A Case of Antineutrophil Cytoplasmic Antibody (ANCA) – Negative Eosinophilic Granulomatosis with Polyangiitis (EGPA) with Nasal Polyps and Peripheral Neuropathy

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis that affects small and medium-sized blood vessels, characterized by asthma, blood and tissue hypereosinophilia, and the presence of extravascular eosinophilic granulomas. In 30% to 40% of patients, antineutrophil cytoplasmic antibodies (ANCAs) can be detected in the blood, which classifies the disease as ANCA-associated vasculitis. However, according to the classification criteria by the American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR), detecting ANCAs in the blood is not a criterion for this disease. We present a case of a 34-year-old woman with chronic rhinosinusitis (CRS) with nasal polyps, asthma, hyposmia, elevated body temperature, weakness, loss of sensation in the feet and hands, and difficulty walking. Neurological diagnostics pointed to an asymmetrical polyneuropathy. Histological analysis of tissue samples from the nasal cavity showed the presence of extravascular hypereosinophilia, where the accumulation of activated eosinophils was most pronounced in the tissue of nasal polyps. EGPA should be considered in cases of refractory CRS with nasal polyps, asthma, peripheral neuropathy, and histological findings of extravascular tissue eosinophilia.

Introduction

According to the latest classification from 2020, chronic rhinosinusitis (CRS) can be divided into primary and secondary, depending on whether the cause of inflammation is a primary infectious or immune factor in the nasal/sinus mucosa, or whether the inflammation occurred as a response of the nasal mucosa to the presence of local or systemic factors: tumor, primary or secondary immunodeficiency, systemic disease, and another. ¹ Various systemic diseases, such as sarcoidosis, granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), Rosai-Dorfman disease, and others, can have frequent manifestations in the mucosa of the nose and paranasal sinuses.^2,3 EGPA, until 2012 known as Churg-Strauss syndrome, is a systemic vasculitis of small to medium-sized blood vessels, which affects the upper and lower respiratory tracts in most cases.^4-6 The disease is sporadic, with a prevalence estimated to range from 10.7 to 13.0 cases per million people.^4-6 It goes through 3 phases: a prodromal period lasting longer than 10 years, in which CRS and asthma dominate, a phase of peripheral eosinophilia, and a phase of systemic eosinophilic vasculitis.^4-6 It most often occurs in the fifth or sixth decade of life, with almost equal prevalence in both sexes, although cases in children have also been recorded.^4-7 Treatment primarily consists of systemic corticosteroids and immunosuppressants (cyclophosphamide, methotrexate, azathioprine).^4-6 However, the last decade has brought us the successful application of biological therapy in the form of monoclonal antibodies, including rituximab, mepolizumab, benralizumab, and dupilumab.^4-6 Variations in the clinical course are quite common.

We present here a case of EGPA in a female patient with CRS, asthma, and polyneuropathy. In the discussion, we provide a brief review of the literature related to this rare clinical entity.

Case Presentation

A 34-year-old female patient was admitted for hospital treatment due to a 15-day elevated body temperature up to 38.5°C, difficulty breathing through the nose, increased mucopurulent nasal secretion, weakness, tingling hands and feet, loss of sensation in the feet and hands, and difficulty walking. She had an impaired sense of smell for the last 2 years. In the medical history, there is data on the treatment of allergic rhinitis and asthma during the last 8 years. Skin prick tests for inhalant allergens showed hypersensitivity to dust mites and animal dander. Therefore, she was previously treated with intranasal and inhaled corticosteroid sprays. Findings on the cranial nerves were without asymmetry. Mimic musculature was preserved in the innervation. The senses of sight, hearing, and balance were not impaired. Neurological problems with the upper and lower extremities first appeared 20 days before admission to the hospital. During the neurological examination after admission to the hospital, hypotrophy of the distal musculature of the arms and legs was observed, with reduced strength and decreased reflexes on both sides. Dorsal and plantar flexion on the right foot was absent. Hypoesthesia of the fingers of both hands and feet was observed. Electroneuromyography (ENMG) indicated an asymmetrical polyneuropathy.

In laboratory findings, C-reactive protein (CRP) and erythrocyte sedimentation were markedly elevated (49.30 mg/L; 79 mm/h, respectively). The blood count was dominated by hypereosinophilia [1.7 × 10⁹/L (28.7%)], while total serum immunoglobulin E (IgE) was also markedly elevated (1054.60 IU/mL). A pulmonology examination, radiographic, and lung function tests indicated moderate-to-severe asthma. A chest X-ray showed transient pulmonary infiltrates, and the lung computed tomography (CT) indicated the presence of nodules. An obstructive defect was indicated by a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC), which was measured as less than 70% or below the fifth percentile. Endoscopic examination of the nasal cavity showed an edematous/violaceous nasal mucosa, with abundant thick secretion and bilateral presence of nasal polyps originating from the middle nasal meatus. Nasal polyp samples and nasal mucosa samples from the middle and inferior turbinates were taken under local anesthesia. A cone-beam computed tomography (CBCT) of the paranasal sinuses showed incomplete opacification of the ethmoid and maxillary sinuses and the left side of the sphenoid sinus and complete opacification of the right side of the sphenoid sinus (Figure 1). Serological findings for anti-neutrophil cytoplasmic antibodies (ANCAs) [myeloperoxidase-ANCA (MPO-ANCA) and proteinase 3-ANCA (PR3-ANCA)] were negative. Histological analysis of tissue samples from the nasal cavity showed, after staining with hematoxylin-eosin and immunohistochemical staining for BMK-13, the presence of extravascular hypereosinophilia, where the accumulation of activated eosinophils was most pronounced in the tissue of nasal polyps (Figure 2).

Figure 1.

Sagittal, coronal, and axial planes of the cone-beam computed tomography (CBCT) showing incomplete opacification of the ethmoid and maxillary sinuses and the left side of the sphenoid sinus, and complete opacification of the right side of the sphenoid sinus.

Figure 2.

Photomicrograph of nasal polyp samples showing, after immunohistochemical staining for BMK-13, the presence of extravascular hypereosinophilia with very intense accumulation of eosinophil groups (arrowheads) [eosinophil major basic protein (MBP; clone BMK-13)] (Original magnification 200×).

After consultation with a rheumatologist, a diagnosis of EGPA was made. The patient was transferred to the rheumatology clinic, where further therapy was carried out. Therapy was started with prednisolone 60 mg/day with a taper and continued with pulse doses of monthly intravenous cyclophosphamide 800 mg for 6 months per NIH protocol. After 1 month, the prednisolone was reduced to 50 mg/day. Nasal obstruction decreased, and the sense of smell and lung functions improved. The patient no longer had episodes of elevated body temperature, and the eosinophil count, CRP, and erythrocyte sedimentation rate normalized. After 2 months of treatment, serum IgE levels decreased to 325.6 IU/mL. There was an improvement in the neurological function. Upper-limb strength improved, lower-limb deficits persisted. Eight months after the start of treatment, the patient is undergoing outpatient follow-up and tolerating the treatment well. Maintenance of remission was attempted with methotrexate (10-25 mg weekly), while glucocorticoids were gradually tapered. Remission was not detected in the patient.

Discussion

EGPA is a disease of unknown origin, but previous research has indicated a connection with environmental, genetic, and immune factors.^4-7 It is a necrotizing vasculitis that affects small and medium-sized blood vessels and is characterized by asthma, blood and tissue hypereosinophilia, and the presence of extravascular eosinophilic granulomas. It was first described by Churg and Strauss in 1951, calling the disease “allergic angiitis with granulomatosis.”^4-7 EGPA goes through 3 phases: (1) a prodromal period with symptoms of CRS and asthma, which may last for several years, (2) a phase of hypereosinophilia dominated by blood eosinophilia, tissue infiltration by eosinophils, and eosinophil-induced organ damage, and (3) systemic necrotizing vasculitis, which can be fatal.^4-7 However, with appropriate therapy, the prognosis is good, with a 10-year survival rate of 78% to 89%.^2,4-7 Variations in the clinical course are quite common, so these phases in the development of EGPA may not always occur as described. Otorhinolaryngological manifestations are very common. Symptoms of CRS with nasal polyps are present in more than 80% of patients and can appear 10 to 15 years before the diagnosis is made.^2,8,9 Otological manifestations can be found in about 58% of EGPA patients, usually in the form of chronic otitis media with effusion and progressive mixed or sensorineural hearing impairment, and occur several years after the diagnosis of the disease is made.^8,9

ANCA concentration is significant in establishing the diagnosis of GPA. However, according to the 2022 classification criteria by the American College of Rheumatology /European Alliance of Associations for Rheumatology (ACR/EULAR), ¹⁰ it is not significant to establish the diagnosis of EGPA (Table 1). ACR/EULAR is not a diagnostic criterion, so the diagnosis of EGPA can be made even if the patient does not meet classification criteria. According to most data from the literature, MPO-ANCA (p-ANCA) serologies were positive in only about 30% to 35% of EGPA cases.^2,4-7,11 On the contrary, according to the ACR/EULAR criteria, positive PR3-ANCA (c-ANCA) titer detection and hematuria are even aggravating factors for the diagnosis of this disease, considering that they are more in favor of the diagnosis of GPA.^10,11 On the other hand, asthma, nasal polyps, and eosinophilia are the most important classification criteria for EGPA. ¹⁰ Nevertheless, based on the detection of ANCA in the blood, EGPA patients can be divided into 2 categories. ANCA-positive EGPA patients usually have asthma, CRS with nasal polyps, renal involvement, purpura, and pulmonary hemorrhage, while the incidence of peripheral neuropathy is relatively high.^2,4-6 In ANCA-negative patients, we have frequent involvement of cardiac structures (eg, pericarditis, cardiomyopathy), gastrointestinal involvement, and elevated body temperature.^2,4-7 In the case of the patient we presented, the course of the disease was somewhat atypical, as she was ANCA-negative and had nasal polyps, asthma, asymmetrical polyneuropathy, and elevated body temperature. Thus, our patient had clinical features of both types of EGPA. The most reliable proof of EGPA is the biopsy from the affected organ for histological/immunohistochemical examination with evidence of vasculitis and eosinophil accumulation in the tissue. ¹² In our patient, the accumulation of activated eosinophils in the nasal polyp tissue was proven based on immunohistochemical tissue staining for the enzyme major basic protein (MBP, clone BMK-13). This enzyme is released in large quantities from the granules of activated eosinophils and locally damages the tissue of the nasal mucosa, creating conditions for its remodeling and formation of nasal polyps. ¹³ A high concentration of total serum IgE, as well as eosinophilia in the blood and tissue of the nasal mucosa/nasal polyps, indicated that the patient’s disease proceeded according to the type of T2 immune response. However, in patients with EGPA, it is not yet known what the trigger is for this systemic disease.^10,11

Table 1.

American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis.

ACR/EULAR criteria
• Asthma/obstructive airway disease (+3)
• Nasal polyps (+3)
• Mononeuritis multiplex (+1)
• Blood eosinophils ⩾ 1 × 109/L (+5) or eosinophilic inflammation on biopsy (+2)
• Positive c-ANCA (PR3-ANCA) titers (−3)
• Hematuria (−1)

A sum of above ⩾6 is required for classification.

Differential diagnosis includes GPA, where patients do not have asthma, and there are atrophic inflammatory changes in the nose and sinuses without the formation of nasal polyps.^2,4-7 Those patients have a high incidence of kidney involvement, and usually a high ANCA titer in the blood samples.^2,4-7 The other differential diagnostic problems are: microscopic polyangiitis (MPA), a systemic necrotizing vasculitis involving small blood vessels and invading lungs, skin, and kidneys; polyarteritis nodosa, a necrotizing vasculitis invading medium-sized arterial blood vessels with frequent neurological manifestations; hypereosinophilic syndrome (HES) with increased eosinophilia and multisystem involvement, but with much higher eosinophil count than those in EGPA and without the formation of granulomas.^2,4-6 Severe courses of EGPA can initially be treated to induce remission with infusion therapy with cyclophosphamide in combination with corticosteroids. Azathioprine or methotrexate is only recommended for the maintenance of remission.^2,4-6,12 However, to prevent relapse, it is better to combine corticosteroids with immunosuppressants in the continuation of therapy.^2,4-6,12 Also, biological therapy using monoclonal antibodies [rituximab (anti-CD20), mepolizumab (anti-IL-5-antibodies), benralizumab (anti-IL-5 receptor-antibodies, anti-CD125), and dupilumab (anti-IL-4Rα and anti-IL-13-antibodies)] in combination with systemic corticosteroids improves the clinical picture of the disease, reduces the possibility of relapse, and improves the prognosis of the disease.^14,15

Conclusion

EGPA should be considered in refractory CRS with nasal polyps, asthma, peripheral neuropathy, and tissue eosinophilia—even when ANCA testing is negative.