Refine
Document Type
- Article (9)
Language
- English (9)
Has Fulltext
- yes (9)
Is part of the Bibliography
- no (9)
Keywords
- - (5)
- growth (2)
- B cell class switch (1)
- Bayesian (1)
- C-reactive protein (1)
- Colaizzi (1)
- HCMV (1)
- Shiny application (1)
- T cell maturation (1)
- allergy (1)
- apoptosis-associated speck-like protein (ASC) (1)
- asthma (1)
- autoinflammation (1)
- biomarker (1)
- calprotectin (1)
- carbohydrates (1)
- case report (1)
- childhood (1)
- complication (1)
- data mining (1)
- diagnostic support (1)
- disease behavior (1)
- ductal closure (1)
- endocarditis (1)
- endoscopy (1)
- epigenome (1)
- exacerbation (1)
- fat (1)
- flow cytometry – methods (1)
- fusarium (1)
- healtcare (1)
- hematopoietic stem cell transplantation (1)
- hospitalization (1)
- human milk (1)
- humanized mice (1)
- ibuprofen (1)
- indomethacin (1)
- inflammasome (1)
- inflammatory bowel disease (1)
- invasive mold infection (1)
- juvenile idiopathic arthritis (1)
- linear discriminant analyses (1)
- milk analysis (1)
- monitoring (1)
- optical imaging analyses (1)
- ordinal regression model (1)
- outcome (1)
- patent ductus arteriosus (1)
- perianal disease (1)
- platelets (1)
- prediction (1)
- preterm infant (1)
- preterm infants (1)
- primary immunodeficiency disease (1)
- principal component analyses (1)
- protein (1)
- questionnaire (1)
- reactivation (1)
- splenic rupture (1)
- standard fortification (1)
- surgery (1)
Institute
- Klinik und Poliklinik für Kinder- und Jugendmedizin (9) (remove)
Publisher
- Frontiers Media S.A. (9) (remove)
Background
The role of platelets for mediating closure of the ductus arteriosus in human preterm infants is controversial. Especially, the effect of low platelet counts on pharmacological treatment failure is still unclear.
Methods
In this retrospective study of 471 preterm infants [<1,500 g birth weight (BW)], who were treated for a patent ductus arteriosus (PDA) with indomethacin or ibuprofen, we investigated whether platelet counts before or during pharmacological treatment had an impact on the successful closure of a hemodynamically significant PDA. The effects of other factors, such as sepsis, preeclampsia, gestational age, BW, and gender, were also evaluated.
Results
Platelet counts before initiation of pharmacological PDA treatment did not differ between infants with later treatment success or failure. However, we found significant associations between low platelet counts during pharmacological PDA therapy and treatment failure (p < 0.05). Receiver operating characteristic (ROC) curve analysis showed that platelet counts after the first, and before and after the second cyclooxygenase inhibitor (COXI) cycle were significantly associated with treatment failure (area under the curve of >0.6). However, ROC curve analysis did not reveal a specific platelet cutoff-value that could predict PDA treatment failure. Multivariate logistic regression analysis showed that lower platelet counts, a lower BW, and preeclampsia were independently associated with COXI treatment failure.
Conclusion
We provide further evidence for an association between low platelet counts during pharmacological therapy for symptomatic PDA and treatment failure, while platelet counts before initiation of therapy did not affect treatment outcome.
In summer 2017, the World Health Organization published 10 facts on asthma, which is known as a major non-communicable disease of high clinical and scientific importance with currently several hundred million people—with many children among them—suffering from air passages inflammation and narrowing. Importantly, the World Health Organization sees asthma as being underdiagnosed and undertreated. Consequently, much more efforts in clinical disease management and research need to be spent on reducing the asthma-related health burden. Particularly, for young approximately 6 months aged patients presenting recurrent bronchitic respiratory symptoms, many parents anxiously ask the doctors for risk prognosis for their children's future life. Therefore, we urgently need to reevaluate if the current diagnostic and treatment measures are in concordance with our yet incomplete knowledge of pathomechanisms on exacerbation. To contribute to this increasing concern worldwide, we established a multicentric pediatric exacerbation study network, still recruiting acute exacerbated asthmatics (children >6 years) and preschool asthmatics/wheezers (children <6 years) since winter 2018 in Germany. The current study that has a currently population comprising 176 study participants aims to discover novel holistic entry points for achieving a better understanding of the poorly understood plasticity of involved molecular pathways and to define biomarkers enabling improved diagnostics and therapeutics. With this study description, we want to present the study design, population, and few ongoing experiments for novel biomarker research.
Clinical Trial Registration: German Clinical Trials Register (Deutsches Register für Klinische Studien, DRKS): DRKS00015738.
Objectives: Several clinical disease activity indices (DAIs) have been developed to noninvasively assess mucosal healing in pediatric Crohn’s disease (CD). However, their clinical application can be complex. Therefore, we present a new way to identify the most informative biomarkers for mucosal inflammation from current markers in use and, based on this, how to obtain an easy-to-use DAI for clinical practice. A further aim of our proof-of-concept study is to demonstrate how the performance of such a new DAI can be compared to that of existing DAIs.
Methods: The data of two independent study cohorts, with 167 visits from 109 children and adolescents with CD, were evaluated retrospectively. A variable selection based on a Bayesian ordinal regression model was applied to select clinical or standard laboratory parameters as predictors, using an endoscopic outcome. The predictive performance of the resulting model was compared to that of existing pediatric DAIs.
Results: With our proof-of-concept dataset, the resulting model included C-reactive protein (CRP) and fecal calprotectin (FC) as predictors. In general, our model performed better than the existing DAIs. To show how our Bayesian approach can be applied in practice, we developed a web application for predicting disease activity for a new CD patient or visit.
Conclusions: Our work serves as a proof-of-concept, showing that the statistical methods used here can identify biomarkers relevant for the prediction of a clinical outcome. In our case, a small number of biomarkers is sufficient, which, together with the web interface, facilitates the clinical application. However, the retrospective nature of our study, the rather small amount of data, and the lack of an external validation cohort do not allow us to consider our results as the establishment of a novel DAI for pediatric CD. This needs to be done with the help of a prospective study with more data and an external validation cohort in the future.
Background: Native breast milk composition displays significant inter- and intra-individual variation which persists after standard fortification with fixed doses and challenges target fortification. This study aims to analyze the macronutrient composition of different commercially available fortifiers and the effect of different fortification strategies on nutritional intake of preterm infants.
Methods: In 103 preterm infants, native breast milk samples were collected from 24-h feeding batches (n = 3,338) and fat, protein and carbohydrate contents were analyzed. Nutrient content was compared for breast milk that had undergone either (i) standard fortification, (ii) targeted fortification, (iii) selective batching according to breast milk composition, or (iv) partial lyophilization. For (i) eight commercially available standard fortifiers were tested. Targeted fortification (ii) involved the addition of single component modulars of either protein, fat or carbohydrates to standard fortified breast milk. Using a mathematical growth model, the combined effect of protein, fat and carbohydrate intake on growth was assessed. The best composition of standard fortifiers as the initial step for target fortification was explored assuming three clinical scenarios for milk analysis.
Results: Macronutrient content was highly variable between native breast milk samples, and this variation was still present after standard fortification, however at elevated macronutrient levels. Standard fortification, breast milk batching, as well as partial lyophilization of human milk resulted in deficient and imbalanced enteral intakes in a significant proportion of infants. Target fortification reduced this variation in a, respectively, higher percentage of samples. The effect size was dependent on the number of measurements per week. The optimum composition of standard fortifiers was dependent on the clinical scenario (measurement frequency) for target fortification.
Conclusions: To provide precise and accurate intakes of macronutrients, breast milk should be target fortified. Standard fortified breast milk can result in excess above recommended intakes of some macronutrients which limits the efficiency of target fortification. Standard fortifiers with improved composition are needed for target fortification.
Inflammasome activation and formation of ASC specks in patients with juvenile idiopathic arthritis
(2023)
Objective
The formation of large intracellular protein aggregates of the inflammasome adaptor ASC is a hallmark of inflammasome activation and characteristic of autoinflammation. Inflammasome activated cells release the highly proinflammatory cytokine IL-1β in addition to ASC specks into the extracellular space. Autoinflammatory activity has been demonstrated in systemic JIA, however minimal data exist on the role of inflammasomes in other JIA subtypes. We therefore investigated, if pyroptotic cells are present in the circulation of oligo- and poly-articular JIA.
Methods
Peripheral blood of JIA patients (n = 46) was investigated for ASC speck formation, a key step in inflammasome activation, by flow cytometry and immunofluorescence. Free ASC and proinflammatory cytokine levels were determined by ELISA and multiplex assay.
Results
Oligo-articular JIA patients showed a significantly increased proportion of ASC speck+ monocytes compared to poly-articular JIA patients. In serum free ASC alone is not sufficient to assess inflammasome activity and does not correlate with ASC speck+ monocytes. Compared to control several cytokines were significantly elevated in samples of JIA patients. JIA serum containing antinuclear antibodies, incubated with ASC specks boosts a secondary inflammation by IL-1β production in macrophages.
Conclusion
For the first time, we detect ex vivo inflammasome activation by ASC speck formation in oligo- and poly-articular JIA patients. Most notably, inflammasome activation was significantly higher in oligo- compared to poly-articular JIA patients. This data suggests that inflammasome derived autoinflammation may have a greater influence in the previously thought autoimmune oligo-articular JIA patients.
Introduction
Primary immunodeficiency disorders (PIDs) are a heterogeneous group of more than 200 rare diseases. Timely diagnosis is of uttermost importance. Therefore, we aimed to develop a diagnostic questionnaire with computerized pattern-recognition in order to support physicians to identify suspicious patient histories.
Materials and methods
Standardized interviews were conducted with guardians of children with PID. The questionnaire based on parental observations was developed using Colaizzis’ framework for content analysis. Answers from 64 PID patients and 62 controls were analyzed by data mining methods in order to make a diagnostic prediction. Performance was evaluated by k-fold stratified cross-validation.
Results
The diagnostic support tool achieved a diagnostic sensitivity of up to 98%. The analysis of 12 interviews revealed 26 main phenomena observed by parents in the pre-diagnostic period. The questions were systematically phrased and selected resulting in a 36-item questionnaire. This was answered by 126 patients with or without PID to evaluate prediction. Item analysis revealed significant questions.
Discussion
Our approach proved suitable for recognizing patterns and thus differentiates between observations of PID patients and control groups. These findings provide the basis for developing a tool supporting physicians to consider a PID with a questionnaire. These data support the notion that patient’s experience is a cornerstone in the diagnostic process.
Predicting complications in pediatric Crohn's disease patients followed in CEDATA-GPGE registry
(2023)
Background
Complications of Crohn's disease (CD) often impair patients' quality of life. It is necessary to predict and prevent these complications (surgery, stricturing [B2]/penetrating [B3] disease behavior, perianal disease, growth retardation and hospitalization). Our study investigated previously suggested and additional predictors by analyzing data of the CEDATA-GPGE registry.
Methods
Pediatric patients (< 18 years) diagnosed with CD with follow up data in the registry were included in the study. Potential risk factors for the selected complications were evaluated by performing Kaplan-Meier survival curves and cox regression models.
Results
For the complication surgery, the potential risk factors older age, B3 disease, severe perianal disease and initial therapy with corticosteroids at the time of diagnosis were identified. Older age, initial therapy with corticosteroids, low weight-for-age, anemia and emesis predict B2 disease. Low weight-for-age and severe perianal disease were risk factors for B3 disease. Low weight-for-age, growth retardation, older age, nutritional therapy, and extraintestinal manifestations (EIM) of the skin were identified as risk factors for growth retardation during the disease course. High disease activity and treatment with biologicals were predictors for hospitalization. As risk factors for perianal disease, the factors male sex, corticosteroids, B3 disease, a positive family history and EIM of liver and skin were identified.
Conclusion
We confirmed previously suggested predictors of CD course and identified new ones in one of the largest registries of pediatric CD patients. This may help to better stratify patients’ according to their individual risk profile and choose appropriate treatment strategies.
Human cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio-luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. Foci of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14+, CD169+, and CD34+ cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4+ T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG+ plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4+ T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel in vivo humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation.
Background
Invasive mold infections are a well-known and life-threatening condition after allogeneic hematopoietic stem cell transplantation (HSCT). While Aspergillus species are recognized as predominant pathogens, Fusarium species should also be considered due to their broad environmental distribution and the expected poor outcome of invasive fusariosis. Particularly, splenic rupture as a complication of disseminated disease has not been reported yet.
Case presentation
Two weeks after allogeneic HSCT for severe aplastic anemia, a 16-year-old boy presented with painful, erythematous skin nodules affecting the entire integument. As disseminated mycosis was considered, treatment with liposomal amphotericin B and voriconazole (VCZ) was initiated. Invasive fusariosis was diagnosed after histological and previously unpublished polymerase chain reaction-based examination of skin biopsies. Microbiological tests revealed Fusarium solani species. Despite stable neutrophil engraftment and uninterrupted treatment with VCZ, he developed mold disease-associated splenic rupture with hypovolemic shock and fungal endocarditis. The latter induced a cardiac thrombus and subsequent embolic cerebral infarctions with unilateral hemiparesis. Following cardiac surgery, the patient did not regain consciousness because of diffuse cerebral ischemia, and he died on day +92 after HSCT.
Conclusion
Invasive fusariosis in immunocompromised patients is a life-threatening condition. Despite antimycotic treatment adapted to antifungal susceptibility testing, the patient reported here developed uncommon manifestations such as splenic rupture and fungal endocarditis.