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Rationale: Daily high-dose aspirin therapy benefits many patients with aspirin-exacerbated respiratory disease but provides no benefit for aspirin-tolerant patients with asthma. Type 2 inflammation...

There is an acute need for advances in pharmacologic therapies and a better understanding of novel drug targets for severe asthma. Imatinib, a tyrosine kinase inhibitor, has been shown to improve forced expiratory volume in 1 s (FEV1) in a clinical trial of patients with severe asthma. In a pilot study, we applied systems biology approaches to epithelium gene expression from these clinical trial patients treated with imatinib to better understand lung function response with imatinib treatment. Bronchial brushings from ten imatinib-treated patient samples and 14 placebo-treated patient samples were analyzed. We used personalized perturbation profiles (PEEPs) to characterize gene expression patterns at the individual patient level. We found that strong responders—patients with greater than 20% increase in FEV1—uniquely shared multiple downregulated mitochondrial-related pathways. In comparison, weak responders (5–10% FEV1 increase), and non-responders to imatinib shared none of these pathways. The use of PEEP highlights its potential for application as a systems biology tool to develop individual-level approaches to predicting disease phenotypes and response to treatment in populations needing innovative therapies. These results support a role for mitochondrial pathways in airflow limitation in severe asthma and as potential therapeutic targets in larger clinical trials.

© 2020 American Academy of Allergy, Asthma & Immunology Background: The cause of severe nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but upstream drivers of local antibody production in nasal polyps are undetermined. Objective: We sought to identify upstream drivers and phenotypic properties of local antibody-expressing cells in nasal polyps from subjects with AERD. Methods: Sinus tissue was obtained from subjects with AERD, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps, and controls without CRS. Tissue antibody levels were quantified via ELISA and immunohistochemistry and were correlated with disease severity. Antibody-expressing cells were profiled with single-cell RNA sequencing, flow cytometry, and immunofluorescence, with IL-5Rα function determined through IL-5 stimulation and subsequent RNA sequencing and quantitative PCR. Results: Tissue IgE and IgG4 levels were elevated in AERD compared with in controls (P

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.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% (PCAmong the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PCIn 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 .).

Antagonists of the type 1 cysteinyl leukotriene receptor (CysLT(1)R) are widely used to treat asthma and allergic rhinitis, with variable response rates. Alveolar macrophages express UDP-specific P2Y(6) receptors that can be blocked by off-target effects of CysLT(1)R antagonists. Sensitizing intranasal doses of an extract from the house dust mite Dermatophagoides farinae (Df) sharply increased the levels of UDP detected in bronchoalveolar lavage fluid of mice. Conditional deletion of P2Y(6) receptors before sensitization exacerbated eosinophilic lung inflammation and type 2 cytokine production in response to subsequent Df challenge. P2Y(6) receptor signaling was necessary for dectin-2–dependent production of protective IL-12p40 and Th1 chemokines by alveolar macrophages, leading to activation of NK cells to generate IFN-γ. Administration of CysLT(1)R antagonists during sensitization blocked UDP-elicited potentiation of IL-12p40 production by macrophages in vitro, suppressed the Df-induced production of IL-12p40 and IFN-γ in vivo, and suppressed type 2 inflammation only in P2Y(6)-deficient mice. Thus, P2Y(6) receptor signaling drives an innate macrophage/IL-12/NK cell/IFN-γ axis that prevents inappropriate allergic type 2 immune responses on respiratory allergen exposure and counteracts the Th2 priming effect of CysLT(1)R signaling at sensitization. Targeting P2Y(6) signaling might prove to be a potential additional treatment strategy for allergy.

The idiosyncratic activation of mast cells (MCs) in response to the administration of nonselective cyclooxygenase (COX) inhibitors is a cardinal feature of aspirin exacerbated respiratory disease (AERD). Older studies using mast cell stabilizing drugs support a critical role for MCs and their products in driving the severe eosinophilic inflammation and respiratory dysfunction that is typical of AERD. Since patients with AERD react to all nonselective COX inhibitors regardless of their chemical structure, the mechanism of MC activation is not due to classical, antigen-induced cross-linking of IgE receptors. Recent studies in both human subjects and animal models have revealed a complex and multifactorial process culminating in dysregulation of MC function, and an aberrant dependency on COX-1-derived prostaglandin E(2) to maintain a tenuous homeostasis. This article reviews the factors most likely to contribute to MC dysregulation in AERD, and the potential diagnostic and therapeutic implications.

BackgroundThe cause of nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but the upstream drivers and cellular mechanisms of local antibody production in AERD remain to be investigated.ObjectiveWe sought to identify the upstream drivers and phenotypic properties of local antibody-secreting cells in nasal polyps and to understand their clinical relevance in AERD.MethodsSinus tissue was obtained from subjects with AERD, aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP), aspirin-tolerant chronic rhinosinusitis without nasal polyps (CRSsNP), and healthy controls. Tissue antibody levels were quantified via ELISA and immunohistochemistry, and were correlated with clinical markers of disease severity. Tissue cytokine mRNA levels were measured with quantitative PCR (qPCR). Antibody-secreting cells were profiled with a combination of single-cell RNA-sequencing (scRNA-seq), flow cytometry and immunofluorescence.ResultsTissue IgE and IgG4 were elevated in AERD compared to controls (pIL5RA, IGHG4, and IGHE in the antibody-associated cells of subjects with AERD compared to CRSwNP. Total plasma cells and IL-5Rα+ plasma cell numbers in the polyp tissue from AERD exceeded those in polyps from CRSwNP (p=0.0051 and p=0.026, respectively) by flow cytometry. With immunofluorescence, we determined that IL-5Rα and IgG4 are co-expressed in antibody-secreting cells in AERD.ConclusionsOur study identifies unique clusters of antibody-secreting cells in AERD defined by enrichment of transcripts encoding IL5RA, IGHG4 and IGHE. We confirm surface expression of IL-5Rα on these cells, and identify T cells as a unique transcriptional source of IL-5. Tissue antibody levels are elevated in AERD and correlate with disease severity. Our findings suggest a role for IL-5 in facilitating local antibody production that may drive features of severe sinus disease.Key MessagesIgG4 and IgE levels are markedly increased in nasal polyp tissue from subjects with AERD compared to aspirin-tolerant CRSwNP.Tissue IgG4 levels positively correlate with disease recurrence.IL-10 mRNA levels are significantly higher in AERD polyp tissue compared to CRSwNP tissue, but differences were not noted for type 2 cytokines or cytokines involved in class switch recombination.IL-5Rα transcript and protein surface expression is elevated in antibody-secreting cells from subjects with AERD and may play a role in facilitating class switching and/or survival of antibody-secreting cells.Capsule SummarySingle-cell RNA-sequencing (scRNA-seq) of whole nasal polyp tissue identified increased IL5RA, IGHE, and IGHG4 expression in the antibody-secreting cell compartment of subjects with aspirin-exacerbated respiratory disease (AERD) compared to aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP). IgE and IgG4 levels are elevated in nasal polyp tissue from subjects with AERD compared to CRSwNP and correlate with disease recurrence.

Plasma tryptase elevation during aspirin-induced respiratory reactions occurs in 50% of reactions despite CysLT(1)R antagonist prophylaxis and identifies lung function decline and extra-respiratory symptoms in aspirin-exacerbated respiratory disease (AERD).

Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory disease characterized clinically by the triad of asthma, nasal polyposis, and pathognomonic respiratory reactions after ingestion of aspirin. It is a distinct syndrome associated with eosinophilic infiltration of respiratory tissues and excessive production of cysteinyl leukotrienes. Despite the consistent clinical phenotype of the respiratory disease, the underlying pathogenesis of the disease remains unclear. In addition to their role in hemostasis, platelets have the capacity to influence the activation state and function of other immune cells during inflammation and to facilitate granulocyte recruitment into the tissues. Platelets also possess a repertoire of potent preformed mediators of inflammation that are released on activation and are a rich source of newly synthesized lipid mediators that alter vascular permeability and smooth muscle tone. Accordingly, platelet activity has been linked to diverse inflammatory diseases, including asthma. Both human and animal studies strongly suggest that platelet activity is uniquely associated with the pathophysiology of AERD. This article summarizes the evidence supporting an effector role for platelets in asthmatic patients in general and in patients with AERD in particular and considers the potential therapeutic implications.

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 D 2 metabolite (PGD-M; 13.6 ± 2.7 vs 7.0 ± 0.8 pmol/mg creatinine [Cr], P P 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 1 inversely correlated with basal urinary levels of both leukotriene E 4 and PGD-M. Blood eosinophil and basophil levels increased and urinary PGD-M levels (2.2 ± 0.8 pmol/mg Cr, P Conclusion Failure to tolerate aspirin desensitization in a subset of patients with AERD is associated with prostaglandin D 2 overproduction. The increase in blood eosinophil and basophil counts during high-dose aspirin therapy might reflect the functional consequences of decreased prostaglandin D 2 release and the therapeutic benefit of aspirin.

Cysteinyl leukotrienes (cysLTs) facilitate mucosal type 2 immunopathology by incompletely understood mechanisms. Aspirin-exacerbated respiratory disease, a severe asthma subtype, is characterized by exaggerated eosinophilic respiratory inflammation and reactions to aspirin, each involving the marked overproduction of cysLTs. Here we demonstrate that the type 2 cysLT receptor (CysLT2R), which is not targeted by available drugs, is required in two different models to amplify eosinophilic airway inflammation via induced expression of IL-33 by lung epithelial cells. Endogenously generated cysLTs induced eosinophilia and expanded group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease–like Ptges−/− mice. These responses were mitigated by deletions of either Cysltr2 or leukotriene C4 synthase (Ltc4s). Administrations of either LTC4 (the parent cysLT) or the selective CysLT2R agonist N-methyl LTC4 to allergen sensitized wild-type mice markedly boosted ILC2 expansion and IL-5/IL-13 generation in a CysLT2R-dependent manner. Expansion of ILC2s and IL-5/IL-13 generation reflected CysLT2R-dependent production of IL-33 by alveolar type 2 cells, which engaged in a bilateral feed-forward loop with ILC2s. Deletion of Cysltr1 blunted LTC4-induced ILC2 expansion and eosinophilia but did not alter IL-33 induction. Pharmacological blockade of CysLT2R prior to inhalation challenge of Ptges−/− mice with aspirin blocked IL-33–dependent mast cell activation, mediator release, and changes in lung function. Thus, CysLT2R signaling, IL-33–dependent ILC2 expansion, and IL-33–driven mast cell activation are necessary for induction of type 2 immunopathology and aspirin sensitivity. CysLT2R-targeted drugs may interrupt these processes.

Background Food allergy is an important public health problem because it affects children and adults, can be severe and even life-threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut-containing foods beginning in infancy.Objectives Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy.Results The addendum provides 3 separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut-containing foods in the health care provider’s office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation.Conclusions Guidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy. Keywords: Food, Peanut, Allergy, Prevention, Guidelines

Background Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, recurrent nasal polyposis, and respiratory reactions on ingestion of COX-1 inhibitors. Increased numbers of platelet-leukocyte aggregates are present in the sinus tissue and blood of patients with AERD compared with that of aspirin-tolerant patients, and platelet activation can contribute to aspirin-induced reactions. Objective We sought to determine whether treatment with prasugrel, which inhibits platelet activation by blocking the type 12 purinergic (P2Y12) receptor, would attenuate the severity of sinonasal and respiratory symptoms induced during aspirin challenge in patients with AERD. Methods Forty patients with AERD completed a 10-week, double-blind, placebo-controlled crossover trial of prasugrel. All patients underwent oral aspirin challenges after 4 weeks of prasugrel and after 4 weeks of placebo. The primary outcome was a change in the provocative dose of aspirin that would elicit an increase in Total Nasal Symptom Score (TNSS) of 2 points. Changes in lung function, urinary eicosanoids, plasma tryptase, platelet-leukocyte aggregates, and platelet activation were also recorded. Results Prasugrel did not significantly change the mean increase in TNSS of 2 points (79 ± 15 for patients receiving placebo and 139 ± 32 for patients receiving prasugrel, P = .10), platelet-leukocyte aggregates, or increases in urinary leukotriene E4 and prostaglandin D2 metabolite levels during aspirin-induced reactions in the study population as a whole. Five subjects (responders) reacted to aspirin while receiving placebo but did not have any reaction to aspirin challenge after the prasugrel arm. In contrast to prasugrel nonresponders (35 subjects), the prasugrel responders had smaller reaction-induced increases in TNSS; did not have significant aspirin-induced increases in urinary leukotriene E4, prostaglandin D2 metabolite, or thromboxane B2 levels; and did not display increases in serum tryptase levels during aspirin reactions on the placebo arm, all of which were observed in the nonresponders. Conclusion In the overall study population, prasugrel did not attenuate aspirin-induced symptoms, possibly because it failed to decrease the frequencies of platelet-adherent leukocytes or to diminish aspirin-induced mast cell activation. In a small subset of patients with AERD who had greater baseline platelet activation and milder upper respiratory symptoms during aspirin-induced reactions, P2Y12 receptor antagonism with prasugrel completely inhibited all aspirin-induced reaction symptoms, suggesting a contribution from P2Y12 receptor signaling in this subset.

Physiologic and pharmacologic studies support the hypothesis that aspirin-exacerbated respiratory disease (AERD) involves fundamental dysregulation in the production of and end-organ responsiveness to both antiinflammatory eicosanoids (prostaglandin E2) and proinflammatory effectors (cysteinyl leukotrienes). The acquired nature of AERD implies a disturbance in a potential epigenetic control mechanism of the relevant mediator systems, which may be a result of incompletely clarified environmental factors (eg, viral or bacterial infections, inhaled pollutants).

NSAIDs that inhibit cyclooxygenase-1 can provoke severe asthma and rhinosinusitis with nasal polyps and eosinophil infiltration. Cysteinyl leukotriene generation by the leukotriene C4 synthase pathway may cause the bronchoconstriction, vascular leak, and mucous secretion.

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

Food allergy is an important public health problem that affects children and adults and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no current treatment for food allergy: the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis and management of food allergy also may vary from one clinical practice setting to another. Finally, because patients frequently confuse nonallergic food reactions, such as food intolerance, with food allergies, there is an unfounded belief among the public that food allergy prevalence is higher than it truly is. In response to these concerns, the National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy. These Guidelines are intended for use by a wide variety of health care professionals, including family practice physicians, clinical specialists, and nurse practitioners. The Guidelines include a consensus definition for food allergy, discuss comorbid conditions often associated with food allergy, and focus on both IgE-mediated and non-IgE-mediated reactions to food. Topics addressed include the epidemiology, natural history, diagnosis, and management of food allergy, as well as the management of severe symptoms and anaphylaxis. These Guidelines provide 43 concise clinical recommendations and additional guidance on points of current controversy in patient management. They also identify gaps in the current scientific knowledge to be addressed through future research.

While the role of mast cells in allergic reactions is unequivocal, their precise functions in asthma remain controversial. Mast cells uniquely populate all vascularized organs and tissues, including the upper and lower respiratory tree, even in healthy individuals. Histologic evidence suggests that asthma is accompanied by a mast cell hyperplasia in the inflamed mucosal epithelium and the adjacent smooth muscle. The mechanisms responsible for constitutive mast cell development have been partly elucidated. Moreover, both in vitro studies and in vivo disease models indicate that mast cells have a remarkably flexible program of gene expression, and this program can be drastically altered by the T-cell-derived Th2 cytokines relevant to asthma. Moreover, the role of mast cells in innate immunity is now firmly established, and the capacity for numerous microbial pathogens to initiate their activation in vitro and in vivo suggest mechanisms by which microbes could initiate disease exacerbations.

Mast cells, historically known for their involvement in type I hypersensitivity, also serve critical protective and homeostatic functions. They directly recognize the products of bacterial infection through several surface receptor proteins, releasing proteases, cytokines, and eicosanoid mediators that recruit neutrophils, limit the spread of bacterial infection, and facilitate subsequent tissue repair. In vitro studies suggest that the spectrum of microbes capable of initiating mast cell activation is broad and extends to common respiratory viruses, mycoplasma, and even products of tissue injury, such as nucleotides. TH2-polarized inflammation elicits a reactive hyperplasia of mast cells at the involved mucosal surfaces in both mice and human subject. Several recombinant TH2 cytokines (IL-3, IL-4, IL-5, and IL-9) act synergistically with stem cell factor to facilitate proliferation of nontransformed human mast cells in vitro. IL-4 induces the expression of critical inflammation-associated genes by human mast cells, such as those encoding leukotriene C4 synthase, Fc(epsilon)RI, and several cytokines. Consequently, priming with IL-4 not only amplifies classical Fc(epsilon)RI-dependent mast cell activation but also dramatically alters the product profile of mast cells activated by innate signals and by chemical mediators of inflammation. Strikingly, IL-4 induces an activation response by mast cells to cysteinyl leukotrienes, which act through a receptor shared with uridine diphosphate to induce cytokine generation without exocytosis. It Is possible that alterations in mast cell phenotype by the TH2 milieu of allergy permits otherwise trivial infections or homeostatic chemical signals to initiate harmful inflammatory cascades and sustain tissue pathology. Drug development must take these nonclassical mast cell activation pathways into account without compromising the beneficial and protective functions of mast cells.

Presentation of Case A four-month-old girl was admitted to another hospital because of cyanosis. The patient had been well until two months earlier, when she began to require up to 45 minutes for her feedings. Three weeks before admission, acral and perioral cyanosis were noted. During the two weeks before admission, she had a nonblanching papular rash over the left parietal region, which was the side on which she slept. During the week before admission, the infant had episodes of vomiting, with each episode occurring several hours after she had eaten cereal. Her mother noted infrequent episodes of tachypnea, cough, . . .

Cysteinyl leukotrienes (cysLTs) are products of arachidonic acid metabolism by the 5-lipoxygenase/leukotriene C4 synthase (5-LO/LTC4S) synthetic pathway. LTC4, the parent cysLT, is rapidly synthesized in response to cellular activation, released by a specific transporter, and converted extracellularly to LTD4 and LTE4 through the sequential actions of extracellular enzymes (1). CysLTs are generated by activated mast cells, eosinophils, basophils, macrophages, and myeloid dendritic cells, all of which constitutively express the requisite enzymes necessary for the formation of LTC4. All are hematopoietic cellular constituents of allergic inflammation. CysLTs signal through at least three cognate receptors, termed the type 1 and type 2 cysLT receptors (CysLT1R and CysLT2R) (2, 3), and GPR99 (4). Because of their potent effects as smooth muscle spasmogens (5) (an effect attributed primarily to CysLT1R), and because of evidence that the production of cysLTs increased during spontaneous asthma exacerbations (6), cysLTs drew early interest as potential mediators of asthma. This led to the development of some of the first molecularly targeted drugs for asthma therapy, the 5-lipoxygenase inhibitor, zileuton, and selective CysLT1R antagonists. Both classes of drugs show efficacy in improving baseline airflow measurements and reducing the frequency of asthma exacerbations (7, 8), supporting the pathobiologic role of the cysLTs in regulating bronchomotor tone in asthma. Advances in molecular biology have significantly expanded our understanding of the potential pathobiologic functions of cysLTs. In mouse models of allergic pulmonary inflammation, cysLTs play a critical role in the induction and amplification of Th2-type immune responses. Mice lacking LTC4S or CysLT1R, with impaired cysLT generation or signaling, respectively, showed a marked reduction in the development of eosinophilic pulmonary inflammation and Th2 immunity in response to intranasal extracts from the house dust mites Dermatophagoides farinae or Dermatophagoides pteronyssinus (Dp) (9–11). CysLT generation in these studies conditioned dendritic cells for Th2 priming via an autocrine/paracrine action at CysLT1R. In another model, intranasal delivery of LTC4 to sensitized mice receiving ovalbumin challenges markedly amplified pulmonary eosinophil recruitment by a pathway involving the activation of CysLT2R on platelets (12). In a model of intranasal sensitization and challenge to the mold Alternaria alternata, the recruitment and activation of type 2 innate lymphoid cells depended on cysLTs (13). Last, in a model of chronic airway inflammation induced by repetitive ovalbumin challenges of sensitized mice, the administration of the CysLT1R antagonist montelukast inhibited peribronchial collagen deposition and airway smooth muscle hyperplasia (14). Although the latter finding supports a potential direct role for cysLTs (and CysLT1R) in driving airway remodeling, the pleiotropic actions of cysLTs at multiple steps in the proximal innate immune response require that downstream effects on structural cells be interpreted with caution. In this issue of the Journal, Trian and colleagues (pp. 538–546) demonstrate a potential pathway by which cysLTs may elicit airway smooth muscle proliferation independent of the proximal immune response (15). They demonstrate that airway smooth muscle cells (ASM) cultured from bronchial biopsies of patients with severe asthma proliferated in response to cysLTs generated by Dp-stimulated airway epithelial cells. ASM from nonasthmatic controls did not respond to the epithelial supernatants and expressed substantially less CysLT1R mRNA and protein than did cells from severe asthmatics. The effect of Dp on epithelial cells was inhibited by antibodies against protease-activated receptor 2, suggesting Dp proteases were responsible for the activation of the 5-LO/LTC4S pathway in this system. Treatment of the epithelial cells with either zileuton or dexamethasone eliminated Dp induction of the growth factor activity and LTC4 synthesis. The epithelial cells showed substantial up-regulation of 5-LO, 5-LO-activating protein, and LTC4S mRNA transcript expression in response to Dp, suggesting epithelial cells (in contrast to hematopoietic cells) may require transcriptional induction to become competent to generate cysLTs at a level sufficient to cause physiologic effects on smooth muscle. The study by Trian and colleagues carries several potential implications and caveats. First, although hematopoietic cells almost certainly provide the majority of cysLTs under virtually all circumstances, the study suggests epithelial cells can inducibly express the 5-LO/LTC4S system and could contribute cysLT synthesis when perturbed by environmental danger signals such as proteases. This would be consistent with previous observations that bronchial epithelial cells up-regulate 5-LO, 5-LO–activating protein, and LTC4S expression in response to stimulation with bradykinin or lipopolysaccharide (16). Second, epithelially derived cysLTs elicited proliferation only in asthmatic ASM, but not control ASM, which was attributed to the markedly higher levels of CysLT1R expression by asthmatic ASM. This phenomenon has not been reported previously and seems at odds with the previous reports that patients with asthma and nonasthmatic controls exhibit equivalent sensitivity to bronchoconstriction elicited by inhalation challenges with LTD4, the preferred ligand for CysLT1R (17, 18). Because the ASM cells used in the study by Trian and colleagues all came from donors with severe disease, it is not possible to determine whether CysLT1R expression by ASM varies with disease severity. The molecular basis for the up-regulated expression of CysLT1R in ASM from patients with severe asthma identified in this study could reflect an epigenetic change, as it is not only evident in cells obtained directly by microdissection but is also retained through multiple passages of culture. Finally, the proliferative action of cysLTs for ASM, which was identified in prior studies (19), suggests a potential application for CysLT1R antagonists in the prevention of airway remodeling. This possibility awaits a carefully done longitudinal study using CysLT1R antagonism with careful monitoring of physiologic and histologic endpoints.

Eosinophils are bone-marrow-derived granulocytes that are involved in both allergic and nonallergic inflammation. They possess a diverse repertoire of functional responses and effector capabilities, including the release of preformed cytotoxic granule proteins, superoxide production, leukotriene biosynthesis, and cytokine production. Each of these functional capabilities is linked to the production of tissue damage and physiologic derangements that are characteristic of human diseases associated with eosinophil-dominated inflammation, such as asthma. This review concerns the biology of eosinophils as it pertains to the pathogenesis of allergic disease.

Objective To review the basic science and translational relevance of lipid mediators in the pathobiology of allergic diseases. Data Sources PubMed was searched for articles using the key terms lipid mediator , prostaglandin , prostanoid , leukotriene , thromboxane , asthma , and allergic inflammation . Study Selections Articles were selected based on their relevance to the goals of this review. Articles with a particular focus on clinical and translational aspects of basic science discoveries were emphasized. Results Lipid mediators are bioactive molecules generated from cell membrane phospholipids. They play important roles in many disease states, particularly in inflammatory and immune responses. Lipid mediators and their receptors are potentially useful as diagnostic markers of disease and therapeutic targets. Conclusions Several useful therapeutic agents have been developed based on a growing understanding of the lipid mediator pathways in allergic disease, notably the cysteinyl leukotriene receptor type 1 antagonists and the 5-lipoxygenase inhibitor, zileuton. Additional receptor agonists and antagonists relevant to these pathways are in development, and it is likely that future pharmacologic treatments for allergic disease will become available as our understanding of these molecules continues to evolve.

104 Transplantation-associated food allergy is most commonly seen in pediatric liver transplant recipients on tacrolimus and may be associated with atopic dermatitis, eosinophilic gastrointestinal disease, poor weight gain, and clinical reactivity to multiple foods. Reducing the dose of tacrolimus and adding mycophenolate mofetil to the immunosuppressive regimen may lead to resolution of this condition. Clinical trials should investigate whether mycophenolate mofetil facilitates resolution or confers protection from transplantation-associated food allergy.

Data from many studies have suggested a rise in the prevalence of food allergies during the past 10 to 20 years. Currently, no curative treatments for food allergy exist, and there are no effective means of preventing the disease. Management of food allergy involves strict avoidance of the allergen in the patient's diet and treatment of symptoms as they arise. Because diagnosis and management of the disease can vary between clinical practice settings, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored development of clinical guidelines for the diagnosis and management of food allergy. The guidelines establish consensus and consistency in definitions, diagnostic criteria, and management practices. They also provide concise recommendations on how to diagnose and manage food allergy and treat acute food allergy reactions. The original guidelines encompass practices relevant to patients of all ages, but food allergy presents unique and specific concerns for infants, children, and teenagers. To focus on those concerns, we describe here the guidelines most pertinent to the pediatric population.

Asthma is a prevalent and complex syndrome with several phenotypic variants. The central features are bronchial inflammation and airway hyperresponsiveness. Many aspects of asthma, such as control of airway hyperresponsiveness, causative factors, and variable responses to treatment, remain poorly understood. This review highlights some of the latest insights into the pathogenesis of asthma that might ultimately bear on the development or choice of treatment modalities.

Background IL-5 is a cytokine critically involved in regulating several aspects of eosinophils including their production, activation, and tissue recruitment. As such, IL-5 may be involved in the pathogenesis of hypereosinophilic syndromes, a group of poorly treated diverse disorders characterized by sustained peripheral blood and/or tissue eosinophilia. Objective We aimed to assess the safety and efficacy of a humanized blocking monoclonal antibody against IL-5 (mepolizumab) in patients with several forms of hyper-eosinophilic syndromes. Methods We performed an open-label trial of anti–IL-5 in which 3 intravenous doses (10 mg/kg, maximum 750 mg) were administered at 4-week intervals to 4 patients with hypereosinophilic syndromes (defined by peripheral blood and/or tissue eosinophilia). The effects of treatment on safety, eosinophil levels (in peripheral blood and/or diseased tissue), pulmonary function, and quality of life were measured over a 28-week period. Results Anti–IL-5 was well tolerated in all patients and lowered peripheral blood eosinophil counts despite ongoing systemic glucocorticoid therapy. The decline in circulating eosinophil counts was sustained for at least 12 weeks after the last dose of anti–IL-5. In addition, anti–IL-5 improved clinical and quality of life measurements. In one patient with striking tissue eosinophilia (eosinophilic esophagitis), anti–IL-5 resulted in a 10-fold reduction in tissue eosinophil levels. Conclusions These results suggest that anti–IL-5 is safe, effective in lowering eosinophil levels, and has potential glucocorticoid-sparing effects in patients with a variety of hyper-eosinophilic syndromes. As such, anti–IL-5 may have significant therapeutic potential for hypereosinophilic syndromes.

Cysteinyl leukotrienes (cys-LTs) are potent mediators of inflammation derived from arachidonic acid through the 5-lipoxygenase/leukotriene C4 synthase pathway. The derivation of their chemical structures and identification of their pharmacologic properties predated the cloning of their classical receptors and the development of drugs that modify their synthesis and actions. Recent studies have revealed unanticipated insights into the regulation of cys-LT synthesis, the function of the cys-LTs in innate and adaptive immunity and human disease, and the identification of a new receptor for the cys-LTs. This review highlights these studies and summarizes their potential pathobiologic and therapeutic implications.