Peter Vadas

Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis

BACKGROUND Platelet-activating factor (PAF) is an important mediator and correlates with anaphylaxis severity. How well PAF correlates with severity relative to histamine or tryptase is not known. OBJECTIVE To analyze the levels of PAF, histamine, and tryptase as a function of severity in patients with acute allergic reactions. METHODS PAF, histamine, and tryptase levels were measured in blood samples collected from 23 healthy volunteers and from 41 patients during acute allergic reactions. Reactions were stratified by severity from grade 1 (least severe) to grade 3 (most severe). RESULTS Among the 3 reaction grades, there were significant differences by ANOVA for PAF (P < .0001). The proportion of elevated PAF values increased across severity groups (P = .0009). Increased PAF levels were observed in 20%, 66.7%, and 100% of the patients with grades 1, 2, and 3 allergic reactions, respectively. While the proportion of elevated histamine values increased from 40% to 57% to 70% across grades 1, 2, and 3, respectively, these were not significantly different (P = .40). For tryptase, the proportion of elevated values increased monotonically from 0 in grade 1 to 4.8% in grade 2 to 60% in grade 3 (P = .0002). CONCLUSIONS The PAF level was significantly elevated in proportion to the severity of acute allergic reactions. Whereas the PAF level was elevated in all patients with severe anaphylaxis, this was not true for either histamine or tryptase. Neither histamine nor tryptase showed as good correlations with severity scores as did PAF. These data are consistent with a pivotal role for PAF as a mediator of anaphylaxis.

Concurrent blockade of platelet-activating factor and histamine prevents life-threatening peanut-induced anaphylactic reactions

BACKGROUND Food anaphylaxis is an acute and life-threatening systemic allergic reaction. Fatality registries place peanut as the most common culprit of fatal and near-fatal reactions in North America. Because prophylaxis and treatment have advanced little in recent years, it is imperative to evaluate novel therapies. OBJECTIVE To investigate the impact of blocking mast cell mediators in a mouse model of peanut-induced anaphylaxis. METHODS Mice were sensitized with peanut protein and cholera toxin via oral gavage weekly for 4 weeks. One week after the last sensitization, separate groups of mice were treated with either a (1) 5-lypoxygenase inhibitor, (2) a platelet-activating factor (PAF) receptor antagonist, (3) histamine receptor antagonists, or (4) a PAF receptor antagonist along with histamine receptor antagonists before peanut challenge. RESULTS Treatment targeting either leukotrienes or histamine alone had no beneficial effects. In contrast, PAF antagonism significantly attenuated the magnitude and duration of the anaphylactic reactions. Particularly, it prevented severe reactions. Moreover, 83% of PAF-treated versus 43% of untreated mice reached recovery within 120 minutes after peanut challenge. Notably, combined blockade of PAF and histamine had a clearly greater beneficial effect. In fact, all but 1 mouse developed mild, if any, anaphylactic reactions. In addition, combination therapy was associated with a significant decrease in vascular leakage and release of vasoactive mediators after peanut challenge. CONCLUSION Combination therapy blocking both PAF and histamine markedly reduces the severity of peanut-induced anaphylaxis, and thus it may be a potential life-saving therapeutic approach in peanut and, likely, other food-induced anaphylaxis.

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.

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.

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.

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.

Relationship between platelet activating factor acetylhydrolase activity and apolipoprotein B levels in patients with peanut allergy

BackgroundPlatelet-activating factor (PAF) is a highly potent phospholipid mediator responsible for the life-threatening manifestations of anaphylaxis. PAF acetylhydrolase (PAF-AH) inactivates PAF and protects against severe anaphylaxis whereas deficiency of PAF-AH predisposes to severe or fatal anaphylaxis. Determinants of PAF-AH activity have not been studied in patients with peanut allergy.ObjectivesTo determine whether plasma PAF-AH activity in patients with peanut allergy is related to formation of circulating complexes with apolipoprotein B (apoB) the main surface protein on low density lipoprotein particles.MethodsPlasma PAF-AH activity and apoB concentrations were measured in 63 peanut allergic patients (35 boys, 28 girls, ages 2 – 19 years). ApoB concentration was measured immunoturbidimetrically using goat anti-human apoB. The correlation between PAF-AH activity and apoB concentration was determined.ResultsA positive correlation was found between PAF-AH activity and apoB concentration (r2 = 0.59, P < 0.0001).ConclusionIn peanut allergic patients, PAF-AH activity strongly correlates with apoB concentration, suggesting the presence of circulating PAF-AH- lipoprotein complexes.

The platelet-activating factor pathway in food allergy and anaphylaxis

The synchronous release of multiple chemical mediators and their combined effects on target organs are responsible for the disruption of homeostasis seen in anaphylaxis. The exocytosis and release of these mediators collectively contribute to the multisystem manifestations of anaphylaxis, but clearly the actions of certain mediators appear to be more prominent and contribute disproportionately to severe and fatal outcomes.