A case of IgG4-related respiratory disease presenting as dupilumab-induced toxicity and severe asthma

A case of IgG4-related respiratory disease presenting as dupilumab-induced toxicity and severe asthma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A case of IgG4-related respiratory disease presenting as dupilumab-induced toxicity and severe asthma A. Leclerc, M. Bellier, M. Lacou, V. Danielo, C. Sagan, C. Defrance, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7869501/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background IgG4-related disease (IgG4-RD) is a systemic immune-mediated disorder characterized by lymphoplasmacytic infiltration that can affect various organs, including lungs and bronchi. It may present as severe asthma with blood eosinophilia, which can delay the diagnosis. Case Presentation We report the case of a 60-year-old woman with a medical history of diabetes mellitus and a 10 pack-year smoking history. She was investigated for chronic cough, nasal polyposis and blood eosinophilia. Pulmonary function tests revealed a severe obstructive ventilatory defect, with an FEV₁/FVC ratio of 0.56 and an FEV₁ of 1.43 L (56% of the predicted value), reversible only after a course of oral corticosteroids. Eosinophilic granulomatosis with polyangiitis was ruled out based on a negative muscle biopsy and internal medicine evaluation. The patient subsequently developed severe asthma, for which biologics were required. After failure of anti-IL-5 therapies, dupilumab was initiated. One month later, she developed acute febrile respiratory failure with bronchocentric nodular opacities and peribronchovascular thickening on CT-scan. Bronchial biopsies showed dense IgG4⁺ plasma cell infiltration (IgG4⁺/IgG⁺ ≥40%). Serum IgG4 was elevated (5.18 g/L). Transparietal lung biopsy revealed a dupilumab-induced pulmonary vasculitis . In this context, this IgG4-RD with bronchial involvement was treated with high-dose corticosteroids, which led to rapid clinical improvement. Rituximab was introduced as a steroid-sparing agent, with favorable outcomes. Conclusions Severe eosinophilic asthma may be the initial manifestation of IgG4-RD involving the airways. This diagnosis should be considered in patients with corticosteroid-dependent asthma and abnormal chest imaging. Histopathological confirmation remains essential for the diagnosis and to guide treatment severe asthma iIgG4-related disease drug-induced toxicity dupilumab Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction IgG4-related disease (IgG4-RD) is a systemic condition characterized by lymphoplasmacytic infiltration that can involve multiple organs (1). It may affect the airways, pleura, lungs, and intrathoracic lymph nodes. Initial presentation may mimic severe asthma associated with blood eosinophilia, which can complicate the diagnostic process and result in delayed recognition of the disease (2). We report a challenging case of IgG4-RD that presented with clinical manifestations suggestive of dupilumab-induced toxicity in a patient with clinical features mimicking severe asthma. Case Presentation A 60-year-old woman was referred to our hospital with febrile acute respiratory failure. Her medical history included type 1 diabetes mellitus, hypertension, and a 10 pack-year smoking history. Two years before, she had been evaluated for chronic cough and dyspnea, classified as grade 1 on the modified Medical Research Council (mMRC) Dyspnea Scale, and associated with nasal polyposis. At that time, pulmonary function testing revealed a severe, reversible obstructive ventilatory defect, with a forced expiratory volume in one second to forced vital capacity ratio (FEV₁/FVC) of 0.69, and an FEV₁ at 48% of the predicted value, improving to 80% after a 3-weeks course of oral corticosteroids. Initial laboratory investigations showed marked blood eosinophilia, with a count of 1.274 G/L, and an elevated serum IgG4 level at 2.86 g/L (normal < 0.87 g/L). High-resolution computed tomography (HRCT) revealed four millimetric pulmonary nodules and peribronchovascular thickening. An 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) scan showed no abnormal metabolic activity. Bronchoalveolar lavage (BAL) fluid analysis showed a lymphocytic alveolitis (32%), while histopathological examination of endobronchial biopsies showed an inflammatory infiltrate composed predominantly of lymphoplasmacytic cells. Eosinophilic granulomatosis with polyangiitis was ruled out following an internal medicine consultation and a negative muscle biopsy. A diagnosis of severe corticosteroid-dependent eosinophilic asthma was subsequently retained. The patient was treated with inhaled long-acting bronchodilators and corticosteroids (beclomethasone/formoterol), along with oral corticosteroids for four months, resulting in corticosteroid dependence at a daily dose of 30 mg. In an attempt to taper oral corticosteroids, she received successive treatments with mepolizumab and benralizumab — monoclonal antibodies targeting interleukin-5 — for six months each, without any clinical improvement. Given the persistence of chronic dyspnea and severe obstructive lung disease, with a lowest recorded FEV₁ of 37% of the predicted value, dupilumab — a monoclonal antibody targeting the interleukin-4 receptor alpha subunit — was initiated. At that time, fractional exhaled nitric oxide (FeNO) level was 188 ppb (normal < 25 ppb). One week after initiating dupilumab, the patient developed progressively worsening dyspnea and cough. One month later, she was admitted to intensive care for acute febrile respiratory failure. Arterial blood gas analysis revealed a partial pressure of oxygen (PaO₂) of 9.4 kPa under an FiO₂ of 50%. On clinical examination, inspiratory crackles were noted at the lung bases. As an extrathoracic manifestation, inflammation of the right ear was observed. Blood eosinophils were measured at 1.240 G/L. Renal function was preserved. Serum IgG4 level was elevated at 5.18 g/L (normal < 0.87 g/L). Immune blood tests, including autoantibodies, remained negative. Chest X-ray revealed a diffuse nodular pattern (Fig. 1 ). Chest CT scan showed bronchocentric nodular consolidations associated with peribronchovascular thickening (Fig. 2 ). BAL fluid analysis revealed 70% macrophages, 26% neutrophils and 4% lymphocytes. Microbiological investigations were negative. Histological examination of bronchial biopsies demonstrated a dense lymphoplasmacytic infiltrate (Fig. 3 ), with an IgG4+/IgG cell ratio exceeding 40% and more than 50 IgG4-positive plasma cells per high-power field (×400) (Fig. 4 ). These findings were consistent with a diagnosis of IgG4-related respiratory disease, providing a likely explanation for the patient’s chronic respiratory symptoms. As no clear etiology could be identified for the acute respiratory deterioration, a transthoracic lung biopsy was performed. In addition to IgG4-positive lymphoplasmacytic infiltration, histological analysis revealed features of vasculitis. Following a multidisciplinary discussion, notably involving the pharmacovigilance department, the diagnosis of dupilumab-induced pulmonary vasculitis was established. Systemic corticosteroid therapy was initiated at a daily dose of 2 mg/kg, resulting in rapid clinical improvement and withdrawal of supplemental oxygen. One month after hospital discharge, the patient showed continued improvement under a tapering corticosteroid regimen. Pulmonary function tests had normalized, with an FEV₁/FVC ratio of 0.73 and an FEV₁ of 86% of the predicted value. Chest X-ray demonstrated marked regression of pulmonary opacities. Rituximab was then introduced as a corticosteroid-sparing agent. At six-month follow-up, chest CT imaging revealed significant resolution of the pulmonary lesions, with only mild residual peribronchovascular thickening and a few subpleural linear opacities (Fig. 5 ). Discussion We report the case of a patient with IgG4-RD and bronchial involvement, initially misinterpreted as a severe corticosteroid-dependent eosinophilic asthma. The diagnosis was established concurrently with a dupilumab-induced pulmonary vasculitis, which occurred following treatment initiation for presumed severe asthma. It illustrates that thorough diagnostic workup is crucial in cases of difficult-to-treat, corticosteroid-dependent asthma, particularly to ensure an accurate diagnosis of severe asthma. IgG4-RD should be systematically considered among potential differential diagnoses. Liu et al. recently published a retrospective study involving 12 patients who initially presented with severe asthma as the first clinical manifestation of IgG4-RD. Mean age at asthma onset was 53.8 years. All patients exhibited blood eosinophilia. The most frequent radiologic findings were bronchial wall thickening and mediastinal lymphadenopathy, while some patients also showed scattered ground-glass opacities or solid nodules on chest CT. Corticosteroid therapy was effective in all cases, with 11 out of 12 patients developing corticosteroid dependence (2). Our case is in line with the findings described by Liu et al. IgG4-RD is a multisystem inflammatory disorder defined by the accumulation of lymphoplasmacytic cells, leading to mass-like lesions in affected organs, which may progress to fibrosis. The disease was initially described in association with autoimmune pancreatitis, as well as involvement of the salivary and lacrimal glands, and the retroperitoneum (1). IgG4-related respiratory disease is relatively uncommon and has only been recognized more recently as a clinical entity (3). Diagnosis can be particularly challenging in the absence of extrathoracic organ involvement. However, thoracic manifestations may represent the sole presentation of IgG4-RD in up to 10% of cases (4,5). Among thoracic forms, bronchopulmonary involvement is one of the most frequently observed patterns, often associated with mediastinal or hilar lymphadenopathy. The American College Rheumatology (ACR) and European League Against Rheumatism (EULAR) published in 2019 the most recent classification and diagnosis criteria for IgG4-RD (6). This classification is mainly appropriate for the most frequently involved organs but appears to be less relevant for bronchopulmonary involvement. The first diagnostic criteria for IgG4-related respiratory disease was published in 2016 and revised in 2022 (7) (8). According to this classification, the diagnosis of IgG4-related respiratory disease for our patient is probable. If we consider other organs involvement (nephromegaly and inflammation of the right auricle), the diagnosis is even definite. To support the diagnosis, increased serum IgG4 levels (> 135 mg/dl) and pathological features are two important criteria. The value of serum IgG4 was very high in our patient and a study reported a diagnostic specificity of 94.8% when the dosage exceeds 2.7 g/L (9). Glucocorticoids are first line agents for IgG4-RD, but there are associated with numerous adverse effects when used chronically. Relapses frequently occur when doses are decreased, as it was the case for our patient. Rituximab can be prescribed in that situation (1). Dupilumab is a monoclonal antibody targeting IL-4Rα, used as maintenance therapy for severe type 2 asthma typically characterized by elevated blood eosinophils and/or increased FeNO. While clinical trials have shown good safety and efficacy profiles, data from real-world settings and long-term follow-up are still limited. Rare cases of eosinophilic pneumonia have been reported, but no vasculitis cases have been documented to date. Here, we report the first case of dupilumab-induced pulmonary vasculitis in a patient with IgG4-related respiratory disease. This case highlights the importance of considering drug-induced vasculitis in patients with atypical respiratory deterioration under biologic therapy. Conclusion Severe eosinophilic asthma may represent the initial manifestation of IgG4-related disease with bronchial involvement. This diagnosis should be considered in case of late-onset, corticosteroid-dependent asthma, particularly when chest CT reveals suggestive abnormalities. Histopathological evaluation remains essential to confirm the diagnosis and to exclude other differential diagnoses. Declarations Ethics approval and consent to participate Not applicable. -Consent to publish Written informed consent for the publication of this case report and associated images was obtained. -Availability of data and material The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. -Competing interests The authors declare that they have no competing interests. -Funding No financial support and sponsorship. -Authors' contributions AL and SD conceived the study, performed the literature review and analysis, and drafted the manuscript. MB, ML, VD, CDP, ALC treated the patients and performed the analysis. CD analyzed the CT scans and performed the analysis. CS analyzed histology data and performed the analysis. SD and FXB revised the manuscript critically. All authors read and approved the submitted manuscript. -Acknowledgements Not applicable Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 09 Dec, 2025 Reviewers agreed at journal 30 Nov, 2025 Reviews received at journal 28 Nov, 2025 Reviewers agreed at journal 23 Nov, 2025 Reviewers invited by journal 20 Nov, 2025 Editor invited by journal 28 Oct, 2025 Editor assigned by journal 28 Oct, 2025 Submission checks completed at journal 28 Oct, 2025 First submitted to journal 15 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7869501","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":551958892,"identity":"92e0b470-6ac7-41d1-9257-2e9401d81a47","order_by":0,"name":"A. 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16:07:57","extension":"html","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":29725,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7869501/v1/a429e3007159f1a4195bec1e.html"},{"id":97367195,"identity":"97e09a1e-db72-401f-b0e1-42761f2099e6","added_by":"auto","created_at":"2025-12-03 16:17:25","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":186787,"visible":true,"origin":"","legend":"\u003cp\u003eChest X-ray at admission, showing a diffuse interstitial nodular pattern.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7869501/v1/bae9675431e9e3710008a95b.jpeg"},{"id":97366896,"identity":"e9aad320-9385-4651-9753-2d481fad831d","added_by":"auto","created_at":"2025-12-03 16:12:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":569388,"visible":true,"origin":"","legend":"\u003cp\u003eCT-scan showing bronchocentric nodular condensations associated with peribronchovascular thickening.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7869501/v1/5642d45b173fd025315b1cb3.png"},{"id":97367326,"identity":"c5067811-a8d1-459e-9e35-0b1fdfe78c6a","added_by":"auto","created_at":"2025-12-03 16:18:12","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":447006,"visible":true,"origin":"","legend":"\u003cp\u003eBronchial biopsies with a dense lymphoplasmacytic infiltrate in the chorion.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7869501/v1/cd0367a04940b8119b5d2509.jpeg"},{"id":97257310,"identity":"8b950a0e-762d-4663-8d8f-98491e8680f0","added_by":"auto","created_at":"2025-12-02 13:39:22","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":449483,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical staining of bronchial biopsy showing IgG4-positive plasma cells. The IgG4⁺/IgG⁺ cell ratio exceeds 40%, with more than 50 IgG4⁺ cells per high-power field (×400).\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7869501/v1/7b892f1c874b1ff9a22c5fa6.jpeg"},{"id":97257319,"identity":"59d5a1f4-1f7f-4df8-b308-6fda9989dc4f","added_by":"auto","created_at":"2025-12-02 13:39:22","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":565538,"visible":true,"origin":"","legend":"\u003cp\u003eChest CT scan performed six months after initiation of rituximab. Previously observed consolidations have resolved whereas mild peribronchovascular thickening persists, along with a few subpleural linear opacities.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7869501/v1/573c3cbf8af3d29d84e6016a.png"},{"id":97664501,"identity":"ab9d3a49-22c7-48bf-bd4b-c6bbd2637602","added_by":"auto","created_at":"2025-12-08 09:06:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2715222,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7869501/v1/63fbcaa4-fcfc-4897-be8d-f5be5a8e7720.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A case of IgG4-related respiratory disease presenting as dupilumab-induced toxicity and severe asthma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIgG4-related disease (IgG4-RD) is a systemic condition characterized by lymphoplasmacytic infiltration that can involve multiple organs (1). It may affect the airways, pleura, lungs, and intrathoracic lymph nodes. Initial presentation may mimic severe asthma associated with blood eosinophilia, which can complicate the diagnostic process and result in delayed recognition of the disease (2).\u003c/p\u003e\u003cp\u003eWe report a challenging case of IgG4-RD that presented with clinical manifestations suggestive of dupilumab-induced toxicity in a patient with clinical features mimicking severe asthma.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 60-year-old woman was referred to our hospital with febrile acute respiratory failure. Her medical history included type 1 diabetes mellitus, hypertension, and a 10 pack-year smoking history.\u003c/p\u003e\u003cp\u003eTwo years before, she had been evaluated for chronic cough and dyspnea, classified as grade 1 on the modified Medical Research Council (mMRC) Dyspnea Scale, and associated with nasal polyposis. At that time, pulmonary function testing revealed a severe, reversible obstructive ventilatory defect, with a forced expiratory volume in one second to forced vital capacity ratio (FEV₁/FVC) of 0.69, and an FEV₁ at 48% of the predicted value, improving to 80% after a 3-weeks course of oral corticosteroids. Initial laboratory investigations showed marked blood eosinophilia, with a count of 1.274 G/L, and an elevated serum IgG4 level at 2.86 g/L (normal \u0026lt; 0.87 g/L). High-resolution computed tomography (HRCT) revealed four millimetric pulmonary nodules and peribronchovascular thickening. An 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) scan showed no abnormal metabolic activity. Bronchoalveolar lavage (BAL) fluid analysis showed a lymphocytic alveolitis (32%), while histopathological examination of endobronchial biopsies showed an inflammatory infiltrate composed predominantly of lymphoplasmacytic cells. Eosinophilic granulomatosis with polyangiitis was ruled out following an internal medicine consultation and a negative muscle biopsy. A diagnosis of severe corticosteroid-dependent eosinophilic asthma was subsequently retained. The patient was treated with inhaled long-acting bronchodilators and corticosteroids (beclomethasone/formoterol), along with oral corticosteroids for four months, resulting in corticosteroid dependence at a daily dose of 30 mg. In an attempt to taper oral corticosteroids, she received successive treatments with mepolizumab and benralizumab — monoclonal antibodies targeting interleukin-5 — for six months each, without any clinical improvement.\u003c/p\u003e\u003cp\u003eGiven the persistence of chronic dyspnea and severe obstructive lung disease, with a lowest recorded FEV₁ of 37% of the predicted value, dupilumab — a monoclonal antibody targeting the interleukin-4 receptor alpha subunit — was initiated. At that time, fractional exhaled nitric oxide (FeNO) level was 188 ppb (normal \u0026lt; 25 ppb). One week after initiating dupilumab, the patient developed progressively worsening dyspnea and cough. One month later, she was admitted to intensive care for acute febrile respiratory failure. Arterial blood gas analysis revealed a partial pressure of oxygen (PaO₂) of 9.4 kPa under an FiO₂ of 50%. On clinical examination, inspiratory crackles were noted at the lung bases. As an extrathoracic manifestation, inflammation of the right ear was observed. Blood eosinophils were measured at 1.240 G/L. Renal function was preserved. Serum IgG4 level was elevated at 5.18 g/L (normal \u0026lt; 0.87 g/L). Immune blood tests, including autoantibodies, remained negative. Chest X-ray revealed a diffuse nodular pattern (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Chest CT scan showed bronchocentric nodular consolidations associated with peribronchovascular thickening (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). BAL fluid analysis revealed 70% macrophages, 26% neutrophils and 4% lymphocytes. Microbiological investigations were negative. Histological examination of bronchial biopsies demonstrated a dense lymphoplasmacytic infiltrate (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), with an IgG4+/IgG cell ratio exceeding 40% and more than 50 IgG4-positive plasma cells per high-power field (×400) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). These findings were consistent with a diagnosis of IgG4-related respiratory disease, providing a likely explanation for the patient’s chronic respiratory symptoms.\u003c/p\u003e\u003cp\u003eAs no clear etiology could be identified for the acute respiratory deterioration, a transthoracic lung biopsy was performed. In addition to IgG4-positive lymphoplasmacytic infiltration, histological analysis revealed features of vasculitis. Following a multidisciplinary discussion, notably involving the pharmacovigilance department, the diagnosis of dupilumab-induced pulmonary vasculitis was established. Systemic corticosteroid therapy was initiated at a daily dose of 2 mg/kg, resulting in rapid clinical improvement and withdrawal of supplemental oxygen. One month after hospital discharge, the patient showed continued improvement under a tapering corticosteroid regimen. Pulmonary function tests had normalized, with an FEV₁/FVC ratio of 0.73 and an FEV₁ of 86% of the predicted value. Chest X-ray demonstrated marked regression of pulmonary opacities. Rituximab was then introduced as a corticosteroid-sparing agent. At six-month follow-up, chest CT imaging revealed significant resolution of the pulmonary lesions, with only mild residual peribronchovascular thickening and a few subpleural linear opacities (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe report the case of a patient with IgG4-RD and bronchial involvement, initially misinterpreted as a severe corticosteroid-dependent eosinophilic asthma. The diagnosis was established concurrently with a dupilumab-induced pulmonary vasculitis, which occurred following treatment initiation for presumed severe asthma. It illustrates that thorough diagnostic workup is crucial in cases of difficult-to-treat, corticosteroid-dependent asthma, particularly to ensure an accurate diagnosis of severe asthma. IgG4-RD should be systematically considered among potential differential diagnoses.\u003c/p\u003e\u003cp\u003eLiu et al. recently published a retrospective study involving 12 patients who initially presented with severe asthma as the first clinical manifestation of IgG4-RD. Mean age at asthma onset was 53.8 years. All patients exhibited blood eosinophilia. The most frequent radiologic findings were bronchial wall thickening and mediastinal lymphadenopathy, while some patients also showed scattered ground-glass opacities or solid nodules on chest CT. Corticosteroid therapy was effective in all cases, with 11 out of 12 patients developing corticosteroid dependence (2). Our case is in line with the findings described by Liu et al.\u003c/p\u003e\u003cp\u003eIgG4-RD is a multisystem inflammatory disorder defined by the accumulation of lymphoplasmacytic cells, leading to mass-like lesions in affected organs, which may progress to fibrosis. The disease was initially described in association with autoimmune pancreatitis, as well as involvement of the salivary and lacrimal glands, and the retroperitoneum (1). IgG4-related respiratory disease is relatively uncommon and has only been recognized more recently as a clinical entity (3). Diagnosis can be particularly challenging in the absence of extrathoracic organ involvement. However, thoracic manifestations may represent the sole presentation of IgG4-RD in up to 10% of cases (4,5). Among thoracic forms, bronchopulmonary involvement is one of the most frequently observed patterns, often associated with mediastinal or hilar lymphadenopathy.\u003c/p\u003e\u003cp\u003e The American College Rheumatology (ACR) and European League Against Rheumatism (EULAR) published in 2019 the most recent classification and diagnosis criteria for IgG4-RD (6).\u003c/p\u003e\u003cp\u003eThis classification is mainly appropriate for the most frequently involved organs but appears to be less relevant for bronchopulmonary involvement. The first diagnostic criteria for IgG4-related respiratory disease was published in 2016 and revised in 2022 (7) (8). According to this classification, the diagnosis of IgG4-related respiratory disease for our patient is probable. If we consider other organs involvement (nephromegaly and inflammation of the right auricle), the diagnosis is even definite. To support the diagnosis, increased serum IgG4 levels (\u0026gt;\u0026thinsp;135 mg/dl) and pathological features are two important criteria. The value of serum IgG4 was very high in our patient and a study reported a diagnostic specificity of 94.8% when the dosage exceeds 2.7 g/L (9).\u003c/p\u003e\u003cp\u003eGlucocorticoids are first line agents for IgG4-RD, but there are associated with numerous adverse effects when used chronically. Relapses frequently occur when doses are decreased, as it was the case for our patient. Rituximab can be prescribed in that situation (1). Dupilumab is a monoclonal antibody targeting IL-4Rα, used as maintenance therapy for severe type 2 asthma typically characterized by elevated blood eosinophils and/or increased FeNO. While clinical trials have shown good safety and efficacy profiles, data from real-world settings and long-term follow-up are still limited. Rare cases of eosinophilic pneumonia have been reported, but no vasculitis cases have been documented to date. Here, we report the first case of dupilumab-induced pulmonary vasculitis in a patient with IgG4-related respiratory disease. This case highlights the importance of considering drug-induced vasculitis in patients with atypical respiratory deterioration under biologic therapy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSevere eosinophilic asthma may represent the initial manifestation of IgG4-related disease with bronchial involvement. This diagnosis should be considered in case of late-onset, corticosteroid-dependent asthma, particularly when chest CT reveals suggestive abnormalities. Histopathological evaluation remains essential to confirm the diagnosis and to exclude other differential diagnoses.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;-Consent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for the publication of this case report and associated images was obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;-Availability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;-Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e-Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo financial support and sponsorship.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;-Authors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAL and SD conceived the study, performed the literature review and analysis, and drafted the manuscript. MB, ML, VD, CDP, ALC treated the patients and performed the analysis. CD analyzed the CT scans and performed the analysis. CS analyzed histology data and performed the analysis. SD and FXB revised the manuscript critically. All authors read and approved the submitted manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e-Acknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"severe asthma, iIgG4-related disease, drug-induced toxicity, dupilumab","lastPublishedDoi":"10.21203/rs.3.rs-7869501/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7869501/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIgG4-related disease (IgG4-RD) is a systemic immune-mediated disorder characterized by lymphoplasmacytic infiltration that can affect various organs, including lungs and bronchi. It may present as \u003cstrong\u003esevere asthma with blood eosinophilia, \u003c/strong\u003ewhich can delay the diagnosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe report the case of a 60-year-old woman with a medical history of diabetes mellitus and a 10 pack-year smoking history. She was investigated for chronic cough, nasal polyposis and blood eosinophilia. Pulmonary function tests revealed a severe obstructive ventilatory defect, with an FEV₁/FVC ratio of 0.56 and an FEV₁ of 1.43 L (56% of the predicted value), reversible only after a course of oral corticosteroids.\u003c/p\u003e\n\u003cp\u003eEosinophilic granulomatosis with polyangiitis was ruled out based on a negative muscle biopsy and internal medicine evaluation. The patient subsequently developed severe asthma, for which biologics were required. After failure of anti-IL-5 therapies, dupilumab was initiated. One month later, she developed acute febrile respiratory failure with bronchocentric nodular opacities and peribronchovascular thickening on CT-scan. Bronchial biopsies showed dense IgG4⁺ plasma cell infiltration (IgG4⁺/IgG⁺ ≥40%). Serum IgG4 was elevated (5.18 g/L). Transparietal lung biopsy revealed a \u003cstrong\u003edupilumab-induced pulmonary vasculitis\u003c/strong\u003e. In this context, this IgG4-RD with bronchial involvement was treated with high-dose corticosteroids, which led to rapid clinical improvement. Rituximab was introduced as a steroid-sparing agent, with favorable outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSevere eosinophilic asthma may be the initial manifestation of \u003c/strong\u003eIgG4-RD\u003cstrong\u003e involving the airways.\u003c/strong\u003eThis diagnosis should be considered in patients with corticosteroid-dependent asthma and abnormal chest imaging. \u003cstrong\u003eHistopathological confirmation\u003c/strong\u003e remains essential for the diagnosis and to guide treatment\u003c/p\u003e","manuscriptTitle":"A case of IgG4-related respiratory disease presenting as dupilumab-induced toxicity and severe asthma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-02 13:39:17","doi":"10.21203/rs.3.rs-7869501/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-12-09T22:17:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"20608149732777246524105275899768811949","date":"2025-11-30T12:19:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-28T17:13:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321349453751540904942960839101782521000","date":"2025-11-23T07:52:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-20T18:23:28+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-28T12:00:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-28T09:23:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-28T09:22:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2025-10-15T14:47:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7fb8b6ca-30ed-41c7-a7f9-1122c8412d97","owner":[],"postedDate":"December 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-02T13:39:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-02 13:39:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7869501","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7869501","identity":"rs-7869501","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}