Hypereosinophilic syndrome with pulmonary and hepatic involvement mimicking autoimmune disease

Abstract

Idiopathic hypereosinophilic syndrome (HES) is defined as blood eosinophilia on at least 2 occasions or evidence of prominent tissue eosinophilia with exclusion of secondary causes, commonly affecting the lungs but rarely the liver. A 44-year-old woman presented with 18 months of progressive dyspnea, cough, and intermittent fever. Investigations revealed marked leukocytosis with hypereosinophilia, cholestatic pattern of liver enzyme elevation, and hypergammaglobulinemia. High-resolution computed tomography of the chest showed bilateral fibrotic changes suggestive of sarcoidosis. Antinuclear antibody testing was strongly positive with a cytoplasmic filamentous pattern, suggesting autoimmune hepatitis or eosinophilic granulomatosis with polyangiitis. Liver biopsy revealed pericellular and portal fibrosis, focal eosinophilic infiltration, mild hepatocellular cholestasis, and occasional multinucleated giant cells. After excluding mimics, a diagnosis of HES with isolated pulmonary and hepatic involvement was established. This case highlights the importance of considering HES in patients with longstanding respiratory symptoms and systemic findings, especially when autoimmune markers may be misleading.

Background

Hypereosinophilic syndrome (HES) is defined by persistent blood eosinophilia with multi-organ complications [1]. It is subclassified into three variants based on pathogenesis: a) Myeloproliferative (primary/neoplastic HES, ~ 20%); b) Lymphocytic (secondary/reactive HES, ~ 30%); c) Idiopathic (~50%) [2].

The definition has evolved. Chusid et al. required: eosinophilia > 1500/mm³ for ≥6 months, unknown cause, and organ involvement. Simon et al. later redefined it as eosinophilia > 1500/mm³ on ≥2 occasions or tissue eosinophilia with symptoms, after excluding secondary causes (parasitic/viral infections, allergies, drug/chemical reactions, hypoadrenalism, neoplasms) [3]. Epidemiology has shifted: earlier studies showed male predominance (9:1, age 20–50 years), while recent data show a near-equal ratio (1:1) [4, 5].

This case report presents idiopathic HES with pneumonitis and hepatitis, both responding well to treatment.

Case report

A 44-year-old woman, without comorbidities, presented with progressive cough for 1.5 years. Initially dry, it became productive over the past 6 months (~70–80 mL/day yellowish-white, non-bloody sputum). She developed dyspnoea (mMRC grade 3) for 1 year, without orthopnoea, nocturnal worsening, seasonal variation, or oedema. Additional symptoms included intermittent low-grade fever, 14 kg weight loss in 6 months, and recurrent painful oral ulcers.

At a local hospital, she was empirically started on anti-tubercular therapy (ATT) for suspected pulmonary TB based on CXR and CT chest findings, despite negative CBNAAT from bronchoalveolar lavage (Fig. 1A). During evaluation, peripheral eosinophilia (1500 cells/mm³) was noted. Following initiation of ATT (isoniazid, rifampicin, pyrazinamide, ethambutol), she developed an erythematous maculopapular rash on both upper limbs, resolving with antihistamines without ATT discontinuation. Due to lack of improvement, she was referred to our centre.

Figure 1.

Chest images in different timelines. Skiagram (AP view, A) on admission showing diffuse pulmonary infiltrates, multiple areas of fibrosis in bilateral lung fields and mild left sided pleural effusion (arrows). High resolution computer tomography images of thorax showing (B) enlarged mediastinal and perihilar lymph nodes with areas of tractional bronchiectasis in bilateral lung fields (arrows); (C) areas of fibrosis (arrow), subpleural reticulations (arrow) with surrounding ground glass attenuation in bilateral lung fields; Perilymphatic and perifissural nodules are also seen in bilateral lung fields; (D) bronchial and bronchiolar wall thickening in bilateral lung fields with diffuse interstitial septal thickening (arrow) along with focal subsegmental areas of consolidation is seen in left lower lobe, fibrotic bands are seen in right middle lobe and left lower lobe; (E) Skiagram (AP view) at 4 weeks of follow up after discharge showing radiological clearing and resolution of effusion.

On admission, she was emaciated (weight 33 kg), febrile (100.4°F), tachypnoeic (RR 26/min), SpO₂ 86% on room air requiring oxygen supplementation. Respiratory examination revealed bilateral fine infrascapular crepitations; other systems were unremarkable.

Differentials considered were tuberculosis, chronic eosinophilic pneumonia (CEP), eosinophilic granulomatosis with polyangiitis (EGPA), allergic bronchopulmonary aspergillosis (ABPA), autoimmune hepatitis (AIH), and IgG4-related disease.

Investigations showed leukocytosis with moderate eosinophilia, cholestatic liver injury, and raised globulins (Table 1). Stool for ova/cysts was negative. Bronchoalveolar lavage was negative for AFB (Ziehl–Neelsen, CBNAAT, MGIT), Nocardia, and fungi.

Table 1.

Blood investigations of the patient.

Investigation	SI unit	Reference range	Day 1	Day 25
Haemoglobin	g/dl	13–17	11.9	10.5
Total leukocyte counts (×1000)	×103 cells/mm3	4–11	12.66	5.67
Differential counts (N/L/M/E)	%	40–70/20–40/2–8/1–6	55/14/11/19	87/10/1.6/0.7
Total platelet counts	×1000 cells/mm3	150–400	597 k	669 k
Total Bilirubin	mg/dl	0.3–1.2	0.65	0.4
Direct Bilirubin	mg/dl	0–0.2	0.29	0.14
Alanine transaminases	U/L	0–50	106	85
Aspartate transaminases	U/L	0–50	205	47
Alkaline phasphatase	U/L	30–120	182	157
Gamma-glutamyl transferase	U/L	0–55 U/L	164	201
Total protein	g/dl	6.6–8.3 gm/gl	7.8	6.1
Albumin	g/dl	3.5–5.2 g/dl	2.7	2.8
Globulin	g/dl	2.5–3.2 g/dl	5.1	3.3
Urea	mg/dl	17–43	20	16
Creatinine	mg/dl	0.72–1.18	0.61	0.55
PT/INR		11.4/0.89	12.2/1.06
Procalcitonin	ng/ml	< 0.5	0.20
Erythrocyte sedimentation rate	mm/hr	0–20	10
C-reactive protein	mg/L	0–1	31.16
Folate	ng/ml	> 5	>24
Vitamin B-12	pmol/L	156–672	1061
HbA1c	%	4.5–5.5	6.1%

Workup for enteric fever, dengue, Leptospira, scrub typhus, malaria, blood and sputum cultures was negative. Viral serology (HAV, HBsAg, HCV, HEV, HIV-1/2) was also negative. Repeat CT chest showed fibrosis, subpleural reticulations, ground-glass attenuation, traction bronchiectasis/bronchiolectasis, and adenopathy—features suggestive of fibrotic sarcoidosis; but serum IgE levels were normal (Fig. 1B-D).

DRESS syndrome was suspected (Regiscar score 2), but excluded since eosinophilia and lung disease preceded ATT by 1.5 years and persisted despite rash resolution. Autoimmune panel revealed ANA strongly positive (3+, titre 1:1000, cytoplasmic filamentous staining), while ENA panel was negative. AIH antibodies (SMA, LKM1, anti-LC1, SLA/LP) were also negative. Tests for Aspergillus (skin test, IgE, IgG, ELISA) were non-reactive; ANCA was negative; IgG4 was normal. Liver biopsy showed pericellular and portal fibrosis with multifocal eosinophilic infiltration around portal tracts, mild hepatocellular cholestasis, multinucleated giant cells, and mild chronic lymphocytic inflammation (Fig. 2A and B).

Figure 2.

Liver biopsy photomicrographs. Section on H&E 200X (A) showing giant cell transformation of hepatocytes (black arrow) with area of confluent necrosis (yellow arrow); section on H&E 400X (B) showing focus of spotty necrosis and an occasional eosinophil in the sinusoid (arrow) with hepatocytes showing feathery degeneration.

Bone marrow aspiration/biopsy revealed eosinophilia without immature eosinophils, blasts, or excess in other cell lines. FIP1L1-PDGFRA fusion gene was negative (FISH). Peripheral smear showed no immature cells, and flow cytometry excluded T-cell clonality.

Based on persistent peripheral eosinophilia, organ involvement (hepatitis, pneumonitis with tissue eosinophilic infiltration), and exclusion of secondary, myeloproliferative, and lymphocytic causes, a diagnosis of idiopathic HES was made. ATT was stopped. She received pulse methylprednisolone 1 g IV daily × 3 days with IVIG 60 g over 3 days, followed by oral prednisolone 1 mg/kg with tapering. Marked clinical improvement was observed: absolute eosinophil count (AEC) reduced to 450 cells/mm³, liver enzymes normalized, crepitations resolved, apparently normal CXR, and she gained 2.5 kg by discharge, indicating a favorable prognosis (Fig. 1E).

Discussion

Hypereosinophilic syndrome (HES) is a rare disorder with variable symptoms, disease severity, and multiorgan involvement, typically affecting middle-aged adults [4]. Respiratory involvement occurs in ~ 63% of patients, often manifesting as cough (productive or dry, sometimes nocturnal), dyspnoea, and wheeze. In contrast, our patient developed type 1 respiratory failure. Notably, no pathognomonic radiological findings exist for HES; overlap with other pulmonary conditions, including drug-induced hypersensitivity, is common [5].

Gastrointestinal manifestations (abdominal pain, diarrhoea, dysphagia, nausea, vomiting, dyspepsia) are reported in 20–30% of patients [6]. Interestingly, our patient had no GI symptoms; workup revealed elevated liver enzymes and biopsy showed multifocal eosinophilic infiltration with moderate portal fibrosis. Eosinophilic hepatitis is an uncommon HES presentation, where autoimmune hepatitis (AIH) and drug-induced liver injury must be excluded [7].

Hepatic histology in HES is described in four patterns: Cholangitis type, Chronic active hepatitis (CAH) type, Vasculopathic type, and Hepatic necrosis type. All demonstrate eosinophilic infiltration of portal tracts, bile ducts, venous system, or hepatic parenchyma. In our case, biopsy findings and steroid responsiveness were consistent with the CAH type.

Historically, HES carried poor outcomes, with median survival of ~ 9 months. Prognosis has markedly improved with corticosteroid therapy, particularly in idiopathic HES [4]. Treatment aims to reduce AEC and prevent organ damage. Asymptomatic or minimally symptomatic patients may not require therapy. For mild–moderate disease, oral corticosteroids are first-line treatment [1]. Patients with life-threatening complications receive high-dose IV steroids (e.g. methylprednisolone 1 mg/kg/day). IVIG offers rapid benefit in progressive disease [8–10]. Prognosis varies with etiology and extent of organ involvement.

Conclusions

HES should be considered as a differential diagnosis in middle-aged patients with chronic respiratory symptoms, peripheral eosinophilia, and eosinophilic hepatitis, particularly when infectious, autoimmune, and other secondary causes are excluded. Despite diagnostic challenges, especially in the presence of positive autoimmune markers, HES typically shows a rapid and favorable response to corticosteroids, with resolution of symptoms and normalization of eosinophil counts.

Authors’ contributions

Author KC & SR: Data collection; Analysis; Writing the draft; Approve Author PKP: Conceptualization; Investigation; Methodology; Resources; Critically review; Approve Author AD, AS, GS: Supervision, Validation, Review & editing; Approve.

Conflict of interest

Authors declare no conflict of interests.

Funding

None declared.

Ethical permission

Not required as case report, but patient consent obtained.