Thorax 2000;55 (Suppl 2):S79–S83 S79

Nasal polyposis, dominated Thorax: first published as 10.1136/thorax.55.suppl_2.S79 on 1 October 2000. Downloaded from inflammation, and

Niels Mygind, Ronald Dahl, Claus Bachert

A is an oedematous mucous membrane computed tomographic (CT) scanning). The which forms a pedunculating process with a overall prevalence rate is probably about slim or broad stalk or base. Nasal polyps origi- 2–4%5–7 which increases with age of the study nate in the upper part of the around the population. Nasal polyposis occurs with a high openings to the ethmoidal sinuses. The polyps frequency in groups of patients with specified extend into the from the middle airway diseases (table 1). meatus, resulting in nasal blockage and re- Although symptomatic nasal polyposis is stricted airflow to the olfactory region. The rare in the general population, much higher polyp stroma is highly oedematous with a vary- figures for the occurrence of isolated nasal ing density of inflammatory cells. Nasal polyps have been obtained from necropsy polyposis, consisting of recurrent, multiple studies. A thorough endoscopic examination of polyps, is part of an inflammatory reaction removed nasoethmoidal blocks and endoscopic involving the mucous membrane of the nose, examination of unselected necropsy specimens , and often the lower airways. have shown polyps in as many as 25–40% of The polyps are easily accessible for immuno- specimens.89 logical and histological studies and an increas- Allergic has a high prevalence rate of ing number of publications have appeared in about 15–20%.10 Most cases in the western recent years, including two monographs.12 world are caused by pollen allergy, having a Nasal polyps have long been associated with seasonal occurrence. In striking contrast to rhinitis and . However, the role of nasal polyposis, which is a disease of middle allergy in the aetiology and pathogenesis of aged people, occurs with its nasal polyps is a controversial issue. It has been highest prevalence in children and young peo- postulated that allergy is an aetiological factor ple and the clinical significance of the diseases for nasal polyposis. If this is so, then it can be decreases with age. expected that allergic patients will have polyps more often than a control population and that Occurrence of nasal polyps in allergic patients with polyps have an increased occur- patients rence of positive allergy testing. Caplin and coworkers11 examined 3000 con- In this paper we will describe the possible secutive atopic patients and found that only connection between nasal polyposis and al- 0.5% had polyps. Bunnag and coworkers12 http://thorax.bmj.com/ lergy, based on an analysis of (1) the occur- reported a 4.5% incidence of nasal polyps in rence of polyps and of allergy, (2) the anatomy 300 patients with allergic rhinitis. Settipane and histology of nasal polyps, (3) the inflam- and ChaVe13 found that only 0.1% of paediatric mation in nasal polyps, (4) the occurrence of patients attending an allergy clinic had nasal positive allergy tests in patients with polyps, (5) polyps. Thus, the prevalence of nasal polyps in the eVect of allergen exposure on nasal allergic patients is low, usually under 5%, symptoms in patients with polyps, and (6) the which is similar to that of the general response to treatment.

population. on October 3, 2021 by guest. Protected copyright. Nasal polyposis with known aetiology While the aetiology of nasal polyposis is Anatomy and histology of nasal polyposis unknown in many patients, in a few cases it is SITE OF POLYP FORMATION Nasal endoscopic examination of a large well defined. Polyps occur in most patients with number of patients with nasal polyposis14 15 and allergic fungal . In this disease the a detailed anatomical examination of necropsy tissue inflammation is typically eosinophil specimens89 have shown that nasal polyps are dominated.3 Department of Nasal polyps frequently occur in patients Respiratory Diseases, Table 1 Prevalence of nasal polyposis in diVerent University Hospital of with cystic fibrosis and in those with primary population subgroups Aarhus, DK-8000 ciliary dyskinesia (Kartagener’s syndrome). Aarhus, Denmark The polyps associated with these diseases are intolerance 36–72% N Mygind Adult asthma 7% not characterised by tissue eosinophilia but by IgE mediated 5% R Dahl lymphocytes in the tissue and Non-IgE mediated 13% leucocytes in the secretions.4 Chronic sinusitis in adults 2% Department of IgE mediated 1% , Non-IgE mediated 5% University Hospital, Occurrence of nasal polyps and of allergy Childhood asthma/sinusitis 0.1% Ghent, Belgium Cystic fibrosis The exact prevalence rate of nasal polyposis in Children 10% C Bachert the general population is not known because Adults 50% there have been few epidemiological studies Allergic 66–100% Correspondence to: Primary ciliary dyskinesia 40% Dr N Mygind and their results depend upon the diagnostic [email protected] methods used (history, rhinoscopy, , Adapted from Settipane et al.1

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mainly situated in the middle meatus and Electrolyte and water transport Thorax: first published as 10.1136/thorax.55.suppl_2.S79 on 1 October 2000. Downloaded from originate from the nasal mucous membrane of The basic elements of Na+ and Cl– movement the outlets (ostia, clefts, recesses) from the in the respiratory surface epithelium may be of paranasal sinuses. This area, so critical for relevance for the understanding of nasal polyp sinus , is also referred to as “the ostio- formation. In the normal nasal mucosa there is meatal complex”. a net absorption of Na+ and very little Cl– It is remarkable that polyps develop exclu- secretion.23 24 In cystic fibrosis (CF), a disease sively from a few square centimetres of airway often associated with polyp formation, there is mucous membrane which often is universally both an absence of the cyclic AMP controlled inflamed. The reason for this is unknown and Cl– channel and abnormal regulation of the one can only speculate about the nature of a Na+ channel.23 24 Increased Na+ and decreased “localisation factor”. In the upper part of the Cl– secretion in CF result in dehydration of nose, including the middle meatus, the airway because of the net movement of water lumen is a narrow slit with only a few milli- into the interstitial space. metres between opposing mucous membranes. Increased Na+ absorption may also be Stammberger14 15 has observed that polyp secondary to chronic inflammation, which is formation predominantly occurs in contact the hallmark of nasal polyposis. Recent find- areas between two opposing mucous mem- ings indicate that the absorption of Na+ is branes. It is known that stimulation of altered, not only in CF polyps but also in epithelial cells induces the generation and non-CF polyps.23 24 These results suggest that release of a series of pro-inflammatory cyto- factors leading to the development of nasal kines, and one can therefore hypothesise that polyposis include pathophysiological changes mechanical stimulation of the surface epithe- in the electrolyte and water transport in the lium in contact areas contributes, or even initi- surface epithelium. ates, the inflammatory reaction in the polyps. Other “localisation factors” may be related GOBLET CELLS to the anatomy of nerve endings, blood vessels, The histopathological picture shows great vari- and mucociliary flow in the thin mucous mem- ations, not only in type of epithelium but also in brane near the border between the nose and goblet cell density in diVerent locations on a paranasal sinuses. single polyp. The density of goblet cells is lower in anterior than in posterior polyps, and much lower than in the normal nasal mucosa.16 SURFACE EPITHELIUM Most of the polyp surface is covered by a ciliated pseudostratified epithelium, but a tran- INNERVATION sitional and squamous epithelium is also The sensory nerves and the autonomic vaso- found, especially in anterior polyps, influenced motor and secretory nerves invariably found in by the inhaled air currents.16 normal and abnormal nasal mucosa cannot be identified within the stroma of polyps, either in

the vicinity of the epithelial basement mem- http://thorax.bmj.com/ Epithelial defects brane or within the walls of blood vessels or There is experimental evidence that cytotoxic glands. A few nerve fibres can be seen in the proteins from eosinophil leucocytes can dam- stalk of some polyps.25 age the respiratory epithelium and induce It is therefore assumed that denervation of 17 bronchial hyperreactivity in asthma. Epithe- nasal polyps causes a decrease in secretory lial defects have apparently also been described activity of the glands and induces an abnormal 18 in nasal polyps, but when polyps are removed vascular permeability, leading to an irreversible carefully and gentle methods are used for fixa- tissue oedema. Nasal polyps develop in areas

tion, dehydration and cutting, the polyp where the lining of the nasal cavity joins that of on October 3, 2021 by guest. Protected copyright. epithelium appears well preserved without the sinuses, and these marginal zones contain 19 defects on scanning electron microscopy. thin nerve fascicles25 which may be more sensi- Although gross epithelial defects do not seem tive to damage from, for example, eosinophil to appear in carefully prepared polyp speci- derived proteins.26 mens, the function of the epithelium may be While the exact cause and mechanism of the 20 impaired and epithelial cell kinetics altered. denervation of the nasal polyps are unknown, it seems likely that the complete loss of auto- Biology of the surface epithelium nomic innervation is a pathogenetic factor in Perturbation of the epithelium, as occurs on the formation of polyps. exposure to chemical, physical and immuno- logical stimuli, can contribute to inflammation SUBMUCOSAL GLANDS by release and activity of cytokines which The glands of nasal polyps diVer markedly influence the growth, diVerentiation, migra- from normal nasal glands.27 While normal tion, and activation of inflammatory cells.21 22 glands are small branched tubulo-alveolar Recent studies have suggested that the airway glands, those in the polyps are long, tubular, epithelium may play a more important role and and of varying shape, size, and type. The influence the pathogenesis of inflammatory normal glands are evenly distributed over the airway diseases. Contact between epithelial mucous membrane, while the glands in the surfaces in the narrow middle meatus may polyps are very unevenly distributed. Their partly explain why polyps are formed specifi- density is more than 10 times less than in the cally in this location, as discussed above. nasal mucosa.27

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All glands in the polyps are pathological, mine content of polyps is much higher than Thorax: first published as 10.1136/thorax.55.suppl_2.S79 on 1 October 2000. Downloaded from showing signs of cystic degeneration with stag- other tissues, and large quantities of free hista- nation of mucus within the distended mine can be measured in the oedema fluid33 tubules,427and without the normal production which fits in with the ultrastructural findings. of secretory component.28 All glands are appar- Arachidonic acid generated mediators are also ently newly formed during the growth of the found in polyp fluid.34 Measurable levels of IgE polyps, which is consistent with their lack of decapeptide in polyp fluid35 support the innervation. suggestion that a membrane event induces the degranulation of mast cells. BLOOD VESSELS AND EXUDATION OF PLASMA The vascularity of polyps is sparse compared with normal nasal mucosa,25 and neither ADHESION MOLECULES, CYTOKINES, AND venous sinusoids nor arteriovenous anastomo- ses are encountered. The venules of the polyps Immunohistochemical data strongly suggest show unusual organisation with respect to their that interactions between the adhesion mol- endothelial cell junctions and the basement ecules VLA-4 and VCAM-1 play an important membrane. Many cell junctions have the role in the extravasation of eosinophils into appearance of a web of villous processes and nasal polyps. Three studies have found consid- are incompletely sealed, while others are wide erable upregulation of VCAM-1 in polyp 25 open. As mentioned above, the blood vessels vasculature,36–39 which supports the finding of of polyps are devoid of nerves. adhesion and transmigration of eosinophils The release of histamine and other inflam- without any eVect on . Both inter- matory mediators (see below) may be an leukin (IL)-3 and IL-4, as well as IL-1 and important factor in causing microvascular tumour necrosis factor (TNF)á can induce plasma exudation, which is highly characteris- VCAM-1 expression in microvascular endo- tic of nasal polyps. The vascular exudation of thelium from the polyps. All these cytokines are plasma suggests that the lamina propria, the expressed in the polyps and, in various combi- basement membrane, the airway epithelium, nations, may have synergistic eVects on and the mucosal surface are furnished with 36 potent plasma derived peptides and proteins, VCAM-1 expression. Another adhesion mol- and that the mucosal macromolecular milieu in ecule, P-selectin, also probably has a role in the initial adhesion of eosinophils to the polyp nasal polyposis is therefore dramatically diVer- 36 39 ent from that of the normal nasal mucosa.20 It endothelium. Chemokines are probably is of particular interest that the process of involved as eosinophil attractants. Although microvascular exudation of plasma may par- limited information exists with regard to their ticipate in the chronic generation of oedema possible role in vivo, reports on RANTES and fluid in nasal polyposis. eotaxin expression in nasal polyps indicate that these chemoattractants participate in the accu- Inflammation in nasal polyps mulation of eosinophils.38 40 Nasal polyposis is the ultimate form of inflam- Several haemopoietic and pro-inflammatory http://thorax.bmj.com/ mation of the upper airways which, for cytokines (GM-CSF, IL-6, IL-8, SCF), capa- unknown reasons, preferably develops in sub- ble of recruiting and activating mast cells and types of inflammatory diseases. As mentioned eosinophils in particular, are upregulated in above, the factors which determine localisation various tissue compartments (epithelium, of the disease to a few square centimetres of the stroma) of nasal polyps.41–43 The inflammatory airways is poorly understood. cells themselves, especially eosinophils, are rich As shown in table 1, nasal polyposis occurs sources of many cytokines including those very frequently in patients with intolerance to

capable of inducing their own diVerentiation on October 3, 2021 by guest. Protected copyright. acetylsalicylic acid and in patients with allergic and activation in an autocrine fashion. Thus, fungal sinusitis. These two aetiologically diVer- nasal polyps can be looked upon as a type of ent diseases have an eosinophil dominated self-perpetuating inflammatory process.44 inflammation as a common feature, and the The presence of large amounts of IL-5 pro- degree of tissue eosinophilia appears to be an tein in most nasal polyp specimens but in no important denominator of the recurrence rate specimens from normal control subjects or of nasal polyps.56In non-eosinophil dominated those with infectious sinusitis indicates that inflammation (cystic fibrosis, primary ciliary IL-5 has a key role in the pathophysiology of dyskinesia) other pathophysiological mecha- 42 nisms may be of importance. eosinophil dominated polyps. This is in contrast to other cytokines which have only marginal quantitative di erences between IGE, MAST CELLS, AND HISTAMINE V The number of epithelial mast cells in nasal polyps and other rhinosinusitis diseases. IL-5 polyps is high.29 Electron microscopic studies levels are significantly higher in polyps of asth- have shown marked and widespread mast cell matic subjects than in those from non- degranulation in all polyps studied, and the asthmatic subjects, which confirms the associ- degree of degranulation is greater than in aller- ation between this cytokine and clinical data in gic rhinitis.30 31 There is evidence that the patients with asthma and polyposis.42 Immuno- changes may extend into the nasal mucosa of histochemistry reveals that IL-5 may be the inferior turbinate in some patients, indicat- predominantly produced by eosinophils which, ing the existence of a more widespread inflam- as mentioned earlier, creates a possible auto- mation of the airway mucosa.32 The total hista- crine loop in nasal polyp tissue.

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Allergy testing in patients with nasal eVect on nasal blockage.50 It is recommended Thorax: first published as 10.1136/thorax.55.suppl_2.S79 on 1 October 2000. Downloaded from

polyposis in international consensus reports that H1 anti- Since Yonge’s original article on the cause of histamines are used in mild cases with nasal polyps published in the BMJ in 1907,45 occasional symptoms, while intranasal cortico- allergy has consistently been proposed as a steroids are recommended in severe cases with cause of polyps. This widespread belief, daily symptoms.51 however, is not supported in published work on On the other hand, there is no clinical or

allergy testing. experimental evidence that H1 Settipane and Chafee13 studied 211 patients are eVective in nasal polyposis. This is remark- with nasal polyps referred to an allergy clinic; able, considering the extensive mast cell 55% had positive allergy skin tests. Since these degranulation in nasal polyps and their ex- patients were selected from a biased population tremely high content of histamine. of whom 77% had positive skin tests, the high frequency of positive allergy skin tests in nasal polyps may be misleading and may reflect the Corticosteroids are the only drugs with a characteristics of the total population. The proven eVect on symptoms and signs of nasal authors conclude that the positive allergy skin polyposis.52 53 They probably relieve symptoms tests in nasal polyps may be a coincidence. by downregulating the expression and produc- Wong and Dolovich46, in a series of 249 tion of cytokines such as IL-5 which eVectively patients undergoing nasal polypectomy, re- reduce the number of eosinophils. The eVects ported a positive skin prick test in 66%. How- of corticosteroids on these processes may be ever, using the same allergen testing panel, enhanced by eVects on haemopoietic mecha- 74% had a positive skin test in a control group nisms arising in the bone marrow.54 of patients undergoing non-polyp nasal sur- Topically applied corticosteroids have been gery. best studied in controlled clinical trials.52 53 Only one study has compared allergy testing They reduce symptoms of rhinitis, improve in patients with nasal polyps and a matched nasal breathing, reduce the size of polyps, and control group. Jamal and Marant47 found a prevent, in part, their recurrence, but they have positive RAST to inhalant allergens in 16.6% none or little eVect on the sense of smell. Topi- of patients with nasal polyps compared with cal steroids can be used alone as basic long 12.5% in an age and sex matched control term treatment in mild cases and can be used group. Drake-Lee48 reported that positive skin with systemic steroids and/or in severe test results are no more common than expected cases. in patients with nasal polyps (25%), making the Systemic steroids have been less well stud- presence of allergy appear to be coincidental. ied; they have an eVect on all types of The evidence therefore suggests that nasal symptoms and pathology, including the sense polyps are not caused by allergy. When polyps of smell.55 This type of treatment, which can and allergy occur together, the question is serve as “medical polypectomy”, is only used whether allergen exposure can aggravate nasal for short periods because of the risk of adverse polyps and cause recurrence. eVects. http://thorax.bmj.com/

EVect of allergen exposure in nasal ALLERGEN SPECIFIC TREATMENT polyposis In one of the two monographs on nasal polyps1 It is logical to assume that allergen exposure the editor writes: “Treatment of is can provoke nasal symptoms in allergic pa- important in preventing recurrences in indi- tients with coincident polyposis. However, an viduals with both nasal polyps and allergies. It ingeniously designed study does not give is appropriate that all patients with nasal polyps support to this assumption. Keith and 49 have an allergy evaluation. Immunotherapy on October 3, 2021 by guest. Protected copyright. coworkers followed nasal symptoms and eosi- with allergen may be used to prevent polyp nophilia during the pollen season in four recurrence in some of these patients who have groups of patients: (1) allergic with polyposis, both nasal polyps and allergies.” (2) non-allergic with polyposis, (3) allergic In our opinion, however, there is no clinical without polyposis, and (4) non-allergic without or experimental evidence in support of the use polyposis. Symptoms and nasal eosinophilia of allergen specific —neither allergen worsened during the pollen season only in avoidance nor immunotherapy—in the treat- allergic patients without polyposis. The au- ment of nasal polyposis. thors concluded that ongoing conditions, perhaps nasal mucosal inflammation, in pa- tients with nasal polyposis may lead to a loss of Conclusions susceptibility to potential additional eVects of Whether allergy is a cause of nasal polyposis is inhaled allergen. a controversial issue. The fact that polyps are characterised by mast cell degranulation and EVect of treatment on nasal polyposis high local levels of IgE and of histamine, and and allergic rhinitis that there is an eosinophil dominated inflam- H1 ANTIHISTAMINES mation driven by cytokines (which are also Hundreds of placebo-controlled studies have operative in allergic inflammation), is compat-

shown the eYcacyofH1 antihistamines in the ible with an allergic aetiology. However, there treatment of allergic rhinitis, with an excellent are strong counterarguments against this. eVect on itching and sneezing, a moderate Nasal polyps do not occur with increased eVect on nasal hypersecretion, and a poor frequency in allergic patients and patients with

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nasal polyps do not appear to have a positive 26 Mygind N. Nasal polyposis. Editorial. J Allergy Clin Immu- Thorax: first published as 10.1136/thorax.55.suppl_2.S79 on 1 October 2000. Downloaded from nol 1982;86:827–9. allergy skin test more often than control 27 Tos M, Mogensen C. Mucous glands in nasal polyps. Arch subjects. Otolaryngol 1977;103:407–13. 28 Nakashima T, Hamashima Y. Loss of secretory activity in We conclude that present evidence is not in the glands of nasal polyps. Ann Otol Rhinol Laryngol 1979; favour of a causal association between allergy 88:210–6. 29 Ruhno J, Howie K, Anderson M, et al. The increased and nasal polyps. Allergen specific therapy has number of epithelial mast cells in nasal polyps and adjacent no proven eYcacy in polyp patients and it is turbinates is not allergy-dependent. Allergy 1990;45:370–4. questionable whether allergy testing is indi- 30 Drake-Lee A, Price J. Ultrastructure of mast cells in normal subjects and patients with perennial allergic rhinitis. J cated in these patients. Nasal polyposis, which Laryngol Otol 1991;105:1006–13. is characterised by eosinophil dominated in- 31 Drake-Lee A, Price J. Mast cell ultrastructure in the inferior turbinate and stroma of nasal polyps. J Laryngol Otol 1997; flammation, is a disease of unknown aetiology. 11:340–5. 32 Drake-Lee A. Mast cells, histamine and other mediators. In: Mygind N, Lildholdt T, eds. Nasal polyposis: an inflamma- 1 Settipane GA, Lund VJ, Bernstein JM, Tos M, eds. Nasal tory disease and its treatment. Copenhagen: Munksgaard, polyps: epidemiology, pathogenesis and treatment. Providence, 1997: 61–7. Rhode Island: The New England and Regional Allergy 33 Drake-Lee AB, McLauhlan P. Clinical symptoms, free Proceedings, 1997. histamine and IgE in nasal polyps. Int Arch Allergy Appl 2 Mygind N, Lildholdt T, eds. 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