A Rare Case of Eosinophilic Granulomatosis with Polyangiitis Following Development of Central Diabetes Insipidus: A Case Report and Literature Review

Abstract

Central diabetes insipidus (CDI) can develop as an acquired systemic disease. However, cases of eosinophilic granulomatosis with polyangiitis (EGPA) with concurrent CDI are rare. We herein report a case of EGPA following CDI. A 68-year-old woman with a 30-year history of sinusitis and asthma developed CDI, followed by severe renal dysfunction with eosinophilia and elevated myeloperoxidase-antineutrophil cytoplasmic antibody levels. A renal biopsy confirmed EGPA. Intensive treatment resulted in dialysis discontinuation, while partial improvement in arginine vasopressin secretion suggested a potential link between EGPA and CDI. We also conducted a literature review on concurrent EGPA and CDI. Clinicians should be aware of EGPA in CDI patients with asthma or sinusitis.

Introduction

Eosinophilic granulomatosis with polyangiitis (EGPA) predominantly affects middle-aged adults and is preceded by bronchial asthma or allergic rhinitis (1-3). The primary clinical manifestations include eosinophilia and systemic or localized vasculitis. Similar to microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), vasculitis symptoms, such as a fever, weight loss, peripheral neuropathy, myalgia, arthralgia, purpura, gastrointestinal bleeding, and pulmonary lesions, are commonly observed.

Central diabetes insipidus (CDI) can develop as an acquired condition with various causes, including lymphocytic hypophysitis and systemic diseases such as vasculitis (especially GPA), sarcoidosis, and systemic lupus erythematosus, as well as surgical interventions, malignancies, and traumatic brain injury (4). However, cases of EGPA with concurrent CDI are extremely rare, and their pathophysiology and clinical characteristics remain poorly understood.

In the present case, a patient with a history of CDI developed EGPA with severe renal impairment. Vasculitis subsequently improved following multidisciplinary treatment. In addition, a mild improvement in arginine vasopressin (AVP) secretion was observed following a multidisciplinary approach, indicating a potential association between EGPA and CDI. We conducted a literature review of cases of concurrent EGPA and CDI to investigate the clinical course of both conditions and the outcomes of CDI following EGPA treatment.

Case Report

A 68-year-old Japanese woman with general malaise and anorexia was referred to our hospital. She had had sinusitis for 45 years and had undergone endoscopic sinus surgery 6 years previously, with a pathological diagnosis of eosinophilic sinusitis. In addition, she had been diagnosed with asthma 38 years prior.

Seventeen months ago, symptoms of thirst, polydipsia, and polyuria had appeared. Urinary, blood, and imaging examinations for polyuria revealed decreased urine osmolality, poor AVP response in a hypertonic saline infusion test, and reduced signal intensity on T1-weighted magnetic resonance imaging (MRI) of the pituitary posterior lobe, leading to a diagnosis of CDI. MRI showed no pituitary tumor or structural abnormalities, and the etiology was considered idiopathic, as lymphocytic hypophysitis, sarcoidosis, lupus, malignancies, trauma, and surgical causes were ruled out by medical history, blood tests, and imaging. In addition, the patient's hormone levels (serum thyroid-stimulating hormone 1.5 mIU/mL, adrenocorticotropic hormone 20.9 pg/mL, luteinizing hormone 27.5 mIU/mL, follicle-stimulating hormone 68.8 mIU/mL, growth hormone 0.21 ng/mL, and prolactin 12.2 ng/mL) were within normal ranges. At that time, myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) was slightly elevated (9.3 U/mL), but there was no evidence of vasculitis, such as purpura or glomerulonephritis. Magnetic resonance angiography revealed no irregularities in the caliber of major cerebral vessels.

Desmopressin was initiated, and her symptoms resolved. Thereafter, serum creatinine ranged from 0.5 to 0.6 mg/dL, and hematuria and urinary protein were negative. Two months before readmission, she developed general malaise and anorexia, which did not improve. She was referred to our hospital and admitted for severe kidney injury, with a serum creatinine level of 4.86 mg/dL.

The patient's vital signs on admission were as follows: blood pressure, 149/70 mmHg; pulse rate, 65 beats per minute, temperature 36.6°C, respiratory rate, 10 beats per minute; pulse oximetry, 98%. The patient lost 7 kg within 1 month. A physical examination revealed no abnormal heart or respiratory sounds, edema of the lower legs, or an obvious skin rash or purpura. Blood tests revealed a white blood cell count of 17,830 /μL (eosinophils, 21%) and marked eosinophilia. Creatinine level was elevated at 5.21 mg/dL, and her C-reactive protein (CRP) level was 8.38 mg/dL, indicating inflammatory changes. MPO-ANCA was positive at 88.8 U/mL. A urinalysis revealed mild microscopic hematuria and proteinuria (Table 1). No significant bacteria were detected in sputum, urine, or blood cultures.

Table 1.

Laboratory Data on Admission.

Laboratory tests	Results	Normal range	Laboratory tests	Results	Normal range
Urinalysis			Sodium (mEq/L)	133	133-145
Protein	1+	-	Potassium (mEq/L)	5.5	3.3-5.1
Occult blood	1+	-	Chloride (mEq/L)	100	95-108
Erythrocytes (/HPF)	1-4	<5	Calcium corrected for serum albumin (mg/dL)	10.5	8.8-10.4
Leukocytes (/HPF)	5-9	<5	Phosphorus (mg/dL)	4.6	2.7-4.6
Protein creatinine ratio (g/gCr)	0.74	<0.15	Ferritin (ng/mL)	461	12-60
β2-microglobulin (mg/L)	0.017	<0.2	C reactive protein (mg/dL)	8.38	<0.3
urinary osmolarity (mOsm/kg·H2O)	339	50-1,300	HbA1c (%)	6.2	4.6-6.2
Bence Jones protein	-	-	Immunoglobulin G (mg/dL)	2,054	870-1,700
Blood test			Immunoglobulin A (mg/dL)	231	110-410
White blood cells (×103/μL)	17.8	4-10	Immunoglobulin M (mg/dL)	112	33-190
Neutrophil (%)	59.7	46-62	Immunoglobulin G4 (mg/dL)	180	11-121
Lymphocyte (%)	12.5	30-40	IgE (IU/mL)	220	<170
Monocyte (%)	5.7	4-7	Serum C3 (mg/dL)	113	80-140
Eosinophil (%)	21.0	3-5	Serum C4 (mg/dL)	29.1	11-34
Hemoglobin (g/dL)	8.9	12-15	CH50 (CH50/mL)	47	30-45
Platelet (×103/μL)	82	150-450	Antinuclear antibody	<40	<40
Aspartate aminotransferase (IU/L)	11	10-35	MPO-ANCA (U/mL)	88.8	<3.5
Alanine aminotransferase (IU/L)	6	10-35	PR3-ANCA (U/mL)	<1.0	<2.0
Lactate dehydrogenase (IU/L)	150	120-245	Anti-GBM antibody (U/mL)	8.4	<7
Total protein (g/dL)	7.4	5.5-8.0	Hepatitis B surface antigen	-	-
Albumin (g/dL)	2.7	3.5-5.5	Anti-Hepatitis C Virus antibody	-	-
Creatinine (mg/dL)	5.21	0.50-0.90	Haptoglobin (mg/dL)	429	19-170
Urea nitrogen (mg/dL)	72.0	8-20	M protein	-	-

Chest computed tomography (CT) revealed multiple consolidations in both lungs (Fig. 1). Electrocardiography and echocardiography showed no abnormalities in the cardiac function. A renal biopsy was performed on day 8 after admission. There were 20 total glomeruli, including 4 globally sclerotic glomeruli, 10 cellular crescents, and 3 fibrocellular crescents. Some of the cellular crescents showed fibrinoid necrosis and Bowman capsule rupture (Fig. 2a). Approximately 50% of the interstitium was infiltrated by inflammatory cells, and numerous eosinophilic infiltrates were observed (Fig. 2b). Fibrinoid necrosis was observed in the interlobular arterial walls (Fig. 2c). An immunofluorescence microscopic examination revealed negative staining for IgG, IgA, IgM, C1q, C3, and C4, and an electron microscopic examination showed no electron-dense deposits. Eosinophil-rich inflammation and necrotizing vasculitis, bronchial asthma, eosinophilic sinusitis, and weight loss as symptoms of vasculitis led to a diagnosis of EGPA.

Figure 1.

Plain chest computed tomography (CT) findings. Newly identified diffuse consolidations were observed in both lungs on admission (left panel, circles). CT findings on day 37 (post-admission) demonstrating improvement in lung consolidation (right panel).

Figure 2.

Light microscopic findings for the renal biopsy specimen. (a) Cellular crescent with fibrinoid necrosis and rupture of Bowman’s capsule (periodic acid-methenamine-silver stain, ×40). (b) Approximately 50% of the interstitium showed inflammatory cell infiltration, with prominent eosinophilic infiltrates (Hematoxylin and Eosin staining, ×20). (c) Fibrinoid necrosis in the wall of interlobular artery (periodic acid-methenamine-silver stain, ×20). b and c are images of the same location.

The patient's five-factor score was 2 (elderly onset and renal failure) and was associated with a poor prognosis (5). According to the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria, the patient met the criteria for a maximum eosinophil count ≥1×10⁹/L (+5), obstructive airway disease (+3), and extravascular eosinophilic predominant inflammation (+2), totaling 6 points or more (6). However, she did not meet the criteria for MPA or GPA based on Watts' algorithm (7). ANCA positivity was inconsistent with typical hypereosinophilic syndrome (HES) (8). Infections such as parasites and allergic bronchopulmonary aspergillosis were absent. Although the patient's serum IgG4 level was elevated, CT revealed no salivary gland, pancreatic, or retroperitoneal masses, and renal pathology showed no significant plasma cell infiltration or characteristic fibrotic lesions. Therefore, IgG4-related diseases were not suspected.

The clinical course of the patient is shown in Fig. 3. Standard intravenous methylprednisolone pulse therapy (1,000 mg/day for 3 days) was initiated on day 9 after admission, followed by maintenance steroid therapy with prednisolone 50 mg/day. Rituximab (RTX; 375 mg/m²) was administered 3 times, and plasma exchange therapy was performed 7 times. After starting treatment, the patient required hemodialysis for a period of time, but this was discontinued, and her creatinine level improved to 2.0 mg/dL. Chest CT on day 37 after admission showed improvement in lung consolidation (Fig. 1). In addition, after the initiation of treatment, head MRI was performed to screen for central nervous system lesions, but no abnormalities, such as cerebral infarction, were found, and the sinusitis had improved compared to the CT findings from one year earlier. Furthermore, compared to head MRI at the time of the CDI diagnosis, there was slight signal recovery in the posterior pituitary lobe (Fig. 4). Desmopressin was discontinued after admission because of renal dysfunction, but after renal function was stabilized, the patient did not show signs of polyuria. Thrombocytopenia (platelet count, 6.0×10⁴/μL) was observed on day 45 of admission. The clinical findings were not consistent with idiopathic thrombocytopenic purpura, thrombotic microangiopathy, or infectious disease. Drug-induced thrombocytopenia was suspected; therefore, the fourth round of RTX administration was discontinued, and omeprazole was discontinued. CRP and MPO-ANCA were negative, and the platelet count recovered to 38.7×10⁴/μL at the time of discharge on day 62. Following the initiation of RTX maintenance therapy without subsequent thrombocytopenia, we retrospectively concluded that omeprazole was likely the cause of the earlier platelet decrease.

Figure 3.

Clinical course. After the diagnosis of eosinophilic granulomatosis with polyangiitis by a renal biopsy, creatinine and C-reactive protein levels decreased following steroid pulse therapy, rituximab, and plasma exchange. Hemodialysis was withdrawn on day 30 of admission.

Figure 4.

Magnetic resonance imaging (MRI) findings. Brain MRI revealed slight signal recovery in the posterior pituitary lobe after treatment (circles).

In a previous study, a hypertonic saline infusion test was used to analyze AVP and serum Na levels in patients with CDI and controls (9). Five months after discharge, the hypertonic saline infusion test was repeated in our patient, revealing a mild improvement in AVP secretion, although it remained within the CDI group limits (Fig. 5).

Figure 5.

Hypertonic saline infusion test conducted five months post-discharge showing mild improvement in arginine vasopressin (AVP) secretion. The 95% prediction intervals for plasma AVP concentrations during a hypertonic saline test are shown by the dotted lines in the control and central diabetes insipidus groups.

Discussion

In the present case, the patient developed acute severe kidney injury 17 months after the diagnosis of CDI, and renal pathology revealed eosinophilic necrotizing vasculitis. Based on the history of bronchial asthma, peripheral eosinophilia, and renal pathological findings, a diagnosis of EGPA was established. Multidisciplinary treatment, including steroids, RTX, and plasma exchange, successfully controlled the patient's condition. Concurrently, improvement in AVP secretion was observed, suggesting a potential association between EGPA and CDI.

EGPA often presents diagnostic challenges owing to its varied clinical course and broad differential diagnoses. EGPA symptoms vary widely depending on the affected organ and disease progression (2). The disease is classically divided into three phases: allergy, eosinophilic infiltration, and vasculitis (10). Typically, it progresses slowly, with the allergic phase sometimes taking 8-10 years before the patient transitions into the next phase. However, phases may be absent, overlapping, or extending, complicating the diagnosis. In addition, the differential diagnoses for EGPA are diverse and include ANCA-associated vasculitis, such as MPA and GPA, HES, parasitic infections, allergic bronchopulmonary aspergillosis, and IgG4-related disease (11). The present patient was diagnosed with EGPA based on a history of asthma and chronic sinusitis, eosinophilia, significant weight loss (7 kg in 1 month), and renal pathology showing eosinophilic necrotizing vasculitis, despite the diverse differential diagnoses and prolonged progression to the vasculitic phase many years after the onset of asthma and sinusitis.

The renal pathology of EGPA is characterized by two mechanisms: necrotizing vasculitis caused by ANCA production from B cells damaging vascular endothelial cells, and interstitial nephritis due to eosinophilic infiltration (1,12). In the present case, both processes overlapped. Remission for severe EGPA was achieved using steroid pulse therapy combined with RTX and plasma exchange. For severe EGPA, the addition of cyclophosphamide or RTX to steroids is recommended (11). RTX is less cytotoxic than cyclophosphamide, is suitable for patients with renal impairment, and has shown greater efficacy in patients with ANCA-positive EGPA than in those with ANCA-negative EGPA (13). There is limited evidence to support the use of plasma exchange in EGPA, although it may be beneficial in ANCA-associated vasculitis with severe renal involvement (14), warranting its use in this case. In addition, mepolizumab, an anti-interleukin-5 monoclonal antibody, is recommended for refractory EGPA and can be considered if prior therapies are insufficient (11).

Our case is notable because CDI preceded EGPA. We reviewed this case alongside three other cases of combined EGPA and CDI (Table 2) (15-17). The average age was 53.5 years old, and 75% of the patients were women. Allergy symptoms varied, and all cases with available data were positive for MPO-ANCA. The sequence and timing of onset varied across the cases, with renal involvement observed only in the current case. Although induction therapies differed, all cases showed improvement in EGPA, and only in the current case was desmopressin successfully discontinued. After EGPA treatment, MRI showed partial recovery of the high signal intensity in the posterior pituitary. The hypertonic saline infusion test also indicated mild improvement in AVP secretion, suggesting an association between EGPA and CDI. However, we could not prove a direct link between EGPA and CDI by a histological examination or imaging tests, and the possibility of an accidental complication of CDI due to immunological mechanisms other than vasculitis and spontaneous resolution of idiopathic CDI cannot be excluded.

Table 2.

Four Cases of Combined EGPA and CDI: a Review Including Our Own Case.

Case	Age/Sex	Allergic symptoms	ANCA type	EGPA/CDI onset sequence and interval	Kidney injury	EGPA Treatment	EGPA outcomes	CDI outcomes	References
1	54/M	Allergic rhinitis	MPO-ANCA	Simultaneous diagnosis	No	Glucocorticoid	Remission	Desmopressin continuation	[15]
2	41/F	Bronchial asthma	NA	CDI→EGPA 3 years	No	Glucocorticoid	Remission	NA	[16]
3	51/F	NA	MPO-ANCA	EGPA→CDI 4 years	No	Cyclophosphamide Rituximab Methotrexate Glucocorticoid	Remission	Desmopressin dose reduction	[17]
4	68/F	Chronic rhinitis Bronchial asthma	MPO-ANCA	CDI→EGPA 17 months	Yes (AKI to CKD)	Glucocorticoid Rituximab Plasma exchange	Remission	Desmopressin discontinuation	Our case

M: male, F: female, NA: not available, ANCA: antineutrophil cytoplasmic antibody, MPO: myeloperoxidase, EGPA: eosinophilic granulomatosis with polyangiitis, CDI: central diabetes insipidus, AKI: acute kidney injury, CKD: chronic kidney disease, MRI: magnetic resonance imaging

Since the recovery of AVP secretion was incomplete, we speculate that the progression of renal impairment, in addition to the mild improvement in AVP secretion, contributed to the withdrawal of desmopressin. Ischemic cerebrovascular lesions are common in EGPA cases with central nervous system involvement (52%) (18). Although no histopathological link was found between EGPA and CDI, MRI at the CDI diagnosis showed no posterior pituitary gland enlargement, eosinophilia was absent, and ANCA levels were mildly elevated. This suggests that posterior pituitary damage was likely due to ischemic injury from vasculitis rather than eosinophilic infiltration.

In the current case, CDI developed after more than 30 years of chronic sinusitis and asthma, followed by EGPA with severe renal involvement approximately 1 year later. Intensive treatment stabilized vasculitis. In EGPA, severe renal impairment can emerge long after the allergic phase, highlighting the importance of careful ongoing follow-up. In the present case, EGPA treatment enabled the discontinuation of desmopressin, with some findings suggesting an improvement in CDI and a potential association between EGPA and CDI. CDI in patients with chronic sinusitis and asthma may be a precursor to EGPA, necessitating close monitoring.

This case report was written in compliance with the Declaration of Helsinki. The patient signed an informed consent form for publication.

The authors state that they have no Conflict of Interest (COI).