Voriconazole-Associated Periostitis: New Insights into Pathophysiology and Management

Abstract

Voriconazole-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.

Keywords: MATRIX MINERALIZATION (BONE MATRIX); OTHER (DISEASES AND DISORDERS OF/RELATED TO BONE); PHARMACOGENOMICS (GENETIC RESEARCH).

Fig. 1

Radiological changes evident 21 months post‐transplant (patient 1). Areas of thick periosteal reaction (arrows) were evident on the middle and proximal phalanges and second metacarpal of the right hand (left image) and right proximal radial shaft (right image).

Fig. 2

Serial technetium‐labeled bone scintigraphy (patient 1) performed in the months after onset of skeletal pain. Images show the emergence and progression of multiple areas of abnormal tracer uptake affecting the vertebrae (thoracic and lumbar), bilateral shoulders, elbows, pelvis, femora, tibias, hands, knees, and mid‐foot joints. In a number of regions, increased uptake corresponded to areas of periosteal new bone formation.

Fig. 3

Plasma fluoride concentration and voriconazole dose versus time from commencement of urinary alkalinization for patient 1. Pretreatment plasma fluoride concentration is unknown (represented by the gray dotted line).

Fig. 4

Serum voriconazole concentration from time of commencement of voriconazole for patient 2. Serum voriconazole levels were persistently subtherapeutic and pain onset occurred 6 weeks after dose escalation.

Fig. 5

Proposed pathophysiological model incorporating case‐specific factors.