Voriconazole-Associated Periostitis: New Insights into Pathophysiology and Management.

Michael J Bennett,Syndia Lazarus,Siok Tey,Matthew I Balcerek,Steven Faux,Laila Girgis,Jerry R Greenfield,Caroline Bachmeier,Roland Ll Zhang,Edward Ad Lewis

doi:10.1002/jbm4.10557

Abstract

ABSTRACTVoriconazole‐associated periostitis (VAP) is an underrecognized and unpredictable side effect of long‐term voriconazole therapy. We report two cases of VAP occurring in the post‐transplant setting: a 68‐year‐old lung transplant recipient who required ongoing voriconazole therapy, in whom urinary alkalinization was used to promote fluoride excretion and minimize voriconazole‐related skeletal toxicity, and a 68‐year‐old stem‐cell transplant recipient with a high voriconazole dose requirement, identified on pharmacogenomic testing to be a CYP2C19 ultrarapid metabolizer, the dominant enzyme in voriconazole metabolism. This is the first reported case of pharmacogenomic profiling in VAP and may explain the variability in individual susceptibility to this uncommon adverse effect. Our findings provide new insights into both the management and underlying pathophysiology of VAP. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Highlights

Voriconazole is a frequently used antifungal in the post-transplant setting and has been associated with periostitis with long-term use.[1]
Excess fluoride exposure has deleterious cellular, mineral, and hormonal effects on bone (Fig. 5). {FIG5} Fluoride has anabolic effects, stimulating osteoblasts to make excessive unpermineralized bone, which accumulates in the periosteal/ endosteal regions.[11]. Deposition of fluorapatite results in denser but brittle bone matrix that is resistant to resorption.[9,12]
Discontinuing voriconazole is the only curative treatment for voriconazole-associated periostitis (VAP), with symptom resolution usually occurring within 2 months post-cessation.[5]. Supportive care involves analgesia, correction of malnutrition, and treatment of hyperparathyroidism with calcium/calcitriol

Summary

Introduction

Voriconazole is a frequently used antifungal in the post-transplant setting and has been associated with periostitis with long-term use.[1] The true prevalence of voriconazole-associated periostitis (VAP) is unknown; retrospective studies suggest this adverse effect may occur in up to 15% of patients on voriconazole.[1,2,3] Risk factors for developing VAP are poorly understood, and treatment options are limited. VAP shares common clinical features with subacute fluoride intoxication, including generalized bone pain, raised alkaline phosphatase (ALP), diffuse periostitis/exostoses on X-ray, and multifocal uptake on radionuclide bone scintigraphy.[2,4,5,6,7]. Discontinuation of voriconazole rapidly normalizes plasma fluoride concentration and resolves clinical and radiological features;(2,5,6) cessation is not always feasible. We report two cases with unique insights into VAP pathophysiology and management

Patient 1

Patient 2

Findings

Discussion