Fluoride Level and Bone Pain As a Predictor of Voriconazole Induced Periostitis

Background:

Voriconazole is a triazole antifungal medication used for prophylaxis in transplant patients or to treat invasive fungal infections. Inflammation of the periosteum causing skeletal pain, known as periostitis, has been an infrequently observed side effect of long‐term voriconazole therapy. Because each molecule of voriconazole contains three fluoride atoms, previous reports have suggested a possible link between excess fluoride and the development of periostitis. Contaminated methylprednisolone injections resulted in a fungal infection outbreak between 2012 and 2013 requiring 195 patients to receive multiple months of voriconazole therapy at St. Joseph Mercy Hospital in Ann Arbor Michigan. During this period, approximately 20 to 30 percent of patients reported skeletal pain, raising concerns for periostitis.

Methods:

A retrospective study was conducted among patients who received voriconazole at St. Joseph Mercy Hospital in Ann Arbor Michigan for fungal infections caused by contaminated methylprednisolone injections during the most recent outbreak. Patients who had skeletal pain were eligible for the study if they received a plasma fluoride level and a whole body scan for evaluation of periostitis. Bone scan results as well as variables including plasma fluoride level, serum voriconazole, creatinine, alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase and voriconazole dose were recorded and compared. A two‐tailed homoscedastic T‐test was used to compare independent variables to bone scan results.

Results:

Among patients who had periostitis, rib and ulna were the most common locations (Fig. 1A). Though skeletal pain was present in all 29 patients who were included in the statistical analysis, plasma fluoride levels were significantly higher in those who had periostitis when compared to those without periostitis (P <0.001) (Fig. 1B). Also, blood alkaline phosphatase level (P = 0.02) and daily voriconazole dose (P < 0.001) differed significantly between the two groups while blood concentrations of creatinine, ALT or bilirubin did not show statistical significance. Discontinuation or dose reduction of voriconazole resulted in improvement of pain in 89% of patients.

Conclusions:

The most recent fungal infection outbreak resulting from contaminated methylprednisolone injections led to large number of patients being treated with voriconazole. Based on our observations, we conclude that high plasma fluoride levels coupled with skeletal pain among patients who are on long‐term voriconazole therapy is highly suggestive of periostitis. Early detection should be sought as discontinuation of the medication is effective at reversing the disease.