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 Table of Contents  
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 133-136

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

Department of Spine Surgery, Lilavati Hospital and Research Center, Mumbai, Maharashtra, India

Date of Submission10-Jan-2021
Date of Decision15-Apr-2021
Date of Acceptance21-Jun-2021
Date of Web Publication02-Feb-2022

Correspondence Address:
Alok Jain
Department of Spine Surgery, Lilavati Hospital and Research Center, Mumbai, Maharashtra.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ISJ.ISJ_8_21

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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.

Keywords: Aspergillus, fungal spondylodiscitis, periostitis, voriconazole

How to cite this article:
Jain A, Kashikar A, Nagad PB, Bhojraj SY. A rare case of voriconazole-induced vertebral periostitis in a patient with invasive aspergillus spondylodiscitis. Indian Spine J 2022;5:133-6

How to cite this URL:
Jain A, Kashikar A, Nagad PB, Bhojraj SY. A rare case of voriconazole-induced vertebral periostitis in a patient with invasive aspergillus spondylodiscitis. Indian Spine J [serial online] 2022 [cited 2022 May 25];5:133-6. Available from: https://www.isjonline.com/text.asp?2022/5/1/133/337148

  Introduction Top

Spondylodiscitis caused by invasive aspergillosis (IA) is a rare condition and usually occurs in immunocompromised subjects. Voriconazole is recommended as the first-line therapy for treatment or prophylaxis for IA,[1] but its long-term use is associated with multiple adverse effects, of which painful periostitis is one of the recently reported rare complications.[2] It usually affects clavicles, ribs, scapula, acetabulum, and hands.[3],[4] To our knowledge, periostitis affecting the vertebral body has not been reported till date, and it may be the first case of voriconazole-induced vertebral periostitis in a known case of IA spondylodiscitis under treatment.

  Case Report Top

A 66-year-old male patient presented with severe mid backache for nine months and significant weight loss (10 kg in four months). He was barely able to stand or walk for more than two minutes. Neurologically, there was no motor or sensory deficit. During these nine months, he underwent multiple spine magnetic resonance imaging (MRI) showing multilevel dorsal spondylodiscitis with no cord compression [Figure 1]. Two consecutive computed tomography (CT)-guided biopsies were done, which proved inconclusive. A trial of empirical anti-Koch’s and broad-spectrum antibiotic therapy was initiated, but there was no improvement.
Figure 1: T1 and T2WI sagittal, coronal STIR magnetic resonance image: multilevel dorsal spine spondylodiscitis involving intervertebral disc and vertebral body D5–D10

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Considering the previously failed biopsies, an open biopsy with D9–D10 hemilaminectomy was done, which revealed positive fungal growth of Aspergillus flavus, and potassium hydroxide staining showed septate fungal hyphae.

Based on the biopsy, oral voriconazole was started (200 mg twice daily), and serum voriconazole levels were monitored at a four-week interval. The voriconazole level was maintained between 2 and 4.5 mg/L. Gradually, the patient showed clinical and radiological improvement. By the end of eight months, the patient could stand and walk for thirty minutes, and an MRI showed significant resolution of soft-tissue and bone marrow edema [Figure 2]. Serologically also, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) reached baseline values.
Figure 2: T2WI sagittal magnetic resonance image eight months after starting voriconazole, showing resolving bone marrow and soft-tissue edema

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However, by the end of nine months of the treatment, the patient’s symptom again started deteriorating, that is, the mid back pain recurred with increased severity and intensity without any radicular symptoms.

Voriconazole-refractory fungal infection was thought of, which could be attributed to:

  • Misdiagnosis or coinfection with another mold

  • Inadequate voriconazole blood levels

  • Voriconazole-induced periostitis.

  • Repeat MRI showed increased bone marrow and soft-tissue edema [Figure 3]. CRP (49 mg/L), ESR (75 mm/h), and alkaline phosphatase (ALP) levels were elevated.
    Figure 3: T2WI sagittal magnetic resonance image showing an increase in bony- and soft-tissue changes in the involved dorsal spine as compared to the previous magnetic resonance imaging shown in [Figure 2]. There is enhancing marrow edema at D3–D6 with D9–D11 endplate and paravertebral enhancing granulation tissue

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    Repeat CT-guided biopsy ruled out coinfection or misdiagnosis, as a culture was negative for Mycobacterium tuberculosis, aerobic, anaerobic, and fungal infections. Moreover, histopathology revealed no granuloma or fungal element (negative periodic acid-Schiff stain). In addition, the serum voriconazole level was maintained (2.43 mg/L), which ruled out the possibility of inadequate serum voriconazole level as well.

    Further investigations showed an elevated serum fluoride level of 8.9 µmol/L (normal: 0.0–4.0 µmol/L) and ALP above 1000 IU/L (normal <130 IU/L) and raised serum beta galactomannan assay (2.3), indicating voriconazole-induced periostitis as a possibility. Based on the literature review,[5] the patient was advised to stop antifungal treatment along with bed rest. A four-week follow-up showed significant clinical improvement with a reduced level of inflammatory marker (CRP, 9.9 mg/L).

    Four months after discontinuing voriconazole, there was no mid back pain, and the patient regained 10 kg weight and could walk comfortably. Repeat MRI showed near-complete resolution of soft-tissue and bone marrow edema [Figure 4].
    Figure 4: T2WI sagittal magnetic resonance image showing near-complete resolution of soft-tissue and vertebral changes and resolution of marrow edema with fatty marrow replacement as compared to magnetic resonance image shown in [Figure 3]

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      Discussion Top

    Voriconazole is a highly fluorinated, third-generation antifungal.[1] One of the rare complications of its long-term use is painful periostitis.[6] Wang et al. reported the first-ever case of voriconazole-induced periostitis in 2009.[3]

    The mechanism by which voriconazole induces periostitis is similar, as in fluorosis. Its structure contains three fluorine atoms that, on hepatic metabolism, increase unbound fluoride levels.[3],[7] This fluoride, when present in large quantities, replaces hydroxyapatite in the bone extracellular matrix as fluorapatite. Fluorapatite, in turn, stimulates the osteoblastic activity, leading to periosteal bone formation and periostitis.[8]

    Moon et al.[5] and Wermers et al.[7] also found in their studies high levels of serum fluoride in patients with periostitis, supporting fluorosis as the mechanism of voriconazole-induced periostitis. They also suggested that monitoring serum fluoride level during voriconazole therapy can help in predicting the development of periostitis. In our case too, serum fluoride was elevated (8.9 µmol/L) when vertebral body periostitis developed, supporting the theory of fluorosis as the mechanism.

    Wang et al. suggested a 13% incidence of periostitis related to fluoride toxicity with long-term voriconazole.[3] However, till date, there has been no reported case in the literature showing vertebral involvement. This may be the first-ever reported case of voriconazole-induced periostitis in multiple vertebral body levels.

    Some of the other conditions that result in multifocal periosteal reaction include hypertrophic osteoarthropathy, thyroid acropachy, venous stasis, and hypervitaminosis A. However, hypertrophic osteoarthropathy arises during adolescence, which symmetrically involves the forearm and legs, and is associated with digital clubbing.[7],[9] Thyroid acropachy only occurs after the treatment of Graves’ disease and usually affects the short tubular bones of the hands and feet,[9] whereas venous stasis apart from periostitis is associated with phlebitis in the lower extremities.[9] Hypervitaminosis A most commonly affects the ulna and metatarsals, and mostly it is unilateral.[10] None of these characteristics were seen in our patient, and therefore, these diagnoses were felt to be less probable.

    In our case, a patient of known IA spondylodiscitis was on voriconazole treatment (for nine months) and showed gradual improvement, but later, the patient started deteriorating clinically, serologically, and radiologically. Differential diagnoses of relapse, coinfection, and voriconazole-induced periostitis were suspected. Repeat CT biopsy showed inconclusive histopathology and negative culture, ruling out the possibility of relapse or coinfection.

    Various studies have manifested that voriconazole-induced periostitis is reversible with the discontinuation of the drug.[5],[7] With this suspicion, an elective trial to stop voriconazole was pursued. The patient showed rapid improvement clinically within four weeks and improved radiology within four months.

    Raised serum fluoride level (8.9 µmol/L) during therapy and a favorable response after discontinuation of treatment strongly support voriconazole-induced periostitis as our most probable diagnosis.

      Conclusion Top

    Clinicians and spine surgeons should be aware of the fact that long-term voriconazole treatment of IA 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 discontinuing voriconazole should be considered.

    Declaration of patient consent

    The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


    We would like to thank Dr. Vasant Nagvekar (MD, Infectious Disease Specialist, Lilavati Hospital, Mumbai) for his valuable contribution and guidance throughout the management for this case report.

    Financial support and sponsorship


    Conflicts of interest

    There are no conflicts of interest.

      References Top

    Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016;63:e1-e60.  Back to cited text no. 1
    Ayub A, Kenney CV, McKiernan FE Multifocal nodular periostitis associated with prolonged voriconazole therapy in a lung transplant recipient. J Clin Rheumatol 2011;17:73-5.  Back to cited text no. 2
    Wang TF, Wang T, Altman R, Eshaghian P, Lynch JP 3rd, Ross DJ, et al. Periostitis secondary to prolonged voriconazole therapy in lung transplant recipients. Am J Transplant 2009;9:2845-50.  Back to cited text no. 3
    Lustenberger DP, Granata JD, Scharschmidt TJ Periostitis secondary to prolonged voriconazole therapy in a lung transplant recipient. Orthopedics 2011;34:e793-6.  Back to cited text no. 4
    Moon WJ, Scheller EL, Suneja A, Livermore JA, Malani AN, Moudgal V, et al. Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain. Clin Infect Dis 2014;59:1237-45.  Back to cited text no. 5
    U.S. Food and Drug Administration. Highlights of prescribing information. Available from: www.accessdata.fda.gov/drugsatfda_docs/label/2017/021266s041,021267s053,021630s031lbl.pdf. [Last accessed on September 24, 2018].  Back to cited text no. 6
    Wermers RA, Cooper K, Razonable RR, Deziel PJ, Whitford GM, Kremers WK, et al. Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy. Clin Infect Dis 2011;52:604-11.  Back to cited text no. 7
    Whyte MP, Totty WG, Lim VT, Whitford GM Skeletal fluorosis from instant tea. J Bone Miner Res 2008;23:759-69.  Back to cited text no. 8
    Bucknor MD, Gross AJ, Link TM Voriconazole-induced periostitis in two post-transplant patients. J Radiol Case Rep 2013;7:10-7.  Back to cited text no. 9
    Sidhu HS, Venkatanarasimha N, Bhatnagar G, Vardhanabhuti V, Fox BM, Suresh SP Imaging features of therapeutic drug-induced musculoskeletal abnormalities. Radiographics 2012;32:105-27.  Back to cited text no. 10


      [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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