In anaphylaxis

The role of atopy in anaphylaxis has not completely been resolved. On the one hand there is for example no evidence of a higher risk of severe reactions in venom-allergic patients. A recent study by Sturm et al. [38] indicated that patients with high total IgE levels predominantly developed mild to moderate reactions. By contrast, atopy may increase the risk and severity of systemic reactions in beekeepers and their family numbers [39]. On the other hand, atopy and in particular allergic asthma are risk factors for food allergy and therefore are also important risk factors for food-induced anaphylaxis. This is most likely also true for exercise-induced anaphylaxis, but also non-IgE-dependent anaphylaxis induced by NSAIDs or contrast media. 

The route of antigen administration can alter the speed of antigen access to the circulation and, thus, the systemic symptoms in anaphylaxis models. For example, allergen ingestion typically induces anaphylaxis that includes gastrointestinal symptoms, such as diarrhea [4]. These intestinal anaphylaxis models in mice are dependent on IgE-induced mast cell activation, and the release of PAF and serotonin (rather than histamine) [1,4]. 

Simons FE, Frew AJ, Ansotegui IJ, Bochner BS. 8 Golden DB, Finkelman FD. Leung DY. Lotvall J. Marone G, Metcalfe DD. Muller U, Rosenwasser LJ. Sampson HA. Schwartz LB. van Hage M, Walls AF 9 Risk assessment in anaphylaxis current and future approaches. J Allergy Clin Immunol 2007 120 S2-S24. lO... 

Anaphylaxis is the most dramatic and potentially catastrophic manifestation of allergic disorders. It can affect virtually any organ including the cardiovascular system. Cardiovascular collapse and hypotensive shock in anaphylaxis have been attributed to peripheral vasodilation, enhanced vascular permeability and plasma leakage, rather than any direct effect on the myocardium. However, there is increasing experimental and clinical evidence that the human heart is a site and target of anaphylaxis. 

In conclusion, these in vitro and in vivo studies clearly indicate that the human heart can be viewed as both a site and a target in anaphylaxis. 

Histamine is a critical mediator in anaphylactic reactions. It is a diamine produced by decarboxylation of the amino acid histidine in the Golgi apparatus of mast cells and basophils. Once secreted, it is rapidly metabolized by histamine methyltransferase [2]. Plasma histamine levels are elevated in anaphylaxis, reaching a concentration peak at 5 min and declining to baseline by 30-60 min [3]. Therefore, histamine samples for assessing an anaphylactic reaction should be obtained within 15 min of the onset of the reaction. Urinary metabolites of histamine may be found for up to 24 h. 

Two immunoassays have been developed to measure tryptase in human fluids, one that measures mature a/(3-tryptases, i.e. total tryptase, available commercially, and one developed by Schwartz et al. [7] that measures both mature (3-tryptase and immature a/(3-tryptases. This distinction is of clinical relevance since immature tryptases reflect mast cell burden whereas mature tryptases indicate mast cell activation. Thus, for the diagnosis of anaphylaxis it would be extremely important to be able to differentiate between acute anaphylaxis and increases in tryptase due to increase in numbers of mast cells as happens in mastocytosis. Total tryptase would be high in both conditions, whereas mature tryptase will be only high in anaphylaxis but negligible in mastocytosis. 

Schwartz LB Diagnostic value of tryptase in anaphylaxis and mastocytosis 2. Immunol Allergy Clin North Am 2006 26 451-463. 

Risk assessment in anaphylaxis current and future approaches. J Allergy Clin Immunol 2007 120(suppl) ... 

While in anaphylaxis caused by other frequent elicitors like food and drugs, allergen-specific immunotherapy is not established, immimotherapy with Hymenoptera venoms has been shown to be effective in three prospective controlled trials (table 4) [38-40] and also in a number of studies where patients were submitted to a sting challenge with the responsible insect during venom immimotherapy (table 5) [44]. While over 90% of vespid venom-allergic patients are fully protected and do not develop any... 

Hj-antagonists alone, such as cimetidine or ranitidine, have a modest effect on cutaneous flush reaction and maybe also on the heart [14, 52]. However, when applied they should be given together with Hj-antagonists. There are some studies showing a beneficial effect of combined H - and Hj-antagonist treatment or pretreatment in anaphylaxis [46, 53]. 

Winbery SL, Lieberman PL Histamine and antihistamines in anaphylaxis. Clin Allergy Immunol 2002 17 287-317. 

Marone G, Bova M, Detoraki A. Onorati AM. Rossi FW, Spadaro G The human heart as a shock organ in anaphylaxis. Novartis Found Symp 2004 257 133-149. 

In this review, we will describe the pharmacologic activity of epinephrine in anaphylaxis, the evidence base for its use, epinephrine dosing and routes of administration, epinephrine autoinjector use in first-aid treatment, reasons for failure to inject epinephrine promptly, reasons for occasional apparent lack of response, and future directions in epinephrine research. 

Strength of recommendation for use as initial treatment of first choice in anaphylaxis ... 

With regard to epinephrines potential adverse cardiac effects, it is important to remember that in anaphylaxis, the heart is a target organ. Mast cells located between myocardial fibers, in perivascular tissue, and in the arterial intima are activated through IgE and other mechanisms to release chemical mediators of inflammation, including histamine, leukotriene C4, and prostaglandin D2. Coronary artery spasm, myocardial injury, and cardiac dysrhythmias have been documented in some patients before epinephrine has been injected for treatment of anaphylaxis, as well as in patients with anaphylaxis who have not been treated with epinephrine [11, 12]. 

Given the unexpected occurrence of anaphylaxis, the rapidity with which symptoms evolve after exposure to the trigger, and the observation that delay in epinephrine injection is associated with fatality [15, 16], randomized controlled trials of epinephrine in anaphylaxis will not be easy to conduct however, it is time to consider the possibility of performing such trials. Future directions with regard to studies of the optimal dose and optimal route of administration of epinephrine in anaphylaxis that do not involve a placebo control will be outlined at the end of this review [17]. 

Epinephrine is administered by a variety of different routes in anaphylaxis, except for the oral route, which is not feasible because of rapid inactivation of epinephrine in the gastrointestinal tract by catechol-O-methyltransferase and monoamine oxidase [9]. The initial intramuscular epinephrine doses of 0.3-0.5 mg currently recommended for adults with anaphylaxis are low compared with the doses required for resuscitation following cardiac arrest [1, 2,4,18]. 

In anaphylaxis, epinephrine appears to have an optimal benefit-to-risk ratio when it is administered promptly by intramuscular injection [1-6]. 

There are no new medications available for the acute treatment of anaphylaxis [17]. Epinephrine, with its multiple relevant life-saving pharmacologic actions, is likely to remain the initial drug of choice in anaphylaxis for the foreseeable future. 

Ongoing epinephrine research relevant to human anaphylaxis is critically important. In its absence, the use of epinephrine in anaphylaxis treatment in the 21st century will continue to be based mostly on clinical experience, or worse, on expedience, instead of on clinical science. 

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