Eosinophilic pleural effusion and stroke with cutaneous vasculitis: Two cases of dupilumab‐induced hypereosinophilia

Abstract

Treatment with the anti-IL-4 receptor alpha antibody dupilumab can cause increases in blood eosinophils, typically without adverse effects.1, 2 This blood eosinophil increase is probably caused by an inhibition of the endothelial expression of VCAM-1 and ICAM-1 which is essential for eosinophil extravasation and dependent on IL-4 receptor alpha.3 We report cases of dupilumab-induced hypereosinophilia with severe adverse effects occurring within the first 6 weeks after treatment initiation. Case 1: A 49-year-old man (15 pack years until 2017) with severe intrinsic, adult-onset asthma and CRSwNP (not previously treated with biologics) suffered from recurrent asthma exacerbations requiring prednisolone bursts despite high-dose ICS/LABA/LAMA treatment. There were no other chronic diseases. In January 2020, poor asthma control (ACT: 8 points), a reduced FEV1 (67% predicted), elevated blood eosinophils (800/µl, 12%) and high FeNO (66 ppb) were documented. Due to the high FeNO value and the well-established beneficial effects of dupilumab on CRSwNP,4 treatment with dupilumab (200 mg every 2 weeks) was started on February 6th. Subsequently, asthma control, sense of smell and nasal airflow improved. However, the patient presented on March 18th with severe left-sided chest pain, chest X-ray revealed pleural effusion (Figure 1). Dupilumab was stopped and the patient was admitted to hospital where massive blood eosinophilia (10.530 eosinophils/µl; 50.2%) was recorded. Serum p-ANCA and c-ANCA titres were negative (<1:10). Thoracocentesis drained 2500 ml of an eosinophilic exudate (56 g protein/dl; 14.4 million leucocytes/ml: 58% eosinophils). Prednisolone treatment (0.5 mg prednisolone per kg body weight per day, for 2 weeks) led to clinical improvement. On April 2nd, benralizumab treatment was started and prednisolone treatment was stopped. In November 2020, asthma control was good (ACT: 25 points), FEV1 improved (105% predicted), eosinophils were undetectable (0/µl). The pleural effusion was completely resolved (Figure 1). Case 2: A 66-year-old woman (never-smoker) with severe intrinsic, adult-onset asthma (not previously treated with biologics) suffered from recurrent asthma exacerbations (one led to resuscitation/mechanical ventilation) requiring prednisolone bursts, despite high-dose ICS/LABA and montelukast treatment. In addition to asthma, she suffered from chronic lower back pain (due to herniated discs) and diffuse arthritis (with no established specific diagnosis): both conditions were treated with paracetamol on an as-needed basis. In October 2020, asthma control was poor (ACT: 6 points), FEV1 reduced (53% predicted), FeNO high (89 ppb) and eosinophils low (10 eosinophils/µl; 0.1%). There was no pharmacological explanation for these surprisingly low eosinophil counts. She denied taking prednisolone or being treated with prednisolone since August 2020, and there was no documented treatment with other immunosuppressants or with biologics. However, a non-informed use or treatment with systemic immunosuppressants since August 2020 cannot be excluded. Due to the high FeNO value, and the absence of blood eosinophilia (precluding treatment with biologics targeting the IL-5 pathway) or allergies (precluding treatment with omalizumab), treatment with dupilumab was initiated on October 27th (300 mg every 2 weeks). Asthma control improved in the following weeks, with no further exacerbations (this was communicated in a phone call). On 2 December 2020, she was hospitalized with atrial fibrillation. Despite anticoagulation, acute right-sided hemiparesis and aphasia occurred on December 9th. In the stroke unit, right-side predominant tetraparesis, dysphasia, hemianopia to the right, neglect to the left, reduced consciousness and massive blood eosinophilia (10.961 eosinophils/µl; 41.9%) were detected. MRI showed diffuse cerebral infarctions (Figure 2A), biopsies of new livid cutaneous maculae revealed vasculitis and vascular occlusions (Figure 2B). Serum p-ANCA and c-ANCA titres were negative (<1:10). High-dose methylprednisolone treatment (1000 mg/day) was immediately started and then tapered, dupilumab was stopped. Neurologic symptoms strongly improved in the following weeks and asthma control was good (the latter was communicated in a phone call). Further prednisolone tapering is planned. In previous case series, none of the patients developed >8000 eosinophils/µl blood within the first 12 months of dupilumab treatment, and there were no cardiac, pulmonary or neurologic complications.2, 5 Bilateral stroke after 6 months of dupilumab treatment was reported in a 20-year-old man with atopic dermatitis, however, eosinophils were not measured.6 A 56-year-old man with severe asthma suffered an eosinophilic pneumonia after 5 months of dupilumab treatment, with eosinophils increasing from 660 to 2714/µl.7 In our cases, organ complications occurred already within the first 6 weeks of treatment, and were accompanied by excessive increases in blood eosinophils. Indeed, all complications were related to eosinophilia: (1) the pleural effusion was eosinophilic and resolved completely after prednisolone and benralizumab treatment, (2) there was no other explanation for a newly emerged cutaneous vasculitis, (3) the stroke was either due to vasculitis or thromboembolic events, even in the latter case, eosinophilia-associated hypercoagulability8 probably plays a role. We conclude that dupilumab treatment can, in rare cases, lead to (1) excessive blood eosinophilia (>10,000 eosinophils/µl) with (2) organ complications (3) within the first 6 weeks of therapy. We, therefore, recommend to monitor blood eosinophils in the first weeks after treatment initiation and/or after discontinuation of oral corticosteroid treatment, even if a lower dupilumab dose (200 mg) is chosen (case 1) or eosinophils are low at baseline (case 2). Treatment with the anti-IL-4 receptor alpha antibody dupilumab can increase blood eosinophils in patients with severe asthma, typically without adverse clinical effects. We report two patients with severe asthma who developed excessive blood eosinophilia (>10,000 eosinophils/µl) with severe adverse effects within the first 6 weeks after initiation of dupilumab treatment. A 49-year-old man developed left-sided eosinophilic pleural effusion, a 66-year-old woman developed atrial fibrillation, a stroke (with diffuse bilateral infarctions) and vasculitis of the skin. We conclude that dupilumab treatment can lead to severe hypereosinophilia with organ complications in the first 6 weeks of treatment. We, therefore, recommend to monitor blood eosinophil counts in the first weeks after dupilumab treatment initiation. The authors report no conflict of interest regarding this report. Patients gave their consent to publish the cases anonymously.

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