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Use of Mepolizumab in Adult Patients with Cystic Fibrosis and An Zhang et al. Allergy Asthma Clin Immunol (2020) 16:3 Allergy, Asthma & Clinical Immunology https://doi.org/10.1186/s13223-019-0397-3 CASE REPORT Open Access Use of mepolizumab in adult patients with cystic fbrosis and an eosinophilic phenotype: case series Lijia Zhang1, Larry Borish2,3, Anna Smith2, Lindsay Somerville2 and Dana Albon2* Abstract Background: Cystic fbrosis (CF) is characterized by infammation, progressive lung disease, and respiratory failure. Although the relationship is not well understood, patients with CF are thought to have a higher prevalence of asthma than the general population. CF Foundation (CFF) annual registry data in 2017 reported a prevalence of asthma in CF of 32%. It is difcult to diferentiate asthma from CF given similarities in symptoms and reversible obstructive lung function in both diseases. However, a specifc asthma phenotype (type 2 infammatory signature), is often identifed in CF patients and this would suggest potential responsiveness to biologics targeting this asthma phenotype. A type 2 infammatory condition is defned by the presence of an interleukin (IL)-4high, IL-5high, IL-13high state and is suggested by the presence of an elevated total IgE, specifc IgE sensitization, or an elevated absolute eosinophil count (AEC). In this manuscript we report the efects of using mepolizumab in patients with CF and type 2 infammation. Results: We present three patients with CF (63, 34 and 24 year of age) and personal history of asthma, who displayed signifcant eosinophilic infammation and high total serum IgE concentrations (type 2 infammation) who were treated with mepolizumab. All three patients were colonized with multiple organisms including Pseudomonas aeruginosa and Aspergillus fumigatus and tested positive for specifc IgE to multiple allergens. We examined the efect of mepolizumab on patients’ lung function (FEV1), blood markers of type 2 infammation, systemic corticosteroid use and frequency of CF exacerbations. One patient had a substantial increase in lung function after starting mepolizumab and all three patients had a substantial beneft in regards to reduced oral CCS use. While none of the patients showed signifcant changes in the exacerbation rates there was markedly reduced requirements for oral CCS with exacerbations. In addition, mepolizumab had a positive efect on type 2 infammatory markers, reducing markers of allergic infammation in all 3 patients. Conclusions: Mepolizumab appears to have a positive efect on clinical course in patients with CF presenting with a type 2 phenotype characterized by allergic sensitization and hyper-eosinophilia. Keywords: Cystic fbrosis, Mepolizumab, Asthma, Allergic bronchopulmonary aspergillosis/mycosis, Type 2 infammation Background Cystic fbrosis (CF) is caused by an autosomal recessive function defciency of the transmembrane regulator (CFTR) protein [1]. CFTR is a cAMP regulated chloride *Correspondence: [email protected] 2 Department of Medicine, University of Virginia School of Medicine, PO channel that is expressed on the apical membranes of Box 800546, Charlottesville, VA 22908, USA epithelial cells [2]. Tese changes can lead to signifcant Full list of author information is available at the end of the article defects in host anti-bacterial defenses. CF is characterized © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang et al. Allergy Asthma Clin Immunol (2020) 16:3 Page 2 of 5 by extensive infammation, progressive lung disease, and infammation and thereby improve lung function, slow respiratory failure. Neutrophils, B and T-lymphocytes remodeling, and decrease exacerbation rates, especially are markedly increased within the airway epithelium in patients whose exacerbations were associated with [3, 4]. Although the relationship is not well understood, eosinophilic infammation. In this article, we present patients with CF are thought to have a higher prevalence three patients with CF and signifcant eosinophilic of asthma than the general population. CF Foundation infammation who were treated with mepolizumab. We (CFF) annual registry data in 2017 reported a prevalence examined the efect of mepolizumab on patients’ lung of asthma in CF of 32%. It is difcult to diferentiate function (FEV1), blood markers of type 2 infammation asthma from CF given similarities in symptoms, lung [indicated by total IgE and Absolute Eosinophil Count function variability, and bronchodilator responses in (AEC)], and frequency of CF exacerbations. both diseases. However, a specifc asthma phenotype characterized by a type 2 infammatory signature can Case presentation often be identifed in CF patients. Patient 1 is a 63-year-old white woman with CF A type 2 infammatory lung condition is defned by the homozygous delF508. She was colonized chronically presence of an interleukin (IL)-4high, IL-5high, IL-13high with Pseudomonas aeruginosa, methicillin resistant state. Tis signature can refect cytokine production Staphylococcus aureus (MRSA), Aspergillus fumigatus, by both the adaptive immune [type 2 T helper (T2) and Exophiala. Over the past 5 years, she presented yearly efector lymphocytes] or innate immune system [innate with 3 or more CF exacerbations requiring admission lymphoid type 2 (ILC2) cells, mast cells, eosinophils, and to the hospital and intravenous antibiotics. Beginning others] [5, 6]. Type 2 (T2) infammation is suggested by in 2016, during her exacerbations, she developed the presence of elevated total immunoglobulin E (IgE), positive markers for type 2 infammation (Fig. 1a), with specifc IgE sensitization (determined via ImmunoCap ® eosinophil levels ranging from 300 to 1500/µL and IgE assay), or elevated absolute eosinophil count (AEC) in the levels of 25–700 IU/mL and pulmonary infltrates on circulation. But more compelling evidence is the presence Chest X-ray (CXR). Specifc IgE testing revealed positive of increased eosinophil markers, type 2 cytokines, or type results for cat (she had two indoor cats) and dog dander 2 cytokine-producing cells in the airway (or sputum), and and 2 fungi (Alternaria alternata, Aspergillus fumigatus). possibly also elevated numbers of circulating T2 efector A diagnosis of allergic bronchopulmonary aspergillosis lymphocytes [7–9]. In CFTR-defcient mice, naïve CD4+ (ABPA) was entertained. During exacerbations, she T-cells demonstrate a T2 bias in vitro in response to presented with increased cough, sputum production, Aspergillus fumigatus, with elevated IL-4 in the lungs chest congestion, chest tightness and wheezing that was and allergen-specifc IgE in the serum. Moreover, CFTR relieved by systemic corticosteroid (CCS) treatment. knockout T cells demonstrate a bias to develop a robust Subsequently, she became CCS dependent. She also T2 response to Aspergillus fumigatus antigens, with received futicasone/salmeterol metered dose inhaler and increased levels of IL-13 and IL-4 [10, 11]. Tis T2 bias montelukast. Ivacaftor/Tezacaftor was started in 2018 has also been studied in patients with Pseudomonas after FDA approval. In an efort to decrease systemic CCS aeruginosa-infections, who have higher levels of in context of difcult to control CFRD, she was begun on pulmonary CCR4+CD4+ (T2) efector cells and elevated therapy with mepolizumab (100 mg SQ every 28 days) on expression of IL-4 and IL-13. Tese levels correlated July, 2018. Prior to initiation of mepolizumab, baseline inversely with FEV1 [12]. In the absence of Pseudomonas, FEV1 was 60% predicted (calculated as the mean between a robust type 2 response represents an independent risk two best values over 12 months) and she demonstrated factor for future infection with this pathogen, suggesting large variability in her FEV1% predicted (variability was that type 2 infammation can be a stereotypic response 23% calculated as the diference between the highest that develops independently of infection [13]. and the lowest FEV1 over 12 months). After beginning Mepolizumab is a humanized monoclonal antibody mepolizumab she was able to decrease her prednisone of targeting IL-5 that ofers therapeutic benefts for use from 20 to 5 mg daily. However, her baseline FEV1 eosinophilic asthma [14]. In severe asthma with high percent predicted did not change and she continued blood eosinophil counts, it reduces exacerbation to have large variability in FEV1% predicted (20%) frequency by 32% or more and also has a corticosteroid- between measurements. Of note, 9 months after starting sparing efect [15]. However, there is limited research mepolizumab her total IgE concentration
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