Voriconazole-Induced Periostitis Deformans: A Mimicker of Hypertrophic Pulmonary Osteoarthropathy

Abstract

. Calcium, vitamin D, parathyroid hormone, urate, creatinine, and inflammatory markers were normal. Serum voriconazole and beta-crosslinks (a marker of bone resorption) were normal. Given the elevated ALP, periostitis, osteophytic reactions and lack of clubbing, he was diagnosed with voriconazole-induced periostitis deformans (VIPD). Voriconazole was discontinued and symptoms and ALP improved within 3 months. DiscussionVoriconazole is a triazole antifungal used to treat invasive fungal infections which are commonly encountered in immunocompromised hosts. Fluoride is a major component of this antifungal, and is central in the pathophysiology of VIPD through stimulation of osteoblasts.1 Classically VIPD presents with diffuse bony pain and swelling, elevated serum ALP and fluoride levels, dense periosteal reaction on radiographs, as well as multiple areas of uptake on bone scintigraphy.2,3 Despite the aforementioned abnormalities, voriconazole troughs are often within normal limits. 4 It differs from hypertrophic pulmonary osteoarthropathy in its predilection for distinct areas such as the ribs, irregular and dense periosteal reactions, and lack of clubbing and joint effusions. 2,3Symptoms typically resolve soon after discontinuing voriconazole. 2,5Figure 1. Hand radiographs are notable for multifocal periosteal reaction involving the metacarpals, and proximal and middle phalanges in an asymmetrical manner. The patient is skeletally immature. Anatomic alignment and joint spaces are preserved.

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

“…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 ].…”

“…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 ].…”

“…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 , …”

“…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 ].…”

“…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 ].…”