Bilateral leg pain and swelling with abnormal imaging findings in a patient with voriconazole

Hyeon Mu Jang; Hyeonwoo Kwon; Yunsuk Choi; Sung-Han Kim

doi:10.3904/kjim.2024.070

A 58-year-old female was admitted to a hospital for progressive both leg pain and swelling for 1 month. She has a history of myelofibrosis, transformed into acute myeloid leukemia, and received allogeneic hematopoietic stem cell transplantation (HSCT) 2 months ago. One month after HSCT, she was diagnosed as probable invasive pulmonary aspergillosis and received oral voriconazole. After 1 month of voriconazole therapy, she was admitted for progressive swelling and tenderness on both foot and ankle (around malleolus). Absolute neutrophil count was 2,000 u/L (reference value 2,500–7,000 u/L). The blood level of C-reactive protein was 13.6 mg/dL (reference value 0–0.6 mg/dL), creatine kinase 11 U/L (reference value 25–200 U/L), and alkaline phosphatase 351 IU/L (reference value 44–147 IU/L). Empirical cefazolin for possible cellulitis showed no improvement. Bilateral lower leg X-ray showed diffuse thin linear periosteal reaction in both tibia and fibula and diffuse soft tissue swelling in both lower legs (Fig. 1). Magnetic resonance imaging (MRI) of bilateral lower leg revealed diffuse high signal intensity and enhancement along the periosteum of tibia and fibula (Fig. 2).

What is the diagnosis?

DIAGNOSIS: VORICONAZOLE-ASSOCIATED PERIOSTITIS

Blood voriconazole level was 2.7 μg/mL (therapeutic range 1.0–6.0 μg/mL). Imaging suggested possible periostitis. After discontinuation of voriconazole, symptoms started to improve within a month and resolved in a year.

Voriconazole contains three fluoride atoms, when compared to posaconazole and fluconazole which contain two [1-3]. The previous study showed that voriconazole develops hyper-fluorosis, potentially associated with periostitis, whereas other azoles such as fluconazole and posaconazole has lower risk for this condition [4] The most common symptom for voriconazole-associated periostitis is localized diffuse bone pain [5-8]. Radiographs show periosteal reaction, periosteal bone formation and periosteal thickening [8]. Computed tomography reveals periosteal reaction and exostoses [9]. MRI showed thick and irregular periosteal edema along the outer cortical surfaces of the bilateral proximal femoral shafts indicative of periostitis [9-11]. Symptoms usually resolves after discontinuation of voriconazole.

Notes

CRedit authorship contributions

Hyeon Mu Jang: conceptualization, methodology, investigation, data curation, writing - original draft, writing - review & editing; Hyeonwoo Kwon: conceptualization, resources, investigation, data curation, writing - review & editing; Yunsuk Choi: writing - review & editing; Sung-Han Kim: conceptualization, resources, investigation, data curation, writing - review & editing, project administration

Conflicts of interest

The authors disclose no conflicts.

Funding

This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI23C0266).

Figure 1.

X-ray of right lower leg and foot X-ray. Diffuse thin linear reaction in tibia (arrow).

Figure 2.

Magnetic resonance imaging of the right lower leg and foot X-ray. Diffuse high signal intensity and enhancement along the periosteum of tibia (arrow).

REFERENCES

1. Chai S, Zhan JL, Zhao LM, Liu XD. Safety of triazole antifungals: a pharmacovigilance study from 2004 to 2021 based on FAERS. Ther Adv Drug Saf 2022;13:20420986221143266.

2. Wermers RA, Cooper K, Razonable RR, et al. Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy. Clin Infect Dis 2011;52:604–611.

3. Klatt ME, Eschenauer GA. Review of pharmacologic considerations in the use of azole antifungals in lung transplant recipients. J Fungi (Basel) 2021;7:76.

4. Thompson GR 3rd, Bays D, Cohen SH, Pappagianis D. Fluoride excess in coccidioidomycosis patients receiving long-term antifungal therapy: an assessment of currently available triazoles. Antimicrob Agents Chemother 2012;56:563–564.

5. Wang TF, Wang T, Altman R, et al. Periostitis secondary to prolonged voriconazole therapy in lung transplant recipients. Am J Transplant 2009;9:2845–2850.

6. Pampaloni MH. Voriconazole-associated periostitis in a heart transplant patient. J Clin Case Rep 2012;2:166.

7. Cormican S, Adams N, O’Connell P, McErlean A, de Freitas D. Voriconazole-induced periostitis deformans: serial imaging in a patient with ANCA vasculitis. Skeletal Radiol 2018;47:191–194.

8. Reber JD, McKenzie GA, Broski SM. Voriconazole-induced periostitis: beyond post-transplant patients. Skeletal Radiol 2016;45:839–842.

9. Li Z, Wu C, Wang C, Deng Z. Spectrum of voriconazole-associated periostitis in clinical characteristics, diagnosis and management. Infection 2022;50:1217–1224.

10. Davis DL. Voriconazole-related periostitis presenting on magnetic resonance imaging. Clin Cases Miner Bone Metab 2015;12:78–81.

11. Raghavan M, Hayes A. Voriconazole-associated soft tissue ossification: an undescribed cause of glenohumeral joint capsulitis. Skeletal Radiol 2014;43:1301–1305.