Living Donor Lung Transplantation After Hematopoietic Stem Cell Transplantation From the Same Donor: A Risk Worth Taking.

Living donor (LD) lung transplantation (LT) represents an exceptional procedure in Western countries. However, in selected situations, it could be a source of unique advantages, besides addressing organ shortage. We report a successful case of father-to-child single-lobe LT, because of the complications of hematopoietic stem cell transplantation from the same donor, with initial low-dose immunosuppressive therapy and subsequent early discontinuation. Full donor chimerism was hypothesized to be a mechanism of transplant tolerance, and this postulated immunological benefit was deemed to outweigh the risks of living donation and the possible drawbacks of single compared with bilateral LT. Favorable size matching and donor's anatomy, accurate surgical planning, and specific expertise in pediatric transplantation also contributed to the optimal recipient and donor outcomes. Ten months after LD LT, the patient's steadily good lung function after withdrawal of immunosuppressive therapy seems to confirm the original hypothesis.

Cerebral autoregulation in traumatic brain injury: ultra-low-frequency pressure reactivity index and intracranial pressure across age groups.

BACKGROUND: The ultra-low-frequency pressure reactivity index (UL-PRx) has been established as a surrogate method for bedside estimation of cerebral autoregulation (CA). Although this index has been shown to be a predictor of outcome in adult and pediatric patients with traumatic brain injury (TBI), a comprehensive evaluation of low sampling rate data collection (0.0033 Hz averaged over 5 min) on cerebrovascular reactivity has never been performed. OBJECTIVE: To evaluate the performance and predictive power of the UL-PRx for 12-month outcome measures, alongside all International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) models and in different age groups. To investigate the potential for optimal cerebral perfusion pressure (CPPopt). METHODS: Demographic data, IMPACT variables, in-hospital mortality, and Glasgow Outcome Scale Extended (GOSE) at 12 months were extracted. Filtering and processing of the time series and creation of the indices (cerebral intracranial pressure (ICP), cerebral perfusion pressure (CPP), UL-PRx, and deltaCPPopt (ΔCPPopt and CPPopt-CPP)) were performed using an in-house algorithm. Physiological parameters were assessed as follows: mean index value, % time above threshold, and mean hourly dose above threshold. RESULTS: A total of 263 TBI patients were included: pediatric (17.5% aged ≤ 16 y) and adult (60.5% aged > 16 and < 70 y and 22.0% ≥ 70 y, respectively) patients. In-hospital and 12-month mortality were 25.9% and 32.7%, respectively, and 60.0% of patients had an unfavorable outcome at 12 months (GOSE). On univariate analysis, ICP, CPP, UL-PRx, and ΔCPPopt were associated with 12-month outcomes. The cutoff of ~ 20-22 for mean ICP and of ~ 0.30 for mean UL-PRx were confirmed in all age groups, except in patients older than 70 years. Mean UL-PRx remained significantly associated with 12-month outcomes even after adjustment for IMPACT models. This association was confirmed in all age groups. UL-PRx resulted associate with CPPopt. CONCLUSIONS: The study highlights UL-PRx as a tool for assessing CA and valuable outcome predictor for TBI patients. The results emphasize the potential clinical utility of the UL-PRx and its adaptability across different age groups, even after adjustment for IMPACT models. Furthermore, the correlation between UL-PRx and CPPopt suggests the potential for more targeted treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05043545, principal investigator Paolo Gritti, date of registration 2021.08.21.

Current Endovascular Management of Arterial Complications After Pediatric Liver Transplantation in a Tertiary Center.

PURPOSE: Pediatric liver transplant surgery is burdened by arterial complications whose endovascular treatment is not standardized. We report the outcomes of a cohort of pediatric recipients with hepatic artery complications treated by endoluminal procedures. MATERIALS AND METHODS: From December 2019 to December 2022, consecutive transplanted pediatric patients who underwent endovascular treatment of hepatic artery complications were reviewed. The analysis included: type of complication (occlusion, stenosis, pseudoaneurysm); onset (acute = < 15 days, subacute = 15-90 days, late = > 90 days); endovascular technique (angioplasty, stenting); complications and outcomes. Technical success was defined as the opacification of the hepatic artery at the final angiogram with < 50% residual stenosis and no pseudoaneurysms. Clinical success was defined by graft's and patient's survival. RESULTS: Seventeen patients (8 males; median age 33 months, IQR 9-103) underwent 21 hepatic arteriography procedures for predominantly acute or subacute occlusions (n = 7) or stenosis (n = 11) with concurrent pseudoaneurysms (n = 4). Primary and secondary technical success was achieved in 13/18 and 3/3 procedures, respectively, with overall technical success of 76%. Angioplasty alone was successful in 5/21 procedures; stent-retriever thrombectomy was performed in one occlusion with thrombosis; stenting was required in 9/17 (53%) patients. Clinical success was obtained in 14/17 (82%) patients with hepatic artery patency after a median of 367 days (IQR 114.5-500). Clinical failure occurred in 3 permanent occlusions, with 2 deaths and 1 re-transplantation. Procedure-related complications included minor events in 3/17 (18%) patients and 1/17 (6%) death. CONCLUSION: In liver transplanted children with hepatic artery complications, endovascular treatment may provide clinical success, with stenting often required in acute and subacute conditions. LEVEL OF EVIDENCE: Level 4.

Italian pediatric intensive care units admitting critically ill cancer children: results from a national survey.

BACKGROUND: Pediatric patients affected by oncologic disease have a significant risk of clinical deterioration that requires admission to the intensive care unit. This study reported the results of a national survey describing the characteristics of Italian onco-hematological units (OHUs) and pediatric intensive care units (PICUs) that admit pediatric patients, focusing on the high-complexity treatments available before PICU admission, and evaluating the approach to the end-of-life (EOL) when cared in a PICU setting. METHODS: A web-based electronic survey has been performed in April 2021, involving all Italian PICUs admitting pediatric patients with cancer participating in the study. RESULTS: Eighteen PICUs participated, with a median number of admissions per year of 350 (IQR 248-495). Availability of Extracorporeal Membrane Oxygenation therapy and the presence of intermediate care unit are the only statistically different characteristics between large or small PICUs. Different high-level treatments and protocols are performed in OHUs, non depending on the volume of PICU. Palliative sedation is mainly performed in the OHUs (78%), however, in 72% it is also performed in the PICU. In most centers protocols that address EOL comfort care and treatment algorithms are missing, non depending on PICU or OHU volume. CONCLUSIONS: A non-homogeneous availability of high-level treatments and in OHUs is described. Moreover, protocols addressing EOL comfort care and treatment algorithms in palliative care are lacking in many centers.

Fulminant echovirus 11 hepatitis in male non-identical twins in northern Italy, April 2023.

Echovirus 11 (E11) has recently been associated with a series of nine neonatal cases of severe hepatitis in France. Here, we present severe hepatitis caused by E11 in a pair of twins. In one of the neonates, the clinical picture evolved to fulminant hepatitis. The E11 genome showed 99% nucleotide identity with E11 strains reported in the cases in France. Rapid genome characterisation using next generation sequencing is essential to identify new and more pathogenetic variants.

Venous outflow obstruction in pediatric left lateral segment split liver transplantation.

BACKGROUND: Venous outflow obstruction (VOO) is a known cause of graft and patient loss after pediatric liver transplantation (LT). We analyzed the incidence, risk factors, diagnosis, management, and outcome of VOO in a large, consecutive series of left lateral segment (LLS) split LT with end-to-side triangular venous anastomosis. METHODS: We evaluated data collected in our prospective databases relative to all consecutive pediatric liver transplants performed from January 2006 to December 2021. We included in this study children undergoing LLS split liver transplant with end-to-side triangular anastomosis. Diagnosis of VOO was based on clinical suspicion and radiological confirmation. RESULTS: VOO occurred in 24/279 transplants (8.6%), and it was associated with lower graft weight (p = .04), re-transplantation (p = .008), and presence of two hepatic veins (p < .0001). In presence of two segmental veins' orifices, the type of reconstruction (single anastomosis after venoplasty or double anastomosis) was not significantly related to VOO (p = .87). Multivariable analysis indicated VOO as a risk factor for graft lost (hazard ratio 3.21, 95% confidence interval 1.22-8.46; p = .01). Percutaneous Transluminal Angioplasty (PTA) was effective in 17/22 (77%) transplants. Surgical anastomosis was redone in one case. Overall six grafts (25%) were lost. CONCLUSION: VOO after LLS split LT with end-to-side triangular anastomosis is an unusual but critical complication leading to graft loss in a quarter of cases. The occurrence of VOO was associated with lower graft weight, re-transplantation, and presence of two hepatic veins. PTA was safe and effective to restore proper venous outflow in most cases.

Evaluation and application of ultra-low-frequency pressure reactivity index in pediatric traumatic brain injury patients.

PURPOSE: While clinical practice suggests that knowing the cerebral autoregulation (CA) status of traumatic brain injury (TBI) patients is crucial in assessing the best treatment, evidence in pediatric TBI (pTBI) is limited. The pressure reactivity index (PRx) is a surrogate method for the continuous estimation of CA in adults; however, calculations require continuous, high-resolution monitoring data. We evaluate an ultra-low-frequency pressure reactivity index (UL-PRx), based on data sampled at ∼5-min periods, and test its association with 6-month mortality and unfavorable outcome in a cohort of pTBI patients. METHODS: Data derived from pTBI patients (0-18 years) requiring intracranial pressure (ICP) monitoring were retrospectively collected and processed in MATLAB using an in-house algorithm. RESULTS: Data on 47 pTBI patients were included. UL-PRx mean values, ICP, cerebral perfusion pressure (CPP), and derived indices showed significant association with 6-month mortality and unfavorable outcome. A value of UL-PRx of 0.30 was identified as the threshold to better discriminate both surviving vs deceased patients (AUC: 0.90), and favorable vs unfavorable outcomes (AUC: 0.70) at 6 months. At multivariate analysis, mean UL-PRx and % time with ICP > 20 mmHg, remained significantly associated with 6-month mortality and unfavorable outcome, even when adjusted for International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT)-Core variables. In six patients undergoing secondary decompressive craniectomy, no significant changes in UL-PRx were found after surgery. CONCLUSIONS: UL-PRx is associated with a 6-month outcome even if adjusted for IMPACT-Core. Its application in pediatric intensive care unit could be useful to evaluate CA and offer possible prognostic and therapeutic implications in pTBI patients. CLINICALTRIALS: GOV: NCT05043545, September 14, 2021, retrospectively registered.

Risk factors for intubation in severe bronchiolitis: a useful tool to decide on an early intensive respiratory support.

BACKGROUND: Bronchiolitis is the most frequent lower airway infection leading hospitalization in children younger than 2 years. RSV is the typical common cause, followed by rhinovirus. Criteria for Pediatric Intensive Care Unit (PICU) admission are not defined by guidelines. METHODS: A retrospective analysis of children with severe bronchiolitis admitted from 2013 to 2016 to our PICU was performed to identify the risk factors associated with intubation in this population. Fourteen variables were studied: sex, weight, age, nationality, provenience, duration of symptoms, risk factors for bronchiolitis development, recurrence, apnea, SpO2 in air, Modified Wood's Clinical Asthma score (M-WCAS), microbiological results, medical treatment, CPAP therapy. The relationship between these variables and the need for mechanical ventilation were explored using univariate and multivariate logistic regression analysis. A ROC analysis was used to identify cut-off for the continuous variables identified as risk factors for intubation in multivariate analysis. RESULTS: We enrolled 93 patients: 19 of them (20.4%) were intubated. Univariate and multivariate analysis demonstrated that a M-WCAS Score ≥7, SpO2 ≤75% and apnea were significantly associated to intubation in children with severe bronchiolitis. CONCLUSIONS: Cut-off values of the variables identified as risk factors for intubation may represent an important tool for pediatricians to decide a prompt and appropriate intensive respiratory support.

Association between cuffed tracheal tube use and reduced ventilator-associated pneumonia and conditions after elective cardiac surgery in infants and young children.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a serious complication in children after cardiac surgery that may result from micro-aspiration. However, the current recommendation to use cuffed tracheal tubes (TTs) versus uncuffed TTs in children is still uncertain. Our main aim was to evaluate the incidence of VAP, ventilator-associated tracheobronchitis (VAT) and ventilator-associated conditions (VAC) in children up to five years old who underwent elective cardiac surgery. METHODS: Single-center, prospective before-and-after study at a tertiary pediatric intensive care unit (PICU) in Italy. 242 patients (121 in each group) through the following periods: phase I (from Jan 2017 to 20th Feb 2018), during which children were intubated with uncuffed TTs; phase II (from 21th Feb 2018 to Feb 2019), during which children were intubated with cuffed TTs. RESULTS: Data were collected using an electronic dedicated database. Median age was five months. The use of cuffed tubes reduced the risk of VAC and VAP respectively 15.8 times (95% CI 3.4-73.1, P=0.0008) and 14.8 times (95% CI 3.1-71.5, P=0.002). No major related airway complications were observed in the cuffed TTs group. Average treatment effect, calculated after propensity score matching, confirmed the significant effect of cuffed TTs on VAC and VAP. CONCLUSIONS: Our study suggests a marked reduction of VAP and VAC associated with use of a cuffed versus uncuffed TT in infants and children ≤5 years of age after elective cardiac surgery. A randomized clinical trial is needed to confirm these results and define the impact of use of a cuffed versus uncuffed TT across other relevant ICU outcomes and non-cardiac PICU patients.

Fibrinolytic Proteins and Factor XIII as Predictors of Thrombotic and Hemorrhagic Complications in Hospitalized COVID-19 Patients.

Introduction: In a prospective cohort of hospitalized COVID-19 patients, an extensive characterization of hemostatic alterations by both global and specific assays was performed to clarify mechanisms underlying the coagulopathy and identify predictive factors for thrombotic and hemorrhagic events during hospitalization. Materials and Methods: Intensive care unit (ICU; n = 46) and non-ICU (n = 55) patients were enrolled, and the occurrence of thrombotic and hemorrhagic events was prospectively monitored. At study inclusion, thromboelastometry together with the measurement of specific coagulation proteins and hypercoagulation markers was performed. Results: Patients (median age 67 years) showed significantly shorter clot formation time together with greater maximum clot firmness by thromboelastometry, increased levels of F1 + 2 and D-dimer, as biomarkers of hypercoagulability, and of procoagulant factors V, VIII, IX, XI, and fibrinogen, while FXIII was significantly reduced. The concentration of fibrinolytic proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were elevated in the overall cohort of patients. Many of these hemostatic alterations were significantly greater in ICU compared to non-ICU subjects and, furthermore, they were associated with inflammatory biomarker elevation [i.e., interleukin 6 (IL-6), C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), and procalcitonin]. After enrollment, 7 thrombosis and 14 major bleedings occurred. Analysis of clinical and biological data identified increased t-PA, PAI-1, and NLR values as independent predictive factors for thrombosis, while lower FXIII levels were associated with bleeding. Conclusion: This study demonstrates alterations in all different hemostatic compartments analyzed, particularly in severe COVID-19 conditions, that strongly correlated with the inflammatory status. A potential role of fibrinolytic proteins together with NLR and of FXIII as predictors of thrombotic and hemorrhagic complications, respectively, is highlighted.

Endothelium Activation Markers in Severe Hospitalized COVID-19 Patients: Role in Mortality Risk Prediction.

Introduction Endothelial damage and hypercoagulability are major players behind the hemostatic derangement of SARS-CoV-2 infection. Aim In this prospective study we assessed endothelial and inflammatory biomarkers in a cohort of COVID-19 patients, aiming to identify predictive factors of in-hospital mortality. Methods COVID-19 patients hospitalized in intensive care (ICU) and non-ICU units at 2 Bergamo (Italy) hospitals from March 23 to May 30, 2020, were enrolled. Markers of endothelium activation including von-Willebrand factor (vWF), soluble thrombomodulin (sTM), and fibrinolytic proteins (t-PA and PAI-1) were measured. Additionally, D-dimer, Fibrinogen, FVIII, nucleosomes, C reactive protein (CRP) and procalcitonin were assessed. Results Sixty-three (45 ICU, and 18 non-ICU) patients, with a median age of 62 years were analyzed. Increased plasma levels of D-dimer, FVIII, fibrinogen, nucleosomes, CRP, and procalcitonin were observed in the whole cohort. Extremely elevated vWF levels characterized all patients (highest values in ICU-subjects). After a median time of 30 days, death occurred in 13 (21%) patients. By multivariable analysis, vWF-activity, neutrophil-count and PaO2/FiO2 were significantly associated with death. Using these variables, a linear score with 3-risk groups was generated that provided a cumulative incidence of death of 0% in the low-, 32% in the intermediate-, and 78% in the high-risk group. Conclusions COVID-19-induced hemostatic abnormalities are exacerbated by the severity of the disease and strongly correlate with the inflammatory status, underlying the link between coagulation, endothelial activation, and inflammation. Our study provides evidence for a role of vWF, together with neutrophils and PaO2/FiO2, as a significant predictor of in-hospital mortality by SARSCoV-2 infection.

Arterioportal Fistulas (APFs) in Pediatric Patients: Single Center Experience with Interventional Radiological versus Conservative Management and Clinical Outcomes.

Arterioportal fistulas (APFs) are uncommon vascular abnormalities with a heterogeneous etiology. In pediatric orthotopic liver transplantation (OLT), APFs are frequently iatrogenic, following percutaneous liver interventions. The aim of this study was to report the 10-year experience of a tertiary referral center for pediatric OLT in the interventional radiological (IR) and conservative management of acquired APFs. A retrospective search was performed to retrieve pediatric patients (<18 years old) with a diagnosis of APF at color Doppler ultrasound (CDUS) or computed tomography angiography (CTA) from 2010 to 2020. Criteria for IR treatment were the presence of hemodynamic alterations at CDUS (resistive index <0.5; portal flow reversal) or clinical manifestations (bleeding; portal hypertension). Conservatively managed patients served as a control population. Clinical and imaging follow-up was analyzed. Twenty-three pediatric patients (median age, 4 years; interquartile range = 11 years; 15 males) with 24 APFs were retrieved. Twenty patients were OLT recipients with acquired APFs (16 iatrogenic). Twelve out of twenty-three patients were managed conservatively. The remaining 11 underwent angiography with confirmation of a shunt in 10, who underwent a total of 16 embolization procedures (14 endovascular; 2 transhepatic). Technical success was reached in 12/16 (75%) procedures. Clinical success was achieved in 8/11 (73%) patients; three clinical failures resulted in one death and two OLTs. After a median follow-up time of 42 months (range 1-107), successfully treated patients showed an improvement in hemodynamic parameters at CDUS. Conservatively managed patients showed a stable persistence of the shunts in six cases, spontaneous resolution in four, reduction in one and mild shunt increase in one. In pediatric patients undergoing liver interventions, APFs should be investigated. Although asymptomatic in most cases, IR treatment of APFs should be considered whenever hemodynamic changes are found at CDUS.

The impact of a standardized perioperative management on hospital mortality after the Norwood procedure in a low volume center: results and perspectives.

BACKGROUND: Mortality of newborns with Hypoplastic Left Heart Syndrome (HLHS) is mainly concentrated after Norwood procedure (NP) stage 1 palliation (S1P) and between S1P and stage 2 palliation (S2P). Standardized management of these patients may help to control hospital mortality. Aim of the study was to evaluate the impact on hospital mortality of a standardized perioperative management (SPM) for newborns requiring S1P in a low volume center for NP. METHODS: A consecutive series of patients undergoing S1P from January 1, 2002 to December 31, 2006 were retrospectively compared, by a "before and after" design, with those receiving a SPM (i.e. use of selective cerebral perfusion, near infrared spectroscopy, delayed sternal closure, modified ultrafiltration) from January 1, 2007 to December 31, 2018. Demographic, intraoperative and postoperative characteristics were collected. Univariate and multivariate analyses assessed differences before and after SPM. RESULTS: 91 newborns underwent S1P in the considered period; of 74 eligible patients, 25 didn't receive SPM, while 49 received SPM. Hospital mortality after S1P was 31% (CI 21-44%). The introduction of a SPM didn't affect hospital mortality both at the univariate (28% vs 29%, p = 0,959) and at the multivariate analysis (HR 1.85, p=0.62). Mortality was 12% (CI 6-25%) between hospital discharge after S1P and S2P and 8% (CI 3-22%) between S2P and S3P. CONCLUSIONS: The use of a SPM for HLHS newborns requiring S1P was not effective in reducing hospital mortality in a low volume center. We suggest a collaboration between Italian Pediatric Cardiac Centers to manage HLHS patients.

Post-operative heparin reduces early venous thrombotic complications after orthotopic paediatric liver transplantation.

BACKGROUND: Despite significant improvements in surgical techniques and medical care, thrombotic complications still represent the primary cause of early graft failure and re-transplantation following paediatric liver transplantation. There is still no standardized approach for thrombosis prevention. MATERIALS AND METHODS: The study aimed to evaluate the effectiveness of early intravenous unfractionated heparin started 12 hours postoperatively at 10 UI/kg per hour and used a retrospective "before and after" design to compare the incidence of early thrombotic complications prior to (2002-2010) and after (2011-2016) the introduction of heparin in our institute. RESULTS: From 2002 to 2016, 479 paediatric patients received liver transplantation in our institution with an overall survival rate over one year of 0.91 (95% CI: 0.87-0.94). Of 365 eligible patients, 244 did not receive heparin while 121 did receive heparin. We reported a lower incidence of venous thrombosis (VT) in the group treated with heparin: 2.5% (3/121) vs 7.9% (19/244) (p=0.038). All clinical and laboratory variables considered potential risk factors for VT were studied. By multivariate stepwise Cox proportional hazards models, heparin prophylaxis resulted significantly associated to a reduction in VT (HR=0.29 [95% CI: 0.08-0.97], p=0.045), while age <1 year was found to be an independent risk factor for VT (HR=2.62 [95% CI: 1.11-6.21]; p=0.028). DISCUSSION: Early postoperative heparin could be considered a valid and safe strategy to prevent early VT after paediatric liver transplantation without a concomitant increase in bleeding. A future randomised control trial is mandatory in order to strengthen this conclusion.

Modified pediatric lung ultrasound score compared with computed tomography for assessment of lung aeration in children.

BACKGROUND: Lung ultrasound can be used to assess lung density and aeration at the bedside. Few authors have investigated scores based on the ultrasonographic interstitial syndrome for this purpose, but none have compared them with the gold standard computed tomography in children. METHODS: Children <10 kilograms undergoing a chest computed tomography for clinical purposes at a tertiary hospital Pediatric Intensive Care Unit were enrolled in the study. An ultrasound scan was performed shortly after computed tomography. Each hemithorax was divided in six zones, and each zone was scored: 1, no B lines; 2, <3 B lines; 3, >3 well separated B lines; 4, crowded, coalescent B lines; 5, white lung; 6, consolidation. The pediatric lung ultrasound score was obtained by adding all zones. Interobserver variation for two separate operators was calculated. RESULTS: Ten children, median age 95 days (range 23-721) were enrolled. Mean pediatric lung ultrasound score had a significant correlation with lung density (r=0.68) and percentage of hypoaerated lung (r=0.51). Median density and percentage of hypoaerated lung increased along the ultrasound patterns values (P<0.05) although not all patterns were significantly different from adjacent ones in the pairwise comparison. Interobserver variability in scoring of ultrasonographic patterns was moderate. CONCLUSIONS: The pediatric lung ultrasound score correlates with lung density and percentage of hypoaerated lung measured with computed tomography.

Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management.

Whole-exome sequencing (WES) is a powerful and comprehensive tool for the genetic diagnosis of rare diseases, but few reports describe its timely application and clinical impact on infantile cardiomyopathies (CM). We conducted a retrospective analysis of patients with infantile CMs who had trio (proband and parents)-WES to determine whether results contributed to clinical management in urgent and non-urgent settings. Twenty-nine out of 42 enrolled patients (69.0%) received a definitive molecular diagnosis. The mean time-to-diagnosis was 9.7 days in urgent settings, and 17 out of 24 patients (70.8%) obtained an etiological classification. In non-urgent settings, the mean time-to-diagnosis was 225 days, and 12 out of 18 patients (66.7%) had a molecular diagnosis. In 37 out of 42 patients (88.1%), the genetic findings contributed to clinical management, including heart transplantation, palliative care, or medical treatment, independent of the patient's critical condition. All 29 patients and families with a definitive diagnosis received specific counseling about recurrence risk, and in seven (24.1%) cases, the result facilitated diagnosis in parents or siblings. In conclusion, genetic diagnosis significantly contributes to patients' clinical and family management, and trio-WES should be performed promptly to be an essential part of care in infantile cardiomyopathy, maximizing its clinical utility.

Infantile ATP7B-Related End-Stage Liver Disease: An Exceptional Wilson Disease Phenotype From Consecutive Generations.

Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism typically presenting after 3 years of age. We describe a girl presenting with neonatal cholestasis rapidly progressing to end-stage liver disease. She presented hepatosplenomegaly, neurological impairment, Coombs-negative hemolytic anemia, central hypothyroidism. A patient-parents whole exome sequencing identified a homozygous state for ATP7B mutations causing WD in the proband (p.Gln7fs/p.His1069Gln) and her mother (p.His1069Gln/p.His1069Gln), who was then confirmed to have cirrhotic WD. A causative role of copper toxicity due to ATP7B loss of function was indicated by the presence of extrahepatic features of WD, consistent tests of copper metabolism-including a 7-fold increase in liver copper-and similarity of patient's liver gene expression profile and ultrastructure with that of WD models. This exceptionally early presentation could result from the combination of the ATP7B impairment and the intrauterine copper overload due to maternal undiagnosed WD.

COVID-19 and children with Down syndrome: is there any real reason to worry? Two case reports with severe course.

BACKGROUND: Down syndrome (DS) is characterized by a series of immune dysregulations, of which interferon hyperreactivity is important, as it is responsible for surging antiviral responses and the possible initiation of an amplified cytokine storm. This biological condition is attributed to immune regulators encoded in chromosome 21. Moreover, DS is also characterized by the coexistence of obesity and cardiovascular and respiratory anomalies, which are risk factors for coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). CASE PRESENTATION: A total of 55 children were admitted to the pediatric ward in Bergamo, between February and May 2020 for COVID-19. Here, we describe the cases of two children with DS and a confirmed COVID-19 diagnosis who had a severe course. In addition, both cases involved one or more comorbidities, including cardiovascular anomalies, obesity, and/or obstructive sleep apnea. CONCLUSIONS: Our observations indicate that children with DS are at risk for severe COVID-19 disease course.

Efficacy and safety of exogenous surfactant therapy in patients under 12 months of age invasively ventilated for severe bronchiolitis (SURFABRON): protocol for a multicentre, randomised, double-blind, controlled, non-profit trial.

INTRODUCTION: Some evidence indicates that exogenous surfactant therapy may be effective in infants with acute viral bronchiolitis, even though more confirmatory data are needed. To date, no large multicentre trials have evaluated the effectiveness and safety of exogenous surfactant in severe cases of bronchiolitis requiring invasive mechanical ventilation (IMV). METHODS AND ANALYSIS: This is a multicentre randomised, placebo-controlled, double-blind study, performed in 19 Italian paediatric intensive care units (PICUs). Eligible participants are infants under the age of 12 months hospitalised in a PICU, suffering from severe acute hypoxaemic bronchiolitis, requiring IMV. We adopted a more restrictive definition of bronchiolitis, including only infants below 12 months of age, to maintain the population as much homogeneous as possible. The primary outcome is to evaluate whether exogenous surfactant therapy (Curosurf, Chiesi Pharmaceuticals, Italy) is effective compared with placebo (air) in reducing the duration of IMV in the first 14 days of hospitalisation, in infants suffering from acute hypoxaemic viral bronchiolitis. Secondary outcomes are duration of non-invasive mechanical ventilation in the post-extubation phase, number of cases requiring new intubation after previous extubation within 14 days from randomisation, PICU and hospital length of stay (LOS), duration of oxygen dependency, effects on oxygenation and ventilatory parameters during invasive mechanical respiratory support, need for repeating treatment within 24 hours of first treatment, use of other interventions (eg, high-frequency oscillatory ventilation, nitric oxide, extracorporeal membrane oxygenation), mortality within the first 14 days of PICU stay and before hospital discharge, side effects and serious adverse events. ETHICS AND DISSEMINATION: The trial design and protocol have received approval by the Italian National Agency for Drugs (AIFA) and by the Regional Ethical Committee of Verona University Hospital (1494CESC). Findings will be disseminated through publication in peer-reviewed journals, conference/meeting presentations and media. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, issue date 22 May 2019. NCT03959384.

Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy.

Importance: Many patients with coronavirus disease 2019 (COVID-19) are critically ill and require care in the intensive care unit (ICU). Objective: To evaluate the independent risk factors associated with mortality of patients with COVID-19 requiring treatment in ICUs in the Lombardy region of Italy. Design, Setting, and Participants: This retrospective, observational cohort study included 3988 consecutive critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinating center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network from February 20 to April 22, 2020. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by real-time reverse transcriptase-polymerase chain reaction assay of nasopharyngeal swabs. Follow-up was completed on May 30, 2020. Exposures: Baseline characteristics, comorbidities, long-term medications, and ventilatory support at ICU admission. Main Outcomes and Measures: Time to death in days from ICU admission to hospital discharge. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional hazards regression. Results: Of the 3988 patients included in this cohort study, the median age was 63 (interquartile range [IQR] 56-69) years; 3188 (79.9%; 95% CI, 78.7%-81.1%) were men, and 1998 of 3300 (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. At ICU admission, 2929 patients (87.3%; 95% CI, 86.1%-88.4%) required invasive mechanical ventilation (IMV). The median follow-up was 44 (95% CI, 40-47; IQR, 11-69; range, 0-100) days; median time from symptoms onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days; median length of ICU stay was 12 (95% CI, 12-13; IQR, 6-21) days; and median length of IMV was 10 (95% CI, 10-11; IQR, 6-17) days. Cumulative observation time was 164 305 patient-days. Hospital and ICU mortality rates were 12 (95% CI, 11-12) and 27 (95% CI, 26-29) per 1000 patients-days, respectively. In the subgroup of the first 1715 patients, as of May 30, 2020, 865 (50.4%) had been discharged from the ICU, 836 (48.7%) had died in the ICU, and 14 (0.8%) were still in the ICU; overall, 915 patients (53.4%) died in the hospital. Independent risk factors associated with mortality included older age (hazard ratio [HR], 1.75; 95% CI, 1.60-1.92), male sex (HR, 1.57; 95% CI, 1.31-1.88), high fraction of inspired oxygen (Fio2) (HR, 1.14; 95% CI, 1.10-1.19), high positive end-expiratory pressure (HR, 1.04; 95% CI, 1.01-1.06) or low Pao2:Fio2 ratio (HR, 0.80; 95% CI, 0.74-0.87) on ICU admission, and history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and type 2 diabetes (HR, 1.18; 95% CI, 1.01-1.39). No medication was independently associated with mortality (angiotensin-converting enzyme inhibitors HR, 1.17; 95% CI, 0.97-1.42; angiotensin receptor blockers HR, 1.05; 95% CI, 0.85-1.29). Conclusions and Relevance: In this retrospective cohort study of critically ill patients admitted to ICUs in Lombardy, Italy, with laboratory-confirmed COVID-19, most patients required IMV. The mortality rate and absolute mortality were high.