The sinusitis spectrum

CRS has been defined by the Sinus and Allergy Health Partnership as a group of disorders characterized by inflammation of the nasal and paranasal sinus mucosa of at least 12 consecutive weeks’ duration. This chronic disorder can be viewed as a spectrum of pathology, ranging from localized processes to systemic disorders. Understanding this “sinusitis spectrum” may be helpful in identifying those patients at increased risk for failing conventional therapies, and in tailoring the treatment approach to fit a patient’s individual needs.

At one end of the sinusitis spectrum is the patient with “local” disease. These patients tend to have clear anatomic factors predisposing toward sinus infection. Anatomic obstructions, such as conchae bullosae and septal deviations, are examples of local factors that may obstruct normal mucociliary flow. Additionally, patients with an isolated polyp or neoplasm may be classified as having local disease. Such local factors can usually be readily identified on nasal endoscopy or sinus imaging, and can be routinely addressed with conventional endoscopic surgical approaches.

At the other end of the sinusitis spectrum are those patients with “systemic” disease. These patients have an underlying systemic disorder leading to diffuse inflammation of the sinonasal mucosa, often with polyp formation, which places them at heightened risk for recurrent sinus infections. Individuals who may be classified in this category include those with triad asthma, granulomatous disease, cystic fibrosis, immunodeficiency, and primary ciliary dyskinesia. These systemic patients are at highest risk for failing conventional medical and surgical therapies used to treat CRS.

Within this sinusitis spectrum, there are a large number of patients who fall somewhere in the middle, between locals and systemics. This group of patients is referred to as “intermediates.” They may have a combination of localized and systemic disease. Many of these patients, however, when treated with standard medical and surgical therapies, fare quite well ( Fig. 1 ).

The sinusitis spectrum.

Pathophysiology

Traditionally, CRS was understood to be the end stage of a disease process characterized by multiple acute bacterial infections. This theory, however, has been supplanted by the recognition that CRS is characterized by an aberrant inflammatory response in the sinonasal mucosa. Although initiating events may vary, it is well understood that inflammation causing mucosal obstruction at sinus ostia triggers a cascade of events including impaired mucociliary clearance with stasis and bacterial overgrowth. In the absence of systemic disease, such as cystic fibrosis or an immune deficiency, a number of different paradigms have been postulated to explain the heightened sinonasal inflammatory response seen in CRS.

Although controversy exists as to whether bacteria play a direct or indirect role in the pathophysiology of CRS, antibiotic therapy remains a mainstay of treatment. Theories to explain how the presence of bacteria within the paranasal sinuses may trigger a noninfectious inflammatory process include the superantigen and biofilm theories.

It has long been recognized that certain bacteria secrete proteins called exotoxins, which are damaging to the host organism. A superantigen is a highly potent exotoxin that has been associated with dramatic disease processes, such as the toxic shock syndrome triggered by Staphylococcus aureus’ production of superantigen. Recent interest has focused on the potential role of superantigens in triggering sinonasal inflammation. A recent study by Bernstein and colleagues demonstrated toxin-producing S aureus in the nasal mucus adjacent to polyps in 55% of patients with chronic hyperplastic sinusitis and nasal polyposis. The corresponding variable β T-cell receptor site was also noted to be up-regulated. Although an understanding of the superantigen link to CRS continues to evolve, it seems that microbial superantigens bind to T-cell receptors and major histocompatibility complex II molecules in a fashion that bypasses the typical route of antigen presentation, resulting in an enhanced activation of the host T-cell population. This cascade results in massive cytokine release and eosinophilic activation with consequent mucosal insult and inflammation.

The biofilm theory has also been postulated to explain the pathologic role of bacteria in the CRS process. Biofilms are created when bacteria bind to a surface and generate a community of microorganisms in a matrix attached to a surface. Bacteria in a biofilm state have a reduced metabolic state and do not provoke the exuberant systemic response elicited by free-floating bacteria. They demonstrate decreased susceptibility to systemic and local antibiotic therapy. In addition, they intermittently release free-floating bacteria that can serve as a continuous nidus of infection. Although biofilms have been identified on the surface of sinus mucosa of patients with CRS, the significance of these biofilms remains a subject of continued investigation.

Atopic disease is also recognized as playing a key role in the pathophysiology of CRS. Although the epidemiologic association between CRS and allergy is well established, a causal relationship remains more elusive. In one study that examined the presence of allergy among patients undergoing functional endoscopic sinus surgery, 80% of patients were noted to have elevated specific IgE levels. These epidemiologic observations, however, fail to provide an explanation of the causal relationship between allergy and CRS. One mechanism that may help to explain such a causal relationship is the induction of mucosal edema and sinus ostia obstruction through the release of allergic mediators and cytokines. Additionally, it has been shown that in patients undergoing sinus surgery, surgical outcomes are enhanced by treatment of underlying inhalant allergy.

Allergic fungal sinusitis has emerged as a clinically distinct subset of CRS, and merits special consideration in this discussion. Diagnostic criteria for allergic fungal sinusitis include eosinophilic mucin-containing noninvasive fungal hyphae and Charcot-Leyden crystals on microscopic examination. Patients with this disorder typically present with nasal polyposis, characteristic radiographic findings, immunocompetence, and allergy. Although theories to explain the phenomenon of allergic fungal sinusitis abound, the core principle is based on the premise that it is the inflammatory response to fungus, rather than the mere presence of fungus. In 1999, the concept of a nonallergic fungal inflammatory process was described by Ponikau and coworkers who identified hyphae in over 90% of patients with CRS. Eosinophils were also noted to be migrating into the mucus in characteristic clusters. In this study population, allergy to fungus failed to correlate with CRS. The suggested terminology was changed from allergic fungal rhinosinusitis to eosinophilic fungal rhinosinusitis. Questions and controversy continue to surround the significance of fungi in CRS.

Pathophysiology

Traditionally, CRS was understood to be the end stage of a disease process characterized by multiple acute bacterial infections. This theory, however, has been supplanted by the recognition that CRS is characterized by an aberrant inflammatory response in the sinonasal mucosa. Although initiating events may vary, it is well understood that inflammation causing mucosal obstruction at sinus ostia triggers a cascade of events including impaired mucociliary clearance with stasis and bacterial overgrowth. In the absence of systemic disease, such as cystic fibrosis or an immune deficiency, a number of different paradigms have been postulated to explain the heightened sinonasal inflammatory response seen in CRS.

Although controversy exists as to whether bacteria play a direct or indirect role in the pathophysiology of CRS, antibiotic therapy remains a mainstay of treatment. Theories to explain how the presence of bacteria within the paranasal sinuses may trigger a noninfectious inflammatory process include the superantigen and biofilm theories.

It has long been recognized that certain bacteria secrete proteins called exotoxins, which are damaging to the host organism. A superantigen is a highly potent exotoxin that has been associated with dramatic disease processes, such as the toxic shock syndrome triggered by Staphylococcus aureus’ production of superantigen. Recent interest has focused on the potential role of superantigens in triggering sinonasal inflammation. A recent study by Bernstein and colleagues demonstrated toxin-producing S aureus in the nasal mucus adjacent to polyps in 55% of patients with chronic hyperplastic sinusitis and nasal polyposis. The corresponding variable β T-cell receptor site was also noted to be up-regulated. Although an understanding of the superantigen link to CRS continues to evolve, it seems that microbial superantigens bind to T-cell receptors and major histocompatibility complex II molecules in a fashion that bypasses the typical route of antigen presentation, resulting in an enhanced activation of the host T-cell population. This cascade results in massive cytokine release and eosinophilic activation with consequent mucosal insult and inflammation.

The biofilm theory has also been postulated to explain the pathologic role of bacteria in the CRS process. Biofilms are created when bacteria bind to a surface and generate a community of microorganisms in a matrix attached to a surface. Bacteria in a biofilm state have a reduced metabolic state and do not provoke the exuberant systemic response elicited by free-floating bacteria. They demonstrate decreased susceptibility to systemic and local antibiotic therapy. In addition, they intermittently release free-floating bacteria that can serve as a continuous nidus of infection. Although biofilms have been identified on the surface of sinus mucosa of patients with CRS, the significance of these biofilms remains a subject of continued investigation.

Atopic disease is also recognized as playing a key role in the pathophysiology of CRS. Although the epidemiologic association between CRS and allergy is well established, a causal relationship remains more elusive. In one study that examined the presence of allergy among patients undergoing functional endoscopic sinus surgery, 80% of patients were noted to have elevated specific IgE levels. These epidemiologic observations, however, fail to provide an explanation of the causal relationship between allergy and CRS. One mechanism that may help to explain such a causal relationship is the induction of mucosal edema and sinus ostia obstruction through the release of allergic mediators and cytokines. Additionally, it has been shown that in patients undergoing sinus surgery, surgical outcomes are enhanced by treatment of underlying inhalant allergy.

Allergic fungal sinusitis has emerged as a clinically distinct subset of CRS, and merits special consideration in this discussion. Diagnostic criteria for allergic fungal sinusitis include eosinophilic mucin-containing noninvasive fungal hyphae and Charcot-Leyden crystals on microscopic examination. Patients with this disorder typically present with nasal polyposis, characteristic radiographic findings, immunocompetence, and allergy. Although theories to explain the phenomenon of allergic fungal sinusitis abound, the core principle is based on the premise that it is the inflammatory response to fungus, rather than the mere presence of fungus. In 1999, the concept of a nonallergic fungal inflammatory process was described by Ponikau and coworkers who identified hyphae in over 90% of patients with CRS. Eosinophils were also noted to be migrating into the mucus in characteristic clusters. In this study population, allergy to fungus failed to correlate with CRS. The suggested terminology was changed from allergic fungal rhinosinusitis to eosinophilic fungal rhinosinusitis. Questions and controversy continue to surround the significance of fungi in CRS.