Voriconazole-induced periostitis.

Voriconazole is a fluorinated drug from the triazole group that is widely used in the prophylaxis and treatment of fungal infections in immunosuppressed patients. Chronic use of this medication can generate, as an adverse effect, a multifocal, asymmetric, diffuse and nodular periosteal reaction, associated with severe and disabling skeletal pain and elevated alkaline phosphatase and serum fluoride. Radiography is the imaging technique of choice for periostitis diagnosis. In general, clinical manifestations and radiographic findings disappear, when the drug is discontinued. We report the clinical case of a 44 year-old woman diagnosed with acute myeloid leukemia, who developed an invasive fungal infection treated with voriconazole after a stem cell transplant. Nine months after starting antifungal treatment, she manifested symptoms and radiological signs compatible with periostitis. Due to clinical suspicion, we decided to suspend voriconazole, with consequent resolution of clinical manifestations and radiological findings.

Spectrum of Voriconazole-Induced Periostitis With Review of the Differential Diagnosis.

OBJECTIVE: Voriconazole is an antifungal medication used primarily for the treatment of Candida and Aspergillus infections. A fairly newly described side effect of long-term voriconazole use is periostitis. The purpose of this article is to describe the main differential consideration-hypertrophic osteoarthropathy-and other differential diagnoses, including venous stasis, thyroid acropachy, and hypervitaminosis A. CONCLUSION: With knowledge of imaging appearance, clinical manifestations, and outcomes, radiologists can make an accurate diagnosis of voriconazole-induced periostitis, and clinical teams can initiate appropriate management.

A vexing case of bone pain in a renal transplant recipient: Voriconazole-induced periostitis.

Immunosuppression increases the risk of opportunistic infections including fungal infections in solid organ transplant recipients. Voriconazole is used to treat invasive aspergillus infections but prolonged usage may rarely lead to periostitis. Increased plasma fluoride concentration leading to osteoblastic upregulation is thought to be the catalyst, and symptom reversal occurs with discontinuation of the offending agent. A renal transplant recipient who was on voriconazole for invasive aspergillosis developed diffuse debilitating symmetrical bone pain. Having ruled out other neurological, metabolic, and drug etiologies, voriconazole-induced periostitis was diagnosed. Increased plasma fluoride level was documented, but bone scan was non-specific. A therapeutic discontinuation of voriconazole and switch to posaconazole provided rapid symptom resolution. The patient accidently restarted voriconazole as an outpatient resulting in the same symptomology, and thus provided further evidence that this was drug related. Voriconazole-induced periostitis is a described entity in immunosuppressed solid organ transplant patients who are treated with a prolonged course of voriconazole. This case study is novel in that it demonstrates drug induced periostitis in a renal transplant recipient who developed debilitating periostitis within a short time after starting voriconazole and equally rapid resolution once it was discontinued. We conclude that patients treated with voriconazole should be routinely monitored for periostitis.

Voriconazole-induced periostitis deformans: serial imaging in a patient with ANCA vasculitis.

OBJECTIVES: A 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 METHODS: The mycologist recommended long-term treatment with voriconazole after initial recovery. RESULTS: After 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. CONCLUSIONS: Periostitis 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.

Adverse effects of voriconazole: Over a decade of use.

Voriconazole use has increased since the drug's introduction in 2002, and new and unique adverse effects are emerging as patients undergo prolonged therapy. Most concerning is the increased risk of cutaneous malignancies, primarily squamous cell carcinoma (SCC); this risk is duration dependent and the associated malignancies tend to be more aggressive and multifocal. Voriconazole is also associated with phototoxicity (which may be a precursor to malignancy), periostitis, hallucinations and encephalopathy, peripheral neuropathy, alopecia, nail changes, hyponatremia, and other adverse effects. Some toxicities (neuropsychiatric and gastrointestinal including hepatic) are seen in clear association with supratherapeutic serum voriconazole levels; thus, careful monitoring of voriconazole levels is a critical component of safe drug use. Guidelines for screening for adverse effects after long-term voriconazole use may be beneficial and need to be established.

Voriconazole-induced periostitis: beyond post-transplant patients.

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.

Case 215: voriconazole-induced periostitis.

History A 74-year-old woman presented with multifocal bone pain, including pain in multiple ribs, bilateral shoulders, and bilateral hips. The pain began several months before presentation and was quite severe, ultimately necessitating control with narcotics. At examination, strength in both lower extremities was slightly reduced, sensation and reflexes were intact, and range of motion was full, though painful. There were no notable constitutional symptoms of fever or weight loss. Laboratory work-up was remarkable for elevated alkaline phosphatase level (277 U/L [4.6 mkat/L]). The patient had undergone left lung transplantation 8 years prior for pulmonary fibrosis. A thorough pulmonary work-up for the cause of fibrosis, which included gathering an exposure, occupational, allergy, and previous infectious history, and a rheumatoid work-up were negative. The patient's posttransplantation course was complicated by bronchiolitis obliterans from chronic rejection and by recent pulmonary embolism, for which she was undergoing anticoagulation therapy at the time of presentation. Additionally, the patient experienced repeated pulmonary infections with Aspergillus, leading to multiple hospitalizations and long-term antifungal prophylaxis with voriconazole. A bone scan from an outside hospital was reviewed, and further imaging was performed.

Elevated fluoride levels and periostitis in pediatric hematopoietic stem cell transplant recipients receiving long-term voriconazole.

Azole therapy is widely utilized in hematopoietic stem cell transplant (HCT) recipients for the treatment of aspergillus. Complications of voriconazole treatment related to its elevated fluoride content have been described in adults, including reports of symptomatic skeletal fluorosis. We review fluoride levels, clinical, and laboratory data in five pediatric HCT recipients on long-term voriconazole therapy, all found to have elevated serum fluoride levels. Two patients had toxic fluoride levels, one infant had symptoms of significant pain with movement and radiographs confirmed skeletal fluorosis. Monitoring fluoride levels in children, especially with skeletal symptoms, should be considered in patients on long-term voriconazole.

Voriconazole-induced periostitis post transplant: an illustrative review of thoracic computed tomography imaging manifestations.

Voriconazole, first commercially approved in 2002 as a second-generation antifungal agent, is commonly used in the immunocompromised setting as both a therapeutic and prophylactic agent. Since 2009, scattered case reports and small case series have detailed a secondary drug-related hyperfluorosis-induced painful periostitis that can occur in the treated patient population. We present a pictorial review of the thoracic imaging manifestations utilizing 3 illustrative cases in the setting of both solid organ and bone marrow transplantation. Knowledge of the relatively characteristic radiographic appearance and distribution, when coupled with the appropriate clinical context and associated laboratory findings, is important in narrowing an otherwise relatively broad differential diagnosis.

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.

Reversible skeletal disease and high fluoride serum levels in hematologic patients receiving voriconazole.

We here investigate the occurrence of fluoride intake-associated alterations in patients with hematologic disease on triazol antifungal medication. Clinical, laboratory, and radiology data of overall 43 patients with hematologic malignancies taking voriconazole (n = 20), posaconazole (n = 8), and itraconazole (n = 4), and a hematologic patient control group (n = 11) are described. Bone pain and radiologic evidence of periostitis were exclusively observed in patients receiving long-term voriconazole. Cessation of treatment led to clinical improvement in all cases. In line with clinical evidence, fluoride serum concentration was elevated in patients receiving voriconazole (median, 156.5 µg/L; interquartile range, 96.8 µg/L; normal < 30 µg/L) but not in the other treatment groups (P < .001 for all comparisons vs voriconazole). We conclude that serum fluoride levels were elevated on average 5-fold above normal levels in hematologic patients receiving voriconazole. Clinically relevant skeletal disease was associated with renal insufficiency and above 10-fold elevated fluoride levels, and was reversible on termination of voriconazole treatment.

Voriconazole-associated soft tissue ossification: an undescribed cause of glenohumeral joint capsulitis.

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.

Voriconazole-Induced Periostitis: A Mimicker of Skeletal Coccidioidomycosis.

BACKGROUND Coccidioidomycosis is caused by the fungi Coccidioides immitis and Coccidioides posadasii, which are endemic to the southwestern United States and other countries of the Western Hemisphere. Pulmonary coccidioidomycosis is the most common form of coccidioidomycosis. Rarely, coccidioidal infection disseminates to meninges, bones, skin, and soft tissues. While fluconazole remains the first line of treatment and is used for most patients, voriconazole is used in selected refractory cases of coccidioidomycosis. Voriconazole has more fluorine molecules than other azoles, and over time the fluorine molecules in voriconazole can cause disorganized bone formation in the periosteal region (periostitis), causing generalized bony pain, and radiographically can mimic skeletal coccidioidomycosis. While voriconazole-induced periostitis has been noted in aspergillosis and other infections, it has not been reported commonly in patients with coccidioidomycosis. CASE REPORT We present a case of a 50-year-old female patient with a diagnosis coccidioidal meningitis who was refractory to fluconazole and was treated with voriconazole. She presented with bony pain, which was initially radiographically attributed to multifocal skeletal coccidioidal infection. Reflecting upon the patient's history and serum levels of fluoride and bone alkaline phosphatase, a diagnosis of voriconazole-induced periostitis was made. Discontinuation of the voriconazole resulted in resolution of the periostitis. CONCLUSIONS Voriconazole-induced periostitis should be considered in patients with musculoskeletal pain with a history of voriconazole treatment or with laboratory abnormalities, such as elevated fluoride levels and/or bone alkaline phosphatase. Discontinuation of voriconazole reverses the condition promptly.

Voriconazole-induced periostitis in a patient with HIV treated for coccidioidomycosis meningitis.

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.

Voriconazole-induced periostitis causing arthralgias mimicking a flare of granulomatosis with polyangiitis.

We describe a case of voriconazole-induced periostitis that occurred in a 68-year-old woman with granulomatosis with polyangiitis. Our patient presented with months of severe hip pain limiting her daily activities, which was initially felt to be a flare of her granulomatosis with polyangiitis. However, upon further review, she had an elevated alkaline phosphatase and periostitis on her hip radiograph; voriconazole was held, and within 2 days she had marked improvement in her pain. Although this clinical syndrome is well documented in transplant patients, it is a rare complication in patients with autoimmune disorders. However, it is important because it may cause severe arthralgias that can mimic a flare of rheumatic diseases.