A case of eosinophilic granulomatosis with polyangiitis complicated with a similar condition to IgG4 related lung disease

A 41-year-old Chinese male was admitted to our hospital because of a 3-year history of recurrent productive cough and new onset of recurrent hemoptysis and fever for 6 months. Three years ago, the patient had been admitted to the local hospital because of cough and expectoration, and the chest computed tomography (CT) scan revealed bilateral lower lung infection. Not much improvement of respiratory symptoms had been observed, although treatments of anti-infection and anti-tuberculosis had been administrated in turn. Besides, the patient suffered a new onset of intermittent symmetric pain of limb joints, swelling of the upper eyelid, and erythematous maculopapular rash on the dorsal surfaces of the metacarpophalangeal joint, bilateral elbow joint, and proximal interphalangeal joint. Both lower limbs developed a livedo reticularis appearance after standing for approximate 5 min. Six months before admission, the patient experienced hemoptysis and developed a fever with maximum temperature of 38.5 °C. The frequency of redness and swelling of upper eyelids increased with and left and right eyelids alternated once a week. The new soybean-sized subcutaneous nodules with tenderness were found on the bilateral finger pulp. High potency anti-infection, anti-tuberculosis and anti-fungus treatment were given but demonstrated ineffectiveness with accelerated cough and expectoration. The patient had a 3-year history of sinusitis and family history of asthma. And he had no previous history of smoking and drinking.

Physical examination showed redness and swelling of right eyelid, and gastrocnemius tenderness. And fine moist rales and wheezes were heard in both lower lung fields. An erythematous maculopapular rash on the dorsal surfaces of the metacarpophalangeal joint of the right hand and dark red pigmentation on the right elbow were found. Laboratory studies revealed lightly elevated leukocyte count (10.73 × 10^⁹/L), and markedly increased eosinophil count and percentage (1.26 × 10^⁹/L, 11.7%), erythrocyte sedimentation rate (99 mm/h) and C-reactive protein (167 mg/L). Further laboratory studies showed increased levels of serum IgG (30.8 g/L) and highly elevated levels of serum IgG4 (24.5 g/L). Tests for IgE levels, complement system, Anti-nuclear antibody, anti-extractable nuclear antigen antibody, dermatomyositis-associated antibodies, myeloperoxidase-ANCA, proteinase-3-ANCA, anti-cardiolipin antibody, anti-cyclic citrullinated peptide antibody and rheumatoid factor were all normal. The ultrasounds of parotid gland, submandibular gland, thyroid, heart were all normal. Pulmonary function tests showed severe mixed pulmonary ventilation dysfunction, moderate pulmonary diffusion function,negative bronchodilation test. And the diurnal variation of peak expiratory flow (PEF) was more than 10% and the value of fractional exhaled nitric oxide was also high (26 ppb). A chest CT scan revealed diffuse ground-glass opacities in both lungs and patches with increased density and blurred edges (Fig. 1a-b). A CT scan of the sinuses showed ethmoid sinusitis on the left side and maxillary sinusitis bilaterally. Bronchoscopy did not find any abnormalities and bronchoalveolar lavage fluid showed normal cellular counts and eosinophil count. Bone marrow puncture showed active proliferation of bone marrow cells, in which the proportion of osinophils was 12%, and no abnormal pathological cells were observed. The genetic analyses showed normal FIP1L1/PDGFRα and ETV6-PDGFRβ fusion genes. Pathological examination of lung biopsy showed fibrosis, infiltration of lymphocytes, plasma cells and histocytes, and the presence of eosinophils in small vessels of bronchiolar walls. Immunohistochemistry revealed CD38+, CD138+, IgG+, and IgG4+ cells in which the ratio of IgG4+ to IgG+ plasma cells was greater than 40% and there were more than 10 IgG4+ plasma cells per high-power field (Fig. 2). The skin biopsy showed enriched infiltration in the vasculature and interstitial spaces of the whole dermis by eosinophils, neutrophils, and lymphoid tissue, along with focal fibrinoid necrosis in the reticular dermis (Fig. 3).

There are no commonly accepted diagnostic criteria for EGPA. And the classification criteria for EGPA defined by American College of Rheumatology (ACR) was widely used by clinician [7]. It is composed of six criteria for EGPA: (1) asthma, (2) eosinophilia>10%, (3) neuropathy(mono- or poly-neuropathy), (4) non-fixed pulmonary infiltrates, (5)paranasal sinus abnormality, (6) extravascular eosinophil infiltration on biopsy finding. When four or more of the above six criteria are present, vasculitis can be classified as EGPA with a sensitivity of 85% and specificity of 99.7%. Our patient had typical symptoms (cough, shortness of breath) and physical sign (wheezes in lower lungs) of asthma for more than 3 years. And the average daily diurnal PEF variability was more than 10%. Besides, the patient had the family history of asthma plus with high value of fractional exhaled nitric oxide. Therefore, the diagnosis of asthma was established. The possible cause for the negative bronchodilation test is that the patient was taking inhaled budesonide-formoterol (inhaled corticosteroids-long-acting beta₂-agonist drug, ICS-LABA) medication to relieve shortness of breath before admission and during hospitalization. Furthermore, the percentage of blood eosinophil was 11.7%, which was more than 10%. The patient also had a 3-year history of sinusitis, which was also confirmed by CT scan of sinuses. The chest CT scan showed non-fixed pulmonary infiltration, with multiple patches in both lungs and ground-glass opacities. Moreover, the skin biopsy showed enriched eosinophil infiltration in the vessels and interstitial spaces of the dermis. Therefore, the patient was diagnosed as EGPA with following diagnostic basis: asthma, peripheral blood eosinophilia (>10%), paranasal sinusitis, transient pulmonary infiltration and eosinophil infiltration of the skin.

We discontinued all of the patient’s medications which had been prescribed before admission. Immunosuppressive treatment with intravenous methylprednisolone (80 mg × 3d, 40 mg × 3d)was started and followed by oral methylprednisolone (40 mg/d). Seven days later, respiratory symptoms, like cough and expectoration, were improved. Hemoptysis, fever, redness and swelling of eyelid and polyarthralgia were all completely disappeared. The follow-up laboratory tests showed reduced eosinophils count and percentage (0.07 × 10^⁹/L, 0.40%), and serum IgG4 level (16.6 g/L). After discharge, treatment of oral methylprednisolone with 35 mg/d and intravenous cyclophosphamide (0.4 g per 2 week) were both administrated. One month later, cough, expectoration, maculopapular rash, subcutaneous nodules, reticulated blemishes were all completely disappeared. Gastrocnemius tenderness was also reduced. The follow-up laboratory tests showed further decreased eosinophils count and percentage (0.01 × 10^⁹/L, 0.10%) and serum IgG4 level (7.41 g/L). The follow-up thoracic CT scan showed that bilateral lung lesions were also significantly improved (Fig. 1c-d). Summary of the patient’s symptoms and corresponding treatment was described in the Table 1.