Stephen R. Durham

Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)

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, I. Agache, N. A t-Khaled, C. Bachert, M. S. Blaiss, S. Bonini, L.-P. Boulet, P.-J. Bousquet, P. Camargos, K.-H. Carlsen, Y. Chen, A. Custovic, R. Dahl, P. Demoly, H. Douagui, S. R. Durham, R. Gerth van Wijk, O. Kalayci, M. A. Kaliner, Y.-Y. Kim, M. L. Kowalski, P. Kuna, L. T. T. Le, C. Lemiere, J. Li, R. F. Lockey, S. Mavale-Manuel , E. O. Meltzer, Y. Mohammad, J. Mullol, R. Naclerio, R. E. O Hehir, K. Ohta, S. Ouedraogo, S. Palkonen, N. Papadopoulos, G. Passalacqua, R. Pawankar, T. A. Popov, K. F. Rabe, J. Rosado-Pinto, G. K. Scadding, F. E. R. Simons, E. Toskala, E. Valovirta, P. van Cauwenberge, D.-Y. Wang, M. Wickman, B. P. Yawn, A. Yorgancioglu, O. M. Yusuf, H. Zar Review Group: I. Annesi-Maesano, E. D. Bateman, A. Ben Kheder, D. A. Boakye, J. Bouchard, P. Burney, W. W. Busse, M. Chan-Yeung, N. H. Chavannes, A. Chuchalin, W. K. Dolen, R. Emuzyte, L. Grouse, M. Humbert, C. Jackson, S. L. Johnston, P. K. Keith, J. P. Kemp, J.-M. Klossek, D. Larenas-Linnemann, B. Lipworth, J.-L. Malo, G. D. Marshall, C. Naspitz, K. Nekam, B. Niggemann, E. Nizankowska-Mogilnicka, Y. Okamoto, M. P. Orru, P. Potter, D. Price, S. W. Stoloff, O. Vandenplas, G. Viegi, D. Williams

Long-term clinical efficacy of grass-pollen immunotherapy.

BACKGROUND Pollen immunotherapy is effective in selected patients with IgE-mediated seasonal allergic rhinitis, although it is questionable whether there is long-term benefit after the discontinuation of treatment. METHODS We conducted a randomized, double-blind, placebo-controlled trial of the discontinuation of immunotherapy for grass-pollen allergy in patients in whom three to four years of this treatment had previously been shown to be effective. During the three years of this trial, primary outcome measures were scores for seasonal symptoms and the use of rescue medication. Objective measures included the immediate conjunctival response and the immediate and late skin responses to allergen challenge. Cutaneous-biopsy specimens obtained 24 hours after intradermal allergen challenge were examined for T-cell infiltration and the presence of cytokine-producing T helper cells (TH2 cells) (as evidenced by the presence of interleukin-4 messenger RNA). A matched group of patients with hay fever who had not received immunotherapy was followed as a control for the natural course of the disease. RESULTS Scores for seasonal symptoms and the use of rescue antiallergic medication, which included short courses of prednisolone, remained low after the discontinuation of immunotherapy, and there was no significant difference between patients who continued immunotherapy and those who discontinued it. Symptom scores in both treatment groups (median areas under the curve in 1995, 921 for continuation of immunotherapy and 504 for discontinuation of immunotherapy; P=0.60) were markedly lower than those in the group that had not received immunotherapy (median value in 1995, 2863). Although there was a tendency for immediate sensitivity to allergen to return late after discontinuation, there was a sustained reduction in the late skin response and associated CD3+ T-cell infiltration and interleukin-4 messenger RNA expression. CONCLUSIONS Immunotherapy for grass-pollen allergy for three to four years induces prolonged clinical remission accompanied by a persistent alteration in immunologic reactivity.

Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling

Th subsets are defined according to their production of lineage-indicating cytokines and functions. In this study, we have identified a subset of human Th cells that infiltrates the epidermis in individuals with inflammatory skin disorders and is characterized by the secretion of IL-22 and TNF-alpha, but not IFN-gamma, IL-4, or IL-17. In analogy to the Th17 subset, cells with this cytokine profile have been named the Th22 subset. Th22 clones derived from patients with psoriasis were stable in culture and exhibited a transcriptome profile clearly separate from those of Th1, Th2, and Th17 cells; it included genes encoding proteins involved in tissue remodeling, such as FGFs, and chemokines involved in angiogenesis and fibrosis. Primary human keratinocytes exposed to Th22 supernatants expressed a transcriptome response profile that included genes involved in innate immune pathways and the induction and modulation of adaptive immunity. These proinflammatory Th22 responses were synergistically dependent on IL-22 and TNF-alpha. Furthermore, Th22 supernatants enhanced wound healing in an in vitro injury model, which was exclusively dependent on IL-22. In conclusion, the human Th22 subset may represent a separate T cell subset with a distinct identity with respect to gene expression and function, present within the epidermal layer in inflammatory skin diseases. Future strategies directed against the Th22 subset may be of value in chronic inflammatory skin disorders.

Prevalence and rate of diagnosis of allergic rhinitis in Europe

To measure the prevalence of allergic rhinitis among European adults and the proportion of undiagnosed subjects, a two-step, cross-sectional, population-based survey in Belgium, France, Germany, Italy, Spain, and the UK was undertaken. Step one of the study involved screening for allergic rhinitis by telephone interview, based on history of symptoms and/or self-awareness of the condition. Step two undertook confirmation of allergic rhinitis in a subset of the subjects screened positive; this was performed by a clinical diagnosis conducted in three to five clinical centres per country, including specific immunoglobulin E tests and a disease-specific questionnaire. A total of 9,646 telephone interviews were conducted between February and April 2001. Self-awareness of allergic rhinitis was reported by 19% of the subjects. Physician-based diagnosis of allergic rhinitis was reported by 13% of the subjects. In step two, 725 clinical assessments were conducted between May and August 2001. A total of 411 of patients, who underwent step two, had investigator-confirmed allergic rhinitis. Among patients with investigator-confirmed allergic rhinitis, 45% had not reported a previous diagnosis by a physician. Prevalence of subjects with clinically confirmable allergic rhinitis estimated by combining step one and step two data ranged from 17% in Italy to 29% in Belgium with an overall value of 23%. This large-scale study confirms that allergic rhinitis has a high prevalence in western Europe and is frequently undiagnosed.

Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis

We report the results of a double-blind, placebo-controlled trial in nine cystic fibrosis (CF) subjects receiving cationic liposome complexed with a complementary DNA encoding the CF transmembrane conductance regulator (CFTR), and six CF subjects receiving only liposome to the nasal epithelium. No adverse clinical effects were seen and nasal biopsies showed no histological or immuno-histological changes. A partial restoration of the deficit between CF and non-CF subjects of 20% was seen for the response to low Cl− perfusion following CFTR cDNA administration. This was maximal around day three and had reverted to pretreatment values by day seven. In some cases the response to low Cl− was within the range for non-CF subjects. Plasmid DNA and transgene-derived RNA were detected in the majority of treated subjects. Although these data are encouraging, it is likely that transfection efficiency and the duration of expression will need to be increased for therapeutic benefit.

Rhinosinusitis: Establishing definitions for clinical research and patient care

Background There is a need for more research on all forms of rhinosinusitis. Progress in this area has been hampered by a lack of consensus definitions and the limited number of published clinical trials. Objectives To develop consensus definitions for rhinosinusitis and outline strategies useful in clinical trials. Methods Five national societies, The American Academy of Allergy, Asthma and Immunology; The American Academy of Otolaryngic Allergy; The American Academy of Otolaryngology Head and Neck Surgery; The American College of Allergy, Asthma and Immunology; and the American Rhinologic Society formed an expert panel from multiple disciplines. Over two days, the panel developed definitions for rhinosinusitis and outlined strategies for design of clinical trials. Results Committee members agreed to adopt the term “rhinosinusitis” and reached consensus on definitions and strategies for clinical research on acute presumed bacterial rhinosinusitis, chronic rhinosinusitis without polyposis, chronic rhinosinusitis with polyposis, and classic allergic fungal rhinosinusitis. Symptom and objective criteria, measures for monitoring research progress, and use of symptom scoring tools, quality-of-life instruments, radiologic studies, and rhinoscopic assessment were outlined for each condition. Conclusion The recommendations from this conference should improve accuracy of clinical diagnosis and serve as a starting point for design of rhinosinusitis clinical trials.

Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma

BACKGROUND We have examined whether the local eosinophilia provoked by inhalational allergen challenge of patients with atopic asthma is associated with the appearance, in vivo, of activated TH2-type T helper lymphocytes. METHODS Fifteen patients with atopic asthma had bronchial wash and bronchoalveolar lavage (BAL) 24 hours after allergen or diluent challenge separated by at least 21 days. RESULTS There was an increase in eosinophils in both bronchial wash (p = 0.01) and BAL (p = 0.02) after allergen challenge but not after diluent challenge. Activation of CD4+ BAL T cells was suggested by an increase in the expression of CD25 shown by flow cytometry after allergen challenge, when compared with diluent (p = 0.02). There was no evidence of activation of CD8 T cells. By in situ hybridization after allergen challenge as compared with diluent, increases were shown in the numbers of cells expressing mRNA for interleukin-4 (IL-4) (p = 0.005), IL-5 (p = 0.01), and granulocyte-macrophage colony-stimulating factor (p = 0.03) but not IL-3, IL-2, or interferon-gamma. In situ hybridization of BAL cells after immunomagnetic separation of CD2-positive and CD2-negative cell populations showed that IL-4 and IL-5 mRNAs were associated with T lymphocytes after allergen challenge. BAL and bronchial wash eosinophilia closely correlated with maximal late fall in forced expiratory volume in 1 second after allergen challenge. CONCLUSION Cytokines produced by activated TH2-type CD4+ T cells in the airway may contribute to late asthmatic responses by mechanisms that include eosinophil accumulation.

Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis*

Allergic rhinitis is a common condition which, at its most severe, can significantly impair quality of life despite optimal treatment with antihistamines and topical nasal corticosteroids. Allergen injection immunotherapy significantly reduces symptoms and medication requirements in allergic rhinitis but its use is limited by the possibility of severe systemic reactions. There has therefore been considerable interest in alternative routes for delivery of allergen immunotherapy, particularly the sublingual route. The objective was to evaluate the efficacy of sublingual immunotherapy (SLIT), compared with placebo, for reductions in symptoms and medication requirements. The Cochrane Controlled Clinical Trials Register, MEDLINE (1966–2002), EMBASE (1974–2002) and Scisearch were searched, up to September 2002, using the terms (Rhin* OR hay fever) AND (immunotherap* OR desensiti*ation) AND (sublingual). All studies identified by the searches were assessed by the reviewers to identify Randomized Controlled Trials involving participants with symptoms of allergic rhinitis and proven allergen sensitivity, treated with SLIT or corresponding placebo. Data from identified studies was abstracted onto a standard extraction sheet and subsequently entered into RevMan 4.1. Analysis was performed by the method of standardized mean differences (SMD) using a random effects model. P‐values < 0.05 were considered statistically significant. Subgroup analyses were performed according to the type of allergen administered, the age of participants and the duration of treatment. Twenty‐two trials involving 979 patients, were included. There were six trials of SLIT for house dust mite allergy, five for grass pollen, five for parietaria, two for olive and one each for, ragweed, cat, tree and cupressus. Five studies enrolled exclusively children. Seventeen studies administered the allergen by sublingual drops subsequently swallowed, three by drops subsequently spat out and two by sublingual tablets. Eight studies involved treatment for less than 6 months, 10 studies for 6–12 months and four studies for greater than 12 months. All included studies were double‐blind placebo‐controlled trials of parallell group design. Concealment of treatment allocation was considered adequate in all studies and the use of identical placebo preparations was almost universal. There was significant heterogeneity, most likely due to widely differing scoring systems between studies, for most comparisons. Overall there was a significant reduction in both symptoms (SMD −0.42, 95% confidence interval −0.69 to −0.15; P = 0.002) and medication requirements [SMD −0.43 (−0.63, −0.23); P = 0.00003] following immunotherapy. Subgroup analyses failed to identify a disproportionate benefit of treatment according to the allergen administered. There was no significant reduction in symptoms and medication scores in those studies involving only children but total numbers of participants was too small to make this a reliable conclusion. Increasing duration of treatment does not clearly increase efficacy. The total dose of allergen administered may be important but insufficient data was available to analyse this factor.

Consensus statement on the treatment of allergic rhinitis.

Allergic rhinitis (AR) is a high-prevalence disease in many developed countries, affecting about 10±20% of the general population (1±5). Several studies based on questionnaire and objective testing or medical examination indicate an increasing prevalence of AR in European countries over the last decades (6, 7). AR is characterized by nasal itching, sneezing, watery rhinorrhoea, and nasal obstruction. Additional symptoms such as headache, impaired smell, and conjunctival symptoms can be associated. According to the time of exposure, AR can be subdivided into perennial, seasonal, and occupational disease. Perennial AR (PAR) is most frequently caused by dust mites and animal dander. Seasonal AR (SAR) is related to a wide variety of pollen allergens including grasses, Parietaria, Ambrosia, Artemisia, birch, olive, hazelnut, and cypress. The morbidity of SAR obviously depends on the geographic region, the pollen season of the plants, and the local climate. Several other conditions can cause similar symptoms and are referred to as nonallergic (noninfectious) rhinitis: NARES (nonallergic rhinitis with eosinophilia syndrome); aspirin sensitivity; endocrine, occupational, postinfectious, and side-effects of systemic drugs; abuse of topical decongestants (rhinitis medicamentosa); and idiopathic rhinitis. Furthermore, diseases such as nasal polyposis, chronic sinusitis, cystic ®brosis, Wegeners disease, benign or malignant tumours, etc. have to be excluded carefully. Therefore, current guidelines (4) emphasize the importance of an accurate diagnosis of patients presenting with rhinitis symptoms. In fact, several causes may commonly coexist in the same *European Academy of Allergology and Clinical Immunology. Allergy 2000: 55: 116±134 Printed in UK. All rights reserved Copyright # Munksgaard 2000

Clinical efficacy and immune regulation with peanut oral immunotherapy

BACKGROUND Oral immunotherapy (OIT) has been thought to induce clinical desensitization to allergenic foods, but trials coupling the clinical response and immunologic effects of peanut OIT have not been reported. OBJECTIVE The study objective was to investigate the clinical efficacy and immunologic changes associated with OIT. METHODS Children with peanut allergy underwent an OIT protocol including initial day escalation, buildup, and maintenance phases, and then oral food challenge. Clinical response and immunologic changes were evaluated. RESULTS Of 29 subjects who completed the protocol, 27 ingested 3.9 g peanut protein during food challenge. Most symptoms noted during OIT resolved spontaneously or with antihistamines. By 6 months, titrated skin prick tests and activation of basophils significantly declined. Peanut-specific IgE decreased by 12 to 18 months, whereas IgG(4) increased significantly. Serum factors inhibited IgE-peanut complex formation in an IgE-facilitated allergen binding assay. Secretion of IL-10, IL-5, IFN-gamma, and TNF-alpha from PBMCs increased over a period of 6 to 12 months. Peanut-specific forkhead box protein 3 T cells increased until 12 months and decreased thereafter. In addition, T-cell microarrays showed downregulation of genes in apoptotic pathways. CONCLUSION Oral immunotherapy induces clinical desensitization to peanut, with significant longer-term humoral and cellular changes. Microarray data suggest a novel role for apoptosis in OIT.