Current Allergy and Asthma Reports

, Volume 12, Issue 2, pp 163–174

Pathogenesis and Management of Nasal Polyposis in Cystic Fibrosis

Authors

    • Cystic Fibrosis Center, Department of Paediatrics, Paediatric PulmonologyJena University Hospital
  • Assen Koitschev
    • Division of Paediatric Otorhinolaryngology and Otology, Department of OtorhinolaryngologyKlinikum Stuttgart
Sinusitis (ML Kowalski, Section Editor)

DOI: 10.1007/s11882-012-0250-y

Cite this article as:
Mainz, J.G. & Koitschev, A. Curr Allergy Asthma Rep (2012) 12: 163. doi:10.1007/s11882-012-0250-y

Abstract

Beginning in preschool age, during their lives, up to 50% of cystic fibrosis (CF) patients experience obstructing nasal polyposis (NP), which is rare in non-CF children. Pathogenetic factors of NP in general and especially in CF are still obscure. However, defective epithelial ion transport from mucosal glands plays a central role in CF, and viscous secretions impair mucociliary clearance, promoting chronic pathogen colonization and neutrophil-dominated chronic inflammation. Presently, CF-NP is not curable but can be clinically stabilized, though the large variety of proposed treatment modalities indicates a lack of standardization and of evidence of treatment efficacy. When conservative measures are exhausted, surgical intervention combining individually adapted endoscopic sinus surgery and supportive conservative treatment is performed. Topical steroids, approved as the gold standard for non-CF NP, may be beneficial, but they are discussed to be less effective in neutrophilic inflammation, and CF-specific antimicrobial and mucolytic therapy, as is true of all treatment modalities, urgently requires evaluation by controlled clinical trials within interdisciplinary networks.

Keywords

Nasal polyposisCystic fibrosisUpper airwaysRhinosinusitisNoseOstiomeatal complexInflammationMucociliary clearancePathogen colonizationPseudomonas aeruginosaStaphylococcus aureusTopical therapySteroidsMucolyticsAntibioticsMacrolidesSinonasal inhalationNasal lavageRhinoscopySinonasal surgeryFESSNeutrophilInterleukinsIL-8Quality of life

Introduction

Autosomal recessive cystic fibrosis (CF) is based on defective cystic fibrosis transport regulator (CFTR) gene function, encoded on the q31 region of the long arm of chromosome 7 [1, 2] The resulting multiorgan disease affects every segment of the airways, the ductal system of the pancreas, hepatobiliary system, and male ductus deference as principal sites.

Almost all CF patients reveal upper airway involvement in CT scans [3], but only 10% report clinical symptoms of chronic rhinosinusitis (CRS) without specific questioning [4]. However, an increasing percentage of CF patients experience obstructing nasal polyposis (NP) [5], in some cases beginning at preschool age [6]. In contrast, NP is very rare in non-CF pediatric patients.

Recently, Feuillet-Fieux et al. [7] reviewed 12 studies for correlations between CF-NP and severity of the overall disease. In brief, patients with homozygosity for F508del and other severe mutations appear to have an elevated risk of NP [8, 9], but nevertheless, NP was not clearly correlated with a poor outcome with CF: pulmonary function in CF patients with NP was not significantly reduced, in comparison to NP-negatives, and some studies even reported better lung function in those with CF-NP. Also, better nutritional status in CF-NP patients was seen in three of four studies assessing the issue [8, 10, 11].

On the other hand, pulmonary colonization with Pseudomonas aeruginosa was significantly correlated with CF-NP in three of four studies, and prevalence of NP increased with duration of colonization with the pathogen: 10 years (n = 45) in NP-positive patients versus 5.8 years (n = 68) in NP-negative patients [9]. Additionally, two studies reported an association of CF-NP with higher rates of acute exacerbations and hospitalizations.

Whereas Cimmino et al. [11] noted significantly more NP among CF patients with allergic sensitization to Aspergillus fumigatus, such a correlation could not be ascertained by Hadfield et al. [12] or Henriksson et al. [9], who did not detect a significant correlation between allergy in general and CF-NP.

All together, pathogenetic factors of NP in general and especially in CF are still obscure. Obviously, there is no single etiologic factor, and chronic inflammation plays a central role. The missing causal explanation leads to symptomatic management of NP in CF. This paper focuses on management of CRS with NP in CF patients.

Clinical Definition of Chronic Rhinosinusitis and Nasal Polyposis

The EAACI Position Paper on Rhinosinusitis and Nasal Polyps [13] defines rhinosinusitis clinically as inflammation of the nose and the paranasal sinuses characterized by two or more of the following symptoms:
  • Blockage/congestion

  • Discharge: anterior/postnasal drip

  • Facial pain/pressure

  • Reduction in or loss of smell, and/or endoscopic signs:

  • Polyps

  • Mucopurulent discharge from middle meatus

  • Edema/mucosal obstruction primarily in middle meatus, and/or radiographic mucosal changes within the sinus system.

Depending on duration, the disease can be divided into acute/intermittent (<12 weeks with complete resolution of symptoms) and chronic/persistent (>12 weeks of symptoms with no complete resolution).

CRS is the major finding, and NP is considered a subgroup of this entity. The differentiation between CRS with or without NP must be based on the presence of polyps as confirmed by endoscopy prior to any surgery. Once surgery has altered the anatomy of the lateral nasal wall, the presence of polyps is defined as pedunculated lesions, as opposed to cobblestoned mucosa, more than 6 months after surgery on endoscopic examination.

Pathogenesis of Nasal Polyposis in Cystic Fibrosis

The frequency of NP in CF patients varies considerably within the published literature [14]. This variability can be explained by selection of patients, sample sizes, age groups, and examiners’ experience with nasal endoscopy.

As a principle, the prevalence of NP in CF patients appears to be age dependent, with an increase during adolescence, but rarely exceeding 50% of the population examined. In 117 patients in a single center, the prevalence was 18.2% in patients younger than 6 years of age and rose to 44.8% among adolescents [5]. These numbers are consistent with previous studies, pointing to a high rate of polyposis in pediatric CF patients [5, 15, 16].

However, that nearly half of all CF patients never suffer from obstructive polyposis indicates a multifactorial etiology [17]. Chronic opportunistic infection of the mucosa, which is rare in non-CF NP-patients, could be the most likely specific factor with regard to polyposis development in CF [18]. The leading pathogens that colonize the lower airways on the sinonasal area of CF patients are Staphylococcus aureus and P. aeruginosa, which remain the main cause of pulmonary destruction and preliminary death among CF patients [19, 20••].

Pathogen colonization of the upper and lower airways in CF is not facilitated by immunologic deficiencies. Defective epithelial ion transport causes production of less hydrated fluids with increased viscoelasticity [21]. This is the cause of secondary impaired mucociliary clearance and disturbed drainage of the airway system.

These changes apparently take place in CF sinonasal mucosa, as shown by recent histologic studies by Schraven at al. [22••] comparing CF with non-CF NP. Mucosal glands from CF patients were histologically characterized by a predominance of mucous with dilated glandular ducts, whereas mucosal glands of non-CF patients were of the serous type, resembling the glands of patients with healthy mucosa [23]. At the same time, the vascularization pattern was similar in CF and non-CF patients, without dilatation or differences in vascularization density.

Duct dilatation and proliferation of mucus glands in CF-NP appear to be the histologic correlate of impaired mucus consistence, facilitating pathogen colonization and mucosal inflammation. Inflammation of the narrowing between the nasal cavity and the paranasal sinuses (called the “ostiomeatal complex”) promotes ostial obstruction, causing hypoxia and increasing carbon dioxide partial pressure within sinuses and thus inducing a vicious circle of mucosal edema and impaired mucociliary function.

The combination of deficient mucociliary clearance and chronic pathogen colonization in CF patients leads to a clearly different pattern of inflammatory markers in the upper and lower airways compared with patients with idiopathic NP [24] or healthy controls. Neutrophils appear to play a central role in CF airway inflammation. Histologically, they are the predominant inflammatory cell population within CF-NP [23, 2527], whereas polyps in non-CF patients are dominated by eosinophils. However, some age dependence may occur in CF airway inflammation [22••], as NP from CF children revealed more mast cells and plasma cells compared with non-CF NP [23, 2527]. Additionally, CF nasal polyp tissue reveals increased levels of interleukin (IL)-8, IL-1β, and myeloperoxidase in comparison with healthy nasal mucosa [28]. The stimulated defense mechanism released by neutrophils themselves causes mucosal damage and prolongs inflammation in chronic sinusitis [29]. Allergies are found in CF as frequently as in the non-CF population, so they must be regarded as possible (but not specific) triggers in CF-NP [30].

Diagnostic Nasal Lavage

Diagnostic nasal lavage (NL) is an easy, repeatable, and noninvasive method to sample airway surface liquid and nasal secretions for microbiological and biochemical analysis [20••]. It may help improve understanding of pathophysiology in CRS with and without NP [31].

Like CF-NP tissue, NL fluid is dominated by neutrophils and their associated inflammatory markers, whereas NL fluid in idiopathic NP is characterized by eosinophilia, even though the presence of eosinophils has also been reported in CF airways [27, 3234].

Age-related dynamics can be identified in nasal secretions. NL obtained from infants with CF did not reveal significant amounts of inflammatory cells or the cytokines IL-6, IL-8, or IL-10 [32]. Elevated IL-8 has been reported in CF patients even without infectious exacerbation, indicating that neutrophil inflammation could be present in CF airways without bacterial infection [35, 36]. To conclude, CF-NP is not specifically correlated with any pattern of inflammatory cells, cytokines, or other inflammatory markers obtained from serum, nasal secretions, or histologic samples.

Diagnostics and Staging

In general, objective staging of CRS relies on endoscopic examination and radiological imaging. Simple scores were defined by Lund and Mackay [37] for CT and by Lund and Kennedy [38] for endoscopy findings. However, the subjective burden of disease varies considerably among CF- and non-CF patients and does not correlate with the objective scores. Therefore, especially in CF patients, most clinicians make therapeutic decisions based on personal experience and patients’ complaints rather than on objective criteria. Instruments (eg, questionnaires) for measuring the subjective quality of life (QoL) play an increasing but still complementary role in the discussion of treatment options.

Without specific questioning, patients rarely complain about sinonasal symptoms. Due to early onset during childhood, many patients appear to “adapt” to rhinosinusitis symptoms and pay more attention to potentially severe pulmonary and/or gastrointestinal manifestations of CF. Nevertheless, rhinosinusitis and NP symptoms impair QoL to a much greater degree than currently recognized. In this regard, Gliklich and Metson [39], who assessed the impact of CRS on QoL in non-CF patients, found significantly higher QoL measures of bodily pain and social functioning for sinusitis patients than in patients with angina, congestive heart failure, chronic obstructive pulmonary disease, or back pain.

Imaging

Remarkably, there is a poor correlation between imaging, endoscopic or manometric findings and clinical burden of CRS. The purpose of radiological imaging of inflammatory lesions in the paranasal sinuses is to characterize the extent and localization of lesions and anatomic details, and thus to predict possible benefit from sinus surgery.

Prior to surgical intervention, tomographic imaging appears mandatory. Spiral multislice CT represents the gold standard today. From a surgical point of view, it provides the most precise anatomic information. However, even under optimized low-dose protocol conditions, the radiation exposure is unavoidable.

Recently, digital volume tomography (also known as “cone beam CT”) offered new diagnostic opportunities with a focus on bone structures of the skull. Compared with conventional CT diagnostics, it leads to an up to 80% reduction of the radiation with quality comparable to that of spiral CT.

However, if available, MRI is preferred, especially in children [40]. It allows better differentiation of mucosa, polyps, mucoceles, or orbital and intracranial complications, but it does not directly display bony structures (Fig. 1a and b). Thus, surgeons may be challenged by adapting to the unusual “negative” presentation of bony margins by MRI. Further disadvantages of MRI are longer acquisition time, higher costs of examination, need for sedation in younger children, and inability to examine patients in case of claustrophobia.
https://static-content.springer.com/image/art%3A10.1007%2Fs11882-012-0250-y/MediaObjects/11882_2012_250_Fig1_HTML.gif
Fig. 1

a and b, Axial and coronar MRI of obstructive bilateral polyposis (*) in a 14-year-old girl with cystic fibrosis. c–e, Consecutive steps of polyposis removal by powered instrumentation (#) at the right side of the same patient. At the end of surgery, the medially dislocated but covered by normal mucosa middle turbinate is clearly visible. Oscillating microdebriders allow very precise resection of polyps under protection of unaffected mucosa. Powered instruments are especially useful in revision cases

Therapeutic Management

The large variety of proposed treatment modalities for CF-related NP indicates lack of standardization and of evidence of effective treatment [22••, 41].

Conservative Treatment

Systemic drug application is not proven to have any therapeutic effect on NP in CF. In a recent Cochrane review [42], three trials including 166 non-CF patients treated with systemic steroids for NP were identified. Polyps appeared to have diminished in size and symptoms appeared to have reduced; however, the moderate to low quality of the studies did not allow overall quantification of such effects, and in the short courses of therapy reported, no significant adverse effects were seen. However, this strategy has not been evaluated for CF-NP patients, and the risks in CF are even more pronounced, including endogenous pancreatic insufficiency (diabetes), osteoporosis, and chronic pathogen colonization.

Thus, rhinologic symptoms are usually treated by topical approaches. However, methodologic limitations of drug deposition with regard to nasal and paranasal areas require discussion (Table 1).
Table 1

Topical application of therapeutic agents in CRS with and without NP

Method of topical application

Comments

Perspectives

Nasal sprays

Only reach the lower and middle nasal turbinate [48] but regularly no deposition is achieved into paranasal sinuses

Applicable to improve upper airway passage and for application of secondary agents

Nasal drops

Usually no deposition is achieved into paranasal sinuses

Applicable to improve upper airway passage and for application of secondary agents

Possibly more effective when applied in the head “down and forward” position [90, 91]

Addition of therapeutic agents to nasal lavages

Therapeutic concept that is addressed below with regard to topical application of antibiotics [6466]

Small and only partially controlled clinical trials report positive effects

Nasal inhalation

Conventional inhalative drugs do not reach the paranasal sinuses without surgical widening of sinus ostia [46]

For paranasal sinuses: limited to early postoperative therapy

Sinonasal inhalation of vibrating aerosols

With topical antibiotic and mucolytic treatment (discussed below) [49]

First promising clinical trials

With topical steroids: possibly a method to deposit agents at bases of NP within paranasal sinuses

Prospective clinical trials required

CRS chronic rhinosinusitis, NP nasal polyposis

Nasal Lavage

Already in yogic traditions in ancient India, saline irrigation was performed to liberate the upper airways from secretions, mucus, and crusts. Until now, this method had been applied as an adjunct to medical treatment using isotonic (0.9%) or buffered hypertonic saline, which can additionally contain NaHCO3, K2SO4, and sparse amounts of other ions. The standard method is applied with the head anteflected above a sink and rinsing 250 mL (∼125 mL/nostril) of saline from one nostril to the other, commonly during elevation of the soft palate.

A Cochrane review pointed to therapeutic saline irrigation in non-CF patients to improve CRS symptoms and disease-specific QoL scores [43]. Moderately hypertonic solutions evidently improved mucociliary clearance [44, 45]. However, saline was not as efficient as topical steroids (TS) [43]. Many CF patients report positive effects of saline irrigation on CRS symptoms, but controlled studies concerning this treatment modality in CF are still lacking.

All in all, there is no evidence for therapeutic NL alone reducing the presence or size of NP in CF, or in NP within other diseases. However, clearance of nasal secretions and mucus should reduce sinonasal load with pathogens and inflammatory agents, which could have effects on mucosal inflammatory processes, including NP growth. Longitudinal data including rhinoscopic findings and NL assessing pathogens and inflammatory markers could clarify this question.

Deposition of Active Drugs to the Paranasal Sinuses

Without surgical widening of sinus ostia, conventional inhalative drugs do not reach the paranasal sinuses [46]. In contrast, the recently developed Pari Sinus and Pari Vibrent nebulizers which generate pulsating aerosols (44.5 and 25 Hz, respectively), enable medicament deposition to the upper airways and paranasal sinuses, as proven by in vitro and in vivo studies [47, 48••]. Recently, we published the first double-blind, placebo-controlled, crossover trial of sinonasal inhalation of dornase alfa (see below) in CF patients performed with Pari Sinus [49••]. CRS symptoms assessed by the Sinonasal Outcome Test 20 (SNOT-20) were reduced significantly compared with sinonasal inhalation of isotonic saline.

Active Drugs

Table 2 provides a list of active drugs used in treatment.
Table 2

Conservative therapeutic agents in CRS with and without NP

Conservative therapeutic option

Details

Evidence in CF-NP

Comments

Nasal saline irrigations: isotonic (0.9%); buffered; hypertonic (see below)

Douche; irrigation; rinsing; large particle nebulization; sprays

Not sufficiently investigated

Yes (to clear secretions and crusts)

Topical decongestants

Oxymetazoline, phenylephrine, xylometazoline, etc.

No effect on polyp size [92]; extended use: rhinitis medicamentosa [93]

Helpful to apply other topical drugs in congested nasal airways (<7 d)

Steroids

Topical (spray or drops)

CF evidence for reduction in NP size

Yes (to reduce obstruction; NP); further studies required

Topical (sinonasal inhalation)

Could reach NP bases within paranasal sinuses

Possibly (controlled trials required)

Systemic (short course)

Non-CF evidence for reduction of NP size

Possibly (further trials required)

Intrapolyp injection

Not sufficiently investigated

Controlled trials required

Antibiotics

Topical

Controlled trials required

Systemic

Controlled trials required

Immunomodulators

Macrolides

Effects in patients with elevated IL-8 ? [75]

Controlled CF trials required

Ibuprofen

Possibly (controlled CF trials required)

Antimycotics

No evidence [94]

Not unless mucosal mycosis is identified

Mucolytics

Dornase alfa

First trials [53, 54]

Possibly (further trials required)

Hypertonic saline; spray; sinonasal inhalation

First trials ongoing

Possibly

Bacterial lysates

No evidence [95]

No

Allergen avoidance

Only in patients with allergy

Antihistaminics

Only in patients with allergy

Humanized anti–IL-5 monoclonal antibodies

Only in patients with allergy

CF cystic fibrosis, CRS chronic rhinosinusitis, IL interleukin, NP nasal polyposis

Dornase Alfa

Neutrophils’ degradation liberates large amounts of DNA, significantly enhancing the viscosity of CF airway secretions [50]. Dornase alfa, a recombinant human deoxyribonuclease, reduces the viscosity of secretions by cleaving extracellular DNA [51]. In CF pulmonary disease, bronchial inhalation of dornase alfa was shown to improve pulmonary function and decrease respiratory exacerbations [52].

Nasal inhalation of dornase alfa was assessed in 5 CF patients after sinus surgery in a retrospective preliminary study [53], compared with 15 CF patients without this treatment. Patients with dornase alfa inhalation were reported to have less mucosal edema and no recurrence of NP within 3 years. This preliminary study was followed by a randomized, prospective, double-blind trial on postoperative nasal inhalation of dornase alfa or placebo in CF-related CRS by Cimmino et al. [54], which confirmed better control of nasal symptoms in the dornase group with significantly improved rhinoscopic findings. However, the authors did not present data on polyp sizes before and after therapy in both treatment arms.

In our trials on sinonasal inhalation of dornase alfa with the Pari Sinus [49••] in CF patients without recent surgery, sinonasal symptoms improved significantly, and, as in the postoperative trial by Cimmino et al. [54], pulmonary function improved with verum, comprising the united airway hypothesis.

Hypertonic Saline

Presently, we are performing a German multicentric study on sinonasal inhalation of hypertonic and isotonic saline with the Pari Sinus with a protocol analogous to our studies on sinonasal inhalation with dornase alfa. As shown by Cochrane reviews on pulmonary treatment in CF, this inexpensive agent supports airway clearance, reduces exacerbation frequency, and improves the overall course of the disease [55•].

Topical Steroids

The effect of TS on CRS with or without NP by depressing inflammatory cells within the mucosa and in the epithelial lining fluid is undoubted [56]. In eosinophilia-dominated NP exists “grade A” evidence for reducing nasal symptoms of blockage, discharge, and polyp size, and improving QoL [57]. Therefore, TS are the primary therapy of choice in allergic and idiopathic CRS in adults and children for short- and long-term treatment [58].

The CF-related NP, dominated by neutrophil inflammatory cells [12], is not supposed to be as sensitive to TS as eosinophilic-dominated allergic NP. However, some studies reported positive effects of TS on CF-related NP [59, 60].

A very recent Cochrane review [61] on this subject identified a single-center trial by Hadfield et al. [12] from 2000 as the only publication fulfilling the criteria of relevant double-blind, placebo-controlled; randomized; and quasi-randomized controlled studies. It included 46 CF patients with NP aged greater than 16 years who received betamethasone sodium diphosphate (n = 22) as nasal drops twice daily for 6 weeks or placebo (n = 24) by an identical vehicle. Betamethasone was effective in reducing the size of polyps assessed by endoscopic grading using the Lund and Mackay [37] system, whereas the placebo had no effect. However, no difference was found in nasal symptom scores between the two groups as assessed by visual analogue staging system. Betamethasone was associated with an increased report of mild side effects such as discomfort and nasal bleeding (three patients, all in the treatment group), without statistical significance.

Furthermore, the risk of bias in the study was estimated as high, as because it was not completed by more than half of the enrolled patients (22 of 46), the authors did not rate dropouts as critical bias, and the follow-up period (6 weeks) was very short. All together, Beer et al. [61•] underlined the urgent need for a large and well-designed clinical trial examining medical therapies for CF-NP with adequate power and sufficiently long follow-up periods. As CF and non CF NP frequently generate from the paranasal sinuses, topical steroid therapy into the sinuses should be most effective. As nasal sprays or drops are not relevantly deposited in this segment, prospective controlled trials on sinonasal inhalation with topical steroids should be of special interest.

In summary, in cases of limited polyposis, administration of topical nasal steroids may result in some polyp shrinkage and relief from the associated symptoms [60, 62, 63].

Antibiotics

In primarily or secondarily impaired airway clearance as the cause of CRS with or without NP, sinonasal pathogen colonization is a crucial factor. Nevertheless, there is no evidence for an effect of antibiotic treatment on the presence and size of NP in CF.

Addition of antibiotics such as tobramycin or colistin to NLs is a therapeutic concept [64, 65], for example, performed by serial maxillary sinus lavage with tobramycin, 20 mg [66], added to the last 50 mL of irrigant of NL with 250 mL of saline. Graham et al. [66], who assessed therapeutic effects by serial MRI scans of the paranasal sinuses, noted a prolonged increase in sinus aeration after antibiotic lavage.

Bronchial inhalation of antibiotics is an established gold standard in CF pulmonary therapy, with high evidence levels for tobramycin, colistin, and aztreonam [67•]. Inhalation was proven to be the method for highest deposition of antibiotics in CF mucus compared with intravenous or oral application. Deposition of inhalative therapeutic agents to the nose and the paranasal sinuses appears to be a therapeutic option that avoids the systemic side effects of oral or intravenous antibiotics.

Presently, we are performing pilot trials on sinonasal inhalation of tobramycin and colistin with the Pari Sinus. First analysis showed that P. aeruginosa counts in NL from CF patients with sinonasal colonization of the pathogen were reduced more frequently with antibiotics than isotonic saline [68]. Besides, in the small pilot cohort, the antibiotic appeared to have a positive effect on symptoms (SNOT-20). Further studies including larger collectives are required for final evidence of effectiveness and to assess effects of sinonasal antibiotic inhalation on the presence and size of NP in CF patients [69, 70].

In CF patients with chronic pulmonary colonization with P. aeruginosa, long-term systemic treatment with macrolides such as azithromycin evidently reduces airway inflammation and pulmonary destruction, as proven by large epidemiologic and experimental studies [71]. This approach could be interesting for treatment of CF-related CRS with or without NP [72, 73]. In this regard, CF nasal epithelial cell production of IL-8 was shown to be directly reduced by macrolides [74]. Yamada et al. [75] assessed the size of NP and IL-8 levels in NL during administration of macrolides in non-CF NP patients. In those with primary elevated IL-8 levels in NL (which is typical of CF), NP size was reduced during macrolide treatment and IL-8 decreases in NL were correlated with the reduction in NP size, whereas no relevant changes were found in patients with basically low IL-8. It is possible that non–IL-8–mediated inflammation was the reason for failure of a recent long-term, randomized controlled study involving treatment of recalcitrant non-CF CRS patients with and without NP with low-dose azithromycin [76].

However, in CF patients with their predominant neutrophil and IL-8–mediated inflammation and frequent colonization of the sinonasal area with pathogens such as P. aeruginosa, prospective, controlled trials on the effects of macrolide treatment on the presence and size of NP would be of special interest.

Ibuprofen

High-dose ibuprofen was shown to inhibit neutrophil activation and migration in CF lungs as well as the release of lysosomal enzymes. In a double-blind, placebo-controlled trial, Konstan et al. [77] showed that among CF patients who took high-dose ibuprofen consistently for 4 years, progression of lung disease was significantly slowed compared with those receiving placebo. Lindstrom et al. [78] questioned CRS symptoms in a retrospective study on 235 CF patients treated with ibuprofen. Nineteen of these 235 patients self-reported CRS (a surprisingly low proportion according to data on prevalence of CRS in CF [79]), and 12 of them were diagnosed with NP. All patients who had received ibuprofen doses of 25 to 60 mg/kg per day for 6 to 80 months reported absence of their NP at some point during the ibuprofen therapy course. Also, this anti-inflammatory approach would require prospective, controlled trials for evaluation of the potential in CF-related NP.

Other Immunomodulatory Approaches in Nasal Polyposis Therapy

In non-CF NP [80], fibroblasts are discussed as the primary cell type contributing to pathophysiologic processes in NP architecture by releasing biologically active factors such as RANTES (Regulated on Activation, Normal T-cell Expressed and Secreted), IL-1β, tumor necrosis factor-α [81], and granulocyte-macrophage colony-stimulating factor [82]. Such inflammatory mediators and differentiation factors could be influenced by anti-inflammatory drugs such as ibuprofen, nimesulidum, cyclooxygenase (COX)-1 and COX-2 inhibitors and budesonide. Beata et al. [80] assessed in vitro fibroblast cultures grown from non-CF NP and their proliferation under the mentioned therapeutic substances. The authors found inhibition of NP fibroblast growth by budesonide and a specific COX-2 inhibitor, rofecoxib.

As recently reported, therapy with two injections of 750 mg of mepolizumab, a humanized anti–IL-5 monoclonal antibody, significantly reduced severe eosinophilic NP in a double-blind, placebo-controlled trial [83]. However, the transfer of these promising results from patients with predominantly eosinophilic NP to CF patients with predominantly neutrophilic NP appears difficult.

Surgical Management

Surgical intervention is performed after conservative medical measures are exhausted. Unfortunately, polyposis in CF patients is not curable but can be clinically stabilized by a combination of individually adapted endoscopic sinus surgery and supportive conservative treatment.

Sinus surgery in CF patients has been shown to be safe when performed in specialized centers by skilled rhinologists [84]. However, the principles of minimal invasivity of functional endoscopic sinus surgery (FESS), as described by its proponents [85], for non-CF-patients are modified to a more extensive approach due to the specific indications in CF patients. Unfortunately, objective indication criteria for FESS in CF are still lacking.

CF patients and their families usually experience intensive medical treatment very early in childhood. Therefore, even in severe cases, the discussion of invasive procedures can be very challenging. Most of these patients had symptoms of nasal obstruction, nasal discharge, postnasal drip, headache, and facial pain. Consequently, the indication is based on subjective severity of nasal symptoms and pulmonary status rather than on endoscopic or CT/MRI findings.

Along with clinical and endoscopy status, the imaging adds important information for selecting CF patients who may benefit from FESS. Therefore, we recommend MRI as the most sensitive imaging method prior to surgery, especially in children.

Three major maxillary MRI patterns could be differentiated [40]:
  1. 1.

    Air-filled sinuses with mucosal thickening

     
  2. 2.

    Fluid-filled sinus lumen with moderate/advanced mucosal thickening

     
  3. 3.

    Streaky-shaped sinus lumen with advanced mucosal thickening and minimal fluid content mostly associated with obstructive polyposis (Fig. 1).

     

The streaky-shaped pattern in MRI favorably correlates with surgical indication. Numerous CF patients with advanced maxillary opacification have normal aeration of the ethmoid sinuses. This demonstrates that in CF patients, in contrast to non-CF patients, advanced maxillary sinus disease may exist as a single entity (comparable to a mucocele) not secondary to polyposis. Such patients usually report limited nasal symptoms not requiring surgery. In our practice, the indication for surgery was best accepted by patients with severe nasal obstruction.

In non-CF patients, the surgical technique of FESS relies on the ability of the mucosa to recover to its normal function after removing of the “bottleneck” of the paranasal sinus system in the ethmoid. In contrast, CF patients present with a “systemic” disturbance to clear the viscous mucus. Therefore, the surgical procedure must be more extensive, especially concerning drainage of the maxillary sinus, in order to create larger apertures and enable easier drainage of the mucus and supportive measures such as inhalations or irrigations.

Due to the mucus consistency and chronic bacterial infection, the mucociliary clearance remains poor, and thickened secretions are vulnerable to developing crusts. This is supposed to be one of the main causes of recurrent polyposis requiring revision surgery in CF patients (Table 3) [86]. Another reason may be the delayed healing of postoperatively traumatized mucosa in CF. Chronic infection might stimulate growth of granulation tissue clinically appearing as recurrent polyposis. In children and adolescents, a planned second-look sinus surgery after a period of 6 to 12 weeks helps achieve stable mid- and long-term results.
Table 3

Recurrence rates of NP after paranasal sinus surgery in CF patients

Source (year)

Patients, n

Mean age, y

Mean follow-up, mo

Recurrence rate, n (%)

Cuyler [96] (1992)

10

9.1

36.0

10/10 (100)

Nishioka et al. [97] (1995)

21

12.3

34.3

6/13 (46)

Rowe-Jones et al. [27] (1997)

46

23.0

28.2

21/46 (46)

Coste et al. [98] (1997)

12

12.6

>36.0

11/12 (92)

Triglia and Nicollas [99] (1997)

27

12.6

39.0

12/27 (44)a

Schulte and Kasperbauer [84] (1998)

23

18.5

>24.0

6/7 (86)

Yung et al. [100] (2002)

12

8.0b

48.0b

12/12 (100)

Keck and Rozsasi [86] (2007)

26

14.6

23.0

18/26 (69)

Rickert et al. [87•] (2010)

33

10.1

87.6

14/33 (42)c

CF cystic fibrosis, NP nasal polyposis

(Adapted from Keck and Rozsasi [86].)

aAfter 1 y

bMedian

cMean 2 revisions/patient

The use of powered instrumentation and high-definition video endoscopy considerably improved our capabilities to remove polyposis without destroying unaffected mucosa. These techniques are especially useful in revision cases (Fig. 1). However, recurrence rates remain high (Table 3) [86, 87•], and retrospective studies did not find a significant improvement of lung function and reduction in pathogen colonization after FESS in children with CF [88, 89•].

Despite minimally invasive approaches of modern FESS, surgery is followed by large mucosa defects. A combination of systemic and local antibiotic treatment and topical corticoids minimizes inflammatory reaction and promotes healing. During the past 15 years, different after-care regimens were proposed, but none developed to a standard. Multicenter, placebo-controlled studies appear urgently needed to help define an optimal postoperative algorithm.

Conclusions

In the life-threatening inherited disease CF, CRS and NP are much more frequent than currently expected and than diagnosed in routine care. Therefore, CRS and obstructing NP impair climatic and filtering functions of the upper airways, and the sinonasal area was found to harbor pathogens such as P. aeruginosa, the primary causative agent for pulmonary destruction in CF.

Whereas the pathogenesis of NP in general remains unclear, the causative inflammation in CF is characterized by impaired mucociliary clearance, the resulting bacterial colonization, and neutrophil-dominated host reaction.

The variety of therapeutic concepts reveals the lack of standardization and evidence of efficacy for CF-NP treatment, which unfortunately is not curable but can be clinically stabilized. Thereby, in CF, the mucosal defect persists after surgery, leading to high relapse rates and together with lacking evidence for most conservative measures, this points to the urgent need for multicentric interdisciplinary prospective and controlled scientific approaches for CF-NP.

Acknowledgment

The authors thank Franziska Doht and Dr. Ruth Michl for their support in preparation of the manuscript.

Disclosure

Dr. Mainz has served on advisory boards for Grunenthal, Gilead, and Pharmaxis; has had travel expenses covered by Novartis, Pari, Roche, Infectopharm, and MSD; and has conducted clinical trials on behalf of Luxemburgian and Germany CF Foundations and Pari Germany, Roche, Infectopharm, and Forest.

Dr. Koitschev reported no potential conflicts of interest relevant to this article.

Copyright information

© Springer Science+Business Media, LLC 2012