Pathophysiology of nasal obstruction and meta-analysis of early and late effects of levocetirizine
J. Patou
Department of Otorhinolaryngology, Upper Airways Research Laboratory, Ghent University Hospital, Ghent, Belgium and
Search for more papers by this authorP. Van Cauwenberge
Department of Otorhinolaryngology, Upper Airways Research Laboratory, Ghent University Hospital, Ghent, Belgium and
Search for more papers by this authorC. Bachert
Department of Otorhinolaryngology, Upper Airways Research Laboratory, Ghent University Hospital, Ghent, Belgium and
Search for more papers by this authorJ. Patou
Department of Otorhinolaryngology, Upper Airways Research Laboratory, Ghent University Hospital, Ghent, Belgium and
Search for more papers by this authorP. Van Cauwenberge
Department of Otorhinolaryngology, Upper Airways Research Laboratory, Ghent University Hospital, Ghent, Belgium and
Search for more papers by this authorC. Bachert
Department of Otorhinolaryngology, Upper Airways Research Laboratory, Ghent University Hospital, Ghent, Belgium and
Search for more papers by this authorSummary
Nasal obstruction, also referred to as congestion, blockage or stuffiness, is a crucial symptom in allergic rhinitis (AR) and may affect sleep as well as quality of life. Early- and late-phase-allergic reactions both contribute to nasal obstruction, although it primarily represents a major symptom in the chronic allergic reaction. A complex network of inflammatory and neurogenic phenomena relates to chronic nasal obstruction, including the subepithelial accumulation of inflammatory cells, particularly mast cells and eosinophils, and the release of neuropeptides. Nasal obstruction is a difficult-to-treat symptom. Vasoconstrictors (decongestants) and intranasal corticosteroids, due to their anti-inflammatory properties, have mainly been used for relieving the nasal passages from the congested mucosa. However, there is accumulating evidence recently that the latest-generation potent antihistamines have decongestant properties in AR. This paper aims to review the pathophysiologic background of nasal obstruction and the evidence for an antihistamine, levocetirizine, in relieving nasal congestion. A meta-analysis on the early and late effects of levocetirizine on nasal obstruction under artificial and natural allergen exposure conditions is presented, demonstrating convincingly that levocetirizine shows a consistent effect on nasal obstruction as early as over the first 2 h and sustained over 6 weeks.
References
- 1 Jessen M, Malm L. Definition, prevalence and development of nasal obstruction. Allergy 1997; 52 (Suppl. 40): 3–6.
- 2 Corey JP, Houser SM. Nasal congestion: a review of its etiology, evaluation and treatment. Ear Nose Throat J 2000; 79: 690–702.
- 3 Horak F. Impact and modulation of nasal obstruction. Allergy 2002; 57 (Suppl. 75): 25–8.
- 4 Hilberg O. Objective measurement of nasal airway dimensions using acoustic rhinometry: methodological and clinical aspects. Allergy 2002; 57 (Suppl. 70): 5–39.
- 5 Ottaviano G, Scadding GK, Coles S, Lund VJ. Peak nasal inspiratory flow; normal range in adult population. Rhinology 2006; 44: 32–5.
- 6 Hsu PP, Han HN, Chan YH et al. Quantitative computer-assisted digital-imaging upper airway analysis for obstructive sleep apnoea. Clin Otolaryngol Allied Sci 2004; 29: 522–9.
- 7 Wustenberg EG, Huttenbrink KB, Hauswald B, Hampel U, Schleicher E. Optical Rhinometry. Continuous, direct measurement of swelling of the nasal mucosa with allergen provocation, Real-time monitoring of the nasal provocation test using optical rhinometry. HNO 2004; 52: 798–806.
- 8 Wang DY, Raza T, Gordon BR. Control of nasal obstruction in perrenial allergic rhinitis. Curr Opin Allergy Clin Immunol 2004; 4: 165–70.
- 9 Widdicombe J. Microvascular anatomy of the nose. Allergy 1997; 52 (Suppl. 40): 7–11.
- 10 Eccles R. Nasal airflow in health and disease. Acta Otolaryngol 2000; 120: 560–95.
- 11 Dahl R, Mygind N. Mechanisms of airflow limitation in the nose and lungs. Clin Exp Allergy 1998; 28 (Suppl. 2): 17–25.
- 12 Andersson M, Rimmer J, Salome C, Greiff L, Persson C. Dual symptomatic and exudative nasal responses are not characteristics of perennial allergic rhinitis. Acta Otolaryngol 2001; 121: 407–13.
- 13 Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001; 57 (Suppl. 5): S147–334.
- 14 Wang D, Smitz J, Waterschoot S, Clement P. An approach to the understanding of the nasal early-phase reaction induced by nasal allergen challenge. Allergy 1997; 52: 162–7.
- 15 Terada N, Hamano N, Hohki G, Konno A, Shirotore K, Togawa K. Late phase response in nasal mucosa closely correlated with immediate phase reaction and hyperreactivity to histamine. Acta Otolaryngol 1998; 118: 392–7.
- 16 Haberal I, Corey JP. The role of leukotrienes in nasal allergy. Otolaryngol Head Neck Surg 2003; 129: 274–9.
- 17 Wang D, Clement P, Smitz J, De Waele M, Derde M-P. Correlations between complaints, inflammatory cells and mediator concentrations in nasal secretions after nasal allergen challenge and during natural allergen exposure. Int Arch Allergy Immunol 1995; 106: 278–85.
- 18 Bousquet J, Vignola AM, Campell AM, Michel F-B. Pathophysiology of allergic rhinitis. Int Arch Allergy Immunol 1996; 110: 207–18.
- 19 Hansen I, Klimek L, Mösges R, Hörmann K. Mediators of inflammation in the early and the late phase of allergic rhinitis. Curr Opin Allergy Clin Immunol 2004; 4: 159–63.
- 20 Canonica GW. Introduction to the nasal and pulmonary allergy cascade. Allergy 2002; 57 (Suppl. 75): 8–12.
- 21 Durham SR. The inflammatory nature of allergic disease. Clin Exp Allergy 1998; 28 (Suppl. 6): 20–24.
- 22 Wagenmann M, Baroody FM, Cheng CC et al. Bilateral increases in histamine after unilateral allergen challenge. Am J Respir Crit Care Med 1997; 155: 426–31.
- 23 Okuda M, Watase T, Mezawa A, Liu CM. The role of leukotriene D4 in allergic rhinitis. Ann Allergy 1988; 60: 537–40.
- 24 Rajakulasingam K, Polosa R, Lau LC, Church MK, Holgate ST, Howarth PH. Comparative nasal effects of bradykinin and histamine: influence on nasal airways resistance and plasma protein exudation. Thorax 1993; 48: 324–9.
- 25 Doyle WJ, Boehm S, Skoner DP. Physiologic responses to intranasal dose-response challenges with histamin, metacholine, bradykinin, and prostaglandin in adult volunteers with and without nasal allergy. J Allergy Clin Immunol 1990; 86: 924–35.
- 26 Lane AP, Drake AF, Warren DW. Perceptual and physiologic effects of histamine challenge on nasal breathing. Am J Rhinol 2000; 14: 1–5.
- 27 Walker KB, Serwonska MH, Valone FH et al. Distinctive patterns of release of neuroendocrine peptides after nasal challenge of allergic subjects with ryegrass antigen. J Clin Immunol 1988; 8: 108–13.
- 28 Rasp G, Hochstrasser K. Tryptase in nasal fluid is a useful marker of allergic rhinitis. Allergy 1993; 48: 72–74.
- 29 Juliusson S, Holmberg K, Baumgarten CR, Olsson M, Enander I, Pipkorn U. Tryptase in nasal lavage fluid after local allergen challenge. Relationship to histamine levels and TAME-esterase activity. Allergy 1991; 46: 459–65.
- 30 Di Lorenzo G, Mansueto P, Melluso M et al. Allergic rhinitis to grass pollen: measurement of inflammatory mediators of mast cell and eosinophils in native nasal fluid lavage and in serum out of and during pollen season. J Allergy Clin Immunol 1997; 100 (6 Part 1): 832–7.
- 31 Wagenmann M, Baroody FM, Desrosiers M et al. Unilateral nasal allergen challenge leads to bilateral release of prostaglandin D2. Clin Exp Allergy 1996; 26: 371–8.
- 32 Howarth PH. Leukotrienes in rhinitis. Am J Respir Care Med 2000; 161: 133–6.
- 33 Knani J, Campbell A, Enander I, Peterson CG, Michel FB, Bousquet J. Indirect evidence of nasal inflammation assessed by titration of inflammatory mediators and enumeration of cells in nasal secretions of patients with chronic rhinitis. J Allergy Clin Immunol 1992; 90 (6 Part 1): 880–9.
- 34 Rajakulasingam K, Polosa R, Church MK, Holgate TS, Howarth PH. Kinins and rhinitis. Clin Exp Allergy 1992; 22: 734–40.
- 35 Proud D. The kinin system in rhinitis and asthma. Clin Rev Allergy Immunol 1998; 16: 351–64.
- 36 Baraniuk JN, Silver PB, Kaliner MA, Barves PJ. Perennial rhinitis subjects have altered vascular, glandular and neural responses to bradykinin nasal provocation. Int Arch Allergy Immunol 1994; 103: 202–8.
- 37
Austin CE,
Foreman JC.
A study of the action of bradykinin and bradykinin analogues in the human nasal airway.
J Physiol
1994; 15: 351–6.
10.1113/jphysiol.1994.sp020255 Google Scholar
- 38 Henriksen AH, Sue-Chu M, Lingaas Holmen T, Langhammer A, Bjermer L. Exhaled and nasal NO levels in allergic rhinitis: relation to sensitisation, pollen season and bronchial hyperresponsiveness. Eur Respir J 1999; 13: 301–6.
- 39 Kharitonov S, Rajakulasingam K, O'Connor B, Durham S, Barnes P. Nasal nitric oxide is increased in patients with asthma and allergic rhinitis and may be modulated by nasal glucocorticoids. J Allergy Clin Immunol 1997; 99: 58–64.
- 40 Arnal JF, Didier A, Rami J et al. Nasal nitric oxide is increased in allergic rhinitis. Clin Exp Allergy 1997; 27: 358–62.
- 41 Miadonna A, Tedeschi A, Leggieri E et al. Behavior and clinical relevance of histamine and leukotrienes C4 and B4 in grass pollen-induced rhinitis. Am Rev Respir Dis 1987; 136: 357–62.
- 42 Howarth PH, Salagean M, Dokic D. Allergic rhinitis: not purely a histamine-related disease. Allergy 2000; 55: 7–16.
- 43 Shaw RJ, Fitzharris P, Cromwell O, Wardlaw AJ, Kay AB. Allergen-induced release of sulphidopeptide leukotrienes (SRS-A) and LTB4 in allergic rhinitis. Allergy 1985; 40: 1–6.
- 44 Bisgaard H, Olsson P, Bende M. Effect of leukotriene D4 on nasal mucosal blood flow and nasal airway resistance and nasal secretion in humans. Clin Exp Allergy 1986; 16: 289–97.
- 45 Mosimann BL, White MV, Hohman RJ, Goldrich MS, Kaulbach HC, Kaliner MA. Substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide increase in nasal secretions after allergen challenge in atopic patients. J Allergy Clin Immunol 1993; 92: 95–104.
- 46 Devillier P, Dessanges JF, Rakotosihanaka F et al. Nasal response to substance P and methacholine in subjects with and without allergic rhinitis. Eur Respir J 1988; 1: 356–61.
- 47 Braunstein G, Fajac I, Lacronique J, Frossard N. Clinical and inflammatory responses to exogenous tachykinins in allergic rhinitis. Am Rev Respir Dis 1991; 144: 630–5.
- 48 Konno A, Numata T, Terada N, Hanazawa T, Nagata H, Motosugi H. Role of substance P in the vascular response of nasal mucosa in nasal allergy. Ann Otol Rhinol Laryngol 1996; 105: 648–53.
- 49 Fang S, Shen C, Ohyama M. Distribution and quality of neuroendocrine markers in allergic rhinitis. Acta Otolaryngol 1998; 118: 398–403.
- 50 Rangi SP, Sample S, Serwonska MH, Lenahan GA, Goetzl EJ. Mediation of prolonged increases in nasal mucosal blood flow by calcitonin gene-related peptide (CGRP). J Clin Immunol 1990; 10: 304–10.
- 51 Bachert C. Histamine – a major role in allergy? Clin Exp Allergy 1998; 28 (Suppl 6): 15–9.
- 52 Horak F, Stubner UP, Zieglmayer R, Harris AG. Effect of desloratadine versus placebo on nasal airflow and subjective measures of nasal obstruction in subjects with grass pollen-induced allergic rhinitis in an allergen-exposure unit. J Allergy Clin Immunol 2002; 109: 956–61.
- 53 Kirkegaard J, Secher C, Borum P, Mygind N. Inhibition of histamine-induced nasal symptoms by the H1 antihistamine chlorpheniramine maleate: demonstration of topical effect. Br J Dis Chest 1983; 77: 113–22.
- 54 Hilberg O, Grymer LF, Pedersen OF. Nasal histamine challenge in nonallergic and allergic subjects evaluated by acoustic rhinometry. Allergy 1995; 50: 166–73.
- 55 Mygind N, Secher C, Kirkegaard J. Role of histamine and antihistamines in the nose. Eur J Respir Dis 1983; 128 (Suppl.): 16–20.
- 56 Wood-Baker R, Lau L, Howarth PH. Histamine and the nasal vasculature: the influence of H1 and H2-histamine receptor antagonism. Clin Otolaryngol Allied Sci 1996; 21: 348–52.
- 57 Taylor-Clark T, Sodha R, Warner B, Foreman J. Histamine receptors that influence blockage of the normal human nasal airway. Br J Pharmacol 2005; 144: 867–74.
- 58 Varty LM, Gustafson E, Laverty M, Hey JA. Activation of histamine H3 receptors in human nasal mucosa inhibits sympathetic vasoconstriction. Eur J Pharmacol 2004; 484: 83–9.
- 59 Shahab Riad, Phillips DE, Jones AS. Prostaglandins, leukotrienes and perennial rhinitis. J Laryngol Otol 2004; 118: 500–7.
- 60 Togias A. Unique mechanistic features of allergic rhinitis. J Allergy Clin Immunol 2000; 105: S599–604.
- 61 Turner P, Dear J, Scadding G, Foreman JC. Role of kinins in seasonal allergic rhinitis: icatibant, a bradykinin B2 receptor antagonist, abolishes the hyperresponsiveness and nasal eosinophilia induced by antigen. J Allergy Clin Immunol 2001; 107: 105–13.
- 62 Conboy PJ, Jones NS. The nose and nitric oxide: a review. Clin Otolaryngol 2000; 25: 337–41.
- 63 Kawamoto H, Takumida M, Takeno S, Watanabe H, Fukushima N, Yajin K. Localisation of nitric oxide synthase in human nasal mucosa with nasal allergy. Acta Otolaryngol 1998; 539: 65–70.
- 64 Lane A, Prazma J, Baggett H, Rose A, Pillsbury H. Nitric oxide is a mediator of neurogenic vascular exudation in the nose. Otolaryngol Head Neck Surg 1997; 116: 294–300.
- 65 Maniscalco M, Sofia M, Carratu L, Higenbotam T. Effect of nitric oxide inhibition on nasal airway resistance after nasal allergen challenge in allergic rhinitis. Eur J Clin Invest 2001; 31: 462–6.
- 66 Silkoff P, Cole P, Roth Y, Chapnik J, Mcclean P, Zamel N. Nasal nitric oxide does not control basal nasal patency or acute congestion following allergen challenge in allergic rhinitis. Ann Otol Rhinol Laryngol 1999; 108: 368–72.
- 67 Pastorello E, Galeazzo G, Incorvaia C, Segala M, Fumagalli M, Gandini R. Comparison of rhinomanometry, symptom score, and inflammatory cell counts in assessing the nasal late-phase reaction to allergen challenge. J Allergy Clin Immunol 1994; 93: 85–92.
- 68 Ciprandi G, Cirillo I, Vizzaccaro A, Milanese M, Tosca MA. Nasal obstruction in patients with seasonal allergic rhinitis: relationships between allergic inflammation and nasal airflow. Int Arch Allergy Immunol 2004; 134: 34–40.
- 69 Ciprandi G, Cirillo I, Vizzaccaro A, Milanese M, Tosca MA. Airway function and nasal inflammation in seasonal allergic rhinitis and asthma. Clin Exp Allergy 2004; 34: 891–6.
- 70 Howarth PH. Mediators of nasal blockage in allergic rhinitis. Allergy 1997; 52 (Suppl. 40): 12–8.
- 71 Higashi N, Taniguchi M, Mita H, Ishii T, Akiyama K. Nasal blockage and urinary leukotriene E4 concentration in patients with seasonal allergic rhinitis. Allergy 2003; 58: 476–80.
- 72 Naclerio R. Clinical manifestations of the release of histamine and other inflammatory mediators. J Allergy Clin Immunol 1999; 103: S382–5.
- 73 Fajac I, Frossard N. Neuropeptides of the nasal innervation and allergic rhinitis. Rev Mal Respir 1994; 11: 357–67.
- 74 Baraniuk JN, Kaliner MA. Neuropeptides and nasal secretion. J Allergy Clin Immunol 1990; 86: 620–7.
- 75 Fajac I, Braunstein G, Ickovic MR, Lacronique J, Frossard N. Selective recruitment of eosinophils by substance P after repeated allergen exposure in allergic rhinitis. Allergy 1995; 50: 970–5.
- 76 Riederer A, Knipping S, Fischer A, Unger J. Current immunohistochemical results of localization of vasoactive intestinal polypeptide (VIP) in nasal mucosa of the human. Laryngo-rhino-otologie 1995; 74: 611–4.
- 77 Aoki Y, Qiu D, Zhao GH, Kao PN. Leukotriene B4 mediates histamine induction of NF-kappaB and IL-8 in human bronchial epithelial cells. Am J Physiol 1998; 274 (6 Part 1): L1030–9.
- 78 Bakker RA, Schoonus SB, Smit MJ, Timmerman H, Leurs R. Histamine H(1)-receptor activation of nuclear factor-kappa B: roles for G beta gamma- and G alpha(q/11)-subunits in constitutive and agonist-mediated signaling. Mol Pharmacol 2001; 60: 1133–42.
- 79 Ying S, Meng Q. The effect of levocetirizine on histamine and cytokine-induced up-regulation of eotaxin by endothelial cells. Allergy 2002; 57 (Suppl. 73): 146.
- 80 Giustizieri ML, Albanesi C, Fluhr J, Gisondi P, Norgauer J, Girolomoni G. H1 histamine receptor mediates inflammatory responses in human keratinocytes. J Allergy Clin Immunol 2004; 114: 1176–82.
- 81 Michel L, Jean-Louis F, Boland S, Pellet C, Dubertret L. Inhibition by levocetirizine of VCAM-1 production in human dermal endothelial cells in vitro. Allergy 2003; 58 (Suppl. 74): 305.
- 82 Jazrawi E, Stirling R, Chung KF. Effect of Ievocetirizine on eotaxin-induced eosinophil chemotaxis with and without interleukin-5 priming in vitro. Allergy 2001; 56 (Suppl. 68): 138.
- 83 Thomson L, Blaylock MG, Sexton DW, Campbell A, Walsh GM. Cetirizine and levocetirizine inhibit eotaxin-induced eosinophil transendothelial migration through human dermal or lung microvascular endothelial cells. Clin Exp Allergy 2002; 32: 1187–92.
- 84 Gutzmer R, Wittmann M, Kapp A, Werfel T. Direct immunomodulatory effects of levocetirizine on lymphocytes. Allergy 2003; 58 (Suppl. 74): 305.
- 85 Michel L, Jean-Louis F, Dubertret L. Pharmacological study of levocetirizine in lgE-dependent hypersensitivity cutaneous reaction in grass pollen allergic volunteers: demonstration of mediator release and eosinophil recruitment modulation by levocetirizine. Allergy 2001; 56 (Suppl. 68): 150–1.
- 86 Ciprandi G, Cirillo I, Vizzaccaro A, Tosca MA. Levocetirizine improves nasal obstruction and modulates cytokine pattern in patients with seasonal allergic rhinitis: a pilot study. Clin Exp Allergy 2004; 34: 958–64.
- 87 Ciprandi G, Cirillo I, Vizzaccaro A et al. Desloratadine and levocetirizine improve nasal symptoms, airflow, and allergic inflammation in patients with perennial allergic rhinitis: a pilot study. Int Immunopharmacol 2005; 5: 1800–8.
- 88 Reichmuth D. Allergic rhinitis. Drugs Today (Barcelona) 2001; 37: 283–309.
- 89 Ciprandi G, Cirillo I-G, Vizzaccaro A, Tosca M-A. Levocetirizine improves nasal symptoms and airflow in patients with perennial allergic rhinitis: a pilot study. Eur Ann Allergy Clin Immunol 2005; 37: 25–29.
- 90 Azzolina A, Bongiovanni A, Lampiasi N. Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cells. Biochim Biophys Acta 2003; 1643: 75–83.
- 91 Stübner P, Zieglmayer R, Horak F. A direct comparison of the efficacy of antihistamines in SAR and PAR: randomised, placebo-controlled studies with levocetirizine and loratadine using an environmental exposure unit–the Vienna Challenge Chamber (VCC). Curr Med Res Opin 2004; 20: 891–902.
- 92 Day JH, Briscoe MP, Rafeiro E, Ratz JD. Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental Exposure Unit (EEU). Int J Clin Pract 2004; 58: 109–18.
- 93 Horak F, Zieglmayer PU, Zieglmayer R, Kavina A, Lemell P. Levocetirizine has a longer duration of action on improving total nasal symptoms score than fexofenadine after single administration. Br J Clin Pharmacol 2005; 60: 24–31.
- 94 Potter PC. Levocetirizine is effective for symptom relief including nasal congestion in adolescent and adult (PAR) sensitized to house dust mites. Allergy 2003; 58: 893–9.
- 95 Bachert C, Bousquet J, Canonica GW et al. Levocetirizine improves quality of life and reduces costs in long-term management of persistent allergic rhinitis. J Allergy Clin Immunol 2004; 114: 838–44.
- 96 Horak F, Stubner P, Zieglmayer R et al. Controlled comparison of the efficacy and safety of cetirizine 10 mg o.d. and fexofenadine 120 mg o.d. in reducing symptoms of seasonal allergic rhinitis. Int Arch Allergy Immunol 2001; 125: 73–79.
- 97 Day JH, Briscoe MP, Rafeiro E, Ratz JD. Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental Exposure Unit (EEU). Int J Clin Pract 2004; 58: 109–18.
- 98 Hore I, Georgalas C, Scadding G. Oral antihistamines for the symptom of nasal obstruction in persistent allergic rhinitis–a systematic review of randomized controlled trials. Clin Exp Allergy 2005; 35: 207–12.