A Case of IgG 4-Related Disease Admitted with CRP Elevation of Unknown Origin

We describe the case of a 32-year-old man with C-reactive protein (CRP) elevation of unknown origin who was transferred to Juntendo University Hospital on suspicion of systemic viral infection. Whole-body computed tomography (CT) showed enlargement of the para-aortic, common iliac and axillary lymph nodes. Laboratory data showed elevated levels of immunoglobulin (Ig)G4. Axillary lymph node biopsy was performed to investigate suspected IgG4-related disease, revealing marked infiltration of IgG4-positive plasma cells. Various imaging modalities and laboratory tests have recently become available. However, most neoplastic diseases need invasive testing such as biopsy to reach a definitive diagnosis. Clinicians should not hesitate to obtain pathological specimens to definitively diagnose patients with suspected neoplastic disease.


Introduction
One of the characteristics of the Department of General Medicine at Juntendo University Hospital is its ability to examine fever of unknown origin (FUO) and inflammatory diseases of unknown etiology.We describe the case of a 32-year-old man with C-reactive protein (CRP) elevation of unknown cause and report the process involved in making a definitive diagnosis.

Case presentation
A 32-year-old man presented to a clinic 6 months after noticing bilateral axillary lymph node enlargement.Blood testing showed CRP elevation, but no other significant abnormality.Whole-body computed tomography (CT) was performed to evaluate other lesions and showed enlargement of the para-aortic, common iliac and axillary lymph nodes.Small nodular lesions in both lung fields and bronchial wall thickness were detected (Figure -1).Splenomegaly was also revealed.Systemic viral infection such as human immunodeficiency virus (HIV) infection was suspected and he was transferred to Juntendo University Hospital for further evaluation.Past medical history included bronchial asthma and type 2 diabetes.The patient was allergic to buckwheat, was a non-smoker and drank alcohol socially.He had no history of travelling outside of Japan, no pets, no contact with animals, and no history of having sex with men.Laboratory data at our hospital showed elevated CRP and hyperproteinemia (Table-1A).We performed additional blood tests, showing elevated levels of immunoglobulin (Ig)G and IgE.Levels of soluble interleukin-2 receptor (sIL-2R) were also elevated.Negative results were obtained for antinuclear antibody (ANA) and no antibody statuses showed evidence of active viral infection (Table-1B).Acid-fast staining and culture of a gastric aspiration specimen yielded negative results.Additional blood testing was performed, revealing an elevated level of IgG4 (438 mg/dl).Left axillary lymph node biopsy was performed to investigate suspected IgG4-related disease (IgG4-RD).Pathological examination showed marked infiltration of plasma cells into lymphatic sinuses.Neither atypical lymphocytes nor malignant cells were detected.Immunohistochemistry demonstrated IgG-positive plasma cells, with > 50 IgG4-positive plasma cells per high-power field and an IgG4/IgG ratio > 40% (Figure -2).The patient was therefore diagnosed with IgG4-RD.

Discussion
IgG4-RD has recently been recognized as a systemic disease with IgG4-positive plasma cells infiltrating into various organs and lymph nodes.IgG4-RD has been shown to be related to various diseases, including autoimmune pancreatitis (AIP), Ridelʼ s thyroiditis, interstitial nephritis, inflammatory pseudotumor, and retroperitoneal fibrosis.As the symptoms and pathological findings of IgG4-RD depend on the location of the lesions, establishing criteria suitable for all patients with IgG4-RD is difficult.Comprehensive diagnostic criteria for IgG4-RD have therefore been proposed, and we diagnosed IgG4-RD in the present case according to those suggested by Umehara et al. 1) The patient had bronchial asthma and was allergic to buckwheat.IgG and IgE levels were both elevated.The Th2-type cytokines IL-4 and IL-13 induce isotype switching of B cells to both IgE and IgG4 2) 3) .Allergic manifestations and IgG4-RD are reportedly related 4) .Some IgG4-RD patients display allergic symptoms such as asthma, atopy and eosinophilia, up to 40% of cases reportedly present with sinusitis and bronchial asthma 5) .The allergic history of the patient might thus have been related to IgG4-RD.
Lymphadenopathy is a common clinical manifestation.Patients with IgG4-RD often have a good general condition at the time of diagnosis and generally present with no fever or constitutional symptoms 6) .Because IgG4-RD may occur in various organs and the clinical manifestations are not specific, patients sometimes visit departments of general medicine, and we actually diagnose some cases of IgG4-RD.The disease usually shows good response to steroid therapy.Here we show 2 cases of IgG4-RD which we have experienced.Case 1 was 59-year-old Japanese man who had appetite loss and back pain.He was diagnosed by inguinal lymph node and renal biopsy.Serum IgG4 level was 1,970 mg/dl.Case 2 was 70-year-old Japanese man and biopsy was performed from nasal polyp and lachrymal gland.He had systemic lymphadenopathy and also variety of complication such as sepsis, hypothyroid function, pericarditis, pleurisy, post peritoneal fibrosis, and pseudo liver tumor.Serum IgG4 level was 2,230 mg/dl.For both cases, elevation of IgG4 level and histopathological findings (infiltration of plasma cells) were key remarks.Both had oral steroid for treatment and the symptoms got improved.

Figure- 1
Figure-1 Computed tomography (CT) A, B. Small nodular lesions and bronchial wall thickness in both lungs.C. Enlargement of bilateral axillary lymph nodes.D. Enlargement of para-aortic lymph nodes.

Table 1
A. Laboratory data on first examination at Juntendo University Hospital.B. Additional laboratory data.
To find such kind of important diseases, we have to check additional symptoms.They are continuous fever, loss of body weight, fatigue and elderly age.Lymphadenopathy getting bigger or systemic lymphadenopathy also needs detailed examination.Z-score is known for scoring system whether to perform lymph node biopsy 7) (Table-2).In this case, although Z-score is relatively low (-3), continuous inflammation and systemic lymphadenopathy supported to perform biopsy.Various noninvasive imaging modalities and laboratory tests are now available.However, most neoplastic diseases need invasive testing such as biopsy to reach a definitive diagnosis.As is often said,"tissue is the issue" , and clinicians should not hesitate to obtain pathological specimens to reach the definitive diagnosis in patients with suspected neoplastic disease.