Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase.

BACKGROUND: Severe side effects during venom immunotherapy (VIT) are associated with a variety of risk factors. OBJECTIVE: Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters, which are routinely recorded during patient evaluation, with the frequency of severe reactions requiring an emergency intervention during the buildup phase of VIT. METHODS: In this observational prospective multicenter study, we enrolled 680 patients with established honeybee or vespid venom allergy who underwent VIT. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, degree of preceding sting reaction, preventive antiallergic medication before therapy, time between last preceding sting reaction and VIT, venom specific IgE concentration, and type of buildup procedure. Relative rates were calculated with generalized additive models. RESULTS: Fifty-seven patients (8.4%) required an emergency intervention during buildup because of a severe systemic reaction. The frequency of interventions increased significantly with higher BTC (log-linear association; adjusted odds ratio, 1.56; 95% CI, 1.15-2.11; P < .005). The predictive power of BTC was markedly greater when VIT was performed for vespid venom allergy than for bee venom (for bee VIT, no significant association; for vespid VIT, log-linear association; adjusted odds ratio, 2.33; 95% CI, 1.28-4.26; P = .005). The most important other factor significantly associated with severe reactions during the buildup phase of VIT was bee venom allergy. CONCLUSION: Before vespid VIT, measurement of baseline serum tryptase concentration should be used to identify patients with a high risk for side effects. Patients with bee venom allergy require a particularly high degree of surveillance during VIT.

Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase-a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity.

BACKGROUND: Severe anaphylaxis to honeybee or vespid stings is associated with a variety of risk factors, which are poorly defined. OBJECTIVE: Our aim was to evaluate the association of baseline serum tryptase concentrations and other variables routinely recorded during patient evaluation with the frequency of past severe anaphylaxis after a field sting. METHODS: In this observational multicenter study, we enrolled 962 patients with established bee or vespid venom allergy who had a systemic reaction after a field sting. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, and the number of preceding minor systemic reactions before the index field sting. A severe reaction was defined as anaphylactic shock, loss of consciousness, or cardiopulmonary arrest. The index sting was defined as the hitherto first, most severe systemic field-sting reaction. Relative rates were calculated with generalized additive models. RESULTS: Two hundred six (21.4%) patients had a severe anaphylactic reaction after a field sting. The frequency of this event increased significantly with higher tryptase concentrations (nonlinear association). Other factors significantly associated with severe reactions after a field sting were vespid venom allergy, older age, male sex, angiotensin-converting enzyme inhibitor medication, and 1 or more preceding field stings with a less severe systemic reaction. CONCLUSION: In patients with honeybee or vespid venom allergy, baseline serum tryptase concentrations are associated with the risk for severe anaphylactic reactions. Preventive measures should include substitution of angiotensin-converting enzyme inhibitors.

[GERD and respiratory tract diseases]. / GERD a choroby ukladu oddechowego.

Gastroesophageal reflux disease (GERD) depends on acid reflux into the distal oesophagus. The typical symptoms of GERD are heartburn, dysphagia, chest discomfort and acid regurgitation. Besides typical symptoms GERD could by manifested by extraesophageal signs. There is increasing number of studies showing that GERD and respiratory diseases coexist frequently.

The concentration of kynurenine in rat model of asthma.

Asthma is a chronic inflammatory disease that involves the immune system activation. Evidence is accumulating about the role of kynurenine pathway in the immune system regulation. The kynurenine pathway includes several metabolites of tryptophan, among others kynurenine (KYN). To study the immunological system regulation in asthma a simple and sensitive models of asthma are required. In the present study we induced rat model of asthma using ovalbumin (OVA) sensitization followed by challenge with OVA. The development of asthma has been confirmed by plasma total IgE measurement and the histological examination. The concentration of KYN has been determined in plasma, lungs and liver by high-performance liquid chromatography (HPLC). In OVA sensitized rats the concentration of total IgE was statistically significantly increased as compared to VEH sensitized control groups (437.6 +/- 97.7 kU/l vs 159.2 +/- 22.7 kU/l, respectively; p< 0.01). In asthmatic animals, the number of eosinophils, neutrophils and mast cells increased considerably, and epithelial lesion and the increase in airway epithelium goblet cells and edema of bronchial mucosa were present. We did not observe any significant changes in the concentration of KYN in plasma, lungs or liver between studied groups. In conclusion, the concentration of KYN remains unchanged in asthmatic animals as compared to control groups. Further studies using rat model of asthma are warranted to establish the role of kynurenine pathway regulation in asthma.

Experimental asthma in rats.

Animal models of asthma have been used for over 100 years. The accuracy of extrapolations from animal models to human asthmatics is highly dependent on the species of animal selected. The rat, in comparison with other animals, demonstrates many features of airway allergy and allergic asthma that are similar to the human conditions. The following features of human asthma can be effectively investigated in a rat model of the disease: cellular infiltration of the lung, antigen-specific IgE production, and a predominant Th2 response. The majority of available models of asthma are restricted to the acute inflammatory response following a short period of allergen exposure. The frequently used model of ovalbumin (OVA) sensitization and challenge replicates the inflammatory process in the airways.

[Thrombin activatable fibrinolysis inhibitor (TAFI) in allergic asthma patients]. / Aktywowany trombina inhibitor fibrynolizy (TAFI) w astmie alergicznej.

Increased thrombin generation occurs in the airways of asthmatic patients. Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme which after activation by a thrombin-thrombomodulin complex inhibits fibrinolysis. The aim of this study was to evaluate TAFI concentration and activity in plasma of bronchial asthma patients challenged with Dermatophagoides pteronyssinus (Dp) extracts. The study was performed on 23 asthma patients mean age 28.7 +/- 9.8 years with a typical history and positive skin prick test with Dp allergens. Seventeen patients developed both early asthmatic reaction (EAR) and late asthmatic reaction (LAR), 6 patients developed only EAR. Blood was collected before allergen challenge (AO), 1 (A1), 8 (A2) and 24 hours (A3) after allergen challenge. Five healthy persons, mean age 24.5 +/- 3.6 years with negative skin prick tests to common aeroallergens served as negative controls. Healthy controls underwent sham bronchial provocation with 0.9% solution of NaCl. TAFI antigen and activity, levels of thrombin-antithrombin III complexes (TAT) and prothrombin fragments F 1+2 were measured in plasma by ELISA method. At A0 in dual responders mean TAFI concentration (101.4 +/- 23.82%) and activity (19.6 +/- 5.92 microg/ml) were higher than in healthy controls (69.35 +/- 21.49%; p < 0.05 and 10.49 +/- 3.53 microg/ml; p = 0.01; respectively). Significant fall in TAFI plasma concentration was detected at A1 and the decreased concentration of TAFI persisted until A3 (85.15 +/- 26.36%; p < 0.05). No significant change in plasma TAFI concentration was observed in healthy controls or in patients who responded with an EAR only. Allergen induced inflammation is associated with significant changes in plasma TAFI concentration.

[Tissue factor and tissue factor pathway inhibitor during specific bronchial challenge in allergic asthma patients]. / Czynnik tkankowy i inhibitor zewnatrzpochodnej drogi krzepniecia w czasie swoistej próby prowokacyjnej u chorych z astma, alergiczna.

Allergic asthma is characterized by bronchial inflammation and repair processes at the same time, that cause increased airway obstruction. Recent evidences suggest that monocytes and macrophages may play important role in allergic inflammation. Activated by proinflammatory factors they can express tissue factor (TF) and tissue factor pathway inhibitor (TFPI). The aim of the present study was to evaluate TF and TFPI in plasma of bronchial asthma patients. The study was performed on 17 asthma patients with documented Dermatophagoides pteronyssinus (Dp) allergy. 15 healthy persons served as negative control. Specific bronchial challenge with Dp extracts was performed in asthma patients. Blood was collected before allergen challenge--A0, during the early asthmatic reaction (EAR)--A0 during the late asthmatic reaction (LAR)--A2, and 24 hours after administration of the first allergen dose--A3. The concentrations of TF and TFPI were measured by ELISA method. The concentration of TF in asthmatic patients was significantly higher as compared with healthy controls. In patients that developed only EAR, the concentration of TF increased at A1, then decreased at time when LAR should be developed (A2) and it was comparable with beginning values 24 hours after starting the challenge. In patients that developed EAR and LAR, the mean TF concentration increased during EAR (A,) with subsequent decline during LAR (A2). 24 hours after starting the challenge the TF concentration was higher than beginning values (A3). The concentration of TFPI in patients that developed only EAR was significantly higher than the values in healthy controls. It decreased during EAR (A1) and increased 24 hours after starting the challenge (A3). The mean concentration of TFPI in patients that developed EAR and LAR was not significantly higher than the values in healthy controls. It increased during EAR and LAR with the highest values 24 hours after starting the challenge. Coagulation system seems to be activated during allergic inflammation after allergen challenge. Increased levels of TF and TFPI in asthma patients may be connected with chronic bronchial inflammation and remodeling of bronchial wall.

Antithrombotic effect of captopril and enalapril in young rats.

Angiotensin converting enzyme inhibitors (ACE-Is) are the main drugs used in the treatment of essential hypertension and congestive heart failure in adults. Recently, we have demonstrated the antithrombotic effect of captopril (CAP) and enalapril (ENA) in venous thrombosis model in adult rats. One might also suggest the beneficial effect of those drugs on hemostasis in young individuals. Two months old male Wistar rats were used in the study. Acute administration of CAP at a dose of 50 and 100 mg kg(-1) significantly reduced the venous thrombus weight. Dose-dependent reduction in the thrombus weight was also observed in ENA (3, 10, 30 mg kg(-1))-treated rats. Strong reduction in the thrombus weight was also seen after chronic administration of CAP (2 x 25 mg kg(-1)) and ENA (1 x 15 mg kg(-1)). Both drugs given chronically reduced the frequency of thrombi. Systolic blood pressure was reduced to similar extent after acute and chronic application of the drugs. CAP shortened euglobulin clot lysis time (ECLT) when given acutely (100 mg kg(-1)) and chronically (2 x 25 mg kg(-1)). ENA decreased ECLT only when given at multiple doses (1 x 15 mg kg(-1)). None of the drugs changed prothrombin time or activated partial tromboplastin time. We conclude that CAP and ENA possess antithrombotic effect in young individuals. Activation of the fibrinolytic pathway seems to play an important role in the mechanism of their antithrombotic action.

Nitric oxide-dependent antiplatelet action of AT1-receptor antagonists in a pulmonary thromboembolism in mice.

The aim of this study was to determine whether AT1-receptor antagonists could inhibit platelet activation-dependent pulmonary thromboembolism in mice and to investigate the involvement of nitric oxide in this action. Losartan, its active metabolite EXP3174, and valsartan given intraperitoneally 1 hour before the thrombotic challenge (in doses of 3, 10, or 30 mg/kg) protected mice from death or hind-limb paralysis in response to intravenous injection of a mixture of collagen and epinephrine; losartan was effective in all doses used, whereas EXP3174 and valsartan reduced mortality only in the two higher doses. The protective action of EXP3174 and valsartan was abolished when nitric oxide synthase was inhibited with l-NAME, whereas that of losartan was only partially reduced. Moreover, only losartan protected mice from death caused by intravenous injection of the thromboxane A2 mimetic U46619 and this action was preserved in l-NAME-pretreated animals. Our results demonstrate the ability of AT1-receptor antagonists to inhibit platelet activation in vivo in a nitric oxide-dependent mechanism. Stronger antiplatelet activity of losartan, most likely due to its blockade of thromboxane A2/prostaglandin H2 receptor, could be of potential clinical relevance, particularly in conditions in which synthesis of endogenous nitric oxide is impaired.

The plasmin system in airway remodeling.

Recent studies suggest that the plasmin system plays an active role in tissue remodeling. Plasmin degrades the extracellular matrix (ECM), either directly removing glycoproteins from ECM or by activating matrix metalloproteinases (MMPs). PAI-1 blocking MMPs may prevent ECM degradation, but inhibiting fibrinolysis leads to fibrin accumulation and fibrosis. Components of the plasmin system including tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), and plasminogen activator inhibitors PAI-1 and PAI-2 are synthesised by airway cells, and inflammatory mediators affect their expression. The plasmin system, in turn, actively influences the production of inflammatory mediators and growth factors, extending pathological structural changes in the airway. Modulation of the plasmin system might be a new pharmacological strategy that could inhibit the development of airway remodeling.

Antithrombotic effect of captopril and losartan is mediated by angiotensin-(1-7).

It is well established that renin-angiotensin system blockers exert NO/prostacyclin-dependent antithrombotic effects. Because some beneficial effects of these drugs are mediated by angiotensin (Ang)-(1-7), in the present study we examined if their antithrombotic action could be mediated by Ang-(1-7). Intravenous infusion of Ang-(1-7) (1, 10, or 100 pmol/kg per minute for 2 hours) into rats developing venous thrombosis caused 50% to 70% reduction of the thrombus weight. This effect was dose-dependently reversed by cotreatment with A-779 (selective Ang-[1-7] receptor antagonist) or EXP 3174 (angiotensin type 1 receptor antagonist) but not by PD 123,319 (angiotensin type 2 receptor antagonist). Similarly, the antithrombotic effects of captopril (ACE inhibitor) and losartan (angiotensin type 1 receptor blocker) were attenuated by A-779 in a dose-dependent manner. The effect of Ang-(1-7) was completely abolished by concomitant administration of NO synthase inhibitor (N(G)-nitro-L-arginine methyl ester) and prostacyclin synthesis inhibitor (indomethacin), as has been shown previously for captopril and losartan. Thus, the antithrombotic effect of renin-angiotensin system blockers involves Ang-(1-7)-evoked release of NO and prostacyclin.