Pathophysiology
CRS is primarily a disease of inflammation and can result from several triggers, which may explain why it has many different phenotypes. The two most common phenotypes are CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP). Fig. 1 is an anterior view comparing normal anatomy to that of nasal polyposis. Although symptoms may be identical histologically and immunologically, these two phenotypes differ greatly.
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Figure 1.
A, Normal anatomy of left nasal cavity. B, Right nasal cavity with nasal polyp. IT, inferior turbinate; MT, middle turbinate; NP, nasal polyp; S, septum.
Traditional thought held that immunologically CRSsNP was primarily the result of a T-helper 1 (TH1)–driven immune response and that CRSwNP resulted from a TH2-driven response. In a basic immune response, CD4 lymphocytes are driven to produce cytokines to eliminate the pathogen. Antigen-presenting cells alert T cells via the major histocompatibility complex type II. The interaction of the antigen-presenting cells and cosignaling molecules polarize a naïve T cell into a TH1 or a TH2 pathway. The TH1 pathway produces a cascade of cytokines that trigger cell-mediated immunity and phagocytic inflammation by natural killer cells and cytotoxic T cells. This triggers a significant proinflammatory response, with an increase in transforming growth factor-β, interleukin (IL)-2, and IL-10. The TH2 pathway leads to the recruitment of eosinophils, polymononuclear cells, and immunoglobulin E (IgE) antibody production. Although prevailing opinion may have been that CRSwNP and CRSsNP is simply a spectrum of the same disease, analysis of inflammatory mediators beyond neutrophil versus eosinophil is distinctly different. CRSsNP shows an increased number of activated T cells, increased fibrosis and high levels of transforming growth factor-β; CRSwNP shows increased IL-5, eosinophils, and high levels of IgE with significant edema but little to no fibrosis; however, it has been found that both TH1 and TH2 responses can drive the formation of nasal polyps, with white populations typically having the established TH2 eosinophilic polyposis and some Asian populations having TH1-driven neutrophilic polyposis. This indicates that there is partial overlap and that these diseases may not be mutually exclusive. At present, researchers are separating and defining these two phenotypes to eventually predict comorbidities, recurrence after surgery, or response to innovative treatment. Clearly, the ability to distinguish these two entities will become increasingly important.
Allergic fungal sinusitis (AFS) is a third subtype of CRS that is radiographically and histologically distinct. Typically, type 1 hypersensitivity, nasal polyps, characteristic CT findings, presence of fungi on direct microscopy or culture, and allergic mucin are the five characteristics that describe AFS. Although clinical symptoms may appear identical to other forms of CRS, AFS may be easily distinguished radiographically because often there is unilateral or asymmetric involvement of the sinuses. Bony expansion and remodeling can be impressive and is seen in approximately 20% of patients. The double density sign frequently is used to describe the serpiginous appearance of mucin, fungal debris, and polypoid concretions within the sinuses.
Evidence is mounting that biofilms play an important role in the etiology and persistence of CRS. Pathogens can exist in a protected state called a "biofilm." A biofilm is a sessile community of bacteria that forms a protective mucoid matrix. Biofilms irreversibly adhere to the sinus mucosa and bacteria within the colony exist at multiple different levels of metabolic activity. These characteristics allow the colony to be extremely resistant to both host defenses and antimicrobial agents (Fig. 2). Various studies have identified biofilms on the mucosa of patients with CRS. In a study that evaluated sinus surgical outcomes, the presence of biofilm was found to significantly reduce the success rates of surgery. Specifically, the presence of Staphylococcus aureus as a single biofilm or in a colony of multiple species was strongly associated with worse postoperative symptom scores and signs of continued mucosal inflammation.
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Figure 2.
The role of biofilms.
There are many comorbidities to consider with CRS. Researchers developed the unified airway concept during the past 15 years, which proposes that because the respiratory mucosa from the middle ear and nose to the bronchioles is identical, it shares the same physiology and susceptibility to inflammation. The unified airway model explains the overlap and comorbidities that are associated with inflammatory diseases such as allergic rhinitis, chronic rhinosinusitis, and asthma.
Epidemiologic studies report that the prevalence of asthma in patients with allergic rhinitis is 20% to 35%. Patients with chronic sinusitis have a 20% prevalence of asthma and a 40% to 85% prevalence of allergic rhinitis. Consistent with the unified airway theory, multiple studies demonstrate that medical treatment of sinusitis and allergic rhinitis leads to better control of a patient's asthma and vice versa. The 2007 National Asthma Prevention Expert Panel Report 3 recognized sinusitis and allergies as comorbid conditions that aggravate asthma and impede its treatment. If skin testing for aeroallergens is clinically indicated, the panel recommends it in patients with asthma and maximally treating identified allergies with medications or immunotherapy. Similarly, the AAO-HNS recommends allergy testing and treatment to control chronic sinusitis. There also is emerging evidence that immunotherapy may play a role in the treatment of AFS.
In some patients with CRS and asthma, the disease is exacerbated by aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). Often, this sensitivity occurs as part of a triad that includes nasal polyposis, asthma, and aspirin sensitivity, and is known as aspirin-exacerbated respiratory disease or Samter's triad. Aspirin and some NSAIDs block cyclooxygenase-1, thereby decreasing the production of anti-inflammatory prostaglandins such as prostaglandin E2. Arachidonic acid metabolites are shunted toward the production of leukotrienes, which are potent mediators of inflammation in the upper and lower airways. In this subgroup of patients, these metabolites can cause symptoms ranging from rhinorrhea and nasal obstruction to chest tightness and bronchospasm. Treatment requires the avoidance of all NSAIDs, and in some cases, aspirin desensitization is necessary.
Patients with immunodeficiency may account for 8% to 20% of patients with persistent or recurrent sinusitis. Patients with recurrent sinus infections, pneumonias, skin abscesses, or gastrointestinal symptoms should be evaluated for immunodeficiency with quantitative Ig levels (IgA, IgM, IgG) and vaccine responsiveness status through titer evaluation such as antipneumococcal titers. Human immunodeficiency virus testing, and if positive, CD4 counts are warranted. Typically, these patients complain of symptom recurrence shortly after the completion of antibiotic therapy. In patients with chronic sinusitis, Chee et al found an unexpectedly high incidence of immune dysfunction, the majority of which were common variable immune deficiencies. Culture-directed antibiotic therapy is the treatment of choice in patients with immunodeficiencies and specific deficiencies may be supplemented by intravenous or subcutaneous immunoglobulin.
In patients who continually fail medical management for chronic sinusitis, genetic evaluation is warranted. Children presenting with nasal polyposis should have a workup to rule out cystic fibrosis (CF). Nasal polyps are present in 20% to 50% of patients with CF. Although the role of endoscopic sinus surgery to improve lung function in CF is debatable, multiple studies have shown a significant improvement in QOL in these patients following sinus surgery. In addition, other ciliary dyskinesia, including primary ciliary dyskinesia, Kartagener syndrome, and Young syndrome, is associated with an increased incidence of CRS and nasal polyps.
Many patients with hypereosinophilic syndromes or autoimmune diseases may present with chronic sinusitis. In middle-aged patients with asthma and new-onset chronic sinus symptoms, Churg-Strauss disease may be considered. The four cardinal symptoms of Churg-Strauss are bronchial asthma, chronic sinusitis, eosinophilic vasculitis, and granulomas. Anterior rhinoscopy may demonstrate severe crusting, open sores, and nasal polyposis. Wegener granulomatosis is an autoimmune disease that typically presents in adulthood and frequently has physical examination findings similar to Churg-Strauss. The list below provides a differential diagnosis to consider when evaluating the confounding factors as well as the possible comorbidities to consider in chronic sinusitis.
Inflammatory
Gastroesophageal reflux
Rhinitis
Allergies
Churg-Strauss disease
Trauma
Orbital fracture
Nasofacial fractures
Autoimmune
Wegener granulomatosis
Sarcoidosis
Metabolic
Pregnancy
Hypothyroidism
Infectious
Human immunodeficiency virus
Dental abscess
Iatrogenic
Foreign body
Smoking
Neoplastic
Juvenile nasal angiofibroma
Congenital
Adenoid hypertrophy
Thronwaldt cyst
Young syndrome
Kartagener syndrome
CF
Common variable immunodeficiency