The prevalence, heterogeneity and severity of in type 2 inflammatory
diseases, including asthma and atopic dermatitis (AD), continue to rise,
especially in children and adolescents, who are bearing the highest
burden in terms of morbidity and health care
expenditure.1 Although allergen immunotherapy has
disease‐modifying properties and confers long‐term clinical benefit
after cessation of treatment, its indication is still limited to
patients with clinically significant immunoglobulin E (IgE)-mediated
respiratory allergies.2 Most treatments available
today merely provide long-term relief of symptoms, making it
increasingly clear that new targeted approaches for the management of
allergic diseases are required.
Type 2 inflammation is sustained by a specific subset of cytokines, such
as interleukin (IL)‐4, IL‐5, IL‐13, and IgE, resulting in the
recruitment of cells such as eosinophils, basophils, and mast cells into
the affected tissues.1
Type 2 responses are initiated with the disruption of the respiratory
and, to a minor extent, epidermal epithelial barrier by exposures to
allergens, viruses, bacteria, and other environmental triggers.
Epithelial cells release IL-25, IL-33, and thymic stromal lymphopoietin
(TSLP), which stimulate Th2 cells, type 2 innate lymphoid cells (ILC2),
and invariant natural killer T cells (NKT cells) to secrete Th2
cytokines and to activate dendritic cells (DCs).1 This
results in further differentiation and clonal expansion of Th2 cells and
activation of ILC2 cells, as well as tissue eosinophilia. Activated Th2
cells and ILC2 cells mainly release IL-4 and IL-13, which both have a
central role in many of the pathobiological tissue changes, including
airway inflammation and remodeling in asthma and epidermal barrier
dysfunction in AD.3 Additionally, mast cells,
basophils, and eosinophils also secrete IL-4 and IL-13. Their biological
functions are exerted through the binding of two receptor (IL-4R)
subtypes, both sharing the common IL‐4Rα.1 IL‐4R plays
a key role in the IgE class-switch in B cells and the production of
allergen specific IgE antibodies and in the activation of other immune
cells, such as mast cells, basophils, and macrophages. IL-13 and, to a
lesser extent, IL-4 stimulate globet cell hyperplasia, increase mucus
production and proliferation of smooth muscle cells in the airways; in
the skin, IL-4 and IL-13 promote barrier dysfunction on epidermis by
downregulating expression of filaggrin in normal keratinocytes, as well
as increasing susceptibility to infections by inhibiting production of
antimicrobial peptides.1 In addition, it has been
demonstrated that the chronic activation of the IL-4R pathway alters
immunotolerance by promoting the complete subversion of Treg cells into
Th2 cells, thus expanding and maintaining the type 2 inflammation.
Since IL-4 promotes the production of IgE, type 2 inflammation is
related to elevated serum IgE and is generally associated with atopy in
the pediatric age. IgE has a crucial role in allergic reactions, being
implicated in both the early and late phase of allergic
response.4 IgE also has different immunomodulatory
functions, including upregulation of IgE receptors, enhancement of mast
cell survival, and promotion of Th2 cytokine expression.
Both IL-4 and IL-13 synergistically promote eosinophil migration to
tissues.1 IL-5, another key cytokine released from
both Th2 cells and ILC2 cells, has a pivotal role in the induction,
maintenance, and amplification of tissue and systemic eosinophilic
inflammation. As mast cells and basophils, eosinophils produce a variety
of cytokines and growth factors, including IL-5, capable of perpetuating
this inflammatory vicious circle.5 Upon activation,
eosinophils release major basic protein (MBP) and other granule
proteins, as well as lipid mediators and oxygen radicals, that result in
epithelial damage, alteration of repair processes, and induction of
fibrosis. These effects are mostly implicated in airway hyperreactivity
and remodeling in asthma.5
With the increasing recognition of the role of type 2 immune responses
in asthma and AD, several biologics targeting IL-4, IL-5, and IL-13, as
well as IgE, have been proposed to treat severe allergic disease in the
pediatric age. They include anti-IgE antibody (omalizumab), anti-IL-5
antibody (mepolizumab), and anti-IL4Rα antibody (dupilumab), the latter
blocking the effects of IL-13 and IL-4 together.5
For children with severe therapy resistant asthma omalizumab,
mepolizumab and dupilumab are all available options. Omalizumab is
licensed for moderate to severe allergic asthma in patients ≥ six years
old.6 Several randomized controlled trials and
real‐life studies have shown that Omalizumab reduces the rate of asthma
exacerbations and hospital admissions in children.7,8By possibly increasing anti-viral response (IFN‐α) from DCs, omalizumab
also reduces virus‐associated exacerbations. Omalizumab is generally
well tolerated, with a low risk (0.1‐0.2%) of anaphylaxis and
injection-site reactions as the most common self-limiting adverse events
(AEs).9
Children with severe eosinophilic asthma, who fail to respond or are not
eligible to omalizumab, are the best candidates for a trial of
mepolizumab. While extensive pediatric data are available for
omalizumab, only 34 participants aged 12 years and older were included
in the mepolizumab trials.5 Mepolizumab reduced asthma
attacks and hospitalizations and led to a reduction in dose of
maintenance oral corticosteroids.5 In the 6–11 years
age group, safety and pharmacokinetic data are available, with only
minimal efficacy data.5 However, mepolizumab is
currently licensed for severe eosinophilic asthma in children aged six
years and over in Europe. A phase 2 trial (NCT03292588) is actively
recruiting children to explore the effect of mepolizumab adjunctive
therapy in preventing asthma exacerbations.
Dupilumab is the first biologic agent targeting both key cytokines of
type 2 inflammation (IL-4 and IL-13) and is currently approved in adults
and adolescents for use against moderate-to-severe AD and
moderate-to-severe asthma with an eosinophilic phenotype or with oral
corticosteroid-dependent asthma. Dupilumab is also licensed in adults
only for severe chronic rhinosinusitis with nasal
polyps.1 The efficacy of dupilumab was first
investigated in adolescents with moderate-to-severe AD. A clinically and
statistically meaningful improvement was achieved in in adolescents
receiving dupilumab rather than placebo. The most common AEs reported in
the dupilumab group were injection-site reactions and conjunctivitis,
the latter being well recognized AE of dupilumab in AD
trials.1 In dupilumab asthma trials, only 5,6% of
recruited participants were aged 12–17 years. In these adolescents,
dupilumab was shown to reduce severe asthma exacerbations, improve lung
function, and reduce oral corticosteroid use compared with placebo. The
only AE to have occurred in the adolescent patient population was
injection-site reactions, whereas conjunctivitis was not
reported.1
Since evidence of type 2 inflammation is observed across multiple
diseases beyond asthma and AD, dupilumab is being investigated as a
potential novel treatment in other type 2 inflammatory diseases, such as
allergic rhinitis, chronic rhinosinusitis with nasal polyps, and food
allergy.10 Clinical trials of dupilumab on adolescents
and younger children with type 2 inflammatory diseases are ongoing, and
their results are highly awaited.1
In conclusion, a better understanding of type 2 inflammatory pathways is
essential to implement targeted therapeutic strategies in children with
allergic diseases, such as severe forms of asthma and AD. Given that
studies comparing different biologics are still lacking, there is the
need for large pediatric trials, including children with type 2 diseases
to expand efficacy data, explore safety issues, and identify predictive
biomarkers of biologic therapies.
References :
- Licari A, Castagnoli R, Marseglia A, et al. Dupilumab to Treat Type 2
Inflammatory Diseases in Children and Adolescents. Paediatr
Drugs . 2020 Mar 11.
- Leonardi S, Vitaliti G, Marseglia GL, et al. Function of the airway
epithelium in asthma. J Biol Regul Homeost Agents . 2012;26(1
Suppl):S41-8.
- La Rosa M, Lionetti E, Leonardi S, et al. Specific immunotherapy in
children: the evidence. Int J Immunopathol Pharmacol . 2011;24(4
Suppl):69-78.
- Ciprandi G, Marseglia GL, Castagnoli R, et al. From IgE to clinical
trials of allergic rhinitis. Expert Rev Clin Immunol .
2015;11(12):1321-33.
- Licari A, Manti S, Castagnoli R, et al. Targeted Therapy for Severe
Asthma in Children and Adolescents: Current and Future Perspectives.Paediatr Drugs . 2019;21(4):215-237.
- Licari A, Castagnoli R, Panfili E, et al. An Update on Anti-IgE
Therapy in Pediatric Respiratory Diseases. Curr Respir Med Rev .
2017;13(1):22-29.
- Licari A, Castagnoli R, Denicolò C, et al. Omalizumab in Children with
Severe Allergic Asthma: The Italian Real-Life Experience. Curr
Respir Med Rev . 2017;13(1):36-42.
- Montella S, Baraldi E, Cazzato S, et al. Severe asthma features in
children: a case-control online survey. Ital J Pediatr .
2016;42:9.
- Licari A, Manti S, Chiappini E, et al. Severe asthma in children:
Current goals and unmet needs. Pediatr Allergy Immunol . 2020;31
Suppl 24:40-42.
- Licari A, Caimmi S, Bosa L, et al. Rhinosinusitis and asthma: a very
long engagement. Int J Immunopathol Pharmacol.2014;27(4):499-508.