Congenital chylothorax: a prospective nationwide epidemiological study in Germany.

BACKGROUND: Congenital chylothorax (CCT) is a rare disease of unknown aetiology. Treatment approaches vary; none has been evaluated prospectively. OBJECTIVE: To prospectively determine incidence, treatment and outcome of infants with CCT born in Germany in 2012. DESIGN: CCT was defined as non-traumatic chylous pleural effusion within 28 days after birth. As part of the Surveillance Unit for Rare Pediatric Conditions in Germany (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland), all paediatric departments (n=432) received monthly reporting cards to notify the study centre of CCT cases, which were analysed based on anonymised questionnaires and discharge summaries. Data are shown as median (range) or n/N. RESULTS: Of 37 cases reported, 28 met inclusion criteria. Questionnaires and/or discharge summaries were available for 27/28. Assuming complete reporting, the incidence of CCT was 1:24 000. Nine infants suffered from proven or suspected syndromal anomalies, most frequently Noonan syndrome (5/9). Postnatally, 23 required mechanical ventilation, 3 continuous positive airway pressure; only 1 had no respiratory support. 17 infants were treated with inotropes/vasopressors, 25 required pleural drainage for 11 (1-36) days. In 13 infants, enteral feeds were withheld initially; 25 received medium-chain triglyceride diet at some time, 9 were treated with octreotide or somatostatin. 18 infants survived without, 6 with sequelae attributable to the underlying disorder; 3 infants died (median age at death 37 (2-144) days). Duration of hospital stay in survivors was 51 (20-127) days. Infants treated with octreotide or somatostatin had similar outcomes compared with those not treated. CONCLUSIONS: Based on this small observational study, CCT seems to have a favourable prognosis if not associated with genetic disorders.

Intravenous sildenafil in the management of pulmonary hypertension associated with congenital diaphragmatic hernia.

BACKGROUND: Pulmonary artery hypertension (PAH) is a significant cause of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). The phosphodiesterase-5 inhibitor sildenafil may be beneficial as a pulmonary vasodilator in CDH. Use of oral preparations of sildenafil may be restricted by feeding delays and intolerance. This study assessed the cardiorespiratory effects of a newly available intravenous (IV) preparation of sildenafil in CDH. OBJECTIVES: The objective of the article is to assess the acute effects of IV sildenafil infusion on myocardial function, pulmonary artery pressure (PAP), and oxygenation in infants with CDH. METHODS: Retrospective case review of infants with CDH who received continuous IV sildenafil. Physiological and echocardiographic data were reviewed to obtain oxygenation index (OI), PAP, patent ductus arteriosus (PDA) flow, myocardial tissue Doppler velocities, and right ventricular output (RVO) at 48 hours presildenafil, and at 24 to 48 hours and 72 to 96 hours after commencing IV sildenafil. RESULTS: A total of nine infants received IV sildenafil at a dose of 100 to 290 µg/kg/h after CDH repair but before enteral feeding. Pre-IV sildenafil PAP was ≥ systemic blood pressure in all infants, systolic and diastolic right ventricular myocardial velocities were impaired. After 72 to 96 hours of IV sildenafil, OI and Fio 2 were significantly reduced. Ratio of right-to-left to left-to-right PDA flow was > 1 pre-IV sildenafil and < 1 post-IV sildenafil. CONCLUSIONS: IV sildenafil infusion was associated with improved oxygenation. Prospective trials of IV sildenafil are required to determine effects on longer term outcome.

A conversion formula for comparing pulse oximeter desaturation rates obtained with different averaging times.

OBJECTIVE: The number of desaturations determined in recordings of pulse oximeter saturation (SpO2) primarily depends on the time over which values are averaged. As the averaging time in pulse oximeters is not standardized, it varies considerably between centers. To make SpO2 data comparable, it is thus desirable to have a formula that allows conversion between desaturation rates obtained using different averaging times for various desaturation levels and minimal durations. METHODS: Oxygen saturation was measured for 170 hours in 12 preterm infants with a mean number of 65 desaturations <90% per hour of arbitrary duration by using a pulse oximeter in a 2-4 s averaging mode. Using 7 different averaging times between 3 and 16 seconds, the raw red-to-infrared data were reprocessed to determine the number of desaturations (D). The whole procedure was carried out for 7 different minimal desaturation durations (≥ 1, ≥ 5, ≥ 10, ≥ 15, ≥ 20, ≥ 25, ≥ 30 s) below SpO2 threshold values of 80%, 85% or 90% to finally reach a conversion formula. The formula was validated by splitting the infants into two groups of six children each and using one group each as a training set and the other one as a test set. RESULTS: Based on the linear relationship found between the logarithm of the desaturation rate and the logarithm of the averaging time, the conversion formula is: D2 = D1 (T2/T1)(c), where D2 is the desaturation rate for the desired averaging time T2, and D1 is the desaturation rate for the original averaging time T1, with the exponent c depending on the desaturation threshold and the minimal desaturation duration. The median error when applying this formula was 2.6%. CONCLUSION: This formula enables the conversion of desaturation rates between different averaging times for various desaturation thresholds and minimal desaturation durations.

Treatment of Muckle-Wells syndrome: analysis of two IL-1-blocking regimens.

OBJECTIVES: Muckle-Wells syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1ß monoclonal antibody, can abolish excess IL-1ß. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies. METHODS: Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed. RESULTS: The study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumab-treated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles. CONCLUSIONS: IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.

Critical coarctation in an extremely low birth weight pre-term infant.

Neonatal interventions for critical aortic coarctation may be associated with considerable morbidity and mortality if the patient is extremely premature. We report the successful treatment of critical coarctation in a 25-week, 740-gram infant using initial clipping of the duct until continued prostaglandin E1 infusion delayed end-to-end anastomosis 7 weeks later.

NLRP3 E311K mutation in a large family with Muckle-Wells syndrome--description of a heterogeneous phenotype and response to treatment.

INTRODUCTION: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment. METHODS: A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab. RESULTS: All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-α, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab. CONCLUSION: The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.

Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome.

OBJECTIVE: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive interleukin-1 (IL-1) release. It is characterized by severe fevers, rashes, arthralgia, and conjunctivitis, leading to sensorineural deafness and amyloidosis. The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1. The aim of this study was to determine the short- and long-term efficacy and safety of anakinra therapy in children and adults with severe MWS. METHODS: A single-center observational study was performed. Standardized assessments included clinical features, the Disease Activity Score (DAS) for MWS, classic and novel markers of inflammation, and patient-derived measures of health status. The primary outcome was a score of <10 on the DAS for MWS at 2 weeks and at the last followup visit. Measures of MWS disease activity were investigated using descriptive statistics and paired comparative analysis. RESULTS: A total of 12 patients with severe MWS (5 children and 7 adults) received anakinra for a median of 11 months (range 5-14 months). The median followup was 11 months (range 5-14 months). Disease activity was significantly lower in all patients at 2 weeks (P = 0.0005). Organ manifestations of MWS improved, as did all patient-derived measures of health status, markers of inflammation, and hearing loss in 2 of the patients. Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity. Treatment was well tolerated, and no serious adverse events were observed. CONCLUSION: Anakinra was found to be a safe and effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well as long-term. Anakinra therapy should therefore be considered in children and adults with severe MWS disease requiring IL-1 blockade.

Quantitative assessment of ventricular function using three-dimensional SSFP magnetic resonance angiography.

PURPOSE: To evaluate three-dimensional (3D), free-breathing, steady-state free precession (SSFP) magnetic resonance angiography (MRA) for volumetric assessment of ventricular function. MATERIALS AND METHODS: In 18 subjects (mean age = 21.5 years) 3D datasets of the heart and great vessels were acquired using an ECG-triggered, free-breathing SSFP technique with a T2-preparation prepulse. Data were acquired during end-systole (ES) and end-diastole (ED) for assessment of stroke volumes (SVs). Through-plane flow measurements of the great arteries were performed as well as 2D-cine SSFP imaging for comparison. For image analysis of the 3D SSFP datasets a simplex mesh model was used. Papillary muscles were excluded from ventricular volumes using thresholds. Intra- and interobserver variability (Bland-Altman analysis) and correlations (Pearson's coefficient) between volumetric and flow measurements were assessed. RESULTS: ES and ED datasets were acquired successfully in all subjects. The best correlation was observed between flow vs. 3D SSFP SV for the LV (r = 0.85, mean difference = -1.0 mL) and the RV (r = 0.89, mean difference = -2.2 mL) with high intra- (LV: r = 0.93; RV: r = 0.94) and interobserver (LV: r = 0.91; RV: r = 0.93) reproducibility. CONCLUSION: 3D SSFP datasets combined with semiautomatic segmentation algorithms allow highly accurate and reproducible assessment of left (LV) and right ventricular (RV) SVs in free-breathing subjects.