Bloodstream infections exacerbate incidence and severity of symptomatic glucocorticoid-induced osteonecrosis.
Animals
Antineoplastic Agents, Hormonal
/ adverse effects
Bacteremia
/ complications
Child
Dexamethasone
/ adverse effects
Follow-Up Studies
Humans
Incidence
Male
Mice
Mice, Inbred BALB C
Osteonecrosis
/ epidemiology
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ blood
Prognosis
Prospective Studies
Retrospective Studies
Severity of Illness Index
Tennessee
/ epidemiology
acute lymphoblastic leukemia
bacteremia
glucocorticoid
lipopolysaccharide
osteonecrosis
Journal
Pediatric blood & cancer
ISSN: 1545-5017
Titre abrégé: Pediatr Blood Cancer
Pays: United States
ID NLM: 101186624
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
10
10
2018
revised:
21
12
2018
accepted:
10
01
2019
pubmed:
14
2
2019
medline:
19
12
2019
entrez:
14
2
2019
Statut:
ppublish
Résumé
Osteonecrosis is a common toxicity associated with glucocorticoid (e.g., dexamethasone and prednisone) treatment of children with acute lymphoblastic leukemia (ALL), but risk factors are incompletely defined. Infections are also a common complication of ALL therapy. Lipopolysaccharide (LPS) is used experimentally to mimic infection-related systemic effects. To our knowledge, the contribution of systemic infections to the risk of glucocorticoid-induced osteonecrosis has not been investigated. Patients with ALL on St. Jude Total Therapy XV (n = 365) were assessed for documented bacteremia prior to development of osteonecrosis, which was confirmed by MRI, and graded using the National Cancer Institute's Common Terminology for Adverse Events (version 3.0). In a preclinical model, Balb/cJ mice treated with dexamethasone plus or minus LPS were assessed for frequency and severity of osteonecrosis and arteriopathy. We found that patients with ALL who experienced bacteremia had a higher frequency of symptomatic osteonecrosis (≥grade 2) than those who did not (OR: 1.88; 95% CI, 1.03-3.41, P = 0.038). LPS exacerbated experimental dexamethasone-induced osteonecrosis. Mice treated with dexamethasone plus LPS had a higher incidence of osteonecrosis (P = 0.00086) and arteriopathy (P = 0.0047) than did those treated with dexamethasone alone, and the severity of osteonecrosis (P = 0.00045) and arteriopathy (P = 0.0048) was also more pronounced with the addition of LPS treatment. The increase in osteonecrosis was not explained by any alteration of dexamethasone pharmacokinetics by LPS. These data identify systemic infection during ALL therapy as a novel risk factor in the development of glucocorticoid-induced osteonecrosis.
Sections du résumé
BACKGROUND
Osteonecrosis is a common toxicity associated with glucocorticoid (e.g., dexamethasone and prednisone) treatment of children with acute lymphoblastic leukemia (ALL), but risk factors are incompletely defined. Infections are also a common complication of ALL therapy. Lipopolysaccharide (LPS) is used experimentally to mimic infection-related systemic effects. To our knowledge, the contribution of systemic infections to the risk of glucocorticoid-induced osteonecrosis has not been investigated.
PROCEDURE
Patients with ALL on St. Jude Total Therapy XV (n = 365) were assessed for documented bacteremia prior to development of osteonecrosis, which was confirmed by MRI, and graded using the National Cancer Institute's Common Terminology for Adverse Events (version 3.0). In a preclinical model, Balb/cJ mice treated with dexamethasone plus or minus LPS were assessed for frequency and severity of osteonecrosis and arteriopathy.
RESULTS
We found that patients with ALL who experienced bacteremia had a higher frequency of symptomatic osteonecrosis (≥grade 2) than those who did not (OR: 1.88; 95% CI, 1.03-3.41, P = 0.038). LPS exacerbated experimental dexamethasone-induced osteonecrosis. Mice treated with dexamethasone plus LPS had a higher incidence of osteonecrosis (P = 0.00086) and arteriopathy (P = 0.0047) than did those treated with dexamethasone alone, and the severity of osteonecrosis (P = 0.00045) and arteriopathy (P = 0.0048) was also more pronounced with the addition of LPS treatment. The increase in osteonecrosis was not explained by any alteration of dexamethasone pharmacokinetics by LPS.
CONCLUSIONS
These data identify systemic infection during ALL therapy as a novel risk factor in the development of glucocorticoid-induced osteonecrosis.
Identifiants
pubmed: 30758124
doi: 10.1002/pbc.27669
pmc: PMC6472979
mid: NIHMS1011642
doi:
Substances chimiques
Antineoplastic Agents, Hormonal
0
Dexamethasone
7S5I7G3JQL
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e27669Subventions
Organisme : NIGMS NIH HHS
ID : GM115279
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA142665
Pays : United States
Organisme : NIH HHS
ID : CA21765
Pays : United States
Organisme : NCI NIH HHS
ID : CA142665
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM115279
Pays : United States
Informations de copyright
© 2019 Wiley Periodicals, Inc.
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