The impact of allergic rhinitis on bronchial asthma

Transcription

1 The impact of allergic rhinitis on bronchial asthma Jonathan Corren, MD Los Angeles, Calif. During the past century, practicing clinicians have frequently observed that allergic rhinitis and asthma coexist in the same patients. Despite a wealth of data supporting an association between rhinitis and asthma, it has remained controversial whether the presence of rhinitis predisposes an individual to the development of asthma and whether nasal dysfunction causes asthma to worsen. Despite these uncertainties, there is a growing body of literature suggesting that appropriate treatment of allergic rhinitis results in improvements in asthma symptoms and lower airway function. In this review, data from a variety of clinical and laboratory studies will be highlighted to help clarify our understanding of this complex and important relation. EPIDEMIOLOGIC RELATION BETWEEN RHINITIS AND ASTHMA Many cross-sectional studies have demonstrated that rhinitis and asthma commonly occur together. Many studies have reported that nasal symptoms occur in 28% to 78% of patients with asthma, 1-3 as compared with approximately 5% to 20% of the general population. 4 Generally, these data were drawn from a variety of epidemiologic studies and clinical settings in which neither were patients interviewed in a standardized fashion nor were sensitive instruments used for detecting rhinitis. A more recent study, which utilized a standardized questionnaire in 478 patients, demonstrated that rhinitis is nearly a universal phenomenon in patients with allergic asthma, occurring in 99% of adults and 93% of adolescents. 5 Conversely, asthma has also been shown to affect up to 38% of patients with allergic rhinitis, 1, 3 which is substantially higher than the 3% to 5% prevalence noted in the general population. 6 The onset of rhinitis and asthma appears to be temporally related; a number of studies in children, adolescents, and adults have shown that upper airway symptoms either preceded or started at the same time as asthma in 59% to 85% of patients with both diseases. 3, 5, 7, 8 Although these studies suggest that rhinitis often begins before the onset of lower airway symptoms, prospective studies are required to accurately assess the From the University of California at Los Angeles School of Medicine and Allergy Research Foundation, Inc. Reprint requests: Jonathan Corren, MD, UCLA School of Medicine, Allergy Research Foundation, Inc., Wilshire Blvd., Suite 200, Los Angeles, CA J Allergy Clin Immunol 1998;101:S Copyright 1998 by Mosby, Inc /98 $ /0/86496 actual risk of developing asthma in patients with rhinitis alone. Settipane et al. 9 recently published the results of a prospective, 23-year follow-up study of 690 college freshmen who had no evidence of bronchial asthma. Students who reported nasal symptoms in 1961 developed asthma three times more often (10.5%) than individuals without rhinitis (3.6%). Although patients with rhinitis appear to be more likely to develop asthma, it has not been possible to predict which patients are at greatest risk for manifesting lower airway symptoms. Patients with allergic rhinitis and no clinical evidence of asthma frequently exhibit bronchial hyperresponsiveness to bronchoconstrictor agents such as methacholine or histamine This high incidence of hyperresponsiveness has caused some investigators to postulate that bronchial hyperreactivity may represent an intermediate phase between nasal allergy and symptomatic asthma. Although at least two small investigations suggested that lower airway hyperresponsiveness conferred a higher risk for developing symptoms and signs of asthma, 12, 13 future large-scale, prospective studies will be needed to confirm these findings. Recent pharmacoeconomic studies have attempted to correlate the presence of rhinitis with asthma severity and healthcare costs attributable to asthma. In an analysis of a database of 1261 asthmatics, Huse et al. 14 compared patients with significant nasal allergy with those who had mild or no symptoms of nasal disease. These investigators noted that patients with more severe rhinitis were much more likely to have nocturnal awakening due to asthma (19.6% versus 11.8%, respectively), moderate to severe asthma as defined by the National Asthma Education Program (60.2% versus 51.2%, respectively), or work loss related to asthma (24.1% versus 21.1%, respectively). Similarly, Halpern and coworkers 15 observed that patients with symptomatic rhinitis used more asthma medications, particularly more inhaled and supplemental oral corticosteroids. Judging from these recent investigations, one can postulate that allergic rhinitis may also be related to increased asthma severity and the use of more potent antiasthma medications. Although these data suggest that rhinitis may be contributing to asthma, an alternative explanation for this association may be that nasal inflammation is a marker for increasing dysfunction of the entire respiratory tract. The possibility of a cause-and-effect relation is better addressed by therapeutic studies of rhinitis therapy in patients with asthma. S352

2 J ALLERGY CLIN IMMUNOL VOLUME 101, NUMBER 2, PART 2 Corren S353 FIG. 1. PC 20 values expressed as milligrams per milliliter of methacholine for individual subjects at baseline and after 6 weeks of study. Geometric mean values are denoted by horizontal bars with 95% confidence intervals. Intergroup difference comparing change from baseline, p Adapted with permission from Corren J, et al. J Allergy Clin Immunol 1992;90: EFFECTS OF RHINITIS THERAPY ON ASTHMA Physicians often note anecdotally that treatment of allergic nasal disease results in improvements in asthma symptoms and pulmonary function. However, there have been relatively few well-controlled, large-scale clinical trials that have attempted to quantify this effect. Intranasal corticosteroids Several small studies have examined the efficacy of topical intranasal corticosteroids in patients with allergic rhinitis and mild asthma. Two of these trials addressed the role of prophylactic, preseasonal treatment with nasal corticosteroids in patients with primarily seasonal symptoms. Welsh and coworkers 16 compared the effects of intranasal beclomethasone dipropionate, flunisolide, and cromolyn versus placebo in patients with ragweedinduced rhinitis. Both of the topical corticosteroids were significantly more effective in reducing nasal symptoms than was either cromolyn or placebo. Unexpectedly, in 58 of the subjects who also had mild ragweed asthma, lower airway symptoms were also significantly improved in the patients receiving intranasal corticosteroids. Corren and coworkers 17 later examined the effects of seasonal administration of intranasal beclomethasone dipropionate on bronchial hyperresponsiveness in patients with fall rhinitis and mild asthma. Compared with baseline values, bronchial responsiveness to inhaled methacholine worsened significantly in the placebo group but did not change in the group using active treatment (Fig. 1). Together, these two small trials suggest that prevention of seasonal nasal inflammation with topical corticosteroids reduces subsequent exacerbations of allergic asthma. Other studies have examined the effects of intranasal corticosteroids in patients with chronic perennial allergic rhinitis and mild asthma. The first study to document these effects used intranasal budesonide in children with severe allergic rhinitis and concomitant asthma. 18 Four weeks of active therapy significantly reduced the objective measures of nasal obstruction as well as daily asthma symptoms and exercise-induced bronchospasm. In a subsequent study of patients with perennial rhinitis and asthma, Watson et al. 19 evaluated the effects of intranasal beclomethasone dipropionate on chest symptoms and bronchial responsiveness to methacholine. After 4 weeks of active treatment, asthma symptoms were significantly reduced, as was airway reactivity to methacholine. As an adjunct to this study, the investigators performed a radiolabeled deposition study of the beclomethasone aerosol and found that less than 2% of the drug was deposited into the chest area. These studies demonstrate that intranasal corticosteroids are effective in improving lower airway symptoms and bronchial hyperresponsiveness in patients with chronic, established nasal disease, and asthma. In view of the fact that the corticosteroid spray did not penetrate into the lungs, the study by Watson et al. 19 also asserts that the reduction observed in asthma was due to improvements in nasal function rather than direct effects of the medication on the lower airways. Antihistamines The presence of histamine in the lower airways has been correlated with bronchial obstruction, 20 and histamine has long been thought to play a role in bronchial asthma. However, early studies of first-generation antihistamines showed minimal improvements in bronchial asthma, 21 and initial small trials of second-generation antihistamines yielded mixed results However, two recent large-scale clinical studies using an antihistamine alone and an antihistamine-decongestant combination both resulted in significant improvements in asthma control. Grant et al. 27 demonstrated that seasonal symptoms of rhinitis and asthma were significantly attenuated in patients treated with cetirizine 10 mg once daily. In a second study using loratadine 5 mg plus pseudoephedrine 120 mg twice daily in patients with seasonal allergic rhinitis and asthma, Corren et al. 28 demonstrated that asthma symptoms, peak expiratory flow rates, and FEV 1 were all significantly improved in patients taking active therapy. In reviewing data from these and similar trials, it is difficult to determine whether the salutory effects of antihistamines in asthma can be attributed to direct effects on lower airway physiology or are due to improvements in rhinitis. Because many of the currently available agents appear to have weak or transient effects on resting airway tone, benefits to the lower airway may in fact be due to modulation of upper airway function. 29 The above studies have shown that treatment of rhinitis may result in improvements in asthma symptoms, lower airway caliber, and bronchial hyperresponsiveness and suggest that nasal disease contributes to the pathophysiology of asthma. In selected patients, treatment of rhinitis may reduce symptoms of mild asthma to such an extent that the use of potential first-line, prophylactic antiasthma drugs, such as inhaled cromolyn or nedocromil, may prove unnecessary. Before these results can be generalized to patients with moderate to severe asthma, future trials of rhinitis therapies will need to be

3 S354 Corren J ALLERGY CLIN IMMUNOL FEBRUARY 1998 FIG. 2. Changes in PC 20 from baseline 0800 (8 AM) at 1200 (12 PM) and 1600 (4 PM) in individual subjects after nasal challenge. Data are expressed in doubling dilutions of methacholine; means are indicated by horizontal bars (n 10 for both treatments). Adapted with permission from Corren J, et al. J Allergy Clin Immunol 1992;89: TABLE I. Putative mechanisms linking rhinitis to asthma Direct effects Neural (nasal-bronchial) reflex Postnasal drip of inflammatory cells and/or mediators from the nose into the lower airways Absorption of inflammatory cells and/or mediators from the nose into the systemic circulation and ultimately the lung Indirect effects Nasal obstruction causing reduction in filtration, humidification, and warming function of the nose conducted in these groups of patients as well. In addition, trials of new medications for rhinitis, such as topical intranasal antihistamines and anticholinergics, will provide physicians with valuable information about the use of these medications in asthma. PATHOPHYSIOLOGY OF THE UPPER-LOWER AIRWAY CONNECTION Although there is increasing evidence that allergic rhinitis may influence the clinical course of asthma, the mechanisms connecting upper and lower airway dysfunction are not entirely understood. A variety of theories have been invoked, including both direct and indirect effects of nasal dysfunction on the lower airways (Table I). Nasal-bronchial reflex Early mechanistic studies investigated the effects of several mucosal irritants on lower airway function in normal human subjects. In 1969, Kaufman and Wright 30 applied silica particles onto the nasal mucosa of individuals without lower airway disease and noted significant, immediate increases in lower airway resistance. Bronchospasm induced by nasal silica was blocked by both FIG. 3. Changes of FEV 1 after exercise. Exercise was performed with mouth breathing, nasal breathing, and spontaneous breathing. Mean SE values are shown. Adapted with permission from Shturman-Ellstein R, et al. Am Rev Resp Dis 1978;118: resection of the trigeminal nerve 31 and systemic administration of atropine. Fontanari and coworkers 32 recently reevaluated the possibility of a neural connection between the upper and lower airways by using cold, dry air as the nasal stimulus. These investigators demonstrated that nasal exposure to very cold air caused an immediate and profound increase in pulmonary resistance that was prevented by both topical nasal anesthesia and cholinergic blockade induced by inhalation of ipratroprium bromide. Both these studies strongly suggest the presence of a reflex involving irritant receptors in the upper airway (afferent limb) and cholinergic nerves in the lower airway (efferent limb). Subsequent studies used challenge materials considered to be more biologically relevant to allergic rhinitis, including histamine, whole pollen particles, and allergen extracts. Yan and Salome 33 performed nasal histamine challenges in subjects with perennial rhinitis and stable asthma and observed that FEV 1 was reduced by 10% or more immediately after provocation in eight of 12 subjects. Importantly, radiolabeling studies were performed as part of this study that demonstrated that histamine was not deposited into the lower airways. However, other studies that used histamine, allergen, or both failed to demonstrate bronchoconstriction after nasal provocation. This discrepancy in results may be partly explained by the type of patients who participated in these studies. Whereas Yan and Salome investigated subjects with perennial, symptomatic nasal disease, the majority of other studies examined asymptomatic patients outside of their pollen season. Certainly, a substantial degree of heterogeneity exists between patients in their lower airway response to nasal stimulation. In addition to neurally mediated bronchospasm, it has also been postulated that a nasal allergic reaction might result in an alteration in lower airway responsiveness. Corren et al 38 investigated the effects of nasal allergen provocation on nonspecific bronchial responsiveness to methacholine. Ten subjects with seasonal allergic rhinitis

4 J ALLERGY CLIN IMMUNOL VOLUME 101, NUMBER 2, PART 2 Corren S355 and asthma were selected for study; all patients related worsening of their asthma to the onset of hay fever symptoms. Nonspecific bronchial responsiveness was significantly increased 30 minutes after nasal challenge and persisted for 4 hours (Fig. 2). As radionuclide studies demonstrated no evidence of allergen deposition into the lungs, it seems unlikely that these increases in airway reactivity can be attributed to direct effects of allergen. In addition, the rapidity with which these changes occurred suggests the possibility of a reflex mechanism. Postnasal drip of inflammatory material Patients frequently complain that postnasal drip triggers episodes of coughing and wheezing. Early studies investigating the possibility of aspiration of nasal secretions demonstrated that substances placed in the upper respiratory tract could later be recovered from the tracheobronchial tree. 39, 40 More recently, Huxley et al 41 investigated pharyngeal aspiration during sleep both in healthy subjects and in patients with depressed sensorium. With the use of a radiolabeled marker that was intermittently released into the nose, pulmonary aspiration was detected in a significant number of both the normal and the ill subjects. Bardin et al., 42 however, were unable to document significant aspiration of radionuclide in a study of 13 patients with chronic rhinosinusitis and asthma. Although postnasal drip appears to be a plausible explanation connecting nasal disease to asthma, more definitive studies in humans are required to confirm this theory. Mouth breathing caused by nasal obstruction Nasal blockage resulting from tissue swelling and secretions may cause a shift from the normal pattern of nasal breathing to predominantly mouth breathing. Previous work has shown that mouth breathing associated with nasal obstruction resulted in worsening of exerciseinduced bronchospasm, whereas exclusive nasal breathing significantly reduced asthma after exercise (Fig. 3). 43 Improvements in asthma associated with nasal breathing may be the result of superior humidification and warming of inspired air before it reaches the lower airways. 44 Similarly, it would be expected that airborne allergens and pollutants would also be less likely to enter the lungs during periods of normal nasal function. It is difficult to determine which of these experimental mechanisms is most important in linking the nose to the lower airways. In all likelihood, however, several of these phenomena may contribute in some way to alterations in lung physiology in patients with allergic rhinitis and asthma. CONCLUSIONS During the past several years, there has been a growing awareness of the importance of rhinitis in patients with bronchial asthma. Recent epidemiologic findings correlate worsening asthma strongly with the presence of severe rhinitis, and clinical trials with a variety of rhinitis therapies have shown significant beneficial effects in mild asthma. Future studies will be important to determine which rhinitis patients are at greatest risk for developing asthma and whether early intervention is capable of preventing the progression to lower airway disease. REFERENCES 1. Blair H. Natural history of childhood asthma: 20-year follow-up. Arch Dis Child 1977;52: Smith JM. Epidemiology and natural history of asthma, allergic rhinitis and atopic dermatitis (eczema). In: Middleton E, editor. Allergy, principles and practice. 3rd ed. St. Louis, Mo.: CV Mosby Co.; Pedersen PA, Weeke ER. Asthma and allergic rhinitis in the same patients. Allergy 1983;38: Settipane GA. Allergic rhinitis update. Otolaryngol Head Neck Surg 1986;94: Kapsali T, Horowitz E, Diemer F, Togias A. Rhinitis is ubiquitous in allergic asthmatics [abstract]. J Allergy Clin Immunol 1997;99:S Evans R III, Mullally DI, Wilson RW, et al. National trends in the morbidity and mortality of asthma in the US: prevalence, hospitalization and death from asthma over two decades: Chest 1987;91:65S-74S. 7. Arsdel PP, Motulsby KP. Frequency and hereditability of asthma and allergic rhinitis in students. Acta Genet 1959;9: Maternowski CJ, Mathews KP. The prevalence of ragweed pollinosis in foreign and native students at a midwestern university and its implications concerning methods for determining inheritance of atopy. J Allergy 1962;33: Settipane RJ, Hagy GW, Settipane GA. Long-term risk factors for developing asthma and allergic rhinitis: a 23-year follow-up study of college students. Allergy Proc 1994;15: Madonini E, Briatico-Vangosa G, Pappacoda A, Maccagni G, Cardani A, Saporiti F. Seasonal increase of bronchial reactivity in allergic rhinitis. J Allergy Clin Immunol 1987;79: Ramsdale EH, Morris MM, Roberts RS, Hargreave FE. Asymptomatic bronchial hyperresponsiveness in rhinitis. J Allergy Clin Immunol 1985;75: Townley RG, Ryo UY, Kolotkin B, Kang B. Bronchial sensitivity to methacholine in current and former asthmatic and allergic rhinitis patients and control subjects. J Allergy Clin Immunol 1975;56: Braman SS, Barrows AA, DeCotiis BA, Settipane GA, Corrao WM. Airway hyperresponsiveness in allergic rhinitis: a risk factor for asthma. Chest 1987;91: Huse DM, Harte SC, Russel MW, et al. Allergic rhinitis may worsen asthma symptoms in children: the International Asthma Outcomes Registry [abstract]. Am J Respir Crit Care Med 1996;153:A Halpern M, Richner R, Togias A, et al. Allergic rhinitis may increase asthma costs [abstract]. Am J Respir Crit Care Med 1996;153:A Welsh PW, Stricker EW, Chu-Pin C, et al. Efficacy of beclomethasone nasal solution, flunisolide and cromolyn in relieving symptoms of ragweed allergy. Mayo Clin Proc 1987;62: Corren J, Adinoff AD, Buchmeier AD, Irvin CG. Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma. J Allergy Clin Immunol 1992;90: Henriksen JW, Wenzel A. Effect of an intranasally administered corticosteroid (budesonide) on nasal obstruction, mouth breathing and asthma. Am Rev Respir Dis 1984;130: Watson WTA, Becker AB, Simons FER. Treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: effect on lower airway responsiveness. J Allergy Clin Immunol 1993;91: Casale TB, Wood D, Richerson HB, et al. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with methacholine bronchial hyperresponsiveness. J Clin Invest 1987;79:

5 S356 Corren J ALLERGY CLIN IMMUNOL FEBRUARY Karlin JM. The use of antihistamines in asthma. Ann Allergy 1972;30: Taytard A, Beaumont D, Pujet JC, Sapene M, Lewis PJ. Treatment of bronchial asthma with terfenadine: a randomized controlled trial. Br J Clin Pharmacol 1987;24: Rafferty P, Jackson L, Smith R, Holgate ST. Terfenadine, a potent H 1 -receptor antagonist in the treatment of grass pollen sensitive asthma. Br J Clin Pharmacol 1990;30: Wood-Baker R, Smith R, Holgate ST. A double-blind, placebo controlled study of the effect of the specific histamine H 1 -antagonist, terfenadine, in chronic severe asthma. Br J Clin Pharmacol 1995;39: Bruttman G, Pedraii P, Arendt C, Rihoux JP. Protective effect of cetirizine in patients suffering from pollen asthma. Ann Allergy 1990;64: Dijkman JH, Hekking PRM, Molkenboer JF, et al. Prophylactic treatment of grass pollen-induced asthma with cetirizine. Clin Exp Allergy 1990;20: Grant JA, Nicodemus CF, Findlay SR, et al. Cetirizine in patients with seasonal allergic rhinitis and concomitant asthma: prospective, randomized, placebo-controlled trial. J Allergy Clin Immunol 1995; 95: Corren J, Harris A, Aaronson D, et al. Efficacy and safety of loratadine plus pseudoephedrine in patients with seasonal allergic rhinitis and mild asthma. J Allergy Clin Immunol 1997;100: Spector S, Lee N, McNutt B, et al. Effect of terfenadine in asthmatic patients. Ann Allergy 1992;69: Kaufman J, Wright GW. The effect of nasal and nasopharyngeal irritation on airway resistance in man. Am Rev Respir Dis 1969;100: Kaufman J, Chen JC, Wright GW. The effect of trigeminal resection on reflex bronchoconstriction after nasal and nasopharyngeal irritation in man. Am Rev Respir Dis 1970;101: Fontanari P, Burnet H, Zattara-Harmann MC, Jammes Y. Changes in airway resistance induced by nasal inhalation of cold dry, dry, or moist air in normal individuals. J Appl Physiol 1996;81: Yan K, Salome C. The response of the airways to nasal stimulation in asthmatics with rhinitis. Eur J Respir Dis 1983;64: Hoehne JH, Reed CE. Where is the allergic reaction in ragweed asthma? J Allergy Clin Immunol 1971;48: Schumacher MJ, Cota KA, Taussig LM. Pulmonary response to nasal-challenge testing of atopic subjects with stable asthma. J Allergy Clin Immunol 1986;78: Littell NT, Carlisle CC, Millman RP, Braman SS. Changes in airway resistance following nasal provocation. Am Rev Respir Dis 1990; 141: Small P, Bisken N. The effects of allergen-induced nasal provocation on pulmonary function in patients with perennial allergic rhinitis. Am J Rhinol 1989;3: Corren J, Adinoff AD, Irvin CG. Changes in bronchial responsiveness following nasal provocation with allergen. J Allergy Clin Immunol 1992;89: Mullen WV, Wyder CT. Experimental lesions of lungs produced by the inhalation of fluid from the nose and throat. Am Rev Tuberc 1920;4: McLaurin JG. Chest complications of sinus disease. Ann Otol Rhinol Laryngol 1932;41: Huxley EJ, Viroslav J, Gray WR, Pierce AK. Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am J Med 1978;64: Bardin PG, Van Heerden BB, Joubert JR. Absence of pulmonary aspiration of sinus contents in patients with asthma and sinusitis. J Allergy Clin Immunol 1990;86: Shturman-Ellstein R, Zeballos RJ, Buckley JM, Souhrada JF. The beneficial effect of nasal breathing on exercise-induced bronchoconstriction. Am Rev Respir Dis 1978;118: Griffin MP, McFadden ER, Ingram RH. Airway cooling in asthmatic and nonasthmatic subjects during nasal and oral breathing. J Allergy Clin Immunol 1982;69:354-9.