TY  - JOUR
A1  - Härtel, Christoph
A1  - Spiegler, Juliane
A1  - Fortmann, Ingmar
A1  - Astiz, Mariana
A1  - Oster, Henrik
A1  - Siller, Bastian
A1  - Viemann, Dorothee
A1  - Keil, Thomas
A1  - Banaschewski, Tobias
A1  - Romanos, Marcel
A1  - Herting, Egbert
A1  - Göpel, Wolfgang
T1  - Breastfeeding for 3 months or longer but not probiotics is associated with reduced risk for inattention/hyperactivity and conduct problems in very-low-birth-weight children at early primary school age
JF  - Nutrients
N2  - (1) Background: We aimed to evaluate the effect of proposed “microbiome-stabilising interventions”, i.e., breastfeeding for ≥3 months and prophylactic use of Lactobacillus acidophilus/ Bifidobacterium infantis probiotics on neurocognitive and behavioral outcomes of very-low-birthweight (VLBW) children aged 5–6 years. (2) Methods: We performed a 5-year-follow-up assessment including a strength and difficulties questionnaire (SDQ) and an intelligence quotient (IQ) assessment using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-III test in preterm children previously enrolled in the German Neonatal Network (GNN). The analysis was restricted to children exposed to antenatal corticosteroids and postnatal antibiotics. (3) Results: 2467 primary school-aged children fulfilled the inclusion criteria. In multivariable linear regression models breastfeeding ≥3 months was associated with lower conduct disorders (B (95% confidence intervals (CI)): −0.25 (−0.47 to −0.03)) and inattention/hyperactivity (−0.46 (−0.81 to −0.10)) as measured by SDQ. Probiotic treatment during the neonatal period had no effect on SDQ scores or intelligence. (4) Conclusions: Prolonged breastfeeding of highly vulnerable infants may promote their mental health later in childhood, particularly by reducing risk for inattention/hyperactivity and conduct disorders. Future studies need to disentangle the underlying mechanisms during a critical time frame of development.
KW  - breastfeeding
KW  - probiotic prophylaxis
KW  - preterm children
KW  - strength and difficulties
KW  - inattention/hyperactivity
KW  - intelligence
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216319
SN  - 2072-6643
VL  - 12
IS  - 11
ER  - 
TY  - JOUR
A1  - Humberg, Alexander
A1  - Fortmann, Ingmar
A1  - Siller, Bastian
A1  - Kopp, Matthias Volkmar
A1  - Herting, Egbert
A1  - Göpel, Wolfgang
A1  - Härtel, Christoph
T1  - Preterm birth and sustained inflammation: consequences for the neonate
JF  - Seminars in Immunopathology
N2  - Almost half of all preterm births are caused or triggered by an inflammatory process at the feto-maternal interface resulting in preterm labor or rupture of membranes with or without chorioamnionitis (“first inflammatory hit”). Preterm babies have highly vulnerable body surfaces and immature organ systems. They are postnatally confronted with a drastically altered antigen exposure including hospital-specific microbes, artificial devices, drugs, nutritional antigens, and hypoxia or hyperoxia (“second inflammatory hit”). This is of particular importance to extremely preterm infants born before 28 weeks, as they have not experienced important “third-trimester” adaptation processes to tolerate maternal and self-antigens. Instead of a balanced adaptation to extrauterine life, the delicate co-regulation between immune defense mechanisms and immunosuppression (tolerance) to allow microbiome establishment is therefore often disturbed. Hence, preterm infants are predisposed to sepsis but also to several injurious conditions that can contribute to the onset or perpetuation of sustained inflammation (SI). This is a continuing challenge to clinicians involved in the care of preterm infants, as SI is regarded as a crucial mediator for mortality and the development of morbidities in preterm infants. This review will outline the (i) role of inflammation for short-term consequences of preterm birth and (ii) the effect of SI on organ development and long-term outcome.
KW  - preterm infants
KW  - sustained inflammation
KW  - sepsis
KW  - microbiome
KW  - neurocognitive outcome
KW  - chronic pulmonary insufficiency of prematurity
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235019
SN  - 1863-2297
VL  - 42
ER  - 
TY  - JOUR
A1  - Pagel, Julia
A1  - Twisselmann, Nele
A1  - Rausch, Tanja K.
A1  - Waschina, Silvio
A1  - Hartz, Annika
A1  - Steinbeis, Magdalena
A1  - Olbertz, Jonathan
A1  - Nagel, Kathrin
A1  - Steinmetz, Alena
A1  - Faust, Kirstin
A1  - Demmert, Martin
A1  - Göpel, Wolfgang
A1  - Herting, Egbert
A1  - Rupp, Jan
A1  - Härtel, Christoph
T1  - Increased Regulatory T Cells Precede the Development of Bronchopulmonary Dysplasia in Preterm Infants
JF  - Frontiers in Immunology
N2  - Regulatory T cells (Tregs) are important for the ontogenetic control of immune activation and tissue damage in preterm infants. However, the role of Tregs for the development of bronchopulmonary dysplasia (BPD) is yet unclear. The aim of our study was to characterize CD4+ CD25+ forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well-phenotyped preterm infants (n = 382; 23 + 0 – 36 + 6 weeks of gestational age) with a focus on the first 28 days of life and the clinical endpoint BPD (supplemental oxygen for longer than 28 days of age). In a subgroup of preterm infants, we characterized the immunological phenotype of Tregs (n = 23). The suppressive function of Tregs on CD4+CD25- T cells was compared in preterm, term and adult blood. We observed that extreme prematurity was associated with increased Treg frequencies which peaked in the second week of life. Independent of gestational age, increased Treg frequencies were noted to precede the development of BPD. The phenotype of preterm infant Tregs largely differed from adult Tregs and displayed an overall naïve Treg population (CD45RA+/HLA-DR-/Helios+), especially in the first days of life. On day 7 of life, a more activated Treg phenotype pattern (CCR6+, HLA-DR+, and Ki-67+) was observed. Tregs of preterm neonates had a higher immunosuppressive capacity against CD4+CD25- T cells compared to the Treg compartment of term neonates and adults. In conclusion, our data suggest increased frequencies and functions of Tregs in preterm neonates which display a distinct phenotype with dynamic changes in the first weeks of life. Hence, the continued abundance of Tregs may contribute to sustained inflammation preceding the development of BPD. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.
KW  - regulatory T cells
KW  - Tregs
KW  - bronchopulmonary dysplasia
KW  - BPD
KW  - preterm infant
KW  - neonate
KW  - Foxp3
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212409
SN  - 1664-3224
VL  - 11
ER  - 
TY  - JOUR
A1  - Twisselmann, Nele
A1  - Pagel, Julia
A1  - Künstner, Axel
A1  - Weckmann, Markus
A1  - Hartz, Annika
A1  - Glaser, Kirsten
A1  - Hilgendorff, Anne
A1  - Göpel, Wolfgang
A1  - Busch, Hauke
A1  - Herting, Egbert
A1  - Weinberg, Jason B.
A1  - Härtel, Christoph
T1  - Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation
JF  - Frontiers in Immunology
N2  - Preterm infants are highly susceptible to sustained lung inflammation, which may be triggered by exposure to multiple environmental cues such as supplemental oxygen (O\(_2\)) and infections. We hypothesized that dysregulated macrophage (MФ) activation is a key feature leading to inflammation-mediated development of bronchopulmonary dysplasia (BPD) in preterm infants. Therefore, we aimed to determine age-dependent differences in immune responses of monocyte-derived MФ comparing cord blood samples derived from preterm (n=14) and term (n=19) infants as well as peripheral blood samples from healthy adults (n=17) after lipopolysaccharide (LPS) exposure. Compared to term and adult MФ, LPS-stimulated preterm MФ showed an enhanced and sustained pro-inflammatory immune response determined by transcriptome analysis, cytokine release inducing a RORC upregulation due to T cell polarization of neonatal T cells, and TLR4 surface expression. In addition, a double-hit model was developed to study pulmonary relevant exposure factors by priming MФ with hyperoxia (O\(_2\) = 65%) or hypoxia (O\(_2\) = 3%) followed by lipopolysaccharide (LPS, 100ng/ml). When primed by 65% O\(_2\), subsequent LPS stimulation in preterm MФ led to an exaggerated pro-inflammatory response (e.g. increased HLA-DR expression and cytokine release) compared to LPS stimulation alone. Both, exposure to 65% or 3% O\(_2\) together with subsequent LPS stimulation, resulted in an exaggerated pro-inflammatory response of preterm MФ determined by transcriptome analysis. Downregulation of two major transcriptional factors, early growth response gene (Egr)-2 and growth factor independence 1 (Gfi1), were identified to play a role in the exaggerated pro-inflammatory response of preterm MФ to LPS insult after priming with 65% or 3% O\(_2\). Preterm MФ responses to LPS and hyperoxia/hypoxia suggest their involvement in excessive inflammation due to age-dependent differences, potentially mediated by downregulation of Egr2 and Gfi1 in the developing lung.
KW  - preterm infants
KW  - sustained inflammation
KW  - macrophages
KW  - hyperoxia
KW  - hypoxia
KW  - infection
KW  - bronchopulmonary dysplasia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250356
SN  - 1664-3224
VL  - 12
ER  - 
TY  - JOUR
A1  - Fortmann, Ingmar
A1  - Dammann, Marie-Theres
A1  - Humberg, Alexander
A1  - Siller, Bastian
A1  - Stichtenoth, Guido
A1  - Engels, Geraldine
A1  - Marißen, Janina
A1  - Faust, Kirstin
A1  - Hanke, Kathrin
A1  - Goedicke-Fritz, Sybelle
A1  - Derouet, Christoph
A1  - Meyer, Sascha
A1  - Stutz, Regine
A1  - Kaiser, Elisabeth
A1  - Herting, Egbert
A1  - Göpel, Wolfgang
A1  - Härtel, Christoph
A1  - Zemlin, Michael
T1  - Five year follow up of extremely low gestational age infants after timely or delayed administration of routine vaccinations
JF  - Vaccines
N2  - This study is aimed at detecting the rate of untimely immunization in a large cohort of extremely low gestational age neonates (ELGANs) of the German Neonatal Network (GNN) and at addressing risk factors for delayed vaccination and associated long-term consequences. We performed an observational study of the GNN between 1st January 2010 and 31st December 2019. The immunization status for the hexavalent and pneumococcal immunization was evaluated in n = 8401 preterm infants <29 weeks of gestation. Univariate analysis and logistic/linear regression models were used to identify risk factors for vaccination delay and outcomes at a 5-year follow-up. In our cohort n = 824 (9.8%) ELGANs did not receive a timely first immunization with the hexavalent and pneumococcal vaccine. Risk factors for delayed vaccination were SGA status (18.1% vs. 13.5%; OR 1.3; 95% CI: 1.1–1.7), impaired growth and surrogates for complicated clinical courses (i.e., need for inotropes, necrotizing enterocolitis). At 5 years of age, timely immunized children had a lower risk of bronchitis (episodes within last year: 27.3% vs. 37.7%; OR 0.60, 95% CI: 0.42–0.86) but spirometry measures were unaffected. In conclusion, a significant proportion of ELGANs are untimely immunized, specifically those with increased vulnerability, even though they might particularly benefit from the immune-promoting effects of a timely vaccination.
KW  - immunization
KW  - prematurity
KW  - trained immunity
KW  - long-term outcome
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239592
SN  - 2076-393X
VL  - 9
IS  - 5
ER  - 
TY  - JOUR
A1  - Hanke, Kathrin
A1  - Rausch, Tanja K.
A1  - Sosnowski, Runa
A1  - Paul, Pia
A1  - Spiegler, Juliane
A1  - Müller, Mirja
A1  - König, Inke R.
A1  - Göpel, Wolfgang
A1  - Herting, Egbert
A1  - Härtel, Christoph
T1  - Early skin-to-skin contact does not affect cerebral tissue oxygenation in preterm infants <32 weeks of gestation
JF  - Children
N2  - Aim: It was the aim of our study to determine the regional cerebral tissue oxygenation saturation (rcSO\(_2\)) as an additional monitoring parameter during early skin-to-skin contact (SSC) in preterm infants with a gestational age of <32 gestational weeks. Methods: We conducted two observational convenience sample studies using additional monitoring with near-infrared spectroscopy (NIRS) in the first 120 h of life: (a) NIRS 1 (gestational age of 26 0/7 to 31 6/7 weeks) and (b) NIRS 2 (gestational age of 24 0/7 to 28 6/7 weeks). The rcSO\(_2\) values were compared between resting time in the incubator (period I), SSC (period II) and handling nursing care (period III). For the comparison, we separated the sequential effects by including a “wash-out phase” of 1 h between each period. Results: During the first 120 h of life 38/53 infants in NIRS 1 and 15/23 infants in NIRS 2 received SSC, respectively. We found no remarkable differences for rcSO\(_2\) values of NIRS 1 patients between SSC time and period I (95% confidence interval (CI) for the difference in %: SSC vs. period I [1; 3]). In NIRS 2, rcSO\(_2\) values during SSC were only 2% lower compared with period I [median [1. quartile; 3. quartile] in %; 78 [73; 82] vs. 80 [74; 85]] but were similar to period III [78 [72; 83]]. In a combined analysis, a small difference in rcSO\(_2\) values between SSC and resting times was found using a generalized linear mixed model that included gender and gestational age (OR 95% CI; 1.178 [1.103; 1.253], p < 0.0001). Episodes below the cut-off for “hypoxia”; e.g., <55%, were comparable during SSC and periods I and III (0.3–2.1%). No FiO\(_2\) adjustment was required in the vast majority of SSC episodes. Conclusions: Our observational data indicate that rcSO\(_2\) values of infants during SSC were comparable to rcSO\(_2\) values during incubator care and resting time. This additional monitoring supports a safe implementation of early SSC in extremely preterm infants in NICUs.
KW  - regional cerebral oxygenation saturation
KW  - near infrared spectroscopy
KW  - skin-to-skin contact
KW  - preterm infants
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262290
SN  - 2227-9067
VL  - 9
IS  - 2
ER  - 
TY  - JOUR
A1  - Boeckel, Hannah
A1  - Karsten, Christian M.
A1  - Göpel, Wolfgang
A1  - Herting, Egbert
A1  - Rupp, Jan
A1  - Härtel, Christoph
A1  - Hartz, Annika
T1  - Increased expression of anaphylatoxin C5a-receptor-1 in neutrophils and natural killer cells of preterm infants
JF  - International Journal of Molecular Sciences
N2  - Preterm infants are susceptible to infection and their defense against pathogens relies largely on innate immunity. The role of the complement system for the immunological vulnerability of preterm infants is less understood. Anaphylatoxin C5a and its receptors C5aR1 and -2 are known to be involved in sepsis pathogenesis, with C5aR1 mainly exerting pro-inflammatory effects. Our explorative study aimed to determine age-dependent changes in the expression of C5aR1 and C5aR2 in neonatal immune cell subsets. Via flow cytometry, we analyzed the expression pattern of C5a receptors on immune cells isolated from peripheral blood of preterm infants (n = 32) compared to those of their mothers (n = 25). Term infants and healthy adults served as controls. Preterm infants had a higher intracellular expression of C5aR1 on neutrophils than control individuals. We also found a higher expression of C5aR1 on NK cells, particularly on the cytotoxic CD56\(^{dim}\) subset and the CD56\(^-\) subset. Immune phenotyping of other leukocyte subpopulations revealed no gestational-age-related differences for the expression of and C5aR2. Elevated expression of C5aR1 on neutrophils and NK cells in preterm infants may contribute to the phenomenon of “immunoparalysis” caused by complement activation or to sustained hyper-inflammatory states. Further functional analyses are needed to elucidate the underlying mechanisms.
KW  - preterm infants
KW  - C5a
KW  - C5aR1
KW  - neutrophils
KW  - NK cells
KW  - innate immunity
KW  - sepsis
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321196
SN  - 1422-0067
VL  - 24
IS  - 12
ER  -