Ophthalmic vascular manifestations in eosinophil-associated diseases: a comprehensive analysis of 57 patients from the CEREO and EESG networks and a literature review

Introduction Eosinophils have widespread procoagulant effects. In daily practice, eosinophil-related cardiovascular toxicity consists of endomyocardial damage, eosinophilic vasculitis and arterial or venous thrombosis. Here we aim to report on the clinical features and treatment outcomes of patients with unexplained ophthalmic vascular manifestations and eosinophilia. Methods We conducted a retrospective, multicenter, observational study and a literature review of patients with eosinophilia (≥0.5 x109/L) and concomitant ophthalmic vascular manifestations independent of the underlying eosinophilic disease but with no alternative cause for ophthalmic manifestations. Results Fifty-seven patients were included (20 from the observational study and 37 from the literature review). Ophthalmic vascular features were the initial manifestation of eosinophil-related disease in 34 (59%) patients and consisted of 29 central retinal artery occlusions, six branch retinal artery occlusions, five central retinal vein occlusions, two branch retinal vein occlusions, seven retinal vasculitides, two retinal vasospasms, 12 Purtscher’s retinopathies, 13 anterior ischemic optic neuropathies and two posterior ischemic optic neuropathies. The median [IQR] absolute eosinophil count at onset of ophthalmic vascular manifestations was 3.5 [1.7-7.8] x109/L. Underlying eosinophil-related diseases included eosinophilic granulomatosis with polyangiitis (n=32), clonal hypereosinophilic syndrome (HES) (n=1), idiopathic HES (n=13), lymphocytic HES (n=2), adverse drug reactions (n=3), parasitosis (n=2), polyarteritis nodosa (n=1), IgG4-related disease (n=1), eosinophilic fasciitis (n=1) and primary sclerosing cholangitis (n=1). Other extra-ophthalmologic arterial or venous thromboses related to eosinophilia were reported in four (7%) and nine (16%) patients, respectively. Visual prognosis was poor: only eight (10%) patients achieved full recovery of ophthalmologic symptoms. After a median follow-up of 10.5 [1-18] months, one patient (3%) had a recurrence of an ophthalmic vascular manifestation, and three patients (10%) had a recurrence of other vascular symptoms (deep vein thrombosis in two and pulmonary embolism in one patient). At the time of recurrence, absolute eosinophil counts were above 0.5 x109/L in all cases (n=4). Discussion This study broadens the spectrum of vascular manifestations associated with hypereosinophilia by adding ophthalmic vascular manifestations. In patients with ophthalmological vascular manifestations and hypereosinophilia, aggressive treatment of the underlying pathology (and normalization of blood count) should be implemented.

Inflammation, University of Lille, CHU Lille, Lille, France, 25 Department of Internal Medicine, Ambroise Pare Hospital, Assistance Publique-Ho ˆpitaux de Paris, Boulogne, France, 26 Department of Internal Medicine, Lyon University Hospital, Lyon, France, 27 Department of Internal Medicine, Foch Hospital, Suresnes, France Introduction: Eosinophils have widespread procoagulant effects.In daily practice, eosinophil-related cardiovascular toxicity consists of endomyocardial damage, eosinophilic vasculitis and arterial or venous thrombosis.Here we aim to report on the clinical features and treatment outcomes of patients with unexplained ophthalmic vascular manifestations and eosinophilia.
Methods: We conducted a retrospective, multicenter, observational study and a literature review of patients with eosinophilia (≥0.5 x10 9 /L) and concomitant ophthalmic vascular manifestations independent of the underlying eosinophilic disease but with no alternative cause for ophthalmic manifestations.

Introduction
Blood and/or tissue eosinophilia is a hallmark feature of multiple allergic, infectious, inflammatory, and neoplastic disorders (1).Eosinophils have widespread effects.These include the production of procoagulant phospholipids and the production of tissue factor and activated factor XII, both of which promote the genesis of thrombin (2)(3)(4).Eosinophils also release major basic protein (MBP, which contributes to platelet activation) (5,6), eosinophilic cationic protein, eosinophil peroxidase and platelet activation factor, all of which foster thrombus formation (7,8).According to the latest International Cooperative Working Group on Eosinophil Disorders (ICOG-Eo), both venous and/or arterial thromboses occurring in patients with absolute eosinophil counts (AEC) > 1.5 x10 9 /L are Hypereosinophilic Syndrome (HES)defining features (9).
Here, we aim to report on the clinical picture and treatment outcomes of patients with ophthalmic vascular manifestations and eosinophilia, and ultimately to provide a data-driven practical therapeutic algorithm.

Study design and inclusion criteria
We conducted a retrospective, multicenter, observational study.Centers involved in the French National Reference Center for HES (CEREO) and in the European Eosinophilic Granulomatosis with Polyangiitis study group as well as 1 US center of EGPA expertise (National Jewish Health, NJH) were queried to identify patients with: (i) at least one episode of ophthalmic vascular manifestation (CRAO, branch retinal artery occlusion (BRAO), CRVO, branch retinal vein occlusion (BRVO), Purtscher's retinopathy, retinal vasculitis or ION); (ii) concomitant absolute eosinophilia count (AEC) ≥ 0.5 x10 9 /L when the ophthalmic vascular manifestation occurred.Exclusion criteria were the presence of any condition, comorbidity or concomitant treatment leading to thrombophilia (either constitutional or acquired), cardiac embolism, rhythmic heart disease, tight carotid stenosis (NASCET ≥70%) homolateral to the retinal involvement or other causes of Purtscher's retinopathy (e.g.acute pancreatitis, head trauma or thrombotic microangiopathy), ION (e.g.giant cell arteritis) as well as the presence of anti-myeloperoxydase (MPO) anti-neutrophil cytoplasmic autoantibodies.A comprehensive list of exclusion criteria is provided in the Supplementary Appendix.

Literature review
The PUBMED database was searched for English-language publications released up to April 2023, using the following combination of MeSH terms: (i) 'hypereosinophilic syndrome' (or any term referring to a condition embedded within the spectrum of clonal, reactive (including lymphocytic HES, drug-induced or paraneoplastic eosinophilia) and idiopathic HES (including singleorgan and systemic eosinophil-associated diseases)); (ii) and a MeSH term referring to an ophthalmic vascular manifestation (e.g., retinal artery occlusion, retinal vein occlusion, retinal vasculitis, retinal diseases, optic neuropathy).Reference lists from selected publications were screened for additional relevant studies.

Baseline measurements
All cases were reviewed by the investigators (EC, MG) considering the entire follow-up.Using a standardized de-identified case report form, demographic (including cardiovascular and venous thromboembolism risk factors), clinical, laboratory and imaging findings at the time of the ophthalmic vascular manifestation as well as during follow-up were collected.For each patient, the underlying process underpinning blood hypereosinophilia was assessed according to the International COoperative study Group on Eosinophil disorders (ICOG-Eo) terminology (9) and thus considered as either clonal (i.e.neoplastic, including FIP1L1:: PDGFRA myeloid neoplasm with eosinophilia), reactive (including all conditions that lead to the production of type 2 inflammationrelated cytokines and thereby to non-clonal HE), overlapping (when embodied within the spectrum of autoimmune diseases, e.g.MPO ANCA-negative EGPA (23), IgG4-related disease (24), or eosinophilic fasciitis ( 25)), or idiopathic.

Outcomes
For patients with ≥ 3 months of follow-up, and after exclusion of patients with single-flare eosinophilia (parasitosis and drug-induced eosinophilia), studied outcomes included visual acuity at last followup, the recurrence of either ophthalmic or extra-ophthalmologic vascular events, the occurrence of ophthalmic complications (e.g.retinal neovascularization, intravitreal hemorrhage or neovascular glaucoma), and death.Full ophthalmic recovery was defined as the resolution of ophthalmologic symptoms (full correction of visual acuity, visual field normalization, no recurrence of transient monocular blindness).Partial recovery was defined as partial improvement in visual acuity and/or visual field.

Patient characteristics are reported as median [interquartile] ([IQR]
) and frequency (percentage) for continuous and categorical variables, respectively.Visual acuity was converted into the log of the minimum angle of resolution (logMAR).Patient subsets were differentiated based on the subtype of vascular manifestation (arterial involvement vs. venous thrombosis vs. Purtscher's retinopathy).Visual outcomes were compared using the Chi-squared test and continuous variables were compared using the Kruskal Wallis test.

Ethical and regulatory considerations
All methods were carried out in accordance with relevant guidelines and regulations (i.e. the Good Clinical Practice protocol, the Declaration of Helsinki principles and the MR004 French legislation regarding observational retrospective studies) and this study was approved by the independent ethics committee of Foch Hospital (IRB00012437, approval number 23-03-04).

Patient identification and baseline characteristics
One hundred and twenty-three patients were screened through the CEREO, EESG and NJH databases, and 55 case reports (corresponding to 56 patients) treated for eosinophilia and concomitant ophthalmic vascular manifestations were identified through the literature review.Overall, 57 patients fulfilled inclusion criteria (20 from the observational study and 37 from the literature review, Figure 1).Their main characteristics are reported in Table 1.Thirty-two (56%) were male and their median age at ophthalmic manifestation onset was 54 [44-65] years.Thirty-six (58%) had at least one cardiovascular risk factor, three (5%) had a prior history of cardiovascular disease and four (7%) had a prior history of venous thromboembolism.Among the 55 patients with available data, only one (2%) developed ophthalmic vascular involvement despite ongoing treatment with both antiplatelets and anticoagulants.

Outcomes
Full details of patients' outcomes are provided in Table 2.Among the 50 (88%) patients with available follow-up data (including 30 with more than three months of follow-up), the median follow-up after the initial ophthalmic vascular manifestation was 10.5 [1-18] months.One (3%) patient had a recurrence of ophthalmic vascular manifestation (CRVO) and three (10%) patients had another vascular event (lower limb deep vein thrombosis n=2, pulmonary embolism n=1).In all cases, AEC was above 0.5 x10 9 /L at time of recurrence.At last followup, only six patients (12%) achieved full recovery.Sixteen patients (32%) achieved partial recovery, 23 patients (46%) stabilized once under treatment, while the condition of the remaining five patients (10%) worsened despite therapy.By comparison with patients with arterial involvement, the rate of ophthalmic recovery was higher in patients with either Purtscher's retinopathy or venous involvement (recovery achieved in 8/10 eyes with Purtscher's retinopathy and in 4/5 eyes with venous involvement vs 18/53 eyes with arterial involvement, p=0.019).Patients with venous involvement or Purtscher's retinopathy had a better visual acuity at last follow-up than patients with arterial involvement (median logmar 0 [0-0], 1 [0-2.3]and 0.5 [0.2-0.8] for patients with venous, arterial involvement and Purtscher's retinopathy  respectively; p= 0.038).Of note, the levels of baseline absolute eosinophil counts did not correlate with long-term visual outcomes, and there were no significant differences regarding the final visual acuities of patients who received antiplatelets vs. anticoagulants as well as in patients who received only corticosteroids vs. those who received both corticosteroids and immunosuppressants (data not shown).Three (10%) patients developed retinal neovascularization with subsequent intravitreal hemorrhage during follow-up.During follow-up, four patients died of pulmonary infection, MRSAinduced septic shock, endomyocardial fibrosis and hepatitis (a single patient each).Both patients who died of sepsis were treated by systemic corticosteroids (in addition to methotrexate or mepolizumab, a single patient each).
The visual prognosis of EGPA patients was poor and the median final visual acuity was 2 [0.1-2.4]logmar.Among the fourteen patients with at least three months of follow-up, only one patient recovered completely and three achieved partial recovery, whereas two patients worsened and eight had a stability of their visual acuity.Moreover, three patients (21%) had a new vascular event during follow-up (lower limb deep vein thrombosis, n=2; pulmonary embolism, n=1).None of the 32 EGPA patients died during follow-up.

Discussion
Recent advances have led to the better understanding of the mechanisms driving the pro-coagulant effects of eosinophils (26), and reported cases of arterial and venous thrombotic manifestations related to eosinophilia have increased (11,(15)(16)(17)19).Likewise, the spectrum of eosinophilia-related cardiovascular toxicity has now broadened beyond the scope of eosinophilic cardiomyopathy (10).Some studies have recently highlighted peculiar phenotypes e.g., thromboangiitis obliterans-like disease (14), eosinophilia-associated coronary vasospasm (16) or ischemic strokes of border zone distribution (17).Here, we shed further light on the diversity of eosinophil-induced vascular symptoms and report on various ophthalmic vascular manifestations occurring within the fullspectrum of eosinophil-related diseases, either as first disease manifestation or during follow-up.
Intracardiac thrombus and peripheral arterial emboli were the main features reported in the review of HES-related cardiovascular manifestations reported by Ogbogu et al (10).Likewise, in the main series of patients with HES, ophthalmic vascular manifestations have rarely been reported (19,27,28), and mostly consist of case reports or small case series (20-22).In their 2019 review of 189 patients with idiopathic eosinophilic vasculitis, Lefevre et al. reported on only one case of CRAO and one case of retinal vasculitis (12).Among 151 patients with FIP1L1::PDGFRA-related HES, only one case of CRAO was reported (19) and in another series of 26 patients with CD3 -CD4 + lymphocytic HES, none presented with ophthalmic symptoms (27).Dupilumab-induced Purtscher's retinopathy with eosinophilia reported herein is in line with dupilumab-induced eosinophilic vasculitis that our group has previously reported (29).EGPA is the only eosinophil-associated disease for which ophthalmic vascular manifestations have been more extensively depicted, with predominant arterial involvement and poor visual prognosis despite treatment with corticosteroids (30,31).
Here, we report on a wide variety of ophthalmic vascular manifestations related to eosinophil-associated disorders, that clustered into three main clinical pictures (i.e.arterial or venous retinal occlusions and Purtscher's retinopathy), with one in three patients having bilateral involvement.There was no clear correlation between the clinical picture and underlying eosinophil-related diseases, supporting the fact that eosinophilia, whatever its cause, can lead to ophthalmologic vascular toxicity.Nevertheless, both clonal and lymphocytic HES were rare (one and two patients respectively), and EGPA was never reported in the setting of Purtscher's retinopathy.Strikingly, other (and most often concomitant) extra-ophthalmologic vascular manifestations related to eosinophilia were reported in up to 15% of patients, including organ or life-threatening events e.g., ischemic strokes, acute coronary syndrome, gastrointestinal tract ischemia, or inferior vena cava thrombosis.Although skin, lung and gastrointestinal symptoms are the most frequent manifestations of HES, the latter is a multifaceted disease and some patients have prominent vascular manifestations, including catastrophic antiphospholipid syndrome-like presentation (11).As expected (32)(33)(34)(35), the visual prognosis was poor (with only six patients achieving full recovery and significant loss of visual acuity at last follow-up), especially in patients with ION or CRAO.
In this series, patients had few cardiovascular risk factors and no major risk factor for venous thromboembolism, suggesting that their ophthalmic manifestations indeed were the consequence of eosinophil-related toxicity.There is strong evidence substantiating the procoagulant effects of eosinophils and their direct toxicity on the vascular endothelium.First, injury-induced venous thrombosis is drastically reduced in both eosinophil-deficient and eosinophildepleted mice (2).Moreover, eosinophils are potent producers of tissue factor (2-4), can produce procoagulant phospholipids and activate factor XII, which both stimulate the intrinsic coagulation degranulation) could also correlate with outcomes.
Regardless of these limitations, this studythe first longitudinal analysis dedicated to ophthalmic vascular manifestations occurring during eosinophil-related diseasesemphasizes the fact that eosinophilia (whatever the underlying disease) can lead to ophthalmic vascular toxicity.It provides useful data for both ophthalmologists and physicians involved in the field of eosinophil-related disorders and suggests that, in a subset of patients with otherwise unexplained ophthalmic vascular manifestation and eosinophilia, long-term normalization of AEC is advisable to prevent the recurrence of vascular manifestations.Further large-scale studies are needed to confirm these preliminary findings, and collaborative endeavors are welcome.

FIGURE 1 Flow
FIGURE 1Flow-chart showing the search strategy and inclusion/exclusion criteria for the study population.

FIGURE 2
FIGURE 2 Color fundus photography and spectral domain optical coherence tomography (SD-OCT) of a 43-year-old woman with eosinophilia and central retinal artery occlusion (CRAO) in the left eye.(A) Color fundus photography illustrates a retinal whitening of the posterior pole indicative of a CRAO with preservation of the cilioretinal artery.(B) SD-OCT shows hyperreflectivity in the temporal middle and inner retinal layer hyperreflectivity consistent with CRAO and cilioretinal artery sparing.

TABLE 1
Baseline demographic, clinical, biological and treatment features of patients with ophtalmic vascular manifestations and eosinophilia.

TABLE 2
Outcomes of patients with ophthalmic vascular manifestations and eosinophilia.