Katherine N. Cahill

Prostaglandin D2: A dominant mediator of aspirin-exacerbated respiratory disease

BACKGROUND Aspirin desensitization followed by high-dose aspirin therapy is routinely performed for patients with aspirin-exacerbated respiratory disease (AERD). Little is known about the contributions of mediators other than cysteinyl leukotrienes to aspirin reactions and to the therapeutic benefit of high-dose aspirin therapy. OBJECTIVE We investigated differences in urinary eicosanoid metabolite levels and blood eosinophil counts in patients with AERD who tolerate and those who fail aspirin desensitization and also in patients with AERD who were successfully treated with high-dose aspirin therapy. METHODS Twenty-nine patients with AERD were stratified into those who tolerated aspirin desensitization (group I) and those who did not (group II). Urine was analyzed for eicosanoid metabolites at baseline, during aspirin reactions, and during high-dose aspirin therapy. Blood was analyzed for cell differentials at baseline and during aspirin therapy. RESULTS Basal prostaglandin D2 metabolite (PGD-M; 13.6 ± 2.7 vs 7.0 ± 0.8 pmol/mg creatinine [Cr], P < .05) and thromboxane metabolite (TX-M; 1.4 ± 0.3 vs 0.9 ± 0.1 pmol/mg Cr, P < .01) levels were higher in group II than in group I. During aspirin reactions, PGD-M levels remained unchanged, whereas TX-M levels (0.7 ± 0.1 pmol/mg Cr, P = .07) tended to decrease in group I. In contrast, PGD-M levels increased dramatically in group II (61.3 ± 19.9 pmol/mg Cr, P < .05), whereas TX-M levels did not change. The decrease in FEV1 inversely correlated with basal urinary levels of both leukotriene E4 and PGD-M. Blood eosinophil and basophil levels increased and urinary PGD-M levels (2.2 ± 0.8 pmol/mg Cr, P < .001) decreased on 2 months of high-dose aspirin therapy in group I. CONCLUSION Failure to tolerate aspirin desensitization in a subset of patients with AERD is associated with prostaglandin D2 overproduction. The increase in blood eosinophil and basophil counts during high-dose aspirin therapy might reflect the functional consequences of decreased prostaglandin D2 release and the therapeutic benefit of aspirin.

Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies

Monoclonal antibodies are important therapeutic tools, but their usefulness is limited in patients who experience acute infusion reactions, most of which are consistent with type I hypersensitivity reactions including anaphylaxis. Patients who experience acute infusion reactions face the prospect of stopping treatment or switching to an alternative, and potentially more toxic or inferior treatment. Another option that overcomes the treatment hurdle of these reactions is rapid desensitization, a procedure in which the offending agent is re-administered in a step-wise, highly controlled fashion. While the risk of reactions is not completely eliminated, desensitization has proven to be a highly effective re-administration strategy for most patients who otherwise would not be able to tolerate their monoclonal antibody therapy owing to drug-induced anaphylaxis. This article reviews the current literature on desensitization and other readministration protocols to monoclonal antibodies with an emphasis on four agents: rituximab, infliximab, cetuximab and trastuzumab.

KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma

BACKGROUND Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast‐cell homeostasis. We conducted a proof‐of‐principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyperresponsiveness, a physiological marker of severe asthma, as well as on airway mast‐cell numbers and activation in patients with severe asthma. METHODS We conducted a randomized, double‐blind, placebo‐controlled, 24‐week trial of imatinib in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20% (PC20). Patients also underwent bronchoscopy. RESULTS Among the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC20 increased by a mean (±SD) of 1.73±0.60 doubling doses in the imatinib group, as compared with 1.07±0.60 doubling doses in the placebo group (P=0.048). Imatinib also reduced levels of serum tryptase, a marker of mast‐cell activation, to a greater extent than did placebo (decrease of 2.02±2.32 vs. 0.56±1.39 ng per milliliter, P=0.02). Airway mast‐cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group. CONCLUSIONS In patients with severe asthma, imatinib decreased airway hyperresponsiveness, mast‐cell counts, and tryptase release. These results suggest that KIT‐dependent processes and mast cells contribute to the pathobiologic basis of severe asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01097694.)

Safety, Costs, and Efficacy of Rapid Drug Desensitizations to Chemotherapy and Monoclonal Antibodies

BACKGROUND Rapid drug desensitization (RDD) is used to address hypersensitivity reactions to chemotherapeutics and monoclonal antibodies, allowing patients to be treated with optimal pharmacological agents. RDD protocols are tailored to each individual patients reaction and needs, and protect against anaphylaxis, but overall risks, costs, and benefits have not been determined. OBJECTIVE We investigated the safety, efficacy, costs, and life expectancy of patients in a large population undergoing RDD. METHODS We analyzed 2177 RDD procedures performed in 370 patients with cancer, vasculitis, and hematological and connective tissue diseases who presented 402 reactions. A subgroup of carboplatin allergic patients with ovarian cancer treated with RDD was analyzed for costs and life expectancy and compared with a nonallergic control group. RESULTS RDD allowed all patients to receive safely the full dose of the medication to which they were reactive. A gradual increase in the fraction of outpatient desensitizations from 81% to 98% was achieved through risk stratification. Of the 2177 desensitizations, 93% had no or mild reactions whereas 7% had moderate to severe reactions, which did not preclude the completion of the treatment, and there were no deaths. Overall health costs in the carboplatin allergic group were not higher than those in the nonallergic group treated with standard of care. Administration of carboplatin through RDD was as effective as standard administration with a nonsignificant increase in life expectancy in desensitized patients as compared with nonallergic, nondesensitized controls. CONCLUSIONS RDD is cost effective and safe for allergic patients with cancer and chronic disease to remain on first line therapy.

Injection-site reaction to etanercept: role of skin test in the diagnosis of such reaction and successful desensitization.

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Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease

Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E2 (PGE2), which elicits antiproliferative effects mediated through the E prostanoid (EP)2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE2 and a selective EP2 agonist (P < 0.0001 at 1 μM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P < 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP4, and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP2 promoter correlated strongly with baseline EP2 mRNA (r = 0.80; P < 0.01). These studies suggest that the EP2 promotor is under epigenetic control, and one explanation for PGE2 resistance in AERD is an epigenetically mediated reduction of EP2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome.

Tolerance of daily low-dose aspirin does not preclude aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, eosinophilic nasal polyposis, rhinosinusitis, and respiratory reactions to COX-1 inhibitors including aspirin and other nonsteroidal anti-inflammatory drugs. Patients with AERD with symptoms refractory to guideline-based management of asthma, nasal polyposis, or rhinosinusitis benefit from aspirin desensitization and treatment with high-dose aspirin. Daily doses of at least 300 mg of aspirin, with some patients requiring up to 1300 mg, are effective in reducing the burden of disease. Studies investigating daily doses of lower than 300 mg have yielded inconsistent results, with the weight of evidence suggesting that low doses of aspirin are not effective. Clinical observation suggests that a subset of patients with AERD report taking daily low-dose (81 mg) aspirin for months to years without clinical history of an adverse reaction to aspirin. These patients come to attention because of recurrent eosinophilic nasal polyposis. When they undergo oral aspirin challenge after holding their daily aspirin for 10 days, they develop stereotypical respiratory reactions. To our knowledge, such patients with AERD have not been previously described in the literature. The goal of the present study was to identify a group of these patients and investigate their characteristics, with attention to their response to treatment with high-dose aspirin. We performed a retrospective chart review of 163 subjects with AERD who were referred to Brigham and Women’s Hospital or Massachusetts General Hospital for evaluation of possible AERD and who agreed to participate in our AERD registry between September 2013 and August 2014. We identified subjects who were taking 81 mg aspirin daily at the time of AERD evaluation and who reported no clinical history of aspirin hypersensitivity. All subjects who were taking daily low-dose aspirin at the time of AERD evaluation stopped taking aspirin for at least 10 days and then underwent aspirin challenge. The electronic medical record was reviewed for all subjects. Comprehensive clinical and questionnaire data were available for 91 subjects. There were 7 subjects (4.3% of 163) with AERD who had tolerated chronic daily aspirin (81-mg aspirin group). Six of the 7 subjects underwent positive aspirin challenge tests at our institution and developed a characteristic upper and/or lower airway reaction; the seventh reported a positive nonsteroidal anti-inflammatory drug challenge done elsewhere. Their demographic characteristics are given in Table I, and aspirin challenge results are given in Table II. The dose of aspirin that provoked a clinical reaction was 81 mg or less in 5 of the 6 patients. Subjects in the 81 mg aspirin group were significantly older at the time of aspirin challenge than other subjects with AERD (59.6 vs 48.3 years; P < .05), though there was no significant difference between groups in time between subjectreported onset of nasal polyposis and date of aspirin challenge. There was no significant difference between groups in the number of lifetime polypectomies, but fewer subjects in the 81mg aspirin group had a clinical history of asthma (5 of 7 vs 83 of 84; P < .05). Of the subjects in the 81-mg aspirin group, one started taking daily low-dose aspirin before the onset of AERD symptoms and another started taking daily low-dose aspirin before the onset of nasal polyps but had had mild intermittent asthma since childhood. Five had symptoms of AERD at the time they started taking daily low-dose aspirin. Of these, 3 were not taking montelukast and 2 could not recall their use of montelukast when they initiated daily low-dose aspirin. Four subjects in the 81-mg aspirin group were desensitized to aspirin and began high-dose aspirin therapy of at least 325 mg twice daily, and have been followed for a mean of 26 months (range, 5-37 months). Since beginning high-dose aspirin, none has required repeat polypectomy and all report improvement in nasal symptoms. Those with asthma (n 1⁄4 3) report improvement in asthma symptoms, with increases in FEV1 of 12.2%, 15.3%, and 41.4% at the first visit after the initiation of high-dose aspirin, which occurred 6, 12, and 6 weeks after aspirin desensitization, respectively. The patient whose FEV1 increased by 41.4% restarted zileuton, which he had temporarily stopped taking, around the same time that he started taking high-dose aspirin. Of the remaining 3 subjects in the 81-mg aspirin group, 2 will pursue polypectomy before aspirin desensitization and 1 has elected not to pursue highdose aspirin therapy. There are several explanations for why some patients with AERD apparently tolerate daily low-dose aspirin. First, they may initiate daily aspirin early in the clinical course of AERD before they develop aspirin hypersensitivity. However, only 1 subject in our group began taking baby aspirin before the onset of AERD symptoms. Second, the use of montelukast at the time of aspirin initiation could blunt their reaction, producing a “silent desensitization,” though most of the subjects we studied were not taking montelukast when they began taking daily low-dose aspirin. Given our findings, the most likely explanation is that they develop a reaction to their first ingestion of low-dose aspirin, but fail to connect the reaction with their aspirin use and subsequently become desensitized to aspirin through daily use. Although asthma is a prominent clinical feature of AERD, it is possible to have AERD without asthma. Subjects in our 81-mg aspirin group had significantly lower prevalence of asthma than did subjects who had not been taking aspirin daily. Patients with AERD who have more severe asthma may be less likely to tolerate daily low-dose aspirin without clinically obvious

Aspirin-Exacerbated Diseases: Advances in Asthma with Nasal Polyposis, Urticaria, Angioedema, and Anaphylaxis

Aspirin-exacerbated diseases are important examples of drug hypersensitivities and include aspirin-exacerbated respiratory disease (AERD), aspirin- or non-steroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema, and aspirin- or NSAID-induced anaphylaxis. While each disease subtype may be distinguished by unique clinical features, the underlying mechanisms that contribute to these phenotypes are not fully understood. However, the inhibition of the cyclooxygenase-1 enzyme is thought to play a significant role. Additionally, eosinophils, mast cells, and their products, prostaglandins and leukotrienes, have been identified in the pathogenesis of AERD. Current diagnostic and treatment strategies for aspirin-exacerbated diseases remain limited, and continued research focusing on each of the unique hypersensitivity reactions to aspirin is essential. This will not only advance the understanding of these disease processes, but also lead to the subsequent development of novel therapeutics that patients who suffer from aspirin-induced reactions desperately need.

Automated identification of an aspirin-exacerbated respiratory disease cohort

Background: Aspirin‐exacerbated respiratory disease (AERD) is characterized by 3 clinical features: asthma, nasal polyposis, and respiratory reactions to cyclooxygenase‐1 inhibitors (nonsteroidal anti‐inflammatory drugs). Electronic health records (EHRs) contain information on each feature of this triad. Objective: We sought to determine whether an informatics algorithm applied to the EHR could electronically identify patients with AERD. Methods: We developed an informatics algorithm to search the EHRs of patients aged 18 years and older from the Partners Healthcare system over a 10‐year period (2004‐2014). Charts with search terms for asthma, nasal polyps, and record of respiratory (cohort A) or unspecified (cohort B) reactions to nonsteroidal anti‐inflammatory drugs were identified as “possible AERD.” Two clinical experts reviewed all charts to confirm a diagnosis of “clinical AERD” and classify cases as “diagnosed AERD” or “undiagnosed AERD” on the basis of physician‐documented AERD‐specific terms in patient notes. Results: Our algorithm identified 731 “possible AERD” cases, of which 638 were not in our AERD patient registry. Chart review of cohorts A (n = 511) and B (n = 127) demonstrated a positive predictive value of 78.4% for “clinical AERD,” which rose to 88.7% when unspecified reactions were excluded. Of those with clinical AERD, 12.4% had no mention of AERD by any treating caregiver and were classified as “undiagnosed AERD.” “Undiagnosed AERD” cases were less likely than “diagnosed AERD” cases to have been seen by an allergist/immunologist (38.7% vs 93.2%; P < .0001). Conclusions: An informatics algorithm can successfully identify both known and previously undiagnosed cases of AERD with a high positive predictive value. Involvement of an allergist/immunologist significantly increases the likelihood of an AERD diagnosis.

Aspirin-exacerbated respiratory disease: Mediators and mechanisms of a clinical disease

Aspirin-exacerbated respiratory disease (AERD) is characterized by adult-onset asthma and severe chronic eosinophilic rhinosinusitis with nasal polyposis. AERD is not consistently associated with atopy, although serum total IgE levels can be increased. Steady-state levels of urinary or nasal lavage fluid mast cell activation products (histamine and tryptase) and leukotriene (LT) E4, the stable metabolite of the cysteinyl leukotrienes (cysLTs), exceed those found in patients with aspirin-tolerant asthma and sinonasal disease. Administration of aspirin or other drugs that inhibit COX-1 causes sharp additional increases in mast cell products, as well as marked incremental increases in LTE4 levels, with accompanying decreases in lung function and increases in sinonasal dysfunction (Fig 1, A and B). The bronchoconstriction during reactions can be attenuated by the administration of cromolyn or nedocromil, implying a role for mast cells. Although COX-1 inhibitors likely cause reactions by depleting homeostatic prostaglandin (PG) E2, which stabilizes mast cells through PGE2 receptor 2, the permissive factors responsible for ongoingmast cell activation and cysLT production remain poorly understood. Identifying causativemechanisms could lead to targeted and effective therapy for AERD.