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Background Voriconazole-induced periostitis is predominantly reported in adults, with pediatric cases being exceedingly rare. Case presentation This report describes an 8-year-old boy with voriconazole-induced periostitis presenting with finger pain and nodules, initially suspected to be bone tumors. The patient had been on voriconazole for two years and seven months to treat Aspergillus pneumonia and had been hospitalized for six months due to chronic graft-versus-host disease following hematopoietic stem cell transplantation and total body irradiation for severe congenital neutropenia. The patient presented with a five-month history of pain and a one-month history of a mass in the middle finger of his right hand. Radiographs revealed bone formation outside the cortical bone in the proximal phalanx of the right middle finger and the distal ulna. Differential diagnoses included benign bone-forming tumors, such as osteochondroma post-total body irradiation, and bizarre parosteal osteochondromatous proliferation. The diagnosis of voriconazole-induced periostitis was confirmed as new sites of periostitis became apparent during the disease course. Conclusions Voriconazole-induced periostitis should be considered, even in pediatric patients, when multiple nodular periosteal reactions are observed in immunosuppressed patients undergoing long-term voriconazole therapy.

A 52-year-old woman with overlap syndrome and interstitial pneumonia underwent immunosuppressive therapy and she was suspected to suffer from pulmonary aspergillosis. Oral voriconazole was initiated, and a rapid elevation of alkaline phosphatase (ALP) occurred after 4 weeks. After 2 months, the patient presented diffuse pain in bilateral skeletal regions, and bone scintigraphy revealed bilateral multiple areas of increased radiotracer uptake. We suspected the skeletal involvement as voriconazole-induced periostitis. Actually, the plasma fluoride level was increased. Voriconazole was replaced with itraconazole, and after 3 weeks, the patient stopped complaining of bone pain concomitant with the decrease in ALP. Voriconazole-induced periostitis is a rare condition but had previously been reported in solid organ or patients with bone marrow transplant who received a long-term voriconazole therapy. Our present case is distinctive of previous ones, because it occurred in a patient with connective tissue disease which had its rapid progression.

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.

Background. We describe a heart transplant patient with painful periostitis and exostoses who was receiving long-term therapy with voriconazole, which is a fluoride-containing medication. Elevated plasma and bone fluoride levels were identified. Discontinuation of voriconazole therapy led to improvement in pain and reduced fluoride and alkaline phosphatase levels. Methods. To determine whether voriconazole is a cause of fluoride excess, we measured plasma fluoride levels in 10 adult post-transplant patients who had received voriconazole for at least 6 months and 10 post-transplant patients who did not receive voriconazole. To assess the effect of renal insufficiency on fluoride levels in subjects receiving voriconazole, half were recruited on the basis of a serum creatinine level of ≥1.4 mg/dL on their most recent measurement, whereas the other 5 subjects receiving voriconazole had serum creatinine levels <1.4 mg/dL. All control subjects had serum creatinine levels of ≥1.4 mg/dL. Patients were excluded from the study if they received a fluorinated pharmaceutical other than voriconazole. Results. All subjects who received voriconazole had elevated plasma fluoride levels, and no subjects in the control group had elevated levels (14.32 μmol/L ± 6.41 vs 2.54 ± 0.67 μmol/L; P<.001). Renal function was not predictive of fluoride levels. Plasma fluoride levels remained significantly higher in the voriconazole group after adjusting for calcineurin inhibitor levels and doses. Half of the voriconazole group subjects had evidence of periostitis, including exostoses in 2 patients. Discontinuation of voriconazole therapy in patients with periostitis resulted in improvement of pain and a reduction in alkaline phosphatase and fluoride levels. Conclusions. Voriconazole is associated with painful periostitis, exostoses, and fluoride excess in posttransplant patients with long-term voriconazole use.

Over the past few years, several reports of periostitis affecting patients treated with voriconazole appeared in the literature. As rheumatologists are likely to be called to see such patients, a review of the reported cases was undertaken. A systematic search of Pubmed and Google scholar for case reports, case series and observational studies was undertaken. Twenty-six articles including 23 case reports/case series (total 40 patients), a prospective study and two retrospective studies of 58 cases were included. Age ranged from 3 months to 77 years. Eleven cases (27.5 %) were male and 29 cases (72.5 %) were female. The duration of treatment varied from 6 weeks to 8 years (mean 53.6, SD 77.4 weeks). Most cases presented with diffuse skeletal pain affecting various sites in association with elevated alkaline phosphatase. Periostitis is increasingly reported and should be considered in patients taking voriconazole who present with bone pain and/or alkaline phosphatase elevation.

Voriconazole-induced periostitis is a rare adverse effect in patients on long-term therapy, characterised by periosteal inflammation and associated bony pain. The accompanying lab abnormalities (elevated serum alkaline phosphatase and fluoride) and characteristic imaging findings (uptake of radionuclide tracer on nuclear bone scan) are critical for diagnosis. The disease process is thought to be secondary to excess fluoride from voriconazole which stimulates bone formation and decreases osteoclast bone resorption. Management includes stopping voriconazole and switching to another agent.

ObjectivesA 61-year-old with acute granulomatosis and polyangiitis developed Aspergillus fumigatus pneumonia after admission to the intensive care unit with a small bowel perforation. This occurred after immunosuppression (intravenous methylprednisolone, intravenous cyclophosphamide, and plasmapheresis) for his initial presentation with stage 3 acute kidney injury.Materials and methodsThe mycologist recommended long-term treatment with voriconazole after initial recovery.ResultsAfter 7 months of treatment, the patient complained of joint pain and swelling in his hands. Radiographs, computed tomography, and single-photon emission computed tomography appearances were consistent with periostitis. A diagnosis of Voriconazole-induced periostitis deformans was made and the voriconazole was stopped. Plasma fluoride level was 278 μg/L (normal range < 50 μg/L). Discontinuation of voriconazole led to clinical improvement.ConclusionsPeriostitis deformans due to fluorosis is a rare complication of voriconazole treatment. The imaging in our case is unusually dramatic. We were able to track the evolution of periosteal reactions over serial imaging.

Voriconazole-induced periostitis (VIP) is a rare but increasingly encountered entity since Food and Drug Administration (FDA) approval of the second generation antifungal medication in 2002. Literature reports most commonly include transplant recipients on immunosuppressive therapy simultaneously requiring antifungal therapy. Nontransplant patients receiving long-term voriconazole have an equal risk of developing the disease, but may experience a delay in diagnosis due to a lack of familiarity with the process outside of the post-transplant and/or immunosuppressed population. We present a case of VIP in a nontransplant, immunocompetent patient on suppressive antifungal therapy for prior abdominal aortic stent graft fungal infection. Radiologist review of current medications and recognition of periostitis on multiple imaging modalities may hasten the diagnosis and lead to earlier treatment and resolution of symptoms.

Fluorosis (the integration of fluoride into bone structure) and promotion of bone formation by osteoblast stimulation is the proposed mechanism of voriconazole-related periostitis.2,3 Risk factors for fluorosis include renal impairment, long-term use of voriconazole at therapeutic doses, slow drug metabolism and elevated fluoride levels.2 Unlike voriconazole, other fluorinated triazoles (e.g., fluconazole and posaconazole) are not associated with periostitis.2 Drug-induced reversible periostitis has also been described in connection with prostaglandin E14 and interleukin-11.5

Voriconazole-related periostitis has been increasingly described in the literature over the last several years as a recognizable disease entity, especially in lung transplant patients. This relationship should be considered when approaching immunosuppressed patients presenting with diffuse bone pain and imaging findings of periostitis. We present a case of voriconazole-associated periostitis, capsular and enthesial ossification and glenuhumeral capsulitis in a patient with a hematologic malignancy. To the authors’ knowledge, soft tissue ossification associated with voriconazole has not been described in the radiology literature.