Skeletal fluorosis after prolonged voriconazole therapy
Isabelle Viel-Thériault, MD FRCP(C), Henrique Bittencourt, MD FRCP(C), Julie Autmizguine, MD FRCP(C), Philippe Ovetchkine, MD FRCP(C)
Paediatrics & Child Health 25(1)7-8 (2020)
A 6-year-old girl underwent allogeneic hematopoietic stem cell transplantation for a relapsing acute myelogenous leukemia. She developed severe chronic graft-versus-host disease which required immunosuppressive therapies, including a prolonged course of high-dose steroids. She also presented a thrombotic microangiopathy complicated by renal failure requiring dialysis.
Eleven months after transplantation, she was diagnosed with pulmonary and cerebral aspergillosis, prompting initiation of intravenous voriconazole. Unusually high doses were needed (11 mg/kg/dose every 8 hours) in order to achieve therapeutic plasmatic trough concentrations above 1 to 2 mg/L. After 2 months, she was transitioned to oral voriconazole at equivalent dosing.
Six months after being on oral voriconazole, she complained of fatigue and diffuse musculoskeletal pain, initially attributed to her steroid treatment. Radiographs (Figure 1) of her femurs showed diffuse osteopenia and pronounced bilateral periosteal reactions with exostosis (arrows).
The diagnosis of osseous fluorosis induced by prolonged voriconazole therapy was suspected and confirmed by a very high fluoride plasma concentration of 27.0 [micro]mol/L (0.25 to 1.0 [micro]mol/L). Her alkaline phosphatase level was also increased at 627 U/L (134 to 518 U/L), with a known normal baseline level preceding therapy. Voriconazole was discontinued and oral posaconazole was substituted in its place. Five months after voriconazole discontinuation, her musculoskeletal symptoms resolved...
"Voriconazole is the first-line therapy for invasive aspergillosis. Voriconazole and its metabolite (NO-voriconazole) contain three fluoride atoms, and long-term treatment can lead to elevated plasma fluoride levels, increasing the risk of skeletal fluorosis by enhancing osteoblast proliferation (1)."
Moon WJ, Scheller EL, Suneja A, Livermore JA, Malani AN, Moudgal V, Kerr LE, Ferguson E, Vandenberg DM - "Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain" Clin Infect Dis 59(9):1237-45 (2014) doi: 10.1093/cid/ciu513. Epub 2014 Jul 3. PMID: 24992954; PMCID: PMC4351342.
Background. Voriconazole is a triazole antifungal medication used for prophylaxis or to treat invasive fungal infections. Inflammation of the periosteum resulting in skeletal pain, known as periostitis, is a reported side effect of long-term voriconazole therapy. The trifluorinated molecular structure of voriconazole suggests a possible link between excess fluoride and periostitis, as elevated blood fluoride has been reported among patients with periostitis who received voriconazole.
Methods. Two hundred sixty-four patients from Michigan were impacted by the multistate outbreak of fungal infections as a result of contaminated methylprednisolone injections. A retrospective study was conducted among 195 patients who received voriconazole therapy at St Joseph Mercy Hospital during this outbreak. Twenty-eight patients who received both bone scan and plasma fluoride measurements for skeletal pain were included in the statistical analyses. Increased tracer uptake on bone scan was considered positive for periostitis. The primary outcome measure was the correlation between plasma fluoride and bone scan results.
Results. Blood fluoride (P < .001), alkaline phosphatase (P = .020), daily voriconazole dose (P < .001), and cumulative voriconazole dose (P = .027) were significantly elevated in patients who had periostitis compared with those who did not. Discontinuation or dose reduction of voriconazole resulted in improvement of pain in 89% of patients.
Conclusions. High plasma fluoride levels coupled with skeletal pain among patients who are on long-term voriconazole therapy is highly suggestive of periostitis. Initial measurement of fluoride may be considered when bone scan is not readily available. Early detection should be sought, as discontinuation of voriconazole is effective at reversing the disease.
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