Rhinosinusitis and Nasal Polyps PDF

41 Rhinosinusitis and Nasal Polyps Claus Bachert, Nan Zhang, Philippe Gevaert CONTENTS Introduction, 659...

41 Rhinosinusitis and Nasal Polyps Claus Bachert, Nan Zhang, Philippe Gevaert CONTENTS Introduction, 659 Chronic Rhinosinusitis With Nasal Polyps, 663 Acute and Chronic Rhinosinusitis Without Nasal Polyps, 659 Summary, 669 be present for at least 12 weeks to differentiate chronic rhinosinusitis SUMMARY OF IMPORTANT CONCEPTS (CRS) from acute rhinosinusitis (ARS). Acute rhinosinusitis (ARS) generally is preceded by a viral upper respiratory It recently has been proposed that structural changes in the extracel- tract infection and usually requires no antibiotic treatment; less than 4% lular matrix, such as fibrosis of the ostiomeatal complex, develop pri- of patients may require antibiotic treatment for bacterial infection and marily, and that mucosal inflammation may follow secondarily.3 This (frontal) sinus pain. However, rare complications need to be recognized and initial pathophysiologic sequence then leads to temporary impairment treated appropriately. of ventilation and drainage of the sinuses, with consequent development Chronic rhinosinusitis (CRS) affects 10% to 15% of the general population of persistent obstruction of the ostiomeatal complex in chronic fibrotic (in the United States and the European Union), is more common in patients sinus disease, also referred to as CRS without nasal polyps (CRSsNP).2,4 with allergic rhinitis and smokers and often is associated with higher rates CRS with nasal polyps (CRSwNP), by contrast, is characterized by a of airway comorbidity such as asthma. hyperplastic, edematous remodeling pattern, with a lack of transforming The two major phenotypes of the chronic disorder are CRS with and CRS growth factor-β (TGF-β) signaling and collagen deposition. Furthermore, without nasal polyps; remodeling is mainly regulated by transforming growth underlying diseases such as allergic rhinitis, cystic fibrosis (CF), immune factor-β (TGF-β) expression. Within the nasal polyp group, endotypes are deficiency, or primary cilia dyskinesia may give rise to sinusitis mani- characterized by the presence of T helper (Th2) cytokines. Interleukin (IL)-5, festations, or severe inflammation may accompany aspirin sensitivity immunoglobulin E (IgE), eosinophilic-cationic protein (ECP) and IgE to staphy- or comorbid asthma. Thus CRS is clinically heterogeneous, and further lococcal superantigens indicate severe type 2 inflammation. research is needed to determine the relevant etiologic conditions and A disease-modifying role has been established for Staphylococcus aureus pathophysiologic causes for its phenotypes and endotypes.1 in severe nasal polyp disease and comorbid asthma, characterized by tissue An increasing body of knowledge on the involvement and regulation eosinophilia and local polyclonal IgE synthesis. of inflammatory cells, cytokines, and chemokines has emerged from For medical treatment of CRS, topical or oral glucocorticosteroids and anti- studies on different subgroups of diseases with paranasal inflamma- biotics are the main options. Surgery should be considered only after drug tion.5,6 The investigation of inflammatory and remodeling factors is treatment has failed, but even after surgery, drug treatment needs to be mandatory to identify specific patterns and to differentiate between continued. sinusitis subgroups to develop and predict the outcome of specific new Evidence-based new treatment approaches for type 2 nasal polyp endotypes therapeutic interventions.6,7 In this chapter, the phenotypes CRSsNP may include biotherapeutics such as dupilumab, omalizumab, or mepolizumab; and CRSwNP are considered separately. biomarkers need to be identified to predict therapeutic responses. ACUTE AND CHRONIC RHINOSINUSITIS WITHOUT NASAL POLYPS INTRODUCTION Epidemiology Sinusitis is one of the three most common health care complaints, with Sinusitis is an inflammatory disease with a prevalence that has been high socioeconomic costs, including lost school or work days for children estimated at 10% to 30% in Europe and 15% in the U.S. population.4,8,9 and adults. Sinusitis means inflammation of the paranasal mucous ARS is a common health complaint, affecting more than 1 billion persons membranes, which may be triggered by viral, bacterial, or fungal infec- annually in the United States. The prevalence of CRS exceeds that of tions and often starts in and certainly involves the nasal cavity (rhino- other chronic conditions. As suggested by trends in amounts of money sinusitis).1 A clinical definition of rhinosinusitis was proposed and since spent for sinusitis treatment, this disease seems to be increasing in refined by a working group of European otolaryngologists and is now prevalence and imposes a considerable economic burden and health internationally accepted (i.e., EPOS 2012).2 This definition states that care costs. A recent European multicenter study estimated the prevalence the diagnosis of rhinosinusitis is based on symptoms and their duration of CRS measured by questionnaire at 10.9% of the population; smoking but also includes endoscopic and/or radiologic criteria. Symptoms must increased the odds even further.10 A strong association between CRS 659 Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 660 SECTION E Respiratory Tract and asthma also is recognized. CRS (typically with polyps) in the absence rhinitis or common cold. With the common cold, symptoms usually of nasal allergies is associated with late-onset asthma.11 peak at day 2 or 3 and are expected to decrease at day 5 after the onset Even an uncomplicated viral upper respiratory tract infection (the of the infection. Complete and spontaneous resolution of symptoms “common cold”) would induce not only rhinitis but, in a majority of usually occurs by 7 to 10 days. In cases of acute viral rhinosinusitis, cases, also sinusitis, as detected by computed tomography (CT) studies.12 symptoms also peak within 2 to 3 days of onset, decline gradually Thus the term rhinosinusitis is widely accepted nowadays, in part because thereafter, and disappear again within 7 to 14 days. Cases that deviate of studies showing concomitant rhinitis and sinusitis as confirmed by from this pattern usually are not solely viral in origin.9,15 In general, increased cytokine levels in the turbinates corresponding to the tissue the illness course appears to be longer in bacterial infection.2 changes in the diseased sinuses. The definition introduced by Fokkens and colleagues2 to characterize rhinosinusitis states that the diagnosis of CRS is based on not only Pathogenesis and Etiology symptoms and their duration but also endoscopic or radiologic criteria The paranasal sinuses are cavities that are only partially present at birth (Box 41.1). Signs and symptoms include nasal congestion and discharge, (maxillary and ethmoidal sinuses) but develop in childhood from the facial pressure, and loss of the sense of smell. In addition, changes on ethmoidal sinuses into otherwise compact bone of the forehead and the endoscopic examination of inflammation and/or CT scan must be sphenoidal region. Their presence and size are dependent on healthy present. conditions during this period of life and are quite variable. Each sinus In chronic sinusitis, clinical manifestations generally are the same is lined with ciliated pseudostratified columnar epithelium with goblet as in acute disease but last more than 12 weeks, or complete resolution cells, which transport mucus into the nasal cavities by way of small ostia. of symptoms fails to occur. In some patients with chronic disease, These ostia also provide ventilation of the sinuses, which is dependent however, symptoms may be diffuse, or the clinical problem may consist on the airflow in the nasal cavity. The anatomic structures of the sinuses of a single symptom such as headache (e.g., from isolated sphenoiditis) are complex and variable. The ostiomeatal complex, consisting of the or postnasal drip, and some patients may not be aware of sinus involve- maxillary infundibulum, the frontal recess, the ethmoidal bulla, and the ment, especially if concomitant asthma exists. A comprehensive diagnostic middle meatus, has been identified as a key region for ventilation and evaluation should therefore be considered in patients with long-standing drainage of the maxillary, anterior ethmoidal cells, and frontal sinuses. nasal complaints or lower airway disease. Sinus CT imaging is manda- Normal sinuses are free of bacterial growth. Various bacteria, however, tory for the diagnosis. are involved in acute bacterial rhinosinusitis. Payne and Benninger Most of the classifications of sinusitis are made on the basis of the performed a meta-analysis of 25 studies on the microbiology of acute temporal course of the illnesses, such as duration and frequency of bacterial rhinosinusitis by analyzing the prevalence of the most common episodes. Sinusitis may be characterized as acute, recurrent acute, or bacteria in the middle nasal meatus and the maxillary sinus. Cultures chronic, with acute exacerbations of chronic sinusitis an additional of the maxillary sinus samples found bacteria with the following fre- category.2,9 ARS is sudden in onset, and each episode may last up to 12 quencies: 26% grew Streptococcus pneumoniae; 28%, Haemophilus influ- enzae; 6%, Moraxella catarrhalis; and 8%, Staphylococcus aureus.13 These findings correlated with those in the middle meatus, where these same BOX 41.1 European Position Paper on bacterial species were found in 34%, 29%, 11%, and 14% of samples, Sinusitis and Nasal Polyposis (EPOS) respectively. Definition of Acute and Chronic Rhinosinusitis Acute bacterial rhinosinusitis is considered a complication of acute viral rhinosinusitis. Viral infections of the nose and sinuses induce With and Without Nasal Polyps multiple changes in the nose, which increase the risk for bacterial super- Inflammation of the nose and the paranasal sinuses characterized by two or infection. These changes include epithelial damage and affect humoral more symptoms—any of which may be first or second: and cellular defense mechanisms. However, bacterial superinfection is Nasal blockage/obstruction/congestion limited to 0.5% to 2% of acute viral upper respiratory tract infections.2 Nasal discharge (anterior/posterior nasal drip) Only in limited cases is acute bacterial rhinosinusitis thought to develop Facial pain/pressure without a previous viral infection. Reduction or loss of smell In chronic maxillary sinusitis, by contrast, anaerobic bacteria alone and either or mixed infections with facultative anaerobes and aerobes (e.g., with Endoscopic signs—one or more of the following: S. aureus, coagulase-negative staphylococci, Pseudomonas aeruginosa) Polyps are predominant. Unfortunately, studies show substantial variation.2 A Mucopurulent discharge primarily from middle meatus study identified species, by clone sequence analysis, belonging to 34 Edema/mucosal obstruction primarily in middle meatus genera, with species of the genera Pseudomonas, Citrobacter, Haemophilus, and/or Propionibacterium, Staphylococcus, and Streptococcus being numerically Computed tomography changes dominant.14 Mucosal changes within the ostiomeatal complex and/or sinuses It is unclear, however, whether bacterial infections truly contribute to chronic sinusitis pathophysiology or may instead just be secondary Acute Rhinosinusitis: to the local milieu in an obstructed sinus that encourages bacterial 12 weeks Without complete resolution of symptoms Clinical Features (Phenotypes) From Fokkens WJ, Lund VJ, Mullol J, et al. EPOS 2012: European ARS is a common disorder that is divided into acute viral rhinosinusitis position paper on rhinosinusitis and nasal polyps 2012. A summary and acute bacterial rhinosinusitis and usually is preceded by a viral for otorhinolaryngologists. Rhinology 2012;50:1-12. Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  CHAPTER 41 Rhinosinusitis and Nasal Polyps 661 weeks. If symptoms of a common cold worsen after 5 days of onset, or persist for longer than 10 days, and are more prolonged and/or severe than normally experienced with a viral infection, the diagnosis of ARS, either viral or bacterial, is probable. Symptoms should resolve completely after adequate treatment. Recurrent ARS is defined by symptoms and clinical findings consistent with ARS, with more than four episodes per year. Each episode may last up to 12 weeks. Between episodes, symptoms are absent without the use of concurrent antibiotic therapy. CRS is defined as presence of symptoms for more than 12 weeks in adults and is characterized by persistent CT changes in the sinus even after aggres- sive medical treatment. Children are more susceptible to viral upper respiratory infections, are exposed to higher rates of infection through child care facilities, and have a less mature immune system. Consequently, more episodes (more than 6 per year) of disease are required for the definition of childhood CRS. Furthermore, ARS in children may be subdivided into Fig. 41.1 Computed tomography scan of the midface in a patient with severe and nonsevere forms, according to the degree of symptoms, chronic sinusitis. Bilateral opacification of the ostiomeatal complex and accompanying fever, or orbital involvement. the maxillary sinuses is evident. The association between sinusitis and asthma has long been appreci- ated. Up to 70% of patients with asthma also present with sinusitis as confirmed on sinus x-ray examination. Furthermore, strong circumstan- tial evidence suggests that CRS may be linked to chronic lung disease, BOX 41.2 Differential Diagnosis of Chronic especially severe asthma. As reported in different studies, radiographic Rhinosinusitis sinus abnormalities are frequently found in children and adults with Infectious rhinitis: viral upper respiratory tract infections asthma exacerbations, and drug management of sinusitis or sinus surgery Allergic rhinitis: seasonal, perennial, occupational results in significant improvement in asthma symptoms and exacerbations Nonallergic rhinitis: vasomotor rhinitis, nonallergic rhinitis with eosinophilia and in reduction of corticosteroid use for asthma. The mechanisms by syndrome, aspirin sensitivity which sinusitis influences asthma, however, are not well understood. Rhinitis medicamentosa Allergic and nonallergic rhinitis may also give rise to sinusitis. Naclerio Rhinitis secondary to pregnancy, hypothyroidism and co-workers16 presented several hypotheses to explain a link between Atopic rhinitis allergy, tissue edema, and vascular congestion causing obstruction of Anatomic abnormalities: severe septal deviation, foreign body sinus drainage and finally nasal and sinus inflammation. There is, Nasal polyps however, no convincing evidence of a change in ostial patency or of an Inverted papilloma, benign and malignant tumors increased incidence of purulent sinusitis related to seasonal rhinitis. It Cerebrospinal fluid leak, meningoencephaloceles has therefore been suggested that perennial allergic (and nonallergic) Mucoceles rather than seasonal rhinitis may predispose to sinusitis. Furthermore, Wegener granulomatosis allergy represents a poor prognostic factor for the outcome of sinus Cocaine abuse surgery in some studies. Specific or topical infections Fungal sinus disease Patient Evaluation, Diagnosis, Ophthalmologic or neurologic diseases and Differential Diagnosis Evaluation of the character, severity, and location of symptoms and identification of the duration and course of disease, comorbid illnesses, and underlying pathologic condition, as well as earlier management tumor, meningoceles, or mucoceles. Magnetic resonance imaging (MRI) attempts, are essential to provide a working diagnosis of sinusitis. Ante- is particularly sensitive for the evaluation of fungal sinusitis and exten- rior rhinoscopy may show hyperemia and swelling of the inferior tur- sion of disease into the brain. binates, structural deformities of the septum, and even purulent secretions Because nasal cultures do not necessarily give an adequate picture from the sinuses (middle meatus). Endoscopy, mostly performed with of the organisms responsible for sinusitis, the indication to sample a rigid scope after nasal decongestion is achieved, is a rapid and easy secretions from the sinus itself by puncture is limited to patients with method to evaluate the middle nasal meatus and the ostiomeatal complex, infections resistant to treatment or immunocompromised hosts (e.g., posterior nasal structures, and the nasopharynx. In children, fiberoptic HIV-seropositive persons, chemotherapy recipients, people with diabetes, rhinoscopy is a convenient alternative to rigid endoscopy and also permits acutely ill patients in intensive care units). examination of the pharynx and larynx. The differential diagnosis is outlined in Box 41.2. In clinical practice, Standard sinus radiographs may be used for the diagnosis of acute nasal obstruction and headache are frequently encountered. Consider- frontal or maxillary sinusitis but often do not provide additional infor- ations in the differential diagnosis for facial pain and headache include mation over history alone. Ultrasound imaging is of limited value but migraine, tension, cluster and rebound headaches, cranial neuralgia, may be used in pregnant women to avoid exposure to radiation. CT and atypical facial pain. Furthermore, eye diseases and problems with helps to define the extent of the disease, anatomic abnormalities, and accommodation may cause periorbital pain sensations. When indicated, changes in the ostiomeatal complex and provides a “map” for surgery a neurologic and/or ophthalmologic examination should be performed (Fig. 41.1). CT also is indicated for evaluation of orbital or cerebral to exclude other causes. Unilateral nasal obstruction, possibly with pain complications of sinusitis, for the preoperative evaluation of chronic or bloody discharge, is always suggestive of a sinister pathologic entity sinusitis, and in the diagnosis of all sinister pathologic entities such as such as tumors developing in the nasal, paranasal, or nasopharyngeal Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 662 SECTION E Respiratory Tract Symptoms Suggestive of Chronic Rhinosinusitis ,QLWLDOHYDOXDWLRQ ‡0HGLFDOKLVWRU\PDMRUPLQRUV\PSWRPV ‡*HQHUDOH[DPLQDWLRQ ‡$QWHULRUUKLQRVFRS\QDVDOHQGRVFRS\ ‡(YDOXDWLRQRIXQGHUO\LQJGLVHDVHDQGFRPRUELGFRQGLWLRQV ‡&RPSXWHGWRPRJUDSK\ &7 VFDQ QRWLQDQDFXWHHSLVRGH 6SHFLDOLQGLFDWLRQV GLIIHUHQWLDOGLDJQRVLVDQGXQGHUO\LQJGLVHDVH  ‡$OOHUJ\WHVWV ‡0LFURELRORJ\ HYHQWXDOO\VLQXVSXQFWXUH ‡&KDOOHQJHWHVWIRUDVSLULQVHQVLWLYLW\ ‡1DVDOF\WRORJ\ HRVLQRSKLOVQHXWURSKLOV ‡0DJQHWLFUHVRQDQFHLPDJLQJ 05, Fig. 41.3 The mucosa in chronic sinusitis without nasal polyps is char- ‡&LOLDU\IXQFWLRQVWXGLHV ‡%LRSV\ acterized by basement membrane thickening, goblet cell hyperplasia, ‡%ORRGH[DPLQDWLRQV :HJHQHUJUDQXORPDWRVLVLPPXQRGHILFLHQFLHV subepithelial edema, and mononuclear cell infiltration with few eosinophils ‡6RGLXPFKORULGHWHVW IRUF\VWLFILEURVLV (evident on EG2 staining). Original magnification ×200. ‡(OHFWURQPLFURVFRS\ IRUFLOLDU\IXQFWLRQ ‡*HQHWLFDQDO\VHV ‡&RQVXOWDWLRQVRIRWKHUVSHFLDOWLHV HJRSKWKDOPRORJ\QHXURORJ\ strategies against the infection come into play. First, a nonspecific Fig. 41.2 Algorithm for the diagnosis of chronic rhinosinusitis. phase is activated wherein the mucus and its contents (e.g., lysozyme and defensins) play a major role. Vascular endothelial growth factor (VEGF) functions in an autocrine manner to promote nasal epithelial cavities. A flow diagram to support the diagnosis and differential diag- cell growth and to inhibit apoptosis.18 Deficiencies in epithelial immune nosis of chronic sinusitis is presented in Fig. 41.2. barrier function and the production of antimicrobial proteins presum- ably may compromise the interaction between the host and external Complications immune stimuli.19 Complications of bacterial sinusitis are rare nowadays, because most As a second line of defense, the innate and adaptive immune response patients with acute sinusitis are treated with adequate antibiotics; however, is activated, with induction of an inflammatory reaction.2 The innate orbital complications may develop in children and adolescents, with immune system operates through phagocytosis of the microorganisms bacterial infections penetrating from the ethmoid or the frontal sinus by neutrophils, monocytes, and macrophages. The adaptive immunity through the thin bone of the orbital frame. The first sign typically is reacts on antigen presentation through formation of immune products reddish swelling of the medial upper eyelid (cellulitis), which may develop (T helper type 1 lymphocytes and antibodies), which can generate a into a subperiosteal abscess, an intraorbital or eyelid abscess, or an specific response against the invading organism. orbital phlegmona. These abscesses need to be drained urgently by The pathophysiology of chronic infection of the nose without nasal surgical intervention. With even partial associated loss of vision, the polyps has been extensively investigated. In the sinus fluid from surgical patient may require immediate hospitalization for surgical care and patients with CRSsNP, inflammatory cells are predominantly neutrophils, intravenous antibiotic treatment. An orbital phlegmona may lead to a as is observed in ARS, but a low percentage of eosinophils, mast cells, thrombosis of the cavernous sinus, with possible intracranial infection and basophils also may be found. The mucosal lining in CRSsNP is and complete loss of vision. characterized by basement membrane thickening, goblet cell hyperplasia, In adults, an empyema of the frontal sinus may lead to meningitis, subepithelial edema, and mononuclear cell infiltration (Fig. 41.3). In an epidural or subdural brain abscess with typical signs of meningitis, a study evaluating the percentage of eosinophils (of 1000 inflammatory and increased intracranial pressure. In these rare cases, immediate cells counted per vision field), less than 10% were eosinophils (overall intervention using a combined inpatient rhinologic and neurosurgical mean, 2%) in 31 patients with untreated CRSsNP, whereas in 123 with approach is indicated. Osteomyelitis of the frontal bone also necessitates untreated CRSwNP, 108 samples showed more than 10% eosinophils surgical intervention and long-term antibiotic treatment. Recurrent (overall mean, 50%).20 These observations suggest that tissue eosinophilia episodes of meningitis may arise from bony defects in the frontal skull is not a hallmark of chronic sinusitis in the absence of polyp formation, base or the sphenoid sinus and require closure of the defect to prevent with major differences in the pathophysiology of both sinus diseases. future risks. Fungal disease, if invasive, can penetrate bony structures This division in CRSsNP and CRSwNP also suggests different types and the orbit, cheek, and brain. Chronic closure of the frontal, ethmoidal, of remodeling of the diseased mucosa, which have been shown to be or sphenoidal sinuses may furthermore lead to the development of a regulated by factors such as the transforming growth factor (TGF)-β pyomucocele, which should be surgically drained through the nose. family and their receptors, the metalloproteinases (MMPs)—enzymes responsible for extracellular matrix degradation contributing to edema Pathophysiology formation—and their tissue inhibitors (TIMPs).1,21 In short, TGF-βI A variety of physical and biochemical barriers prevent entry from infec- and TGF-β2 protein expression, expression of their receptors TGF-βRI tious agents into the nose. Important barriers are the skin and airway and TGF-βRIII, and consequent collagen deposition are upregulated mucosa.17 If microorganisms penetrate the nose, two main defensive in CRSsNP, whereas expression of TGF-β1 protein and its receptors R1 Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  CHAPTER 41 Rhinosinusitis and Nasal Polyps 663 and R2 and collagen deposition are downregulated in CRSwNP tissues.22 and CRSwNP did not demonstrate a beneficial effect with use of azithro- This differential regulation also was confirmed in a study in Asian mycin in any patient group.27 patients, with MMP-7 and MMP-9 being upregulated in CRSsNP and Surgery is indicated for acute sinusitis in case of complications, CRSwNP; however, TIMP-1 and TIMP-4 were low in nasal polyps, sinusitis resistant to adequate medical treatment, and in chronic sinus- perhaps facilitating edema formation.23 Recent findings suggest that itis after unsuccessful drug treatment. Today, functional endoscopic the upregulation of TGF-β could be an early step in the pathophysiol- sinus surgery (FESS) is the standard procedure for chronic sinus disease ogy of CRSsNP, especially in the region of the ostiomeatal complex, and has been proven to reduce symptoms, as well as to increase the and may even precede inflammation.3 Additional factors involved in quality of life, along with decreased morbidity compared with more formation of edema or fibrosis are the complement system and other invasive procedures in earlier use. The aim of surgery is to restore sinus fibrinolytic components.24,25 ventilation and drainage by opening the key areas and preserve sinus The typical cytokine pattern of CRSsNP disease consists of pro- mucosa, which has the potential to regenerate. Possible complications inflammatory and neutrophil-associated cytokines, including IL-1β, of FESS include severe bleeding, orbital trauma, and cerebrospinal tumor necrosis factor (TNF)-α, and IL-8, resulting in increased neu- fluid leaks, with secondary complications such as meningitis or cere- trophil activation (myeloperoxidase [MPO]). In contrast with CRSwNP, bral damage; however, in experienced hands, complications are not which is characterized by an eosinophil-rich Th2-dominated cytokine more common with endonasal approaches than with the former open pattern with high IL-5 and low TGF-β concentrations, CRS shows a procedures. Th1-biased immune response with high interferon (IFN)-γ and an elevated TGF-β signal.6 CHRONIC RHINOSINUSITIS WITH NASAL POLYPS Treatment Epidemiology Because ARS is mostly preceded by a viral infection, the first step in The prevalence of CRSwNP in the general population is considered to treatment is symptomatic relief. Accordingly, short-term topical and be low. Valid epidemiologic studies are lacking, and the fact that an oral decongestants are given to decrease congestion, and a pain reliever endoscopic examination is necessary for diagnosis further complicates is added for muscle ache, sore throat, and headache. such approaches. A postal questionnaire survey of a population-based, A newer treatment option is topical and systemic corticosteroids. A random sample of 4300 adult women and men aged 18 to 65 years was study in uncomplicated ARS showed that an intranasal corticosteroid, performed in southern Finland.28 The prevalence of CRSwNP was 4.3%, mometasone furoate, used in a dose of 200 µg twice daily, produced and CRSwNP and aspirin sensitivity were associated with an increased significant symptomatic improvement compared with amoxicillin and risk of asthma. The incidence of nasal polyps is higher in men than in placebo and did not predispose the patient to disease recurrence or women and significantly increases after the age of 40 years. bacterial infection.26 Additional evidence suggests that topical corticoster- The prevalence of allergy in patients with CRSwNP has been reported oids given as adjunctive treatment along with antibiotics may provide to range from 10% to 54%, and a clear relationship between allergy greater benefit in reducing nasal symptoms, including obstruction, and and CRSwNP has not been shown. Furthermore, nasal polyps occur headache than that obtained with antibiotics alone.2 Oral corticosteroids more frequently in asthma patients with aspirin sensitivity and CF.29 can contribute to relief of facial pain and headache in ARS. Other drugs Approximately 40% to 80% of patients with aspirin sensitivity suffer including mucolytics, homeopathics, and saline irrigation have not been from polyposis, and about 15% of polyposis patients have aspirin sen- shown to be effective.2 sitivity. Asthma frequently coincides with CRSwNP, and nonallergic Medical treatment of acute bacterial sinusitis aims to eradicate late-onset asthma is significantly more frequently linked to polyps bacterial growth in the sinuses, restore ventilation and drainage, and compared with early-onset allergic asthma. decrease the inflammatory process. With S. pneumoniae, H. influen- In a large series of patients with CF, mainly neutrophilic nasal zae, and M. catarrhalis representing the most common bacteria asso- polyposis was noted in 37% to 48%.30 When polyps occur in chil- ciated with acute sinusitis, first-choice antibiotics include amoxicillin, dren and adolescents, CF should always be considered. Cystic fibrosis second-generation cephalosporins, or eventually amoxicillin plus cla- is the most common fatal inherited disease among whites, affecting vulanic acid; in penicillin-allergic subjects, alternative choices include approximately 1 in 2000 live births. The basic metabolic derangement trimethoprim-sulfamethoxazole, azithromycin, and clarithromycin. is related to a mutation in the gene regulating the chloride transport For these antibiotics, a significant and similar therapeutic efficacy in epithelial cells. The position of the apical membrane-bound protein, versus placebo has been demonstrated, although the frequency of CF transmembrane conductance regulator (CFTR), is affected, leading side effects is higher with amoxicillin plus clavulanic acid than with to a decrease in apical chloride transport and a thickening of mucus nonpenicillins.2 Of note, however, only about 2% to 4% of cases of secretions. Extensive population studies have demonstrated that the community-acquired ARS actually represent a bacterial infection; the most frequent CFTR mutation associated with CF is a deletion of the vast majority are considered to be of viral origin.2,9 The use of anti- three nucleotides encoding phenylalanine 508 (F508) and is found in biotics should therefore be restricted to severe cases of presumably 73.2% of all patients with CF.30 Other conditions associated with nasal bacterial sinusitis with signs such as fever in adults, general malaise, polyps include Churg-Strauss syndrome and Kartagener syndrome (situs unilateral frontal headache, or emerging complications, or in patients with inversus). immunodeficiency. In CRSsNP, the role of bacteria has been challenged, and the benefit Pathogenesis, Etiology, and Clinical of antibiotic treatment is questionable; however, antibiotics are indicated Features (Phenotypes) for acute exacerbations. Long-term topical corticosteroid treatment may Nasal polyps are edematous semitranslucent masses in the nasal and have beneficial effects on nasal and sinus pain symptoms and has also paranasal cavities, originating mostly from the mucosal linings of helped to avoid surgery during the treatment period.2 Antibiotics such the sinuses and prolapsing into the nasal cavities. CRSwNP is not a as macrolides may have antiinflammatory and antibacterial effects, which consistent disease; on the basis of mediator and cytokine content, may have beneficial effects in chronic sinusitis if used long-term. Of it currently may be subdivided into different endotypes as outlined note, however, a multicenter European study in patients with CRSsNP in Fig. 41.4.2,31 Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 664 SECTION E Respiratory Tract 0 20 40 60 80 100 80 60 40 20 0 % CRSsNP % no N 1 o asthma n IL-22 IL-5 2 - t y negative MPO IL8 IL6 IFN-γ p 3 e 2 4 MPO IL8 IL6 IL-17 + IL-22 IFN-γ 5 6 IL-5 IgE ECP IFN-γ T MPO IL8 IL6 y IL-5 7 IL-22 p e positive IL-17 + IL-22 IFN-γ 8 2 IL-5 S. aureus 9 IL-5 MPO IL8 IL6 IL-17 + IL-22 high IgE + super- SE-IgE % CRSwNP % asthma antigen 10 ECP 100 80 60 40 20 0 20 40 60 80 100 Fig. 41.4 Endotyping of CRS. (From Tomassen P, Vandeplas G, van Zele T, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol 2016;137(5):1449–56.) without polyposis, and may serve as a valid marker to estimate the duration, presence, and extent of disease. Of interest, whereas chronic sinusitis often is associated with headache and facial pain, nasal polyposis itself rarely causes pain despite the fact that most of the sinuses, includ- ing the frontal sinuses, are opacified. Viral infections frequently cause prolonged episodes of severely obstructed nasal passages and colored secretions, with subsequent bacterial infection. Infections also may be associated with a temporary growth of the polyps and, if persistent, accelerate the course of disease. Inhalant allergens do not seem to induce additional complaints or to cause polyps. Patients also often report worsened nasal congestion and discharge after consuming alcoholic beverages. Allergic Rhinitis. Although elevated total IgE is found in polyp fluid, skin prick tests for inhalant allergens reveal no difference between atopic and nonatopic subjects with polyps in terms of correlating with con- centrations of IgE or numbers of eosinophils.32 It was demonstrated that skin prick tests do not predict total IgE levels in polyp homog- Fig. 41.5 Endoscopic view of nasal polyps protruding from the middle enates.33 By contrast, local total IgE concentrations are high, most likely meatus. owing to local production of S. aureus enterotoxins (SEs), which act as superantigens and induce polyclonal IgE formation.34 An increased total IgE in serum in combination with a lack or low concentrations of allergen-specific IgE antibodies to inhalant allergens may indi- cate polyclonal IgE formation, especially in patients with comorbid The diagnosis of nasal polyps is based on the finding of pale gray, asthma. round or bag-shaped mucosal protrusions from the sinuses into the nasal cavity (Fig. 41.5), which on cut section prove to be gelatinous or Asthma. CRSwNP frequently is found in association with asthma and watery masses. Most nasal polyps arise from the clefts of the middle nonspecific bronchial hyperresponsiveness. In studies involving a large nasal meatus and ethmoidal cells and prolapse into the nose. Some series of patients with CRSwNP, asthma was found in 20% to 70%.35 polyps originate in the maxillary, sphenoid, or frontal sinuses. Several reports have demonstrated evidence of bronchial hyperreactivity Symptoms and signs of CRSwNP are similar to those in CRSsNP in patients with CRSwNP, even in those without a history of asthma, (see Box 41.1), but depending on the extent of polyp masses within especially in nonatopic patients.36 A long-term follow-up study of patients the nasal cavities, symptoms and complaints vary. The typical history with CRSwNP confirmed that the incidence of subsequent clinically in the development of nasal polyps is a “cold that persisted over months significant bronchial asthma was higher than in the general population. or years,” with nasal obstruction and discharge as the most prominent Of interest, in patients with CRSwNP and asymptomatic bronchial symptoms. With time, hyposmia or anosmia develops, and additional hyperreactivity, an eosinophilic bronchial inflammation similar to that complaints such as a feeling of fullness are present. Anosmia is a typical observed in asthma with CRSwNP, is observed in the tissue, whereas symptom for nasal polyps, differentiating it from chronic sinusitis in patients with CRSwNP without bronchial hyperreactivity, such Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  CHAPTER 41 Rhinosinusitis and Nasal Polyps 665 inflammation is absent. These findings may support the classification of patients with CRSwNP into two groups: those with current or future lower airway involvement and those without. The medical or surgical treatment of CRSwNP may have a favorable impact on the control of asthma in those subjects. Aspirin Sensitivity. In 1922, Widal described a symptom triad of aspirin sensitivity, corticosteroid-dependent asthma, and nasal polyposis, which was made more widely known by Samter and Beers later, result- ing in the use of the term Samter’s triad to describe this condition. Initial symptoms usually appear in the third or fourth decade of life and consist of nasal congestion, rhinorrhea, postnasal drip, and hypos- mia, based on persistent mucosal inflammation. Within a few years, CRSwNP and bronchial asthma develop. Aspirin sensitivity is suspected after a typical respiratory reaction that can be confirmed by oral provo- cation test.37 Of 500 patients registered at the European Network on Aspirin-Induced Asthma (AIANE), almost 80% complained of nasal blockage accompanied by rhinorrhea. Acute asthma and/or rhinitis attacks are caused by ingestion of aspirin and other nonsteroidal anti- inflammatory drugs (NSAIDs) that share the ability to inhibit the enzymes cyclooxygenase (COX)-1 and -2, although pure COX-2 inhibi- Fig. 41.6 Computed tomography scan obtained in a patient with a fungal tors are usually but not uniformly tolerated, implicating COX-1 inhibi- infection of the right maxillary sinus. Heterogeneous opacification and tion as the inciting factor in such reactions.38 At least 15% of patients calcification with increased attenuation are typical findings. with an aspirin-provoked asthma and rhinitis attack are unaware of their aspirin sensitivity, indicating that formal aspirin challenge is nec- essary to fully diagnose the disease. The full typical clinical picture of aspirin-exacerbated respira- peanut butter–like secretions) filling the sinuses. Of interest, S. aureus tory disease (AERD) is characterized by increased blood eosinophil regularly forms biofilms with fungi in AFS, contributing to IgE formation, counts, an increase of eosinophils in the nasal and bronchial mucosa, and geographic variation has been documented, with a higher incidence and elevated cysteinyl-leukotriene concentrations in the tissue and in the southern United States than in northern locations.40 urine, which further increases after aspirin exposure.39 Thus far, no Invasive forms should be differentiated on the basis of clinical find- validated laboratory blood test is available to establish the diagnosis, ings at presentation, either as indolent chronic, slowly destructive disease, which must then be based on oral, bronchial, or nasal provocation tests which is endemic in Sudan and caused mostly by Aspergillus flavus, or (see Chapter 78). as a fulminant acute, necrotizing form in immunocompromised hosts (e.g., AIDS, CD4+ counts less than 50 cells/mL, or neutrophil counts Fungal Disease. Sinusitis may be caused not only by viruses and less than 1000 cells/mL), mostly caused by Aspergillus fumigatus and bacteria but also by fungi, which may either infiltrate the mucosa and often lethal within days of onset because of hematogenous dissemina- the surrounding tissue (invasive forms) or remain extramucosal (non- tion despite high-dose intravenous antifungal treatment. invasive forms). Fungal sinusitis is currently divided into four primary categories: acute/fulminant (invasive), chronic/indolent (invasive), Cystic Fibrosis. Chronic lung disease and pancreatic insufficiency fungus ball (noninvasive), and allergic fungal sinusitis (AFS, noninva- dominate the clinical picture of CF and determine associated mortality. sive). Of these, AFS is the most common form and is associated with Involvement of the nose and sinuses is common in patients with CF; nasal polyps. however, sinus problems very rarely contribute to the risk of death. The fungus ball, also referred to as a mycetoma, is mostly unilateral, Sinusitis is almost always detected in radiologic investigations in patients often in association with symptomatic chronic maxillary sinusitis and with CF, even if many of these patients have no sinonasal complaints. little mucosal tissue reaction in an immunocompetent host. Imaging The incidence of CRSwNP in CF varies, ranging from 6% to 48%, and studies (CT or MRI) may show heterogeneous opacification, calcifica- CRSwNP is found in children of 5 years of age and older. A study of tion with increased attenuation in CT (Fig. 41.6), and hypointense 211 Caucasian adults with CF reported that 37% had CRSwNP.41 Fifty signal characteristics on T2-weighted MRI sequences secondary to the percent of the children between 4 and 16 years of age who present presence of calcium in the fungal concretion. Within the sinus, creamy with CRSwNP have CF. On the other hand, genes responsible for CF or claylike secretions typically are found. A possible dentogenic pathway may be associated with the development of CRS in the general popula- has to be excluded, and removal of the fungus ball by means of sinus tion.42 The sweat chloride test (for increased electrolytes) remains the surgery represents the treatment of choice. simplest and the most reliable laboratory procedure to screen for and Fungi associated with the development of allergic fungal rhinosi- diagnose CF. nusitis (AFS) are ubiquitous and predominantly of the dematiaceous Mucosal changes in CF generally affect the paranasal cavities bilater- family (Aspergillus, Rhizopus, Alternaria, Curvularia, Bipolaris specifera, ally, possibly causing facial deformities such as hypertelorism in chil- and others). Exposure alone to these fungi, however, appears to be insuf- dren. Furthermore, the development of the frontal and sphenoid sinuses ficient to initiate disease. AFS mostly develops in atopic young hosts, along may be disturbed, resulting in hypoplasia or even absence. Radiologic with nasal polyps, and immediate hypersensitivity skin testing specifically signs such as the bulging of the lateral nasal wall and the erosion of for the fungus may yield positive results, with an elevated serum total the uncinate process seem to be characteristic of CF (Fig. 41.7). The IgE and fungus-specific IgE and possibly IgG4. The sinus mucosa shows bacteriology of maxillary sinuses in CF reveals an infection in 95% of a characteristic eosinophilic inflammation, with allergic mucin (seen as all cases, with predominant organisms being Pseudomonas aeruginosa, Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 666 SECTION E Respiratory Tract S. aureus, H. influenzae, and anaerobes. Unfortunately, the response is performed, with special attention to mucosal structures and the to antimicrobial therapy often is suboptimal compared with that in involvement of the sinuses (Fig. 41.8). A CT scan is mandatory before persons without CF. sinus surgery is considered and also must be available during the pro- Because of the ubiquitous and persistent nature of the disease and cedure to inform the surgeon about anatomic variations. An MRI scan its often transient beneficial effects, sinus surgery should only be per- may be helpful for the diagnosis of fungal disease or tumor or if intra- formed in case of severe symptoms or before lung transplantation. The cranial extension of disease is suspected. development of FESS has decreased the morbidity of sinus surgery and To determine extension of disease within the nose and the sinuses, reduced the recurrence of nasal polyposis in CF. A careful postoperative endoscopy and CT scan–based staging systems have been proposed and follow-up evaluation by the surgeon is mandatory but often difficult partially validated.43 These systems may prove useful for medical com- in young patients, and these patients also need to be carefully monitored munication and for the evaluation of therapeutic responses. The endo- by pediatric CF units. scopic staging system (Box 41.3) is based mainly on the assumption that polyp growth starts from the middle nasal meatus and then extends, Patient Evaluation, Diagnosis, in a two-dimensional manner, toward the floor of the nose. The fact and Differential Diagnosis that the nasal cavity is three-dimensional, however, may sometimes Diagnosis of CRSwNP is made by rigid nasal endoscopy. To investigate have a negative impact on the reproducibility of this system when used the extent of disease within the sinuses, a CT scan with coronal sections by different investigators. The radiologic staging system includes all sinuses and the ostiomeatal complex bilaterally (Box 41.4). A smell test, skin prick testing for inhalant allergens, and eventually cytologic examination of nasal secretions for eosinophils and a blood sample for an eosinophil count may provide additional information. In some cases, endoscopically guided microbiology from the middle meatus or biopsy may help direct the optimal treatment. Because nasal polyps may represent a part of a systemic disease, comprehensive history and further investigations may be necessary. Asthma, aspirin sensitivity, Churg-Strauss syndrome, inhalant allergies, CF, and other lung diseases should be considered. Because the symptomatology of nasal polyps is rather nonspe- cific, nasal endoscopy should be performed to confirm the diagnosis BOX 41.3 Endoscopic Staging System for Nasal Polyposis Score Right Left 0 No polyps present 1 Polyps confined to the middle meatus 2 Polyps beyond the middle meatus (reaching the inferior turbinate or medial to the middle turbinate) 3 Polyps almost or completely obstructing the nasal cavity Adapted from Lund VJ, Kennedy DW. Quantification for staging Fig. 41.7 Computed tomography scan obtained in a child with cystic sinusitis. The Staging and Therapy Group. Ann Otol Rhinol Laryngol fibrosis shows typical bulging of the lateral nasal walls. Suppl 1995;167:17-21. A B Fig. 41.8 Computed tomography scans obtained in patients with nasal polyposis. (A) Central disease, rep- resenting an early stage of polyposis. (B) Near-total “white-out,” a late-stage manifestation. Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  CHAPTER 41 Rhinosinusitis and Nasal Polyps 667 BOX 41.4 A Radiologic Staging System for Sinusitis Structural Component Scoringa Right Left Maxillary sinus: 0, 1, 2 Anterior ethmoid: 0, 1, 2 Posterior ethmoid: 0, 1, 2 Sphenoid: 0, 1, 2 Frontal sinus: 0, 1, 2 Ostiomeatal complex: 0, 2b Total a 0 = no abnormalities; 1 = partial opacification; 2 = total opacification. b Ostiomeatal complex: 0 = no occlusion; 2 = occluded. Adapted from Lund VJ, Kennedy DW. Quantification for staging sinusitis. The Staging and Therapy Group. Ann Otol Rhinol Laryngol Suppl 1995;167:17-21. Fig. 41.9 Eosinophils, seen as pink-staining cells (labeled with EG2 antibody), accumulate in the subepithelial regions and also are diffusely distributed in the tissue of a mature polyp. Original magnification ×200. and exclude other diseases. Turbinate hypertrophy, concha bullosa, CRSsNP, or adenoid hypertrophy also may cause nasal obstruction. Although nasal polyps have a characteristic appearance on nasal endoscopy, inverting papillomas, benign or malignant tumors, or even meningoencephaloceles may be mistaken for nasal polyps. Any uni- lateral obstruction, nose bleeding, or crusting should be intensively investigated. Apical eosinophilic Pathophysiology inflammation Histomorphologic characterization of polyp tissue reveals epithelial damage, a thickened basement membrane, and stromal tissue ranging Central in nature from edematous to fibrotic, with a reduced number of vessels pseudocyst and glands, but virtually no neural structure—hence the lack of tissue area sensation. The stroma of mature polyps is mainly characterized by its edematous nature, consisting of supporting fibroblasts and fibrin, and infiltrating inflammatory cells, which are localized around “empty” pseu- docyst formations.44 Among the inflammatory cells, eosinophils staining positive for the anti–eosinophil cationic protein (ECP) antibody EG2 (i.e., activated eosinophils) are a prominent and characteristic finding Fig. 41.10 Numerous subepithelial eosinophils in the luminal compart- in approximately 80% of polyps (Fig. 41.9), whereas lymphocytes and ment of an early-stage polyp, adjacent to the central pseudocyst area. neutrophils are the predominant cells in CF and primary ciliary dys- Original magnification ×200. kinesia. More recent evidence confirms that accumulations of plasma cells, macrophages, innate lymphocytes (ILC)2s and activated IL-2 receptor-positive T cells also are characteristic of eosinophil-rich nasal polyposis.6,45 The presence of numerous subepithelial EG2-positive eosinophils autocrine role for this cytokine in the activation of eosinophils. Treat- has been documented in the luminal compartment of the early- ment of eosinophil-infiltrated polyp tissue with neutralizing anti-IL-5 stage polyp, where they form a cap over the central pseudocyst area monoclonal antibodies, but not anti-IL-3 or anti–GM-CSF monoclonal (Fig. 41.10). The extracellular matrix degradation, albumin reten- antibodies, in vitro caused eosinophil apoptosis and decreased tissue tion, and edema formation are likely to result from the relative defi- eosinophilia.46 ciency of TGF-β, a profibrotic factor, and from the imbalance between The ultimate way to test for the role of IL-5 and eosinophils in the matrix metalloproteinases MMP-7 and MMP-9, their natural tissue pathogenesis of CRSwNP is by antagonizing this cytokine, as done in inhibitors (TIMPs). an interventional study in patients with the disorder.47 Eosinophils, Early studies on the cytokine profile in polyps versus control tissue however, show variable sensitivity to IL-5, owing to a different level demonstrated the presence of a range of mediators linked to eosino- of expression of the IL-5 receptor α (IL-5Rα) isoforms in relation- phil growth and activation, including granulocyte-macrophage colony- ship to activation state, maturation, and localization in the body. stimulating factor (GM-CSF), IL-3, IL-5, and IFN-γ. IL-5 represents a At the local tissue level, the membrane-anchored IL-5Rα isoform is key cytokine among those mediators and is independent of the atopic downregulated, whereas the secreted IL-5Rα variant is upregulated in status of the patient.5 Actually, the highest concentrations of IL-5, nasal polyp tissue, but eosinophils are still activated.48 Gevaert and which correspond to ECP measurements, were found in polyp tissue colleagues evaluated the effect of a single intravenous infusion of a in subjects with nonallergic asthma and aspirin sensitivity. Further- humanized antihuman IL-5 monoclonal antibody, reslizumab, on more, eosinophils were positively stained for IL-5, suggesting a possible nasal polyps in a double-blind, placebo-controlled two-center study.47 Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 668 SECTION E Respiratory Tract A single injection of reslizumab was well tolerated and reduced blood The rate of nasal colonization of S. aureus is significantly increased eosinophil numbers and serum and nasal concentrations of ECP for in patients with polyps versus control subjects and parallels the severity up to 8 weeks. A subsequent study using mepolizumab achieved a of airway disease; a colonization rate of 88% was found in aspirin- significant reduction of the polyp score and markers of eosinophilic sensitive asthma patients with polyps.34 In up to 80% of polyps from inflammation versus placebo, which was objectively evaluated by these patients, SE IgE can be found locally. a CT scan.7 S. aureus is among the most frequently found bacteria in CRS, as Eosinophil recruitment is mediated mainly by the chemokines confirmed by culture-independent techniques.14 S. aureus seems specifi- RANTES (regulated upon activation, normal T cell–expressed and cally associated with eosinophilic inflammation and nasal polyps and secreted) (i.e., CCL5) and eotaxins, in cooperation with IL-5. The expres- may form biofilms to serve as a nidus of infection and allow the microbe sion of eotaxin-2 (CCL24), a CCR3 chemokine, was found to be the to survive antibiotic treatment56; this organism also may penetrate into most prominent of the chemokines investigated. An elegant study using the mucosa to reside intramucosally and intracellularly.57 The recent three-color immunofluorescence staining demonstrated that both the finding of a switch of the macrophage type from M1 to M2, induced number of eosinophils and the proportion of vessels positive for vascular by the Th2 cytokine milieu, may explain an underlying defect in the cell adhesion molecule-1 (VCAM-1) (CD106) were significantly increased defense of the mucosa; M2 macrophages are limited in their ability to in nasal polyps compared with turbinate mucosa in the same patients.49 phagocytize and kill the organism.58 M2 macrophages also may produce Treatment with topical glucocorticosteroids decreased the density of CCL18, a chemokine, leading to the recruitment of lymphocytes and eosinophils and the expression of VCAM-1 in polyps, as well as the dendritic cells and the activation of fibroblasts, thereby supporting the expression of eotaxin and IL-5, resulting in a marked reduction of local inflammation.59 tissue eosinophils. Gram-positive S. aureus constitutively can release classical and egc Of particular interest is the analysis of the local T cell pattern, (enterotoxin gene cluster) locus–derived enterotoxins (i.e., SEs) that which—together with ILC2s, mast cells, and others—may drive eosino- have superantigen activity and effectively modify the functions of T philic inflammation in polyps. As discussed previously, the number of and B cells, eosinophils, and other inflammatory as well as structural activated Th2 cells is increased in polyp tissue over that in control tissue cells. SE stimulation may lead to a Th2-polarized eosinophilic inflam- samples, which corresponds to an increase in soluble IL-2Rα and IL-5 mation and further impairment of Treg function, as well as multiclonal protein levels.6 An analysis of signal transduction factors revealed an IgE production, as has been shown for atopic dermatitis. Follicle-like upregulation of GATA3, corresponding to the upregulation of Th2 structures, specifically binding enterotoxins, contain IgE-generating cytokines, but a downregulation of Foxp3, corresponding to down- plasma cells within the polyp tissue.60 Of interest, IgE antibodies to regulation of regulatory T cells (Tregs), in polyps versus control tissue enterotoxins also can be found in the serum of a majority of patients specimens.50 These findings could point to a deficit in a natural Treg with severe asthma, indicating that the same principles also may apply response, providing an explanation for the persistent inflammation for the lower airways.61 typical of polyp disease. Because Tregs mediate their effects primarily Once present in the mucosa, S. aureus may continuously form via TGF-β, a deficiency in the synthesis and release of this growth and enterotoxins with superantigenic activity. Enterotoxins in animal fibrosis factor could result in a lack of suppression of eosinophil activa- models have been shown to break tolerance and sustain severe tion. TGF-β inhibits the synthesis of IL-5, abrogates the survival- airway inflammation.62,63 In humans, superantigens induce a strong prolonging effect of hematopoietins (IL-5 and GM-CSF) on eosinophils, cytokine release from T cells, thus amplifying the Th2 response in the and impairs extracellular matrix repair. A deficit in Tregs has been tissue and suppressing Tregs, to induce granulocyte migration and demonstrated for nasal polyps, in contrast with CRSsNP.50 With this survival. Superantigens increase IgE, IgG/IgG4, and IgA synthesis.64,65 deficit, different T helper cell patterns can obviously prevail, being pre- Specifically, Staphylococcus aureus enterotoxin A (SEA) and toxic dominantly Th2-driven in the European population but Th17-driven shock syndrome toxin-1 (TSST-1) have the potential to induce the in Asian patients.51 polyclonal formation of IgE against hundreds of allergens, including Nasal polyps contain large quantities of B lymphocytes and plasma inhalant allergens and the enterotoxins as well.32,34 The functionality of cells producing immunoglobulins such as IgA, IgG, and IgE. The expres- locally produced IgE antibodies, even in nonatopic patients, has sion of B cell–activating factor of the TNF family (BAFF), an important recently been demonstrated.33 The presence of IgE antibodies to staph- regulator of class switching recombination and immunoglobulin pro- ylococcal enterotoxins (SE IgE antibodies) and the increase in local duction, has been shown to be upregulated52 and linked to the presence total IgE significantly increases the risk of suffering from comorbid of autoantibodies, in particular, nuclear-targeted anti–double-stranded asthma.66 In line with these findings, SE IgE in serum also has been shown DNA (anti-dsDNA) IgG and IgA antibodies.53 to be associated with asthma in teenagers and with severe refractory Local class-switch to IgE and mucosal production of IgE has been asthma in adult patients.67 Recently, “superallergens,” serine-protease–like demonstrated within polyp tissue.54 proteins, released by S. aureus have been identified.68 New therapeutic principles may arise from these findings, including antibiotic therapy Role of Staphylococcus aureus Enterotoxins. Early studies have and anti-IgE.69 shown that tissue IgE concentrations and the number of IgE-positive cells may be increased in nasal polyps, suggesting the possibility of local Treatment IgE production. This concept was supported by a study demonstrating The management of nasal polyps involves medical approaches, based that the concentrations of IL-5, eotaxin, LTC4/D4/E4, low-affinity IgE mainly on the use of topical or systemic corticosteroids, and surgical receptor (sCD23), ECP, and total IgE were significantly higher in polyp procedures, ranging from the extraction of polyps within the nasal tissue than in nonpolyp tissue. A detailed analysis of IgE indicated for lumen to an extended sphenoethmoidectomy, to eradicate all polyp the first time that IgE antibodies to staphylococcal enterotoxins (SEs) tissue. Because nasal polyposis is a chronic disease with a high rate were present in polyp tissue and that these were associated with a more of recurrence in about a third of patients, the recognition of patients severe local eosinophilic inflammation, suggesting a potential role for at risk of recurrence will be beneficial; such approaches are currently SEs as disease modifiers.55 under development, based on endotyping of nasal polyp disease into Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  CHAPTER 41 Rhinosinusitis and Nasal Polyps 669 non–type 2 and moderate or severe type 2 inflammation.31 A combined treatment of asthma per year, improvement in olfaction, and reduction medical and surgical treatment strategy is recommended for long-term in use of systemic corticosteroids, although these findings are not con- control of polyps. firmed in randomized controlled trials. Owing to gastrointestinal side In patients with nasal polyps, intranasal corticosteroids have well- effects of aspirin and a relapse of risk in case of noncompliance, however, documented, albeit modest, efficacy in reducing symptoms of blockage, this therapy is not routinely used. Moreover, aspirin desensitization rhinorrhea, and occasionally hyposmia; however, symptoms recur within does not appear to modify the long-term course of the asthma or sinus weeks to months of discontinuation of treatment.2 The beneficial effects disease, and long-term studies after surgery are lacking. on nasal obstruction and polyp masses also have been documented by Both surgical intervention and the use of systemic and long-term objective methods such as peak nasal inspiratory flow, rhinomanometry, topical corticosteroids are recommended in the treatment of AFS.73 rhinometry, and smell tests. Topical corticosteroids also may reduce Monitoring the total serum IgE can be helpful in the clinical follow-up the incidence of polyp recurrence after surgery. The treatment may be of these patients, because an increase in total serum IgE was found to inadequate for severe bilateral polyps, however, and polyp growth may have significant predictive value for the need of recurrent surgical inter- be observed despite treatment. vention. Antifungals are indicated only for invasive forms of sinus mycosis Systemic corticosteroids—for example, beginning with 32 mg of or in immunocompromised patients. prednisolone and stepwise reducing the dose during a 14- to 20-day Sinus surgery is indicated in patients resistant to conservative therapy; oral course—are effective in reducing polyp size and symptoms for a however, early surgical intervention may alter the course of disease. A short period of time. Of note, however, repeated applications of oral study in 205 patients with asthma and aspirin sensitivity found surgery corticosteroid bursts may lead to systemic side effects, such as impaired to improve asthma control for relatively long periods.4 No data are bone metabolism, and should be avoided if possible.70 available on the evolution of asymptomatic bronchial hyperreactivity On the basis of theoretical considerations, it has been proposed that in patients with nasal polyposis, however, and in individual patients, antileukotriene therapy would be successful in patients with aspirin asthma symptoms may emerge after surgery. This development prob- sensitivity or recurrences after surgery. However, a recent 1 year post- ably represents the natural course of the disease, rather than a true operative study did not show an advantage of montelukast plus topical shift from upper to lower airway disease. A retrospective study of 80 GCS over topical GCS therapy alone. patients who underwent surgery with an average follow-up period of Antibiotics are indicated in the case of superimposed bacterial infec- 3 years demonstrated a significant improvement in relief of sinusitis tion. Doxycycline treatment for 3 weeks was demonstrated to significantly, symptoms and asthma complaints and reduced need for medication albeit modestly, reduce polyp size and may be combined with topical in more than 80% of the subjects.4 The significant incidence of revi- GCS in daily use.69 sion surgery in this series, however, suggests the need for a novel sur- Sinus surgery, specifically FESS, which may involve powered instru- gical approach and close long-term follow-up with intense medical ments (e.g., shaver, navigation aids) is now the standard procedure, management. with good short-term results in patients resistant to medical treatment. In recent years, innovative treatment options based on an under- However, to prevent recurrence long-term, the complete removal of standing of the underlying pathomechanisms in type 2 inflamma- the mucosa from the sinuses—including the frontal and sphenoid tion in nasal polyposis were developed.31 These include the principles sinuses—may be indicated in severe type 2 inflammation. Extensive of anti-IgE (omalizumab (Bachert 2015)),74 anti-IL5 (reslizumab, postoperative care and follow-up are also required to preserve the post- mepolizumab (7)) and anti-IL4 receptor alpha (dupilumab (Bachert operative results and prevent polyp regrowth. An individualized man- 2016)).75 A recent study with mepolizumab also showed that the need agement for nasal polyposis may combine long-term topical corticosteroids for surgery can be reduced with an anti-IL5 strategy.76 The results of (drops or rinses, rather than spray), a limited number of short-term Phase-3 studies will finally decide on the registration of these bio- systemic corticosteroids, and surgery. In a 20-year follow-up study of logicals, with their implementation in treatment algorithms to be 41 patients with nasal polyps, 85% of patients still had persistent disease, discussed. with anosmia reported in 61%.71 Eight subjects, including seven with aspirin sensitivity, had undergone 11 or more surgical operations during the 20-year period. Eradication of severe disease by standard surgery SUMMARY remains an exception. ARS generally is preceded by a viral upper respiratory tract infection In AERD, conservative treatment possibilities consist of: (1) avoid- and may rarely need to be treated with antibiotics or glucocorticoste- ance of aspirin and other NSAIDs, which may prevent acute, drug- roids. Less than 4% of patients require antibiotic treatment. A few induced exacerbations but does not prevent progression of disease; (2) complications (orbital, intracranial) will need to be recognized and oral and/or topical glucocorticosteroids; (3) leukotriene receptor antago- treated appropriately. Advances in antiviral treatment options could be nists or synthesis inhibitors, although efficacy may be modest; and (4) relevant for specific patients. in selected cases, aspirin desensitization. To prevent exacerbations, the CRS with and without nasal polyps can be defined as two different ingestion of aspirin and COX-inhibiting NSAIDs must be avoided, disease phenotypes on the basis of clinical presentation; underlying whereas selective COX-2 inhibitors (celecoxib, rofecoxib) usually are pathomechanisms allow the differentiation into endotypes, relevant for well tolerated.72 Although systemic corticosteroids have proved effective, prognosis of asthma comorbidity and disease recurrence (Fig. 41.11). they cause side effects in long-term usage. Consequently, leukotriene- These new insights present opportunities to develop new therapeutic modifying drugs deserve further trials to determine their role in the options that are specific for certain disease endotypes, characterized by treatment regimen. the presence of IL-5 or IgE to staphylococcal superantigens within the Aspirin desensitization consists of administering incrementally tissue. In these selected patients, treatment with anti-IL5, anti-IL4 recep- increasing oral doses, to reach a maintenance dose of 325 to 650 mg tor alpha, or anti-IgE monoclonal antibodies has been shown to be once or twice daily. This induces a refractory period of a few days. promising, albeit in small studies. The registration of specific treatment Continuous treatment over years may lead to a significant decrease in options may result in new options and improved outcomes in patients the number of sinus infections per year and in hospitalizations for with severe chronic upper airway disease. Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 670 SECTION E Respiratory Tract “CRS” Chronic rhinosinusitis “NP” Nasal polyposis CD3, CD25, CD68, Neutros, CD3, CD25, CD138, CD68, Neutros, Eos IFN-γ, TGF-β↑, IL-1 IL-5, eotaxin, TGF-β↓, ECP, IgE Fig. 41.11 A schematic comparison of major mediators in chronic rhinosinusitis versus nasal polyposis. Transforming growth factor-β(TGF-β), a key mediator inducing fibrosis, is increased in chronic rhinosinusitis. ECP, Eosinophilic cationic protein; Eos, eosinophils; IFN-γ, interferon-γ; IgE, immunoglobulin E; IL, interleukin; Neutros, neutrophils. REFERENCES 10. Hastan D, Fokkens WJ, Bachert C, et al. Chronic rhinosinusitis in Europe—an underestimated disease. A GA2LEN study. Allergy Introduction 2011;66:1216–23. 1. Van Crombruggen K, Zhang N, Gevaert P, et al. Pathogenesis of chronic 11. Jarvis D, Newson R, Lotvall J, et al. Asthma in adults and its association rhinosinusitis: inflammation. J Allergy Clin Immunol 2011;128:728–32. with chronic rhinosinusitis: the GA2LEN survey in Europe. Allergy 2. Fokkens WJ, Lund VJ, Mullol J, et al. EPOS 2012: European position 2011;67:91–8. paper on rhinosinusitis and nasal polyps 2012. A summary for 12. Gwaltney JM Jr, Phillips CD, Miller RD, et al. Computed tomographic otorhinolaryngologists. Rhinology 2012;50:1–12. study of the common cold. N Engl J Med 1994;330:25–30. 3. Van Bruaene N, Perez-Novo C, Van Crombruggen K, et al. Inflammation 13. Payne SC, Benninger MS. Staphylococcus aureus is a major pathogen in and remodelling patterns in early stage chronic rhinosinusitis. Clin Exp acute bacterial rhinosinusitis: a meta-analysis. Clin Infect Dis Allergy 2012;42:883–90. 2007;45:e121–7. 4. Bachert C, van Cauwenberghe P. Nasal polyposis and sinusitis. In: 14. Stressmann FA, Rogers GB, Chan SW, et al. Characterization of bacterial Adkinson NF Jr, Middleton E, editors. Middleton’s allergy: principles & community diversity in chronic rhinosinusitis infections using novel practice. 6th ed. Philadelphia: Mosby; 2003. culture-independent techniques. Am J Rhinol Allergy 2011;25:e133–40. 5. Bachert C, Wagenmann M, Hauser U, et al. IL-5 synthesis is upregulated in 15. Meltzer EO, Hamilos DL, Hadley JA, et al. Rhinosinusitis: developing human nasal polyp tissue. J Allergy Clin Immunol 1997;99(6 Pt 1):837–42. guidance for clinical trials. J Allergy Clin Immunol 2006;118(Suppl. 6. Van Zele T, Claeys S, Gevaert P, et al. Differentiation of chronic sinus 5):S17–61. diseases by measurement of inflammatory mediators. Allergy 16. Naclerio RM, deTineo ML, Baroody FM. Ragweed allergic rhinitis and 2006;61:1280–9. the paranasal sinuses. A computed tomographic study. Arch Otolaryngol 7. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized Head Neck Surg 1997;123:193–6. anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy 17. Mims C, Dockrell HM, Goering RV, et al. Medical microbiology. 3rd ed. Clin Immunol 2011;128:989–95. Philadelphia: Mosby; 2004. 18. Lee HS, Myers A, Kim J. Vascular endothelial growth factor drives Acute and Chronic Rhinosinusitis Without Nasal Polyps autocrine epithelial cell proliferation and survival in chronic 8. Moss AJ, Parsons VL. Current estimates from the National Health Interview rhinosinusitis with nasal polyposis. Am J Respir Crit Care Med Survey. United States, 1985. Vital Health Stat 1986;10:i–iv, 1–182. 2009;180:1056–67. 9. Meltzer EO, Hamilos DL, Hadley JA, et al. Rhinosinusitis: establishing 19. Tieu DD, Kern RC, Schleimer RP. Alterations in epithelial barrier definitions for clinical research and patient care. J Allergy Clin Immunol function and host defense responses in chronic rhinosinusitis. J Allergy 2004;114(Suppl. 6):155–212. Clin Immunol 2009;124:37–42. Downloaded for Francisco de la Garza ([email protected]) at University of Monterrey from ClinicalKey.com by Elsevier on December 19, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  CHAPTER 41 Rhinosinusitis and Nasal Polyps 671 20. Jankowski R. Eosinophils in the pathophysiology of nasal polyposis. Acta 45. Tojima I, Kouzaki H, Shimizu S, et al. Group 2 innate lymphoid cells are Otolaryngol 1996;116:160–3. increased in nasal polyps in patients with eosinophilic chronic 21. Van Bruaene N, Bachert C. Tissue remodeling in chronic rhinosinusitis. rhinosinusitis. Clin Immunol 2016;170:1–8. Curr Opin Allergy Clin Immunol 2011;11:8–11. 46. Simon HU, Yousefi S, Schranz C, et al. Direct demonstration of delayed 22. Van Bruaene N, Derycke L, Perez-Novo CA, et al. TGF-beta signaling and eosinophil apoptosis as a mechanism causing tissue eosinophilia. J collagen deposition in chronic rhinosinusitis. J Allergy Clin Immunol Immunol 1997;158:3902–8. 2009;124:253–9.e1–2. 47. Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL-5 levels determine 23. Li X, Meng J, Qiao X, et al. Expression of TGF, matrix metalloproteinases, the response to anti-IL-5 treatment in patients with nasal polyps. J and tissue inhibitors in Chinese chronic rhinosinusitis. J Allergy Clin Allergy Clin Immunol 2006;118:1133–41. Immunol 2010;125:1061–8. 48. Gevaert P, Bachert C, Holtappels G, et al. Enhanced soluble interleukin-5 24. Van Zele T, Coppieters F, Gevaert P, et al. Local complement activation in receptor alpha expression in nasal polyposis. Allergy 2003;58:371–9. nasal polyposis. Laryngoscope 2009;119:1753–8. 49. Jahnsen FL, Haraldsen G, Aanesen JP, et al. Eosinophil infiltration is 25. Sejima T, Holtappels G, Bachert C. The expression of fibrinolytic related to increased expression of vascular cell adhesion molecule-1 in components in chronic paranasal sinus disease. Am J Rhinol Allergy nasal polyps. Am J Respir Cell Mol Biol 1995;12:624–32. 2011;25:1–6. 50. Van Bruaene N, Pérez-Novo CA, Basinski TM, et al. T-cell regulation in 26. Meltzer EO, Bachert C, Staudinger H. Treating acute rhinosinusitis: chronic paranasal sinus disease. J Allergy Clin Immunol comparing efficacy and safety of mometasone furoate nasal spray, 2008;121:1435–41, 1441.e1–3. amoxicillin, and placebo. J Allergy Clin Immunol 2005;116:1289–95. 51. Zhang N, Van Zele T, Perez-Novo C, et al. Different types of T-effector 27. Videler WJ, Badia L, Harvey RJ, et al. Lack of efficacy of long-term, cells orchestrate mucosal inflammation in chronic sinus disease. J Allergy low-dose azithromycin in chronic rhinosinusitis: a randomized controlled Clin Immunol 2008;122:961–8. trial. Allergy 2011;66:1457–68. 52. Kato A, Peters A, Suh L, et al. Evidence of a role for B cell-activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis Chronic Rhinosinusitis With Nasal Polyps with nasal polyps. J Allergy Clin Immunol 2008;121:1385–92.e1–2. 28. Hedman J, Kaprio J, Poussa T, et al. Prevalence of asthma, aspirin 53. Tan BK, Li QZ, Suh L, et al. Evidence for intranasal antinuclear intolerance, nasal polyposis and chronic obstructive pulmonary disease in autoantibodies in patients with chronic rhinosinusitis with nasal polyps. J a population-based study. Int J Epidemiol 1999;28:717–22. Allergy Clin Immunol 2011;128:1198–206.e1. 29. Settipane GA. Epidemiology of nasal polyps. Allergy Asthma Proc 54. Gevaert P, Nouri-Aria KT, Wu H, et al. Local receptor revision and class 1996;17:231–6. switching to IgE in chronic rhinosinusitis with nasal polyps. Allergy 30. Feuillet-Fieux MN, Lenoir G, Sermet I, et al. Nasal polyposis and cystic 2013;68(1):55–63. fibrosis (CF): review of the literature. Rhinology 2011;49:347–55. 55. Zhang N, Gevaert P, van Zele T, et al. An update on the impact of 31. Tomassen P, Vandeplas G, van Zele T, et al. Inflammatory endotypes of Staphylococcus aureus enterotoxins in chronic sinusitis with nasal chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy polyposis. Rhinology 2005;43:162–8. Clin Immunol 2016;137(5):1449–56.