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      A case of chronic eosinophilic pneumonia in a patient treated with dupilumab

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          Abstract

          The increasing knowledge on inflammatory pathways has driven the development of targeted biological therapies for severe refractory asthma. Among the recently developed biologics, the fully human monoclonal antibody dupilumab is an interesting therapeutic option, given its ability to inhibit the biological effects of both IL-4 and IL-13. We describe the case of a male, Caucasian, 56-year-old patient with allergic and eosinophilic severe asthma. Given the poor asthma control, he started treatment with add-on dupilumab, and after the tenth injection, he presented with a fever and bilateral pulmonary thickening. A significant increase in blood eosinophilia was also reported. The patient underwent a fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB/TBB). BAL revealed eosinophils alveolitis (60%) while TBB showed findings compatible with chronic eosinophilic pneumonia (CEP). After prolonged treatment with oral corticosteroids, the clinical picture improved with resolution of CEP. Since the beginning of dupilumab treatment, simultaneously to a great improvement in asthma control, the patient showed a progressive increase in blood eosinophils count and subsequent onset of clinical-radiological pattern suggestive of CEP. Based on published data, dupilumab may have induced an alteration of the complex immunological pathway of our patient. This pathway is affected by both allergic and eosinophilic asthmatic endotypes, and consequently, the concomitant action of allergenic stimuli and eosinophils may have caused the appearance of eosinophilic pneumonia. To our knowledge, this is the first reported case of CEP as a possible severe side effect of dupilumab administration.

          Most cited references18

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          Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis.

          Eosinophils are associated with helminth immunity and allergy, often in conjunction with alternatively activated macrophages (AAMs). Adipose tissue AAMs are necessary to maintain glucose homeostasis and are induced by the cytokine interleukin-4 (IL-4). Here, we show that eosinophils are the major IL-4-expressing cells in white adipose tissues of mice, and, in their absence, AAMs are greatly attenuated. Eosinophils migrate into adipose tissue by an integrin-dependent process and reconstitute AAMs through an IL-4- or IL-13-dependent process. Mice fed a high-fat diet develop increased body fat, impaired glucose tolerance, and insulin resistance in the absence of eosinophils, and helminth-induced adipose tissue eosinophilia enhances glucose tolerance. Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs.
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            Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort.

            U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.
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              IL-4 and IL-13 signaling in allergic airway disease.

              Aberrant production of the prototypical type 2 cytokines, interleukin (IL)-4 and IL-13 has long been associated with the pathogenesis of allergic disorders. Despite tremendous scientific inquiry, the similarities in their structure, and receptor usage have made it difficult to ascertain the distinct role that these two look-alike cytokines play in the onset and perpetuation of allergic inflammation. However, recent discoveries of differences in receptor distribution, utilization/assembly and affinity between IL-4 and IL-13, along with the discovery of unique innate lymphoid 2 cells (ILC2) which preferentially produce IL-13, not IL-4, are beginning to shed light on these mysteries. The purpose of this chapter is to review our current understanding of the distinct roles that IL-4 and IL-13 play in allergic inflammatory states and the utility of their modulation as potential therapeutic strategies for the treatment of allergic disorders.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                TCRM
                tcriskman
                Therapeutics and Clinical Risk Management
                Dove
                1176-6336
                1178-203X
                10 July 2019
                2019
                : 15
                : 869-875
                Affiliations
                [1 ]Department of Medical Specialties, Pneumology Unit, Azienda USL di Reggio Emilia, Arcispedale Santa Maria Nuova- IRCCS , Reggio Emilia, Italy
                [2 ]Pneumology Unit, A. Perrino Hospital , Brindisi, Italy
                [3 ]Department of Pathology, Azienda USL-IRCCS di Reggio Emilia , Reggio Emilia, Italy
                [4 ]Allergy & Respiratory Diseases, University of Genoa , Genoa, Italy
                Author notes
                Correspondence: Francesco MenzellaDepartment of Medical Specialties, Pneumology Unit, Arcispedale Santa Maria Nuova, Azienda USL-IRCCS di Reggio Emilia , Via Amendola 2, 42122Reggio Emilia, ItalyTel +39 052 229 6073Fax +39 052 229 6182Email francesco.menzella@ 123456ausl.re.it
                Article
                207402
                10.2147/TCRM.S207402
                6636310
                31371974
                35200f72-a098-4bc6-9375-0dba512a355d
                © 2019 Menzella et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 02 March 2019
                : 11 June 2019
                Page count
                Figures: 4, References: 22, Pages: 7
                Categories
                Case Report

                Medicine
                monoclonal antibodies,dupilumab,severe asthma,eosinophilic pneumonia,eosinophils,fiberoptic bronchoscopy

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