Severe acute respiratory syndrome coronavirus 2 infection in those on mepolizumab therapy

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),¹ continues to cause morbidity and mortality across the world. The expert recommendation is to continue biologic therapy unchanged in severe eosinophilic asthma^{2 , 3} but concern has been expressed as eosinopenia may be a risk factor for worse disease outcomes.^{4 , 5} Here, we report the outcomes of 4 patients from centers in the United Kingdom, Italy, and North America with COVID-19, while receiving treatment with mepolizumab, an anti–interleukin 5 monoclonal antibody, which reduces eosinophils to within the reference range.⁶

Case 1 is a 64-year-old White man with a history of childhood-onset asthma, atopy, and rhinitis, whose asthma control deteriorated in his mid-40s. Despite treatment with high-dose inhaled corticosteroids (ICS), long-acting β-agonist (LABA), leukotriene receptor antagonist (LTRA), macrolides, and intranasal steroids, his disease remained poorly controlled with an asthma control questionnaire 6 (ACQ-6) score of 3.1, regular exacerbations, marked airflow limitation (forced expiratory volume in 1 second [FEV1] of 44%) and blood eosinophil count of at least 500 cells/μL. Mepolizumab was started in 2013 with a consequent reduction in eosinophil counts (200 cells/μL) and exacerbations (4 to 1 per year). In March 2020, he presented to the emergency department after 10 days of fever, dyspnea, cough, and central pleuritic chest pain. He had mild wheeze on auscultation, reduced peak expiratory flow (130, normally 250) but was apyrexial, and a chest radiograph (CXR) found no radiological evidence of pulmonary infiltrates. Blood test results revealed eosinopenia (0 cells/μL), elevated C-reactive protein (147 mg/L), and SARS-COV-2 was confirmed by polymerase chain reaction (PCR). He was treated for asthma exacerbation and discharged home. After 2 weeks, he still felt fatigued, but his respiratory symptoms had otherwise settled.

Case 2 is a 61-year-old White man with late-onset asthma, chronic sinusitis, nasal polyposis, and bronchiectasis with gastroesophageal reflux disease, obstructive sleep apnea, hypertension, and hypercholesterolemia. Despite treatment with high-dose ICS, LABA and LTRA therapy, he had poor disease control with an ACQ-5 score of 2.83 and regular exacerbations. He was sensitized to house dust mite, had marked airflow limitation (FEV1 64%), and raised blood eosinophil counts greater than 900 cells/μL. He was started on mepolizumab in 2019 and, in parallel to a reduction in blood eosinophils (to 70 cells/μL), saw improvement in his FEV1 (increased by 450 mL), reduction in exacerbations, and improvement in ACQ-5. In March 2020, he presented to the emergency department in acute respiratory failure after 5 days of fever, breathlessness, cough, chest tightness, and anosmia. Admission investigations revealed new unilateral CXR changes and blood eosinopenia (0 cells/μL), and real-time PCR was positive for SARS-COV-2. He was admitted for treatment with supplementary oxygen, ceftriaxone, azithromycin, dexamethasone, and intermediate-dose enoxaparin. He required continuous positive airway pressure ventilatory support and was given tocilizumab due to clinical suspicion of COVID-19-related cytokine storm. The patient was discharged home after 13 days and, after a period of convalescence at home, reported resolution of his respiratory symptoms.

xCase 3 is a 66-year-old White woman with childhood-onset asthma and chronic rhino-conjunctivitis, 15 pack-year smoking history, and history of using biomass heating. Her comorbidities included type 2 diabetes (requiring insulin), myocardial infarction, and gastroesophageal reflux disease. Spirometry measured an FEV1 of 500ml (29% predicted) with an FEV1-to-forced vital capacity of 47%; she required overnight and ambulatory (2 L/min) oxygen therapy and was treated with high-dose inhaled ICS, LABA, long-acting muscarinic antagonist, and LTRA therapy. In view of her recurrent exacerbations and elevated blood eosinophil counts (440 cells/μL), she was given methylprednisolone 20 mg/day (intolerant of other oral corticosteroids) before starting mepolizumab in September 2019. At 6 months, blood eosinophil counts had reduced (to 0 cells/μL) as had ACQ-5 (from 3.67 to 1); methylprednisolone was discontinued, although she continued to exacerbate. In March 2020, she presented to the emergency department with a 2-day history of fever, dyspnea, and epigastric pain. Clinical examination and CXR were unremarkable, but real-time PCR was positive for SARS-COV-2. She was discharged home to self-isolate and 3 weeks later, repeat nasopharyngeal swabs were negative, and dyspnea had improved, although fatigue and sporadic episodes of chest tightness persisted.

Case 4 is a 22-year-old African American woman who suffered multiple episodes of extensive deep vein thrombosis, pulmonary emboli, and interatrial clots associated with an elevated lupus anticoagulant and poor anticoagulation compliance. The bone marrow aspirate for investigation of persistent peripheral blood eosinophilia (1700 cells/μL) exhibited no blasts. She was started on prednisolone for hypereosinophilia (hypereosinophilic syndrome) and trialed a number of steroid-sparing agents, which were discontinued owing to noncompliance and recurrent hypereosinophilia. Mepolizumab (750 mg intravenous every 4 weeks) was started in 2003 through the compassionate use program by GlaxoSmithKline. Steroids and interferon alpha were tapered off by 2015, and blood eosinophil levels have reduced to a sustained level of 200 cells/μL. However, owing to new pancytopenia associated with GATA 2 haploinsufficiency, she is currently awaiting a bone marrow transplant. In July 2020, she presented to the local emergency department with a 2-day history of headache and diffuse body ache. Clinical examination was unremarkable, as was the CXR and head computed tomography results. Her blood eosinophil count was 100 cells/μL, PCR was positive for SARS-COV-2, and the patient was discharged home to self-isolate. Two weeks later, she reported a complete resolution of all symptoms.

Here, we report COVID-19 outcomes for 4 patients receiving mepolizumab therapy. At presentation with SARS-CoV-2 infection, they exhibited a further reduction in their eosinophil counts, consistent with the observation that eosinopenia may have a diagnostic use for COVID-19.⁷ The mechanisms behind this observation are not fully understood⁸; there is no evidence that this represents eosinophilic infiltration of pulmonary tissue⁹ and so may represent diminished eosinophil progenitor generation by other cytokines such as GM-CSF. Despite all these patients being treated with mepolizumab, only 1 patient in this series required hospitalization and ventilatory support—this patient had recognizable risk factors for admission and death in COVID-19, namely: male sex, older age, and chronic cardiac disease.¹⁰ Nevertheless, they recovered without immediate evidence of long-term respiratory consequences, though this will need further tracking. These outcomes are in keeping with the lack of consistent evidence that patients with eosinophil-associated diseases or treatment with eosinophil-targeting therapies should have an altered outcome in COVID-19⁸ and supports the position papers that biologics, such as mepolizumab, should be continued unchanged.