Advancing sepsis clinical research: harnessing transcriptomics for an omics-based strategy - a comprehensive scoping review

Sepsis continues to be recognized as a significant global health challenge across all ages and is characterized by a complex pathophysiology. In this scoping review, PRISMA-ScR guidelines were adhered to, and a transcriptomic methodology was adopted, with the protocol registered on the Open Science Framework. We hypothesized that gene expression analysis could provide a foundation for establishing a clinical research framework for sepsis. A comprehensive search of the PubMed database was conducted with a particular focus on original research and systematic reviews of transcriptomic sepsis studies published between 2012 and 2022. Both coding and non-coding gene expression studies have been included in this review. An effort was made to enhance the understanding of sepsis at the mRNA gene expression level by applying a systems biology approach through transcriptomic analysis. Seven crucial components related to sepsis research were addressed in this study: endotyping (n = 64), biomarker (n = 409), definition (n = 0), diagnosis (n = 1098), progression (n = 124), severity (n = 451), and benchmark (n = 62). These components were classified into two groups, with one focusing on Biomarkers and Endotypes and the other oriented towards clinical aspects. Our review of the selected studies revealed a compelling association between gene transcripts and clinical sepsis, reinforcing the proposed research framework. Nevertheless, challenges have arisen from the lack of consensus in the sepsis terminology employed in research studies and the absence of a comprehensive definition of sepsis. There is a gap in the alignment between the notion of sepsis as a clinical phenomenon and that of laboratory indicators. It is potentially responsible for the variable number of patients within each category. Ideally, future studies should incorporate a transcriptomic perspective. The integration of transcriptomic data with clinical endpoints holds significant potential for advancing sepsis research, facilitating a consensus-driven approach, and enabling the precision management of sepsis

Multimodality Imaging to Detect Rejection, and Cardiac Allograft Vasculopathy in Pediatric Heart Transplant Recipients—An Illustrative Review

The three most common modalities of graft surveillance in pediatric heart transplant (HT) recipients include echocardiography, coronary angiography, and endomyocardial biopsy (EMB). The survival outcomes after HT in children have improved considerably in recent years. However, allograft rejection and cardiac allograft vasculopathy remain the leading cause of death or re-transplantation. The routine surveillance by EMB and coronary angiography are invasive and risky. Newer noninvasive echocardiographic techniques, including tissue Doppler imaging (TDI), 2-D speckle tracking echocardiography, CT coronary angiography (CTCA), cardiovascular magnetic resonance (CMR), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) and invasive techniques such as intravascular ultrasound (IVUS), functional flow reserve (CFR) of coronary arteries, optical coherence tomography (OCT), have emerged as powerful tools which may help early recognition of sub-clinical rejection, response to treatment, early detection, and progression of CAV. The multimodality imaging approach, including noninvasive and invasive tests, is the future for the transplanted heart to detect dysfunction, rejections, and early CAV. This review illustrates noninvasive and invasive imaging techniques currently used or could be considered for clinical use in detecting heart transplant rejection, dysfunction, and CAV in children

Elective and non-elective endomyocardial biopsy in heart transplant patients and procedural outcomes: An IMPACT registry analysis

BACKGROUND: Endomyocardial biopsies are standard of care for transplant surveillance, however the procedural risks are not well established, especially in children. The purpose of the study was therefore to assess procedural risks and outcomes associated with elective (surveillance) biopsies and non-elective (clinically indicated) biopsies. METHODS: We used the NCDR IMPACT registry database for this retrospective analysis. Patients undergoing an endomyocardial biopsy were identified using the procedural code, with a diagnosis of heart transplantation required. Data regarding indication, hemodynamics, adverse events and outcomes was gathered and analyzed. RESULTS: A total of 32 547 endomyocardial biopsies were performed between 2012-2020; 31 298 (96.5%) elective and 1133 (3.5%) were non-elective biopsies. Non-elective biopsy was more commonly performed in infants and in those above 18 years of age, in female and in Black race patients and in those with non-private insurance (all p \u3c .05) and showed hemodynamic derangements. Overall rate of complications was low. Combined major adverse events were more common in non-elective patients, with sicker patient profile, use of general anesthesia and femoral access with overall decline in these events over time. CONCLUSIONS: This large-scale analysis shows safety of surveillance biopsies and that non-elective biopsies carry a small but significant risk of major adverse event. Patient profile impacts the safety of the procedure. These data may serve as important comparison point for newer non-invasive tests and for bench marking, especially in children

Impact of the pediatric ABO policy change on listings, transplants and outcomes for children younger than 2 years listed for heart transplantation in the U.S.: ABO incompatible pediatric heart transplantation

BACKGROUND: We assessed the impact of the liberalized ABO pediatric policy change on candidate characteristics and outcomes for children undergoing heart transplant (HT). METHODS: Children \u3c2 years undergoing HT with ABO strategy reported at listing and HT from 12/2011-11/2020 to the Scientific Registry of Transplant Recipients database were included. Characteristics at listing, HT and outcomes during the waitlist and post-transplant were compared pre- (12/16/11 - 7/6/16), and post-policy change (7/7/16-11/30/20). RESULTS: The percentage of ABO incompatible (ABOi) listings did not increase immediately post-policy change (p=0.93), however, ABOi transplants increased by 18% (p\u3c.0001). At listing, both pre- and post-policy change, ABOi candidates had higher urgency status, renal dysfunction, lower albumin and required more cardiac support (IV inotropes, mechanical ventilation) than those listed ABO compatible (ABOc). On multivariable analysis, there were no differences in waitlist mortality between children listed ABOi compared to ABOc pre-policy (aHR 0.80, 95% CI 0.61-1.05, p=.10) or post-policy change (aHR 1.2, 95% CI 0.85-1.6, p=0.33). Post-transplant graft survival was worse for ABOi transplanted children pre-policy (aHR 1.8, 95% CI 1.1-2.8, p=.014), but not significantly different post-policy change (aHR 0.94, 95% CI 0.61-1.4, p=.76). Post-policy change, ABOi listed children had significantly shorter waitlist times (p\u3c0.05). CONCLUSION: The recent pediatric ABO policy change has significantly increased the percentage of ABOi transplantations and decreased waitlist times for children listed ABOi. This change in policy has resulted in broader applicability and actual performance of ABOi transplantation with equal access to ABOi or ABOc organs, and thus eliminated potential disadvantage of only secondary allocation to ABOi recipients

Clinical and Hematological Outcomes of Aminocaproic Acid Use During Pediatric Cardiac ECMO

Bleeding and thrombosis-related complications are common in pediatric cardiac patients supported by extracorporeal membrane oxygenation (ECMO) and are associated with morbidity and mortality. The purpose of this study was to evaluate the utility of aminocaproic acid (ACA), an antifibrinolytic agent, as it pertains to bleeding in pediatric cardiac patients on ECMO. This included a retrospective cohort study of pediatric cardiac patients receiving ACA while supported on ECMO between 2013 and 2017. For each patient, data were collected in three time intervals: the 24 hours before ACA initiation, and then 0–24 and 24–48 hours following ACA initiation. For each time frame, bleeding, component transfusion, and laboratory data were collected and analyzed. A total of 62 patients were included, representing 42% of our cardiac ECMO patients during the time period. ACA was initiated at 16.3 ± 8.7 hours following initiation of ECMO. The mean bleeding rate before ACA was 10.57 mL/kg/h, which reduced to 7.8 mL/kg/h in the 24-hour period after initiation of ACA and a further decrease to 3.65 mL/kg/h during the 24- to 48-hour time period following ACA initiation. ACA administration was associated with reduction in bleeding (p < .001) and packed red blood cell transfusions (p = .02), administration of fresh frozen plasma (p < .001), platelets (p = .017), cryoprecipitate (p = .05), factor VII (p = .002), and Cell Saver (p = .005). Hemoglobin and platelet count were stable, whereas prothrombin time (PT), partial thromboplastin time, and international normalized ratio (INR) showed significant reduction over the time course. ACA administration was not associated with specific adverse effects. A clinically significant reduction in bleeding amount, red blood cell transfusions, and other hematologic interventions occurred following ACA administration for pediatric patients on ECMO. Wider consideration for ACA use as a part of a multipronged strategy to manage bleeding during ECMO should be considered

Recent Era Outcomes of Mechanical Circulatory Support in Children With Congenital Heart Disease as a Bridge to Heart Transplantation

The objective of the study is to compare the clinical characteristics, risk factors, and overall survival (waitlist and posttransplant) outcomes in children with congenital heart disease (CHD) bridged to transplantation with either a ventricular assist device (VAD) versus extracorporeal membrane oxygenation (ECMO) versus no mechanical circulatory support (MCS) in the recent era. The study included 2,899 primary heart transplantations in patients \u3c18 years with CHD between 2010 and 2019 from the United Network Organ Sharing database. Patients who had ECMO or VAD at listing or while listed were included, and their waitlist and posttransplant outcomes were compared with CHD patients who did not require MCS. Of all, 464 (16%) had ECMO and 200 (7%) VAD at the time of or during the listing. The VAD utilization increased over the last decade (4% in 2010 to 10% in 2019, p \u3c 0.01). The 90 days post-MCS survival was better with VAD than ECMO (67 vs. 49%, p \u3c 0.01). The transplantability rate at 90 days was decreased with younger age (odds ratio [OR], 0.91; 95% CI, 0.86-0.95), lower body mass index (BMI) (OR, 0.93; 95% CI, 0.89-0.98) and lower albumin \u3c3g/dl (OR, 0.6; 95% CI, 0.53-0.7). The multivariate model predicted that lower BMI (OR, 1.12; 95% CI, 1.06-1.18), pretransplant ECMO (OR, 2.19; 95% CI, 1.39-3.45), and higher bilirubin (OR, 1.15; 95% CI, 0.97-1.36) decreased 1-year posttransplant survival. Patients transplanted with VAD had better 1-year survival than ECMO (88 vs. 70%, p = 0.01). Waiting list survival of children with CHD supported by VAD is better compared to ECMO. The 1-year posttransplantation outcome of CHD patients supported by VAD is similar to the no MCS patients and better than ECMO-supported patients. There is no significant difference in post-HT survival between patients transitioned from ECMO to VAD while listed and those with VAD-first

Heart Failure with Preserved Ejection Fraction in Children

Diastolic dysfunction (DD) refers to abnormalities in the mechanical function of the left ventricle (LV) during diastole. Severe LVDD can cause symptoms and the signs of heart failure (HF) in the setting of normal or near normal LV systolic function and is referred to as diastolic HF or HF with preserved ejection fraction (HFpEF). Pediatric cardiologists have long speculated HFpEF in children with congenital heart disease and cardiomyopathy. However, understanding the risk factors, clinical course, and validated biomarkers predictive of the outcome of HFpEF in children is challenging due to heterogeneous etiologies and overlapping pathophysiological mechanisms. The natural history of HFpEF varies depending upon the patient\u27s age, sex, race, geographic location, nutritional status, biochemical risk factors, underlying heart disease, and genetic-environmental interaction, among other factors. Pediatric onset HFpEF is often not the same disease as in adults. Advances in the noninvasive evaluation of the LV diastolic function by strain, and strain rate analysis with speckle-tracking echocardiography, tissue Doppler imaging, and cardiac magnetic resonance imaging have increased our understanding of the HFpEF in children. This review addresses HFpEF in children and identifies knowledge gaps in the underlying etiologies, pathogenesis, diagnosis, and management, especially compared to adults with HFpEF