Background
Eosinophilic granulomatosis with polyangiitis(EGPA), previously called Churg-Straus syndrome, is a rare systematic disorder histopathologically characterized with eosinophilic infiltration, extravascular granulomas and necrotizing vasculitis predominantly affecting small to medium-sized vessels [
1]. Recent research described the epidemiologic and demographic features of EGPA which showed a prevalence rates of two to 22.3 per million and the annual incidence rates of 0.5–3.7 per million and incidence peak occurred at the age of 30 to 40 or 55 to 64 year-old [
2]. The clinical manifestations of EGPA are involved with severe asthma, allergic rhinitis, blood and tissue eosinophilia with cardiac, gastrointestinal, skin, renal involvement and peripheral neuropathy. And EGPA is classically considered as a Th2-mediated disease and can be subclassified as antineutrophil cytoplasmic antibodies (ANCAs) positive, which are only found in 30–40% patients with EGPA, and ANCA-negative EGPA [
3,
4]. However, the accurate diagnosis of EGPA is often difficult, because of the similar or overlapping clinical manifestations to chronic eosinophilic pneumonia, hypereosinophilic syndrome, other primary systemic vasculitis, and hyper-immunoglobulin G4 syndrome [
5]. IgG4-related disease (IgG4-RD) is a novel systemic immune-mediated fibro-inflammatory condition involving multiple organs, and characterized by markedly increased serum IgG4 level, lymphoplasmacytic infiltration with abundant IgG4-positive plasmacytes, storiform fibrosis and obliterative phlebitis [
6]. However, clinical data found increased level of serum IgG4 and/or elevated serum IgG4/IgG ratio in patients with active EGPA. And increases in IgG4 positive plasma cells were also found in the tissue biopsies from patients with EGPA [
5]. Similarity between these two diseases often causes the diagnostic dilemma to differentiate them. Herein, we report a case of EGPA patient with a pathological condition similar to IgG4-related lung disease and discuss the similarity and the key difference between these two conditions. The report aims to improve the awareness of these two rare clinical diseases and prevent the diagnostic dilemma in clinical practice.
Discussion and conclusion
The present report shows a rare case of EGPA complicated with marked elevation of serum IgG4 concentration and abundant IgG4+ plasmacytes infiltration in the lung tissue, which lead to the a diagnostic difficulty regarding whether IgG4-related lung disease should be concluded to this patient. The updated comprehensive diagnostic criteria for IgG4-RD includes: (1)clinical manifestation with typical diffuse/localized swelling or masses in single/multiple organs; (2)elevated serum IgG4 concentrations(>1.35 g/L); (3) characteristic histopathological examination showing significant lymphocytes and plasmacytes infiltrate, fibrosis and enriched infiltration of IgG4+ plasmacytes with ratio of IgG4+ to IgG+ cells >40% and >10 IgG4+ plasma cells per high-power field [
8]. Definite IgG4-RD was established by suggestive organ involvement, combination with highly increased serum IgG4 levels and characteristic histological manifestations. However, storiform fibrosis and obliterative phlebitis with lymphoplasmacytic infiltration, two specific histopathological features in the patients with IgG4-RD, and involvement of other organs (lacrimal or salivary gland, lymph nodes, pancreas or kidney etc.) were absent in our case, which hesitated us whether it is reasonable to give a diagnosis of IgG4-RD simultaneously. No organ-specific diagnostic criteria has been established for IgG4-related lung disease. Markedly elevated serum IgG4 level and enriched infiltration of IgG4+ plasma cells in this patient may implicate the diagnosis for IgG4-RD, but we could not confirm whether eyelids swelling and lung lesions (diffuse ground glass, patchy density) were resulted from IgG4-RD.
In recent years, elevation of serum IgG4 level and/or IgG4+ plasma cells infiltrate were found in multiple lung diseases, such as pulmonary malignancy, granulomatosis with polyangiitis, EGPA, interstitial pneumonias, multicentric castleman’s disease [
6]. A high ratio of IgG4 to IgG positive plasma cell (>40%) and >50 IgG4+ plasma cells in a high-power filed without extra-thoracic manifestation of IgG4-RD have been reported in 5 patients with surgical lung biopsy-proved idiopathic interstitial pneumonia in a retrospective study [
9]. EGPA may be also accompanied by elevated serum IgG4 levels. Several studies have showed elevated serum IgG4 level [
10,
11] and/or infiltration of IgG4-positive plasma cell in the tissue biopsy, two crucial features in patients with IgG4-RD, among EGPA patients [
12,
13]. Nobuhiro et al. described a EGPA case with a similar clinical condition of IgG4-related kidney disease, in which the patient was involved with a high serum IgG4 level, salivary gland swelling, tubulointerstitial nephropathy and infiltrate of IgG4 positive plasmacytes in the renal tissue, although the ratio of IgG4+ plasma cells to all IgG+ plasma cells is about 10% (less than 40%). Suguru et al. presented a case showing numerous infiltration of IgG4-positive plasma cells (about 50%) in the right upper eyelid and high serum IgG4 concentration (119 mg/dl) during the disease course of EGPA [
13]. Besides, the ratio of serum IgG4 to IgG and IgG4 levels were elevated in the disease course. Furthermore, a study found that there was no significant difference in IgG subclasses between IgG4-RD and EGPA [
11]. A European retrospective multicenter observational study in patients with diagnosis of ANCA-associated vasculitides and IgG4-RD concomitantly showed that lymphoplasmacytic infiltration with IgG4/IgG ratio>40% and/or> 10 IgG+ plasma cell per high-power field was noted in the kidney, orbital mass or aorta biopsy [
14]. On the other hand, studies showed that up to 50% of patients with IgG4-RD have a clinical history of allergic condition, such as asthma, sinusitis [
15]. Marked eosinophilia and highly elevated IgE levels, which are features of EGPA, have also been commonly reported in patients with IgG4-RD. [
16,
17] All above studies demonstrated a diagnostic dilemma and overlapped immunopathogenetic mechanisms existed in the disease course of these two diseases. Or whether IgG4-RD can be developed from EGPA?
Up-regulated responses of T helper (Th) 2 cell and T regulatory (Treg) cells and their cytokines (interleukin (IL)-4, IL-5, IL-13, IL-10 and transforming growth factor beta 1) play a key role in the pathogenesis of IgG4-RD. [
15] EGPA is classically considered as a Th2 cellular-mediated immune-inflammatory disease, in which high levels of Th2-associated cytokines (IL-4, IL-5 and IL-13) are secreted and precipitates a B-cell response resulting in the production of IgE, IgG4 and ANCA and simultaneously increases expression and secretion of eotaxin-3 guiding eosinophil to the endothelium and tissues resulting in the eosinophilia and damage of organs [
4]. The cytokines IL-4, IL-5, IL-13 have been demonstrated to be involved in triggering the production of IgE or generation of IgE-producing plasma cells and promoting the production of IgG4 [
18]. Besides, IgG4, a Th2-dependent IgG subclass, and IgE both can be induced by allergens [
19]. More importantly, IgE can be switched into IgG4 under the effect of IL-4 and IL-13, which indicates elevated levels of IgG4 in the Th2-immune responses may be associated with the increases of IgE. Above evidences seem to well explain, to some extent, why EGPA and IgG4-RD share common clinical manifestations, like asthma and allergy, markedly elevated IgG4 levels, and abundant infiltration of IgG4 positive plasma cells. And we consider whether our patient was just during the early stage of IgG4-RD. Or maybe EGPA interact with IgG4-RD and the disease course of EGPA can promote the onset of IgG4-RD due to the overlap pathogenesis.
In summary, giving a diagnosis of IgG4-RD may be challenging in such cases and requires a comprehensive consideration with clinical symptoms, laboratory examinations and histopathologic studies. We gave the patient the diagnosis of EPGA complicated with probable IgG4-RD eventually. Fortunately, recommended first-line therapy for EPGA and IgG4-RD are both immunosuppressive therapy with glucocorticoids [
6,
20]. In our case, the patient received intravenous methylprednisolone and adjuvant treatment with intravenous pulses of cyclophosphamide because of involvement of multiple organs. The patient’s pulmonary and systemic symptoms, pulmonary lesions, laboratory tests for blood eosinophil count and serum IgG4 levels were all significantly improved with above treatment.
In conclusion, it is the first report showing markedly elevated serum IgG4 levels and abundant infiltration of IgG4 positive plasma cells in the lung tissue simultaneously in patient with EGPA, which strongly suggest us that EGPA and IgG4-RD may share an overlapped pathogenesis in local and systemic IgG4 response. We consider that EGPA and IgG4-RD may intersect in the course of disease and, in some extent, the development of one disease can influence the onset of another disease. Further studies should be required to investigate the potential mechanism.
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