Introduction

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, is a rare systemic vasculitis of unknown etiology, which is typically characterized by bronchial asthma, significant eosinophilia, and necrotizing vasculitis [1]. EGPA has three progressive phases: a prodromal allergic phase, such as bronchial asthma and rhinosinusitis; an eosinophilic phase; a vasculitis phase. The American College of Rheumatology published the following six clinical criteria for the diagnosis of EGPA: asthma, eosinophilia >10% in a differential white blood cell count, mononeuropathy or polyneuropathy, transient pulmonary opacities on chest X-ray, paranasal sinus abnormality, and a biopsy specimen containing a blood vessel showing eosinophil infiltration in the extravascular areas [2]. The presence of four or more of these 6 clinical criteria yields a sensitivity of 85% and a specificity of 99.7% for EGPA. After the diagnosis, we started an induction therapy based on glucocorticoids and cyclophosphamide, as suggested by KDIGO guidelines [3], achieving clinical remission.

Clinical case

In February 2021 a 60-year-old man, who is also a skilled cyclist, was admitted to the Nephrology department of the San Giovanni Evangelista Hospital (Tivoli) to investigate a symptomatology that had arisen over the previous months and worsened in the last few weeks, to the point of limiting normal everyday activities. After consulting various specialists, ASA-intolerance syndrome was diagnosed by an allergologist. In December 2020, due to the worsening clinical conditions, he was hospitalized in the General Medicine ward of Subiaco Hospital. Following acute kidney injury, a renal consult was required, and the patient was transferred to the Nephrology ward in Tivoli’s Hospital. Physical examination revealed the presence of livedo reticularis of the four limbs, purpura of the lower limbs, arthritis of the ankles, and low-grade fever; the patient showed intense asthenia, loss of appetite, retrosternal heartburn, hypoesthesia of the right lower limb and a scarcely pharmacologically controlled asthma. He also reported weight loss (about 5 kg in the last 6 months). In anamnesis, we found two recent episodes of severe bronchospasm, which had led him to access the nearest emergency room.

Blood chemistry tests, summarized in Table I, and diagnostic investigations revealed a rapidly progressing renal failure, hyper-eosinophilia (4.7 thousand/μL eosinophils, 44% of total leukocytes), pulmonary opacities on chest computed tomography (CT) (Figure 1), and sinusitis of the paranasal sinuses, with abundant inflammatory tissue in the paranasal sinuses visible on CT of the facial massif (Figure 2). Two consecutive nasopharyngeal swab tests (PCR, confirming SARSCoV-2 infection) were negative, as were HIV antibodies.

Table I: Laboratory parameters before hospital admission, during recovery and at the follow up of the induction phase

The search for antibodies directed against neutrophil cytoplasm (ANCA) revealed a high level of pANCA (pANCA ++, ELISA anti-MPO 666 UI/ml) associated with an increment of the indicators of inflammation. The renal ultrasound examination showed kidneys within the norm with a hyper-echogenicity of the parenchymal tissue. Within a few days from hospitalization, active urine sediment with associated microhematuria and proteinuria (1.5 gr/24h) was highlighted, with a progressive worsening of the renal function. The hypoesthesia of the right lower limb, which had worsened during the stay in our Nephrology Division, was investigated through electroneurography (ENG), with findings consistent with multiple mononeuropathy of the right lower limb, specifically involving the peroneal and tibial nerve, likely caused by vasculitis. Also, the cardiac function was reduced, as confirmed by a contractile dysfunction on echocardiogram with an ejection fraction (EF) of 50% and a diastolic disfunction of II grade. We investigated the cardiac damage with blood tests too; CPK was 18 UI/L and BNP 34 pg/ml (within the normal range). The differential diagnoses of the case are reported in Table II.

Table II: Differential diagnoses of the clinical case

Based on the criteria of the American Society of Rheumatology, subsequently revised in the Consensus of Chapel Hill in 1994, a diagnosis of eosinophilic granulomatosis with polyangiitis was made. The four necessary criteria were all present: asthma, hyper-eosinophilia >10% at the complete blood count (CBC), transient/migrant pulmonary opacity, and inflammatory abnormalities of the paranasal sinuses. The Birmingham Vasculitis Activity Score (BVAS) was 44, thus demonstrating an active disease. The Five Factor Score [4], indicating short and long-term prognosis in vasculitis, was 1 out of 4 (doubled risk for mortality due to the pathology in 5 years). Furthermore, the positivity of high content ANCA was hinting at a long-term negative prognosis with risk of permanent organ-specific impairment and early mortality.

The induction therapy consisted in high-dosage intravenous glucorticoids; following the guidelines of the main nephrology and rheumatological scientific societies, it was decided to associate cyclophosphamide to glucocorticoids, in an attempt to improve the short and long-term prognosis. According to the Cyclops protocol, cyclophosphamide was administered intravenously and, subsequently, orally, with high dosages of glucocorticoids, according to regimen for pulsed CYC. The patient received 1 g/day intravenous methylprednisolone for 3 days, followed by oral prednisone (1 mg/kg/day oral, tapered to 0.4 mg/kg/day by month 3). Cyclophosphamide IV was adjusted for renal function and the first dose was 12.5 mg/kg IV in pulses; at week 2 the patient showed an increase of renal function (eGFR >50 ml/min/1.73 m²), so we decided to give the full dose of 15 mg/kg in IV pulses. At week 4, cyclophosphamide was also given at the full dose, without any adverse reaction. After three IV pulses, we agreed an oral therapy with the patient, at a dosage of 5 mg/kg orally for 3 days at weeks 7, 10, 13, 16, 19, 22 and 25, until remission. When the patient achieved remission, we opted for a maintenance therapy with Methotrexate (15 mg/week) and foline (10 mg/week). After 9 months of treatment, the patient reported a considerable improvement of the symptoms, which at that point did not necessitate any more pharmacological interventions. The eosinophils value was 0 cells/mm³ (Figure 3), the inflammation indexes were back to normal, and the renal function appeared significantly improved (Figure 4). Skin findings and the hypoesthesia of the right lower limb were completely regressed. An echocardiogram showed complete resolution of cardiac involvement, with normal contractile function and EF of 64%. During the induction phase, perfectly tolerated by the patient, the only thing to report is the appearance of a condition of hypogammaglobulinemia, in the absence of a significant increase in infectious events. The patient is currently continuing maintenance therapy with glucocorticoids and methotrexate, without any noteworthy problems.

Discussion

EGPA is a rare ANCA-associated vasculitis. In Europe the incidence rate is 0.5-6.8 new cases/year per million people [5]. The prevalence is higher at northern latitudes compared to southern Europe [6]. The disease occurs most commonly in 40–60-year-old people [5,8]. No sex predominance has been demonstrated [6].

The frequent detection of ANCA (mainly antibodies to myeloperoxidase), in 30-40% of cases, also suggests the disease is autoimmune. ANCA-positive patients are more commonly diagnosed with glomerulonephritis and mononeuritis, whereas ANCA-negative ones show more frequently endocardial, myocardial, and pulmonary eosinophilic infiltrates [5,8,9,10].

Interstitial lung disease has become the most diagnosed type of lung disease since 2020, due to the eruption of COVID-19 after the outbreak of SARS-CoV2 in Wuhan. Since then, there has been an important shift in epidemiology, aetiology, and outcome of pulmonary diseases. Moreover, our patient was affected by acute kidney damage, purpura, mononeuropathy, and cardiac involvement, all of which are also described in the COVID-19 disease. However, he was tested with two consecutive nasopharyngeal swab tests (PCR), both negative.

EGPA typically develops in three phases:

1) The allergic phase, characterized by the occurrence of asthma, allergic rhinitis, and sinusitis. In this case, the patient has a history of asthma;

2) The eosinophilic phase, in which the main pathological finding is the eosinophilic organ infiltrations (e.g., lungs, heart, and gastrointestinal system);

3) The vasculitic phase, characterized by purpura, peripheral neuropathy, and constitutional symptoms. Of interest, in this case, the kidney, pulmonary, cardiac, and nerve involvement. The vasculitic phase is typically preceded by constitutional symptoms (e.g., fever, weight loss, fatigue) [5]. Peripheral neuropathy is a key feature of this phase, affecting approximately 70% of the patients. The neuropathy is characterized by axonal damage in electrophysiological studies, and frequently affects the peroneal, tibial, ulnar, and median nerves; the most common pattern is mono neuritis multiplex, often complicated by asymmetric foot or wrist drop, which may progress to symmetric or asymmetric polyneuropathy.

Kidney involvement is present in approximately a third of the patients. The prevailing picture is ANCA-associated necrotizing crescentic glomerulonephritis [11].

The presence of 4 or more ACR classification criteria, including bronchial asthma, eosinophilia (more than 10%), paranasal sinus abnormalities, migratory or transient eosinophilic pulmonary infiltrates, extravascular eosinophil infiltration on biopsy, and mono- or polyneuropathy, has a sensitivity of 85% and a specificity of 100% [5,8,10]. We identified 5 of the 6 clinical criteria from the American College of Rheumatology. Furthermore, the diagnosis was strongly supported by the presence of ANCAs and anti-MPOs.

Differential diagnosis is important in reno-pulmonary syndromes. The most common pathologies are systemic rheumatic diseases, such as systemic lupus erythematosus. It is extremely important to exclude infections and malignancies since the immunosuppressive therapy could worsen these conditions. In this clinical case, the presence of hyper-eosinophilia and the absence of cavitations/nodules at chest CT scan, led us to a diagnosis of EGPA, instead of rheumatic diseases.

The treatment of EGPA depends on disease severity or risk stratification. Therapeutic agents used for the management of EGPA have a very real risk of adverse effects and must be used with care, even as the clinician recognizes the life-threatening nature of the vasculitis itself. For patients with milder diseases, oral glucocorticoids may be sufficient, whereas patients with the generalized active disease will usually require therapy with cytotoxic agents such as methotrexate, azathioprine, cyclophosphamide, or mycophenolate mofetil [12,13].

The main drugs for the treatment of EGPA are glucocorticoids, associated with cyclophosphamide or rituximab if FFS ≥1, as indicated by all the most recent guidelines [3,14,15,16,17,18]. In organ- or life-threatening manifestations, the recommended starting dose of prednisone is 1 mg/kg/day with a maximal daily dose of 80 mg for 2-3 weeks, with tapering to a minimal supporting dose selected individually to control the symptoms and minimize the adverse effects of treatment. Methylprednisolone (7.5-15 mg/kg/day) can be used as pulse therapy for life-threatening manifestations [14,15]. Many patients require steroid treatment for a long time or even for a lifetime as relapses of the disease frequently appear with decreased glucocorticoid dosage. Despite rapid tapering of glucocorticoids are recommended in some, more recent, nephrological and rheumatological guidelines [3,17], we decided to treat our patient with a high dosage of glucocorticoid for the notable hyper-eosinophilia and the presence of poor-prognosis factors. The higher dose is used for patients with more severe vasculitis. The American College of Rheumatology [16] does not specify the correct tapering dose, allowing clinicians to choose. We decided, despite the PEXIVAS recommendations, to maintain high doses of GCC during induction therapy.

Once the disease manifestations have come under control, the glucocorticoid dose is gradually tapered over approximately 12 to 18 months, as tolerated [13]. In the case of organ- or life-threatening manifestations, glucocorticoids in combination with cyclophosphamide are prescribed [14,15]. If EGPA is severe, treatment with high-dose glucocorticoids or immunosuppressants may be required to prevent organ damage. For ANCA-positive patients with renal involvement or refractory disease, immunosuppression with cyclophosphamide or rituximab can be considered [6, 14]. Insufficient data are available for EGPA to make a clear recommendation regarding this choice. Based on the EULAR/ERA-EDTA [15] recommendations for the management of ANCA-associated vasculitis, cyclophosphamide was preferred (88% of strength of vote) by experts in the treatment of EGPA over rituximab (59% strength of vote). Nevertheless, rituximab is a safe and important alternative to standard therapy in EGPA, both for refractory and relapsing diseases, especially for ANCA-positive patients, and for newly diagnosed patients when traditional cytotoxic drugs are contraindicated or undesirable [19]. Due to the rare occurrence of EGPA, and the variety of its clinical manifestations, the diagnosis and treatment of this disease can be challenging.

As maintenance therapy, we decided to use Methotrexate instead of Azathioprine because of clinical reasons (the severe arthritis pattern of this case, particularly problematic for a manual laborer) and of the patient’s personal choices (to receive one Methotrexate injection administered as a single weekly dose of 15 mg IM). Maritati, et al. [20] have recently demonstrated that Methotrexate may be effective and safe for remission-maintenance in AAV and this approach was particularly appreciated by our patient.

Conclusions

A correct differential diagnosis is crucial in the choice of treatment. This case report presents peculiar manifestations of EGPA, treated with an induction therapy based on steroids and cyclophosphamide. After an almost 1-year-long observation we can report that the patient achieved complete remission and did not develop any complications during induction and maintenance therapy, except hypogammaglobulinemia after cyclophosphamide.

The early start of the therapy resulted in the sudden disappearance of the reported symptoms and the normalization of the altered blood chemistry parameters. The time between the onset of a severe disease and its diagnosis is crucial for treatment, which must be tailored and consider short- and long-term risk.

References

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