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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 29  |  Issue : 3  |  Page : 469-477

Update of pathogenesis and management of nasal polyposis


1 Department of Otolaryngology, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
2 Department of Surgery, ENT Division, College of Medicine and Health Science, Sultan Qaboos University, Muscat, Oman
3 ENT Department, Electrical Hospital, Ministry of Electricity, Cairo, Egypt; Department of ENT, Ibri Referral Hospital, Ministry Of Health, Ibri, Oman

Date of Submission20-Jan-2015
Date of Acceptance27-May-2015
Date of Web Publication23-Jan-2017

Correspondence Address:
Fawzy Fayaz
MBBCh, Kafer Al Mosulaha, Shebine Al Kom City, Menoufiya Governorate, Menoufiya, 32511, Egypt

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.198570

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  Abstract 

Objectives
The goal of this article is to review important and recent findings relating to the pathogenesis and management of nasal polyposis (NP). The rationale for a disease classification based on histopathological characteristics and current concepts in therapeutic approach toward managing the condition are summarized.
Data sources
The data sources are PubMed systemic reviews and all materials on the internet from 2004 to 2014.
Study selection
The initial search presented 6692 articles, of which 40 met the inclusion criteria: systemic review, clinical trial types II and III, meta-analysis, published in English language, published in peer-reviewed journals, and focusing on epidemiology, pathogenesis, and management of NP.
Data extraction
If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included ethical approval, eligibility criteria specified, appropriate controls, and adequate information.
Data synthesis
Recommendations received were revised for the strength of evidence and strength of recommendation then available data were tabulated.
Findings
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a predominantly inflammatory disease associated with dysregulated interaction between sinus epithelium and the innate lymphoid system. Recent research suggests that chronic rhinosinusitis is neither an eosinophilic nor a neutrophilic disorder. The goal in CRSwNP/ eosinophilic chronic rhinosinusitis is to create a wide postsurgical corridor rather than simple polypectomy for effective delivery of topical anti-inflammatory therapy.
Conclusion
New classification of CRSwNP based on the endotyping characters will facilitate the development of managements and establish genetic associations, demonstrate biomarkers for disease subgroups, and test novel therapeutic targets until the question of NP control has been answered.

Keywords: diagnosis, management, nasal polyposis, pathogenesis, polyps


How to cite this article:
El Banhawy O, Al Abri R, Khalil Y, Shafy IA, Fayaz F. Update of pathogenesis and management of nasal polyposis. Menoufia Med J 2016;29:469-77

How to cite this URL:
El Banhawy O, Al Abri R, Khalil Y, Shafy IA, Fayaz F. Update of pathogenesis and management of nasal polyposis. Menoufia Med J [serial online] 2016 [cited 2020 Sep 21];29:469-77. Available from: http://www.mmj.eg.net/text.asp?2016/29/3/469/198570


  Introduction Top


Nasal polyposis (NP) is one of the most common mass lesions of the nose and was first described 4000 years ago in ancient Egypt. The prevalence of NP is reported from 0.2 to 4.3% worldwide, with a ratio of 2-3: 1 between male and female individuals. In children, NP is relatively rare and has a close relationship with asthma and cystic fibrosis. NP is a multifactorial condition that is often associated with many diseases and pathogenic disorders, such as allergy, infection, cystic fibrosis, asthma, and aspirin intolerance; the underlying mechanisms interlinking these pathologic conditions to NP formation remain unclear; and NP usually presents between the ages of 30 and 60 years. There is a strong male predominance, ranging between 2: 1 and 4: 1 male to female [1],[2] ; the general histopathological classification of nasal polyps is eosinophil-dominated and neutrophil-dominated inflammation. The more common histopathological type is eosinophil-dominated inflammation (63-95%) [3] . Population-based studies of chronic rhinosinusitis with nasal polyposis (CRSwNP) from Sweden, Korea, Finland, and France report the prevalence of CRSwNP to lie between 0.5 and 4.3% [4] . Autopsy studies reveal a higher prevalence between 2 and 42%, with more polyps found in dissected nasoethmoidal blocks and endoscopic sinus surgery (ESS) than with anterior rhinoscopy alone [5] . Men and women are both affected by CRSwNP, with some discordance in the literature as to which sex is more frequently affected. In general, nasal polyps occur in all races and become more common with age, with the average age of onset being 42 years [4] . The clinical evaluation of patients with polyps begins with a detailed history. The primary complaints are nasal obstruction and olfactory dysfunction. Headaches are possible in this setting; severe headaches are not typical. The physical examination evaluates for signs of the sinus disease spreading beyond the sinus cavities, such as proptosis or double vision indicating involvement of the orbits by expansion of the sinuses or neurologic symptoms. Endoscopic evaluation visualizes the nasal cavity better than an anterior examination with a nasal speculum, and it can be used for collection of cultures of purulent secretions to guide medical intervention or for the diagnosis of small polyps. Be aware of unilateral polyps, because ~30% of such cases are tumors that require a distinct work-up and treatment [6] . When patients have persistent symptoms despite optimal medical treatment or a complication is suspected based on the history or physical examination, a sinus computed tomography scan is recommended, and it can be useful when the clinician is suspicious of malignancy, extra sinus involvement by inflammatory disease, or a severe headache initially suspected of not being of sinus origin [6] . With regard to the etiology of CRSwNP, numerous hypotheses have been proposed with a great deal of overlap, supporting a multifactorial basis. One classification method separates potential contributing entities into host and environmental factors but fails to illustrate causal relationships and host-environment interactions ([Table 1]) [7] . CRSwNP in the Caucasian population is associated with high tissue eosinophilia and increased T-helper (Th)-2 cytokine expression [interleukin (IL)-5 and IL-13], as well as nasal obstruction and smell loss. Meanwhile, chronic rhinosinusitis with nasal polyps may have more Th-1 polarization and less eosinophilic infiltration. However, these characterizations may not hold true for other ethnic populations [8] . Treatment of CRSwNP is a challenge because the disease is heterogeneous, with multiple mechanisms leading to the same clinical end point [9] . In addition, few treatments have been studied in randomized trials. Apart from intranasal and oral steroids, most other treatment options have failed to prove efficacy. One must also note that children differ from adults in their pathophysiology because their immune system is not fully mature. In addition, NP in children warrants consideration of cystic fibrosis as a diagnosis. The unifying theme for the treatment of nasal polyps is that chronic, severe mucosal inflammation needs to be controlled; acute infections need to be treated with antibiotics (ideally culture directed); and surgery is reserved for medical failure to provide access for postoperative topical anti-inflammatory treatment [10] . The goals of treatment are to eliminate or reduce polyp size, restore nasal breathing, restore the sense of smell, reduce symptoms of rhinitis, reduce the number of bacterial infections, and prevent recurrence [6] . Corticosteroids have been the mainstay of treatment of NP. Topical intranasal corticosteroids are more effective for chronic rhinosinusitis with polyps than for chronic rhinosinusitis without polyps. Oral steroids have been shown to reduce the polyp size and symptoms temporarily, but the optimum dose has not been established, and many regimens exist. The reduction in polyp size with oral steroids can be extended by the use of intranasal steroids after the systemic treatment is concluded [11] . Antibiotics are used to eliminate infection and reduce inflammation. Only one of seven randomized, placebo-controlled studies of topical antibiotics showed a positive effect [12] . Short-term oral antibiotics have been used for the treatment of acute exacerbations of chronic rhinosinusitis. Studies on the long-term use of antibiotics for their anti-inflammatory properties have had mixed results. Doxycycline had a modest and significant effect on patients with nasal polyps, potentially because of dual antibacterial and anti-inflammatory effects [13] .
Table 1 Host and environmental factors in the pathogenesis of nasal polyposis


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Surgery is clearly indicated for intracranial and intraorbital complications, mucoceles, anatomic variations, allergic fungal disease, massive polyps with bony remodeling, and antrochoanal polyps. However, the category leading to the majority of surgical interventions is that of patients who are symptomatic despite medical treatment. Smith and colleagues showed better improvement in quality of life, with a 1-year follow-up of patients electing ESS experiencing significantly higher levels of improvement in outcomes compared with patients managed by medication alone. In addition, subjects in a crossover cohort who initially elected medical management experienced improvement in several outcomes after crossing over to ESS [14] . The surgical approach aims at removing inflamed sinus tissue and bony septae within the sinus cavities. A large audit of patients at 5 years after surgery in England and Wales showed a 20% revision rate overall but marked and persistent improvement in results on the Sino-Nasal Outcome Test, a quality of life measure. Worse outcomes for surgery are found for patients who have aspirin-exacerbated respiratory disease, asthma, and frontal sinus disease [15] .


  Materials and methods Top


Search strategy

We searched PubMed systemic reviews for papers (2004-2014) using 'nasal polyposis', 'polyps', 'diagnosis', and 'management' as keywords.

Study selection

All the studies were independently assessed for inclusion. They were included if they fulfilled the following inclusion criteria: systemic review, clinical trial types II and III, meta-analysis, published in English language, published in peer-reviewed journals, and focusing on epidemiology, pathogenesis, and management of NP. If a study had several publications on certain aspects, we used the latest publication giving the most relevant data.

Data extraction

If the studies did not fulfill the above criteria, they were excluded: report without peer review, not within national research programs, and letters/comments/editorials/news.

Quality of evidence

The evidence-based methodology applied when research to select the studies by systematic reviews, clinical trials II and III and meta-analysis were selected. Recommendations received were revised for the strength of evidence and strength of recommendation then available data were tabulated.

Strength of evidence

Evidence was obtained from the following:

Ia evidence from meta-analysis of randomized controlled trials;

Ib evidence from at least one randomized controlled trial;

IIa evidence from at least one controlled study without randomization;

IIb evidence from at least one other type of quasi-experimental study;

III evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies, and case-control studies;

IV evidence from expert committee reports or opinions or clinical experience of respected authorities, or both.

Strength of recommendation

The strength of recommendation was graded as follows:

  1. Directly based on category I evidence
  2. Directly based on category II evidence or extrapolated recommendation from category I evidence
  3. Directly based on category III evidence or extrapolated recommendation from category I or II evidence
  4. Directly based on category IV evidence or extrapolated recommendation from category I, II, or III evidence.


Data synthesis

Recommendations received both strength of evidence and strength of recommendation ratings, and available data are tabulated.


  Results Top


Study selection and characteristics

We searched PubMed systemic reviews for papers (2004-2014); initially 6692 records were found, which reduced to 70 after they were filtered by systemic reviews, meta-analysis, full text, humans, and published in English; after screening of titles and abstracts, the number reduced to 39 studies, plus one study from the authors ([Figure 1]).
Figure 1: Flow chart of study selection.

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Phenotypes and endotypes of chronic rhinosinusitis with nasal polyposis

Extensive scientific evidence is accumulating that justifies a differentiation of sinus disease not only by phenotype but also by recognition of more detailed endotypes by differences in pathogenic mechanisms that can be discerned by the presence of particular patterns of biomarkers. Definition of different endotypes is mandatory for the development of a better understanding of the pathophysiology of chronic rhinosinusitis (CRS) and holds promise for guiding the development of innovative therapeutic approaches based on that knowledge ([Figure 2]) [9] .
Figure 2: Phenotype and endotype of chronic rhinosinusitis (CRS). IL, interleukin; IgE, immunoglobulin E. Phenotyping and endotyping of CRS was based on recently published findings on asthma comorbidity and recurrence after surgery (Ghent classification of CRS). Licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

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Histological characteristics

Polyps may be roughly classified into one of two types: eosinophilic nasal polyp and noneosinophilic nasal polyp (neutrophil dominant). Tissue eosinophil proportion of more than 11% is a criterion for eosinophilic allergic polyp. When using this criterion, the proportion of eosinophilic allergic polyp among nasal polyps was 62.7% [16] . Nasal polyp had significantly higher levels of eosinophilic markers (eosinophils, eotaxin, and eosinophil cationic protein) compared with CRS, controls, and cystic fibrosis with nasal polyp (CF-NP). Nasal polyp and CF-NP were discriminated by edema from CRS and controls, with CF-NP displaying a very prominent neutrophilic inflammation. On the basis of cellular and mediator profiles, we suggest that CRS, NP, and CF-NP are distinct disease entities within the group of chronic sinus diseases [8] .

Genetic and genetic polymorphism associated with nasal polyposis

Many genes and gene products have been implicated in chronic sinusitis with polyps, and the search for causative genes has led to the discovery of numerous candidates [17] . Pathway analysis applied to these candidate genes identified common central molecules (tumor necrosis factor-nuclear factor kB) that are likely to be key mediators of the disease process. Novel therapies targeting these molecules may be applicable for the treatment of chronic sinusitis with polyps [17] . Genetic association in NP was associated with specific polymorphisms only when it occurred with related phenotypes. Results suggest that this genetic background plays a more relevant role in the development of the associated clinical features of NP than in simple polyposis [18] .

New concept in the pathophysiology of nasal polyposis

Van Bruaene and colleagues have indicated a number of pathophysiologic differences between the early-stage polyps and mature polyps that have not been described before in CRSwNP patients. The epithelial loss was more prominent in the early-stage polyps in the middle turbinate in CRSwNP patients, coupled with increased numbers of especially M2-type macrophages and markedly high expression of fibronectin. Taken together, these findings suggest that aggravated epithelial damage and fibronectin expression play a crucial role in the adhesion and penetration of the basement membrane by bacteria in the initial stages of polyp formation. Similarly, the increased numbers of macrophages in the polyp area of the middle turbinate CRSwNP suggest a defective host defense mechanism in the early stage of the disease. In contrast, a fibrotic response builds up a defense mechanism involving increased deposition of dense collagen fiber bundles in the underlying mucosa to prevent spread and generalization of edema and inflammation. Overall, these findings suggest a complex network of processes in the formation of the CRSwNP, including gross epithelial damage and repair reactions, eosinophil and macrophage cell infiltration, and tissue remodeling. Furthermore, remodeling appears to occur in parallel, rather than subsequent, to inflammation, as has been shown in CRS patients without nasal polyps [19] .

Role of Staphylococcus aureus Scientific Name Search  effects in nasal polyposis

Nasal polyp's pathogenesis still remains obscure, in the past few years. A recent study aimed to document both the adaptive immune responses that characterize Staphylococcus aureus-biofilm-associated CRS and the relative contributions of staphylococcal superantigens and S. aureus biofilms in the inflammatory make-up of this disease. S. aureus enterotoxins, which act as T-cell and B-cell superantigens, induce an intense eosinophilic inflammatory process of the upper and lower airways with polyclonal IgE production unrelated to atopy ([Figure 3]) [20] .
Figure 3: Pathomechanisms of chronic rhinosinusitis with nasal polyposis (CRSwNP). In a TH2-type microenvironment with general lack of regulatory T (Treg) cell function, interleukin (IL)-5 induces eosinophilia, and IL-4 and IL-13 induce local IgE production. An alternatively activated macrophage subset contributes to the inflammation. The activation of epithelium colonized by bacteria and fungi leads to release of proinflammatory chemokines and cytokines with increased thymic stromal lymphopoietin (TSLP) and IL-32 levels. Activated epithelial cells die, with apoptosis resulting in a compromised epithelial barrier. Bachert et al. (2014), licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

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Pathophysiological mechanism of nasal polyposis

There are two important mechanisms implicated in the pathophysiology of NP that have recently received much research attention, and highlight aspects in which these mechanisms intersect: airway remodeling process and S. aureus superantigens on CRSwNP ([Figure 4]) [21] .
Figure 4: Illustration of the influence of Staphylococcus aureus (in orange) on the remodeling process in nasal polyposis. Pezato et al. [21], licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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T-cell subsets in patients with chronic rhinosinusitis

The differentiation of NPs with IL-5-expressing Th-2-biased versus non-Th-2-biased polyps is of clinical relevance. In contrast, neutrophilic polyps are associated mainly with increased levels of interferon-g, IL-17, or both. Interferon-g and IL-17 are also predominant in neutrophilic, cystic-fibrosis-related polyp disease. A mixed cytokine profile, which can be classified as a Th-0 profile, has been demonstrated, and the possible existence of Th-22 and Th-17 cells as novel subsets requires further investigation in patients with different forms of CRS [9] .

New surgical concept

The goal of sinus surgery is to create permanent wide access for long-term topical therapy rather than for relieving sinus obstruction or promoting sinus drainage and aeration [22] .

Anatomical consideration for Arabic patients

Anatomical variations of sinuses from Oman or the Arab world revealed that type 3 Karos classification (low lying cribriform plate) is present in over a third of the Omani population, which is in contrast to the Caucasian and Indian populations where type 1 and type 2 are more common, respectively [23] .

Cone beam technology

Cone beam technology is becoming increasingly available and is associated with lower radiation exposure than conventional imaging. A study comparing cone beam computed tomography with multislice computed tomography for the sinuses in an anthropomorphic phantom model showed that the effective dose of cone beam computed tomography was 30 μSv as compared with 200 and 1400 μSv for low-dose and standard protocols using multislice computed tomography [24] .

Pulsating aerosols for intranasal corticosteroid

Pulsating aerosols can deliver significant doses into posterior nasal spaces and paranasal sinuses, providing alternative therapy options before and after sinus surgery ([Figure 5]) [25] .
Figure 5: Comparison of deposition distribution of nasal pump spray (a) and pulsating aerosol application (b) in a healthy volunteer (superposition of the lateral gamma camera image with an individual representative sagittal MRI slice). Möller et al. [25], this is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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  Discussion Top


In daily clinical practice of an ENT-Allergology center, different forms of rhinitis, such as allergic, nonallergic, and rhinosinusitis with or without NP, are seen. Therefore, the specialist must adopt increasingly complex diagnostic and instrumental methods for diagnosis and management. In fact, only a detailed diagnosis allows to characterize and optimally treat nasal diseases [26] . The patient should undergo thorough diagnostic work-up, where family history must not be excluded, and accompanied by imaging, functional, and immunological evaluations. There is a high 'global' familial incidence of allergy, asthma, and NP, not only between first-degree and second-degree relatives (44.9 and 31.9%) but also in third-degree and fourth-degree ones (23%). These data confirm the fact that, for some diseases, genetic background has a crucial role and should be taken into consideration [27] .

Nasal polyps are tumor-like, hyperplastic swellings of the nasal mucosa, most commonly originating from within the ostiomeatal complex; the prevalence is estimated at 0.2-4% in worldwide studies [28] . Key to understanding this philosophy is the acknowledgement that both CRSwNP and normal patients are exposed to the same allergens, fungi and bacteria (including S. aureus), yet only the first group has a heightened proinflammatory immune response. Recent evidence suggests a crucial role for the epithelial-derived cytokines that mediate the cells of the immune system [29] . Nasal polyps are thought to be a manifestation of chronic inflammation, where they represent the final common pathway of several disease processes, the trigger for which is still unknown. There are numerous theories including hereditary factors, anatomical factors, systemic and local allergy, and infection [6] . Nasal polyps are likely to represent the end result of many different mechanisms, and the search for a single etiological factor may be in vain. Regardless of trigger, the end result is a failure to mount an appropriate immune response to antigens in the nose and sinuses, resulting in chronic inflammation [29] . The management of CRSwNP involves both medical and surgical approaches and remains a controversial subject.

A variety of intranasal corticosteroids form the mainstay of conservative management, with good evidence for their efficacy. A number of randomized, placebo-controlled trials document statistically significant improvements in subjective symptom scores, polyp size, and objective nasal flow rates following topical steroid use [30] . Symptoms of nasal obstruction can be controlled in anywhere from 50 up to 80% of patients. However, clinical studies indicate that the management of anosmia is poor, especially when compared with systemic steroids. Adverse effects from nasal steroids are few, and range from epistaxis to headaches and dizziness. Using the more modern formulations, such as fluticasone or mometasone, there is minimal systemic absorption and the dose is well below that required for adrenal suppression. A meta-analysis to assess the effectiveness of topical steroids has shown that intranasal corticosteroids are effective in the treatment of rhinosinusitis and that prior sinus surgery and direct sinus delivery methods enhance their effectiveness [31] .

Systemic steroids (often termed medical polypectomy) have also been shown to be effective. Two randomized controlled trials comparing placebo with systemic steroids show benefit with oral prednisolone [32] . The use of oral steroids is limited by their toxicity, with adverse effects including weight gain, immunosuppression, and adrenal suppression. A Cochrane review supports the use of systemic steroids in the treatment of NP [33] . A recent systematic review by Poetker and colleagues identified five RCTs supporting the use of oral steroids in the short-term management of CRSwNP ([Table 2]) [35] .
Table 2 Randomized controlled trials evaluating oral steroids in chronic rhinosinusitis with nasal polyposis


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There is a case report by Miao, prepared in 2010, that an Australian patient suffering from nasal polyps and chronic rhinosinusitis had four surgical excisions of nasal polyps treated by Chinese herbal decoction plus acupuncture, and large amounts of mucus disappeared. Nasal polyps did not recur. A recurrence has not occurred for 3½ years. The application of the herbal decoction plus acupuncture effectively prevented the recurrence of nasal polyps in this case. Therefore, further research is warranted in this classic method of treatment [36] .


  Conclusion Top


  1. Curative treatment is hard to achieve in polyposis, and management is primarily aimed at reducing symptom severity. It is therefore important to include a measurement of health-related quality of life when assessing the severity of disease or outcome of treatment.
  2. Nasal polyps are not associated with allergy but can be associated with asthma, aspirin sensitivity, cystic fibrosis, allergic fungal sinusitis, and Churg-Strauss syndrome.
  3. Unilateral polyps may be a sign of malignancy and should be properly investigated.
  4. Children with nasal polyps should be referred for further testing for cystic fibrosis.
  5. Aspirin sensitivity should be suspected in severely affected polyp patients, especially those with recurrent polyps and intrinsic asthma.
  6. Phenotyping of all patients is mandatory.
  7. The appropriate management for nasal polyps must focus on controlling the common inflammatory process rather than on treatment of polyps per se.
  8. All patients should have a trial of medical treatment before surgery unless the nature of the polyps is in doubt.
  9. The goal of sinus surgery is to create permanent wide access for long-term topical therapy.
  10. Alternative medicine is a new hope for management of NP.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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  [Table 1], [Table 2]


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