Placental clearance not synthesis tempers exaggerated pro-inflammatory cytokine response in neonates exposed to chorioamnionitis.

BACKGROUND: The source and clearance of cytokines in the fetal circulation in term pregnancies complicated by chorioamnionitis remains unclear as are the contributions of placental transport, synthesis, and clearance. The objectives of the study were to determine (1) fetal and/or placental contributions to synthesis and/or clearance of inflammatory and anti-inflammatory cytokines in term pregnancies complicated by chorioamnionitis and (2) whether this differs in pregnancies further complicated by fetal hypoxia. METHODS: Prospective cohort study of pregnancies >37 weeks gestational age that included: Group 1, uncomplicated cesarean delivery without labor (n = 20); Group 2, uncomplicated vaginal delivery (n = 30); Group 3, pregnancies complicated by chorioamnionitis (n = 10); Group 4, complicated by chorioamnionitis + fetal hypoxia (n = 10). Umbilical arterial (UmA) and venous (UmV) blood were assayed for IL-1ß, IL-2, IL-6, IL-8, TNFα, and IL-10. RESULTS: IL-6 and IL-8 were below assay detection in UmA and UmV blood in Group 1 and increased in Group 2 (P < 0.01), UmA¼UmV (P < 0.01). Their concentrations increased further in Groups 3 and 4 (P = 0.003), UmA¼UmV. Placental clearance was concentration dependent that approaches saturation in the presence of chorioamnionitis. CONCLUSIONS: Marked increases in fetal synthesis of IL-6 and IL-8 occur in chorioamnionitis. Synthesis increase further when complicated by fetal hypoxia. Cytokine removal occurs via placental concentration-dependent mechanisms, potentially contributing to adverse fetal effects. IMPACT: The source and role of the placenta in synthesis and/or clearance of inflammatory mediators in term pregnancies complicated by clinical chorioamnionitis are unclear; however, conventional wisdom suggests the placenta is their source. This is the first study demonstrating that circulating concentrations of fetal IL-6 and IL-8 in clinical chorioamnionitis ± birth asphyxia in term pregnancies are of fetal origin. Circulating fetal inflammatory cytokines are cleared by concentration-dependent placental mechanisms that are nearly saturated in chorioamnionitis ± fetal hypoxia. These observations provide additional insight into understanding the fetal immune response in term pregnancies complicated by clinical chorioamnionitis.

Proteoglycans in Toll-like receptor responses and innate immunity.

The extracellular matrix (ECM) is an active and dynamic feature of tissues that not only provides gross structure but also plays key roles in cellular responses. The ever-changing microenvironment responds dynamically to cellular and external signals, and in turn influences cell fate, tissue development, and response to environmental injury or microbial invasion. It is therefore paramount to understand how the ECM components interact with each other, the environment and cells, and how they mediate their effects. Among the ECM components that have recently garnered increased attention, proteoglycans (PGs) deserve special note. Recent evidence strongly suggests that they play a crucial role both in health maintenance and disease development. In particular, proteoglycans dictate whether homeostasis or cell death will result from a given injury, by triggering and modulating activation of the innate immune system, via a conserved array of receptors that recognize exogenous (infectious) or endogenous (tissue damage) molecular patterns. Innate immune activation by proteoglycans has important implications for the understanding of cell-matrix interactions in health and disease. In this review, we will summarize the current state of knowledge of innate immune signaling by proteoglycans, discuss the implications, and explore future directions to define progress in this area of extracellular matrix biology.

Multicenter study assessing physicians' and transport teams' attitudes and expectations about utilizing telemedicine to manage critical neonatal transports.

BACKGROUND: Managing critically ill neonates has unique challenges, and the transport team plays an important role in stabilizing and facilitating the transfer of these neonates from lower-level nurseries to tertiary centers, and the use of telemedicine in transport (tele-transport) can potentially benefit patient care. We conducted a multicenter study to assess the readiness for utilizing telemedicine as an adjunct to guide the care of critically ill neonates among physicians and transport team members (TTMs). This is the first multicenter study that explored physicians' and TTMs' perceptions of telemedicine usage and its value in neonatal transport. METHODS: A confidential, voluntary survey on pre-implementation attitudes toward telemedicine usage during neonatal transport was conducted as part of a quality improvement initiative. This survey involved physicians and TTMs from four academic institutions whose responses were entered into an online survey using REDCap®. The survey inquired about satisfaction with the current practice of phone consultation and the perception of using telemedicine to optimize the management of neonates during transport. RESULTS : The overall response rate for the survey was 60.1%; 82 of 127 (64.6%) physicians and 64 of 116 (55.2%) TTMs responded to the surveys. Half of the physicians and less than one-fourth of the TTMs had prior experience with telemedicine other than that used on neonatal transport. TTMs expressed greater concern about the inconvenience of video (55% vs. physicians 35% agree or strongly agree) and its time consumption (84% vs. physicians 50%). More than 70% of physicians and less than half of TTMs endorsed the potential for added value and quality improvement with video capability. Almost half of TTMs reported concern about video calls reducing their autonomy in patient care. Physicians expressed confidence in management decisions they would make after video calls (72% confident or very confident) and less confidence (49%) about both the phone assessment by TTMs and their decisions based on phone assessment. In contrast, TTMs were confident or very confident (94%) in both sharing their assessment over the phone and executing patient management after a phone call, compared with 70% for decisions made after video calls. CONCLUSIONS : Physicians and TTMs had distinct opinions on the use of telemedicine during neonatal transport. Physicians were more likely than TTMs to agree with statements about the potential for improving quality of care, while TTMs were more likely than physicians to say video calls would be time-consuming and inconvenient. We speculate some differences may stem from the TTMs' concern about losing their autonomy. Therefore, during implementation, it is critical for physicians and TTMs to agree on a shared mental model of indications for telemedicine during transport and its value to the patient care.

Chronic lung disease in full-term infants: Characteristics and neonatal intensive care outcomes in infants referred to children's hospitals.

OBJECTIVE: To describe characteristics, outcomes, and risk factors for death or tracheostomy with home mechanical ventilation in full-term infants with chronic lung disease (CLD) admitted to regional neonatal intensive care units. STUDY DESIGN: This was a multicenter, retrospective cohort study of infants born ≥37 weeks of gestation in the Children's Hospitals Neonatal Consortium. RESULTS: Out of 67,367 full-term infants admitted in 2010-2016, 4886 (7%) had CLD based on receiving respiratory support at either 28 days of life or discharge. 3286 (67%) were still hospitalized at 28 days receiving respiratory support, with higher mortality risk than those without CLD (10% vs. 2%, p < 0.001). A higher proportion received tracheostomy (13% vs. 0.3% vs. 0.4%, p < 0.001) and gastrostomy (30% vs. 1.7% vs. 3.7%, p < 0.001) compared to infants with CLD discharged home before 28 days and infants without CLD, respectively. The diagnoses and surgical procedures differed significantly between the two CLD subgroups. Small for gestational age, congenital pulmonary, airway, and cardiac anomalies and bloodstream infections were more common among infants with CLD who died or required tracheostomy with home ventilation (p < 0.001). Invasive ventilation at 28 days was independently associated with death or tracheostomy and home mechanical ventilation (odds ratio 7.6, 95% confidence interval 5.9-9.6, p < 0.0001). CONCLUSION: Full-term infants with CLD are at increased risk for morbidity and mortality. We propose a severity-based classification for CLD in full-term infants. Future work to validate this classification and its association with early childhood outcomes is necessary.

A comparison of newer classifications of bronchopulmonary dysplasia: findings from the Children's Hospitals Neonatal Consortium Severe BPD Group.

OBJECTIVE: To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population. STUDY DESIGN: Data from the Children's Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between BPD severity and death, tracheostomy, or length of stay, relative to No BPD references. RESULTS: Mortality was highest in 2019 NRN Grade 3 infants (aOR 225), followed by 2018 NICHD Grade 3 (aOR 145). Infants with lower BPD grades rarely died (<1%), but Grade 2 infants had aOR 7-21-fold higher for death and 23-56-fold higher for tracheostomy. CONCLUSIONS: Definitions with 3 BPD grades had better discrimination and Grade 3 2019 NRN had the strongest association with outcomes. No/Grade 1 infants rarely had severe outcomes, but Grade 2 infants were at risk. These data may be useful for counseling families and determining therapies for infants with BPD.

SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway.

The pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here, we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induced inflammatory cytokines and chemokines, including IL-6, IL-1ß, TNFα, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and nucleocapsid (N) proteins. When stimulated with extracellular S protein, human and mouse lung epithelial cells also produced inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly were non-inflammatory, but elicited an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-κB pathway in a MyD88-dependent manner. Further, such an activation of the NF-κB pathway was abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein-induced IL-6, TNF-α, and IL-1ß in wild-type, but not Tlr2-deficient mice. Notably, upon recognition of S protein, TLR2 dimerizes with TLR1 or TLR6 to activate the NF-κB pathway. Taken together, these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.

Decreasing Continuous Positive Airway Pressure Failure in Preterm Infants.

BACKGROUND AND OBJECTIVES: Many preterm infants stabilized on continuous positive airway pressure (CPAP) at birth require mechanical ventilation (MV) during the first 72 hours of life, which is defined as CPAP failure. Our objective was to decrease CPAP failure in infants ≤29 weeks' gestational age (GA). METHODS: A quality improvement bundle named OPTISURF was implemented for infants ≤29 weeks' GA admitted on CPAP, consisting of stepwise escalation of CPAP and less invasive surfactant administration guided by fractional inspired oxygen concentration ≥0.3. The CPAP failure rate was tracked by using control charts. We compared practice and outcomes of a pre-OPTISURF cohort (January 2017 to September 2018) to a post-OPTISURF cohort (October 2018 to December 2019). RESULTS: Of the 216 infants ≤29 weeks' GA admitted to NICU on CPAP, 125 infants belonged to the pre-OPTISURF cohort (OSC) and 91 to the post-OSC. Compared with the pre-OSC, a higher proportion of infants in the post-OSC received CPAP 7 cm H2O within 4 hours of life (7% vs 32%; P < .01). The post-OSC also had lower rates of CPAP failure (54% vs 11%; P < .01), pneumothoraces (8% vs 1%; P < .03), need for MV (58% vs 31%; P < .01), and patent ductus arteriosus treatment (21% vs 9%; P = .02). Additionally, in a subgroup analysis, CPAP failure was lower in the post-OSC among infants 23 to 26 weeks (79% vs 27%; P < .01) and 27 to 29 weeks' GA (46% vs 3%; P < .01). CONCLUSIONS: Implementation of a quality improvement bundle including CPAP optimization and less invasive surfactant administration decreased CPAP failure and need for MV in preterm infants.

TeleNICU: Extending the reach of level IV care and optimizing the triage of patient transfers.

BACKGROUND: The use of telemedicine to provide care for critically ill newborn infants has significantly evolved over the last two decades. Children's Health System of Texas and University of Texas Southwestern Medical Center established TeleNICU, the first teleneonatology program in Texas. OBJECTIVE: To evaluate the effectiveness of Tele Neonatal Intensive Care Unit (TeleNICU) in extending quaternary neonatal care to more rural areas of Texas. MATERIALS AND METHODS: We conducted a retrospective review of TeleNICU consultations from September 2013 to October 2018. Charts were reviewed for demographic data, reasons for consultation, and consultation outcomes. Diagnoses were classified as medical, surgical, or combined. Consultation outcomes were categorized into transferred or retained. Transport cost savings were estimated based on the distance from the hub site and the costs for ground transportation. RESULTS: TeleNICU had one hub (Level IV) and nine spokes (Levels I-III) during the study period. A total of 132 direct consultations were completed during the study period. Most consultations were conducted with Level III units (81%) followed by level I (13%) and level II (6%) units. Some common diagnoses included prematurity (57%), respiratory distress (36%), congenital anomalies (25%), and neonatal surgical emergencies (13%). For all encounters, 54% of the patients were retained at the spoke sites, resulting in an estimated cost savings of USD0.9 million in transport costs alone. The likelihood of retention at spoke sites was significantly higher for medical diagnoses compared to surgical diagnoses (89% vs. 11%). CONCLUSION: Telemedicine effectively expands access to quaternary neonatal care for more rural communities, helps in the triage of neonatal transfers, promotes family centered care, and significantly reduces health care costs.

Association of time of first corticosteroid treatment with bronchopulmonary dysplasia in preterm infants.

OBJECTIVE: To evaluate the association between the time of first systemic corticosteroid initiation and bronchopulmonary dysplasia (BPD) in preterm infants. STUDY DESIGN: A multi-center retrospective cohort study from January 2010 to December 2016 using the Children's Hospitals Neonatal Database and Pediatric Health Information System database was conducted. The study population included preterm infants <32 weeks' gestation treated with systemic corticosteroids after 7 days of age and before 34 weeks' postmenstrual age. Stepwise multivariable logistic regression was used to assess the association between timing of corticosteroid initiation and the development of Grade 2 or 3 BPD as defined by the 2019 Neonatal Research Network criteria. RESULTS: We identified 598 corticosteroid-treated infants (median gestational age 25 weeks, median birth weight 760 g). Of these, 47% (280 of 598) were first treated at 8-21 days, 25% (148 of 598) were first treated at 22-35 days, 14% (86 of 598) were first treated at 36-49 days, and 14% (84 of 598) were first treated at >50 days. Infants first treated at 36-49 days (aOR 2.0, 95% CI 1.1-3.7) and >50 days (aOR 1.9, 95% CI 1.04-3.3) had higher independent odds of developing Grade 2 or 3 BPD when compared to infants treated at 8-21 days after adjusting for birth characteristics, admission characteristics, center, and co-morbidities. CONCLUSIONS: Among preterm infants treated with systemic corticosteroids in routine clinical practice, later initiation of treatment was associated with a higher likelihood to develop Grade 2 or 3 BPD when compared to earlier treatment.

Qualitative indications for tracheostomy and chronic mechanical ventilation in patients with severe bronchopulmonary dysplasia.

BACKGROUND: The decision to pursue chronic mechanical ventilation involves a complex mix of clinical and social considerations. Understanding the medical indications to pursue tracheostomy would reduce the ambiguity for both providers and families and facilitate focus on appropriate clinical goals. OBJECTIVE: To describe potential indications to pursue tracheostomy and chronic mechanical ventilation in infants with severe BPD (sBPD). STUDY DESIGN: We surveyed centers participating in the Children's Hospitals Neonatal Consortium to describe their approach to proceed with tracheostomy in infants with sBPD. We requested a single representative response per institution. Question types were fixed form and free text responses. RESULTS: The response rate was high (31/34, 91%). Tracheostomy was strongly considered when: airway malacia was present, PCO2 ≥ 76-85 mmHg, FiO2 ≥ 0.60, PEEP ≥ 9-11 cm H2O, respiratory rate ≥ 61-70 breaths/min, PMA ≥ 44 weeks, and weight <10th %ile at 44 weeks PMA. CONCLUSIONS: Understanding the range of indications utilized by high level NICUs around the country to pursue a tracheostomy in an infant with sBPD is one step toward standardizing consensus indications for tracheostomy in the future.

Development and implementation of a teleneonatology program: Opportunities and challenges.

Teleneonatology, encompassing all telemedicine applications in neonatal medicine, is evolving with innovative applications for use in all aspects of neonatal care. In this chapter, we discuss the key components of and a framework for the development, implementation and evaluation of a program based on existing literature and our own program. We also review some important barriers to implementation and potential solutions. We hope that this review will serve as a guide for those seeking to develop and implement other new teleneonatology programs.

A brief history of telemedicine and the evolution of teleneonatology.

Over a century of innovations in technology and medical care have led to the current day capabilities in telemedicine. In this chapter, we discuss the evolution of telemedicine over the last century and highlight various applications in neonatal care. We hope this chapter demonstrates the exponential adoption of telemedicine, particularly in neonatology, and the breadth and depth of the technology being used.

Cardiovascular impact and sequelae of bronchopulmonary dysplasia.

The development, growth, and function of the cardiac, pulmonary, and vascular systems are closely intertwined during both fetal and postnatal life. In utero, placental, environmental, and genetic insults may contribute to abnormal pulmonary alveolarization and vascularization that increase susceptibility to the development of bronchopulmonary dysplasia (BPD) in preterm infants. However, the shared milieu of stressors may also contribute to abnormal cardiac or vascular development in the fetus and neonate, leading to the potential for cardiovascular dysfunction. Further, cardiac or pulmonary maladaptation can potentiate dysfunction in the other organ, amplify the risk for BPD in the neonate, and increase the trajectory for overall neonatal morbidity. Beyond infancy, there is an increased risk for systemic and pulmonary vascular disease including hypertension, as well as potential cardiac dysfunction, particularly within the right ventricle. This review will focus on the cardiovascular antecedents of BPD in the fetus, cardiovascular consequences of preterm birth in the neonate including associations with BPD, and cardiovascular impact of prematurity and BPD throughout the lifespan.

SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway.

Pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induces inflammatory cytokines and chemokines including IL-6, IL-1ß, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and neucleocapsid (N) proteins. When stimulated with extracellular S protein, human lung epithelial cells A549 also produce inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly are non-inflammatory, but elicit an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-κB pathway in a MyD88-dependent manner. Further, such an activation of the NF-κB pathway is abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induces IL-6, TNF-a, and IL-1 ß in wild-type, but not Tlr2-deficient mice. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.

CD44 and RHAMM expression patterns in the human developing lung.

BACKGROUND: The hyaluronan (HA) receptors CD44 and RHAMM (CD168) are involved in cellular proliferation, differentiation, and motility. As previously investigated, HA and RHAMM expression in human neonatal lungs correlates to gestational age (GA) and air content. METHODS: CD44 immunofluorescence was analyzed in postmortem lung samples from infants (n = 93; 22-41 GA) by digital image analysis together with clinical data, including RHAMM expression, lung air, and HA content by hierarchical clustering. RESULTS: Five groups were defined according to RHAMM/CD44 expression, GA, and postnatal age (PNA): extremely to very preterm (EVP; 22-31 GA; Groups 1-2), moderately preterm to term (MPT; 31-41 GA; Groups 3-4), and mixed preterm to term (27-40 GA; Group 5). CD44 correlated linearly with RHAMM in MPT (r = 0.600; p < 0.004). In EVP, high CD44 and low RHAMM corresponded with high PNA and lung air content independently of HA and GA (Group 1 vs 2; p < 0.05). In MPT, high and low CD44 corresponded with low and high RHAMM independently of GA, HA, and lung air content (Group 3 vs 4; p < 0.001). No correlation between CD44 and GA/PNA at death was observed. CONCLUSIONS: A linear correlation between CD44 and RHAMM expression occurs during the late saccular phase of lung development at birth, whereas postnatal influences on CD44 and RHAMM expression in extremely to very preterm infants cannot be excluded. IMPACT: The interplay between CD44 and RHAMM, two receptors of hyaluronic acid, can be dependent on the lung developmental stage at birth. This is the second study that analyzes the distribution pattern of CD44 in the human lung during development and the first study performed with quantitative analysis of CD44 expression together with RHAMM expression in the human lung. Our results suggest a relationship in a subset of infants between CD44 and RHAMM expression, which appears at birth during the late saccular stage but not during the earlier stages of lung development.

Emerging Role of the NLRP3 Inflammasome and Interleukin-1ß in Neonates.

Infection and persistent inflammation have a prominent role in the pathogenesis of brain injury and cerebral palsy, as well as other conditions associated with prematurity such as bronchopulmonary dysplasia. The NLRP3 inflammasome-interleukin (IL)-1ß pathway has been extensively studied in adults and pre-clinical models, improving our understanding of innate immunity and offering an attractive therapeutic target that is already contributing to clinical management in many auto-inflammatory disorders. IL-1 blockade has transformed the course and outcome of conditions such as chronic infantile neurological, cutaneous, articular (CINCA/NOMID) syndrome. Inflammasome activation and upregulation has recently been implicated in neonatal brain and lung inflammatory disease and may be a novel therapeutic target.

Transient neonatal antibiotic exposure increases susceptibility to late-onset sepsis driven by microbiota-dependent suppression of type 3 innate lymphoid cells.

Extended early antibiotic exposure in the neonatal intensive care unit is associated with an increased risk for the development of late-onset sepsis (LOS). However, few studies have examined the mechanisms involved. We sought to determine how the neonatal microbiome and intestinal immune response is altered by transient early empiric antibiotic exposure at birth. Neonatal mice were transiently exposed to broad-spectrum antibiotics from birth for either 3- (SE) or 7-days (LE) and were examined at 14-days-old. We found that mice exposed to either SE or LE showed persistent expansion of Proteobacteria (2 log difference, P < 0.01). Further, LE mice demonstrated baseline translocation of E. coli into the liver and spleen and were more susceptible K. pneumoniae-induced sepsis. LE mice had a significant and persistent decrease in type 3 innate lymphoid cells (ILC3) in the lamina propria. Reconstitution of the microbiome with mature microbiota by gavage in LE mice following antibiotic exposure resulted in an increase in ILC3 and partial rescue from LOS. We conclude that prolonged exposure to broad spectrum antibiotics in the neonatal period is associated with persistent alteration of the microbiome and innate immune response resulting in increased susceptibility to infection that may be partially rescued by microbiome reconstitution.