Immunoglobulin G4-related lung disease mistaken for pulmonary tuberculosis: A case report

Abstract

BACKGROUND

Immunoglobulin G4-related disease (IgG4-RD) is a persistent and progressive autoimmune condition marked by inflammation and fibrotic changes in the affected tissues. Cases of IgG4-RD causing pulmonary lesions are relatively rare, and some may be misdiagnosed as pulmonary tuberculosis.

CASE SUMMARY

In this report, we present an uncommon instance of IgG4-related lung disease, which was diagnosed through lung tissue biopsy conducted via puncture. A 67-year-old male was hospitalized with a two-month history of cough and sputum production. Chest computed tomography (CT) revealed infiltrative pulmonary tuberculosis in both upper lungs. However, the initial diagnosis was unclear, and the patient received HZRE quadruple therapy for tuberculosis at a local hospital. After 45 days of anti-tuberculosis treatment, the patient's cough and sputum worsened, and he began coughing up blood, prompting transfer to our hospital. Serum tests revealed elevated IgG4 levels. A biopsy of a right lung showed localized fibrous and extensive plasma cell infiltration, with 30-40 IgG4-positive cells per high-power field, and an IgG4/IgG ratio of 40%. These findings led to a diagnosis of IgG4-related lung disease. Following treatment with prednisone and mycophenolate mofetil, follow-up lung CT scans showed significant lesion improvement.

CONCLUSION

The chest CT findings of IgG4-RD are diverse and nonspecific, often leading to misdiagnosis as pulmonary tuberculosis, especially in primary care settings with limited diagnostic resources. We confirmed the diagnosis of IgG4-related lung disease through histological examination.

Key Words: IgG4-related lung disease; Lung tissue biopsy; Percutaneous lung puncture; Steroid drugs; Case report

Core Tip: Immunoglobulin G4-related disease is a fibrotic inflammatory disease that affects almost all organs and primarily occurs in middle-aged to elderly male patients. It can occur in the mediastinum, airways, lungs, and pleura and is most commonly associated with manifestations outside the chest, which are usually nonspecific. The prognostic characteristics have not yet been determined. Diagnosis relies on a thorough assessment of clinical, biological, and histological findings, as there are no specific biomarkers. Differential diagnoses must always be considered, especially when the disease affects a single organ, is incidentally found on imaging studies, or is unexpectedly diagnosed on pathological specimens.

INTRODUCTION

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) represents a chronic and progressive autoimmune disorder that is distinguished by the presence of inflammation and fibrosis in the tissues that are involved[1]. A hallmark of IgG4-RD is the infiltration of IgG4-positive plasma cells and lymphocytes into various tissues. This condition has the potential to impact multiple organ systems, encompassing the biliary tract, renal system, retroperitoneum, prostate, aorta, pericardium, lungs, thyroid gland, lymph nodes, meninges, and the integumentary system[2]. Thoracic involvement in IgG4-RD has only recently been described[3]. It can present as interstitial pneumonia, inflammatory pseudotumors, bronchitis, and pleuritis[4]. Cases of IgG4-RD causing pulmonary lesions are relatively rare, and some may be misdiagnosed as pulmonary tuberculosis. In this study, we present an uncommon instance of IgG4-related lung disease, which was identified through a lung tissue biopsy obtained via a percutaneous lung puncture procedure.

CASE PRESENTATION

Chief complaints

A 67-year-old Chinese man was hospitalized with a two-month history of cough and sputum production.

History of present illness

The patient had been coughing and producing sputum for 2 months. Chest computed tomography (CT) revealed infiltrative pulmonary tuberculosis in both upper lungs. However, the initial diagnosis was still unclear, and the patient received quadruple HZRE therapy for tuberculosis at a local hospital. After 45 days of anti-tuberculosis treatment, the patient's cough and sputum worsened, and he started coughing up blood, leading to his transfer to our hospital for further evaluation and treatment.

History of past illness

No history of chronic conditions such as hypertension, diabetes, or heart disease.

Personal and family history

No family history of tuberculosis.

Physical examination

Upon admission, the patient’s temperature was 36.0 °C. The breath sounds on the right side were found to be reduced, while no abnormal heart sounds were detected. There was no observed dyspnea or respiratory distress. No rales or crackles were detected on auscultation. His oxygen saturation level was 97% on room air.

Laboratory examinations

The patient’s hemoglobin level was 107 g/L, uric acid level was 616 μmol/L, and erythrocyte sedimentation rate was 81 mm/hour. Vasculitis-related antibodies and immunoglobulin levels were within normal ranges. Acid-fast staining of sputum and bronchoalveolar lavage fluid, TBNDA, T-SPOT tuberculosis, and tuberculosis antibody tests were all negative. Tumor markers were also within the normal ranges. Serum IgG4 levels were elevated (2.80 g/L). Pathological examination of the right lung biopsy revealed localized fibrous tissue hyperplasia and extensive plasma cell infiltration (Figure 1), with 30-40 IgG4-positive cells per high-power field, and an IgG4/IgG ratio of 40% (Figure 2).

Figure 1 Pathological assessment showed localized fibrous tissue hyperplasia and extensive plasma cell infiltration.

Figure 2 A total of 30-40 immunoglobulin G4-positive cells per high-power field, and an immunoglobulin G4/immunoglobulin G ratio of 40%.

Imaging examinations

Cardiac ultrasonography revealed mild tricuspid and pulmonary valve insufficiencies. Abdominal ultrasonography revealed multiple cysts in the left kidney and mild prostatic hyperplasia with stone formation. Chest CT indicated bilateral lung infection with a high likelihood of tuberculosis, chronic bronchitis, pulmonary emphysema, and bilateral upper-lobe pulmonary bullae (Figure 3A).

Figure 3 Axial unenhanced thoracic computed tomography. A: Before treatment. Showing distal bronchial distension and traction bronchiectasis (orange arrow), glass opacities (yellow arrow) and a mass in the right superior lobe (black arrow); B: Computed tomography (CT) scan showing that the mass had shrunk and the ground-glass lesions had cleared after 2 months of corticosteroid therapy (35 mg/day oral prednisolone and mycophenolate mofetil 0.5 g bid); C: Chest CT scan at 6 months of treatment showing that the mass had shrunk further; D: Chest CT obtained 1 year after treatment. Chest CT shows that only cord-like shadows remained.

FINAL DIAGNOSIS

The patient was diagnosed with IgG4-related lung disease.

TREATMENT

Following treatment with corticosteroids [oral prednisone (PSL) at 35 mg/day] and immunosuppressants (mycophenolate mofetil at 0.5 g bid) for 1 year, the dosage was reduced to PSL 5 mg/day as maintenance therapy.

OUTCOME AND FOLLOW-UP

Follow-up chest CT scans at 2 and 6 months of treatment showed significant improvement in lung lesions (Figure 3B-D).

DISCUSSION

IgG4 is the smallest subclass of immunoglobulin G, accounting for approximately 5% of total IgG. It is generally considered non-inflammatory because of its inability to activate the complement system, form immune complexes[5], or effectively bind Fc gamma receptors, thereby limiting antibody-dependent cell-mediated cytotoxicity[6]. Therefore, the role of IgG4 in the pathogenesis of IgG4-RD remains incompletely understood[7]. Innate immunity plays a significant role in the development of gG4-RD. M2 macrophages, which are anti-inflammatory in nature are closely associated with the fibrotic processes characteristic of the disease. These cells are frequently observed in fibrotic regions, and their numbers have been positively correlated with the extent of tissue fibrosis[8]. Recent studies suggests that pulmonary IgG4-RD is linked to Th2-dominant immune dysregulation[9].

Herein, we present a case of IgG4-related lung disease initially misdiagnosed as tuberculosis. We confirmed the diagnosis of IgG4-related lung disease by histological assessment. The patient met the diagnostic criteria for IgG4-related disease. Clinical signs of thoracic involvement are observed in over 10% of cases. These signs are typically nonspecific and vary depending on the location of the lesion, and may include cough, dyspnea, hemoptysis, asthma-like symptoms, or chest pain[10].

Diagnosing IgG4-RD can be challenging for several reasons. First, chest CT scans are the most commonly used imaging method for assessing IgG4-RD thoracic lesions. The chest manifestations of IgG4-RD are diverse and nonspecific[11,12], often leading to misdiagnose as pulmonary tuberculosis, particularly in primary care settings with limited diagnostic resources. Second, although elevated serum IgG4 levels are part of the diagnostic criteria, they are elevated in only 50% of active IgG4-RD cases. Moreover, approximately 5% of healthy individuals may have elevated serum IgG4 levels. Therefore, serum IgG4 levels alone are insufficient for a definitive diagnosis. IgG4-positive plasma cells are also observed in lung tissue across a range of different conditions, such as inflammatory myofibroblastic tumors, non-specific interstitial pneumonia, usual interstitial pneumonia, and necrotizing granulomatous inflammation[13]. These findings suggest that both the quantification of IgG4-positive plasma cells and the ratio of IgG4 to IgG-positive plasma cells may help differentiate true IgG4-related lung disease from its mimics[14]. Third, IgG4-RD often presents as a systemic disease affecting multiple organs. In such cases, the presence of extrapulmonary lesions may provide diagnostic indications. However, the CT imaging characteristics of IgG4-related pulmonary lesions are not specific, which further complicates the diagnostic process. On CT, IgG4-RD resembles lung tumors and nonspecific interstitial pneumonia. However, the main pathological characteristics of IgG4-RD, such as bundled fibrosis and soft lymphoplasmacytic venulitis, are not present in lung tumors or nonspecific interstitial pneumonia[15]. Certain tumor markers may help distinguish between IgG4-related lung disease and lung cancers.

An international consensus statement on IgG4-RD was published in 2015[16] based on expert opinions and a review of existing evidence. It recommends the use of glucocorticoids as a first-line treatment for IgG4-RD, typically at a dose of 0.6 mg/kg. Clinical improvement is usually observed within the first 2 weeks of therapy. After 2-4 weeks at the initial dose, glucocorticoids are generally tapered gradually over a period of 3-6 months. In the present case, mycophenolate mofetil was added to prednisone, which proved to be significantly effective. However, disease-modifying anti-rheumatic drugs (such as azathioprine, mycophenolate mofetil, cyclosporine, and methotrexate) are less effective at inducing remission, they can be useful as steroid-sparing agents[17]. Due to lack of prospective clinical trials[18], experts consensus is divided on whether disease-modifying anti-rheumatic drugs should be introduced early in the course of treatment[17].

Rituximab is utilized more frequently among patients whose conditions have either relapsed or display resistance to glucocorticoid monotherapy or where the administration of glucocorticoids is likely to result in significant adverse effects[19,20]. Inebilizumab reduces the incidence of flares associated with IgG4-RDs and enhances the probability of achieving flare-free complete remission within 1 year. These findings underscore the significance of CD19-targeted B cell depletion as a viable therapeutic strategy for managing IgG4-RD[21,22]. Currently, an international randomized controlled clinical trial is being conducted utilizing anti-CD19 monoclonal antibodies, specifically obexelimab[23], as a B-cell-targeted therapy, with promising results emerging. Furthermore, preliminary evidence suggests the potential effectiveness of interleukin-4-targeted therapies, such as dupilumab[24].

CONCLUSION

IgG4-RD is a fibrotic inflammatory disease that affects almost all organs and primarily occurs in middle-aged to elderly male patients. It can occur in the mediastinum, airways, lungs, and pleura and is most commonly associated with manifestations outside the chest, which are usually nonspecific. The prognostic characteristics have not yet been determined. Diagnosis relies on a thorough assessment of clinical, biological, and histological findings, as there are no specific biomarkers. Differential diagnoses must always be considered, especially when the disease affects a single organ, is incidentally found on imaging studies, or is unexpectedly diagnosed on pathological specimens. Monitoring IgG4 concentrations revealed an early relapse in some patients. Although IgG4 concentrations decreased with glucocorticoid treatment in most patients in whom they were elevated at baseline, they remained above the normal values[25]. Therefore, the long-term management plan for patients involves monitoring IgG4 levels and obtaining regular lung CT scans. Patients may have to use corticosteroids or immunosuppressants for long periods. This can lead to both bacterial and fungal infections.

ACKNOWLEDGEMENTS

We would like to express our sincere gratitude to all authors for their invaluable contributions to this study. Additionally, we extend our heartfelt appreciation to the patient who participated in this case.