Therapeutic plasma exchange for life-threatening pediatric disorders.

INTRODUCTION: Therapeutic plasma exchange (TPE) is acknowledged to be an effective treatment in life-threatening pediatric disorders. Apheresis for pediatric diseases has been poorly investigated, and most studies to date featured small numbers of patients and lacked control groups. The objective of the present study was to evaluate the tolerance of TPE in pediatric patients. MATERIALS AND METHODS: A retrospective cohort study via a web-based electronic case report form including pediatric patients referred for TPE between January 2005 and December 2014. RESULTS: A total of 78 patients (median [range] age: 9.8 [0.53-17.93]) and 731 TPE procedures were analyzed. The indications were antibody-mediated rejection (n = 33; 42%) and desensitization therapy (n = 5; 6%) after solid organ or hematopoietic stem cell transplantation, thrombotic microangiopathy (n = 17; 22%), pediatric inflammatory diseases (n = 16; 21%), kidney diseases (n = 6; 8%), and hyperviscosity syndrome (n = 1; 1%). On average, each patient underwent six procedures during the first session [range: 1-19]. In the 2 weeks following the start of a session, 72 patients (92%) presented a total of 311 adverse events (AEs) potentially related to TPE. The risk of AEs was not related to the indication for TPE, the intensity of care, venous access, plasma substitute use, or body weight. None of the deaths was related to the TPE. CONCLUSION: We studied one of the largest retrospective pediatric cohorts described to date. Our experience of TPE children's TPE feasibility concerned specific, life-threatening conditions and otherwise treatment-refractory diseases.

Efficacy and safety of prolonged-release tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus - a Phase 2, open-label, single-arm, one-way crossover study.

There are limited clinical data regarding prolonged-release tacrolimus (PR-T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR-T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate-release tacrolimus (IR-T), on a 1:1 mg total-daily-dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy-confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole-blood trough levels (target 3.5-15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6-17.7% of patients across follow-up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug-related treatment-emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR-T to PR-T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.

Comparative pharmacokinetics of tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus to prolonged-release tacrolimus formulation.

This study was a Phase II, open-label, multicenter, single-arm, cross-over study comparing the pharmacokinetics (PK) of tacrolimus in stable pediatric kidney, liver, or heart allograft recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). In Days -30 to -1 of screening period, patients received their IR-T-based regimen; during Days 1-7, patients received study IR-T (same dose as screening). On Day 7, the first 24-hours PK profile was taken; patients were then converted to PR-T (1 mg:1 mg), with a second 24-hours PK profile taken on Day 14. The primary end-point was tacrolimus area under the blood concentration-time curve over 24 hours (AUC24 ); secondary end-points were maximum concentration Cmax and concentration at 24 hours C24 . The predefined similarity interval for confidence intervals (CIs) of least squares mean (LSM) ratios was 80%-125%. The PK analysis set comprised 74 pediatric transplant recipients (kidney, n = 45; liver, n = 28; heart, n = 1). PR-T:IR-T LSM ratio (90% CI) was similar overall for AUC24 , max , and C24 , and for kidney and liver recipients for AUC24 (LSM ratio, kidney 91.8%; liver 104.1%) and C24 (kidney 90.5%; liver 89.9%). Linear relationship was similar between AUC24 and C24 , and between PR-T and IR-T (rho 0.89 and 0.84, respectively), suggesting that stable pediatric transplant recipients can be converted from IR-T to PR-T at the same total daily dose, using the same therapeutic drug monitoring method.

A Dilated Cardiomyopathy Revealing a Neuroblastoma: Which Link?

Acute cardiac dysfunctions associated to neuroblastoma have rarely been reported. Cases already described are mainly related to high blood pressure, and rarely to an "acute catecholamine cardiomyopathy" more frequently found in adults with pheochromocytoma or secreting paraganglioma. We here report a case of an 8-month-old infant with severe acute cardiac failure with dilated cardiomyopathy and moderate ischemic myocardial signs, revealing a favorable histoprognosis neuroblastoma. After specific treatment, evolution was favorable, and cardiac function completely recovered. The association of reversible ischemic signs with high plasmatic level of catecholamines suggests the existence of a catecholamine-induced acute cardiac dysfunction which imitates a Tako-Tsubo syndrome in neuroblastoma.

High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood.

Acyl-CoA dehydrogenase family, member 9 (ACAD9) mutation is a frequent, usually fatal cause of early-onset cardiac hypertrophy and mitochondrial respiratory chain complex I deficiency in early childhood. We retrospectively studied a series of 20 unrelated children with cardiac hypertrophy and isolated complex I deficiency and identified compound heterozygosity for missense, splice site or frame shift ACAD9 variants in 8/20 patients (40%). Age at onset ranged from neonatal period to 9 years and 5/8 died in infancy. Heart transplantation was possible in 3/8. Two of them survived and one additional patient improved spontaneously. Importantly, the surviving patients later developed delayed-onset neurologic or muscular symptoms, namely cognitive impairment, seizures, muscle weakness and exercise intolerance. Other organ involvement included proximal tubulopathy, renal failure, secondary ovarian failure and optic atrophy. We conclude that ACAD9 mutation is the most frequent cause of cardiac hypertrophy and isolated complex I deficiency. Heart transplantation in children surviving neonatal period should be considered with caution, as delayed-onset muscle and brain involvement of various severity may occur, even if absent prior to transplantation.

Myocardial inflammation on cardiovascular magnetic resonance predicts left ventricular function recovery in children with recent dilated cardiomyopathy.

AIMS: To analyse the predictive role of myocardial inflammation assessed by cardiac magnetic resonance (CMR) on the outcome of recently diagnosed dilated cardiomyopathy in children. METHODS AND RESULTS: Over a period of 4 years, 66 children underwent CMR within 2 weeks after the diagnosis of dilated cardiomyopathy. CMR sequences sensitive for oedema, hyperaemia, and irreversible injury were applied: unenhanced cine steady-state free precession (SSFP), black-blood-prepared T1-weighted images, T2-weighted images, gadolinium-enhanced T1-weighted images (EGE), and late gadolinium-enhanced (LGE) images. Inflammatory cardiomyopathy defined as the presence of at least two CMR criteria was diagnosed in 31/66 children (CMR positive) while no criterion was present in the remaining 33 (CMR-negative). Only two patients had one positive criterion and were excluded from subsequent analysis. After a mean follow-up of 24 months, LV function recovery (LV ejection fraction >55%) was more frequent in the CMR-positive group (24 vs. 11, P < 0.05). The presence of myocardial inflammation and elevated troponin levels at baseline were the two predictors of LV function recovery with an odds ratio of 3.76 (P = 0.02) and 2.76 (P = 0.03), respectively, in a logistic regression model. Persisting LGE was rare in patients of the CMR-positive group at control CMR (6/22) and was never observed in the CMR-negative group (0/16). CONCLUSION: The presence of myocardial inflammation on CMR at time of diagnosis of a dilated cardiomyopathy in children is a strong predictor of LV recovery.

MicroRNAs as non-invasive biomarkers of heart transplant rejection.

AIM: Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection. METHODS: We included 113 heart transplant recipients from four referral French institutions (test cohort, n = 60, validation cohort, n = 53). In the test cohort, we compared patients with acute biopsy-proven allograft rejection (n = 30) to matched control patients without rejection (n = 30), by assessing microRNAs expression in the heart allograft tissue and patients concomitant serum using RNA extraction and qPCR analysis. Fourteen miRNAs were selected on the basis of their implication in allograft rejection, endothelial activation, and inflammation and tissue specificity. RESULTS: We identified seven miRNAs that were differentially expressed between normal and rejecting heart allografts: miR-10a, miR-21, miR-31, miR-92a, miR-142-3p miR-155, and miR-451 (P < 0.0001 for all comparisons). Four out of seven miRNAs also showed differential serological expression (miR-10a, miR-31, miR-92a, and miR-155) with strong correlation with their tissular expression. The receiver-operating characteristic analysis showed that these four circulating miRNAs strongly discriminated patients with allograft rejection from patients without rejection: miR-10a (AUC = 0.975), miR-31 (AUC = 0.932), miR-92a (AUC = 0.989), and miR-155 (AUC = 0.998, P < 0.0001 for all comparisons). We confirmed in the external validation set that these four miRNAs highly discriminated patients with rejection from those without. The discrimination capability of the four miRNAs remained significant when stratified by rejection diagnosis (T-cell-mediated rejection or antibody-mediated rejection) and time post-transplant. CONCLUSION: This study demonstrates that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the serum, suggesting their potential relevance as non-invasive biomarkers in heart transplant rejection.

Kawasaki disease: an unexpected etiology of shock and multiple organ dysfunction syndrome.

OBJECTIVE: Severe forms of Kawasaki disease (KD) associated with shock have recently been reported in which a greater number of coronary artery abnormalities (CAA) were observed. In this study, we analyzed organ involvement not restricted to cardiovascular aspects in severe KD and assessed whether their outcome is different than in common forms. DESIGN: Retrospective study. SETTING: A 12-bed pediatric intensive care unit (PICU) in a university hospital setting. PATIENTS: All patients managed in the PICU with a diagnosis of KD from 1 January 2001 to 30 April 2009. RESULTS: Eleven patients were admitted because of moderate febrile shock without initial KD diagnosis. Median age was 75 months (6-175) with a male:female ratio of 1.4. KD was diagnosed and treated after a delay of 1 day (0-2), for a total of 7 days (5-9) after fever onset. Seven patients (63%) developed CAA after 21 days (6-30) with complete regression within a delay of 120 days (18-240). Nonspecific encephalopathy (n = 6) as well as acute kidney injury (n = 10) were also observed. Multiple organ dysfunction syndrome (MODS) occurred in eight patients. Although predicted mortality according to the PELOD score [21 (10-43)] ranged from 20% to up to 50%, all 11 children survived with no sequelae. CONCLUSION: Moderate shock is the main reason for PICU admission in children suffering from KD. These forms can be associated with surprising MODS. Despite the severity of symptoms, all patients survived without any sequelae, hence the need for proper diagnosis and rapid treatment of these unusual severe forms.

Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders.

BACKGROUND: TGFBR2 mutations were recognized recently among patients with a Marfan-like phenotype. The associated clinical and prognostic spectra remain unclear. METHODS AND RESULTS: Clinical features and outcomes of 71 patients with a TGFBR2 mutation (TGFBR2 group) were compared with 50 age- and sex-matched unaffected family members (control subjects) and 243 patients harboring FBN1 mutations (FBN1 group). Aortic dilatation was present in a similar proportion of patients in both the TGFBR2 and FBN1 groups (78% versus 79%, respectively) but was highly variable. The incidence and average age for thoracic aortic surgery (31% versus 27% and 35+/-16 versus 39+/-13 years, respectively) and aortic dissection (14% versus 10% and 38+/-12 versus 39+/-9 years) were also similar in the 2 groups. Mitral valve involvement (myxomatous, prolapse, mitral regurgitation) was less frequent in the TGFBR2 than in the FBN1 group (all P<0.05). Aortic dilatation, dissection, or sudden death was the index event leading to genetic diagnosis in 65% of families with TGFBR2 mutations, versus 32% with FBN1 mutations (P=0.002). The rate of death was greater in TGFBR2 families before diagnosis but similar once the disease had been recognized. Most pregnancies were uneventful (without death or aortic dissection) in both TGFBR2 and FBN1 families (38 of 39 versus 213 of 217; P=1). Seven patients (10%) with a TGFBR2 mutation fulfilled international criteria for Marfan syndrome, 3 of whom presented with features specific for Loeys-Dietz syndrome. CONCLUSIONS: Clinical outcomes appear similar between treated patients with TGFBR2 mutations and individuals with FBN1 mutations. Prognosis depends on clinical disease expression and treatment rather than simply the presence of a TGFBR2 gene mutation.

Perflubron dosing affects ventilator-induced lung injury in rats with previous lung injury.

OBJECTIVES: Randomized controlled trials of partial liquid ventilation in acute respiratory distress syndrome have been negative. Reasons for this failure may reside in the use of too large doses of perfluorocarbon. The objective was to evaluate whether various doses of perflubron affect ventilation-induced injury in edematous lungs in different ways. DESIGN: Prospective, controlled animal study. SETTING: Research laboratory of a university. SUBJECTS: Male Wistar rats weighing 300+/-20 g. INTERVENTIONS: Separate groups of rats were injected with alpha-naphtylthiourea to produce mild permeability pulmonary edema. They were then given 0, 7 (low), 13 (moderate), or 20 mL/kg (near functional residual capacity) perflubron doses and mechanically ventilated with a large (33 mL/kg) tidal volume for 15 mins. MEASUREMENTS AND MAIN RESULTS: 125I-albumin distribution space was used to assess lung microvascular permeability. Quasi-static respiratory system pressure-volume curves were analyzed. Administration of low and moderate perflubron doses significantly improved respiratory mechanics and reduced the ventilator-induced permeability alterations to the level observed in rats that were not ventilated. By contrast, a perflubron dose that was near functional residual capacity increased end-inspiratory plateau pressure and aggravated the permeability alterations due to high tidal volume ventilation. CONCLUSIONS: Near functional residual capacity but not low perflubron dose worsens ventilation-induced lung injury of preinjured lungs. This may provide some explanation for the negative results of the recent clinical trials, and it stresses the importance of the amount of perflubron used for partial liquid ventilation.

Culture-negative pericarditis caused by Neisseria meningitidis serogroup C.

We describe a case of primary purulent culture-negative pericarditis caused by Neisseria meningitidis serogroup C occurring in an 8-month-old previously healthy boy, which was detected in pericardial fluid by broad-spectrum PCR amplification.

Use of bovine jugular vein to reconstruct the right ventricular outflow tract: early results.

OBJECTIVE: We evaluate early results of bovine jugular vein conduits in the pulmonary outflow. METHODS: Between April 2000 and September 2001, 31 conduits were placed in the outflow of the right ventricle. Patients who received a conduit as a staged surgical procedure were excluded (n = 3). Implantation age ranged from 0 to 21 years (median, 3.4 years). Conduit diameter ranged from 12 to 20 mm (median, 14 mm). Transthoracic echocardiography was performed at discharge and 3 months after surgery. Patients with significant pulmonary regurgitation and/or stenosis underwent cardiac catheterization. RESULTS: Four patients died during the follow-up period. Three deaths were unrelated to the conduit. One death was related to the complete thrombosis of the conduit. At 3 months evaluation, pulmonary valve regurgitation was absent or trivial in 19, mild in 2 and severe in 3 of 24 survivors. Four patients had nonfatal conduit-related complications. A transient thrombus formation within 1 leaflet was noted postoperatively in a patient with a moderate pulmonary regurgitation. Three patients required reoperation 3 to 5.8 months after the implantation for conduit failure (mean, 4.3 months). Cardiac catheterization before replacement revealed an aneurysmal dilation of the conduit below a severe stenosis of the pulmonary bifurcation due to important neointimal proliferation. CONCLUSIONS: Early failure of bovine jugular vein valved conduits can occur because of exaggerated intimal proliferation or thrombotic process within the conduit. Because of these complications, close echocardiographic follow-up is mandatory during the first weeks after implantation.