Malglycemia is associated with poor outcomes in pediatric and adolescent hematopoietic stem cell transplant patients

Abstract

Malglycemia (hypoglycemia, hyperglycemia, and/or glycemic variability) in adult hematopoietic stem cell transplant (HSCT) recipients is associated with increased infection, graft-versus-host disease, organ dysfunction, delayed engraftment, and mortality. Malglycemia has not been studied in pediatric HSCT recipients. This study aimed to characterize the incidence and consequences of malglycemia in this population. Medical records for a cohort of 344 patients, age 0 to 30 years, who underwent first HSCT from 2007 to 2016 at Children's Hospital Colorado were retrospectively reviewed. Glucose data were analyzed in intervals and assessed for potential risk factors and associated outcomes. Malglycemia occurred in 43.9% of patients. Patients with a day 0 to 100 mean glucose of 100 to 124 mg/dL had a 1.76-fold (95% confidence interval [CI], 1.10-2.82; P = .02) increased risk of death and patients with a day 0 to 100 mean glucose ≥ 125 mg/dL had a 7.06-fold (95% CI, 3.84-12.99; P < .0001) increased risk of death compared with patients with a day 0 to 100 mean glucose < 100 mg/dL. For each 10 mg/dL increase in pre-HSCT glucose, there was a 1.11-fold (95% CI, 1.04-1.18; P = .0013) increased risk of post-HSCT infection. These adverse impacts of malglycemia occurred independent of transplant type, graft-versus-host disease, and steroid therapy. Malglycemia in the pediatric HSCT population is independently associated with significantly increased risk of morbidity and mortality. Further research is required to evaluate the utility of glucose control to mitigate these relationships and improve HSCT outcomes. This trial was registered at www.clinicaltrials.gov as #NCT03482154.

Conflict of interest statement

Conflict-of-interest disclosure: G.P.F. has served as a consultant for Abbott Diabetes Care and an advisory board member for Dexcom and conducts research sponsored by Medtronic, Dexcom, Bigfoot Biomedical, Tandem Diabetes Care, Insulet, and Novo Nordisk. M.R.V. has served as a consultant for Fate Therapeutics and B-MoGen Biotechnologies. R.P.W. has received grants and personal fees from Dexcom, Novo Nordisk, MannKind Corporation, and Eli Lilly and Company for unrelated work. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Distribution of patient mean blood glucose values by time interval. Although the medians (of mean) glucose values were in the normal range at each time interval analyzed, the distribution demonstrates skew toward hyperglycemia. The dashed lines represent the normal range of nonfasting glucose, which is 70 to 140 mg/dL.

Figure 2.

Time to morbidity and mortality by day −14 to +100 mean glucose category. On days −14 to +100, there was a statistically significant difference in time to infection (A; P < .0001), time to ICU hospitalization (B; P = .004), OS (C; P < .0001), and TRM (D; P < .0001) among patients with a mean glucose level of <100 mg/dL, 100 to 124 mg/dL, and ≥125 mg/dL. The number of patients at risk at each time point are shown in the table below each graph.

Figure 3.

Hazard ratios for time to infection by mean glucose (relative to a reference value of mean glucose of 100 mg/dL) stratified by HSCT type for each time interval and adjusted for the interaction between HSCT type and glucose. (A) Pre-HSCT mean glucose. (B) Days 0 to 30 mean glucose. (C) Days 0 to 100 mean glucose. (D) Days −14 to +100 mean glucose. The association between mean glucose at any interval and time to infection was modified by HSCT type. Patients who underwent allogeneic HSCT continued to demonstrate that increased mean glucose was associated with shorter time to infection, whereas patients who underwent autologous HSCT demonstrated slightly longer time to infection with increased mean glucose.

Figure 4.

Adjusted odds ratios of infection subtypes for each incremental 10-mg/dL increase in mean glucose. Odds ratios for SBI, viremia/viruria, and fungal infection are adjusted for age group, HSCT type, pretransplant radiation, GVHD, and post-HSCT steroids. After adjusting for age group, pre-HSCT radiation, HSCT type, severe (grade 2, grade 4, or chronic) GVHD diagnosis, and post-HSCT steroids, the risk of SBI and fungal infection increased with increased mean glucose at all time intervals, and the risk of viremia/viruria increased with increased pre-HSCT and days 0 to 100 mean glucose. For example, with each 10-mg/dL increase in pretransplant glucose, there was a 29.8% (95% CI, 12.4-49.9) increase in SBI (P < .0001), a 26.0% (95% CI, 6.8-48.8) increase in viremia/viruria (P = .006), and a 27.0% (95% CI, 3.1-56.3) increase in fungal infection (P = .02). Similar relationships were noted for the days 0 to 100 interval. After adjusting for the aforementioned variables, there was an increased risk for GVHD (grade 3 or 4 or chronic) with increasing days 0 to 100 mean glucose.