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Voriconazole-induced arthritis, enthesitis and periostitis. PROCEEDINGS OF SINGAPORE HEALTHCARE 2023. [DOI: 10.1177/20101058221149575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
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.
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Guarascio AJ, Bhanot N, Min Z. Voriconazole-associated periostitis: Pathophysiology, risk factors, clinical manifestations, diagnosis, and management. World J Transplant 2021; 11:356-371. [PMID: 34631468 PMCID: PMC8465512 DOI: 10.5500/wjt.v11.i9.356] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/19/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
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.
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Affiliation(s)
- Anthony J Guarascio
- Department of Pharmacy, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, United States
| | - Nitin Bhanot
- Division of Infectious Disease, Medicine Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, United States
| | - Zaw Min
- Division of Infectious Disease, Medicine Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, United States
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Review of Pharmacologic Considerations in the Use of Azole Antifungals in Lung Transplant Recipients. J Fungi (Basel) 2021; 7:jof7020076. [PMID: 33499209 PMCID: PMC7911495 DOI: 10.3390/jof7020076] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 12/15/2022] Open
Abstract
Mold-active azole antifungals are commonly prescribed for the prevention of invasive fungal infections in lung transplant recipients. Each agent exhibits a unique pharmacologic profile, an understanding of which is crucial for therapy selection and optimization. This article reviews pharmacologic considerations for three frequently-used azole antifungals in lung transplant recipients: voriconazole, posaconazole, and isavuconazole. Focus is drawn to analysis of drug-interactions, adverse drug reactions, pharmacokinetic considerations, and the role of therapeutic drug monitoring with special emphasis on data from the post-lung transplant population.
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Elmore S, Wisse A, Chapin RW, Whelan TP, Silver RM. Voriconazole-associated periostitis presenting as hypertrophic osteoarthropathy following lung transplantation report of two cases and review of the literature. Semin Arthritis Rheum 2019; 49:319-323. [PMID: 31103239 DOI: 10.1016/j.semarthrit.2019.04.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/17/2019] [Accepted: 04/22/2019] [Indexed: 01/30/2023]
Abstract
BACKGROUND Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of skin and osseous tissue frequently associated with underlying pulmonary disorders. Cardinal features include digital clubbing, periostitis and significant joint and bone pain. A number of recent reports have emerged of HOA and periostitis occurring in association with the antifungal agent voriconazole. METHODS We present two additional cases of voriconazole-induced HOA and periostitis in lung transplant recipients with a review the medical literature. RESULTS In both cases, symptoms were painful and severe enough to require opioid medication. Rapid improvement occurred within days of voriconazole cessation. A review of existing literature revealed an additional 17 cases of voriconazole-induced HOA and periostitis in lung transplant patients. CONCLUSION We highlight the importance of recognizing the association of voriconazole with painful HOA and periostitis in lung transplant patients receiving antifungal therapy. Management of this painful condition involves cessation of voriconazole therapy, which may necessitate alternative anti-fungal drug therapies as well as adjustment of immunosuppressive drug dosage since voriconazole is a strong drug-inducer.
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Affiliation(s)
- Stephen Elmore
- Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 822, Charleston, SC 29401, USA
| | - Amy Wisse
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical University of South Carolina, Charleston, SC 29401, USA
| | - Russell W Chapin
- Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC 29401, USA
| | - Timothy P Whelan
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical University of South Carolina, Charleston, SC 29401, USA
| | - Richard M Silver
- Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 822, Charleston, SC 29401, USA.
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Spectrum of Voriconazole-Induced Periostitis With Review of the Differential Diagnosis. AJR Am J Roentgenol 2018; 212:157-165. [PMID: 30403528 DOI: 10.2214/ajr.18.19991] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
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.
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Sircar M, Kotton C, Wojciechowski D, Safa K, Gilligan H, Heher E, Williams W, Thadhani R, Tolkoff-Rubin N. Voriconazole-Induced Periostitis & Enthesopathy in Solid Organ Transplant Patients: Case Reports. ACTA ACUST UNITED AC 2016; 4:8-17. [PMID: 27990445 PMCID: PMC5158005 DOI: 10.4236/jbm.2016.411002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background Voriconazole 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. Aim Here we present two cases of voriconazole-induced periostitis in solid organ transplant patients. Case Presentation Voriconazole 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. Conclusions Voriconazole 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.
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Affiliation(s)
- Monica Sircar
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Camille Kotton
- Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - David Wojciechowski
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Kassem Safa
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Hannah Gilligan
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Eliot Heher
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Winfred Williams
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Ravi Thadhani
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Nina Tolkoff-Rubin
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
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Voriconazole-induced periostitis: a new rheumatic disorder. Clin Rheumatol 2016; 36:609-615. [DOI: 10.1007/s10067-016-3341-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 06/22/2016] [Accepted: 06/22/2016] [Indexed: 02/04/2023]
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Rheinboldt M, Delproposto Z, Agarwal R. Voriconazole-induced periostitis post transplant: an illustrative review of thoracic computed tomography imaging manifestations. Transpl Infect Dis 2015; 17:859-63. [DOI: 10.1111/tid.12451] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 06/29/2015] [Accepted: 08/13/2015] [Indexed: 11/30/2022]
Affiliation(s)
- M. Rheinboldt
- Department of Radiology; Henry Ford Hospital; Detroit Michigan USA
| | - Z. Delproposto
- Department of Radiology; Henry Ford Hospital; Detroit Michigan USA
| | - R. Agarwal
- Department of Radiology; Northwestern University Hospital; Chicago Illinois USA
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Skaug M, Spak C, Oza U. Painful periostitis in the setting of chronic voriconazole therapy. Proc (Bayl Univ Med Cent) 2014; 27:350-2. [PMID: 25484509 DOI: 10.1080/08998280.2014.11929156] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
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.
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Affiliation(s)
- Margaret Skaug
- Department of Radiology (Skaug, Oza) and Division of Infectious Diseases, Department of Internal Medicine (Spak), Baylor University Medical Center at Dallas
| | - Cedric Spak
- Department of Radiology (Skaug, Oza) and Division of Infectious Diseases, Department of Internal Medicine (Spak), Baylor University Medical Center at Dallas
| | - Umesh Oza
- Department of Radiology (Skaug, Oza) and Division of Infectious Diseases, Department of Internal Medicine (Spak), Baylor University Medical Center at Dallas
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Raghavan M, Hayes A. Voriconazole-associated soft tissue ossification: an undescribed cause of glenohumeral joint capsulitis. Skeletal Radiol 2014; 43:1301-5. [PMID: 24699891 DOI: 10.1007/s00256-014-1865-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 02/07/2014] [Accepted: 03/05/2014] [Indexed: 02/02/2023]
Abstract
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.
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Affiliation(s)
- Meera Raghavan
- Department of Diagnostic Imaging, Musculoskeletal Radiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA,
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Moon WJ, Scheller EL, Suneja A, Livermore JA, Malani AN, Moudgal V, Kerr LE, Ferguson E, Vandenberg DM. Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain. Clin Infect Dis 2014; 59:1237-45. [PMID: 24992954 DOI: 10.1093/cid/ciu513] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
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.
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Affiliation(s)
- Woo J Moon
- Department of Internal Medicine, St Joseph Mercy Hospital
| | - Erica L Scheller
- Department of Molecular and Integrative Physiology, University of Michigan
| | - Anupam Suneja
- Department of Internal Medicine, St Joseph Mercy Hospital
| | | | - Anurag N Malani
- Department of Internal Medicine, St Joseph Mercy Hospital Section of Infectious Diseases
| | - Varsha Moudgal
- Department of Internal Medicine, St Joseph Mercy Hospital Section of Infectious Diseases
| | - Lisa E Kerr
- Department of Pharmacy, St Joseph Mercy Hospital, Ann Arbor, Michigan
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