Relationship between Asthma and Rhinitis: Epidemiologic, Pathophysiologic, and Therapeutic Aspects
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Epidemiologic Links: Atopy
Asthma and rhinitis are frequently associated withatopy with preferential sensitization to airborneallergens. Atopic diseases can manifest them-selves at different sites on the body and can pre-sent as urticaria, allergic rhinitis, atopic dermati-tis, conjunctivitis, food allergy, and asthma.
Allergic Rhinitis and Asthma Prevalence
Allergic rhinitis is an important health problem andaffects up to 40% of the worldwide population.1,2Its prevalence in the Canadian population isbetween 10 and 25%.1 Forty percent of allergicrhinitis patients have asthma, and as much as 94%of allergic asthma patients have allergic rhinitis.36In Canada, the current prevalence of asthma is8.4%7 whereas worldwide prevalence varies from1.6 to 37%.1
Allergic Rhinitis as a Risk Factor for AsthmaSettipane and colleagues conducted a prospec-tive study on a cohort consisting of young university students to determine the long-termrisk factors for developing asthma and allergicrhinitis.8 The follow-up study 23 years laterrevealed that the incidence of asthma and allergicrhinitis increases with age. Furthermore, the pres-ence of allergic rhinitis and positive results ofallergen skin tests were shown to be important riskfactors of asthma development. Patients with aller-gic rhinitis have a threefold greater chance ofdeveloping asthma. Interestingly, the relief ofrhinitis symptoms over time correlates with theimprovement of asthma symptoms. Patients withmore severe and persistent rhinitis are at a higherrisk of developing asthma.9 A strong associationbetween perennial rhinitis and asthma in nonatopicsubjects was also demonstrated in the EuropeanCommunity Respiratory Health Survey.10
To better understand the possible links betweenasthma and allergic rhinitis, the World HealthOrganization, through the Allergic Rhinitis and itsImpact on Asthma (ARIA) program, examinedthe impact of allergic rhinitis on asthma.2 TheARIA study concluded that allergic rhinitis is a
Relationship between Asthma and Rhinitis:Epidemiologic, Pathophysiologic, and Therapeutic AspectsCeline Bergeron, MD, MSc; Qutayba Hamid, MD, PhD
AbstractOver the last few years, the evidence of links between rhinitis and asthma has been strengthened. Thishas led to the introduction of the concept of united airway disease. Rhinitis and asthma appear to beinterrelated at the epidemiologic level and at the pathophysiologic level. This article reviews current epi-demiologic and pathophysiologic evidence of the relationship between rhinitis and asthma and discussesthe effect of treatment of one site on the other site.
C. Bergeron, Q. HamidMeakins-Christie Laboratories,McGill University, Montreal, QuebecCorrespondence to: Qutayba Hamid, MD, PhD, Meakins-Christie Laboratories, McGill University, 3626 St-UrbainStreet, Montreal, PQ H2X 2P2
82 Allergy, Asthma, and Clinical Immunology / Volume 1, Number 2, Spring 2005
major chronic respiratory disease owing to itsprevalence, impact on quality of life, impact onschool and work performance and productivity,economic burden, and links to asthma. Accordingto the ARIA study and previous observations,allergic and nonallergic rhinitis should be con-sidered risk factors for asthma, along with otherknown risk factors.
The mucous membranes of both the upper and thelower airways are covered by a pseudostratifiedcolumnar ciliated epithelium with a continuousbasement membrane. For this reason, these airwaysshare a mucosal susceptibility to inhaled allergens. The obvious anatomic difference is thepresence of smooth muscle in the lower airway as opposed to large venous sinusoids and prominent glands within the submucosa in theupper airway. The following section describessimilarities and dissimilarities between rhinitisand asthma pathologies.
Exposure to an allergen triggers an immediatereaction coordinated by mast cells and their medi-ators such as histamines, leukotrienes, andprostaglandins. In allergic rhinitis, this immediatereaction leads to nasal congestion and runny nosefrom an increase in vascular permeability. Inasthma, the immediate reaction results in bron-chospasm. Late-phase reaction occurs in bothasthma and rhinitis following allergen exposure andis mainly triggered by CD4+ T cells.11 Allergicrhinitis and asthma share many pathologic features.In fact, the same profile of inflammation, media-tors, and adhesion molecules can be observed inupper- and lower-airway allergic diseases. Thereis a common cellular inflammation pattern char-acterized by eosinophil, mast-cell, and CD4+ T-cellinfiltration.12,13 Mediators (including histamine;cysteinyl leukotrienes; interleukin [IL]-4, IL-5,IL-13; regulated on activation, normal T-cellexpressed and secreted [RANTES] chemokine; and
eotaxin) are expressed in both upper and lower air-ways.14,15 Although the initial inflammationinduced by allergens is similar in upper and lowerairways, the long-term structural consequencesdiffer. The respiratory epithelium is disrupted inbronchial asthma whereas only minimal epithelialshedding is observed in allergic rhinitis. The sub-epithelial basement membrane is thickened withan increased amount of collagen deposition inasthma. Although this thickening can also occurin the upper airway in rhinitis, the extent of thisprocess is less than that seen in the lower airwayin asthma.16
Allergic Rhinitis, Airway Hyperresponsiveness,and Asthma
It is well established that 40% of nonasthmaticpatients with allergic rhinitis have increased air-way hyperresponsiveness.17 Allergen nasal chal-lenge or seasonal allergen exposure leads toincreased airway hyperresponsiveness in rhinitispatients.18,19 The number of eosinophils in thesputum correlates with nonspecific airway hyper-responsiveness not only in asthma but also inallergic seasonal rhinitis.20 Nasal eosinophilia cor-relates with bronchial reactivity in allergic childrenwho have both asthma and rhinitis.21 Gaga and col-leagues found eosinophilic infiltration in the nasalmucosa of asthmatic patients even in the absenceof rhinitis.22 The relationship between nasal allergyand asymptomatic airway hyperresponsivenesssupports the concept of one airway, one disease.
Nonallergic Rhinitis and Nonallergic Asthma
An inflammatory pattern has been characterizedin asthmatic children suffering from allergic rhini-tis and in those with nonallergic rhinitis.23 Sur-prisingly, both groups have a typical T-helper 2(Th2) cytokine inflammatory pattern as measuredin rhino-sinusal lavage. Nonatopic or intrinsicasthmatic patients have an inflammatory patternsimilar to that of atopic asthma patients althoughthis nonatopic group has been less extensivelystudied. Increased levels of IL-3, IL-4, IL-5,
Relationship between Asthma and Rhinitis Bergeron and Hamid 83
granulocyte-macrophage colony-stimulating fac-tor (GM-CSF), and eosinophils were found inendobronchial biopsy specimens from nonatopicasthma patients.24-27 Even in the absence of anallergic process, rhinitis and asthma share simi-lar inflammatory profiles, linking both diseases.Epidemiologic studies are consistent with thesefindings, as nonatopic rhinitis has also beenreported to be an independent risk factor fordeveloping asthma.2
To better understand the allergen relationshipbetween upper and lower airways, many studieshave examined this paradigm, using nasal orbronchial allergen challenge and observing itseffect on the opposite site of the airway.
Effect of Nasal Allergen Exposure on Lower Airways
Nasal allergen challenge increases eosinophilsand adhesion molecules in both nasal and bronchialbiopsy specimens from nonasthmatic patients withrhinitis.28 Chakir and colleagues also showed thatnatural pollen exposure is associated with anincrease in lymphocyte numbers, eosinophilrecruitment, and IL-5 expression in the bronchialmucosa of nonasthmatic persons with allergicrhinitis.29 In another study, Chakir and colleaguesshowed that allergic nonasthmatic patients withseasonal pollen-induced rhinitis had airway patho-logic changes (as seen in bronchial biopsy spec-imens) similar to those observed in asthmaticpatients.30 These changes consisted of cellularinfiltration, mucosal edema, increased epithelialdesquamation, and focal basement-membranethickening.
Effect of Lower-Airway Allergen Exposure on Nasal Mucosa
Segmental bronchial allergen challenge in nonasth-matic allergic rhinitis patients leads to a decrease
in nasal peak inspiratory flow and a concomitantincrease in nasal symptomatology.31 It alsoincreases eosinophils, eotaxin-positive cells, andIL-5 expression in nasal mucosa biopsy speci-mens31 and decreases mast cells.32 The decrease inthe number of mast cells is attributed to a higherrate of degranulation.
Mechanisms That Might Explain the Linkbetween Upper and Lower Airways
A number of mechanisms have been suggested toexplain the link between upper and lower air-ways and the concept of united airway disease.They include genetic factors, an anatomic linkbetween upper and lower airways, neural inter-action between the nose and the lower airway, andmediator- or inflammatory-cell circulation. Inflam-matory mediators can reach the lower airwayfrom the upper airway through the airway pas-sages. They might also be able to reach the lowerairway through the blood. A number of thesemediators, such as histamine, cysteinylleukotrienes, and some cytokines, have the abil-ity to spill over into the systemic circulation.However, very few data support this concept,and most of the cytokines have a very short half-life and do not act in an endocrine fashion. Inman33and Denburg34 suggested that inflammatory medi-ators such as IL-5 and GM-CSF can travel fromthe lung to the bone marrow, where they couldstimulate the proge