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Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplant. Sep 18, 2021; 11(9): 356-371
Published online Sep 18, 2021. doi: 10.5500/wjt.v11.i9.356
Voriconazole-associated periostitis: Pathophysiology, risk factors, clinical manifestations, diagnosis, and management
Anthony J Guarascio, Department of Pharmacy, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, United States
Nitin Bhanot, Zaw Min, Division of Infectious Disease, Medicine Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, United States
ORCID number: Anthony J Guarascio (0000-0001-9019-8847); Nitin Bhanot (0000-0002-9505-0910); Zaw Min (0000-0002-5708-954X).
Author contributions: Guarascio AJ and Min Z contributed equally to the initial version of paper; Bhanot N reviewed and revised the paper; all authors provided collaborative patient care, discussions, and full authorship of the manuscript.
Conflict-of-interest statement: All authors have no conflict-of-interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zaw Min, MD, Assistant Professor, Division of Infectious Disease, Medicine Institute, Allegheny General Hospital, Allegheny Health Network, 420 East North Avenue, Suite 407, Pittsburgh, PA 15212, United States. zaw.min@ahn.org
Received: April 7, 2021
Peer-review started: April 7, 2021
First decision: July 8, 2021
Revised: July 19, 2021
Accepted: August 27, 2021
Article in press: August 27, 2021
Published online: September 18, 2021

Abstract

Voriconazole use has been associated with osteoarticular pain and periostitis, likely due to high fluoride content in the drug formulation. This phenomenon has been described primarily with high dosage or prolonged course of voriconazole therapy in immunocompromised and transplant patient populations. Patients typically present with diffuse bony pains associated with elevated serum alkaline phosphatase and plasma fluoride levels in conjunction with radiographic findings suggestive of periostitis. We provide a comprehensive review of the literature to highlight salient characteristics commonly associated with voriconazole-induced periostitis.

Key Words: Voriconazole, Periostitis, Fluoride, Fluorosis, Alkaline phosphatase

Core Tip: Voriconazole-induced periostitis is rare, and typically presents as bone pain following months of voriconazole treatment. Fluoride, present in voriconazole, deposits within the bony matrix causing bone pains and high serum alkaline phosphatase (ALP) with or without elevated plasma fluoride level. Evidence of periostitis is typically observed on skeletal imaging. Symptom relief occurs shortly after discontinuation of voriconazole, and normalization of serum ALP occurs in the following weeks to months. We herein discuss the pathophysiology and diagnosis of voriconazole-induced periostitis, its prevalence in different patient populations, and clinical outcomes.



INTRODUCTION

A 19-year-old male presented with pain on his left foot that progressed to the right foot, both hips, and shoulders over a month. He was unable to bear weight on his feet due to excruciating pain. His past medical history was significant for hypertrophic obstructive cardiomyopathy and subsequent orthotopic heart transplantation approximately 1 year prior to presentation. The patient’s post-transplant period was complicated by hypoxic respiratory failure due to invasive pulmonary aspergillosis, diagnosed by diffuse pulmonary infiltrates on computed tomography (CT) chest, elevated serum Aspergillus galactomannan enzyme immunoassay 4.8 (normal, < 0.5 optical density index), and growth of Aspergillus flavus from bronchoalveolar lavage culture. Combination therapy with voriconazole and micafungin was initiated given severity of the disease. Micafungin was discontinued once serum voriconazole trough concentration reached target therapeutic level > 1 mg/L (normal, 1-5.5 mg/L). The voriconazole dose was sequentially increased to 550 mg every 12 h which yielded serum voriconazole therapeutic trough concentration of 1.6 mg/L. The patient had received a total of approximately 11 mo of voriconazole prior to presentation with diffuse osteoarticular pain and tenderness.

Physical examination revealed significant point tenderness on elbows, shoulders, and ankles. Extensive dental fluorosis was noted in the patient’s teeth as well (Figure 1). Significant laboratory findings included an elevated total serum alkaline phosphatase (ALP) level of 423 IU/L (normal, 39-117 IU/L) with high fractionated bone ALP of 308 IU/L (normal, 12-43 IU/L). Total bilirubin and transaminases were within normal limits. A serum voriconazole trough level was therapeutic target at 2 mg/L. Plasma fluoride level was normal at 0.4 mg/L (normal, 0.2-3.2 mg/L). Serum ionized calcium, vitamin D levels, and parathyroid hormone tests were all within normal limits. Multiple myeloma screen was negative. Suspicion of voriconazole-induced periostitis was entertained.

Figure 1
Figure 1 Whitish specks and discoloration, evidence of dental fluorosis, noted on the patient’s teeth.

A skeletal survey was performed; it demonstrated thickening and elevation of periosteum on clavicle, humeri, and femur, suggestive of periostitis (Figure 2). A technetium-99m nuclear bone scan revealed diffuse abnormal radiotracer uptake over bilateral feet, proximal femurs, proximal humeri, and clavicles (Figure 3). In totality, these findings suggested a diagnosis of voriconazole-induced periostitis. The antifungal therapy was discontinued. Patient reported improvement of foot pain one week following the drug discontinuation. He was able to ambulate without assistance and tolerate physical therapy two weeks after discontinuation of voriconazole. The serum fluoride level became undetectable after voriconazole cessation for 3 wk. Normalization of serum ALP was achieved approximately one month after discontinuation of the drug. Fluoride deposits on the teeth, however, remained for a year after voriconazole discontinuation. No other antifungal agent was substituted and there has been no recurrence of invasive pulmonary aspergillosis to date.

Figure 2
Figure 2 X-ray of bones showed evidence of skeletal fluorosis. A: Periosteal elevation (arrows) on the left clavicle and proximal left humerus; B: Fluffy periostitis (arrows) on the right humerus; and C: Periosteal reaction (arrows) on the proximal left femur.
Figure 3
Figure 3 Whole body nuclear bone scan. Increased radiotracer uptake (bright white spots) on clavicles, humeri, and femurs (A), as well as feet (B).
BACKGROUND

Voriconazole is a triazole antifungal and is considered the treatment of choice for invasive aspergillosis[1]. It is also recommended for preemptive treatment or universal antifungal prophylaxis in patients with solid organ and hematopoietic stem cell transplant (HSCT)[1,2]. Although voriconazole is generally well tolerated, common adverse effects include visual and auditory hallucinations, peripheral neuropathy, hepatotoxicity (elevation of hepatic transaminase levels), phototoxicity, cutaneous cancers, cardiac arrhythmias from prolonged QTc interval, alopecia, nail changes, hyponatremia, and hyperkalemia[3,4]. Uncommon side-effect of drug-induced periostitis due to prolonged voriconazole therapy has been described in various case reports[3].

We performed a comprehensive literature search in PubMed®, PubMed Central®, and Google Scholar®, using the words “fluconazole”, “itraconazole”, “voriconazole”, “posaconazole”, “isavuconazole”, in combination with “bone pain”, and “periostitis”. The search retrieved all articles identifying association of periostitis with voriconazole. We did not find articles of periostitis from other triazoles. We obtained and reviewed the full texts of all articles and collected data for analysis.

DISCUSSION

A total of 89 cases of voriconazole-induced periostitis were reviewed (Table 1), including 2 pediatric patients, one 14-year-old lung transplant patient and one 3-mo-old stem cell transplant recipient[5-53]. Cases were published in the format of case reports (limited 1 case in an article, 19 articles)[7,9,10,16,19,22,25,27,30,32,34,37,38,40,42,43,45,47,51], case series (> 1 case in an article, 9 articles)[5,8,11,15,18,23,35,39,48], image section (12 articles)[12,13,17,21,28,31,33,36,46,49,50,53], photo quiz (1 article)[20], conference abstracts (5 articles)[6,14,24,26,29], letter to the editor (2 articles)[41,44], and clinicopathologic conference (1 article)[52]. One case report was published in both Danish and English, and it was included in our analysis because there was ample amount of information in English[51]. Table 1 summarizes those 89 cases with relevant patients’ baseline characteristics, voriconazole daily dose, duration of voriconazole therapy, voriconazole trough concentration, indication of voriconazole therapy, immunocompromised status, serum ALP and its bony fraction, plasma fluoride level, imaging study, and clinical outcomes. Not all information was available in reported cases, especially cases published in image section of the journal and conference abstracts likely due to limitation of word counts per the journal and conference requirements.

Table 1 List of published cases of voriconazole-induced periostitis.
Ref.
Total cases
Total daily dose, mg (number of cases) at time of diagnosis of periostitis
Duration of therapy, mo (number of cases)
Voriconazole trough (1-5.5 mg/L, normal range) at the time of diagnosis of periostitis
Immunocompromised state (number of cases)
Indication of voriconazole therapy (number of cases)
Serum ALP (normal range U/L)
Bone ALP isoenzyme, (normal range U/L)
Plasma fluoride level, (normal range)
Imaging performed
Sites of bony involvement
Resolution of symptoms following voriconazole discontinuation (number of cases)
[5]5400 (5)15; 16; 26; 6; 21 N/A; N/A; N/A; N/A; N/ALung transplant (5)Antifungal prophylaxis (5)726 (31-103); 531; 404; 212; 111263 (12-84); 300; N/A; N/A; N/AN/A; N/A; N/A; N/A; N/AX-ray, bone scanTibiae, fibulae, femurs, ulnae, radii, shoulders, scapulae, sacroiliac joints, ischia, humeri, clavicles, manubrium, ribs, anklesWithin 2 wk (1); Within 3 d (1); Within 1 wk (1); N/A (2)
[6]1N/A1 N/AAllogeneic stem cell transplantAntifungal prophylaxis ElevatedN/AN/AX-ray, MRIRadius, metatarsals, fibulae, tibiae, calcaneusWithin 2 mo
[7]140031 N/ALung transplantAntifungal prophylaxis433 (40-125)188 (20/71) N/AX-ray, CT scan, bone scanhand phalanges, ribs Within 1 mo
[8]5200 (1); N/A (4)30 (1); N/A (4)N/ALung transplant (5)Antifungal prophylaxis (3); N/A (2)N/AN/AN/AX-ray, CT scan, bone scanhand phalanges, clavicles, humerus, scapula, ribs, femur, knee, pubic rami, sacral iliac joint N/A (5)
[9]1N/AN/AN/ALung transplantN/AN/AN/AN/AX-rayMultiple phalanges, ulnar shaftItraconazole replacement
[10]112006 0.77Acute myelogenous LeukemiaDisseminated Fusarium infection525 (45-277) 351 (4-110)24.3 (1-4 µmol/L)X-ray, bone scanHands, forearms, humeri, femurs, pelvis, knee, feetImprovement within 1 wk, complete resolution within 3 wk
[11]6400 (5); NA (1)6; 7; 53; 16; 16; 21N/A; 0.3; 2.8; 2.1; 1.0; 5.0 Heart transplant (1); Lung transplant (3); Kidney transplant (1); Stem cell transplant (1)Invasive pulmonary aspergillosis (1); N/A (5)521 (50-130); 361; 323; 243; 178; 229N/A; 268 (12-42); N/A; N/A; N/A; N/A20.7 (1-4 µmol/L); 27; 11.4; 7.5; 15.9; 13.2X-ray, bone scanFingers, wrists, elbows, legs, feet, ribs Within 2 mo (2); Itraconazole replacement, improvement within 1 month (1); N/A (3)
[12]1N/A9N/AHeart transplantInvasive Pulmonary aspergillosis280N/AN/ACT scan, bone scanRibs, sternum, humerus, forearm, femur, tibia, spineN/A
[13]14001.5N/ALiver transplantCerebral Aspergillus infection420 (30-120)N/A10.2 (1-4 µmol/L)X-ray, bone scanFemur, tibia, fibula, radius, ulna, ribs, scapulaeAmphotericin B replacement, rapid resolution
[14]1N/A12N/AAllogenic stem cell transplantInvasive Aspergillus sinusitis and lung infection475 (39-117)152 (7-22)N/AX-ray, bone scanPhalanges, elbows, humerus, femur Within 1 wk
[15]3N/A (3)3.3; 6; 7.5N/A; N/A; N/AAllogeneic stem cell transplant (3)NA (3)195 (35-104); 384; 202N/A; N/A; N/AN/A; 363 (<30 µg/L); 316X-ray, CT scan, bone scanEntire skeleton, spine, pelvis, hands, phalangesWithin 4 d (1); NA (2)
[16]1N/A5 N/AHeart transplantInvasive pulmonary aspergillosis304 (31-95)90.8 (5.6-29 µg/L)N/AX-ray, CT scan, bone scanHumerus, femur, ribs Improvement within 2 wk
[17]1N/A4 N/AN/AFungal endophthalmitisN/AN/AN/AX-ray, bone scanRadial and pretibial diaphysis, radius, ulna, tibia, fibulaWithin 5 d
[18]2N/A (2)5 (1); N/A (1)N/AHeart Transplant (1); Stem Cell Transplant (1)Antifungal prophylaxis (heart transplant); NA (stem cell transplant)304 (29-111); 245N/A; N/AN/A; N/AX-ray, CT scan, bone scanRibs, clavicles, humeri, radii, ulnae, femurs, tibia, metacarpals, phalangesN/A
[19]140011N/AGranulomatosis with PolyangiitisInvasive pulmonary aspergillosis464 N/AN/AX-ray, CT scanFemurImprovement within 2 d, resolution within 1 wk; posaconazole replacement
[20]1N/A62.1Chronic granulomatous diseaseAspergillus knee septic arthritis380 (54-130)N/A133 (< 20 µg/L)X-ray, bone scanRibs, clavicles, humerus, tibiaPosaconazole replacement, improvement within 2 wk
[21]14009N/ALung transplantPulmonary aspergillosis359 (40-150)N/AN/ACTScapulae, ribs, radius, ulnaN/A
[22]16004 3Mixed connected tissue disorder (overlap syndrome)Pulmonary aspergillosis1060 (115-359)89.3 (3.8-22.6 µg/L)24.9 (1-4 µmol/L)CT, MRI, bone scanScapulae, ribs, femursWithin 3 wk
[23]21800; 500; 600; 1300; 700; 800; 500; 700; 500; 700; 700; 1100; 900; 700; 900; 700; 900; 900; 800; 700; 10007; 7.3; 5.5; 5; 5.5; 6.6; 4.9; 5.3; 4.6; 5; 4; 4.8; 5.5; 5.5; 6.3; 5.9; 7.5; 6.8; 5; 4.71.1; 2.3; 3.3; 4; 1.4; 2.6; 3; 3.8; 1.6; 1.5; 5.4; 1.3; 4.2; 1.5; 0.5; 1.5; 3.2; 2.5; 0.5; 2.5; 2Malignancy (2); DM (2); CKD (1); None (16)Exserohilum rostratum, or Aspergillus fumigatus meningitis (contaminated methylprednisolone acetate injection)114 (27-120); 281; 362; 362; 452; 226; 168; 221; 97; 155; 202; 848; 208; 238; 123; 277; 442; 244; 231; 256; 228N/A11.05 (< 5.26 µmol/L); 10.53; 10.0; 14.74; 14.74; 13.16; 0.0; 12.63; 12.11; 14.21; 18.95; 16.84; 14.21; 10.53; 13.69; 8.42; 17.90; 8.95; 21.06; 10.53; 14.21Bone scanRadius, ulna, tibia, fibula, clavicle, scapula, femur, ribs2 wk to 5 mo (8); residual pain (2); 5/10 with symptom improvement in 2-8 wk following dose reduction
[24]1N/AN/AN/ALung transplantCladosporium pneumoniaelevatedN/AN/AX-rayHands, knees, feetItraconazole replacement, improvement over hospital course
[25]1N/A12 N/AAcute Myelogenous LeukemiaFungal sinusitisN/AN/AN/AX-ray, CT scan, MRI, Bone scanClavicle, humerus, ribLess than 2 wk
[26]180034.1Liver TransplantAspergillus brain abscessN/AN/A16.3 (0.3-2.2 µmol/L)X-rayRadius, humerus, scapulae, ribs, appendicular skeletonN/A
[27]18 mg/kg36 N/AMixed connective tissue diseaseExtra-pulmonary histoplasmosis585 (35-104)N/AN/AX-ray, SPECT/CT scan, bone scanRadius, ulna, scapulae, femur, shoulders, spine, knees, ankleN/A
[28]14004 N/AAllogeneic stem cell transplantFungal pneumoniaN/AN/AN/ABone scanClavicle, rib, hip, femur, tibia, fibulaWithin 4 d
[29]1 (14-year-old)N/AN/AN/ALung transplantN/AN/AN/AN/AX-ray, Bone scanPhlanges, metatarsals, tibia and long bones, clavicles, scapula, sternum, pelvic bonesN/A
[30]14005N/ALung transplantAntifungal therapy for abnormal bronchoalveolar lavage332 (no normal range)N/AN/AX-ray, MRIHipsItraconazole replacement; improvement within 2 wk, resolution within 4 wk
[31]160010N/AT-cell prolymphocytic leukemiaCerebral histoplasmosis200 (25-100)N/AN/AX-ray, Bone scanClavicles, ribs, tibia, fibulaWithin 2 d
[32]1N/A2 3.9Liver transplantScedosporium brain abscessN/AN/AElevatedN/AN/APosaconazole replacement, resolution
[33]1400N/AN/AHeart transplantPulmonary aspergillosis323 (40-115)N/A0.15 (0.02-0.08 mg/dL)X-rayHumerusImprovement within 5 d, resolution within 2 mo
[34]18003 4.1Liver transplantAspergillus brain abscessesN/AN/A16.3 (0.3-2.2 µmol/L)X-ray, Bone scanRadius, humerus shafts, scapulaeResolved rapidly after cessation of voriconazole
[35]3400; 400; 4003.3 (1); 6.5 (1) N/A (1)NA (3)Lung transplant; stem cell transplant; liver transplantFungal infection (1); fungal pneumonia (2)215 (0-140); 181-501; 500-1000N/AN/ACT scanSternum, vertebrae, ribs, scapulae, appendicular skeleton, ribsN/A
[36]1N/AN/AN/ALung transplantPulmonary aspergillosis277 (no normal range)N/AN/ABone scan, FDG-PET, CT scanRibs, clavicle, acetabulum, hipsN/A
[37]1 (3-mo-old infant)N/A4.5 N/AStem cell transplantDisseminated aspergillosis2,416 (95-380)1,581 (43-208)23.8 (1-4 µmol/L)X-rayFemur, tibia, fibula, Posaconazole replacement; improvement within 2 d, resolution within 1 wk
[38]1N/A36N/A0Candida glabrata abdominal aortic graft infectionN/A129 (0-20 µg/L)23.6 (1-4 µmol/L)X-ray, Bone scanRibs, humeri, tibiae, Elbow, hand, carpometacarpal joint, Within 3 wk
[39]2800 (1); NA (1)2 (1); 7 (1)N/A (2)Liver transplant (1); heart transplant (1)Scedosporium brain abscess (2)N/AN/A> 24 (1-4 µmol/L); 26X-ray, Bone scanSternoclavicular joints, elbows, wrists, hands, knees, ankles, feet, tibia, fibula, bilateral hip, ribs, spine, scapulae, clavicles acetabula femur, metatarsalsPosaconazole replacement, improvement in several weeks (1)
[40]1N/A6TherapeuticStem cell transplantationInvasive fungal lung infection341 (40-125)N/AN/AMRI, X-rayHand phalangesImprovement within 1 wk
[41]12004.4 N/AStem cell transplantationN/AnormalN/AN/AX-ray, CT scan, Bone scanTibiae, finger phalanges, malleolus Itraconazole replacement, resolution within 4 mo
[42]160010 4Granulomatosis with polyangiitispulmonary aspergillosis> 1,000 (< 130)N/A278 (< 50 µg/L)X-ray, CT scan, Bone scanPhlanges, radius, ulna, metacarpals, tibia, ribs, femurRapid improvement
[43]140048 moN/ALung transplantPulmonary aspergillosis673 (35-125)203 (0-20 µg/L)N/AX-ray, MRI, Bone scanMetacarpals, phalanges, midfeet, femurs, pubic bone, acetabula, radius, ulna, humeral heads, ribs, clavicles, skullImprovement within 3 mo
[44]180033.22Lung transplantN/A4.71 (0.92-2.15 microkat/L)N/AN/ABone ScanFingers, humeri, scapula, elbows, femurs, tibiae, ribsWithin 5 d
[45]16007N/ADMAspergillus skull bone osteomyelitisN/AN/AN/AX-ray, Bone scanExtremities, ribs, and spineResolved
[46]1N/AN/AN/AStem cell transplantN/AN/AN/AN/AX-ray, CT, bone scanClavicle, humeri, scapulae, ribs, femursN/A
[47]170031.9Renal transplantPulmonary aspergillosisN/AN/A68 (1-4 µmol/L)SPECT, bone scanKnees, claviclesWithin 48 h
[48]2NA (1); 600 (1)3 (1); 17 (1)N/A; N/ALung transplant; lung transplantAntifungal prophylaxisN/A; N/AN/A; N/AN/A; N/AX-ray, bone scanFingers, toes, ulnar bones, humeri, shoulders, femurs, tibiaWithin 1 wk; Within 10 d
[49]112004 Within recommended range (no value provided)Stem cell transplantPulmonary aspergillosis457 (40-130)N/AN/ASPECTSkull bones, pelvic bones, femurs, humerusSwitched to Posaconazole; Within 3 wk
[50]1N/A96N/ALung transplantAntifungal Prophylaxis724 (34-123)N/AN/AX-rayHands, wrists> 7 mo
[51]1120049.90Invasive aspergillosis (lung, brain)-post-influenza and pneumococcal infection1900 (no normal range)N/AN/ASingle-photon emission CTExtremitiesResolved
[52]11006N/A0Aspergillus sinusitis and brain abscess1495 (4-147)N/A5.3 (1-4 µmol/L)X-ray, bone scanHands, ankles, and foot2 mo
[53]140048N/AStem cell transplantAntifungal Prophylaxis144 (35-104)N/AN/AX-ray, bone scanTibia, fibulaN/A

Based on the high incidence of voriconazole-induced periostitis in certain patient populations, we have categorized the reported patients into 3 major groups, namely solid organ transplant (SOT) patients, hematologic malignancy and HSCT patients, and immunocompetent hosts. Patients with malignancy[23], diabetes mellitus[23,45], chronic kidney disease[23], chronic granulomatous disease[20], granulomatosis with polyangiitis[19,42], and mixed connective tissue disease[22,27] were not included in the immunocompetent patient category.

The vast majority of voriconazole-associated periostitis cases have been reported in SOT recipients (n = 40, 45%)[5,7,8,11-13,16,18,21,24,26,29,30,32-36,39,43,44,47,48,50], immunocompetent hosts (n = 19, 21.34%)[23,38,51,52], hematologic malignancy and HSCT patients (n = 18, 20.3%)[6,10,11,14,15,18,25,28,31,35,37,40,41,46,49,53]. It is followed by autoimmune diseases (n = 4, 4.44%), including 2 patients with granulomatosis with polyangiitis[19,42], and 2 patients with mixed connective tissue disease[22,27]. One patient (1.12%) had underlying primary immunodeficiency disease (chronic granulomatous disease) and developed periostitis on voriconazole therapy for Aspergillus septic arthritis of the knee[20]. Two patients (2.22%) with underlying diabetes mellitus, 2 patients (2.22%) with unspecified malignancy, and 1 patient (1.12%) with chronic kidney disease had voriconazole-induced periostitis while being treated for Exserohilum rostratum or Aspergillus fumigatus meningitis from contaminated methylprednisolone epidural steroid injection[23]. One patient (1.12%) with diabetes mellitus complicated with periostitis after 7 mo of voriconazole therapy for Aspergillus skull bone osteomyelitis[45]. One patient’s (1.12%) details did not include the immune status of the host[17].

Table 2 summarizes the median voriconazole daily dose with inter-quartile range, median duration of therapy with inter-quartile range, and medial voriconazole trough level in each major patient category. The daily voriconazole dose was reported in 59 cases, consisting of 24 SOT patients[5,7,8,11,13,21,26,30,33-35,39,43,44,47,48], 8 hematologic malignancy and HSCT recipients[10,11,28,31,35,49,53], 18 immunocompetent hosts[23,51,52], and 9 others[19,22,23,42,45]. The duration of voriconazole therapy was described in 77 cases (30 SOT patients[5,7,8,11-13,16,18,21,26,30,32,35,39,43,44,47,48,50], 16 HSCT recipients[6,10,11,14,15,28,31,35,37,40,41,49,53], 18 immunocompetent hosts[23,38,51,52], and 13 others[19,20,22,23,27,42,45]. The voriconazole trough level was mentioned in 38 cases, including 9 SOT patients[11,26,32,34,44,47], 2 HSCT recipients[10,11], 17 immunocompetent hosts[23,51], and 10 others[20,22,23,42].

Table 2 List of reporting cases with voriconazole median daily dose, median duration of therapy, and its median trough concentration in different major patient groups.
Type of patients
Median voriconazole daily dose, (interquartile range), and number of cases
Median duration of voriconazole therapy in months, (interquartile range), number of cases months
Median voriconazole trough concentration in mg/L, number of cases
All patients600 mg, (400-800 mg), 59 patients[5,7,8,10,11,13,19,21-23,26,28,30,31,33-35,42-45,47-49,51-53]6 mo, (4.6 – 10 mo), 77 patients[5-8,10-16,18-23,26-28,30-32,35,38-45,47-53]2.4 mg/L, 38 patients[10,11,20,22,23,26,32,34,42,44,47,51]
Solid organ transplants400 mg, (400-450 mg), 24 patients[5,7,8,11,13,21,26,30,33-35,39,43,44,47,48]7 mo (3 – 17 mo), 30 patients[5,7,8,11-13,16,18,21,26,30,32,35,39,43-44,47,48,50]3.22 mg/L, 9 patients[11,26,32,34,44,47]
Hematologic malignancy and hematopoietic stem cell transplants400 mg, (400-750 mg), 8 patients[10,11,28,31,35,49,53]6 mo (4.3–10.5 mo), 16 patients[6,10,11,14,15,28,31,35,37,40,41,49,53]0.885 mg/L, 2 patients[10,11]
Immunocompetent hosts700 mg, (700-875 mg), 18 patients[23,51,52]5.6 mo, (4.9–6.8 mo), 18 patients[23,38,51,52]2.5 mg/L, 17 patients[23,51]
Fluoride metabolism, voriconazole metabolism, and pathophysiology of voriconazole-associated periostitis

Fluoride is an inorganic anion of fluorine, and its sources include ingestion of water, salt, sugar, and milk, or topical from toothpastes and mouth rinses[54]. The benefits of fluoride to humans consist of anti-dental caries formation and enhancement of bone strength[55,56]. About 80%-90% of ingested fluoride is absorbed in the stomach and small intestine, and the unabsorbed fluoride is excreted in the feces[54]. A majority of absorbed fluoride is distributed to bone and dental enamel[54,57]. The kidneys excrete 60% of daily ingested fluoride in persons with normal renal function[54,58].

Voriconazole is a broad-spectrum triazole antifungal medication. The oral bioavailability of voriconazole is estimated to be 96%[4]. The pharmacokinetics of voriconazole is non-linear due to saturation of its metabolic pathway[4]. The hepatic cytochrome P450 enzyme, predominantly CYP2C19, is responsible for voriconazole metabolism. Due to CYP2C19 enzyme genetic polymorphisms, a person with a rapid CYP2C19 enzyme metabolizer, for example, would require a higher dose of voriconazole to achieve therapeutic drug concentration[4,59]. Less than < 2% of the absorbed voriconazole is excreted unchanged in the urine[4].

Triazole antifungal agents contain varying amounts of fluorine (Figure 4). Fluconazole, posaconazole, and isavuconazole are difluorinated triazoles while itraconazole does not have fluorine content. Voriconazole contains three fluorine atoms, and a 400-mg dose of voriconazole contains a substantial 65 mg of fluoride[11]. In comparison, the fluoride content of the municipal tap water is 1 mg per liter[60]; and, thus daily fluoride consumption from municipal tap water has been estimated at only 2 to 4 mg per day[10,60].

Figure 4
Figure 4 Chemical structures of triazole antifungal medications (fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole). “F” stands for fluorine atom (with permission and courtesy from Dr. Harrold, Division of Pharmaceutical, Administrative and Social Sciences; Duquesne University School of Pharmacy).

Absorbed excess fluoride is incorporated into the crystal structure of bony matrix called hydroxyapatite, forming fluorapatite[61]. Unlike normal calcium hydroxyapatite, high fluroapatite deposit causes disorganized osteoblastic reaction, resulting in periosteal thickening or ossification (seen as periosteal elevation on X-ray), exostosis, and osteosclerosis, a condition known as skeletal fluorosis[54]. Prolonged stimulation of osteoblast activity (evidenced by increased radiotracer uptake on the nuclear bone scan) results in generalized bone pain, exostosis, fractures from increased bony brittleness, a high total serum and bony ALP level, and elevated plasma fluoride concentration[62,63].

Some authors proposed there is a fluoride-independent mechanism that could cause periostitis from voriconazole drug per se[64]. In vitro, voriconazole exerts a direct drug effect and increases expression of cytokines, vascular endothelial growth factor and platelet-derived growth factor. Those cytokines, in turn, augment human osteoblast activity. Free fluoride levels in culture supernatants of osteoblasts exposed to voriconazole were measured and they were within normal range, indicating a possible direct voriconazole drug-induced periostitis[64]. However, this hypothesis has not been widely accepted.

The appendicular skeletons (bones of the shoulder girdle, pelvis bones, upper limbs and lower limbs) are mainly affected. In axial skeleton, only ribs are notably involved. High concentration of fluoride deposits may occur on dental enamel, causing dental fluorosis, which appears as white streaks or specks as seen in our patient (Figure 1)[54].

Voriconazole-induced periostitis in the SOT recipients

Among 40 patients with SOT, lung transplants accounted for 26 patients (65%)[5,7-9,11,21,24,29,30,35,36,43,44,48,50], followed by 6 liver transplants (15%)[13,26,32,34,35,39], 6 orthotopic heart transplants (15%)[11,12,16,18,33,39], and 2 kidney transplants (5%)[11,47]. It is not unexpected that majority of these cases occurred in lung transplant recipients as invasive pulmonary fungal infection is most commonly seen post-lung transplantation[2]. One third of lung transplant patients (n = 6, 23%) developed periostitis on the treatment dose regimen of voriconazole[21,24,30,35,36,43]. Indication of voriconazole therapy was not mentioned in 8 patients (31%) of lung transplant recipients with periostitis[8,9,11,29,44]. Interestingly, 12 (46%) out of 26 lung transplant patients developed voriconazole-related periostitis while receiving low daily dose (200-400 mg) of voriconazole prophylaxis as the use of antifungal prophylaxis with this agent is a common practice in lung transplant recipients[2,5,7,8,48,50,65].

Twenty-four SOT patients reported daily voriconazole doses, and the median daily dose was 400 mg (range 200-800 mg) with the interquartile range of 400-450 mg[5,7,8,11,13,21,26,30,33-35,39,43,44,47,48]. Duration of therapy was reported in 30 SOT patients; the median duration was 7 mo (range 1.5-96 mo) with the interquartile range of 3-17 mo[5,7,8,11-13,16,18,21,26,30,32,35,39,43,44,47,48,50].

Voriconazole trough levels were described in 9 out of 40 SOT patients with periostitis[11,26,32,34,44,47], and trough concentrations were reported with the normal range (1-5.5 mg/L) in 8 patients[11,26,32,34,44,47]. One patient’s voriconazole trough level was sub-therapeutic at 0.3 mg/L while receiving a total daily dose of 400 mg for 7 mo[11]. The median voriconazole trough level was 3.22 mg/L (range 0.3-5.0 mg/dL). Plasma fluoride levels were described in 13 SOT recipients, and all were elevated[11,13,26,33,34,39,47].

Voriconazole-induced periostitis in the immunocompetent hosts

The second most common patient population reported in the literature with voriconazole-related periostitis is in patients with apparent immunocompetent status (n = 19, 21.32%)[23,38,51,52]. Sixteen out of 19 patients with periostitis were observed in patients with Exserohilum rostratum or Aspergillus fumigatus meningitis from contaminated methylprednisolone epidural steroid injection[23]. Eighteen patients reported daily voriconazole dose and duration of voriconazole therapy[23,51,52] while 17 patients included voriconazole trough levels in their reporting[23,51]. Among 19 immunocompetent patients, the median daily dose of voriconazole was 750 mg (range 500-1300 mg) with the interquartile range of 700-875 mg[23,38,51,52], which was notably higher than doses observed in SOT recipients presenting with periostitis (Table 2). These data are likely skewed by large number of fungal meningitis cases in this patient group[23]. Higher voriconazole target troughs (2-6 mg/L) are commonly recommended for the treatment of the central nervous system fungal infection[66]; and, higher voriconazole dosages are typically required to attain the target voriconazole troughs. The median voriconazole trough level was 2.5 mg/L (range 0.5-9.9 mg/L), and the median duration of voriconazole therapy was 5.3 mo (range 4-7.5 mo) with the interquartile range of 4.9-6.8 mo (Table 2). All cases, except 1 patient, had elevated blood fluoride concentration at least twice above the normal range[23,38,52]. Compared to the SOT patients with voriconazole-induced periostitis, the higher median dose of voriconazole with shorter median duration of therapy was noted in patients without underlying apparent immunocompromising condition (Table 2).

Voriconazole-induced periostitis in hematologic malignancy and HSCT patients

In this category, there were a total of 18 patients (20.3%, out of 89 total patients) identified, comprising 3 patients with hematologic malignancy and 15 HSCT recipients[6,10,11,14,15,18,25,28,31,35,37,40,41,46,49,53]. One of the stem cell transplant patients was a 3-mo-old infant[37]. Notably, less than half of the cases (8 patients) reported the daily dose of voriconazole[10,11,28,31,35,49,53] whereas more than two-third of cases (16 patients) described the duration of voriconazole therapy[6,10,11,14,15,28,31,35,37,40,41,49,53]. The median dose was 400 mg (range 200-1200 mg) with the interquartile range of 400-750 mg (Table 2). The median duration of voriconazole therapy was 6 mo (range 1-48 mo) with the interquartile range of 4.3-10.5 mo (Table 2). Only 2 cases reported voriconazole trough concentrations (0.77 mg/L and 1.0 mg/L) at the time of diagnosis of periostitis[10,11]. Two other cases stated voriconazole trough levels within the recommended therapeutic range, without reporting specific values[40,49]. Plasma fluoride levels were only available in 5 patients, and were all 5-10 times above the normal range[10,11,15,37].

Upon evaluation of these 3 largest groups of patients (SOT, immunocompetent patients, and HSCT), there seems to be a trend that suggests higher daily dose of voriconazole (more than 600 mg daily dose) and longer duration of therapy (more than 5.6 mo) may pose a higher risk of developing periostitis (Table 2). Voriconazole-induced peritonitis has been reported with total daily doses as low as 100 mg, highlighting a particular relationship with prolonged exposure of voriconazole and periostitis[52]. Due to genetic CYP2C19 polymorphisms and the potential for various drug-drug interactions, voriconazole therapeutic drug monitoring is commonly performed[59]. Efficacy and safety data suggest optimal target voriconazole trough levels of 1-5.5 mg/L[2,66-68].

As previously noted, patients who rapidly metabolize voriconazole due to CYP2C19 genetic polymorphisms may require higher doses to maintain target trough levels, subsequently exposing patients to higher levels of fluoride intake. Likewise, it has been reported that significantly higher daily and cumulative voriconazole doses were observed in patients with voriconazole-induced periostitis[23]. In our review, patients displayed either therapeutic or sub-therapeutic voriconazole trough levels. These data suggest that voriconazole trough levels do not need to be supra-therapeutic to develop periostitis, and the drug levels alone are not a predictor of periostitis incidence.

All except one patient in our analysis displayed significantly elevated plasma fluoride concentration, indicating its potential utility for the diagnosis of periostitis[10,11,13,15,20,22,23,26,32-34,37-39,42,47,52]. Symptomatic patients with skeletal pain along with plasma fluoride levels greater than 8 μmol/L (normal, < 5.26 μmol/L) has been previously reported as a highly sensitive (95%) and specific (100%) measure for periostitis[23]. Generalization of this finding may be limited as it was a small study and variable normal values of plasma fluoride concentration were used in reported cases (Table 1). Thus, clinicians should observe if the normal value of plasma fluoride from the local laboratory is the same as that in the study. It is also important to note that no correlation between voriconazole drug levels and plasma fluoride levels has been found[69].

Other triazole antifungal medications and periostitis

Itraconazole has no fluorine atom in drug formulation (Figure 4). There were cases where voriconazole was replaced by itraconazole with resolution of symptoms[9,11,24,30,41]. Posaconazole is a difluorinated triazole and it yields around 21.7 mg of fluoride per 400-mg dose[10], 3 times lower than that of voriconazole. Posaconazole was not found to cause fluoride elevations in a small hematologic malignancy patient cohort[15]. Some patients with voriconazole-associated periostitis had successfully transitioned to posaconazole without recurrence of similar symptoms[19,20,32,37,39,49]. It is unclear how much fluoride content is available in a 186 mg-tablet of isavuconazole. There are only 2 fluorine atoms in isavuconazole, and thus, it may be safely assumed that the total fluoride content in isavuconazole is less than that of voriconazole. There have not been any published cases of periostitis associated with itraconazole, posaconazole or isavuconazole therapy. Our patient received 1100 mg per day of voriconazole, nearly 180 mg of fluoride daily (approximately 60 times normal daily fluoride consumption from water) for an 11-mo time period until the time of diagnosis of periostitis.

Diagnosis of voriconazole-induced periostitis

The most common clinical manifestation is localized diffuse bony pain from skeletal fluorosis, mainly affecting fingers, wrists, elbows, shoulders, clavicles, toes, ankles, knees, and hips. Thoracic rib pain can be present if fluorosis involves ribs. Either high dose voriconazole or prolonged duration of therapy would heighten the clinical suspicion of periostitis. Total serum ALP levels and its bony fraction, if measured, are consistently elevated upon diagnosis of periostitis. Voriconazole trough concentrations are usually within the normal range (1-5.5 mg/L). High plasma fluoride level would strongly support the diagnosis of periostitis; but, normal or low plasma fluoride level does not exclude it[23]. The X-ray of bones typically demonstrates periosteal reaction with elevation and thickening. The technetium 99m-nuclear bone scan shows high radiotracer uptake due to increased osteoblastic action. Typically, skeletal X-ray and nuclear bone scan are sufficed in diagnosis of periostitis[70]. In some reported cases, advanced imaging modalities, such as single-photon emission CT, fluorodeoxyglucose-positron emission tomography, and magnetic resonance imaging were utilized[22,25,27,30,36], likely because of elusive etiology of periostitis and less awareness of voriconazole as the cause of periostitis. Those advanced imaging studies are, though, not recommended to be the first choice of imaging study[70]. Discontinuation of voriconazole usually results in rapid resolution of symptoms. No mortality from voriconazole-induced periostitis has been reported.

Summary

In summary, based on extensive reported cases, several observations can be made regarding voriconazole-induced periostitis: (1) Immunocompromised patients constitute majority of the cases; (2) Generalized osteoarticular pain is a cardinal clinical symptom; (3) White streaks or specks on teeth (dental fluorosis) can be seen in some patients; (4) Higher voriconazole dose or the longer duration of voriconazole therapy increases the risk of voriconazole-induced periostitis; (5) Patients on antifungal prophylactic dosing with voriconazole are not spared and they can develop periostitis; (6) Elevation of serum ALP with normal transaminases and bilirubin is a major laboratory indicator for initial clinical suspicion of periostitis in patients with bone pain on voriconazole therapy; (7) Voriconazole trough levels are typically within the therapeutic range; (8) High plasma fluoride levels assist in diagnosis of periostitis (skeletal fluorosis); (9) X-ray and nuclear bone scans are commonly utilized to localize periosteal reaction/thickening and increased bone turnover activity, respectively; (10) Complete and rapid resolution of symptoms is achieved on cessation of voriconazole therapy; and (11) Safe transition to itraconazole, posaconazole, or isavuconazole is recommended, if clinically needed, since there have not been reported cases of periostitis from other triazole antifungal medications.

CONCLUSION

Voriconazole-induced periostitis occurs mainly in post-transplant period following high dose (median 600 mg daily) or prolonged course of voriconazole therapy (median 5.6 mo). Key diagnostic parameters include diffuse bone pain, white specks on the teeth, elevated serum ALP and plasma fluoride levels, with positive nuclear bone scan and radiology findings. Removal of offending agent, voriconazole in this case, would be the mainstay of therapy with resolution of bone pain. Due to lack of fluoride in itraconazole and low fluoride content in posaconazole or isavuconazole, voriconazole may be substituted by other appropriate triazole antifungal drugs if clinically indicated.

ACKNOWLEDGEMENTS

We would like to thank Marc W. Harrold, RPh, Ph.D.; Professor, Division of Pharmaceutical, Administrative and Social Sciences; Duquesne University School of Pharmacy for creating the triazole antifungal chemical structures utilized for Figure 4. We would also extend our thanks to Dr. William M. Peterson II, MD, Division of Musculoskeletal Imaging, Allegheny General Hospital, Allegheny Health Network, for guidance on representative radiologic images (skeletal X-ray and whole body nuclear bone scan).

Footnotes

Manuscript source: Invited manuscript

Specialty type: Transplantation

Country/Territory of origin: United States

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): 0

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Capone D S-Editor: Chang KL L-Editor: A P-Editor: Zhang YL

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