Thrombotic Features as the Primary Cause of SARS-CoV-2 Related Acute Abdomen in Children.

OBJECTIVES: We performed a retrospective case control study to evaluate the histological characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive pediatric patients undergoing laparoscopic exploration for acute abdomen symptoms. To our knowledge this is the first study that analyzes histopathological characteristics of abdominal tissues in SARS-CoV-2 children. STUDY DESIGN: We enrolled 8 multisystem inflammatory syndrome in children (MIS-C) patients and 4 SARS-CoV-2 positive patients who underwent intestinal resection versus 36 control appendectomies from 2 pediatric tertiary referral centers between March 2020 and July 2021. Surgical resection samples were evaluated on several histological sections focusing on general inflammatory pattern and degree of inflammation. Peculiar histological features (endotheliitis and vascular thrombosis) were semi-quantitatively scored respectively in capillary, veins, and arteries. RESULTS: All SARS-CoV-2 related surgical samples showed thrombotic patterns. Those patterns were significantly less frequent in SARS-CoV-2 negative appendectomies ( P = 0.004). The semi-quantitative score of thrombosis was significantly higher ( P = 0.002) in patients with SARS-CoV-2 related procedures. CONCLUSIONS: Our results showed that SARS-CoV-2 can cause thrombotic damage in abdominal tissues both in the acute phase of the infection (SARS-CoV-2 related appendectomies) and secondary to cytokine storm (MIS-C).

Left ventricle dysfunction in patients with critical neonatal pulmonary stenosis: echocardiographic predictors. A single-center retrospective study.

Background: The aim of this study is to identify echocardiographic predictors of transient left ventricle dysfunction after pulmonary valve balloon dilatation (PVBD), in neonates with pulmonary valve stenosis (PVS) and atresia with intact septum (PAIVS) at birth. Methods: The study includes patients admitted at the Bambino Gesù Children Hospital from January 2012 to January 2017. Clinical, echocardiographic and cardiac catheterization data before and after PVBD were retrospectively analyzed. Results: Twenty-nine infants were included in the study (21 male and eight female). The median age was 5.8 ± 7.1 days. Eight patients developed transient LV dysfunction (three PAIVS and five PVS) and comparing data before and after the procedure, there was no difference in right ventricle geometrical and functional parameters except for evidence of at least moderate pulmonary valve regurgitation after PVBD. Conclusion: Moderate to severe degree pulmonary valve regurgitation was significant associated to LV dysfunction (p < 0.05) in PVS and PAIVS patients.

New Onset Cardiac Murmur and Exertional Dyspnea in an Apparently Healthy Child: A Rare Localization of Obstructive Myxoma in the Right Ventricle Outflow Tract without Pulmonary Embolization-A Case Report and Literature Review.

Myxomas are slowly growing benign neoplasms which are rare in children. Up to 80% can be located in the left atrium and generate symptoms such as embolism, cardiac failure, fever and weight loss. Rarely, myxomas can be detected in the right ventricle outflow tract, causing arrhythmias, pulmonary emboli and sudden death. We report the case of a 13-year-old healthy child brought to the Emergency Department (ED) of the Children's Hospital Bambino Gesù, Rome, for recent dyspnea, chest pain on exertion and new onset cardiac murmur. Patient underwent medical examination and echocardiogram with the finding of a rounded and lobulated voluminous mass in the right ventricle outflow tract (RVOT) which caused severe obstruction. The contrast computed tomography (CT) scan confirmed the presence of a heterogeneously enhancing soft-tissue mass occupying the RVOT with no evidence of pulmonary embolization. The mass was surgically excised, and the pathologic examination confirmed our suspicion of myxoma. Our experience suggests that myxoma can have mild clinical symptoms, the presentation may be non-specific, and diagnosis can be a challenge Careful examination and a diagnostic imaging workup, primarily with the transthoracic echocardiogram, are needful to make a rapid differential diagnosis and to better manage surgical treatment and follow-up.

MIS-C: A COVID-19-as sociated condition between hypoimmunity and hyperimmunity.

Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-ß, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM, NCF1, MCM4, FCN3, and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1, NOD2, and MEF. Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management.

Immunophenotyping of peripheral blood cells allows to discriminate MIS-C and Kawasaki disease.

Background: The pathogenesis of the novel described multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) is still debated as it is not clear if they are the same or different nosological entities. However, for both the diseases a rapid and unequivocal diagnosis is mandatory to start the therapy before the onset of severe complications. In this study, we aimed to evaluate the white cell populations in MIS-C and KD as potential markers to discriminate between the two diseases. Methods: We studied white cell populations by flow cytometry in 46 MIS-C and 28 KD patients in comparison to 70 age-matched healthy children. Results: MIS-C patients had a significant lymphopenia that involved both B and T populations while KD patients showed a significant neutrophilia and thrombocythemia. Granulocyte/lymphocyte ratio helped to diagnose both MIS-C and KD with a high diagnostic sensitivity, while a multivariate analysis of granulocyte and T lymphocyte number contributed to discriminate between the two diseases. Conclusions: The relevant lymphopenia observed in MIS-C patients suggests that the disease would be a post-infectious sequel of COVID-19 immunologically amplified by a massive cytokine release, while the significant neutrophilia and thrombocythemia observed in KD confirmed that the disorder has the genesis of a systemic vasculitis. The analysis of a panel of circulating cells may help to early diagnose and to discriminate between the two diseases. Supplementary Information: The online version contains supplementary material available at 10.1186/s41231-022-00128-2.

Biomarkers of Endothelial Damage in Distinct Phases of Multisystem Inflammatory Syndrome in Children.

Endothelial hyperinflammation and vasculitis are known hallmarks of acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C). They are due to the direct effect of the virus on endothelial cells enhanced by pro-inflammatory modulators and may cause venous/arterial thrombosis. Therefore, it is essential to identify patients with endothelial damage early in order to establish specific therapies. We studied the monocyte chemoattractant protein 1 (MCP-1), the perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), and the vascular endothelial growth factor A (VEGF-A) in serum from 45 MIS-C patients at hospital admission and 24 healthy controls (HC). For 13/45 MIS-C patients, we measured the three serum biomarkers also after one week from hospitalization. At admission, MIS-C patients had significantly higher levels of MCP-1 and VEGF-A than the HC, but no significant differences were observed for pANCA. While after one week, MCP-1 was significantly lower, pANCA was higher and VEGF-A levels were not significantly different from the admission values. These findings suggest an involvement of epithelium in MIS-C with an acute phase, showing high MCP-1 and VEGF-A, followed by an increase in pANCA that suggests a vasculitis development. The serum biomarker levels may help to drive personalized therapies in these phases with anticoagulant prophylaxis, immunomodulators, and/or anti-angiogenic drugs.

Distinctive Phenotype of Multisystem Inflammatory Syndrome in Children Associated with SARS-CoV-2 According to Patients' Age: A Monocentric Experience.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a disease temporally related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it is characterized by fever, conjunctival injections, rash, gastrointestinal symptoms, and cardiovascular complications. We evaluated the clinical presentation, laboratory findings, imaging features, therapeutic interventions, and hospital course of a monocentric cohort, and we analyzed these findings according to two age groups. Methods: Patients with MIS-C admitted to a Tertiary Care Pediatric Hospital from November 2020 to November 2021 were considered for the enrollment. Results: Overall, 35 consecutive patients were included. Most of the children did not require intensive care unit at the admission. The clinical presentation of MIS-C slightly differs according to age groups. Mucocutaneus involvement was more frequent in younger patients, while abdominal symptoms were present in 54% of patients aged less than 5 years and in 95% of patients aged more than 5 years (p < 0.05). In addition, the number of cases with troponin above the normal reference value was significantly higher in older patients (77%) compared to younger cases (15%) (p < 0.01). Conclusions: MIS-C is a new emerging condition and represents a challenge to pediatricians due to the severity of presentation. Further studies to better characterize the long-term outcome of MIS-C patients are mandatory.

Liver and Pancreatic Involvement in Children with Multisystem Inflammatory Syndrome Related to SARS-CoV-2: A Monocentric Study.

Liver and pancreatic involvement in children with Multisystem Inflammatory Syndrome related to SARS-CoV-2 (MIS-C) has been poorly investigated so far. We reviewed a cohort of MIS-C patients to analyze the prevalence of acute liver injury (ALI) and pancreatic injury and their correlation with clinical outcomes. Demographic, clinical, laboratory and imaging features of children with MIS-C at admission and during hospital stay were prospectively collected. Fifty-five patients (mean age 6.5 ± 3.7 years) were included. At admission, 16 patients showed ALI and 5 had increased total serum lipase. During observation, 10 more patients developed ALI and 19 more subjects presented raised pancreatic enzymes. In comparison to those with normal ALT, subjects with ALI were significantly older (p = 0.0004), whereas pancreatic involvement was associated to a longer duration of hospital stay compared with patients with normal pancreatic enzymes (p = 0.004). Time between hospital admission and onset of ALI was shorter compared to the onset of raised pancreatic enzymes (3.2 ± 3.9 versus 5.3 ± 2.7 days, respectively; p = 0.035). Abdominal ultrasound showed liver steatosis in 3/26 (12%) and hepatomegaly in 6/26 (16%) patients with ALI; 2 patients presented enlarged pancreas. Although liver and pancreatic involvement is commonly observed in MIS-C patients, it is mild in most cases with a complete recovery.

Predictors of survival in paediatric mitral valve surgery: the impact of age at operation at late follow-up.

OBJECTIVES: The aim of this study was to elucidate predictors of death and reintervention after mitral valve (MV) surgery in children. METHODS: A single-centre retrospective study was performed enrolling 142 patients younger than 18 years who underwent primary index surgical mitral repair or replacement at Bambino Gesù Children's Hospital in Rome from July 1982 to April 2020. Patients with complete, transitional or partial atrioventricular septal defect and patients with single ventricle physiology were excluded. Patients were stratified according to the age group: group 1 (<1 year old), group 2 (1-5 years old) and group 3 (>5 years old). The composite primary outcome was freedom from death or transplant. The secondary outcome was freedom from redo MV surgery. RESULTS: Transplant-free survival was 89% at 5 years and 88% at 10 years. Stratified by age, group 1 had poorer outcome in comparison with other groups (log-rank test P = 0.105). Both univariate and multivariate analyses showed that age <1 year was a significant risk factor for death or transplant (P = 0.044). Age <1 year was associated with increased risk of reoperation (aHR = 3.38, P = 0.009), while the presence of genetic syndrome (aHR = 0.22) and preoperative EF% (aHR = 0.97) were protective factors for reoperation. CONCLUSIONS: The overall survival and freedom from reoperation in children undergoing MV surgery still need improvements. Younger age was a significant risk factor for death and reintervention both after repair and replacement of the MV. In particular, infants and neonates have a three-fold risk for death compared to children.

Brugada Pattern in a Child with Severe SARS-CoV-2 Related Multisystem Inflammatory Syndrome.

This report presents the first case of Brugada pattern complicated by a supraventricular arrhythmia in a child with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C). A 7-year-old boy came to our Emergency Department with 7 days of abdominal pain and fever. MIS-C was diagnosed on the basis of the clinical, laboratory and instrumental tests. On admission, ECG showed type 1 Brugada pattern in the right precordial leads. During hospitalization the onset of supraventricular arrhythmias complicated the clinical picture. This case underlines management complexity of supraventricular arrhythmic events, different from atrial fibrillation, in patients with Brugada pattern in the context of a systemic inflammatory condition with significant cardiac involvement. All potential therapeutic choices should be considered to ensure the best outcomes.

Predictors of survival in paediatric mitral valve replacement.

OBJECTIVES: The aim of this study was to identify the predictors of death and of reintervention after mitral valve replacement (MVR) in children. METHODS: A single-centre retrospective study was performed including 115 patients under the age of 18 undergoing MVR between 1982 and 2019. For all patients, the ratio of prosthetic valve size (diameter in mm) to weight (kg) at surgery was calculated and long-term result was assessed. The primary outcome was freedom from mitral valve (MV) re-replacement. The composite secondary outcome was freedom from death or transplant. RESULTS: Fifty-four patients had a previous surgical attempt to MV repair. The median age at surgery was 5.5 years (interquartile range 1.21-9.87). Death/transplant-free survival was 77 ± 4% at 5 years and 72 ± 5% at 10 years. Univariate analysis showed a size/weight ratio higher than 2 and age <2 years as significant risk factors for death or transplant. Freedom from MV re-replacement at 5 and 10 years was 90 ± 3% and 72 ± 6%, respectively. Biological prosthesis implanted at first replacement (P = 0.007) and size/weight ratio higher than 2 (P = 0.048) were predictors of reoperation. Significant upsizing (P < 0.0001) of mitral prosthesis was observed at re-replacement. CONCLUSIONS: MVR is a viable strategy in children with unrepairable MV disease. Mortality can be predicted based on size/weight ratio and age <2 years. MV re-replacement can be performed with low morbidity and mortality and a larger-size prosthesis can often be placed at the time of redo.

Left ventricular (LV) pacing in newborns and infants: Echo assessment of LV systolic function and synchrony at 5-year follow-up.

BACKGROUND: Small retrospective studies reported that left ventricular (LV) pacing is likely to preserve LV function in children with isolated congenital complete atrioventricular block (CCAVB). The aim of this study was to prospectively evaluate LV contractility and synchrony in a cohort of neonates/infants at pacemaker implantation and follow-up. METHODS: Patients with CCAVB who underwent LV pacing were evaluated with electrocardiogram and echocardiogram in a single-center, prospective study. Data were collected at implantation, at 1-month and every year of follow-up, up to 5 years. LV ventricular dimensions (diameters and volumes), systolic function (ejection fraction [EF] and global longitudinal strain [GLS]), and synchrony were evaluated. Data are reported as median (25th-75th centiles). RESULTS: Twenty consecutive patients with CCAVB underwent pacemaker implantation (12 single-chamber pacemaker [VVIR] and eight dual-chamber pacemaker [DDD]) with epicardial leads: 17 on the LV apex and three on the free wall. Age at implantation was 0.3 months (1 day-4.5 months). Patients showed good clinical status, normal LV dimensions, preserved systolic function, and synchrony at 60 (30-60) months follow-up. EF increased to normal values in patients with preimplantation EF <50%. Presence of antibodies and pacing mode (DDD vs VVIR) had no impact on the outcome. CONCLUSIONS: LV pacing preserved LV systolic function and synchrony in neonates and infants with CCAVB at 5-year follow-up. LV EF improved in patients with low preimplantation EF. Pacing mode or the presence of autoantibodies did not demonstrated an impact on LV contractility and synchrony.

Evidence of impaired longitudinal strain in pre-Fontan palliation in functional single left ventricle.

BACKGROUND: We evaluated two-dimensional speckle-tracking echocardiography longitudinal strain (L2DSE) in functionally single left ventricles (LV). METHODS: We retrospectively analyzed 21 patients with functionally single LV. We divided patients into two groups according to pre-Fontan cardiac catheterization data: group 1, adequate data for Fontan procedure and group 2, inadequate data. RESULTS: LV strain correlated with predicted pressure in the Fontan system (r = 0.64; P = 0.003), pressure in the Glenn system (r = 0.57; P = 0.010), and transpulmonary gradient (r = 0.59; P = 0.008), but not with left atrial pressure (r = 0.292; P = 0.226) or ejection fraction (r = 0.254; P = 0.294). In multiple regression analysis, four-chamber LV strain was correlated with predicted pressure in the Fontan (ß = 0.642: P = 0.003), whereas no association was found with LV ejection fraction (ß = 0.254; P = 0.294), or time from Glenn palliation (ß = 0.082; P = 0.893). When dividing the population into two groups according to catheterization data, significantly lower four-chamber longitudinal 2DSE (-25.8 ±â€Š3.2 vs.-19.5 ±â€Š5.1; P = 0.004) was found to be not suitable for the Fontan procedure, as compared with those who underwent successful Fontan completion. CONCLUSION: Regardless of ejection fraction, four-chamber L2DSE is associated with high predicted pressure in the Fontan system. Patients with hemodynamic data unsuitable for Fontan operation have significantly lower mean longitudinal strain parameters. 2DSE may represent a valuable tool in assessing patients with single LV physiology and might provide useful pre-Fontan information.

Outcome for Conservative Surgery for the Correction of Severe Mitral Valve Regurgitation in Children: A Single-Center Experience.

Evolving reconstructive techniques have progressively become the preferred approach for treatment of pediatric mitral valve regurgitation. We present our experience in a cohort of patients undergoing surgical correction for severe mitral regurgitation. Fifty-five patients (age 1 month-18 years; median 5 years) were included in the present analysis. Different surgical techniques were used (posterior leaflet augmentation in 25, isolated cleft closure in 12, Alfieri-type procedure in 10, annuloplasty in 5, with artificial chordae in 2, and quadrangular resection with chordal transposition in 1). Follow-up time ranged from 1 to 192 months (median 38[IQR 12-54] months). Operative and follow-up mortality was 0%. Reintervention in the whole population occurred in 31% of patients. However, when first surgery was performed under 2 years of age (no = 17), reintervention reached nearly 50%. The degree of residual mitral regurgitation at follow-up remained stable after surgery, while a significant increase in mean transmitral gradient was observed over time (paired t test = 0.03). In multivariable Cox-regression analysis, post-surgical transmitral gradient was the only independent predictor for reintervention (p = 0.017; HR 2.4; 95%CI 1.2-5.1), after correcting for differences in age at surgery, type of reintervention, mitral annulus dimension, and BSA at the first surgery. ROC curve demonstrated that a post-surgical transmitral mean gradient value > 5 mmHg, was predictive for reintervention (AUC = 0.89; Youden index = 0.44). Our study suggests that the use of conservative technique strategy achieves satisfactory functional results in infants and children with severe MR, although the rate of reoperation in younger patients remains substantial. Post-operative moderate mitral stenosis was the strongest predictor for reoperation.

Cardiac Abnormalities in Children with Autosomal Recessive Polycystic Kidney Disease.

BACKGROUND: No previous study has defined the prevalence of cardiac geometric and mechanical function abnormalities through the analysis of advanced echocardiographic parameters in children with autosomal recessive polycystic kidney disease (ARPKD). AIM: The purpose of this study was to evaluate cardiac geometry and function through advanced echocardiography in a well-characterized sample of pediatric patients with ARPKD. METHODS: Standard echocardiograms were obtained in 27 children with ARPKD (0-18 years) and in 88 healthy children of similar age, gender distribution, and body build. Left ventricular (LV) hypertrophy was defined as LV mass > 45g/(m2.16 + 0.09) and cardiac remodeling was defined by age-adjusted relative wall thickness (RWT). Systolic function was assessed by ejection fraction, midwall fractional shortening (mFS), and global longitudinal (GLS) and circumferential strain (GCS). RESULTS: Patients with ARPKD exhibited a higher LV mass index as compared to controls, and a more concentric LV geometry (both p < 0.001). Accordingly, the prevalence of abnormal LV geometry was significantly higher in ARPKD (33 vs. 0%; p < 0.005). No differences could be observed in the two groups for ejection fraction or GLS (both p = n.s.), while a significantly lower mFS (p < 0.05) as well as GCS (p < 0.001) could be observed. In the analysis of covariance, both LV mass index and RWT remained significantly higher in the ARPKD group, while mFS and GCS remained significantly lower (all p < 0.05). The prevalence of subclinical systolic dysfunction was significantly higher in patients with ARPKD as compared with control subjects (33 vs. 0%; p < 0.001). CONCLUSIONS: Children with ARPKD show significantly impaired cardiac phenotype, characterized by high rates of LV abnormal geometry paired with systolic mechanical dysfunction.