Special items in Chronic Rhinosinusitis

5.1. Complications of Chronic Rhinosinusitis

Complications associated with CRSwNP and CRSsNP are less dramatic and rarer than those that can occur in ARS but may be difficult to manage

Complications of CRSwNP & CRSsNP are rare and are largely due to effects on the surrounding bone. They include bone erosion and expansion due to mucocoeles or polyps, osteitis and metaplastic bone formation and occasionally optic neuropathy. Generally these are far less documented in the literature than those associated with acute infection and inflammation. In some cases, they may be considered as simply a manifestation of the natural history of the condition.
The following may be included:
  1. Mucocoele formation
  2. Osteitis
  3. Bone erosion and expansion
  4. Metaplastic bone formation
  5. Optic neuropathy
There is no evidence that CRS is associated with neoplastic change, either benign or malignant. A few case reports refer to orbital, intracranial and osseous complications typical of ARS can occur in CRS but are almost always secondary to a superimposed acute infective episode.

Complications in CRS generally result from an imbalance in the normal process of bone resorption, regeneration and remodelling
5.1.2. Mucocoele formation
A mucocoele is an epithelial-lined sac completely filling the paranasal sinus and capable of expansion as opposed to an obstructed sinus which simply contains mucus (1369). Mucocoeles are relatively rare and usually uni-locular (92%) and unilateral (90%). The exact pathogenesis is unknown though is often associated with obstruction of sinus outflow and some form of chronic inflammation or infection. Studies of inflammatory markers suggest an active process analogous to that seen in odontogenic cysts at the mucocoele bone interface (1370). However, in one third of cases, no obvious cause for the initiation of this process can be found (1371). Where an associated pathology can be identified, it is most often chronic rhinosinusitis with or without nasal polyposis, cystic fibrosis or allergic/eosinophilic fungal rhinosinusitis, in either case with or without surgical intervention. The time interval from potential initiating event to clinical presentation varies from 22 months to 23 years (1371). Growth is generally slow unless an acute bacterial infection produces a pyocoele. (Figures 5.1-5.2)
The distribution of mucocoeles within the sinuses is interesting, occurring most often in the fronto-ethmoid region (86%). The maxillary sinus is least often affected. Consequently the patients most often present with orbital symptoms and signs (axial proptosis, lateral and inferior displacement of the globe, diplopia).

A mucocoele is an epithelial-lined sac completely filling the paranasal sinus and capable of expansion as opposed to an obstructed sinus which simply contains mucus which sometimes occurs in CRS, though not exclusively and which is managed surgically

In fronto-ethmoidal mucocoeles, visual acuity is rarely at risk unless a pyocoele develops whereas visual loss may be the presenting clinical feature with sphenoidal mucocoeles.

The histology of the mucocoele lining is also variable, but is generally composed of pseudostratified columnar epithelium with some squamous metaplasia, goblet cell hyperplasia and a cellular infiltrate dependant on the degree and type of chronic (and acute) inflammation i.e. neutrophils, eosinophils, macrophages, monocytes and plasma cells (1373). Treatment is by marsupialisation, which can be undertaken endoscopically in the majority of cases. No repair of the dehiscent bone is required as long as the lining mucosa is undisturbed and remodelling of the expanded bone can be anticipated with time. A review of the literature shows an overall success rate of >90%, particularly in those undergoing endoscopic surgery alone. Recurrence is higher in those who have undergone previous surgery, have CRS with nasal polyposis, fistulas to the upper eyelid and who have had the more complex disease, which may require combined external and endoscopic surgical approaches. (Table 5.1.1) (1374-1380).
5.1.3. Osteitis
This process has often been reported in association with CRS and might be regarded as part of the pathophysiological process rather than a complication. Animal experiments in rabbits by Kennedy, Senior and others in the late 1990's suggested that the presence of osteitis acted as a stimulant to persistent mucosal inflammation with osteoclastic resorption of bone within and adjacent to infected sinuses (1023, 1382). These pathological changes in the bone were observed in 92% of rabbit models on the infected side and even in 52% on the contralateral non-inoculated side suggesting a route of spread via the enlarged Haversian canal systems (1383).

Osteitis can be associated with CRS but its role, if any, in the pathogenesis of CRS remains unclear

Bone remodelling with accompanying neo-osteogenesis has been demonstrated histologically in the ethmoid bone of patients with CRS (1384). The extent of bone remodelling correlated with severity of disease as evidenced by the LundMackay CT score. Radionucleotide scintigraphy has been used to show increased bone turnover consistent with osteitis in CRS as compared to normal controls (1385). Interestingly this was greatest in the maxilla and ethmoid whereas clinically it is more often observed and problematic in the frontal and sphenoid. A prospective study of 121 patients undergoing endoscopic sinus surgery for CRS was assessed for radiological and histological evidence of osteitis (1022). CT showed neo-osteogenesis in 36% whereas osteitis was confirmed histologically in 53%. (Figure 5.4)
A thorough review of the literature by Videler et al. (1030) confirmed an association of osteitis with CRS but its role, if any, in the pathogenesis of CRS remains unclear. A variety of grading systems have been used to classify the osteitis, usually based on CT appearances (Table 5.1.2) (1022, 1386, 1387).

An earlier prospective case-control study by Georgalas et al. (1388) of 102 patients undergoing CT for CRS were compared with a cohort of age and gender matched non-CRS controls using a variety of parameters including a Global Osteitis Scoring Scale. The severity of osteitis correlated with extent of mucosal disease (as assessed by the Lund-Mackay score)(p<0.001), duration of symptoms (p<0.01) and previous surgery (p<0.001) but there was no correlation between osteitis and symptoms including facial pain and headache. There are no studies at present on management.
5.1.4. Bone erosion and expansion
The converse process to bone sclerosis associated with osteitis is the bone thinning and erosion seen in the more aggressive forms of CRS with nasal polyposis (CRSwNP) (Fig. 5.1.) This is distinct from true mucocoele formation and most often affects the ethmoids where the lamina papyracea may become even thinner than normal and bow into the orbit (1389). This is accompanied by expansion of the opacified ethmoid cells and is usually a bilateral process, resulting in displacement of the orbital contents. Ultimately the lamina becomes dehiscent, most often anteriorly, adjacent to the nasolacrimal system and may be associated with epiphora.

Bone erosion and expansion is the converse process to osteitis seen in the more aggressive forms of CRSwNP

In severe cases a marked pseudohyperteliorism can result. An early study looking at plain x-rays of patients with CRSwNP (1390) showed that widening of the ethmoids was found in 20% of cases and that this correlated with the age at onset of symptoms rather than length of symptoms. The skull base may also be affected, simulating a neoplastic process (1391). Both thickening and thinning of the walls of the paranasal sinuses can occur in the same patient. Foreknowledge of these changes from CT scanning is a pre-requisite to safe surgery. They are particularly marked in cases of allergic (eosinophilic) fungal rhinosinusitis where 80% of cases show evidence of bone erosion (1392) (Fig. 5.3).
5.1.5. Osseous metaplasia
Rarely osseous metaplasia can be found in the upper aerodigestive tract in response to chronic inflammation with or without polyposis and/or previous surgery. New bone formation occurs with a well-developed Haversian system and bone marrow where one would not expect to encounter it i.e. within the lumen of the paranasal sinuses or nasal cavity in contradistinction to the osteitis seen in the walls of paranasal sinuses. This can achieve impressive proportions, obstructing the nose and impacting on the orbit, producing a benign looking mass on CT composed of bone hyperdensities and softtissue which may require surgical removal, if only to exclude a neoplastic process (1393-1395) (Figure 5.5).
5.1.6. Optic neuropathy
Optic neuropathy has been reported in association with CRS principally affecting the sphenoid or posterior ethmoid region, even without expansion as in a mucocoele but usually in the presence of bone erosion between the sinus and orbital apex. This may occur with eosinophilic fungal rhinosinusitis (1396). Visual improvement can be anticipated when emergency decompression is undertaken if the visual loss was partial but in patients with pre-operative blindness, recovery is rare (1397). Endoscopic approaches are most often recommended usually in combination with systemic steroids though no trials have been performed due to the rarity and heterogeneous presentation of the cases.

5.2 CRS with and without NP in relation to the lower airways
5.2.1. Introduction

Due to its strategic position at the entry of the airway, the nose plays a crucial role in airway homeostasis. By warming up, humidifying and filtering incoming air, the nose is essential in the protection and homeostasis of the lower airways (1398). The nose and bronchi are linked anatomically, are both lined with a pseudo-stratified respiratory epithelium and equipped with an arsenal of innate and acquired immune defence mechanisms. It is not hard to imagine that nasal conditions causing nasal obstruction may become a trigger for lower airway pathology in susceptible individuals. In chronic sinus disease with nasal polyps (NP), total blockage of nasal breathing may occur, hence bypassing nasal functions that may be relevant in preventing lower airway disease. It is however evident that the nasobronchial interaction is not restricted to bronchial repercussions of hampered nasal air conditioning. Nose and bronchi seem to communicate via mechanisms such as neural reflexes and systemic pathways. Bronchoconstriction following exposure of the nose to cold air suggests that neural reflexes connect nose and lung (1399). However, Koskela et al. (1400) reported on facial cooling rather than nasal cold dry air being responsible for bronchoconstriction in COPD. The neural interaction linking the release of inflammatory mediators in the bronchi following a nasal inflammatory stimulus has recently been shown by bronchial release of neural mediators after selective nasal allergen provocation (1401). However, the precise neural pathways linking nose and bronchi still remain incompletely understood (1401). Recently, the systemic nature of the interaction between nose and bronchi has received more attention. Indeed, many inflammatory diseases of the upper airways show a systemic immunologic component involving the blood stream and bone marrow (1402). In addition to the systemic and neural interaction, genetic factors may as well play a role in the manifestation of nasal and/or bronchial disease (1403). In spite of the fact that aspiration of nasal contents may take place in neurologically impaired individuals, it is not clear whether micro-aspiration of nasal contents plays a role in the development or severity of bronchial disease (1404).
5.2.2. Asthma and Chronic Rhinosinusitis

CRS with/without NP and asthma / COPD are diseases that often occur together

Bronchial asthma is considered a comorbid condition of CRS. In a recent large-scale European survey, the strong association between CRS and asthma was confirmed (13). CRS in the absence of nasal allergies was associated with late-onset asthma (13). In some centres, around 50% of patients with CRS have clinical asthma (1405, 1406). Interestingly, most patients with CRS who do not report to have asthma show bronchial hyperresponsiveness when given a metacholine challenge test (1405). In the studies mentioned above, the differentiation of CRS with/without NP was not possible (13) or made (1405, 1406).
Radiologic imaging of the sinuses has demonstrated sinonasal inflammatory opacification in the majority of patients with severe asthma (1406, 1407). However, these epidemiologic and radiologic data should be interpreted with caution as they may reflect a large referral bias.
Histopathologic features of CRS and asthma largely overlap. Heterogeneous eosinophilic inflammation and features of airway remodelling like epithelial shedding and basement membrane thickening are found in the mucosa of CRS and asthma (1405). Cytokine patterns in sinus tissue of CRS highly resemble those of bronchial tissue in asthma (524), explaining the presence of eosinophils in both conditions. Therefore, eosinophil degranulation proteins may cause damage to the surrounding structures and induce symptoms at their location in the airway. Finally, lavages from CRS patients show that eosinophils were the dominant cell type in both nasal and broncho-alveolar lavages in the subgroup of patients with CRS with asthma (1086). Beside the similarities in pathophysiology, sinusitis has been etiologically linked to bronchial asthma, and vice versa. As is the case in allergic airway inflammation, sinusitis and asthma can affect and amplify each other via the systemic route, involving interleukin IL-5 and the bone marrow. In both CRS and allergic asthma, similar pro-inflammatory markers are found in the blood. Recently, nasal application of Staphylococcus aureus enterotoxin B has been shown to aggravate the allergeninduced bronchial eosinophilia in a mouse model (1408). However, the interaction between both rhinosinusitis and asthma is not always clinically present, as Ragab et al. (1086) found no correlation between rhinosinusitis and asthma severity. However, patients with asthma showed more CT scan abnormalities than nonasthmatic patients (1409), and CT scan abnormalities in severe asthmatic patients correlated with sputum eosinophilia and pulmonary function (1407).

The interaction between chronic upper and lower airway inflammation has primarily been studied in allergy and not in CRS

Endoscopic sinus surgery (ESS) for CRS aims at alleviating sinonasal symptoms but also improves bronchial symptoms and reduces medication use for bronchial asthma (1410-1413). After a mean follow-up period of 6.5 years, 90% of asthmatic patients reported their asthma was better than it had been before the ESS, with a reduction of the number of asthma attacks and medication use for asthma (1414). Also in children with chronic rhinosinusitis and asthma, sinus surgery improves the clinical course of asthma, reflected by a reduced number of asthma hospitalizations and schooldays missed (1415). Lung function in asthma patients with CRS was reported to benefit from ESS by some authors (1413, 1416, 1417), but denied by others (1410, 1412, 1415). Of note, not all studies show beneficial effects of ESS on asthma (1418). The reason for the inconsistency in study results between studies relates to the heterogeneity and small number of patients included in these studies, and difference in outcome parameters studied. Interestingly, the presence of lower airway disease may have a negative impact on the outcome after ESS. Outcomes after ESS were significantly worse in the asthma compared to the non-asthma group (1411, 1417). Poor outcomes after ESS have also been reported in patients with aspirin-intolerant asthma (1215, 1419, 1420). On the other hand, other authors report that asthma does not represent a predictor of poor symptomatic outcome after primary (1219, 1421) or revision ESS (1409). In a series of 120 patients undergoing ESS, Kennedy (762) reports that asthma did not affect the outcome after ESS when comparing patients with equally severe sinus disease, except for the worst patients, in which asthma did adversely affect the outcome.
Interestingly, Ragab et al. (1422) published the first randomized prospective study of surgical compared to medical therapy of 43 patients with CRS with/without NP and asthma. Medical therapy consisted of a 12 weeks course of erythromycin, alkaline nasal douches and intranasal corticosteroid preparation, followed by intranasal corticosteroid preparation tailored to the patients' clinical course. The surgical treatment group underwent ESS followed by a 2-week course of erythromycin, alkaline nasal douches and intranasal corticosteroid preparation, 3 months of alkaline nasal douches and intranasal corticosteroid, followed by intranasal corticosteroid preparation tailored to the patients' clinical course. Both medical as well as surgical treatment regimens for CRS were associated with subjective and objective improvements in asthma state. Interestingly, improvement in upper airway symptoms correlated with improvement in asthma symptoms and control.

The presence of asthma is a negative predictor of outcome after ESS for CRS w/s NP
5.2.3. Asthma and Chronic Rhinosinusitis with NP
Seven percent of asthma patients have NP compared to lower percentages in the non-asthma population (505). In non-atopic asthma and late onset asthma, NP are diagnosed more frequently (10-15%). Alternatively, up to 60 % of patients with NP have lower airway involvement, assessed by history, pulmonary function and histamine provocation tests (1423). Aspirin-induced asthma is a distinct clinical syndrome characterized by the triad aspirin sensitivity, asthma and NP and has an estimated prevalence of one percent in the general population and ten percent among asthmatics (1424).

Increased nasal colonization by Staphylococcus aureus and presence of specific IgE directed against Staphylococcus aureus enterotoxins were found in NP patients (661). Interestingly, rates of colonization and IgE presence in NP tissue were increased in subjects with NP and co-morbid asthma or aspirin sensitivity. By their super-antigenic activity, enterotoxins may activate inflammatory cells in an antigen-unspecific way. Indeed, nasal application of Staphylococcus aureus enterotoxin B is capable of aggravating experimental allergic asthma (1408).
No well-conducted trials on the effects of medical therapy for NP on asthma have been conducted so far. After ESS for NP in patients with concomitant asthma, a significant improvement in lung function and a reduction of systemic steroid use was noted, whereas this was not the case in aspirin intolerant asthma patients (1420). In a small series of patients with NP, endoscopic sinus surgery did not affect the asthma state (1425). However, nasal breathing and quality of life improved in most patients. Data on effects of surgery for NP on asthma mostly point towards a beneficial effect of surgery on different parameters of asthma. Ehnhage et al. investigated the effects of FESS followed by fluticasone proprionate nasal drops 400 μg twice daily on nasal and lower airway parameters in 68 asthmatics with NP. It was conducted over 21 weeks and the effects of FESS on nasal and lower airway parameters were examined. FESS significantly improved mean asthma symptom scores and daily PEFR and all the nasal parameters measured (1426). Batra et al. (1420) reported a significant improvement in lung function (FEV1) and a reduction in OCS use after FESS in 17 patients with NP and oral corticosteroid dependent asthma. In a series of 13 patients with nasal polyposis and asthma, Uri et al. (1425) reported that FESS did not improve the asthma state in patients with massive nasal polyposis. However, there was a significant decrease in oral corticosteroid and bronchodilator inhaler usage. In a subgroup of 35 patients with NP and asthma, Ragab et al. (1427) reported that FESS had a subjective and objective tendency for asthma improvement. Although the study results are not always consistent, overall it would appear that FESS has a positive effect on asthma in nasal polyposis.

5.2.4. Cystic fibrosis and rhinosinusitis
Bilateral NP in children are often a clinical sign of CF (1428). Sinonasal inflammation is found in most CF patients, with NP being present in 1/3 of CF patients. Rhinosinusitis may often be a presenting symptom of the so-called atypical CF patient with normal or borderline sweat test result and carrying only one mild mutation of the CFTR gene (1428). A significant association exists between broncho-alveolar lavage and sinus cultures in cystic fibrosis patients (1429). Children with CF undergoing sinus surgery may experience some improvement of lung function parameters, although this change may not be uniform (1430). Large-scale prospective studies on the effects of FESS on lower airway function in CF are lacking.

5.2.5. COPD and rhinosinusitis
The upper airways of COPD patients remain less studied than in asthma in spite of the fact that a majority of COPD patients presenting at an academic unit of respiratory disease do experience sinonasal symptoms (1431, 1432). Several proinflammatory mediators have been found in nasal lavages of COPD patients (1432) and nasal symptoms corresponded with the overall impairment of the quality of life (1431). Recently, a high number of patients with bronchiectasis have shown to present with rhinosinusitis symptoms, radiologic abnormalities on CT scans (1433) and have a reduced smell capacity (1434). The impact of upper airway treatment in patients with COPD and bronchiectasis still needs to be properly investigated.
5.3. Cystic Fibrosis
5.3.1. Summary

There is increasing evidence that multiple genetic and protein expression differences in CF patients may contribute to their tendency to develop CRS. Future studies may identify genomeand proteome-level therapeutic targets, which may be used to prevent or lessen the severity of CRS in CF patients. Topical nasal dornase alfa, nasally inhaled or irrigated antibiotics, and saline irrigations have all been shown to improve outcomes in CF patients with CRS, both as monotherapy or combined with ESS. ESS also improves outcomes in CF patients with CRS. Future prospective studies are needed to further elucidate the role of medical and surgical therapy in CF patients with CRS.

5.3.2. Introduction
Cystic fibrosis (CF) is the most common lethal recessive disorder in Caucasians. It is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CTFR) gene on chromosome 7, which leads to production of a defective chloride channel. This in turn causes improper salt balance and thick tenacious secretions in CF patients. Since Bulgarelliet al. (1435) and others reported sinusitis in patients with pulmonary and pancreatic manifestations of cystic fibrosis, it has been recognized that patients with cystic fibrosis are prone to the development of early and refractory chronic rhinosinusitis (CRS). While mucous stasis and impaired mucociliary transport play a significant role, the full range of factors at play in this association have yet to be elucidated. Chronic bacterial infections and host inflammatory response cause stasis and damage in the sinuses, lungs, and gastrointestinal system, and it is thought that high mucus viscosity leads to obstruction of sinus ostia, dysfunction of ciliary clearance, and recurrent polyposis and paranasal sinus infections.

5.3.3. Anatomic, histopathologic, and physiologic factors in Cystic Fibrosis patients with Chronic Rhinosinusitis
Histopathologic studies have found several differences in expressed proteins found in CF and control patients, particularly proteins involved in the various inflammatory pathways. Additionally, studies have found altered glandular structure in CF patient sinonasal mucosa. Studies have examined anatomic differences in CF patients, such as hypoplasia or decreased aeration in the sinus cavities of CF patient. The prevalence of heterozygous CFTR gene mutations in patients with chronic rhinosinusitis has also been examined. Bacteriology/Mycology
The bacteriology and the association between pathogenic bacteria found in bronchoalveolar lavages (BAL) and paranasal cavity cultures in patients with cystic fibrosis (CF) has recently been the subject of investigation (1429). In CF patients who underwent functional endonasal endoscopic sinus surgery (FESS) culture samples obtained from bronchoalveolar lavages and paranasal cavities most frequently demonstrated Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus viridans. Statistical analysis revealed a statistically significant association between paranasal cavity cultures and lower airway bronchoalveolar lavage cultures for P. aeruginosa and S. aureus. Another study reviewed 30 consecutive CF patients undergoing ESS for the presence of sinus fungal isolates (1436). Thirty-three percent of fungal cultures were positive, with two patients newly diagnosed with allergic fungal sinusitis. The opportunistic pathogen Pseudomonas aeruginosa is a frequent colonizer of the airways of patients suffering from cystic fibrosis (CF). In a study it was observed in several children that the paranasal sinuses constitute an important niche for the colonizing bacteria in many patients. The paranasal sinuses often harbor distinct bacterial subpopulations, and in the early colonization phases there seems to be a migration from the sinuses to the lower airways, suggesting that independent adaptation and evolution take place in the sinuses. Importantly, before the onset of chronic lung infection, lineages with mutations and antibiotic-resistant clones are part of the sinus populations. Thus, the paranasal sinuses potentially constitute a protected niche of adapted clones of P. aeruginosa, which can intermittently seed the lungs and pave the way for subsequent chronic lung infections (1437). It has been suggested that P. aeruginosa can adapt or acclimate to the environment in the lungs, during growth in anoxic parts of the paranasal sinuses (1438). Arachidonic Acid Metabolism
Patients with CF are known to have increased pro-inflammatory cytokine, leukotriene, and prostaglandin production. The staining patterns of cyclooxygenase 1 and 2 (COX-1 and -2) and 12-Lipoxygenase lipoxygenase (12-LO) in the sinonasal epithelium and submucosal glands of CF and non-CF patients with chronic rhinosinusitis (CRS) demonstrates a significant elevation in the staining of columnar epithelium and submucosal glands for COX-2 and 12-LO in CF patients compared to control CRS patients (1439). No significant differences were noted for the staining intensity of COX-1, 5-LO, or 15-LO. The upregulation of COX-1 and COX-2 in nasal polyps in patients with cystic fibrosis has also been examined (1440). The degree of mRNA and protein expression of COX-1 and COX-2 in the nasal mucosa of patients with CF was examined using RT-PCR and Western blot analysis. COX-1 and COX-2 mRNA levels were significantly higher in CF nasal polyps versus control nasal mucosa, but no significant difference was found between CF nasal polyps and non-CF nasal polyps. COX-1 and COX-2 protein levels were significantly higher in CF nasal polyps versus both nasal mucosa controls and non-CF nasal polyps, suggesting that upregulation in the expression of COX-1 and COX-2 might be related to the high production of prostanoids reported in CF patients.

CF patients with CRS show upregulation in COX, MUC/mucin, and surfactant gene expression, as well as increased L-selectin mediated lymphocyte localization and adhesion. Paranasal sinus development is often decreased in CF patients. Mucous Production and Glandular Histology
A study of paediatric CF patients and non-CF patients with CRS with polyps who underwent sinus surgery examined surgically obtained sinus specimens of each group using conventional histology and immunohistochemistry (1441). CF patients showed dilated glandular ducts and a predominance of mucous glands with a significantly elevated number of plasma cells and mast cells, but not eosinophils, compared to non-CF patients. Another study examined the histologic and morphometric characteristics of paranasal sinus mucosa of paediatric CRS controls and paediatric CF patients with CRS (1442). The number of goblet cells (GCs) and mucin-expressing cells and the submucosal gland (SMG) area was determined, as well as the cellular localization and expression of MUC5AC and MUC5B mucins. A significantly increased area (4.4-fold) of submucosal glands (SMGs) was detected in the sinus mucosa of patients with CRS/CF compared with controls. Neither GC hyperplasia nor increased expression of MUC5AC was observed in the CRS/CF group, but there was a positive trend toward increased glandular MUC5B expression in the CRS/CF cohort. Colocalization of MUC5AC and MUC5B expression was observed in a subset of GCs. A study examined the microscopic ultrastructural mucosal changes in paediatric CF patients, comparing the nasal mucosa of patients without chronic inflammation as controls and specimens of duodenal mucosa of patients with CF (1443). The mucosa of CF patients showed seromucous glands displaying abnormal morphological structures with wide mucous cells and cystic dilatation under a thick layer of respiratory epithelium with a high proportion of goblet cells. The glandular cells showed inhomogeneous heterogeneous glandular droplets in the supranuclear cell portion. The nuclei contained dispersed chromatin as a sign of increased activity and the structures of the Golgi apparatus were clearly detectable. Alterations in surfactant gene expression (SPA1, A2, and D) in various forms of inflammatory CRS, including CF, has been examined (1444). Patients with CF showed significantly increased SPA1, SPA2, and SPD mRNA when compared with controls. Patients with CRS with nasal polyposis also demonstrated elevated SPA1, SPA2, and SPD, but lower levels than CF patients. Patients with allergic fungal sinusitis (AFS) had increased SPA1, SPA2, and SPD, but the increases were not significant versus healthy controls. Inflammatory Mediators
The alteration in various inflammatory pathways in CF patients has been examined. A study compared the inflammatory-cell and cytokine profiles of CRS patients with CF, adults with, and control patients with no allergies or sinus disease (862). Immunohistochemical analysis found a higher number of neutrophils, macrophages, and cells expressing messenger RNA for interferon gamma and interleukin-8 in patients with CF vs. non-CF patients with CRS or in controls. The number of eosinophils and cells expressing messenger RNA for IL-4, IL-5, and IL-10 was higher in patients with CRS versus those with CF and controls. Subgroups of patients with CRS were identified by inflammatory mediator profile in another study (620). Sinonasal mucosal tissue from nasal polyp (NP) patients, CF patients with nasal polyps (CF-NP), CRSsNP patients and control patients were stained for CD3, CD25, CD68, CD20, myeloperoxidase (MPO), CD138, eotaxin, interleukin IL-1beta, IL-2sRalpha, IL-5, interferon IFN-gamma, IL-8, transforming growth factor TGF-beta1, and tumour necrosis factor-alpha. NP and CF-NP patients showed increased numbers and activation of T cells, while only NP patients displayed an increase in plasma cells. NP patients had significantly higher levels of eosinophilic markers (eosinophils, eotaxin, and eosinophil cationic protein (ECP)) compared with CRS, controls and CF-NP. CRS was characterized by a Th1 polarization with high levels of IFN-gamma and TGF-beta, while NP showed a Th2 polarization with high IL-5 and IgE concentrations. NP and CF-NP were discriminated by oedema from CRS and controls, with CF-NP displaying a very prominent neutrophilic inflammation. The expression of the endothelial L-selectin ligand was examined in patients with nasal polyps, including CF patients (18). Selectins are a family of glycoproteins essential for leukocyte recruitment, and L-selectin is expressed by most circulating leukocytes. L-selectins on leukocytes and their counter-receptors on endothelial cells (such as CD34) have been shown to be involved in leukocyte recruitment in chronic rhinosinusitis without nasal polyps. CD34 is a cell-cell adhesion molecule also required for T cells to enter lymph nodes, and binds to L-selectin. CD34 is expressed on lymph node endothelia whereas the L-selectin to which it binds is on the T cell. The sialylated Lewis X Antigen (sLe(x)) is another reported selectin ligand. Patients with NP showed a decrease in the number of CD34+ vessels while the number of eosinophils and the percentage of vessels expressing endothelial sulfated (sLe(x)) tetrasaccharide epitopes was upregulated in all groups of simple NP. Tissue eosinophilia but not the percentage of endothelial sulfated sLe(x) epitopes was also increased in NP patients with aspirin intolerance. Results in CF NP patients were similar to those observed for simple NP. Antro-choanal polyps were characterized by low numbers of tissue eosinophils and relatively few vessels expressing endothelial sulfated sLe(x) epitopes. Anatomic Variations
Variations in temporal bone pneumatization (TBP) and paranasal sinus pneumatization (PSP) in CF patients were assessed by computed tomography (1445). Genotype data for patients with CF was determined. TBP did not differ between CF, CRS and controls. PSP was less developed in the CF group than the CRS and control groups. CRS and controls did not differ in PSP. The DeltaF508 status correlated with poorer PSP, but greater TBP. PSP was impaired in CF, and DeltaF508 homozygosity was related to poor PSP. TBP was well preserved in the CF population and DeltaF508 homozygosity correlated with greater TBP.

5.3.4. Heterozygous and Homozygous CTFR Mutations and CRS

Evidence suggests that even CFTR-mutation heterozygotes may be more likely to experience CRS when compared to the normal wild-type CFTR population.

Several studies have examined the prevalence of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene in the CRS population, and whether heterozygous mutations predispose patients to CRS (1446). One study examined the DNA of CRS patients and controls for 16 mutations accounting for 85% of CF alleles in the general population (1351). Chronic rhinosinusitis patients with 1 CF mutation were evaluated for a CF diagnosis by sweat chloride testing, nasal potential difference measurement, and DNA analysis for additional mutations. Of 147 patients with CRS and 123 CRS-free control volunteers 11 CRS patients were found to have a CF mutation (DeltaF508, n = 9; G542X, n = 1; and N1303K, n = 1). Diagnostic testing excluded CF in 10 of these patients and led to CF diagnosis in one patient. The proportion of CRS patients who were found to have a CF mutation (7%) was significantly higher than in the control group (2%). Nine of the 10 CF carriers had the CTFR gene polymorphism M470V, and M470V homozygotes were significantly overrepresented in the remaining 136 CRS patients. Another study surveyed 261 obligate CFTR heterozygotes and a control group of 201 individuals negative for a standard mutation panel for possible CF-related conditions such as asthma, bronchiectasis, pneumothorax, allergic bronchopulmonary aspergillosis, sinusitis, nasal polyps, gallstones, liver cirrhosis, diabetes, pancreatitis, bone fractures, and hypertension (1447). There was no difference between heterozygotes and controls, with the exception of hypertension (carriers 28/261, controls 7/201, p = 0.004), and, in males, nasal polyps (carriers 7/126, controls 0/102, p value = 0.0178), and, again, hypertension (carriers 17/126, controls 5/102, p value = 0.0407). The investigated CF-related conditions were no more frequent in CF heterozygotes than in control subjects, with the exception of a higher rate of hypertension overall in heterozygotes and a higher rate of nasal polyposis in male CF heterozygotes. When age-matched carriers and controls were compared these differences disappeared, suggesting that age differences in the groups with significant differences in nasal polyps and hypertension may have contributed. A study in an isolated population practicing a communal lifestyle with common environmental exposures examined genetic variation underlying susceptibility to CRS using linkage analysis (1337). Using physical examination, medical interviews, and a review of medical records, eight individuals with CRS were identified from 291 screened. These eight individuals were related to each other in a single 60 member, nine-generation pedigree. A genomewide screen for loci influencing susceptibility to CRS using 1123 genome-wide markers was conducted and the largest linkage peak was on chromosome 7q31.1-7q32.1, 7q31 and included the CFTR locus again indicating that CTFR mutations may be a marker for CRS. Genotyping of 38 mutations in the CFTR gene did not reveal variation accounting for this linkage signal. In the paediatric population a study examined 58 white children who had chronic rhinosinusitis, none of whom satisfied diagnostic criteria for CF, who underwent sweat testing and genotyping for CFTR mutations using an assay that detects 90% of mutations seen in this ethnic group (1448). Of the patients tested 12.1% harboured CFTR mutations as compared with the expected rate of 3% to 4% in this ethnic group. The mutations included DeltaF508, R117H, and I148T. Only 1 child had a borderline abnormal sweat test. Two of the patients experienced recurrent Pseudomonas aeruginosa rhinosinusitis, and both were DeltaF508 heterozygotes. Three other children with no detectable CFTR mutation had borderline elevated sweat-test results. A related study examined the prevalence of chronic rhinosinusitis in known cystic fibrosis carriers (1449). Obligate CF carriers (parents of patients with CF) were assessed by a sinus disease questionnaire and a subgroup of participants was evaluated by a physician for signs and symptoms of CRS. Of 147 obligate CF carriers 36% had self-reported CRS. Twenty-three CF carriers (14 with and 9 without CRS based on self-reporting in the questionnaire) were clinically evaluated and of these7 were diagnosed as having CRS (all 7 with self-reported CRS), while another 6 had allergic rhinitis or recurrent acute rhinosinusitis (all 6 with self-reported CRS), and 10 had no evidence of active sinus disease (1 with self-reported CRS).
Another study examined 126 cystic fibrosis patients, 90 with typical clinical features and 36 with atypical phenotypes (1450). Genetic tests were carried out to determine the genotype of CFTR gene. Cytological examination of nasal mucosa was carried out in all the patients. In 71.5% of patients with cystic fibrosis, infectious chronic non-specific rhinosinusitis was found. Other types of rhinosinusitis such as acute infectious, chronic allergic and non-allergic with eosinophilia were found in 21.4% of patients, whereas in 7.1% of patients no clinical symptoms of rhinosinusitis were found. Nasal polyps were found in 18.3% of patients with cystic fibrosis: in 21 patients with a typical form and in 2 patients with an atypical form. Nasal polyps were more frequent in groups with the genotype consisting of both "strong" mutations than in the group with unknown or "mild" mutations.
Conclusion: There is Level II and III evidence that significant immunologic differences exist in the CF population with CRS versus non-CF CRS patients. COX-1 and COX-2 are upregulated in CF patients with CRS, leading to increased prostaglandin levels. Level III data also suggests an increase in mucous gland proliferation, surfactant gene expression, and MUC mucin gene expression is also seen in CF patients with CRS, and L-selectin receptors involved in lymphocyte localization and adhesion are also increased in CF patients with CRS. There are conflicting level II and III reports on whether CFTR-mutation heterozygotes are more likely to experience CRS, but the predominance of level II and III data suggests that patients who are heterozygous carriers of CF mutations are more predisposed to CRS when compared to the normal wild-type CFTR population. Level II and III data suggests that the bacteriology of bronchial cultures in CF patients often correlates with the bacteriology of sinonasal cultures.

There is Level IB evidence to support the use of nasally inhaled dornase alfa in CF patients with CRS, and level II and III evidence supporting the use of nebulized or irrigated topical antibiotics in CF patients with CRS.
5.3.5. Medical Therapy in Cystic Fibrosis and Chronic Rhinosinusitis Dornase Alfa

Two studies have examined the use of dornase alfa (the mucolytic agent Pulmozyme) in CF patients with CRS. One study reported on the efficacy of dornase alfa as a postoperative adjunct in CF patients with CRS in a double-blind placebocontrolled trial on 24 patients with cystic fibrosis and chronic sinusitis (1451). The patients underwent sinonasal surgery during a 3-year period and received once-daily doses of either dornase alfa (2.5 mg) or hypotonic saline solution (5 mL of 0.876% w/v NaCl solution) beginning 1 month after surgery and for a 12-month period. Primary outcomes were nasal-related symptoms and nasal endoscopic appearance; secondary outcomes were forced expiratory volume in 1 second, nasal computed tomography findings, and saccharine clearance test results. Patients were evaluated before and after treatment. All postoperative outcomes were significantly improved for both treatments at 1 month (P<.05); primary outcomes were improved at 24 and 48 weeks in the group receiving dornase alfa (P<.05), and at 12 weeks in the group receiving placebo. Secondary outcomes were better in the dornase alfa group (P<.01) than in the placebo group at 12 months except for the saccharine clearance test results. In particular, median relative difference in forced expiratory volume in 1 second between dornase alfa and placebo was significantly improved in the dornase alfa group (P<.01). Nasally inhaled dornase alfa was superior to hypotonic saline for improving forced expiratory volume in 1 second, nasal computed tomography findings, and saccharine clearance test results. Another double-blinded placebo-controlled crossover trial examined sinonasal inhalation of dornase alfa in CF patients (1452). Primary outcome parameters were assessed by the Sino-Nasal Outcome Test (SNOT-20) and ventilated volume as measured by magnetic resonance imaging. Five CF patients were randomized to inhale either dornase alfa or 0.9% NaCl for 28 days and, after a wash-out period of 28 days, crossed over to the alternative treatment. Normal saline was not associated with relevant changes in SNOT-20 scores while dornase alfa significantly improved quality of life as measured by the SNOT-20. MRI results showed no definite trend. Topical Antimicrobial Therapy in CF Patients with CRS
One systematic review examined the evidence for topical antimicrobial therapy in CRS, including some data specifically looking at cystic fibrosis patients with CRS (1453). A search of the MEDLINE, EMBASE, and CINAHL databases; Cochrane Central Register of Controlled Trials (3rd Quarter 2007); and Cochrane Database of Systemic Reviews (3rd Quarter 2007) databases yielded seven controlled trials with five of these double blinded and randomized. Only one of the randomized trials showed a positive outcome. Overall, there was low-level corroborative evidence for the use of topical anti-bacterials. They found evidence for the use of nasal irrigation or nebulization rather than delivery by nasal spray. For the antibacterial studies, the highest level of evidence was for studies that used postsurgical patients and culture-directed therapy. Both stable and acute exacerbations of CRS appeared to benefit from topical antimicrobials. The evidence in the subgroup of cystic fibrosis patients with CRS seemed to indicate that topical antibiotics should not be first-line management for Cruet were useful in patients refractory to topical steroids and oral antibiotics. Gene Therapy
A single phase II, randomized double blind placebocontrolled trial of tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, was identified (1454). TgAAVCF was given to 23 patients with a dose of 100,000 replication units of tgAAVCF administered to one maxillary sinus, while the contralateral maxillary sinus received a placebo treatment as a control. Neither the primary efficacy endpoint (the rate of relapse of recurrent sinusitis) nor secondary endpoints (sinus transepithelial potential difference (TEPD), histopathology, sinus fluid interleukin IL-8 measurements) achieved statistical significance when comparing treated to control sinuses within patients. One secondary endpoint, measurements of IL-10 in sinus fluid, was significantly increased in the tgAAVCF-treated sinus relative to the placebo-treated sinus at day 90 after vector instillation. The tgAAVCF administration was well tolerated, without adverse respiratory events or enhanced inflammation in sinus histopathology and the Phase II trial confirmed the safety of tgAAVCF but provided little support of its efficacy in the within-patient controlled sinus study.
Conclusion: There is Level IB evidence to support the use of nasally inhaled dornase alfa in CF patients with CRS, with dornase alfa demonstrating an improvement in nasal-related symptoms, nasal endoscopic appearance, FEV1, and CT findings vs. inhaled hypo- and isotonic saline. There is level II and III evidence supporting the use of nebulized or irrigated topical antibiotics as a second-line therapy for CF patients with CRS. There is level IB data demonstrating the safety of tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, but no therapeutic benefit vs. control vector in reducing frequency of sinusitis, decreasing IL-8 levels, or decreasing histopathological evidence of inflammation. Further randomized controlled trials on oral and topical steroids and antimicrobials in CF patients with CRS are needed.

5.3.6. Surgical Therapy in Cystic Fibrosis and Chronic Rhinosinusitis

Data on surgical therapy for CF patients with CRS is primarily level III but supports the safety and efficacy of endoscopic sinus surgery in CF patients. ESS in the Adult CF Population
Several retrospective studies and case series have examined the efficacy of endoscopic sinus surgery in the CF population, but no randomized controlled trials specifically on CF and CRS were identified. One prospective, non-randomized study examining ESS in CF patients was identified (1455). One study used a retrospective medical record review of the extent of nasal polyposis endoscopically in a cystic fibrosis population before the first surgical intervention and the effect of the severity of preoperative polyposis on the need for revision ESS in the CF population (1456). Patients with a clinical preoperative diagnosis of cystic fibrosis and sinusitis were graded preoperatively with the extent of polyps prospectively graded into 3 groups before the first surgical intervention [no polyps (grade A), mild polyposis (grade B), and extensive polyposis (grade C)]. The number of patients needing revision ESS and the mean time to revision ESS were compared among the 3 groups: 14 patients required revision surgery: 3 with mild polyps and 11 with extensive polyps. Mean time to revision surgery was 39.7 months for those with grade B and 23.8 months for those with grade C and the rate of revision ESS was significantly different among the 3 groups. A nested case-control study examined the outcomes following endoscopic sinus surgery in adult patients with cystic fibrosis compared matched controls without CF (1456). Preoperative CT and preoperative/postoperative endoscopic findings and changes in two disease-specific quality-of-life (QoL) instruments were evaluated both preoperatively and postoperatively. Preoperative CT scores and endoscopy scores were significantly worse in CF patients. Postoperative endoscopy scores were significantly worse for CRS patients with CF, although the degree of improvement on endoscopy within each group was no different and both groups experienced similar improvement in QoL after ESS.

The benefit of endoscopic mega-antrostomy for recalcitrant maxillary sinusitis in CRS patients including CF patients was examined in a retrospective review of patients who underwent endoscopic maxillary mega-antrostomy (EMMA) for recalcitrant maxillary sinusitis (1457). Relevant comorbid factors included prior Caldwell-Luc or maxillofacial surgery (16/42), cystic fibrosis (11/42), asthma (11/42), and IgG deficiency (3/42). Seventy-four percent of patients reported complete resolution of symptoms while 26% reported partial symptomatic improvement. EMMA appeared to be effective and safe for the management of recalcitrant maxillary sinus disease, including the CF subset of patients.
A prospective trial examined the efficacy of endoscopic surgery with serial antimicrobial lavage (ESSAL) in CF patients, comparing ESSAL in 32 patients to conventional sinus surgery without serial antimicrobial lavage in 19 controls (1455). Conventionally treated patients underwent nasal polypectomy, ethmoidectomy, antrostomy, or Caldwell-Luc operation while the ESSAL approach incorporated preoperative rhinosinuscopy and computed tomography, endoscopic surgery, a postoperative course of antral antimicrobial lavage, and monthly maintenance antimicrobial lavage via brief antral catheterization. The main outcome measure was intensity and frequency of sinus surgery after initial presentation. The two groups were similar in clinical presentation, including the presence of nasal polyposis. The ESSAL group had fewer operations per patient, fewer Caldwell-Luc procedures, and a decrease in repeated surgery at 1-year and 2-year follow-ups.

CF patients tend to have worse preoperative CT and endoscopy scores than non-CF CRS patients, but the degree of improvement on endoscopy and the improvement in QoL after ESS tends to be similar in CF and non-CF patients. ESS with serial antimicrobial lavage has been shown to be superior to surgery alone in CF patients, and CF patients may benefit from mega-antrostomies for recalcitrant disease

Several other retrospective, Level III studies examined the safety and efficacy of ESS in the CF population. A retrospective study on the effect of ESS on CF with nasal polyposis found that the patients had a 50% chance either of their symptoms returning to preoperative severity or of undergoing a second endoscopic sinus procedure, by 18 to 24 months of postoperative followup (1458). Patients with predominantly infective symptoms of mucopurulent rhinorrhoea and pain had a significantly better outcome than patients with predominantly nasal blockage. The chance of the infective symptom group of patients suffering symptom deterioration back to the preoperative state or undergoing a second endoscopic sinus operation was 37% of that of the nasal blockage symptom group. A retrospective study on functional endoscopic ethmoidectomy (FEE) in patients with CF found that symptoms improved or disappeared in 9/12 cases between 1 and 3 years of follow-up and in 5/7 cases after 3 years of follow-up with a good or mild anatomical result recorded in 6/12 cases between 1 and 3 years of follow-up and in 5/7 cases after 3 years of follow-up. During follow-up, a new surgical procedure (limited in 8 patients and complete in 3 patients) was often necessary. A retrospective review of complications of ESS in patients with demonstrated a complication rate of 11.5%, which compared favourably with the non-CF ESS complication rates of 0-17% reported in the literature. A related study on the effectiveness of sinus surgery in CF patients status post lung transplant reviewed ESS in 37 patients with cystic fibrosis after lung transplantation and found ESS to be successful in 54% and partially successful in 27% of patients (1459). A significant correlation was found between negative sinus aspirates and negative BAL and between positive sinus aspirates and positive BAL. Successful sinus management led to a significantly lower incidence of tracheobronchitis and pneumonia. ESS in the Paediatric CF Population
A retrospective review of paediatric patients with CF treated for recurrent sinusitis Duplechain et al. (1460) examined the role of ESS in. The charts of 32 children were retrospectively reviewed. All children underwent surgery performed by one of two physicians. The presence of polyps in the population with cystic fibrosis was significant; 86% of patients (12 of 14) in the CF group demonstrated polyps at the time of surgery, whereas polyps were detected in only 16% of the patients (3 of 18) with non-CF CRS. Eighty-nine percent (eight of nine) of intraoperative sinus culture samples were culture positive for Pseudomonas species in the CF group, while none of the samples taken from the group with non-CF showed Pseudomonas organisms. ESS was safe, well-tolerated, and effective in the paediatric CF and non-CF populations. Another retrospective study examined the relationship between CF and ESS (1461). Sixteen paediatric and 1 adult patients with previously diagnosed CF, documented chronic sinus disease and nasal polyposis that had failed long-term maximal medical management underwent ESS. The patients or their parents rated the pre- and postoperative severity and frequency of their symptoms associated with chronic sinus disease. There was no change in the relative health of patients as measured by the number of hospitalizations but there was a significant improvement in the quality of life. There was a marked decline in the frequency of nasal obstruction, nasal discharge and postnasal drip and a high level of patient satisfaction following FESS.

Data on surgical therapy for CF patients with CRS is primarily level III. The available data supports the use of ESS in CF-related CRS, and supports its safety and efficacy in retrospective studies. The level III data also suggested that the rate of complications is similar to non-CF patients, that ESS is safe in paediatric CF patients, and that patients with more severe polyposis tended to require repeat surgery more frequently. Two level IIA studies were identified. One prospective case control study demonstrated that while CF patients tended to have worse preoperative CT scores and endoscopy scores and worse postoperative endoscopy scores, the degree of improvement on endoscopy and the improvement in QoL after ESS tended to be similar in CF and non-CF patients. Another level IIA, prospective trial demonstrated that endoscopic surgery with serial antimicrobial lavage (ESSAL) was superior to surgery alone in CF patients, with the ESSAL group having fewer operations per patient, fewer Caldwell-Luc procedures, and a decrease in repeated surgery at 1-year and 2-year follow-ups. Randomized controlled trials are lacking.
5.4 Aspirin exacerbated respiratory disease
5.4.1. Summary

The presence of aspirin sensitivity in a patient with rhinosinusitis/asthma is associated with severe and protracted eosinophylic airway disease requiring comprehensive management of all components of the syndrome. The diagnosis of ASA-hypersensitivity initially based on a history should be confirmed/excluded with oral, nasal or bronchial provocation testing with aspirin. Avoidance of aspirin/non-steroidal antiinflammatory drugs (NSAIDs) should be recommended and the airway disease management should follow general guidelines, with emphasis on adequate dose of topical steroids. If sinus surgery is performed the beneficial effects may extend to bronchial asthma. Desensitization and maintenance treatment with aspirin may be valuable alternative for some patients.

5.4.2. Introduction

Presence of hypersensitivity to aspirin/NSAID's in a patient with chronic rhinosinusitis heralds severe, hyperplastic sinus disease with high polyps recurrence after sinus surgery

The presence of hypersensitivity to aspirin or other NSAIDs in a patient with rhinosinusitis and nasal polyposis is associated with a particularly persistent and treatment-resistant form of the disease, coexisting usually with severe asthma and referred to as the "aspirin triad" (1462). Since the chronicity of the upper and lower airway inflammation is not related to NSAIDs intake or avoidance, and NSAIDs only occasionally may exacerbate symptoms the term Aspirin Exacerbate Respiratory Disease (AERD) has been recently propose to describe this syndrome (1463, 1464).The prevalence of nasal polyposis in aspirin-sensitive asthmatics may be as high as 60-70%, as compared to less than 10 % in the population of aspirin-tolerant asthmatics (1465). The unusual severity of the upper airway disease in these patients is reflected by high recurrence of nasal polyps, and frequent need for endoscopic sinus surgery (1466, 1467). Rhinosinusitis in aspirin hypersensitive patients with nasal polyposis is characterized by involvement of all sinuses and nasal passages and the thickness of hypertrophic mucosa is significantly higher in AERD patients as documented with computer tomography (1468).

5.4.3. Pathomechanism of acute ASA-induced reactions
In ASA-sensitive patients acute nasal symptoms (sneezing, rhinorrhoea and congestion) may be induced by challenge with oral or intranasal aspirin but also with other cross-reacting NSAIDs .The mechanism of these acute adverse reactions has been attributed to inhibition by NSAIDs of an enzyme cyclooxygenase-1, with subsequent inflammatory cell activation and release of both lipid and non-lipid mediators (1469, 1470). The ASA-induced nasal reaction is accompanied by an increase in both glandular (lactoferrin, lysozyme) and plasma (albumin) proteins in nasal secretions indicating a mixed response, involving both glandular and vascular sources (1471). Concomitant release of both mast cell (tryptase, histamine) and eosinophil (ECP) specific mediators into nasal washes clearly indicate activation of both types of cells (1472-1474). Increased concentration of cysteinyl leukotrienes in nasal secretion was also observed within minutes after ASA-challenge although the cellular source of leukotrienes has not been determined (1475). In parallel with inflammatory mediator release an influx of leucocytes into nasal secretions occurred with significant enrichment in eosinophils (1474).
The mechanisms of hypersensitivity to aspirin/ NSAID's is not immunological, but is related to cyclooxygenase inhibition and involves several abnormalities of the arachidonic acid metabolism

5.4.4. Pathomechanism of chronic rhinosinusitis and nasal polyposis in patients with AERD
Although the pathogenesis of chronic eosinophilic inflammation of the airway mucosa and nasal polyposis in ASA-sensitive patients, does not seem to be related to intake of aspirin or other NSAIDs it has been speculated that the pathomechanism underlying rhinosinusitis and nasal polyposis in aspirin-sensitive patients may be different from that in aspirin tolerant patients (1467, 1476)

Cells and cytokine profile
A marked tissue eosinophilia is a prominent feature of rhinosinusitis and nasal polyposis in ASA-hypersensitive patients and accordingly significantly more ECP was released from nonstimulated or stimulated nasal polyp dispersed cells from ASAsensitive patients (1477, 1478). An increased number of eosinophils in the tissue has been linked to distinctive profile of cytokine expression with upregulation of several cytokines related to eosinophil activation and survival ( e.g. IL-5, GMC-SF, RANTES, eotaxin) (902, 1479, 1480). It has been suggested that overproduction of IL-5 might be a major factor responsible for an increased survival of eosinophils in the nasal polyps resulting in increased intensity of the eosinophilic inflammation particularly in aspirin-sensitive patients (1481). In fact decreased apoptosis was documented in polyps from aspirin-sensitive patients, and increased infiltration with eosinophils was associated with prominent expression of CD45RO+ activated/memory cells and this cellular pattern was related to clinical features of rhinosinusitis (1482). Bachert at al (542) demonstrated, that IgE-antibodies to Staphylococcal enterotoxins ( SAEs) were present in nasal polyp tissue and their concentration correlated with the levels of ECP, eotaxin and IL-5. These relations seemed to be particularly evident in ASA-sensitive patients suggesting that an increased expression of IL-5 and ECP in polyp tissue from ASA-sensitive patients may be related to the presence of SAE that can exert direct effects on eosinophil proliferation and survival or may act as a superantigen to trigger a T-cell mediated inflammatory reaction (1483-1485). Not only activated eosinophils but also mast cells are abundant in the nasal polyps tissue from ASA-sensitive patients (824, 1486). The density of mast cells was correlated with the number of polypectomies, implicating an important role for these cells in the pathogenesis of nasal polyposis. Stem cell factor (SCF) also called c-kit ligand is a multi-potent cytokine generated by nasal polyp epithelial cells and critical for differentiation, survival, chemotaxis and activation and of human mast cells but also involved in eosinophil activation and degranulation. SCF expression in nasal polyp epithelial cells in culture correlated closely with the density of mast cells in nasal polyp tissue and was significantly higher in asthmatic patients with aspirin hypersensitivity as compared to aspirin tolerant patients (1483). In the nasal polyp tissue from AERD patients expression of metalloproteinase TIMP-1 was found to be significantly reduced and the MMP-9/TIMP-1 ratio was significantly increased in the compared with both aspirin tolerant and patients without nasal polyps, indicating for the importance of metalloproteinases expression in polyps remodelling and inflammatory changes (1487).
Recently, microarray technology was used to examine gene expression in nasal polyps of aspirin sensitive patients. It has been demonstrated that nasal polyps from AERD patients have distinct transcriptional and methylation signatures (1029, 1488, 1489). Furthermore , using proteomics based approaches several proteins that exhibited differential expression between ATA and AERD patients were identify , although at present pathophysiological and functional significance of these findings is not clear yet (1490, 1491).
5.4.5. Abnormalities in arachidonic acid metabolism
Since Szczeklik et al. (1492) reported an increased susceptibility of nasal polyps cells from ASA-sensitive patients to the inhibitory action of aspirin , arachidonic aid metabolism abnormalities have been considered a distinctive feature of nasal polyps in this subpopulation of patients. A significantly lower generation of PGE2 by nasal polyps and, nasal polyp epithelial cells as well as a decreased expression of COX-2 in nasal polyps of these patients were reported (1055, 1493). Low expression of COX-2 mRNA in nasal polyps from ASA-sensitive patients was in turn linked to a downregulation of NF-ΚB activity and to abnormal regulation of COX-2 expression mechanisms at the transcriptional level (1494, 1495). Since PGE2 has significant anti-inflammatory activity, including inhibitory effect on eosinophil chemotaxis and activation, it has been speculated that an intrinsic defect in local generation of PGE2 or abnormal balance between PGD2/PGE2 could contribute to development of more severe eosinophilic inflammation in aspirin-sensitive patients (1496). Although a significant deficit of PGE2 was demonstrated in polyp tissue of ASA-sensitive as compared to ASA-tolerant patients, decreased expression of COX-2mRNA seem to be a feature of nasal polyposis also in patients without ASA-sensitivity representing more general mechanism involved in the growth of nasal polyps (595). On the other hand the percentages of neutrophils, mast cells, eosinophils, and T cells expressing prostaglandin EP2, but not EP1, EP3, or EP4 receptors , were significantly reduced in the aspirin-sensitive compared with non aspirin-sensitive patients suggesting a potential regulatory abnormality of inflammatory cells at the receptor level (1497). . Cysteinyl leukotrienes have been implicated in the pathogenesis of chronic mucosal inflammation in ASA-sensitive patients and some studies demonstrated an increased production of cysteinyl leukotrienes in nasal polyps of ASA-sensitive asthmatics as compared to aspirin tolerant patients in vitro (1498, 1499) but these observations could not be reproduced in vivo when nasal washes were analysed (1471, 1475). Similarly when nasal polyp dispersed cells were cultured basal and stimulated release of LTC4 was found to be similar in nasal polyp cells from ASA-sensitive and ASA-tolerant patients (902). More recently an increased expression of enzymes involved in production of leukotrienes (5-LOX and LTC4 synthase) and an increased generation of LTC4/D4/E4 in nasal polyp tissue from ASAsensitive patients were found (1500-1502). Cysteinyl leukotriene production correlated with tissue ECP concentration both in ASA-sensitive and ASA-tolerant polyps suggesting that these mediators may be linked to tissue eosinophilia rather that to aspirin-sensitivity . On the other hand an increased expression of leukotriene LT1 receptors was found in the nasal mucosa of ASA-sensitive patients, suggesting local hyper-responsiveness to leukotrienes in this subpopulation of patients (1496, 1503). More recently other arachidonic acid metabolites generated on 15-LOX pathway have been associated with nasal polyposis in AA-sensitive patients. In nasal polyp epithelial cells from ASAsensitive but not ASA-tolerant patients aspirin triggers 15-HETE generation, suggesting the presence of a specific abnormality of 15-LO pathway in these patients (1493). Upregulation of 15-lipoxygenase and decreased production of the antiinflammatory 15-LO metabolite lipoxin A4 found in nasal polyp tissue from ASA-sensitive patients further points to a distinctive but not yet understood role for 15-LO metabolites in nasal polyps.
In summary, presence of hypersensitivity to aspirin or other NSAID heralds not only more severe and protracted clinical course of chronic rhinosinusitis/nasal polyps by is also associated with distinct pattern of cellular, biochemical and molecular markers of inflammation.
5.4.6. Natural history
A history of chronic rhinosinusitis and or asthma usually precedes the development of hypersensitivity to aspirin. In some patients the beginning of the disease is associated with flu-like infection, which is followed by development of chronic intractable rhinosinusitis with nasal polyps and appearance of asthma (515) Rhinosinusitis and asthma once developed run protracted course which is independent of avoidance of aspirin and other NSAIDs (1463). Although patients usually report nasal symptoms typical for non-allergic rhinitis, exacerbations of symptoms on exposure to both seasonal and perennial inhalant allergens are reported by significant proportion of patients (1466). Rhinosinusitis in patients with AERD is complicated by mucosal hypertrophy and polyps formation : the prevalence of nasal polyposis varies from 60% to 90% if diagnosed by rhinoscopy. On computer tomography polypoid mucosal hypertrophy is present in up to 100 % of patients and is more extensive in ASA-sensitive as compared to ASA-tolerant patients with nasal polyposis (1468). Nasal polyposis has a high tendency to recurrence after surgery ; the recurrence rate in ASA-sensitive patients is several times higher even after ESS (1504).
A subgroup of ASA-sensitive patients manifests a reaction exclusively in the upper respiratory tract; they do not have asthma, but clinical picture of the nasal disease (hyperthrophic rhinosinusitis) in these patients is similar to that observed in patients with ASA-triad (1505). Although some of these patients may evolve with time to a full aspirin triad, their risk of developing asthma in the future is not known.

5.4.7. Diagnosis of AERD

Oral challenge with aspirin or nasal / bronchial provocation with lysine aspirin are reliable tools to confirm/exclude hypersensitivity to aspirin/ NSAID's

The diagnosis of ASA-hypersensitivity is based on a history of adverse reaction precipitated with ASA or other non-steroidal anti-inflammatory drug. In asthmatic patients with negative history and /or those who have never been exposed to NSAIDs, but have additional risk factors (rhinosinusitis, nasal polyposis, history of near fatal reactions), the risk of adverse reaction is further increased and provocation testing my be required (1506). Oral challenge is the reference standard for the diagnosis of hypersensitivity to aspirin and other NSAIDs and several protocols for oral aspirin provocation have been developed and described (1507, 1508). Inhalation challenge with lysine-aspirin (a soluble form of acetylsalicylic acid ) has been introduced by Bianco et al. in 1977 (1509) and in Europe is often used to confirm/ exclude aspirin sensitivity in patients with bronchial asthma. Inhalation test is faster and safer to perform than oral challenge (the reaction is usually easily reversible by with nebulized beta2 agonists) and both tests have similar sensitivity and specificity (1510, 1511). Nasal provocation test with lysine aspirin is also a possible tool to diagnose hypersensitivity to aspirin providing that the clinical symptoms are combined with the objective and standardized technique of airflow measurement for assessment of the results (1512). The test is rapid and safe and can be performed in an outpatients setting even in asthmatic patients with low pulmonary function not suitable for bronchial provocation. In experienced hands the sensitivity of intranasal aspirin provocation is approaching performance of bronchial challenge (1512, 1513).
More recently in vitro tests measuring aspirin-specific peripheral blood leukocytes activation have been proposed for the diagnosis of aspirin sensitivity. The newly developed in vitro tests (FLOW CAST and ASPITest) seem to demonstrated promising performance , but require further investigations and validation before becoming routine tools for confirming the presence of aspirin hypersensitivity (1477).
5.4.8. Management of patients with AERD

Selective COX-2 inhibitors (celecoxib) are well tolerated by aspirin sensitive asthmatics and are good alternative NSAID's for patients with aspirin triad

Patient education and careful avoidance of ASA and other NSAIDs in sensitive patients seem to be of high importance, since aspirin may be a cause of severe asthmatic attack (1510). In most patients acetaminophen in low or moderate doses (below 1000 mg) can be recommended as an alternative antipyretic or analgesic drug. Preferential COX-2 inhibitors (nimesulide, meloxicam) are also tolerated by the majority, but not all, hypersensitive patients and can be recommended in an individual patient after tolerability is proved by oral challenge. Selective COX-2 inhibitors (celecoxib) are well tolerated by aspirin sensitive asthmatics and could be ideal alternative NSAIDs for patients with aspirin triad (1514).

Antileukotrienes are not more effective in aspirin-sensitive as compared to aspirin-tolerant patients

The presence of aspirin sensitivity in a patient with asthma/ rhinosinusitis heralds severe and protracted disease of the respiratory tract, characterized with eosinophilic inflammation and requiring comprehensive management of all components of the syndrome . Management of asthma and rhinosinusitis in AERD patient should follow general guidelines, but several specific measures for AERD should be considered. Standard treatment for rhinosinusitis includes high doses of topical steroids, antibiotics and occasional bursts of oral corticosteroids to control symptoms and slow down nasal polyps recurrence. Although antileukotriene drugs may also be effective in in AERD patients, they are not more effective than in ASA-tolerant (1515, 1516). At certain stage of the disease surgical procedures (polypectomy, functional endoscopic sinus surgery or ethmoidectomy) are usually needed to relieve symptoms of CRS and to remove polypoid tissue from sinuses (1517). Beneficial effects of sinus surgery may extend to bronchial asthma (1518), although patients with AERD seem to respond less well to surgical intervention (1419, 1420, 1519-1521).

Nasal/sinus surgery (polypectomy, functional endoscopic sinus surgery or ethmoidectomy) may be less effective in patients with AERD

In order to control asthma symptoms and lower airway inflammation inhaled glucocorticosteroids in relevant doses, often in combination with long acting beta-2 agonists, are recommended but in about 50% of patients chronic treatment with oral prednisone may be necessary to control the disease. There is some indication that by giving repeated doses of ASA after the initial adverse reaction a desensitization can be achieved (1522-1526) (Evidence level D).

Desensitization and maintenance treatment with aspirin alleviate upper airway symptoms and decrease rate of polyp recurrence in some patients

An alternative, but not well documented approach is intranasal desensitization and prolonged treatment with soluble lysine aspirin, which may reduce recurrence rate for nasal polyps in AERD patients (1527-1530).
5.5. Immunodeficiencies and Chronic Rhinosinusitis
5.5.1. Primary Immunodeficiencies

The association between rhinosinusitis and primary immunodeficiencies (PID) can be examined in one of two ways: 1. Those patients presenting to their primary care physicians or otorhinolaryngologists with recurrent acute rhinosinusitis (RARS) or chronic rhinosinusitis (CRS) who may have an underlying PID contributing to their clinical symptoms or
2. Patients presenting to immunologists with a variety of infections who may have RARS/CRS as one aspect of their clinical picture.

In the first situation, among CRS patients who are referred for immune evaluation, up to half may have T lymphocyte dysfunction (560), while roughly 20% have decreased IgG, IgA or IgM (560, 1531). In addition, nearly 10% have common variable immune deficiency (CVID) (560,1532). Among CRS patients who underwent FESS and had immune workup, 72% had low baseline pneumococcal titres, while 11-67% had an inadequate functional response to pneumococcal vaccine (1531,1533) and these patients had lower serum IgA (1533). These studies were conducted at tertiary institutions, thus it is possible that there is significant selection bias.
In the second situation, when examining patients with PIDs, CVID is the most frequent symptomatic primary immunodeficiency in North America and Europe, with an incidence between 1:25,000 and 1:66,000 (1534). Among CVID patients, 36 to 78% present with CRS (1534,1535). In another large cohort of multiple forms of PID (1536), the most common diagnosis was IgA deficiency (30%), followed by IgG subclass deficiency (26%) and hypogammaglobulinemia (23%), with CVID being present in 15%. Less common were combined B and T cell defects (11%), phagocytic defects (8%) and complement defects (3%). RARS was present in 41% of this cohort and CRS in 40% (1537). In patients with decreased response to pneumococcal vaccine, thus a functional antibody deficiency, 77% have rhinosinusitis (1538). Diagnosis
The diagnosis of PID can be difficult. Up to 20% of the population may have an IgG subclass deficiency but be clinically asymptomatic. Up to 90% of IgA deficient patients are asymptomatic (1539). Thus a clinically significant diagnosis requires both a defect in antibody responsiveness, as well as recurrent infections. The diagnostic delay between presentation with symptoms and definitive diagnosis ranges from 4.7 to 15 years (1534, 1536, 1540). Between 53 and 90% of adult and paediatric patients with agammaglobulinemia or CVID present with CT findings of CRS (1541). These upper airway findings do not correlate with pulmonary imaging and most commonly include mucosal thickening. Bone sclerosis and polyposis are less common (1542). Treatment
Treatment for IgG deficiency is typically intravenous immunoglobulin (IVIG) and/or prophylactic antibiotics. While these treatments may improve overall survival and decrease the rate of serious life threatening infections, they do not appear to prevent radiographic development of CRS (1542) and their clinical benefit in CRS is not proven (1534). During clinical follow up of CVID patients, 54 to 63% develop CRS in spite of IVIG (1535, 1540). Patients with CVID have persistent inflammation in sinus mucosa and positive bacterial and viral cultures despite IVIG (1541). Those with selective IgA deficiencies have increased IgG and IgM and the increase in inflammatory mediators is not as significant (1543). Most authors do not recommend IVIG routinely for clinically asymptomatic IgG deficiency patients and this is typically used in less than 10% of patients (1539). Surgery for patients with PID has not been thoroughly studied. Limited series examining a variety of patients with immune dysfunction contained only a select number of patient with immunoglobulin deficiency, thus are inconclusive (1544). Referral
The question of when the otorhinolaryngologist should perform an immunologic evaluation or refer to an immunologist for a patient with CRS or RARS is not well established. It would seem prudent to conduct such an evaluation in children with recurrent respiratory tract infections in order to identify PIDs as early as possible and initiate treatment that will impact overall survival. It would also seem prudent to conduct such investigations in adults with multiple system infections, such as otitis media, bronchitis or pneumonias or those that fail standard medical and surgical treatments for CRS. However, widespread immunologic screening in all adult CRS patients who respond to routine therapies, would likely uncover laboratory abnormalities that are clinically insignificant and do not require treatment (1539).

5.5.2. Acquired immunodeficiencies
In contrast to patients with PIDs who typically present with viral or bacterial rhinosinusitis, patients with acquired immunodeficiencies can develop rhinosinusitis in a variety of forms, including non-fungal acute rhinosinusitis (ARS), chronic rhinosinusitis (CRS), or fungal forms, most often acute invasive fungal rhinosinusitis (AIFRS) or even described more recently, fungus balls. Acquired immunodeficiencies that may predispose patients to rhinosinusitis include immunosuppression due to transplant, diabetes mellitus, medications or malignancies or human immunodeficiency virus (HIV). Organ transplants: Solid organ transplant patients often have hepatic or renal failure prior to transplant and thus are immunocompromised from their primary disease state, but even after transplant they remain at risk for development of rhinosinusitis due to immunosuppressive medications. Prior to transplant, Moon (1545) found CRS was present in 28 of 996 (2.8%) pre-liver transplant patients. Twenty-two of these patients had no treatment for CRS prior to transplantation. This untreated CRS was associated with aggravated symptoms after transplantation, but no increase in infectious or overall mortality. Similarly, another study found that preoperative CTмof patients awaiting organ transplant demonstrated 64% had radiographic abnormalities, however 77% of these patients were asymptomatic with normal endoscopy, thus routine CT scans prior to transplant is not indicated (1546). One retrospective review of ESS in 7 patients awaiting liver transplant reported that operative blood loss was an average of 495 mL and 2 cases were stopped due to excessive bleeding. Higher blood loss was associated with more severe liver disease. Four of seven patients subsequently underwent transplant (1547). Thus ESS is feasible in these patients, however it is not without risk and the benefits are not established. Post-transplant acute invasive fungal rhinosinusitis (AIFRS) becomes a major concern. Sun (1548) reported an overall mortality of 52% in ninety solid organ transplant patients with rhinoorbital-cerebral zygomycosis. Central nervous system (CNS) involvement was present in 56% with isolated CNS involvement in only 2%. Sinus disease was most frequent in maxillary sinus (80%), followed by ethmoid (65%), sphenoid (45%) and frontal sinus (22%). Compared to diabetes mellitus (DM) patients, transplant patients had a lower likelihood of orbital and sinonasal involvement, but higher likelihood of CNS invasion. Lipid formulations of amphotericin B correlated with lower mortality in transplant patients. Hematopoietic stem cell transplantation (HSCT)
Similar to solid organ transplant, patients undergoing hematopoietic stem cell transplantation (HSCT), are at risk of developing rhinosinusitis prior to transplant due to their underlying malignancy, as well as post-transplant from their immunosuppression. A number of studies have looked at preHSCT screening for rhinosinusitis, and have generally concluded they are not useful in asymptomatic patients. A retrospective review of 100 patients who underwent HSCT found that there was no increased risk of developing CRS postHSCT for patients with disease on pre-HSCT screening CT, sinus symptoms at time of transplant, tobacco use, asthma, allergies, low IgG or prior history of CRS. Patients with graft versus host disease (GVHD) were 4.3 times more likely to develop CRS postHSCT (1549). Ortiz (1550) found no evidence of disease on 77% of pre-HSCT scans and 61% of post-HSCT scans, thus concluding CT staging prior to HSCT is not useful in predicting post-HSCT CRS. This was corroborated by Moeller (1551). Prior to HSCT, 71 patients underwent evaluation for rhinosinusitis. Sixty-five percent were asymptomatic. All patients who required medical or surgical treatment had symptoms and positive endoscopy and/or CT. Won (1552) evaluated 252 HSCT patients. Nine percent had sinusitis prior to HSCT and this increased to nearly 16% post-HSCT. Patients with pre-HSCT rhinosinusitis had a high occurrence of post-HSCT rhinosinusitis (34 vs. 14%), but again, CT scans alone were not predictive of post-HSCT rhinosinusitis. However, in pre-HSCT patients who are clinically symptomatic and have CT evidence of CRS, medical or surgical intervention for CRS prior to HSCT reduced the rate of post-HSCT CRS. Routine CT scans and clinical evaluation in asymptomatic patients was not useful.
When examining clinical symptoms, Arulrajah (1553) found that children who are status post HSCT had more severe sinus disease on CT associated with symptoms of rhinorrhoea, nasal congestion or cough when compared to immunocompetent children, however the immunocompetent children still had significant symptoms. Hematologic malignancies
Acute invasive fungal rhinosinusitis (AIFRS) can be a life threatening infection in patients with hematologic malignancies that requires aggressive medical and surgical intervention. A retrospective review of 46 patients with AIFRS found Aspergillus was the most common pathogen and AIFRS developed more commonly in patients with acute myeloid leukaemia (AML) and prolonged neutropenia > 10 days. Bony erosion and extra sinus infiltration was found in 33% of patients and 41% patients died within 6 weeks (1554). Zappasodi (1555) reported on seven cases of AIFS in patients with acute leukaemia with neutropenia. Facial pain was the initial symptom in all cases, associated with fever in 6 of 7. CT demonstrated unilateral involvement, endoscopy and biopsy confirmed diagnosis. Resolution required improvement in neutropenia, as well as surgical debridement and antifungals. There is controversy over the benefits of antifungal prophylaxis in these patients (1556). One study found that patients with invasive zygomycosis infections were more likely to have sinus involvement and be on voriconazole prophylaxis than those patients who developed invasive aspergillus infections (1557). HIV
The prevalence of CRS in HIV infected adults ranges from 12-14.5% (1558, 1559). The presence of sinusitis was not associated with an increased risk of death (1559). In adults with AIDS, there is a higher incidence of fever, postnasal discharge and more severe CT findings (1558). In a retrospective review of 471 HIVinfected children, 7.8% had CRS and 6.5% had ARS. Lower CD4 lymphocytes were seen in children with CRS, while those over 6 years of age with ARS had higher CD4 counts. Children less than 6 years old who were taking protease inhibitors presented with a higher prevalence of ARS (1560). Diabetes Mellitus (DM) Uncontrolled
DM is among the leading causes of AIFRS in most series. AIFRS in DM patients may more commonly involve the orbit or sinuses and less commonly involve the CNS when compared to transplant patients (1548). Mortality appears to be higher in AIFRS associated with DM when compared to that associated with hematologic malignancies (1561). Diagnosis
The diagnosis of AIFRS depends upon maintaining a high clinical suspicion in the immunocompromised patient population. Symptoms and radiographic findings can often be subtle, as these infections appear to begin in the nasal cavity (1562) and prompt biopsy is required to establish the diagnosis. Unilateral nasal cavity thickening has been reported as the most common finding in AIFRS (1563). The most sensitive imaging study for detecting early changes of AIFRS is extrasinus invasion on MRI (1564). Treatment and outcomes
A retrospective review of 45 cases of AIFRS included patients with hematologic malignancy (28 patients), DM (10 patients), solid organ transplant (3 patients), chronic steroid use (3 patients) and HIV (1 patient). The overall mortality was 18%. Twenty five percent of patients with hematologic malignancy died and had no recovery of their neutrophil count. Forty percent of DM patients died of AIFRS. The mortality rate for Mucor was 29% and for Aspergillus it was 11% (1561). AIFRS can be treated surgically with endoscopic or open approaches with similar outcomes. Overall survival in a retrospective review was 57% in open surgery group (7 patients) and 47% in endoscopic group (19 patients) (260). Ruping (1565) reported on 41 patients with invasive zygomycosis, including those with malignancy (63%), DM (17%) and solid organ transplant (9.8%). Sites of infection included the lungs (58%), soft tissues (19%), sinoorbital region (19%), and CNS (15%). Overall survival was 51%. Antifungal prophylaxis did not prevent development of invasive zygomycosis, however, treatment with liposomal amphotericin B was associated with improved response and survival. Early detection and reversal of the underlying disease process and immunosuppression is as important as the surgical and antifungal therapies (1566). Fungus ball
In addition to AIFRS, immunocompromised patients can develop non-invasive fungus balls that present differently than fungus balls in immunocompetent patients (1567). In a retrospective review of 24 patients, 11 of 24 had some degree of immunocompromise. These immunocompromised patients (organ transplant or DM) were more likely to have aspergillus and non-dilated sinus ostia.

5.6. Allergic fungal rhinosinusitis
5.6.1. Introduction

There is much debate regarding the role of fungi in CRSwNP and whether the diagnostic group of AFRS truly represents a unique disease. In spite of our limited knowledge regarding the pathophysiology of CRSwNP, there is a subset of patients as defined by the classic Bent-Kuhn criteria for AFRS who demonstrate some phenotypic differences when compared to other CRSwNP patients. The original Bent-Kuhn diagnostic criteria (721) consist of the following:
  1. Nasal polyposis,
  2. Fungi on staining,
  3. Eosinophilic mucin without fungal invasion into sinus tissue,
  4. Type I hypersensitivity to fungi and
  5. Characteristic radiological findings with soft tissue differential densities on CT scanning.
Although used widely since their inception, many of these criteria are not unique to AFRS patients. All CRSwNP patients have nasal polyposis by definition, with a large proportion of them also demonstrating eosinophilic mucin without fungal invasion. Furthermore, as fungal detection techniques improve, so does the sensitivity to detect them, with some studies demonstrating fungal presence in almost 100% of patients, both controls and CRS patients (592, 1568). Consequently it appears that type I hypersensitivity and characteristic CT findings are the only unique factors in Bent and Kuhn's criteria for AFRS that allow it be distinguished from other forms of sinus disease. Subsequently, a number of authors have found other factors particular to AFRS. Demographically, AFRS patients are younger, more likely to be African American and present with more significant bone erosion/expansion than other CRSwNP patients (728,1569,1570).
While some have reported immunologic differences, with AFRS demonstrating increased mean serum total IgE and IgG antiAlternaria antibodies when compared to CRSwNP (723), this has not been conclusively demonstrated as others report no significant differences (727-729, 1571). Many questions remain unanswered:
Are there any significant underlying immunologic differences between AFRS and other forms of CRSwNP? What is the relevance of fungi or fungal specific IgE to the pathophysiology of AFRS? Do these factors truly play a role in the immunologic response or are they simply a defining marker of the disease state?

5.6.2. Medical therapy
Most reports on treatment options for AFRS are combined into larger series addressing CRSwNP patients and this issue is covered elsewhere in this document. It is therefore difficult to discern if there are varying effects in the AFRS population as opposed to the entire CRSwNP population. In general, medical therapies have been divided into oral and topical steroids, oral and topical anti-fungals, leukotriene antagonists and immunotherapy. In all but the mildest cases of AFRS, it is felt that medical therapy alone without surgical intervention, is not effective in the long term, thus most efficacy studies examining medical treatments have been performed post operatively Oral steroids
Oral steroid studies specific to AFRS patients have generally been conducted in the postoperative setting where benefit has been demonstrated. In a prospective, randomized doubleblinded, placebo-controlled (DBPC) trial in AFRS patients examining the effectiveness of postoperative oral steroids, as well as the side effects of such treatments, patients received oral prednisolone (50 mg qd x 6 weeks, then additional 6 week taper) or placebo for two weeks after surgery (1572). All patients received fluticasone nasal spray and oral itraconazole for 12 weeks. At 12 week follow up, symptoms and endoscopy were improved in the oral steroid group. All 12 patients in the steroid group suffered from weight gain, 5 developed Cushinoid features, 2 developed acne and 1 developed steroid induced diabetes mellitus. At 18 months of follow up, patients who stopped all treatment, including topical steroids, developed recurrent disease. It is unclear if postoperative oral steroids for 12 weeks had an impact at 18 months. A number of other non-placebo controlled case series have been reported with highly variable dosing protocols and durations, but generally reporting a positive effect when using postoperative oral steroids (1573-1578). Topical steroids
It does not appear that prospective studies on the effects of topical steroids alone have been conducted in the AFRS population. A case controlled study of surgery alone vs. surgery plus the combination of postoperative oral and topical steroid spray in AFRS patients demonstrated benefits of the combined therapy at a minimum of 2 year follow up, as 50% of the no steroid group recurred, while only 15% of the combined steroid group recurred (1579). Subcutaneous Immunotherapy (SCIT)
SCIT may have efficacy in the short term (3-4 years), however, its long-term efficacy is unclear. Fortunately, there are a number of reports of both high dose and low dose subcutaneous immunotherapy that have all demonstrated safety (1580). A large retrospective, series reported that compliance with immunotherapy for all fungal and non-fungal antigens was beneficial in preventing recurrence of disease. A 3-4 year course of subcutaneous immunotherapy (SCIT) demonstrated benefit 12-26 months after discontinuation (1581) and prolonged courses of systemic steroids were not used in these patients (1582). However a subsequent study by the same group on a smaller subset of patients with longer term follow up ranging from 46 to 138 months failed to demonstrate any benefit of SCIT with 60% of SCIT patients having normal mucosa or only mild oedema on endoscopy, while 100% of non-SCIT patients having normal mucosa or mild oedema (1583). This study was not randomized and obviously has the potential for bias in selecting treatment arms. Anti-fungal therapy
It is unclear if such therapies have a differing effect in the AFRS subset of patients. Limited non-placebo controlled case series have reported benefits of systemic anti-fungal therapies in patients with AFRS (28, 1584). This is in contrast to a Cochrane review of topical and systemic anti-fungal therapies in all CRS patients, which failed to demonstrate any benefit (1585). Leukotriene antagonist
One case report of improvement on leukotriene antagonist therapy has been reported (1586). Surgical therapy
Most clinical series describe surgical therapy to remove polyps and eosinophilic fungal mucin followed by aggressive medical therapies described above. Generally from the literature it appears that surgery both alone and in combination with other medical treatments leads to improved outcomes. A retrospective review reported that incomplete removal of all fungal and eosinophilic mucin contributed to disease recurrence and the need for revision surgery (1588).
Champagne et al. (1589) demonstrated that in AFRS patients, African American patients had higher CT and endoscopy scores, but similar SNOT20 scores. At 12 months postoperatively, SNOT20 and endoscopy scores improved in all patient groups with significantly greater improvement in women. In this series, all patients were treated postoperatively with saline irrigations, topical nasal steroid spray, oral antibiotics and a one-month oral steroid taper. Their maintenance treatment consisted of topical nasal steroid spray, nasal saline, montelukast, budesonide irrigations and month long bursts of oral steroids for exacerbations. Thus it is difficult to isolate the impact of surgery alone.
The placebo arm of the Rupa study (1572) was treated with nasal steroid spray and oral itraconazole during the postoperative period. At 6 weeks, 5 of 12 patients had endoscopic recurrence of their disease severe enough to withdraw from the study. At 12 weeks, 4 of the remaining 7 patients had complete or partial relief of symptoms with only 1 of those patients having normal endoscopy, thus their recurrence rate at 12 weeks with surgery plus nasal steroids and oral intraconazole was 11/12 (92%). The recurrence rate in the placebo arm of the Ikram study that did not receive oral or topical steroids (1579) was lower at 50% at 2 years. Overall recurrence rates after surgery has been reported from 10% to 100% (1590).
5.7. Paediatric Chronic Rhinosinusitis
5.7.1. Summary

CRS in children is not as well studied as the same entity in adults. Multiple factors contribute to the disease including bacteriologic and inflammatory factors. The adenoids are a prominent contributor to this entity in the pediatric age group. The mainstay of therapy is medical with surgical therapy reserved for the minority of patients who do not respond to medical treatment.

5.7.2. Classification and Diagnosis
CRS in children is defined similar to adults as an inflammation of the nose and the paranasal sinuses characterized by two or more symptoms, one of which should be either nasal blockage/ obstruction/congestion or nasal discharge (anterior/posterior nasal drip):
± facial pain/pressure,
± cough;
and either endoscopic signs of disease and/or relevant changes on the CT scan of the sinus.

The clinical diagnosis of CRS in children is challenging related to the overlap of symptoms with other common childhood nasal diseases such as viral upper respiratory tract infections, adenoid hypertrophy/adenoiditis and allergic rhinitis as well as the challenges related to physical examination. The EPOS2012 group felt that it was impossible to differentiate CRS from adenoid hypertrophy/adenoiditis in young children. Furthermore, studies examining the incidence of abnormalities in the paranasal sinuses on CT scans obtained for clinical reasons not related to CRS in children have shown a percentage of sinus radiographic abnormalities ranging from 18% (1591) to 45% (1592) with one study actually showing a Lund McKay score average of 2.8 in a similar pediatric population without symptoms of rhinosinusitis (1593). It has also been suggested that only a Lund-Mackay score over 5 is indicative for CRS in children (1594). Adding to the challenge in making the diagnosis is the fact that symptoms consistent with the diagnosis of CRS such as purulent rhinorrhea and cough are very common in the pediatric age group, and the symptoms of CRS are often subtle and the history is limited to the observations and subjective evaluation by the child's parent. Because some younger children might not tolerate nasal endoscopy, clinicians are sometimes hindered in their physical examination and have to rely on history and or imaging studies for appropriate diagnosis.

Studies examining clinical characteristics of pediatric patients with CRS suggest that the four most common clinical symptoms are cough, rhinorrhea, nasal congestion, and post nasal drip with a slightly higher predominance of chronic cough (527, 1595). Tatli et al found that 66% of children undergoing evaluation for chronic cough (>4 weeks duration, excluding recent upper respiratory tract infections) had CT scan abnormalities in the paranasal sinuses which were mild in 14%, moderate in 19%, and severe in 33% of the patients (480). In those children, the most frequent symptoms reported, other than cough, included rhinorrhea, sniffling, and halitosis

A thorough history of the timing of symptoms is critical to attempt to understand the category of disease that best applies to each patient. A very common clinical scenario in children presenting to the otorhinolaryngologist's office is that of chronic rhinosinusitis with upper respiratory tract infection-induced acute exacerbations. In this document, we characterize CRS as symptoms lasting 12 weeks or longer without symptom free periods.

5.7.3. Prevalence
The exact prevalence of chronic rhinosinusitis (CRS) in children is difficult to determine as only a small percentage of cases present to the physician's office. Many studies that address prevalence have been performed in select populations typically in children who have upper respiratory complaints. In one such study, CT scans were obtained in 196 children 3-14 years of age presenting with chronic rhinorrhoea, nasal congestion and cough (1596). Maxillary involvement was noted in 63%, ethmoid involvement in 58% and sphenoidal sinus involvement in 29% of the children of the youngest age groups. The incidence of abnormalities decreased to 10% of the ethmoids, 0% of sphenoids, but 65% of the maxillaries being involved in the older, 13-14 year old, age group. In a prospective study, all new patients (ages 2-18 years) presenting to 2 allergy practices with upper respiratory tract symptoms for at least 3 months were investigated with a CT scan to determine sinus abnormalities (1597). In 91 eligible patients, 63% had chronic sinusitis with clinical signs and positive CT findings and 36% had no sinus disease. The best association between symptoms and CT scan abnormalities was noted when the symptoms of rhinorrhoea, cough, and the absence of sneezing were combined.
Furthermore, age was the single most important risk factor associated with chronic sinusitis, with 73% of 2-6 year olds, and 74% of 6-10 year olds having sinus CT abnormalities as opposed to the low incidence of sinus abnormalities detected in only 38% of children over 10 years of age.

There are few studies that follow the prevalence over time and they suggest a decrease in the prevalence of rhinosinusitis after age 6-8 years (8 , 1598 , 1599). There is also evidence to suggest that children with a family history of atopy or asthma who attend daycare in the first year of life have 2.2 times higher odds of having doctor-diagnosed sinusitis than children who do not attend daycare (1600).
5.7.4. Effects on Quality of life

CRS has a negative impact on quality of life

CRS in children leads to impaired quality of life. In a study of children with recurrent and CRS failing medical treatment and requiring surgical intervention, Cunningham and colleagues administered generic parental and childhood quality of life questionnaires (1601). The results showed significant impairment of the quality of life of these children and, surprisingly, significantly lower quality of life scores than that of children with other common chronic childhood diseases such as asthma, attention deficit hyperactivity disorder, juvenile rheumatoid arthritis, and epilepsy. The differences were most marked in the physical domains of the quality of life questionnaires such as bodily pain and limitation in physical activity. The SN-5 survey, a disease specific tool was validated as a measure of change over time in sinonasal symptoms (1602). It consists of 5 domains, which include sinus infection, nasal obstruction, allergy symptoms, medication use, emotional distress, and activity limitations, and is filled by the parents reflective of the previous 4 weeks. The survey's reproducibility, validity, and responsiveness to change was ascertained in a study of 85 children aged 2-12 years suffering from sinonasal symptoms for 1 month or longer, and it has been shown to correlate with CT scan scores in patients with CRS suggesting that it can be used as a substitute for repeated CT scans in clinical follow up (1603). There is also limited evidence showing improvement of quality of life (using the SN-5 tool) in patients with CRS after surgical intervention (adenoidectomy or endoscopic sinus surgery) (1604).

5.7.5. Anatomical factors

It is not clear whether anatomic abnormalities have any contribution to CRS in children

Similar to adults, the ostiomeatal complex (OMC) is believed to be the critical anatomic structure in rhinosinusitis and is entirely present, though not at full size, in newborns. Changes occurring in the anterior ethmoids are known to impair drainage through the OMC, resulting in chronic maxillary sinusitis and, occasionally, frontal sinusitis. Sivalsi et al studied the anatomical variations of the paranasal sinuses in paediatric patients with CRS (1605). A pneumatized middle concha was the most common anatomic variation, followed by pneumatisation of the superior concha, Haller cell, and agger nasi cell. Compared with adults, nasal septal deformities tended to be less common. In another study, Al-Qudah examined the CT scans of 65 children with persistent symptoms of CRS (>3months) after maximal medical treatment and identified anatomical abnormalities and correlated those to extent of disease in the paranasal sinuses (1606). In his population, the most common abnormality was an agger nasi cell, followed by concha bullosa, paradoxical middle turbinate and Haller's cell. In addition to listing the abnormalities, this study actually performed correlation analyses between the anatomical abnormalities and the extent of sinusitis and found no significant correlation. The limitation of both studies is that they did not include a control group without rhinosinusitis making it difficult to assess the importance of these changes in the genesis of chronic sinus inflammation.
Actually, the second study and studies in adults suggest that despite the common occurrence of these anatomical factors, they do not seem to correlate with the degree and existence of CRS.

5.7.6. Pathophysiology Bacteriology

The pathogens involved in CRS are difficult to identify due to low bacterial concentration rates, inconsistent data, and because most cultures are obtained at the time of surgery after patients have been treated with antibiotic therapy. Muntz and Lusk reported bacteriologic findings in 105 children with CRS when they obtained cultures from the anterior ethmoid cell at the time of endoscopic sinus surgery (1607). The most common bacterial species recovered were alpha hemolytic streptococci and Staphylococcus aureus, followed by S. pneumoniae, H. influenzae, and M. catarrhalis. Anaerobic organisms were grown from 6% of specimens. Brook et al also reported that the incidence of anaerobic organisms recovered increased with chronic infections (477). In 1981, his group obtained sinus cultures from 37 of 40 children with CRS and isolated anaerobic organisms from all specimens (1608). The most common organisms were anaerobic gram-positive cocci, followed by other anaerobic organisms including Bacteroides species and Fusobacteria. Aerobes were recovered in 38% of these cultures and included Streptococci, Staphylococci and few Hemophilus species.

Hsin and colleagues performed maxillary sinus taps for irrigation in 165 children with symptoms of CRS for≥12 weeks and abnormal radiographs (1609). Of the 295 sinuses tapped, the most commonly isolated organisms were α-hemolytic Streptococcus (21%), Hemophilus influenza (20%), Streptococcus pneumonia (14%), coagulase negative Staphylococcus (13%), and Staphylococcus aureus (9%). Anaerobes were identified in 8% of the isolates. When examining the susceptibility of the organisms over time, an increase rate of resistance of Hemophilus influenza to ampicillin was noted. In a study evaluating the effect of the introduction of the heptavalent pneumococcal conjugate vaccine on the bacteriology of rhinosinusitis in children, McNeil and colleagues evaluated all cultures of the paranasal sinuses that yielded Streptococcus pneumonia at Texas Children's hospital between 2007 and 2008 (1610). These were all obtained from children with the diagnosis of chronic or recurrent rhinosinusitis and out of the 24 cultures, 23 were non vaccine serotypes, with serotype 19A accounting for 50% of the isolates and exhibiting high rates of antimicrobial resistance. Biofilms
Biofilms are complex aggregations of bacteria distinguished by a protective and adhesive matrix and have recently been implicated in CRS. They form when planktonic bacteria adhere and coalesce to various surfaces via glycoconjugate moieties and form well organized ecosystems within the human host. These ecosystems are well suited for conditions of environmental stress and altered oxygen tension, and it is thought that 99% of bacteria exist in biofilm form. Biofilms are also characterized by surface attachment, structural heterogeneity, genetic diversity, complex community interactions, and an extracellular matrix of polymeric substances, which all contribute to their resistance to antibiotic treatment (1611). Intermittently, planktonic bacteria shed from the biofilm, migrate, and colonize other surfaces. It is therefore hypothesized that biofilms may provide a chronic reservoir for bacteria and may be responsible for the resistance to antibiotics seen in pediatric patients with CRS. Sanclement and colleagues evaluated sinus mucosa obtained at the time of surgery for CRS for the presence of biofilms and, in a mixed adult and pediatric population, demonstrated the presence of biofilms in 24 out of 30 (80%) specimens (1611). Although the existence of biofilms is now well documented in adults with rhinosinusitis, more research is needed to clearly characterize their contribution to the pathophysiology of CRS in children. Role of adenoids
The adenoids are in close proximity to the paranasal sinuses and adenoidectomy has been shown to be effective in resolving the symptoms in a proportion of children with CRS (see below). In an attempt to explain these findings, Zuliani et al. collected adenoid specimens obtained from children with CRS and obstructive sleep apnea and examined them for the presence of biofilms using electron microscopy (1612). They found that a large percentage (88-99%) of the mucosal surface area of all the specimens from children with CRS was covered with a dense biofilm. This was in contrast with the adenoids obtained from patients with sleep apnea where modest percentages (0- 6.5%) of the surface area were found to be covered by biofilm. Although the number of specimens in this study was small, the work provides a potential explanation for the improvement seen with adenoidectomy in antibiotic-resistant CRS.

In a study comparing middle meatal swabs and adenoid core cultures in children with hypertrophied adenoids and chronic or recurrent sinusitis, Elwany and colleagues found that the bacteria were very similar in both locations and included coagulase-negative staphylococci, Staphylococcus aureus, Streptococcus pneumonia, Haemophilus influenza and group A streptococci (1613). They also found that adenoid core culture had a positive predictive value of 91.5 in forecasting the middle meatal culture results and a negative predictive value of 84.3, suggesting that the bacterial reservoir in the adenoids mirrors the bacteriology isolated close to the paranasal sinuses in these children. Another line of evidence to support the role of the adenoids as a bacterial reservoir in CRS in children comes from the observation that bacterial isolation rates from adenoids of children undergoing adenoidectomy increased significantly according to sinusitis grade on radiographs (1614). This was especially true of Hemophilus influenza and Streptococcus pneumonia. In contrast, children with nasal discharge who had a CT scan of the sinuses and underwent adenoidectomy were investigated and the results showed no correlation between the size of the adenoids and the severity of disease on CT scan as gauged by the Lund McKay score (1615). This suggests that the nasal discharge could be due to adenoiditis alone and that the bacterial reservoir of the adenoids more than their size was important in the relationship between CRS and the adenoids.

There is also some evidence that supports a contribution of the adenoids as an immunological organ in children with CRS. One study compared immunoglobulin expression in adenoid tissues of patients with adenoid hyperplasia compared to those with CRS and showed a significantly lower expression of IgA in the adenoids of children with CRS with no difference in expression of the other immunoglobulins (1616). This could suggest that the adenoids of patients with CRS are not able to mount the local immune response expected of them. Obviously whether this is a primary or secondary occurrence (related to chronic infection) cannot be elucidated from this study which only evaluated adenoids at one point in time. Shin and colleagues examined adenoids obtained from children with and without CRS and showed higher levels of tissue-remodeling cytokines, transforming growh factor TGF-β1, matrix metalloprotease MMP-2, MMP-9, and tissue inhibitor of metalloprotease TIMP-1 in the CRS patients, again supporting a relationship between the adenoids and the status of the sinuses in children with CRS (1617).

In summary, data related to the role of adenoids in CRS is emerging but the studies are small and mostly evaluate the adenoids after their removal from the site. They do suggest a role for the adenoids in patients with CRS, both from a bacteriologic and immunologic perspective. Most of these studies however, do not really shed light on the relative contribution of adenoiditis proper vs CRS in chronic nasal symptomatology in children. Cellular Studies
Studies of the cellular response in pediatric CRS indicate that eosinophils and CD4+ lymphocytes play a significant role in tissue inflammation. Baroody and colleagues found higher numbers of eosinophils in the sinus mucosa of older children (Median age = 7 years, range: 3-16 years) obtained at the time of surgery for CRS as compared to sphenoid sinus mucosal specimens of adults with no previous history of sinusitis (1618).

The inflammatory reaction in the sinus tissues of children with CRS is rich in lymphocytes and exhibits less eosinophilia and epithelial disruption compared to adults

Lymphocytes, particularly the CD4+ population, were also increased in the sinus mucosa of children with CRS irrespective of allergic status (1619). In similar studies performed in younger children with CRS (median age= 3.9 yrs) Chan and colleagues compared maxillary sinus biopsies from these children to archival adult maxillary sinus tissues (1620). The pediatric mucosa had more neutrophils, and significantly more lymphocytes, while the adult mucosa was richer in eosinophils and major basic protein positive cells. They also noted less epithelial disruption and thickening of the basement membrane in children compared to the adults. In a similar study using immunohistochemistry to evaluate different inflammatory cells, the same group showed higher numbers of CD8+ cells, neutrophils, macrophages, B lymphocytes, and plasma cells in younger children with CRS compared to adults (1621). In a similar study, Berger and colleagues compared sinus specimens obtained from children with CRS to tissues obtained from adults (1622). The children were older (mean age=11.6±2.9 years) and their tissues had fewer eosinophils and lesser epithelial disruption than the adult specimens. There were large numbers of T lymphocytes, and extensive fibrosis in the lamina propria in half the specimens, findings comparable to the adult specimens. In children with nasal polyps, vascular endothelial growth factor-expressing cells and intra-polyp blood-vessel density were higher in polyp specimens as compared to the chronically inflamed tissue of children without nasal polyposis (1008). In general these limited studies suggest fewer eosinophils and less epithelial disruption in the tissues of children with CRS compared to their adult counterparts.
5.7.7. Comorbid Diseases Allergic Rhinitis

Allergic rhinitis is a common coexisting disease in pediatric patients with CRS. The data about the association between the 2 diseases in children is variable. In a series of 42 patients with CRS refractory to medical treatment on which a RAST test as well as a CT scan was available, 40% of the patients were atopic and 60% were nonatopic (1623). In the same study, patients with a positive RAST test were found to have a significantly higher CT score compared to the patients with negative RAST testing. While this study supports the relationship of a positive allergy test to CRS, the population was mixed children and adults with a mean age of 28 years and a range from 2-61 years. In a study of 100 children with a clinical diagnosis of sinusitis and abnormal plain sinus radiographs in Thailand, the authors report a positive skin test to common aeroallergens in 53% of the patients again suggesting a correlation between the 2 diseases (1624).
In contrast, a study from Belgium evaluated CT scans from allergic children and adults and noted the presence of sinus opacification in 61% of allergic children and 58% of adults (1625). This data was compared to previous studies of nonallergic children and adults showing the incidence of sinusitis changes on CT to be similar (64% in children and 57.5% in adults) suggesting the lack of an important role of allergy in sinus abnormalities on CT scan. In their study of children with chronic respiratory symptoms who underwent allergy evaluation and CT scanning, Nguyen and colleagues found no correlation between atopic status and sinus abnormality and the prevalence of sinus disease was essentially similar in the atopic patients (63%) versus the nonatopics (75%) (1597). Finally, a more recent study showed positive allergy tests in 30% of 351 Italian children with CRS, a prevalence that was not much different than that of allergy in the general population (32%) (1626). When age was examined, the incidence of positive allergy testing was significantly higher in children older than 6 years as compared to those younger than 3 years of age. Thus the causal relationship between allergies and CRS in children is still controversial but probably non-existent. Asthma
Asthma is another disease that is commonly associated with CRS in the pediatric age group. Rachelefsky and colleagues reported on treatment outcomes in 48 nonrandomized children with moderate to severe asthma and co-morbid CRS (1627). After pharmacologic or surgical intervention for sinusitis, 80% of these children were able to discontinue asthma medications. Furthermore, asthma recurred when sinusitis subsequently relapsed. In another study, Tosca and colleagues identified 18 children, 5-12 yrs of age, with poorly controlled asthma and co-morbid CRS (1628). The patients were treated for 14 days with antibiotics, intranasal and systemic steroids, and were evaluated at baseline, after treatment, and 1 month later. In addition to improvement in their nasal symptoms, patients had a significant improvement in spirometry, wheezing, and inflammatory markers in nasal lavage. These and other studies support the concept that clinical control of CRS may be important in optimizing the control of difficult-to-treat asthma. However, the limitations of most available studies include the lack of good controls or randomization to different treatment modalities and therefore, the relationship between CRS and asthma in children remains largely descriptive. Gastroesophageal Reflux Disease (GERD)
GERD has also been associated with rhinosinusitis in several studies. Phipps et al conducted a prospective study of 30 pediatric patients with chronic rhinosinusitis who underwent 24-hour pH probe and found that 63% of children with CRS had GE reflux (1629). In addition, 79% of children experienced improvement in rhinosinusitis symptoms after medical treatment of GERD. In a large case control study at Texas Children's hospital, 1,980 children with gastroesophageal reflux disease and 7,920 controls (ages 2-18 yrs) were identified based on ICD-9 codes (1630). The number of cases with a concomitant diagnosis of sinusitis was significantly higher in the children with GERD (4.19%) compared to the control group (1.35%). Another retrospective study by Bothwell showed that treatment for GERD in patients with CRS (no placebo control) allowed many patients to improve and to obviate planned surgical procedures (1631). The differential diagnosis between GERD and post nasal drip can be difficult. Although some evidence supports an association between GERD and CRS, more controlled studies are required to strengthen this association and validate it and routine anti-reflux treatment of children with CRS is not warranted. Immunodeficiency
Shapiro et al prospectively evaluated the immune function of children referred to their offices over a 1-year period with recurrent rhinosinusitis despite maximal medical therapy (1632).. Of 61 patients (2-13 yrs of age), 34 showed some abnormality in immune studies with depressed IgG3 levels and poor response to pneumococcal antigen 7 being most common. Sethi and colleagues reported the following immune deficits in 20 patients (ranging from 3 to 51 years) with recurrent/ chronic rhinosinusitis: isolated IgA and IgG1 deficiency, low immunoglobulin levels with poor response to pneumococcal vaccine, and low immunoglobulin levels with normal vaccine responses (1633). Costa Carvalho and colleagues evaluated the humoral immune response in 27 children (7-15 years) with chronic or recurrent sinusitis (292). One patient had IgA and IgG2 deficiency, and another had IgG3 deficiency. Eight and 12 of 27 patients had IgG2 and IgG3 serum levels below 2.5th percentile, respectively and no patient had an abnormal response to vaccination. In an open label, pilot, study, Ramesh and colleagues treated 6 patients with CRS refractory to medical management with IVIG for 1 year and compared their response during treatment to the 1 year before therapy (1634). Treatment resulted in a decrease in antibiotic intake (183 to 84 days) and episodes of sinusitis (9 to 4 per year), and CT scans showed significant improvement. Based on the above evidence, it seems prudent to evaluate immune function in the child with chronic/ recurrent rhinosinusitis with an immunoglobulin quantitation and titers to tetanus and diphtheria as well as pneumococcal titers. If responses are abnormal, a repeat set of titers post pneumococcal vaccination is appropriate. Primary Ciliary Dyskinesia
The normal movement of mucus by mucociliary transport toward the natural ostia of the sinuses and eventually to the nasopharynx can be disrupted by any ciliary dysfunction or mucosal inflammation. The most common cause of ciliary dysfunction is primary ciliary dyskinesia (PCD), an autosomal recessive disorder involving dysfunction of cilia and present in 1 of 15,000 of the population (1635). Half the children with PCD also have situs inversus, bronchiectasis, and CRS and are known as Kartagener's syndrome. The diagnosis should be suspected in a child with atypical asthma, bronchiectasis, chronic wet cough and mucus production, rhinosinusitis, chronic and severe otitis media (especially with chronic drainage in children with ear tubes) (8). Screening tests for PCD include nasal nitric oxide (lower levels than controls) and in vivo tests such as the saccharin test, which documents slower mucociliary transit time. Specific diagnosis requires examination of cilia by light and electron microscopy, which is usually available in specialized centers. The most commonly described structural abnormality involves lack of outer dynein arms, or a combined lack of both inner and outer dynein arms (86). Contrary to some thoughts that the prolonged inflammation associated with PCD would lead to nasal polyposis in adults, a review of 30 children with PCD in one center showed none with nasal polyposis despite the fact that the children were debilitated by CRS as documented by SNOT20 scores (1636). Cystic fibrosis
Cystic fibrosis is a genetic disease with autosomal recessive inheritance that affects approximately 1 in 3500 newborns. It is caused by a mutation in the CFTR gene on chromosome 7, which leads to disruption in cAMP-mediated chloride secretion in epithelial cells and exocrine glands. This leads to increased viscosity of secretions resulting in bronchiectasis, pancreatic insufficiency, CRS and nasal polyposis. The prevalence of chronic sinusitis is very high and nasal polyps occur in between 7 and 50 % of affected patients (1450, 1637). In fact, this is one of the few causes of nasal polyposis in children. A lengthier discussion of this disorder is presented in the chapter devoted to this entity.

5.7.8. Diagnostic Workup
A complete physical exam should follow a carefully obtained medical and family history. The nasal exam in children should begin with anterior rhinoscopy examining the middle meatus, inferior turbinates, mucosal character and presence of purulent drainage. This is often feasible in younger children using the larger speculum of the otoscope. Topical decongestion may improve visualization but may not always be tolerated in younger children. Nasal endoscopy which will allow superior visualization of the middle meatus, adenoid bed and nasopharynx is strongly recommended in children who are able to tolerate the examination. An oral cavity exam may reveal purulent drainage, cobblestoning of the posterior pharyngeal wall, or tonsillar hypertrophy. The finding of nasal polyps in children is unusual and, if seen on exam, should raise the suspicion for cystic fibrosis or allergic fungal sinusitis. Although there is no supportive data, nasal polyps might be more common in children than previously appreciated as evidenced by a report from Taiwan (1008) and anecdotal personal communications from Europe. Obviously, antrochoanal polyps occur in children but those are usually unilateral and the rest of the sinuses are clear, which would help differentiate that entity from CF or bilateral nasal polyposis. Allergic fungal sinusitis also presents with a rather unique clinical picture which includes expansile nasal polyps and characteristic CT and MRI findings (1638).

Following the history and physical examination, appropriate diagnostic tests should be considered. Allergy skin testing or serologic testing should be considered in children with CRS. Immunodeficiency testing should be pursued in children with recurrent or chronic disease, poor response to medical treatment, history of other infectious diseases (such as recurrent pneumonia or otitis media) or when unusual organisms are cultured from the sinus contents.

In patients who have not responded to conventional medical treatment, obtaining a culture may be useful in directing further therapy. In children, data regarding the usefulness of this approach are limited. Orobello and colleagues cultured the middle meatus at the time of endoscopic sinus surgery in children with chronic rhinosinusitis and then obtained cultures from the maxillary antrum and the ethmoids during the procedure (1639). They reported a strong association between cultures of the middle meatus and cultures of the maxillary (83%) and ethmoid sinuses (80%). In a recent study, Hsin and colleagues obtained middle meatal cultures and maxillary sinus aspirates under general anesthesia from children with rhinosinusitis unresponsive to medical treatment (1640). Endoscopic sampling provided a sensitivity of 75%, a specificity of 88.9%, a positive predictive value of 96%, a negative predictive value of 50%, and an accuracy of 50%, making it a little less favorable compared to results from adult studies. In a more recent study by the same group, the correlation between maxillary sinus taps and middle meatal cultures improved when the middle meatal sample was obtained by suction aspiration (correlation 87%) as opposed to swabs (correlation 66%) (1609). We reserve this technique for the older children who have a complicated course and who are likely to tolerate rigid endoscopy in the office setting. If general anesthesia is needed, one should revert to the gold standard, which is obtaining a culture from the maxillary sinus itself by antral puncture, a technique that also allows the potential benefit of sinus irrigation.
Interdisciplinary consultations are useful in evaluating the pediatric patient with medically refractory disease. Consultants may include those in the disciplines of allergy-immunology, infectious disease, pulmonary or genetics to aid in further workup.

Not any CT scan abnormality indicates relevant clinical CRS in children

While the diagnosis of chronic rhinosinusitis in the pediatric population is generally made on clinical grounds, computed tomography (CT) is the imaging modality of choice (279). Findings on plain radiographs have been shown not to correlate well with those from CT scans in the context of chronic/recurrent sinus disease (281). In a prospective study where children with chronic sinus symptoms were imaged using both modalities, the findings on plain radiographs did not correlate with those on CT scans in 75% of the 70 patients studied (281). About 45% of the patients had normal findings on plain radiographs of at least one sinus with an abnormality of that sinus shown on CT scan, and almost 35% of the patients had an abnormality of at least one sinus on plain radiographs but that sinus was normal on CT scan. Thus, the most useful modality for the diagnosis of rhinosinusitis in children is the CT scan. A recent study compared CT scans obtained in 66 patients (mean age 8 years) satisfying the clinical criteria of CRS to those obtained in a group of 192 control children (mean age 9 years) for nonsinusitis reasons (1594). The scans were graded using the LundMackay system and the analysis showed that adopting a Lund cutoff score for diseased vs nondiseased patients of 5 offers a sensitivity and specificity of 86% and 85% respectively in making an appropriate diagnosis. Lund scores of 2 or less, have an excellent negative predictive value, whereas scores of 5 or more have an excellent positive predictive value.

In uncomplicated CRS, scanning is reserved to evaluate for residual disease and anatomic abnormalities after maximal medical therapy. Abnormalities in the CT scan are assessed in the context of their severity and correlation with the clinical picture and guide the plan for further management which might include surgical intervention. In children with the clinical diagnosis of rhinosinusitis, the most commonly involved sinus is the maxillary sinus (99%) followed by the ethmoid sinus (91%) (1595). Magnetic resonance (MR) imaging of the sinuses, orbits, and brain should be performed whenever complications of rhinosinusitis are suspected.

Adenoidectomy is successful in improving CRS in 50% of operated children. Whether this is due to the fact that the symptoms were related to adenoiditis per se or to the elimination of the contribution of the adenoids to sinus disease is not clear

CT scans provide an anatomic road map for surgical treatment and are also useful for identifying areas of bony erosion or attenuation (1641). Two examples of sinonasal diseases with characteristic radiologic appearances are allergic fungal sinusitis (AFS) and cystic fibrosis. In AFS, expansile disease may attenuate the bony skull base or orbital wall on CT. In addition, a speckled pattern of high attenuation ("starry sky") on both soft tissue and bone window settings correlates with the presence of thick allergic mucin and associated calcifications that may be noted intra-operatively. MRI T1 images show low signal in areas of fungal mucin, and T2 images show central signal void in areas of fungal mucin with high signal in peripheral inflamed mucosa (1638). In patients with cystic fibrosis, CT scans characteristically demonstrate pan-opacification of the sinuses and medial displacement of the lateral nasal wall, which may obstruct the nasal passages (1642).

Finally, it has to be emphasized that the physical exam and history alone do not help in differentiating between adenoiditis and CRS, especially in the younger child. As detailed above a high Lund-Mackay score on the CT scan (>5) might be more suggestive of CRS than adenoiditis but further studies are clearly required to help distinguish these 2 entities.