Isolated IgG4-related lung disease: a case report

Introduction

Background

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder that can involve multiple organs, with pulmonary involvement occurring in a subset of patients. IgG4-related lung disease (IgG4-RLD) typically affects middle-aged to elderly males, with nonspecific clinical symptoms including cough, dyspnea, and chest pain. Radiological findings are diverse, including nodules, ground-glass opacities, consolidations, and bronchovascular thickening. Given the ambiguity of its clinical and radiological presentations, IgG4-RLD frequently mimics various other lung disorders, such as cryptogenic organizing pneumonia, tuberculosis, primary bronchogenic carcinoma, metastatic nodules, fungal infections, or granulomatosis with polyangiitis.

Rationale and knowledge gap

Diagnosing IgG4-RLD is particularly difficult because of its heterogeneity and the complexity of distinguishing it from other conditions. Multiple noninvasive and invasive diagnostic tests may be required to reach a definitive diagnosis. However, there is limited literature describing the diagnostic utility of combining endobronchial ultrasound-guided transbronchial lung cryobiopsy (EBUS-GS-TBLC) in patients with antibiotic-resistant pulmonary lesions. Furthermore, the role of non-steroidal immunosuppressive regimens (e.g., cyclosporine plus mycophenolate mofetil) in IgG4-RLD remains underreported.

Objective

This case report aims to describe the clinical, radiological, and pathological features of a patient with IgG4-RLD who presented with recurrent fever and chest pain unresponsive to multiple antibiotics. It also highlights the diagnostic value of EBUS-GS-TBLC combined with cryobiopsy and documents a successful response to cyclosporine and mycophenolate mofetil, providing a reference for clinicians when encountering similar challenging cases. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0130/rc).

Case presentation

A 60-year-old male patient presented with recurrent antibiotic treatment failures for pneumonia. Initial symptoms included fever, chest pain, and cough with hemoptysis. Following his first admission on February 18, 2025, a chest computed tomography (CT) scan revealed an infection localized in the right upper lobe, prompting treatment with levofloxacin and acyclovir. Despite treatment, the condition worsened, accompanied by cough and sputum. Further diagnostic procedures involved several bronchoscopies and next-generation sequencing. Over several months, the patient was treated with multiple antibiotic therapies, including levofloxacin, nemonoxacin malate, ceftizoxime and amoxicillin. However, the patient’s condition did not improve. He was a non-smoker and had professional experience working in a hospital setting. In 2021, he had undergone hormone therapy for 3 months due to an episode of conjunctivitis.

The patient’s vital signs were recorded as follows: temperature 36.7 ℃, respiratory rate 21 breaths per minute, heart rate 84 beats per minute, oxygen saturation 95% on room air, blood pressure 120/78 mmHg, and body mass index 22.5 kg/m². On physical examination, he exhibited no signs of acute distress. Chest auscultation revealed no inspiratory and expiratory wheezing or wet rales in both lungs. Additionally, no palpable lymphadenopathy was observed in the supraclavicular, cervical, or axillary regions. The cardiac, neurological, abdominal, and dermatological examinations were predominantly unremarkable.

A complete blood count revealed an absolute white blood cell count of 7.48×10⁹/L, neutrophil percentage of 61.5%, lymphocyte percentage of 27.8%, hemoglobin of 137 g/L, and platelet count of 305×10⁹/L. C-reactive protein levels (60.89 mg/L; reference <4 mg/L) and erythrocyte sedimentation rate (66 mm/h; reference <15 mm/h) were elevated. IgG was 14.30 g/L. IgG4 was elevated to 266 mg/dL. B-type natriuretic peptide (21 pg/mL; reference <100 pg/mL), procalcitonin (0.02 ng/mL; reference <0.046 ng/mL), and D-dimer (0.75 µg/mL; reference <0.5 µg/mL) were in the normal ranges. Non-oxygenated arterial blood gas analysis revealed the following: pH 7.46, PaCO₂ 38 mmHg, PaO₂ 69 mmHg, blood glucose 7.0 mmol/L, and lactate level 2.0 mmol/L. Liver and kidney function tests were normal. Chest CT scan demonstrated a high-density irregular mass in the right upper lung lobe surrounded by multiple ground-glass shadows and cords (Figure 1).

Figure 1 CT findings. (A,B) Chest CT displaying high density, irregular mass in the right upper lung lobe, surrounded by multiple ground glass opacities and cords before therapy. (C,D) One month after treatment, the irregular mass in the right upper lobe was significantly reduced. (E,F) Three months after treatment, the irregular mass in the right upper lobe had almost disappeared. The upper right corner shows an enlarged view focused on the right lung. CT, computed tomography.

Bronchoscopy revealed inflammatory changes in the bronchi of both lung lobes, with prominent terminal bronchioles in the right upper lobe (Figure 2). Bronchoalveolar lavage cytology displayed a white blood cell count of 350/mL, with neutrophils accounting for 26%, lymphocytes 31%, eosinophils 1%, monocytes 27%, and epithelial cells 15%. Bacterial, fungal, and viral cultures were negative. Bronchoalveolar lavage cytology was also negative. A radial ultrasound probe was inserted into the terminal bronchiole of the right upper lobe, revealing an irregular echoic area distal to B1ai (Figure 2). EBUS-GS-TBLC and brushings were performed at this site. Parameters of case operation: (I) endoscopic model: Olympus BF-P290 radial EBUS bronchoscope (outer diameter 4.2 mm); (II) guide sheath size: GS 1.95 mm dedicated guide sheath; (III) cryoprobe: Erbe 1.1mm flexible cryoprobe; (IV) procedure modification: given that the inner diameter of the B1ai subsegmental bronchus is only 2.4 mm, a guide sheath pre-dilation combined with low negative pressure respiratory-synchronized scope insertion was carried out; a freezing time of 4 seconds was used, and there were no complications such as bronchial mucosal tear or bleeding, with specimens sent for pathological and cytological analyses. Cytological examination revealed scattered lymphocytes without specific pathological changes. Next-generation metagenomic sequencing of alveolar lavage fluid samples identified multiple bacteria that typically colonize the oral mucosa and gingiva, mainly Prevotella oris, Streptococcus salivarius, and Veillonella parvula.

Figure 2 (A) Bronchoscopy revealed inflammatory changes in the right upper lobe. (B) A radial ultrasound probe was inserted into the right upper lobe’s terminal bronchiole, revealing an irregular echoic area distal to B1ai.

Histopathological examination of the cryobiopsy sample revealed a small amount of fragmented tissue with areas of bleeding and clotting, and minimal mucus. Some tissue surfaces were covered by pseudo-stratified ciliated columnar epithelium. The lamina propria exhibited fibrous tissue hyperplasia with infiltration of abundant lymphocytes, plasma cells, and some neutrophils (Figure 3). Immunohistochemistry revealed: Special staining for acid-fast bacilli and Grocott methenamine silver revealed no evidence of mycobacteria, pneumocystis, or fungal elements. IgG4 immuno-staining displayed predominant positive plasma cells, >50 cells/high powered field (HPF), IgG4-positive cells/IgG-positive cells > 50% (Figure 3).

Figure 3 (A,B) Photomicrograph revealed infiltrating lymphocytes and plasma cells within the bronchovascular bundles (hematoxylin and eosin-staining). Original magnification ×40 (A) and ×100 (B). (C) Immunohistochemistry demonstrating IgG-positive infiltrates. Original magnification ×100. (D) IgG4 immunostaining revealing predominant lgG4+ plasma cells, with an IgG4+/IgG+ percentage greater than 50%. Original magnification ×100.

In 2021, he had undergone hormone therapy for 3 months due to an episode of conjunctivitis. During this period, the patient experienced fractures and long-term insomnia, and the patient has existing Diabetes Mellitus with poor blood glucose control, and the patient refuses long-term hormone therapy. Following evaluation by the rheumatology department, the patient began receiving oral cyclosporine (50 mg, once daily) and mycophenolate mofetil (0.75 g oral, twice daily). After 1 month of treatment, a follow-up chest CT scan revealed significant improvement in the volume of the localized lesion in the right upper lobe. Treatment was continued, and another follow-up chest CT after 2 months confirmed significant improvement in the volume of the localized lesion in the right upper lobe.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Strengths and limitations

In the diagnosis of IgG4-RD, it is necessary to count the number of IgG4-positive plasma cells and also conduct a careful assessment of the space distribution and fibrosis pattern of lesions. Therefore, to conduct reliable pathological diagnosis, it is necessary to obtain a sufficiently large quantity of tissue samples with good histological structure. Transbronchial lung cryobiopsy (TBLC) is based on rapid freezing, and a cryoprobe is used to adhere to and collect pulmonary tissue. This mode can obtain a relatively large amount of tissue from the lung parenchyma, airway mucosa and submucosa. Compared with traditional forceps biopsy, TBLC has a small crush artefact and can better retain the original shape of alveolar structures, bronchial glands, blood vessels, interstitial fibrotic framework, etc. Some case series have confirmed that TBLC is a diagnostic indicator of IgG4-related disease. Manoharan and Gaspar (1) have reported a case of IgG4-related interstitial lung disease that was diagnosed by TBLC. Yamakawa et al. (2) have found that there is IgG4-mediated inflammatory infiltration in the bronchial glands of TBLC specimens. According to the research, for patients with lesions mainly in the airway wall and bronchial glands that do not affect the alveoli significantly, TBLC can obtain submucosal airway tissue that is difficult to obtain with traditional transbronchial alveolar biopsy. Torii et al. (3) reported in 2024 that there was a rare case of IgG4-RD with multiple central airway nodules and mucosal oedema. Minekawa et al. (4) have also shown that TBLC can be used for the diagnosis of IgG4-RD with central airway involvement. TBLC has the following three advantages over traditional transbronchial lung biopsy (TBLB) in the diagnosis of IgG4-related lung disease. First of all, a relatively large number of samples will reduce the sampling error caused by the dispersion of pulmonary lesions; at the same time, it will reduce the false-negative rate due to insufficient focal sampling and thus improve the overall diagnostic sensitivity. Secondly, in order to show the changes in the bronchovascular bundle, obliterative phlebitis and interstitial fibrosis, there must be an upper-down conservation of the tissue structure; otherwise, it would not be a characteristic microscopic feature of inflammation. Thirdly, a relatively large number of cells can be obtained from TBLC for many types of supporting tests. In addition to IgG and IgG4 immunohistochemistry, elastic fibre staining, Ziehl-Neelsen acid-fast staining, fungal special stains and lymphoma exclusion immunophenotyping can also be carried out at the same time to simplify the whole differential diagnosis workup.

At present, the clinical data are not very rich. Direct prospective studies on the effects of TBLC for IgG4-RD have only been conducted to some extent so far and large-scale comparative cohort studies have not been carried out. There are no paired head-to-head comparisons of TBLB and TBLC in terms of specimen size, plasma cell burden and the proportion of IgG4-positive plasma cells. It is believed that TBLC has good diagnostic value based on general studies of diffuse interstitial lung disease. It has a good diagnostic effect and is in line with the standardised peri-procedural protocols for the prevention and treatment of haemorrhage and pneumothorax; otherwise, there would be no reason to take a sample.

Despite the above shortcomings, published case reports have reached a general consensus in the clinical community that TBLC should be carried out when the radiological signs are atypical, traditional biopsies cannot obtain sufficient tissue, or lesions occur in anatomically complex areas such as the central airway and mediastinal lymph nodes. For patients with suspected IgG4-related lung disease who have not yet received an official diagnosis from TBLB or percutaneous needle aspiration biopsy, TBLC can be a good non-invasive method to obtain a sample, and it should be performed before an invasive surgical lung biopsy. In the future, some centers will apply the standard pathological scoring system to carry out paired comparison studies and determine the sensitivity and specificity of TBLC for IgG4-RD.

Comparison with similar research

Glucocorticoids (GCs) are still considered to be the initial treatment for IgG4-RLD (5). Some patients are also given a combination of GCs and at least one other immunosuppressant drug; thus, they may be in remission without steroids or reduce the need for steroids earlier (6,7). Some studies have found that, at present, immunosuppressive therapy can be used to reduce the need for steroids or eliminate steroid dependency in some people, such as B-cell depletion therapy. Muller et al. (8) have shown in their studies that IgG4-RLD is good responder to rituximab induction and maintenance therapy, so it may be used to treat some rare steroid-dependent or refractory lung diseases. However, it has not been shown that monotherapy with immunosuppressants is suitable for patients with IgG4-RLD who are against glucocorticoids, have steroid-related risks intolerance, or are not tolerant of steroids. Corcoran et al. (9) reported that immunomodulatory agents including cyclophosphamide, mycophenolate mofetil and azathioprine were administered to patients who suffered disease relapse after failing monotherapy with prednisolone. The therapeutic regimen applied in this case was individually tailored for patients with steroid intolerance and is not regarded as standard first-line therapy.

Explanations of findings

According to the 2020 revised comprehensive diagnostic criteria, establishing an IgG4-RD diagnosis requires the integration of suggestive clinical and radiological features, serological markers, and characteristic histopathological findings (10). (I) Clinical and radiological features: one or more organs display diffuse or localized swelling or a mass or nodule characteristic of IgG4-RD. In single organ involvement, lymph node swelling is omitted; (II) serological diagnosis: Serum IgG4 levels >135 mg/dL; (III) pathological diagnosis: positivity for two of three criteria: (i) Dense lymphocyte and plasma cell infiltration with fibrosis; (ii) ratio of IgG4-positive plasma cells/IgG-positive cells >40% and the number of IgG4-positive plasma cells >10 HPF; (iii) typical tissue fibrosis, particularly storiform fibrosis, or obliterative phlebitis. Diagnosis: definite: (I) + (II) + (III); probable: (I) + (III); possible: (I) + (II). According to the revised diagnostic criteria for IgG4-related respiratory disease (IgG4-RRD) in 2022, four conditions need to be met: new symptoms of the lungs upon examination, elevated IgG4 in the blood, pathological changes in the lungs, and other signs of IgG4-RD in other areas of the body (11). Chest CT in this person has pulmonary infiltrative lesions, and serum IgG4 is high. Histological examination of the lung tissue shows a large amount of lymphocytes and plasma cells in the interstitium, about 40% to 50% of them produce IgG4 and many per high-power field, along with fibrosis around these cells. The above results are in line with histological category 3a, and in addition, immunohistochemistry and special stains of the pathological samples did not show mycobacteria, Pneumocystis jirovecii or fungi that are acid-fast bacilli positive and GMS-negative. Metagenomic next-generation sequencing of bronchoalveolar lavage fluid was negative for pathogens. Laboratory tests include the number of T-cells and all subsets, rheumatological screening tests, autoantibody tests, etc., all of which are normal. There was no hypocomplementemia, and based on the chest imaging results, high serum IgG4 levels and histological category 3a, the patient met the combined diagnostic criteria for IgG4-RD according to the 2022 revised diagnostic criteria. Therefore, it was diagnosed as a definite case of IgG4-related respiratory disease.

Implications and actions needed

The management of IgG4-RD is evolving, primarily based on expert insights and retrospective analyses, alongside emerging findings from limited prospective investigations. Treatment approaches are needed to consider the severity of organ involvement and the recurrent nature of the disease, with glucocorticoids serving as the initial therapeutic option for inducing remission (12). However, patients afflicted with IgG4-RD usually belong to an older age group with comorbidities that pose significant contraindications to corticosteroid use, such as diabetes, glaucoma, hypertension, and osteoporosis. Optimal management for these individuals ideally involves avoiding glucocorticoids. The application of immunosuppressive agents should be aimed at diminishing the cumulative toxicity associated with extended glucocorticoid treatment, particularly in patients susceptible to relapse, who may require repeated courses of corticosteroid.

Conclusions

IgG4-related interstitial lung disease presents with nonspecific symptoms such as fever, chest pain, and cough with hemoptysis, which is often confused with infections or tumors. Diagnosis requires clinical, radiological features, elevated IgG4 levels, and pathology demonstrating lymphocyte and plasma cell infiltration with fibrosis and specific IgG4-positive cell ratios. Bronchoscopy, particularly EBUS-guided biopsy, is crucial for diagnosing this disease, improving the detection of peripheral lung lesions, and ruling out infections or malignancies. Glucocorticoids are the initial treatment for inducing remission. However, immunosuppressants are indicated for patients with contraindications or frequent relapses, reducing steroid toxicity. Regular chest imaging (for example, CT) is necessary to monitor lesions and assess treatment response, with adjustments made for adverse drug reactions.

Acknowledgments

The authors would like to express their sincere gratitude to the patient for their courage and cooperation in sharing his medical journey. His willingness to participate in this case report has significantly contributed to the advancement of medical knowledge.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0130/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0130/prf

Funding: This work was supported by 2025 Gansu Province Disease Prevention and Control Research Projects (Nos. GSJKKY2025-03 and GSJKKY2025-36) and the 2025 Annual Research Project on Strengthening the Awareness of the Chinese National Community (No. 2025-YJXM-08).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0130/coif). All authors report the funding from 2025 Gansu Province Disease Prevention and Control Research Projects (Nos. GSJKKY2025-03 and GSJKKY2025-36), and the 2025 Annual Research Project on Strengthening the Awareness of the Chinese National Community (No. 2025-YJXM-08). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Manoharan B, Gaspar BL. Cryo-transbronchial lung biopsy in the diagnosis of IgG4-related lung disease. Med J Armed Forces India 2023;79:S288-91. [Crossref] [PubMed]
2. Yamakawa H, Takemura T, Tsumiyama E, et al. IgG4-related Bronchial Gland Inflammation Proved by Transbronchial Cryobiopsy. Am J Respir Crit Care Med 2020;201:1554-6. [Crossref] [PubMed]
3. Torii A, Oshima K, Iwakoshi A, et al. A case with multiple nodules and mucosal oedema of the trachea and both bronchi induced by IgG4-related disease. BMC Pulm Med 2024;24:115. [Crossref] [PubMed]
4. Minekawa K, Tamura K, Kawai M, et al. IgG4-related disease with central airway involvement diagnosed by cryobiopsy. Thorax 2025;80:955-6. [Crossref] [PubMed]
5. Duarte F, Tavares A, Soares D, et al. IgG4-Related Disease: A Rare Case of Simultaneous Lung and Retroperitoneal Involvement. Cureus 2022;14:e28521. [Crossref] [PubMed]
6. Matsui S, Hebisawa A, Sakai F, et al. Immunoglobulin G4-related lung disease: clinicoradiological and pathological features. Respirology 2013;18:480-7. [Crossref] [PubMed]
7. Sun X, Liu H, Feng R, et al. Biopsy-proven IgG4-related lung disease. BMC Pulm Med 2016;16:20. [Crossref] [PubMed]
8. Muller R, Ebbo M, Habert P, et al. Thoracic manifestations of IgG4-related disease. Respirology 2023;28:120-31. [Crossref] [PubMed]
9. Corcoran JP, Culver EL, Anstey RM, et al. Thoracic involvement in IgG4-related disease in a UK-based patient cohort. Respir Med 2017;132:117-21. [Crossref] [PubMed]
10. Umehara H, Okazaki K, Kawa S, et al. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. Mod Rheumatol 2021;31:529-33. [Crossref] [PubMed]
11. Handa T, Matsui S, Yamamoto H, et al. The 2022 revised diagnostic criteria for IgG4-related respiratory diseases. Respir Investig 2023;61:755-9. [Crossref] [PubMed]
12. Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4 related disease. BMJ 2020;369:m1067. [Crossref] [PubMed]