Defining the Outcome Markers and Therapeutic Role for Omalizumab in Treatment of Allergic Bronchopulmonary Aspergillosis

Because other biologics had not proved effective, it was a milestone when omalizumab was approved for treatment of moderate to severe allergic asthma in Australia in 2002, the United States 2003, and the European Union in 2005. By 2016, there was U.S. Food and Drug Administration approval for administration of omalizumab for asthma for children ages 6 to 11. The primary outcome marker from pivotal trials was numbers of exacerbations of asthma, not improvement in pulmonary physiology, such as forced expiratory volume in 1 second (FEV1). It has become clear over time that not all treatments or interventions reduce exacerbations of asthma even if improving other intriguing therapeutic targets and biomarkers of asthma. Omalizumab binds to the Cε3 domain of the Fc region of immunoglobulin E (IgE) in blood and interstitial fluid so as to inhibit IgE binding to mast cells and basophils via FcεRI. In a study of 3 patients with allergic rhinitis with a baseline mean total serum IgE concentration of 432 IU/mL, who received intravenously administered omalizumab, within 7 days, there were 99% and 88% reductions, respectively, in free IgE concentration and expression of FcεRI⍺ on basophils.1MacGlashan Jr., D.W. Bochner B.S. Adelman D.C. Jardieu P.M. Togias A. McKenzie-White J. et al.Down-regulation of FcεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody.J Immunol. 1997; 158: 1438-1445Crossref PubMed Google Scholar,2Beck L.A. Marcotte G.V. MacGlashan Jr., D. Togias A. Saini S. Omalizumab-induced reductions in mast cell FcεRI expression and function.J Allergy Clin Immunol. 2004; 114: 527-530Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar Accompanying these changes was a 90% decrease in basophil histamine release triggered by the house dust mite allergen, Der p I.1MacGlashan Jr., D.W. Bochner B.S. Adelman D.C. Jardieu P.M. Togias A. McKenzie-White J. et al.Down-regulation of FcεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody.J Immunol. 1997; 158: 1438-1445Crossref PubMed Google Scholar,2Beck L.A. Marcotte G.V. MacGlashan Jr., D. Togias A. Saini S. Omalizumab-induced reductions in mast cell FcεRI expression and function.J Allergy Clin Immunol. 2004; 114: 527-530Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar Tryptase-positive cells in the skin remained similar in numbers, whereas FcεRI⍺-positive cells, although not reduced within a week like basophils, were reduced by 90% by days 70 and 196.2Beck L.A. Marcotte G.V. MacGlashan Jr., D. Togias A. Saini S. Omalizumab-induced reductions in mast cell FcεRI expression and function.J Allergy Clin Immunol. 2004; 114: 527-530Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar From the clinical perspective, omalizumab caused large reductions in induration in the allergen-induced acute phase skin test at days 70 and 196 from a mean 20 to 5 mm.2Beck L.A. Marcotte G.V. MacGlashan Jr., D. Togias A. Saini S. Omalizumab-induced reductions in mast cell FcεRI expression and function.J Allergy Clin Immunol. 2004; 114: 527-530Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar Indeed, omalizumab causes reductions in both early and late phase responses after allergen challenge in the skin, lungs, and gastrointestinal tract. In addition, omalizumab binds to surface-bound IgE on IgE-switched B lymphocytes (via the FcεRII) and also inhibits the binding of IgE to CD23.3Okayama Y. Matsumoto H. Odajima H. Takahagi S. Hide M. Okubo K. Roles of omalizumab in various allergic diseases.Allergol Internat. 2020; 69: 167-177Crossref PubMed Scopus (45) Google Scholar The CD23 is important for regulation of IgE synthesis and is critical for IgE-facilitated presentation of allergens as IgE-allergen complexes bind to CD23 on B cells.4Klunker S. Saggar L.R. Seyfert-Margolis V. Asare A.L. Casale T.B. Durham S.R. et al.Combination treatment with omalizumab and rush immunotherapy for ragweed-induced allergic rhinitis: inhibition of IgE-facilitated allergen binding.J Allergy Clin Immunol. 2007; 120: 688-695Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Why consider these actions of the oldest biologic in our armamentarium? In this issue of the Journal of Allergy and Clinical Immunology—In Practice, Jin et al5Jin M. Douglass J.A. Elborn J.S. Agarwal R. Calhoun W.J. Lazarewicz S. et al.Omalizumab in allergic bronchopulmonary aspergillosis: a systematic review and meta-analysis.J Allergy Clin Immunol Pract. 2023; 11: 896-905Abstract Full Text Full Text PDF Scopus (3) Google Scholar present findings from a literature review of omalizumab as add-on treatment for allergic bronchopulmonary aspergillosis (ABPA). The authors extended the literature by analyzing reports of 49 studies (with 267 patients) and 14 case series (186 patients) to prepare their qualitative systematic review and quantitative meta-analysis.5Jin M. Douglass J.A. Elborn J.S. Agarwal R. Calhoun W.J. Lazarewicz S. et al.Omalizumab in allergic bronchopulmonary aspergillosis: a systematic review and meta-analysis.J Allergy Clin Immunol Pract. 2023; 11: 896-905Abstract Full Text Full Text PDF Scopus (3) Google Scholar Administration of omalizumab as add-on therapy for ABPA resulted in reduced exacerbations, fewer courses of oral corticosteroids, reduced maintenance oral corticosteroid dosages, improved FEV1 (by 11.9%), and reduced patient-reported symptoms using the Asthma Control Test.5Jin M. Douglass J.A. Elborn J.S. Agarwal R. Calhoun W.J. Lazarewicz S. et al.Omalizumab in allergic bronchopulmonary aspergillosis: a systematic review and meta-analysis.J Allergy Clin Immunol Pract. 2023; 11: 896-905Abstract Full Text Full Text PDF Scopus (3) Google Scholar It is worth recalling results of a randomized placebo-controlled, cross-over trial of omalizumab, 375 mg subcutaneously every 2 weeks for 4 months, in patients with ABPA whose asthma was not controlled with inhaled corticosteroid (beclomethasone dipropionate, equivalent of 1,100 μg/d), a long action beta-adrenergic agonist, and in 6 of 13 patients, daily prednisolone.6Voskamp A.L. Gillman A. Symons K. Sandrini A. Rolland J.M. O'Hehir R.E. et al.Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis.J Allergy Clin Immunol Pract. 2015; 3: 192-199Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar There was a wash-out interval of 3 months. The mean total IgE concentration was 2,314 IU/mL (346–7,860 IU/mL). Nevertheless, the primary outcome of change in numbers of exacerbations of asthma was found to be sharply reduced during omalizumab treatment (2 total: 1 each in 2 participants) compared with placebo treatment (12 total in 6 participants).6Voskamp A.L. Gillman A. Symons K. Sandrini A. Rolland J.M. O'Hehir R.E. et al.Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis.J Allergy Clin Immunol Pract. 2015; 3: 192-199Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Concomitant immunological findings during omalizumab treatment included reduced basophil sensitivity to Aspergillus fumigatus and reduced presence of IgE and FcεRI on basophil surfaces.6Voskamp A.L. Gillman A. Symons K. Sandrini A. Rolland J.M. O'Hehir R.E. et al.Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis.J Allergy Clin Immunol Pract. 2015; 3: 192-199Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar This study provided evidence that patients with ABPA who have elevated total serum IgE concentrations can benefit from omalizumab treatment. The signature characteristic of ABPA is pulmonary infiltrates with eosinophilia also known as pulmonary eosinophilia. The infiltrates classically appear in the upper and/or middle lobe, and because they may be relatively asymptomatic, and thus untreated, compared with the similar area of consolidation from a bacterial pneumonia, result in bronchiectasis, an irreversible injury to proximal (central) bronchi. Computed tomography of the lungs may show pathognomonic high-attenuation mucus plugs. The serial measurement of total serum IgE shows at least a doubling of the IgE concentration compared with baseline with onset of the pulmonary infiltrates from ABPA. Some unmet clinical needs include (1) how best to prevent the pulmonary infiltrates from ABPA that can lead to bronchiectasis or more severe asthma or cystic fibrosis, (2) how to prevent emergence of bronchiectasis, pulmonary fibrosis (bronchiolitis obliterans), or worsening of persistent asthma in newly diagnosed patients with ABPA, (3) how to determine what are informative, therapeutic dose-response characteristics for omalizumab and other biologics for ABPA and, by analogy, for severe, persistent asthma with fungal sensitization, (4) how to maintain the improved state of ABPA when the biologic therapy has been discontinued, and (5) how to identify the exacerbation-prone patients with ABPA whether in the setting of asthma or cystic fibrosis. Might it be combinations of biologics such as targeting IgE and interleukin-5/eosinophils or upstream barrier-derived alarmins, like thymic stromal lymphopoietin? Can there be more efficacious oral or inhaled antifungal therapies? Lastly, we need to raise or maintain our clinical acuity regarding early diagnosis and treatment of patients with ABPA and continue investigative efforts to find more effective, targeted, and safe approaches to prevent bronchiectasis and pulmonary fibrosis or adverse effects from oral corticosteroids and current antifungal medications. Omalizumab in Allergic Bronchopulmonary Aspergillosis: A Systematic Review and Meta-AnalysisThe Journal of Allergy and Clinical Immunology: In PracticeVol. 11Issue 3PreviewAn unmet clinical need exists in the management of treatment-refractory allergic bronchopulmonary aspergillosis (ABPA). Omalizumab has shown promising effects in case series and cohort studies; however, evidence to support its routine clinical use is lacking. Full-Text PDF Open Access