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The role of allergy in chronic rhinosinusitis
Immunol Allergy Clin N Am 24 (2004) 45 – 57
The role of allergy in chronic rhinosinusitis John W. Steinke, PhD*, Larry Borish, MD Asthma and Allergic Disease Center, Beirne Carter Center for Immunology Research, University of Virginia Health System, Box 801355, Charlottesville, VA 22908 – 1355, USA
Historically, sinusitis has been divided into three categories (acute, subacute, and chronic sinusitis) based on disease duration. Patients with chronic sinusitis have symptoms for more than 6 weeks. At the time this terminology was developed, all sinusitis cases were believed to be infectious, and this idea led to the prominent use of antibiotics and surgical drainage as treatment. It now is clear, however, that most patients with chronic sinusitis do not have an infectious disorder [1,2]. This finding has led to the need to develop more appropriate terminology to describe the myriad of conditions that make up chronic sinusitis. Four major pathophysiologic processes are responsible for chronic sinusitis. A small subset of patients has chronic infectious sinusitis. This subset typically involves patients with underlying humoral immune deficiencies, HIV infection, Kartagener syndrome, and cystic fibrosis. Most patients with chronic sinusitis have an inflammatory disorder with prominent hyperplasia of immune cells. Chronic inflammatory sinusitis is believed to result from chronic or recurrent occlusion of the sinus ostia secondary to viral rhinitis, allergic rhinitis (AR), anatomic predisposition, or other causes. These processes lead to recurrent acute bacterial infections, possibly in association with barotrauma of the sinus cavities and damage to the respiratory epithelium, ciliary destruction, mucous gland and goblet cell hyperplasia, bacterial colonization, and ultimately chronic inflammatory changes. The inflammatory component of this form of sinusitis consists of a mononuclear cell infiltrate and may produce nasal polyps. Eosinophils are not a feature of chronic inflammatory sinusitis. When caused by anatomic occlusion, chronic inflammatory sinusitis is generally responsive to surgical interventions [3,4]. Because it is defined by the prominent expression of eosinophils and to distinguish it from chronic inflammatory sinusitis, the other idiopathic immune
* Corresponding author. E-mail address: [email protected] (J.W. Steinke). 0889-8561/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0889-8561(03)00108-5
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inflammatory disease is referred to as chronic hyperplastic eosinophilic sinusitis (CHES). This disease frequently is associated with nasal polyposis (NP), asthma, allergic (IgE) sensitization to aeroallergens (atopy), and aspirin sensitivity. Patients with CHES often are referred to allergists. In contrast to chronic inflammatory sinusitis, CHES does not respond well to surgery [3]. The role of AR in CHES is the primary focus of this article. The final condition associated with chronic sinusitis is allergic fungal sinusitis (AFS). This condition presumably represents a severe variant of CHES that is associated with the colonization of fungi within the sinus cavities and the presence of an IgE-like and T helper cell type 2 (TH2)-like lymphocyte – mediated allergic inflammatory response. Immune and allergic mechanisms of AFS are discussed by Davis and Kita elsewhere in this issue.
Immune mechanisms of chronic hyperplastic eosinophilic sinusitis CHES with or without NP is an inflammatory disease that is characterized by the accumulation of eosinophils, fibroblasts, mast cells, goblet cells, and TH2-like lymphocytes [5,6]. The prominent accumulation of eosinophils is the diagnostic feature of this condition [5,7,8,64]. This diagnosis can only be established unambiguously on pathologic examination of tissue taken from the disease site. The sinus tissue demonstrates a marked increase in cells—including lymphocytes, fibroblasts, and eosinophils—that express mRNA transcripts and protein for cytokines responsible for eosinophil differentiation (interleukin [IL]-5), survival (IL-3, IL-5, granulocyte-macrophage colony-stimulating factor [GMCSF]), recruitment (CCL11 [eotaxin]) and activation (CCL11, CCL5 [RANTES], IL-3, IL-5, GM-CSF, tumor necrosis factor a [TNF-a]) [9 – 14]. Cysteinyl leukotrienes (CysLTs) are expressed prominently in CHES tissue and contribute to the eosinophilic inflammation [15]. The finding that eosinophils are a prominent source of these cytokines and CysLTs suggests that CHES –NP is a disease of unregulated inflammation in which eosinophils, once recruited, provide the growth factors that are necessary for their further differentiation, recruitment, proliferation, activation, and survival. Eosinophil and basophil progenitors or colony-forming units (Eo/B CFU) are bone marrow-derived mononuclear cells that express CD34, CD35, and IL-5 receptors that are capable of responding to appropriate cytokine signals to differentiate into mature basophils and eosinophils [16]. Eo/B CFU are increased in numbers in the blood and bone marrow of atopic patients, and further increases in their number are observed after allergen exposure [16]. These progenitors also are observed in nasal polyp tissue [17]. This situation provides a localized pool of cells that, given the proper signals (eg, IL-5, GM-CSF), can mature and provide a source for the eosinophils (and basophils) that characterize this condition. Patients with CHES become colonized with numerous bacteria and often experience recurrent bacterial infections superimposed on their chronically diseased mucosa. When sinus cultures are performed well using appropriate sterilization, sinus puncture, and quantification, these studies have demonstrated polymicrobial organisms and nonvirulent organisms
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present at low titer [1,2]. In combination with the prominent absence of neutrophils [8] and the failure to respond to multiple courses of broad-spectrum antibiotics, these observations support the increasing recognition that CHES is not an infectious disease. Although not likely to represent a cause of CHES, as discussed by Bachert in another article in this issue, bacteria may be relevant to the pathophysiology of CHES through their ability to provide antigens and immune adjuvants, such as endotoxin and superantigens, that may contribute to the severity of this condition [18,19]. In addition to this putative role for bacterial colonization and fungal sensitization (as discussed by Davis and Kita in another article in this issue), a unique form of CHES is driven by the overproduction and overresponsiveness to CysLTs that is characteristic of the aspirin-intolerant asthma sinusitis triad [20 – 22]. This article focuses on the role of allergy in the pathophysiology of CHES.
Epidemiology of allergy in chronic sinusitis Up to 53% of individuals with AR have sinusitis [23], and similarly, 25% to 58% of individuals with sinusitis have AR [7,24]. Sensitivity to multiple allergens and to perennial allergens, such as dust mites, increase the risk for CHES [25]. More than 50% of individuals with perennial AR have abnormal sinus radiographs [23,26]. Similarly, elevated levels of serum total IgE is a risk factor for the presence of severe chronic sinusitis [27]. These studies support the concept that chronic sinusitis is an atopic disease that strongly is associated with the presence of IgE sensitization to aeroallergens. The mechanisms by which aeroallergens might produce CHES are not inherently obvious.
Mechanisms linking allergic rhinitis to chronic sinusitis Direct aeroallergen reaction Aeroallergens gain access to the nares (and lungs) by being drawn into the respiratory tract through the process of inspiration. Inspiration directly cannot drive aeroallergens into the sinus cavities. This act can be accomplished only by way of diffusion, a process dependent on the particles remaining airborne for a sufficient period of time, something unlikely to happen given their size. Nor are particles likely to be carried into the sinuses on the mucociliary blanket insofar as mucociliary flow, when functioning, is in the opposite direction and CHES is a disease characterized by atrophic and damaged epithelium and ciliary destruction [28]. Insofar as CHES and AR generally are associated with occlusion of the ostiomeatal complex, this occlusion precludes entry of aeroallergens into the sinus cavities. Studies described later in this article that were performed with insufflated, radiolabeled ragweed particles have confirmed the inability of these particles to enter the sinuses [29,30].
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Infection Acute bacterial sinusitis occurs as a complication of AR, presumably secondary to occlusion of the sinus ostia and stagnation within the sinus cavities [24]. Insofar as the chronic sinusitis that complicates AR is rarely an infectious disease, the development of CHES cannot be ascribed to occlusion of the ostiomeatal complex (OMC). Chronic or recurrent occlusion of the sinus ostia may be responsible for the development of chronic inflammatory sinusitis, but this mechanism cannot explain the development of an eosinophilic inflammatory process within the sinuses.
Neurologic reflex A nasal – sinus neurologic reflex mediated by the cholinergic pathway is supported by some data but is unlikely to explain what is predominantly an inflammatory disease characterized by activated eosinophils and TH2-like lymphocytes. A neurologic reflex does not explain the data described later in this article regarding the ability of ipsilateral allergen exposure in one nares to produce or exacerbate inflammation within the contralateral maxillary sinus [31].
Systemic allergic mechanisms The link between AR and sinusitis is ascribed best to a systemic inflammatory process similar to that which develops between AR and asthma (discussed by Denburg and Keith in another article in this issue). Nasal allergen challenges in sensitive individuals produce radiographic changes of the maxillary sinuses, including edema and opacification [32]. Nasal allergen challenges in allergic individuals produce significant increases in levels of eosinophils, eosinophil cationic protein, histamine, and albumin in the nose and maxillary sinus [33]. Similarly, insufflation of ragweed particles into the nares and the naturally occurring exposure to allergen during the ragweed season produce sinus hyperemia and increased metabolic activity [29,30]. In one study, sinus lavage specimens from both maxillary sinuses were collected and analyzed after a nasal allergen challenge that was performed in only one side of the nose. Albumin levels and eosinophil counts were increased significantly in these specimens with no significant differences detected in specimens obtained from the ipsilateral and contralateral maxillary sinuses [31]. The development of disease in both sinuses precludes a neurally mediated mechanism but is consistent with a systemic response. In sensitized subjects, allergen exposure activates immune cells, including T helper cell lymphocytes, dendritic cells, mononuclear cells, mast cells, and other immune cells within the nares and in nasal-associated lymphatic tissues. Allergenic peptides loaded on dendritic cells readily migrate to nasal-associated lymphatic tissue. T helper cell lymphocytes, presumably having the TH2-like phenotype, also can migrate from the nasal airway to nasal lymphatic tissue and
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the bone marrow, as has been described for the migration of T lymphocytes from the asthmatic airway to the bone marrow in murine asthma models. Cells newly activated in the nasal airway by allergen may include locally produced eosinophil precursors [34]. The cytokines associated with allergic inflammation do not function hormonally. TH2-associated cytokines, such as IL-4, IL-5, and IL-13, cannot be identified in serum samples and are unlikely to access the bone marrow at a concentration that are sufficient enough to drive hematopoietic differentiation. TH2-like cells, including cells newly differentiated from naı¨ve cells in nasal lymphatic tissue or reactivated memory cells present within the nasal tissue, migrate to the bone marrow. The ability of activated cytokine-expressing cells to circulate provides cytokines with the ability to function at a distance [35]. Once delivered to the bone marrow, these TH2-like cells stimulate the production of inflammatory cells, including basophils, eosinophils, and mast cell precursors [16,36,37]. These newly generated inflammatory cells enter the circulatory system and infiltrate susceptible tissues such as sinuses (or lungs) [16], exacerbating sinusitis (and asthma) [37]. Selective recruitment of the inflammatory cells into the sinuses (and lungs) occurs only in the presence of preexisting disease, whereby these tissues are induced to express appropriate homing (adhesion) molecules, such as vascular cell adhesion molecule 1, and chemoattractants, such as CCL11 (eotaxin) and CysLTs. All of these factors have been found in tissue of patients with CHS –NP [5,13,15,38]. Presumably, the direct recirculation of these allergic inflammatory cells occurs between the nares, local lymphatic tissue, and sinuses. Subjects without preexisting sinusitis (or nonasthmatics) do not have these addressins and chemotaxins in their airways and do not have the machinery necessary to recruit inflammatory cells into their sinuses (or lungs) during exacerbations of rhinitis (Fig. 1). Although this systemic model of the role for allergen-mediated exacerbation of CHES has not been studied extensively for sinusitis, this model is supported by studies evaluating the linkage between AR and asthma. In individuals with seasonal AR (SAR), nasal allergen provocation (performed in a fashion demonstrated not to give the allergen access to the lungs) produces inflammatory changes in the upper and lower airways, including increased adhesion-molecule expression, eosinophil infiltration, and bronchial hyperreactivity [39,40]. The immune mechanisms that mediate this systemic response to allergen are discussed by Denburg and Keith elsewhere in this issue. Experimental infections with rhinovirus in atopic individuals increased granulocyte colony-stimulating factor (G-CSF) expression in the nose and sputum and increased neutrophil concentrations in nasal secretions, sputum, bronchial lavage specimens, and blood [41,42]. As with the allergen challenge model, rhinovirus does not access the lower airway, so a direct mechanism of action cannot be ascribed. The implication of this study was that rhinovirus induction of G-CSF (and other colonystimulating factors) in the nares led to increased bone marrow production of neutrophils. Newly synthesized neutrophils egressed from the marrow and migrated back to the nares, but because of the previously induced expression of intercellular adhesion molecule 1 and other adhesion molecules in the
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asthmatic lung and local production of appropriate chemoattractants, these cells also migrated into the lower airway. Increased systemic inflammation occurs as a complication of allergen-induced and nonallergic causes of rhinitis and may contribute to the exacerbations of asthma frequently seen in individuals with these underlying conditions. A similar mechanism could drive the recruitment of inflammatory cells from the circulation into the sinuses of subjects whose sinuses have the appropriate adhesion molecules and chemokines after a nasal allergen challenge or natural exposure to allergen.
Therapeutic implications A huge problem confounding the evaluation of the clinical interventions of AR as putative therapeutic modalities for CHES has been the absence of validated criteria to assess the presence and severity of sinusitis. Traditionally, studies have used clinical criteria to evaluate the sinuses, including presence of such symptoms as purulent nasal drainage, nasal congestion, frontal headaches, and cough. None of these criteria is specific for the sinuses, but they largely reflect the presence of nasal disease (purulent drainage) or lower respiratory tract disease (cough). Even the relevance of frontal headaches to sinus disease is unclear, as the sinuses do not seem to have pain sensory nerves. Clinical studies that have compared sinusitis symptom scores with CT scans show that clinical scores are often little better than random in predicting the presence and severity of sinusitis [27,43 –46]. The absence of validated objective criteria for assessing the presence of CHES or responsiveness to therapeutic interventions has rendered most sinusitis studies meaningless. Systemic corticosteroids (CCSs) arguably would benefit CHES through their ability to directly attenuate eosinophilia and other components of the inflammation of this disorder. In contrast to systemic CCSs, as previously described for aeroallergens, it is unlikely that intranasal CCSs directly can access the sinus cavities. Although various maneuvers have been proposed to promote the drainage of nasal CCSs into the sinuses, the likely presence of occlusion of the OMC precludes their direct access, although this effect may be achieved partially in subjects who have undergone functional endoscopic sinus surgery. The more interesting question, which relevant to the concepts raised in this article, is whether topical intranasal CCSs can, through indirect means, mitigate the inflammatory component of CHES. The ability of intranasal CCSs to locally reduce cytokine production (including IL-4, IL-5, GM-CSF, TNF-a) in the nares, inhibit the function of T helper cell lymphocyte, and inhibit activation of eosinophils and eosinophil precursors in the nares supports the concept that these agents should provide systemic anti-inflammatory efficacy [47,48]. Such a model is consistent
Fig. 1. Overview of mechanism by which allergen immune activation can induce inflammation in sinus tissue. R, receptor; VCAM-1, vascular adhesion molecule 1; VLA-4, very late antigen 4.
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with data that intranasal CCSs can, without accessing the lower airway, mitigate seasonal or allergen-induced worsening of bronchial hyperreactivity [49,50]. Intranasal CCSs can reduce nasal polyps; this effect presumably reflects, in part, the ability of intranasal CCSs to directly access the polyp tissue. Intranasal CCSs have been investigated as an adjuvant therapy for acute infectious sinusitis, a condition in which they are likely to promote drainage. The role of intranasal CCSs in CHES has not been addressed adequately in a properly performed controlled clinical trial with appropriate outcome criteria (ie, criteria not involving symptom scores). Leukotriene modifiers CysLTs have important pro-inflammatory capabilities, the most important of which is their ability to promote eosinophilic inflammation in the airways and nasal mucosa. Other activities include increasing airway smooth muscle hyperreactivity, increasing vascular permeability, stimulating mucous secretion, inducing chemotaxis, and decreasing mucociliary clearance [15]. Leukotriene D4 (LTD4) can synergize with IL-5 in the bone marrow or GM-CSF in the peripheral blood to promote eosinophilopoiesis and to promote differentiation of Eo/B CFU [51]. This effect is blocked partially by the addition of montelukast, a CysLT1 receptor antagonist [51]. Clinical trials of leukotriene modifiers in asthma and SAR have shown reductions in circulating absolute eosinophil counts [52]. The authors demonstrated an increased presence of CysLTs in polyp tissue from patients with CHES, as compared with tissue from patients with chronic inflammatory sinusitis or healthy sinus tissue [15]. In addition to increased levels of CysLTs, patients with CHES had an increase in the mRNA transcripts for the proteins involved in the metabolic pathway of leukotriene synthesis. Increased CysLT expression was correlated with increased circulating eosinophils. Leukotriene modifiers reduce tissue eosinophilia in asthma [53] and are likely to provide benefit in CHES through direct reduction of eosinophil recruitment and activation in the sinuses and through their ability to indirectly block the systemic humoral pathway connecting AR with systemic allergic disease in the sinuses (and lungs). CysLT1 receptor antagonists (zafirlukast, montelukast) have been suggested to have efficacy in CHES– NP in uncontrolled trials [54]. In the only placebo-controlled trial of a leukotriene modifier in CHES, the 5-lipoxygenase inhibitor zileuton was shown to reduce polyp size and restore sense of smell [55]. Allergen avoidance and immunotherapy Allergen avoidance and immunotherapy have never been studied as therapeutic modalities for the treatment of the allergic component of CHES. To the extent that CHES may develop through systemic activation of TH2-like lymphocytes and eosinophils by way of the mechanisms outlined in this article, allergen avoidance could be a useful intervention. Immunotherapy induces tolerance in allergen-
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specific T helper cell lymphocytes, and this effect is associated with their reduced production of cytokines, including IL-4, IL-5, IL-13, and interferon g [56]. Immunotherapy also may act to induce the differentiation of IL-10 – producing allergen-specific T-cell regulatory lymphocytes [57,58]. These functions of immunotherapy should reduce the systemic pro-inflammatory effects of AR and reduce the secondary recruitment of eosinophils, basophils and other inflammatory cells into the sinuses. No study of immunotherapy or allergen avoidance has ever been performed using proper outcome parameters, so the presumptive beneficial effects of these methods remain hypothetical. The best argument is to use allergen avoidance and immunotherapy only in subjects whose allergic rhinitis warrants the use of these interventions and to hope for a gratuitous beneficial influence on CHES. New biotechnology approaches Given the pathophysiologic similarities between CHES and asthma and the likelihood that these conditions are similar or perhaps identical disease processes affecting the upper and lower airways, respectively, it seems likely that new biotechnology-derived therapies that are designed to treat severe asthma are likely to produce similar benefits for CHES. Clinical experience with humanized anti-IgE (omalizumab) in asthma suggests that such treatment lessens allergeninduced IgE-mediated activation of mast cells and basophils and attenuates acute allergic reactions [59]. Through these mechanisms, humanized anti-IgE greatly attenuates the frequency and severity of asthma exacerbations; however, anti-IgE seems to have less efficacy in improving day-to-day asthma symptoms, suggesting that it may not be reducing airway inflammation independent of acute allergic reactions. These observations suggest that analogous to asthma humanized anti-IgE may not ameliorate CHES, although it may reduce the severity of acute CHES exacerbations in patients with AR that is associated with allergic exposures or arguably secondary to upper respiratory viral infections. Another treatment intervention showing some promise in asthma is the neutralization of TNF with soluble TNF receptor (etanercept) or humanized anti-TNF (infliximab). TNF is an important component of asthmatic inflammation [60] and CHES [10]. As a major cytokine of the innate immune system, TNF is likely to be critically important in initiating immune responses to allergens and promoting the recruitment and activation of inflammatory cells in the airways. In a preliminary uncontrolled study, etanercept was shown to markedly improve lung function and, more importantly, to dramatically reduce bronchial hyperreactivity, suggestive of an anti-inflammatory influence. These treatments are intriguing candidates as therapeutic interventions in CHES [61]. Insofar as CHES is defined by the accumulation of activated eosinophils, it seems likely that interventions designed to attenuate eosinophilic inflammation will be beneficial in this disorder. The experience with humanized anti-IL-5 (mepolizumab) in asthma supports the ability of this intervention to greatly attenuate the bone marrow eosinophilopoietic response associated with asthma
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[62]. This treatment also should work to reduce the systemic response to AR and the secondary recruitment of eosinophils into the sinuses of patients with AR and CHES. As a single intervention, however, this medication was unable to sufficiently reduce tissue eosinophilia to produce a therapeutic benefit in asthma. This finding was believed to reflect the complementary role of other cytokines, including GM-CSF, in promoting the activation and differentiation of eosinophilic precursors [51]. This failure also may have reflected roles for constitutive (IL-5 – independent) eosinophilopoiesis and the need to attenuate expression of eosinophil-specific chemokines (eg, inhibition of CCL11 [eotaxin] using chemokine receptor CCR3 antagonists) or eosinophil-specific adhesion molecules (eg, through the use of very late antigen 4 antagonists) [63]. No single agent is likely to be effective for CHES, and, as suggested by the mepolizumab studies, it will be necessary to synergistically block the systemic bone marrow component of CHES and local factors that are critical for inflammatory cell recruitment. The common association of CHES with allergy and the concept that AR may produce a systemic process perpetuating the inflammation of this disorder provide useful insights into the pathophysiology of CHES and provide important leads into the development of potential therapies.
Summary CHES is characterized by unregulated proliferation of eosinophils, TH2-like lymphocytes, fibroblasts, goblet cells, and mast cells. In more than 50% of subjects, it is found in association with the allergic rhinitis. The instillation of allergens onto the nasal mucosa is associated with worsening inflammation within the sinuses and an influx with eosinophils. In this article, the authors argue that the activation of TH2-like lymphocytes in the allergic nares leads to the differentiation and activation of immune cells, including eosinophils and basophils, from precursors present in the nasal tissue and bone marrow. In subjects with preexisting CHES, the presence of specific adhesion and chemotactic molecules in the sinuses promotes the recruitment of these newly generated cells from the circulation.
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J.W. Steinke, L. Borish / Immunol Allergy Clin N Am 24 (2004) 45–57 ship of computed tomographic findings to allergy, asthma, and eosinophilia. JAMA 1994;271: 363 – 7. Al-Rawi MM, Edelstein DR, Erlandson RA. Changes in nasal epithelium in patients with severe chronic sinusitis: a clinicopathologic and electron microscopic study. Laryngoscope 1998;108: 1816 – 23. Slavin RG, Zilliox AP, Samuels LD. Is there such an entity as allergic sinusitis? J Allergy Clin Immunol 1988;81:284A. Borts MR, Slavin RG. Further studies in allergic sinusitis using SPECT. J Allergy Clin Immunol 1989;83:302A. Baroody FM, Saengpanich S, deTineo M, Haney L, Votypka V, Naclerio RM. Nasal allergen challenge leads to bilateral maxillary sinus eosinophil influx. J Allergy Clin Immunol 2002; 109:S84. Pelikan Z, Pelikan-Filipek M. Role of nasal allergy in chronic maxillary sinusitis—diagnostic value of nasal challenge with allergens. J Allergy Clin Immunol 1990;86:484 – 91. Baroody FM, deTineo M, Haney L, Clark K, Blair C, Naclerio RM. Influx of eosinophils into the maxillary sinus after nasal challenge with allergen. J Allergy Clin Immunol 2000;105:S70. Linden M, Svensson C, Andersson M, Greiff L, Andersson E, Denburg JA, et al. Circulating eosinophil/basophil progenitors and nasal mucosal cytokines in seasonal allergic rhinitis. Allergy 1999;54:212 – 9. Wood LJ, Inman MD, Denburg JA, O’Byrne PM. Allergen challenge increases cell traffic between bone marrow and lung. Am J Respir Cell Mol Biol 1998;18:759 – 67. Gaspar Elsas MI, Joseph D, Elsas PX, Vargaftig BB. Rapid increase in bone-marrow eosinophil production and responses to eosinopoietic interleukins triggered by intranasal allergen challenge. Am J Respir Cell Mol Biol 1997;17:404 – 13. Inman MD, Ellis R, Wattie J, Denburg JA, O’Byrne PM. Allergen-induced increase in airway responsiveness, airway eosinophilia, and bone-marrow eosinophil progenitors in mice. Am J Respir Cell Mol Biol 1999;21:473 – 9. Jahnsen FL, Haraldsen G, Aanesen JP, Haye R, Brandtzaeg P. Eosinophil infiltration is related to increased expression of vascular cell adhesion molecule-1 in nasal polyps. Am J Respir Cell Mol Biol 1995;12:624 – 32. Corren J, Adinoff AD, Irvin CG. Changes in bronchial responsiveness following nasal provocation with allergen. J Allergy Clin Immunol 1992;89:611 – 8. Braunstahl GJ, Overbeek SE, Kleinjan A, Prins JB, Hoogsteden HC, Fokkens WJ. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol 2001;107:469 – 76. Gern JE, Vrtis R, Grindle KA, Swenson C, Busse WW. Relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection. Am J Respir Crit Care Med 2000; 162:2226 – 31. Jarjour NN, Gern JE, Kelly EA, Swenson CA, Dick CR, Busse WW. The effect of an experimental rhinovirus 16 infection on bronchial lavage neutrophils. J Allergy Clin Immunol 2000; 105:1169 – 77. Pfister R, Lutolf M, Schapowal A, Glatte B, Schmitz M, Menz G. Screening for sinus disease in patients with asthma: a computed tomography-controlled comparison of A-mode ultrasonography and standard radiography. J Allergy Clin Immunol 1994;94:804 – 9. Bresciani M, Paradis L, Des Rouches A, Vernhet H, Vachier J, Godard P, et al. Rhinosinusitis in severe asthma. J Allergy Clin Immunol 2001;107:73 – 80. ten Brinke A, Grootendorst DC, Schmidt JT, de Bruıˆne FT, van Buchern MA, Sterk PJ, et al. Chronic sinusitis in severe asthma is related to sputum eosinophilia. J Allergy Clin Immunol 2002;109:621 – 6. Peters E, Hatley TK, Crater SE, Phillips CD, Platts-Mills TAE, Borish L. Sinus computed tomography scan and markers of inflammation in vocal cord dysfunction and asthma. Ann Allergy Asthma Immunol 2003;90:316 – 22.
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[47] Barnes PJ. Mechanisms of action of glucocorticoids in asthma. Am J Respir Crit Care Med 1996; 154:S21 – 7. [48] Wood LJ, Sehmi R, Gauvreau GM, Watson RM, Foley R, Denburg JA, et al. An inhaled corticosteroid, budesonide, reduces baseline but not allergen-induced increases in bone marrow inflammatory cell progenitors in asthmatic subjects. Am J Respir Crit Care Med 1999;159: 1457 – 63. [49] 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;90:250 – 6. [50] Watson WT, Becker AB, Simons FE. Treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: effect on lower airway responsiveness. J Allergy Clin Immunol 1993;91:97 – 101. [51] Braccioni F, Dorman SC, O’Byrne PM, Inman MD, Denburg JA, Parameswaran K, et al. The effect of cysteinyl leukotrienes on growth of eosinophil progenitors from peripheral blood and bone marrow of atopic subjects. J Allergy Clin Immunol 2002;110:96 – 101. [52] Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med 1998;158:1213 – 20. [53] Pizzichini E, Leff JA, Reiss TF, Hendeles L, Boulet L-P, Wei LX, et al. Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J 1999; 14:12 – 8. [54] Parnes SM, Churna AV. Acute effects of antileukotrienes on sinonasal polyposis and sinusitis. ENT Journal 2000;79:18 – 21. [55] Dahlen B, Nizankowska E, Szczeklik A, Zetterstrom O, Bochenek G, Kumlin M, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 1998;157:1187 – 94. [56] Akdis CA, Blesken T, Akdis M, Wuthrich B, Blaser K. Role of interleukin 10 in specific immunotherapy. J Clin Invest 1998;102:98 – 106. [57] Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 2002;8:1024 – 32. [58] Francis JN, Till SJ, Durham SR. Induction of IL-10CD4CD25 T cells by grass pollen immunotherapy. J Allergy Clin Immunol 2003;111:1255 – 61. [59] Milgrom H. Is there a role for treatment of asthma with omalizumab? Arch Dis Child 2003;88: 71 – 4. [60] Borish L, Mascali JJ, Rosenwasser LJ. IgE-dependent cytokine production by human peripheral blood mononuclear phagocytes. J Immunol 1991;146:63 – 7. [61] Babu K, Arshad SH, Howarth PH, Chauhan AJ, Bell EJ, Puddicombe S, et al. Soluble tumor necrosis factor alpha (TNF-alpha) receptor (enbrel) as an effective therapeutic strategy in chronic severe asthma. J Allergy Clin Immunol 2003;111:S277. [62] Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003;167:199 – 204. [63] Mochizuki A, Tamura N, Yatabe Y, Onodera S, Hiruma T, Inaba N, et al. Suppressive effects of F-1322 on the antigen-induced late asthmatic response and pulmonary eosinophilia in guinea pigs. Eur J Pharmacol 2001;430:123 – 33. [64] Ferguson BJ. Eosinophilic mucin rhinosinusitis: a distinct clinicopathological entity. Laryngoscope 2000;110:799 – 813.
The role of allergy in chronic rhinosinusitis John W. Steinke, PhD*, Larry Borish, MD Asthma and Allergic Disease Center, Beirne Carter Center for Immunology Research, University of Virginia Health System, Box 801355, Charlottesville, VA 22908 – 1355, USA
Historically, sinusitis has been divided into three categories (acute, subacute, and chronic sinusitis) based on disease duration. Patients with chronic sinusitis have symptoms for more than 6 weeks. At the time this terminology was developed, all sinusitis cases were believed to be infectious, and this idea led to the prominent use of antibiotics and surgical drainage as treatment. It now is clear, however, that most patients with chronic sinusitis do not have an infectious disorder [1,2]. This finding has led to the need to develop more appropriate terminology to describe the myriad of conditions that make up chronic sinusitis. Four major pathophysiologic processes are responsible for chronic sinusitis. A small subset of patients has chronic infectious sinusitis. This subset typically involves patients with underlying humoral immune deficiencies, HIV infection, Kartagener syndrome, and cystic fibrosis. Most patients with chronic sinusitis have an inflammatory disorder with prominent hyperplasia of immune cells. Chronic inflammatory sinusitis is believed to result from chronic or recurrent occlusion of the sinus ostia secondary to viral rhinitis, allergic rhinitis (AR), anatomic predisposition, or other causes. These processes lead to recurrent acute bacterial infections, possibly in association with barotrauma of the sinus cavities and damage to the respiratory epithelium, ciliary destruction, mucous gland and goblet cell hyperplasia, bacterial colonization, and ultimately chronic inflammatory changes. The inflammatory component of this form of sinusitis consists of a mononuclear cell infiltrate and may produce nasal polyps. Eosinophils are not a feature of chronic inflammatory sinusitis. When caused by anatomic occlusion, chronic inflammatory sinusitis is generally responsive to surgical interventions [3,4]. Because it is defined by the prominent expression of eosinophils and to distinguish it from chronic inflammatory sinusitis, the other idiopathic immune
* Corresponding author. E-mail address: [email protected] (J.W. Steinke). 0889-8561/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0889-8561(03)00108-5
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inflammatory disease is referred to as chronic hyperplastic eosinophilic sinusitis (CHES). This disease frequently is associated with nasal polyposis (NP), asthma, allergic (IgE) sensitization to aeroallergens (atopy), and aspirin sensitivity. Patients with CHES often are referred to allergists. In contrast to chronic inflammatory sinusitis, CHES does not respond well to surgery [3]. The role of AR in CHES is the primary focus of this article. The final condition associated with chronic sinusitis is allergic fungal sinusitis (AFS). This condition presumably represents a severe variant of CHES that is associated with the colonization of fungi within the sinus cavities and the presence of an IgE-like and T helper cell type 2 (TH2)-like lymphocyte – mediated allergic inflammatory response. Immune and allergic mechanisms of AFS are discussed by Davis and Kita elsewhere in this issue.
Immune mechanisms of chronic hyperplastic eosinophilic sinusitis CHES with or without NP is an inflammatory disease that is characterized by the accumulation of eosinophils, fibroblasts, mast cells, goblet cells, and TH2-like lymphocytes [5,6]. The prominent accumulation of eosinophils is the diagnostic feature of this condition [5,7,8,64]. This diagnosis can only be established unambiguously on pathologic examination of tissue taken from the disease site. The sinus tissue demonstrates a marked increase in cells—including lymphocytes, fibroblasts, and eosinophils—that express mRNA transcripts and protein for cytokines responsible for eosinophil differentiation (interleukin [IL]-5), survival (IL-3, IL-5, granulocyte-macrophage colony-stimulating factor [GMCSF]), recruitment (CCL11 [eotaxin]) and activation (CCL11, CCL5 [RANTES], IL-3, IL-5, GM-CSF, tumor necrosis factor a [TNF-a]) [9 – 14]. Cysteinyl leukotrienes (CysLTs) are expressed prominently in CHES tissue and contribute to the eosinophilic inflammation [15]. The finding that eosinophils are a prominent source of these cytokines and CysLTs suggests that CHES –NP is a disease of unregulated inflammation in which eosinophils, once recruited, provide the growth factors that are necessary for their further differentiation, recruitment, proliferation, activation, and survival. Eosinophil and basophil progenitors or colony-forming units (Eo/B CFU) are bone marrow-derived mononuclear cells that express CD34, CD35, and IL-5 receptors that are capable of responding to appropriate cytokine signals to differentiate into mature basophils and eosinophils [16]. Eo/B CFU are increased in numbers in the blood and bone marrow of atopic patients, and further increases in their number are observed after allergen exposure [16]. These progenitors also are observed in nasal polyp tissue [17]. This situation provides a localized pool of cells that, given the proper signals (eg, IL-5, GM-CSF), can mature and provide a source for the eosinophils (and basophils) that characterize this condition. Patients with CHES become colonized with numerous bacteria and often experience recurrent bacterial infections superimposed on their chronically diseased mucosa. When sinus cultures are performed well using appropriate sterilization, sinus puncture, and quantification, these studies have demonstrated polymicrobial organisms and nonvirulent organisms
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present at low titer [1,2]. In combination with the prominent absence of neutrophils [8] and the failure to respond to multiple courses of broad-spectrum antibiotics, these observations support the increasing recognition that CHES is not an infectious disease. Although not likely to represent a cause of CHES, as discussed by Bachert in another article in this issue, bacteria may be relevant to the pathophysiology of CHES through their ability to provide antigens and immune adjuvants, such as endotoxin and superantigens, that may contribute to the severity of this condition [18,19]. In addition to this putative role for bacterial colonization and fungal sensitization (as discussed by Davis and Kita in another article in this issue), a unique form of CHES is driven by the overproduction and overresponsiveness to CysLTs that is characteristic of the aspirin-intolerant asthma sinusitis triad [20 – 22]. This article focuses on the role of allergy in the pathophysiology of CHES.
Epidemiology of allergy in chronic sinusitis Up to 53% of individuals with AR have sinusitis [23], and similarly, 25% to 58% of individuals with sinusitis have AR [7,24]. Sensitivity to multiple allergens and to perennial allergens, such as dust mites, increase the risk for CHES [25]. More than 50% of individuals with perennial AR have abnormal sinus radiographs [23,26]. Similarly, elevated levels of serum total IgE is a risk factor for the presence of severe chronic sinusitis [27]. These studies support the concept that chronic sinusitis is an atopic disease that strongly is associated with the presence of IgE sensitization to aeroallergens. The mechanisms by which aeroallergens might produce CHES are not inherently obvious.
Mechanisms linking allergic rhinitis to chronic sinusitis Direct aeroallergen reaction Aeroallergens gain access to the nares (and lungs) by being drawn into the respiratory tract through the process of inspiration. Inspiration directly cannot drive aeroallergens into the sinus cavities. This act can be accomplished only by way of diffusion, a process dependent on the particles remaining airborne for a sufficient period of time, something unlikely to happen given their size. Nor are particles likely to be carried into the sinuses on the mucociliary blanket insofar as mucociliary flow, when functioning, is in the opposite direction and CHES is a disease characterized by atrophic and damaged epithelium and ciliary destruction [28]. Insofar as CHES and AR generally are associated with occlusion of the ostiomeatal complex, this occlusion precludes entry of aeroallergens into the sinus cavities. Studies described later in this article that were performed with insufflated, radiolabeled ragweed particles have confirmed the inability of these particles to enter the sinuses [29,30].
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Infection Acute bacterial sinusitis occurs as a complication of AR, presumably secondary to occlusion of the sinus ostia and stagnation within the sinus cavities [24]. Insofar as the chronic sinusitis that complicates AR is rarely an infectious disease, the development of CHES cannot be ascribed to occlusion of the ostiomeatal complex (OMC). Chronic or recurrent occlusion of the sinus ostia may be responsible for the development of chronic inflammatory sinusitis, but this mechanism cannot explain the development of an eosinophilic inflammatory process within the sinuses.
Neurologic reflex A nasal – sinus neurologic reflex mediated by the cholinergic pathway is supported by some data but is unlikely to explain what is predominantly an inflammatory disease characterized by activated eosinophils and TH2-like lymphocytes. A neurologic reflex does not explain the data described later in this article regarding the ability of ipsilateral allergen exposure in one nares to produce or exacerbate inflammation within the contralateral maxillary sinus [31].
Systemic allergic mechanisms The link between AR and sinusitis is ascribed best to a systemic inflammatory process similar to that which develops between AR and asthma (discussed by Denburg and Keith in another article in this issue). Nasal allergen challenges in sensitive individuals produce radiographic changes of the maxillary sinuses, including edema and opacification [32]. Nasal allergen challenges in allergic individuals produce significant increases in levels of eosinophils, eosinophil cationic protein, histamine, and albumin in the nose and maxillary sinus [33]. Similarly, insufflation of ragweed particles into the nares and the naturally occurring exposure to allergen during the ragweed season produce sinus hyperemia and increased metabolic activity [29,30]. In one study, sinus lavage specimens from both maxillary sinuses were collected and analyzed after a nasal allergen challenge that was performed in only one side of the nose. Albumin levels and eosinophil counts were increased significantly in these specimens with no significant differences detected in specimens obtained from the ipsilateral and contralateral maxillary sinuses [31]. The development of disease in both sinuses precludes a neurally mediated mechanism but is consistent with a systemic response. In sensitized subjects, allergen exposure activates immune cells, including T helper cell lymphocytes, dendritic cells, mononuclear cells, mast cells, and other immune cells within the nares and in nasal-associated lymphatic tissues. Allergenic peptides loaded on dendritic cells readily migrate to nasal-associated lymphatic tissue. T helper cell lymphocytes, presumably having the TH2-like phenotype, also can migrate from the nasal airway to nasal lymphatic tissue and
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the bone marrow, as has been described for the migration of T lymphocytes from the asthmatic airway to the bone marrow in murine asthma models. Cells newly activated in the nasal airway by allergen may include locally produced eosinophil precursors [34]. The cytokines associated with allergic inflammation do not function hormonally. TH2-associated cytokines, such as IL-4, IL-5, and IL-13, cannot be identified in serum samples and are unlikely to access the bone marrow at a concentration that are sufficient enough to drive hematopoietic differentiation. TH2-like cells, including cells newly differentiated from naı¨ve cells in nasal lymphatic tissue or reactivated memory cells present within the nasal tissue, migrate to the bone marrow. The ability of activated cytokine-expressing cells to circulate provides cytokines with the ability to function at a distance [35]. Once delivered to the bone marrow, these TH2-like cells stimulate the production of inflammatory cells, including basophils, eosinophils, and mast cell precursors [16,36,37]. These newly generated inflammatory cells enter the circulatory system and infiltrate susceptible tissues such as sinuses (or lungs) [16], exacerbating sinusitis (and asthma) [37]. Selective recruitment of the inflammatory cells into the sinuses (and lungs) occurs only in the presence of preexisting disease, whereby these tissues are induced to express appropriate homing (adhesion) molecules, such as vascular cell adhesion molecule 1, and chemoattractants, such as CCL11 (eotaxin) and CysLTs. All of these factors have been found in tissue of patients with CHS –NP [5,13,15,38]. Presumably, the direct recirculation of these allergic inflammatory cells occurs between the nares, local lymphatic tissue, and sinuses. Subjects without preexisting sinusitis (or nonasthmatics) do not have these addressins and chemotaxins in their airways and do not have the machinery necessary to recruit inflammatory cells into their sinuses (or lungs) during exacerbations of rhinitis (Fig. 1). Although this systemic model of the role for allergen-mediated exacerbation of CHES has not been studied extensively for sinusitis, this model is supported by studies evaluating the linkage between AR and asthma. In individuals with seasonal AR (SAR), nasal allergen provocation (performed in a fashion demonstrated not to give the allergen access to the lungs) produces inflammatory changes in the upper and lower airways, including increased adhesion-molecule expression, eosinophil infiltration, and bronchial hyperreactivity [39,40]. The immune mechanisms that mediate this systemic response to allergen are discussed by Denburg and Keith elsewhere in this issue. Experimental infections with rhinovirus in atopic individuals increased granulocyte colony-stimulating factor (G-CSF) expression in the nose and sputum and increased neutrophil concentrations in nasal secretions, sputum, bronchial lavage specimens, and blood [41,42]. As with the allergen challenge model, rhinovirus does not access the lower airway, so a direct mechanism of action cannot be ascribed. The implication of this study was that rhinovirus induction of G-CSF (and other colonystimulating factors) in the nares led to increased bone marrow production of neutrophils. Newly synthesized neutrophils egressed from the marrow and migrated back to the nares, but because of the previously induced expression of intercellular adhesion molecule 1 and other adhesion molecules in the
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asthmatic lung and local production of appropriate chemoattractants, these cells also migrated into the lower airway. Increased systemic inflammation occurs as a complication of allergen-induced and nonallergic causes of rhinitis and may contribute to the exacerbations of asthma frequently seen in individuals with these underlying conditions. A similar mechanism could drive the recruitment of inflammatory cells from the circulation into the sinuses of subjects whose sinuses have the appropriate adhesion molecules and chemokines after a nasal allergen challenge or natural exposure to allergen.
Therapeutic implications A huge problem confounding the evaluation of the clinical interventions of AR as putative therapeutic modalities for CHES has been the absence of validated criteria to assess the presence and severity of sinusitis. Traditionally, studies have used clinical criteria to evaluate the sinuses, including presence of such symptoms as purulent nasal drainage, nasal congestion, frontal headaches, and cough. None of these criteria is specific for the sinuses, but they largely reflect the presence of nasal disease (purulent drainage) or lower respiratory tract disease (cough). Even the relevance of frontal headaches to sinus disease is unclear, as the sinuses do not seem to have pain sensory nerves. Clinical studies that have compared sinusitis symptom scores with CT scans show that clinical scores are often little better than random in predicting the presence and severity of sinusitis [27,43 –46]. The absence of validated objective criteria for assessing the presence of CHES or responsiveness to therapeutic interventions has rendered most sinusitis studies meaningless. Systemic corticosteroids (CCSs) arguably would benefit CHES through their ability to directly attenuate eosinophilia and other components of the inflammation of this disorder. In contrast to systemic CCSs, as previously described for aeroallergens, it is unlikely that intranasal CCSs directly can access the sinus cavities. Although various maneuvers have been proposed to promote the drainage of nasal CCSs into the sinuses, the likely presence of occlusion of the OMC precludes their direct access, although this effect may be achieved partially in subjects who have undergone functional endoscopic sinus surgery. The more interesting question, which relevant to the concepts raised in this article, is whether topical intranasal CCSs can, through indirect means, mitigate the inflammatory component of CHES. The ability of intranasal CCSs to locally reduce cytokine production (including IL-4, IL-5, GM-CSF, TNF-a) in the nares, inhibit the function of T helper cell lymphocyte, and inhibit activation of eosinophils and eosinophil precursors in the nares supports the concept that these agents should provide systemic anti-inflammatory efficacy [47,48]. Such a model is consistent
Fig. 1. Overview of mechanism by which allergen immune activation can induce inflammation in sinus tissue. R, receptor; VCAM-1, vascular adhesion molecule 1; VLA-4, very late antigen 4.
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with data that intranasal CCSs can, without accessing the lower airway, mitigate seasonal or allergen-induced worsening of bronchial hyperreactivity [49,50]. Intranasal CCSs can reduce nasal polyps; this effect presumably reflects, in part, the ability of intranasal CCSs to directly access the polyp tissue. Intranasal CCSs have been investigated as an adjuvant therapy for acute infectious sinusitis, a condition in which they are likely to promote drainage. The role of intranasal CCSs in CHES has not been addressed adequately in a properly performed controlled clinical trial with appropriate outcome criteria (ie, criteria not involving symptom scores). Leukotriene modifiers CysLTs have important pro-inflammatory capabilities, the most important of which is their ability to promote eosinophilic inflammation in the airways and nasal mucosa. Other activities include increasing airway smooth muscle hyperreactivity, increasing vascular permeability, stimulating mucous secretion, inducing chemotaxis, and decreasing mucociliary clearance [15]. Leukotriene D4 (LTD4) can synergize with IL-5 in the bone marrow or GM-CSF in the peripheral blood to promote eosinophilopoiesis and to promote differentiation of Eo/B CFU [51]. This effect is blocked partially by the addition of montelukast, a CysLT1 receptor antagonist [51]. Clinical trials of leukotriene modifiers in asthma and SAR have shown reductions in circulating absolute eosinophil counts [52]. The authors demonstrated an increased presence of CysLTs in polyp tissue from patients with CHES, as compared with tissue from patients with chronic inflammatory sinusitis or healthy sinus tissue [15]. In addition to increased levels of CysLTs, patients with CHES had an increase in the mRNA transcripts for the proteins involved in the metabolic pathway of leukotriene synthesis. Increased CysLT expression was correlated with increased circulating eosinophils. Leukotriene modifiers reduce tissue eosinophilia in asthma [53] and are likely to provide benefit in CHES through direct reduction of eosinophil recruitment and activation in the sinuses and through their ability to indirectly block the systemic humoral pathway connecting AR with systemic allergic disease in the sinuses (and lungs). CysLT1 receptor antagonists (zafirlukast, montelukast) have been suggested to have efficacy in CHES– NP in uncontrolled trials [54]. In the only placebo-controlled trial of a leukotriene modifier in CHES, the 5-lipoxygenase inhibitor zileuton was shown to reduce polyp size and restore sense of smell [55]. Allergen avoidance and immunotherapy Allergen avoidance and immunotherapy have never been studied as therapeutic modalities for the treatment of the allergic component of CHES. To the extent that CHES may develop through systemic activation of TH2-like lymphocytes and eosinophils by way of the mechanisms outlined in this article, allergen avoidance could be a useful intervention. Immunotherapy induces tolerance in allergen-
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specific T helper cell lymphocytes, and this effect is associated with their reduced production of cytokines, including IL-4, IL-5, IL-13, and interferon g [56]. Immunotherapy also may act to induce the differentiation of IL-10 – producing allergen-specific T-cell regulatory lymphocytes [57,58]. These functions of immunotherapy should reduce the systemic pro-inflammatory effects of AR and reduce the secondary recruitment of eosinophils, basophils and other inflammatory cells into the sinuses. No study of immunotherapy or allergen avoidance has ever been performed using proper outcome parameters, so the presumptive beneficial effects of these methods remain hypothetical. The best argument is to use allergen avoidance and immunotherapy only in subjects whose allergic rhinitis warrants the use of these interventions and to hope for a gratuitous beneficial influence on CHES. New biotechnology approaches Given the pathophysiologic similarities between CHES and asthma and the likelihood that these conditions are similar or perhaps identical disease processes affecting the upper and lower airways, respectively, it seems likely that new biotechnology-derived therapies that are designed to treat severe asthma are likely to produce similar benefits for CHES. Clinical experience with humanized anti-IgE (omalizumab) in asthma suggests that such treatment lessens allergeninduced IgE-mediated activation of mast cells and basophils and attenuates acute allergic reactions [59]. Through these mechanisms, humanized anti-IgE greatly attenuates the frequency and severity of asthma exacerbations; however, anti-IgE seems to have less efficacy in improving day-to-day asthma symptoms, suggesting that it may not be reducing airway inflammation independent of acute allergic reactions. These observations suggest that analogous to asthma humanized anti-IgE may not ameliorate CHES, although it may reduce the severity of acute CHES exacerbations in patients with AR that is associated with allergic exposures or arguably secondary to upper respiratory viral infections. Another treatment intervention showing some promise in asthma is the neutralization of TNF with soluble TNF receptor (etanercept) or humanized anti-TNF (infliximab). TNF is an important component of asthmatic inflammation [60] and CHES [10]. As a major cytokine of the innate immune system, TNF is likely to be critically important in initiating immune responses to allergens and promoting the recruitment and activation of inflammatory cells in the airways. In a preliminary uncontrolled study, etanercept was shown to markedly improve lung function and, more importantly, to dramatically reduce bronchial hyperreactivity, suggestive of an anti-inflammatory influence. These treatments are intriguing candidates as therapeutic interventions in CHES [61]. Insofar as CHES is defined by the accumulation of activated eosinophils, it seems likely that interventions designed to attenuate eosinophilic inflammation will be beneficial in this disorder. The experience with humanized anti-IL-5 (mepolizumab) in asthma supports the ability of this intervention to greatly attenuate the bone marrow eosinophilopoietic response associated with asthma
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[62]. This treatment also should work to reduce the systemic response to AR and the secondary recruitment of eosinophils into the sinuses of patients with AR and CHES. As a single intervention, however, this medication was unable to sufficiently reduce tissue eosinophilia to produce a therapeutic benefit in asthma. This finding was believed to reflect the complementary role of other cytokines, including GM-CSF, in promoting the activation and differentiation of eosinophilic precursors [51]. This failure also may have reflected roles for constitutive (IL-5 – independent) eosinophilopoiesis and the need to attenuate expression of eosinophil-specific chemokines (eg, inhibition of CCL11 [eotaxin] using chemokine receptor CCR3 antagonists) or eosinophil-specific adhesion molecules (eg, through the use of very late antigen 4 antagonists) [63]. No single agent is likely to be effective for CHES, and, as suggested by the mepolizumab studies, it will be necessary to synergistically block the systemic bone marrow component of CHES and local factors that are critical for inflammatory cell recruitment. The common association of CHES with allergy and the concept that AR may produce a systemic process perpetuating the inflammation of this disorder provide useful insights into the pathophysiology of CHES and provide important leads into the development of potential therapies.
Summary CHES is characterized by unregulated proliferation of eosinophils, TH2-like lymphocytes, fibroblasts, goblet cells, and mast cells. In more than 50% of subjects, it is found in association with the allergic rhinitis. The instillation of allergens onto the nasal mucosa is associated with worsening inflammation within the sinuses and an influx with eosinophils. In this article, the authors argue that the activation of TH2-like lymphocytes in the allergic nares leads to the differentiation and activation of immune cells, including eosinophils and basophils, from precursors present in the nasal tissue and bone marrow. In subjects with preexisting CHES, the presence of specific adhesion and chemotactic molecules in the sinuses promotes the recruitment of these newly generated cells from the circulation.
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