Histamine anaphylaxis

The answers are 25-e, 26-b, 27-a. (Hardmanr pp 67—68. Katzung, pp 30, 134.) Anaphylaxis refers to an acute hypersensitivity reaction that appears to be mediated primarily by immunoglobulin E (IgE). Specific antigens can interact with these antibodies and cause sensitized mast cells to release vasoactive substances, such as histamine. Anaphylaxis to penicillin is one of the best-known examples the drug of choice to relieve the symptoms is epinephrine. 

Chloro-oxazolo[4,5-/i]quinoline-2-carboxylic acid methyl ester was the most active compound in tests for inhibitors of antigen-induced release of histamine in vitro from rat peritoneal mast cells (IC50 of 0.3 p,M) and as inhibitors of IgE-mediated passive cutaneous anaphylaxis in the rat (ED50 (intraperitoneal) of 0.1 mg/kg in dose 0.5 mg/kg as an inhibitor of the test)—10 times and 60 times more potent, respectively, than the disodium salt of cromoglycic acid (85JMC1255). 

There are also other immimological mechanisms, especially via IgG or IgM antibodies with immune complex formation, which can lead to similar clinical conditions [20, 34, 42] as has been shown in dextran anaphylaxis (table 1). Triggering of mast cells and basophils leads to release of various vasoactive mediators, among which histamine was the first recognized in 1908 (fig. 3,4) [6]. 

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]. 

Few prospective studies of induced anaphylaxis have been performed in human subjects to imderstand the molecular basis of systemic anaphylaxis, because of the potentially rapid, Ufe-threatening outcome. Accordingly, various models of anaphylaxis have been estabUshed in laboratory animals, particularly mice, and extensively studied to clarify the underlying mechanisms. Such studies revealed that the classical pathway utilizing mast cells, IgE and histamine cannot explain all cases of anaphylaxis. 

Fig. 2. IgG-mediated systemic versus local anaphylaxis, a IgG-mediated systemic anaphylaxis. When allergen-IgG immune complexes are formed in the circulation, basophils immediately capture them through IgG receptors on their surface and are activated to release PAF, that in turn act on vascular endothelial cells, leading to increased vascular permeability, b Passive cutaneous anaphylaxis. When allergen-IgG immune complexes are formed in the skin, they stimulate tissue-resident mast cells to release chemical mediators such as histamine, leading to local inflammation. 

Basophils Release Platelet-Activating Factor Instead of Histamine to Induce IgG-Mediated Systemic Anaphylaxis... 

Studies have now started to clarify the role of histamine Hi and H2 receptors in the cardiovascular manifestations of anaphylaxis. However, histamine can activate H3 and H4 receptors [56, 57]. Levi and coworkers [58-60] identified H3 receptors as inhibitory heteroreceptors in cardiac adrenergic nerve endings. This suggests a mechanism by which endogenous histamine can activate norepinephrine release in normal and ischemic conditions [61,62]. The functional identification ofH3 receptors in the human heart [59] means that these receptors might be directly and/or indirectly involved in the cardiovascular manifestations of anaphylactic reactions. 

Vigorito C, Russo P, Picotti GB, Chiariello M, Poto S, Marone G Cardiovascular effects of histamine infusion in man. J Cardiovasc Pharmacol 1983 5 531. Patterson LJ, Milne B Latex anaphylaxis causing heart block role of ranitidine. Can J Anaesth 1999 46 776. 

Mast cells express high-affinity IgE Fc receptors (FceRI) on their surface, contain cytoplasmic granules which are major sources of histamine and other inflammatory mediators, and are activated to release and generate these mediators by IgE-dependent and non-IgE-dependent mechanisms [1]. Disturbances either in the release of mast cell mediators or in mast cell proliferation are associated with clonal mast cell disorders including monoclonal mast cell activation syndrome (MMAS) and mastocytosis respectively, which are in turn associated with some cases of anaphylaxis [2], Molecular mechanisms have been identified which may link increased releasability of mast cell mediators and conditions leading to increased mast cell numbers [3]. Patients with mastocytosis have an increased risk to develop anaphylaxis [4, 5] and those with anaphylaxis may suffer from unrecognized mastocytosis or may display incomplete features of the disease [6-8]. 

If patients have experienced anaphylaxis, the identification of any possible elicitor is important to help avoid further episodes. With skin tests and specific IgE antibodies combined with history, a relevant allergy may be detected. Cellular tests monitoring basophil histamine release or basophil activation may be helpful in some patients who resist diagnosis by standard means [26,31]. 

The latest consensus on the definition and management [1] of anaphylaxis agrees on the lack of imiversally accepted diagnostic criteria and reliable laboratory biomarkers to confirm the clinical impression. Sometimes it is not feasible to obtain the samples within the optimum time frame. Moreover, in spite of a correct collection of samples, histamine and/or tryptase are within normal levels. Hence, new markers should be explored and further research into the role of selected mediators is urgently needed. Recently however, studies from animal models have shown promising results. In this chapter we will seek to review our current knowledge on confirmed or putative markers for the in vitro diagnosis of 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. 

Finally, it is worth mentioning that tryptase levels do not differentiate between immunologic and non-immimological mast cell activation and do not contribute to the identification of the cause of the anaphylactic reaction. To date, very few mediators [10] apart from histamine and tryptase have been investigated as markers for anaphylaxis. Recent studies also include other mediators that we will only examine briefly. A more extensive review can be found elsewhere [2,11]. 

The detection of reactions mediated by specific IgE to agents triggering anaphylaxis may be achieved by means of serological methods serum-specific IgE, or by means of cellular tests which determine the release of basophil mediators (leukotrienes and histamine) or by means of the analysis of basophil expression markers, a technique known as the basophil activation test (BAT). 

As immediately after the reaction, elevated plasma histamine and serum or plasma tryptase levels of histamine and tryptase have been found [31, 34], an anaphylaxis may be confirmed by blood samples for histamine analysis drawn as soon as possible after the reaction and for tryptase drawn 1-2 h after onset of symptoms [31]. Tryptase values have to be compared to baseline levels. 

Opioids. Reactions to morphine, codeine phosphate, meperidine, fentanyl and its derivatives are uncommon. Because of their direct histamine-releasing properties, especially regarding morphine and codeine, distinction between anaphylaxis and non-immune-mediated histamine release is not always easy. Only 12 cases were recorded in the last 2 years epidemiologic survey in France, 9 of them being related to morphine administration [9]. 

Histamine concentrations are maximal almost immediately, decrease thereafter with a half-life of about 20 min, and should be assayed within the first hour of a reaction. The sensitivity of this test for the diagnosis of anaphylaxis was estimated at 75%, the specificity at 51%, the positive predictive value at 75% and the negative predictive value at 51%. Tryptase reaches a peak in the patient s serum 30 min after the first clinical manifestations. Its half-life is 90 min, and the levels usually decrease over time. In a recent series, the sensitivity was estimated at 64%, specificity at 89.3%, positive predictive value at 92-95%, and negative predictive value at 54.3% [9]. 

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

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]. 

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