Index: December 2010
Clinical Focus:Respiratory Care
Clinical Focus: Respiratory Medicine
- Asthma and the athlete
- Vocal cord dysfunction
- Exercise-induced asthma
- Exercise-induced bronchospasm
- Obesity and COPD
- Relationship between COPD and nutrition intake
- Treatment options for steroid-induced osteoporosis in men
- Treatments for asthma
- Bronchodilators, anticholinergics
- Metered-dose vs other types of inhalers
- Respiratory infections in winter sports athletes
- Asthma in elite athletes
- Pulmonary rehabilitation and physical activity
- Fitness and long-term oxygen therapy/lung transplantation
- Airflow function and the metabolic syndrome
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Keywords: seasonal allergic rhinitis; asthma; risk factors; clinical phenotypes
The association between persistent allergic rhinitis (AR) and asthma is well validated and characterized, both in children and adults.1 The concept of “one airway, one approach” is rigorously validated and implemented by the latest guidelines for diagnosis and treatment of AR in Allergic Rhinitis and its Impact on Asthma (ARIA). Asthma and AR are comorbid conditions,1 with AR being a major risk factor for the occurrence of asthma and lack of asthma control.2-4 However, there are fewer and less convincing data on the risk of developing asthma in seasonal AR (SAR). Also, there are no data on the clinical phenotypes of asthma associated with SAR.
The local Ethics Committee (Institutional Review Board) approved the study protocol for this cross-sectional study conducted within a private setting. Adults and children (aged 5–11 years) with physician-diagnosed SAR were selected from the private practice database. One hundred ninety-six patients were contacted by phone, 165 (84.18%) attended the clinic and received both written and oral information, and 115 (58.67%) adult subjects or parents/legal guardians provided oral consent to participate in the study.
Seasonal allergic rhinitis was diagnosed by the combination of history (symptoms elicited by a seasonal allergen) and a positive skin prick test to ≥ 1 of the seasonal allergens (grasses, trees, weeds).
Patients with SAR were evaluated at inclusion for:
Demographic features (age, sex)
History of SAR and asthma
Clinical examination, including height, weight, and body mass index
Examination by an ear, nose, and throat specialist confirming AR and excluding other nasal pathologies
Atopic status (Common aeroallergens tested were from house dust mites, cats, dogs, cockroaches, mold, grass pollen, tree pollen, and weed pollen. A skin-prick test was positive if the wheal diameter of the allergen histamine was > 1 mm and the mean wheal size was ≥ 3 mm).
Nasal allergen provocation test for cases where the clinically relevant allergen could not be clearly identified by history and skin prick test
Lung function (European Respiratory Society [ERS]/American Thoracic Society [ATS] guidelines): forced expiratory volume in 1 second (FEV1) with reversibility testing 15 minutes after use of a bronchodilator
Exhaled nitric oxide (FeNO) (NIOX Mino®; Aerocrine, Solna, Sweden).
Asthma risk factors (see below)
Asthma was confirmed by the combination of history, clinical examination, and the presence of airway hyperreactivity (defined as an increase of FEV1 by ≥ 12% and > 200 mL 15 minutes after inhalation of salbutamol 400 μg per spacer). Increased FeNO > 25 ppb (NIOX Mino®) was considered an additional diagnostic criteria for asthma.
The following risk factors for asthma were considered in the multiple regression analysis: male sex; family history of asthma; breastfeeding < 2 months for the children group; history of tobacco smoking exposure (pre- and post-birth) for the children group; history of environmental tobacco smoking exposure or active smoking for the adult group; obesity (body mass index > 25 kg/m2); history of exposure to pets; history of exposure to molds; increased total serum immunoglobulin E (IgE) (enzyme-linked immunosorbent assay [ELISA]); polysensitization (sensitization to 3 seasonal pollens with different structures); mixed sensitization (seasonal and perennial allergens); severe rhinitis (ARIA criteria); lack of specific immunotherapy with allergen (SIT) for rhinitis preceding asthma diagnosis; and as treatment for SAR, SIT was administered as monthly subcutaneous injections with only 1 allergen extract selected as being most relevant for patient’s symptoms (history and nasal provocation test).
The choice of the risk factors was based on previously published studies on risk factors for asthma in patients with persistent AR.
Clinical phenotypes of SAR and asthma were characterized using the k-means cluster analysis method with silhouette profiling. Statistical significance was considered for cluster means of > 0.6.
Cluster analysis5,6 refers to a group of multivariate mathematical algorithms that broadly perform 2 distinct functions: 1) quantification of similarity between individuals within a population on the basis of the (multiple) specified variables; and 2) grouping of individuals into clusters such that similarity between members of the same clusters is strong and between different clusters is weak.
The principal advantage of performing cluster analysis is objectivity because of inclusion of multiple variables that assume equal weighting, thus minimizing a priori bias. Cluster analysis was validated in previous studies for classification of clinical asthma phenotypes7 and of severe asthma phenotypes in the Severe Asthma Research Program (SARP).8 The method offers a novel multidimensional approach for identifying asthma phenotypes. It corrects for the subjectivity and poor coherence that characterize the actual definition of asthma phenotypes.
Data were analyzed for 115 subjects with SAR: 33 children (mean age, 8.27 ± 1.77 years) and 82 adults (mean age, 34.12 ± 10.59 years). All subjects were Caucasian, with no ethnic differences.
The major seasonal sensitizing allergen identified was grass, both in children (96.97%) and adults (98.78%). Mean SAR duration was 3.36 ± 2.12 years for children, and 9.01 ± 7.49 years for adults.
All patients with SAR received oral antihistamine (desloratadine, levocetirizine), and in addition, 92% of children and 83% of adults required an intranasal steroid (mometasone furoate or fluticasone propionate). In 30% of cases in children and 17% of cases in adults, topical ocular drops with olopatadine were added to control ocular symptoms.
Asthma was confirmed in 22 (66.7%) children and in 57 (69.5%) adults with SAR. Fifteen (68%) children and 43 (75.4%) adults had been previously diagnosed with asthma, and the others were diagnosed at inclusion. Seasonal AR preceded asthma diagnosis, with 2.9 ± 2.0 years in children and within 5.57 ± 1.9 years in adults. Thirteen (59.1%) children and 35 (61.4%) adults had intermittent asthma with symptoms present only during the pollen season; the others had persistent asthma symptoms. The incidence of uncontrolled asthma was 7 (77.8%) in children with SAR and persistent asthma, and 8 (61.5%) in children with SAR and intermittent asthma. In adults, the incidence of uncontrolled asthma was 10 (45.5%) for subjects with persistent asthma and 8 (22.9%) for subjects with intermittent asthma. Asthma was treated with montelukast in 14 (63.6%) children and 34 (59.6%) adults and with inhaled steroids in 1 (4.5%) child and 9 (15.8%) adults.
Table 1 depicts the incidence of analyzed risk factors for asthma. Because only 2 (6.06%) children were obese, obesity was not included in the multiple regression analysis of asthma risk factors in children with SAR. Independent risk factors for asthma were lack of SIT preceding asthma diagnosis, both for children (P = 0.008132) and adults (P = 0.000017), and mixed sensitization for children (P = 0.035694) (Tables 2, 3).
Using the cluster analysis method with silhouette profiling, we identified 2 main clinical asthma phenotypes in children and 3 main asthma phenotypes in adults. In children with SAR, the most frequently encountered asthma phenotype was characterized by the following risk factors for asthma: breastfeeding < 2 months and severe rhinitis. This phenotype was identified in 16 (63.6%) subjects. The second asthma phenotype in children identified in 8 (36.4%) subjects was characterized by the following risk factors: male sex, polysensitization, and severe rhinitis (Figure 1).
Asthma phenotypes in adults were: polysensitization and severe rhinitis in 30 (52.6%) patients; male sex, exposure to pets, and severe rhinitis in 11 (19.3%) patients, and high total serum IgE and polysensitization in 16 (28.1%) patients (Figure 2).
This study demonstrates that asthma is frequently associated with SAR, with SAR preceding the development of asthma. Lack of SIT is an independent risk factor for asthma both in children and adults with SAR, whereas mixed sensitization (seasonal and perennial allergens) is a risk factor only for children.
The incidence of asthma in patients with SAR observed in this study is highly significant (66.7% in children and 69.5% in adults) and is very close to the incidence cited for asthma in patients with persistent AR.1 In all the cases, SAR preceded asthma. However, because this is a cross-sectional study, we cannot firmly conclude that SAR is a risk factor for developing asthma.
Our results clearly indicate lack of SIT is a risk factor for asthma both in adults and children with SAR. These results are in concordance with a prospective 10-year study, which proved the role of allergen-specific immunotherapy in children with AR in preventing symptoms of asthma.9 Preventing asthma could be another benefit of SIT in treating AR apart from the potential for early and significant cost savings in children with AR who are treated with immunotherapy. Greater use of this treatment in children could significantly reduce AR-related morbidity and its economic burden.10 There are no data on the potential of SIT in preventing asthma in adults with AR. In our study, however, lack of SIT was an independent risk factor for asthma in adults with SAR.
Specific immunotherapy has been used for many years, but although many studies show clinical efficacy, its mechanism of action is still not clearly understood. Earlier studies showed that SIT increases allergen-specific protective IgG4, while decreasing the pro-allergenic IgE. Other studies have shown decreased allergen presentation by mucosal dendritic cells migrating in regional lymph nodes, reduced eosinophil and lymphocyte migration to nasal and bronchial mucosa, and reduced inflammatory mediator release from basophils, eosinophils, and mast cells. More recent studies have proposed that SIT works through inhibition of T-helper 2 (Th2) lymphocytes, which preferentially produce cytokines that promote allergic responses. Allergen-specific immunotherapy from Th2 to Th1 may induce T-regulatory cells (T-regs), which inhibit Th2 through direct contact via CTLA4 or through inhibitory cytokines, such as interleukin (IL)-10.11-13 Which of these mechanisms are useful for preventing asthma in patients with AR is subject to further research.
Sensitization to both seasonal and perennial allergens is an independent risk factor for asthma only in children with SAR. On one hand, the result is not surprising because many studies confirmed the leading role of perennial allergens as a risk factor for asthma.1,14 On the other hand, mixed sensitization was present as a risk factor only for children with SAR and not for adults, whereas other studies implicated perennial allergens as a risk factor for asthma also in adults with AR.
In our study, other well-validated risk factors for asthma in patients with persistent AR, such as family history, polysensitization, increased total serum IgE, severe rhinitis, or exposure to tobacco smoking were not validated by the multiple regression analysis. However, some of the risk factors are present as phenotypic traits in the cluster analysis.
This is the first study describing asthma phenotypes in adults and in children with SAR according to the associated risk factors for asthma. In children with SAR, the association between breastfeeding for < 2 months and severe rhinitis was the most frequently encountered asthma phenotype, whereas in adults with SAR, the association between polysensitization and severe rhinitis is the dominant phenotype.
The presence of short or no breastfeeding as a phenotypic trait of asthma in children with SAR is in concordance with other studies identifying breastfeeding as a protective factor for the appearance of asthma.14-18 The other phenotype of asthma in children with SAR associates male sex and polysensitization, both of which have been demonstrated as risk factors for asthma in children.1,14,18,19 Severe rhinitis is present in both phenotypes and is also demonstrated as a risk factor for asthma.1,20
In adults, severe rhinitis and polysensitization are encountered in 2 of 3 asthma phenotypes. While severe rhinitis is clearly demonstrated as a definite risk factor for asthma in adults, polysensitization is less clear-cut in its relationship to the risk of asthma. This relationship is also unclear in children, although a recent study shows that increased total serum IgE is a risk factor for asthma only in the presence of specific sensitization.21 In another study, atopy increased the risk of new-onset asthma in adults by 12% to 21%, with total serum IgE and sensitization to cats being independent predictors for asthma.22 The presence of male sex as a risk factor describing an adult asthma phenotype is surprising because it is known that after puberty asthma is more frequent and more severe in females.22,23 However, none of the studies demonstrating female sex as a risk factor for asthma included patients with SAR and asthma. Exposure to pets as a phenotypic trait of asthma in adults with SAR is also surprising. Although there is controversy regarding this in children,24-26 none of the studies evaluated exposure to pets as a risk factor for developing asthma in adults.
The cross-sectional nature of the study may hinder the results. However, many risk factors for asthma were validated in retrospective and cross-sectional trials.27 The study might also be biased being a single-center study and is low powered in the children’s subgroup. A multicenter longitudinal study validating our observations is warranted.
This study validates risk factors and clinical phenotypes of asthma in patients with SAR, an aspect frequently neglected by current studies. Some of the identified risk factors and phenotypic traits are concordant with those described for asthma in patients with persistent AR: lack of specific allergen immunotherapy in children, mixed sensitization (seasonal and perennial allergens), breastfeeding < 2 months and male sex in children, polysenzitization, and severe rhinitis, both in children and adults. The study also identified new risk factors and phenotypic traits for asthma in adults with SAR, such as male sex and exposure to pets.
- Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63(suppl 86): 8–160.
- Thomas M. Allergic rhinitis: evidence for impact on asthma. BMC Pulm Med. 2006;6(suppl 1):S4.
- Linneberg A, Henrik Nielsen N, Frølund L, Madsen F, Dirksen A, Jørgensen T; Copenhagen Allergy Study. The link between allergic rhinitis and allergic asthma: a prospective population-based study. The Copenhagen Allergy Study. Allergy. 2002;57(11):1048–1052.
- Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as an independent risk factor for adult-onset asthma. J Allergy Clin Immunol. 2002;109(3):419–425.
- Everitt BS, Landau S, Leese M. Cluster Analysis. 4th ed. London, England: Hodder Arnold; 2001.
- Hartigan JA. Clustering. Annu Rev Biophys Bioeng. 1973;2:81–101.
- Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178(3):218–224.
- Moore WC, Meyers DA, Wenzel SE, et al; National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med. 2010;181(4):315–323.
- Jacobsen L, Niggemann B, Dreborg S, et al; The PAT Investigator Group. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007;62(8):943–948.
- Hankin CS, Cox L, Lang D, et al. Allergen immunotherapy and health care cost benefits for children with allergic rhinitis: a large-scale, retrospective, matched cohort study. Ann Allergy Asthma Immunol. 2010;104(1):79–85.
- Jayasekera NP, Toma TP, Williams A, Rajakulasingam K. Mechanisms of immunotherapy in allergic rhinitis. Biomed Pharmacother. 2007;61(1):29–33.
- Akdis M, Akdis CA. Therapeutic manipulation of immune tolerance in allergic disease. Nat Rev Drug Discov. 2009;8(8):645–660.
- James LK, Durham SR. Update on mechanisms of allergen injection immunotherapy. Clin Exp Allergy. 2008;38(7):1074–1088.
- Midodzi WK, Rowe BH, Majaesic CM, Saunders LD, Senthilselvan A. Early life factors associated with incidence of physician-diagnosed asthma in preschool children: results from the Canadian Early Childhood Development cohort study. J Asthma. 2010;47(1):7–13.
- Scholtens S, Wijga AH, Brunekreef B, et al. Breast feeding, parental allergy and asthma in children followed for 8 years. The PIAMA birth cohort study. Thorax. 2009;64(7):604–609.
- Oddy WH. The long-term effects of breastfeeding on asthma and atopic disease. Adv Exp Med Biol. 2009;639:237–251.
- Gdalevich M, Mimouni D, Mimouni M. Breast-feeding and the risk of bronchial asthma in childhood: a systematic review with meta-analysis of prospective studies. J Pediatr. 2001;139(2):261–266.
- Subbarao P, Mandhane PJ, Sears MR. Asthma: epidemiology, etiology and risk factors. CMAJ. 2009;181(9):E181–E190.
- Omenaas E, Svanes C, Janson C, et al. What can we learn about asthma and allergy from the follow-up of the RHINE and the ECRHS studies? Clin Respir J. 2008;2(suppl 1):45–52.
- Bousquet J, Bachert C, Canonica GW, et al; Extended Global Allergy and Asthma European Network, World Allergy Organization and Allergic Rhinitis and its Impact on Asthma Study Group. Unmet needs in severe chronic upper airway disease (SCUAD). J Allergy Clin Immunol. 2009;124(3):428–433.
- Gergen PJ, Arbes SJ Jr, Calatroni A, Mitchell HE, Zeldin DC. Total IgE levels and asthma prevalence in the US population: results from the National Health and Nutrition Examination Survey 2022–2006. J Allergy Clin Immunol. 2009;124(3):447–453.
- Antó JM, Sunyer J, Basagaña X, et al. Risk factors of new-onset asthma in adults: a population-based international cohort study. Allergy. 2010;65(8):1021–1030.
- Van den Berge M, Heijink HI, van Oosterhout AJ, Postma DS. The role of female sex hormones in the development and severity of allergic and non-allergic asthma. Clin Exp Allergy. 2009;39(10):1477–1481.
- Gaffin JM, Phipatanakul W. The role of indoor allergens in the development of asthma. Curr Opin Allergy Clin Immunol. 2009;9(2):128–135.
- Kerkhof M, Wijga AH, Brunekreef B, et al. Effects of pets on asthma development up to 8 years of age: the PIAMA study. Allergy. 2009;64(8):1202–1208.
- Simpson A, Custovic A. Pets and the development of allergic sensitization. Curr Allergy Asthma Rep. 2005;5(3):212–220.
- Asher MI, Stewart AW, Mallol J, et al; ISAAC Phase One Study Group. Which population level environmental factors are associated with asthma, rhinoconjunctivitis and eczema? Review of the ecological analyses of ISAAC Phase One. Respir Res. 2010;11:18.
Cristina Ciobanu, MD 2
1Transylvania University, Spatarul Luca Arbore nr.16, Brasov 500112, Romania.
Correspondence: Ioana Agache, MD, PhD, Transylvania University, Spatarul Luca Arbore nr.16, Brasov 500112, Romania.
E-mail: [email protected]
Back to the table of contents for the December 2010 issue
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Tissue Healing in Sports Injuries