Fibrosis In Pediatric Patients Research Articles

A skin-interfaced, miniaturized platform for triggered induction, capture and colorimetric multicomponent analysis of microliter volumes of sweat

Eccrine sweat can serve as a source of biomarkers for assessing physiological health and nutritional balance, for tracking loss of essential species from the body and for evaluating exposure to hazardous substances. The growing interest in this relatively underexplored class of biofluid arises in part from its non-invasive ability for capture and analysis. The simplest devices, and the only ones that are commercially available, exploit soft microfluidic constructs and colorimetric assays with purely passive modes of operation. The most sophisticated platforms exploit batteries, electronic components and radio hardware for inducing sweat, for electrochemical evaluation of its content and for wireless transmission of this information. The work reported here introduces a technology that combines the advantages of these two different approaches, in the form of a cost-effective, easy-to-use device that supports on-demand evaluation of multiple biomarkers in sweat. This flexible, skin-interfaced, miniaturized system incorporates a hydrogel that contains an approved drug to activate eccrine sweat glands, electrodes and a simple circuit and battery to delivery this drug by iontophoresis through the surface of the skin, microfluidic channels and microreservoirs to capture the induced sweat, and multiple colorimetric assays to evaluate the concentrations of chloride, zinc, and iron. As demonstrated in healthy human participants monitored before and after a meal, such devices yield results that match those of traditional laboratory analysis techniques. Clinical studies that involve cystic fibrosis pediatric patients illustrate the use of this technology as a simple, painless, and reliable alternative to traditional hospital systems for measurements of sweat chloride.

Shear wave elastography as a non-invasive tool for staging liver fibrosis in children: A study in Algerian pediatric patients.

Traditionally, liver biopsy has been the gold standard for fibrosis staging. However, it is an invasive, expensive and uncomfortable procedure that is associated with the risk of complications. Thus, non-invasive methods such as shear wave elastography (SWE) have been developed as potential alternatives to liver biopsy. The aim of this study is to evaluate the diagnostic performance of SWE in pediatric patients with liver fibrosis, specifically in a group of Algerian children and to determine whether this method can be a reliable alternative to liver biopsy. This prospective, descriptive, monocentric study evaluated the non-invasive diagnostic performance of 2D-SWE in assessing liver fibrosis in pediatric patients. The assessment was carried out using various statistical methods, including Spearman's correlation coefficient, Kappa concordance coefficients, regression analysis, as well as the calculation of area under the receiver operating characteristic (AUROC) values and corresponding cut-off points based on the receiver operating characteristic (ROC) curve. Our study found that 2D-SWE is strongly correlated with liver biopsy in estimating liver fibrosis in children, with a correlation coefficient greater than 0.8. Furthermore, the Kappa correlation coefficients exceeded 0.8, indicating a strong agreement between 2D-SWE and liver biopsy results. The AUROC value was not less than 0.9 for significant fibrosis and above (≥ F2), indicating that it has satisfactory diagnostic performance in detecting liver fibrosis in children. 2D-SWE shows promise as a non-invasive method for evaluating liver fibrosis in children, offering a potential alternative to liver biopsy. Larger studies are needed to substantiate the findings of this study and to confirm the accuracy and reliability of 2D-SWE for assessing liver fibrosis in children.

Left ventricular strain-volume loops and myocardial fibrosis in pediatric patients with Duchenne muscular dystrophy

BackgroundThe left ventricular strain–volume loop (SVL) combines changes in global longitudinal strain (GLS) and LV volume across a cardiac cycle, providing insight into cardiac dynamics. This study explored the association between left ventricular SVL and presence of fibrosis, assessed with late gadolinium enhancement, in patients with Duchenne muscular dystrophy (DMD). Methods and results34 pediatric patients with DMD were included. Feature tracking analysis was used to assess endocardial GLS and volumetric measurements to construct the SVL. Mean age at the time of assessment was 14 ± 3 and 11 ± 2 years old (p < 0.01) in the group with (n = 18) versus without fibrosis (n = 16), respectively. Left ventricular ejection fraction was not significantly different between groups (fibrosis: 56.4 ± 3.8% versus without fibrosis: 54.0 ± 6.3%, p = 0.18). After adjusting for age, the late diastolic slope of the SVL was significantly associated with presence of fibrosis (OR 0.39 [95% CI 0.18–0.85]; area under the receiver operating characteristic curve: 0.83 [95% CI 0.70–0.97]) No significant association was observed for peak strain and fibrosis (OR 1.15 [95% CI 0.86–1.546]). ConclusionA lower late diastolic slope of the left ventricular SVL, related to the interplay between longitudinal deformation and volume changes late in diastole, is associated with presence of myocardial fibrosis in pediatric patients with DMD.

Update on Cystic Fibrosis in Pediatric Patients.

Cystic fibrosis is an inherited, multisystem disease that affects the gastrointestinal system in numerous ways. This article reviews the nutritional, gastrointestinal, and hepatobiliary manifestations of cystic fibrosis with an emphasis on the effects of CFTR modulator therapy. The life expectancy of individuals with cystic fibrosis has increased substantially in recent years. CFTR modulator therapy improves pulmonary function and results in weight gain. An individualized approach to nutrition is encouraged. Pancreatic exocrine function may improve with intervention early in life. The use of non-invasive methods to screen for hepatobiliary involvement is recommended. Highly effective CFTR modulators lead to increased survival and improved quality of life for many individuals. Their effects on gastrointestinal symptoms and hepatobiliary disease are not fully understood. Patient-reported outcome measures and biomarkers are important clinical endpoints for studying the effects of modulators.

Left ventricular deformation and myocardial fibrosis in pediatric patients with Duchenne muscular dystrophy

BackgroundLeft ventricular (LV) strain and rotation are emerging functional markers for early detection of LV dysfunction and have been associated with the burden of myocardial fibrosis in several disease states. This study examined the association between LV deformation (i.e., LV strain and rotation) and extent and location of LV myocardial fibrosis in pediatric patients with Duchenne muscular dystrophy (DMD). Methods and results34 pediatric patients with DMD underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) to assess LV myocardial fibrosis. Offline CMR feature-tracking analysis was used to assess global and segmental longitudinal and circumferential LV strain, and LV rotation. Patients with fibrosis (n = 18, 52.9%) were older than those without fibrosis (14 ± 3 years (yrs) vs 11 ± 2 yrs., p = 0.01). There was no significant difference in LV ejection fraction (LVEF) between subjects with and without fibrosis (54 ± 6% vs 56 ± 4%, p = 0.18). However, lower endocardial global circumferential strain (GCS), but not LV rotation, was associated with presence of fibrosis (adjusted Odds Ratio 1.25 [95% CI 1.01–1.56], p = 0.04). Both GCS and global longitudinal strain correlated with the extent of fibrosis (r = .52, p = 0.03 and r = .75, p < 0.01, respectively). Importantly, segmental strain did not seem to correspond to location of fibrosis. ConclusionA lower global, but not segmental, strain is associated with presence and extent of LV myocardial fibrosis in pediatric DMD patients. Therefore, strain parameters might detect structural myocardial alterations, however currently more research is needed to evaluate its value (e.g., prognostic) in clinical practice.

P213 Post-acute sequelae of COVID-19 in children with cystic fibrosis: a case-control study

This study was aimed to evaluate the prevalence and characteristics of post-acute sequelae of COVID-19 (PASC) in cystic fibrosis (CF) pediatric patients, including clinical data, persistent symptoms, change in pulmonary exacerbations and self-rated health.

P321 Impact of short-term CFTR modulators treatment on changes in nutritional and glucose status in cystic fibrosis paediatric patients with different glucose tolerance

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are drugs that could change the course of the disease in cystic fibrosis (CF) patients and also nutrition status and glucose metabolism. Our study aimed to assess the impact of CFTR modulators treatment on nutritional and glucose status in CF pediatric patients with different glucose tolerance.

Evaluation of serum VIP and aCGRP during pulmonary exacerbation in cystic fibrosis: A longitudinal pilot study of patients undergoing antibiotic therapy.

Objective monitoring of improvement during treatment of pulmonary exacerbation can be difficulty in children when pulmonary function testing cannot be obtained. Thus, the identification of predictive biomarkers to determine the efficacy of drug treatments is of high priority. The major aim of the current study was to investigate the serum levels of vasoactive intestinal peptide (VIP) and alpha calcitonin gene related peptide (aCGRP) of cystic fibrosis pediatric patients during pulmonary exacerbation and post-antibiotic therapy, and possible associations of their levels with different clinicopathological parameters. 21 patients with cystic fibrosis were recruited at onset of pulmonary exacerbation. Serum was collected at time of admission, three days post-antibiotic therapy, and two weeks post-antibiotic therapy (end of antibiotic therapy). Serum VIP and aCGRP levels were measured using ELISA. Overall least square means of serum aCGRP level but not VIP changed from time of exacerbation to completion of antibiotic therapy (p = 0.005). Serum VIP was significantly associated with the presence of diabetes mellitus (p = 0.026) and other comorbidities (p = 0.013), and with type of antibiotic therapy (p = 0.019). Serum aCGRP level was significantly associated with type of antibiotic therapy (p = 0.012) and positive Staphylococcus aureus microbiology test (p = 0.046). This study could only show significant changes in serum aCGRP levels following treatment of pulmonary exacerbations. Future studies with larger sample size are required to investigate the clinical importance of VIP and aCGRP in cystic fibrosis patients.

Magnetic resonance elastography in evaluation of liver fibrosis in children with chronic liver disease

BackgroundMagnetic resonance elastography (MRE) has been used to stage liver fibrosis in adults. We aimed to assess the agreement between the Ishak scoring system and magnetic resonance elastography-measured liver stiffness (MRE-LS) in children. This study included all the children who underwent abdominal MRE and liver biopsies between February 2018 and January 2021. The correlation between MRE-LS and Ishak fibrosis stage, MRE parameters, and clinical and biochemical markers affecting this relationship was investigated.ResultsA total of 52 patients (31 male; a median age of 11.8 years) were included in the study. The MRE-LS values were significantly different between Ishak fibrosis stages (p = 0.036). With a cut-off value of 2.97 kilopascals, MRE-LS had sensitivity, specificity, PPV, NPV and accuracy values of 90.9%, 82.9%, 58.8%, 97.1%, and 84.6%, respectively, for differentiating mild/moderate fibrosis (F0, 1, 2, 3) from severe fibrosis (F ≥ 4). Although MRE-LS was moderately correlated with Ishak fibrosis score and histological activity index and weakly correlated with aspartate aminotransferase, hepatic steatosis, and R2*, only Ishak fibrosis score was a significant predictor of MRE-LS. MRE-measured spleen stiffness was weakly correlated with the Ishak fibrosis score.ConclusionsMRE has high sensitivity and specificity for evaluating liver fibrosis in children. MRE may be used to evaluate liver fibrosis in pediatric patients.

Comprehensive Proteomics Analysis Identifies CD38-Mediated NAD+ Decline Orchestrating Renal Fibrosis in Pediatric Patients With Obstructive Nephropathy

Obstructive nephropathy is one of the leading causes of kidney injury and renal fibrosis in pediatric patients. Although considerable advances have been made in understanding the pathophysiology of obstructive nephropathy, most of them were based on animal experiments and a comprehensive understanding of obstructive nephropathy in pediatric patients at the molecular level remains limited. Here, we performed a comparative proteomics analysis of obstructed kidneys from pediatric patients with ureteropelvic junction obstruction and healthy kidney tissues. Intriguingly, the proteomics revealed extensive metabolic reprogramming in kidneys from individuals with ureteropelvic junction obstruction. Moreover, we uncovered the dysregulation of NAD+ metabolism and NAD+-related metabolic pathways, including mitochondrial dysfunction, the Krebs cycle, and tryptophan metabolism, which led to decreased NAD+ levels in obstructed kidneys. Importantly, the major NADase CD38 was strongly induced in human and experimental obstructive nephropathy. Genetic deletion or pharmacological inhibition of CD38 as well as NAD+ supplementation significantly recovered NAD+ levels in obstructed kidneys and reduced obstruction-induced renal fibrosis, partially through the mechanisms of blunting the recruitment of immune cells and NF-κB signaling. Thus, our work not only provides an enriched resource for future investigations of obstructive nephropathy but also establishes CD38-mediated NAD+ decline as a potential therapeutic target for obstruction-induced renal fibrosis.

Noninvasive assessment and risk factors of liver fibrosis in pediatric patients with beta thalassemia major using transient elastography

BackgroundIn beta-thalassemia major (TM) patients, levels of liver iron overload and the presence of chronic hepatitis C are directly correlated with the onset and severity of liver fibrosis. A noninvasive approach that can evaluate cirrhosis and liver fibrosis in these patients is transient elastography (TE). We aimed to find out the role of noninvasive elastography in the assessment of liver fibrosis in young beta-thalassemia major patients receiving frequent blood transfusions. Identifying the patients' risk factors for liver fibrosis is another goal. The study comprised 53 patients, all of whom had a thorough history-taking procedure, clinical examination, and investigations such as CBC, serum ferritin, HCV and HBV serology, and liver function testing. It was carried out transient elastography to find liver fibrosis.ResultsAccording to transient elastography, 52.8% of the patients had severe fibrosis (F2 and higher). 9.4% of people had positive HCV serology results. Significant liver fibrosis was correlated with all serum ferritin levels (708.2 ± 182.1, 3213.5 ± 1272.9, nonsignificant vs. significant fibrosis), HCV infection, age, blood transfusion frequency, and irregular chelation therapy. But no significant correlation regarding sex and BMI was detected.ConclusionTransient elastography is an alternate noninvasive approach that assesses liver fibrosis in beta-thalassemia major patients. The risk of liver fibrosis is related to iron overload, HCV seropositivity, advanced age, frequent blood transfusion, and irregular chelation therapy.

235.5: Poly (ADP-Ribose) Polymerase (PARP) Expression in Renal Allografts Augments the Development of Epithelial-Tomesenchymal Transition (EMT), Transplant Glomerulopathy, And Interstitial Fibrosis in Pediatric Patients With Antibodymediated Rejection

Introduction: PARP activation is known to increase inflammation, but its role in developing EMT, interstitial fibrosis (IF), and transplant glomerulopathy (TG) are still unclear. Therefore we investigate the role of PARP in the development of EMT, IF, and TG in recipients with antibody-mediated rejection (AMR). Method: Expressions of tubular and glomerular PARP, α-SMA, TNF-α, TGF-β, and HLA-DR, were studied in 45 pediatric cases with AMR. Tubular α-SMA expression was noted as tubular EMT. Peritubular capillary (PTC) and interstitial leukocytes were highlighted with PARP, TNF-α, HLA-DR, and CD68. Follow-up biopsies were analyzed for IF and TG development. Results: PARP expression in tubules, glomeruli, and infiltrated leukocytes was positively correlated with PTC, glomerular, and interstitial leukocyte and macrophage infiltration (p<0.001). Tubular and glomerular PARP expression also correlated with PTC and interstitial leukocyte PARP, TNF- α, TGF-β, and HLA-DR expression (p<0.001). Tubular α-SMA expression (EMT development) positively correlated with tubular, glomerular, PTC, interstitial, PARP, TNF-α, HLA-DR, and CD68 expression (p<0.01). PARP expression increased in tubules, PTCs, interstitium, and glomeruli with the intensity of C4d expression (p<0.01). Response to rejection treatment decreases with increasing tubular, interstitial, PTC, glomerular PARP, TNF-α, HLA-DR, and CD68 expression (p<0.01). IF development time was negatively correlated with the increasing PTC and interstitial leukocyte and macrophage infiltration (p<0.001). The incidence of IF and TG development was found to increase with an increasing degree of renal PARP expression and tubular EMT development (p<0.01). Additionally, the IF development time shortened with increasing PARP, HLA-DR, TNF-α, TGF-β, α-SMA expression in inflammatory and tubular cells (P<0.01). The mean graft survival time decreased with increasing interstitial, tubular PARP, and α-SMA expression (p<0.01). The 5-year graft survival was 96% for recipients with negative tubular PARP while 60%, 19%, and 18% for recipients with grade1, grade 2, and grade 3 tubular PARP expression, respectively (p<0.001). Conclusion: Increased PARP activation leads to early graft loss by augmenting inflammation and IF by activating inflammatory signaling pathways and tubular cells myofibroblastic differentiation (EMT). Therefore, we suggest that PARP inhibitor drugs combined with immunosuppressive therapy may control inflammation and fibrosis to prevent early graft loss.

Investigating an Increased Incidence of Burkholderia Cepacia Among Non-Cystic Fibrosis Pediatric Patients

<h3>Background</h3> Burkholderia cepacia Complex (BCC), commonly identified in patients with Cystic Fibrosis (CF), has been associated with outbreaks from contaminated medications (Abdelfattah 2018) and devices (Lucero, 2011). An increase of BCC in cultures of non-CF patients prompted an investigation including an assessment of commonalities such as medications, procedures, staffing, equipment, and treatment locations. Our journey to identify a source and implement control measures led to a yearlong, multi-facility outbreak investigation with support and involvement of the Massachusetts Department of Public Health and the Centers for Disease Control. <h3>Methods</h3> Literature review of past outbreaks aided in narrowing our scope of potential sources. Chart reviews helped identify commonalities across patients, however, these commonalities did not elucidate a root cause. Through the Burkholderia cepacia Research Laboratory & Repository at the University of Michigan, whole-genome sequencing identified matching isolates. Over 20 patients and 50 environmental isolates from our facility were evaluated. <h3>Results</h3> Three distinct BCC clusters were identified: a larger cluster of 10 patients with Burkholderia cenocepacia recA subgroup and two smaller clusters of 2 patients each with a matching Burkholderia cepacia indeterminate species. Despite environmental sampling not identifying a source, our Respiratory program re-educated staff on not storing respiratory equipment within the splash zone of a sink and use of sterile water for all respiratory care items. Additionally, a policy was formalized for reprocessing of custom tracheostomies, and we transitioned to single-use temperature probes for one of our ventilators. Ultimately, new information suggested the primary source was external to our facility. <h3>Conclusions</h3> Early identification of outbreaks in healthcare facilities and evaluation of all possible causes is central to Infection Prevention. Ongoing surveillance and analysis utilizing established epidemiologic methods are essential to successfully minimizing the adverse effects to patients.

Accuracy of noninvasive fibrosis scores in predicting advanced fibrosis in pediatric patients after liver transplantation

Liver biopsy is the gold standard to stage fibrosis in liver disease. Several scoring systems have been studied to predict advanced fibrosis in liver disease. Those scores have not been validated in pediatric liver transplant patients. Evaluate the performance of three fibrosis scores (FSc) in assessing the presence of advanced fibrosis (AF) in children after orthotopic liver transplantation (OLT). Patients < 20 years of age who underwent liver biopsy post-OLT with laboratory values within 1month of the biopsy were included. Fibrosis was determined by an experienced pathologist (F0-4). We defined AF as F3-4. The following FSc were calculated: AST/ALT ratio, APRI, and FIB-4 index. Receiver operating characteristic curve analysis was done to assess the FSc performance in predicting AF. A total of 232 biopsies were analyzed, of those 42 (18.1%) showed AF (F3-4). FIB-4 was significantly higher in patients with AF compared to those without AF [median value of 1.1 [0.7, 3.0] and 0.6 [0.2, 1.4], respectively (p=.02)]; however, FIB-4 had satisfactory accuracy to diagnose AF with significant overlap and AUC of 0.68 (CI 0.56-0.81). Cutoff points of 0.2 and 3.03 were used to rule in and rule out AF, respectively. AST/ALT and APRI were not significantly different between patients with and without AF. Even though FIB-4 had satisfactory accuracy in detecting AF in pediatric transplant patients, noninvasive hepatic FSc developed in adults still performed poorly. Our results highlight the need to develop a reliable pediatric FSc.

Hypoxia inducible factor (HIF1A) is associated with increased right ventricular fibrosis by T1 mapping cardiac magnetic resonance in patients with repaired tetralogy of Fallot

Abstract Background Right ventricular fibrotic remodeling has been identified pre- and postoperatively in patients with tetralogy of Fallot (ToF) and linked to adverse outcomes. Polymorphisms of hypoxia inducible factor-1-alpha (HIF1α) have been associated with fibrotic burden by cardiac magnetic resonance (CMR) late gadolinium enhancement imaging. Their association with diffuse fibrotic myocardial remodeling is unknown. Purpose We sought to determine whether polymorphisms in hypoxia inducible factor (HIF1α) are related to CMR markers of diffuse myocardial fibrosis in pediatric patients with repaired ToF. Methods Patients with repaired ToF who had undergone CMR with T1 mapping as well as whole genome sequencing were included. Myocardial native T1 was quantified using a modified Look-Locker inversion recovery sequence and measured in the left ventricular free wall, the interventricular septum, and the right ventricular free wall. Patients who had at least one functioning allele of HIF1α were compared to those who did not using Mann Whitney U test for continuous variables and chi-square or Fischer test for discrete variables. Data are displayed in Table 1 as median (IQR) for continuous variables and frequency (percentage) for discrete variables. Results 46 patients had both CMR and whole genome sequencing. Only one HIF1α variant was identified in the cohort and present in 13 patients. There were no significant differences in demographics, surgical variables, right or left ventricular volumes or function between the groups (Table 1). Despite a trend towards a lower age at the time of CMR (11.3 vs 13.7 years; p=0.07), patients with HIF1α had higher native T1 values (1094 vs. 1050; p=0.027; Table 1) in the right ventricular outflow tract myocardium, reflecting increased diffuse interstitial ventricular fibrosis in patients with the HIF1α variant. Conclusion Hypoxia-inducible factor is associated with imaging markers of increased diffuse right ventricular fibrosis late after repair of tetralogy of Fallot. Funding Acknowledgement Type of funding sources: None. Table 1

The role of sonoelastography in the evaluation of hepatic fibrosis in pediatric patients

The role of sonoelastography in the evaluation of hepatic fibrosis in pediatric patients

P056 Intestinal current measurement (ICM) in cystic fibrosis paediatric patients - a pilot study

P056 Intestinal current measurement (ICM) in cystic fibrosis paediatric patients - a pilot study

Two-dimensional ultrasound shear wave elastography for identifying and staging liver fibrosis in pediatric patients with known or suspected liver disease: a clinical effectiveness study.

Ultrasound shear wave elastography (SWE) measures liver stiffness noninvasively, but few studies have defined cutoff values for detecting liver fibrosis in pediatric patients using 2-D ultrasound SWE. To evaluate the diagnostic performance of 2-D ultrasound SWE and define cutoff values for liver fibrosis in pediatric patients, using Canon (Toshiba) Aplio ultrasound systems. This was an institutional review board-approved retrospective study of patients (≤18years old) who had undergone both liver 2-D ultrasound SWE and percutaneous liver biopsy within 6months. Liver biopsies were staged using the METAVIR (fibrosis) scoring system. Continuous data were compared using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was used to evaluate diagnostic performance. Forty-six patients, with a median age of 11.5years (interquartile range: 8.0-14.3years), were included. Twenty-three patients were male (50%). Twenty-seven patients had a METAVIR fibrosis score of F0-1, and 19 patients had a score of F2-4. For differentiating METAVIR F0-1 from F2--4, the area under the ROC (AuROC) was 0.75 (95% confidence interval [CI]: 0.60-0.90). A cutoff of >1.89m/s yielded sensitivity of 73.7% (95% CI: 51.2-88.2) and specificity of 77.8% (95% CI: 59.2-89.4). For the subset of patients without histological hepatic steatosis (n=35), the AuROC was 0.86 (95% CI: 0.71-1.0). The same cutoff of >1.89m/s yielded a sensitivity of 80.0% (95% CI: 54.8-93.0) and specificity of 95.0% (95% CI 76.4-99.7). Two-dimensional ultrasound SWE distinguishes patients with no/mild fibrosis from those with moderate/severe fibrosis with good sensitivity and specificity. Diagnostic performance is comparable to that published for magnetic resonance elastography and is likely adversely impacted by steatosis.

P183 Increase of HLA-G in plasma of cystic fibrosis paediatric patients treated with Docosahexaenoic acid (DHA)

P183 Increase of HLA-G in plasma of cystic fibrosis paediatric patients treated with Docosahexaenoic acid (DHA)

P034 Prevalence of cystic fibrosis paediatric patients with p.Arg1162X mutation in southern Brazil: a migration flow outcome

P034 Prevalence of cystic fibrosis paediatric patients with p.Arg1162X mutation in southern Brazil: a migration flow outcome