14 research outputs found
Experimental proof of symptom reduction in cold urticaria patients by increasing the dose of desloratadine
Hintergrund und Zielsetzung Nicht-sedierende Antihistaminika (nsAH) stellen
die Therapie der ersten Wahl bei der Behandlung der Kälteurtikaria (KU) und
anderer Urtikariaerkrankungen dar. Die aktuellen EAACI/GA2LEN/EDF/WAO-
Leitlinien empfehlen eine bis zu vierfache Steigerung der Standarddosis von
nsAH bei Patienten, die auf eine solche Therapie nicht zufriedenstellend
ansprechen. Bisher gibt es jedoch nur wenig Belege für diese Empfehlung, da
kontrollierte Studien fehlen. In der vorliegenden Arbeit werden durch
objektive bildgebende Methoden die Wirkungen von 5 mg und 20 mg Desloratadin
(DL) sowie Placebo auf kälteinduzierte urtikarielle Hautveränderungen
dargelegt. Material und Methoden Es wurde eine prospektive, randomisierte,
doppelblinde, Cross-Over-Studie mit 30 KU-patienten durchgeführt. Die
Patienten erhielten täglich Placebo, 5 mg oder 20 mg DL für jeweils 7 Tage.
Zwischen den Therapien erfolgte eine 14-tägige Auswaschphase. Am Ende jeder
Behandlung wurden die Patienten einer standardisierten Kälteprovokation mit
TempTest® 2.0 und 2.1 unterzogen. Entwicklung und Ausmaß der provozierten
urtikariaspezischen Hautreaktion wurde mittels Volumetrie und Thermographie
gemessen. Schwellentemperaturen und Schwellenzeiten (CTT, CSTT) wurden
bestimmt. Ebenso wurden Kälteurtikaria-spezifische Symptome und unerwünschte
Ereignisse (AE) erfasst. Ergebnisse Die Gabe von 5 mg und 20 mg DL über 7 Tage
resultierte bei den KU-Patienten in einer signifikanten Reduktion des Volumens
der kälteinduzierten Quaddeln sowie des hyperthermen Hautareals und
verbesserte die Werte der CTT und CSTT im Vergleich zu Placebo. Die Behandlung
mit 20 mg DL pro Tag lieferte eine noch größere Reduzierung des Volumens der
kälteinduzierten Quaddeln als auch der Werte für CTT und CSTT verglichen zu 5
mg DL täglich. Pruritus und Beschwerdefreiheit wurden unter der hohen Dosis DL
im Gegensatz zu Placebo und zur Standardtherapie ebenfalls signifikant
verbessert. Beide Dosierungen wurden gut vertragen. Es kam zu keinem Anstieg
von Somnolenz oder anderen AE unter 20 mg DL. Schlussfolgerung Diese Studie
zeigt, dass die Standarddosis von DL die Symptome der KU nach standardisierter
Kälteprovokation mittels TempTest® signifikant verbessert. Die Steigerung auf
das vierfache der Standarddosis ermöglicht eine weitere Verbesserung der
Symptome über die Ergebnisse mit 5 mg DL und Placebo hinaus, ohne einen
Anstieg von AE nach sich zu ziehen. Somit unterstützt diese Arbeit die
aktuellen Empfehlungen der Leitlinie, dass eine Dosissteigerung der nsAH von
Vorteil für Patienten ist, die nicht zufriedenstellend auf die Standarddosis
ansprechen.Background and Rationale Non-sedating antihistamines (nsAH) are the
recommended first line treatment for patients with acquired cold urticaria
(ACU) and other Urticaria forms. The current EAACI/GA2LEN/EDF/WAO guidelines
call for updosing of nsAH up to four times of the standard dose in urticaria
patients who do not respond satisfactorily to that dose. As of now, however,
there is little evidence to support this recommendation due to a lack of
controlled studies. This Study assesses the effects of 5 mg and 20 mg of
desloratadine (DL) and placebo on cold-induced urticarial lesions by using
objective methods of imaging. Material and Methods A prospective, randomized,
double-blind, three-way crossover trial involving 30 ACU patients was
performed. Eligible patients received placebo, DL 5 mg and DL 20 mg once a day
each for 7 days, separated by 14 day washout periods. At the end of each
treatment phase, patients were subjected to cold provocation testing with the
TempTest® 2.0 und 2.1 system. The development and extent of the provoked
urticarial skin reaction was assessed using volumetric and thermographic
imaging. Critical temperature and stimulation time thresholds (CTT, CSTT) were
measured. ACU symptoms and adverse events (AE) were assessed. Results In ACU
patients, DL administration for 7 days at both the 5 mg and 20 mg dose
resulted in significant reductions in the volume of cold-induced wheals, areas
of hyperthermic skin and improved CTT and CSTT results, as compared with
placebo. Treatment with DL 20 mg/day provided a significantly greater
reduction in cold-induced weal volume and CTT and CSTT values as compared to
DL 5 mg/day. Pruritus and the total symptom control were significantly
improved under high dose therapy compared to placebo and DL at standard dose.
It was well tolerated at both doses and there was no increased rate of
somnolence or other AE under 20 mg DL. Conclusion This study shows that DL at
standard and high doses significantly improved objective signs of ACU provoked
by standardized cold exposure using the TempTest® system. Increasing the dose
of DL to four times the standard dose offered significant improvements over
those provided by DL 5mg and placebo without an increase in AE. This study
supports the suggestion of the current guideline that increased doses of nsAH
may be of benefit in ACU patients who do not respond satisfactorily to
standard doses
RIKADA Study Reveals Risk Factors in Pediatric Primary Cardiomyopathy
Background: Cardiomyopathies are heterogeneous diseases with clinical presentations varying from asymptomatic to life-threatening events, including severe heart failure and sudden cardiac death. The role of underlying genetic and disease-modulating factors in children and adolescents is relatively unknown. In this prospective study, in-depth phenotypic and genetic characterization of pediatric patients with primary cardiomyopathy and their first-degree family members (FMs) was performed. Outcome was assessed to identify clinical risk factors.
Methods and Results: Sixty index patients with primary cardiomyopathy (median age: 7.8 years) and 124 FMs were enrolled in the RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study. Family screening included cardiac workup and genetic testing. Using cardiologic screening, we identified 17 FMs with cardiomyopathies and 30 FMs with suspected cardiomyopathies. Adverse events appeared in 32% of index patients and were more common in those with lower body surface area (P=0.019), increased NT-proBNP (N-terminal pro-brain natriuretic peptide; P<0.001), and left ventricular dysfunction (P<0.001) and dilatation (P=0.005). The worst prognosis was observed in dilated and restrictive cardiomyopathies. Genetic variants of interest were detected in patients (79%) and FMs (67%). In all 15 families with at least 1 FM with cardiomyopathy, we found a variant of interest in the index patient. Increased number of variants of interest per patient was associated with adverse events (P=0.021). Late gadolinium enhancement was related to positive genotypes in patients (P=0.041).
Conclusions: Lower body surface area, increased NT-proBNP, left ventricular dysfunction or dilatation, late gadolinium enhancement, and increased number of variants of interest were associated with adverse outcome and should be considered for risk assessment in pediatric primary cardiomyopathies.
Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03572569
Left ventricular rotation and right–left ventricular interaction in congenital heart disease: the acute effects of interventional closure of patent arterial ducts and atrial septal defects
Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3
The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel‐based next‐generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP
Familial Recurrent Myocarditis Triggered by Exercise in Patients With a Truncating Variant of the Desmoplakin Gene
BACKGROUND: Variants of the desmosomal protein desmoplakin are associated with arrhythmogenic cardiomyopathy, an important cause of ventricular arrhythmias in children and young adults. Disease penetrance of desmoplakin variants is incomplete and variant carriers may display noncardiac, dermatologic phenotypes. We describe a novel cardiac phenotype associated with a truncating desmoplakin variant, likely causing mechanical instability of myocardial desmosomes.
METHODS AND RESULTS: In 2 young brothers with recurrent myocarditis triggered by physical exercise, screening of 218 cardiomyopathy-related genes identified the heterozygous truncating variant p.Arg1458Ter in desmoplakin. Screening for infections yielded no evidence of viral or nonviral infections. Myosin and troponin I autoantibodies were detected at high titers. Immunohistology failed to detect any residual DSP protein in endomyocardial biopsies, and none of the histologic criteria of arrhythmogenic cardiomyopathy were fulfilled. Cardiac magnetic resonance imaging revealed no features associated with right ventricular arrhythmogenic cardiomyopathy, but multifocal subepicardial late gadolinium enhancement was present in the left ventricles of both brothers. Screening of adult cardiomyopathy cohorts for truncating variants identified the rare genetic variants p.Gln307Ter, p.Tyr1391Ter, and p.Tyr1512Ter, suggesting that over subsequent decades critical genetic/exogenous modifiers drive pathogenesis from desmoplakin truncations toward different end points.
CONCLUSIONS: The described novel phenotype of familial recurrent myocarditis associated with a desmoplakin truncation in adolescents likely represents a serendipitously revealed subtype of arrhythmogenic cardiomyopathy. It may be caused by a distinctive adverse effect of the variant desmoplakin upon the mechanical stability of myocardial desmosomes. Variant screening is advisable to allow early detection of patients with similar phenotypes
Author response for "Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of <i>TNNI3</i>"
Toward evidence-based diagnosis of myocarditis in children and adolescents: Rationale, design, and first baseline data of MYKKE, a multicenter registry and study platform
Aims The aim of this registry is to provide data on age-related clinical features of suspected myocarditis and to create a study platform allowing for deriving diagnostic criteria and, at a later stage, testing therapeutic interventions in patients with myocarditis. Study design and results After an initial 6-month pilot phase, MYKKE was opened in June 2014 as a prospective multicenter registry for patients from pediatric heart centers, university hospitals, and community hospitals with pediatric cardiology wards in Germany. Inclusion criteria consisted of age 12 years), show higher proportions of males, and document a high prevalence of severe disease courses in pediatric patients with suspected myocarditis. Severe clinical courses and early adverse events were more prevalent in younger patients and were related to severely impaired leftventricular ejection fraction at initial presentation. Summary MYKKE represents a multicenter registry and research platform for children and adolescents with suspected myocarditis that achieve steady recruitment and generate a wide range of real-world data on clinical course, diagnostic workup, and treatment of this group of patients. The baseline data reveal the presence of 2 age peaks and provide important insights into the severity of disease in children with suspected myocarditis. In the future, MYKKE might facilitate interventional substudies by providing an established collaborating network using common diagnostic approaches