T cell reactivity in neonates from an East and a West German city--results of the LISA study

BACKGROUND: Within an ongoing birth cohort study (LISA) the cytokine production of cord blood T cells was compared between neonates from Leipzig (East Germany) and Munich (West Germany). The aim of this study was to analyse regional differences and influencing factors of the immune status. METHODS: Cytokine production was measured in a randomly selected subgroup of 158 children from the LISA (Life style - Immune system - Allergy) cohort by intracellular cytokine staining. Information on family "atopy" history (FAH) and home characteristics was obtained from questionnaires. RESULTS: Reduced numbers of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) producing T cells were found in association with biparental FAH and housing renovation during pregnancy. In addition, cytokine production was influenced by season. In Munich, the frequency of biparental FAH and of renovation measures during pregnancy was significantly higher as compared to Leipzig. Neonates from Munich showed significantly decreased amounts of IFN-gamma and TNF-alpha and elevated levels of interleukin-4 (IL-4) producing T cells. Differences in cytokine production between Munich and Leipzig were influenced by season (IL-4) and housing renovation (IFN-gamma, TNF-alpha). CONCLUSIONS: Since differences in the T cell cytokine production of neonates in Munich and Leipzig are independent from FAH our findings may provide evidence for the impact of environmental factors upon the fetal immune system.     

Are radiographic indices reliable indicators for quantitative bone mineral density and vitamin D status after femoral neck fractures? A retrospective study in 112 elderly patients

Background

Radiographic parameters and indices obtained from hip x-rays are a potential tool to promptly estimate bone quality in elderly hip fracture patients. Preoperative decision in whether to use cemented or cement augmented implants might be supported by this information and thus improve patient safety. Subsequently, this study was conducted to evaluate radiographic parameters as a prescreening tool for bone quality.

Methods

A retrospective analysis of 112 elderly patients with a femoral neck fracture after low-energy trauma was performed (81 % female, 19 % male). Three radiological indices were calculated on hip x-rays: cortical index antero-posterior CTI (ap), cortical index lateral CTI (lat) and canal to calcar ratio CCR. These indices were analyzed for correlations with DXA T-Scores and serum 25-hydroxyvitamin D (25(OH)D) using the Spearman test.

Results

Median age of patients was 80 (IQR 72–86) years. A linear correlation was found for CTI (lat) and T-Score at the total hip (p?<?0.001, r?=?0.589), femoral neck (p?=?0.005, r?=?0.405) and the lumbar spine (p?=?0.002, r?=?0.299). A significant correlation was also indicated between CTI (lat) and 25(OH)D (p?=?0.002, r?=?0.293). CTI (lat) at a cut-off level of 0.4 showed a sensitivity of 79 % and a specificity of 56 % in predicting a T-score?≤??2.5 at the total hip. Gender specific analysis revealed a higher sensitivity (100 %) and specificity (73 %) of CTI (lat) at a cut-off level of 0.4 for men. For severe vitamin D deficiency (<10 ng/ml) sensitivity and specificity were 75 % and 65 %.

Conclusion

Radiographic indices as the CTI (lat) exhibit a direct correlation to BMD and serum 25OH vitamin D levels. A CTI (lat) cut-off level of 0.4 is recommended for identifying patients at risk of osteoporosis expressed by T-Scores?≤??2.5 and severe vitamin D deficiency.

     

Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR

Severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) are inborn errors of immune function that require prompt diagnosis and treatment to prevent life-threatening infections. The lack of functional T or B lymphocytes in these diseases serves as a diagnostic criterion and can be applied to neonatal screening. A robust triplex PCR method for quantitation of T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs), using a single Guthrie card punch, was developed and validated in a cohort of 2560 anonymized newborn screening cards and in 49 original stored Guthrie cards from patients diagnosed with SCID, XLA, ataxia-telangiectasia, Nijmegen-breakage-syndrome, common variable immunodeficiency, immunoglobulin A deficiency, or X-linked hyper-IgM syndrome. Simultaneous measurement of TREC and KREC copy numbers in Guthrie card samples readily identified patients with SCID, XLA, ataxia-telangiectasia and Nijmegen-breakage-syndrome and thus facilitates effective newborn screening for severe immunodeficiency syndromes characterized by the absence of T or B cells.     

Impaired polysaccharide responsiveness without agammaglobulinaemia in three patients with hypomorphic mutations in Bruton Tyrosine Kinase—No detection by newborn screening for primary immunodeficiencies

Hypomorphic mutations in the gene encoding Bruton tyrosine kinase (BTK) may result in milder phenotypes and delayed diagnosis of B-cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa-deleting-recombination-excision circles (KRECs) reliably identifies classical X-linked agammaglobulinaemia (XLA) patients with profound B-cell lymphopenia at birth but has not been evaluated in patients with residual BTK function. We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinaemia. One patient had an invasive pneumococcal infection at the age of 4 years. All three patients (two brothers) had visible tonsils, normal to slightly decreased immunoglobulin G levels, undetectable pneumococcal antibodies despite pneumococcal conjugate vaccinations, no antibody response after a diagnostic polysaccharide vaccination as well as profound B-cell lymphopenia with residual B-cell differentiation. BTK mutations were identified by Sanger sequencing. BTK staining and phosphorylation assays were performed on peripheral B cells. KREC copy numbers were determined from dried blood spots obtained within the first week of life as well as once at the age of 8, 6 and 3 years, respectively. BTK staining showed residual protein expression. Also, residual BTK activity could be demonstrated. KREC copy numbers from dried blood spots were above the threshold set for detection of patients with profound B-cell lymphopenia. Male patients with impaired polysaccharide responsiveness should be evaluated for B-cell lymphopenia followed by BTK analyses irrespective of immunoglobulin levels or tonsil size.     

Bacterial bone and joint infections in childhood--a review. 3. Bacterial arthritis

This overview presents the most important topics of etiology, pathogenesis, diagnostics, differential diagnostics and treatment of septic arthritis in children. A child with bacterial arthritis is always a case of emergency. Only immediate and adequate treatment can avoid permanent sequelae. Medical care for these patients should be done always in close cooperation of pediatricians, pediatric surgeons, radiologists, and sometimes orthopedists.     

Effects of indoor painting and smoking on airway symptoms in atopy risk children in the first year of life results of the LARS-study. Leipzig Allergy High-Risk Children Study

INTRODUCTION: The Leipzig Allergy High-Risk Children Study (LARS) is a prospective nested cohort control study about the influence of chemical indoor exposure in dwellings on the health outcome of atopy-risk children during the first years of life. DESIGN AND METHODS: 475 premature children and children with allergic risk factors have been selected out of the 1995/1996 birth cohort in the city of Leipzig. Twenty-five volatile organic compounds (VOC) were measured in the infant's bedrooms using passive sampling systems for 4 weeks after birth. The babies underwent a medical examination at the age of six weeks and 1 year. The parents answered a questionnaire. RESULTS: Correlations between VOC exposures and infections were calculated by multiple logistic regression. Selected VOC show a direct association to actually painted dwellings (OR = 2.4; 95% Cl 1.1-5.3). An increase of risk of pulmonary infections was observed in infants aged 6 weeks if restoration (painting OR 5.6; 95% Cl 1.3-24.0) or flooring connected with painting had occurred during the pregnancy period. Higher concentration of styrene (> 2.0 micrograms/m3, indicator for flooring) elevated the risk of pulmonary infections in six-week-old infants (OR = 2.1; 95% Cl 1.1-4.2). Environmental benzene > 5.6 micrograms/m3 increased the risk of airway infections in six-week-old babies (OR = 2.4; 95% Cl 1.28-4.48). Smoking in the dwelling (OR = 2.0; 95% Cl 1.1-3.5) as well as restoration (OR = 1.9; 95% Cl 1.1-3.5) are also risk factors of the development of wheezing in the one-year-old child. CONCLUSIONS: The data give indications in order to prevent allergies and chronic lung diseases in atopy risk children exposure to chemicals from indoor air should be minimised from birth on.     

Atypische Epstein-Barr-Virus(EBV)-Infektionen im Kindes- und Jugendalter

The clinical syndrome of acute infectious mononucleosis is predominantly a disease of older children and adolescents. Primary EBV infection in younger infants is often subclinical. Complications may affect any organ system and are usually mild. In the majority of cases acute infectious mononucleosis has an excellent prognosis. Severly immuncompromised children and adolescents (i. e. under immunosuppressive therapy, after stem cell transplantation) may develop EBV⁺ B-cell lymphoproliferative disorders and malignant B-cell lymphoma. In this review, mainly the following forms of atypical EBV infections are described in detail: Fulminant, mostly fatal acute infectious mononucleosis following primary EBV infection may occur 1) sporadically (approx. 1 per 3000 cases of acute infectious mononucleosis), 2) in aprox. 60% of boys with X-linked lymphoproliferative disease (XLP), and 3) in very rare cases of a fulminant EBV+ T-cell lymphoproliferative disorder. No efficient therapy exists so far. Early allogeneic stem cell transplantation in boys with XLP may prevent fatal acute infectious mononucleosis and other complications. Chronic active EBV (CAEBV) infection is characterized by recurrent clinical episodes of severe infectious mononucleosis over months or years and additional unusual clinical signs and complications such as coronary artery aneurisms, hypersensitivity to mosquito bites and hydroa vacciniforme, as well as an markedly increased risk for malignant lymphoma, mostly of a T-cell type. In general, prognosis of CAEBV infection is poor. Allogeneic stem cell transplantation may lead to clinical remission. EBV-associated hemophagocytic syndrome may occur as an independent disorder [EBV-related hemophagocytic lymphhistiocytosis (EBV-HLH)] or as a serious complication of fatal infectious mononucleosis or CAEBV infection. Early treatment with etoposide, cyclosporine A and corticosteroids may improve the otherwise poor prognosis. The pathogenesis of atypical EBV infections is not known in most cases. Further molecular and immunologic studies may help to characterize these severe disorders and to develop more specific and more efficient therapies.     

Treatment of patients with primary antibody deficiencies in Germany

BACKGROUND: Primary antibody deficiencies are the most common forms of primary immunodeficiencies (PID). Recurrent bacterial infections and the risk of progressive structural tissue damage are the most serious complications of these diseases. Substitution therapy with polyvalent immunoglobulins (Ig) has been established as the standard therapy in PID for several decades now. METHODS: During summer 2002 German PID treaters were interviewed in a survey in order to assess the present status of immunoglobulin therapy in German patients with antibody deficiencies. A disease questionnaire was used during standardized interviews. Information was sought on the treating physician and center, the kind of immunodeficiency and its complications. Furthermore, details on the Ig therapy, routine diagnostic procedures and concomitant medication were asked. RESULTS: 13 pediatricians and 5 specialists for internal medicine who treated a total of about 230 patients with CVID/XLA participated in the interviews. Most of the patients received Ig substitution therapy, most frequently as intravenous immunoglobulin (IVIG) infusions in a hospital outpatient setting. Approximately 14 % of the substituted patients received subcutaneous immunoglobulin (SCIG), mostly as self-infusions at home. At the time of the interviews SCIG had not yet been licensed in Germany. The mean monthly dose was 0.4 g per kg bodyweight, both in IVIG and SCIG treatment and most centers aimed at trough IgG levels of 5 to 6 g/l. CONCLUSIONS: The majority of centers followed current guidelines concerning monthly immunoglobulin doses and desired IgG trough levels, but often aimed at the lower end of these recommendations.