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.

Severe pulmonary hypertension in a neonate caused by premature closure of the ductus arteriosus following maternal treatment with diclofenac: a case report.

The administration of non-steroidal antiinflammatory drugs (NSAID) has occasionally been related to fetal and neonatal cardiopulmonary, gastrointestinal, cerebral and renal complications. This report describes a term newborn with severe persistent pulmonary hypertension due to premature closure of the ductus arteriosus following a 5 day maternal treatment with diclofenac two weeks before delivery. Pulmonary hypertension only responded to unusually high doses of inhaled NO. The treatment was necessary for 22 days suggesting structural alteration of pulmonary vasculature. The child recovered, but tricuspid regurgitation persisted, presumably because of irreversible ischemic damage of one papillary muscle. This is the first reported case of persistent pulmonary hypertension of the newborn (PPHN) in association with maternal diclofenac treatment and represents a most severe form of PPHN induced by NSAID.

Prevalence and outcome of intracranial haemorrhage in haemophiliacs--a survey of the paediatric group of the German Society of Thrombosis and Haemostasis (GTH).

UNLABELLED: A survey among centres of the paediatric group of the GTH was performed to evaluate the prevalence and outcome of haemophiliacs with intracerebral haemorrhage. A questionnaire sent to the centres covered the following points: number of patients with severe, moderate and mild haemophilia A and B; for each patient with ICH: birth date, age at bleeding, aetiology and neurological sequelae. Overall, 30 ICH in 744 haemophiliacs (4.0%) were reported by 17/40 centres (42.5%). There was no significant difference between the prevalence of patients with haemophilia A and B (3.5% vs. 6.3%) and among the age groups. Bleeding was diagnosed within 1 week of birth in 11/27 patients (41%). For 3 patients, no age-related information was given. The most important factor was trauma (17/30 = 57%), either during birth (9/30 = 30%) or later in life (8/30 = 27%). Seizures were common, occurring in 19/30 patients (63%). As 1 patient died after posttraumatic ICH, the neurological outcome of 29 patients could be evaluated. Psychomotor and statomotor retardation and cerebral palsy were reported in 17/29 (59%), 15/29 (51%) and 13/29 (45%) patients respectively. Only 7/29 (24%) showed no neurological sequelae. Severity of deficits was not correlated with birth date but to age at bleeding. Older children showed a better neurological outcome than neonates. CONCLUSION: The frequency and outcome of ICH in haemophiliacs have not changed in our cohort over the past 20 years. Trauma at birth is an important risk factor for ICH in patients with haemophilia A or B. Intracranial haemorrhages in older children are rare, and a better outcome may be expected.

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.

[Thrombolysis of modified Blalock-Taussig shunts in childhood with recombinant tissue-type plasminogen activator]. / Thrombolyse von modifizierten Blalock-Taussig-Shunts im Kindesalter mit rekombinantem Gewebeplasminogenaktivator.

Since 1983, when c-DNA was isolated, recombinant tissue plasminogen activator (rtPA), an endothelial-cell-produced activator of fibrinolysis is used, more increasingly often in therapy of thrombosis. Whereas some studies have been published regarding efficacy and safety rtPA in different thrombotic states of adults, only case reports exist in children. Doses vary widely (0.8-6 mg/kg/d), bleeding complications are reported in up to 50%. We report on four infants with complex cyanotic congenital heart disease who developed an early post-operative thrombosis of a modified Blalock-Taussig shunt. By local low dosage application of rtPA we could achieve a complete lysis of the thrombus in three of our four patients. In one patient we were unsuccessful due to a distal stenosis of the shunt. This infant required repeat surgery with creation of a central aortopulmonary shunt. We saw severe bleeding in one, requiring transfusion of packed cells, and formation of a perigraft reaction in another patient. In our experience local application of rtPA in low doses is a good therapeutical option in patients with thrombosis of aorto-pulmonary shunts, especially in the first postoperative days.

[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.