Food-induced anaphylaxis and cofactors - data from the anaphylaxis registry.

Food allergens are frequent causes of anaphylaxis. In particular in children and adolescents they are the most frequent elicitors of severe allergic reactions, and in adults food allergens rank third behind insect venom and drugs. Since July 2006 severe allergic reactions from Germany, Austria, and Switzerland are collected in the anaphylaxis registry. Currently 78 hospitals and private practises are connected. From July 2006 until February 2009 1,156 severe allergic reactions were registered. Among children and adolescents (n = 187, age range from 3 months to 17 years) food allergens were the most frequent triggers, comprising 58% of cases. In the adult group (n = 968, 18 - 85 years) food allergens were in the third position (16.3%) behind insect venom and drugs. In children legumes (31%) and in particular peanuts were frequently responsible food allergens, followed by tree nuts (25%) with hazelnut being the most frequent elicitor. In adults fruits (13.4%) most often induced severe food-dependent anaphylaxis, but also animal products (12.2%); among these most frequently crustaceans and molluscs. Cofactors were often suspected in food-dependent anaphylaxis, namely in 39% of the adult group and in 14% of the pediatric group. In adults drugs (22%) and physical activity (10%) were reported to be the most frequent cofactors, in children physical activity was suspected in 8.7% and drugs in 2.6%. Concomitant diseases like atopic dermatitis, allergic asthma, or allergic rhinoconjunctivitis were reported in 78% of children and adolescents and in 67% of the adults. In conclusion, food-induced anaphylaxis, its cofactors and concomitant diseases are age-dependent. The data offers to identify risk factors of anaphylaxis.

Hemostatic changes following the modified Fontan operation (total cavopulmonary connection).

Thromboembolism is a serious complication after Fontan operation, which may be caused by alterations of the coagulation system. We therefore investigated pro- and anticoagulant factors in 20 patients aged 4 to 21 years, 4 to 63 months following total cavopulmonary connection. Furthermore we compared markers of thrombin activation and fibrinolysis and in vitro clotting and clot-lysis to age-matched healthy subjects. Compared to results of age-matched controls, the Fontan operated individuals had significant decreases in levels of protein C (0.88 U/ml in controls, 0.67 U/ml in patients; p <0.001) and protein S (1.05 in controls, 0.93 U/ml in patients; p <0.05). Moreover, half of the patients had high values of FVIII (>1.5 IU/ml), which are associated with an increased thrombotic risk. These changes may result in enhanced generation of thrombin and plasmin, indicated by our finding of increased thrombin-antithrombin III (TAT) and plasmin-antiplasmin (PAP) levels and a similar trend in prothrombin fragments F1+2. Clot lysis tests, global coagulation tests, red blood cell count, liver enzymes AST, ALT, but not GGT, were generally within the normal ranges.

Thrombolysis in newborns and infants.

This review analyses literature reports from 1970 to 1998 assessing the use of streptokinase (SK), urokinase (UK) or recombinant tissue-type plasminogen activator (rt-PA) for thrombolytic therapy in neonates and infants. From 1970 to 1998 182 infants were reported to have received SK (n = 54; 29.5%), UK (n = 41; 22.5%) or rt-PA (n = 87; 48%). During thrombolytic therapy no concomitant heparin administration or low dose heparin therapy (5 U/kg/h) were recorded. To perform reocclusion prophylactics heparin was reinitiated at the end of thrombolytic therapy usually in the recommended dosage of 20 U/ kg/h. The overall thrombolytic patency rate in neonates varied from 39% to 86%. Besides bleeding from local puncture sites or recent catheterisation sites (10.4%), pulmonary embolism was reported in 1.1% of the 182 infants. Major bleeding complications, i.e. pulmonary bleeding (0.6%), gastrointestinal bleeding (0.6%) or intraventricular haemorrhage (IVH 2.7%) are rarely reported side effects and only 2 thrombolysis related deaths due to haemorrhage were mentioned. Bleedings reported in the central nervous system (n = 4) mainly occurred in preterm infants (n = 3). In conclusion, data of this preliminary analysis suggest that there is no big difference (p = 0.09; chi2-test) in the efficacy rate between the 3 thrombolytic agents used in the first year of life. In each case an assessment must be made with respect to the relative benefit conferred by thrombolytic therapy in preventing organ or limb damage versus the potential side effects, costs and inconvenience for the childhood patient. Controlled prospective multicentre studies on thrombolytic therapy in neonates and infants are recommended to evaluate patency rates and adverse effects for the different thrombolytic agents used.

Incidence and significance of 22q11.2 hemizygosity in patients with interrupted aortic arch.

Interruption of the aortic arch (IAA) is a severe malformation of the heart with known association to DiGeorge syndrome (DGS) and 22q11.2 hemizygosity. The aim of this study was to establish incidence and significance of 22q11.2 hemizygosity in an unbiased sample of patients with IAA. All 15 children with IAA who were referred to our hospital in a 3-year period were tested by chromosome and fluorescence in situ hybridization (FISH) analysis with the probes D22S75, Tuplel, and cHKAD26 and by a set of 10 simple tandem repeat polymorphic (STRP) markers. In nine of 11 children with IAA type B, 22q11.2 hemizygosity was demonstrated by FISH and STRP analysis, but in none of the four children with type A. In all but one child, deletion size was approximately 3 Mb. The girl with the smaller deletion of approximately 1.5 Mb differed because of an Ullrich-Turner syndrome-like phenotype and severe T-cell defect. Additionally, in one patient with phenotypic signs of DGS, a small deletion distal to the known DGS region containing the marker D22S308 was suspected by STRP analysis. One deletion was shown to be inherited from a healthy father and one IAA type A recurred in a sib. T-cell anomalies were evident in eight of the nine children with classical deletion, five of whom suffered also from hypoparathyroidism. With respect to cause and clinical course, IAA type A and B were shown to represent different entities. This study showed that variable symptoms of 22q11.2 hemizygosity may cluster.

Emergency correction of coagulation for mitral valve replacement in an orally anticoagulated 17-year-old patient with pronounced hepatic dysfunction.

A 17-year-old patient with Shone's disease had to be readmitted to the hospital 3 months after implantation of an artificial aortic valve because of extreme mitral insufficiency with consecutive pulmonary edema and hepatic dysfunction. He had been orally anticoagulated and presented with a high international normalized ratio of 6.7. Emergency replacement of the mitral valve was possible only after administration of prothrombin-complex concentrate, as vitamin K(1) and fresh frozen plasma did not correct the hemostatic defect sufficiently.

Intermittent administration of furosemide versus continuous infusion in the postoperative management of children following open heart surgery.

OBJECTIVE: To compare the amount of furosemide needed to fulfil defined criteria for renal output if given intermittently or as a continuous infusion and to compare the effect of these two regimens on hemodynamic variables and urine electrolyte concentrations. DESIGN: Prospective randomized study of postoperative hemodynamically stable pediatric cardiac patients. The patients were given furosemide according to the urine output, either as an intermittent bolus injection or as a continuous infusion. SETTING: Pediatric intensive care unit in a university hospital. PATIENTS: The patients were randomly assigned before admission to either the intermittent i.v. or the continuous furosemide i.v. infusion group. MEASUREMENTS AND RESULTS: Demographic and hemodynamic data were recorded for a maximum of 72 h, as were furosemide dose, urine output, and fluid and inotropic drug requirements. Forty-six patients completed the study. Maximal hourly urine output was significantly higher in the intermittent group. A significantly lower dose of furosemide in the intermittent group produced the same 24-h urine volume as in the continuous infusion group. CONCLUSIONS: Intermittent furosemide administration may be recommended in hemodynamically stable postoperative pediatric cardiac patients because of less drug requirement. However, the high maximal urine output may cause hemodynamic problems in patients who depend on high inotropic support.

Age-related reference values for activation markers of the coagulation and fibrinolytic systems in children.

The physiology of the hemostatic system in infancy and childhood is different from that in adulthood. Despite differences in several components of the coagulation and fibrinolytic systems, there is no evidence that children are at greater risk for hemorrhagic or thrombotic problems compared with adults (1,2). Advances in understanding of the biochemistry of the hemostatic mechanism have led to the development of sensitive immunochemical methods for measuring peptides or enzyme-inhibitor complexes that are liberated with the activation of the coagulation and fibrinolytic systems in vivo (3). Activation markers of coagulation and fibrinolysis have been measured in newborns, infants and children with a variety of underlying disorders (4-16). However, reference ranges for children of different age groups have hitherto not been established. The aim of the present study was to document thrombin-antithrombin III-complex (TAT), prothrombin fragment 1 + 2 (F1 + 2), plasmin-alpha 2-antiplasmin-complex (PAP) and D-dimer in healthy children and to determine whether age-related differences can be demonstrated.

Percutaneous endovascular catheter aspiration thrombectomy of severe superior vena cava syndrome.

We report a combined percutaneous endovascular approach, including thrombus aspiration and catheter directed local thrombolysis, followed by systemic thrombolytic therapy to treat severe superior vena cava syndrome in a 2 and 1/2 week old infant. This procedure was performed on the fifth postoperative day after major surgery. No treatment complications were observed. The only predisposing condition for thrombosis was a central venous line. No other acquired or genetic risk factors for thrombosis could be found.

[Results of percutaneous transluminal angioplasty in renal artery stenosis during the period 1978-1986]. / Resultaten van percutane transluminale angioplastiek bij nierarteriestenosen in de periode 1978-1986.

UNLABELLED: Two hundred and thirteen patients with hypertension and renal artery stenosis were treated with percutaneous transluminal renal angioplasty (PTRA). The angiographic appearance was typical of atherosclerosis in 134 patients and of fibromuscular dysplasia (FMD) in 52 patients, and could not reliably be classified in one of these groups in 27. In these patients 272 renal artery stenoses were treated. In 81% of these patients the PTRA was technically successful. The antihypertensive result in this group of 210 patients was positive (cure or improvement) in 80%. The life-table results after 5 years show cure or improvement in the atherosclerotic group (n = 35) in 80.27%, in the FMD group (n = 20) in 88.83% and in the unclassified group (n = 10) in 74.27%. One patient died from a mesenteric thrombosis and one from a myocardial infarction which both occurred within a few days after PTRA. Accordingly, the mortality was less than 1%. IN CONCLUSION: PTRA appears to be a good treatment of renovascular hypertension caused by atherosclerosis or FMD, with good long-term antihypertensive effects.

Plasmatic [corrected] factor XIII reduces severe pleural effusion in children after open-heart surgery.

Chylous effusions frequently occur after cardiac surgery due to severe damage to the lymphatic system, thus indicating that the insertion of a chest tube may be necessary. Factor XIII (FXIII) is discussed as being essential for wound healing. The aim of this retrospective study was to evaluate whether the application of a single dose of FXIII results in a reduced amount of pleural effusion, leading to an earlier release of patients from the hospital. The cases of 40 children with severe chylous effusions after open-heart surgery were examined. Twenty patients received FXIII and were compared to 20 age- and weight-matched patients who did not receive FXIII. Major parameters included the amount of effusion before and 1 and 3 days after the application of FXIII; the duration of chest tubes; the total amount of fluid loss via drainage; and the period of hospitalization. FXIII levels in plasma showed an inverse correlation with fluid loss. After application of a single dose of FXIII, a significant reduction of pleural effusion within the first 24 hours was detected. However, no difference was observed between the two groups when comparing the total amount of pleural effusions within the first 72 hours. Finally, the duration of hospitalization did not differ between the FXIII-treated and the control group. A single application of FXIII rapidly reduces the amount of chylous effusions in the early period after open-heart surgery. This effect is detectable only for 24 hours after the treatment and does not alter the further clinical outcome. Prospective clinical trials are warranted to determine if repeated application or a higher dose of FXIII may improve the clinical outcome of chylous leakages in children after open-heart surgery.

The natural history of the immune response to exogenous factor VIII in severe haemophilia A.

The development of inhibitory antibodies to factor VIII (fVIII) in severe haemophilia A patients is a serious therapeutic complication. Using a highly sensitive immunoprecipitation (IP) assay which measures all anti-fVIII antibodies, we have tested severe haemophilic plasmas from two clinical studies. Inhibitor titres in the range of 0.4 to 1 Bethesda units/ml (BU/ml) could not be verified by IP as being due to an immune response to fVIII in 35% of plasmas tested. Low fVIII recoveries were likewise correlated with the presence of antibodies in 29% of plasmas tested. However, 16% of plasmas without inhibitor titres had immune responses as measured by IP. The rapidity of antibody appearance did not allow their effective detection by IP before development of inhibitor titres. These results suggest that the IP assay can provide a valuable confirmation of anti-fVIII antibody production when the Bethesda assay is low or negative and where clinical observations suggest their presence, but they cannot be used reliably to detect early immune responses.

Low factor VIII recovery in haemophilia A patients without inhibitor titre is not due to the presence of anti-factor VIII antibodies undetectable by the Bethesda assay.

Measurements of factor VIII (FVIII) recovery in previously untreated patients with haemophilia A were done as part of the clinical trial of safety and efficacy of the recombinant FVIII, Recombinate. In 22 of 72 assessable patients, positive inhibitor titres > or = 0.6 Bethesda units mL-1 were detected by the Bethesda assay in one or more plasma samples, and the remaining 50 patients were negative at all timepoints. Of the latter group, 16 individuals without inhibitors unexpectedly had both normal (111) and low (52) recoveries during the study. We investigated the possibility that other antibodies not detectable in the Bethesda assay were responsible for the low recovery, by using a highly sensitive immunopreciptation (IP) assay for detection of all antiFVIII antibodies. Eight of the 16 patients with low and normal recoveries did indeed have antibodies detected by the IP assay, and the remaining eight were negative. Four antibody-positive individuals had insignificantly low titres, and the other four had modest to high titres. In the latter group, antibodies were found with similar frequencies and titre in plasmas from patients with low or normal recovery. Low recovery in haemophilia A patients without inhibitor titres must therefore be attributed to factors other than antiFVIII.

Detection of all anti-factor VIII antibodies in haemophilia A patients by the Bethesda assay and a more sensitive immunoprecipitation assay.

Plasmas from 40 haemophilia A patients enrolled in a study by the paediatric group of the German Society on Thrombosis and Hemostasis were tested by the Bethesda assay for inhibitor antibodies and by a more sensitive immunoprecipitation assay (IP) for all antifactor VIII antibodies. Of the 26 severe, 11 moderate and three mild haemophiliacs, 18, two, and none, respectively, had positive Bethesda titres after several factor VIII infusions. In 275 plasmas with Bethesda titres of 0, 0.6--1.0, > 1--5, and > 5--655, the IP responses were 0-238, 0--61, 0--786, and 43--6141, respectively, and a reliable positive IP titre was > 4.2. The overlapping ranges of IP titres indicated large differences in the ratio of inhibitory to noninhibitory antibodies in individual plasmas. In five of seven patients with Bethesda titres of 0.6--1, the IP titres were < 4.2, suggesting a lack of precision of Bethesda titres < or = 1. Detection of the primary immune response was found in only three patients by IP assay before a positive Bethesda assay. This precludes early, reliable testing of which patients will be immunologically responsive. In four patients undergoing immune tolerance therapy, antifactor VIII antibodies were still detectable by the IP assay in the absence of a Bethesda titre, which indicates that antibodies were completely eradicated in none of the patients. Our results show that the use of both the Bethesda and IP assays can provide more accurate detection of antifactor VIII antibodies in all patients.

Overwhelming postsplenectomy infection with vaccine-type Streptococcus pneumoniae in a 12-year-old girl despite vaccination and antibiotic prophylaxis.

This report describes a 12-year-old girl who developed vaccine-type pneumococcal septicemia (type 4, Danish nomenclature) 2 years after splenectomy for recurrent idiopathic thrombocytopenia despite vaccination with the 23-valent vaccine 4 weeks before surgery and antibiotic prophylaxis with penicillin V. The disease presented as high fever with shivering and vomiting followed by disseminated petechiae and a deteriorated general condition. Initial laboratory studies showed severe sepsis with leucocytopenia and thrombocytopenia, a markedly elevated CRP, and disseminated intravascular coagulation. Despite antibiotic treatment, which was initiated with clindamycin, cefotaxime and trimethoprim/sulfamethoxazole and was switched to cefotaxime and penicillin after the result of the blood culture had been obtained, the patient had to be ventilated, and hemofiltration became necessary because of acute renal insufficiency. Furthermore, she required amputation of all her toes because of severe necrosis. No type-specific pneumococcal antibody titers were detected during and after infection. It remains unclear whether the susceptibility to Streptococcus pneumoniae was due to primary failure of antibody production or a decline in antibody levels after vaccination. Patients and/or their relatives should be informed that neither vaccination nor continuous antibiotic prophylaxis can guarantee full protection against infection with S. pneumoniae in patients after splenectomy.

[Life threatening menorrhagia in thrombasthenia. (Glanzmann-Naegeli) thrombasthenia]. / Lebensbedrohliche Menorrhagie bei Thrombasthenie. (Thrombasthenia Glanzmann-Naegeli).

Glanzmann's Thrombasthenia is a rare inherited disorder of platelet aggregation with normal platelet count and humoral coagulation. It is caused by the deficiency or functional disorder of platelet membrane glycoproteins IIb und IIIa. This complex is considered to be a receptor for fibrinogen. Menorrhagia often occurs as a clinical manifestation of affected females. We report a case of severe menorrhagia in a 13-year-old girl during her third menstrual cycle. She needed several red blood cell transfusions. The bleeding could only be stopped by administration of Lynestrenol.

Age-related differences in a clot lysis assay after adding different plasminogen activators in a plasma milieu in vitro.

PURPOSE: The fibrinolytic system is involved in a wide variety of biological phenomena and differs physiologically in newborns compared to older children or adults. Because the newborn has hypoplasminogenemia and a possible existence of a dysfunctional plasminogen with normal adult levels of plasminogen activator inhibitor type 1 and alpha 2-antiplasmin and elevated levels of plasminogen activator inhibitor type 2, it could be expected that the response to standard concentrations and doses of plasminogen activators would be reduced. PATIENTS AND METHODS: We have studied the kinetics of in vitro fibrinolysis after adding different concentrations of streptokinase(SK), urokinase(UK), and recombinant tissue plasminogen activator(rt-PA) by use of a microtiter clot lysis assay. RESULTS: Geometrical dilution rows showed characteristic dose response curves. After clot formation a rapid lysis was seen with all plasminogen activators. The 50% lysis time correlated to the plasminogen activator dose and showed no differences among normal adults, children aged 1-6 years, and children age 7-14 years. Newborns demonstrated a significantly prolonged 50% lysis time with all urokinase concentrations. The 50% lysis time with recombinant tissue plasminogen activator and streptokinase was significantly prolonged only at high concentrations, whereas we could not see any differences at lower concentrations. CONCLUSION: The experience with thrombolytic agents in newborns is limited, and no controlled investigations have been reported. Our results of the fibrinolytic potential in a plasma milieu in vitro after adding different plasminogen activators can be helpful to establish dosage guidelines for thrombolytic therapy in newborns and older children.