IgG4-related disease (IgG4-RD) is a recently recognized fibroinflammatory condition that typically presents as tumefactive lesions involving one or more organs showing dense lymphoplasmacytic infiltrate containing increased IgG4-positive plasma cells, storiform fibrosis, and nonnecrotizing vascular inflammation on histologic examination.¹ IgG4-RD may affect the lung as well as virtually any body site. Pulmonary manifestations of IgG4-RD are varied, with an involvement of not only the lung parenchyma but also the pleura, the mediastinum, and the thoracic lymph nodes. In a cross-sectional study, 16 of 114 patients (14%) with IgG4-RD were found to have lung or pleural involvement, in the presence or absence of other extrapulmonary manifestations such as type I autoimmune pancreatitis (AIP).^2,3

Patients with IgG4-RD involving the lung have similar epidemiologic features to those with extrapulmonary disease with an average age of 69 years and male predominance (70% to 80%).³ Approximately 50% of patients with pulmonary IgG4-RD have respiratory symptoms including cough, dyspnea on exertion, and chest pain, while the remaining patients present with incidentally found radiologic abnormalities in the absence of significant respiratory symptoms.^2,4,5,6 Constitutional symptoms such as high fever and remarkable weight loss are uncommon. Overall, the clinical manifestations in pulmonary IgG4-RD patients are nonspecific.^2,4,5,6 No known risk factors such as smoking or inhalation exposure have been identified in these patients.

Patients with pulmonary IgG4-RD reveal various patterns of abnormalities. Four types of intrapulmonary lesions in chest CT scan have been reported^5,7: (1) thickening of bronchovascular bundles and interlobular septa, (2) solid nodules resembling primary lung cancer, (3) interstitial involvement, and (4) round-shaped ground-glass opacities. The rounded opacities may vary in size from subcentimeter to > 5 cm in diameter. The opacity can manifest as solid or ground-glass attenuation. The margin of the opacity may be smooth or irregular and spiculated. In some patients, patchy consolidation and ground-glass opacities may suggest organizing pneumonia.^5,8,9,10 In others, reticular opacities and honeycombing may predominate similar to the findings seen in nonspecific interstitial pneumonia or idiopathic pulmonary fibrosis, respectively.^5,11,12 Infiltrates along bronchovascular bundles and interlobular septa may raise the suspicion of sarcoidosis especially when accompanied by thoracic lymphadenopathy.⁵ Some patients may present with pleural effusion or nodular lesions involving the pleura.^5,13 Mediastinal and/or hilar lymphadenopathy is not uncommon and may be seen with or without parenchymal lung involvement.^{2,14,15,16,17,18} On 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning, abnormal FDG uptake can be observed in IgG4-related lung lesions and thus will not help distinguish IgG4-related lung nodule or mass from lung cancer.

Serum IgG4 level is elevated in the majority of patients with pulmonary as well as extrapulmonary IgG4-RD.^2,5,11,17,19 A serum level of IgG4 > 135 mg/dL, the upper normal used in many laboratories, has been reported in 1,586 of 1,883 (84%) of patients in a large-scale study.¹⁹ The mean serum IgG4 level was 760 mg/dL.¹⁹ Sensitivity and specificity of elevated serum IgG4 level with respect to IgG4-RD are not precisely known in pulmonary IgG4-RD or in IgG4-RD in general. It has been well recognized, however, that there is a broad spectrum of diseases that have elevated serum IgG4 level above 135 mg/dL without evidence of IgG4-RD.²⁰ Thus, one should be aware of the fact that merely elevated serum IgG4 level is neither sufficient nor necessary for the diagnosis of IgG4-RD.

Recent studies have purported that plasmablast concentration in peripheral blood on flow cytometry could be a useful biomarker not only for the initial diagnosis but also for following disease activity of the patients with IgG4-RD.^21,22 By flow cytometry, plasmablast concentration can be measured by gating CD19^lowCD38⁺CD20-CD27⁺ cells. Concentration of IgG4+ plasmablasts can be also determined by flow cytometry.²¹ Additional studies are required, however, before plasmablast concentration by flow cytometry can be widely used as a clinical test.

Mild to moderate eosinophilia is found in 34% of IgG4-RD patients, but this finding is nonspecific. Elevated C-reactive protein (CRP) levels were reported in 23% of cases; even in the setting of multiorgan disease, however, elevations in serum CRP are generally modest and are less pronounced than in erythrocyte sedimentation rate. Polyclonal hypergammaglobulinemia (total serum IgG levels >1,800 mg/dL) was reported in 313 of 510 (61%). Serum IgE level was elevated in 58%.^{7,23,24,25,26,27,28} No specific autoantibody has been described consistently in patients with IgG4-RD, but the presence of nonspecific antibodies prevalent to other immune-mediated conditions is not uncommon; antinuclear antibody (ANA) and rheumatoid factor (RF) are found in nearly 30% and 20%, respectively. Hypocomplementemia is quite common especially in the patients with renal involvement by IgG4-RD.²⁰