Voriconazole-associated periostitis: Pathophysiology, risk factors, clinical manifestations, diagnosis, and management

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]	5	400 (5)	15; 16; 26; 6; 21	N/A; N/A; N/A; N/A; N/A	Lung transplant (5)	Antifungal prophylaxis (5)	726 (31-103); 531; 404; 212; 111	263 (12-84); 300; N/A; N/A; N/A	N/A; N/A; N/A; N/A; N/A	X-ray, bone scan	Tibiae, fibulae, femurs, ulnae, radii, shoulders, scapulae, sacroiliac joints, ischia, humeri, clavicles, manubrium, ribs, ankles	Within 2 wk (1); Within 3 d (1); Within 1 wk (1); N/A (2)
[6]	1	N/A	1	N/A	Allogeneic stem cell transplant	Antifungal prophylaxis	Elevated	N/A	N/A	X-ray, MRI	Radius, metatarsals, fibulae, tibiae, calcaneus	Within 2 mo
[7]	1	400	31	N/A	Lung transplant	Antifungal prophylaxis	433 (40-125)	188 (20/71)	N/A	X-ray, CT scan, bone scan	hand phalanges, ribs	Within 1 mo
[8]	5	200 (1); N/A (4)	30 (1); N/A (4)	N/A	Lung transplant (5)	Antifungal prophylaxis (3); N/A (2)	N/A	N/A	N/A	X-ray, CT scan, bone scan	hand phalanges, clavicles, humerus, scapula, ribs, femur, knee, pubic rami, sacral iliac joint	N/A (5)
[9]	1	N/A	N/A	N/A	Lung transplant	N/A	N/A	N/A	N/A	X-ray	Multiple phalanges, ulnar shaft	Itraconazole replacement
[10]	1	1200	6	0.77	Acute myelogenous Leukemia	Disseminated Fusarium infection	525 (45-277)	351 (4-110)	24.3 (1-4 µmol/L)	X-ray, bone scan	Hands, forearms, humeri, femurs, pelvis, knee, feet	Improvement within 1 wk, complete resolution within 3 wk
[11]	6	400 (5); NA (1)	6; 7; 53; 16; 16; 21	N/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; 229	N/A; 268 (12-42); N/A; N/A; N/A; N/A	20.7 (1-4 µmol/L); 27; 11.4; 7.5; 15.9; 13.2	X-ray, bone scan	Fingers, wrists, elbows, legs, feet, ribs	Within 2 mo (2); Itraconazole replacement, improvement within 1 month (1); N/A (3)
[12]	1	N/A	9	N/A	Heart transplant	Invasive Pulmonary aspergillosis	280	N/A	N/A	CT scan, bone scan	Ribs, sternum, humerus, forearm, femur, tibia, spine	N/A
[13]	1	400	1.5	N/A	Liver transplant	Cerebral Aspergillus infection	420 (30-120)	N/A	10.2 (1-4 µmol/L)	X-ray, bone scan	Femur, tibia, fibula, radius, ulna, ribs, scapulae	Amphotericin B replacement, rapid resolution
[14]	1	N/A	12	N/A	Allogenic stem cell transplant	Invasive Aspergillus sinusitis and lung infection	475 (39-117)	152 (7-22)	N/A	X-ray, bone scan	Phalanges, elbows, humerus, femur	Within 1 wk
[15]	3	N/A (3)	3.3; 6; 7.5	N/A; N/A; N/A	Allogeneic stem cell transplant (3)	NA (3)	195 (35-104); 384; 202	N/A; N/A; N/A	N/A; 363 (<30 µg/L); 316	X-ray, CT scan, bone scan	Entire skeleton, spine, pelvis, hands, phalanges	Within 4 d (1); NA (2)
[16]	1	N/A	5	N/A	Heart transplant	Invasive pulmonary aspergillosis	304 (31-95)	90.8 (5.6-29 µg/L)	N/A	X-ray, CT scan, bone scan	Humerus, femur, ribs	Improvement within 2 wk
[17]	1	N/A	4	N/A	N/A	Fungal endophthalmitis	N/A	N/A	N/A	X-ray, bone scan	Radial and pretibial diaphysis, radius, ulna, tibia, fibula	Within 5 d
[18]	2	N/A (2)	5 (1); N/A (1)	N/A	Heart Transplant (1); Stem Cell Transplant (1)	Antifungal prophylaxis (heart transplant); NA (stem cell transplant)	304 (29-111); 245	N/A; N/A	N/A; N/A	X-ray, CT scan, bone scan	Ribs, clavicles, humeri, radii, ulnae, femurs, tibia, metacarpals, phalanges	N/A
[19]	1	400	11	N/A	Granulomatosis with Polyangiitis	Invasive pulmonary aspergillosis	464	N/A	N/A	X-ray, CT scan	Femur	Improvement within 2 d, resolution within 1 wk; posaconazole replacement
[20]	1	N/A	6	2.1	Chronic granulomatous disease	Aspergillus knee septic arthritis	380 (54-130)	N/A	133 (< 20 µg/L)	X-ray, bone scan	Ribs, clavicles, humerus, tibia	Posaconazole replacement, improvement within 2 wk
[21]	1	400	9	N/A	Lung transplant	Pulmonary aspergillosis	359 (40-150)	N/A	N/A	CT	Scapulae, ribs, radius, ulna	N/A
[22]	1	600	4	3	Mixed connected tissue disorder (overlap syndrome)	Pulmonary aspergillosis	1060 (115-359)	89.3 (3.8-22.6 µg/L)	24.9 (1-4 µmol/L)	CT, MRI, bone scan	Scapulae, ribs, femurs	Within 3 wk
[23]	21	800; 500; 600; 1300; 700; 800; 500; 700; 500; 700; 700; 1100; 900; 700; 900; 700; 900; 900; 800; 700; 1000	7; 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; 4.7	1.1; 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; 2	Malignancy (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; 228	N/A	11.05 (< 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; 14.21	Bone scan	Radius, ulna, tibia, fibula, clavicle, scapula, femur, ribs	2 wk to 5 mo (8); residual pain (2); 5/10 with symptom improvement in 2-8 wk following dose reduction
[24]	1	N/A	N/A	N/A	Lung transplant	Cladosporium pneumonia	elevated	N/A	N/A	X-ray	Hands, knees, feet	Itraconazole replacement, improvement over hospital course
[25]	1	N/A	12	N/A	Acute Myelogenous Leukemia	Fungal sinusitis	N/A	N/A	N/A	X-ray, CT scan, MRI, Bone scan	Clavicle, humerus, rib	Less than 2 wk
[26]	1	800	3	4.1	Liver Transplant	Aspergillus brain abscess	N/A	N/A	16.3 (0.3-2.2 µmol/L)	X-ray	Radius, humerus, scapulae, ribs, appendicular skeleton	N/A
[27]	1	8 mg/kg	36	N/A	Mixed connective tissue disease	Extra-pulmonary histoplasmosis	585 (35-104)	N/A	N/A	X-ray, SPECT/CT scan, bone scan	Radius, ulna, scapulae, femur, shoulders, spine, knees, ankle	N/A
[28]	1	400	4	N/A	Allogeneic stem cell transplant	Fungal pneumonia	N/A	N/A	N/A	Bone scan	Clavicle, rib, hip, femur, tibia, fibula	Within 4 d
[29]	1 (14-year-old)	N/A	N/A	N/A	Lung transplant	N/A	N/A	N/A	N/A	X-ray, Bone scan	Phlanges, metatarsals, tibia and long bones, clavicles, scapula, sternum, pelvic bones	N/A
[30]	1	400	5	N/A	Lung transplant	Antifungal therapy for abnormal bronchoalveolar lavage	332 (no normal range)	N/A	N/A	X-ray, MRI	Hips	Itraconazole replacement; improvement within 2 wk, resolution within 4 wk
[31]	1	600	10	N/A	T-cell prolymphocytic leukemia	Cerebral histoplasmosis	200 (25-100)	N/A	N/A	X-ray, Bone scan	Clavicles, ribs, tibia, fibula	Within 2 d
[32]	1	N/A	2	3.9	Liver transplant	Scedosporium brain abscess	N/A	N/A	Elevated	N/A	N/A	Posaconazole replacement, resolution
[33]	1	400	N/A	N/A	Heart transplant	Pulmonary aspergillosis	323 (40-115)	N/A	0.15 (0.02-0.08 mg/dL)	X-ray	Humerus	Improvement within 5 d, resolution within 2 mo
[34]	1	800	3	4.1	Liver transplant	Aspergillus brain abscesses	N/A	N/A	16.3 (0.3-2.2 µmol/L)	X-ray, Bone scan	Radius, humerus shafts, scapulae	Resolved rapidly after cessation of voriconazole
[35]	3	400; 400; 400	3.3 (1); 6.5 (1) N/A (1)	NA (3)	Lung transplant; stem cell transplant; liver transplant	Fungal infection (1); fungal pneumonia (2)	215 (0-140); 181-501; 500-1000	N/A	N/A	CT scan	Sternum, vertebrae, ribs, scapulae, appendicular skeleton, ribs	N/A
[36]	1	N/A	N/A	N/A	Lung transplant	Pulmonary aspergillosis	277 (no normal range)	N/A	N/A	Bone scan, FDG-PET, CT scan	Ribs, clavicle, acetabulum, hips	N/A
[37]	1 (3-mo-old infant)	N/A	4.5	N/A	Stem cell transplant	Disseminated aspergillosis	2,416 (95-380)	1,581 (43-208)	23.8 (1-4 µmol/L)	X-ray	Femur, tibia, fibula,	Posaconazole replacement; improvement within 2 d, resolution within 1 wk
[38]	1	N/A	36	N/A	0	Candida glabrata abdominal aortic graft infection	N/A	129 (0-20 µg/L)	23.6 (1-4 µmol/L)	X-ray, Bone scan	Ribs, humeri, tibiae, Elbow, hand, carpometacarpal joint,	Within 3 wk
[39]	2	800 (1); NA (1)	2 (1); 7 (1)	N/A (2)	Liver transplant (1); heart transplant (1)	Scedosporium brain abscess (2)	N/A	N/A	> 24 (1-4 µmol/L); 26	X-ray, Bone scan	Sternoclavicular joints, elbows, wrists, hands, knees, ankles, feet, tibia, fibula, bilateral hip, ribs, spine, scapulae, clavicles acetabula femur, metatarsals	Posaconazole replacement, improvement in several weeks (1)
[40]	1	N/A	6	Therapeutic	Stem cell transplantation	Invasive fungal lung infection	341 (40-125)	N/A	N/A	MRI, X-ray	Hand phalanges	Improvement within 1 wk
[41]	1	200	4.4	N/A	Stem cell transplantation	N/A	normal	N/A	N/A	X-ray, CT scan, Bone scan	Tibiae, finger phalanges, malleolus	Itraconazole replacement, resolution within 4 mo
[42]	1	600	10	4	Granulomatosis with polyangiitis	pulmonary aspergillosis	> 1,000 (< 130)	N/A	278 (< 50 µg/L)	X-ray, CT scan, Bone scan	Phlanges, radius, ulna, metacarpals, tibia, ribs, femur	Rapid improvement
[43]	1	400	48 mo	N/A	Lung transplant	Pulmonary aspergillosis	673 (35-125)	203 (0-20 µg/L)	N/A	X-ray, MRI, Bone scan	Metacarpals, phalanges, midfeet, femurs, pubic bone, acetabula, radius, ulna, humeral heads, ribs, clavicles, skull	Improvement within 3 mo
[44]	1	800	3	3.22	Lung transplant	N/A	4.71 (0.92-2.15 microkat/L)	N/A	N/A	Bone Scan	Fingers, humeri, scapula, elbows, femurs, tibiae, ribs	Within 5 d
[45]	1	600	7	N/A	DM	Aspergillus skull bone osteomyelitis	N/A	N/A	N/A	X-ray, Bone scan	Extremities, ribs, and spine	Resolved
[46]	1	N/A	N/A	N/A	Stem cell transplant	N/A	N/A	N/A	N/A	X-ray, CT, bone scan	Clavicle, humeri, scapulae, ribs, femurs	N/A
[47]	1	700	3	1.9	Renal transplant	Pulmonary aspergillosis	N/A	N/A	68 (1-4 µmol/L)	SPECT, bone scan	Knees, clavicles	Within 48 h
[48]	2	NA (1); 600 (1)	3 (1); 17 (1)	N/A; N/A	Lung transplant; lung transplant	Antifungal prophylaxis	N/A; N/A	N/A; N/A	N/A; N/A	X-ray, bone scan	Fingers, toes, ulnar bones, humeri, shoulders, femurs, tibia	Within 1 wk; Within 10 d
[49]	1	1200	4	Within recommended range (no value provided)	Stem cell transplant	Pulmonary aspergillosis	457 (40-130)	N/A	N/A	SPECT	Skull bones, pelvic bones, femurs, humerus	Switched to Posaconazole; Within 3 wk
[50]	1	N/A	96	N/A	Lung transplant	Antifungal Prophylaxis	724 (34-123)	N/A	N/A	X-ray	Hands, wrists	> 7 mo
[51]	1	1200	4	9.9	0	Invasive aspergillosis (lung, brain)-post-influenza and pneumococcal infection	1900 (no normal range)	N/A	N/A	Single-photon emission CT	Extremities	Resolved
[52]	1	100	6	N/A	0	Aspergillus sinusitis and brain abscess	1495 (4-147)	N/A	5.3 (1-4 µmol/L)	X-ray, bone scan	Hands, ankles, and foot	2 mo
[53]	1	400	48	N/A	Stem cell transplant	Antifungal Prophylaxis	144 (35-104)	N/A	N/A	X-ray, bone scan	Tibia, fibula	N/A

ALP: Alkaline phosphatase; MRI: Magnetic resonance imaging; CT: Computer tomography; FDG-PET: β-2-[18F]-Fluoro-2-deoxy-D-glucose-positron emission tomography; DM: Diabetes mellitus.