Recent Advances in Understanding the Pathophysiology of Rhinosinusitis
Summary
Rhinosinusitis is a disease with a multifactorial etiology and hence diverse phenotypes. Based on the duration of symptoms, acute rhinosinusitis (ARS) is differentiated from chronic rhinosinusitis (CRS), where nasal polyps (NPs) may be endoscopically present or visible on computed tomography (CT) scan imaging. The presenting symptoms of rhinosinusitis, as well as the endoscopic or radiologic presentation, may vary among patients. Both external and endogenous factors may play a role in the development of rhinosinusitis ( Fig. 3.1 ). Several endogenous factors, such as anatomical abnormalities, humoral and cellular immune disorders, including allergy, hormonal factors, and acquired or congenital disturbances of the mucociliary clearance, have all been associated with the development and/or chronicity of rhinosinusitis. In addition, external factors, such as microbial agents causing infection and/or colonization, and iatrogenic factors may underlie the development of rhinosinusitis. Prior to any medical therapy or surgical intervention for rhinosinusitis, it is crucial to obtain a detailed understanding of the different factors that are involved in the development of sinonasal disease, as this insight is crucial for a proper diagnosis and for obtaining an optimal therapeutic effect.
This chapter provides a comprehensive overview of the current insight into the different factors that are associated with rhinosinusitis.
Introduction
Upper airway inflammation is a common condition affecting the entire population. Both the common cold and ARS are highly prevalent but self-limiting conditions ( Fig. 3.2 ). CRS is one of the most common health care problems, with significant direct medical costs and a severe impact on lower airway disease and general health outcomes.1 The paucity of accurate epidemiologic data on CRS and NPs contrasts with the more abundant information on microbiology and the diagnosis of and treatment options for these conditions. Until recently, giving an accurate estimate of the prevalence of CRS remained speculative, because of the heterogeneous nature of the disorder and the diagnostic imprecision used in publications. In a survey on the prevalence of chronic conditions, it was estimated that CRS, defined as having “sinus trouble” for more than 3 months in the year before the interview, affects 15.5% of the total population of the United States,2 ranking this condition second in prevalence among all chronic conditions. Of note, the prevalence rate of CRS was substantially higher in females, with a female-to-male ratio of 6:4. However, the prevalence of doctor-diagnosed CRS is much lower, with a prevalence of 2% using ICD-9 (ninth revision of the International Classification of Diseases) codes.3 By screening a population without ear, nose, and throat complaints, which may be considered representative of the general population in Belgium, Gordts et al4 reported that 6% of subjects suffered from chronic nasal discharge, and 40% had signs of mucosal swelling > 3 mm on magnetic resonance imaging (MRI). A large-scale survey involving 57,128 individuals in 19 centers in 12 countries throughout Europe, as reported in the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS),1 revealed an overall prevalence of CRS by EPOS criteria of 10.9% (range 6.9–27.1%). CRS was more common in smokers than nonsmokers (OR [odds ratio] 1.7: 95%, CI [confidence interval] 1.6–1.9). Interestingly, the prevalence of self-reported physician-diagnosed CRS within medical centers was highly correlated with the prevalence of EPOS-diagnosed CRS.
Notwithstanding the limited number of good epidemiologic studies on CRS, it represents a common disorder of multifactorial origin. A list of factors that are believed to be etiologically linked to CRS is discussed below.
Caution
CRS represents a common disorder, affecting up to 10 to 15% of the total population.
Rhinosinusitis Definitions and Phenotypes
Rhinosinusitis represents a heterogeneous group of diseases, with different underlying etiologic factors and with a variety of clinical manifestations. Several definitions and subgroups of rhinosinusitis defined in the past tried to incorporate etiologic factors into the definition. However, the multifactorial etiology of ARS and CRS does not allow the clinician to pick out one factor as being the single cause for the development of rhinosinusitis. Therefore, in EPOS, the international expert panelists dealing with rhinosinusitis reported a new consensus on the definition of rhinosinusitis.1 The presence of two sinonasal symptoms is a pre requisite for the diagnosis of rhinosinusitis, with either nasal obstruction or secretions being present, with or without facial pain or headache, and smell dysfunction.
Because none of these symptoms are absolutely specific for rhinosinusitis, history should be supplemented by nasal examination, preferably nasal endoscopy, demonstrating edema, secretions, or polyps at the level of the middle meatus, and by skin prick testing in the case of suspicion of allergy. Indeed, nasal obstruction not only may be a manifestation of rhinosinusitis, but also may be present in patients with anatomical pathology and in patients with rhinitis. Headache may be a manifestation of rhinosinu sitis, but it also may have a neurologic or vascular origin. Nasal secretions are a hallmark of rhinosinusitis, rhinitis, and adenoid hypertrophy in children, as well as other rare endonasal conditions. Smell dysfunction is typical of NP disease, but hyposmia may be found in severe rhinitis, and neurologic pathology may present with smell disorder. Therefore, it is accepted that rhinitis and rhinosinusitis sform a spectrum of disease, with rhinosinusitis being at the more severe end. Of note, asymptomatic individuals with CT scan abnormalities are not diagnosed as having rhinosinusitis.
Caution
Rhinosinusitis is defined as a symptomatic inflammation of sinonasal cavities and is diagnosed by history and consistent nasal endoscopy and/or CT scan changes. Asymptomatic CT scan abnormalities are not considered rhinosinusitis.
As defined in EPOS,1 ARS comprises of viral ARS (common cold) and postviral ARS. A small percentage of the patients with postviral ARS will have bacterial ARS. Common cold/acute viral rhinosinusitis is defined as duration of symptoms for less than 10 days. Acute postviral rhinosinusitis is defined as an increase of symptoms after 5 days or persistent symptoms after 10 days with less than 12 weeks duration.
Acute bacterial rhinosinusitis is suggested by the presence of at least three symptoms/signs of:
Discolored discharge (with unilateral predominance) and purulent secretion in cavum nasi
Severe local pain (with unilateral predominance)
Fever (> 38 °C)
Elevated ESR/CRP
“Double sickening” (i.e., a deterioration after an initial milder phase of illness)
Chronic rhinosinusitis is defined as symptoms and signs of sinusitis lasting for more than 12 weeks. In EPOS 2012 a new concept was introduced: “difficult to treat rhinosinusitis.” The patients have persistent symptoms of rhino-sinusitis despite appropriate treatment (recommended medication and surgery).
The major virtue of the EPOS document lies in the fact that definitions for clinical practice, as well as for epidemiologic and clinical research, are provided to otorhinolaryngologists and to other medical specialists who do not need nasal endoscopy or CT scan for diagnosis or first-line treatment of these patients. This information is available online at www.epos.org.
It is currently not understood whether acute recurrent rhinosinusitis necessarily develops into CRS, which then possibly gives rise to polyp growth, or whether these entities develop independently of each other. All of these items may be referred to as rhinosinusitis, meaning “inflammation of the nose and sinuses.” For didactic reasons and for future clinical and research purposes, a differentiation of these entities is preferred. The EPOS expert committee therefore agreed on the differentiation between ARS, CRS without NPs, and CRS with NPs. The ill-defined group of “hyperplastic CRS,” which may represent an overlap between CRS and NP, is abandoned, as well as other definitions, such as allergic rhinosinusitis. Therefore, the currently proposed definitions of ARS and CRS without and with NP may represent an oversimplification of the complex pathology of sinonasal inflammatory disease but reflect duration of pathology without an attempt to make etiologic statements.
Inflammation in Rhinosinusitis
Symptomatic inflammation of the sinonasal mucosa is the diagnostic criterion for defining rhinosinusitis.
As a self-limiting disease, ARS rarely causes orbital or intracranial complications. Consequently, mucosal tissue from subjects with acute bacterial rhino sinusitis has not been extensively studied. In contrast, the inflammatory changes in sinus mucosa of chronic sinus disease and NP are better studied. In the sinus fluid of patients with CRS without NP undergoing surgery, the inflammatory cells are predominantly neutrophils, as observed in ARS, but a small number of eosinophils, mast cells, and basophils may also be found. The mucosal lining in CRS is characterized by basement membrane thickening, goblet cell hyperplasia, subepithelial edema, and mononuclear cell infiltration. In a study evaluating the percentage of eosinophils, 31 patients with untreated CRS without NP all had < 10% eosino phils (overall mean of 2% of total white blood cells), whereas in 123 untreated NP specimens, 108 samples showed > 10% eosinophils (overall mean 50%).6 These observations suggest that tissue eosinophilia is not a hallmark of CRS without NP formation and that there are major differences in the pathophysiology of both sinus diseases.
Histomorphological characterization of NP tissue reveals frequent epithelial damage, a thickened basement membrane, and edematous to sometimes fibrotic stromal tissue, with a reduced number of vessels and glands but virtually no neural structure. The stroma of mature polyps is mainly characterized by its edematous nature and consists of supporting fibroblasts and infiltrating inflammatory cells, localized around “empty” pseudocyst formations.7 Among the inflammatory cells, EG2+ (activated) eosinophils are a prominent and characteristic feature in ~80% of polyps, whereas lymphocytes and neutrophils may also be prominent cell types in NPs, especially in cystic fibrosis (CF) and CRS. Eosinophils are localized around the vessels, glands, and directly beneath the mucosal epithelium.
The early processes of polyp growth have been studied in NPs < 5 mm growing on normal-looking mucosa of the middle turbinate in patients with bilateral polyps.8 Numerous subepithelial EG2+ eosinophils were present in the luminal compartment of the early-stage polyp, forming a cap over the central pseudocyst area. In contrast, mast cells were scarce in the polyp tissue, but they were normally distributed in the pedicle and the adjacent mucosa, which had a normal appearance. This contrasts with mature polyps, where degranulated mast cells and eosinophils are often diffusely distributed in the polyp tissue. Fibronectin deposition was noticed around the eosinophils in the luminal compartment of the early-stage polyp, was accumulated subepithelially, and formed a networklike structure in the polyp center and within the pseudocysts. The presence of myofibroblasts was limited to the central pseudocyst area. Interestingly, albumin and probably other plasma proteins were deposited within the pseudocysts, adjacent to the eosinophil infiltration. These observations suggest a central deposition of plasma proteins, regulated by the subepithelial eosinophilic inflammation, as a pathogenetic principle of polyp formation and growth.
Bachert at al9 reported mucosal polyclonal immunoglobulin E (IgE) in NP tissue, which is functional in response to allergen and Staphylococcus aureus enterotoxin B.10 The role of S. aureus in NP disease is still under investigation due to its potent proinflammatory potential via the production of enterotoxins. The enterotoxins of S. aureus may initiate or aggravate an immune response involving IgE production and eosinophilic inflammation.11,12 Intriguingly, the presence of IgE directed against Staphylococcus enterotoxins is associated with asthma in patients with NPs.13
Factors Associated with Acute Rhinosinusitis
Pathogens
Superinfection of bacteria on mucosa damaged by viral infection during a virally induced common cold is considered to be the most important cause of ARS.1 The most frequent bacterial species isolated from the maxillary sinuses of patients with ARS are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, the latter being more common in children. Other streptococcal species, anaerobic bacteria, and S. aureus cause a small percentage of cases. Resistance patterns of the predominant pathogens vary considerably. The prevalence and degree of antibacterial resistance in common respiratory pathogens are increasing worldwide.14 The association between antibiotic consumption and the prevalence of resistance is proven. In light of this association and the growing problem of bacterial resistance, it is important to stress that antiinflammatory treatment with intranasal steroids may be as effective as oral antibiotics for the treatment of uncomplicated ARS.15
Ciliary Impairment
Normal mucociliary flow is a significant defense mechanism in the prevention of ARS. Viral rhinosinusitis results in the loss of cilia and ciliated cells, with a maximum around 1 week after the infection. Three weeks after the beginning of the infection, the number of cilia and ciliated cells increases to nearly normal. However, as a sign of regeneration, immature short cilia (0.7–2.5 µ [microns] in length) are often seen.16 The impaired mucociliary function during viral rhinosinusitis results in an increased sensitivity to bacterial infection. Also, in animal experimental work, it was shown that early after exposure to pathogenic bacteria, such as S. pneumoniae, H. influenzae, and Pseudomonas aeruginosa, a significant loss of ciliated cells from sinus mucosa with a corresponding disruption of normal mucociliary flow was found.17
Allergy
Several review articles on sinusitis have suggested that atopy predisposes to rhinosinusitis.18 This theory is attractive, given the popularity of the concept that disease in the ostiomeatal (OM) area contributes to sinus disease by swelling of the mucosa at the level of the OM area with obstruction of the sinus ostia, reduction of ventilation, and mucus retention that might be more prone to become infected. Other pathways may explain why allergic inflammation may predispose to ARS. Nasal inspiration of allergens or sneezing may lead to deposition of allergens onto the sinus mucosa with induction of inflammation in the sinus cavities. Systemic immune mediators released by allergic inflammation may be involved in the development of ARS in allergic rhinitis due to upregulation of expression of adhesion molecules in the sinus mucosa. All of these arguments have not been confirmed by studies investigating the association between allergies and sinus disease.18 So far, there are no prospective reports on the incidence of infective rhino-sinusitis in populations with and without clearly defined allergic rhinitis. In addition, clinical experience does not provide us with the impression of higher prevalence of ARS in patients with allergic rhinitis.
Factors Associated with Recurrent Acute Rhinosinusitis
A subgroup of patients seen at the outpatient department of otorhinolaryngology present with recurrent acute sinus disease with symptom-free intervals between the acute episodes. In general, these patients are treated medically with success. In cases of recurrent disease despite adequate medical treatment or in case of orbital or neural complications, these patients may undergo endoscopic sinus surgery with a high success rate.
The reasons for recurrence of ARS may be diverse and do not differ significantly from those found in CRS. Therefore, these factors are discussed in Chapter 4.
Factors Associated with Chronic Rhinosinusitis
Ciliary Impairment
Ciliary function plays an important role in the clearance of sinuses and the prevention of chronic inflammation. Malfunction of the ciliary clearance may be a congenital or acquired condition. Any upper respiratory tract infection is associated with ciliary loss and dysfunction that may take several weeks to be fully restored. This so-called secondary ciliary dyskinesia is found in patients with common cold, ARS, and CRS and is considered to be reversible when the infectious or inflammatory trigger is not present anymore. The acquired transient ciliary dysfunction contrasts with the permanent lack or dysfunction of mucociliary transport in patients with Kartagener syndrome and primary ciliary dyskinesia (PCD). All inhaled particles are trapped within the mucus that cannot be cleared to the nasopharynx due to the lack of properly functioning cilia. These patients usually have a lifelong history of secretions in the nose and respiratory infections starting before the age of 6 months, usually not confined to the upper respiratory tract. In patients with CF, the inability of the cilia to transport the viscous mucus causes ciliary malfunction and consequently CRS. NPs are present in ~40% of patients with CF.19
Note
Secondary ciliary dyskinesia needs to be differentiated from the rare condition of primary ciliary dyskinesia.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
