Complications of switching from anti–IL-5 or anti–IL-5R to dupilumab in corticosteroid-dependent severe asthma

Abstract

Clinical Implications•In rare cases, anti–IL-4/13 for severe asthma can cause hypereosinophilia, with sudden deterioration of asthma, eosinophilic tissue infiltration, and eosinophilic granulomatosis with polyangiitis–like symptoms. Prednisone-dependent patients with asthma who switched from anti–IL-5 to anti–IL-4/13 treatment may be particularly at risk for these serious complications. •In rare cases, anti–IL-4/13 for severe asthma can cause hypereosinophilia, with sudden deterioration of asthma, eosinophilic tissue infiltration, and eosinophilic granulomatosis with polyangiitis–like symptoms. Prednisone-dependent patients with asthma who switched from anti–IL-5 to anti–IL-4/13 treatment may be particularly at risk for these serious complications. Currently, 5 biologic therapies have been approved for the add-on treatment of severe asthma. They all block type 2 inflammatory pathways, either by targeting IgE (omalizumab), the IL-5 pathway (mepolizumab, reslizumab, benralizumab), or the IL-4/13 pathway (dupilumab).1Krings J.G. McGregor M.C. Bacharier L.B. Castro M. Biologics for severe asthma: treatment-specific effects are important in choosing a specific agent.J Allergy Clin Immunol Pract. 2019; 7: 1379-1392Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar If asthma control to one biologic is incomplete, patients often switch between treatments.2Eger K. Kroes J.A. ten Brinke A. Bel E.H. Long-term therapy response to anti–IL-5 biologics in severe asthma—a real-life evaluation.J Allergy Clin Immunol Pract. 2021; 9: 1194-1200Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar This can be done safely from anti-IgE to anti–IL-5s, but only limited data exist about switching from anti–IL-5 to anti–IL-4/13 biologics.3Mümmler C. Munker D. Barnikel M. Veit T. Kayser M. Welte T. et al.Dupilumab improves asthma control and lung function in patients with insufficient outcome during previous antibody therapy.J Allergy Clin Immunol Pract. 2021; 9: 1177-1185.e4Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 4Dupin C. Belhadi D. Guilleminault L. Gamez A.S. Berger P. De Blay F. et al.Effectiveness and safety of dupilumab for the treatment of severe asthma in a real-life French multi-centre adult cohort.Clin Exp Allergy. 2020; 50: 789-798Crossref PubMed Scopus (39) Google Scholar, 5Pérez de Llano L.A. Dacal Rivas D. Cosío B.G. Mepolizumab and reslizumab, two different options for severe asthma patients with prior failure to omalizumab.Allergy. 2020; 75: 940-942Crossref PubMed Scopus (4) Google Scholar One important difference between these 2 classes of biologics is that anti–IL-5s induce a profound decrease in blood eosinophil counts, whereas anti–IL-4/13 biologics induce a transient increase in blood eosinophils as shown by the phase 3 studies in which 4% to 14% of patients developed predominantly asymptomatic blood eosinophilia.1Krings J.G. McGregor M.C. Bacharier L.B. Castro M. Biologics for severe asthma: treatment-specific effects are important in choosing a specific agent.J Allergy Clin Immunol Pract. 2019; 7: 1379-1392Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,6Castro M. Corren J. Pavord I.D. Maspero J. Wenzel S. Rabe K.F. et al.Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma.N Engl J Med. 2018; 378: 2486-2496Crossref PubMed Scopus (803) Google Scholar,7Rabe K.F. Nair P. Brusselle G. Maspero J.F. Castro M. Sher L. et al.Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma.N Engl J Med. 2018; 378: 2475-2485Crossref PubMed Scopus (526) Google Scholar In this case series, we describe 4 patients who developed unexpected eosinophilic complications after initiation of dupilumab. All were previously treated with an anti–IL-5 biologic for oral corticosteroid (OCS)-dependent asthma. Although most of them had been able to reduce or discontinue prednisone use during anti–IL-5 treatment, 3 were still OCS-dependent, while all suffered from refractory sinonasal disease and/or poor lung function with high levels of exhaled nitric oxide, prompting a trial with dupilumab on the assumption of an activated IL-4/13 pathway. The first patient (female, 59 years) switched from benralizumab to dupilumab, and soon developed worsening of chronic sinusitis symptoms. Despite intensifying her maintenance prednisone treatment from 10 to 20 mg/d, symptoms worsened and she developed dyspnea and fever. Blood eosinophil counts had increased from 108 to 5080 cells/μL, and chest computed tomography revealed diffuse bilateral consolidations (Figure 1). Bronchoalveolar lavage showed 6% eosinophils (despite prednisone), a negative Galactomannan assay and fungal culture, and a few Haemophilus influenzae colonies. Serologic test results for common parasitic infections were negative. We diagnosed her with eosinophilic pneumonia, increased prednisone to 60 mg/d, and discontinued dupilumab (Table I). Shortly after, she developed an acute coronary syndrome followed by cardiac arrest, with return of spontaneous circulation after 20 minutes of cardiopulmonal resuscitation. A coronary angiogram showed multiple distal occlusions, and anticoagulation therapy was initiated. One week after discharge from the intensive care unit, she developed focal unilateral neurologic deficits due to multiple ischemic cerebrovascular events. Antiphospolipid and anti–nuclear cytoplasmic antibodies (ANCAs) were negative, and cardiac magnetic resonance imaging did not show myocarditis or intracardiac thrombus formation. Fortunately, she gradually recovered, prednisone dose was tapered to 10 mg/d, and benralizumab was restarted later. Currently, she still suffers from dyspnea on exertion.Table IAsthma outcome parameters before anti–IL-5 treatment and before and after initiation of dupilumabOutcomePatient 1Patient 2Patient 3Patient 4Age (y)59354863Sex (F/M)FMFFBefore anti–IL-5 treatment Asthma exacerbations (n/y)“Frequent”>10“Frequent”“Frequent” ACQ score>4>4>2>3 Prednisolone (mg/d)15404032.5 FEV1 (% predicted)58%38%54%68% Blood eosinophils (cells/μL)∗Highest historical eosinophil counts and Feno levels before the initiation of anti–IL-5 biologics.119016702200760 Feno (ppb)∗Highest historical eosinophil counts and Feno levels before the initiation of anti–IL-5 biologics.159>300221NA Total IgE (IU/L)166375336696 Specific IgE to aspergillus (IU/L)<0.351.630.370.61 ANCA IFT screeningNegativeNegativeNegativeNegative Successive biologic treatmentsMepolizumabMepolizumabMepolizumabMepolizumabBenralizumabReslizumabReslizumabReslizumabBenralizumabBenralizumabBefore dupilumab†Most recent values before the initiation of dupilumab. Asthma exacerbations (n/y)1232 ACQ score2.004.172.831.17 Prednisolone (mg/d)507.532.5 FEV1 (% predicted)84%35%30%43% Blood eosinophils (cells/μL)1005009060 Feno (ppb)3911264205After dupilumab‡Most recent values before acute therapy of adverse events. Asthma exacerbationsNoNoNoNo ACQ score2.501.330.170.00 Prednisolone (mg/d)10-200522.5 FEV1 (% predicted)NANANA71% Blood eosinophils (cells/μL)5080486410103956 Feno (ppb)NANANA19Complications and acute therapies Rapid asthma worseningYesYesYesNo Cardiovascular eventsYesNoNoYes Pulmonary infiltratesYesNANAYes Prednisolone (mg/d)60302030 Anti–IL-5 therapyNoReslizumabBenralizumabMepolizumab§Mepolizumab 300 mg subcutaneous (high dosage).ACQ, Asthma control questionnaire; F, female; Feno, fractional exhaled nitric oxide; IFT, immune fluorescence test; M, male; NA, not available.∗ Highest historical eosinophil counts and Feno levels before the initiation of anti–IL-5 biologics.† Most recent values before the initiation of dupilumab.‡ Most recent values before acute therapy of adverse events.§ Mepolizumab 300 mg subcutaneous (high dosage). Open table in a new tab ACQ, Asthma control questionnaire; F, female; Feno, fractional exhaled nitric oxide; IFT, immune fluorescence test; M, male; NA, not available. The second patient (male, 35 years) switched from reslizumab to dupilumab. He had eliminated prednisone 6 months earlier. On the basis of our previous experience, we closely monitored eosinophil counts. Although he initially reported excellent improvement of sinonasal symptoms, his asthma relapsed in full force after the third administration of dupilumab, with eosinophil counts up to 1020 cells/μL. Immediately, prednisone 30 mg/d was restarted, but his clinical condition worsened and blood eosinophils continued to rise to nearly 5000 cells/μL. We then decided to restart reslizumab treatment and only then his asthma stabilized. The prednisone dose could be tapered, but sinonasal blockage recurred. The third patient (female, 47 years) switched from reslizumab to dupilumab as well, and also showed initially substantial improvement of sinonasal symptoms. However, when tapering maintenance prednisone dose from 7.5 to 5 mg/d, she experienced serious worsening of her asthma and her blood eosinophil counts increased from 90 to 1100 cells/μL. Having learned from the 2 earlier cases, we swiftly increased her prednisone dose, discontinued dupilumab, and initiated benralizumab. Soon thereafter, her asthma improved, but sinonasal symptoms recurred. The fourth patient (female, 63 years) switched from benralizumab to dupilumab after a washout period of 1 year. Her asthma had not improved on anti–IL-5 therapy, but showed good response to dupilumab. Eosinophil counts stayed low, and she cautiously tapered her prednisone (30 to 22.5 mg/d). After 8 administrations of dupilumab, she suddenly developed dysarthria and left-sided neurologic deficit as a result of a minor stroke. She did not report any asthma symptoms, but eosinophils had abruptly risen to 3940 cell/μL and a computed tomography scan showed new bilateral pulmonary consolidations. We immediately increased her prednisone dose, discontinued dupilumab, and started high-dose (300 mg) mepolizumab on the assumption of a flare of ANCA-negative eosinophilic granulomatosis with polyangiitis (EGPA). Currently, the patient's asthma is stable, but she still has minor neurological sequelae. These cases illustrate that greatly elevated blood eosinophil levels after anti–IL-4/13 initiation are not always benign. Two of our patients developed life-threatening events and 2 others acute severe asthma worsening. Transient eosinophilia is commonly observed after initiation of dupilumab, but is mostly asymptomatic and probably due to inhibited trafficking of eosinophils to the tissues resulting from reduced chemotaxis.6Castro M. Corren J. Pavord I.D. Maspero J. Wenzel S. Rabe K.F. et al.Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma.N Engl J Med. 2018; 378: 2486-2496Crossref PubMed Scopus (803) Google Scholar,8Jonstam K. Swanson B.N. Mannent L. Cardell L.O. Tian N. Wang Y. et al.Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis.Allergy. 2019; 74: 743-752Crossref PubMed Scopus (77) Google Scholar Several cases have been reported about dupilumab-induced hypereosinophilia accompanied by respiratory symptoms or pulmonary infiltrates, and 1 case of a patient who clinically deteriorated and required high-dose prednisone after switching from anti–IL-5 to anti–IL-4/13.3Mümmler C. Munker D. Barnikel M. Veit T. Kayser M. Welte T. et al.Dupilumab improves asthma control and lung function in patients with insufficient outcome during previous antibody therapy.J Allergy Clin Immunol Pract. 2021; 9: 1177-1185.e4Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar,6Castro M. Corren J. Pavord I.D. Maspero J. Wenzel S. Rabe K.F. et al.Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma.N Engl J Med. 2018; 378: 2486-2496Crossref PubMed Scopus (803) Google Scholar,9Menzella F. Montanari G. Patricelli G. Cavazza A. Galeone C. Ruggiero P. et al.A case of chronic eosinophilic pneumonia in a patient treated with dupilumab.Ther Clin Risk Manag. 2019; 15: 869-875Crossref PubMed Scopus (28) Google Scholar These cases recovered with OCS only, which was not the case in our patients. The reason why our patients developed these severe events after switching from anti–IL-5 to anti–IL-4/13 is not completely understood. Although patients 2 and 3 did not strictly meet the criteria, we hypothesize that our patients may have originally suffered from a latent ANCA-negative EGPA, previously misdiagnosed as severe eosinophilic asthma with high levels of blood eosinophils masked by OCS maintenance therapy (Table I). By switching to anti–IL-4/13, anti–IL-5s were discontinued without supplementing OCS to original doses. Subsequently, the eosinopenia induced by anti–IL-5 gradually wore off, while at the same time anti–IL-4/13 concomitantly had an eosinophil-elevating effect. These events may all have contributed to a very high eosinophil count with a subsequent flare of EGPA, including eosinophilic tissue infiltration and end-organ damage. Although no end-organ damage occurred in patients 2 and 3, we observed a similar pattern of rapid clinical deterioration with a concomitant sharp increase in eosinophils as in patient 1, so we acted quickly before organ damage would occur. Clearly, treatment with dupilumab was not able to reverse this deterioration. The fourth patient had stopped anti–IL-5 1 year before anti–IL-4/13 initiation. Although OCSs were tapered very slowly, tapering below a certain dose may have triggered hypereosinophilia and associated complications. What can we learn from these 4 cases? First, one should always keep in mind that patients with severe asthma who are OCS-dependent can have underlying (ANCA-negative) EGPA. Second, on rare occasions, anti–IL-4/13 biologics such as dupilumab may induce hypereosinophilia, with sudden deterioration of asthma, tissue infiltration by eosinophils, and EGPA-like symptoms such as thromboembolic events. Therefore, our current strategy is to stop dupilumab and (re)start anti–IL-5 therapy if eosinophils rise to more than 1000 cells/L and asthma symptoms worsen. Finally, eosinophilic complications may occur after switching from an anti–IL-5 to an anti–IL-4/13 monoclonal despite an initial favorable response. This illustrates that activated IL-5 and IL-4/13 pathways can simultaneously contribute to airway inflammation in patients with severe asthma, implying that only combined blockage of the 2 pathways will result in optimal disease control in these patients. This could be achieved by treating patients with 2 biologics at the same time, but ideally the next generation of biologics for asthma will target both pathways so that serious complications as described in these cases will never occur again.

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