Letter to the Editor
Mepolizumab in severe asthma exacerbation in a respiratory ICU—a successful off-label use
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Evolution of most common lung alterations before (left column) and after (right column) initiation of treatment with elexacaftor-tezacaftor-ivacaftor. In every scenario lung consolidation either drastically decreased in extension or completely resolved. Bronchial wall thickening is widely reduced. Tree-in-bud nodules and pleural effusion disappeared (shown in patient C). Bronchiectasis are unchanged in extent and size. <span class="elsevierStyleItalic">Fat arrow</span>: parenchymal consolidation; <span class="elsevierStyleItalic">thin arrow</span>: bronchial wall thickening; <span class="elsevierStyleItalic">arrow-head</span>: tree-in-bud appearance; <span class="elsevierStyleItalic">curved arrow</span>: pleural effusion.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "V. Fainardi, K. Skenderaj, A. Ciuni, S. Esposito, N. Sverzellati, G. Pisi" "autores" => array:6 [ 0 => array:2 [ "nombre" => "V." "apellidos" => "Fainardi" ] 1 => array:2 [ "nombre" => "K." "apellidos" => "Skenderaj" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Ciuni" ] 3 => array:2 [ "nombre" => "S." "apellidos" => "Esposito" ] 4 => array:2 [ "nombre" => "N." "apellidos" => "Sverzellati" ] 5 => array:2 [ "nombre" => "G." "apellidos" => "Pisi" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2531043722002811?idApp=UINPBA00004E" "url" => "/25310437/0000002900000005/v1_202309041851/S2531043722002811/v1_202309041851/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S2531043723000533" "issn" => "25310437" "doi" => "10.1016/j.pulmoe.2023.03.001" "estado" => "S300" "fechaPublicacion" => "2023-09-01" "aid" => "1853" "copyright" => "Sociedade Portuguesa de Pneumologia" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "cor" "cita" => "Pulmonol. 2023;29:435-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter to the Editor</span>" "titulo" => "Chronic thromboembolic pulmonary hypertension – the challenging approach of a young patient with distal disease" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "435" "paginaFinal" => "437" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1757 "Ancho" => 3500 "Tamanyo" => 587928 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Imaging findings before and after combined treatment with pulmonary vasodilator therapy and balloon pulmonary angioplasty.</p> <p id="spara002" class="elsevierStyleSimplePara elsevierViewall">Capture A: Vascular and pulmonary findings of chronic thromboembolism on CT pulmonary angiography. (A1) and (A2) Axial plane images reveal main pulmonary artery dilation (arrow), linear filling defects within pulmonary arterial vessels – webs (arrowhead), caused by residual thrombotic material, and bronchial arteries dilation followed by abrupt transition of size, irregularity and stenosis of multiple peripheral arteries (short arrows). (A3) Mosaic perfusion pattern (MinIP reconstruction image, coronal plane) defined by variable lung attenuation and due to heterogeneity of lung parenchyma, in which hypoperfused peripheral regions have low attenuation (*) compared to those of normal lung perfusion.</p> <p id="spara003" class="elsevierStyleSimplePara elsevierViewall">Capture B: Comparison of chest X-ray before and after treatment (B1 and B2, respectively). (B1) Severe cardiomegaly, dilation of the right atrium (*), dilation of the main pulmonary artery and right pulmonary enlargement (arrows). (B2) Almost normal chest x-ray after treatment.</p> <p id="spara004" class="elsevierStyleSimplePara elsevierViewall">Captures C to E: Comparison of transthoracic echocardiogram images before and after treatment (C1-E1 and C2-E2, respectively). (C1) End-diastolic short-axis view showing severe right ventricle (RV) dilation and interventricular septum deviation to the left caused by RV pressure overload (interventricular septal D-shape – short arrows), significantly impairing left ventricle diastolic filling. (D1) and E1) Apical four-chamber end-diastolic view (D) and Doppler mid-systolic image (E) showing initial dilated and hypertrophied RV (arrowheads), severely dilated right atrium (RA), associated with severe tricuspid regurgitation with an estimated PSAP of 88 mmHg. After treatment there was a significant decrease in right chambers’ size with only mild tricuspid regurgitation and improvement of LV diastolic filling.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Martinho, R. Calé, F. Ferreira, S. Alegria, A. Santos, A.C. Vieira, D. Repolho, S. Vitorino, C. Saraiva, H. Pereira" "autores" => array:10 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Martinho" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Calé" ] 2 => array:2 [ "nombre" => "F." "apellidos" => "Ferreira" ] 3 => array:2 [ "nombre" => "S." "apellidos" => "Alegria" ] 4 => array:2 [ "nombre" => "A." "apellidos" => "Santos" ] 5 => array:2 [ "nombre" => "A.C." "apellidos" => "Vieira" ] 6 => array:2 [ "nombre" => "D." "apellidos" => "Repolho" ] 7 => array:2 [ "nombre" => "S." "apellidos" => "Vitorino" ] 8 => array:2 [ "nombre" => "C." "apellidos" => "Saraiva" ] 9 => array:2 [ "nombre" => "H." "apellidos" => "Pereira" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2531043723000533?idApp=UINPBA00004E" "url" => "/25310437/0000002900000005/v1_202309041851/S2531043723000533/v1_202309041851/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter to the Editor</span>" "titulo" => "Mepolizumab in severe asthma exacerbation in a respiratory ICU—a successful off-label use" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "438" "paginaFinal" => "440" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "H.C. Rodrigues, C. Martins, E. Fragoso, C. Lopes, P. Azevedo" "autores" => array:5 [ 0 => array:4 [ "nombre" => "H.C." "apellidos" => "Rodrigues" "email" => array:1 [ 0 => "henriquecabritarodrigues@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0002" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0001" ] ] ] 1 => array:3 [ "nombre" => "C." "apellidos" => "Martins" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] ] ] 2 => array:3 [ "nombre" => "E." "apellidos" => "Fragoso" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] ] ] 3 => array:3 [ "nombre" => "C." "apellidos" => "Lopes" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0002" ] ] ] 4 => array:3 [ "nombre" => "P." "apellidos" => "Azevedo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidade de Cuidados Intensivos Respiratórios, Serviço de Pneumologia, Centro Hospitalar Universitário Lisboa Norte, Portugal" "etiqueta" => "a" "identificador" => "aff0001" ] 1 => array:3 [ "entidad" => "Unidade Multidisciplinar de Asma Grave, Serviço de Pneumologia, Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal" "etiqueta" => "b" "identificador" => "aff0002" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0001" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Hospital de Santa Maria, Serviço de Pneumologia - Avenida, Professor Egas Moniz, 1649-028 Lisboa, Portugal." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1996 "Ancho" => 3333 "Tamanyo" => 312165 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Case report timeline following the CARE guidelines<span class="elsevierStyleBold">.</span></p> <p id="spara002" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: EOS – eosinophils; CT – computerized tomography; ED – emergency department; ICU – intensive care unit; FeNO – fraction of exhaled nitric oxide; FEV1 – forced expiratory volume in first second; PBT – post bronchodilation test; SC – subcutaneous; ICS – inhaled corticosteroid; LABA – long-acting beta-agonist; LAMA – long-acting muscharinic antagonist.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="para0001" class="elsevierStylePara elsevierViewall">Severe eosinophilic asthma is a clinical phenotype of asthma; the underlying mechanism is an eosinophilic inflammatory pattern in the airway, characterized by recurrent exacerbations and poor disease control. Both in atopic and non-atopic subphenotypes, IL-5 plays a major role across the pathway of eosinophilic inflammation.<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a></p><p id="para0002" class="elsevierStylePara elsevierViewall">Pharmacological agents targeting IL-5 have shown to significantly reduce severe exacerbations and oral corticosteroids (OCS) use in severe eosinophilic asthma patients, particularly in those with higher eosinophilic count and a history of frequent exacerbations.<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> Mepolizumab is an anti-IL5 monoclonal antibody, approved as an add-on therapy in both allergic and non-allergic patients with severe eosinophilic asthma, and recommended on step 5 of the 2022 GINA guidelines.<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a></p><p id="para0003" class="elsevierStylePara elsevierViewall">Despite the continuous decrease in asthma mortality, severe asthma exacerbations still represent the highest contribution for all-cause mortality during the first month following the event.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a></p><p id="para0004" class="elsevierStylePara elsevierViewall">Therefore, this report addresses a potential additional role of anti-IL5 in treating acute refractory severe asthma exacerbations and reduce its mortality. We report an off-label use of mepolizumab in a patient without previous maintenance treatment, during a life-threatening asthma attack.</p><p id="para0005" class="elsevierStylePara elsevierViewall">A 25-year-old female presented to the emergency department complaining of severe dyspnea, wheezing and cough, with progressive worsening in the previous 4 weeks. The patient had history of allergic asthma without any maintenance therapy, having abandoned anti-asthmatic treatment during childhood. The patient did not mention any comorbidities, medication, or smoking habits, nor any asthma related exacerbations.</p><p id="para0006" class="elsevierStylePara elsevierViewall">On admission the patient was restless, showing signs of respiratory distress, and decreased pulmonary sounds. Chest x-ray showed parenchymal hyperinflation with no signs of infiltrates. Blood gas assessment showed severe hypoxemia, normocapnia and no other alterations. Given the persistent signs of tachypnea, paradoxical breathing, and high oxygen requirements, the patient was promptly admitted to a respiratory ICU, and initiated on invasive mechanical ventilation. In the following hours the patient evolved with refractory bronchospasm and severe blood gas deterioration with pH 6.85 and carbon dioxide partial pressure (PaCO<span class="elsevierStyleInf">2</span>) 145 mmHg, under pressure-regulated volume control-mode (settings: tidal volume 380 mL; respiratory frequency 22 cycles per minute; positive end-expiratory pressure, PEEP 0 mmHg, inspiratory to expiratory ratio 1:4). Blood tests at admission and prior to corticosteroid administration revealed blood eosinophils of 11% (2680/µL) and no other alterations. In the subsequent days, and despite adjusted ventilatory settings, deep sedation, analgesia, muscle paralysis and anti-asthmatic and bronchodilator therapy [inhaled salbutamol (200 mcg q4h), ipratropium (80 mcg q4h) and beclomethasone (500 mcg q8h), IV methylprednisolone (125 mg q6h – withdrawal after 6 days), IV aminophylline (240 mg q12h), IV magnesium sulphate (2 g q12h), IV salbutamol (5–10 mcg/min intermittently during 3 days), IV ketamine (0.5–1.25 mg/kg/h intermittently during 5 days)], mechanical ventilation remained a challenge, considering dynamic hyperinflation, high auto-PEEP values (maximum 12 cmH2O), and high peak inspiratory pressures. No CT scan or bronchoscopy was performed in the acute phase due to the hemodynamic instability and the absence of infiltrates in the chest x-ray. Eosinophilic granulomatosis with polyangiitis (EGPA) was not fully ruled out; however, no symptoms of ear, nose, and throat involvement nor systemic vasculitis manifestations were present, and serum cANCA were negative.</p><p id="para0007" class="elsevierStylePara elsevierViewall">On the 4th day of ventilatory support,100 mg mepolizumab was administered subcutaneously, as an off-label last-resort attempt to recover from the critical ventilatory state. After 48 h of mepolizumab injection, we observed a clinical improvement, normalization of PaCO<span class="elsevierStyleInf">2</span>, peak pressures, and residual auto-PEEP. Then, the patient started IV corticosteroids tapering, and was weaned from mechanical ventilation and extubated on the 11th day of ventilation. No minor or serious adverse effects were registered. The timeline of the patient's clinical evolution is shown in <a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>.</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><p id="para0008" class="elsevierStylePara elsevierViewall">The patient was discharged from the ICU after 19 days. At 1-month follow-up, systematic assessment revealed variable airflow limitation with a FEV<span class="elsevierStyleInf">1</span> of 72% (2410 mL) and FVC of 89% (3420 mL), a positive post-bronchodilation test, with FEV<span class="elsevierStyleInf">1</span> reaching 82% (2760 mL), high serum total IgE levels 650 IU/mL, high fraction of exhaled nitric oxide (FeNO) 56 ppb, and sensitization to house dust mites. Eosinophilic count was depleted (1% – 100/µL), and thoracic and sinus CT were normal. Clinical improvement was documented through validated quality-of-life questionnaires related to rhinitis – Self Assessment of Allergic Rhinitis and Asthma (SACRA) and asthma – Asthma Quality of Life Questionnaire (AQLQ). The Asthma Control Test at 1-month follow-up documented symptomatic improvement (ACT-19). The patient maintained follow-up at the severe asthma outpatient clinic, and has been under inhaled treatment with high dose ICS/LABA, LAMA, anti-leukotrienes and mepolizumab for two years, with present adequate asthma control (ACT-22) and only one documented mild eosinophilic exacerbation.</p><p id="para0009" class="elsevierStylePara elsevierViewall">Although its outcomes have been studied for medium/long term, pharmacokinetic studies with mepolizumab identified pronounced and maximal reductions in eosinophil count 3–4 days after infusion and estimated at ∼85% relative to baseline, with a single administration.<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> This short-term benefit, together with a vast local and multicenter experience regarding its safety and effectiveness as a corticosteroid-sparing agent, guided its choice over other anti-IL5 agents.<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a></p><p id="para0010" class="elsevierStylePara elsevierViewall">Other studies have previously reported the use of mepolizumab, reslizumab and omalizumab in severe asthma exacerbations, also with similar degrees of success.<a class="elsevierStyleCrossRefs" href="#bib0008"><span class="elsevierStyleSup">8–10</span></a> Benralizumab, a monoclonal antibody against IL5‐Rα, has also proven to induce a rapid response to treatment during exacerbations of severe asthma, with peak flow improvements after four days of administration,<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a> eosinophil count suppression, and 19% increase in FEV<span class="elsevierStyleInf">1</span> after 48 h.<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> We posit that, in this case, the observed objective improvement in the ventilatory mechanic pressures 48 h after mepolizumab can be interpreted as an equivalent outcome.</p><p id="para0011" class="elsevierStylePara elsevierViewall">Starting mepolizumab during an exacerbation and continuing it after follow-up assessment represented a unique approach, with short and long-term benefits. The early response to mepolizumab proved to be crucial in limiting the eosinophilic inflammatory pathway, allowing for a faster corticosteroid withdrawal, and being of paramount importance in reversing a critical ventilatory state, refractory to high dose corticosteroids and bronchodilators. Its off-label use has also revealed a good safety profile.</p><p id="para0012" class="elsevierStylePara elsevierViewall">The main limitation of our case is the deficient phenotype assessment of the previous asthma diagnosis. We also could not fully rule out other diagnoses of eosinophilic also disorders such as EGPA; however, mepolizumab 100 mg every 4 weeks has also been shown to be effective in controlling respiratory manifestation of EGPA.<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a></p><p id="para0013" class="elsevierStylePara elsevierViewall">This case supports the hypothesis of a novel role for mepolizumab in acute settings in refractory severe exacerbations of eosinophilic asthma.</p><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Ethical considerations</span><p id="para0014" class="elsevierStylePara elsevierViewall">Written permission for off-label use was obtained from the legal representative of the patient.</p><p id="para0015" class="elsevierStylePara elsevierViewall">This study was retrospectively approved by the Institutional Ethic Committee.</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Informed consent</span><p id="para0016" class="elsevierStylePara elsevierViewall">Appropriate written informed consent was obtained from the patient for the publication of this case report.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0001" "titulo" => "Ethical considerations" ] 1 => array:2 [ "identificador" => "sec0002" "titulo" => "Informed consent" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-06-27" "fechaAceptado" => "2023-03-08" "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1996 "Ancho" => 3333 "Tamanyo" => 312165 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Case report timeline following the CARE guidelines<span class="elsevierStyleBold">.</span></p> <p id="spara002" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: EOS – eosinophils; CT – computerized tomography; ED – emergency department; ICU – intensive care unit; FeNO – fraction of exhaled nitric oxide; FEV1 – forced expiratory volume in first second; PBT – post bronchodilation test; SC – subcutaneous; ICS – inhaled corticosteroid; LABA – long-acting beta-agonist; LAMA – long-acting muscharinic antagonist.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec1" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib0001" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnosis and management of eosinophilic asthma: a US perspective" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H.H. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 47 | 36 | 83 |
| 2024 September | 91 | 46 | 137 |
| 2024 August | 83 | 52 | 135 |
| 2024 July | 89 | 50 | 139 |
| 2024 June | 60 | 40 | 100 |
| 2024 May | 75 | 43 | 118 |
| 2024 April | 59 | 39 | 98 |
| 2024 March | 88 | 25 | 113 |
| 2024 February | 70 | 33 | 103 |
| 2024 January | 230 | 50 | 280 |
| 2023 December | 90 | 35 | 125 |
| 2023 November | 108 | 64 | 172 |
| 2023 October | 168 | 90 | 258 |
| 2023 September | 185 | 74 | 259 |
| 2023 August | 56 | 16 | 72 |
| 2023 July | 81 | 23 | 104 |
| 2023 June | 50 | 26 | 76 |
| 2023 May | 44 | 56 | 100 |
| 2023 April | 52 | 46 | 98 |
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