Monitoring of omalizumab therapy in children and adolescents.

BACKGROUND: Omalizumab is a successfully implemented supplementary therapy for improving asthma control in children aged 6 years and older with severe persistent allergic asthma. The dosage of omalizumab depends on body weight and IgE level, yet no parameter has been established to guide dosage changes during therapy. Clinical studies in patients with allergic asthma or allergic rhinitis revealed a clinically relevant improvement by using omalizumab leading to concentrations of free serum IgE reported to be lower than 50 ng/ml. Therefore, only the question concerning the concentrations of free IgE used in a therapy with omalizumab is regarded of clinical importance, while total IgE (free and omalizumab-bound IgE) increases during treatment. PATIENTS AND METHODS: Ten patients, 8 to 17 years of age, received therapy with omalizumab due to severe allergic asthma. In addition, the patients had pronounced rhinoconjunctivitis, food allergy, insect sting allergy, and/or neurodermitis. The total IgE in the serum was measured in the patients 3 - 6 months before each omalizumab injection as a potential progress parameter (Sandwich-Immunoassay ADVIA Centaur). RESULTS: Six months after beginning of the therapy with omalizumab, a significant decrease of the total IgE concentration was found, in comparison to the baseline values (p < 0.003). In all patients the tolerability of omalizumab was very good: there was a reduction in the frequency of the asthma exacerbations and rescue medications. All patients reported a clearly improved quality of life. CONCLUSIONS: A general increase in IgE was not observed in any of the children we treated with omalizumab. Apart from the development of routine assays to determine free serum IgE levels, the significance of the total serum IgE as a suitable control of an omalizumab therapy should be further investigated in controlled studies with regard to sensitivity and specificity. In order to only administer the lowest necessary dose of omalizumab especially in children and adolescents, the establishment of laboratory parameters (free IgE and/or total IgE) to adequately monitor the therapy is urgently needed. Patients undergoing an omalizumab therapy require medical supervision at close intervals.

[Important aspects in pediatric care of children and adolescents with chronic disease using the example of bronchial asthma]. / Wichtige Aspekte bei der Betreuung chronisch kranker Kinder und Jugendlicher am Beispiel des Asthma bronchiale.

When treating children or adolescents with chronic disease one should take the specific age-related features of the course of disease, differential diagnosis, and the psychosocial environment, as well as the avoidance of complications and side effects of therapy into account. These may impair the patient's physical and psychosocial development and quality of life in the context of family, school and occupational life. Continued care of growing children from the start of the disease when they are infants to the point when they assume personal responsibility as adults is one of the major concerns of the pediatrician. This concept requires interdisciplinary cooperation and a large body of personnel which would include training programs, inclusion of family members and in some cases psychosomatic therapy. Given the increasing prevalence of chronic diseases in this age group and their sociopolitical significance it is important to activate preventive potentials in terms of content and structure - by quality assurance - especially to avoid long-term complications. Various care structures are used in Europe to achieve this goal. Asthma is the most common chronic disease in children and adolescents. It influences quality of life as well as the child's personal, educational and occupational development to a significant extent. The special aspects of the treatment of these patients will be addressed to illustrate the therapy of chronic disease.

Reduced prevalence of obesity in children with primary fructose malabsorption: a multicentre, retrospective cohort study.

BACKGROUND: Studies in animals and in man have demonstrated that excessive consumption of fructose can cause all components of the metabolic syndrome. OBJECTIVE: To investigate the impact of a condition resulting in decreased absorption of fructose, on obesity. METHODS: In a multicentre study, we analyzed a cohort of paediatric patients with suspected primary fructose malabsorption (FM). Patients with chronic intestinal diseases were excluded. The final cohort comprised 628 patients. RESULTS: 302 patients were diagnosed with primary FM (48.1%). The proportion of obese patients was lower among FM patients, compared to non-FM patients (2.3 vs. 6.1%, P = 0.029). Logistic regression analysis with inclusion of various covariates showed that FM was negatively associated with obesity (OR 0.35, 95% CI [0.13; 0.97]). We discuss several mechanisms involving the metabolic, endocrine and gastrointestinal system. CONCLUSIONS: Our data indicate that primary FM is negatively associated with childhood obesity.

Imaging of chronic inflammatory bowel disease with 18F-FDG PET in children and adolescents.

Standard for diagnosis of inflammatory bowel disease (IBD) is the endoscopy of the stomach and the intestine. Aim of this study was to determine the value of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in pediatric patients with mild to moderate IBD.We included 23 children and adolescents between 8 and 17 years (median 15 years, 13 boys, 10 girls) in this retrospective study in a routine clinical setting. Diagnoses were Crohn's disease in 19 and ulcerative colitis in 4 cases.3 children had a conventional FDG-PET, 20 patients a combined FDG-PET-computed tomography exam. All children had upper and lower intestinal endoscopy with biopsy and a Hydro-MRI exam to assess the jejunum and proximal ileum. The gastrointestinal tract was divided in 7 segments: Stomach plus duodenum, jejunum and proximal ileum, terminal ileum, cecum plus ascending colon, transverse colon, descending colon, and rectosigmoid.Superficial gastric lesions were missed, gastric ulcerations were detected. For the stomach, the sensitivity was 0.25, the specificity was 1.00, the positive predictive value was 1.00, for the lower intestine (terminal ileum and colon) the values were 0.74, 0.88, and 0.96; for the terminal ileum 0.89, 0.75 and 0.94, respectively.The sensitivity and specificity for of ileal and colonic lesions is high. FDG-PET has to be discussed as a tool for the determination of extent and degree of inflammation, especially in those parts of the small bowel that are not accessible to endoscopy. This has to be weighed against the additional radiation exposure administrated.

Coeliac disease diagnosis: ESPGHAN 1990 criteria or need for a change? Results of a questionnaire.

BACKGROUND AND OBJECTIVES: A revision of criteria for diagnosing coeliac disease (CD) is being conducted by The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). In parallel, we have performed a survey aimed to evaluate present practices for CD among paediatric gastroenterologists and to learn their views on the need for modification of present criteria for CD diagnosis. PATIENTS AND METHODS: Questionnaires were distributed to experienced paediatric gastroenterologists (ESPGHAN members) via the Internet. RESULTS: Overall, 95 valid questionnaires were available for analysis, pertaining to 28 different countries, with the majority of responders treating patients with CD for >15 years. Only about 12% of the responders comply with present criteria, noncompliance being related mainly to the challenge policy. Approximately 90% request a revision and modification of the present criteria. Forty-four percent want to omit the small bowel biopsy in symptomatic children with positive anti-tissue transglutaminase immunoglobulin (Ig) A or endomysial IgA antibodies, especially if they are DQ2/DQ8 positive. For silent cases detected by screening with convincingly positive anti-tissue transglutaminase IgA or EMA IgA, about 30% consider that no small bowel biopsy should be required in selected cases. Adding human leukocyte antigen typing in the diagnostic workup was asked for by 42% of the responders. As for gluten challenge, a new policy is advocated restricting its obligation to cases whenever the diagnosis is doubtful or unclear. CONCLUSIONS: Based on these opinions, revision of the ESPGHAN criteria for diagnosing CD is urgently needed.

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease.

OBJECTIVE: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved. METHODS: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing. RESULTS: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative. CONCLUSIONS: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.

[Prophylactic prenatal therapy with intravenous immunoglobulins for patients at risk for neonatal haemochromatosis]. / Prophylaktische pränatale Therapie mit intravenösen Immunglobulinen bei Risiko für eine Neonatale Hämochromatose.

Neonatal haemochromatosis (NH) is a connatal hepatopathy that is lethal in 32% and necessitates liver transplantation in 63% of the survivors. The classical diagnostic criteria of extrahepatic siderosis do not apply in all patients who are suspected to have NH. The hypothesis of NH as an alloimmune disease is supported by the quantitative immunohistochemical proof of C5b-9 complement complexes on the hepatocytes of liver biopsy material. This has opened a new perspective in the therapy and prophylaxis for this severe disease. Prophylactic therapy with intravenous immunoglobulins (IVIG) for mothers at risk can prevent a relevant NH in most cases.

Partial splenic embolization as an alternative to splenectomy in hypersplenism--single center experience in 16 years.

PROBLEM: In young patients with hypersplenism splenectomy implies a lifelong increased risk for post-splenectomy infection. Especially in children, whose immune system is not yet completely matured, the risk for some bacterial infection may increase after splenectomy because the spleen helps to defend against encapsulated bacteria like pneumococci, meningococci and haemophilus influenzae. We present partial splenic embolization as an alternative to surgical splenectomy. METHOD: Partial splenic embolization was performed in 17 patients from 1-31 years with hypersplenism of various etiologies and was achieved by selective catheterization of splenic arteries and injection of 150-355 µm polyvinyl alcohol particles (Ivalon (®)). After the intervention the patients received an intensified analgesic regimen and antibiotics to avoid concurrent infectious complications. RESULTS: Partial splenic embolization represented between 30-60% of the splenic volume and was followed in general by an immediate increase of all blood cells and symptoms of hypersplenism were reduced. In 2 patients the procedure was repeated because the result of the first embolization was insufficient in one patient and became necessary in another in the long run. Post-procedural side effects included fever, abdominal pain, ascites and pleural effusions. There were no acute infections in any patient. CONCLUSION: Our monoinstitutional experiences over 16 years offer, partial splenic embolization in patients with hypersplenism from miscellaneous reasons as a low-risk alternative to surgical splenectomy. The procedure can be repeated as necessary, but it is always a temporary palliation depending on the underlying disease which often leads to liver transplantation. Using intensive analgesia and antibiotics side effects were tolerable, and patients could be discharged after a few days.

[Acanthamoeba meningoencephalitis: a case in an adolescent female patient with systemic lupus erythematosus]. / Acanthamöben-Meningoenzephalitis : Ein Fall bei einer jugendlichen Patientin mit systemischem Lupus erythematodes.

Meningoencephalitis caused by Acanthamoeba spp . is a rare opportunistic infection, difficult to diagnose and difficult to treat, which causes death in almost all cases. We report the neuropathologic findings of a 16-year-old girl with systemic lupus erythematosus (SLE) treated with immunosuppression who died of fulminant Acanthamoeba meningoencephalitis. Neuropathologic examination revealed multiple supratentorial and infratentorial hemorrhagic necrotizing lesions with encephalitis and vasculitis with mixed inflammatory infiltrates, fibrinoid necrosis of vessel walls, and local leptomeningitis. Acanthamoeba in the lesions may be misinterpreted as macrophages. Taking them into differential diagnostic consideration, cytological differences should be detected, and relevant additional stains for reliable differentiation of these cells can be performed. To our knowledge, this is the first published case of Acanthamoeba meningoencephalitis in a patient with SLE in Germany.

Capnovolumetry: a new tool for lung function testing in children with asthma.

In capnovolumetry, the expiratory CO2 concentration of exhaled air is plotted against the volume and thereby allows to determine functional dead space volumes. This method might offer additional information in lung function testing in children and adolescents with bronchial asthma. We aimed at determining whether a bronchospasmolysis (BSL) effect in the lower airways could also be detected by capnovolumetry as reflected by changes in the functional threshold dead space volumes (VDT). In 47 patients (aged 4-16 years) with a mild persistent bronchial asthma, VDT were determined before and after bronchodilation prior to starting therapy with inhaled steroids and after 6 months of treatment. Additionally, spirometry and body plethysmography were performed in all patients. There were significantly higher VDT values after BSL before and after 6 months of therapy (P<0.0001). VDT values before BSL were tendatively higher after 6 months of therapy compared with baseline values (P=0.07). VDT values correlated with parameters derived from conventional pulmonary function testing, i.e. vital capacity, forced expiratory volume in 1 s (FEV1), and maximum expiratory flow (MEF50). As VDT values particularly reflect the volumes of the lower bronchi this method may provide supplementary information to conventional lung function tests which are based on breathing mechanics. This seems to be especially helpful in situations where body plethysmography is not available or cooperation in forced expiration manoeuvres is insufficient.

Reduction of the total IgE level by omalizumab in children and adolescents.

BACKGROUND: Current data from clinical studies show that patients with severe allergic asthma experience a significant improvement from omalizumab. The early and late allergic reactions are inhibited by formation of complexes with free circulating immunoglobulin E (IgE), independent of which antigen activates the allergic cascade. The dosage of omalizumab depends on body weight and IgE level, yet no parameter has been established to guide dosage changes during therapy. The aim of this study was to investigate the value of the determination of total IgE by ADVIA Centaur assay to monitor the therapy progress. PATIENTS AND METHODS: Nine patients, 8 to 17 years of age, received therapy with omalizumab due to severe allergic bronchial asthma. In addition, the patients had pronounced rhinoconjunctivitis, food allergy, insect sting allergy, and/or neurodermitis. The total IgE in the serum (Sandwich-Immunoassay ADVIA Centaur) was measured in the patients once monthly before each omalizumab injection as a potential progress parameter. RESULTS: Six months after the beginning of therapy with omalizumab, a significant decrease of the total IgE concentration was found, in comparison to the baseline values (p < 0.01). In all patients, the tolerability of omalizumab was very good; there was a reduction in the frequency of the asthma exacerbations and rescue medications. The dosage of inhaled glucocorticoids could be lowered. All patients reported a clearly improved quality of life. CONCLUSIONS: The increase of the total IgE concentrations after administration of omalizumab described in the literature could not be confirmed. The value of total serum IgE as a progress parameter should be investigated in controlled studies with regard to sensitivity and specificity of the respective assays. The establishment of a test procedure for therapeutic monitoring appears urgently necessary, so that the appropriate dosage of omalizumab is applied in children and adolescents. Patients receiving omalizumab therapy should be closely monitored.

High diagnostic value of 18F-FDG-PET in pediatric patients with chronic inflammatory bowel disease.

Diagnosis of chronic inflammatory bowel disease (IBD) in children requires noninvasive, atraumatic diagnostic tools that depict localization and acuity of inflammation and yield only a low radiation dose. This retrospective analysis evaluates the diagnostic potential of FDG-PET. Twenty-six consecutive FDG-PET scans of 23 patients (age: 2-16, years, 14 M, 9 F) with suspected IBD were analyzed in this retrospective study. Results were compared to endoscopic, histologic, and abdominal ultrasound (US) finding. In these examinations, presence of inflammation was evaluated in each patient in 8 bowel segments (score 1-4). Standardized uptake values (SUVs) for FDG-PET were measured for all segments. Sensitivity, specificity, and accuracy were calculated using histology as the standard of reference on a segment-based analysis (pathologic if inflammation score > or = 3 or SUV(max)/SUV(liver)>1.2). With histology as the standard of reference, FDG-PET showed a sensitivity/specificity/accuracy of 98%/68%/8%/3 as compared to endoscopy (90%/75%/82%) and US (56%/92%/75%). For the small bowel, FDG-PET was even more reliable (100%/86%/90%). Because of its high sensitivity and accuracy,FDG-PET is an excellent, noninvasive diagnostic tool for IBD. Depicting inflammation in the whole bowel, while being not traumatic, it is attractive for use especially in children. FDG-PET is especially reliable for the small bowel and can inform application of topical therapy.

Pathophysiology in Microvillus inclusion disease.

Microvillus inclusion disease (MID) is a congenital disorder with the clinical signs of watery diarrhea often beginning in the first days of life. The main pathological features of the disease include a villus atrophy and an accumulation of periodic acid-Schiff (PAS)-positive material within the apical cytoplasm of enterocytes on the light microscopy level. Electron microscopic criteria are pathognomonic consisting of an increased amount of secretory granules preferentially in crypt epithelial cells and of the presence of microvillus inclusion bodies (MIBs) which are most frequently found in villus enterocytes. Until now the basic molecular defects have not been disclosed completely. In this review we discuss the actual pathogenetic hypothesis and the therapeutic options besides small bowel transplantation.

[Definitions of celiac disease--statement of an expert group from the German Society for Celiac Disease]. / Verlaufsformen und Definitionen der Zöliakie--Stellungsnahme einer Expertengruppe der Deutschen Zöliakie-Gesellschaft.

Celiac disease may have different manifestations and the clinical course can be very heterogeneous. Thus, management and treatment of celiac disease can be difficult and therefore requires individual patient care. In this article an expert group from the German Society for Celiac Disease (Deutsche Zöliakie-Gesellschaft) defines the different manifestations of celiac disease. In the past these definitions were often used differently. The consequent usage of these definitions may diminish uncertainties in clinical practice and lead to a more standardized management of the disease which is likely to improve patient care.

Gastrointestinal symptoms and permeability in patients with juvenile idiopathic arthritis.

OBJECTIVE: Examining for gastrointestinal involvement in juvenile idiopathic arthritis is an important part of diagnostic and therapeutic procedures. Only few scientific data are available. METHODS: In a prospective study, 41 patients with juvenile idiopathic arthritis were examined for clinical and laboratory data of gastrointestinal involvement. Sugar absorption tests with lactulose, mannitol, and sucrose were applied to assess gastric and intestinal mucosal lesions. Faecal albumin and alpha 1-antitrypsin levels were measured to examine gastrointestinal protein loss, a test for occult blood in stool was administered and Helicobacter pylori serology was performed. RESULTS: 39% of our study population complained of chronic abdominal pain. The patient group showed increased sucrose excretion (p = 0.002), but a normal lactulose/mannitol ratio compared with healthy controls (p = 0.472). 21% of the patients had an elevated faecal alpha 1-antitrypsin level, but only one patient showed occult blood loss. There was no correlation between risk factors and clinical or laboratory signs of gastrointestinal involvement. CONCLUSION: We conclude that a high percentage of children and adolescents with juvenile idiopathic arthritis treated with non-steroidal antiinflammatory drugs show clinical or laboratory signs of gastrointestinal involvement.

[Life-threatening theophylline intoxication: a variant of Munchhausen syndrome by proxy]. / Lebensbedrohliche Theophyllin-Intoxikation im Rahmen eines Münchhausen-by-proxy-Syndroms.

We report of a prematurely born infant, who was admitted to hospital at the age of 6 months due to seizures. The seizures continued despite of an improved electroencephalogram due to varying medications. The boy had episodes of hypokaliaemia, diarrhea, and tachycardia which were treated in critical care unit. Not before 3 months of continued treatment and diagnostic work up in three different hospitals had passed the underlying poisoning with theophylline by the mother was proved. The toxicity of theophylline is well known. Adverse reactions occur frequently during theophylline therapy. There are numerous reports of suicidal intoxications with theophylline. Non-accidental poisoning with theophylline has not yet been reported in the context of Munchausen syndrome by proxy.

Oral mannose therapy persistently corrects the severe clinical symptoms and biochemical abnormalities of phosphomannose isomerase deficiency.

Phosphomannose isomerase (PMI) deficiency (CDG-Ib) is a newly recognized disorder of mannose and glycoprotein metabolism. PMI deficiency manifests itself mainly as a gastrointestinal disorder with protein-losing enteropathy and life-threatening intestinal bleeding. Hypoglycaemia is an additional prominent symptom. In contrast to phosphomannomutase deficiency (CDG-Ia), there are no neurological symptoms. PMI deficiency blocks the endogenous mannose formation from glucose. Exogenous oral mannose supply bypasses the enzymatic block and leads to the disappearance of all symptoms in the patient. The striking ultrastructural abnormalities of the rough endoplasmatic reticulum of the duodenal epithelial cells completely normalize and the hypoglycosylation disappears, as evidenced by the normal isoelectric focusing pattern of serum transferrin, the standard diagnostic procedure for recognition of CDG. This paper includes a detailed description of the clinical symptomatology of the first-ever diagnosed and treated patient with PMI deficiency and a 5-y follow-up study of mannose therapy.