Alkis G. Togias, MD*

                        ABSTRACT                                        RHINITIS AND ASTHMA: THE CONCEPT OF A
                                                                        CHRONIC INFLAMMATORY AIRWAY SYNDROME
        We currently advocate the concept that non-                     INVOLVING LOCAL AND SYSTEMIC COMPONENTS
    infectious rhinitis and asthma should be regarded
    as one syndrome with manifestations in both the                          It has now become quite clear that, at least in the
    nasal and the lower airways. Therefore, man-                        case of allergic rhinitis and asthma, the entire airways
    agement of these conditions should consider tar-                    are diseased. Patients with allergic or even nonallergic
    geting both sites of the respiratory tract. Although                chronic inflammatory rhinitis, who have no clinical
    the pathophysiology of allergic rhinitis and asth-                  evidence of asthma, show lower airway inflammation,
    ma is almost identical when the immunologic and
                                                                        as well as functional lower airway abnormalities, rang-
    inflammatory aspects are considered, tissue dif-
    ferences render some of the humoral mediators of
                                                                        ing from bronchial hyperresponsiveness to early airway
    the allergic reaction more important in one or the                  closure, as documented by increased ratio of residual
    other part of the respiratory tract. In accordance                  volume to total lung capacity.1 On the other hand, the
    to this concept, antihistamines are more effective                  prevalence of symptoms of rhinitis in patients with asth-
    in rhinitis and have little, if any, effect in asthma,              ma exceeds 85%2,3 and even those few asthmatics with
    whereas leukotriene receptor antagonists seem to                    no nasal complaints show inflammation in their nasal
    have stronger effects in asthma. Also, beta-                        mucosa.4 Notably, in individuals with asthma and rhini-
    adrenergic agonists, which act as smooth muscle                     tis, the severity of the nasal airways component tracks in
    relaxants, have only a role in asthma, whereas                      parallel with that of the lower airways. These observa-
    alpha agonists, which act as vasoconstrictors,                      tions support the notion that rhinitis and asthma are
    only in rhinitis. In this brief review article, we                  elements of a single inflammatory syndrome that affects
    summarize current management strategies in
                                                                        the entire airway tract. We advocate that rhinitis and
    rhinitis and asthma viewed as one condition. In
    discussing these strategies, we will refer to a
                                                                        asthma should be managed as a single entity.
    number of presentations and discussions that took                        At this point, when only rhinitis is present, there
    place at the 2003 meeting of the World Allergy                      is no evidence that any form of intervention towards
    Organization in Vancouver, Canada that were                         lower airway disease is justified, although, in the
    selected for coverage in this Advanced Studies                      future, if we identify lower airway abnormalities that
    in Medicine issue.                                                  constitute risk factors for developing asthma, they
    (Adv Stud Med. 2004;4(7A):S513-S516)                                may need to be managed. From a recent, prospective
                                                                        study, it has become clear that, at least in adults, not
                                                                        only is rhinitis a risk factor for the development of
                                                                        asthma, but that the risk for asthma increases with
    *Associate Professor of Medicine, Division of Clinical              increased severity of the upper airway disease.5 On
Immunology, Johns Hopkins University School of Medicine,                the basis of current knowledge, vigorous treatment
Baltimore, Maryland.                                                    of rhinitis, as well as vigilance for lower airway dis-
    Address correspondence to: Alkis Togias, MD, Johns
Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview                 ease in patients with rhinitis and no asthma are jus-
Circle, Baltimore MD 21224. E-mail:                   tifiable strategies.

Advanced Studies in Medicine   s                                                                                            S513

    In patients with rhinitis and asthma, ie, with the                 of leukotrienes. Among the shared properties, differ-
chronic inflammatory airway syndrome manifested in                     ences in relative potency should be noted, the most
its entirety, there is evidence that appropriate                       evident being the at least 1000-fold stronger contractile
management of rhinitis may benefit asthma. This                        effect of leukotrienes on the human airway smooth
hypothesis has been tested in several studies, in the                  muscle.10 Third, evidence has accumulated that hista-
majority of which the results were supportive. In                      mine and leukotrienes are not just molecules with effec-
2 recently published retrospective analyses, patients                  tor functions on target tissues such as the smooth
with International Classification of Diseases codes for                muscle, but that they play a role in immune functions
asthma and rhinitis who received treatment for their                   and in inflammatory events. Several reports have indi-
upper airway condition had reduced numbers of asth-                    cated that histamine activates immune cells including
ma-related hospitalizations and emergency department                   lymphocytes, dendritic cells, and macrophages. For
visits, compared with those who did not receive rhinitis               example, as discussed by Dr Marone (page S495), hista-
treatment.6,7 In explaining the impact of rhinitis on asth-            mine induces release of beta-glucuronidase, a potent
ma, one should note that allergic reactions induced in                 lysosomal enzyme, from human lung macrophages and
the nose can alter lower airway function and can induce                this effect is blocked by a H1-receptor antagonist. The
lower airway inflammation.8 The mechanism(s) of the                    stimulatory effects of leukotrienes on various immune
vertical interaction between the nasal and the lower air-              cells have recently started being unveiled. It is now clear,
ways are not known, although several hypotheses have                   for example, that leukotrienes have multiple effects on
been proposed.1 The currently most attractive hypoth-                  the biology of eosinophils, from induction of matura-
esis is that of inflammation propagating systemically                  tion to prolongation of eosinophil survival.11
from the upper to the lower airways, with the partici-                     Given the multiplicity of the biologic effects, the
pation of elements of the innate and the adaptive                      complementarity and, perhaps, the synergy between
immune system.9 This underlines the concept that                       histamine and leukotrienes, it is reasonable to raise the
pharmacological management of the chronic inflam-                      possibility that antagonists to these mediators will
matory airway syndrome may frequently require an                       show impressive strength, when utilized together. Such
agent that targets the systemic inflammatory compo-                    strength may also derive from the fact that the thera-
nent. Ideally, systemic steroids could play this role, but             peutic effects of these agents cover the entire allergic
their safety profile precludes their use in this context.              respiratory syndrome, as opposed to targeting a single
                                                                       component. Indeed, leukotriene receptor antagonists
OPTIMAL USAGE OF ANTIHISTAMINES AND                                    now have indications for both asthma and allergic
LEUKOTRIENE RECEPTOR ANTAGONISTS                                       rhinitis. A study by Keith et al, summarized on page
                                                                       S529, also proposes that they may be effective in nasal
    In patients with chronic allergic airway syndrome,                 polyposis. In another study, Price and colleagues
it is pertinent to take into account basic information                 reported at the World Allergy Organization meeting
derived from many years of research. First, the ele-                   that a leukotriene receptor antagonist added to an
mentary allergic reaction (immunoglobulin E-mediat-                    inhaled glucocorticosteroid was superior to doubling
ed immediate hypersensitivity) involves the release of                 the dose of the steroid in the subgroup of asthma sub-
histamine and sulfidopeptide leukotrienes (peptide                     jects who also had a physician diagnosis of rhinitis (see
leukotrienes, or simply, leukotrienes) upon mast cell                  page S527). Antihistamines are successfully used in
and basophil activation. Other allergic mediators are                  allergic rhinitis, but studies in asthma have not been, in
probably also released but their significance is less                  general, positive.12 The potential role of antihistamines
appreciated given the fact that no specific antagonists                in asthma is discussed in more detail in the summary of
exist. Second, histamine and leukotrienes act on target                the presentation of Dr Wilson at the World Allergy
tissues through distinct receptors, but share several                  Organization meeting (see page S517), that we have
biologic properties such as airway smooth muscle con-                  included in this issue. In 1997, Roquet and colleagues
striction, induction of vascular permeability, and                     published their findings of a study where they com-
vasodilation. They also have some distinct properties;                 bined a leukotriene receptor anatgonist and an antihist-
for example, direct activation of neural reflexes, at least            amine in order to inhibit the early and the late phase of
in the nasal airways, is a function of histamine, but not              an allergen inhalation challenge in subjects with allergic

S514                                                                                                         Vol. 4 (7A)   s   July 2004

 asthma.13 Their results were quite impressive and                      made by the pharmaceutical industry to develop glu-
 offered evidence of additive effect. More recently, a                  cocorticosteroids with more favorable safety and effi-
 study has suggested that, in mild asthma, combination                  cacy profiles and the newest available agents reflect this
 treatment with an antihistamine and a leukotriene                      work. Currently, another inhaled steroid, ciclesonide,
 receptor antagonist may be equally effective as the                    is under development; this agent appears to have the
 combination of a nasal and an inhaled glucocortico-                    safest clinical profile so far, and some of its properties
 steroid.14 It should be noted that a leukotriene receptor              are reviewed by the summary of a presentation by Dr
 antagonist alone is generally inferior to a low-moder-                 Kaliner at the World Allergy Organization meeting
 ate dose of an inhaled glucocorticosteroid in mild to                  (see page S520). Although topical steroids have a wide
 moderate asthma. There is quite some controversy as                    spectrum of anti-inflammatory activity that covers the
 to whether the combination of an antihistamine with                    majority of pathologic elements identified in the
 a leukotriene receptor antagonist is as potent as a nasal              chronic inflammatory airway syndrome, some aspects
 steroid in the treatment of allergic rhinitis. A couple of             of inflammation and, most importantly, some aspects
 recent studies have indicated that this may, indeed, be                of altered physiology, may not be responsive to steroid
 the case, while a couple of others have found the nasal                treatment. For example, there have been questions as
 steroid to be more effective. On the basis of the above,               to whether, at least in the lower airways, inhaled
 our utilization of combination treatment with an anti-                 steroids can suppress leukotriene production, since
 histamine and a leukotriene receptor antagonist                        they do not appear to inhibit mast cell activation.16
 should be considered as an alternative management                      Also, some of the functional airway abnormalities that
 approach (instead of a nasal and an inhaled steroid) in                have now been well demonstrated in asthma are unaf-
 patients with the mild persistent form of the chronic                  fected by inhaled steroid treatment.17 The latter prob-
 allergic airway syndrome and the choice may be left to                 lem may derive from the fact that there is no
 the patient, in an effort to improve the adherence fac-                convincing evidence that steroids can reverse structur-
 tor. In moderate to severe disease, the role of topical                al airway abnormalities that are operative in this syn-
 glucocorticosteroids is pertinent and there is no evi-                 drome (airway remodeling).
 dence at this point that an antihistamine/leukotriene                       Given the above limitations, one should consider
 receptor antagonist combination will be as effective.                  the use of topical steroids together with an agent that
                                                                        provides direct symptom relief. In allergic rhinitis,
 OPTIMAL USAGE OF TOPICAL GLUCOCORTICOSTEROIDS                          there is little evidence that the addition of an antihist-
                                                                        amine or a leukotriene receptor antagonist improves
     Topical glucocorticosteroids remain the most effec-                clinical outcomes, although well-designed studies tar-
 tive form of treatment in chronic inflammatory airway                  geting this question have not been performed. In the
 syndrome. In those patients with full manifestation of                 lower airways, the addition of an agent that has airway
 the syndrome, to achieve maximum effectiveness, topical                smooth muscle-relaxing effects to an inhaled steroid
 steroids need to be used in the nasal and the lower air-               has been proven a better option in managing moder-
 ways simultaneously. In patients with persistent rhinitis              ate or severe persistent asthma, compared to doubling
 but with mild intermittent asthma, several studies have                or even quadrupling the inhaled steroid dose.18,19 That
 indicated that the use of nasal steroids benefits the func-            second agent can be a long-acting beta-adrenergic ago-
 tion of the lower airways.1 Yet, a few other studies have              nist, a leukotriene receptor antagonist, or even low-
 failed to detect such beneficial effect.                               dose theophylline. In mild persistent asthma, there is
     Like all treatment options, topical steroids have                  little justification for the use of a second controller, in
 their limitations. In the nasal airways, for example,                  addition to an inhaled steroid or to a leukotriene
 20% of patients obtain no relief.15 In the lower air-                  receptor antagonist.20 In moderate asthma, the addi-
 ways, the dose response to inhaled steroids is relatively              tion of a long-acting beta-adrenergic agonist to a fixed
 flat and the dose needs to probably be quadrupled, if                  dose of an inhaled steroid has been more effective than
 one wants to assess the possibility of better effective-               the addition of a leukotriene receptor antagonist. Also,
 ness with increased dose. Most of the time, this will                  the ability to combine the inhaled steroid with the
 result in a total steroid load in which systemic effects               long-acting beta-agonist in a single inhalation device
 can become evident. Considerable efforts have been                     has made this approach very practical and has

Advanced Studies in Medicine   s                                                                                             S515

improved patient adherence. Yet, it should be noted                           8. Braunstahl GJ, Overbeek SE, Kleinjan A, Prins JB,
that there may be patients whose lung function deteri-                            Hoogsteden HC, Fokkens WJ. Nasal allergen provocation
                                                                                  induces adhesion molecules expression and tissue
orates when treated with beta2-adrenergic agonists.21,22                          eosinophilia in upper and lower airways. J Allergy Clin
These are primarily individuals with the Arg/Arg poly-                            Immunol. 2001;107(3):469-376.
morphism at position 16 of the beta2-adrenergic recep-                        9. Togias A. Systemic effects of local allergic disease.
tor. Approximately 25% of African Americans and                                   J Allergy Clin Immunol. 2004;113(1, suppl):S8-S14.
                                                                              10. Drazen JM. Comparative contractile responses to sulfi-
around 13% of European Americans express this geno-
                                                                                  dopeptide leukotrienes in normal and asthmatic human sub-
type. Currently, only one product combining the long-                             jects. Ann NY Acad Sci. 1988;524:287-297.
acting beta-agonist salmeterol with the steroid                               11. Bendeira-Melo C, Weller PF. Eosinophils and cysteinyl
fluticasone is available in the United States. Another                            leukotrienes. Prostaglandins Leukot Essent Fatty Acids.
product combining formoterol and budesonide is                                    2003;69(2-3):135-143.
                                                                              12. Van Ganse E, Kaufman L, Derde MP, Yernault JC, Delaunois
already in use in several countries and is under evaluation                       L, Vincken W. Effects of antihistamines in adult asthma:
in the United States. This product may have the advan-                            a meta-analysis of clinical trials. Eur Respir J. 1997;
tage that it could be used in adjustable dosing schemes.                          10(10):2216-2224.
One Canadian and one European study exploring this                            13. Roquet A, Dahlen B, Kumlin E, et al. Combined antagonism
                                                                                  of leukotrienes and histamine produces predominant inhibi-
possibility in the context of managing asthma exacerba-
                                                                                  tion of allergen-induced early and late phase airway
tions were presented at the World Allergy Organization                            obstruction in asthmatics. Am J Respir Crit Care Med.
meeting and are summarized in this issue.                                         1997;155(6):1856-1863.
                                                                              14. Wilson AM, Orr LC, Sims EJ, Dempsey OJ, Lipworth BJ.
                                                                                  Antiasthmatic effects of mediator blockade versus topical
                                                                                  corticosteroids in allergic rhinitis and asthma. Am J Respir
                      REFERENCES                                                  Crit Care Med. 2000;162(4, pt 1):1297-1301.
                                                                              15. White P, Smith H, Baker W, Davis W, Frew A. Symptom
                                                                                  control in patients with hay fever in UK general practice:
1. Togias A. Rhinitis and asthma: evidence for respiratory sys-                   how well are we doing and is there a need for allergen
   tem integration. J Allergy Clin Immunol. 2003;111(6):                          immunotherapy? Clin Exp Allergy. 1998;28(3):266-270.
   1171-1183.                                                                 16. Schleimer RP, Schulman ES, MacGlashan DW Jr, et al.
2. Kapsali T, Horowitz E, Togias A. Rhinitis is ubiquitous in                     Effects of dexamethasone on mediator release from human
   allergic asthmatics. J Allergy Clin Immunol. 1997;99:S138                      lung fragments and purified human lung mast cells. J Clin
   [abstract].                                                                    Invest. 1983;71(6):1830-1835.
3. Linneberg A, Henrik Nielsen N, Frolund L, Madsen F,                        17. Scichilone N, Togias A. The role of lung inflation in airway
   Dirksen A, Jergensen T. The link between allergic rhinitis                     hyperresponsiveness and in asthma. Curr Allergy Asthma
   and allergic asthma: a prospective population-based study.                     Rep. 2004;4(2):166-174.
   The Copenhagen Allergy Study. Allergy. 2002;                               18. Greening AP, Ind PW, Northfield M, Shaw G. Added sal-
   57(11):1048-1052.                                                              meterol versus higher-dose corticosteroid. Lancet.
4. Gaga M, Lambrou P, Papageorgiou N, et al. Eosinophils                          1994;344(8917):219-224.
   are a feature of upper and lower airway pathology in non-                  19. Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of
   atopic asthma, irrespective of the presence of rhinitis. Clin                  inhaled formoterol and budesonide on exacerbations of
   Exp Allergy. 2000;30(5):663-669.                                               asthma. N Engl J Med. 1997;337(20):1405-1411.
5. Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as                 20. O’Byrne PM, Barnes PJ, Rodreguez-Roison R, et al. Low
   an independent risk factor for adult onset asthma. J Allergy                   dose inhaled budesonide and formoterol in mild persistent
   Clin Immunol. 2002;109(3):419-425.                                             asthma: the OPTIMA randomized trial. Am J Respir Crit
6. Crystal-Peters J, Neslusan C, Crown WH, Torres A. Treating                     Care Med. 2001;164(8, pt 1):1392-1397.
   allergic rhinitis in patients with comorbid asthma: the risk of            21. Israel E, Drazen JM, Liggett SB, et al. The effect of polymor-
   asthma-related hospitalizations and emergency department                       phisms of the beta(2)-adrenergic receptor on the response
   visits. J Allergy Clin Immunol. 2002;109(1):57-62.                             to regular use of albuterol in asthma. Am J Respir Crit Care
7. Corren J, Manning BE, Thompson SF, Hennessy S, Strom                           Med. 2000;162(1):75-80.
   BL. Rhinitis therapy and the prevention of hospital care for               22. Lee DK, Currie GP, Hall IP, Lima JJ, Lipworth BJ. The arginine-
   asthma: a case-control study. J Allergy Clin Immunol.                          16 b2-adrenoreceptor polymorphism predisposes to bron-
   2004;113(3):415-419.                                                           choprotective subsensitivity in patients treated with formoterol
                                                                                  and salmeterol. Br J Clin Pharm. 2004;57(1):68-75.

S516                                                                                                                     Vol. 4 (7A)   s   July 2004

To top