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• W3141983959 abstract "Some severe asthmatic patients experience frequent bacterial respiratory tract infections, which contribute significantly to their disease burden, and often are attributed to their use of systemic corticosteroids and comorbid bronchiectasis. We report a case of a 58-year-old woman who had prednisone-dependent asthma and exacerbations with intense mixed eosinophilic and neutrophilic bronchitis. Autosomal dominant hyper-IgE syndrome, which is a primary immunodeficiency characterized by elevated IgE, eosinophilia, and recurrent infections, caused by a novel pathogenic mutation in STAT3 was identified as the cause of her airway disease. We believe that this is the first report of the demonstration of an IL-5 driven eosinophilia that is associated with a STAT3 mutation that was treated successfully with an anti-IL5 biological. Some severe asthmatic patients experience frequent bacterial respiratory tract infections, which contribute significantly to their disease burden, and often are attributed to their use of systemic corticosteroids and comorbid bronchiectasis. We report a case of a 58-year-old woman who had prednisone-dependent asthma and exacerbations with intense mixed eosinophilic and neutrophilic bronchitis. Autosomal dominant hyper-IgE syndrome, which is a primary immunodeficiency characterized by elevated IgE, eosinophilia, and recurrent infections, caused by a novel pathogenic mutation in STAT3 was identified as the cause of her airway disease. We believe that this is the first report of the demonstration of an IL-5 driven eosinophilia that is associated with a STAT3 mutation that was treated successfully with an anti-IL5 biological. Autosomal dominant hyper-IgE syndrome (HIES) is a primary immunodeficiency caused by mutations in STAT3. We report a novel mutation in STAT3, which encodes the signal transducer and activator of transcription 3 (STAT3) transcription factor, as the cause of recurrent pleiotropic eosinophilic and neutrophilic bronchitis. This, we believe, is the first report of response to anti-IL5 therapy for prednisone-dependent eosinophilia in HIES. A 58-year-old woman who was a never smoker with a physician-confirmed diagnosis of asthma presented with chronic productive cough, dyspnea, and recurrent chest infections. She had many episodes of pneumonia since childhood and a pulmonary abscess that required right pneumonectomy at age 20 years. She also had recurrent cutaneous abscesses, oropharyngeal candidiasis, chronic rhinosinusitis, and atopic dermatitis. Her parents and siblings did not have recurrent infections or atopy, but her son had severe atopic dermatitis and skin abscesses. At initial evaluation, her serum IgE was elevated (20,700 IU/mL), and her IgA was low, but her IgG and IgM were normal. Her blood eosinophils were elevated (range, 0.2 to 1.6 × 109/L), and her sputum cytometry showed mixed neutrophilia and eosinophilia (neutrophils 87.3% [normal, <64%]; eosinophils, 8.2% [normal, <2%]; total cell count, 14.7 × 106/g [normal, <10 × 106/g]). Her spirometry showed a mixed obstructive and nonobstructive pattern (FEV1, 0.82 L [38% predicted] and FVC, 1.40 L [51% predicted]). She was sensitized to Aspergillus fumigatus (specific IgE, 14.4 kU/L) but tested negative for aspergillus precipitins. Her thoracic CT scan showed left lower lobe bronchiectasis with mucus plugging. These were consistent with her diagnosis at that time of allergic bronchopulmonary aspergillosis, and she was being treated with inhaled and systemic corticosteroids, long-acting bronchodilators, and nebulized hypertonic saline solution. She continued to have frequent flares of her respiratory symptoms that were associated with both intense sputum eosinophilia and neutrophilia. She was started empirically on immunoglobulin replacement therapy (0.6 g/kg every 4 weeks IV), which reduced the frequency of her pulmonary infections from approximately six to two per year. She required 10 to 12.5 mg/d of prednisone for control of her airway and sinus symptoms and sputum eosinophilia. Given her many infections and elevated IgE, next generation sequencing was performed for primary immunodeficiency. A genetic panel of 298 genes showed she was heterozygous for a missense mutation in exon 15 of STAT3 ([NM_139276.2: c.1418C>T; p.Ala473Val]), which is consistent with HIES. This variant, which affects the DNA-binding domain of the STAT3 protein, has not been reported in the ClinVar,1Landrum M.J. Lee J.M. Benson M. et al.ClinVar: improving access to variant interpretations and supporting evidence.Nucleic Acids Res. 2018; 46: D1062-D1067Crossref PubMed Scopus (1027) Google Scholar gnomAD,2Karczewski K.J. Francioli L.C. et al.Genome Aggregation Database ConsortiumThe mutational constraint spectrum quantified from variation in 141,456 humans.Nature. 2020; 581: 434-443Crossref PubMed Scopus (1711) Google Scholar or 1000 Genomes3The 1000 Genomes Project ConsortiumA global reference for human genetic variation.Nature. 2015; 526: 68-74Crossref PubMed Scopus (6929) Google Scholar databases, so we sought to confirm that the mutation was pathogenic. We performed in silico analysis of the variant using MutationTaster4Schwarz J.M. Cooper D.N. Schuelke M. Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age.Nat Methods. 2014; 11: 361-362Crossref PubMed Scopus (2112) Google Scholar and Polyphen-2,5Adzhubei I.A. Schmidt S. Peshkin L. et al.A method and server for predicting damaging missense mutations.Nat Methods. 2010; 7: 248-249Crossref PubMed Scopus (8522) Google Scholar both of which predicted it to be damaging. Her National Institutes of Health HIES score,6Grimbacher B. Schäffer A.A. Holland S.M. et al.Genetic linkage of hyper-IgE syndrome to chromosome 4.Am J Human Genet. 1999; 65: 735-744Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar which is used to identify cases without genetic testing, also classified her as HIES. Consistent with previous reports of missense mutations affecting the DNA-binding domain, we showed that her CD4+ T cells maintained normal phosphorylation of STAT3 after IL-6 stimulation7Minegishi Y. Saito M. Tsuchiya S. et al.Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.Nature. 2007; 448: 1058-1062Crossref PubMed Scopus (759) Google Scholar (data not shown), her T-helper (Th)17 cells were low at 0.38% of CD4+ T-cells,8Schimke L.F. Sawalle-Belohradsky J. Roesler J. et al.Diagnostic approach to the hyper-IgE syndromes: immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis.J Allergy Clinical Immunol. 2010; 126: 611-617.e1Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar and her total and class-switched memory B cells were reduced significantly.9Speckmann C. Enders A. Woellner C. et al.Reduced memory B cells in patients with hyper IgE syndrome.Clin Immunol. 2008; 129: 448-454Crossref PubMed Scopus (54) Google Scholar We confirmed that her son is heterozygous for the same mutation. To investigate potential mechanisms of her eosinophilia, we measured Th1 and Th2 cytokines in cell-free sputum supernatant (Eve Technologies, Calgary, AB, Canada). IL-5 was significantly elevated. Th17 cytokines were predictably low (Fig 1A). Because she continued to require 10 mg of prednisone to control her sputum eosinophilia, we treated her with the anti-IL5 receptor monoclonal antibody, benralizumab (30 mg subcutaneously every 4 weeks for 3 months, followed by every 8 weeks). This reduced her peripheral eosinophils from a peak of 3.5 × 109 to 0 × 109/L, abolished the sputum eosinophilia, resolved her cough and sputum production, and permitted tapering of her prednisone to 2 mg daily. The most common cause of mixed eosinophilic and neutrophilic bronchitis in patients with asthma are concomitant allergic sensitization and airway infections, as seen in allergic bronchopulmonary aspergillosis. This case illustrates the importance of also considering primary immunodeficiencies. The mechanism of eosinophilia in primary immunodeficiencies, including HIES, is unknown. The significant reduction in sputum IL-5 concentrations and normalization of blood and sputum eosinophilia with benralizumab,10Nair P. Wenzel S. Rabe K.F. et al.Oral glucocorticoid-sparing effect of benralizumab in severe asthma.N Engl J Med. 2017; 376: 2448-2458Crossref PubMed Scopus (478) Google Scholar improvement in asthma with prednisone-sparing, and known role of IL-5 in asthma11Hamid Q. Azzawi M. Ying S. et al.Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma.J Clin Invest. 1991; 87: 1541-1546Crossref PubMed Scopus (729) Google Scholar,12Mukherjee M. Forero D.F. Tran S. et al.Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena.Eur Respir J. 2020; 56: 2000117Crossref PubMed Scopus (27) Google Scholar suggest an IL-5 dependent mechanism of eosinophilia in HIES that was contributing to her disease process. We speculate loss of Th2 inhibition by various feedback mechanisms (Fig 1B) as a putative explanation for increased IL-5. The reason for decreased Th17 cytokines with benralizumab is unclear because Th17 cells are not known to express the IL-5 receptor, but innate lymphoid type 3 cells, which are less well characterized, may express it. It is, however, reassuring that this was not associated with increased airway infections.13Poznanski S.M. Mukherjee M. Zhao N. et al.Asthma exacerbations on benralizumab are largely non-eosinophilic.Allergy. 2021; 76: 375-379Crossref PubMed Scopus (12) Google Scholar The increase in IL-13 likely reflects the decrease in prednisone from 10 to 2 mg daily, the baseline elevated IL-13 in HIES,14Gudmundsson K.O. Sigurjonsson O.E. Gudmundsson S. Goldblatt D. Weemaes C.M.R. Haraldsson A. Increased expression of interleukin-13 but not interleukin-4 in CD4+ cells from patients with the hyper-IgE syndrome.Clin Exp Immunol. 2002; 128: 532-537Crossref PubMed Scopus (18) Google Scholar and potentially counter regulation in the context of IL5-blockade, which has been reported in patients with severe asthma.12Mukherjee M. Forero D.F. Tran S. et al.Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena.Eur Respir J. 2020; 56: 2000117Crossref PubMed Scopus (27) Google Scholar In summary, we provide the first evidence of the role of IL-5 in STAT3 mutation-related eosinophilia and the efficacy of an anti-IL5 biologic in HIES. Author contributions: A. A. and P. N. conceptualized and wrote the manuscript, and supervised all the molecular and genetic assessments. C. A., J. W. and P. N. provided clinical care. C. R., and S. W. critically revised the manuscript for important intellectual content. Financial/nonfinancial disclosures: S. W. has served on advisory boards for AstraZeneca, Novartis, Teva, Sanofi, GSK, ALK, CSL Behring, Takeda, Aralez, Pediapharm, AbbVie, and Kaleo, outside the submitted work. P. N. reports grants and personal fees for advisory boards from AstraZeneca, GSK, Methapharm, Novartis, Teva, Sanofi and Roche; and personal fees from Merck and Equillium, outside the submitted work. None declared (A A., J. W., C. R., C. A.). Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript." @default.
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• W3141983959 title "Benralizumab for Prednisone-Dependent Eosinophilic Asthma Associated With Novel STAT3 Loss of Function Mutation" @default.
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