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ABSTRACT: Background: Staphylococcal enterotoxin B (SEB) is a superantigen known to be a modulator of chronic airway inflammation in mice and humans, yet little is known about the mechanisms that regulate its interaction with the innate immune system. We investigated this mechanism in a murine model of allergic airway inflammation induced by OVA (ovalbumin) in the presence of SEB. Methods: Superantigen-induced allergic inflammation was studied in IL-1R knock-out (KO) mice exposed to OVA+SEB. Multicolor flow cytometry was used to analyze the inflammatory cell profile in airways and lymph nodes. Production of IL-4, IL-5, IL-10, and IL-13 in lymph nodes was assessed by Luminex technology. Results: In wild-type mice, endonasal instillation of OVA+SEB induced a pulmo-nary inflammation, characterized by an increase in the number of eosinophils, T cells, and dendritic cells and in the production of Th2 cytokines and OVA-specific IgE. In IL-1R KO mice exposed to OVA+SEB, attraction of CD4+ cells and production of Th2 cytokines were reduced. However, knocking out IL-1R did not affect any of the features of allergic airway inflammation, such as bronchial eosinophilia, OVA-specific IgE production and goblet cell metaplasia. Conclusion: We provide new insights into the mechanisms of airways allergy development in the presence of bacterial superantigen. The asthma features induced by OVA+SEB, such as bronchial eosinophilia, goblet cell proliferation, production of OVA-specific IgE and increase in inflammatory dendritic cells, are IL-1R independent. Yet, IL-1R signaling is crucial for CD4 cell accumulation and Th2 cytokine production.
01/2013;
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ABSTRACT: BACKGROUND: Staphylococcal enterotoxin B (SEB) is a superantigen known to be a modulator of chronic airway inflammation in mice and humans, yet little is known about the mechanisms that regulate its interaction with the innate immune system. We investigated this mechanism in a murine model of allergic airway inflammation induced by OVA (ovalbumin) in the presence of SEB. METHODS: Superantigen-induced allergic inflammation was studied in IL-1R knockout (KO) mice exposed to OVA+SEB. Multicolor flow cytometry was used to analyze the inflammatory cell profile in airways and lymph nodes. Production of IL-4, IL-5, IL-10, and IL-13 in lymph nodes was assessed by Luminex technology. RESULTS: In wild-type mice, endonasal instillation of OVA+SEB induced a pulmonary inflammation, characterized by an increase in the number of eosinophils, T cells, and dendritic cells and in the production of Th2 cytokines and OVA-specific IgE. In IL-1R KO mice exposed to OVA+SEB, attraction of CD4+ cells and production of Th2 cytokines were reduced. However, knocking out IL-1R did not affect any of the features of allergic airway inflammation, such as bronchial eosinophilia, OVA-specific IgE production and goblet cell metaplasia. CONCLUSION: We provide new insights into the mechanisms of airways allergy development in the presence of bacterial superantigen. The asthma features induced by OVA+SEB, such as bronchial eosinophilia, goblet cell proliferation, production of OVA-specific IgE and increase in inflammatory dendritic cells, are IL-1R independent. Yet, IL-1R signaling is crucial for CD4 cell accumulation and Th2 cytokine production.
Allergy 01/2013; · 6.27 Impact Factor
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J. Bousquet,
N. Khaltaev,
A. A. Cruz,
J. Denburg,
W. J. Fokkens,
A. Togias,
T. Zuberbier,
C. E. Baena-Cagnani,
G. W. Canonica,
C. Van Weel, [......],
B. Niggemann,
E. Nizankowska-Mogilcka,
Y. Okamoto,
M. P. Orru,
P. Potter,
D. Price,
S. W. Stoloff,
O. Vandenplas,
G. Viegi,
D. Williams
Allergic Rhinitis and Its Impact on Asthma (ARIA). 01/2013;
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ABSTRACT: A new concept of immunogenic cell death (ICD) has recently been proposed. The immunogenic characteristics of this cell death mode are mediated mainly by molecules called 'damage-associated molecular patterns' (DAMPs), most of which are recognized by pattern recognition receptors. Some DAMPs are actively emitted by cells undergoing ICD (e.g. calreticulin (CRT) and adenosine triphosphate (ATP)), whereas others are emitted passively (e.g. high-mobility group box 1 protein (HMGB1)). Recent studies have demonstrated that these DAMPs play a beneficial role in anti-cancer therapy by interacting with the immune system. The molecular pathways involved in translocation of CRT to the cell surface and secretion of ATP from tumor cells undergoing ICD are being elucidated. However, it has also been shown that the same DAMPs could contribute to progression of cancer and promote resistance to anticancer treatments. In this review, we will critically evaluate the beneficial and detrimental roles of DAMPs in cancer therapy, focusing mainly on CRT, ATP and HMGB1.
Cell Death & Disease 01/2013; 4:e631. · 5.33 Impact Factor
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M Bonini, C Bachert,
C E Baena-Cagnani,
A Bedbrook,
J L Brozek,
G W Canonica,
A A Cruz,
W J Fokkens,
R Gerth van Wijk,
L Grouse, [......],
G K Scadding,
H J Schünemann,
D M Thomas,
M Triggiani,
A Yorgancioglu,
O M Yusuf,
T Zuberbier,
R Pawankar,
J Bousquet,
S Bonini
Current Opinion in Allergy and Clinical Immunology 12/2012; · 4.11 Impact Factor
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P W Hellings,
G Scadding,
I Alobid, C Bachert,
W J Fokkens,
R Gerth van Wijk,
P Gevaerts,
J Guilemany,
L Kalogjera,
J Mullol,
G Passalacqua,
E Toskala,
C M van Drunen
[show abstract]
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ABSTRACT: This Executive Summary of the EAACI Task Force document on Diagnostic Tools in Rhinology provides the readers with an over- view of the currently available tools for diagnosis of nasal and sino-nasal disease, published in full version in the first issue of Clini- cal and Translational Allergy. A panel of European experts in the field of Rhinology have contributed to this consensus document on Diagnostic Tools in Rhinology. Important issues related to history taking, clinical examination and additional investigative tools for evaluation of the severity of nasal and sinonasal disease are briefly highlighted in this executive summary.
Rhinology 12/2012; 50(4):339-52. · 1.32 Impact Factor
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P Gevaert,
K T Nouri-Aria,
H Wu,
C E Harper,
P Takhar,
D J Fear,
F Acke,
N De Ruyck,
G Banfield,
H H Kariyawasam, C Bachert,
S R Durham,
H J Gould
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ABSTRACT: BACKGROUND: Chronic rhinosinusitis with nasal polyps (NP) and allergic rhinitis (AR) is characterized by local Th2 inflammation and up-regulation of IgE; however, IgE in NP is 'polyclonal' and allergen specific, whereas IgE in AR is 'oligoclonal' and allergen specific. Germinal center (GC) reactions occur in AR, while only the formation of GC-like structures in NP is described. The aim of this study was to investigate the involvement of local IgE production, class switch recombination, and receptor revision in NP. METHODS: We compared the levels of local IgE, germline gene transcripts, and mature Ig mRNA expression, recombination activating gene (RAG1 and RAG2), key markers of Th2 inflammation, and GC reactions in NP tissue vs AR and control tissue. Nasal mucosa was immunostained for the co-expression of RAG1 and RAG2 in B cells, plasma cells, and T cells, using dual or triple immunofluorescence (IF). RESULTS: In NP, local IgE level and key markers of local class switching are increased compared with AR and normal controls (NC). In NP, switch circle transcripts reveal ongoing local class switch recombination to IgE. Up to 30% of B cells, plasma cells, and T cells in nasal polyps re-express both RAG1 and RAG2, required for receptor revision. RAG1 and RAG2 mRNA concentrations are increased in NP and correlated with the magnitude of inflammation and the presence of S. aureus enterotoxin (superantigen)-specific IgE in the nasal polyp mucosa. CONCLUSION: Our results provide the first evidence of local receptor revision and class switching to IgE, and B-cell differentiation into IgE-secreting plasma cells in NP.
Allergy 11/2012; · 6.27 Impact Factor
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W W Carr,
P Ratner,
U Munzel,
R Murray,
D Price,
W Canonica,
J Mullol,
C Virchow,
P Lieberman,
E Meltzer, C Bachert
[show abstract]
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ABSTRACT: Intranasal corticosteroids are considered the most effective therapy for moderate-to-severe seasonal allergic rhinitis (SAR) andrecommended first line in guidelines. It is uncertain whether intranasal antihistamines have comparable efficacy. This study was designed to compare the efficacy of azelastine (AZE; 137 micrograms/spray) and fluticasone propionate (FP; 50 micrograms/spray), bothgiven as 1 spray/nostril bid (i.e., approved dosing regimen in the United States), in SAR via a post hoc analysis of data from a previously published direct-comparison study. Six hundred ten moderate-to-severe SAR patients ( more than or equal to 12 years old) were randomized into a double-blind, placebo-controlled, parallel-group trial. The primary efficacy variable was change from baseline in reflective total nasal symptom score (rTNSS (morning and evening), over 14 days. Reflective total ocular symptom score (rTOSS) was a key secondary variable. Reflective total of seven symptom scores (rT7SS [nasal plus ocular symptoms]) and time to more than or equal to 50% reduction from baseline in these key parameters were also analyzed. AZE and FP reduced rTNSS from baseline by a similardegree (-3.25 versus -3.84; p = 0.2014). Patients experienced comparable improvement in rTOSS (-2.62 versus -2.17; p = 0.2371) and rT7SS (-5.83 versus -6.05; p = 0.7820). FP was superior to AZE in alleviating rhinorrhea (-1.15 versus -0.87;p = 0.0433), but AZE showed comparable efficacy for all other nasal and ocular symptoms. There was no clinically orstatistically significant difference between AZE (-1.17) and FP (-1.43) for reduction in the overall rhinitis quality of life questionnaire score (although FP, but not AZE, significantly differed from placebo). A similar proportion of patients in the AZEand FP groups achieved a 50% reduction in rTNSS. However, more AZE patients (53.0%) exhibited a 50% reduction inrTOSS by day 14 versus FP (39.6%), and less than or equal to 3 days faster (p = 0.028). Intranasal AZE (137 micrograms/spray) and intranasalFP (50 micrograms/spray), both 1 spray/nostril b.i.d., had comparable efficacy in symptom control in moderate-to-severe SAR.
Allergy and Asthma Proceedings 11/2012; · 2.17 Impact Factor
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J Bousquet,
H J Schünemann,
B Samolinski,
P Demoly,
C E Baena-Cagnani, C Bachert,
S Bonini,
L P Boulet,
P J Bousquet,
J L Brozek, [......],
M Wickman,
S Wöhrl,
J Wright,
B P Yawn,
P K Yiallouros,
H J Zar,
M E Zernotti,
N Zhong,
M Zidarn,
T Zuberbier
[show abstract]
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ABSTRACT: Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified AR as mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIA World Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children.
The Journal of allergy and clinical immunology 10/2012; · 9.17 Impact Factor
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P W Hellings,
W J Fokkens,
C Akdis, C Bachert,
C Cingi,
D Dietz de Loos,
P Gevaert,
V Hox,
L Kalogjera,
V Lund,
J Mullol,
N G Papadopoulos,
G Passalacqua,
C Rondón,
G Scadding,
M Timmermans,
E Toskala,
N Zhang,
J Bousquet
[show abstract]
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ABSTRACT: State-of-the-art documents like ARIA and EPOS provide clinicians with evidence-based treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS), respectively. The currently available medications can alleviate symptoms associated with AR and RS. In real life, a significant percentage of patients with AR and CRS continue to experience bothersome symptoms despite adequate treatment. This group with so-called severe chronic upper airway disease (SCUAD) represents a therapeutic challenge. The concept of control of disease has only recently been introduced in the field of AR and CRS. In case of poor control of symptoms despite guideline-directed pharmacotherapy, one needs to consider the presence of SCUAD but also treatment-related, diagnosis-related and/or patient-related factors. Treatment-related issues of uncontrolled upper airway disease are linked with the correct choice of treatment and route of administration, symptom-oriented treatment and the evaluation of the need for immunotherapy in allergic patients. The diagnosis of AR and CRS should be reconsidered in case of uncontrolled disease, excluding concomitant anatomic nasal deformities, global airway dysfunction and systemic diseases. Patient-related issues responsible for the lack of control in chronic upper airway inflammation are often but not always linked with adherence to the prescribed medication and education. This review is an initiative taken by the ENT section of the EAACI in conjunction with ARIA and EPOS experts who felt the need to provide a comprehensive overview of the current state of the art of control in upper airway inflammation and stressing the unmet needs in this domain.
Allergy 10/2012; · 6.27 Impact Factor
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ABSTRACT: Chronic rhinosinusitis (CRS) is a multifactorial disease of the upper airways with a high prevalence (approximately 11%) in the general population. Different immune and inflammatory mechanisms are involved in its pathogenesis. Alterations in the arachidonic acid pathway (leading to an imbalanced production of eicosanoids) have been linked to the pathophysiology of different diseases especially nasal polyposis, asthma, and aspirin-exacerbated respiratory disease. Furthermore, viral and bacterial infections have been identified as important factors amplifying the pro-inflammatory reactions in these pathologies. This review summarizes the impact of an imbalance in the eicosanoid pathway and the effect of Staphylococcus aureus enterotoxins on the regulation of the pro-inflammatory network in CRS and their translation into disease severity.
Allergy 09/2012; 67(11):1347-56. · 6.27 Impact Factor
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ABSTRACT: Airway diseases such as chronic rhinosinusitis, asthma, and chronic obstructive pulmonary disorder are characterized by inflammation and remodeling. Among inflammatory and extracellular matrix regulatory cytokines, transforming growth factor-beta (TGF-β) stands central, as it possesses both important immunomodulatory and fibrogenic activities, and should be considered a key for understanding inflammation and remodeling processes. This review will briefly summarize the recent findings on the role of TGF-β1, from the view points of inflammation and remodeling, and discuss the role of TGF-β in the upper and lower airway diseases. This may reveal new perspectives in the understanding of airway inflammation and remodeling processes and may open innovative treatment strategies for the regulation of TGF-β1.
Allergy 08/2012; 67(10):1193-202. · 6.27 Impact Factor
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ABSTRACT: Free light chain (FLC) concentrations are demonstrated to be increased in different inflammatory disorders and are proposed to mediate mast cell-dependent immune responses. A role for mast cells is suggested in chronic rhinosinusitis with nasal polyposis (CRSwNP), which is characterized by a local Th2 inflammatory response. However, clear mast cell-activating factors are not always apparent. In this study, the presence of FLCs in CRS patients with or without nasal polyps (CRSw/sNP) was investigated and the effect of different treatments on FLC expression was analyzed.
Nasal tissue, nasal secretion, and serum of control patients, patients with CRSwNP, and CRSsNP were analyzed for the presence of kappa and lambda FLC. The expression of FLCs in nasal polyp tissue was investigated using immunohistochemistry. In addition, FLC was measured in serum and nasal secretion of nasal polyp patients treated with methylprednisolone, doxycycline, anti-IL-5, or placebo.
Free light chain concentrations were increased in nasal secretion and mucosal tissue homogenates in patients with chronic rhinosinusitis, and this effect was most prominent in CRSwNP patients. Immunohistochemical analysis confirmed the increased FLC concentrations in nasal polyp tissue. In CRSwNP patients, treatment with methylprednisolone or anti-IL-5 resulted in the reduction in systemic or local FLC concentrations, respectively.
The presence of FLC in CRSwNP and CRSsNP suggests a possible role in mediating the local immune reaction in the paranasal cavities. Furthermore, the decrease in local FLCs after treatment with anti-IL-5 presumes that IL-5 creates an environment that favors FLC production.
Allergy 07/2012; 67(9):1165-72. · 6.27 Impact Factor
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ABSTRACT: Chronic rhinosinusitis (CRS) affects more than 10% of the European population and is often associated with asthma. Phenotypes of CRS can be differentiated based on mucosal remodelling and inflammatory patterns. Understanding the role of central mediators, such as interleukin-5, in these different phenotypes may lead to the development of specific therapeutic approaches. The impact of staphylococcal superantigens has been shown to further modify the immune response, contributing to persistent severe disease via the activation of T and B cells and the formation of local IgE. It is clear that these mechanisms are involved in the systemic spread of upper airway disease with resulting asthma comorbidity, when IgE antibodies to staphylococcal enterotoxins are present at measurable levels in serum. Recent findings point to superantigens as possible causal agents in the intrinsic form of severe asthma, and an anti-IgE strategy has shown promising therapeutic potential in nonatopic patients with nasal polyps and asthma. These findings should lead to a clinically relevant endotyping of patients with upper and lower airway disease and to a new understanding of the role of IgE 'above atopy'.
Journal of Internal Medicine 05/2012; 272(2):133-43. · 5.48 Impact Factor
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E Pace,
V Scafidi,
D Di Bona,
L Siena,
G Chiappara,
M Ferraro,
S La Grutta,
S Gallina,
R Speciale,
A Ballacchino, C Bachert,
J Bousquet,
M Gjomarkaj
[show abstract]
[hide abstract]
ABSTRACT: Chronic rhinosinusitis (CRS) is an inflammation of the nose and of the paranasal sinuses. The involvement of the respiratory epithelium in the mechanisms of CRS is poorly understood.
Among proteins expressed by nasal epithelial cells in CRS, IL-19 may have key functions. We here aimed to determine the expression and regulation of IL-19.
Nasal biopsies from normal subjects (n = 12), subjects with CRS but without nasal polyps (NP) (CRSsNP, n = 12) and with CRS with NP (CRSwNP, n = 15) were collected. Human Asthma Gene Array and real-time PCR were used to evaluate gene expression, western blot analysis and immunohistochemistry for protein expression. Results for IL-19 were confirmed by real-time PCR. The constitutive and stimulated (LPS, TGF β) expression of IL-19 and cell proliferation were evaluated in a nasal epithelial cell line (RPMI 2650).
Human Asthma Gene Array showed an increased IL-19 gene expression in NP from patients with CRS in comparison with normal subjects. Real-time PCR confirmed the IL-19 mRNA up-regulation in patients with CRSwNP and showed an up-regulation of IL-19, at lower extent, in patients with chronic rhinosinusitis without nasal polyps (CRSsNP) in comparison with normal subjects. Western blot analysis confirmed that IL-19 is increased also at protein level in patients with CRSwNP in comparison with normal subjects. In NP, IL-19 is highly expressed in the metaplastic nasal epithelium when compared to normal or hyperplastic epithelium. LPS stimulation increased IL-19 expression, and recombinant IL-19 increased cell proliferation in nasal epithelial cells.
IL-19 is overexpressed in the epithelium in CRSwNP and increases epithelial cell proliferation.
Allergy 05/2012; 67(7):878-86. · 6.27 Impact Factor
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HNO 04/2012; 48(7):544-555. · 0.40 Impact Factor
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B.A. Stuck, C. Bachert,
P. Federspil,
W. Hosemann,
L. Klimek,
R. Mösges,
O. Pfaar,
C. Rudack,
H. Sitter,
M. Wagenmann,
K. Hörmann
HNO 04/2012; 55(10):758-777. · 0.40 Impact Factor
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Wytske J Fokkens,
Valerie J Lund,
Joachim Mullol, Claus Bachert,
Isam Alobid,
Fuad Baroody,
Noam Cohen,
Anders Cervin,
Richard Douglas,
Philippe Gevaert, [......],
Marek Kowalski,
David Price,
Herbert Riechelmann,
Rodney Schlosser,
Brent Senior,
Mike Thomas,
Elina Toskala,
Richard Voegels,
De Yun Wang,
Peter John Wormald
[show abstract]
[hide abstract]
ABSTRACT: The European Position Paper on Rhinosinusitis and Nasal Polyps 2012 is the update of similar evidence based position papers published in 2005 and 2007. The document contains chapters on definitions and classification, we now also proposed definitions for difficult to treat rhinosinusitis, control of disease and better definitions for rhinosinusitis in children. More emphasis is placed on the diagnosis and treatment of acute rhinosinusitis. Throughout the document the terms chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are used to further point out differences in pathophysiology and treatment of these two entities. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. Last but not least all available evidence for management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is analyzed and presented and management schemes based on the evidence are proposed. This executive summary for otorhinolaryngologists focuses on the most important changes and issues for otorhinolaryngologists. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.
Rhinology 03/2012; 50(1):1-12. · 1.32 Impact Factor
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A Yorgancıoğlu,
C Özdemir,
Ö Kalaycı,
A F Kalyoncu, C Bachert,
C E Baena-Cagnani,
T B Casale,
Y Z Chen,
A A Cruz,
P Demoly, [......],
Y Mohammad,
J Mullol,
K Ohta,
N G Papadopoulos,
R Pawankar,
B Samolinski,
H J Schünemann,
O M Yusuf,
T Zuberbier,
J Bousquet
[show abstract]
[hide abstract]
ABSTRACT: Allergic rhinitis and asthma represent global health problems for all age groups. Asthma and rhinitis frequently co-exist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization (WHO) workshop in 1999 and was published in 2001. ARIA has reclassified allergic rhinitis as mild/moderate-severe and intermittent/persistent. This classification schema closely reflects the impact of allergic rhinitis on patients. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of allergic rhinitis and asthma co-morbidities based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation). ARIA has been disseminated and implemented in over 50 countries of the world. In Turkey, it is important to make a record of ARIA achievements and to identify the still unmet clinical, research and implementation needs in order to strengthen the 2011 EU Priority on allergy and asthma in children.
Tuberkuloz ve toraks 03/2012; 60(1):92-7.
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Prof Jean Bousquet,
J Bousquet,
J M Anto,
P Demoly,
H J Schünemann,
A Togias,
M Akdis,
C Auffray, C Bachert,
T Bieber, [......],
M Wickman,
D Williams,
S Wöhrl,
J Wright,
A Yorgancioglu,
O M Yusuf,
H J Zar,
M E Zernotti,
M Zidarn,
N Zhong
[show abstract]
[hide abstract]
ABSTRACT: Abstract
Concepts of disease severity, activity, control and responsiveness
to treatment are linked but different. Severity refers to
the loss of function of the organs induced by the disease process
or to the occurrence of severe acute exacerbations. Severity
may vary over time and needs regular follow-up. Control
is the degree to which therapy goals are currently met.
These concepts have evolved over time for asthma in guidelines,
task forces or consensus meetings. The aim of this paper
is to generalize the approach of the uniform definition of severe
asthma presented to WHO for chronic allergic and associated
diseases (rhinitis, chronic rhinosinusitis, chronic urticaria
and atopic dermatitis) in order to have a uniform definition
of severity, control and risk, usable in most situations. It
is based on the appropriate diagnosis, availability and accessibility
of treatments, treatment responsiveness and associated
factors such as comorbidities and risk factors. This uniform
definition will allow a better definition of the phenotypes
of severe allergic (and related) diseases for clinical
practice, research (including epidemiology), public health
purposes, education and the discovery of novel therapies.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 01/2012; · 2.83 Impact Factor
