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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naive CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ss repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978), Projekt DEAL; German Federal Ministry of Education and Research (BMBF) [01GM0896, 01GM1111B, 01GM1517C, 01EO1303, 01ZZ1801B]; EU [HEALTHF2-2008-201549]; Novartis; GlaxoSmithKline; LFB; UCB UK; Plasma Protein Therapeutics Association (PPTA),; Care-for-Rare Foundation; PROimmune e.V; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [39087428]; UK National Institute of Health Research; Great Ormond Street Hospital Biomedical Research Centre, Open Access funding enabled and organized by Projekt DEAL. The ESID Registry was supported by the German Federal Ministry of Education and Research (BMBF 01GM0896, 01GM1111B, 01GM1517C, 01EO1303 and 01ZZ1801B) EU grant no. HEALTHF2-2008-201549 (EURO-PADnet), the pharmaceutical companies Novartis, GlaxoSmithKline, LFB, and UCB UK, the Plasma Protein Therapeutics Association (PPTA), the Care-for-Rare Foundation, PROimmune e.V, LFB, and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence StrategyEXC 2155 RESIST-Project ID 39087428. EGD is supported by the UK National Institute of Health Research and the Great Ormond Street Hospital Biomedical Research Centre.

NAD(P)HX dehydratase (NAXD) catalyzes the recovery of toxic derivatives of nicotinamide adenine dinucleotides which play an essential role in mitochondrial metabolism. Mutations in NAXD were recently shown to cause early-onset neurodegeneration exacerbated by febrile illness. Here, we report a novel homozygous stop-gain variant in NAXD in an infant who presented with a fulminant course of autoinflammation, dermatitis, colitis, and cystic encephalomalacia beginning at 3 weeks of age. Our findings support the central role of NAXD-mediated metabolite repair for normal tissue function and implicate innate immune processes in the pathogenesis of NAXD deficiency.

We report the natural history, clinical manifestations, genetics, and immunohematological findings in 14 patients from 11 families with ARPC1B deficiency, delineating the spectrum of the disease that appears progressive and challenging to manage clinically.

Background Pulmonary complications are responsible for high morbidity and mortality rates in patients with the rare immunodeficiency disorder STAT3 hyper-IgE syndrome (STAT3-HIES). The aim of this study was to expand knowledge about lung disease in STAT3-HIES. Methods The course of pulmonary disease, radiological and histopathological interrelations, therapeutic management, and the outcome of 14 STAT3-HIES patients were assessed. Results The patients' quality of life was compromised most by pulmonary disease. All 14 patients showed first signs of lung disease at a median onset of 1.5 years of age. Lung function revealed a mixed obstructive-restrictive impairment with reduced FEV1 and FVC in 75% of the patients. The severity of lung function impairment was associated with Aspergillus fumigatus infection and prior lung surgery. Severe lung tissue damage, with reduced numbers of ATP-binding cassette sub-family A member 3 (ABCA3) positive type II pneumocytes, was observed in the histological assessment of two deceased patients. Imaging studies of all patients above 6 years of age showed severe airway and parenchyma destruction. Lung surgeries frequently led to complications, including fistula formation. Long-term antifungal and antibacterial treatment proved to be beneficial, as were inhalation therapy, chest physiotherapy, and exercise. Regular immunoglobulin replacement therapy tended to stabilize lung function. Conclusions Due to its severity, pulmonary disease in STAT3-HIES patients requires strict monitoring and intensive therapy.

Pediatric rheumatology 19(1), 38 (2021). doi:10.1186/s12969-021-00510-8, Published by BioMed Central, London

Background: Investigating the role of children in the COVID-19 pandemic is pivotal to prevent the virus spreading. In most cases, children infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) develop non-specific symptoms or are asymptomatic. Therefore, the infection rate among this age group remains unclear. Seroprevalence studies, including clinical questionnaires, may contribute to our understanding of the time course and clinical manifestations of SARS-CoV-2 infections. Methods: SARS-CoV-2-KIDS is a longitudinal, hospital-based, multicentre study in Germany on the seroprevalence of anti-SARS-CoV-2 immunoglobulin G, as determined by an Enzyme-Linked Immunosorbent Assay in children (aged ≤17 years). A study-specific questionnaire provided additional information on clinical aspects. Findings: This analysis included 10,358 participants recruited from June 2020 to May 2021. The estimated anti-SARS-CoV-2 seroprevalence increased from 2·0% (95% confidence interval (95% CI) 1·6, 2·5) to 10·8% (95% CI 8·7, 12·9) in March 2021, without major change afterwards and was higher in children with migrant background (on average 6·6% vs. 2·8%). In the pandemic early stages, children under three years were 3·5 (95% CI 2·2, 5·6) times more likely to be seropositive than older children, with the levels equalising in later observations. History of self-reported respiratory tract infections or pneumonia was associated with seropositivity (OR 1·8 (95% CI 1·4, 2·3);2·7 (95% CI 1·7, 4·1)). Interpretation: The majority of children in Germany do not have detectable SARS-CoV-2 IgG. To some extent, this may reflect the effect of differing containment measures implemented in the federal states. Detection levels might have been greater in certain age groups or migrant background. Lifting containment measurements is likely to cause a general increase in respiratory tract infections, which already pose a challenge to paediatric medical care during regular winter seasons. This challenge might become critical with additional infections caused by SARS-CoV-2.

Primary immunodeficiency disorders (PIDs) are often associated with autoimmune disease due to the dysregulation of the immune system and distributed central and peripheral tolerance. In many inborn immune deficiencies, lymphocytes may be present but they are dysfunctional, allowing for the development of excessive autoreactivity skipping negative selection process and resultant autoimmune disease. This chapter summarizes the clinical approaches to the main immune dysregulations including hemophagocytic lymphohistiocytosis syndromes, autoimmunity with lymphoproliferation and autoimmunity without lymphoproliferation.

Das Update ist eine Zusammenfassung des im neuen Handbuch (7. Auflage) erscheinenden Kapitels uber Infektion mit Humanem Immundefizienz-Virus (HIV) der Deutschen Gesellschaft fur padiatrische Infektiologie sowie der derzeit in Uberarbeitung befindlichen Leitlinie HIV-Infektion der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AMWF) im Kindesalter. Es werden die neuesten Empfehlungen hinsichtlich Therapie der padiatrischen HIV-Infektion, supportiven Therapien und Pravention der vertikalen HIV-Transmission und Postexpositionsprophylaxe nach akzidenteller HIV-Exposition vorgestellt.

Background: About one quarter of children affected with cancer die. For children and their families, the end-of-life period is highly distressing. Aim: This study focused on how end-of-life care in pediatric cancer patients changed over a period of 10 years and if changes in pediatric palliative care structures were associated with quality of care. Design: Over a 10-year period, all pediatric oncology departments in one German federal state were invited to participate in a repeated cross-sectional cohort study at three time-points (2005, 2010, 2015). Departments invited parents whose children died due to cancer 5 years earlier to participate. Identical semi-structured interviews were conducted with each cohort by the Survey of Caring for Children with Cancer. In addition, departments provided information on their pediatric palliative care infrastructure. Participants: In total, 124 families participated; 73% of interviews were conducted with mothers, 18% with fathers, and 9% with both parents. Results: Parents’ perception of symptom occurrence, symptom burden, and effectiveness of symptom-related treatment remained stable over the 10-year period. Over time, the availability of pediatric palliative care ( p Conclusion: Advances in the availability of pediatric palliative care were associated with improvement in some aspects of quality of care (e.g. location of death) while other aspects, such as effectiveness of symptom management, remained unchanged. Further research is required to determine whether additional improvement in structural quality may increase the effectiveness of symptom management.

Severe bacterial infection (SBI) poses a significant clinical problem as its mortality and morbidity is still unacceptably high. A systematic literature analysis was performed with an emphasis on recent meta analyses examining the specificity and sensitivity of conventional inflammation biomarkers (C-reactive protein, procalcitonin, interleukin-6, interleukin-8) for diagnosing SBI. Most inflammation biomarkers do not show high sensitivity and are of limited value regarding SBI detection. To the practicing clinician, the sole use of inflammation markers is not useful for differentiating between viral or bacterial origin of infection in an individual patient. Thus, only in combination with clinical biometric markers, taken from patient history and physical examination, is the analysis of inflammation biomarkers to some degree helpful in clinical practice. To date, their sensitivity and specificity have been best captured in the field of neonatology, where levels of interleukin-6 have been measured in combination with relevant perinatal factors. The indiscriminate use of inflammation biomarkers for the diagnosis of SBI may lead to over diagnosis. Novel technologies for pathogen detection and more precise measurement of the host-response using microarrays, allowing for simultaneous detection of multiple genes or proteins, promise to improve the value of laboratory biomarkers for the diagnosis of SBI.Statement of novelty: Presented here is an up-to-date systematic analysis of C-reactive protein and inflammation biomarkers with regard to their use in the diagnosis of SBI. I question whether a broad use of C-reactive protein is useful in patients presenting with infection. The results of the systematic analysis are put into context with recent concerns about over-diagnosing in medicine. This paper is adapted from a publication in the German journal Monatsschrift Kinderheilkunde.

Die Untersuchung von Laborbiomarkern wird im klinischen Alltag des Kinderarztes extrem haufig eingesetzt. Auf Basis einer breiten Literatursuche wird die Evidenz zum Einsatz von Biomarkern fur das Management von Infektionen, insbesondere von schweren bakteriellen Infektionen (SBI), analysiert. Vor dem Hintergrund der physiologischen Entzundungsreaktion wird die Rolle klassischer Entzundungsmarker wie C‑reaktives Protein (CRP) und Prokalzitonin (PCT), von Zytokinen und hamatologischen Markern (z. B. Blutbild) sowie neuer Laborverfahren (z. B. Transkriptom- und Proteomanalysen) bei der Infektionsdiagnostik in ubersichtlicher Form dargestellt. Es wird diskutiert, ob ein generelles Screening mit Labormarkern in der Notfallsituation sinnvoll ist, ob Laborbiomarker zwischen bakteriellen und nichtbakteriellen Infektionen unterscheiden konnen und wie gut sie sich fur die Fruherkennung und die Verlaufsbeurteilung von SBI eignen. Statistisch gesehen sind die Konzentrationen klassischer Biomarker wie CRP und PCT bei bakteriellen Infektionen zwar hoher als bei viralen Infektionen, im Einzelfall hilft der einzelne CRP- oder PCT-Wert aber nicht bei der Unterscheidung. Die Kombination der Befunde aus Anamnese/korperlicher Untersuchung (klinisch-biometrische Biomarker) und Laborbiomarkern stellt den erfolgreichsten Ansatz zur Fruherkennung von SBI dar. Mit Ausnahme der Neonatologie fehlen Daten aus gut durchgefuhrten klinischen Studien, um den Nutzen der Laborbiomarker fur die Verlaufsbeurteilung und die Steuerung der Therapie zu belegen. Ein kritischerer Einsatz von Laborbiomarkern in Praxis und Klinik als bisher ist angezeigt, um unnotige Eingriffe und Therapien bei Kindern zu vermeiden.

Contains fulltext : 229571.pdf (Publisher’s version ) (Closed access) BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

BACKGROUND Monoclonal antibodies (mAb) and fusion proteins (FP) are increasingly being used in children and adolescents. In this review, we analyze the evidence for their safety and efficacy in the treatment of the most common chronic inflammatory diseases. METHODS We systematically searched PubMed, AWMF.org, and other databases for high-quality trials (i.e., randomized controlled trials with clinical primary endpoints) and guidelines published at any time up to 10 December 2018 that dealt with mAb and FP that are approved for pediatric use. The search term was "monoclonal anti- body/fusion protein [e. g. adalimumab] AND children." RESULTS The 620 hits included 25 high-quality trials (20 of them manufacturer- sponsored) on 9 mAb/FP (omalizumab, adalimumab, etanercept, ustekinumab, infliximab, golimumab, anakinra, canakinumab, tocilizumab, and abatacept), as well as 6 guidelines (3 each of levels S3 and S2k) on the treatment of bronchial asthma, psoriasis, juvenile idopathic arthritis, and chronic inflammatory bowel diseases. For none of these conditions are mAb and FP the drugs of first choice. Adverse drug effects are rare but sometimes severe (infection, immune dysregulation, tumors). CONCLUSION The retrieved trials have deficiencies that make it difficult to reliably evaluate the efficacy, safety, and utility of mAb/FP for children and adolescents with chronic inflammatory diseases. mAb/FP nonetheless represent a treatment option to be considered in case conventional immune-modulating drugs are ineffective. Researcher-initiated, high-quality trials and manufacturer-independent, systematic long-term evaluations of adverse effects (e.g., tumors) are sorely needed.

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment. peerReviewed

Objective To investigate the clinical presentation and medical treatment of patients with systemic juvenile idiopathic arthritis (JIA) during the first year of illness. Our study focused on 3-year outcomes in a subsample of patients who were followed up longitudinally. Methods From 2000 to 2013, 597 patients with systemic JIA and a disease duration of ≤12 months were recorded in the National Pediatric Rheumatologic Database. Among those patients, 3-year outcome data were available for 133. These data included the clinical Juvenile Arthritis Disease Activity Score in 10 joints (JADAS-10) and the physician's global assessment score (on a numerical rating scale), as well as assessment of joint involvement, growth retardation, and patient-reported outcomes. Results The median clinical JADAS-10 declined significantly, from 7 in 2000 to 2 in 2013, while the proportion of patients with inactive disease increased from 19% in 2000 to 41% in 2013. The rate of treatment with systemic glucocorticoids and disease-modifying antirheumatic drugs (DMARDs) remained stable from 2000 to 2013. By 2013, the proportion of patients with systemic JIA who were treated with biologic DMARDs had increased to 20%. At 3-year follow-up, 72% of patients with systemic JIA had inactive disease, and 77% had no functional limitations. Growth retardation was associated with persistently high disease activity and continuing treatment with systemic glucocorticoids. At the 3-year follow-up, one-third of patients were still being treated with systemic glucocorticoids. Conclusion The proportion of patients with inactive disease has increased over the past decade. Possible explanations may include improved access to specialized care, additional treatment options, and earlier or faster step-up treatment. However, challenges in the management of systemic JIA remain, as ∼30% of patients continue to present with ongoing active disease.

Background Current national immunisation schedules differ between countries in terms of vaccine formulation, timing of vaccinations and immunisation programme funding and co-ordination. As a result, some HIV infected paediatric population may be left susceptible to vaccine preventable infections. Vaccines used in healthy population should be subjected to high quality ethical research and be explicitly validated for use in children with special vaccination needs such as those infected with HIV. This survey was completed to assess current vaccination practices and attitudes toward vaccination among pediatricians who care for vertically HIV infected children. Methods An online questionnaire was completed by 46 experts in paediatric HIV-infection from the Paediatric European Network for Treatment of AIDS (PENTA). Data were collected between November 2013 and March 2014. Results 46 units looking after 2465 patients completed the questionnaire. The majority of units (67%) reported that common childhood immunisation were administered by the family doctor or local health services rather than in the HIV specialist centre. Vaccination histories were mostly incomplete and difficult to obtain for 40% of the studied population. Concerns were reported regarding the use of live attenuated vaccines, such as varicella and rotavirus, and these were less frequently recommended (61% and 28% of the units respectively). Monitoring of vaccine responses was employed in a minority of centres (41%). A range of different assays were used resulting in diverse units of measurement and proposed correlates of protection. Conclusion Vaccination practices for perinatally HIV-infected children vary a great deal between countries. Efforts should be made to improve communication and documentation of vaccinations in healthcare settings and to harmonise recommendations relating to additional vaccines for HIV infected children and the use of laboratory assays to guide immunisation. This will ultimately improve coverage and vaccine induced immunity in this vulnerable patient group.

Severe combined immunodeficiencies (SCID) comprise a group of genetic diseases characterized by abrogated development of T lymphocytes. In some case reports of atypical SCID patients elevated proportions of γδ T lymphocytes have been reported. However, it is unknown whether these γδ T cells modulate or reflect the patient's clinical phenotype. We investigated the frequency of elevated γδ T cell proportions and associations with clinical disease manifestations in a cohort of 76 atypical SCID patients. Increased proportions of γδ T lymphocytes were present in approximately 60% of these patients. Furthermore, we identified positive correlations between elevated proportions of γδ T cells and the occurrence of CMV infections and autoimmune cytopenias. We discuss that CMV infections might trigger an expansion of γδ T lymphocytes, which could drive the development of autoimmune cytopenias. We advocate that atypical SCID patients should be screened for elevated proportions of γδ T lymphocytes, CMV infection and autoimmune cytopenias.

Background Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting. Methods In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) (https://aid-register.de). Data for this retrospective TCZ study were documented by 13 centers. Results From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1–18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%. Conclusion Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%. Trial registration The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

Objectives Somatic development is impaired in children with congenital heart defects (CHDs), and head circumference seems to be a strong predictor of neurodevelopmental prognosis. The aim of this study was to generate up-to-date reference values for the somatic development (head circumference, body weight, and length/height) of children with CHDs. Study design Our study population consisted of all patients included in the PAN study (Pravalenz angeborener Herzfehler bei Neugeborenen in Deutschland), which was conducted prospectively over a 3-year study period by the Competence Network for Congenital Heart Defects. All children with mild, moderate, and severe CHDs born in 2006-2009 in Germany were enrolled. For computing of z-scores, only children with the following characteristics were included: appropriate for gestational age, nonsyndromic disease, term or post-term delivery, and no cardiac surgery. Results There were 2818 patients included. New z-scores for the described somatic measures of children with mild, moderate, and severe CHDs were computed. Comparisons with the KiGGS study (Gesundheit von Kindern und Jugendlichen in Deutschland) and the Berlin Longitudinal Study revealed significantly lower measurements for all measures—most notably in children with severe CHDs and/or cardiac surgery. In our cohort, no catch-up growth was seen after cardiac surgery. Conclusion Children with severe CHDs demonstrated the most abnormal pattern in growth, including head circumference before and after cardiac surgery, which is indicative of accompanying brain pathology unrelated to operative injury.

Item does not contain fulltext BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

Immunotherapy has been a long wish among immunologists. In the late 19th century, the first proof of immunotherapy was probably the successful treatment of diphtheria by Emil von Behring, using serum (Behring and Kitasato 1890). In 1952, Ogden Bruton showed that patients devoid of immunoglobulins (X-linked agammaglobulinemia) can successfully be treated with plasma containing polyclonal antibodies (Bruton et al. 1952). In 1981, Paul Imbach and colleagues demonstrated that polyclonal antibody preparations can be used to treat immune-mediated disease (idiopathic thrombocytopenic purpura (ITP)) (Imbach et al. 1981).

Background Absent T-cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CIDs) and "atypical" SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound combined immunodeficiency (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions. Objectives We sought to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. Methods In this prospective and retrospective observational study, we recruited nontransplanted patients with P-CID aged 1 to 16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. Results A total of 51 patients were recruited (median age, 9.6 years). Thirteen of 51 had a genetic diagnosis of "atypical" SCID and 14 of 51 of CID. About half of the patients had less than 10% naive T cells, reduced/absent T-cell proliferation, and at least 1 significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) underwent transplantation within 1 year of enrolment, and 5 of 51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution. Conclusions The P-CID study for the first time characterizes a group of patients with nontypical SCID T-cell deficiencies from a therapeutic perspective. Because genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in patients with P-CID.

Mutations in SLC46A1 result in a defect of the proton coupled folate transporter (PCFT) and are the basis of hereditary folate malabsorption (HFM). Patients with HFM frequently present with neurodevelopmental delay and megaloblastic anemia. Some cases may be complicated by additional lymphopenia and immunodeficiency. We report a patient with a new homozygous mutation in the SLC46A1 gene. The boy presented with early-onset pancytopenia and secondary immunodeficiency. We provide clinical and molecular observations that extend the phenotypic description of HFM and highlight diagnostic as well as therapeutic pitfalls in this rare condition.

Primare Immundefekte (PID) werden nach der International Union of Immunological Societies (IUIS) klassifiziert. Die haufigste Indikation zur Immunglobulingabe stellt die Gruppe der „Immundefekte, bei denen ein Antikorpermangel im Vordergrund steht“ dar. Von der Dosierung uber die Applikationsart bis hin zum Management unerwunschter Wirkungen mussen dabei wichtige Aspekte beachtet werden.

Primare (angeborene) Immundefekte haben ihre Ursache in Gendefekten, die sowohl das angeborene als auch das adaptive Immunsystem betreffen konnen. Menschen mit einem Immundefekt fallen vorwiegend durch rezidivierende Infektionen auf. Die meisten Erstdiagnosen werden im Kindesalter gestellt. Dazu gehoren zellulare Immundefekte, Storungen der Phagozytenfunktion und andere primare Immundefekte. Antikorpermangelerkrankungen, insbesondere der variable Immundefekt (CVID), und Komplementdefekte konnen sich jedoch erst im Erwachsenenalter manifestieren. Eine pathologische Infektanfalligkeit bei Erwachsenen ist definiert als mehr als 3 therapiebedurftige (antibiotikapflichtige) Infektionen uber je 4 Wochen Dauer pro Jahr. Die klinischen Leitmotive der Immundefizienz sind pathologische Infektanfalligkeit und Immundysregulation. Erstere zeichnet sich aus durch haufige und schwere Infektionen, deren Erreger, Lokalisation und Verlauf oft ungewohnlich sind. Unter Immundysregulation werden Granulome, Autoimmunkrankheiten, rezidivierende Fieberschube/chronische Entzundung, Ekzemneigung, Lymphoproliferation und chronische Darmentzundung zusammengefast. Zur Diagnostik und Therapie von primaren Immundefekten gibt es konsens- und evidenzbasierte Leitlinien. Die Therapie ist abhangig von der Art des Immundefekts und reicht von Immunglobulinsubstitution bei Antikorpermangelerkrankungen bis zu Stammzelltransplantation bei schweren zellularen Immundefekten.

Objectives The aim was to analyse factors influencing the individual colchicine dose in children with FMF, to evaluate the impact of dose adjustment on the clinical course and inflammation and to identify clinical parameters and biomarkers that predict dose increase in the near future. Methods Data from 409 paediatric FMF patients (4566 visits) derived from the national auto-inflammatory diseases registry were analysed. Serum concentrations of S100 molecules were determined by ELISA. Results The age-dependent colchicine dose is influenced by the present genotype. The body surface area is the anthropometric parameter that correlates best with the applied dosages. Colchicine introduction and dose increase lead to significant reduction of clinical symptoms and inflammation. During established colchicine therapy, an increase of one single biomarker increases the likelihood of a dose increment in the next 12 months with a factor of 1.62-1.94. A combination of biomarkers including S100 molecules increases this odds ratio up to 4.66 when analysing all patients and up to 7.27 when analysing patients with a high risk of severe disease. Conclusion Colchicine therapy is currently guided mainly by the occurrence of clinical symptoms and serological inflammation. Other factors, such as the genotype, the body surface area and biomarkers, will help to manage colchicine therapy in a more individualized fashion. The additional analysis of S100 molecules as sensitive biomarkers will help to identify patients at risk for dose increases in the near future.

In patients with 3-hydroxy-3-methylglutaryl(HMG)-CoA lyase deficiency (OMIM 246450), five pregnancies have been described worldwide, which were either terminated or resulted in severe metabolic sequelae during pregnancy or delivery. Here, we report on a patient with HMG-CoA lyase deficiency, who underwent two uncomplicated pregnancies. The 19-year-old patient was admitted because of recurrent vomiting and nausea. Diagnostics revealed pregnancy at week 8 of gestation. Metabolic analyses revealed normal lactate and blood glucose levels and normal acid-base status. Urine organic acid analysis showed an elevated excretion of 3-CH3-glutaric acid, 2,3-CH3-glutaconic acid, and 3-CH3-3-OH-glutaric acid. Oral treatment with carnitine and glucose wes administered intravenously during the period of nausea and vomiting. After clinical recovery, a diet with 0.89 g/kg of protein/d and 38 kcal/kg body weight/d was given. Meals were taken every 3 h. Additionally, 70 g of starch was given at midnight to maintain normoglycemia at night time. Peripartum, a complete parenteral nutrition, was delivered through a central venous catheter. The patient delivered a healthy male infant by Caesarean section at week 38 of gestation (Apgar 9/10/10) and remained metabolically stable throughout the peripartum period. Postpartum nutrition was gradually changed from parenteral to oral diet. Two years later, the patient became pregnant again and presented with hyperemesis gravidarum. With metabolic monitoring and treatment as before no decompensation occurred. At week 38 of gestation, she delivered a healthy female infant by elective Caesarian section (Apgar 9/10/10). This case report describes the metabolic and obstetric management of two pregnancies in a patient with HMG-CoA lyase deficiency with favorable outcome without metabolic complications.

Background Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. Methods Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. Results The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (Cmax) was 160-200 nM and after 6 hours, the effective concentration (Ceff) was Conclusion Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable Ceff of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

Currently, management of antibody deficient patients differs significantly among caregivers. Evidence and consensus based (S3) guidelines for the treatment of primary antibody deficiencies were developed to improve the management of these patients.

Familial Mediterranean fever (FMF) is an autoinflammatory disease and belongs to the heterogeneous group of hereditary recurrent fever syndromes (HRFs). Aims: The aims of the study were to determine the incidence of FMF in Germany and to describe the spectrum of pyrin mutations and the clinical characteristics in children. A prospective surveillance of children with HRF including FMF was conducted in Germany during a time period of 3 years by the German paediatric surveillance unit for rare paediatric diseases (ESPED). Monthly inquiries were sent to 370 children’s hospitals (Clinic-ESPED, n1) and to 23 laboratories (Laboratory-ESPED, n2). Inclusion criteria were children ≤16 years of age, disease-associated pyrin mutations, and more than three self-limiting episodes of fever >38.5 °C with increased inflammation markers. In n1, 122 patients with FMF and 225 pyrin mutations were identified. Ninety-two of 122 (75 %) children were of Turkish origin. The minimum incidence of FMF was estimated to be 3 (95 % CI: 2.48–3.54) per 106 person-years in the whole children population and 55 (95 % CI: 46–66) per 106 person-years in Turkish children living in Germany. N1 U n2 amounted to 593 asymptomatic and symptomatic carriers of 895 mutations (overlap of 73 cases with 134 mutations). p.Met694Val (45 %), p.Met680Ile (14 %), p.Val726Ala (12 %), and p.Glu148Gln (11.5 %) were the most common pyrin mutations. Conclusions: Despite FMF being the most frequent of the HRFs, its incidence in Germany is low. Twenty-five to 50 FMF patients ≤16 years are newly diagnosed per year. The disease is most commonly observed in individuals of Turkish ancestry.

Hintergrund Hereditare rekurrierende Fiebersyndrome (HRF) sind seltene autoinflammatorische Erkrankungen (AID). Sie sind durch rezidivierende, selbstlimitierende, systemische Entzundungsreaktionen gekennzeichnet und gehen mit einer Dysregulation der angeborenen Abwehr einher.

Die HIV-Infektion bei Kindern und Jugendlichen unterscheidet sich masgeblich von der HIV-Infektion bei Erwachsenen. Dies spiegelt sich insbesondere im Infektionsmodus, in der viralen Dynamik bei unreifem Immunsystem und im klinischen Verlauf wider und beeinflusst unter anderem auch die Entwicklung des Kindes oder Jugendlichen. Neben virologischen, immunologischen und epidemiologischen Aspekten ist auch die psychosoziale Situation sehr unterschiedlich. Die genannten Aspekte und die Tatsache, dass deutlich weniger Wirkstoffe fur die Therapie von Kindern zur Verfugung stehen, erfordern eigene Leitlinien fur die HIV-Therapie bei Kindern und Jugendlichen. Die Padiatrische Arbeitsgemeinschaft AIDS (PAAD) hat diese Leitlinie auf der Basis neuer Studienergebnisse, geanderter internationaler Leitlinien und neuer Arzneimittel 2011 aktualisiert.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and adolescents. Immunomodulatory drugs are used frequently in its treatment. Using the nominal group technique (NGT) and Delphi method, we created a multidisciplinary, evidence- and consensus-based treatment guideline for JIA based on a systematic literature analysis and three consensus conferences. Conferences were headed by a professional moderator and were attended by representatives who had been nominated by their scientific societies or organizations. 15 statements regarding drug therapy, symptomatic and surgical management were generated. It is recommended that initially JIA is treated with NSAID followed by local glucocorticoids and/or methotrexate if unresponsive. Complementing literature evidence with long-standing experience of caregivers allows creating guidelines that may potentially improve the quality of care for children and adolescents with JIA.

Primare Immundefekte sind potenziell lebensbedrohliche Erkrankungen. Auch wenn in den letzten Jahren zunehmend mehr immunologische Defekte klinisch und molekulargenetisch charakterisiert wurden, so werden primare Immundefekt in der taglichen Praxis oftmals noch zu spat erkannt. Vor dem Hintergrund, dass eine fruhe Diagnosestellung die Morbiditat und Mortalitat der betroffenen Patienten senken kann, wurde daher im Auftrag der Arbeitsgemeinschaft Padiatrische Immunologie (API) und der Deutschen Gesellschaft fur Immunologie (DGfI) eine interdisziplinare S2-Leitlinie zur Diagnostik von Primaren Immundefekten erstellt. Grundlage der Leitlinie sind im Wesentlichen Expertenmeinungen auf der Basis bereits verfugbarer Leitlinien und Empfehlungen aus Deutschland und anderen Landern, erganzt durch Daten aus Studien, die die getroffenen Kernaussagen unterstutzen (Evidenzgrad III). Unter Beteiligung von 20 Vertretern aus 14 Fachgesellschaften, Verbanden und Vereinigungen entstand eine konsensbasierte Leitlinie mit reprasentativer Entwicklergruppe und strukturierter Konsensusfindung (S2k). Der nominale Gruppenprozess zur Konsensusfindung fand unter Moderation einer Vertreterin der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (e.V.) (AWMF) im April 2011 statt. Die aufgestellten Kernaussagen wurden diskutiert und im strukturierten Konsensverfahren abgestimmt. Insbesondere wurden modifizierte Warnzeichen fur primare Immundefekte formuliert und immunologische Notfallsituationen definiert.

Die Standardisierung der Therapie der Juvenilen Idiopathischen Arthritis (JIA) hat zu einer Verbesserung der Lebensqualitat von Kindern und Jugendlichen mit JIA gefuhrt. Um die Versorgungsqualitat dieser Patienten weiter zu erhohen, ist eine Aktualisierung der bisherigen S2-Leitlinie von 2008 erforderlich. Durch eine neue systematische Literaturanalyse (Stichworter: juvenile idiopathic (rheumatoid) arthritis, therapy; Suchbegrenzungen (Limits) in PUBMED: humans, published in the last 3 years, all child: 0–18 years, clinical trial; Stichtag 15.01.2011) wurden 17 relevante Studien gefunden. Studien zur Diagnostik der JIA, Uveitis, Impfung, Transition wurden ausgeschlossen. Zu moderierten Konsensuskonferenzen wurden Vertreter folgender Fachgesellschaften und Vereinigungen eingeladen: Berufsverband der Kinder- und Jugendarzte (BVKJ), Deutsche Gesellschaft fur Kinder- und Jugendmedizin (DGKJ), Deutsche Gesellschaft fur Rheumatologie (DGRh), Deutsche Ophthalmologische Gesellschaft (DOG), Deutsche Rheuma-Liga Bundesverband, Verein zur Forderung und Unterstutzung rheumatologisch erkrankter Kinder und deren Eltern, Vereinigung fur Kinderorthopadie, Zentraler Verband der Physiotherapeuten und Krankengymnasten (ZVK). Die Konsensuskonferenzen fanden unter > 95% Teilnahme statt. Konsensus-Statements wurden formal per Nominale Gruppentechnik und im Delphiverfahren gewonnen. Zu den Themen medikamentose, symptomatische und chirurgische Therapie wurden aktualisierte Statements im Konsens erarbeitet und nach Kriterien evidenzbasierter Medizin bewertet. Neue, relevante Studien sind in der 2. Auflage der S2-Leitlinie fur die Therapie der JIA berucksichtigt.