[Overweight in primary school-age children. Prevalence and risk factors]. / Gewichtsentwicklung im frühen Grundschulalter. Prävalenz, Inzidenz und Risikofaktoren für Übergewicht und Adipositas.

BACKGROUND: Various studies show that pre-school age is a sensitive period for the development of overweight and obesity. During a longitudinal study between 2010 and 2013, the municipal health authority (city of Frankfurt) in cooperation with the university children's hospital investigated the development of weight in children aged 5 to 8. MATERIALS AND METHODS: The weight and height of a collective of 5720 children were measured (2010/11). In addition, nutritional and exercise habits, as well as media consumption was documented for 4758 children through a questionnaire during the school enrolment procedure. The weight and height of 3481 children were measured again in the second grade (2012/13). RESULTS: Over a period of 24 months, the percentage of overweight (not obese) children increased from 7.5 to 9.4 % and that of obese children from 4.5 to 5.0 %. 164 of 2818 children with a normal initial weight (5.8 %) changed to percentile class overweight or obese. 79 of 260 children who were initially overweight, not obese (30 %), changed to the group of normal weight, but only 4 out of 156 obese children (3 %). Increased TV consumption (> 1 h per day), availability of their own television, lack of physical activity, and consumption of high-calorie drinks were risk factors for the development of overweight during the primary school age. 72 % of parents of overweight children and 22 % of obese children falsely classified their children as normal weight. CONCLUSIONS: Targeted education about the risk of obesity in the primary school age and offers for early intervention should be established in the healthcare services concerned.

Thromboembolic events associated with immunoglobulin treatment.

OBJECTIVE: Due to an increasing number of reported thromboembolic events (TEE) after the administration of one intravenous immunoglobulin (IVIG) and one subcutaneous immunoglobulin (SCIG), pharmacovigilance and laboratory data were collected to analyse the root cause and assess the reporting frequency of TEEs for various IG products. METHODS: Paul-Ehrlich-Institut retrospectively analysed 228 reports of TEEs associated with six different IG products and estimated annual TEE-reporting rates based on worldwide sale figures over a period of 6 years (2006-2011). In addition, non-activated partial thromboplastin time (NAPTT) testing was performed to capture pro-coagulant potential of six IG products (four IVIG and two SCIG). RESULTS: For three IVIGs, the drug-related TEE-reporting rates remained stable from 2006 to 2011 (0-0·83 cases per 1000 kg IVIG distributed). In contrast, the TEE rate of one IVIG increased significantly from 0·33 cases in 2006 to nearly nine cases in 2010 (P < 0·001). The NAPTT testing of IG products with a low TEE rate revealed a NAPTT time >200 s and a NAPTT ratio >0·8, whereas TEE-associated batches of IG products with an increased TEE rate had a NAPTT ratio <0·8. After modifications of manufacturing processes, a normalization of NAPTT results and a decrease in TEE rates could be demonstrated.

Benefit of transfusion-related acute lung injury risk-minimization measures--German haemovigilance data (2006-2010).

OBJECTIVE: Based on the frequency of immune-mediated and non-immune-mediated transfusion-related acute lung injury (TRALI), the effect of risk-minimization measures was evaluated during a period of 5 years (2006-2010). Risk-minimization measures were implemented in 2008/2009, consisting of exclusion of female donors with a history of pregnancy or exclusion of female donors with human leucocyte antigen (HLA)/human neutrophil alloantigen (HNA) antibodies. METHODS: TRALI was confirmed according to the criteria of the International Haemovigilance Network. Based upon the results of donor testing of white-blood-cell antibodies (WBC-Ab) against HLA or HNAs, confirmed cases were classified as immune- or non-immune-mediated TRALI. Reporting rates were calculated on the basis of the annually transfused blood components, and pre- and post-implementation periods were compared. RESULTS: In total, 60 immune-mediated (75%) and 20 non-immune-mediated (25%) TRALI reactions were confirmed. A total of 68 (64 women and four men) donors were involved: seven red-blood-cell concentrates donors (13%), six platelet concentrate donors (10%), and 48 fresh frozen plasma (FFP) donors (77%). The reporting rate of immune-mediated TRALI caused by FFP decreased continuously; from 12·71 per million units in 2006/2007 to 6·81 per million units in 2008/2009 and no case in 2010. CONCLUSION: The comparison of the pre- and the post-implementation period demonstrated a significantly reduced risk of TRALI events comparing 2006/2007 with 2010 (P-value: <0·01). Furthermore, no case of TRALI-induced fatality occurred after the implementation of risk-minimization measures.

[Evaluation of measures aimed to reduce serious adverse transfusion reactions (hemovigilance data from 1997 to 2008)]. / Bewertung der Massnahmen zur Reduktion schwerwiegender Transfusionsreaktionen (Hämovigilanzdaten von 1997 bis 2008).

On the basis of reports of serious transfusion reactions, measures aimed to improve the safety standard of the manufacturing process of blood components were evaluated from 1997-2008. Measures of the Paul-Ehrlich-Institut (PEI) as well as recommendations of the Advisory Committee "Blood" were considered. Reporting frequencies before and after the implementation of measures were compared. After the implementation of NAT pool testing, a reduction of virus transmission was seen for red blood cell concentrates (RBC) from 1.0/10(6) to 0.5/10(6) units and for platelet concentrates (PC) from 3.0/10(6) to 0.0/10(6) units. After the implementation of a pre-donation sampling, however, no reduction of bacterial infections associated with PC administration (>9.0/10(6)) was identified. To reduce the frequency of TRALI associated with FFP administration (11.2/10(6) units), the use of plasma from male donors or female donors without a history of pregnancy was established in September 2009. Without specific measures of risk reduction, the reporting frequency of severe allergic transfusion reaction increased for all blood components during the investigation period (from 0.8/10(6) to 6.2/10(6) RBC units). The benefit of measures to improve safety standards should be evaluated repeatedly by collecting precise hemovigilance data.

Frequency and severity of transfusion-related acute lung injury--German haemovigilance data (2006-2007).

OBJECTIVE: In an observational cohort study (2006-2007) the Paul-Ehrlich-Institut collected epidemiological data to investigate the frequency and causes of TRALI. METHODS: Diagnosis of TRALI was confirmed according to criteria of the European Haemovigilance Network. Subsequent testing of white blood cell antibodies (WBC-Ab) against HLA or human neutrophil alloantigens was performed. RESULTS: Of a total of 187 reported TRALI cases, 44 could be confirmed consisting of 35 cases of antibody-mediated TRALI and nine cases of non-immune-mediated TRALI. Eight of 44 affected patients (18%) had a fatal outcome, seven cases with WBC-Ab positive plasma donors and one case with red blood cell donors. WBC antibodies were found in one male and 39 female donors. In 34 female donors, a history of pregnancy was confirmed. WBC-Ab positive donors presented four HLA class I antibodies, 15 HLA class II antibodies, 13 HLA class I and class II antibodies, one HNA-2a, and seven HNA-3a antibodies. WBC antibodies matching with recipient antigens were found exclusively in 28 female donors; 26 FFP donors, one platelet donor and one red blood cell donor. Reporting frequency of immune-mediated TRALI was 1:66,000 for fresh frozen plasma, 1:2.86 million for red blood cell concentrates and 1:420,000 for platelet concentrates. Reporting frequency of TRALI-related fatalities was 1:285,000 for FFP. SUMMARY: Haemovigilance data show the significance of female donors with a history of pregnancy for the development of antibody-mediated TRALI. Manufacturing of FFP from male plasma and female donor screening for WBC-Ab could represent preventive measures.

The German Haemovigilance System--reports of serious adverse transfusion reactions between 1997 and 2007.

Data of the German Haemovigilance System were collected from 1997 to 2007 and assessed on the basis of pre-defined safety standards. Suspected cases of serious adverse reactions following transfusions reported to the Paul-Ehrlich-Institut were evaluated on the basis of national criteria, and the definitions of International Society of Blood Transfusion (ISBT) in compliance with defined causality criteria. The suspected cases were rated as confirmed and unconfirmed transfusion reactions. Assessment of causality took into consideration the clinical course of the adverse reaction and, if necessary, information about donation and manufacturing. Of the 5128 suspected serious adverse reactions, 1603 could be confirmed. Referring to the absolute figures, acute transfusion reactions (e.g. allergic reactions, hypotension and dyspnoea) were recorded most frequently, followed by transfusion-related acute lung injury (TRALI), haemolytic reactions, transfusion-related bacterial infections and virus infections. The majority of the 52 transfusion-related fatalities (14 each) were due to TRALI and acute transfusion reactions (mostly severe allergic reactions). Referred to the blood products administered, immune TRALI cases and TRALI-related fatal courses were most frequently reported after administration of fresh frozen plasma (FFP) (15/10(6) and 3.5/10(6) units, respectively), transfusion-related bacterial infections after administration of platelet concentrates (7/10(6) units), acute haemolytic transfusion reactions after administration of red blood cell concentrates (2.3/10(6)units) and acute transfusion reactions after administration of red blood cell or platelet concentrates (7.8/10(6) and 13/10(6) units, respectively). Despite the high safety standard required for blood products in Germany, there is still room for reducing the frequency of isolated cases of transfusion reactions by targeted action.

Disease progression in HIV-1 infected children and adolescents--results of a German-Austrian cohort study.

OBJECTIVE: The Paediatric Working Group AIDS (PAAD) initiated a prospective cohort study in order to investigate disease progression in HIV- infected children and adolescents and the effect of antiretroviral treatment regimes. PATIENTS AND METHODS: Between 1998 and 2003, paediatric centres documented HIV-infected patients under clinical care using a questionnaire for basic data and annual follow up. Main outcome measures were: use of antiretroviral therapy, adverse events, disease progression and change of therapeutic regimes. RESULTS: 174 HIV- infected paediatric patients were followed up in 12 centres in Germany and Austria between 1998 and 2003. Initially 54 (31%) patients had no antiretroviral therapy, 35 (20%) received a two-drug regimen (ART) and 85 patients (49%) a highly active antiretroviral therapy (HAART>or=3 drugs). After an observation period of 5 years, 8 patients (4%) had no therapy, 17 (10%) were on ART and 134 patients on HAART (77%). The number of patients with salvage therapy (>or=4 drugs) increased from 5 (3%) to 15 patients (9%). 72 of 166 treated patients (43%) had no change of their drug regimes, 68 patients (41%) had one change and 26 patients (16%)>or=2 changes. Main reasons for changes were increased viral load (49%), immunologic deterioration (21%) and adverse events (14%). During the follow up period no patient died. According to the CDC classification, disease progression was seen in 48 of 174 patients (28%), of whom 20 had deteriorations of clinical categories (A, B, C) and 28 of immunologic categories. Using Kaplan-Meier curves, the mean time from study onset until change of clinical categories was 61 months for patients on HAART, 26 months for patients on ART and 14 months for patients without ART. CONCLUSION: In paediatric patients with HIV infection, disease progression has declined substantially by introduction of HAART. Superiority of HAART compared with ART was demonstrated. Non-adherence as well as other reasons for treatment failure have to be studied more carefully.

Immune tolerance induction with mycophenolate-mofetil in two children with haemophilia B and inhibitor.

Immune tolerance induction (ITI) in haemophilia B patients with inhibitor should be carefully considered because of the relatively poor (25%) overall success rate and the high risk of complications. ITI in combination with an immunosuppressive treatment was started in two children with haemophilia B with factor IX (FIX) inhibitor. To avoid anaphylactic reactions and inhibitor boost, the FIX replacement therapy was stopped and patients received a treatment with recombinant activated factor VII (rFVIIa). After disappearance of FIX inhibitor, a combination of mycophenolate-mofetil (MMF), dexamethasone (DEXA) and intravenous immunoglobulin (IVIG) and a high dose FIX replacement therapy was started. Immune tolerance could be induced in patient 2, whereas eradication of FIX inhibitor was incomplete in patient 1. Both patients benefited from the immune suppressive treatment and FIX replacement therapy was tolerated without any allergic complications. Neither development of a nephrotic syndrome nor a severe bleeding episode was observed. Strategies to induce tolerance in haemophilia B patients with inhibitors need to be explored in a systematic way. Given the low frequency of disease and even lower incidence of inhibitors, prospective randomized studies may not be possible. International registry-based retrospective and prospective data collection could play the key role in the study of the outcome variables in ITI for haemophilia B.

Need for therapeutic drug monitoring in HIV-1 infected children receiving efavirenz doses according to international guidelines.

BACKGROUND: International guidelines for the treatment of HIV-1 infected children recommend efavirenz plus nucleoside reverse transcriptase inhibitor combination therapy for first line therapy. Until now little is known about the steady state pharmacokinetics of efavirenz in children. METHODS: 11 HIV-1 infected children at the age of 4 to 10 years received efavirenz according to body weight adjusted dose recommendations at 10 -15 mg/kg body weight. All children were non nucleoside reverse transcriptase inhibitor (NNRTI) naive, 5/11 received efavirenz as first line therapy. Efavirenz plasma concentrations were assessed before daily dose and 1, 2, 4, 8, 24 h post-dose after medication by established HPLC. RESULTS: 7 of 11 children exhibited efavirenz plasma concentrations below targeted ranges. Mean (95% CI) minimum concentrations (C subsetmin) was 1293 ng/mL (range: 889 -1697) and maximum concentration (C subsetmax) was 5552 ng/mL (3951 - 7153) and the mean area under the time-concentration curve at steady state (AUCss) was 63608 ng*h/mL (44222 - 82989). The linear regression analysis of bodyweight adjusted efavirenz AUCss showed a close correlation between dose/bodyweight and plasma concentrations (r superset2 = 0.79). Efavirenz doses below 12.5 mg/kg lead to an AUC < 60000 ng*h/mL in 7 of 8 cases. Higher efavirenz doses exhibited an AUC within the recommended therapeutic range of 60000 - 120000 ng*h/mL (n = 3). CONCLUSIONS: The data show insufficient plasma concentrations for some children despite efavirenz dosing according to recommendations. Antiretroviral therapy needs to be carefully adjusted in children. Therapeutic drug monitoring is strongly recommended to meet efavirenz plasma levels within the therapeutic range.

Modified magnetic resonance imaging score compared with orthopaedic and radiological scores for the evaluation of haemophilic arthropathy.

Twenty-four joints (10 knees and 14 ankles), with at least one manifestation of bleeding (proven by sonographic assessment), of 15 patients with haemophilia were investigated prospectively. For magnetic resonance imaging (MRI) evaluation, the MRI scale of Nuss et al. was modified to a MRI score (max. 13 points/joint) to allow a comparison with the physical examination score (max. 12 points) and the radiological score (Pettersson score; max. 13 points). The number of joint bleeds correlated well with the degree of arthropathy P < 0.01). In all 16 joints with a maximum of two bleeds, no alterations were found by physical examination, or radiological and MRI assessment. Joints with three bleeds had physical examination scores between 0 and 2, Pettersson scores from 0 to 3 and MRI scores of 2. Joints with four or more bleeds had physical examination scores ranging between 3 and 7, radiological scores between 7 and 12 and MRI scores between 3 and 8. The MRI score describes initial joint alterations more precisely and earlier than other assessments, allowing a discerning estimation of the degree of arthropathy, as well as a follow-up of haemophilic arthropathy and an improvement after change of treatment. In addition, the modified MRI score seems to differentiate better between early and advanced signs of arthropathy than the MRI scale of Nuss et al.

[Evaluation of haemophilic arthropathy--a comparison of MRI and Pettersson score]. / Bewertung der hämophilen Arthropathie - MRT- und Pettersson Score im Vergleich.

PURPOSE: In order to compare score values, joint alterations in haemophilic patients on early and late prophylaxis were assessed and evaluated by X-ray radiography and magnetic resonance imaging (MRI) in a prospective study. PATIENTS AND METHODS: 24 joints (10 knees and 14 ankles) of 15 haemophilic patients, with at least one manifestation of bleeding (proven by sonographic assessment) were investigated. Radiological and MRI investigations were done after complete resorption of bleeding. For radiological evaluation a Petterson score (max. 13 points), and for MRI evaluation a modified MRI score (max. 13 points) according to Nuss et al. were used. RESULTS: Good correlation could be demonstrated between the number of joint bleedings and the degree of arthropathy. 16 joints with maximal 2 bleedings had no alteration on both MRI and radiological assessment. Joints with 3 bleedings had Pettersson score from 0 - 3 points and MRI scores of 2 points. Joints with greater-than-or-equal 4 bleedings had a radiological score between 7 and 12 points, MRI scores ranged from 3 to 8 points. CONCLUSION: Increasing severity of heamophilic arthropathy could be demonstrated initially by the MRI score and later by the Pettersson score depending on the number of bleedings. The MRI score describes initial joints alterations more precisely and earlier than the Pettersson score, allowing a discerning estimation of the degree and a follow-up of haemophilic arthropathy.

Preliminary experiences with triple therapy including nelfinavir and two reverse transcriptase inhibitors in previously untreated HIV-infected children.

OBJECTIVE: In an intent-to-treat study increase in CD4 cell count, reduction of viral load, clinical benefit and adverse reactions were examined in HIV-infected previously treatment-naive children taking triple therapy. METHODS: sixteen HIV-infected children in category A or B on antiretroviral triple therapy were followed-up for a period of 12 months. In group I eight patients received zidovudine, lamivudine and nelfinavir; in group II eight patients received stavudine, didanosine and nelfinavir. Viral load and CD4 cell count were measured every 4-8 weeks. Plasma nelfinavir levels were assessed once in all patients at baseline and monitored in patients with increasing viral load. RESULTS: No significant differences were observed between treatment groups in terms of CD4 cell counts and viral load. A median viral load reduction of 2.8 log10 (range, 1.4-4.2 log10) was achieved over a period of 12 months in both groups. Viral load < 500 copies/ml was found in 69% of patients and viral load < 50 copies/ml in 44% of patients after 12 months. Median CD4 cell count increased from 656 x 10(6) to 850 x 10(6) cells/l after 3 months and was maintained at 813 x 10(6) cells/l after 12 months of treatment. Main side-effects were diarrhoea, rash and hyperlipidaemia. Except for application problems, both regimens were well tolerated. Appropriate formula and individual counselling must be performed during the first weeks of treatment in order to achieve good compliance in paediatric patients. CONCLUSION: Triple antiretroviral therapy shows a stronger and more sustained reduction of viral load in HIV-infected children compared with studies combining two nucleoside analogues.