Severe pediatric COVID-19: a review from the clinical and immunopathophysiological perspectives.

BACKGROUND: Coronavirus disease 2019 (COVID-19) tends to have mild presentations in children. However, severe and critical cases do arise in the pediatric population with debilitating systemic impacts and can be fatal at times, meriting further attention from clinicians. Meanwhile, the intricate interactions between the pathogen virulence factors and host defense mechanisms are believed to play indispensable roles in severe COVID-19 pathophysiology but remain incompletely understood. DATA SOURCES: A comprehensive literature review was conducted for pertinent publications by reviewers independently using the PubMed, Embase, and Wanfang databases. Searched keywords included "COVID-19 in children", "severe pediatric COVID-19", and "critical illness in children with COVID-19". RESULTS: Risks of developing severe COVID-19 in children escalate with increasing numbers of co-morbidities and an unvaccinated status. Acute respiratory distress stress and necrotizing pneumonia are prominent pulmonary manifestations, while various forms of cardiovascular and neurological involvement may also be seen. Multiple immunological processes are implicated in the host response to COVID-19 including the type I interferon and inflammasome pathways, whose dysregulation in severe and critical diseases translates into adverse clinical manifestations. Multisystem inflammatory syndrome in children (MIS-C), a potentially life-threatening immune-mediated condition chronologically associated with COVID-19 exposure, denotes another scientific and clinical conundrum that exemplifies the complexity of pediatric immunity. Despite the considerable dissimilarities between the pediatric and adult immune systems, clinical trials dedicated to children are lacking and current management recommendations are largely adapted from adult guidelines. CONCLUSIONS: Severe pediatric COVID-19 can affect multiple organ systems. The dysregulated immune pathways in severe COVID-19 shape the disease course, epitomize the vast functional diversity of the pediatric immune system and highlight the immunophenotypical differences between children and adults. Consequently, further research may be warranted to adequately address them in pediatric-specific clinical practice guidelines.

Polymyxin for the treatment of intracranial infections of extensively drug-resistant bacteria in children after neurosurgical operation.

BACKGROUND: Increased meningitis caused by extensively drug-resistant bacillary presents a significant challenge in antibiotic selection. The aim of our study was to evaluate the efficacy and safety of polymyxin in the treatment of post-neurosurgical meningitis due to the extensively drug-resistant bacillary in children. METHODS: We performed a retrospective study on post-neurosurgical meningitis caused by the extensively drug-resistant bacillary in children, who were treated with polymyxin for ≥ 3 days. RESULTS: Among five post-neurosurgical meningitis cases that were included, the children were infected by Acinetobacter baumannii (n = 3), Klebsiella pneumonia (n = 1), and Pseudomonas aeruginosa (n = 1). The drug susceptibility test showed that they were extensively drug-resistant bacillary. Two patients received intravenous polymyxin E. Three children received intravenous combined with intraventricular injection of polymyxin B. One patient infected by Klebsiella pneumonia eventually died of septic shock. No serious adverse effects of polymyxin were observed. CONCLUSIONS: Polymyxin is a safe and effective therapy for post-neurosurgical, multidrug-resistant bacillary meningitis in children.

Induction of apoptosis and ferroptosis by a tumor suppressing magnetic field through ROS-mediated DNA damage.

Magnetic field (MF) is being used in antitumor treatment; however, the underlying biological mechanisms remain unclear. In this study, the potency and mechanism of a previously published tumor suppressing MF exposure protocol were further investigated. This protocol, characterized as a 50 Hz electromagnetic field modulated by static MF with time-average intensity of 5.1 mT, when applied for 2 h daily for over 3 consecutive days, selectively inhibited the growth of a broad spectrum of tumor cell lines including lung cancer, gastric cancer, pancreatic cancer and nephroblastoma. The level of intracellular reactive oxygen species (ROS) increased shortly after field exposure and persisted. Subsequently, pronounced DNA damage and activation of DNA repair pathways were identified both in vitro and in vivo. Furthermore, use of free radical scavenger alleviated DNA damage and partially reduced cell death. Finally, this field was found to inhibit cell proliferation, and simultaneously induced two types of programmed cell death, apoptosis and ferroptosis. In conclusion, this tumor suppressing MF could determine cell fate through ROS-induced DNA damage, inducing oxidative stress and activation of the DNA damage repair pathways, eventually lead to apoptosis and ferroptosis, as well as inhibition of tumor growth.

High shear stress-induced pulmonary hypertension alleviated by endothelial progenitor cells independent of autophagy.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disease characterized by lung endothelial cell dysfunction and vascular remodeling. Endothelial progenitor cells (EPCs) have been proved to be a potential therapeutic strategy to treat PH. Autophagy has been found to be protective to hypoxia-induced PH. In this study, we applied high shear stress (HSS)-induced PH, and examined whether EPCs confer resistance against HSS-induced PH through autophagy. METHODS: Pulmonary microvascular endothelial cells (PMVECs) were cultured under HSS with pro-inflammatory factors in an artificial capillary system to mimic the PH condition. Levels of p62, a selective autophagy substrate, were quantified by western blotting. Cell viability was determined by trypan blue exclusion test. RESULTS: The p62 level in PMVECs was increased at 4 hours after HSS, peaked at 12 hours and declined at 24 hours. The cell viability gradually decreased. Compared with PMVECs cultured by empty medium, in cells cultured by EPC-conditioned medium (EPC-CM), the cell viability was significantly higher; however, p62 levels were also significantly higher, suggesting inhibition of autophagy by EPC-CM. Adding choloquine to suppress autophagy decreased the cell viability of PMVECs under PH. CONCLUSIONS: EPC-CM could suppress the autophagic activity of PMVECs in HSS-induced PH. However, suppression of autophagy leads to cell death. EPCs could fight against PH through cellular or molecular pathways independent of autophagy. But it is not proved if induction of autophagy could be a potential strategy to treat HSS-induced PH as hypoxia-induced PH.

Repair of ventricular septal defect with Eisenmenger syndrome after bosentan treatment.

We report a patient with ventricular septal defect (VSD) and Eisenmenger syndrome. The patient was treated with bosentan for 12 weeks, with a decrease in pulmonary vascular resistance index (PRVi) from 18.84 to 9.63 Wood unit (WU) m2 , and underwent successful corrective repair of the VSD after 12 weeks of bosentan therapy.

[Emergency use of extracorporeal membrane oxygenation in pediatric critically ill patients].

OBJECTIVE: The history of clinical application of extracorporeal membrane oxygenation (ECMO) has been more than 30 years. But in China, there were only a few ECMO centers with limited successful cases reported by the end of twentieth century. The high morbidities and mortalities in current pediatric ECMO practice are noted in China. Therefore, it is necessary to review the experience on rescue use of ECMO in critically ill pediatric patients. METHOD: A retrospective analysis was done for patients who had been receiving ECMO treatment to rescue refractory cardiorespiratory failure from different causes in a hospital between July 2007 and May 2011. RESULT: A total of 12 patients were treated with ECMO; 7 of them were male and 5 female, they aged 6 days to 11 years, weighed 2.8 - 35 (17.21 ± 11.64) kg. The underlying causes of cardiorespiratory failure were as follows: two cases with acute respiratory distress syndrome (ARDS) leading to respiratory failure, 4 with failure of weaning from cardiopulmonary bypass, 3 with fulminant myocarditis, 1 with right ventricular cardiomyopathy leading to repeated cardiac arrest, 1 with preoperative severe hypoxemia, and 1 with anaphylactic shock complicated with massive pulmonary hemorrhage and severe hypoxemia. Of the 12 cases, 3 were established ECMO (E-CPR) while underwent chest compression cardiopulmonary resuscitation (CPR). The mean ECMO support time was 151.75 (15 - 572) h. Seven patients (58.33%) were weaned from ECMO, 6 patients (50.00%) were successfully discharged. Six cases had bleeding from sutures, 2 cases with severe bleeding underwent thoracotomy hemostasis, 2 presented with acute renal failure. Infection was documented in 3 cases, hyperbilirubinemia in 2 cases, lower limb ischemia in 1 case, hyperglycemia in 3 cases, disseminated intravascular coagulation in 1 case, membrane lung leakage in 2 cases, systemic hemolysis in 3 cases, oxygenator failure in 2 cases and oxygenator thrombosis in one case. During the follow-up between 6 months and 4.5 years, 5 patients survived with good quality of life, without any documented central nervous system disorders. One case survived with the right lower extremity disorder from ischemic damage. His motor function has been improved following orthopedic operation at one year after discharge. CONCLUSION: ECMO is a justifiable alternative treatment for reversible severe cardiopulmonary failure in critically ill children.

Captopril induced reversible acute renal failure in a premature neonate with double outlet right ventricle and congestive heart failure.

BACKGROUND: captopril is well tolerated in most patients. There is no report of acute deterioration in renal function after administration of captopril in neonates with congestive heart failure secondary to congenital heart defects with large left-to-right shunts. METHODS: we report a premature neonate with double outlet right ventricle and congestive heart failure who developed acute renal failure after administration of captopril at a low dose of 0.1 mg/kg per 8 hours. RESULTS: on the third day after captopril therapy, the levels of serum creatinine and blood urea nitrogen increased to 2.6 mg/dl and 73 mg/dl respectively, and hyperkalemia appeared. Captopril was discontinued immediately. On the fourth day, the infant developed oliguria which persisted for 24 hours and resolved on the fifth day when the serum potassium normalized to 4.5 mmol/L. The level of serum creatinine peaked at 3.9 mg/dL on the sixth day and gradually decreased to normal on the ninth day after administration of captopril. The captopril-induced acute renal failure resolved completely after cessation of the drug. CONCLUSIONS: attention should be given to captopril therapy in premature neonates with congestive heart failure secondary to congenital heart disease with large left-to-right shunts. Routine hemodynamic examination and biochemical monitoring are suggested before and during captopril therapy.

Extracorporeal membrane oxygenation for the treatment of children with severe hemodynamic alteration in perioperative cardiovascular surgery.

BACKGROUND: This article summarizes the use of extracorporeal membrane oxygenation (ECMO) for the treatment of children with severe hemodynamic alteration in perioperative cardiovascular surgery. METHODS: Four children with congenital heart disease (CHD) (3 boys and 1 girl, aged 6 days to 4 years and weighing 2.8-15 kg) associated with severe heart failure and/or hypoxemia were treated with ECMO cardiopulmonary support in perioperative cardiovascular surgery between July 2007 and July 2008. We retrospectively analyzed the medical records of the 4 children. RESULTS: Of the 4 children, 2 survived and 2 died. The survivors were treated with venoarterial (VA) ECMO due to severe low output syndrome after arterial switch operation. They were weaned successfully from 22-hour and 87-hour ECMO support, and discharged 20 days and 58 days after ECMO explantation, respectively. The other boy treated with venovenous ECMO died of severe hypoxemia and metabolic acidosis. The other girl with VSD, treated with VA ECMO because of failure to wean from cardiopulmonary bypass, died from irreversible heart failure 11 hours after ECMO explantation. The main complications in this series included pulmonary hemorrhage, blood tamponade, surgical site bleeding, hemolysis and hyperbilirubinemia. CONCLUSIONS: ECMO is an effective therapy for patients with severe heart failure in the perioperative cardiovascular surgery. The keys to successful ECMO are selection of indications, time to set up ECMO, and good management of complications during ECMO.

Effect of open heart surgery with cardiopulmonary bypass on peripheral blood lymphocyte apoptosis in children.

Children undergoing cardiopulmonary bypass (CPB) operations have an increased risk for the development of immunosuppression and severe infection. Lymphocyte apoptosis plays an important role in regulating immune responses. This study aimed to investigate the effect of open heart surgery with CPB on peripheral blood lymphocyte (PBL) apoptosis and the possible mechanism of lymphocyte apoptosis in infants and young children. This study enrolled 20 consecutive infants and children as a CPB group and 20 age-matched children who underwent patent arterial duct closure without CPB as control subjects. Samples were taken from peripheral blood after induction of anesthesia (preoperatively) and again 24 h after the operations. The degree of apoptosis and the expression level of Fas (CD95) on PBL were measured using flow cytometry. The percentage of lymphocyte apoptosis significantly increased after surgery in both groups, but it was much higher in the children with CPB than in those without CPB (14.46%+/-4.83% vs. 7.33%+/-1.43%; p<0.01). The expression level of Fas in the individuals with CPB was significantly higher than in those without CPB (52.80%+/-8.80% vs. 37.82%+/-6.32%; p<0.01). As shown by the study findings, both surgical stress and CPB can induce PBL apoptosis, which may lead to lymphopenia after open heart surgery with CPB for infants and young children.

[Risk factors for capillary leak syndrome in children with tetralogy after operation].

OBJECTIVE: To determine risk factors of capillary leak syndrome(CLS) in children with tetralogy after operation. METHODS: Clinical data were retrospectively collected and analyzed from 32 tetralogy cases with CLS and 50 cases without CLS(control group), who received operation under cardiopulmonary bypass (CBP) in our hospital from October 2002 to December 2006. Risk factors with statistical significance were screened with univariate logistic regression analysis, independent risk factors of CLS were determined with multivariate logistic regression analysis. Postoperative outcome was compared between CLS group and control group. RESULT: Logistic analysis showed that the risk factors for CLS were age(OR=6.783), duration of CBP(OR=4.756)and MGoon index (OR=3.826). There were statistical differences in injection of colloid, time of inotropic drugs and ventilation between CLS and control groups(P<0.01). Eight CLS cases underwent peritoneal dialysis and 2 CLS cases died. CONCLUSION: The risk factors of CLS in children with tetralogy after CBP are age, duration of CBP and MGoon index.

[Extracorporeal membrane oxygenation treatment of a neonate with severe low cardiac output syndrome following open heart surgery].

OBJECTIVE: To summarize the experience of extracorporeal membrane oxygenation (ECMO) to rescue a neonate with severe low cardiac output syndrome following open heart surgery. METHODS: The patient was a male, 2 d, 2.8 kg, G3P2 full-term neonate with gestational age 40 weeks, born by Cesarean-section with Apgar score of 10 at 1 min. He was admitted due to severe dyspnea with oxygen desaturation and heart murmur on the second day after birth. Physical examination showed clear consciousness, cyanosis, dyspnea, RR 70 bpm and a grade II/6 heart murmur. Bp was 56/45 mm Hg (1 mm Hg = 0.133 kPa) and SpO2 around 65%. Blood WBC 13.1 x 10(9)/L, N 46.1%, Hb 238 g/L, Plt 283 x 10(9)/L, CRP < 1 mg/L. Echocardiographic findings: TGA + ASD + PDA with left ventricular ejection fraction (LVEF) of 60%. After supportive care and prostaglandin E1 (5 ng/kg/min) treatment, his condition became stable with SpO2 85 - 90%. On the 6(th) day of life, the baby underwent an arterial switch procedure + ASD closing and PDA ligation. The time of aorta clamp was 72 mins. The cool 4:1 blood cardioplegia was given for 2 times during aortal clamp. Ultrafiltration was used. The internal and external volumes were almost equal and the electrolytes and blood gas and hematocrit (36%) were normal during extracorporeal bypass. Due to a failure (severe low cardiac output) to wean from cardiopulmonary bypass (263 min) with acidosis (lactate 8.8 mmol/L), low blood pressure (< 39/30 mm Hg), increased LAP (> 20 mmHg), bloody phlegm, decreased urine output [< 1 ml/(kg.h)], a V-A ECMO was used for cardio-pulmonary support. ECMO setup: Medtronic pediatric ECMO package (CB2503R1), carmeda membrane oxygenator and centrifugal pump (bio-console 560) were chosen. Direct cannulation of the ascending aorta (Edward FEM008A) and right atrium (TF018090) was performed using techniques that were standard for cardiopulmanory bypass. The ECMO system was primed with 400 ml blood, 5% CaCl(2)1g, 5% sodium bicarbonate 1.5 g, 20% mannitol 2 g, albumin 10 g, and heparin 5 mg. The blood was re-circulated until the temperature was 37 degrees C and blood gases and the electrolytes were in normal range. The patient was weaned from bypass and connected to V-A ECMO. Management of ECMO: the blood flow was set at 150 - 200 ml/kg/min. Venous saturation (SvO2) was maintained at the desired level (75%) by increasing and decreasing extracorporeal blood flow. Systemic blood pressure was maintained at 76/55 - 80/59 mm Hg by adjusting blood volume. Hemoglobin was maintained between 120 - 130 g/L. Platelet count was maintained at > 75,000/mm3 and ACT was maintained at 120 - 190 s. The mechanical ventilation was reduced to lung rest settings (FiO2 35%, RR 10 bpm, PIP 16 cm H(2)O, PEEP 5 cm H2O) to prevent alveolar collapse. Inotropic drug dosages were kept at a low level. RESULTS: The patient was successfully weaned from ECMO following 87 hours treatment. LVEF on day 1, 2 and 3 following ECMO were 20%, 34% and 43% respectively. The circulation was stable after weaning from ECMO with Bp 75/55 mm Hg, HR 160 bpm and LAP 11 mm Hg under inotropic drug suppor with epinephrine [(0.2 microg/(kg.min)], dopamine [(8 microg/(kg.min)], milrinone [(0.56 microg/(kg.min)]. The blood gases after 1 h off-ECMO showed: pH 7.39, PaO2 104 mm Hg, PaCO2 45 mm Hg, lactate 3.8 mmol/L, Hct 35%, K(+) 3.8 mmol/L, Ca(++) 1.31 mmol/L. The serum lactate was normal after 24 h off-ECMO. On day 22 off-ECMO, the baby was successfully extubated and weaned from conventional ventilator. On day 58, the patient was discharged. Serial ultrasound imaging studies revealed no cerebral infarction or intracranial hemorrhage during and after ECMO. At the time of hospital discharge, the patient demonstrated clear consciousness with good activity, normal function of heart, lung, liver and kidney. However, more subtle morbidities, such as behavior problems, learning disabilities should be observed ria long term follow-up. The main ECMO complications were pulmonary hemorrhage, bleeding on the sternal wound, tamponade, hemolysis and hyperbilirubinemia. CONCLUSION: ECMO is an effective option of cardio-pulmonary support for neonate with low cardiac output syndrome following open heart surgery.

Concentrations of brain natriuretic peptide in the plasma predicts outcomes of treatment of children with decompensated heart failure admitted to the Intensive Care unit.

OBJECTIVES: It is known that levels of brain natriuretic peptide predict outcomes of treatment for adults with decompensated heart failure. We hypothesized that it could predict outcomes in children with this condition. METHODS: We divided retrospectively 82 patients with serial measurements of brain natriuretic peptide into 3 groups: those who survived and did not need readmission within less than 60 days; those who survived but needed readmission within less than 60 days; and those who died in hospital or within less than 60 days. Initial and final levels of the peptide correlated with adverse outcomes. RESULTS: The percent change in level of the peptide was minus 78 percent, minus 38 percent, and 138 percent in the readmission-free group, the readmitted, and nonsurviving groups, respectively. Final levels were significantly lower in the readmission-free group than in the readmitted and nonsurviving groups (p equals 0.013 and p is less than 0.00001, respectively) and in the readmitted group than in the nonsurvivors (p equals 0.013). On univariate analysis, the final level, the change in level, and the percentage change in level significantly predicted outcomes (p equals 0.0002, 0.0072 and 0.0005, respectively). On multivariate analysis, only the final level of the peptide significantly predicted outcomes (p equals 0.01). CONCLUSIONS: A final level of brain natriuretic peptide of greater than or equal to 760 picograms per millilitre strongly predicted an adverse outcome. Patients with higher final levels may be at higher risk of death and readmission, suggesting that this variable effectively predicts the response to treatment and prognosis in children with heart failure.

Survey of the use of peripherally inserted central venous catheters in neonates with critical congenital cardiac disease.

Neonates with congenital cardiac disease are a special population. They are often critically ill, and need prolonged intravenous access. To date, no study has evaluated the efficacy and safety of peripherally inserted central venous catheters placed in this unique population. Our goal was to evaluate the use of such catheters in neonates with critical congenital cardiac disease, and to study features such as duration of use, reasons for removal of catheters, and complications. We inserted a total of 124 catheters in 115 neonates with critical congenital cardiac disease who were admitted to the Intensive Care Unit at Texas Children's Hospital from August 2002 to August 2004. The patients had a mean age of 10 days, and a mean weight of 3.1 kilograms. The peripherally inserted catheters were in place for a mean of 22.3 days. Therapy was completed in 76.6% patients at the time of removal of the catheter. The incidence of occlusion, dislodgement, and thrombus was 4.0%, 2.4%, and 1.6%, respectively. The infection rate was 3.6 per 1000 catheter-days, with a median onset on 37 days after placement. We conclude that central venous catheters, when inserted peripherally, provide reliable and safe access for prolonged intravenous therapy in neonates with critical congenital cardiac disease.

[The risk factors of failed extubation after cardiac surgery in infants].

OBJECTIVE: To investigate the risk factors of failed extubation (FE) after cardiac surgery in infants. METHODS: 227 infants (< 1 year of age) who underwent congenital heart surgery in the period between January 2001 and December 2002 were included in this study. Logistic regression analysis was used to assess the risk factors of failed extubation. Odds Ratio was used to suppose the degree of relationship between FE and risk factors. RESULTS: Out of the 227 infants undergoing congenital heart operations, 30 (13.22%) cases failed at the extubation. Risk factors for failed extubation included postoperative duration of ventilation (EOR = 12.0; 95% CI = 4.04 - 35.71; P = 0.000 9), postoperative pneumonia (EOR = 5.33; 95% CI = 1.81 - 15.68; P = 0.002) and preoperative pulmonary hypertension (EOR = 2.80; 95% CI = 1.21 - 10.45; P = 0.041). Postoperative pneumonia and preoperative pulmonary hypertension were the 2 independent risk factors for failed extubation (P < 0.05). CONCLUSIONS: Postoperative pneumonia and preoperative pulmonary hypertension are major risk factors for failed extubation after congenital heart surgery in infants. To prevent and to treat postoperative pneumonia and pulmonary hypertensive crises will be beneficial to the successful extubation.