Alicia M. Kamsheh

BACKGROUND: PPA2 (pyrophosphatase 2) deficiency is a relatively newly recognized condition caused by biallelic variants in the PPA2 gene. The gene encodes the mitochondrial enzyme PPA2, involved in the production of orthophosphate in the mitochondrial matrix. Affected individuals typically present with sudden cardiac death or acute heart failure following common viral illnesses in infants and toddlers, or following exposure to small amounts of alcohol as teenagers. The condition has a high mortality rate in these situations. Here, we explore the clinical presentations and current management of these patients with a view to guiding future emergency clinical management of cases. METHODS: Case records from published and unpublished affected individuals diagnosed with PPA2 deficiency were compiled in a retrospective cohort study of genotypes, phenotypes and clinical management protocols in individuals with biallelic (likely) pathogenic PPA2 variants. RESULTS: We collated 93 affected individuals from 53 families, 14 of which have not previously been reported. Patient presentation is invariably acute, often associated with fatigue, vomiting, seizures and collapse. Generally, presenting individuals received standard emergency management with cardiopulmonary resuscitation and appropriate management of arrhythmia, and here we present compiled clinical management protocols for emergency and ongoing treatment of PPA2-deficient patients. A pronounced inheritance rate of pathogenic alleles from carrier parents is noted, and further research is warranted to confirm and investigate any selective advantage for gametes carrying pathogenic PPA2 variants. CONCLUSIONS: PPA2 deficiency has a high mortality rate following exposure to common childhood viruses in children around and under the age of 3 and in teenagers exposed to ethanol. We have presented current therapeutic approaches gathered from a worldwide survey of clinicians treating their patients, possible pathogenic mechanisms and inheritance peculiarities of the condition and provide a comprehensive review of the current recommendations surrounding patients’ clinical management.

Background: Ventricular assist devices (VAD) are increasingly used to bridge children to heart transplantation, but infection is common. The aim of this study was to determine contemporary prevalence and risk factors for VAD‐associated infection in children. Methods: A retrospective analysis of the ACTION registry evaluated patients with left or single VAD from 01/04/18–04/30/25. Patients were classified by intracorporeal (IC) vs. paracorporeal (PC) VAD and temporary vs. durable paracorporeal cannulas at infection. Patients with and without VAD‐associated infection were compared overall and by VAD type. Risk factors for and one‐year survival after infection were evaluated with multivariate analyses. Results: Of 1527 patients, 442 (28.9%) were on IC and 1085 (71.1%) on PC VAD (964 durable, 121 temporary cannulas). There were 152 (10%) patients who developed VAD‐associated infection, with no difference in one‐year survival. While more patients on PC VAD developed infection overall (PC: n = 94 vs. IC: n = 58), IC VAD patients had a proportionately higher infection rate (13.1% vs. PC durable 9.3% vs. PC temporary 3.3%) ( p < 0.05). Median time to infection was later for IC vs. PC VAD (143 vs. 52.5 days, p < 0.0001). Children with infection were more likely to have severe obesity (17.2% vs. 7.8%) and to be on IC VAD (38.2% vs. 27.9%). Conclusions: Nearly 1 in 10 children developed a VAD‐associated infection, with no difference in one‐year survival. Infection was proportionately higher for IC vs. PC VAD, likely driven by longer time on device. Innovations in driveline management for IC VAD may decrease morbidity for those on long‐term support.

BACKGROUND: Studies have demonstrated that patients with myocarditis may have a higher burden of cardiomyopathy-associated genetic variants than the general population. However, data on children are limited. We compared the prevalence of rare predicted-damaging variants and clinically pathogenic variants in children with dilated cardiomyopathy (DCM) secondary to myocarditis with that in children with DCM alone and in heart-healthy controls. METHODS: Children with DCM secondary to myocarditis and children with DCM alone who underwent exome sequencing as part of a prior cross-sectional study were identified in the Pediatric Cardiomyopathy Registry, a large multicenter registry of children with cardiomyopathy. Controls from the Indiana University Biobank were matched 4:1 with myocarditis cases on genomic similarity. Rare predicted-damaging variants in cardiomyopathy-associated genes were identified using a bioinformatics approach. Clinical guidelines were used to determine clinical pathogenicity. The prevalence of variants was compared across the 3 groups. RESULTS: There were 32 patients with DCM secondary to myocarditis. The prevalence of rare predicted-damaging variants was 34.4% (11/32 [95% CI, 18.6%–53.2%]) in cases compared with 6.3% (8/128 [95% CI, 2.7%–11.9%]) in controls ( P P P =0.17 and P =1.00, respectively). CONCLUSIONS: Children with DCM secondary to myocarditis had a higher burden of variants in cardiomyopathy-associated genes than that of heart-healthy controls. Larger studies will be needed to determine the utility of routine genetic testing in this population.

Background: Tacrolimus is the standard immunosuppressant used in paediatric orthotopic heart transplantation, but it can be associated with rare and life-threatening haemolysis. Methods: Retrospective chart review was used for this case report. Results/Conclusion: We present the case of a 6-year-old heart transplant recipient who developed life-threatening haemolysis in the setting of mycoplasma infection while on tacrolimus immunosuppression that was treated successfully with eculizumab.

Outcomes in patients requiring prolonged inotropes (PI) following surgery for congenital heart disease (CHD) have not been well studied. We aimed to describe the burden of PI use in the immediate postoperative period after CHD surgery and identify risk factors for in-hospital mortality. We conducted a retrospective cohort study using the Pediatric Health Information System® (PHIS) database. Patients 0–18 years with CHD who underwent cardiovascular surgery from 2010 to 2020 were included. Patients who received inotropic medications for > 7 consecutive days after surgery were in the PI group and all others in the control group. Patients who died before 7 days were excluded. Multivariable mixed-effect logistic regression was used to examine risk factors for in-hospital mortality. There were 110,271 patients from 48 centers included, 10,292 in the PI group and 99,979 in the control group. In-hospital mortality was significantly higher in the PI group (24.9% vs. 4.6%, p < 0.001). Ventricular assist device use was rare (1.6%). After adjustment, odds of in-hospital mortality in the PI group was 3.5 (95% CI 3.3–3.8) times higher than in controls. Independent risk factors for in-hospital mortality were age, non-White race, class of CHD, number of complex chronic conditions, preoperative inotrope, preoperative extracorporeal membrane oxygenation, sepsis, stroke, renal failure, number of inotropes at 7 days, and discharge year (p < 0.01 for all). Postoperative PI use in CHD is common and carries a considerable burden of mortality. Additional work is needed to understand which risk factors are modifiable and which patients may benefit from reintervention or advanced heart failure therapies.

Background: There are conflicting data regarding the relationship between center volume and outcomes in pediatric heart transplantation. Previous studies have not fully accounted for differences in case mix, particularly in high‐risk congenital heart disease (CHD) groups. We aimed to evaluate the relationship between center volume and outcomes using the Pediatric Heart Transplant Society (PHTS) Registry and explore how case mix may affect outcomes.Methods: A retrospective cohort study of all pediatric patients in the PHTS Registry who received a heart transplant from 2009 to 2018 was performed. Centers were divided into 5 groups based on average yearly transplant volume. The primary outcome was time to death or graft loss and outcomes were compared using Kaplan–Meier analysis.Results: There were 4583 cases among 55 centers included. There was no difference in time to death or graft loss by center volume in the entire cohort (p = .75), in patients with CHD (p = .79) or in patients with cardiomyopathy (p = .23). There was also no difference in time to death or graft loss by center size in patients undergoing transplant after Norwood, Glenn or Fontan (log rank p = .17, p = .31, and p = .10 respectively). There was a statistically significant difference in outcomes by center size in the positive crossmatch group (p < .0001), though no discernible pattern related to high or low center volume.Conclusions: Outcomes are similar among transplant centers of all sizes, including for high‐risk patient groups with CHD. Future work is needed to understand how patient‐specific risk factors may vary among centers of various sizes and whether this influences patient outcomes.

Cardiac dysfunction due to hypertension (CDHTN) in pediatrics is not well described. We aimed to describe the presentation and outcomes of pediatric CDHTN and identify clinical features associated with resolution of dysfunction. A single-center retrospective cohort study of patients ≤ 21 years with CDHTN from January 2005–September 2020 was performed. Patients with systolic dysfunction without another cause, blood pressure > 95th percentile, and physician judgment that dysfunction was secondary to hypertension were included. Demographics, clinical characteristics, echocardiographic findings, and outcomes were examined using Fisher’s exact and Mann–Whitney U tests. Multiple correspondence analysis was used to explore the relationship of resolution of dysfunction to clinical features. Thirty-four patients were analyzed at a median age of 10.9 (IQR 0.3–16.9) years. Patients were divided into groups < 1 year (n = 12) and ≥ 1 year (n = 22). Causes of hypertension were varied by age, with renovascular disease most common in infants (42%) and medical renal disease most common in older patients (77%). Echocardiography demonstrated mild LV dilation (median LV end-diastolic z-score 2.6) and mild LV hypertrophy (median LV mass z-score 2.4). Most patients (81%) had resolution of dysfunction, particularly infants (92%). One patient died and one patient was listed for heart transplant. None required mechanical circulatory support (MCS). No clinical features were statistically associated with resolution of dysfunction. Hypertension is an important but reversible cause of systolic dysfunction in children. Patients are likely to recover with low mortality and low utilization of MCS or transplantation. Further studies are needed to confirm features associated with resolution of dysfunction.

Introduction: Inpatient rounding serves numerous roles. The American Academy of Pediatrics recommends a family-centered bedside model. Residents identified physical examination teaching during and satisfaction with rounds as areas for improvement. A resident group developed a project utilizing quality improvement (QI) methodology to address these concerns. We aimed to increase the frequency of bedside physical examination teaching most or every day on a single inpatient unit by 20% over 1 year, with secondary goals to increase the percentage of interns spending one hour or more at bedside per day by 10% and intern satisfaction by 15%, without impacting rounding duration. Methods: We developed an organizational structure to complete a long-term resident-led project. Interventions included daily bedside examination teaching on rounds, afternoon examinations, goal communication, topic recording, and a teaching “tip sheet.” Using an institutional QI framework, we utilized iterative plan-do-study-act cycles to implement interventions and surveys to assess outcomes, with rounding efficiency as a balancing measure. Results: The survey response rate was 57%. Bedside teaching frequency increased from a mean of 10% to 61%, perceived time at the bedside increased from 37% to 59%, and rounding satisfaction improved from a rating of 6.7/10 to 7.4/10. Efficiency was not impacted. Conclusions: We improved inpatient rounds bedside physical examination teaching and satisfaction without sacrificing efficiency. This project demonstrates the feasibility and success of a resident-driven education initiative to successfully motivate fellow residents and colleagues across disciplines to enact change. The organizational structure may serve as a model for resident-led QI projects across institutions.