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

Alok Jain; Aaditya Kashikar; Premik B Nagad; Shekhar Y Bhojraj

doi:10.4103/ISJ.ISJ_8_21

CASE REPORTS

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

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

Alok Jain, Aaditya Kashikar, Premik B Nagad, Shekhar Y Bhojraj
Department of Spine Surgery, Lilavati Hospital and Research Center, Mumbai, Maharashtra, India

Date of Submission	10-Jan-2021
Date of Decision	15-Apr-2021
Date of Acceptance	21-Jun-2021
Date of Web Publication	02-Feb-2022

Correspondence Address:
Alok Jain
Department of Spine Surgery, Lilavati Hospital and Research Center, Mumbai, Maharashtra.
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ISJ.ISJ_8_21

Abstract

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

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

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

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

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.

Acknowledgement

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

Nil.

Conflicts of interest

There are no conflicts of interest.

References

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