Fungi in chronic hyperplastic eosinophilic sinusitis

Chronic hyperplastic eosinophilic sinusitis (CHES) is a T-helper (Th)2-like, lymphocyte-initiated, eosinophil-rich inflammatory disease. The complex immune interactions required to orchestrate these processes begin with the presentation of antigen by mature dendritic cells to Th lymphocytes that display the appropriate antigen-specific T-cell receptor. The objective of sinus research must be to identify and target that antigen; this will lead to the cure for this condition. This article reviews numerous models that may be responsible for the pathophysiology of this disorder, including putative roles for allergens, bacteria, and bacterial-derived superantigens, as well as recent interest in fungal-derived antigens. Additionally, we speculate that whatever the inciting cause of CHES may be, it is plausible that once initiated, cellular differentiation pathways may lead to the development of an antigen-independent permanent phase. More than one of these may be valid in different subjects and, furthermore, this list almost assuredly does not explain all cases of CHES. The concept that fungal antigens colonizing the sinuses are responsible for CHES represents an intriguing, but unproven, hypothesis. Presently, the case for the fungus remains circumstantial. The case for fungi will be proved only with definitive proof that T-cells within the sinuses are actively responding to fungal antigens present in the sinus and with the further demonstration that removal of those fungal antigens ameliorates the disease.     

Pathogenesis of aspirin-exacerbated respiratory disease

The underlying respiratory disease is activated by unknown mechanism and results in an intense infiltration of mast cells and eosinophils into the entire respiratory mucosa. These cells synthesize leukotrienes (LTs) at a very high rate and mast cells also release histamine and tryptase and synthesize PGD₂ a vasodilator and bronchoconstrictor. Furthermore, AERD patients under synthesize from arachidonic acid (AA) a peculiar product called lipoxins, which opposes inflammation generated by leukotrienes. Finally, cysLT₁ receptors are over expressed and highly responsive to LTE₄, further augmenting the underlying inflammatory disease. This inflammatory condition is partly inhibited by synthesis of PGE₂ through COX-1. PGE₂ partially inhibits 5-lipogygenase conversion of AA to LTA₄ and blocks release of histamine and tryptase from mast cells. When COX-1 is inhibited by ASA or NSAIDs, PGE₂ synthesis stops and an enormous release of histamine and synthesis of LTs occurs. The upper respiratory reaction is mediated by both histamine and LTs but the bronchospastic reaction is mediated by LTs. The systemic effects of flush, gastric pain and hives are mediated by histamine. Aspirin desensitization can not be explained by disappearance of LT synthesis since urine LTE₄ levels are still elevated at acute ASA desensitization. However, mast cell products such as histamine, tryptase and PGD₂ are no longer released or synthesized at acute desensitization. It is more likely that a diminution in number or function of cysLT receptors accounts for the diminished inflammatory response found in ASA desensitization.     

Fungi in chronic hyperplastic eosinophilic sinusitis: reasonable doubt

Chronic hyperplastic eosinophilic sinusitis (CHES) is a T-helper (Th)2-like, lymphocyteinitiated, eosinophil-rich inflammatory disease. The complex immune interactions required to orchestrate these processes begin with the presentation of antigen by mature dendritic cells to Th lymphocytes that display the appropriate antigen-specific T-cell receptor. The objective of sinus research must be to identify and target that antigen; this will lead to the cure for this condition. This article reviews numerous models that may be responsible for the pathophysiology of this disorder, including putative roles for allergens, bacteria, and bacterial-derived superantigens, as well as recent interest in fungal-derived antigens. Additionally, we speculate that whatever the inciting cause of CHES may be, it is plausible that once initiated, cellular differentiation pathways may lead to the development of an antigen-independent permanent phase. More than one of these may be valid in different subjects and, furthermore, this list almost assuredly does not explain all cases of CHES. The concept that fungal antigens colonizing the sinuses are responsible for CHES represents an intriguing, but unproven, hypothesis. Presently, the case for the fungus remains circumstantial. The case for fungi will be proved only with definitive proof that T-cells within the sinuses are actively responding to fungal antigens present in the sinus and with the further demonstration that removal of those fungal antigens ameliorates the disease.     

The natural history and clinical characteristics of aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinitis, nasal polyps, asthma, and precipitation of asthma and rhinitis attacks after ingestion of aspirin (ASA) and most nonsteroidal anti-inflammatory drugs (NSAIDs). Most information about the disease in the United States has come from small samples of patients. OBJECTIVE: The purpose of this study was to examine the natural history and clinical characteristics of 300 AERD patients, referred to our institution for aspirin desensitization. METHODS: All potential AERD patients were evaluated using a standard questionnaire that included information about clinical characteristics and natural progression of their disease, previous history of reactions to ASA and other NSAIDs, current use of medications, and ethnic backgrounds. All patients underwent oral ASA challenges to prove they had AERD. RESULTS: From patients' history we found that the average age at onset of AERD was 34 years, and that 57% were female. Counting ASA as an NSAID, 33% had previously reacted on two occasions to NSAIDs and 36% on more than three occasions to NSAIDs, whereas only 27% had reacted to one NSAID before they came to us for evaluation. Our patients had averaged 5.5 episodes of sinusitis per year. There were no significant differences in the clinical characteristics or use of medications between genders. Ethnicity was heterogeneous in most participants. CONCLUSIONS: AERD begins in the third decade of life and in both sexes. The disease progressed over the 13 years between historical onset and current evaluation, with more sinusitis and need for controller medications over time. There was no ethnic or familial distribution of AERD.     

Safety of high-dose rofecoxib in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by progressive sinusitis, nasal polyposis, and asthma that begins and continues in the absence of exposure to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Cross-sensitivity to all NSAIDs that inhibit cyclooxygenase-1 (COX-1) occurs in these individuals. Reactions to aspirin and NSAIDs in patients with AERD are largely due to inhibition of COX-1. Despite accumulating data on the safety of COX-2 selective inhibitors in AERD, concern still remains that high doses of a COX-2 inhibitor may be sufficient to induce a cross-reaction. OBJECTIVE: To determine whether high-dose rofecoxib cross-reacts in patients with AERD and asthma. METHODS: Sixty asthmatic patients underwent blinded placebo-controlled oral challenges with 50 mg of rofecoxib. Aspirin sensitivity was subsequently confirmed in all patients with the use of single-blinded aspirin challenges. RESULTS: None of the 60 patients experienced any symptoms, changes in nasal examination results, or declines in lung function during rofecoxib challenge. All 60 patients experienced respiratory reactions to aspirin challenge, with a mean provoking dose of 57 mg. The exact 1-sided 95% confidence interval for the underlying probability of 50 mg of rofecoxib inducing respiratory cross-reactions in patients with AERD is 0 to 0.05, or 0% to 5%. CONCLUSIONS: These results confirm the lack of cross-reactivity of aspirin and the highly selective COX-2 inhibitors in AERD. We suggest that it is time for the labeling of highly selective COX-2 inhibitors to reflect these data and for the warning that patients with AERD in particular and asthmatic patients in general avoid selective COX-2 inhibitors to be removed.     

Intranasal ketorolac challenge for the diagnosis of aspirin-exacerbated respiratory disease.

BACKGROUND: Intranasal administration of aspirin-lysine has been used in Europe for the diagnosis of aspirin-exacerbated respiratory disease. It has a low adverse effect profile and is believed to be safer for asthmatic patients, particularly those with a low baseline forced expiratory volume in 1 second, in whom oral aspirin challenge would be contraindicated. Ketorolac, a nonsteroidal anti-inflammatory drug useful for severe pain, is available in the United States in parenteral form. OBJECTIVE: To determine whether ketorolac nasal challenge has acceptable specificity and sensitivity for diagnosing aspirin-exacerbated respiratory disease. METHODS: Twenty-nine patients with suspected aspirin-exacerbated respiratory disease were challenged with nasal ketorolac before oral challenge and desensitization with aspirin. Symptoms, objective changes in nasal examination findings, and peak nasal inspiratory flow values were recorded. Nasal lavage fluid for cysteinyl leukotriene analysis was collected. Ketorolac doses of 2.1, 5.2, or 7.8 mg were administered and compared with the results of oral aspirin challenge. RESULTS: Eighteen patients had a positive challenge reaction to oral aspirin. Ketorolac nasal inhalation had a sensitivity of 78% and a specificity of 64%. Patients in the reactor group had significantly higher levels of cysteinyl leukotrienes after ketorolac challenge than in the nonreactor group. Mild bronchospasm occurred in 3 patients, and 2 of these occurred at higher starting doses of ketorolac. CONCLUSIONS: Nasal ketorolac administration is a reasonably accurate and safe method for diagnosing aspirin-exacerbated respiratory disease.     

Aspirin challenge and desensitization for aspirin-exacerbated respiratory disease: a practice paper.

Aspirin desensitization is indicated for patients who have aspirin-exacerbated respiratory disease and whose asthma and/or rhinosinusitis is suboptimally controlled with inhaled corticosteroids and leukotriene-modifying drugs. In this practice paper, the general requirements for aspirin desensitization are presented, the locations where desensitizations can be safely performed are outlined, prechallenge patient preparation is discussed, an oral aspirin challenge protocol is presented, treatment of adverse reactions is reviewed, and maintenance of aspirin desensitization is discussed.     

Failure to maintain an aspirin-desensitized state in a patient with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin desensitization is a useful therapy in patients with aspirin-exacerbated respiratory disease. OBJECTIVE: To describe the clinical course of a man with aspirin-exacerbated respiratory disease who was unable to be desensitized to oral aspirin. METHODS: A standard aspirin desensitization protocol was used to achieve a maximum dose of 650 mg of oral aspirin. The patient initially tolerated this dose of aspirin. RESULTS: Within days of desensitization, the patient began to react to 650 mg of aspirin. Monitored challenge with this dose of aspirin led to marked decrease in forced expiratory volume in 1 second and pronounced nasal and ocular symptoms. CONCLUSIONS: We present a patient with classic aspirin-exacerbated respiratory disease, who despite undergoing a standard aspirin desensitization protocol was unable to maintain his desensitized state.     

Natural history and clinical features of aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis, nasal polyposis, asthma and precipitation of asthma, and rhinitis attacks after ingestion of aspirin (ASA) and most other nonsteroidal antiinflammatory drugs (NSAIDs). Although precipitation of asthma attacks by ingestion of ASA and other NSAIDs is considered a hallmark of the syndrome, the respiratory mucosal inflammatory disease process begins and continues in the absence of ongoing or even intermittent exposure to ASA or NSAIDs. The typical patient with AERD is an adult who develops refractory chronic rhinitis in the third or fourth decade of life. The chronic rhinitis evolves into chronic eosinophilic rhinosinusitis with associated nasal polyposis. Anosmia appears in most patients. CT of the sinuses most often demonstrates pansinusitis and patients often undergo multiple sinus operations resulting in only limited temporary benefit. During the evolution of the sinus disease persistent asthma develops. Finally, if patients are exposed to ASA or NSAIDs acute respiratory reactions begin to occur. Despite subsequent avoidance of ASA and other NSAIDs, the respiratory mucosal inflammatory disease persists, often requiring systemic corticosteroids for control of both upper- and lower-respiratory tract symptoms. Adequate control of asthma can often only be accomplished with the simultaneous control of the associated rhinosinusitis. With few exceptions, once AERD develops it remains for the remainder of the patient’s life. Formerly Scripps Clinic and Green Hospital, La Jolla, CA