Exserohilum Infections Associated with Contaminated Steroid Injections

Abstract

The ASCP designates this journal-based CME activity ("ASIP 2013 AJP CME Program in Pathogenesis") for a maximum of 48 AMA PRA Category 1 Credit(s)ä. Physicians should only claim credit commensurate with the extent of their participation in the activity. CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. September 2012 marked the beginning of the largest reported outbreak of infections associated with epidural and intra-articular injections. Contamination of methylprednisolone acetate with the black mold, Exserohilum rostratum, was the primary cause of the outbreak, with >13,000 persons exposed to the potentially contaminated drug, 741 confirmed drug-related infections, and 55 deaths. Fatal meningitis and localized epidural, paraspinal, and peripheral joint infections occurred. Tissues from 40 laboratoryconfirmed cases representing these various clinical entities were evaluated by histopathological analysis, special stains, and IHC to characterize the pathological features and investigate the pathogenesis of infection, and to evaluate methods for detection of Exserohilum in formalin-fixed, paraffin-embedded (FFPE) tissues. Fatal cases had necrosuppurative to granulomatous meningitis and vasculitis, with thrombi and abundant angioinvasive fungi, with extensive involvement of the basilar arterial circulation of the brain. IHC was a highly sensitive method for detection of fungus in FFPE tissues, demonstrating both hyphal forms and granular fungal antigens, and PCR identified Exserohilum in FFPE and fresh tissues. Our findings suggest a pathogenesis for meningitis involving fungal penetration into the cerebrospinal fluid at the injection site, with transport through cerebrospinal fluid to the basal cisterns and subsequent invasion of the basilar arteries. Further studies are needed to characterize Exserohilum and investigate the potential effects of underlying host factors and steroid administration on the pathogenesis of infection. Accepted for publication

The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum

“…Wild-type mice inoculated with Exserohilum demonstrated predominately neutrophilic infiltrates with granulomatous inflammation, multinuclear giant cells, and rare hyphal growth. The types of inflammatory response seen in our model mirrored the inflammatory responses seen in an analysis of 40 patients infected with Exserohilum during the clinical outbreak (69). The correlation between the histology seen in our murine in vivo model and that seen in patients suggests that this may be a robust model for studying dematiaceous mold infections.…”

Black Molds and Melanized Yeasts Pathogenic to Humans

“…Exserohilum species are mainly involved in traumatic infections, such as keratitis (Burges et al 1987;Pauzner et al 1997;Mathews and Maharajan 1999;Joseph et al 2012). Otherwise species may cause invasive infections in immunocompromised patients (Aquino et al 1995), with risk factors including aplastic anemia (Lasala et al 2005;Adler et al 2006) and hematopoietic stem cell transplant (HSCT) (Togitani et al 2007;Ritter et al 2013). Recently, E. rostratum was implicated in a large meningitis outbreak that was traced back to contaminated steroid injections (Lyons et al 2012;Gade et al 2013;Lockhart et al 2013;Smith et al 2013).…”

In Vitro Activities of Eight Antifungal Drugs against a Global Collection of Genotyped Exserohilum Isolates

“…However, at the end of 2012, the meningitis outbreak in the United States due to Exserohilum demonstrated this fungus to be an agent of severe life-threatening infections (4,5). Although several fungi were implicated in the outbreak, the vast majority of infections were caused by Exserohilum rostratum, which was traced to contaminated steroid injections as the source (4)(5)(6)(7)(8). Previously, Exserohilum rostratum, Exserohilum longirostratum, and Exserohilum mcginnisii were reported as opportunistic human pathogens.…”