{'fraction_non_alphanumeric': 0.03294449429560313, 'fraction_numerical': 0.011024227663120114, 'mean_word_length': 5.66268146883006, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 4, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Immunoglobulin G4 Related-Disease: A Rare Presentation With Secondary Hypereosinophilic Syndrome and Eosinophilic Ascites

Immunoglobulin G4 related-disease (IgG4-RD) is a multisystemic immune-mediated fibroinflammatory disease, with a strong predilection for salivary and lacrimal glands, pancreas, biliary tree, lungs, kidneys, aorta, and retroperitoneum. In the case of pancreatic involvement, it manifests as autoimmune pancreatitis. Patients with IgG4-RD usually have mild to moderate eosinophilia in the peripheral blood, however, they may present a secondary hypereosinophilic syndrome (HES). Although there are cases described with severe eosinophilia (> 5,000/µL), the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD considers peripheral eosinophilia above 3,000/µL as an exclusion criterion, although stating that assessment for the presence of exclusion criteria should be individualized depending on a patient’s clinical scenario. Here, we describe the clinical case of a 30-year-old woman who presented with chronic diarrhea and abdominal pain. The diagnostic workup revealed eosinophilic ascites, severe peripheral blood eosinophilia (> 5,000/µL), IgG4 elevation (> 2 × upper normal limit), and also diffuse swelling in the body and pancreatic tail (computed tomography (CT) scan). There was a prompt response to corticosteroid therapy with clinical resolution and continued remission under therapy. The patient was diagnosed with IgG4-RD with secondary HES, explaining the gastrointestinal tract and peritoneum damage in the form of enterocolitis and ascites. Exclusion of alternative diagnosis was made.


Introduction
Immunoglobulin G4 related-disease (IgG4-RD) is a multisystemic immune-mediated fibroinflammatory disease, with a broad spectrum of organ system involvement [1]. IgG4-RD is a relapsing and remitting condition clinically characterized by mass-forming lesions, which has a strong predilection for salivary and lacrimal glands, pancreas, biliary tree, lungs, kidneys, aorta, and retroperitoneum, increased serum IgG4 concentration, and prompt response to glucocorticoid treatment. The histopathological diagnosis of IgG4-RD rests on the combined presence of a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis together with increased numbers of IgG4 + plasma cells [2].
As autoimmune pancreatitis (AIP), pancreatic involvement was among the first described manifestations of the disease and is one of the most commonly involved organs [3]. Clinically, it may present with or without painless jaundice, with the development of hyperglycemia and steatorrhea being uncommon. The most frequently used diagnostic criteria for AIP, under the acronym HISORt, are based on the presence of characteristic histological and imaging features, serology, other organ involvement, and adequate response to corticosteroids [4].
We describe a case of a patient presenting IgG4-RD with secondary HES, with severe eosinophilia causing several organ damage types due to tissue infiltration of eosinophils, explaining the gastrointestinal tract and peritoneum damage in

Case Report
We present a case of a 30-year-old woman with a history of allergic rhinitis and atopy without current medication. She was admitted to our service with chronic diarrhea (started 2 months earlier), with more than seven mucus stools daily, abdominal pain, nausea, vomiting, and increased abdominal perimeter.
The patient suffered worsening of complaints in the first 48 h, with profuse diarrhea, severe abdominal pain, and AEC rising (5.23 × 10 3 /µL). She was put on systemic corticosteroid therapy with a single dose of 125 mg intravenous (IV) methylprednisolone and then 40 mg prednisolone with immediate AEC reduction (Fig. 1), progressive improvement of abdominal complaints, reduction in the number of bowel discharges, and regression of ascites without the need to drain.
The etiologic study of the systemic eosinophilia showed (Table 1) Stool analysis revealed fat droplets and some digested   (Fig. 2); stomach with signs of superficial gastritis; duodenum with a polymorphic inflammatory infiltrate in the chorion with frequent eosinophils; ileus with discrete to moderate polymorphic inflammatory infiltrate in the chorion containing frequent eosinophils expanding the lamina propria, signs of activity and images of transepithelial migration of lymphocytes (Fig. 3); and colon with a slight distortion of the architecture and decreased mucosecretory activity, moderate to intense polymorphic inflammatory infiltrate, containing eosinophils, expanding the lamina propria, subepithelial lymphoid aggregates, and absence of granulomas. Bone marrow (BM) aspirate was performed 7 days after starting corticosteroids, showing normocellular BM, myeloid series without morphological changes, eosinophils, and their precursors with normal morphology, small lymphocytes and condensed chromatin, no suggestive signs of involvement by neoplastic cells. Search for FIP1L1/PDGFRa transcripts using nested RT-PCR was negative. Peripheral blood cytometry showed no changes pointing to lymphoproliferative disease.
On the eighth day of corticosteroid therapy, the abdominal CT scan showed slightly increased homogeneous liver with regular contours and without focal nodular changes; pancreas with globose morphology, diffuse swelling in the body and tail suggestive of autoimmune pancreatitis; multiple mesenteric infracentimetric adenopathies; and small volume ascites. No other relevant findings were observed. A pancreatic biopsy was not performed.
Autoimmune pancreatitis in the context of IgG4-RD was assumed with secondary HES with enterocolitis and eosinophilic ascites. The patient was discharged after 10 days with tapering corticosteroids. Six months later, the patient is being followed as an outpatient. Her condition is stable, without significant symptoms, and she is taking prednisolone 2.5 mg once daily (OD).

Discussion
IgG4-RD is a multisystemic immune-mediated fibroinflammatory disease [1] that can involve the pancreas as an AIP [3]. Regarding AIP criteria (HISORt) [4], our patient fulfills three diagnostic criteria: pancreatic imaging suggestive of autoimmune pancreatitis, serology criteria with IgG4 ≥ 2 times the normal upper limit, and response to steroid treatment with marked improvement pancreatic and extrapancreatic manifestations. The histological criterion was not accessed since pancreatic biopsy was not performed, as it is an invasive procedure; it was not necessary to assume the diagnosis and the patient had a favorable response to treatment. The involvement of the gastrointestinal tract in IgG4-RD may occur, but it is uncommon [3].
HES is a rare syndrome with hypereosinophilia (> 1.5 × 10 3 /µL) and organ damage [5] that can be primary (myeloproliferative), secondary or unknown, being IgG4-RD a secondary cause of HES [8]. In contrast to primary HES, the eosinophilia  secondary to IgG4-RD is usually mild to moderate, typically quite evanescent, ablated by steroids or rituximab therapy [6]. In our patient's case, who presented HES, primary HES was the main differential diagnosis; however, the absence of alterations of the myeloid lineage in BM, negative FIP1L1/PDGFRa gene fusion, and a positive response after starting corticosteroid therapy does not corroborate this diagnosis. Another diagnosis that was considered was ANCA-associated vasculitis, however, it was discarded due to the absence of findings in the immunological study, absence of granulomas, and the absence of elevation of CRP/ESR that usually accompany vasculitis.
Thus, the diagnosis of IgG4-RD was assumed with secondary HES with organ damage at the gastrointestinal tract and ascites.