Relationship between chronic rhinosinusitis and lower airway diseases: An extensive review

Abstract

Significant links between allergic rhinitis and asthma have been reported, and the united airway disease hypothesis is supported by numerous findings in epidemiologic, physiologic, pathologic, and immunologic studies. The impact of allergic rhinitis on asthma has been established. On the other hand, the relationship between chronic rhinosinusitis and lung diseases has been under investigation. Chronic rhinosinusitis is a common disease, and the high prevalence of chronic rhinosinusitis in some kinds of lung diseases has been reported. Recent studies suggest that the treatment of chronic rhinosinusitis has beneficial effects in the management of asthma. Here, we present an overview of the current research on the relationship between chronic rhinosinusitis and lower airway diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis, diffuse panbronchiolitis, primary ciliary dyskinesia, idiopathic bronchiectasis, and allergic bronchopulmonary aspergillosis.

Key Words: Chronic rhinosinusitis, Sinusitis, Asthma, Chronic obstructive pulmonary disease, Cystic fibrosis, Diffuse panbronchiolitis, Primary ciliary dyskinesia, Idiopathic bronchiectasis, Allergic bronchopulmonary aspergillosis

Core tip: Chronic rhinosinusitis is a persisting inflammatory condition of the paranasal sinus. A close relationship between chronic rhinosinusitis and lower airway diseases has been suggested. The purpose of this review is to summarize recent findings on the correlation between chronic rhinosinusitis and lung diseases.

INTRODUCTION

Chronic rhinosinusitis is a common clinical problem, and is a complex inflammatory disease that is poorly understood. Chronic rhinosinusitis is defined by the presence for 12 wk or longer of two or more of the following symptoms: (1) nasal blockage/obstruction/congestion; (2) nasal discharge (anterior/posterior nasal drip); (3) facial pain/pressure; and (4) reduction or loss of smell. One of these should either be nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip). The presence of endoscopic findings [(1) nasal polyps, and/or (2) mucopurulent discharge primarily from the middle meatus, and/or (3) oedema/mucosal obstruction primarily in the middle meatus] and/or mucosal changes within the ostiomeatal complex and/or sinuses revealed by computed tomography is also required[1].

According to the current consensus, chronic rhinosinusitis is subclassified into chronic rhinosinusitis without nasal polyposis (CRSsNP), chronic rhinosinusitis with nasal polyposis (CRSwNP), and allergic fungal rhinosinusitis[1-3]. Chronic rhinosinusitis has complex pathophysiological features, and the etiology of chronic rhinosinusitis is not fully understood. In immunological characteristics, CRSwNP with interleukin (IL)-5-positive cells in nasal polyps can be differentiated from CRSwNP without IL-5-positive cells by different inflammatory patterns (predominance of eosinophils vs neutrophils)[4].

Both pathogen exposure and host condition have significant effects on the onset of chronic rhinosinusitis. The patency of sinus ostia, normal mucociliary function, and healthy immune system are essential factors for the maintenance of normal sinus function. Mucociliary function is remarkably impaired in some diseases such as cystic fibrosis and Kartagener’s syndrome (a type of primary ciliary dyskinesia). Allergic diseases and immunodeficiency may induce chronic rhinosinusitis. A close relationship between chronic rhinosinusitis and lower airway diseases has been suggested[5-9]. The purpose of this review is to summarize current understandings regarding the interaction between chronic rhinosinusitis and lower respiratory conditions. Recently, the term “rhinosinusitis” rather than “sinusitis” has been adopted because sinusitis rarely occurs in the absence of rhinitis[10,11]. In this review, rhinosinusitis and sinusitis are used synonymously.

ASTHMA

The relationship between allergic rhinitis and asthma is now established, and numerous clinical, epidemiological, and biological studies recommend integrated management[12,13]. In the past few decades, the association between chronic rhinosinusitis and asthma has come to be recognized. The presence of rhinosinusitis is associated with more severe asthmatic symptoms in patients with asthma[14]. In epidemiological and radiographic studies, 40% to 90% of asthmatic patients presented abnormal findings on CT scans of their sinuses[15-18].

Several explanations for the association of chronic rhinosinusitis and asthma including the naso-bronchial reflex, pharyngo-bronchial reflex, postnasal drainage of inflammatory mediators from the upper to lower airway, inhalation of dry, cold air and environmental pollutants, and the “shared pathogenesis” of chronic rhinosinusitis and asthma are proposed. The naso-bronchial reflex is mediated by afferent pathways involving the trigeminal nerve and efferent fibers causing bronchoconstriction by means of the vagus nerve. The irritant in the nasal cavity has led to efferent bronchoconstriction[16]. However, the exact mechanisms linking chronic rhinosinusitis and asthma are under debate[19,20].

Severe mucosal inflammation with immune dysregulation is a common feature of chronic rhinosinusitis and asthma[21]. The immunological findings including IL-17, IL-18, IL-25, IL-33, toll-like receptors (TLRs), and thymic stromal lymphopoietin (TSLP) are similar in chronic rhinosinusitis and asthma[22-24]. Transforming growth factor (TGF)-β1 is a major participant in the airway remodeling of asthma, and is also known to play an important role in the tissue remodeling processes and enhanced epithelial immunoreactivity involved in chronic rhinosinusitis[25]. Because the enhanced TGF-β signaling in CRSsNP and reduced TGF-β signaling in CRSwNP is compatible with the remodeling patterns observed in the disease subgroups, TGF-β is characterized as a key switch between CRSsNP and CRSwNP[4]. More than 80% of nasal polyps in Caucasians express IL-5 protein, and more than 50% are eosinophilic, whereas in the Chinese group that was studied, less than 20% express IL-5 protein and less than 10% are eosinophilic[26]. The prevalence of allergic rhinitis, a typical immunoglobulin E (IgE)-mediated type I allergic disease, has been increasing in African continent[27,28]. Allergic rhinitis is significantly more common among asthmatic subjects (76%) than among nonasthmatic subjects (48%) in urban Ghana[29]. The role of IL-5 and eosinophils in chronic rhinosinusitisin in African subjects has not been reported to date, however allergy is the commonest etiological factors for chronic rhinosinusitisin in Nigeria[30]. Although regional differences have been reported, IL-5, a strong secretagogue for human eosinophils, and IgE, specifically IgE against staphylococcal enterotoxins, are identified as indicators of asthma comorbidity in a group of patients with CRSwNP[31].

Blood and sputum eosinophil levels in patients with asthma are directly correlated with sinus mucosal thickening as assessed by computed tomography (CT) scanning[32]. The link between chronic rhinosinusitis and asthma is not only of academic interest, but also an important factor in diagnostic and therapeutic strategy. Asthma phenotypes are very heterogeneous, and inflammation can be predominantly eosinophilic or neutrophilic[33]. Increasing evidence suggests that patients with chronic rhinosinusitis should be evaluated for possible concomitant asthma, and that patients with asthma should always be evaluated for possible nasal and paranasal disease. Both medical and surgical treatments of chronic rhinosinusitis benefit concomitant asthma[34-37]. Although an opposite opinion has been held[38], functional endoscopic sinus surgery is suggested for asthmatic patients including children in whom appropriate medical therapy has failed to resolve sinus disease[39-41].

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Chronic obstructive pulmonary disease (COPD) is one of the most common chronic respiratory diseases. Smoking is the primary risk factor for COPD. The coexistence of upper airway diseases with COPD is not well documented, and only a few authors have studied the role of chronic rhinosinusitis in COPD. Although the available data are limited, a certain relationship between sinonasal disorders and COPD has been suggested[42]. In epidemiological studies, patients with an established diagnosis of COPD have a significantly higher incidence of rhinosinusitis as compared with age-matched control subjects (12.4% vs 2.5%; OR = 6.08; 95%CI: 2.87-12.89)[43]. Another recent study supports these findings[44]. The potential hypotheses for interaction between the upper and lower airways in COPD patients are (1) loss of nasal conditioning function; (2) direct passage of inflammatory mediators and/or microorganisms between upper and lower respiratory tracts; (3) nasobronchial neuronal reflexes; (4) stimulation at one point of the respiratory mucosal surface resulting in a pan-airway inflammatory response; and (5) inflammation caused by smoking[42,45].

Numerous cytokines, chemokines, and other inflammatory factors including TGF-β, tumor necrosis factor-alpha (TNF-α), interferon gamma (IFN-γ), IL-1β, IL-6, IL-8, IL-18, chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, and CXCL11 are involved in COPD[46]. A physiological study using spirometry and acoustic rhinometry showed a significant relationship between nasal patency and pulmonary airflow obstruction in COPD[47]. In immunological studies, COPD has been associated with an increased level of IL-8, a potent neutrophil chemoattractant, in nasal secretion, and patients with COPD have higher nasal concentrations of eotaxin, granulocyte-colony stimulating factor (G-CSF), and IFN-γ than controls[48,49].

Cigarette smoking is the main cause of COPD, and it also induces sinonasal inflammation[50-53]. Smoking is associated with inflammation throughout the airway. The evidence from previous studies provides conflicting data on the relationship between rhinosinusitis and COPD severity. A recent study showed that clinical symptoms, endoscopic score, saccharine test results, cellular profile of nasal lavage, and levels of eicosanoids in nasal lavage in chronic rhinosinusitis patients are not different between COPD stages, and concluded that sinonasal inflammation is not strictly related to COPD severity[54]. Although the coexistence of COPD and chronic rhinosinusitis is frequently observed, further studies are needed to explain the causative role of chronic rhinosinusitis in COPD.

CYSTIC FIBROSIS

Cystic fibrosis is an inherited disease caused by genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for an ATP-regulated ion-channel, which is expressed in many tissues. Although several therapeutic agents have been developed in recent years, no curative therapy exists for cystic fibrosis[55]. Gene therapy is an attractive approach, however the difficulty of gene therapy is reflected by the variable results of the 25 gene therapy trials for cystic fibrosis[55]. Gene therapy using non-viral vectors or viral vectors is actively investigated, however no current gene therapy trial is actively enrolling patients. Because the surface fluid in cystic fibrosis patients has a high NaCl concentration due to dysfunction of the CFTR Cl^- channel, cystic fibrosis airway epithelia fail to kill pathogens[56]. Chronic rhinosinusitis with or without nasal polyposis is common in patients with cystic fibrosis[57,58]. Nasal polyps are present in approximately 40% of chronic rhinosinusitis patients with cystic fibrosis, and the polyps exhibit predominantly neutrophilic, rather than eosinophilic, inflammation[59].

Numerous bacteria are frequently isolated from sinus cultures of chronic rhinosinusitis patients with cystic fibrosis; Pseudomonas aeruginosa as well as Staphylococcus aureus are the most common bacterial species[60]. The same pathogen is commonly found in both the upper and lower respiratory tracts in chronic rhinosinusitis patients with cystic fibrosis, and genotypes of sinus bacteria are shown to be consistent with those in the lower airway, indicating that the nasal cavity and paranasal sinuses may serve as bacterial reservoirs for recurrent lung infection[61].

The management of chronic rhinosinusitis in patients with cystic fibrosis is difficult. Medical management usually consists of daily nasal care, nasal saline irrigations, surfactant lavage, and medications. Oral or intravenous antibiotics, decongestants, antihistamines, topical and/or systemic steroids, dornase alfa, ibuprofen, and N-acetyl cysteine are used as therapeutic agents[62]. Surgical management is indicated for patients who fail medical management. Surgical management of the sinuses in cystic fibrosis patients may improve lower airway outcomes. However, no definitive effect of endoscopic sinus surgery on lung infection has been established[63]. Multiple studies have shown the safety and effectiveness of endoscopic sinus surgery for chronic rhinosinusitis in cystic fibrosis patients. However, overall failure rates requiring revision surgery are high (13% to 89%)[64-70].

Sinus diseases should be routinely evaluated by diagnostic testing (i.e., CT scan) in patients with cystic fibrosis because chronic rhinosinusitis could be a source for lower airway infection[71,72].

DIFFUSE PANBRONCHIOLITIS

Diffuse panbronchiolitis (DPB) is characterized by chronic sinobronchial inflammation, and is a treatable neutrophil-related pulmonary disease. DPB was originally found in Asian populations, and has recently been encountered in Western countries, both clinically and pathologically[73-78]. In DPB, no association with smoking or exposure to fumes or toxic agents has been proven. Human leukocyte antigen (HLA) alleles (HLA-B54 and HLA-A11) are thought to be causal factors for a genetic predisposition to DPB, and these findings suggest a major HLA susceptibility gene for DPB. Untreated DPB generally progresses to bronchiectasis, with resultant respiratory failure and death[79].

Patients with DPB have a history of chronic rhinosinusitis or still have the disease[75,80]. Significant improvement of DPB and concomitant chronic rhinosinusitis has been reported after the use of long-term therapy with macrolide antibiotics[81,82]. Before the 1970s, the prognosis of patients with DPB was poor, with 10-year survival rates of under 40%. However, after the 1980s, long-term erythromycin treatment has increased the 10-year survival rate to over 90%[83].

The mechanisms of the anti-inflammatory properties of macrolides are still being investigated. Macrolides inhibit the production of many proinflammatory cytokines, such as IL-1, IL-6, IL-8, and TNF-β, by suppressing transcription factors including nuclear factor-kappa B and/or activator protein-1[84,85]. It is highly recommended that chronic rhinosinusitis in patients with DPB be treated with 14- and 15-membered macrolides.

PRIMARY CILIARY DYSKINESIA

Primary ciliary dyskinesia is a rare, genetically heterogeneous autosomal recessive disorder characterized by ciliary dysfunction and impaired mucociliary clearance[86]. The clinical effects of primary ciliary dyskinesia include recurrent lower airway infection, bronchiectasis, male infertility, otitis media with effusion, rhinitis, and rhinosinusitis[87-89]. Otitis media with effusion is considered the most common otolaryngologic manifestation of primary ciliary dyskinesia, affecting up to 85% of children with primary ciliary dyskinesia. Chronic rhinitis and chronic rhinosinusitis are found in almost all primary ciliary dyskinesia patients[90,91].

Sinonasal disease in primary ciliary dyskinesia is poorly understood[92]. The prevalence of nasal polyps in chronic rhinosinusitis patients with primary ciliary dyskinesia is low (15% to 30%), and nasal polyps are rarely observed in pediatric patients[93-96]. In the management of the lower airway tract, macrolide therapy has no effect in primary ciliary dyskinesia[81]. Saline nasal irrigation, longterm macrolide therapy, and endoscopic sinus surgery may be beneficial for primary ciliary dyskinesia patients with intractable chronic rhinosinusitis[96-98]. Nasal symptoms usually consist of persistent nasal discharge and blockage; sinus surgery may not be effective in reducing nasal discharge[99]. Because of the lack of evidence in the literature, any surgical intervention should be followed by noninvasive management of chronic rhinosinusitis[90].

IDIOPATHIC BRONCHIECTASIS

Bronchiectasis is defined as abnormal and irreversibly dilated bronchi caused by the loss of the elastic and muscular components of the bronchial and peribronchial tree following recurrent lower airway infection. Bronchiectasis is the result of several different etiologies including cystic fibrosis, primary ciliary dyskinesia, immunodeficiency, tuberculosis, graft-vs-host disease, and inflammatory bowel diseases. The most common causes of bronchiectasis are idiopathic and post-infective damage[87,100]. Regardless of the underlying cause, inflammation in bronchiectasis is predominantly neutrophil driven[101].

Chronic rhinosinusitis was found in 45% to 84% of the cases of patients with idiopathic bronchiectasis[102,103]. A recent study reported a possible association between bronchiectasis and chronic rhinosinusitis[104]. Because the available data is limited, the clinical, histopathological, and immunological characteristics of chronic rhinosinusitis in patients with idiopathic bronchiectasis are largely unknown.

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS

Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease, and is one of the frequent forms of allergic bronchopulmonary mycosis. ABPA is commonly caused by bronchial colonization with Aspergillus fumigatus[105]. A. fumigatus affects approximately 0.7% to 3.5% of asthmatic patients and 7% to 9% of patients with cystic fibrosis[106-108]. Up to 50% of patients with acute severe asthma has A. fumigatus hypersensitivity, and 7% to 15% of cystic fibrosis patients have ABPA[108-111]. Patients with A. fumigatus-mediated chronic asthma or ABPA in cystic fibrosis showed significantly decreased pulmonary function leading to poorer outcomes[112-115]. In addition, antifungal therapy leads to better lung function in A. fumigatus-sensitized cystic fibrosis patients[116].

Allergic fungal rhinosinusitis (AFRS) is a noninvasive form of fungal chronic rhinosinusitis, and has IgE-mediated type I hypersensitivity to fungal proteins[117]. Dematiaceous fungi (such as Bipolaris spicifera or Curvularia lunata) or Aspergillus species (such as A. fumigatus, A. niger, or A. flavus) are commonly detected in allergic mucin, which is the characteristic extramucosal “peanut buttery” viscoelastic, eosinophil-rich material in AFRS[118]. The serological findings of Bipolaris spicifera in AFRS are analogous to those seen with A. fumigatus in ABPA[119]. AFRS has similar clinicopathological features to those in ABPA. However, immunological hypersensitivity is less intense in AFRS compared to that in ABPA[120].

Conflicting opinions have been reported in the incidence of the coexistence of allergic bronchopulmonary fungal disease and AFRS[121,122]. There is a lack of data on the causative and pathophysiologic relationship between ABPA and AFRS, and it has not been proven whether the postnasal drainage of Aspergillus-containing mucus into the lower airways influences the development or severity of ABPA[123]. Postoperative systemic and/or standard topical nasal steroids are recommended in the medical management of AFRS[124]. Further studies are needed to assess relationships in the etiology and management strategy of ABPA and AFRS.

CONCLUSION

To date, numerous studies have been reported about the relationship between upper and lower airway diseases[125]. Chronic rhinosinusitis is frequently coexistent with lung diseases, and has a causative role in the onset and development of chronic lower respiratory diseases. Appropriate assessment and treatment in the upper respiratory tract are necessary to manage united airway diseases.