Thyroid function, thyroid antibodies and early postnatal development in neonates of mothers with thyroid disorders.

BACKGROUND: Thyroid dysfunction during pregnancy is relatively common and can cause obstetric complications and significantly influence fetal development. AIMS: We aimed to evaluate postnatal clinical and laboratory characteristics in the first days of life in infants born to mothers with a thyroid disorder. STUDY DESIGN AND SUBJECTS: We conducted a retrospective single-center study with neonates born between January 2010 and May 2020. Early laboratory parameters and clinical findings in neonates of mothers with different maternal thyroid disorders were analysed. RESULTS: We included 314 newborns of mothers with Hashimoto's thyroiditis, 171 with non-Hashimoto's hypothyroidism, 42 with Graves' disease, 12 with non-Graves' hyperthyroidism, and 190 neonates born to mothers without thyroid dysfunction. No demographic, clinical, and laboratory differences were observed between neonates from mothers with a thyroid disorder and healthy mothers. FT3 and fT4 correlated positively with gestational age (p < 0.001; p < 0.001) and negatively with maximum postnatal weight loss (p = 0.043; p < 0.001). High fT3 values were associated with lower maximum bilirubin levels (p = 0.020). CONCLUSION: Despite an increased morbidity risk due to the transplacental exposure to maternal antibodies, most neonates born to mothers with thyroid disorders show normal postnatal development and thyroid function tests during the first days of life.

Mucha-Habermann disease: a pediatric case report and proposal of a risk score.

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare inflammatory dermatological disease. A case of a 13-year-old boy with FUMHD possibly triggered by mycoplasma infection is presented. Based on FUMHD cases identified in a MEDLINE literature search, demographic, treatment, and outcome data were analyzed. An FUMHD mortality risk score is proposed based on the likelihood ratios of risk factors for a fatal outcome. Our FUMHD case had marked leukopenia and thrombocytopenia at admission. He recovered without systemic immunosuppressive treatment. Literature review revealed 119 FUMHD cases. Overall lethality was 14/119 (12%, CI 6-17%), and lethality in children was lower (1/54, 2%, CI 0-6%) compared to adults (13/65, 20%, CI 11-31%). Risk factors for a fatal outcome (likelihood ratio; P) were sepsis (24.97, P < 0.001), adult vs. pediatric patient age (11.19; P = 0.001), systemic involvement (19.97, P < 0.001), and mucosal involvement (4.58; P = 0.032). The proposed FUMHD mortality risk score = Age/10 + 4 + 4 (if systemic involvement) + 1 (if mucosal involvement) was discriminative (sensitivity 93%, specificity 77%). In FUMHD, immune-suppressive treatment intensity should be balanced against the mortality risk, as infectious complications are a frequent cause of death.

Improved Less Invasive Surfactant Administration Success in Preterm Infants after Procedure Standardization.

Less invasive surfactant administration (LISA) has been introduced at our tertiary Level IV perinatal center since 2016 with an unsatisfactory success rate, which we attributed to an inconsistent, non-standardized approach and ambiguous patient inclusion criteria. This study aimed to improve the LISA success rate to at least 75% within 12 months by implementing a highly standardized LISA approach combined with team training. The Plan Do Study Act method of quality improvement was used for this initiative. Baseline assessment included a review of patient medical records 12 months before the intervention regarding patient characteristics, method success rate, respiratory, and adverse outcomes. A multi-professional team developed a standardized LISA approach and a training program including an educational film, checklists, pocket cards, and team briefings. Twenty-one preterm infants received LISA before and 24 after the intervention. The mean LISA success rate improved from 62% before the intervention to 92% (p = 0.029) after the intervention. Implementing a highly standardized LISA approach and multi-professional team training significantly improved the methods' success rate.

Iatrogenic Blood Loss in Very Low Birth Weight Infants and Transfusion of Packed Red Blood Cells in a Tertiary Care Neonatal Intensive Care Unit.

An adequate blood volume is important for neonatal adaptation. The study objective was to quantify the cumulative iatrogenic blood loss in very low birth weight (VLBW) infants by blood sampling and the necessity of packed red cell transfusions from birth to discharge from the hospital. In total, 132 consecutive VLBW infants were treated in 2019 and 2020 with a median birth weight of 1180 g (range 370-1495 g) and a median length of stay of 54 days (range 0-154 days) were included. During the initial four weeks of life, the median absolute amount of blood sampling was 16.5 mL (IQR 12.3-21.1 mL), sampling volume was different with 14.0 mL (IQR 12.1-16.2 mL) for non-transfused infants and 21.6 mL (IQR 17.5-29.4 mL) for transfused infants. During the entire length of stay, 31.8% of the patients had at least one transfusion. In a generalized logistic regression model, the cumulative amount of blood sampling (p < 0.01) and lower hematocrit at birth (p = 0.02) were independent predictors for the necessity of blood transfusion. Therefore, optimized patient blood management in VLBW neonates should include sparse blood sampling to avoid iatrogenic blood loss.

Comparison of Two Real-Time PCR Assays Targeting Ribosomal Sequences for the Identification of Cystoisospora belli in Human Stool Samples.

Cystoisospora (C.) belli is a coccidian parasite associated with acute or chronic gastroenteritis in immunocompromised patients. Dissatisfactory sensitivity of microscopy as the diagnostic standard approach has been described. Here, we comparatively evaluated two real-time PCRs targeting ribosomal RNA gene sequences of C. belli in stool in a test comparison without a reference standard applying latent class analysis. Therefore, 1000 stool samples from Ghanaian HIV (human immunodeficiency virus) patients (n = 905) as well as military returnees from the tropics (n = 95) were assessed by both assays in parallel. After the exclusion of 33 samples showing PCR inhibition, 29 and 33 positive results were recorded with the 5.8S rRNA gene/ITS-2 sequence PCR and the ITS-2 sequence PCR, respectively, resulting in an accuracy-adjusted prevalence of 3.2%. Nearly perfect agreement between both assays was indicated by Fleiss' kappa of 0.933 with sensitivity and specificity of 92.8% and 100% as well as 100% and 99.8% for the 5.8S rRNA gene/ITS-2 sequence PCR and the ITS-2 sequence PCR, respectively. Both assays proved to be suitable for the diagnosis of C. belli in human stool samples with slightly better sensitivity of the ITS-2 sequence assay, while the 5.8S rRNA gene/ITS-2 sequence PCR may be considered for confirmatory testing.

Whole-Exome Sequencing in Critically Ill Neonates and Infants: Diagnostic Yield and Predictability of Monogenic Diagnosis.

INTRODUCTION: Monogenic diseases play an important role in critically ill neonates and infants treated in the intensive care unit. This study aimed to determine the diagnostic yield of whole-exome sequencing (WES) for monogenic diseases and identify phenotypes more likely associated with a genetic etiology. METHODS: From March 2017 to 2020, a comprehensive diagnostic workup including WES in a single academic center was performed in 61 unrelated, critically ill neonates and infants with an unknown underlying disease within the first year of life. We conducted 59 trio-WES, 1 duo-WES, and 1 single-WES analyses. Symptoms were classified according to the Human Phenotype Ontology. RESULTS: The overall molecular genetic diagnostic rate within our cohort was 46% (28/61) and 50% (15/30) in the subgroup of preterm neonates. Identifying the genetic cause of disease facilitates individualized management in the majority of patients. A positive or negative predictive power of specific clinical features for a genetic diagnosis could not be observed. CONCLUSION: WES is a powerful noninvasive diagnostic tool in critically ill neonates and infants with a high diagnostic rate. We recommend initiating WES as early as possible due to the impact on management and family counseling. Recommendations regarding the clinical utility of WES in critically ill neonates and infants should not be based on the phenotype alone. Here, we present a clinical workflow for the application of WES for critically ill neonates and infants in an interdisciplinary setting.

Hemoconcentration and predictors in Shiga toxin-producing E. coli-hemolytic uremic syndrome (STEC-HUS).

BACKGROUND: Hemoconcentration has been identified as a risk factor for a complicated course in Shiga toxin-producing E. coli-hemolytic uremic syndrome (STEC-HUS). This single-center study assesses hemoconcentration and predictors at presentation in STEC-HUS treated from 2009-2017. METHODS: Data of 107 pediatric patients with STEC-HUS were analyzed retrospectively. Patients with mild HUS (mHUS, definition: max. serum creatinine < 1.5 mg/dL and no major neurological symptoms) were compared to patients with severe HUS (sHUS, definition: max. serum creatinine ≥ 1.5 mg/dL ± major neurological symptoms). Additionally, predictors of complicated HUS (dialysis ± major neurological symptoms) were analyzed. RESULTS: Sixteen of one hundred seven (15%) patients had mHUS. Admission of patients with sHUS occurred median 2 days earlier after the onset of symptoms than in patients with mHUS. On admission, patients with subsequent sHUS had significantly higher median hemoglobin (9.5 g/dL (3.6-15.7) vs. 8.5 g/dL (4.2-11.5), p = 0.016) than patients with mHUS. The product of hemoglobin (g/dL) and LDH (U/L) (cutoff value 13,302, sensitivity 78.0%, specificity of 87.5%) was a predictor of severe vs. mild HUS. Creatinine (AUC 0.86, 95% CI 0.79-0.93) and the previously published score hemoglobin (g/dL) + 2 × creatinine (mg/dL) showed a good prediction for development of complicated HUS (AUC 0.87, 95% CI 0.80-0.93). CONCLUSIONS: At presentation, patients with subsequent severe STEC-HUS had a higher degree of hemoconcentration. This underlines that fluid loss or reduced fluid intake/administration may be a risk factor for severe HUS. The good predictive value of the score hemoglobin (g/dL) + 2 × creatinine (mg/dL) for complicated HUS could be validated in our cohort. A higher resolution version of the Graphical abstract is available as Supplementary Information.

Diagnostic accuracy of interleukin-6 for early-onset sepsis in preterm neonates.

Background: Early-onset sepsis (EOS) is a leading cause of morbidity and mortality among neonates. Yet, accurate diagnosis remains a major challenge in clinical routine.Objective: The aim of this study was to evaluate the diagnostic accuracy of Interleukin-6 (IL-6) in combination with other objective perinatal data for early-onset sepsis (EOS) in preterm neonates.Methods: We conducted a retrospective nested case-control study with preterm neonates with a birth weight < 2000 g born in our NICU between January 2007 and June 2016. Differences of IL-6 levels and other perinatal clinical and laboratory data between neonates with and without EOS were statistically analyzed.Results: Sixty-seven preterm infants with and 115 neonates without EOS were included in this study. Specificity and sensitivity for IL-6 were 72.8% and 75.0%, respectively, with an area under the curve of 0.804 at a cut-off point of 40 ng/l. Depending on the statistical method applied, combining IL-6 with a second perinatal factor led either to an increase of specificity (82.4-100%) or sensitivity (75.0-92.2%).Conclusion: The combination of IL-6 with other perinatal factors can significantly increase specificity and sensitivity in the diagnosis of EOS. However, overall diagnostic accuracy cannot be notably improved as there is a tradeoff between sensitivity and specificity. Although these findings do not necessarily apply in clinical routine, they can be of substantial value in the assistance of individual decision making.

A prospective observational trial evaluating factors predictive of accurate endotracheal tube positioning in neonates and small infants.

BACKGROUND: There is a high incidence of endotracheal tube malposition in neonates and small infants. Yet, verification of accurate endotracheal tube location via radiographic imaging involves radiation exposure. AIMS: This study aimed to identify demographic and clinical parameters associated with accurate endotracheal tube positioning. METHODS: We conducted a prospective single-center study with term and preterm neonates and small infants between January 2018 and November 2019. We investigated correlations between ten variables and accurate endotracheal tube position. RESULTS: One hundred and sixty eight nasal intubations in 139 patients (weight 390-5000 g) were analyzed. An accurate tube position was confirmed by radiographic imaging in 71.4% of the intubations. The endotracheal tube was high in 8.3% and low in 20.2% of the cases. Male gender was the only variable that significantly correlated with an accurate endotracheal tube position (OR 2.5; 95% CI: 1.3, 5.0; P = .010). CONCLUSION: So far, no parameter has proven to be able to predict accurate endotracheal tube position in neonates reliably. These findings emphasize the indispensability of postintubation imaging in neonates and small infants.

Successful Stem Cell Apheresis Using Spectra Optia in a 6 kg Child With Atypical Teratoid/Rhabdoid Tumor.

Peripheral blood stem cell apheresis has become a routine procedure for the collection of peripheral blood stem cells to enable high-dose chemotherapy followed by autologous stem cell transplantation in high-risk pediatric malignancies. However, the procedure remains challenging in very low-weight infants due to high extracorporeal blood volume and citrate toxicity. Our case report demonstrates in detail a successful and complication-free large-volume leukapheresis in a very small infant weighing 6 kg using a Spectra Optia apheresis system after placing a femoral double-lumen Shaldon catheter. Anticoagulation was achieved by citrate dextrose solution without the use of heparin. The total amount of blood being processed during the procedure equaled almost 4 times the total blood volume of the patient. The final apheresis product contained 14.0×10 CD34 cells/kg body weight. The infant was diagnosed with an atypical teratoid/rhabdoid tumor of the thalamus and third ventricle at the age of 3 months and had a history of epileptic seizures.

Effect of hemodialysis on impedance cardiography (electrical velocimetry) parameters in children.

BACKGROUND: Pediatric hemodialysis (HD) patients have a high incidence of cardiovascular morbidity and mortality. The study aim was to investigate whether impedance cardiography (electrical velocimetry, EV) is suitable as a hemodynamic trend monitoring tool in pediatric patients during HD. METHODS: Measurements by EV were obtained before, during, and after HD in a prospective single-center pediatric observational study. In total, 54 dialysis cycles in four different pediatric patients with end-stage kidney disease on chronic HD were included. EV parameters analyzed were heart rate (HR), stroke volume (SV), stroke volume index (SI), cardiac output (CO), cardiac index (CI), thoracic fluid content (TFC), index of contractility (ICON), stroke volume variation (SVV), variation of ICON (VIC), R-R interval (TRR), pre-ejection period (PEP), left ventricular ejection time (LVET), and systolic time ration (STR). Systemic vascular resistance index (SVRI) was calculated. RESULTS: EV did measure significant changes in cardiovascular parameters associated with HD. The following parameters increased after HD: HR (9%), SVV (19%), VIC (33%), PEP (8%), and STR (18%). A decrease after HD was measured in SV (18%), SI (18%), CO (10%), CI (10%), TFC (10%), ICON (7%), TRR (7%), LVET (8%), and LVET (8%). SVRI was not affected by HD. The changes were correlated to ultrafiltration. HD cycles without fluid withdrawal also altered cardiovascular parameters. CONCLUSIONS: Pediatric HD with and without fluid withdrawal changes hemodynamic EV monitoring parameters. Possibly EV may be useful to optimize HD management in pediatric patients.

Intravenous Artesunate for Imported Severe Malaria in Children Treated in Four Tertiary Care Centers in Germany: A Retrospective Study.

BACKGROUND: Intravenous artesunate (ivA) is the standard treatment for severe malaria. Data systematically evaluating the use of ivA in pediatric patients outside malaria-endemic regions are limited. The aim of this case series was to summarize efficacy and safety of ivA for imported severe malaria in children in Germany. METHODS: Our retrospective case series included pediatric patients with imported severe malaria treated with at least 1 dose of ivA (Artesun, Guilin Pharmaceutical; Shanghai, China) at 4 German tertiary care centers. Severe malaria was defined according to World Health Organization criteria. RESULTS: Between 2010 and 2018, 14 children with a median [interquartile range (IQR)] age of 6 (1;9.5) years were included. All children were of African descent. All but 2 patients had Plasmodium falciparum malaria; 1 child had P. vivax malaria and 1 child had P. falciparum and P. vivax co-infection. Median (IQR) parasitemia at admission in patients with P. falciparum was 9.5% (3;16.5). Patients were treated with 1-10 [median (IQR) 3 (3;4)] doses ivA. All but one patient received a full course of oral antimalarial treatment. Parasite clearance was achieved within 2-4 days, with the exception of 1 patient with prolonged clearance of peripheral parasitemia. Three patients experienced posttreatment hemolysis but none needed blood transfusion. Otherwise ivA was safe and well tolerated. CONCLUSIONS: ivA was highly efficacious in this pediatric cohort. We observed episodes of mild to moderate posttreatment hemolysis in approximately one-third of patients. The legal status and usage of potentially lifesaving ivA should be evaluated in Europe.

Cardiovascular Biomarkers in Amniotic Fluid, Umbilical Arterial Blood, Umbilical Venous Blood, and Maternal Blood at Delivery, and Their Reference Values for Full-Term, Singleton, Cesarean Deliveries.

Background: Several cardiovascular biomarkers have regulatory functions in perinatal physiology. Aim: This study aimed to analyze the feto-maternal distribution pattern of biomarkers in samples of amniotic fluid, umbilical arterial blood, umbilical venous blood, and maternal blood samples, and to establish reference values. Each linked sample set consisted of the combined samples obtained in an individual pregnancy. Study design: We performed a prospective, observational, cross-sectional, single-center study. Subjects: The sample cohort included 189 neonates who were born to 170 mothers. A total of 162/189 neonates were full term and 129/189 were delivered by elective cesarean section. Outcome measures: Midregional pro-adrenomedullin (MRproADM [nmol/L]), midregional pro-atrial natriuretic peptide (MRproANP [pmol/L]), brain natriuretic peptide (BNP [pg/mL]), N-terminal pro-brain natriuretic peptide (NTproBNP [pg/mL]), copeptin [pmol/L], and high-sensitive troponin I (hsTnI [pg/mL]) levels were measured. Results: In singleton, full-term, primary cesarean deliveries (n = 91), biomarker levels (median, [IQR]) at delivery were as follows. MRproADM levels in umbilical arterial blood/umbilical venous blood/amniotic fluid/maternal blood were 0.88 (0.20)/0.95 (0.18)/2.80 (1.18)/1.10 (0.54), respectively. MRproANP levels were 214.23 (91.38)/216.03 (86.15)/0.00 (3.82)/50.67 (26.81), respectively. BNP levels were 14.60 (25.18)/22.08 (18.91)/7.15 (6.01)/6.20 (18.23), respectively. NTproBNP levels were 765.48 (555.24)/816.45 (675.71)/72.03 (55.58)/44.40 (43.94), respectively. Copeptin levels were 46.17 (290.42)/5.54 (9.08)/9.97 (7.44)/4.61 (4.59), respectively. Levels of hsTnI were 6.20 (4.25)/5.60 (5.01)/0.45 (1.73)/2.50 (2.40), respectively. Conclusion: We determined reference values for biomarkers in term neonates delivered by primary cesarean section in amniotic fluid, umbilical arterial and venous blood, and maternal blood. Biomarkers in the fetal circulation appear to be of primary fetal origin, except for MRproADM.

Reducing Hematologic Toxicity With Short Course Postexposure Prophylaxis With Zidovudine for HIV-1 Exposed Infants With Low Transmission Risk.

Using retrospectively collected data from 383 infants born to HIV-1-infected mothers receiving antiretroviral therapy, we compared transmission rates and hematologic toxicity between infants receiving 2-week (short course) versus longer duration zidovudine postexposure prophylaxis. Short course resulted in lower hematologic toxicity without evidence of increased vertical transmission risk.

Combined inhibition of receptor tyrosine and p21-activated kinases as a therapeutic strategy in childhood ALL.

Receptor tyrosine kinase (RTK)-dependent signaling has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL) of childhood. However, the RTK-dependent signaling state and its interpretation with regard to biological behavior are often elusive. To decipher signaling circuits that link RTK activity with biological output in vivo, we established patient-derived xenograft ALL (PDX-ALL) models with dependencies on fms-like tyrosine kinase 3 (FLT3) and platelet-derived growth factor receptor ß (PDGFRB), which were interrogated by phosphoproteomics using iTRAQ mass spectrometry. Signaling circuits were determined by receptor type and cellular context with few generic features, among which we identified group I p21-activated kinases (PAKs) as potential therapeutic targets. Growth factor stimulation markedly increased catalytic activities of PAK1 and PAK2. RNA interference (RNAi)-mediated or pharmacological inhibition of PAKs using allosteric or adenosine triphosphate (ATP)-competitive compounds attenuated cell growth and increased apoptosis in vitro. Notably, PAK1- or PAK2-directed RNAi enhanced the antiproliferative effects of the type III RTK and protein kinase C inhibitor midostaurin. Treatment of FLT3- or PDGFRB-dependent ALLs with ATP-competitive PAK inhibitors markedly decreased catalytic activities of both PAK isoforms. In FLT3-driven ALL, this effect was augmented by coadministration of midostaurin resulting in synergistic effects on growth inhibition and apoptosis. Finally, combined treatment of FLT3 D835H PDX-ALL with the ATP-competitive group I PAK inhibitor FRAX486 and midostaurin in vivo significantly prolonged leukemia progression-free survival compared with midostaurin monotherapy or control. Our study establishes PAKs as potential downstream targets in RTK-dependent ALL of childhood, the inhibition of which might help prevent the selection or acquisition of resistance mutations toward tyrosine kinase inhibitors.