Voriconazole-induced Periostitis Research Articles

Associations of cumulative voriconazole dose, treatment duration, and alkaline phosphatase with voriconazole-induced periostitis.

To investigate the associations of cumulative voriconazole dose, treatment duration, and alkaline phosphatase with voriconazole-induced periostitis. One hundred and thirty-one patients with voriconazole use were identified using a clinical informatics tool. Health record data including age, sex, immune status, alkaline phosphatase, voriconazole levels, voriconazole dose, frequency, and treatment duration were collected. Imaging studies during the duration of treatment were reviewed by two radiology trainees and imaging features of voriconazole-induced periostitis were confirmed by a board-certified musculoskeletal radiologist. The length, location in the body, location in the bone, type, and morphology of periostitis lesions were recorded. Incident voriconazole-induced periostitis was defined as new periostitis on imaging after 28days or more of voriconazole treatment in the absence of an alternative diagnosis. Univariate Firth's logistic regression models were performed using cumulative voriconazole dose, treatment duration, and average ALP as predictors and incident VIP as the outcome. There were nine patients with voriconazole-induced periostitis and 122 patients without voriconazole-induced periostitis. The most common lesion location in the body was the ribs (37%) and morphology was solid (44%). A 31.5-g increase in cumulative voriconazole dose was associated with 8% higher odds of incident periostitis. Increased treatment duration (63days) and higher average alkaline phosphatase (50IU/L) were associated with 7% higher odds of periostitis and 34% higher odds of periostitis, respectively. Increased cumulative voriconazole dose, treatment duration, and average alkaline phosphatase were associated with higher odds of voriconazole-induced periostitis.

Voriconazole-Induced Periostitis in a Patient after Orthotopic Liver Transplantation.

Voriconazole-Induced Periostitis in a Patient after Orthotopic Liver Transplantation.

Voriconazole-induced periostitis in a lung transplant recipient

Voriconazole-induced periostitis in a lung transplant recipient

Voriconazole-induced arthritis, enthesitis and periostitis

Voriconazole is a fluoride-containing anti-fungal. Prolonged exposure can result in fluoride deposition within the bone extracellular matrix, resulting in periostitis and arthritis. We report a patient who developed widespread bony pain and polyarthralgia while on voriconazole therapy for COVID-19-associated pulmonary aspergillosis. No associated autoimmune rheumatic disease or alternative cause was noted. Blood investigations showed elevated total serum alkaline phosphatase, bone-specific ALP and fluoride levels, with normal serum voriconazole levels. A whole body nuclear bone scan showed multifocal periostitis. A diagnosis of voriconazole-induced periostitis and arthritis was made. Complete resolution of clinical symptoms with normalisation of the serum ALP occurred within four weeks of voriconazole cessation. While voriconazole-induced periostitis/arthritis is a recognised phenomenon in solid organ and haematopoietic stem cell transplant patients on long-term voriconazole, this case highlights the importance of having a high index of suspicion in other settings including CAPA. Clinical presentation can be mistaken for bony metastatic disease or other inflammatory arthritis.

Spectrum of voriconazole-associated periostitis in clinical characteristics, diagnosis and management.

Previous knowledge about the relationship between voriconazole exposure and periostitis was mainly based on limited case reports and few retrospective studies. The purpose of this study was to assess the clinical characteristics, diagnosis and management of voriconazole-associated periostitis. Case reports and case series from 1998 to November 30, 2021 on periostitis induced by voriconazole were collected for retrospective analysis. Forty four patients (18 male and 26 female) from 34 studies were includedin total. The median age was 58years (29-74). The majority of patients had undergone organ transplantation (50.0%) or suffered from hematologic malignancy (31.81%). The median onset time of symptoms was 6months after the start of voriconazole. The most common initial symptom was diffuse skeletal pain (68.28%) which can be severe and even disabling (66.7%). Ribs (37.21%), femurs (32.56%), scapulae (25.58%), humerus (23.26%), and clavicle (23.26%) were the common involved locations. Most cases were accompanied by different degrees of elevated serum alkaline phosphatase and fluoride level, while some presented with elevated bone-specific alkaline phosphatase. The main radiological features included periosteal reaction and multifocal high radiotracer uptake on bone scintigraphy. The formation of new bone was characterized with bilateral, irregular, nodular, as well as high density. The resolution of symptoms was observed with discontinuation of voriconazole in all patients, of whom 18 patients (52.94%) were relieved within a week. Itraconazole, posaconazole or isavuconazole were safe alternatives to voriconazole in voriconazole-induced periostitis. Voriconazole-induced periostitis is an infrequent complication characterized by bone inflammation involving one or multiple skeletal areas. Bony pain, elevated serum alkaline phosphatase as well as fluoride level are suspicious signs during voriconazole treatment.

A rare case of voriconazole-induced vertebral periostitis in a patient with invasive aspergillus spondylodiscitis

The author illustrates the first ever reported case of voriconazole-induced periostitis of vertebral body. A 66-year-old immunocompetent male patient was diagnosed with multilevel invasive aspergillus spondylodiscitis of dorsal spine and was put on long-term voriconazole therapy for the same. Initially, the patient showed a good response to treatment but later on paradoxically the patient started to deteriorate symptomatically as well as radiologically. Differential diagnosis of misdiagnosis or co-in­fection with an another mold, inadequate voriconazole blood levels, voriconazole-induced periostitis were thought. After a detailed radiological and serological investigation, the patient was diagnosed with voriconazole-induced vertebral periostitis. Based on thorough literature review, discontinuation of voriconazole therapy was opted as treatment. Clinically, the patient started improving within four weeks of cessation of therapy and was symptom-free by the end of four months. Hence, to conclude, clinicians and spine surgeons should be aware of the fact that long-term voriconazole treatment of invasive aspergillosis can be complicated by skeletal fluorosis and painful periostitis. Once the symptoms of periostitis develop, investigations such as skeletal imaging and measurement of serum fluoride levels should be performed and if periostitis deformans is confirmed, reducing the dose or ceasing voriconazole should be considered.

Voriconazole-associated periostitis: Pathophysiology, risk factors, clinical manifestations, diagnosis, and management.

Voriconazole use has been associated with osteoarticular pain and periostitis, likely due to high fluoride content in the drug formulation. This phenomenon has been described primarily with high dosage or prolonged course of voriconazole therapy in immunocompromised and transplant patient populations. Patients typically present with diffuse bony pains associated with elevated serum alkaline phosphatase and plasma fluoride levels in conjunction with radiographic findings suggestive of periostitis. We provide a comprehensive review of the literature to highlight salient characteristics commonly associated with voriconazole-induced periostitis.

Voriconazole-Induced Periostitis Presenting as Diffuse Myalgias (5048)

Voriconazole-Induced Periostitis Presenting as Diffuse Myalgias (5048)

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

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. 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.

Voriconazole-induced phototoxicity, malignancy, and periostitis in a child with autosomal dominant hyper-IgE syndrome

Voriconazole-induced phototoxicity, malignancy, and periostitis in a child with autosomal dominant hyper-IgE syndrome

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

The original version of this paper unfortunately contained mistakes in the affiliations for all authors.

Voriconazole-Induced Periostitis: A Radiographic Progression

We present a case of incidentally discovered Voriconazole-induced periostitis in a patient with chronic lymphocytic leukemia. Voriconazole was initiated approximately two years prior to the periostitis discovery on a chest CT for acute on chronic respiratory failure. Because of the asymptomatic nature of the periostitis and its slow development, it was not reported on imaging for over two years. The periostitis was followed retrospectively over a two-year span from the patient’s surveillance imaging. Although there are several cases of periostitis from chronic Voriconazole use in the literature, this case is made unique in its asymptomatic presentation, allowing for a visual display of periostitis progression over two years. This case highlights the fact that Voriconazole-induced periostitis can be asymptomatic and should, therefore, be readily recognized and include a comprehensive differential.

Hypertrophic Osteoarthropathy: Clinical and Imaging Features.

Hypertrophic osteoarthropathy (HOA) is a medical condition characterized by abnormal proliferation of skin and periosteal tissues involving the extremities and characterized by three clinical features: digital clubbing (also termed Hippocratic fingers), periostosis of tubular bones, and synovial effusions. HOA can be a primary entity, known as pachydermoperiostosis, or can be secondary to extraskeletal conditions, with different prognoses and management implications for each. There is a high association between secondary HOA and malignancy, especially non-small cell lung cancer. In such cases, it can be considered a form of paraneoplastic syndrome. The most prevalent secondary causes of HOA are pulmonary in origin, which is why this condition was formerly referred to as hypertrophic pulmonary osteoarthropathy. HOA can also be associated with pleural, mediastinal, and cardiovascular causes, as well as extrathoracic conditions such as gastrointestinal tumors and infections, cirrhosis, and inflammatory bowel disease. Although the skeletal manifestations of HOA are most commonly detected with radiography, abnormalities can also be identified with other modalities such as computed tomography, magnetic resonance imaging, and bone scintigraphy. The authors summarize the pathogenesis, classification, causes, and symptoms and signs of HOA, including the genetics underlying the primary form (pachydermoperiostosis); describe key findings of HOA found at various imaging modalities, with examples of underlying causative conditions; and discuss features differentiating HOA from other causes of multifocal periostitis, such as thyroid acropachy, hypervitaminosis A, chronic venous insufficiency, voriconazole-induced periostitis, progressive diaphyseal dysplasia, and neoplastic causes such as lymphoma. ©RSNA, 2016.

Voriconazole-Induced Periostitis & Enthesopathy in Solid Organ Transplant Patients: Case Reports.

BackgroundVoriconazole is frequently used to treat fungal infections in solid organ transplant patients. Recently, there have been reports suggesting that prolonged voriconazole therapy may lead to periostitis.AimHere we present two cases of voriconazole-induced periostitis in solid organ transplant patients.Case PresentationVoriconazole was given to two transplant patients-one with a liver transplant and the second with a heart transplant, to treat their fungal infections. Both developed voriconazole-induced toxicity. While undergoing voriconazole therapy, they had incapacitating bone pain. The liver transplant patient had to be taken off voriconazole, and the heart transplant patient succumbed to non-voriconazole related causes.ConclusionsVoriconazole therapy in two solid organ transplant patients resulted in periostitis. We provide potential etiologies underlying voriconazole-induced periostitis, including fluoride toxicity, abnormalities in the pulmonary vascular bed leading to the production of downstream inflammatory mediators, and abnormal pharmacokinetics of hepatic drug metabolism. In addition to monitoring blood voriconazole trough levels, we suggest careful assessment for musculoskeletal pain in patients undergoing voriconazole treatment for two months or more, particularly if their daily dosages of voriconazole exceed 500 mg per day. Appropriate workup should include measurement of alkaline phosphatase, voriconazole trough and fluoride levels as well as a bone scan. Overall, early recognition of voriconazole-induced musculoskeletal toxicity is important for better morbidity outcomes.

Voriconazole Enhances the Osteogenic Activity of Human Osteoblasts In Vitro through a Fluoride-Independent Mechanism

Periostitis, which is characterized by bony pain and diffuse periosteal ossification, has been increasingly reported with prolonged clinical use of voriconazole. While resolution of clinical symptoms following discontinuation of therapy suggests a causative role for voriconazole, the biological mechanisms contributing to voriconazole-induced periostitis are unknown. To elucidate potential mechanisms, we exposed human osteoblasts in vitro to voriconazole or fluconazole at 15 or 200 μg/ml (reflecting systemic or local administration, respectively), under nonosteogenic or osteogenic conditions, for 1, 3, or 7 days and evaluated the effects on cell proliferation (reflected by total cellular DNA) and osteogenic differentiation (reflected by alkaline phosphatase activity, calcium accumulation, and expression of genes involved in osteogenic differentiation). Release of free fluoride, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) was also measured in cell supernatants of osteoblasts exposed to triazoles, with an ion-selective electrode (for free fluoride) and enzyme-linked immunosorbent assays (ELISAs) (for VEGF and PDGF). Voriconazole but not fluconazole significantly enhanced the proliferation and differentiation of osteoblasts. In contrast to clinical observations, no increases in free fluoride levels were detected following exposure to either voriconazole or fluconazole; however, significant increases in the expression of VEGF and PDGF by osteoblasts were observed following exposure to voriconazole. Our results demonstrate that voriconazole can induce osteoblast proliferation and enhance osteogenic activity in vitro. Importantly, and in contrast to the previously proposed mechanism of fluoride-stimulated osteogenesis, our findings suggest that voriconazole-induced periostitis may also occur through fluoride-independent mechanisms that enhance the expression of cytokines that can augment osteoblastic activity.

Painful Periostitis in the Setting of Chronic Voriconazole Therapy

A 72-year-old woman on chronic voriconazole therapy for recurrent histoplasmosis developed a painful forearm mass. Laboratory and imaging findings were consistent with a diffuse periostitis. Her symptoms resolved after discontinuation of voriconazole. To our knowledge, this is the first case of voriconazole-induced periostitis to be reported in a patient with chronic histoplasmosis.

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

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. 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. 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. 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.

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.

Voriconazole-induced periostitis in two post-transplant patients

While drug-related periostitis has been known of for many years, the specific association of diffuse periostitis with voriconazole (most frequently in transplant patients) has only been recently explicitly addressed in the literature. Recognition of the radiologic and clinical manifestations of voriconazole-related periostitis is important for helping to narrow an otherwise broad differential diagnosis. We present two cases that illustrate different radiologic presentations of this painful cause of diffuse periostitis. Case 1 features a 60 year-old woman with a history of orthotopic heart transplant who was hospitalized for "full body pain" with progressively worsening bone tenderness involving the humeri, knees, femurs, hips, and hands. Case 2 describes a 48 year-old man with a history of acute lymphoblastic leukemia status post stem cell transplant who presented with diffuse arthralgias involving bilateral ankles, knees, wrists, and elbows.

Erratum to: Voriconazole-induced periostitis

Erratum to: Voriconazole-induced periostitis