Extrinsic and Intrinsic Modulators of Anaphylaxis.

The severity of anaphylaxis is determined by many factors. The allergenic source as well as the age of the affected individual and the route of allergen exposure encompass the major contributors of the clinical outcome. Moreover, the severity can be modulated further by intrinsic and extrinsic factors. Among these, the genetic predisposition, certain comorbidities such as uncontrolled asthma, and hormonal fluctuations have been proposed as intrinsic and antihypertensive medications or physical activity as extrinsic factors. Recent advances have highlighted immunologic pathways that may exacerbate the response to allergens through receptors on mast cells, basophils, platelets, and other granulocytes. Atopy, platelet-activating factor acetylhydrolase deficiency, hereditary alpha tryptasemia, and clonal mast cell disorders are examples associated with genetic alterations that may predispose to severe anaphylaxis. Identifying risk factors that lower the threshold of reactivity or increase the severity of multisystem reactions is important in the management of this patient population.

Avapritinib versus Placebo in Indolent Systemic Mastocytosis.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. METHODS: We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures. RESULTS: From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events. CONCLUSIONS: In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)

Platelet Activating Factor (PAF): A Mediator of Inflammation.

Platelet-activating factor (PAF) is a phospholipid-derived mediator with an established role in multiple inflammatory states. PAF is synthesized and secreted by multiple cell types and is then rapidly hydrolyzed and degraded to an inactive metabolite, lyso-PAF, by the enzyme PAF acetylhydrolase. In addition to its role in platelet aggregation and activation, PAF contributes to allergic and nonallergic inflammatory diseases such as anaphylaxis, sepsis, cardiovascular disease, neurological disease, and malignancy as demonstrated in multiple animal models and, increasingly, in human disease states. Recent research has demonstrated the importance of the PAF pathway in multiple conditions including the prediction of severe pediatric anaphylaxis, effects on blood-brain barrier permeability, effects on reproduction, ocular diseases, and further understanding of its role in cardiovascular risk. Investigation of PAF as both a biomarker and a therapeutic target continues because of the need for directed management of inflammation. Collectively, studies have shown that therapies focused on the PAF pathway have the potential to provide targeted and effective treatments for multiple inflammatory conditions.

Reproducibility of Symptom Sequences Across Episodes of Recurrent Anaphylaxis.

BACKGROUND: Anaphylactic reactions may present with varying levels of severity, ranging from mild multisystem involvement to severe, and sometimes fatal, anaphylaxis. The severity of anaphylaxis is variable from one reaction to the next within the same individuals. OBJECTIVE: To compare the temporal sequence of symptoms within individuals and between individuals across multiple anaphylactic reactions. METHODS: Patients were evaluated for recurrent anaphylaxis in a tertiary care allergy clinic between 2012 and 2018. At each visit, patients were asked to record the temporal sequence in which symptoms of anaphylaxis appeared. These data were recorded at each visit and retrieved through retrospective chart review. Patients with a history of ≥2 anaphylactic reactions were included; those with anaphylaxis due to multiple allergens were excluded. The Fleiss Kappa method was used to assess reproducibility of the order of appearance of specific symptoms during anaphylaxis within individual patients and between individuals with similar triggers. RESULTS: The mean patient age was 35.6 years (standard deviation = 13.9; range: 1-68 years); 113 of 149 (76%) patients were female. The mean Fleiss Kappa reproducibility score within individuals was 0.94, 5th percentile was 0.53, and 95th percentile was 1.0. The mean Kappa score between individuals was -0.03 (range, -0.14 to 0.05). Among the 16 of 149 patients who recorded reactions of varying severity grades, the mean within-patient Kappa score was 0.96. CONCLUSION: Individual patients experience reproducibly stereotypic anaphylactic reactions over time, which are unique to a given patient, irrespective of the cause of anaphylaxis, including foods, medications, mast cell disorders, and idiopathic anaphylaxis. In contrast, symptom sequences during anaphylaxis are not reproducible between individuals.

Omalizumab for asthma and allergic bronchopulmonary aspergillosis in adults with cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF), omalizumab has been used for difficult-to-treat asthma and allergic bronchopulmonary aspergillosis (ABPA) but safety and efficacy data are limited for this population. METHODS: We assessed patients receiving omalizumab for asthma or ABPA in the Toronto adult CF center between 2005 and 2017. We evaluated treatment safety and efficacy by analyzing changes in FEV1% predicted (FEV1pp) max value, slope and variability captured by the area under the curve (AUC), the cumulative dose of systemic corticosteroids (SCS), use of intravenous (IV) antibiotics and hospitalization days before omalizumab and up to 1 year after treatment initiation. Linear mixed effects model was used for FEV1pp slope and the trapezoidal rule for FEV1pp AUC. RESULTS: Twenty-seven CF patients received omalizumab, 16 (59.3%) for asthma and 11 (40.7%) for ABPA. No significant omalizumab-related adverse effects were observed. In the asthmatic group, the max value of FEV1pp improved on omalizumab and the cumulative dose of SCS decreased. In the ABPA group, the rate of FEV1pp decline (slope) and the variability of FEV1pp (AUC) improved on omalizumab. In ABPA patients, the cumulative SCS dose was not significantly different but 4 (36%) patients decreased their SCS dose by >50% compared to baseline. Days on IV antibiotics and hospital days did not differ significantly before and while on omalizumab therapy. CONCLUSIONS: In adult CF patients with difficult-to-treat asthma or ABPA, omalizumab should be considered. Larger studies are needed to identify patient characteristics that may predict response to omalizumab.

Efficacy of Omalizumab in Indolent Systemic Mastocytosis.

BACKGROUND: Systemic mastocytosis (SM) comprises a heterogeneous group of disorders characterized by the proliferation of clonal mast cells in skin and various internal organs. Omalizumab is an established, labelled therapy for allergic asthma and chronic urticaria, but its experience in the efficacy of SM is limited. METHODS: A retrospective analysis of 6 patients diagnosed with indolent SM treated with omalizumab at St. Michael's Hospital between 2009 and 2018 is described. Reported frequency of anaphylaxis, baseline and follow-up tryptase levels, and SM-related symptoms were captured to measure the control of the disease. RESULTS: Of the 5 patients who had experienced unprovoked anaphylaxis prior to treatment with omalizumab, 3 had no further episodes of anaphylaxis following initiation of omalizumab, while the remaining 2 patients had milder multisystem reactions. Significant improvement in cutaneous symptoms was also observed. CONCLUSION: These data suggest that omalizumab provides benefit to patients with SM who remain highly symptomatic in spite of treatment with conventional therapies.

Severe and near-fatal anaphylactic reactions triggered by chlorhexidine-coated catheters in patients undergoing renal allograft surgery: a case series.

PURPOSE: Although intraoperative anaphylaxis during surgery is a rare event, we describe five patients who experienced perioperative anaphylactic reactions during renal transplantation and were referred for investigation. CLINICAL FEATURES: Skin-prick and intradermal skin tests were done to investigate potential allergies to drugs given perioperatively prior to the development of anaphylaxis, including basiliximab, propofol, cefazolin, cis-atracurium, fentanyl, latex, remifentanil, and chlorhexidine. In addition, in vitro serologic testing for specific IgE was done in patients suspected to have had chlorhexidine anaphylaxis. All five patients were male, with a mean age of 48 yr (range 30-69). Skin testing for all drugs was non-reactive except for chlorhexidine, which was positive in four of five patients (one patient refused intradermal testing). In vitro test results for chlorhexidine-specific IgE were positive in all of the patients. Anesthetic records showed that intraoperative anaphylaxis had occurred immediately after insertion of a chlorhexidine-coated central venous catheter. CONCLUSIONS: Intraoperative insertion of chlorhexidine-coated central venous catheters can trigger life-threatening anaphylaxis in susceptible patients undergoing renal transplantation.

Cholinergic Urticaria with Anaphylaxis: An Underrecognized Clinical Entity.

BACKGROUND: Cholinergic urticaria is a form of physical urticaria triggered by high ambient temperature, strenuous physical activity, and strong emotion. These same triggers may cause multisystem reactions that can be life-threatening. A study of patients with cholinergic urticaria with anaphylaxis was undertaken to describe the demographic and clinical features of this form of anaphylaxis. OBJECTIVE: To describe a cohort of patients with anaphylaxis triggered by high ambient temperature, exertion, and stress. METHODS: Patients from an academic allergy practice in a university teaching hospital were identified by retrospective chart review. RESULTS: A total of 19 patients with recurrent episodes of anaphylaxis due to cholinergic triggers were identified. The female:male ratio was 15:4 (79% females). The mean age of onset was 27.5 years. Patients experienced a mean of 9.41 episodes per year. All 19 patients (100%) reported anaphylaxis triggered by high ambient temperature, 89.5% reported anaphylaxis triggered by strenuous exertion, and 78.9% reported anaphylaxis triggered by stress. Cutaneous involvement was present in 94.7%; 78.9% had upper airway obstructive symptoms, 78.9% had lower airway involvement, 57.9% had gastrointestinal involvement, and 78.9% had cardiovascular manifestations. Anaphylaxis severity scores were grade 1 (mild) in 11.1%, grade 2 (moderate) in 44.4%, and grade 3 (severe) in 44.4%. Baseline tryptase levels were normal in all but 1 patient. CONCLUSIONS: Anaphylaxis due to cholinergic triggers is underreported, with only several case reports in the literature. Reactions are multisystem with cutaneous, upper and lower airway, and cardiovascular involvement in most patients. Manifestations may be life-threatening, and reactions are often severe.

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis.

Anaphylaxis is an acute, severe, life-threatening multisystem allergic reaction resulting from the sudden systemic release of biochemical mediators and chemotactic substances. Release of both preformed granule-associated mediators and newly generated lipid-derived mediators contributes to the amplification and prolongation of anaphylaxis. Platelet-activating factor (PAF) is a potent phospholipid-derived mediator the central role of which has been well established in experimental models of both immune-mediated and non-immune mediated anaphylaxis. It is produced and secreted by several types of cells, including mast cells, monocytes, tissue macrophages, platelets, eosinophils, endothelial cells, and neutrophils. PAF is implicated in platelet aggregation and activation through release of vasoactive amines in the inflammatory response, resulting in increased vascular permeability, circulatory collapse, decreased cardiac output, and various other biological effects. PAF is rapidly hydrolyzed and degraded to an inactive metabolite, lysoPAF, by the enzyme PAF acetylhydrolase, the activity of which has shown to correlate inversely with PAF levels and predispose to severe anaphylaxis. In addition to its role in anaphylaxis, PAF has also been implicated as a mediator in both allergic and nonallergic inflammatory diseases, including allergic rhinitis, sepsis, atherosclerotic disease, and malignancy, in which PAF signaling has an established role. The therapeutic role of PAF antagonism has been investigated for several diseases, with variable results thus far. Further investigation of its role in pathology and therapeutic modulation is highly anticipated because of the pressing need for more selective and targeted therapy for the management of severe anaphylaxis.

Heterogeneity in presentation and treatment of catamenial anaphylaxis.

BACKGROUND: Few reports have documented the uncommon association of the female menstrual cycle with anaphylaxis, an entity known as cyclic or catamenial anaphylaxis. OBJECTIVE: To examine cases of perimenstrual anaphylaxis, focusing on differences in presentation and response to treatment, in the hopes of enriching the description of this rare entity. METHODS: A cohort of 8 women with catamenial anaphylaxis were identified and retrospectively compared with regard to age at onset, organ involvement, diagnostic studies, and response to therapy. RESULTS: The median age at onset was 34 years (range, 14-40 years), and the median number of perimenstrual anaphylactic episodes at presentation was 10 per patient (range, 4-24 per patient). Most had cutaneous and gastrointestinal symptoms. The results of extensive investigations for anaphylactic triggers were negative, and masquerading conditions, such as carcinoid syndrome, pheochromocytoma, and systemic mastocytosis, were ruled out in all patients. Skin test results for progesterone were negative in all but 1 of 4 patients tested. None had elevated total serum IgE levels. Response to suppressive treatments regimens varied considerably, but none treated with high-dose systemic steroids had improvement. Similarly, ketotifen, celecoxib, rofecoxib, and oral contraceptives failed to control the anaphylactic reactions. Although antihistamines failed in 7 patients, 1 had improvement. Others responded to leuprolide, medroxyprogesterone, or salpingo-oophorectomy. CONCLUSION: Whether the mechanism causing cyclical anaphylaxis may involve hypersensitivity to progesterone or prostaglandins, the variable response to suppressive medications in these cases suggests that catamenial anaphylaxis is a heterogeneous disorder in which a number of mechanisms and mediators may play a role. It is an emergent and probably underrecognized entity in the medical literature.

Effect of epinephrine on platelet-activating factor-stimulated human vascular smooth muscle cells.

BACKGROUND: Animal and human data show that platelet-activating factor (PAF) mediates the life-threatening manifestations of anaphylaxis. Although administration of epinephrine is the mainstay of therapy of acute anaphylaxis, the interaction between epinephrine and PAF has not been studied. In particular, the effect of the timing of epinephrine administration on the action of PAF has not been examined. OBJECTIVE: Using human vascular smooth muscle cells (HVSMCs), we examined the effect of timing of epinephrine addition on the action of PAF. METHODS: The effect of epinephrine on PAF-mediated prostaglandin E(2) (PGE(2)) release from human aortic smooth muscle cells was examined. Epinephrine was added at various times before and after PAF stimulation. RESULTS: HVSMCs stimulated with PAF released PGE(2) in a concentration- and time-dependent manner. Whereas preincubation of HVSMCs with epinephrine before the addition of PAF suppressed PGE(2) release, treatment with epinephrine after PAF stimulation was less effective with time after PAF stimulation. PGE(2) release was suppressed by means of preincubation with 8-bromo-cyclic AMP and forskolin. CONCLUSIONS: PAF induced PGE(2) release from HVSMCs in a concentration- and time-dependent manner, and early addition of epinephrine was essential for the control of PAF-induced PGE(2) release. Epinephrine was most effective when administered before stimulation with PAF but was progressively less effective with time after PAF stimulation.