Stephen Doherty,Melissa Mulholland,Michael Shields,Patrick McCrossan

Stephen Doherty,Department of Paediatrics,Royal Belfast Hospital for Sick Children,Belfast BT12 6BA,United Kingdom

Melissa Mulholland,Department of Paediatric Education and Simulation,Royal Belfast Hospital for Sick Children,Belfast BT12 6BA,United Kingdom

Michael Shields,Department of Child Health,Queens University Belfast,Belfast BT12 6BJ,United Kingdom

Patrick McCrossan,Centre of Medical Education,Queens University Belfast,School of Medicine,Belfast BT9 7BL,United Kingdom

Patrick McCrossan,Department of Paediatric Respiratory,Royal Belfast Hospital for Sick Children,Belfast BT12 6BA,United Kingdom

Abstract A 14-year-old girl with poorly controlled asthma attended the difficult-to-treat asthma clinic for review.Although she has eosinophilia and significantly raised immunoglobulin E levels,she is not currently a candidate for omalizumab(Xolair).She also suffers from chronic urticaria,eosinophilic eosophagitis and severe conjunctivitis.You wonder if omalizumab would be effective in treating her multiple atopic conditions,in particular her troublesome conjunctivitis.PubMed was searched using the following search terms:(Omalizumab) or (Xolair)and (conjunctivitis).Searches were conducted in November 2020.Abstracts were selected for full text review if the study population identified asthma as a comorbidity.Non-paediatric studies and those that were not written in English were excluded.The use of omalizumab has the potential to be effective in the treatment of conjunctivitis associated with asthma and other atopic conditions.However,research is needed to address the question,in the form of multicenter,double-blind randomized control trials.

Key Words:Omalizumab;Conjunctivitis;Allergy;Asthma;Pediatrics;Atopy

INTRODUCTION

Scenario

A 14-year-old girl with poorly controlled asthma attended the difficult-to-treat asthma clinic for review.Although she has eosinophilia and significantly raised immunoglobulin E (IgE) levels,she is not currently a candidate for omalizumab (Xolair) due to poor adherence.She attends immunology clinic for spontaneous urticaria which has not improved despite high dose antihistamine.Gastroenterology are treating her for eosinophilic oesophagitis with proton pump inhibitors.During the consultation,you note that she also has severe vernal keratoconjunctivitis (VKC).She reported itching,burning and tearing of her eyes and it was evident at the review that she had marked conjunctival hyperaemia and blepharitis.Although adherence has been an issue in relation to her asthma treatment,she is reportedly compliant with both enteral and topical antihistamine therapy for her conjunctivitis.

You wonder if omalizumab would be effective in treating her multiple atopic conditions,in particular her troublesome conjunctivitis.

STRUCTURED CLINICAL QUESTION

Does treatment with omalizumab (intervention) in children with allergic conjunctivitis as a comorbidity of asthma (population) improve their conjunctivitis symptoms(outcome) compared to current treatment (control)?

SEARCH

PubMed was searched using the following search terms:(Omalizumab) or (Xolair) and(conjunctivitis).Searches were conducted in November 2020.

RESULTS

The literature search returned a total of 31 studies.Abstracts were selected for full text review if the study population identified asthma as a comorbidity.Non-paediatric studies and those that were not written in English were excluded.Following abstract review,5 papers were deemed relevant for full text analysis and all were felt to address the question.Included studies are summarized in Table 1 and graded according to the Oxford Centre for Evidence-based medicine Levels of Evidence[1].

Table 1 Studies assessing the use of omalizumab in conjunctivitis as a comorbidity

DISCUSSION

Hypersensitization of IgE plays an important role in many allergic diseases.This means that patients often have multiple atopic conditions (multimorbidities).Patients with allergic asthma frequently present with other atopic conditions including:Rhinoconjunctivitis/allergic rhinitis,atopic dermatitis,food allergies,chronic spontaneous urticaria,eosinophilic oesophagitis and allergic bronchopulmonary aspergillosis[2].Having these multimorbidities adversely impacts on asthma control and can contribute significantly to the overall burden of the disease[2].

IgE secreted by plasma cells in response to an exposure to allergens play an integral role in the allergic inflammatory cascade.Allergen-specific IgE binds to the surface of mast cells,causing degranulation of certain mediators (including histamine,chymase and tryptase) which are responsible for the classic symptoms of itching,redness and oedema.Omalizumab is a recombinant monoclonal antibody that sequesters free IgE and accelerates the dissociation of the IgE-Fcε receptor I complex[3].This disrupts the IgE-mediated inflammatory cascade.Based on an extensive body of evidence,NICE now recommends use of omalizumab for patients with asthma and chronic spontaneous urticaria (CSU) who meet specific criteria[4,5] (Table 2).Guidance for its use in chronic rhinosinusitis with nasal polyps is expected[6].These conditions are considered in isolation and current guidelines do not account for patients with multiple severe atopic conditions.

Table 2 Current Indications for prescribing omalizumab

Dosing of omalizumab in Asthma is based on age,baseline,pre-treatment serum IgE levels and body weight[7].As a result,a mg/kg dosing value is not usually given.Usual doses range from between 75-600 mg and depending on weight and serum IgE levels,dosing intervals may be fortnightly or monthly.At the upper extremes of weight and serum IgE levels,the theoretical doseviaextrapolation is not licensed and therefore not recommended[7].Currently,there is no guidance for this situation,however other biologics targeting different pathways may be trialed.Dosing in CSU is not dependent on serum IgE levels or body weights[7].Recommendations are to administer 150 mg or 300 mg by subcutaneous injection every 4 wk.Dosing tables for asthma and chronic idiopathic urticaria are included in the appendix.

VKC is a chronic,relapsing condition mainly affecting children.Its pathophysiology involves both IgE and non-IgE mediated reactions[8].The binding of specific allergens to specific IgE’s causes degranulation of mediators leading to symptoms of redness and itching.Later,mediators cause infiltration of eosinophils,neutrophils and macrophages into the tissue.Eosinophils in particular play a major role in inflammation and tissue lesions such as epitheliopathy in VKC[9].The mainstay of treatment is topical immunosuppressive medications and topical steroids.However,these are associated with significant side effects including ocular hypertension,glaucoma and cataract formation.Additionally,a large prospective study by Boniniet al[10] showed that 31% of patients with VKC requiring treatment with topical steroids had no improvement[10].

Four case reports and one case series followed a total of 9 patients with severe conjunctivitis as a comorbidity of asthma.Prior to omalizumab,all patients had worsening ocular symptoms despite topical and oral medications including immunosuppressants and corticosteroids.Omalizumab was associated with clinical improvement in 8 out of the 9 children including a reduction in the use of topical steroids and immunosuppressive therapies.Associated allergic multimorbidities also improved in 6 patients.Asthma control was achieved and lid eczema and atopic dermatitis completely resolved.

In the case report by Rossberget al[11],effect on asthma symptoms was not reported.One patient required commencement of Dupilumab (an alternative monoclonal antibody that inhibits Interluekin-4 and Interleukin-13 signalling[12] mainly due to worsening AD,and reached complete control[11].

One patient in the case series by Doanet al[13] did not respond to omalizumab for either their conjunctivitis or their associated atopic conditions[13].Notably,this patient did not have detectable sensitization to any allergen.This shows the complex and multifactorial pathogenesis of VKC,of which IgE plays a role[8,9].

A study by Heffleret al[14] in 2016 discusses treatment with omalizumab in 2 patients with severe VKC[14].They did not meet our inclusion criteria as neither patient had concomitant asthma,however one patient was a child,in her first decade of life.Omalizumab was administered at 300 mgpermonth for 6 mo.Ocular visual analogue scale (VAS) scores,ophthalmologic examination and conjunctival scrape smears for cytologic examination were the outcomes measured.This is the first case report where cytologic examination has been used as an outcome.After 6 mo,the patient experienced improvement in all outcomes.Ocular VAS scores improved from 8 to 0,eye redness and cobblestone papillae were abolished,and eosinophil levels decreased from 69% to 3% on cytologic examination.

None of the five studies in this literature review report any adverse effects to treatment with omalizumab in children for conjunctivitis.The most common previously reported adverse effects to omalizumab include upper respiratory infections,headaches,arthralgia,pain,fatigue and abdominal discomfort[15].The risk of anaphylaxis is 0.14% in patients receiving omalizumab,similar to other biologic drugs[16].The British National Formulary reports further,rarer side effects,including eosinophilic granulomatosis with polyangiitis (usually associated with reduction of oral corticosteroids) and hypersensitivity reactions[17].

These findings are limited as the studies available were heterogeneous and of low quality.Sample size was small,with only case reports or small case series conducted.The dose,duration and frequency of omalizumab varied between the studies.Some studies used omalizumab as a single therapy and others as combination therapy.An array of different outcome measures were used and different grading systems were applied.Compliance to medication prior to commencing omalizumab was a concern in one case report,making conclusions of symptom improvement due to omalizumab more difficult.

CONCLUSION

The use of omalizumab has the potential to be effective in the treatment of conjunctivitis associated with asthma and other atopic conditions.However,research is needed to address the question,in the form of multicenter,double-blind randomized control trials.