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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 $$(\dot{V}O_2peak 43.9\pm6.6\frac{\frac{ml}{kg}}{min}\min vs.41.9\pm8.8\frac{ml}{kg}/\min)$$ ( V ˙ O 2 p e a k 43.9 ± 6.6 ml kg min min v s . 41.9 ± 8.8 ml kg / min ) . The only differences were in a slightly higher oxygen uptake efficiency slope $$(OUES\;of\;1.6\;\pm0.4\;vs\;1.4\;\pm\;0.4)$$ ( O U E S o f 1.6 ± 0.4 v s 1.4 ± 0.4 ) and higher peak minute ventilation $$\dot VEpeak\;of\;55.2\pm 11.3 ml/min\;vs.\;49.1\;ml\;\pm\;8.8/min)$$ V ˙ E p e a k o f 55.2 ± 11.3 m l / m i n v s . 49.1 m l ± 8.8 / m i n ) in the group of children born preterm. With respect to heart rate recovery $$(-35.3\;\pm\;13.8\;bpm\;vs.\;-37.2\;bpm\;\pm\;14.0\;after\;1\;min)$$ ( - 35.3 ± 13.8 b p m v s . - 37.2 b p m ± 14.0 a f t e r 1 m i n ) and breathing efficiency $$\dot{(V}E/\dot VCO_2\;of\;35.9\;\pm\;4.1\;vs\;34.0\;\pm4.6)$$ ( V ˙ E / V ˙ C O 2 o f 35.9 ± 4.1 v s 34.0 ± 4.6 ) , 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.

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.

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., A simple, inexpensive surrogate SARS‐CoV‐2 neutralization assay is introduced. Ectopic expression of the SARS‐CoV‐2 spike protein confers binding of Ramos‐Ig ‐ or HEK293 cells to plate‐bound recombinant human angiotensin‐converting‐enzyme‐2. This interaction can be blocked with reconvalescent or immune serum or with anti‐receptor‐binding domain antibodies. Bound spike‐expressing cells are quantitated with crystal violet.

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.

Orofacial clefts (OFC) present different phenotypes and severities 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. at first consultation 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 processed and analyzed using next-generation sequencing. We detected a significant increase in alpha diversity and distinct phenotypes, e.g., 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 with 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 (UCLP/BCLP) and palate 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.

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 2-4 (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.

Zusammenfassung Hintergrund Die Qualitätssicherungsrichtlinie Früh- und Reifgeborene (QFR-RL) stellt hohe personelle Anforderungen an Perinatalzentren (PNZ). In dieser Analyse wurde der Erfüllungsgrad der PNZ ermittelt und evaluiert, wie sich die Versorgung weiterer Patientengruppen und freie pflegerische Personalkapazität (pPK) für akut zu versorgende Frühgeborene (FG) darstellt. Methodik Aus einem Verbund von 4 PNZ (Level 1) mit ca. 10 000 Geburten pro Jahr wurde der Anteil der 1:1/1:2-Versorgten, Patientenzahl pro Pflegekraft (Pat/P) und pPK nach Zentrum, Schicht und Wochentag über einen Zeitraum von 5 Monaten bzgl. Erfüllung der QFR-RL bzw. der DGPM-Empfehlungen ausgewertet. Zusätzlich wurden anstehende FG erfasst und mit freier pPK abgeglichen. Ergebnisse Insgesamt konnte die QFR-RL in 88% der Schichten (n=1584) erfüllt werden. Nur ein Zentrum erreichte die geforderten 95%. Der Erfüllungsgrad und die Zahl der eingesetzten Pflege nahm in Spät- zu Nachtdiensten ab (p Schlussfolgerungen Die 1:1-Versorgung und die niedrigere Besetzung in Spät- und Nachdiensten waren Faktoren, die zu Unterschreitung der Vorgaben und schlechterer Versorgung der übrigen Intensivpatienten führten. Dies spiegelte auch der niedrige Erfüllungsgrad der DGPM-Empfehlungen wider. Freie pPK war kaum vorhanden, was die Versorgung der anstehenden FG unter Einhaltung der Vorgaben nahezu ausschloss.

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.

Possible mother-to-child transmission of severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) during pregnancy is 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. Three perinatal SARS-CoV-2 transmissions with mild symptoms in affected neonates were recorded (two cases confirmed by PCR, the third one based on clinical findings). 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, or drug use 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 strongly support COVID19 vaccination recommendations for pregnant women.Trial registration number: NCT04741412Date of registration: November 18, 2020

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.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.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 (p0.001). The ratio of 1:1-care infants was significantly higher when demands were not fulfilled (p0.001). Only 14.1% of imminent preterm infants could have been attended in accordance with the QFR-RL.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.Die Qualitätssicherungsrichtlinie Früh- und Reifgeborene (QFR-RL) stellt hohe personelle Anforderungen an Perinatalzentren (PNZ). In dieser Analyse wurde der Erfüllungsgrad der PNZ ermittelt und evaluiert, wie sich die Versorgung weiterer Patientengruppen und freie pflegerische Personalkapazität (pPK) für akut zu versorgende Frühgeborene (FG) darstellt.Aus einem Verbund von 4 PNZ (Level 1) mit ca. 10 000 Geburten pro Jahr wurde der Anteil der 1:1/1:2-Versorgten, Patientenzahl pro Pflegekraft (Pat/P) und pPK nach Zentrum, Schicht und Wochentag über einen Zeitraum von 5 Monaten bzgl. Erfüllung der QFR-RL bzw. der DGPM-Empfehlungen ausgewertet. Zusätzlich wurden anstehende FG erfasst und mit freier pPK abgeglichen.Insgesamt konnte die QFR-RL in 88% der Schichten (n=1584) erfüllt werden. Nur ein Zentrum erreichte die geforderten 95%. Der Erfüllungsgrad und die Zahl der eingesetzten Pflege nahm in Spät- zu Nachtdiensten ab (p0,001). Der Anteil der 1:1-versorgten FG war bei Nichterfüllung der Vorgaben signifikant erhöht (p0,001). 14,1% der anstehenden FG hätten unter Vorgabenerfüllung versorgt werden können.Die 1:1-Versorgung und die niedrigere Besetzung in Spät- und Nachdiensten waren Faktoren, die zu Unterschreitung der Vorgaben und schlechterer Versorgung der übrigen Intensivpatienten führten. Dies spiegelte auch der niedrige Erfüllungsgrad der DGPM-Empfehlungen wider. Freie pPK war kaum vorhanden, was die Versorgung der anstehenden FG unter Einhaltung der Vorgaben nahezu ausschloss.

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.

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.

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.

Abstract 4696 Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunologic disorder caused by defects in the Fas-induced programmed cell death pathway. Impaired lymphocyte apoptosis results in gradual lymphocyte accumulation and dysregulation of lymphocyte homeostasis. ALPS patients usually suffer from persistent generalized lymphadenopathy, hepato-splenomegaly, immune-mediated cytopenias, and other autoimmune phenomena. A 15-month-old boy was diagnosed with ALPS when he presented with typical symptoms. Lab exams showed a pancytopenia, elevated serum immunoglobulin levels, a peripheral expansion of double-negative T lymphocytes of up to 40% of TCRab+ T cells and impaired lymphocyte apoptosis. Molecular analysis confirmed the diagnosis of a type Ia ALPS by identifying a heterozygous Fas gene mutation (D260H). Despite treatment with repeated pulses of high-dose methylprednisolone, intravenous immunoglobulins, and mycophenolate mofetil (MMF) to control lymphoproliferation and recurrent pancytopenia his disease progressed. At three years of age he developed numerous arterial aneurysms of the iliac, mesenterial, renal, hepatic, right middle meningeal, brachial and femoral arteries up to 2.6 cm in diameter and lymphoproliferation resulting in paraplegia and right arm paresis. Stem cell transplantation was considered, and BMT from a 9/10 matched unrelated donor (MUD) after a reduced intensity conditioning regimen (CR) with Fludarabin (150 mg/m2), Melphalan (140 mg/m2/d) and ATG (60mg/kg) was performed using 5.22 × 106 CD34+ cells/kg body weight. However, graft failure had to be diagnosed on day +27. 53 days after the first BMT a PBSCT from the same donor after myeloablative CR using Busulfan (19.2 mg/kg/d i.v.), Etoposid (30 mg/kg/d), Cyclophosphamid (120 mg/kg/d) and ATG (60mg/kg) was performed (24.5 × 106 CD34+ cells/kg bw). Again, graft failure was seen. At day +55 a third HSCT using PBSCT from another 9/10 MUD after CR with Fludarabin i.v. (160 mg/m2), Thiotepa (5 mg/kg/d), 4 Gy total body irradiation (TBI) and campath (1 mg/kg) was performed. 10.8 × 106 CD34+ cells/kg bw were given intra osseous, 9.8 × 106 CD34+ cells/kg bw were given i.v. Engraftment was slow (Leukos 980 day +35), but chimerism showed 99 % donor cells. Two years later the patient is alive and well, with persistent engraftment and good hematological and immunological function. Arterial aneurysms stopped growing and some have thrombosed. This case illustrates some interesting points. Atypical and unusually severe manifestations of ALPS forced us to perform a HSCT in this patient. In severe ALPS stem cell engraftment is difficult to achieve as previously reported in the Fas deficient lpr mouse model. One reason might be the reduced ability of cytotoxic drugs to induce apoptosis in the Fas deficient recipient T cells. Thus, recipient T cells could persist and kill donor cells resulting in graft failure or rejection. Additionally, increased FasL expression on recipient cells could induce apoptosis in Fas bearing donor stem cells as shown in lpr mice. Also, trapping of infused stem cells in the extremely enlarged liver and spleen could have played a role. A 3rd attempt was therefore designed to overcome graft resistance and proved finally successful. The use of TBI together with campath possibly induced more T cell apoptosis than chemotherapy alone. The intra osseous application probably increased engraftment efficiency by avoiding trapping of stem cells in liver and spleen and possibly by induction of tolerance by intra osseous application as described before. Disclosures: No relevant conflicts of interest to declare.