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.

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 patients	600 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 transplants	400 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 transplants	400 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 hosts	700 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]