key: cord-0854138-lkv2ntqy
authors: Peter, Schmid-Grendelmeier; Peter, Steiger; Mirjam C, Naegeli; Isabel, Kolm; Cécile Valérie, Lang Claudia; Emanual, Maverakis; Marie-Charlotte, Brüggen
title: Benralizumab for severe DRESS in two COVID-19 patients
date: 2020-10-08
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2020.09.039
sha: cf6ab2af2f9f50ea5dab02debcef611e1f513c4c
doc_id: 854138
cord_uid: lkv2ntqy

nan

This report provides first evidence for the IL-5Rα-blocking antibody benralizumab as a 31 treatment option for severe DRESS not responding to first-line treatment; proteomic serum 32 analyses point towards substantial eosinophil-and T cell-related changes induced by the 33 treatment. 34 hypersensitivity reaction that clinically manifests with exanthema, facial edema, enlarged 39 lymph nodes, fever and organ damage at variable degrees (1). Eosinophil expansion in blood 40 is a hallmark of DRESS and eosinophil tissue infiltration a main contributor to the observed 41 organ damage and dysfunction (2). Although high-dose systemic glucocorticoids have not 42 been evaluated in randomized clinical trials, they are currently the first-line therapy for 43 DRESS with organ involvement. However, glucocorticoid-associated adverse events remain 44 high and response rates are variable. Also, regardless of therapy, DRESS patients have a high, 45 5 to 10 percent, mortality rate (2). Here, we report the first use of benralizumab (Fasenra), 46 an interleukin (IL)-5-receptor α-chain-specific humanized monoclonal antibody (IgG1k) 47 initially approved for eosinophilic asthma (3), in two patients with glucocorticoid-48 unresponsive DRESS occurring during coronavirus disease 2019 . The study was 49 approved by the regional ethics review board (EK2020-01029) and conducted according to 50 the Declaration of Helsinki. 51 52 Both patients were treated in the intensive care unit for acute respiratory distress syndrome 53 due to COVID-19. Patient 1, a 54-year-old woman, developed prominent eosinophilia 54 followed 3 days later by cutaneous and systemic DRESS syndrome features (Table 1) . 55

Esomeprazol and piperacillin-tazobactam (details: Figure E1a ), initiated almost 6 weeks prior 56 DRESS onset and administered intermittently, were suspected as most potential culprit drugs 57 and stopped immediately. Patient 2, a 58-year-old man with COVID-19-related multiorgan 58 failure developed widespread maculopapular skin lesions, facial swelling, severe eosinophilia 59 and hepatic dysfunction. The suspected potential culprit drug in his case was midazolam, 60 which had been administered about 3 weeks before the symptoms started ( Figure E1a ). In 61 both patients, skin histopathology from cutaneous lesions on the trunk ( Figure E1b ) RegiSCAR criteria (scores 7 and 8, respectively; Table 1 ). In addition to discontinuing the 65 potential culprit drugs, both patients received high-dose intravenous methylprednisolone 66 (patient 1: 125mg for 3 days, 70mg for 4 days; patient 2: 125mg for 6 days), without 67 improvement. In the setting of worsening eosinophilia (Figure 1a ), deteriorating organ 68 function, and exacerbation of their cutaneous eruption, the decision was made to initiate 69 therapy with benralizumab (Fasenra; 30mg subcutaneously). This decision was based upon 70 the rationale that IL-5/eosinophil axis inhibition has been reported as a successful treatment in 71 platelet derived growth factor receptor alpha-negative hypereosinophilia (4) and that IL-5, 72 eosinophils and the eosinophil degranulation marker eosinophilic cationic protein (ECP) were 73 highly increased. Within two days following benralizumab administration, both patients 74 showed a rapid and substantial drop in blood eosinophils, and, as measured in patient one, 75 ECP ( Figure 1a and Figure E2 ). This was paralleled clinically by an improvement of the 76 patients' cutaneous eruption, and a lowering of liver enzyme levels. Patient one continued to 77 improve over the following 18 days. Patient two, however, developed disseminated 78 intravascular coagulation secondary to COVID-19 and died from cardiac arrest after massive 79 bleeding 17 days after the administration of Fasenra. 80

To explore treatment-induced immunological changes, targeted serum proteomic studies were 81 performed immediately before and one day following Fasenra administration (Online 82 Repository Text; Figure 1b) . This analysis revealed a significant reduction in levels of IL-5, creatinine: 62-106 µmol/l; creatinin kinase: <190 U/L; myoglobin: 28-72 µg/l; AST and ALT: 155 <50 U/l; pancreatic amylase: 13-52 U/l; lipase: 13-60 U/l 156

Variability in the clinical pattern of cutaneous side-effects of drugs 117 with systemic symptoms: does a DRESS syndrome really exist?

New Insights into Drug Reaction with Eosinophilia and Systemic 120 Symptoms Pathophysiology

Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma

Benralizumab 125 for PDGFRA-Negative Hypereosinophilic Syndrome

Drug Reaction with Eosinophilia and 127

Systemic Symptoms (DRESS) syndrome successfully treated with mepolizumab

Mepolizumab rescue therapy for acute 130 pneumonitis secondary to DRESS

132 Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in 133 COVID-19

Eosinophil responses during COVID-19 135 infections and coronavirus vaccination

The 137 Cellular Functions of Eosinophils: Collegium Internationale Allergologicum (CIA) Update