Eosinophilic and basophilic inflammation is present in a large number of allergic and nonallergic airway diseases. These conditions include, but are not limited to, allergic rhinitis, nonallergic rhinitis and rhinosinus-itis, nasal polyposis, allergic and nonallergic asthma, and some forms of COPD. Eosinophils are pivotal in the pathophysiology of most forms of chronic respiratory mucosal inflammation. There is strong evidence for the crucial role of eosinophils in ongoing inflammation and tissue damage. Granules of eosinophils contain toxic basic proteins, the major protein being eosinophilic cationic protein (ECP). Experimental studies on eosinophil function have shown cytotoxic effects on airway epithelium resulting in ciliostasis and lysis of the epithelium. ECP constitutes a well-described and standardized marker for tissue eosinophilia and activation. In addition, it has been demonstrated that recruited luminal airway eosinophils are distinct allergic “inflammatory” professional antigen-presenting cells able to activate primary CD4( ) T-cell responses in regional lymph nodes.
Links Between Upper and Lower Airway Inflammation
Allergic rhinitis is often associated with an increased prevalence of asthma: 20 to 50% of patients with allergic rhinitic will eventually have asthma. Airway inflammation and remodeling can be present in the lower airways of patients with allergic rhinitis, although it is less intense than in patients with asthma. During natural exposure, both the nose and lung come into contact with airborne allergens. Nasal inflammation may influence lower airway inflammatory processes by the release of inflammatory mediators into the circulation or through an effect on BM progenitors or inflammatory cells.
As most clinical trials have been performed during natural allergen exposure, studies evaluating the influence of upper airway disease on lower airways cannot properly assess the influence of nasal inflammation on lower airways. Provocative nasal allergen challenge has been used to help sort out the influences of allergic rhinitis on lower airways and specifically determine the influence of the upper airways on lower airway inflammation. Braunstahl et al performed nasal allergen provocations in allergic rhinitic patients without asthma and in normal control subjects. An increase of eosinophils as well as increased expression of intercellular adhesion molecule-1 was observed in the nasal and bronchial biopsies of allergic rhinitic patients compared with control subjects. However, Beeh et al observed no significant difference in sputum eosinophils following nasal allergen provocation, although sputum ECP and intercellular adhesion molecule were increased. In addition, Braunstahl et al have shown that segmental bronchial allergen challenge can produce nasal eosinophilic inflammation.
Nasal Allergen Challenge: Systemic Effects
In this regard, we recently performed a study using repeated nasal challenges to determine if this can induce lower airway inflammation and to obtain a more accurate model of allergen exposure. Our preliminary results show that a large number of patients with allergic rhinitis with or without asthma can have significant lower airway inflammation after repeated nasal challenge. Our observations expand those from Wilson et al, who showed that despite a significant increase in nasal symptoms and lavage eosinophil counts, a single nasal allergen challenge was not sufficient to elicit a measurable hemopoietic response in circulation, or an increase in sputum eosinophil counts. However, based on animal models (below) and the bulk of evidence from human studies, Eo/B progenitor differentiation and/or migration may be a critical process underlying the inflammatory changes in the lung following allergen provocation in the nose.
Chronic Rhinosinusitis: Local or Systemic Disease?
As was noted, most of the studies performed over the past few decades on BM progenitors in lower airways inflammation have been in atopic, usually asthmatic individuals, with the inclusion, however, of all pertinent control groups (nonatopic, nonasthmatic). We also have gathered a body of evidence on the role of the BM and Eo/B progenitors in allergic rhinitis and nasal polyposis (with or without allergy). Although the “systemic” nature of allergy (ie, its involvement of IgE-producing cells throughout the immune system as well as locally in tissues) is essential to the diagnosis of inhalant allergy, allergic Th2 inflammation can exist as a localized condition in the presence of negative skin-prick test findings. This phenomenon of Th2-mediated Eo/B progenitor mobilization and differentiation has also been established to occur in vitro/ex vivo and as a correlate in vivo, lending even more credence to the clinical relevance of progenitor changes and resultant eosinophilic inflammation in Th2-driven disease.
For example, in the nasal mucosa of some subjects with persistent rhinitis, Powe et al found specific pollen allergen binding similar to that found in individuals with symptoms and positive skin-prick test results, but not in control subjects. Their findings support the concept of localized nasal allergy in “nonatopic” rhinitis patients. Huggins and Brost-off also showed positive nasal allergen challenge results in skin-prick test-negative patients. Finally, a study by Carney et al found that a significant proportion (62%) of patients with idiopathic rhinitis have positive results on nasal challenge, the vast majority to house dust mite allergen. Their findings add to the weight of evidence that suggests “localized allergy” may exist in the absence of systemic atopic “biomarkers.” Thus, the diagnosis of nasal allergy is no longer simple and skin-prick test-negative patients with nasal eosinophilia may require allergen challenge before they can be said to be nonallergic. A parallel finding has been previously reviewed in nasal polyposis with local IgE production in nasal tissue in the absence of positive skin-prick test results. Similar findings have been found in nonallergic asthma. However, the existence of localized allergic inflammation without a systemic IgE response does not at all preclude the active involvement of hemopoietic processes in the development and maintenance of tissue Eo/B responses, as evidenced by the presence of hemopoietic progenitors within nasal polyp and other airway tissues.