IgG4-related lung disease mimicking COPD: case report and review

Abstract

IgG4-RD is a systemic fibroinflammatory condition with a wide range of clinical presentations, including involvement of the respiratory system. While respiratory manifestations are common, IgG4-RD can mimic more prevalent pulmonary conditions, such as asthma or chronic obstructive pulmonary disease (COPD), making diagnosis particularly challenging. In this case report, we describe a patient whose initial symptoms were consistent with COPD, but further investigation revealed that IgG4-RD was the underlying cause. This case highlights the importance of considering IgG4-RD in the differential diagnosis of atypical or treatment-resistant COPD-like presentations to avoid misdiagnosis and ensure timely, appropriate management.

Case presentation

A 48-year-old Chinese male presented with a three-month history of progressive dyspnea, productive cough, and sputum production. He had quit smoking and drinking approximately four months earlier, which coincided with the onset of his respiratory symptoms. Pulmonary function tests revealed an FEV₁/FVC ratio of 66%, indicating mild obstructive ventilatory dysfunction with normal diffusion capacity. A bronchodilator test using 200 µg of Ventolin showed no significant reversibility, and the fractional exhaled nitric oxide (FeNO) test was negative, making asthma less likely. He was initially diagnosed with chronic obstructive pulmonary disease (COPD).

A subtle but initially overlooked clue was his history of recurrent bilateral eyelid edema, which he had not reported previously, as he considered it insignificant. This would later prove relevant to his systemic condition.

His symptoms acutely worsened, with increased dyspnea, chest tightness, cough, and excessive sputum production. He received noninvasive mechanical ventilation, corticosteroids, antibiotics, and symptomatic treatment at a local hospital. Owing to persistent respiratory failure, the patient was transferred to our emergency department, where he required intubation and mechanical ventilation. After stabilization, he was admitted to our department for further evaluation and treatment.

On physical examination, bilateral wheezing was noted, but no other remarkable findings were present. The results of laboratory tests, including complete blood count, liver and renal function, coagulation profile, and serological markers, were within normal limits. The working diagnosis was acute exacerbation of COPD with respiratory failure. However, owing to his atypical features and suboptimal response to standard therapy, further investigations were pursued.

Serum IgG4 levels were markedly elevated at 1974.5 mg/dL (reference range: 10–140 mg/dL). Bronchoscopy revealed bilateral inflammatory changes in the bronchi, which was consistent with airway involvement. Chest CT imaging revealed inflammation of the paranasal sinuses; multiple enlarged lymph nodes in the hilum, mediastinum, and left axilla (Fig. 1A, B) and diffuse thickening of the peribronchovascular interstitium (Fig. 1C, D). Additional CT findings included bilateral pulmonary nodules and spots, nodular thickening of the pericardium, a soft tissue mass from T4 to T10 in the paravertebral region (Fig. 1E, F), and a small pericardial effusion. Abdominal CT revealed no abnormalities.

Fig. 1.

A, B CT images showing mediastinal lymphadenopathy before and after treatment. C, D Peribronchovascular thickening pre- and post-treatment. E, F Paravertebral soft tissue mass observed before and after treatment

PET-CT revealed bilaterally enlarged lacrimal glands with mildly increased metabolic activity in the soft tissue surrounding the T5–T10 vertebral bodies. Mediastinal and hilar lymphadenopathy was associated with increased metabolic activity, suggesting inflammatory proliferative lymphadenopathy. Scattered inflammatory foci were present throughout both lungs.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of the 4R and Group 7 lymph nodes revealed scattered lymphocytes and histiocytes, with approximately 25% of the cells being IgG4 positive. Hematoxylin and eosin (HE) staining at 100 × magnification revealed preserved tissue architecture with lymphoid infiltration, which was consistent with reactive lymphadenopathy and features suggestive of IgG4-related disease (Figs. 2 and 3).

Fig. 2.

Immunohistochemical staining of 4R and Group 7 lymph nodes at 100 × magnification showing IgG4-positive cells

Fig. 3.

Hematoxylin and Eosin (HE) staining of 4R and Group 7 lymph nodes at 100 × magnification showing preserved tissue architecture with lymphoid infiltration

The patient was started on oral prednisone at 30 mg daily, which was tapered to 20 mg and then to 15 mg over two months. From the second month, 12.5 mg of methotrexate was added weekly. This combined immunosuppressive regimen led to marked improvement in patient condition. His symptoms were relieved, and a follow-up CT scan revealed a significant reduction in lymphadenopathy, peribronchovascular thickening, and paravertebral soft tissue involvement (Fig. 1B, D).

The patient continued follow-up for one year, adhering to the prescribed treatment regimen. Repeat spirometry performed at the one-year follow-up demonstrated an FEV₁/FVC ratio of 77.35%, representing normalization of pulmonary function. Given the irreversible nature of airflow limitation in COPD, this finding argued strongly against a diagnosis of chronic obstructive pulmonary disease. Based on his clinical improvement, inhaled corticosteroids were discontinued, and the patient remained symptom-free.

Discussion

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition capable of affecting multiple organs [1]. First recognized as a systemic disease in 2001, IgG4-RD can manifest in various organs, including but not limited to the pancreas, biliary system, salivary glands, and kidneys [1–5]. IgG4-RD can manifest in the lungs with a variety of presentations, often mimicking other conditions such as lung cancer, pneumonia, interstitial lung disease (ILD), and sarcoidosis [6–8]. Recognizing these diverse manifestations is crucial for accurate diagnosis and management [9, 10]. Multiple studies have reported that asthma and pulmonary emphysema with pleural involvement can be common manifestations that are eventually diagnosed as IgG4-related disease (IgG4-RD) [11].

In this case, the initial suspicion of chronic obstructive pulmonary disease (COPD) on the basis of the patient’s history and physical examination highlights the diagnostic challenges in IgG4-RD. Many of the clinical manifestations of IgG4-RD mimic other more common conditions. A comprehensive medical workup, including computed tomography (CT), is crucial for identifying the features that lead to the correct diagnosis. The literature describes seven patterns of thoracic involvement, from which this patient exhibited a nodular pattern alongside peribronchovascular involvement, accompanied by mediastinal, hilar, and axillary lymph node involvement. Elevated immunoglobulin G4 (IgG4) levels serve as a predictive indicator for this disease. Studies report an average specificity ranging from 70 to 80% for elevated IgG4 in diagnosing this condition [12]. A serum IgG4 level exceeding 1500 mg/dL is considered highly specific for confirming a definitive diagnosis of the disease [13]. The application of the 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria provided a structured approach to confirming the diagnosis. The scoring system, which considers lymphocytic infiltration, the serum IgG4 concentration, lacrimal gland involvement, and peribronchovascular thickening, demonstrates how diverse manifestations are integrated into a single diagnostic assessment [14]. The patient's total score of 31, well above the threshold of 20, provides strong support for the IgG4-RD diagnosis (Table 1). However, according to the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD, this patient has two items except for the third item, which includes dense lymphocyte infiltration and a ratio of IgG4-positive plasma cells/IgG-positive cells greater than 40% in this case. We found that ratio was 25%, which we found due to the limitation in the biopsy sample, which was inadequate to obtain an accurate diagnosis [15].

Table 1.

Application of the 2019 ACR/EULAR Classification Criteria for IgG4-Related Disease in a Suspected Case

The 2019 ACR/EULAR classification criteria for IgG4-related disease	Patient assessment
Step 1. Entry criteria Characteristic clinical or radiologic involvement of a typical organ (e.g., pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland [Riedel's thyroiditis]) OR pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs	Yes
Step 2. Exclusion criteria: domains and items	No specific clinical, serological, pathological, and Radiological findings
Step 3. Inclusion criteria:	Dense lymphocytic infiltrate score = 4. Immunostaining score considered 0 due to lack of 40% IgG 4 + cells on histopathology. Serum IgG4 concentration: > 5 × upper limit of normal = 11. Bilateral lacrimal, parotid, sublingual, and submandibular glands: One set of glands involved = 6. Chest: Paravertebral band-like soft tissue in the thorax = 10.

According to the 2019 ACR/EULAR classification criteria for IgG4-related disease, a minimum score of 20 is required for classification. This patient meets the entry criteria, does not meet any exclusion criteria, and has a total inclusion score of 31 (4 + 0 + 11 + 6 + 10), which exceeds the threshold. Therefore, the patient satisfies the criteria for the diagnosis of IgG4-related disease

The diagnosis of IgG4-RD presents significant challenges, particularly due to the difficulty in obtaining adequate tissue samples from specific anatomical sites [16]. While needle biopsies may yield sufficient tissue to exclude differential diagnoses such as malignancy or infection, they often fail to provide the comprehensive histopathological evidence necessary for a definitive IgG4-RD diagnosis. Moreover, insufficient or inconclusive biopsy results do not definitively exclude the disease, as sampling variability and the presence of a fibrotic disease stage characterized by minimal inflammation and scarce IgG4 + plasma cells can hinder accurate histopathological assessment [15]. Clinical diagnoses of IgG4-RD are often based on findings such as storiform fibrosis, obliterative phlebitis, lymphocytic infiltration, and the presence of multiple lung nodules, along with multiple mediastinal and hilar lymph node involvement [14, 16, 17]. While storiform fibrosis and obliterative phlebitis are more common in severe cases and less common in the lymph nodes, salivary glands and lacrimal glands, lymphocytic/plasma cell infiltration is frequently observed in lymph node biopsy samples [15, 18, 19].

In this case, our patient was reluctant to undergo any further invasive procedures, such as a biopsy from a pathological site such as the lacrimal gland biopsy may provide a sufficient amount of tissue for pathological evidence of IgG4-related disease, as studies have shown that the pathological site in the salivary gland is useful for diagnosing IgG4-related disease [20].

Although IgG4-RD can resemble or coexist with COPD, the patient’s FEV₁/FVC improved to 77.35% after one year, which is uncommon in COPD. The successful withdrawal of inhaled steroids without symptom recurrence supports IgG4-RD as the primary cause.

Conclusion

In conclusion, while COPD and IgG4-RD patients may present with similar symptoms, such as cough, dyspnea, and wheezing, their underlying mechanisms differ significantly. COPD is primarily caused by chronic airway inflammation and irreversible lung damage, whereas IgG4-RD involves immune-mediated fibroinflammatory processes that can mimic COPD symptoms. This case highlights the importance of advanced diagnostic techniques, including imaging studies and serum IgG4 levels, in differentiating IgG4-RD from more common pulmonary diseases such as COPD. Elevated IgG4 levels and characteristic histopathological findings are crucial for confirming the diagnosis; however, challenges such as limitations in biopsy sampling, particularly in patients with fibrosis and minimal inflammation, can complicate accurate diagnosis.

Abbreviations

IgG4-RD

Immunoglobulin G4-related disease

COPD

Chronic Obstructive Pulmonary Disease

FEV₁

Forced Expiratory Volume in 1 second

FVC

Forced Vital Capacity

FeNO

Fractional Exhaled Nitric Oxide

CT

Computed Tomography

PET-CT

Positron Emission Tomography - Computed Tomography

EBUS-TBNA

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration

HE

Hematoxylin and Eosin

ACR

American College of Rheumatology

EULAR

European League Against Rheumatism

RCD

Revised Comprehensive Diagnostic (criteria)

ILD

Interstitial Lung Disease

Authors’ contributions

ZT and PLW collected the data and drafted the manuscript. MAAA reviewed the literature. SCC supervised the clinical management and critically revised the manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by the National Key Research and Development Program of China grants 2016YFC1304000 (C Chen); The National Natural Scientific Foundation of China 82170017, 82370085 (C Chen); Zhejiang Provincial Key Research and Development Program 2020C03067 (C Chen).

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

Competing interests

The authors declare no competing interests.