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

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.

Magnetic resonance imaging screening to identify spinal and paraspinal infections associated with injections of contaminated methylprednisolone acetate.

IMPORTANCE: Injection of contaminated methylprednisolone has resulted in an unprecedented nationwide outbreak of Exserohilum rostratum fungal infections, manifested initially as meningitis and/or basilar stroke. Insidious onset of spinal or paraspinal infection at the injection site has been increasingly reported and is occurring months after receipt of injection with the contaminated drug. The clinical findings are often subtle and similar to those that led the patient to undergo the methylprednisolone injection. OBJECTIVE: To determine if patients who had not presented for medical care but who had received contaminated methylprednisolone developed spinal or paraspinal infection at the injection site using contrast-enhanced magnetic resonance imaging (MRI) screening. DESIGN, SETTING, AND PARTICIPANTS: There were 172 patients who had received an injection of contaminated methylprednisolone from a highly contaminated lot (No. 06292012@26) at a pain facility but had not presented for medical care related to adverse effects after the injection. Screening MRI was performed between November 9, 2012, and April 30, 2013. MAIN OUTCOMES AND MEASURES: Number of persons identified with previously undiagnosed spinal or paraspinal infection. RESULTS: Of the 172 patients screened, MRI was abnormal in 36 (21%), showing epidural or paraspinal abscess or phlegmon, arachnoiditis, spinal osteomyelitis or diskitis, or moderate to severe epidural, paraspinal, or intradural enhancement. Of the 115 patients asked about new or worsening back or neck pain, lower extremity weakness, or radiculopathy symptoms, 35 (30%) had at least 1 symptom. Thirty-five of the 36 patients with abnormal MRIs met the Centers for Disease Control and Prevention (CDC) case definition for probable (17 patients) or confirmed (18 patients) fungal spinal or paraspinal infection. All 35 patients were treated with antifungal agents (voriconazole, with or without liposomal amphotericin B), and 24 required surgical debridement. At the time of surgery, 17 of 24 patients (71%), including 5 patients who denied having symptoms, had laboratory evidence of fungal infection. CONCLUSIONS AND RELEVANCE: Among patients who underwent screening MRI to look for infection at the site of injection of contaminated methylprednisolone, 21% had an abnormal MRI, and all but one met CDC criteria for probable or confirmed fungal spinal or paraspinal infection. Screening MRI led to identification of patients who had minimal or no symptoms of spinal or paraspinal infection and allowed early initiation of medical and surgical treatment.