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Keywords:

  • allergic;
  • allergy cascade;
  • asthma;
  • hay fever;
  • rhinitis

Abstract

  1. Top of page
  2. Abstract
  3. The IgE-dependent allergy cascade
  4. Comorbid association between nasal and pulmonary allergy
  5. Discussion and conclusions
  6. References

The early phase of an IgE-dependent allergic reaction is followed by the activation of a complex network of inflammatory phenomena – T lymphocytes, cytokines, mediators, and adhesion molecules – that mediate late and ongoing allergic symptoms. The kinetics of respiratory inflammation following allergen exposure involve the migration of inflammatory cells to the mucosa within about 30 min, increased inflammatory infiltration over the following hours, and then slow subsidence. A relationship between asthma and allergic rhinitis is supported by epidemiological, histological, physiological, and immunopathological data, and by the response of asthma symptoms in rhinitic patients to intranasal corticosteroids and antihistamines. For example, there is no morphological difference between the bronchial inflammatory response following allergen-specific challenge in patients suffering from asthma alone or rhinitis alone. It is the allergen dose that makes the difference in the airway response to allergen in allergic rhinitis and asthma. Recognition of the relationship between asthma and allergic rhinitis has led to the introduction of new diagnostic terminology and treatment recommendations: 1) patients with persistent rhinitis should be evaluated for asthma; 2) patients with persistent asthma should be evaluated for rhinitis; and 3) a strategy should combine the treatment of upper and lower airways in terms of efficacy and safety.

Since the early 1990s, understanding of the complexities of the IgE-dependent allergy cascade has increased dramatically, leading to clarification of the relationship between nasal and pulmonary allergy. It has become evident that respiratory allergy is a disorder of the entire respiratory tract, with different manifestations in the specific target organs of the nose and lungs. This article briefly reviews the current understanding of the IgE-dependent allergy cascade and examines the relationship between nasal and pulmonary respiratory allergy.

The IgE-dependent allergy cascade

  1. Top of page
  2. Abstract
  3. The IgE-dependent allergy cascade
  4. Comorbid association between nasal and pulmonary allergy
  5. Discussion and conclusions
  6. References

An IgE-dependent allergic reaction is characterized by an early-phase and a late-phase reaction (Fig. 1). The early-phase reaction involves the release of histamine and other proinflammatory mediators. In the airways these lead, within seconds or minutes, to vasodilatation, increased permeability, and symptoms of nasal discharge, sneezing, and bronchoconstriction (1). During the early-phase reaction, mast cells release histamine and other preformed elements such as enzymes, hydrolases, and proteoglycans, and also release proinflammatory mediators such as prostaglandins (e.g. PGD2), leukotrienes, platelet-activating factor, bradykinin, and cytokines (e.g. tumour necrosis factor-α and interleukins IL-4, IL-5, IL-6, IL-10, and IL-13) (2). Proinflammatory mediators initiate a complex network of inflammatory phenomena involving adhesion molecules, Th2 T lymphocytes (which mainly release IL-4, IL-5, and IL-13), cytokines, and mediators (Fig. 2). These result in the late and ongoing allergic symptoms of nasal congestion, asthma, and urticaria. For an exhaustive review of the IgE-dependent allergy cascade, the reader is referred to the recent publication of the Allergic Rhinitis and Its Impact on Asthma (ARIA) Workshop Group (2).

image

Figure 1. The IgE-dependent allergy cascade. APC, antigen-presenting cell; B, B lymphocyte; FcεRI, high-affinity receptor for IgE; GM-CSF, granulocyte monocyte colony-stimulating factor; IL, interleukin; PAF, platelet-activating factor; Th2, Th2 T lymphocyte; VCAM-1, vascular cellular adhesion molecule-1.

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image

Figure 2. The allergic reaction. APC, antigen-presenting cell; B, B lymphocyte; Eos, eosinophil; ECP, eosinophil cationic protein; EDX, eosinophil-derived neurotoxin; Fibro, fibroblast; IL, interleukin; iNOS, inducible nitric oxide synthase; ITS, specific immunotherapy; LT, leukotriene; MBP, major basic protein; Neu, neutrophil; Th1, Th1 T lymphocyte; Th2, Th2 T lymphocyte; VCAM-1, vascular cellular adhesion molecule-1.

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One of the earliest and most important actions of proinflammatory effects caused by mast cells is to up-regulate or cause the de novo expression of adhesion molecules on the surface of endothelial cells (selectins) and epithelial cells (integrins). Adhesion molecules are involved in the recruitment of inflammatory cells (eosinophils, basophils, and neutrophils) from the circulation to the site of the inflammatory reaction. Specific adhesion molecules favour the tether/roll of inflammatory cells towards the epithelium (e.g. vascular cellular adhesion molecule-1 (VCAM-1), P-selectin, and L-selectin), the firm arrest of inflammatory cells to the epithelium (e.g. CD18 integrin, intercellular adhesion molecule-1 (ICAM-1), and VCAM-1), and diapedesis (migration) through the epithelium (3). Experimental nasal, conjunctival, and bronchial data indicate that inflammatory cells begin to migrate to the mucosa approximately 30 min after specific challenge, continue to increase during the following 24 h, and then slowly subside (4–7). However, up-regulation of expression of the ICAM-1 molecule is evident on the conjunctival and nasal epithelium of allergic patients, even when they are asymptomatic (8).

Persistent up-regulation of ICAM-1 expression offers a theoretical mechanism for the minimal persistent inflammation that continues in the absence of symptoms when a subthreshold exposure to the allergen persists (8,9). It also suggests a mechanism for the exacerbation of asthma in children during upper respiratory viral infection (10,11); the ICAM-1 molecule is the major receptor for human rhinoviruses (12), which in turn is the main cause of upper respiratory tract viral infections in children.

Comorbid association between nasal and pulmonary allergy

  1. Top of page
  2. Abstract
  3. The IgE-dependent allergy cascade
  4. Comorbid association between nasal and pulmonary allergy
  5. Discussion and conclusions
  6. References

The relationship between asthma and allergic rhinitis is supported by epidemiological studies; by histological, physiological, and immunopathological characteristics; and by the positive effect of intranasal corticosteroids and antihistamines on asthma symptoms in rhinitic patients.

Epidemiological evidence

Early clinical observations showing an association between asthma and allergic rhinitis were confirmed in cross-sectional epidemiological studies (13), as reviewed by Annaesi-Maesano (14). For example, among young Italian men assessed in the mid-1990s, allergic rhinitis was present in 77% of those with asthma (15).

Large longitudinal studies revealed that allergic rhinitis usually precedes the onset of asthma (16–18). Although such results have been interpreted to define allergic rhinitis as a risk factor for the development of asthma, rhinitis appears to be an early stage of combined allergic airways disease. Disease extension probably occurs both upward and downward through the airways. In a recent survey conducted at Genoa University, 99 patients were followed for up to 10 years after the initial diagnosis of allergic rhinitis, allergic asthma, or both (19). During the 10-year follow-up, 32% of rhinitic patients developed asthma and 50% of patients with asthma alone developed rhinitis. A family history for atopy was associated with development of disease, but gender, age, smoking, and skin sensitization were not.

Functional considerations

The structural differences of the upper and lower airways result in different responses to allergic stimuli: rhinorrhoea/blockage in the rigid nose and sinuses, but mucus secretion/bronchoconstriction in the elastic tissues of the lung. Histological similarities and physiological relationships suggest that the respiratory tract is a single morphofunctional entity. The respiratory epithelium (ciliate epithelium and mucinous glands) extends from the smaller bronchi to the upper tract; bronchial/mucosal-associated lymphoid tissues (BALT or MALT) are present in both the upper and lower airways (20). The upper respiratory tract functions as a physical filter, resonator, heat exchanger, and humidifier for inhaled air, the failure of which may compromise the homeostasis of the lower airways (21).

Immunological evidence

The underlying allergic processes are similar in the upper and lower airways (22). Allergic rhinitis and asthma are connected via an immunological response to airborne allergens that is evident throughout the entire body and through bronchial reaction to intranasal challenge.

The body-wide immunological response to airborne allergens is evident by the presence of antigen-specific responses of peripheral blood mononuclear cells (PBMCs), resulting in increased IL-4 production and reduced interferon (IFN)-γ production (23), and by the presence of eosinophilia systemically as well as in secretions from the nose and sputum (22). The specific communication between the upper and lower airways and the bone marrow leading to up-regulation is not yet known, but the bone marrow appears to provide an ongoing source of differentiating inflammatory cells (eosinophils, basophils, and mast cells) to the entire airway (24).

The lower airway response to nasal challenge is demonstrated by morphological changes and by bronchoconstriction. Thickening of the reticular basement membrane is characteristic of airway remodelling in asthma, but similar degrees of thickening are seen in patients with perennial rhinitis and those with perennial allergic asthma (25). There is no morphological difference between the bronchial inflammatory response (cell influx and basement membrane thickening) following allergen-specific challenge in patients suffering from asthma alone or rhinitis alone (Fig. 3) (25,26). Allergen-specific challenge of rhinitic patients also causes a contractile response or increased responsiveness of bronchi (nasobronchial reflex) (20). This may be mediated via cytokine release of mast cells, which are abundantly present throughout the respiratory mucosa (27). The important difference between asthma and rhinitis is that a greater dose of allergen is necessary to cause bronchoconstriction in rhinitic patients (28).

image

Figure 3. Bronchial biopsies obtained after allergen-specific bronchial challenge; the inflammatory changes are superimposable. Reproduced with permission from (40).

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Indirect evidence: outcomes of therapy

β2-adrenergic agonists dilate the elastic lower airways, but are ineffective in the rigid upper airways. In contrast, the structural differences between the upper and lower airways are not a barrier to system-wide effects of other treatments options, such as intranasal corticosteroids and systemic antihistamines. For example, the use of intranasal corticosteroids (e.g. beclomethasone and fluticasone propionate) for rhinitis symptoms significantly reduces bronchial hyperresponsiveness to methacholine and has been shown to improve asthma symptoms (29–31). In a double-blind, double-dummy, placebo-controlled study of rhinitic patients with documented carbachol-induced bronchial hyperresponsiveness, beclomethasone 100 µg given intranasally four times daily – but not by inhalation – reduced bronchial hyperresponsiveness (32). Several studies have documented the efficacy of antihistamine therapy in reducing symptoms of asthma in people with seasonal allergic rhinitis when given alone (33), or in combination with a decongestant (34) or an antileukotriene (35,36). Furthermore, the Early Treatment of Atopic Child (ETAC) study showed that the onset of asthma was prevented by continuous antihistamine treatment in a defined subset of patients (37).

Discussion and conclusions

  1. Top of page
  2. Abstract
  3. The IgE-dependent allergy cascade
  4. Comorbid association between nasal and pulmonary allergy
  5. Discussion and conclusions
  6. References

Increased understanding of the nasal and pulmonary allergy cascade has furthered the appreciation of allergy as a systemic disease, and the role of systemic intervention. This has prompted investigation and development of new therapeutic interventions for respiratory allergy.

Recognizing the comorbid association of nasal and pulmonary allergy (and its related and concurrent manifestation as allergic rhinitis and asthma, respectively) is a major development in the field of allergic respiratory disease. It has led to the introduction of several new terms, including allergic rhinobronchitis (22) and united airways disease (20). However, combined allergic rhinitis and asthma syndrome (CARAS) was recently chosen as most appropriate by the global membership of the World Allergy Organization (38). It has also changed the management of allergy. As recommended by the evidence-based document Allergic Rhinitis and Its Impact on Asthma, written in collaboration with the World Health Organization: 1) patients with persistent rhinitis should be evaluated for asthma; 2) patients with persistent asthma should be evaluated for rhinitis; and 3) a strategy should combine the treatment of upper and lower airways in terms of efficacy and safety (2).

Major international research efforts, such as the International Study of Asthma and Allergies in Childhood (ISAAC), have revealed substantial worldwide variations in the prevalence and labelling of symptoms of allergic rhinoconjunctivitis (39). New points of intervention in the treatment of respiratory allergy, the systemic nature of allergy (manifested as chronic idiopathic urticaria), and changes in the management of allergy are among the topics addressed in other articles in this Supplement to Allergy.

References

  1. Top of page
  2. Abstract
  3. The IgE-dependent allergy cascade
  4. Comorbid association between nasal and pulmonary allergy
  5. Discussion and conclusions
  6. References
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