Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial.

BACKGROUND: Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation. METHODS: This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24. FINDINGS: Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups. INTERPRETATION: Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations. FUNDING: Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).

[SARS-CoV-2 Infection in Pregnancy and Incidence of Congenital Malformations - is there a Correlation? Analysis of 8032 Pregnancies from the CRONOS Registry]. / SARS-CoV-2-Infektion in der Schwangerschaft und Auftreten von angeborenen Fehlbildungen ­ Besteht ein Zusammenhang? Auswertung von 8032 Schwangerschaften aus dem CRONOS-Register.

BACKGROUND: Based on single case reports, the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS) registry, sponsored by the German Society for Perinatal Medicine (DGPM), investigated the likelihood that SARS-CoV-2 infections of the mother in (early) pregnancy cause embryopathies and/or fetopathies. MATERIAL/METHODS: The CRONOS registry enrolled a total of 8032 women with confirmed SARS-CoV-2 infection during pregnancy at more than 130 participating hospitals from April 2020 to February 2023. Both maternal and fetal data were documented and the anonymized multicenter data were analyzed. RESULTS: Of 7142 fully documented pregnancies (including postnatal data), 140 showed congenital malformations. 8.57% of the mothers had had a SARS-CoV-2-infection in the 1st trimester and 36.43% in the 2nd trimester. In 66 cases with congenital malformations (47.14%), the malformation was only detected after the diagnosis of a maternal SARS-CoV-2 infection. The overall prevalence of congenital malformations in this cohort was 1.96%, compared to a prevalence of 2.39% reported in the EUROCAT (European network of population-based registries for the epidemiological surveillance of congenital anomalies) pre-pandemic registry between 2017-2019. DISCUSSION: Our multicenter data argue against a link between maternal SARS-CoV-2 infection in early pregnancy and congenital malformation.

Application of Next-Generation Sequencing to Enterobacter Hormaechei Subspecies Analysis during a Neonatal Intensive Care Unit Outbreak.

INTRODUCTION: The Enterobacter cloacae complex (ECC) species are potential neonatal pathogens, and ECC strains are among the most commonly encountered Enterobacter spp. associated with nosocomial bloodstream infections. Outbreaks caused by ECC can lead to significant morbidity and mortality in susceptible neonates. At the molecular level, ECC exhibits genomic heterogeneity, with six closely related species and subspecies. Genetic variability poses a challenge in accurately identifying outbreaks by determining the clonality of ECC isolates. This difficulty is further compounded by the limitations of the commonly used molecular typing methods, such as pulsed field gel electrophoresis, which do not provide reliable accuracy in distinguishing between ECC strains and can lead to incorrect conclusions. Next-generation sequencing (NGS) offers superior resolution in determining strain relatedness. Therefore, we investigated the clinical pertinence of incorporating NGS into existing bundle measures to enhance patient management during an outbreak of ECC in a level-3 neonatal intensive care unit (NICU) in Germany. METHODS: As the standard of care, all neonates on the NICU received weekly microbiological swabs (nasopharyngeal and rectal) and analysis of endotracheal secretion, where feasible. During the 2.5-month outbreak, colonisation with ECC was detected in n = 10 neonates. The phylogenetic relationship and potential antimicrobial resistance genes as well as mobile genetic elements were identified via bacterial whole-genome sequencing (WGS) using Illumina MiSeq followed by in silico data analysis. RESULTS: Although all ECC isolates exhibited almost identical antimicrobial susceptibility patterns, the WGS data revealed the involvement of four different ECC clones. The isolates could be characterised as Enterobacter hormaechei subspecies steigerwaltii (n = 6, clonal), subsp. hoffmannii (n = 3, two clones) and subsp. oharae (n = 1). Despite the collection of environmental samples, no source of this diffuse outbreak could be identified. A new standardised operating procedure was implemented to enhance the management of neonates colonised with MRGN. This collaborative approach involved both parents and medical professionals and successfully prevented further transmission of ECC. CONCLUSIONS: Initially, it was believed that the NICU outbreak was caused by a single ECC clone due to the similarity in antibiotic resistance. However, our findings show that antibiotic susceptibility patterns can be misleading in investigating outbreaks of multi-drug-resistant ECC. In contrast, bacterial WGS accurately identified ECC at the clonal level, which significantly helped to delineate the nature of the observed outbreak.

"Multisystem Inflammatory Syndrome in Children" (MIS-C) after COVID-19 Infection in the Metropolitan Area of Nuremberg-Erlangen, Germany-Expectations and Results of a Two-Year Period.

BACKGROUND: Multisystemic Inflammatory Syndrome in children (MIS-C) is a rare autoimmune disorder occurring after a latency period following acute SARS-CoV-2 infection. The therapeutic regime of MIS-C is adapted to the therapy of the Kawasaki disease, as clinical symptoms are similar. Since the Kawasaki disease can potentially result in severe symptoms, which may even affect long-term health, it is essential to gain further knowledge about MIS-C. Thus, we aimed to investigate the incidence, symptoms, therapeutical procedure and outcome of MIS-C patients in the metropolitan area of Nuremberg-Erlangen during the SARS-CoV2 pandemic. MATERIAL AND METHODS: Retrospective analysis of clinical charts of MIS-C patients was carried out at three children's hospitals covering the medical care of the metropolitan area of Nuremberg-Erlangen in Germany. Demographic characteristics and symptoms at first visit, their clinical course, therapeutic regime and outcome were recorded within the time period January 2021-December 2022. RESULTS: Analysis of 10 patients (5 male, 5 female) with MIS-C resulting in an incidence of 2.14/100.000 children. The median time between COVID-19 infection and admission to hospital was 5 weeks. The median age was 7 years. Symptoms comprised fever (100%), rash (70%), bilateral non-purulent conjunctivitis (70%) and urticaria (20%). At the time of presentation, diagnosis-defining inflammation parameters were increased and the range for C-reactive protein was 4.13 mg/dL to 28 mg/dL, with a median of 24.7 mg/dL. Procalcitonin was initially determined in six patients (1.92 ng/mL to 21.5 ng/mL) with a median value of 5.5 pg/mL. Two patients displayed leukocytosis and two displayed leukopenia. None of the patients presented coronary pathologies. Nine of the ten patients received intravenous immunoglobulin (IVIG) therapy. In addition, patients received intravenous steroids (80%) and acetylsalicylic acid (80%). CONCLUSION: SARS-CoV virus may rarely exert multiorgan manifestations due to hyperinflammatory immunological processes. Within two years of the COVID-19 pandemic, we identified ten patients with COVID-induced MIS-C in the metropolitan area Nuremberg-Erlangen. In the description of the patient collective, we can confirm that MIS-C is distinguished from the Kawasaki disease by the lack of coronary manifestations. Interestingly, although having monitored all pediatric facilities in the investigated area, we find lower incidences of MIS-C compared to findings in the literature. In conclusion, an overestimation of incidences in the upcoming MIS-C during the pandemic needs to be considered.

Impact of premature birth on cardiopulmonary function in later life.

Pulmonary function is reduced in children after preterm birth. The variety of subgroups ranges from early to late preterm births. Limitations in pulmonary function can be observed even after late preterm birth without signs of bronchopulmonary dysplasia and/or history of mechanical ventilation. Whether this reduction in lung function is reflected in the cardiopulmonary capacity of these children is unclear. This study aims to investigate the impact of moderate to late premature birth on cardiopulmonary function. Cardiopulmonary exercise testing on a treadmill was performed by 33 former preterm infants between 8 and 10 years of age who were born between 32 + 0 and 36 + 6 weeks of gestation and compared with a control group of 19 children born in term of comparable age and sex. The former preterm children achieved comparable results to the term-born controls with respect to most of the cardiopulmonary exercise parameters [Formula: see text]. The only differences were in a slightly higher oxygen uptake efficiency slope [Formula: see text] and higher peak minute ventilation [Formula: see text] in the group of children born preterm. With respect to heart rate recovery [Formula: see text] and breathing efficiency [Formula: see text], there were no significant differences. CONCLUSION:  Children born preterm did not show limitations in cardiopulmonary function in comparison with matched controls. WHAT IS KNOWN: • Preterm birth is associated with reduced pulmonary function in later life, this is also true for former late preterms. • As a consequence of being born premature, the lungs have not finished their important embryological development. Cardiopulmonary fitness is an important parameter for overall mortality and morbidity in children and adults and a good pulmonary function is therefore paramount. WHAT IS NEW: • Children born prematurely were comparable to an age- and sex-matched control group with regards to almost all cardiopulmonary exercise variables. • A significantly higher OUES, a surrogate parameter for VO2peak was found for the group of former preterm children, most likely reflecting on more physical exercise in this group. Importantly, there were no signs of impaired cardiopulmonary function in the group of former preterm children.

Premature birth associated with a favorable course in gestational alloimmune liver disease (GALD): A case report.

Gestational alloimmune liver disease (GALD) is a rare neonatal disorder with high mortality and morbidity. The patients come to caregivers' attention aged a few hours or days. The disease manifests as acute liver failure with or without siderosis. The differential diagnosis of neonatal acute liver failure (NALF) is broad, including mainly immunologic, infectious, metabolic and toxic disorders. The most common cause, however, is GALD followed by herpes simplex virus (HSV) infection. The best suited pathophysiological paradigm of GALD is that of a maternofetal alloimmune disorder. State of the art treatment combines intravenously administered immunoglobulin (IVIG) with exchange transfusion (ET). We report an infant born at 35 + 2 weeks' gestation in whom GALD had a favorable course, of interest because premature birth in our patient may have exerted protective aspects and lessened morbidity in that intrauterine exposure to maternal complement-fixing antibodies was shortened. The diagnosis of GALD was challenging and difficult. We suggest a modified diagnostic algorithm combining clinical findings with histopathologic findings in liver and lip mucosa and, if available, on abdominal magnetic resonance imaging-study focusing on the liver, spleen, and pancreas. This diagnostic workup must be followed by ET and subsequent administration of IVIG without delay.

Evaluating the Use of Neonatal Colonization Screening for Empiric Antibiotic Therapy of Sepsis and Pneumonia.

(1) Background: Since 2013, weekly screening for multidrug-resistant Gram-negative (MDRGN) bacteria has been performed in German neonatal intensive care units (NICU). National guidelines recommend considering these colonization analyses for antibiotic treatment regimens. Our retrospective single center study provides insight into the clinical dichotomy of bacterial colonization and infection rates in neonates. (2) Methods: We analyzed microbiological data of neonates admitted to our tertiary level NICU over nine years. Colonization with MDRGN/Serratia marcescens (SERMA) was compared to microbiological findings in sepsis and pneumonia. (3) Results: We analyzed 917 blood and 1799 tracheal aspirate samples. After applying criteria from the Nosocomial Infection Surveillance for Neonates (NEO-KISS), we included 52 and 55 cases of sepsis and pneumonia, respectively; 19.2% of sepsis patients and 34.5% of pneumonia patients had a prior colonization with MDRGN bacteria or SERMA. In these patients, sepsis was not attributable to MDRGN bacteria yet one SERMA, while in pneumonias, ten MDRGN bacteria and one SERMA were identified. We identified late-onset pneumonia and cesarean section as risk factors for MDRGN/SERMA acquisition. (4) Conclusions: Colonization screening is a useful tool for hygiene surveillance. However, our data suggest that consideration of colonization with MDRGN/SERMA might promote extensive use of last resort antibiotics in neonates.

Orofacial clefts alter early life oral microbiome maturation towards higher levels of potentially pathogenic species: A prospective observational study.

Orofacial clefts (OFC) present different phenotypes with a postnatal challenge for oral microbiota development. In order to investigate the impact of OFC on oral microbiota, smear samples from 15 neonates with OFC and 17 neonates without OFC were collected from two oral niches (tongue, cheek) at two time points, i.e. after birth (T0: Ø3d OFC group; Ø2d control group) and 4-5 weeks later (T1: Ø32d OFC group; Ø31d control group). Subsequently, the samples were analyzed using next-generation sequencing. We detected a significant increase of alpha diversity and anaerobic and Gram-negative species from T0 to T1 in both groups. Further, we found that at T1 OFC neonates presented a significantly lower alpha diversity (lowest values for high cleft severity) and significantly higher levels of Enterobacteriaceae (Citrobacter, Enterobacter, Escherichia-Shigella, Klebsiella), Enterococcus, Bifidobacterium, Corynebacterium, Lactocaseibacillus, Staphylococcus, Acinetobacter and Lawsonella compared to controls. Notably, neonates with unilateral and bilateral cleft lip and palate (UCLP/BCLP) presented similarities in beta diversity and a mixture with skin microbiota. However, significant differences were seen in neonates with cleft palate only compared to UCLP/BCLP with higher levels of anaerobic species. Our findings revealed an influence of OFC as well as cleft phenotype and severity on postnatal oral microbiota maturation.

Age-related Differences in Immune Reactions to SARS-CoV-2 Spike and Nucleocapsid Antigens.

BACKGROUND/AIM: The manifestation and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections show a clear correlation to the age of a patient. The younger a person, the less likely the infection results in significant illness. To explore the immunological characteristics behind this phenomenon, we studied the course of SARS-CoV-2 infections in 11 households, including 8 children and 6 infants/neonates of women who got infected with SARS-CoV-2 during pregnancy. MATERIALS AND METHODS: We investigated the immune responses of peripheral blood mononuclear cells (PBMCs), umbilical cord blood mononuclear cells (UCBCs), and T cells against spike and nucleocapsid antigens of SARS-COV-2 by flow cytometry and cytokine secretion assays. RESULTS: Upon peptide stimulation, UCBC from neonates showed a strongly reduced IFN-γ production, as well as lower levels of IL-5, IL-13, and TNF-α alongside with decreased frequencies of surface CD137/PD-1 co-expressing CD4+ and CD+8 T cells compared with adult PBMCs. The PBMC response of older children instead was characterized by elevated frequencies of IFN-γ+ CD4+ T cells, but significantly lower levels of multiple cytokines (IL-5, IL-6, IL-9, IL-10, IL-17A, and TNF-α) and a marked shift of the CD4+/CD8+ T-cell ratio towards CD8+ T cells in comparison to adults. CONCLUSION: The increased severity of SARS-CoV-2 infections in adults could result from the strong cytokine production and lower potential to immunomodulate the excessive inflammation, while the limited IFN-γ production of responding T cells in infants/neonates and the additional higher frequencies of CD8+ T cells in older children may provide advantages during the course of a SARS-CoV-2 infection.

Diagnostic Utility of Interleukin-6 in Early-Onset Sepsis among Term Newborns: Impact of Maternal Risk Factors and CRP Evaluation.

(1) Background: Interleukin-6 (IL-6) levels act as an early infection marker preceding C-reactive protein (CRP) elevation. This study seeks to analyze IL-6 behavior in suspected early-onset sepsis (EOS) cases among term newborns, comparing it to that of CRP and evaluating IL-6's diagnostic utility. We also aim to assess the impact of maternal risk factors on EOS in term newborns, quantifying their influence for informed decision making. (2) Methods: The retrospective data analysis included 533 term newborns who were admitted to our hospital because of suspected EOS. IL-6, CRP, and the impact of maternal risk factors were analyzed in the context of EOS using binomial test, Chi-squared test, logistic and linear regression. (3) Results: In the cases of EOS, both IL-6 and CRP were elevated. The increase in CRP can be predicted by the initial increase in IL-6 levels. Among the assessed risk factors, intrapartum maternal fever (adjusted odds ratio 18.1; 95% CI (1.7-4.1)) was identified as the only risk factor significantly associated with EOS. (4) Conclusions: Employing IL-6 as an early infection marker enhanced EOS diagnostic precision due to its detectable early rise. However, caution is required, as elevations in IL-6 and CRP levels do not exclusively indicate EOS. Increased CRP levels in healthy newborns with maternal risk factors may be attributed to dynamics of vaginal labor.

Early MDO with a Virtually Planned Distractor in a Neonate with Pierre Robin Sequence.

Pierre Robin sequence (PRS) is characterized by mandibular micrognathia, glossoptosis, and airway obstruction. We report a case of a female infant with PRS in combination with deletion of chromosome 4q and cardiac insufficiency due to an atrioventricular septum defect. The child was transferred to our center from a peripheral hospital with respiratory insufficiency. Initially, respiration was ensured using a continuous positive airway pressure (CPAP) device because a Tuebingen plate was not tolerated. After a pediatric cardiac surgery intervention, CPAP ventilation proved to be insufficient, and the young patient had to be resuscitated and endotracheal intubation was required for recurrent severe respiratory failure. To avoid tracheostomy, an interdisciplinary decision was made to perform an early mandibular distraction. In the fifth week of life, two patient-specific internal distractors were implanted after prior virtual surgery planning. This approach allows for shorter surgical time through preoperative vector planning and fabrication of a patient-specific distractor, in combination with reduced morbidity through maximum protection of adjacent structures such as the tooth follicles and inferior alveolar nerves. An advancement of the mandible by 15 mm could be achieved within 2 weeks. Thereafter, the small patient could be extubated successfully, and there was no further episode of major respiratory insufficiency. We demonstrate that mandibular early distraction with a patient-specific distractor is a successful method to treat severe respiratory insufficiency in PRS, and it can prevent the necessity for tracheostomy with the resulting disadvantages. We provide details concerning our therapeutic algorithm, metric analyses, and a discussion of relevant literature.

Influence of Timing of Antenatal Corticosteroid Administration on Morbidity of Preterm Neonates.

BACKGROUND/AIM: We investigated the impact of the timing of antenatal corticosteroid (ACS) administration on the clinical outcome of preterm infants. PATIENTS AND METHODS: Two hundred and fifty-five preterm infants between 28+0 and 34+0 weeks of gestation were retrospectively assigned to one of two groups: In the first group, ACS was given within 7 days before birth; the second group, did not receive ACS during that period. The primary outcome parameter was respiratory failure (defined by need for continuous positive airway pressure or mechanical ventilation) due to grade 1-4 respiratory distress syndrome (RDS). Secondary outcomes included the rates of intraventricular hemorrhage (IVH), periventricular leukomalacia, and necrotizing enterocolitis. RESULTS: The rate of RDS was significantly higher in the no ACS group (40% vs. 62%, p=0.0009), especially of the more severe grades 24 (n=37 vs. n=48, p=0.0121). In addition, IVH (1% vs. 9%, p=0.0041) and neonatal infections (72% vs. 89%, p=0.0025) were significantly increased. Univariable and multivariable regression analyses showed a lower likelihood of RDS in the ACS group [odds ratio (OR)=0.295] in infants born closer to term (OR=0.907) and following preterm onset of labor (OR=0.495). Similarly, we observed a lower probability of IVH in the ACS group (OR=0.098), with a higher probability of occurrence of IVH in pre-eclampsia/HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet count) (OR=7.914). CONCLUSION: ACS treatment within the last 7 days before birth significantly reduced the risk of RDS and IVH in preterm. These data emphasize that the timing of ACS administration determines its success.

Maternal SARS-CoV-2 infection during pregnancy: possible impact on the infant.

The risk and potential consequences of mother-to-child transmission of severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) during pregnancy are still a matter of debate. We studied the impact of SARS-CoV-2 infection on 56 complete households, including 27 newborns whose mothers were pregnant when exposed to the virus. Two PCR-confirmed perinatal SARS-CoV-2 transmissions with mild symptoms in affected neonates were recorded. In addition, we observed a severe eye malformation (unilateral microphthalmia, optic nerve hypoplasia, and congenital retinopathy) associated with maternal SARS-CoV-2 infection in weeks 5 and 6 of embryonic development. This embryopathy could not be explained by other infectious agents, genetic factors, drug use, or maternal disease during pregnancy. Eight other women with a history of SARS-CoV-2 infection prior to gestational week 12, however, delivered healthy infants.Conclusion: The repeated occurrence of mother-to-child transmission in our cohort with risks that remain incompletely understood, such as long-term effects and the possibility of an embryopathy, should sensitize researchers and stimulate further studies as well as support COVID-19 vaccination recommendations for pregnant women. Trial registration number: NCT04741412. Date of registration: November 18, 2020 What is Known: •Materno-fetal transmission of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) during pregnancy has rarely been reported so far, but was demonstrated in isolated cases. What is New: •In a study of complete households with documented SARS-CoV-2 infection, including a cohort of pregnant women, we observed perinatal coronavirus transmission at a higher frequency than expected. •We also describe a newborn boy with an eye malformation reminiscent of rubella embryopathy but associated with early gestation SARS-CoV-2 infection of his mother. •A coronavirus-related embryopathy, reported here for the first time, is a finding that requires further investigation.

A surrogate cell-based SARS-CoV-2 spike blocking assay.

To monitor infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and successful vaccination against coronavirus disease 2019 (COVID-19), the kinetics of neutralizing or blocking anti-SARS-CoV-2 antibody titers need to be assessed. Here, we report the development of a quick and inexpensive surrogate SARS-CoV-2 blocking assay (SUBA) using immobilized recombinant human angiotensin-converting enzyme 2 (hACE2) and human cells expressing the native form of surface SARS-CoV-2 spike protein. Spike protein-expressing cells bound to hACE2 in the absence or presence of blocking antibodies were quantified by measuring the optical density of cell-associated crystal violet in a spectrophotometer. The advantages are that SUBA is a fast and inexpensive assay, which does not require biosafety level 2- or 3-approved laboratories. Most importantly, SUBA detects blocking antibodies against the native trimeric cell-bound SARS-CoV-2 spike protein and can be rapidly adjusted to quickly pre-screen already approved therapeutic antibodies or sera from vaccinated individuals for their ACE2 blocking activities against any emerging SARS-CoV-2 variants.

[Is the Quality Guideline of Care Delivery of Preterm and Mature Infants (QFR-RL) of the Federal Joint Committee (G-BA) a Quality Risk? - An Analysis of the Fulfillment Rate and the Consequences for Care Delivery to Other IC Patients and Imminent Premature Infants at a Regional Network of Perinatal Centers]. / Qualitätssicherungsrichtlinie Früh- und Reifgeborene des Gemeinsamen Bundesausschusses als Qualitätsrisiko?

BACKGROUND: The quality guideline for care delivery to preterm and mature infants (QFR-RL) places high demands on perinatal centers. In this analysis, the degree of fulfillment was determined. Additionally, care delivery to further patient groups and sufficient nursing staff capacity for care delivery to imminent preterm infants (FG) were evaluated. METHODS: A network of 4 perinatal centers (level 1) with about 10,000 births per year supplied the data on the ratio of 1:1/1:2-care infants, patients per nurse, and nursing staff capacity. This data was statistically evaluated by center, shift, and week day over a period of 5 months for compliance with QFR-RL and DGPM recommendations. Furthermore, imminent preterm infants were recorded and compared with available nursing staff capacity. RESULTS: In total, the QFR-RL was fulfilled in 88% of shifts (n=1,584). Only one center reached the required 95%. The degree of fulfillment and the number of staff nurses declined from late to night shifts (p<0.001). The ratio of 1:1-care infants was significantly higher when demands were not fulfilled (p<0.001). Only 14.1% of imminent preterm infants could have been attended in accordance with the QFR-RL. CONCLUSION: 1:1 care as well as lower nurse staffing in late and night shifts lead to non-fulfillment of requirements and poorer care delivery to other intensive care patients. This was also reflected in the lower degree of fulfillment of DGPM recommendations. Sufficient nursing staff capacity was rare with the consequence that it was almost impossible to deliver care to imminent preterm infants per the guideline.

Safety and immunogenicity of Fc-EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects.

In X-linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather or febrile illness. Fc-EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc-EDA and efficacy if applied prenatally. Anti-drug antibodies were detected after intravenous administration in adult males and nonpregnant females, but not in pregnant women when Fc-EDA was delivered intra-amniotically. Most importantly, there was no detectable immune response to the investigational drug in neonates treated by intravenous infusions and in infants who had received Fc-EDA in utero. In conclusion, the safety profile of this drug encourages further development of prenatal EDA1 replacement therapy.

Childhood polyarteritis nodosa in autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is an uncommon disorder of Fas-mediated apoptosis that results in impaired lymphocyte death and, therefore, disturbed immune homeostasis. Besides presentation with lymphadenopathy and splenomegaly, patients with ALPS have a high incidence of autoimmune phenomena. To our knowledge, this is the first description of polyarteritis nodosa that includes numerous arterial aneurysms in a child with ALPS. Active vasculitis resolved after allogeneic hematopoietic stem cell transplantation. This report of polyarteritis nodosa associated with human ALPS supports previous findings in Fas-deficient mouse models that frequently develop vasculitic manifestations and suggests that apoptotic defects of lymphocytes may play a role in the pathophysiology of systemic vasculitis. Thus, patients with ALPS might be more susceptible to autoimmune vessel inflammation. This case furthermore emphasizes that even rare autoimmune manifestations should be considered and investigated in patients with immunodeficiencies, because that might help in planning treatment strategies for these patients.

Plasticity of dendritic cell function in response to prostaglandin E2 (PGE2) and interferon-gamma (IFN-gamma).

Current evidence suggests that maturing dendritic cells (DCs) acquire a migratory phenotype to induce T cell responses in lymph nodes or a proinflammatory phenotype to condition the microenvironment at peripheral sites. We show that the interplay of PGE(2) and IFN-gamma generates a more complex pattern of mixed DC phenotypes in response to TLR stimulation. DCs activated by the TLR ligand R-848 in the presence of IFN-gamma and PGE(2) produced high levels of IL-12p70 and IL-23, started migration toward CCL19 within only 10 h, and still continued to secrete IL-12p70 without further restimulation following the migration step. The accelerated onset of migration was a result of PGE(2) and was associated with reduced plastic adherence and lower amounts of activated CD29. In contrast, IFN-gamma by itself enhanced cell adhesion and strongly hindered CCR7-mediated migration in the absence of PGE(2). This suggests a new role for IFN-gamma in the direct regulation of DC migration through enhanced cell adhesion, perhaps to support the development of T cell effector functions at peripheral sites. Together, our data are relevant to the development of DC vaccines, as they demonstrate the existence of dual-functional DCs, which as a result of the simultaneous effects of PGE(2) and IFN-gamma, can migrate rapidly toward lymph node chemokines and carry with them a wave of primary cytokines.

Efficient chemokine-dependent migration and primary and secondary IL-12 secretion by human dendritic cells stimulated through Toll-like receptors.

Recent findings have demonstrated the properties of cell migration and cytokine secretion to be mutually exclusive and linked them to different functional subpopulations of dendritic cells (DCs). We studied human monocyte-derived DCs after stimulation with peptidoglycan (PGN), poly(I:C), lipopolysaccharide (LPS), and R848 (resiquimod) and found the resulting mature DCs to express CCR7, to migrate toward CCL19 and to be efficient primary interleukin (IL)-12 producers. Importantly, the potential for secondary production of large amounts of IL-12p70 in response to CD40 ligation was also preserved after stimulation by all Toll-like receptor (TLR) ligands. Differences between the TLR ligands were seen in the primary secretion of IL-12 and IL-23, in the survival of the DCs and in the expression of CD38. Finally, DCs stimulated by R848 were efficient in expanding peptide-specific CD8-positive T cells capable of peptide-specific target cell lysis. Together, our data suggest that TLR ligands induce the generation of mature DCs that integrate migratory and cytokine secretory capacity as well as cytotoxic T lymphocyte (CTL) stimulatory properties.

Functional characterization of monocyte-derived dendritic cells generated under serumfree culture conditions.

The culture of human monocyte-derived dendritic cells (DCs) is typically performed in media containing human or fetal calf serum, supplements with the potential to influence the cells phenotype and their functional properties. Published clinical trails based on serumfree cultured DCs reported the use of the commercially available medium AIMV. In this study, we directly compared DCs generated in AIMV medium ("AIMV/sf-DCs") with DCs generated in RPMI supplemented with 2% human serum ("RPMI/HS-DCs") in functional assays of potential relevance for vaccine application. Using TNF-alpha/PGE(2)/IL-1beta/IL-6 as maturation stimulus, AIMV/sf-DCs revealed to be comparable with RPMI/HS-DCs with regard to phenotypic expression of maturation markers, survival in vitro, migratory capacity and stimulation of lymphocyte proliferation except for CD1a which was expressed on a fraction of DCs only when cultured in serumfree AIMV medium. However, IL-12p70 production in response to Toll-like receptor (TLR) stimulating agents plus IFN-gamma was consistently lower in AIMV medium although also under serumfree culture conditions, nanogram quantities of IL-12 were produced. Together, DCs with functional characteristics important for in vivo application can be generated under defined serumfree conditions; however, medium and/or serum conditions appear to have strong influence on the production of relevant T cell differentiating cytokines.