Proteomic mapping identifies serum marker signatures associated with MIS-C specific hyperinflammation and cardiovascular manifestation.

Multisystem inflammatory syndrome in children (MIS-C) shares several clinical and immunological features with Kawasaki Disease (KD) and pediatric hyperinflammation, but the immuno-phenotypic overlap among these clinical mimics is still incompletely understood. Here we analyzed serum samples from treatment-naïve patients with MIS-C (n = 31) and KD (n = 11), pediatric hyperinflammation (n = 13) and healthy controls (HC, n = 10) by proximity extension assay (PEA) to profile 184 blood biomarkers. Collectively, immunophenotypic overlap between MIS-C and hyperinflammation exceeds overlap with KD. Overexpression of IL-17A in MIS-C and KD could best separate these conditions from hyperinflammatory conditions, while those were hallmarked by overabundance of adenosin deaminase and IL-18. Depletion in serum TNF-related subfamily member 9 (TNFRSF9) and apoptosis inducing ligand (TRAIL) linked with cardiovascular manifestations and myocarditis in MIS-C. Altogether, our analysis highlights important differences in molecular marker signatures also across different MIS-C and KD cohorts and suggests several previously unidentified molecular associations in context of cardiovascular inflammation.

Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.

BACKGROUND: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification. METHODS: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing. FINDINGS: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses. INTERPRETATION: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome. FUNDING: Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Type 1 Interferon-Stimulated Gene Expression and Disease Activity in Pediatric Rheumatic Diseases: No Composite Scores Needed?

OBJECTIVE: Rheumatic diseases are characterized by different patterns of immune overactivation. This study investigated the correlation of whole blood type 1 interferon (IFN) stimulated gene (ISG), IL18, and CXCL9 expression with clinical disease activity in pediatric rheumatic diseases and assessed the required number of ISGs to be included in a composite type 1 IFN score. METHODS: Whole blood-derived RNA and clinical data were collected from 171 mostly pediatric patients with connective tissue diseases (CTDs), systemic autoinflammatory diseases (SAIDs), monogenic interferonopathies (IFNPs) and other inflammatory diseases, and from 38 controls. The expression of six previously established ISGs, IL18, and CXCL9 was assessed by real-time polymerase chain reaction (471 samples). Individual and composite gene expression was assessed, and correlation and threshold analyses were performed. RESULTS: Correlation between ISG expression and clinical disease activity was strongest in CTD, especially in juvenile dermatomyositis (JDM) and IFNP, and modest in patients with SAID. Threshold ISG expression levels for the detection of at least mild clinical disease activity were substantially higher in patients with systemic lupus erythematosus compared with JDM. The correlation of expression levels of limited sets of ISGs and even individual ISGs with clinical disease activity were not inferior to a composite score of six ISGs. CONCLUSION: In a real-world cohort, individual ISG expression levels robustly reflected clinical disease activity in CTD and IFNP, especially in JDM, which would simplify such analyses in clinical routine and be more cost-effective. Threshold levels varied across diseases, potentially reflecting different mechanisms of type 1 IFN overactivation.

Developing a Method for Quantifying Meropenem in Children-Volumetric Adsorptive Microsampling Versus Plasma Sampling.

BACKGROUND: Meropenem is a carbapenem antibiotic often used in pediatric intensive care units due to its broad spectrum of activity. Therapeutic drug monitoring (TDM) is a useful tool to increase the effectiveness of meropenem by adjusting the dose based on plasma levels; however, the relatively large sample volume required for TDM can limit its use in children. Therefore, this study aimed to determine meropenem concentrations and consequently perform TDM effectively using the smallest possible sample volume. Volumetric absorptive microsampling (VAMS) is a sampling technology developed to collect a small, precise volume of blood. For the applicability of VAMS in TDM, plasma concentrations must be reliably calculated from whole blood (WB) collected by VAMS. METHODS: VAMS technology using 10 µL of WB was evaluated and compared with EDTA-plasma sampling. High-performance liquid chromatography with UV detection was applied to quantify meropenem in VAMS and plasma samples after the removal of proteins by precipitation. Ertapenem was used as the internal standard. Samples were collected simultaneously from critically ill children receiving meropenem using VAMS and traditional sampling. RESULTS: It was found that no consistent factor could be determined to calculate meropenem plasma concentrations from the WB, indicating that VAMS was not reliable in the TDM of meropenem. Therefore, to reduce the required sample amount in pediatric patients, a method for quantifying meropenem from 50 µL of plasma with a lower limit of quantification of 1 mg/L was developed and successfully validated. CONCLUSIONS: A simple, reliable, and low-cost method was established using high-performance liquid chromatography-UV to determine the concentration of meropenem in 50 µL of plasma. VAMS using WB does not seem to be suitable for TDM of meropenem.

Continuous Kidney Replacement Therapy Practices in Pediatric Intensive Care Units Across Europe.

Importance: Continuous kidney replacement therapy (CKRT) is the preferred method of kidney support for children with critical illness in pediatric intensive care units (PICUs). However, there are no data on the current CKRT management practices in European PICUs. Objective: To describe current CKRT practices across European PICUs. Design, Setting, and Participants: This cross-sectional survey of PICUs in 20 European countries was conducted by the Critical Care Nephrology Section of the European Society of Pediatric and Neonatal Intensive Care from April 1, 2020, to May 31, 2022. Participants included intensivists and nurses working in European PICUs. The survey was developed in English and distributed using SurveyMonkey. One response from each PICU that provided CKRT was included in the analysis. Data were analyzed from June 1 to June 30, 2022. Main Outcome and Measures: Demographic characteristics of European PICUs along with organizational and delivery aspects of CKRT (including prescription, liberation from CKRT, and training and education) were assessed. Results: Of 283 survey responses received, 161 were included in the analysis (response rate, 76%). The attending PICU consultant (70%) and the PICU team (77%) were mainly responsible for CKRT prescription, whereas the PICU nurses were responsible for circuit setup (49%) and bedside machine running (67%). Sixty-one percent of permanent nurses received training to use CKRT, with no need for certification or recertification in 36% of PICUs. Continuous venovenous hemodiafiltration was the preferred dialytic modality (51%). Circuit priming was performed with normal saline (67%) and blood priming in children weighing less than 10 kg (56%). Median (IQR) CKRT dose was 35 (30-50) mL/kg/h in neonates and 30 (30-40) mL/kg/h in children aged 1 month to 18 years. Forty-one percent of PICUs used regional unfractionated heparin infusion, whereas 35% used citrate-based regional anticoagulation. Filters were changed for filter clotting (53%) and increased transmembrane pressure (47%). For routine circuit changes, 72 hours was the cutoff in 62% of PICUs. Some PICUs (34%) monitored fluid removal goals every 4 hours, with variation from 12 hours (17%) to 24 hours (13%). Fluid removal goals ranged from 1 to 3 mL/kg/h. Liberation from CKRT was performed with a diuretic bolus followed by an infusion (32%) or a diuretic bolus alone (19%). Conclusions and Relevance: This survey study found a wide variation in current CKRT practice, including organizational aspects, education and training, prescription, and liberation from CKRT, in European PICUs. This finding calls for concerted efforts on the part of the pediatric critical care and nephrology communities to streamline CKRT education and training, research, and guidelines to reduce variation in practice.

An Immunological Axis Involving Interleukin 1ß and Leucine-Rich-α2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial.

PURPOSE: A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population. METHODS: Patients' and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1ß were analyzed for single or multiple marker (n = 22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation, and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics. RESULTS: Inflammation in IVIG-resistant KD (n = 16) is hallmarked by over-expression of innate immune mediators (particularly IL-6 > CXCL10 > S100A12 > IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS (n = 13) and MIS-C (n = 4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1ß signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1ß resulted in concentration-dependent LRG1 release. CONCLUSION: Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modeling to associate with IL-1ß signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD.

Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious complication of infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently, neutralising autoantibodies against inflammatory receptor antagonists progranulin and interleukin-1 receptor antagonist (IL-1Ra) were found in adult patients with critical COVID-19. The aim of this study was to investigate the role of such autoantibodies in MIS-C. Methods: In this multicentre, retrospective, cohort study, plasma and serum samples were collected from patients (0-18 years) with MIS-C (as per WHO criteria) treated at five clinical centres in Germany and Spain. As controls, we included plasma or serum samples from children with Kawasaki disease, children with inactive systemic juvenile idiopathic arthritis, and children with suspected growth retardation (non-inflammatory control) across four clinical centres in Germany and Spain (all aged ≤18 years). Serum samples from the CoKiBa trial were used as two further control groups, from healthy children (negative for SARS-CoV-2 antibodies) and children with previous mild or asymptomatic COVID-19 (aged ≤17 years). MIS-C and control samples were analysed for autoantibodies against IL-1Ra and progranulin, and for IL-1Ra concentrations, by ELISA. Biochemical analysis of plasma IL-1Ra was performed with native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signalling reporter assay. Findings: Serum and plasma samples were collected between March 6, 2011, and June 2, 2021. Autoantibodies against IL-1Ra could be detected in 13 (62%) of 21 patients with MIS-C (11 girls and ten boys), but not in children with Kawasaki disease (n=24; nine girls and 15 boys), asymptomatic or mild COVID-19 (n=146; 72 girls and 74 boys), inactive systemic juvenile idiopathic arthritis (n=10; five girls and five boys), suspected growth retardation (n=33; 13 girls and 20 boys), or in healthy controls (n=462; 230 girls and 232 boys). Anti-IL-1Ra antibodies in patients with MIS-C belonged exclusively to the IgG1 subclass, except in one patient who had additional IL-1Ra-specific IgM antibodies. Autoantibodies against progranulin were only detected in one (5%) patient with MIS-C. In patients with MIS-C who were positive for anti-IL-1Ra antibodies, free plasma IL-1Ra concentrations were reduced, and immune-complexes of IL-1Ra were detected. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1Ra was observed in all patients with MIS-C who were positive for anti-IL-1Ra antibodies. Anti-IL-1Ra antibodies impaired IL-1Ra function in reporter cell assays, resulting in amplified IL-1ß signalling. Interpretation: Anti-IL-1Ra autoantibodies were observed in a high proportion of patients with MIS-C and were specific to these patients. Generation of these autoantibodies might be triggered by an atypical, hyperphosphorylated isoform of IL-1Ra. These autoantibodies impair IL-1Ra bioactivity and might thus contribute to increased IL-1ß-signalling in MIS-C. Funding: NanoBioMed fund of the University of Saarland, José Carreras Center for Immuno and Gene Therapy, Dr Rolf M Schwiete Stiftung, Staatskanzlei Saarland, German Heart Foundation, Charity of the Blue Sisters, Bavarian Ministry of Health, the Center for Interdisciplinary Clinical Research at University Hospital Münster, EU Horizon 2020.

Stenotrophomonas maltophilia Infections in Pediatric Patients - Experience at a European Center for Pediatric Hematology and Oncology.

Stenotrophomonas maltophilia is an important nosocomial pathogen in immunocom-promised individuals and characterized by intrinsic resistance to broad-spectrum antibacterial agents. Limited data exists on its clinical relevance in immunocompromised pediatric patients, particularly those with hematological or oncological disorders. In a retrospective single center cohort study in pediatric patients receiving care at a large european pediatric hematology and oncology department, ten cases of invasive S.maltophilia infections (blood stream infections (BSI), 4; BSI and pneumonia, 3, or soft tissue infection, 2; and pneumonia, 1) were identified between 2010 and 2020. Seven patients had lymphoblastic leukemia and/or were post allogeneic hematopoietic cell transplantation. Invasive S.maltophilia infections occurred in a setting of indwelling central venous catheters, granulocytopenia, defective mucocutaneous barriers, treatment with broad-spectrum antibacterial agents, and admission to the intensive care unit. Whole genome sequencing based typing revealed no genetic relationship among four individual S.maltophilia isolates. The case fatality rate and mortality at 100 days post diagnosis were 40 and 50%, respectively, and three patients died from pulmonary hemorrhage. Invasive S.maltophilia infections are an emerging cause of infectious morbidity in patients receiving care at departments of pediatric hematology and oncology and carry a high case fatality rate.

Extracorporeal Membrane Oxygenation in Children With Cancer or Hematopoietic Cell Transplantation: Single-Center Experience in 20 Consecutive Patients.

Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for severe respiratory and/or circulatory failure. Few data exist on the potential benefit of ECMO in immunocompromised pediatric patients with cancer and/or hematopoietic cell transplantation (HCT). Over a period of 12 years, eleven (1.9%) of 572 patients with new diagnosis of leukemia/lymphoma and nine (3.5%) of 257 patients post allogeneic HCT underwent ECMO at our center. Five (45%) and two (22%) patients, respectively, survived to hospital discharge with a median event-free survival of 4.2 years. Experiences and outcomes in this cohort may aid clinicians and families when considering ECMO for individual patients.

Discrimination of COVID-19 From Inflammation-Induced Cytokine Storm Syndromes Using Disease-Related Blood Biomarkers.

OBJECTIVE: Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes. METHODS: Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome. RESULTS: In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes. CONCLUSION: Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19.

Application of two different nasal CPAP levels for the treatment of respiratory distress syndrome in preterm infants-"The OPTTIMMAL-Trial"-Optimizing PEEP To The IMMAture Lungs: study protocol of a randomized controlled trial.

BACKGROUND: Nasal continuous positive airway pressure (CPAP) applies positive end-expiratory pressure (PEEP) and has been shown to reduce the need for intubation and invasive mechanical ventilation in very low birth weight infants with respiratory distress syndrome. However, CPAP failure rates of 50% are reported in large randomized controlled trials. A possible explanation for these failure rates is the application of insufficient low levels of PEEP during nasal CPAP treatment to maintain adequate functional residual capacity shortly after birth. The optimum PEEP level to treat symptoms of respiratory distress in very low birth weight infants has not been assessed in clinical studies. The aim of the study is to compare two different PEEP levels during nasal CPAP treatment in preterm infants. METHODS: In this randomized multicenter trial, 216 preterm infants born at 26 + 0-29 + 6 gestational weeks will be allocated to receive a higher (6-8 cmH2O) or a lower (3-5 cmH2O) PEEP during neonatal resuscitation and the first 120 h of life. The PEEP level within each group will be titrated throughout the intervention based on the FiO2 (fraction of inspired oxygen concentration) requirements to keep oxygenation within the target range. The primary outcome is defined as the need for intubation and mechanical ventilation for > 1 h or being not ventilated but reaching one of the two pre-defined CPAP failure criteria (FiO2 > 0.5 for > 1 h or pCO2 ≥ 70 mmHg in two consecutive blood gas analyses at least 2 h apart). DISCUSSION: Based on available data from the literature, the optimum level of PEEP that most effectively treats respiratory distress syndrome in preterm infants is unknown, since the majority of large clinical trials applied a wide range of PEEP levels (4-8 cmH2O). The rationale for our study hypothesis is that the early application of a higher PEEP level will more effectively counteract the collapsing properties of the immature and surfactant-deficient lungs and that the level of inspired oxygen may serve as a surrogate marker to guide PEEP titration. Finding the optimum noninvasive continuous distending pressure during early nasal CPAP is required to improve CPAP efficacy and as a consequence to reduce the exposure to ventilator-induced lung injury and the incidence of chronic lung disease in this vulnerable population of very preterm infants. TRIAL REGISTRATION: drks.de DRKS00019940 . Registered on March 13, 2020.

Treatment of Children With Cancer and/or Hematopoietic Stem Cell Transplantation in the Intensive Care Unit: Experience at a Large European Pediatric Cancer Center.

Pediatric cancer treatment and hematopoietic stem cell transplantation (HSCT) carry considerable risks of morbidity. We conducted a single-center retrospective analysis of intensive care unit (ICU) admissions in unselected children and adolescents treated for cancer or undergoing HSCT. In a 10-year time period, 140 patients had 188 ICU admissions for a life-threatening condition. Main reasons for ICU admission were respiratory or cardiovascular insufficiency and sepsis. Mortality in the ICU was 19.1% and related to organ failure or acute complications in 77.8% and progress of the underlying malignancy in 22.2%. Mortality rates at 30, 100, and 365 days after discharge from the ICU were 24.5%, 30.9%, and 39.9%. Kaplan-Meier survival probabilities at 5 and 10 years were 46.4% and 39.8%, respectively. Multivariable analysis revealed the number of failed organ systems, the number of prior ICU stays, and days spent in the ICU as parameters independently associated with death. Taken together, the outcome of pediatric cancer and/or HSCT patients admitted to the ICU for life-threatening conditions was not as dismal as reported elsewhere. Most patients benefitted from ICU care, and survival was predominantly compromised by the evolution of complications.

Successful Extracorporeal Life Support in a Pediatric Hematopoietic Stem Cell Transplant Recipient With Periengraftment Respiratory Failure.

The use of extracorporeal life support (ECLS) as ultimate salvage therapy for hematopoietic stem cell transplant recipients remains controversial among oncologists and critical care specialists. Prognosis is poor, particularly after allogeneic transplantation, and literature to guide clinical decision-making is scarce. Our report describes successful ECLS in a pediatric patient undergoing allogeneic hematopoietic stem cell transplantation, who developed acute respiratory failure during severe neutropenia, followed by immediate neutrophil engraftment. This unique case highlights periengraftment respiratory failure as a possible patient subgroup that could benefit from ECLS; and illustrates that the distinct etiologies of respiratory failure and the patients' immune status deserve closer consideration in future studies evaluating ECLS in this high-risk population.

Munchausen by proxy syndrome mimicking systemic autoinflammatory disease: case report and review of the literature.

BACKGROUND: Systemic autoinflammatory diseases (SAIDs) represent a growing number of monogenic, polygenic or multifactorial disorders that are often difficult to diagnose. CASE PRESENTATION: Here we report a patient who was initially erroneously diagnosed and treated for SAID. Symptoms consisted of recurrent fever, erythematous and/or blistering skin lesions, angioedema, susceptibility to bleeding, external ear infections and reversible anisocoria in the absence of laboratory evidence of systemic inflammation. After two and a half years of extensive diagnostic work-up and multiple empirical therapies, a final diagnosis of Munchausen by proxy syndrome (MBPS) was established. CONCLUSIONS: The diagnosis of SAID needs to be carefully reassessed if measurable systemic inflammation is missing, and MBPS should be included in the differential diagnosis.

Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever.

OBJECTIVE: Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF. METHODS: Neutrophils from FMF patients carrying the p.M694V mutation (1 compound heterozygous and 5 homozygous) and neutrophils from 4 healthy control subjects were purified and stimulated in vitro. Neutrophil secretion of S100A12, interleukin-18 (IL-18), IL-1ß, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1ß were also analyzed in 128 clinically and genetically characterized patients with FMF. RESULTS: In vitro, unstimulated neutrophils from p.M694V-positive patients spontaneously secreted more S100A12, IL-18, and caspase 1 compared to neutrophils from healthy controls. Serum concentrations of S100A12 correlated with disease activity and genotype, with the levels being highest in homozygous patients and with compound heterozygotes displaying higher levels than heterozygotes. Compared to individuals negative for the p.M694V mutation, heterozygous, compound heterozygous, or homozygous p.M694V-positive patients had higher serum levels of S100A12 and IL-18 during inactive and subclinical disease. CONCLUSION: The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markers might help to improve patient care and outcomes.

Renal oligo- and anhydramnios: cause, course and outcome--a single-center study.

PURPOSE: To evaluate the outcome of patients with renal oligohydramnios and explore the impact of patient variables on outcome and prognosis. METHODS: A retrospective single-center study was conducted analyzing 104 pregnancies complicated by oligohydramnios of renal origin from 2001 to 2011. Statistical analysis was performed to assess the influence of pre- and postnatal data on pregnancy outcome, morbidity and mortality. RESULTS: Prenatal renal diagnoses were as follows: hydronephrosis/megaureter: n = 21 (20.2 %), aberrance in renal form or location: n = 7 (6.7 %), cystic renal disease: n = 28 (26.9 %), renal dysplasia: n = 24 (23.1 %), renal agenesis: n = 42 (30.4 %), posterior urethral valves: n = 11 (10.6 %). Hydronephrosis/megaureter and late onset of oligohydramnios were prognostic factors for fetal survival, whereas renal agenesis and associated anomalies had a negative impact on pregnancy outcome. Prenatal interventions did not improve prognosis. CONCLUSIONS: Pregnancies complicated by renal oligohydramnios still have a poor outcome. Careful weighing of prognostic factors is necessary to decide about further therapeutic measures.

Infantile fibrosarcoma - an important differential diagnosis of congenital vascular tumors.

We present the case of a female newborn with life-threatening bleeding of a ruptured infantile fibrosarcoma (IFS) and consecutive multiorgan dysfunction syndrome shortly after birth. After stabilization, the tumor could be treated without amputation due to surgery, laser therapy, and chemotherapy. The patient is free of tumor and doing functionally well after 4 years of follow-up.

Circadian variation on oxygen consumption in preterm infants.

OBJECTIVE: We investigated the diurnal variation in oxygen consumption to determine the optimal time periods of calorimetry in preterm infants. METHODS: Oxygen consumption (VO(2)) was measured continuously for 24 h using indirect calorimetry. Twenty-two premature infants with gestational age of 27-31 (31+/-1.7) weeks were enrolled in the study. Heart rate, respiratory rate, oxygen saturation, skin and rectal temperature and physical activity were monitored continuously. RESULTS: The averaged values of VO(2) showed a significant pattern (P<0.0001) of circadian rhythm with a peak in the afternoon and a nadir during the night with significantly differences between the mean VO(2) values. A circadian variation of VO(2) was found in more than 80% of preterm infants and was unrelated to gestational age, physical activity or environmental stress. The infants spent 90.4% of their time sleeping. CONCLUSIONS: These findings indicate the possible existence of an endogenous circadian rhythm of VO(2) in preterm infants beginning shortly after birth. Day-night variations of VO(2) should be considered when VO(2) values are extrapolated from short measurement periods to prevent overestimation of values.

Concomitant Ewing sarcoma and acute lymphoblastic leukemia in a 5-year-old girl.

Malignancies from the Ewing family of tumors and acute lymphoblastic leukemia (ALL) are not known to be associated with each other. A 5-year-old girl was incidentally found to suffer from acute lymphoblastic leukemia during bone marrow staging for Ewing sarcoma of the radius. The simultaneous presence of two distinct neoplasms was confirmed by RT-PCR, with EWS/FLI1 type 1 rearrangement in the bone tumor and TEL/AML1 rearrangement in the marrow. She was treated with chemotherapy, radiotherapy, and surgery and was in remission of both diseases 31 months after diagnosis.