Broad-Spectrum Antibiotics and Risk of Graft-versus-Host Disease in Pediatric Patients Undergoing Transplantation for Acute Leukemia: Association of Carbapenem Use with the Risk of Acute Graft-versus-Host Disease

Variation in the gastrointestinal (GI) microbiota after hematopoietic cell transplantation (HCT) 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 undergoing HCT for acute leukemia. We performed a retrospective analysis in a dataset merged from 2 sources: (1) the Center for International Blood and Marrow Transplant Research, an observational transplantation registry, and (2) the Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to 3 classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) antipseudomonal penicillins, and (3) carbapenems. The primary outcome was grade II-IV aGVHD; secondary outcomes were grade III-IV aGVHD and lower GI GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (subcohort) included transplantation characteristics, GVHD risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2550 patients at 36 centers; the subcohort included 1174 patients. In adjusted models, carbapenems were associated with an increased risk of grade II-IV aGVHD in the full cohort (adjusted odds ratio [aOR], 1.24; 95% confidence interval [CI], 1.02 to 1.51) and subcohort (sub hazard ratio [HR], 1.31; 95% CI, 0.99 to 1.72), as well as with an increased risk of grade III-IV aGVHD (subHR, 1.77; 95% CI, 1.25 to 2.52). Early carbapenem exposure (before 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 HCT recipients to minimize aGVHD risk. Further research is needed to clarify the mechanism underlying this association.

Resource Utilization in Pediatric Patients Supported With Ventricular Assist Devices in the United States: A Multicenter Study From the Pediatric Interagency Registry for Mechanically Assisted Circulatory Support and the Pediatric Health Information System.

BACKGROUND: Few data exist on resource utilization with pediatric ventricular assist devices (VADs). We tested the hypothesis that device type and adverse events are associated with increased resource utilization in pediatric patients supported with VADs. METHODS AND RESULTS: The Pediatric Interagency Registry for Mechanically Assisted Circulatory Support, a national registry of VADs in patients <19 years old, and the Pediatric Health Information System, an administrative database, were merged. Univariate analysis was performed assessing the association of all factors with the total cost and length of stay first. Significant variables (P<0.05) were subjected to multivariable analysis. The study included 142 patients from 19 centers with VAD implants from October 2012 to June 2016. The median age was 9 years (interquartile range [IQR] 2-15), 84 (59%) supported with a continuous-flow VAD. Overall median hospital costs were $750 000 (IQR $539 000 to $1 100 000) with a median hospital length of stay of 81 days (IQR 54-128). On multivariable analysis, device type and postoperative complications were not associated with resource utilization. Factors associated with increased costs included patient age, lower-volume VAD center, being intubated, being on extracorporeal membrane oxygenation, number of complex chronic medical conditions, and length of stay. Among continuous-flow VAD patients, discharge to home before transplant versus remaining hospitalized was associated with lower hospital costs (median $600 000 [IQR $400 000 to $820 000] versus median $680 000 [IQR $500 000 to $970 000], P=0.03). CONCLUSION: VADs in pediatric patients are associated with high resource utilization. Increased resource utilization was associated with lower-volume VAD centers, disease severity at VAD implantation, and the presence of complex chronic medical conditions. Further study is needed to develop cost-effective strategies in this complex population.

Hospital Variation in Intensive Care Resource Utilization and Mortality in Newly Diagnosed Pediatric Leukemia.

OBJECTIVES: To evaluate hospital-level variability in resource utilization and mortality in children with new leukemia who require ICU support, and identify factors associated with variation. DESIGN: Retrospective cohort study. SETTING: Children's hospitals contributing to the Pediatric Health Information Systems administrative database from 1999 to 2011. PATIENTS: Inpatients less than 25 years old with newly diagnosed acute lymphocytic leukemia or acute myeloid leukemia requiring ICU support (n = 1,754). INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Evaluated exposures included leukemia type, year of diagnosis, and hospital-wide proportion of patients with public insurance. The main outcome was hospital mortality. Wide variability existed in the ICU resources used across hospitals. Combined acute lymphocytic leukemia and acute myeloid leukemia mortality varied by hospital from 0% (95% CI, 0-14.8%) to 42.9% (95% CI, 17.7-71.1%). A mixed-effects model with a hospital-level random effect suggests significant variation across hospitals in mortality (p = 0.007). When including patient and hospital factors as fixed effects into the model, younger age, acute myeloid leukemia versus acute lymphocytic leukemia diagnosis, leukemia diagnosis prior to 2005, hospital-wide proportion of public insurance patients, and hospital-level proportion of leukemia patients receiving ICU care are significantly associated with mortality. The variation across hospitals remains significant with all patient factors included (p = 0.021) but is no longer significant after adjusting for the hospital-level factors proportion of public insurance and proportion receiving ICU care (p = 0.48). CONCLUSIONS: Wide hospital-level variability in ICU resource utilization and mortality exists in the care of children with leukemia requiring ICU support. Hospital payer mix is associated with some mortality variability. Additional study into how ICU support could be standardized through clinical practice guidelines, impact of payer mix on hospital resources allocation to the ICU, and subsequent impact on patient outcomes is warranted.

Establishment of an 11-year cohort of 8733 pediatric patients hospitalized at United States free-standing children's hospitals with de novo acute lymphoblastic leukemia from health care administrative data.

BACKGROUND: Acute lymphoblastic leukemia (ALL) accounts for almost one quarter of pediatric cancer in the United States. Despite cooperative group therapeutic trials, there remains a paucity of large cohort data on which to conduct epidemiology and comparative effectiveness research studies. RESEARCH DESIGN: We designed a 3-step process utilizing International Classification of Diseases-9 Clinical Modification (ICD-9) discharge diagnoses codes and chemotherapy exposure data contained in the Pediatric Health Information System administrative database to establish a cohort of children with de novo ALL. This process was validated by chart review at 1 of the pediatric centers. RESULTS: An ALL cohort of 8733 patients was identified with a sensitivity of 88% [95% confidence interval (CI), 83%-92%] and a positive predictive value of 93% (95% CI, 89%-96%). The 30-day all cause inpatient case fatality rate using this 3-step process was 0.80% (95% CI, 0.63%-1.01%), which was significantly different than the case fatality rate of 1.40% (95% CI, 1.23%-1.60%) when ICD-9 codes alone were used. CONCLUSIONS: This is the first report of assembly and validation of a cohort of de novo ALL patients from a database representative of free-standing children's hospitals across the United States. Our data demonstrate that the use of ICD-9 codes alone to establish cohorts will lead to substantial patient misclassification and result in biased outcome estimates. Systematic methods beyond the use of just ICD-9 codes must be used before analysis to establish accurate cohorts of patients with malignancy. A similar approach should be followed when establishing future cohorts from administrative data.

Antithrombin concentrate use in children: a multicenter cohort study.

OBJECTIVE: To describe the off-label use of antithrombin concentrate in tertiary care pediatric hospitals across the US. STUDY DESIGN: This is a retrospective, multicenter, cohort study of 4210 admissions of children younger than 18 years of age who received antithrombin concentrate between 2002 and 2011 within the Pediatric Health Information System administrative database. An on-label admission was defined as an admission with an International Classification of Diseases diagnostic code for a primary hypercoagulable state; admissions without this code were classified as off-label. RESULTS: During the 10-year study period, off-label use of antithrombin concentrate increased 5-fold. Overall, 97% of study subjects received antithrombin off-label. Neonates younger than 30 days of age comprised the largest age group (45.7%) of use; 87% of patients had at least one complex chronic condition, with congenital heart/lung defects being the most prevalent primary diagnosis (36.3%). Extracorporeal membrane oxygenation was the most common procedure associated with antithrombin use (43.7%). CONCLUSIONS: The off-label use of antithrombin concentrate is increasing rapidly, particularly in critically ill children receiving extracorporeal membrane oxygenation, with few parallel studies to substantiate its safety or efficacy. Further preclinical and controlled clinical studies are critical to expanding our knowledge of this drug. In the meantime, antithrombin concentrate should be used judiciously by clinicians and following guidelines instated by hospitals.

Leveraging administrative data to monitor rituximab use in 2875 patients at 42 freestanding children's hospitals across the United States.

OBJECTIVE: To describe the pharmacoepidemiology of rituximab use in children and to estimate the frequency of infectious events within a 1-year period after rituximab exposure. STUDY DESIGN: This is a retrospective cohort study of patients who received rituximab at 1 of 42 children's hospitals contributing data to the Pediatric Health Information System between January 1999 and June 2011. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge diagnosis codes were analyzed to categorize underlying diseases (hematologic malignancies, primary immunodeficiencies, autoimmune diseases, and transplant recipients) and to estimate inpatient infectious complication rates within each category. RESULTS: A total of 2875 patients with 4639 rituximab admissions were identified. The median age at index admission was 11 years (IQR, 5-15 years). The rate of rituximab admissions increased from 3 to 185 per 100,000 admissions per year over the study interval. During the 1-year follow-up period, 463 patients (16%) died. Infectious events were assessed in 2246 of the rituximab-exposed patients; 6.1% were diagnosed with sepsis and 2.0% with septic shock. The frequency of sepsis ranged from 2.4% in patients with autoimmune diseases to 12.2% in those with primary immunodeficiencies. Three patients were assigned an ICD-9-CM discharge diagnosis code for Pneumocystis joroveci pneumonia, 1 patient was assigned an ICD-9-CM discharge diagnosis code for hepatitis B, and 1 patient was assigned an ICD-9-CM discharge diagnosis code for progressive multifocal leukoencephalopathy. CONCLUSION: The use of rituximab has increased significantly in children with a variety of underlying diseases. Based on ICD-9-CM code data, the rates of sepsis and other life-threatening infections after rituximab exposure vary depending on the underlying condition. Based on surveillance of infection using ICD-9-CM diagnosis codes, the rates of opportunistic infections appear to be low.

Widespread use of fresh frozen plasma in US children's hospitals despite limited evidence demonstrating a beneficial effect.

OBJECTIVES: To determine the pattern, prevalence and potential complications of fresh frozen plasma (FFP) use in US pediatric hospitals from 2002-2009. STUDY DESIGN: Retrospective cohort study using the Pediatric Health Information System (PHIS) administrative database, which was queried for FFP admissions using diagnostic, procedural, and billing codes. Demographic data, daily use, and procedural codes were used to describe the patient population and pattern of FFP use. RESULTS: Of 3 252 149 PHIS-recorded admissions, 2.85% had codes consistent with FFP use. This percentage did not change over the course of the study (P=.10). FFP was most commonly administered to children <1 year of age (54%), critically ill children (70%), and those with heart disease (34%). Fifteen percent of FFP-related admissions involved a thrombotic event. The overall mortality rate was 17% and it decreased during the study (P<.001). There was noteworthy variation in the proportion of FFP admissions among participating institutions. CONCLUSIONS: FFP is commonly used in children admitted to PHIS hospitals. Despite recent expert recommendations highlighting the lack of efficacy in many clinical scenarios, the rate of FFP use does not appear to be changing. Randomized, controlled studies are needed to determine appropriate indications for FFP use and evaluate for potential complications.

Off-label recombinant factor VIIa use and thrombosis in children: a multi-center cohort study.

OBJECTIVE: To describe the off-label use of recombinant factor VIIa (rFVIIa) in tertiary care pediatric hospitals across the United States and to assess thrombotic events. STUDY DESIGN: A retrospective multi-center cohort study using the Pediatric Health Information System administrative database. Children 18 years of age or younger who received rFVIIa between 2000 and 2007 were included. A label admission was defined as an admission with an International Classification of Diseases diagnostic code for hemophilia or factor VII deficiency; admissions without these codes were classified as off-label. RESULTS: There were 4942 rFVIIa admissions, representing 3764 individual subjects; 74% (3655) of the admissions were off-label. There was a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007 (from 2 to 20.8 per 10 000 hospital admissions, P < .001). The mortality rate in the off-label group was 34% (1258/3655). Thrombotic events occurred in 10.9% (399/3655) of the off-label admissions. CONCLUSIONS: The off-label use of rFVIIa in hospitalized children is increasing rapidly despite the absence of adequate clinical trials demonstrating safety and efficacy. Thrombotic events are common and mortality is high among patients receiving off-label rFVIIa. Further studies are warranted to determine whether these adverse events are attributable to rFVIIa.