Академический Документы
Профессиональный Документы
Культура Документы
Review
Paediatric Pulmonology and Allergology Department, Hopitaux pediatriques de Nice CHU-Lenval, Nice, F-06200, France
Universite de Nice Sophia Antipolis, Nice, F-06000, France
3
Paediatric Pulmonology and Allergology Department, AP-HP, Hopital Necker Enfants Malades, Paris, F-75015, France
4
Universite Paris Descartes-Paris 5, Paris, F-75005, France
2
EDUCATIONAL AIMS
Be aware of the denition of severe, therapy-resistant asthma and the need to distinguish this from difcult-to-treat asthma
Be aware of the intensive development in new classes of inhaled corticosteroids and bronchodilators
Increase their knowledge of biological therapies targeting inammation and impaired immunity
Discuss the fact that the majority of studies have been conducted in adults and be critical concerning extrapolation to paediatric
populations.
A R T I C L E I N F O
S U M M A R Y
Keywords:
Innovative therapies
Inhaled corticosteroids
Bronchodilators
Anti-cytokine
Omalizumab
Antiviral drugs
Severe asthma accounts for 0.5% of the general paediatric population and 4.5% of children with asthma,
representing the major burden of asthma-health-care-associated costs. After ensuring a diagnosis of
asthma and excluding difcult-to-treat patients with co-morbidities and non-adherence proles, there
remains children with real therapy-resistant asthma for whom the recommendations are to treat beyond
guidelines. We describe new insights into the treatment of severe asthma in children, regarding both
classic drugs (corticosteroids, bronchodilators) and innovative biological therapies targeting airway
inammation and impaired innate immunity. All of these new avenues remain to be studied and
validated in children and will require ne clinical and biological phenotyping.
2014 Elsevier Ltd. All rights reserved.
INTRODUCTION
Severe asthma accounts for 0.5% of the general paediatric
population and 4.5% of children with asthma [1]. Unlike in adults
[2], severe asthma in childhood is strongly associated with atopy
[3], with up to 93.5% of children in the TENOR study showing atopy
[4]. Severe asthma represents the major source of asthma-healthcare-associated costs [5]. We sought to review new insights, both
in traditional asthma treatments (corticosteroids, bronchodilators)
and in new avenues which have been studied primarily in adults,
such as biological, antiviral therapies and thermoplasty, and their
potential transfer to severe, therapy-resistant paediatric asthma.
DEFINITION, PHYSIOPATHOLOGY
The ATS/ERS denition of severe asthma for patients 6 years
old is asthma which, during the previous year, required treatment
with medications according to GINA guidelines steps 4-5, or with
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THERMOPLASTY
Thermoplasty is a new technique approved in 2010 by the FDA
for the treatment of severe, adult asthma, which aims to reduce the
airway smooth muscle mass to decrease bronchial constriction
potency [75]. High cost and the restriction of this technique to
interventional pulmonologists with advanced skills are the
principal limitations to the dissemination of this technique in
adults. In children, the technique is probably unsuitable due not
only to short-term adverse events (worsening of symptoms,
atelectasia and haemoptysis) but mainly because of the limited
calibre of the bronchi and the lack of knowledge regarding the
potential impact on lung growth [75].
HOW TO STRATIFY TREATMENT AND MANAGEMENT?
Phenotyping severe asthma in children is one of the current
great challenges. Initial phenotyping of severe asthma in the 2000s
relied on expert opinions and included clinical and functional
characteristics as well as the type of inammation and response to
corticosteroid testing [19]. Initially identied were the exacerbating child, the child with chronic symptoms, with xed obstruction,
with eosinophilic or with neutrophilic inammation, and those
responding or not to systemic corticosteroids. More recently,
unsupervised phenotyping relying on clustering analysis applied
to many clinical, physiologic and inammatory variables has
identied more-complex phenotypes. These phenotypes are
variable between the different studies, reecting the high
heterogeneity of severe asthma, but the main criteria of
classication remain quite traditional: atopy, age of onset and
obstruction level [76,77]. New, targeted biotherapies, such as
omalizumab, have been developed in line with these clinical
stratications. Nevertheless, the stability and reproducibility of
these phenotypes, and their potential relationships with endotypes, still need to be established. The discovery of molecular
biomarkers specic to each sub-group will be necessary to dene
specic endotypes with distinct pathogenetic mechanisms. This
will be the rst step towards personalized medicine.
This is why present and future phenotypic studies will rely on
molecular- and genetic-based approaches in order to dene
endotypes. The advent of high-throughput technologies, and the
application of systems biology to dening new markers of disease
and response to therapy, will in addition help the development of
strategies for molecular-phenotype-driven treatment. Only these
multi-dimensional approaches, combining unbiased evaluation of
host cells and their responses to surrounding pathogens, will lead
to the discovery of properly dened asthma endotypes. In adults,
Th2-driven and eosinophilic-inammation endotypes, in linkage
with newly identied biomarkers, have been isolated by molecular
phenotyping, with no clear relation with atopy [52]. These
endotypes appear to be responsive to IL-5, IL-4 and IL-13 therapies,
and periostin levels can help in selecting patients and monitoring
therapy [53]. Mepolizumab, moreover, also seems to be efcient in
non-atopic patients with persistent eosinophilia, showing the
absence of a relationship between atopy and the Th2-high
endotype [78]. Genetic stratication of treatment responsiveness
was performed in the WAIT study, adjusting ALOX 5 genotypes to
montelukast response (available at https://clinicaltrials.gov/ identier: NCT01142505). This type of approach could be of particular
interest in non-Th2 severe asthma, in which no denite intrinsic
biomarkers have been identied, and where new LABA, tiotropium,
theophylline, azithromycin and inhaled IFN- beta use could be of
interest.
Data obtained in adults on Th2-high endotypes constitute only
some clues for the future, and a huge scientic effort for the
endotyping of severe asthma in children has to be instigated before
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[34] Chowdhury BA, Seymour SM, Michele TM, Durmowicz AG, Liu D, Rosebraugh
CJ. The risks and benets of indacaterolthe FDAs review. N Engl J Med 2011
Dec 15;365(24):22479.
[35] Busse WW, OByrne PM, Bleecker ER, Lotvall J, Woodcock A, Andersen L, et al.
Safety and tolerability of the novel inhaled corticosteroid uticasone furoate
in combination with the beta2 agonist vilanterol administered once daily for
52 weeks in patients >=12 years old with asthma: a randomised trial. Thorax
2013 Jun;68(6):51320.
[36] Woodcock A, Bleecker ER, Lotvall J, OByrne PM, Bateman ED, Medley H, et al.
Efcacy and safety of uticasone furoate/vilanterol compared with uticasone
propionate/salmeterol combination in adult and adolescent patients with
persistent asthma: a randomized trial. Chest 2013 Oct;144(4):12229.
[37] Bateman ED, OByrne PM, Busse WW, Lotvall J, Bleecker ER, Andersen L, et al.
Once-daily uticasone furoate (FF)/vilanterol reduces risk of severe exacerbations in asthma versus FF alone. Thorax. 2013 Nov 19.
[38] Berger WE, Bensch GW, Weinstein SF, Skoner DP, Prenner BM, Shekar T, et al.
Bronchodilation with mometasone furoate/formoterol fumarate administered
by metered-dose inhaler with and without a spacer in children with persistent
asthma. Pediatr Pulmonol 2013 Sep 9.
[39] Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/
formoterol versus budesonide/formoterol combination therapy in asthma.
Eur Respir J 2007 Apr;29(4):6829.
[40] Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/formoterol vs uticasone/salmeterol inhaled combination in moderate to severe
asthma. Allergy 2007 Oct;62(10):11828.
[41] Giovannini-Chami L, Marcet B, Moreilhon C, Chevalier B, Illie MI, Lebrigand K,
et al. Distinct epithelial gene expression phenotypes in childhood respiratory
allergy. Eur Respir J 2012 May;39(5):1197205.
[42] Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, et al.
Requirement for IL-13 independently of IL-4 in experimental asthma. Science
1998 Dec 18;282(5397):22613.
[43] Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, et al.
Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children.
N Engl J Med 2011 Mar 17;364(11):100515.
[44] Deschildre A, Marguet C, Salleron J, Pin I, Rittie JL, Derelle J, et al. Add-on
omalizumab in children with severe allergic asthma: a 1-year real life survey.
Eur Respir J 2013 Nov;42(5):122433.
[45] Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. A
study to evaluate safety and efcacy of mepolizumab in patients with moderate
persistent asthma. Am J Respir Crit Care Med 2007 Dec 1;176(11):106271.
[46] Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al.
Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J
Med 2009 Mar 5;360(10):97384.
[47] Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E,
et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009 Mar 5;360(10):98593.
[48] Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind,
placebo-controlled trial. Lancet 2012 Aug 18;380(9842):6519.
[49] Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, et al. Roles of epithelial
cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci U S A 2010 Aug
10;107(32):141705.
[50] Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, et al.
Genome-wide proling identies epithelial cell genes associated with asthma
and with treatment response to corticosteroids. Proc Natl Acad Sci U S A 2007
Oct 2;104(40):1585863.
[51] Masuoka M, Shiraishi H, Ohta S, Suzuki S, Arima K, Aoki S, et al. Periostin
promotes chronic allergic inammation in response to Th2 cytokines. J Clin
Invest 2012 Jul 2;122(7):2590600.
[52] Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T-helper
type 2-driven inammation denes major subphenotypes of asthma. Am J
Respir Crit Care Med 2009 Sep 1;180(5):38895.
[53] Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, et al.
Lebrikizumab treatment in adults with asthma. N Engl J Med 2011 Sep
22;365(12):108898.
[54] Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebocontrolled study of tralokinumab in moderate-to-severe asthma. Eur Respir J
2013 Feb;41(2):3308.
[55] Gauvreau GM, Boulet LP, Cockcroft DW, Fitzgerald JM, Carlsten C, Davis BE,
et al. Effects of interleukin-13 blockade on allergen-induced airway responses
in mild atopic asthma. Am J Respir Crit Care Med 2011 Apr 15;183(8):100714.
[56] De Boever EH, Ashman C, Cahn AP, Locantore NW, Overend P, Pouliquen IJ,
et al. Efcacy and safety of an anti-IL-13 mAb in patients with severe asthma: a
randomized trial. J Allergy Clin Immunol 2014 Apr;133(4):98996.
[57] Borish LC, Nelson HS, Lanz MJ, Claussen L, Whitmore JB, Agosti JM, et al.
Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized,
placebo-controlled trial. Am J Respir Crit Care Med 1999 Dec;160(6):181623.
[58] Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al.
Efcacy of soluble IL-4 receptor for the treatment of adults with asthma. J
Allergy Clin Immunol 2001 Jun;107(6):96370.
[59] Steinke JW. Anti-interleukin-4 therapy. Immunol Allergy Clin North Am 2004
Nov;24(4):599614. vi.
[60] Burmeister Getz E, Fisher DM, Fuller R. Human pharmacokinetics/pharmacodynamics of an interleukin-4 and interleukin-13 dual antagonist in asthma. J
Clin Pharmacol 2009 Sep;49(9):102536.
173