Serological responses to immunization during nephrosis in infants with congenital nephrotic syndrome of the Finnish type.

Background: Pretransplant vaccination is generally recommended to solid organ transplant recipients. In infants with congenital nephrotic syndrome (CNS), the immune response is hypothetically inferior to other patients due to young age and urinary loss of immunoglobulins, but data on the immunization response in severely nephrotic children remain scarce. If effective, however, early immunization of infants with CNS would clinically be advantageous. Methods: We investigated serological vaccine responses in seven children with CNS who were immunized during nephrosis. Antibody responses to measles-mumps-rubella -vaccine (MMR), a pentavalent DTaP-IPV-Hib -vaccine (diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b), varicella vaccine, combined hepatitis A and B vaccine, and pneumococcal conjugate vaccine (PCV) were measured after nephrectomy either before or after kidney transplantation. Results: Immunizations were started at a median age of 7 months [interquartile range (IQR) 7-8], with a concurrent median proteinuria of 36,500 mg/L (IQR 30,900-64,250). Bilateral nephrectomy was performed at a median age of 20 months (IQR 14-25), and kidney transplantation 10-88 days after the nephrectomy. Antibody levels were measured at median 18 months (IQR 6-23) after immunization. Protective antibody levels were detected in all examined children for hepatitis B (5/5), Clostridium tetani (7/7), rubella virus (2/2), and mumps virus (1/1); in 5/6 children for varicella; in 4/6 for poliovirus and vaccine-type pneumococcal serotypes; in 4/7 for Haemophilus influenzae type B and Corynebacterium diphtheriae; in 1/2 for measles virus; and in 2/5 for hepatitis A. None of the seven children had protective IgG levels against Bordetella pertussis. Conclusion: Immunization during severe congenital proteinuria resulted in variable serological responses, with both vaccine- and patient-related differences. Nephrosis appears not to be a barrier to successful immunization.

Recurrent Mild Acute Rejections and Donor-specific Antibodies as Risk Factors for Cardiac Allograft Vasculopathy in a National Pediatric Heart Transplant Cohort.

Background: Immune-mediated factors such as acute cellular rejections and donor-specific antibodies (DSAs) are risk factors for cardiac allograft vasculopathy (CAV). We studied a national cohort with a unified setting and thorough protocol endomyocardial biopsy (EMB) data for an association between cellular rejections, especially when mild and recurrent, and DSAs with CAV in pediatric heart transplant (HTx) patients. Methods: This is a retrospective, national cohort study of 94 pediatric HTxs performed between 1991 and 2019 and followed until December 31, 2020. Diagnosis of CAV was based on reevaluation of angiographies. Protocol and indication EMB findings with other patient data were collected from medical records. Associations between nonimmune and immune-mediated factors and CAV were analyzed with univariable and multivariable Cox regression analyses. Results: Angiographies performed on 76 patients revealed CAV in 23 patients (30%). Altogether 1138 EMBs (92% protocol biopsies) were performed on 78 patients (83%). During the first posttransplant year, grade 1 rejection (G1R) appeared in 45 patients (58%), and recurrent (≥2) G1R findings in 14 patients (18%). Pretransplant DSAs occurred in 13 patients (17%) and posttransplant DSAs in 37 patients (39%). In univariable analysis, pretransplant DSAs, appearance and recurrence of G1R findings, and total rejection score during the first posttransplant year, as well as recurrent G1R during follow-up, were all associated with CAV. In multivariable analysis, pretransplant DSAs and recurrent G1R during the first posttransplant year were found to be associated with CAV. Conclusions: Our results indicate that pretransplant DSA and recurrent G1R findings, especially during the first posttransplant year, are associated with CAV after pediatric HTx.

Nasal expression of SARS-CoV-2 entry receptors in newborns.

BACKGROUND: SARS-CoV-2 infection is typically mild in children. Lower expression of SARS-CoV-2 entry receptors in the nasal epithelia have been described in children compared with adults. However, data from newborns are lacking. We compared nasal expression of four SARS-CoV-2 entry receptors between term and preterm newborns and adults. METHODS: Nasal scrape samples were obtained from 28 newborns (17 term and 11 preterm) and 10 adults. Reverse-transcription quantitative PCR was used to measure mRNA expression of ACE2, transmembrane serine protease 2 (TMPRSS2), neuropilin 1 (NRP1) and neuropilin 2 (NRP2) and insulin-like growth factor 1 receptor (IGF1R). RESULTS: Expression levels of ACE2, TMPRSS2, NRP1 and NRP2 were lower in term and preterm newborns and IGF1R lower in term newborns compared with adults (p<0.05). CONCLUSIONS: Both term and preterm newborns, compared with adults, have lower expression of SARS-CoV-2 entry receptors in nasal epithelium.

Heart Transplantation for Early-Onset Anthracycline-Induced Cardiomyopathy Within 5 Months of Chemotherapy Completion.

A 9-year-old boy developed progressive anthracycline-induced cardiomyopathy three months after completion of chemotherapy for osteosarcoma. Five months after completion of chemotherapy, at the age of 10 years, heart transplantation was performed. At 29 months since transplantation, the patient remains free of rejection and recurrence of osteosarcoma. (Level of Difficulty: Intermediate.).

Lung Injury After Neonatal Congenital Cardiac Surgery Is Mild and Modifiable by Corticosteroids.

OBJECTIVES: The present study was performed to determine whether lung injury manifests as lung edema in neonates after congenital cardiac surgery and whether a stress-dose corticosteroid (SDC) regimen attenuates postoperative lung injury in neonates after congenital cardiac surgery. DESIGN: A supplementary report of a randomized, double-blinded, placebo-controlled clinical trial. SETTING: A pediatric tertiary university hospital. PARTICIPANTS: Forty neonates (age ≤28 days) undergoing congenital cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: After anesthesia induction, patients were assigned randomly to receive intravenously either 2 mg/kg methylprednisolone or placebo b, which was followed by hydrocortisone or placebo bolus six hours after weaning from CPB for five days as follows: 0.2 mg/kg/h for 48 hours, 0.1 mg/kg/h for the next 48 hours, and 0.05 mg/kg/h for the following 24 hours. MEASUREMENTS AND MAIN RESULTS: The chest radiography lung edema score was lower in the SDC than in the placebo group on the first postoperative day (POD one) (p = 0.03) and on PODs two and three (p = 0.03). Furthermore, a modest increase in the edema score of 0.9 was noted in the placebo group, whereas the edema score remained at the preoperative level in the SDC group. Postoperative dynamic respiratory system compliance was higher in the SDC group until POD three (p < 0.01). However, postoperative oxygenation; length of mechanical ventilation; and tracheal aspirate biomarkers of inflammation and oxidative stress, namely interleukin-6, interleukin-8, resistin, and 8-isoprostane, showed no differences between the groups. CONCLUSIONS: The SDC regimen reduced the development of mild and likely clinically insignificant radiographic lung edema and improved postoperative dynamic respiratory system compliance without adverse events, but it failed to improve postoperative oxygenation and length of mechanical ventilation.

Postnatal gene expression of airway epithelial sodium transporters associated with birth stress in humans.

INTRODUCTION: Lung fluid clearance is essential for successful postnatal pulmonary adaptation. The epithelial sodium channel (ENaC) and Na-K-ATPase, induced by serum- and glucocorticoid-inducible kinase 1 (SGK1) as well as aquaporins (AQP), represent key players in the switch from fetal lung fluid secretion to absorption and in early postnatal lung fluid balance. Birth stress, including a surge in catecholamines, promotes pulmonary adaptation, likely through the augmentation of epithelial sodium reabsorption. OBJECTIVES: We sought to determine the changes in the airway gene expression of molecules vital to epithelial sodium transport during early pulmonary adaptation, and the association with birth stress reflected in the norepinephrine concentration in the cord blood in humans. METHODS: We included 70 term newborns: 28 born via vaginal delivery and 42 via elective cesarean section. We determined the norepinephrine concentrations in the cord blood using tandem mass spectrometry and collected nasal epithelial cell samples at 2 min, 1 h, and 24 h postnatally to quantify ENaC, Na-K-ATPase, AQP5, and SGK1 mRNAs using RT-PCR. RESULTS: The molecular gene expression involved in airway epithelium sodium transport changed markedly within the first hour postnatally. Newborns born via elective cesarean section exhibited a lower expression of ENaC, Na-K-ATPase, and SGK1. Significant correlations existed between the expressions of ENaC, Na-K-ATPase, and SGK1, and the concentration of norepinephrine in the cord blood. CONCLUSIONS: The association of ENaC, Na-K-ATPase, and SGK1 expression with the cord blood norepinephrine concentration points to the importance of birth stress in promoting lung fluid clearance during early postnatal pulmonary adaptation.

Pediatric Web-Based Chat Services for Caregivers of Children: Descriptive Study.

BACKGROUND: Pediatric physician-led Web-based chat services offer a novel, low-threshold communication channel between caregivers and physicians. OBJECTIVE: Our aim was to describe chat conversations between caregivers and physicians in a Web-based chat service to determine the factors that should be considered when planning a similar chat service. We also aimed to evaluate whether caregivers considered the consultations helpful, whether physicians considered they could answer caregivers' questions, and whether further face-to-face medical contact was needed. METHODS: In September 2015, a private medical center for children in the greater Helsinki area initiated a Web-based chat service, accessible via any device with an internet connection, open from 9 am to 9 pm local time. Four residents in pediatrics, who had performed at least 60% of their 6-year residency program, served as the physicians responsible for chat consultations with caregivers of children. Between October 2015 and March 2016, 343 consecutive consultations were immediately evaluated by a chat physician. On average, caregivers were followed up by email questionnaire 7-14 days later, which 98 caregivers answered a median of 11 (interquartile range, IQR, 7-20) days later. RESULTS: The age of the children whose caregivers contacted the chat service was a median of 2.1 (IQR 0.83-4.69) years, and 29.8% (102/342) of the children were less than 1 year old. The majority (119/343, 34.7%) of the chat conversations took place from 9 am to noon, and infections were the most common concern in over half of cases (189/343, 55.1%). Chat physicians recommended a face-to-face appointment with a physician for that same day in 13.7% (47/343) of the cases. A face-to-face exam was recommended for that same day more often if the chat concerned infection (36/189, 19.0% cases) compared with other reasons (11/154, 7.1%, cases; P=.001). Physicians felt capable of answering caregivers' questions in 72.6% (249/343) of the cases, whereas 93% (91/98) of caregivers considered physicians' answers helpful. Whether caregivers had to take their children to see a physician that same day or whether caregivers' main concern was infection was not found to be associated with whether caregivers considered physicians' answers helpful or not. However, physicians felt more capable of answering caregivers' questions when the main concern was infection. CONCLUSIONS: Parental consultations via Web-based chat service often take place before noon and focus on infection-related issues as well as on the health and illness of very young children. These factors should be considered when planning or setting up such a service. Based on the high satisfaction with the chat service by both physicians and caregivers, Web-based chat services may be a useful way to help caregivers with concerns about their child's health or illness.

Ventilator-derived dynamic respiratory system compliance: Comparison with static compliance in children.

Measurement of dynamic lung compliance during breathing requires measurement of esophageal pressure, whereas static respiratory system compliance (Crs) method requires several airway occlusions. Despite their precision these compliance methods are cumbersome and not suitable for evaluation of pulmonary system in intensive care. The current ventilators display dynamic Crs, which, however, is seldom utilized in clinical practice. We studied the feasibility of ventilator-derived dynamic Crs measurement in pulmonary evaluation after congenital cardiac surgery in children. In 50 children static Crs was measured by double-occlusion technique, and compared with simultaneous ventilator-derived dynamic Crs values. The early postoperative dynamic and static Crs showed a correlation (r = 0.57, p < 0.0001), but static Crs was 48% higher than dynamic (p < 0.0001). Dynamic Crs measurement showed no correlation with radiographic lung edema findings, whereas the static Crs showed a negative correlation with radiographic lung edema scoring (r = -0.50, p = 0.0002). Thus ventilator-derived dynamic Crs seems less reliable in postoperative pulmonary evaluation than static Crs.

Hyperoxia causes miR-34a-mediated injury via angiopoietin-1 in neonatal lungs.

Hyperoxia-induced acute lung injury (HALI) is a key contributor to the pathogenesis of bronchopulmonary dysplasia (BPD) in neonates, for which no specific preventive or therapeutic agent is available. Here we show that lung micro-RNA (miR)-34a levels are significantly increased in lungs of neonatal mice exposed to hyperoxia. Deletion or inhibition of miR-34a improves the pulmonary phenotype and BPD-associated pulmonary arterial hypertension (PAH) in BPD mouse models, which, conversely, is worsened by miR-34a overexpression. Administration of angiopoietin-1, which is one of the downstream targets of miR34a, is able to ameliorate the BPD pulmonary and PAH phenotypes. Using three independent cohorts of human samples, we show that miR-34a expression is increased in type 2 alveolar epithelial cells in neonates with respiratory distress syndrome and BPD. Our data suggest that pharmacologic miR-34a inhibition may be a therapeutic option to prevent or ameliorate HALI/BPD in neonates.

Stress-Dose Corticosteroid Versus Placebo in Neonatal Cardiac Operations: A Randomized Controlled Trial.

BACKGROUND: Corticosteroids can improve the hemodynamic status of neonates with postoperative low cardiac output syndrome after cardiac operations. This study compared a prophylactically administered stress-dose corticosteroid (SDC) regimen against placebo on inflammation, adrenocortical function, and hemodynamic outcome. METHODS: Forty neonates undergoing elective open heart operations were randomized into two groups. The SDC group received perioperatively 2 mg/kg methylprednisolone, and 6 hours after the operation, a hydrocortisone infusion (0.2 mg/kg/h) was started with tapering doses for 5 days. Placebo was administered in a similar fashion. An adrenocorticotropic hormone stimulation test was performed after the therapy. The primary endpoint of the study was plasma concentration of interleukin (IL-6). Secondary clinical outcomes included plasma cortisol, IL-10, C-reactive protein, echocardiographic systemic ventricle contractility evaluated by the Velocity Vector Imaging program, the inotropic score, and time of delayed sternal closure. RESULTS: The IL-6 values of the SDC group were significantly lower postoperatively than in the placebo group. Significantly lower inotropic scores (p < 0.05), earlier sternal closure (p = 0.03), and less deterioration in the systemic ventricle mean delta strain values between the preoperative and the first postoperative assessment (p = 0.01) were detected for the SDC group. The SDC therapy did not suppress the hypothalamic-pituitary-adrenal axis more than placebo. The mean plasma cortisol level did not decline in the placebo group after the operation. CONCLUSIONS: The SDC regimen for 5 days postoperatively in neonates was safe and did not cause suppression of the hypothalamic-pituitary-adrenal axis. Furthermore, the open heart operation per se did not lead to adrenal insufficiency in neonates.

Assessment of extravascular lung water by ultrasound after congenital cardiac surgery.

BACKGROUND: Lung ultrasounds show vertical artifacts known as B-lines in the presence of increased extravascular lung water (EVLW). We aimed to investigate whether lung ultrasound could estimate EVLW after congenital cardiac surgery. METHODS: This prospective observational study comprised 61 children (age range 3 days to 7.4 years) undergoing congenital cardiac surgery. We compared postoperative B-line scores from lung ultrasounds, early postoperative ultrasound as our primary interest, with corresponding postoperative chest radiography (CXR) lung edema scores, with static lung compliance, and with short-term clinical outcome interpreted as time on mechanical ventilation and length of pediatric intensive care unit (PICU) stay. RESULTS: Our findings showed lung ultrasound B-line scores and CXR lung edema scores as correlating 1-6 hr postoperatively (r2 = 0.41, P < 0.0001), on the first postoperative day (r2 = 0.15, P = 0.004) and on the fourth postoperative day (r2 = 0.28, P = 0.008). The B-line score or CXR lung edema score showed no correlation with lung compliance. We found that in multivariable analyses, with length of perfusion and presence of postoperative complications as covariates, both lung ultrasound (P ≤ 0.02) and CXR (P ≤ 0.002) 1-6 hr postoperatively predicted the length of mechanical ventilation and PICU stay. The interobserver variability was less for lung ultrasound B-line score than for CXR lung edema score (P = 0.001). CONCLUSIONS: Our results show that lung ultrasound in assessment of postoperative EVLW predicted length of mechanical ventilation and stay in the PICU, and it had less interobserver variability than CXR. Accordingly, lung ultrasound may complement CXR in assessment of lung edema after surgery for congenital heart defect. Pediatr Pulmonol. 2017;52:345-352. © 2016 Wiley Periodicals, Inc.

Chronic Hypoxemia in Children With Congenital Heart Defect Impairs Airway Epithelial Sodium Transport.

OBJECTIVE: Ambient hypoxia impairs the airway epithelial Na transport, which is crucial in lung edema reabsorption. Whether chronic systemic hypoxemia affects airway Na transport has remained largely unknown. We have therefore investigated whether chronic systemic hypoxemia in children with congenital heart defect affects airway epithelial Na transport, Na transporter-gene expression, and short-term lung edema accumulation. DESIGN: Prospective, observational study. SETTING: Tertiary care medical center responsible for nationwide pediatric cardiac surgery. PATIENTS: Ninety-nine children with congenital heart defect or acquired heart disease (age range, 6 d to 14.8 yr) were divided into three groups based on their level of preoperative systemic hypoxemia: 1) normoxemic patients (SpO2% ≥ 95%; n = 44), 2) patients with cyanotic congenital heart defect and moderate hypoxemia (SpO2 86-94%; n = 16), and 3) patients with cyanotic congenital heart defect and profound systemic hypoxemia (SpO2 ≤ 85%; n = 39). MEASUREMENTS AND MAIN RESULTS: Nasal transepithelial potential difference served as a surrogate measure for epithelial Na transport of the respiratory tract. Profoundly hypoxemic patients had 29% lower basal nasal transepithelial potential difference (p = 0.02) and 55% lower amiloride-sensitive nasal transepithelial potential difference (p = 0.0003) than normoxemic patients. In profoundly hypoxemic patients, nasal epithelial messenger RNA expressions of two airway Na transporters (amiloride-sensitive epithelial Na channel and ß1- Na-K-ATPase) were not attenuated, but instead α1-Na-K-ATPase messenger RNA levels were higher (p = 0.03) than in the normoxemic patients, indicating that posttranscriptional factors may impair airway Na transport. The chest radiograph lung edema score increased after congenital cardiac surgery in profoundly hypoxemic patients (p = 0.0004) but not in patients with normoxemia or moderate hypoxemia. CONCLUSIONS: The impaired airway epithelial amiloride-sensitive Na transport activity in profoundly hypoxemic children with cyanotic congenital heart defect may hinder defense against lung edema after cardiac surgery.

Long-term outcome after treatment of pulmonary atresia with ventricular septal defect: nationwide study of 109 patients born in 1970-2007.

OBJECTIVES: Treatment of pulmonary atresia with ventricular septal defect (PA + VSD) has evolved during recent decades, but it still remains challenging. This study evaluated 41-year experience of outcome, survival and treatment of PA + VSD patients. METHODS: Patient records and angiograms of 109 patients with PA + VSD born in Finland between 1970 and 2007, and treated at the Children's Hospital, Helsinki University Central Hospital, were retrospectively analysed in this nationwide study. RESULTS: Of the 109 patients, 66 (61%) had simple PA + VSD without major aortopulmonary collateral arteries (MAPCAs). Although we observed no difference in overall survival between those with or without MAPCAs, the patients without MAPCAs had better probability to achieve repair (64 vs 28%, P < 0.0003). Only 3 patients were treated by compassionate care. Overall survival was affected by the size of true central pulmonary arteries on the first angiogram (P = 0.001) and whether repair was achieved (P < 0.0001). After successful repair, the survival rate was 93% at 1 year, 91% from the second year, and functional capacity as assessed by New York Heart Association (NYHA) I-II remained in 85% of patients alive at the end of follow-up. Palliated patients at 1, 5, 10 and 20 years of age had Kaplan-Meier estimated survival rates of 55, 42, 34 and 20%, respectively. Patients who underwent repair attempts but were left palliated with right ventricle (RV)-pulmonary artery connection and septal fenestration had better survival than the rest of the palliated patients (P = 0.001). Further, the McGoon index improved after implementation of a systemic-pulmonary artery shunt in the overall PA + VSD population (P < 0.0001). CONCLUSIONS: These findings show that achievement of repair and initial size of true central pulmonary arteries affect survival of patients with PA + VSD. Although the overall survival of patients with MAPCAs showed no difference compared with simple PA + VSD patients, they had a higher risk of remaining palliated. However, palliative surgery may have a role in treatment of PA + VSD because the size of pulmonary arteries increased after placement of systemic-pulmonary artery shunt. In addition, subtotal repair by a RV-pulmonary artery connection and septal fenestration improved survival over extracardiac palliation.

Lung Ultrasound and Static Lung Compliance during Postnatal Adaptation in Healthy Term Infants.

BACKGROUND: B-lines in lung ultrasound can be used to estimate lung liquid. B-lines are ring-down artifacts that arise from alterations to subpleural lung parenchyma. Lung ultrasound has been used to differentiate between diseases causing respiratory symptoms in neonates. B-lines are also seen in healthy infants during postnatal adaptation. Static lung compliance is a measure of the elasticity of the lungs. OBJECTIVES: Our aim was to document lung ultrasound findings, static lung compliance and their relationship during postnatal adaptation in healthy term infants. METHODS: Lung ultrasound and measurement of static lung compliance were performed in 34 infants at ages of 0-4 and 24 h. B-lines in lung ultrasound were scored using a 5-step scale. Separate ultrasound scores for the upper and lower fields were also calculated. RESULTS: A significant decrease in the abundance of B-lines and a concomitant significant improvement in static lung compliance was observed from <4 to 24 h of age. At <4 h the B-lines were significantly more abundant in the lower fields. No significant correlation existed between lung ultrasound and static lung compliance. CONCLUSION: The concomitant decrease in the B-lines in ultrasound and the increase in lung compliance during the first 24 h are likely to reflect clearance of lung liquid.