Skip to main content

Main menu

  • Home
  • Current issue
  • Early View
  • Archive
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • COVID-19 submission information
    • Institutional open access agreements
    • Peer reviewer login
  • Alerts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • Early View
  • Archive
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • COVID-19 submission information
    • Institutional open access agreements
    • Peer reviewer login
  • Alerts
  • Subscriptions

Childhood-onset severe hypereosinophilic asthma: efficacy of benralizumab

Jocelyne Just, Melisande Bourgoin, Flore Amat, Nathalie Cottel, Nathalie Lambert, Stephanie Wanin
ERJ Open Research 2020 6: 00339-2020; DOI: 10.1183/23120541.00339-2020
Jocelyne Just
1AP-HP, Groupe hospitalier Trousseau-La Roche Guyon, Centre de l'Asthme et des Allergies, Paris, France
2Sorbonne - université, Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: jocelyne.just@aphp.fr
Melisande Bourgoin
1AP-HP, Groupe hospitalier Trousseau-La Roche Guyon, Centre de l'Asthme et des Allergies, Paris, France
2Sorbonne - université, Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Flore Amat
1AP-HP, Groupe hospitalier Trousseau-La Roche Guyon, Centre de l'Asthme et des Allergies, Paris, France
2Sorbonne - université, Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nathalie Cottel
1AP-HP, Groupe hospitalier Trousseau-La Roche Guyon, Centre de l'Asthme et des Allergies, Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nathalie Lambert
1AP-HP, Groupe hospitalier Trousseau-La Roche Guyon, Centre de l'Asthme et des Allergies, Paris, France
2Sorbonne - université, Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephanie Wanin
1AP-HP, Groupe hospitalier Trousseau-La Roche Guyon, Centre de l'Asthme et des Allergies, Paris, France
2Sorbonne - université, Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Severe hypereosinophilic asthma in children is extremely rare. This letter adds to the existing literature by providing long-term follow-up, and is the first report of the marked efficacy of benralizumab after failure of other biologic treatments. https://bit.ly/2G7Tc2k

To the Editor:

Hypereosinophilic syndrome (HES) is a group of rare chronic disorders that are defined by an absolute blood eosinophil count (BEC) of at least 1.500×109 cells·L−1 on at least two occasions [1] with absence of secondary causes of eosinophilia (including parasitic infections, malignancy as myeloproliferative variants) and end-organ eosinophilic infiltration with associated damage [2]. In 2006, a working group modified the definition of HES to include other previously distinct disease entities associated with eosinophilia, such as eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg–Strauss syndrome) and chronic eosinophilic pneumonia [3]. EGPA typically occurs in middle-aged adults with asthma, and childhood-onset is rare with a prevalence of 10–13 patients per million people [4, 5]. We report here a series of six children with childhood-onset asthma with oral corticosteroid (OCS) dependence associated with hypereosinophilic asthma with a long-term follow-up and the marked efficacy of benralizumab. The study was declared to the French Data Protection Authority (CNIL) according to the reference methodology MR004. All of the included patients or their parents received an information note and were given the opportunity to oppose the use of their personal data, but no refusals were received.

The median age of the children at the beginning of care was 5.5 years (range 5 to 10 years) and four were male. A descriptive history of the children (at diagnosis and after follow-up) is reported in table 1. All of the patients had severe refractory asthma partially controlled or uncontrolled with multiple attacks often requiring intensive care despite step 5 Global Initiative for Asthma (GINA) treatment [6] including OCS treatment. Pulmonary function revealed an obstructive pattern (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) median 70%; range 57–84% of predicted value) associated with intermittent hypoxaemia for all patients. They all had abnormal chest computed tomography (CT): pulmonary infiltrates and nodules (n=6), pulmonary hyperinflation (n=6) and bronchial wall thickening (n=4). At the time of diagnosis, all patients had upper airway disease: nasal polyposis (n=3) and chronic rhinosinusitis (n=3), associated with vernal kerato-conjunctivitis (n=1). Other likely eosinophilic involvement was refractory gastro-oesophageal reflux (n=1) and cutaneous manifestations (urticaria n=1, atopic dermatitis n=1). All had a normal electrocardiographic pattern and echocardiogram. No signs of renal vasculitis were present. HES was confirmed by repeated high levels of absolute BEC, median peak BEC 1.955×109 cells·L−1 (range 1.550 to 40.400×109 cells·L−1) and median peak fractional exhaled nitric oxide 110 ppb (range 35–247 ppb). Four had eosinophilia: median 7% (range 0–45) in bronchoalveolar lavage. All other causes of HES were ruled out: negative FIP1L1 platelet-derived growth factor receptor A; absence of eosinophilic leukaemia (bone marrow analysis for one patient); and normal blood tryptase levels. None of the patients had allergic bronchopulmonary aspergillosis, autoimmune disease or parasitic infection. Antineutrophil cytoplasmic antibody (ANCA) were negative and C-reactive protein (CRP) values were normal in all patients. Serum IgE levels were elevated in three patients with a median of 217 kU·L−1 (range 66–1447). Positive specific IgE≥0.35 kU·L−1 was found in five patients, specifically for staphylococcal toxins in four.

View this table:
  • View inline
  • View popup
TABLE 1

Patient characteristics

All patients had received long-term treatment with continuous OCS (>1 year) resulting in growth retardation for four. All had received a biologic – omalizumab (6–48 months) then mepolizumab (6–18 months) at recommended doses for children of school age for both biological treatments, which failed to control their asthma. One patient received cyclosporine with partial control but relapsed after 6 months. Finally, all patients received benralizumab for 5 to 12 months (at the same dosage as used in teenagers), which resulted in total asthma control for four and discontinuation of OCS for five.

All of the children of our series were diagnosed as having severe hypereosinophilic asthma. A diagnosis of EGPA was not retained even though they all had four of the six clinical findings for EGPA in accordance with the American College of Rheumatology classification [7] (i.e. asthma, eosinophilia, mononeuropathy/polyneuropathy, non-fixed pulmonary infiltrates on radiography, paranasal sinus abnormality, bloods vessel with extravascular eosinophils). They all received long-term treatment with daily OCS and immunomodulatory agents such as cyclosporine with substantial toxic effects as described in the literature [8]. However, in a more recent paper, Cottin et al. [9] state that a diagnosis of EGPA requires asthma, hypereosinophilia and at least one new-onset extra bronchopulmonary organ manifestation of disease (other than rhinosinusitis or other ear, nose and throat manifestations), which was not present in our cases.

Moreover, conversely to adults, Gendelman et al. [10] showed that children with EGPA were significantly more likely to have lung involvement (p<0.001) and eosinophilic gastroenteritis (p=0.02). Unlike Zwerina's paediatric cases [11], but similar to ours, none of the children in Gendelman et al.'s series [10] had positive ANCA.

Interleukin-5 is a cytokine with a selective role in eosinophil maturation, differentiation, mobilisation, activation and survival, so interleukin-5 inhibition is a logical therapeutic target for EGPA.

In the literature, mepolizumab (a fully humanised, anti-interleukin-5 (anti-IL-5)) has been largely explored in the context of HES syndrome. After proof-of-concept studies [12, 13], a randomised, double-blind, placebo-controlled trial [14] showed that treatment with mepolizumab led to significant reduction, and often discontinuation, of OCS in patients with HES who were negative for FIP1L1-PDGFRA.

Benralizumab, a humanised, afucosylated interleukin-5 receptor α monoclonal antibody with a different mechanism of action compared to other anti-IL-5 agents, reduces BEC by enhancing antibody-dependent cellular cytotoxicity, which represents a potential advantage of this biologic in the treatment of EGPA [15]. It has been explored for the treatment of diseases other than asthma with prominent tissue eosinophilia: a phase II placebo-controlled trial showed that benralizumab reduced BEC and MPO-ANCA in patients with FIP1L1-PDGFR-negative HES, with an improvement in symptoms of bronchial asthma [16].

Our description of severe hypereosinophilic asthma in children adds to the existing literature by providing long-term follow-up. Furthermore, we are the first to report the efficacy of benralizumab after failure of other biologic treatments for five out of six children. Nevertheless, a long follow-up is necessary to confirm the absence of relapse as we have seen with the other biologics in our population. International multicentre controlled studies must confirm this therapeutic option for reducing the rates of steroid-related adverse effects and the risk of mortality in paediatric patients with severe hypereosinophilic asthma.

Footnotes

  • Conflict of interest: J. Just reports grants and personal fees from Novartis, grants from ALK-Abello, and personal fees from Stallergenes, AstraZeneca and Thermo Fisher, outside the submitted work.

  • Conflict of interest: M. Bourgoin reports grants from Stallergène and ALK-Abello, and personal fees from Novartis, outside the submitted work.

  • Conflict of interest: F. Amat has nothing to disclose.

  • Conflict of interest: N. Cottel has nothing to disclose.

  • Conflict of interest: N. Lambert has nothing to disclose.

  • Conflict of interest: S. Wanin has nothing to disclose.

  • Received June 2, 2020.
  • Accepted September 21, 2020.
  • Copyright ©ERS 2020
http://creativecommons.org/licenses/by-nc/4.0/

This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

References

  1. ↵
    1. Simon H,
    2. Rothenberg M,
    3. Bochner B, et al.
    Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol 2010; 126: 45–49. doi:10.1016/j.jaci.2010.03.042
    OpenUrlCrossRefPubMed
  2. ↵
    1. Allen JN,
    2. Davis WB
    . Eosinophilic lung diseases. Am J Respir Crit Care Med 1994; 150: 1423–1438. doi:10.1164/ajrccm.150.5.7952571
    OpenUrlCrossRefPubMed
  3. ↵
    1. Klion AD,
    2. Bochner BS,
    3. Gleich GJ, et al.
    Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol 2006; 117: 1292–1302. doi:10.1016/j.jaci.2006.02.042
    OpenUrlCrossRefPubMed
  4. ↵
    1. Watts RA,
    2. Scott DG
    . Epidemiology of the vasculitides. Curr Opin Rheumatol 2003; 15: 11–16. doi:10.1097/00002281-200301000-00003
    OpenUrlCrossRefPubMed
  5. ↵
    1. Mahr A,
    2. Guillevin L,
    3. Poissonnet M, et al.
    Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener's granulomatosis and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate. Arthritis Rheum 2004; 51: 92–99. doi:10.1002/art.20077
    OpenUrlCrossRefPubMed
  6. ↵
    Global Initiative for Asthma (GINA). https://ginasthma.org/tag/children/
  7. ↵
    1. Masi AT,
    2. Hunder GG,
    3. Lie JT, et al.
    The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33: 1094–1100. doi:10.1002/art.1780330806
    OpenUrlCrossRefPubMed
  8. ↵
    1. Ogbogu PU,
    2. Bochner BS,
    3. Butterfield JH, et al.
    Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 2009; 124: 1319–1325. doi:10.1016/j.jaci.2009.09.022
    OpenUrlCrossRefPubMed
  9. ↵
    1. Cottin V,
    2. Bel E,
    3. Bottero P, et al.
    Revisiting the systemic vasculitis in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): a study of 157 patients by the Groupe d'Etudes et de Recherche sur les Maladies Orphelines Pulmonaires and the European Respiratory Society Taskforce on eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Autoimmun Rev 2017; 16: 1–9. doi:10.1016/j.autrev.2016.09.018
    OpenUrl
  10. ↵
    1. Gendelman S,
    2. Zeft A,
    3. Spalding SJ
    . Childhood onset eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome): a contemporary single-center cohort. J Rheumatol 2013; 40: 929–935. doi:10.3899/jrheum.120808
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Zwerina J,
    2. Eger G,
    3. Englbrecht M, et al.
    Churg-Strauss syndrome in childhood: a systematic literature review and clinical comparison with adult patients. Semin Arthritis Rheum 2009; 39: 108–115. doi:10.1016/j.semarthrit.2008.05.004
    OpenUrlCrossRefPubMed
  12. ↵
    1. Koury MJ,
    2. Newman JH,
    3. Murray JJ
    . Reversal of hypereosinophilic syndrome and lymphomatoid papulosis with mepolizumab and imatinib. Am J Med 2003; 115: 587–589. doi:10.1016/S0002-9343(03)00475-3
    OpenUrlPubMed
  13. ↵
    1. Rosenwasser L,
    2. Rothenberg M
    . IL-5 pathway inhibition in the treatment of asthma and Churg-Strauss syndrome. J Allergy Clin Immunol 2010; 125: 1245–1246. doi:10.1016/j.jaci.2010.04.022
    OpenUrlCrossRefPubMed
  14. ↵
    1. Rothenberg M,
    2. Klion A,
    3. Roufosse F, et al.
    Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med 2008; 358: 1215–1228. doi:10.1056/NEJMoa070812
    OpenUrlCrossRefPubMed
  15. ↵
    1. Kolbeck R,
    2. Kozhich A,
    3. Koike M, et al.
    MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol 2010; 125: 1344–1353. doi:10.1016/j.jaci.2010.04.004
    OpenUrlCrossRefPubMed
  16. ↵
    1. Takenaka K,
    2. Minami T,
    3. Yoshihashi Y, et al.
    Decrease in MPO-ANCA after administration of benralizumab in eosinophilic granulomatosis with polyangiitis. Allergol Int 2019; 68: 539–540. doi:10.1016/j.alit.2019.04.006
    OpenUrl
PreviousNext
Back to top
Vol 6 Issue 4 Table of Contents
ERJ Open Research: 6 (4)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Childhood-onset severe hypereosinophilic asthma: efficacy of benralizumab
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Childhood-onset severe hypereosinophilic asthma: efficacy of benralizumab
Jocelyne Just, Melisande Bourgoin, Flore Amat, Nathalie Cottel, Nathalie Lambert, Stephanie Wanin
ERJ Open Research Oct 2020, 6 (4) 00339-2020; DOI: 10.1183/23120541.00339-2020

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Childhood-onset severe hypereosinophilic asthma: efficacy of benralizumab
Jocelyne Just, Melisande Bourgoin, Flore Amat, Nathalie Cottel, Nathalie Lambert, Stephanie Wanin
ERJ Open Research Oct 2020, 6 (4) 00339-2020; DOI: 10.1183/23120541.00339-2020
Reddit logo Technorati logo Twitter logo Connotea logo Facebook logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Subjects

  • Asthma and allergy
  • Pulmonary pharmacology and therapeutics
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

  • rs2070600 SNP regulates AGER splicing and sputum sRAGE
  • Procoagulant microparticles and COVID-19
  • Cancer referral and interventional pulmonology during COVID-19
Show more Original research letters

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About ERJ Open Research

  • Editorial board
  • Journal information
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Online ISSN: 2312-0541

Copyright © 2023 by the European Respiratory Society