clustered in a short period of time and in the same hospital.<a class="elsevierStyleCrossRefs" href="#bib0010">2,32,36</a> In cases where the outbreak occurs with the same batch of medication, the hypothesis that they may have been generated by impurities in the production, storage or administration of the drug for injection becomes more important.<a class="elsevierStyleCrossRefs" href="#bib0160">32,37</a> The clustering of cases after injection of different anti-angiogenic active ingredients shows that factors other than the patient or the active ingredient of the drug may also play a role.<a class="elsevierStyleCrossRefs" href="#bib0010">2,16</a> This type of epidemiological pattern can be related to both infectious and sterile etiology and therefore requires investigation of the cause of these case series to prevent recurrence.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>It should be noted that we usually find the opposite situation since most cases are reported sporadically, so individual predisposition must play an important role in many cases.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> In any case, these examples show that the causes of the inflammatory phenomenon are complex and multifactorial.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Treatment of these sterile inflammations usually consists of observation for milder cases and the use of topical or systemic corticosteroids if the inflammation is more severe at onset or does not resolve with topical treatment.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> In cases with more severe inflammation or atypical signs, differential diagnosis with infectious processes is essential due to overlapping clinical features and the consequences of delayed treatment. Therefore, many of the doubtful cases should be treated with intravitreal antibiotic medication and sampling when it is impossible to rule out infectious etiology.<a class="elsevierStyleCrossRefs" href="#bib0165">33,39</a>The visual prognosis of these inflammatory reactions is good, taking into account that many of the patients' vision was previously compromised by the underlying retinal pathology.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> Visual recovery takes on average 12 weeks and may be longer. Cases showing a permanent loss of more than two lines of vision are associated with a rapid onset, less vision at presentation, presence of fibrin and older age of the patient.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>Characteristics of the early infectious inflammatory reactionThe incidence of infectious endophthalmitis following intravitreal injection ranges from 0.027 to 0.15% according to available references.<a class="elsevierStyleCrossRefs" href="#bib0050">10,11,40</a> Overall, this incidence is lower than that described for sterile etiologies, particularly in comparison with the new anti-angiogenic drugs.<a class="elsevierStyleCrossRefs" href="#bib0035">7,10,19</a> In contrast to sterile processes, no differences in incidence are found in infectious processes depending on the anti-angiogenic drug injected (<0.1%).<a class="elsevierStyleCrossRefs" href="#bib0070">14,17</a> There are differences when compared to corticosteroid (0.6%) or antiviral (0.1%) injections, where infectious processes seem to be more frequent.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>Regarding the prevention of infectious complications, the use of povidone-iodine 5% pre-injection has been shown to reduce the incidence of infectious complications, as has the use of anaesthetics in non-viscous media.<a class="elsevierStyleCrossRefs" href="#bib0195">39,40</a> Other factors such as the type of anti-angiogenic drug, type of anesthesia, use of gloves and mask, avoidance of talking during injection, use of blepharostat or application of antibiotic before or after injection, do not seem to influence.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>The most frequently isolated microorganisms in cases of infectious endophthalmitis following intravitreal injection are coagulase-negative Staphylococcus, which account for 43–75% of positive cultures.<a class="elsevierStyleCrossRefs" href="#bib0085">17,40–43</a> Specifically after intravitreal injections compared to cataract surgery, there seems to be a certain tendency to find microorganisms from oral or respiratory flora that can cause more severe symptoms, particularly Streptococcus, which is the second cause of infectious endophthalmitis in this context.<a class="elsevierStyleCrossRefs" href="#bib0195">39,44</a> Other atypical pathogens such as Propinebacterium are less frequent after intravitreal injection than in other intraocular surgeries such as cataract surgery.<a class="elsevierStyleCrossRef" href="#bib0210">42</a>Of particular relevance is the low success rate in determining the infectious organism in these cases. Only 30–60% of cultures are positive, with dry vitreous sampling being the most cost-effective.<a class="elsevierStyleCrossRefs" href="#bib0070">14,40,45</a>The onset of symptomatology can be useful to distinguish the nature of the inflammation, infectious processes usually start 2–4 days after intravitreal injection, while inflammatory processes are usually earlier, before 2 days.<a class="elsevierStyleCrossRefs" href="#bib0065">13,16</a> It must be taken into account that there may be sterile inflammatory reactions somewhat later overlapping with the presentation of infectious processes or even later with an average of 24 days after administration of brolucizumab and abicipar pegol for the onset of drug-related inflammation.<a class="elsevierStyleCrossRefs" href="#bib0025">5,46</a>Infectious etiology has a worse visual prognosis, with visual acuity at presentation being less than 0.2 in more than 80% of patients.<a class="elsevierStyleCrossRefs" href="#bib0210">42,44,45</a> In cases of sterile inflammation, vision loss is less at onset and recovery may be complete, in contrast to the poor prognosis of infectious etiology.<a class="elsevierStyleCrossRefs" href="#bib0055">11,45</a>Sometimes, the clinical features of the process can make it difficult to make a differential diagnosis between a sterile or infectious process due to the overlap between the clinical pictures. Some symptoms such as pain or photophobia will be more common in infectious processes.<a class="elsevierStyleCrossRefs" href="#bib0020">4,11,16</a> Pain will be present in nearly all patients (96−100%), and will be severe in most.<a class="elsevierStyleCrossRefs" href="#bib0020">4,11,16</a> Conjunctival injection occurs in 100% of cases, hypopyon in 78−100% and vitritis in 100%.<a class="elsevierStyleCrossRefs" href="#bib0205">41,42</a>In general, the inflammatory reaction in infectious cases is greater, so we will more frequently find corneal edema, fibrin in the anterior chamber and greater cellularity in both the anterior and posterior poles.<a class="elsevierStyleCrossRefs" href="#bib0020">4,14,38</a> Particularly in some series, sterile cases had little or no inflammation in the anterior pole, as opposed to infectious cases.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>It should be remembered that, although clinical features could point to the etiology of the process, they can be misleading. A lower bacterial inoculum or strains with lower virulence may lead to less intense onset symptoms that could be mistaken for sterile. Therefore, our threshold for anti-infective treatment should generally be low.<a class="elsevierStyleCrossRefs" href="#bib0020">4,38</a>The main interest in the correct diagnosis of the etiology of the process is to establish the correct early treatment in infectious cases. It is advisable to instruct our patients to seek consultation in the days following an intravitreal injection, regardless of the presence of pain.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>In the case of infectious etiology, the action protocol has been extrapolated from that of infectious endophthalmitis after cataract surgery; there is insufficient evidence to propose a different action specifically after intravitreal injection. The use of intravitreal antibiotics is mandatory in case of infectious suspicion, and early vitrectomy may help to obtain a more cost-effective sample for analysis and thus improve the prognosis of these patients.<a class="elsevierStyleCrossRefs" href="#bib0190">38,40</a>Characteristics of the late sterile inflammatory reactionIn some cases the inflammatory reaction does not occur early after intravitreal injection, which facilitates the differential diagnosis with infectious endophthalmitis.BrolucizumabBrolucizumab has shown a greater reduction in retinal fluid in patients treated with doses of 6 mg/0.05 ml compared to other antiangiogenic drugs, with early extension of the regimens to 12-week intervals in some patients.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>So far, the only marketed anti-angiogenic drug associated with the development of late inflammatory vasculitis has been brolucizumab. We have already referred to the rates of intraocular inflammation obtained in the phase III and post-hoc analysis of the HAWK and HARRIER trials, which exceed those obtained with aflibercept. However, no significant differences were found when comparing the rates of moderate or severe vision loss for both drugs in patients with intraocular inflammation (6.1–9.5% for brolucizumab and 7.0–8.1% for aflibercept).<a class="elsevierStyleCrossRefs" href="#bib0090">18,19</a> Therefore, following a safety analysis of brolucizumab in the aforementioned trials, it remained in the market.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>In contrast, the injection of brolucizumab 6 mg/every 4 weeks beyond the loading dose was discontinued precisely because of the high incidence of inflammatory adverse effects detected in the MERLIN clinical trial. In fact, the dosage used in this trial is not indicated in the drug's postmarketing label, recommending more widely spaced injections.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>Following these trial results, a post-marketing study found a rate of 15 serious adverse events related to intraocular inflammation per 10,000 injections (retinal vasculitis or retinal occlusion).<a class="elsevierStyleCrossRef" href="#bib0025">5</a> A review of events during the trials showed a rate of intraocular inflammation with concomitant vasculitis of 3.3% and vascular occlusions of 2.1%.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Among patients with intraocular inflammation 72% had retinal vasculitis, and of these 63.9% had retinal occlusions.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>In subsequent retrospective studies of large series of patients, the incidence of these serious inflammatory effects was lower, at 0.6%, than in the context of clinical trials.<a class="elsevierStyleCrossRef" href="#bib0235">47</a>After reviewing data from the HAWK and HARRIER trials, said studies found that intraocular inflammation occurred on average 25 days after starting treatment. This event could occur up to 12–18 months after the start of treatment. But in most cases (75%) it occurred within the first 6 months.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Out-of-trial case series have reproduced this pattern in patients who had received other prior antiangiogenic therapy.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>In sterile endophthalmitis after brolucizumab patients report symptoms common to other inflammatory processes such as vision loss (62%), pain, red eye, light sensitivity, myodesopsia (31%) or scotoma (8%).<a class="elsevierStyleCrossRefs" href="#bib0175">35,48,49</a> In these patients we should always actively look for signs of vasculitis or vascular occlusion which have been reported both with moderate and severe intraocular inflammation at other levels and in the absence or with mild signs of intraocular inflammation (8%).<a class="elsevierStyleCrossRefs" href="#bib0175">35,48</a>The clinical presentation of brolucizumab-associated vasculitis is heterogeneous with reported cases of central, peripheral or multifocal involvement; with compromise of small and large vessels. It usually affects mostly arterial vessels (91%) followed in frequency by venules (79%) and choroidal vessels (48%).<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Associated occlusive phenomena may or may not be found.<a class="elsevierStyleCrossRefs" href="#bib0240">48,49</a>Angiographically they show delayed arterial filling, areas of retinal ischemia (68%), hyperfluorescence and staining of the affected vessels (64%) and contrast leakage in the optic nerve (55%).<a class="elsevierStyleCrossRefs" href="#bib0175">35,48,49</a>Fundus examination reveals: soft exudates, retinal pallor, arterial sheathing (80%), exsanguinated or attenuated vessels (37%), papillary edema, venous tortuosity (64%), perivenular hemorrhages and cherry red staining if the foveal area is affected.<a class="elsevierStyleCrossRef" href="#bib0175">35</a>It should be noted that in this context of brolucizumab treatment and intraocular inflammation together with occlusive phenomena, an extraocular embolic cause is unlikely, so systemic studies are not necessary.<a class="elsevierStyleCrossRefs" href="#bib0240">48,49</a>In this situation, we must analyse the benefit-risk balance of the treatment for each patient, giving rise to various recommendations that we must remember for the use of brolucizumab<a class="elsevierStyleCrossRefs" href="#bib0025">5,50</a>:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•We should ask the patient about a history of previous intraocular inflammation, as this is the greatest risk factor for its development. In addition, there is a clear predominance in females.<a class="elsevierStyleCrossRefs" href="#bib0025">5,47</a></li><li class="elsevierStyleListItem" id="lsti0010">•The patient should be instructed to consult in the event of warning signs: reduced vision, blurred vision, myodesopsia, pain, discomfort, hyperemia or the appearance of new scotomas.<a class="elsevierStyleCrossRef" href="#bib0240">48</a></li><li class="elsevierStyleListItem" id="lsti0015">•If inflammatory signs are present, a complete ophthalmological examination should be performed: slit-lamp examination of anterior and posterior pole, direct or indirect ophthalmoscopy, macular OCT (looking for vitreous cellularity), posterior pole photography (wide field if possible), fluorescein angiography (with peripheral retinal capture) and indocyanine green (in cases where inflammatory or ischemic changes are suspected at the level of the choroid).<a class="elsevierStyleCrossRef" href="#bib0240">48</a></li><li class="elsevierStyleListItem" id="lsti0020">•The median time to presentation is 25 days after the last injection, 166 days from the start of treatment.<a class="elsevierStyleCrossRefs" href="#bib0095">19,49,50</a> Seventy-four percent of inflammatory episodes occur in the first 6 months, 14% between 6 and 12 months and 12% after one year from the start of treatment.<a class="elsevierStyleCrossRef" href="#bib0090">18</a></li><li class="elsevierStyleListItem" id="lsti0025">•At every visit, especially just before injecting the next dose of the drug, the patient should be examined for inflammatory signs in the anterior (cellularity, keratic precipitates, Descemet's folds, flare, corneal edema) and posterior (vascular sheathing, vessel narrowing and occlusion, filling defects, choroidal hypofluorescence and optic nerve leakage).<a class="elsevierStyleCrossRef" href="#bib0025">5</a> In patients with inflammation or diagnostic doubts, we should perform fluorescein angiography and explore the retinal periphery.</li><li class="elsevierStyleListItem" id="lsti0030">•Always consider the differential diagnosis with infectious endophthalmitis, and if in doubt, treat it as such.<a class="elsevierStyleCrossRef" href="#bib0025">5</a></li><li class="elsevierStyleListItem" id="lsti0035">•Start corticosteroid treatment adjusted to the level of inflammation in our patient and discontinue brolucizumab.</li></ul>Treatment of these inflammatory phenomena should be established in proportion to the ocular involvement, always ruling out infectious etiology. In cases of vasculitis or occlusive phenomena, there are expert recommendations regarding the supplementation of topical corticosteroids with intravitreal or systemic administration and the use of immunomodulators. However, there is insufficient evidence on the use of immunomodulators and no recommendations can be made on whether vitrectomy should be performed in these cases.<a class="elsevierStyleCrossRefs" href="#bib0175">35,48</a>The cause of said inflammatory pattern in patients treated with brolucizumab has not been fully established. It has been proposed that the high rate of antibodies to the drug found in patients in the HAWK and HARRIER trials (35–50%) may account for a type III inflammatory reaction in these patients.<a class="elsevierStyleCrossRefs" href="#bib0175">35,49,51</a>Abicipar pegolThe pattern of inflammation resembles in time to presentation the inflammatory reaction to brolucizumab, with an average of 23.3 days to presentation. However, in this case 34.9% of patients with inflammation started after the first injection.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>Most of the reported inflammatory reactions were mild or moderate and resolved spontaneously or after the use of topical corticosteroids.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> 74.5% of patients had no sequelae following this process. Among the most severe cases, 1.8% of patients showed retinal vasculitis. These inflammatory complications increased the rate of treatment discontinuation, and contributed to a higher rate of visual acuity reduction in patients treated with abicipar.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>In the follow-up of patients without inflammatory events, the incidence of inflammatory events fell after the first year and was comparable to that found in the ranibizumab-treated group (0.8% and 2.3% with abicipar Q8 and Q12 vs. 1% with ranibizumab Q4), and less severe than at baseline.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> In addition, the results obtained for drug efficacy were maintained in this extension of the study.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>After modification of the manufacturing process, a reduction in the rate of intraocular inflammation was achieved in the MAPLE study, although patients had a shorter follow-up. This opens the window for a possible optimisation of the safety profile of abicipar pegol in the future through further purification in the production process.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Differential diagnosis: sterile vs. infectiousEarly inflammatory reactionHaving summarised the main characteristics of infectious and sterile inflammatory processes after intravitreal injection, we can anticipate the similarity of some clinical conditions that will make their correct diagnosis difficult. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarises the main characteristics that can help us to differentiate between sterile and infectious conditions.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>We must be aware that the clinic will always be indicative, and none of these characteristics should be diagnostic in itself of the etiology of the process. In general, the tendency should be to carry out early anti-infective treatment in cases where there are doubts about the etiology of the process.The most profitable features for differential diagnosis are: time of debut, presence of pain and some clinical signs such as hyperemia, presence of hypopyon and vitritis.<a class="elsevierStyleCrossRefs" href="#bib0055">11,13,34</a>Cases of sterile inflammation usually occur within the first few days after injection. Infectious processes are usually somewhat later, with an average presentation of 3 days.<a class="elsevierStyleCrossRefs" href="#bib0205">41,42</a>Pain will be systematically present in infectious cases and will be severe in most cases. In contrast, less than half of patients with sterile processes experience pain and if pain is present, it is rarely severe.<a class="elsevierStyleCrossRefs" href="#bib0020">4,11,16,32</a>,<a class="elsevierStyleCrossRefs" href="#bib0170">34,45</a>Signs such as hyperemia or vitritis appear in 100% of infectious patients, and hypopyon is also very frequent (76–100%). In cases of sterile endophthalmitis, its appearance is variable and of lesser severity.<a class="elsevierStyleCrossRefs" href="#bib0080">16,34,41,42</a>,<a class="elsevierStyleCrossRef" href="#bib0240">48</a> Other less frequent signs in sterile phenomena according to some series are palpebral edema or conjunctival chemosis.<a class="elsevierStyleCrossRef" href="#bib0160">32</a>Late inflammatory reactionLate inflammatory reactions associated with new drugs should also be included in the differential diagnosis with infectious endophthalmitis. If we follow the established recommendations and monitor patients at scheduled visits, it will be easier to guide diagnosis, both by the time of presentation and by detecting milder clinic.<a class="elsevierStyleCrossRefs" href="#bib0025">5,50</a>As a starting point, brolucizumab-related inflammatory reactions have shown a female predilection, accounting for more than 80% of cases reported in some series.<a class="elsevierStyleCrossRefs" href="#bib0175">35,52</a> Infectious processes have no gender predilection.Inflammation after injection of the new antiangiogenic drugs typically appears around 20 days after injection, much later than classic acute inflammatory processes or the picture associated with infectious processes. A lower bacterial inoculum or low virulence may delay the onset of symptoms and overlap with that of the late inflammatory reaction to brolucizumab, but these would be atypical infectious conditions.<a class="elsevierStyleCrossRefs" href="#bib0080">16,18,19,41</a>,<a class="elsevierStyleCrossRef" href="#bib0210">42</a>The presence of vasculitis or occlusive phenomena typical of the most severe cases associated with brolucizumab injection does not rule out the presence of an infectious cause. As in acute cases, the presence of conjunctival injection, hypopyon or severe pain should alert us to the possibility of infectious endophthalmitis.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>ConclusionsInterest in inflammatory complications following anti-VEGF injection has increased with the introduction of brolucizumab which shows a higher, and potentially more severe, rate of inflammatory complications than classical antiangiogenics.The overlap of the clinical picture between infectious and sterile processes, the low culture positivity rate and the heterogeneity in terminology are barriers to the correct diagnosis and reporting of inflammatory complications after injection of intravitreal antiangiogenic medication.Sterile conditions begin early after injection or about 20 days later in cases of brolucizumab-associated vasculitis. Infectious processes start on average on the third day after the injection and up to one week after the injection.Severe decrease in visual acuity, severe pain, severe hyperemia, hypopyon and a higher degree of intraocular inflammation should point to infectious processes.In cases in which the etiology of the inflammation is doubtful, we must proceed with very close monitoring of the patient or empirical antimicrobial treatment and sampling to avoid the complications of infectious endophthalmitis. In contrast, sterile phenomena should be treated with observation in the simplest cases or corticosteroids adapted to the amount of inflammation in more severe cases.Conflict of interestRoberto Gallego Pinazo is a consultant for Novartis, Roche, Carl Zeiss Meditec and ORA Clinical, and receives research support from Alcon, Allergan, Celltrion, Heidelberg Engineering, IvericBio, Novartis and Roche.Rosa Dolz Marco is a consultant for Heidelberg Engineering, Novartis and Roche, and receives research support from Celltrion, IvericBIO, Novartis and Roche.Santiago Montolío Marzo, Lourdes Vidal-Oliver and Elena Montolío-Marzo have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres1924322" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1659192" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1924321" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1659191" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Review" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Incidence of sterile intraocular inflammation in different drugs" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "A) Classical antiangiogenics: bevacizumab, ranibizumab, aflibercept" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "B) New anti-angiogenic drugs" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "C) Biosimilars approved by the European Medicines Agency" ] ] ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Characteristics of the early sterile inflammatory reaction" ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Characteristics of the early infectious inflammatory reaction" ] 10 => array:3 [ "identificador" => "sec0050" "titulo" => "Characteristics of the late sterile inflammatory reaction" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Brolucizumab" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Abicipar pegol" ] ] ] 11 => array:3 [ "identificador" => "sec0065" "titulo" => "Differential diagnosis: sterile vs. infectious" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Early inflammatory reaction" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Late inflammatory reaction" ] ] ] 12 => array:2 [ "identificador" => "sec0080" "titulo" => "Conclusions" ] 13 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflict of interest" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-12-12" "fechaAceptado" => "2023-04-13" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1659192" "palabras" => array:6 [ 0 => "Endophthalmitis" 1 => "Uveitis" 2 => "Intravitreal injection" 3 => "Antiangiogenic" 4 => "Age related macular degeneration" 5 => "Brolucizumab" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1659191" "palabras" => array:5 [ 0 => "Endoftalmitis" 1 => "Inyección intravítrea" 2 => "Antiangiogénico" 3 => "Degeneración macular asociada a la edad" 4 => "Brolucizumab" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The recent release of brolucizumab and the development of new antiangiogenic molecules as abicipar pegol has increased the interest towards inflammatory complications after intravitreal drug injection. Those drugs are associated to a higher rate of inflammatory adverse events compared to classic drugs. In this context it is essential to differentiate between sterile and infectious cases for a fast and effective treatment.The clinical similarities between infectious and sterile cases, the high rate of culture negative patients and the heterogeneity in the terminology used are obstacles for a correct diagnosis and report of these complications.Sterile cases appear early after the injection, before 48 h; or 20 days after in brolucizumab-related vasculitis cases. Infectious cases show up around the third day after injection and up to a week after it. A severe visual impairment, severe pain, severe hyperemia, hypopyon and a more severe intraocular inflammatory process are signs of a likely infectious origin.If the cause of the inflammation is uncertain we must follow up the patient closely or “tap and inject” antimicrobial agents in order to prevent the eventual complications of an infectious endophthalmitis. On the other hand, sterile endophthalmitis might be observed in mild cases or treated with steroids according to the severity of the inflammation." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El interés por las complicaciones inflamatorias tras la inyección intravítrea de fármacos antiangiogénicos ha aumentado tras la comercialización de brolucizumab y el desarrollo de nuevas moléculas como el abicipar pegol. Dichos fármacos se asocian a una tasa de complicaciones inflamatorias mayor a los antiangiogénicos clásicos. En este contexto resulta clave el diferenciar procesos infecciosos y estériles para realizar un tratamiento efectivo y precoz.El solapamiento del cuadro clínico entre procesos infecciosos y estériles, la baja tasa de positividad en los cultivos y la heterogeneidad en la terminología son barreras para el correcto diagnóstico y reporte de las complicaciones inflamatorias tras la inyección de medicación antiangiogénica intravítrea.Los cuadros estériles debutan de forma precoz tras la inyección, dentro de las primeras 48 horas; o alrededor de 20 días después en los casos de vasculitis asociada a brolucizumab. Los procesos infecciosos debutan como promedio en el tercer día tras la inyección y hasta una semana después de la misma. La disminución grave de la agudeza visual, dolor severo, hiperemia severa, hipopion y un mayor grado de inflamación intraocular deben orientar hacia procesos infecciosos.En los casos en que exista duda sobre la etiología de la inflamación, debe procederse a un control muy estrecho del paciente o al tratamiento antimicrobiano empírico junto con toma de muestra para evitar complicaciones derivadas de una endoftalmitis infecciosa. Por el contrario, los fenómenos estériles deben ser tratados con observación en los casos más leves o corticoterapia adaptada a la gravedad de inflamación en casos más graves." ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AMD, age-related macular degeneration." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sterile endophthalmitis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Infectious endophthalmitis \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Advocacy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Brolucizumab > ranibizumab, bevazizumab and aflibercept \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No difference between different antiangiogenic drugs. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Start \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Very early <48 h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Slightly later 3–7 days \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epidemiological pattern \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May occur in outbreaks, though mostly sporadically \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Isolated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Visual acuity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mild to moderate decrease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Severe decline, majority <0.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Present in 46%, severe in <10%. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Present between 96 and 100%, severe in the majority \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hippo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Present between 78−100%. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fibrin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Present \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vitritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mild-moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Moderate-severe in 100% of cases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hyperemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Slight \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Present in 100%, severe \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Forecast \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Favourable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serious \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Observation vs. topical/systemic corticosteroids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intravitreal antibiotics and vitrectomy \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Differential characteristics between sterile and infectious endophthalmitis after intravitreal injection of marketed antiangiogenics in patients with AMD." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:52 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Endophthalmitis: a bibliographic review" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.I. 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Differential diagnosis of endophthalmitis after intravitreal drug injection for age related macular degeneration: sterile vs. infectious

Diagnóstico diferencial de las reacciones inflamatorias tras uso de medicación intravítrea en degeneración macular asociada a la edad: estéril vs. infeccioso

S. Montolío-Marzoa,b,

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s.montoliomarzo@gmail.com

Corresponding author.

, L. Vidal-Oliverb, E. Montolío-Marzoc, R. Dolz-Marcoa, R. Gallego-Pinazoa

a Clínica Oftalvist, Valencia, Spain

b FISABIO Oftalmología Médica, Valencia, Spain

c Hospital Clínico Universitario San Carlos, Madrid, Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The term endophthalmitis refers to inflammation of the vitreous and&#47;or aqueous humour&#44; usually secondary to infectious or exogenous etiologies&#46; The first reports of endophthalmitis in the scientific literature date back to 1916&#44; but initially the increase in the number of cataract surgeries and subsequently the rise of intravitreal drug treatment have been responsible for its increased prevalence&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The most commonly used anti-vascular endothelial growth factor &#40;VEGF&#41; drugs have been bevacizumab &#40;Avastin&#174;&#44; Genentech&#44; San Francisco&#44; CA&#44; USA&#41;&#44; ranibizumab &#40;Lucentis&#174;&#44; Genentech&#44; South San Francisco&#44; CA&#44; USA&#41; and aflibercept &#40;Eylea&#174;&#44; Regeneron&#44; Tarrytown&#44; New York&#44; USA&#41;&#46; With the increase in intravitreal injections after entering the market&#44; most of the published literature has been aimed at optimising the injection protocol for the prevention of infectious complications arising from the surgical procedure itself&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In recent years&#44; the introduction of new active ingredients has responded to the market&#39;s need to optimise results&#44; space out treatments and seek new therapeutic targets to broaden current indications&#46; Along with these new active ingredients&#44; new challenges have also arisen in terms of the complications derived from their application&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Both brolucizumab &#40;Beovu&#174;&#59; Novartis&#44; East Hanover&#44; New Jersey&#44; USA&#41; and abicipar pegol &#40;Abicipar&#174;&#44; Allergan&#44; Dublin&#44; Ireland&#41; have been developed to achieve better anatomical and functional outcomes&#44; as well as to space out injections in patients with age-related macular degeneration &#40;AMD&#41; to alleviate the high rates of non-adherence to treatment&#44; and to minimise the incidence of complications arising from surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In addition&#44; the application of these drugs is being extended to other diseases that are also susceptible to treatment with antiangiogenic drugs&#44; such as diabetic macular edema&#44; among others&#46; These new treatments have been accompanied by an increase in reported inflammatory complications following their application&#46; As a result of this trend&#44; interest has grown in the inflammatory adverse effects associated with intravitreal medication and the need to adapt our clinical practice to the new circumstances&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The first cases of severe uveitis and occlusive retinal vasculitis in association with brolucizumab were reported in early 2020&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> However&#44; despite these adverse effects&#44; brolucizumab has continued to be marketed despite several recommendations regarding its use for the prevention of serious adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In case of abicipar pegol&#44; the rate of inflammatory adverse events in the clinical trials were higher than in the ranibizumab-treated group during the first year of follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> This trend appears to be reduced after the first year of treatment in these same patients and also after modification of the drug manufacturing process in a parallel study&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In this context&#44; it is essential to differentiate between infectious and inflammatory etiology in endophthalmitis following intravitreal injection&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> We must bear in mind that depending on the etiology of the inflammation&#44; both the treatment and the prognosis of the process differ&#46; Until now&#44; the report of sterile endophthalmitis was more frequent with the use of intravitreal triamcinolone than antiangiogenic medication&#44; but the use of new molecules is changing this trend&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The aim is to find the key points for the differential diagnosis between processes of sterile inflammatory and infectious etiology after intravitreal injection of anti-angiogenic drugs&#44; in addition to establishing the clinical picture of both entities&#44; their incidence and the variations in the clinical pattern introduced by the new anti-angiogenic drugs&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Material and methods</span><p id="par0045" class="elsevierStylePara elsevierViewall">A narrative literature review was conducted following a literature search in the Pubmed database using &#34;intravitreal injection&#34;&#44; &#34;uveitis&#34;&#44; &#34;inflammation&#34; and &#34;endophthalmitis&#34; as keywords&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Review</span><p id="par0050" class="elsevierStylePara elsevierViewall">The reported incidence of sterile intraocular inflammation following intravitreal injection is 0&#46;005&#8211;4&#46;4&#37; and that of infectious endophthalmitis between 0&#46;027 and 0&#46;15&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;10&#8211;12</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Sterile inflammatory reactions following intravitreal antiangiogenic medication vary from a mild and transient inflammatory reaction to more severe processes that may compromise the long-term visual prognosis&#46; While sterile processes may resolve without major sequelae with appropriate treatment&#44; infectious processes tend to be more severe and are associated with a worse prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">There is much heterogeneity in diagnostic criteria and nomenclature regarding the reporting of sterile inflammatory and infectious complications in the literature&#46; Cases are reported of severe inflammatory processes that are considered infectious based on the clinical condition&#44; without having been able to demonstrate the presence of any microorganism&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Considering that only 30&#8211;60&#37; of cultures are positive after sampling&#44; this is not an uncommon situation&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> It should also be taken into account that there are infectious cases caused by bacterial toxins that will not produce any growth on culture media either and cannot be considered purely sterile processes&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In the case of sterile inflammatory reactions&#44; many go unnoticed because they are mild processes with a tendency to self-resolve&#44; thus underestimating their prevalence&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> To this we add the heterogeneity of the terms used to describe and classify them&#44; grouping them under a common generic term or dividing them according to the location of the ocular involvement&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Incidence of sterile intraocular inflammation in different drugs</span><p id="par0070" class="elsevierStylePara elsevierViewall">The incidence of infectious endophthalmitis does not vary significantly according to the anti-angiogenic agent used&#44; which explains its probable relationship with the surgical procedure rather than the mechanism of the drug itself&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;17</span></a> However&#44; looking at endophthalmitis of a sterile nature&#44; there are significant differences in the incidence rate of sterile inflammation depending on the drug used&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Sigford et al&#46; reviewed prospective studies reporting complications after injection of classical antiangiogenic drugs and found a higher rate of sterile inflammatory complications in patients treated with bevacizumab versus ranibizumab&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> These differences in the rate of sterile inflammatory reactions have increased with the introduction of new anti-angiogenic drugs&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">A&#41; Classical antiangiogenics&#58; bevacizumab&#44; ranibizumab&#44; aflibercept</span><p id="par0075" class="elsevierStylePara elsevierViewall">The incidence of sterile endophthalmitis associated with bevacizumab injection has been reported to be between 0&#46;09 and 1&#46;1&#37; depending on the series consulted&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;12</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The reported incidence associated with ranibizumab injection is lower compared to other anti-VEGFs according to some studies&#44; although these differences have been questioned&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The MARINA and ANCHOR trials reported an incidence of sterile endophthalmitis for ranibizumab of 0&#46;05&#37;&#46; The incidence in the VIEW trial for ranibizumab was 1&#46;5&#37;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> and in the CATT trial it was 0&#46;7&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Reports of higher incidence rates of sterile endophthalmitis for this drug are as high as 2&#37; of cases with post-injection inflammatory phenomena&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In the case of aflibercept 2&#8239;mg&#44; the HAWK and HARRIER trials reported a sterile intraocular inflammation rate of 0&#46;3 and 0&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The incidence in the VIEW trial was 1&#46;1&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> In the various series reported in the literature&#44; the rate of aflibercept-associated sterile ocular inflammation ranges from 0&#46;3&#37; to 14&#46;3&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;18</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The first results of aflibercept 8&#8239;mg are currently being presented at various scientific meetings&#46; The drug has not yet been approved by the FDA for use in our environment&#46; The PULSAR trial appears to have met its objective of demonstrating non-inferiority of aflibercept 8&#8239;mg to standard aflibercept 2&#8239;mg treatment regimens&#46; Intraocular inflammation rates for aflibercept 8&#8239;mg versus aflibercept 2&#8239;mg were 0&#46;7&#37; versus 0&#46;6&#37; in PULSAR&#46; This rate of sterile inflammatory complications should be re-evaluated in post-marketing studies involving patients in routine clinical practice in our practices&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">B&#41; New anti-angiogenic drugs</span><p id="par0095" class="elsevierStylePara elsevierViewall">Following brolucizumab injection in patients with AMD&#44; the incidence of intraocular inflammation in the HAWK and HARRIER trials was 2&#46;2 and 0&#46;8 respectively for 6&#8239;mg doses&#44; and 1&#46;4&#37; for 3&#8239;mg doses&#46; Most of these events were mild and transient forms&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In a subsequent analysis of the same patients included in these trials&#44; the rate of intraocular inflammation found was 4&#46;6&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> In the MERLIN trial with a maintained 4-weekly injection schedule &#40;not recommended in the drug label after marketing&#41;&#44; the rate of ocular inflammation was 9&#46;3&#37;&#44; which is why the trial was stopped&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> The incidence of intraocular inflammation has been reported as high as 14&#46;6&#37; outside these clinical trials&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> In the phase III trials KESTREL and KITE for the extension of indications of brolucizumab also to diabetic macular edema&#44; intraocular inflammation rates of 3&#46;7&#37; and 1&#46;7&#37; respectively for 6&#8239;mg and 4&#46;7&#37; for 3&#8239;mg doses were reported&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> The results for inflammatory complications were only slightly superior in the treatment of diabetic macular edema&#46; It is possible that the pro-inflammatory status of diabetic patients may influence these differences&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The CEDAR&#47;SEQUOIA trials report inflammation rates of 15&#46;4&#37; and 15&#46;3&#37; with treatment extensions of Q8 and Q12&#44; respectively after abicipar pegol injection&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Of these cases&#44; 1&#46;8&#37; of patients developed retinal vasculitis&#46; In the MAPLE trial after modification of drug manufacturing&#44; they reported intraocular inflammation rates of 8&#46;9&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Other recently marketed molecules such as faricimab aim to achieve a longer period between treatments&#44; without decreasing the efficacy achieved or increasing the rate of associated inflammatory complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a> In the TENAYA and LUCERNE clinical trials comparing it with aflibercept 2&#8239;mg for the treatment of AMD&#44; an inflammatory event rate of 2&#37; was reported in both cases&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Similar results have been obtained in the YOSEMITE and RHINE trials comparing aflibercept 2&#8239;mg with faricimab for the control of diabetic macular edema&#44; finding an inflammatory event rate of 2 and 1&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In summary&#44; in case of faricimab we found a rate of sterile inflammatory complications similar to that found with classical antiangiogenics&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> No differential clinical pattern has been reported so far in these inflammatory episodes associated with faricimab injection compared to those found with classical antiangiogenics&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">C&#41; Biosimilars approved by the European Medicines Agency</span><p id="par0110" class="elsevierStylePara elsevierViewall">In addition to new molecules&#44; we must take into account the entry of biosimilars into the European market&#46; Some biosimilars have been approved and widely used in other parts of the world&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In our setting&#44; the European Medicines Agency has approved the use of Ximluci&#174; &#40;STADA Arzneimittel AG&#59; Hessen&#44; Germany&#41;&#44; Byooviz&#174; &#40;Samsung Bioepis&#59; Delft&#44; The Netherlands&#41; and Ranivisio&#174; &#40;Midas Pharma GmbH&#59; Ingelheim&#44; Germany&#41; as biosimilars of ranibizumab for the treatment of AMD&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#8211;29</span></a> Byoviiz&#174; in its phase 3 clinical trial showed an endophthalmitis rate of 0&#46;7&#37;&#44; with 0&#46;15&#37; being sterile phenomena &#40;no cases of retinal vasculitis associated with its use were reported&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In any case&#44; active pharmacovigilance of these new drugs should be maintained to determine their characteristics in clinical practice in our environment&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Characteristics of the early sterile inflammatory reaction</span><p id="par0115" class="elsevierStylePara elsevierViewall">This reaction comprises episodes of inflammation and acute onset without infectious cause that resolve without antibiotic treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> These early acute reactions have been reported after injection of &#34;classical&#34; antiangiogenic drugs&#46; An acute inflammatory reaction following injection of brolucizumab<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> is also possible&#44; and cross-sensitisation to other antiangiogenics following injection of this drug has been proposed&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">These episodes usually occur in the days following the injection&#44; between 24&#8239;h and one week after the intervention&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;32</span></a> Several series report all their cases within the first 3 days&#44; but the time criterion does not allow a certainty diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Usually&#44; said episodes comprise a mild inflammatory reaction with cellularity and&#47;or discrete flare in the anterior chamber&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The process usually tends to self-resolve&#44; so that in a pattern of monthly check-ups a low-grade inflammation will go unnoticed and no treatment will be necessary&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Sometimes this inflammation is more severe and clinically significant&#46; The most frequent clinical manifestations are decreased visual acuity &#40;93&#37;&#41; and myodesopsia &#40;60&#37;&#41; accompanied by vitreous cellularity &#40;81&#37;&#41; and&#47;or anterior chamber cellularity &#40;74&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;33</span></a> Less frequently&#44; we find other symptoms such as corneal edema&#44; conjunctival hyperemia&#44; ocular pain &#40;46&#37; of patients&#44; &#60;10&#37; severe pain&#41;&#44; photophobia &#40;19&#37;&#41;&#44; hypopyon&#44; keratic precipitates&#44; trabeculitis&#44; retinal infiltrates or hemorrhages&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;34</span></a> Some symptoms are associated&#44; as most patients with pain also have hyperemia&#44; and without it the presence of pain is rare&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;33</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Most patients showing acute inflammatory reactions have been previously treated with antiangiogenic drugs&#44; even the same type of drug&#44; without any adverse effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;33</span></a> In the series published by Hahn et al&#46; all patients who were studied for acute sterile inflammatory reaction after injection had been previously treated with another antiangiogenic drug&#44; 33&#37; with the same active substance &#40;in this case aflibercept&#41;&#44; with no previous inflammatory complications&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Similarly&#44; retreatment after an inflammatory episode does not necessarily involve complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> In the series published by Chong et al&#46; 48&#37; of patients received bevacizumab injection after a previous episode of inflammation and only 6&#46;8&#37; showed a new inflammatory episode&#44; although in these patients the virulence of the process was much higher than in the initial episode&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">We found cases of sterile etiology clustered in a short period of time and in the same hospital&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;32&#44;36</span></a> In cases where the outbreak occurs with the same batch of medication&#44; the hypothesis that they may have been generated by impurities in the production&#44; storage or administration of the drug for injection becomes more important&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;37</span></a> The clustering of cases after injection of different anti-angiogenic active ingredients shows that factors other than the patient or the active ingredient of the drug may also play a role&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;16</span></a> This type of epidemiological pattern can be related to both infectious and sterile etiology and therefore requires investigation of the cause of these case series to prevent recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">It should be noted that we usually find the opposite situation since most cases are reported sporadically&#44; so individual predisposition must play an important role in many cases&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In any case&#44; these examples show that the causes of the inflammatory phenomenon are complex and multifactorial&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Treatment of these sterile inflammations usually consists of observation for milder cases and the use of topical or systemic corticosteroids if the inflammation is more severe at onset or does not resolve with topical treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In cases with more severe inflammation or atypical signs&#44; differential diagnosis with infectious processes is essential due to overlapping clinical features and the consequences of delayed treatment&#46; Therefore&#44; many of the doubtful cases should be treated with intravitreal antibiotic medication and sampling when it is impossible to rule out infectious etiology&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;39</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The visual prognosis of these inflammatory reactions is good&#44; taking into account that many of the patients&#39; vision was previously compromised by the underlying retinal pathology&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Visual recovery takes on average 12 weeks and may be longer&#46; Cases showing a permanent loss of more than two lines of vision are associated with a rapid onset&#44; less vision at presentation&#44; presence of fibrin and older age of the patient&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Characteristics of the early infectious inflammatory reaction</span><p id="par0160" class="elsevierStylePara elsevierViewall">The incidence of infectious endophthalmitis following intravitreal injection ranges from 0&#46;027 to 0&#46;15&#37; according to available references&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11&#44;40</span></a> Overall&#44; this incidence is lower than that described for sterile etiologies&#44; particularly in comparison with the new anti-angiogenic drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;10&#44;19</span></a> In contrast to sterile processes&#44; no differences in incidence are found in infectious processes depending on the anti-angiogenic drug injected &#40;&#60;0&#46;1&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;17</span></a> There are differences when compared to corticosteroid &#40;0&#46;6&#37;&#41; or antiviral &#40;0&#46;1&#37;&#41; injections&#44; where infectious processes seem to be more frequent&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Regarding the prevention of infectious complications&#44; the use of povidone-iodine 5&#37; pre-injection has been shown to reduce the incidence of infectious complications&#44; as has the use of anaesthetics in non-viscous media&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;40</span></a> Other factors such as the type of anti-angiogenic drug&#44; type of anesthesia&#44; use of gloves and mask&#44; avoidance of talking during injection&#44; use of blepharostat or application of antibiotic before or after injection&#44; do not seem to influence&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The most frequently isolated microorganisms in cases of infectious endophthalmitis following intravitreal injection are coagulase-negative <span class="elsevierStyleItalic">Staphylococcus</span>&#44; which account for 43&#8211;75&#37; of positive cultures&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;40&#8211;43</span></a> Specifically after intravitreal injections compared to cataract surgery&#44; there seems to be a certain tendency to find microorganisms from oral or respiratory flora that can cause more severe symptoms&#44; particularly <span class="elsevierStyleItalic">Streptococcus</span>&#44; which is the second cause of infectious endophthalmitis in this context&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;44</span></a> Other atypical pathogens such as <span class="elsevierStyleItalic">Propinebacterium</span> are less frequent after intravitreal injection than in other intraocular surgeries such as cataract surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Of particular relevance is the low success rate in determining the infectious organism in these cases&#46; Only 30&#8211;60&#37; of cultures are positive&#44; with dry vitreous sampling being the most cost-effective&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;40&#44;45</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">The onset of symptomatology can be useful to distinguish the nature of the inflammation&#44; infectious processes usually start 2&#8211;4 days after intravitreal injection&#44; while inflammatory processes are usually earlier&#44; before 2 days&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;16</span></a> It must be taken into account that there may be sterile inflammatory reactions somewhat later overlapping with the presentation of infectious processes or even later with an average of 24 days after administration of brolucizumab and abicipar pegol for the onset of drug-related inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;46</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Infectious etiology has a worse visual prognosis&#44; with visual acuity at presentation being less than 0&#46;2 in more than 80&#37; of patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;44&#44;45</span></a> In cases of sterile inflammation&#44; vision loss is less at onset and recovery may be complete&#44; in contrast to the poor prognosis of infectious etiology&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;45</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Sometimes&#44; the clinical features of the process can make it difficult to make a differential diagnosis between a sterile or infectious process due to the overlap between the clinical pictures&#46; Some symptoms such as pain or photophobia will be more common in infectious processes&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;11&#44;16</span></a> Pain will be present in nearly all patients &#40;96&#8722;100&#37;&#41;&#44; and will be severe in most&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;11&#44;16</span></a> Conjunctival injection occurs in 100&#37; of cases&#44; hypopyon in 78&#8722;100&#37; and vitritis in 100&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;42</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">In general&#44; the inflammatory reaction in infectious cases is greater&#44; so we will more frequently find corneal edema&#44; fibrin in the anterior chamber and greater cellularity in both the anterior and posterior poles&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;14&#44;38</span></a> Particularly in some series&#44; sterile cases had little or no inflammation in the anterior pole&#44; as opposed to infectious cases&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">It should be remembered that&#44; although clinical features could point to the etiology of the process&#44; they can be misleading&#46; A lower bacterial inoculum or strains with lower virulence may lead to less intense onset symptoms that could be mistaken for sterile&#46; Therefore&#44; our threshold for anti-infective treatment should generally be low&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;38</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">The main interest in the correct diagnosis of the etiology of the process is to establish the correct early treatment in infectious cases&#46; It is advisable to instruct our patients to seek consultation in the days following an intravitreal injection&#44; regardless of the presence of pain&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">In the case of infectious etiology&#44; the action protocol has been extrapolated from that of infectious endophthalmitis after cataract surgery&#59; there is insufficient evidence to propose a different action specifically after intravitreal injection&#46; The use of intravitreal antibiotics is mandatory in case of infectious suspicion&#44; and early vitrectomy may help to obtain a more cost-effective sample for analysis and thus improve the prognosis of these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;40</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Characteristics of the late sterile inflammatory reaction</span><p id="par0215" class="elsevierStylePara elsevierViewall">In some cases the inflammatory reaction does not occur early after intravitreal injection&#44; which facilitates the differential diagnosis with infectious endophthalmitis&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Brolucizumab</span><p id="par0220" class="elsevierStylePara elsevierViewall">Brolucizumab has shown a greater reduction in retinal fluid in patients treated with doses of 6&#8239;mg&#47;0&#46;05&#8239;ml compared to other antiangiogenic drugs&#44; with early extension of the regimens to 12-week intervals in some patients&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">So far&#44; the only marketed anti-angiogenic drug associated with the development of late inflammatory vasculitis has been brolucizumab&#46; We have already referred to the rates of intraocular inflammation obtained in the phase III and <span class="elsevierStyleItalic">post-hoc</span> analysis of the HAWK and HARRIER trials&#44; which exceed those obtained with aflibercept&#46; However&#44; no significant differences were found when comparing the rates of moderate or severe vision loss for both drugs in patients with intraocular inflammation &#40;6&#46;1&#8211;9&#46;5&#37; for brolucizumab and 7&#46;0&#8211;8&#46;1&#37; for aflibercept&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a> Therefore&#44; following a safety analysis of brolucizumab in the aforementioned trials&#44; it remained in the market&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">In contrast&#44; the injection of brolucizumab 6&#8239;mg&#47;every 4 weeks beyond the loading dose was discontinued precisely because of the high incidence of inflammatory adverse effects detected in the MERLIN clinical trial&#46; In fact&#44; the dosage used in this trial is not indicated in the drug&#39;s postmarketing label&#44; recommending more widely spaced injections&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Following these trial results&#44; a post-marketing study found a rate of 15 serious adverse events related to intraocular inflammation per 10&#44;000 injections &#40;retinal vasculitis or retinal occlusion&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> A review of events during the trials showed a rate of intraocular inflammation with concomitant vasculitis of 3&#46;3&#37; and vascular occlusions of 2&#46;1&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Among patients with intraocular inflammation 72&#37; had retinal vasculitis&#44; and of these 63&#46;9&#37; had retinal occlusions&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">In subsequent retrospective studies of large series of patients&#44; the incidence of these serious inflammatory effects was lower&#44; at 0&#46;6&#37;&#44; than in the context of clinical trials&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">After reviewing data from the HAWK and HARRIER trials&#44; said studies found that intraocular inflammation occurred on average 25 days after starting treatment&#46; This event could occur up to 12&#8211;18 months after the start of treatment&#46; But in most cases &#40;75&#37;&#41; it occurred within the first 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Out-of-trial case series have reproduced this pattern in patients who had received other prior antiangiogenic therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">In sterile endophthalmitis after brolucizumab patients report symptoms common to other inflammatory processes such as vision loss &#40;62&#37;&#41;&#44; pain&#44; red eye&#44; light sensitivity&#44; myodesopsia &#40;31&#37;&#41; or scotoma &#40;8&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;48&#44;49</span></a> In these patients we should always actively look for signs of vasculitis or vascular occlusion which have been reported both with moderate and severe intraocular inflammation at other levels and in the absence or with mild signs of intraocular inflammation &#40;8&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;48</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">The clinical presentation of brolucizumab-associated vasculitis is heterogeneous with reported cases of central&#44; peripheral or multifocal involvement&#59; with compromise of small and large vessels&#46; It usually affects mostly arterial vessels &#40;91&#37;&#41; followed in frequency by venules &#40;79&#37;&#41; and choroidal vessels &#40;48&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Associated occlusive phenomena may or may not be found&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;49</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">Angiographically they show delayed arterial filling&#44; areas of retinal ischemia &#40;68&#37;&#41;&#44; hyperfluorescence and staining of the affected vessels &#40;64&#37;&#41; and contrast leakage in the optic nerve &#40;55&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;48&#44;49</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">Fundus examination reveals&#58; soft exudates&#44; retinal pallor&#44; arterial sheathing &#40;80&#37;&#41;&#44; exsanguinated or attenuated vessels &#40;37&#37;&#41;&#44; papillary edema&#44; venous tortuosity &#40;64&#37;&#41;&#44; perivenular hemorrhages and cherry red staining if the foveal area is affected&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">It should be noted that in this context of brolucizumab treatment and intraocular inflammation together with occlusive phenomena&#44; an extraocular embolic cause is unlikely&#44; so systemic studies are not necessary&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;49</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">In this situation&#44; we must analyse the benefit-risk balance of the treatment for each patient&#44; giving rise to various recommendations that we must remember for the use of brolucizumab<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;50</span></a>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0280" class="elsevierStylePara elsevierViewall">We should ask the patient about a history of previous intraocular inflammation&#44; as this is the greatest risk factor for its development&#46; In addition&#44; there is a clear predominance in females&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;47</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0285" class="elsevierStylePara elsevierViewall">The patient should be instructed to consult in the event of warning signs&#58; reduced vision&#44; blurred vision&#44; myodesopsia&#44; pain&#44; discomfort&#44; hyperemia or the appearance of new scotomas&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0290" class="elsevierStylePara elsevierViewall">If inflammatory signs are present&#44; a complete ophthalmological examination should be performed&#58; slit-lamp examination of anterior and posterior pole&#44; direct or indirect ophthalmoscopy&#44; macular OCT &#40;looking for vitreous cellularity&#41;&#44; posterior pole photography &#40;wide field if possible&#41;&#44; fluorescein angiography &#40;with peripheral retinal capture&#41; and indocyanine green &#40;in cases where inflammatory or ischemic changes are suspected at the level of the choroid&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0295" class="elsevierStylePara elsevierViewall">The median time to presentation is 25 days after the last injection&#44; 166 days from the start of treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;49&#44;50</span></a> Seventy-four percent of inflammatory episodes occur in the first 6 months&#44; 14&#37; between 6 and 12 months and 12&#37; after one year from the start of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0300" class="elsevierStylePara elsevierViewall">At every visit&#44; especially just before injecting the next dose of the drug&#44; the patient should be examined for inflammatory signs in the anterior &#40;cellularity&#44; keratic precipitates&#44; Descemet&#39;s folds&#44; flare&#44; corneal edema&#41; and posterior &#40;vascular sheathing&#44; vessel narrowing and occlusion&#44; filling defects&#44; choroidal hypofluorescence and optic nerve leakage&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In patients with inflammation or diagnostic doubts&#44; we should perform fluorescein angiography and explore the retinal periphery&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0305" class="elsevierStylePara elsevierViewall">Always consider the differential diagnosis with infectious endophthalmitis&#44; and if in doubt&#44; treat it as such&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0310" class="elsevierStylePara elsevierViewall">Start corticosteroid treatment adjusted to the level of inflammation in our patient and discontinue brolucizumab&#46;</p></li></ul></p><p id="par0315" class="elsevierStylePara elsevierViewall">Treatment of these inflammatory phenomena should be established in proportion to the ocular involvement&#44; always ruling out infectious etiology&#46; In cases of vasculitis or occlusive phenomena&#44; there are expert recommendations regarding the supplementation of topical corticosteroids with intravitreal or systemic administration and the use of immunomodulators&#46; However&#44; there is insufficient evidence on the use of immunomodulators and no recommendations can be made on whether vitrectomy should be performed in these cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;48</span></a></p><p id="par0320" class="elsevierStylePara elsevierViewall">The cause of said inflammatory pattern in patients treated with brolucizumab has not been fully established&#46; It has been proposed that the high rate of antibodies to the drug found in patients in the HAWK and HARRIER trials &#40;35&#8211;50&#37;&#41; may account for a type III inflammatory reaction in these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;49&#44;51</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Abicipar pegol</span><p id="par0325" class="elsevierStylePara elsevierViewall">The pattern of inflammation resembles in time to presentation the inflammatory reaction to brolucizumab&#44; with an average of 23&#46;3 days to presentation&#46; However&#44; in this case 34&#46;9&#37; of patients with inflammation started after the first injection&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0330" class="elsevierStylePara elsevierViewall">Most of the reported inflammatory reactions were mild or moderate and resolved spontaneously or after the use of topical corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> 74&#46;5&#37; of patients had no sequelae following this process&#46; Among the most severe cases&#44; 1&#46;8&#37; of patients showed retinal vasculitis&#46; These inflammatory complications increased the rate of treatment discontinuation&#44; and contributed to a higher rate of visual acuity reduction in patients treated with abicipar&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0335" class="elsevierStylePara elsevierViewall">In the follow-up of patients without inflammatory events&#44; the incidence of inflammatory events fell after the first year and was comparable to that found in the ranibizumab-treated group &#40;0&#46;8&#37; and 2&#46;3&#37; with abicipar Q8 and Q12 vs&#46; 1&#37; with ranibizumab Q4&#41;&#44; and less severe than at baseline&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In addition&#44; the results obtained for drug efficacy were maintained in this extension of the study&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0340" class="elsevierStylePara elsevierViewall">After modification of the manufacturing process&#44; a reduction in the rate of intraocular inflammation was achieved in the MAPLE study&#44; although patients had a shorter follow-up&#46; This opens the window for a possible optimisation of the safety profile of abicipar pegol in the future through further purification in the production process&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Differential diagnosis&#58; sterile vs&#46; infectious</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Early inflammatory reaction</span><p id="par0345" class="elsevierStylePara elsevierViewall">Having summarised the main characteristics of infectious and sterile inflammatory processes after intravitreal injection&#44; we can anticipate the similarity of some clinical conditions that will make their correct diagnosis difficult&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarises the main characteristics that can help us to differentiate between sterile and infectious conditions&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0350" class="elsevierStylePara elsevierViewall">We must be aware that the clinic will always be indicative&#44; and none of these characteristics should be diagnostic in itself of the etiology of the process&#46; In general&#44; the tendency should be to carry out early anti-infective treatment in cases where there are doubts about the etiology of the process&#46;</p><p id="par0355" class="elsevierStylePara elsevierViewall">The most profitable features for differential diagnosis are&#58; time of debut&#44; presence of pain and some clinical signs such as hyperemia&#44; presence of hypopyon and vitritis&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;13&#44;34</span></a></p><p id="par0360" class="elsevierStylePara elsevierViewall">Cases of sterile inflammation usually occur within the first few days after injection&#46; Infectious processes are usually somewhat later&#44; with an average presentation of 3 days&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;42</span></a></p><p id="par0365" class="elsevierStylePara elsevierViewall">Pain will be systematically present in infectious cases and will be severe in most cases&#46; In contrast&#44; less than half of patients with sterile processes experience pain and if pain is present&#44; it is rarely severe&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;11&#44;16&#44;32</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;45</span></a></p><p id="par0370" class="elsevierStylePara elsevierViewall">Signs such as hyperemia or vitritis appear in 100&#37; of infectious patients&#44; and hypopyon is also very frequent &#40;76&#8211;100&#37;&#41;&#46; In cases of sterile endophthalmitis&#44; its appearance is variable and of lesser severity&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;34&#44;41&#44;42</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Other less frequent signs in sterile phenomena according to some series are palpebral edema or conjunctival chemosis&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Late inflammatory reaction</span><p id="par0375" class="elsevierStylePara elsevierViewall">Late inflammatory reactions associated with new drugs should also be included in the differential diagnosis with infectious endophthalmitis&#46; If we follow the established recommendations and monitor patients at scheduled visits&#44; it will be easier to guide diagnosis&#44; both by the time of presentation and by detecting milder clinic&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;50</span></a></p><p id="par0380" class="elsevierStylePara elsevierViewall">As a starting point&#44; brolucizumab-related inflammatory reactions have shown a female predilection&#44; accounting for more than 80&#37; of cases reported in some series&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;52</span></a> Infectious processes have no gender predilection&#46;</p><p id="par0385" class="elsevierStylePara elsevierViewall">Inflammation after injection of the new antiangiogenic drugs typically appears around 20 days after injection&#44; much later than classic acute inflammatory processes or the picture associated with infectious processes&#46; A lower bacterial inoculum or low virulence may delay the onset of symptoms and overlap with that of the late inflammatory reaction to brolucizumab&#44; but these would be atypical infectious conditions&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;18&#44;19&#44;41</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p><p id="par0390" class="elsevierStylePara elsevierViewall">The presence of vasculitis or occlusive phenomena typical of the most severe cases associated with brolucizumab injection does not rule out the presence of an infectious cause&#46; As in acute cases&#44; the presence of conjunctival injection&#44; hypopyon or severe pain should alert us to the possibility of infectious endophthalmitis&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclusions</span><p id="par0395" class="elsevierStylePara elsevierViewall">Interest in inflammatory complications following anti-VEGF injection has increased with the introduction of brolucizumab which shows a higher&#44; and potentially more severe&#44; rate of inflammatory complications than classical antiangiogenics&#46;</p><p id="par0400" class="elsevierStylePara elsevierViewall">The overlap of the clinical picture between infectious and sterile processes&#44; the low culture positivity rate and the heterogeneity in terminology are barriers to the correct diagnosis and reporting of inflammatory complications after injection of intravitreal antiangiogenic medication&#46;</p><p id="par0405" class="elsevierStylePara elsevierViewall">Sterile conditions begin early after injection or about 20 days later in cases of brolucizumab-associated vasculitis&#46; Infectious processes start on average on the third day after the injection and up to one week after the injection&#46;</p><p id="par0410" class="elsevierStylePara elsevierViewall">Severe decrease in visual acuity&#44; severe pain&#44; severe hyperemia&#44; hypopyon and a higher degree of intraocular inflammation should point to infectious processes&#46;</p><p id="par0415" class="elsevierStylePara elsevierViewall">In cases in which the etiology of the inflammation is doubtful&#44; we must proceed with very close monitoring of the patient or empirical antimicrobial treatment and sampling to avoid the complications of infectious endophthalmitis&#46; In contrast&#44; sterile phenomena should be treated with observation in the simplest cases or corticosteroids adapted to the amount of inflammation in more severe cases&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interest</span><p id="par0420" class="elsevierStylePara elsevierViewall">Roberto Gallego Pinazo is a consultant for Novartis&#44; Roche&#44; Carl Zeiss Meditec and ORA Clinical&#44; and receives research support from Alcon&#44; Allergan&#44; Celltrion&#44; Heidelberg Engineering&#44; IvericBio&#44; Novartis and Roche&#46;</p><p id="par0425" class="elsevierStylePara elsevierViewall">Rosa Dolz Marco is a consultant for Heidelberg Engineering&#44; Novartis and Roche&#44; and receives research support from Celltrion&#44; IvericBIO&#44; Novartis and Roche&#46;</p><p id="par0430" class="elsevierStylePara elsevierViewall">Santiago Montol&#237;o Marzo&#44; Lourdes Vidal-Oliver and Elena Montol&#237;o-Marzo have no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The recent release of brolucizumab and the development of new antiangiogenic molecules as abicipar pegol has increased the interest towards inflammatory complications after intravitreal drug injection&#46; Those drugs are associated to a higher rate of inflammatory adverse events compared to classic drugs&#46; In this context it is essential to differentiate between sterile and infectious cases for a fast and effective treatment&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The clinical similarities between infectious and sterile cases&#44; the high rate of culture negative patients and the heterogeneity in the terminology used are obstacles for a correct diagnosis and report of these complications&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Sterile cases appear early after the injection&#44; before 48&#8239;h&#59; or 20 days after in brolucizumab-related vasculitis cases&#46; Infectious cases show up around the third day after injection and up to a week after it&#46; A severe visual impairment&#44; severe pain&#44; severe hyperemia&#44; hypopyon and a more severe intraocular inflammatory process are signs of a likely infectious origin&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">If the cause of the inflammation is uncertain we must follow up the patient closely or &#8220;tap and inject&#8221; antimicrobial agents in order to prevent the eventual complications of an infectious endophthalmitis&#46; On the other hand&#44; sterile endophthalmitis might be observed in mild cases or treated with steroids according to the severity of the inflammation&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El inter&#233;s por las complicaciones inflamatorias tras la inyecci&#243;n intrav&#237;trea de f&#225;rmacos antiangiog&#233;nicos ha aumentado tras la comercializaci&#243;n de brolucizumab y el desarrollo de nuevas mol&#233;culas como el abicipar pegol&#46; Dichos f&#225;rmacos se asocian a una tasa de complicaciones inflamatorias mayor a los antiangiog&#233;nicos cl&#225;sicos&#46; En este contexto resulta clave el diferenciar procesos infecciosos y est&#233;riles para realizar un tratamiento efectivo y precoz&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El solapamiento del cuadro cl&#237;nico entre procesos infecciosos y est&#233;riles&#44; la baja tasa de positividad en los cultivos y la heterogeneidad en la terminolog&#237;a son barreras para el correcto diagn&#243;stico y reporte de las complicaciones inflamatorias tras la inyecci&#243;n de medicaci&#243;n antiangiog&#233;nica intrav&#237;trea&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Los cuadros est&#233;riles debutan de forma precoz tras la inyecci&#243;n&#44; dentro de las primeras 48 horas&#59; o alrededor de 20 d&#237;as despu&#233;s en los casos de vasculitis asociada a brolucizumab&#46; Los procesos infecciosos debutan como promedio en el tercer d&#237;a tras la inyecci&#243;n y hasta una semana despu&#233;s de la misma&#46; La disminuci&#243;n grave de la agudeza visual&#44; dolor severo&#44; hiperemia severa&#44; hipopion y un mayor grado de inflamaci&#243;n intraocular deben orientar hacia procesos infecciosos&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">En los casos en que exista duda sobre la etiolog&#237;a de la inflamaci&#243;n&#44; debe procederse a un control muy estrecho del paciente o al tratamiento antimicrobiano emp&#237;rico junto con toma de muestra para evitar complicaciones derivadas de una endoftalmitis infecciosa&#46; Por el contrario&#44; los fen&#243;menos est&#233;riles deben ser tratados con observaci&#243;n en los casos m&#225;s leves o corticoterapia adaptada a la gravedad de inflamaci&#243;n en casos m&#225;s graves&#46;</p></span>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sterile endophthalmitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Infectious endophthalmitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Advocacy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Brolucizumab&#8239;&#62;&#8239;ranibizumab&#44; bevazizumab and aflibercept&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No difference between different antiangiogenic drugs&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Start&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Very early &#60;48 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Slightly later 3&#8211;7 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epidemiological pattern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May occur in outbreaks&#44; though mostly sporadically&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Isolated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Visual acuity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mild to moderate decrease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Severe decline&#44; majority &#60;0&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Present in 46&#37;&#44; severe in &#60;10&#37;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Present between 96 and 100&#37;&#44; severe in the majority&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hippo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Present between 78&#8722;100&#37;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fibrin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Present&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vitritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mild-moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate-severe in 100&#37; of cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hyperemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Slight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Present in 100&#37;&#44; severe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Forecast&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Favourable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serious&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Observation vs&#46; topical&#47;systemic corticosteroids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intravitreal antibiotics and vitrectomy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Differential characteristics between sterile and infectious endophthalmitis after intravitreal injection of marketed antiangiogenics in patients with AMD&#46;</p>"
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      "titulo" => "References"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;I&#46; Wade"
                            1 => "T&#46;D&#46; Whitescarver"
                            2 => "C&#46;R&#46; Ashcroft"
                            3 => "S&#46;D&#46; Hobbs"
                            4 => "B&#46; Purt"
                            5 => "A&#46;K&#46; Reddy"
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                    0 => array:2 [
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                      "Revista" => array:7 [
                        "tituloSerie" => "Int Ophthalmol&#46;"
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                        "volumen" => "41"
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                        "paginaFinal" => "4161"
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                          "etal" => true
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Nonadherence or nonpersistence to intravitreal injection therapy for neovascular age-related macular degeneration&#58; a mixed-methods systematic review"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Okada"
                            1 => "P&#46; Mitchell"
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                            2 => "L&#46;H&#46; Lima"
                            3 => "G&#46;G&#46; Emerson"
                            4 => "E&#46;B&#46; Rodrigues"
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                    0 => array:1 [
                      "Revista" => array:6 [
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                0 => array:2 [
                  "contribucion" => array:1 [
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                            2 => "I&#46; Maruko"
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                        "tituloSerie" => "Retina&#46;"
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                            0 => "P&#46;J&#46; Rosenfeld"
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                    0 => array:2 [
                      "doi" => "10.1016/j.ajo.2020.05.012"
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                        "tituloSerie" => "Am J Ophthalmol&#46;"
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                0 => array:2 [
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                          "etal" => true
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                            2 => "C&#46;C&#46; Wykoff"
                            3 => "A&#46; Chang"
                            4 => "R&#46;N&#46; Khurana"
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                            0 => "R&#46;M&#46; Hussain"
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                        "tituloSerie" => "Expert Opin Biol Ther&#46;"
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                      "titulo" => "Clinical outcomes and treatment course of eyes with neovascular age-related macular degeneration following the development of endophthalmitis"
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                          "autores" => array:6 [
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                            3 => "A&#46;M&#46; Dersch"
                            4 => "A&#46;J&#46; Capone"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Distinguishing between infectious endophthalmitis and noninfectious inflammation following intravitreal anti-VEGF injection"
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Article information

ISSN: 21735794
Original language: English

DOI:10.1016/j.oftale.2023.04.014

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