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original article Allergo J Int (2020) 29:181–186 https://doi.org/10.1007/s40629-020-00128-4 Omalizumab in three children with severe vernal keratoconjunctivitis Siri Rossberg · Uwe Pleyer · Susanne Lau Received: 15 April 2020 / Accepted: 27 April 2020 / Published online: 26 May 2020 © The Author(s) 2020 Summary improvement of the clinical grading scale from VKC Background Vernal keratoconjunctivitis (VKC) is grade 3–4 to grade 1–2. One patient had a relapse a rare, recurrent form of ocular allergy that can be mainly of his AD and achieved complete control of refractory to topical and systemic treatment. It typi- AD and VKC by introduction of dupilumab. cally presents as acute and chronic keratoconjunctival Conclusion Although the clinical beneﬁt of omal- inﬂammation that may lead to visual impairment due izumab in asthma and chronic spontaneous urticaria to corneal ulcers and scaring. Patients often suf- (CSU) has been established in several clinical trials, fer from atopic IgE-driven comorbidities, especially there are very little data about its effect on severe VKC. atopic eczema. Children are frequently affected and In addition to few previously reported cases we can often do not tolerate topical treatment well, especially report the rapid effectiveness of omalizumab in VKC if photophobia and pain impair therapy adherence. clinically and in terms of quality of life. Randomized We present three children with severe VKC who were trials are needed to include omalizumab in third-line not controlled by ﬁrst- and second-line topical and treatment of VKC for prevention of visual impairment systemic therapy and ﬁnally responded to treatment and further sequelae such as corneal damage. with the monoclonal anti-IgE antibody omalizumab as third-line treatment. Keywords Allergic conjunctivitis · Atopic dermatitis · Methods and results We retrospectively analyzed three IgE · Allergic asthma · Therapy patients with VKC having failed response to ﬁrst- and Abbreviations second-line treatment. All three boys had very early AD Atopic dermatitis allergic rhinoconjunctivitis from age 1–3 with poly- AKC Atopic keratoconjunctivitis sensitization: birch, grass pollen, house dust mite, CACC Comprehensive Allergy Center Charité and/or pets. All received subcutaneous or sublin- CsA Cyclosporine A gual immunotherapy (SCIT/SLIT) for birch and/or CSU Chronic spontaneous urticaria grass pollen without major success. Two patients DSCG Disodium cromoglycate (e.g. cromolyn) had comorbidities: allergic asthma and severe atopic ECP Eosinophil cationic protein dermatitis (AD). For at least 6 months after the ﬁrst MMP Matrix metalloproteases administration, monoclonal anti-IgE antibody oma- SCIT Subcutaneous immunotherapy lizumab (150 or 300 mg) was administered subcu- SLIT Sublingual immunotherapy taneously every 2–6 weeks in all patients achieving Th2 T helper-2 VKC Vernal keratoconjunctivitis S. Rossberg · Prof. Dr. S. Lau () Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité Universitätsmedizin Introduction Berlin, Augustenburger Platz 1, 13353 Berlin, Germany firstname.lastname@example.org Vernal keratoconjunctivitis (VKC) can present as a se- vere eye condition extensively impairing patient’s U. Pleyer quality of life due to photophobia, foreign body sen- Department of Ophthalmology, Charité Universitätsmedizin Berlin, Berlin, Germany sation, itching, pain, visual impairment, and limited K Omalizumab in three children with severe vernal keratoconjunctivitis 181 original article social activity . The distinction to other ocular and persistent symptoms and ﬁnally grade 5 (evolu- allergies can be challenging. Early stages of VKC tion) with remission and ﬁbrosis with absent or mild might be difﬁcult to discriminate from atopic kerato- occasional symptoms. conjunctivitis (AKC), often presenting together with The therapeutic concepts in treating VKC comprise atopic dermatitis as comorbidity. VKC usually occurs topical and systemic approaches. Major aims are to within the ﬁrst decade of life, predominantly in young stop inﬂammation and remodeling in order to pre- males without eyelid involvement in contrast to AKC vent long-term damage of the cornea and visual im- showing additional blepharoconjunctivitis . An pairment. Furthermore, quality of life and prevention Italian prospective study (patients 3–100 years of age) of social distancing is a main goal especially in chil- estimated a VKC prevalence of 6.5%; 64.5% of these dren. Recently, biologicals targeting immunological patients were under 14 years of age . pathways have also been used as off-label treatment. VKC occurs with three main presentations: the Patients with severe ocular symptoms and photopho- most frequent limbal form (54%) shows the charac- bia not responding to antiallergic treatment need to teristic Trantas dots at the limbus due to eosinophilic be referred to an experienced center. Alongside re- inﬁltration, the tarsal form with the disease’s hallmark duction in allergen exposure and avoidance of wind giant papillae, cobblestoning, hypersecretion and the and sun, patients need to be educated to reduce ad- third form presents as a combination of both . ditional physical damage by itching. A cold compress Severe photophobia can be an indicator of further on the eyelid may reduce itching; furthermore, rinsing complications such as keratitis and severe corneal ul- of the eye with cool physiological saline solution may ceration/erosions leading to corneal residual scarring remove cellular debris and toxic substances . and thus visual impairment. In its tarsal presentation, Medical treatment according to disease stages im- allergic sensitization seems to be more causative . plies antiallergic eye drops like ketotifen, other topical VKC shows differences in its pathophysiology com- mast cell stabilizers like cromolyn (DSCG) and sys- paring nonatopic (absence of sensitization and atopic temic nonsedating antihistamines as ﬁrst-line treat- comorbidities) and the atopic condition. In atopic ment. From disease grade 3, additionally dual acting individuals, the presence of speciﬁc IgE in serum antiallergic agents, i.e., mast cell stabilizer in a com- and in tears is observed. The high concentration bination of DSCG and lodoxamide, having inhibitory of tissue mast cells and IgE dependent high afﬁnity effects on eosinophil and neutrophil migration  Fcε-receptor activation inducing histamine release and, thus, downregulating ICAM-1 expression  seem to be the key reaction for the proinﬂamma- can be applied. More frequently, short-term topi- tory cascade in the atopic background of VKC . cal steroids (dexamethasone/predisolone) are used In addition to an increased number of conjuncti- as ﬁrst- and second-line treatment. However, given val mast cells, eosinophilic inﬂammation, CD4+ Th2 their well-known adverse effects such as glaucoma or (T helper-2) lymphocytes and proinﬂammatory cy- cataract the use is limited to short-term application. tokines like interleukin (IL) 4 and 5 but also matrix In recent years, topical cyclosporine A (CsA 1–2% in metalloproteases (MMP) have been identiﬁed in tears oil bases) or other calcineurin inhibitors are com- of VKC patients . Eosinophil-derived mediators, monly applied as second-line treatment. Topical CsA MMP, and collagenases damage the corneal epithe- has been found to be effective and safe in VKC and re- lium and the basement membrane. IL-5, eotaxin, and cently became certiﬁed in some parts of Europe . ECP (eosinophil cationic protein) in tears were found Systemic administration of the leukotriene receptor to correlate with disease severity . In nonatopic antagonist montelukast has been used in severely forms, a direct T cell response, enzyme activation, affected VKC patients as third-line treatment, how- altered expression of neurotransmitters and receptors ever, without controlled trials. Furthermore, systemic leading to hyperreactivity and tissue remodeling are treatment with CsA is used in some patients with considered underlying conditions . Disease exacer- severe atopic dermatitis and comorbid VKC or AKC bation can be triggered either by allergen re-exposure as third-line treatment. Omalizumab as a mono- (if allergy plays a role) or, more frequently, by nonspe- clonal anti-IgE antibody blocking the IgE high-afﬁnity ciﬁc stimuli such as sunlight, wind, and dust. Many receptor on mast cells and basophils and, thus, me- patients with VKC therefore have less symptoms dur- diator release was used in the treatment of several ing winter months, although latent persistent clinical patients with severe AKC and VKC [12–15] with vari- activity occurs . able outcome. In case of seasonal and even perennial Bonini et al.  introduced a clinical grading scale VKC with associated sensitizations the causative ap- to improve distinction from other ocular allergies as proach of subcutaneous immunotherapy should be well as to deﬁne ﬁve disease stages for uniﬁcation and introduced despite limited evidence in VKC [2, 4, 8, international studies. Grade 0 is absence of symptoms 16]. In summary, a signiﬁcant proportion of patients (quiescent), grade 1 mild and occasional symptoms, with serious VKC under topical treatment suffer from grade 2A mild to moderate intermittent and grade 2B recurrent insufﬁciently controlled symptoms, which mild to moderate persistent symptoms, grade 3 mod- may result in ﬁbrotic remodelling of the eye, followed erate to severe persistent symptoms, grade 4 severe by visual impairment. Especially children are often 182 Omalizumab in three children with severe vernal keratoconjunctivitis K original article Table 1 Patient characteristics, duration and dose of omalizumab and response to treatment Age at Atopic comor- Sensitization Therapy before omalizumab was Age at Duration and dosage VKC grade and VKC grade manifes- bidity started omal- of omalizumab visual acuity and visual tation of izumab treatment subcuta- (VA) before acuity (VA) VKC introduc- neously omalizumab after omal- tion was started izumab treat- ment Patient A 4 years Allergic Birch Systemic and topical antihis- 10 years 11 months Grade 3-4 Grade 1 (male) rhinoconjunc- grass tamines cetirizine/levocabastine 300 mg/14 days no visual no visual tivitis, mugwort topical corticosteroid dexam- impairment impairment asthma cat ethasone dog topical cyclosporine A guinea pig house dust mite Patient B 6months Allergic Birch Systemic and topical antihis- 6 years Age 6 years: Grade 4 Grade 1 (male) rhinoconjunc- grass tamines cetirizine/levocabastine 8 weeks VA right 0.6/ VA: right 1.0/ tivitis mugwort leukotriene receptor antagonist 300 mg/4 weeks left 0.8 left 1.0 house dust montelukast Age 7 years: mite topical corticosteroid dexam- 4months ethasone 150 mg/6 weeks topical cyclosporine A Age 8 years: 1 × 150 mg in April Patient C 5 years Allergic Birch Systemic and topical antihis- 7 years 6months Grade 4 Grade 2 (male) rhinoconjunc- grass tamines cetirizine/levocabastine 300 mg/14 days VA: right 0.5/ VA: right 1.0/ tivitis, atopic mugwort leukotriene receptor antagonist left 0.4 left 0.8 dermatitis, cat montelukast asthma dog topical corticosteroid dexam- horse ethasone house dust topical and systemic cy- mite closporine A reluctant towards topical treatment with eye drops tem (Phadia AB, Uppsala, Sweden). Parents and pa- which need to be applied several times a day. At the tients agreed to off-label use and to this publication. Comprehensive Allergy Center Charité (CACC), we interdisciplinary treat children with severe VKC and Results report our experience of systemic treatment with the biological omalizumab as third-line treatment and Three male patients suffered from early allergic off-label use in children not responding to ﬁrst- and rhinoconjunctivitis already at age 1–3 years. All pre- second-line treatment, being a pilot for a potential sented with polysensitization primarily to pollen al- randomized trial in the near future. lergens and over time additionally to house dust mite and/or pets (Table 1). They had received allergen immunotherapy as subcutaneous or sublingual treat- Methods ment (SCIT/SLIT) for birch and/or grass pollen. Addi- We retrospectively analyzed three VKC patients who tional comorbidities were allergic asthma and atopic failed to respond to ﬁrst- and second-line treatment. dermatitis (patient C was severely affected). Follow- Patients were recruited in the outpatient clinic of up time during and after omalizumab treatment was Charité Medical University, Department of Pediatric 11 months–3.5 years. Omalizumab treatment was Allergy and Pulmonology and Department of Oph- well tolerated by all patients and no side effects were thalmology. Medical insurance companies were ap- observed. proached to cover costs of an off-label treatment with monoclonal anti-IgE antibody omalizumab (Xolair ). Patient A The dose of omalizumab was calculated correspond- ing to the allergic asthma treatment by weight and At age 4, seasonal VKC was diagnosed with severe total IgE serum levels. The time interval between complaints from February to October. Treatment with injections depended on the absolute dose per month. systemic/topical antihistamines, followed by topical VKC grading according to Bonini  as well as visual corticosteroid and CsA did not reach complete symp- impairment was assessed during the treatment phase. tom control. Comorbid asthma triggered by pets and For visual acuity Snellen charts were used; all children pollen allergens was treated with inhaled corticos- were able to pass the test. Sodium ﬂuorescein stain- teroids. Three years of subcutaneous allergen im- ing, used to detect corneal epithelial defects, allowed munotherapywithbirch andgrass pollenextract did grading of superﬁcial corneal alterations. Speciﬁc sen- not achieve amelioration of eye symptoms. Sensitiza- sitization was either measured by skin prick test or in tion (speciﬁc serum IgE) to birch, grass (CAP 6), mug- serum samples with Thermo Fisher ImmunoCAP sys- wort pollen (CAP 4), cat, dog, horse and guinea pig K Omalizumab in three children with severe vernal keratoconjunctivitis 183 original article Fig. 1 Patient A: a vernal keratoconjunctivitis (VKC) grade 3, c 9 months after treatment with omalizumab every 2 weeks presenting with Trantas dots as sign of eosinophilic infiltration 300mg subcutaneously, neovascularization regressed (VKC at 10 years of age; b corneal pannus with neovasculariza- grade 1) tion and mucus discharge 10 months later (VKC grade 3–4); (CAP 3), and house dust mite (CAP 2). At age 10, total Patient C IgE was 766 kU/l. Seasonal VKC grade 3–4 (conjunc- tival papillae, Trantas dots, corneal pannus with neo- Since infancy, patient C has had severe atopic der- vascularization and mucus secretion 10 months later) matitis without remission and later perennial rhinitis with visual impairment was observed without ade- and intermittent asthma. At age 5, perennial VKC quate response to topical treatment. Omalizumab was grade 4 (giant papillae, severe corneal erosions) was administered for 11 months every 2 weeks at a dose diagnosed. Treatment with systemic and topical an- of 300 mg subcutaneously, which resulted in improve- tihistamines, topical corticosteroid, and topical CsA ment to VKC grade 1 (Fig. 1). Further follow-up over was insufﬁcient. The patient experienced extreme 3.5 years showed no relapse of VKC. photophobia and social distancing. School atten- dance was not possible during spring and summer time. Ultimately, amnion membrane transplantation Patient B was performed in another clinic in May 2017 at the As an infant at age 6 months, seasonal VKC grade 3 age of7because ofcorneal damage (shieldulcer). (severe photophobia with keratitis, conjunctival papil- Systemic CsA was started due to VKC and worsened lae, limbal irritation) due to birch pollen was observed atopic dermatitis, but VKC did not improve. Sensi- with recurrent symptoms from April–September in the tization to pollen (birch, grass, mugwort), pet and years thereafter. During spring and summer time sys- house dust mite allergen was observed with a total temic/topical antihistamines and leukotriene receptor IgE of 1295 kU/l. Due to a lack of response to sys- antagonist montelukast were given with incomplete temic and topical immunosuppressive treatment and remission, followed by topical corticosteroid and CsA. the increasing corneal damage (shield ulcer), oma- From age 5–7 years, sublingual immunotherapy with lizumab treatment was administered every 2 weeks a birch pollen extract (droplets) was applied without with 300 mg subcutaneously for 6 months. After the major improvement. At age 6, VKC grade 2b was di- ﬁrst administration of omalizumab, a clear improve- agnosed in spring time (April), but with no response ment of VKC from grade 4 to 2 was observed (Fig. 2). to topical treatment with dexamethasone and CsA. Systemic CsA was stopped, but the patient deteri- Monoclonal anti-IgE antibody omalizumab (2 × 150 orated again regarding the skin and eye condition. mg) was started during summer (August) with a quick After reintroduction of systemic CsA (dose 3 mg/kg response within days. After 4 weeks, treatment with body weight) improvement to VKC stage 2 was ob- omalizumab was repeated due to a slight relapse served. Complete remission of atopic dermatitis and (mild conjunctivitis). Again complete remission of VKC was achieved by the introduction of monoclonal symptoms occurred and no complaints during winter anti-IL4/IL13 receptor antibody dupilumab (150 mg time were reported. At age 7, seasonal VKC grade 4 subcutaneously every 14 days). with visual impairment right eye 0.4 and left eye 0.7 was observed in April with a total IgE of 1753 kU/l. Discussion Omalizumab treatment was given for 4 months every 6 weeks at a dose of 150 mg subcutaneously. Improve- Omalizumab is a recombinant humanized mono- ment to VKC grade 1 was observed after one week. clonal anti-IgE antibody used for the treatment of No further treatment was needed during that year. At asthma and CSU [17, 18]. In this case series that age 8, again one injection 150 mg omalizumab was included patients with atopic comorbidities and pol- administered during spring with rapid response. No ysensitization, anti-IgE treatment seemed a plausible further treatment was needed. approach. Two of three patients suffered from vi- sual impairment. Extreme photophobia hampered a normal social life, like school visits and sports. 184 Omalizumab in three children with severe vernal keratoconjunctivitis K original article Fig. 2 Patient C: a, b corneal erosions at 7 years of age (sodium fluorescein staining), VKC grade 4; c 4 weeks after a single administration of 300mg omalizumab subcutaneously with completely re-epithelialized cornea (VKC grade 2) Omalizumab was administered for 1–11 months in with systemic CsA mainly due to severe atopic der- different seasons and a remarkable improvement in matitis and reached complete control with the bio- clinical ﬁndings and quality of life was achieved, e.g., logical dupilumab. school attendance and sports activities. Two patients Due to the often reported self-limiting course of were treated with omalizumab only during one season the disease, probably no long-term use of anti-IgE is or for less than a year, respectively, whereas one pa- to be expected in patients with severe VKC. Therefore, tient was treated over three seasons. The acceptance Simpson and Lee suggest the single use of anti-IgE by of subcutaneous injections was excellent; no side ef- reporting a 54-year-old patient with VKC to be suc- fects were reported during the treatment phase. This cessfully treated with a single application of 300 mg is in accordance with the observations from asthma omalizumab . Our experience in children indi- and CSU treatment . Successful treatment with cates that at least 2 months of treatment are neces- omalizumab and reduction of eosinophil levels in sary to achieve long-lasting control in the particular conjunctival smears as a possible proof of concept season, at least in the ﬁrst year of treatment. One was reported previously in two VKC patients . patient needed omalizumab in several seasons; how- Similar to our observation, four patients with VKC ever, the natural course of the disease showed less in another case series responded very well following disease activity and complete remission in the third a 6-month omalizumab treatment cycle. Interestingly, year of treatment only after one injection (patient B). after cessation of treatment no relapse occurred . If ﬁrst- and second-line treatment fail, omalizumab as Doan et al. reported three out of four patients with a biological treatment might have the potential to pre- VKC improving during omalizumab therapy . In vent progression. In particular, individuals at risk with addition, single case reports underline our experience. corneal involvement are possible candidates since vi- A 12-year-old boy with VKC, asthma, allergic rhinitis, sual impairment may persist or take months for often and atopic dermatitis was successfully treated over incomplete functional recovery. 18 months every 4 weeks with 300 mg omalizumab . Another 15-year-old female patient with VKC Conclusion was treated over 2 years with omalizumab gaining full remission; however, treatment had to be reinitiated We report the rapid clinical effectiveness of mono- after 4 months of discontinuation when symptoms clonal anti-IgE antibody omalizumab in VKC and im- relapsed . proved quality of life, especially in severe cases not VKC often requires a multidisciplinary approach re- responding to other therapeutic approaches. Treat- garding diagnosis of concomitant atopic conditions ment was safe and well tolerated. Randomized trials and treatment options. In our case series, a more se- are needed to include omalizumab in third-line treat- vere baseline grade, younger age at disease onset, and ment of VKC. a higher grade of ocular inﬂammation were associated Acknowledgements This work has been facilitated through with the highest risk of poor visual outcome, demand- collaboration within the Comprehensive Allergy Center Char- ing a more intense treatment approach. Onset of VKC ité (CACC). before 3.5 years of life was the strongest factor asso- Author Contribution All three authors were involved in the ciated with a severe course of the disease and visual treatment of patients and in writing of the manuscript. They impairment . Within a disease classiﬁcation and agree to the publication. regression tree model to identify risk factors aiming Funding Open Access funding provided by Projekt DEAL. at standardized treatment, photophobia was the key symptom to identify corneal involvement . But Compliance with ethical guidelines even in patient B who showed a very early start of VKC at less than one year of age, disease remission to Conﬂict of interest S. Rossberg, U. Pleyer and S. Lau have stage 1 was achieved after administering omalizumab no direct conﬂict of interest regarding this article. However, for 6 months. Patient C needed additional treatment K Omalizumab in three children with severe vernal keratoconjunctivitis 185 original article outside this publication, the following conﬂict of interest 9. Bonini S, Schiavone M, Bonini S, Magrini L, Lischetti P, statement can be made: S. Lau has received honoraria from Lambiase A, et al. Efﬁcacy of lodoxamide eye drops on mast Boehringer, ALK, Sanoﬁ-Genzyme, Allergopharma, Nutricia, cells and eosinophils after allergen challenge in allergic DBV and ALK and participated as PI and deputy in studies conjunctivitis. Ophthalmology. 1997;104:849–53. funded by Allergopharma, Boehringer, Aimmune and DBV. 10. 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