Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain

Abstract

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.

Keywords: contaminated methylprednisolone injection; fluorosis; fungal infection; periostitis; voriconazole.

Figure 1.

Breakdown of the patients who received voriconazole therapy. Total number of patients who received therapy with voriconazole at St Joseph Mercy Hospital for fungal infections caused by contaminated methylprednisolone injections and their subsequent clinical evaluations. “Bone Pain”: number of patients who reported skeletal pain; “No Pain”: number of patients who had no reported skeletal pain; “Fl > 8”: plasma fluoride levels >8 µmol/L, “Fl < 8”: plasma fluoride level <8 µmol/L; “Bone Scan (+)”: number of bone scans positive for periostitis and its percentage; “Pain Unknown”: number of patients who did not receive either bone scan or fluoride measurement and therefore were excluded from data extraction; “Fl Not Measured” and “Bone Scan Not Ordered”: these tests were not obtained during the treatment period.

Figure 2.

Correlation between voriconazole dose, plasma fluoride, and serum alkaline phosphatase (ALP). Daily voriconazole dose at the time of blood draw was positively correlated with both plasma fluoride (A) and serum ALP (B). In contrast, cumulative voriconazole dose was not correlated with either measurement (C and D).

Figure 3.

Computed tomography (CT) and whole-body bone scan of periostitis. A, Chest CT was obtained in this patient to further evaluate for rib pain. B and C, Magnified images of the bilateral ribs. B, Magnified image of right posterior rib has evidence of periosteal inflammation and thickening consistent with periostitis (arrowheads). C, Left midshaft of the rib in an uninvolved area that does not have periostitis does not show periosteal layer thickening as shown in (B). D, Posterior whole-body bone scan of the same patient showing bilateral posterior rib periostitis.

Figure 4.

Posterior view of the whole-body bone scan, before and after voriconazole discontinuation. This patient had evidence of right rib periostitis approximately 5 months after beginning voriconazole (A). Approximately 11 months after discontinuation of voriconazole, a repeat bone scan shows no evidence of periostitis (B).