2-Year Outcomes After Complete or Staged Procedure for Tetralogy of Fallot in Neonates.

2019

1570-1579

2019 Sep 24

1558-3597

BACKGROUND: There is ongoing debate about the best strategy to treat patients with tetralogy of Fallot who are symptomatic in the neonatal period.

OBJECTIVES: The aim of this study was to compare the outcomes of complete versus staged surgery (i.e., initial palliative procedure for possible later complete repair).

METHODS: A retrospective cohort study was performed using the Pediatric Health Information System database, including patients who underwent complete or staged tetralogy of Fallot repair prior to 30 days of age. The primary outcome was death during 2-year follow-up after the initial procedure. Inverse probability-weighted Cox and logistic regression models were used to examine the association between surgical approach group and mortality while accounting for patient- and hospital-level factors. Causal mediation analyses examined the role of intermediate variables.

RESULTS: A total of 2,363 patients were included (1,032 complete and 1,331 staged). There were 239 deaths. Complete neonatal repair was associated with a significantly higher risk for mortality during the 2-year follow-up period (hazard ratio: 1.51; 95% confidence interval: 1.05 to 2.06), between 7 and 30 days after the initial procedure (hazard ratio: 2.29; 95% confidence interval: 1.18 to 4.41), and during the initial hospital admission (odds ratio: 1.72; 95% confidence interval: 1.15 to 2.62). Post-operative cardiac complications were more common in the complete repair group and mediated the differences in 30-day and 2-year mortality.

CONCLUSIONS: Complete surgical repair for neonates with tetralogy of Fallot is associated with a significantly higher risk for early and 2-year mortality compared with the staged approach, after accounting for patient and hospital characteristics. Post-operative cardiac complications mediated these findings.

10.1016/j.jacc.2019.05.057

J. Am. Coll. Cardiol.

31537267

Comparative Costs of Management Strategies for Neonates With Symptomatic Tetralogy of Fallot.

2022

1170-1180

2022 Mar 29

1558-3597

BACKGROUND: Recent data have demonstrated that overall mortality and adverse events are not significantly different for primary repair (PR) and staged repair (SR) approaches to management of neonates with symptomatic tetralogy of Fallot (sTOF). Cost data can be used to compare the relative value (cost for similar outcomes) of these approaches and are a potentially more sensitive measure of morbidity.

OBJECTIVES: This study sought to compare the economic costs associated with PR and SR in neonates with sTOF.

METHODS: Data from a multicenter retrospective cohort study of neonates with sTOF were merged with administrative data to compare total costs and cost per day alive over the first 18 months of life in a propensity score-adjusted analysis. A secondary analysis evaluated differences in department-level costs.

RESULTS: In total, 324 subjects from 6 centers from January 2011 to November 2017 were studied (40% PR). The 18-month cumulative mortality (P = 0.18), procedural complications (P = 0.10), hospital complications (P = 0.94), and reinterventions (P = 0.22) did not differ between PR and SR. Total 18-month costs for PR (median $179,494 [IQR: $121,760-$310,721]) were less than for SR (median: $222,799 [IQR: $167,581-$327,113]) (P < 0.001). Cost per day alive (P = 0.005) and department-level costs were also all lower for PR. In propensity score-adjusted analyses, PR was associated with lower total cost (cost ratio: 0.73; P < 0.001) and lower department-level costs.

CONCLUSIONS: In this multicenter study of neonates with sTOF, PR was associated with lower costs. Given similar overall mortality between treatment strategies, this finding suggests that PR provides superior value.

10.1016/j.jacc.2021.12.036

J Am Coll Cardiol

35331412

Medical Outcomes, Quality of Life, and Family Perceptions for Outpatient vs Inpatient Neutropenia Management After Chemotherapy for Pediatric Acute Myeloid Leukemia.

2021

e2128385

2021 Oct 01

2574-3805

<p><strong>Importance: </strong>Pediatric acute myeloid leukemia (AML) requires multiple courses of intensive chemotherapy that result in neutropenia, with significant risk for infectious complications. Supportive care guidelines recommend hospitalization until neutrophil recovery. However, there are little data to support inpatient over outpatient management.</p>

<p><strong>Objective: </strong>To evaluate outpatient vs inpatient neutropenia management for pediatric AML.</p>

<p><strong>Design, Setting, and Participants: </strong>This cohort study used qualitative and quantitative methods to compare medical outcomes, patient health-related quality of life (HRQOL), and patient and family perceptions between outpatient and inpatient neutropenia management. The study included patients from 17 US pediatric hospitals with frontline chemotherapy start dates ranging from January 2011 to July 2019, although the specific date ranges differed for the individual analyses by design and relative timing. Data were analyzed from August 2019 to February 2020.</p>

<p><strong>Exposures: </strong>Discharge to outpatient vs inpatient neutropenia management.</p>

<p><strong>Main Outcomes and Measures: </strong>The primary outcomes of interest were course-specific bacteremia incidence, times to next course, and patient HRQOL. Course-specific mortality was a secondary medical outcome.</p>

<p><strong>Results: </strong>Primary quantitative analyses included 554 patients (272 [49.1%] girls and 282 [50.9%] boys; mean [SD] age, 8.2 [6.1] years). Bacteremia incidence was not significantly different during outpatient vs inpatient management (67 courses [23.8%] vs 265 courses [29.0%]; adjusted rate ratio, 0.73; 95% CI, 0.56 to 1.06; P = .08). Outpatient management was not associated with delays to the next course compared with inpatient management (mean [SD] 30.7 [12.2] days vs 32.8 [9.7] days; adjusted mean difference, -2.2; 95% CI, -4.1 to -0.2, P = .03). Mortality during intensification II was higher for patients who received outpatient management compared with those who received inpatient management (3 patients [5.4%] vs 1 patient [0.5%]; P = .03), but comparable with inpatient management at other courses (eg, 0 patients vs 5 patients [1.3%] during induction I; P = .59). Among 97 patients evaluated for HRQOL, outcomes did not differ between outpatient and inpatient management (mean [SD] Pediatric Quality of Life Inventory total score, 70.1 [18.9] vs 68.7 [19.4]; adjusted mean difference, -2.8; 95% CI, -11.2 to 5.6). A total of 86 respondents (20 [23.3%] in outpatient management, 66 [76.7%] in inpatient management) completed qualitative interviews. Independent of management strategy received, 74 respondents (86.0%) expressed satisfaction with their experience. Concerns for hospital-associated infections among caregivers (6 of 7 caregiver respondents [85.7%] who were dissatisfied with inpatient management) and family separation (2 of 2 patient respondents [100%] who were dissatisfied with inpatient management) drove dissatisfaction with inpatient management. Stress of caring for a neutropenic child at home (3 of 3 respondents [100%] who were dissatisfied with outpatient management) drove dissatisfaction with outpatient management.</p>

<p><strong>Conclusions and Relevance: </strong>This cohort study found that outpatient neutropenia management was not associated with higher bacteremia incidence, treatment delays, or worse HRQOL compared with inpatient neutropenia management among pediatric patients with AML. While outpatient management may be safe for many patients, course-specific mortality differences suggest that outpatient management in intensification II should be approached with caution. Patient and family experiences varied, suggesting that outpatient management may be preferred by some but may not be feasible for all families. Further studies to refine and standardize safe outpatient management practices are warranted.</p>

10.1001/jamanetworkopen.2021.28385

JAMA Netw Open

34709389

Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group.

2021

2021 Oct 13

1097-0142

<p><strong>BACKGROUND: </strong>The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials.</p>

<p><strong>METHODS: </strong>P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n&nbsp;=&nbsp;495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods.</p>

<p><strong>RESULTS: </strong>In randomized trials (cumulative prescribed doxorubicin dose, 100-360&nbsp;mg/m ; median follow-up, 18.6&nbsp;years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600&nbsp;mg/m ; median follow-up, 16.6-18.4&nbsp;years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377&nbsp;±&nbsp;145&nbsp;mg/m ) was 1.6% (vs 0% in P9754; P&nbsp;=&nbsp;.13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P&nbsp;=&nbsp;.02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P&nbsp;=&nbsp;.35).</p>

<p><strong>CONCLUSIONS: </strong>Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.</p>

10.1002/cncr.33974

Cancer

34644414

The influence of mechanical Circulatory support on post-transplant outcomes in pediatric patients: A multicenter study from the International Society for Heart and Lung Transplantation (ISHLT) Registry.

2021

2021 Jun 11

1557-3117

<p><strong>BACKGROUND: </strong>Mechanical circulatory support (MCS) is increasingly being used as a bridge to transplant in pediatric patients. We compare outcomes in pediatric patients bridged to transplant with MCS from an international cohort.</p>

<p><strong>METHODS: </strong>This retrospective cohort study of heart-transplant patients reported to the International Society for Heart and Lung Transplantation (ISHLT) registry from 2005-2017 includes 5,095 patients &lt;18 years. Pretransplant MCS exposure and anatomic diagnosis were derived. Outcomes included mortality, renal failure, and stroke.</p>

<p><strong>RESULTS: </strong>26% of patients received MCS prior to transplant: 240 (4.7%) on extracorporeal membrane oxygenation (ECMO), 1,030 (20.2%) on ventricular assist device (VAD), and 54 (1%) both. 29% of patients were &lt;1 year, and 43.8% had congenital heart disease (CHD). After adjusting for clinical characteristics, compared to no-MCS and VAD, ECMO had higher mortality during their transplant hospitalization [OR 3.97 &amp; 2.55; 95% CI 2.43-6.49 &amp; 1.42-4.60] while VAD mortality was similar [OR 1.55; CI 0.99-2.45]. Outcomes of ECMO+VAD were similar to ECMO alone, including increased mortality during transplant hospitalization compared to no-MCS [OR 4.74; CI 1.81-12.36]. Patients with CHD on ECMO had increased 1 year, and 10 year mortality [HR 2.36; CI 1.65-3.39], [HR 1.82; CI 1.33-2.49]; there was no difference in survival in dilated cardiomyopathy (DCM) patients based on pretransplant MCS status.</p>

<p><strong>CONCLUSION: </strong>Survival in CHD and DCM is similar in patients with no MCS or VAD prior to transplant, while pretransplant ECMO use is strongly associated with mortality after transplant particularly in children with CHD. In children with DCM, long term survival was equivalent regardless of MCS status.</p>

10.1016/j.healun.2021.06.003

J Heart Lung Transplant

34253457

Broad spectrum antibiotics and risk of graft-versus-host disease in pediatric patients transplanted for acute leukemia: association of carbapenem use with risk of acute GVHD.

2021

177.e1-177.e8

2021 Feb

2666-6367

<p>Variation in the gastrointestinal microbiota after hematopoietic cell transplantation has been associated with acute graft-versus-host disease (aGVHD). Because antibiotics induce dysbiosis, we examined the association of broad-spectrum antibiotics with subsequent aGVHD-risk in pediatric patients transplanted for acute leukemia. We performed a retrospective analysis in a dataset merged from two sources: (1) Center for International Blood and Marrow Transplant Research, an observational transplant registry, and (2) Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to three classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) anti-pseudomonal penicillins and (3) carbapenems. The primary outcome was grade 2-4 aGVHD; secondary outcomes were grade 3-4 aGVHD and lower gastrointestinal (GI) GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (sub-cohort) included transplant characteristics, GVHD-risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2,550 patients at 36 centers; the sub-cohort included 1,174 patients. In adjusted models, carbapenems were associated with an increased risk of grade 2-4 aGVHD in the full cohort (aOR 1.24, 95%CI 1.02-1.51) and sub-cohort (subHR 1.31, 95%CI 0.99-1.72), as well as with an increased risk of grade 3-4 aGVHD (subHR 1.77, 95%CI 1.25-2.52). Early carbapenem exposure (prior to day 0) especially impacted aGVHD-risk. For antipseudomonal penicillins the associations with aGVHD were in the direction of increased risk but were not statistically significant. There was no identified association between broad-spectrum cephalosporins and aGVHD. Carbapenems, more than other broad spectrum antibiotics, should be used judiciously in pediatric transplant patients to minimize aGVHD-risk. Further research is needed to clarify the mechanism underlying this association.</p>

10.1016/j.jtct.2020.10.012

Transplant Cell Ther

33718896

Identifying relapses and stem cell transplants in pediatric acute lymphoblastic leukemia using administrative data: Capturing national outcomes irrespective of trial enrollment.

2020

e28315

2020 May 11

1545-5017

<p><strong>INTRODUCTION: </strong>Our objectives were to design and validate methods to identify relapse and hematopoietic stem cell transplantation (HSCT) in children with acute lymphoblastic leukemia (ALL) using administrative data representing hospitalizations at US pediatric institutions.</p>

<p><strong>METHODS: </strong>We developed daily billing and ICD-9 code definitions to identify relapses and HSCTs within a cohort of children with newly diagnosed ALL between January 1, 2004, and December 31, 2013, previously assembled from the Pediatric Health Information System (PHIS) database. Chart review for children with ALL at the Children's Hospital of Philadelphia (CHOP) and Texas Children's Hospital (TCH) was performed to establish relapse and HSCT gold standards for sensitivity and positive predictive value (PPV) calculations. We estimated incidences of relapse and HSCT in the PHIS ALL cohort.</p>

<p><strong>RESULTS: </strong>We identified 362 CHOP and 314 TCH ALL patients in PHIS and established true positives by chart review. Sensitivity and PPV for identifying both relapse and HSCT in PHIS were&nbsp;&gt;&nbsp;90% at both hospitals. Five-year relapse incidence in the 10&nbsp;150-patient PHIS cohort was 10.3% (95% CI 9.8%-10.9%) with 7.1% (6.6%-7.6%) of children underwent HSCTs. Patients in higher-risk demographic groups had higher relapse and HSCT rates. Our analysis also identified differences in incidences of relapse and HSCT by race, ethnicity, and insurance status.</p>

<p><strong>CONCLUSIONS: </strong>Administrative data can be used to identify relapse and HSCT accurately in children with ALL whether they occur on- or off-therapy, in contrast with published approaches. This method has wide potential applicability for estimating these incidences in pediatric ALL, including patients not enrolled on clinical trials.</p>

10.1002/pbc.28315

Pediatr Blood Cancer

32391940

HIV Testing Among Adolescents With Acute Sexually Transmitted Infections.

2020

2020 Mar 16

1098-4275

<p><strong>BACKGROUND AND OBJECTIVES: </strong>Rates of sexually transmitted infections (STIs) have increased over the decade. Guidelines recommend HIV testing with incident STIs. Prevalence and factors associated with HIV testing in acute STIs are unknown in adolescents. Our objective was to determine the prevalence of completed HIV testing among adolescents with incident STIs and identify patient and health care factors associated with HIV testing.</p>

<p><strong>METHODS: </strong>Retrospective study of STI episodes (gonorrhea, <em>Chlamydia,</em>&nbsp;trichomoniasis, or syphilis) of adolescents between 13 and 24 years old from July 2014 to December 2017 in 2 urban primary care clinics. We performed mixed effects logistic regression modeling to identify patient and health care factors associated with HIV testing within 90 days of STI diagnosis.</p>

<p><strong>RESULTS: </strong>The 1313 participants contributed 1816 acute STI episodes. Mean age at STI diagnosis was 17.2 years (SD = 1.7), 75% of episodes occurred in females, and 97% occurred in African Americans. Only half (55%) of acute STI episodes had a completed HIV test. In the adjusted model, female sex, previous STIs, uninsured status, and confidential sexual health encounters were associated with decreased odds of HIV testing. Patients enrolled in primary care at the clinics, compared with those receiving sexual health care alone, and those with multipathogen STI diagnoses were more likely to have HIV testing.</p>

<p><strong>CONCLUSIONS: </strong>HIV testing rates among adolescents with acute STIs are suboptimal. Patient and health care factors were found to be associated with receipt of testing and should be considered in clinical practice.</p>

10.1542/peds.2019-2265

Pediatrics

32179661

Disparities in pediatric acute myeloid leukemia (AML) clinical trial enrollment.

2019

1-9

2019 Feb 07

1029-2403

<p>Equal access to clinical trial enrollment is important to ensure that findings are generalizable to the broader population. This study aimed to evaluate disparities in enrollment on pediatric oncology clinical trials. We assessed the relationship between patient characteristics and enrollment on COG trial AAML1031 in a cohort of pediatric patients with AML in the Pediatric Health Information System. The associations of enrollment with outcomes were evaluated. Non-Hispanic Black patients, infants, and patients from zip codes with a lower proportion of poverty were less likely to enroll (30% vs. 61%, p = .004; 34% vs. 58%, p = .003; 46% vs. 58%, p = .02). On-therapy mortality was similar among enrolled and nonenrolled patients (7.3% vs. 8.9%, p = .47). Differences in early mortality were more pronounced among nonenrolled patients compared to enrolled patients (3.0% vs. 0.5%, p = .03). Understanding the etiology of these disparities will inform strategies to ensure balanced access to clinical trials across patient populations.</p>

10.1080/10428194.2019.1574002

Leuk. Lymphoma

30732497

Mortality, Resource Utilization And Inpatient Costs Vary Among Pediatric Heart Transplant Indications: A Merged Data Set Analysis From The United Network For Organ Sharing And The Pediatric Health Information Systems (UNOS-PHIS) Databases.

2018

2018 Nov 25

1532-8414

<p><strong>BACKGROUND: </strong>Merging UNOS and PHIS databases have enabled a more granular analysis of pediatric heart transplant outcomes and resource utilization. We evaluated whether transplant indication at time of transplantation was associated with mortality, resource utilization and inpatient costs during the first year post-transplant.</p>

<p><strong>METHODS: </strong>We analyzed transplant outcomes and resource utilization between 2004 and 2015. Patients were categorized as congenital (CHD), myocarditis or cardiomyopathy based on UNOS-defined primary indication. CHD complexity subgroup analyses (single ventricle, complex, and simple biventricular CHD) were also performed.</p>

<p><strong>RESULTS: </strong>Of 2251 transplants (49% CHD, 5% myocarditis, 46% cardiomyopathy), CHD recipients were younger (2 [IQR 0-10] vs. 6 [IQR 0-12] vs. 7 [IQR 1-14] years, respectively; p&lt;0.001) and less likely to have ventricular assist device (VAD) at transplant (CHD 3%, myocarditis 27%, cardiomyopathy 13%; p&lt;0.001). Patients with single ventricle CHD had the longest waitlist and were least likely to receive a VAD pre-transplant. After adjusting for patient-level factors, transplant recipients with single ventricle CHD had the greatest mortality during transplant-admission and at 1-year (vs. cardiomyopathy, OR 11.8 [95% CI 5.9-23.6] and OR 6.0 [95% CI 3.6-10.2], respectively). Mortality was similar between patients with myocarditis and cardiomyopathy. Post-transplant length of stay (LOS) was longer in transplant recipients with CHD than myocarditis or cardiomyopathy (25 [IQR 15-45] vs. 21 [IQR 12-35] vs. 16 [IQR 12-25] days; p&lt;0.001), partially related to longer duration of ICU-level care (ICU LOS 8 [IQR 4-20] vs. 6 [IQR 4-13] vs. 5 [IQR 3-8] days; p&lt;0.001). Similarly, patients with CHD had higher median post-transplant costs than myocarditis or cardiomyopathy ($415k [IQR $201-503k] vs. $354k [IQR $179-390k] vs. $284k [IQR $145-319k]; p&lt;0.001) that persisted after adjusting for patient-level factors (CHD vs. cardiomyopathy Adjusted Cost Ratio 1.4 [95% CI 1.4-1.5]) and was primarily driven by longer LOS. Over 50% were readmitted during first year post-transplant, although readmission rates were similar across transplant indications (p=0.42).</p>

<p><strong>CONCLUSION: </strong>Children with CHD, particularly single ventricle patients, require substantially greater hospital resource utilization and have significantly worse outcomes during the first year after heart transplant compared to other indications. Further work is aimed at identifying modifiable pre-transplant risk factors, such as pre-transplant conditioning with VAD support and cardiac rehabilitation, to improve post-transplant outcomes and reduce resource utilization in this complex population.</p>

10.1016/j.cardfail.2018.11.014

J. Card. Fail.

30485789