Fungal Genetics and Biology xxx (2013) xxx–xxx Contents lists available at ScienceDirect Fungal Genetics and Biology journal homepage: www.elsevier.com/locate/yfgbi Review Insights into fungal pathogenesis from the iatrogenic epidemic of Exserohilum rostratum fungal meningitis ⇑ David Andes a, Arturo Casadevall b, a The Departments of Medicine (Infectious Diseases) and Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53705-2281, United States b The Departments of Microbiology & Immunology and Medicine, Albert Einstein College of Medicine, Bronx, NY, United States article info abstract Article history: In 2012 the medical community in the United States faced an unprecedented outbreak of fungal menin- Received 15 July 2013 gitis caused by Exserohilum rostratum associated with injections of contaminated lots of methyprednil- Accepted 23 August 2013 sone acetate. Rapid response by public health authorities led to the identification of the cause of the Available online xxxx outbreak and the epidemic quickly abated, even though new cases were still being reported many months later. Although the cause of the outbreak is known there are many uncertainties regarding the Keywords: management of infected individuals and the long term risk for those who were exposed to this organism. Exserohilum rostratum The epidemic of E. rostratum infections illustrates how an organism that normally has low pathogenic Fungal potential for humans can transform into a very dangerous pathogen when conditions are changed such Meningistis that skin barriers are breached while it is simultaneously delivered with an immunosuppressive drug. Furthermore, this epidemic highlights the potential threats to human and animal health from the fungal kingdom. Ó 2013 Published by Elsevier Inc. In late 2012 the medical community in the United States was curred in individuals given injectable steroids contaminated with confronted by an outbreak of meningitis cases caused by an organ- fungal spores (Anonymous, 2002) and outbreak of Aspergillosis fol- ism that only very rarely caused disease in humans, a fungus lowed the use of a contaminated spinal anesthetic in Sri Lanka known as Exserohilum rostratum (Kainer et al., 2012; Kauffman (Rodrigo et al. 2007). Decades ago outbreaks of zygomycosis were et al., 2013; Kerkering et al., 2013; Smith et al., 2013). The cause associated with the use of contaminated bandages (Antoniadou, of the epidemic was eventually traced to the use of methyprednil- 2009). These episodes highlight the enormous potential of contam- sone acetate (MPA) injections contaminated with E. rostratum (tel- inating fungi to cause disease when inadvertently introduced into eomorph Setosphaeria) as a result of poor manufacturing practices the human host as part of contaminated therapies. In fact, as of at the New England Compounding Center (Lockhart et al., 2013). May 2013 the Centers for Disease Control (CDC, Atlanta, GA) was Cases were reported in 20 of the 23 states where the product investigating a new outbreak of fungal meningitis associated with was used. By mid-2013 the epidemic had abated as the contami- a different compounding pharmacy (Kuehn, 2013). nated MPA vials were withdrawn from clinical practice. However, In the United States there are over half a million epidural injec- as of July 1, 2013 the total case count stood at 749 with 61 deaths tions each year and infection is a rare complication that is usually and new cases continued to be reported, with three deaths in June caused by skin bacteria (Cooper and Sharpe, 1996; Hooten et al., 2013, many months after initial infection. This episode constitutes 2004). In contrast, the overall case rate for infection with E. rostra- the largest iatrogenic fungal outbreak in the United States. Hence, tum was near 4% of more than 13,500 exposed individuals, of this outbreak has a known cause and may not repeat itself but this which over 90% were exposed through an epidural, paraspinal, or tragic episode provides us with new insights into the potential for spinal injection, with the remainder having joint or peripheral fungi to cause disease and the conditions where fungal infection injections. Hence, the majority of the clinical manifestations ob- can progress to disease. Incidentally, the 2012–2013 fungal epi- served during the E. rostratum outbreak reflected the mode of demic from contaminated drugs was not the first time that such infection, which involved direct inoculation of the fungal cells into an iatrogenic disaster had occurred. Over a decade ago several normally sterile body sites. The distribution of clinical presenta- cases of Exophiala (Wangiella) dermatitides fungal meningitis oc- tions was as follows: 391 (52%) cases of meningitis, 323 (43%) cases of local paraspinal infections, 60 (15%) cases of arachnoiditis and 33 (4%) cases of septic arthritis. The total percentage exceeds ⇑ Corresponding author. Address: Albert Einstein College of Medicine, 1300 100% because some individuals had more than one condition. Morris Park Ave, Bronx, NY 10461, United States. The early cases mostly involved meningitis complicated by poster- E-mail address: [email protected] (A. Casadevall). 1087-1845/$ - see front matter Ó 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fgb.2013.08.014 Please cite this article in press as: Andes, D., Casadevall, A. Insights into fungal pathogenesis from the iatrogenic epidemic of Exserohilum rostratum fungal meningitis. Fungal Genet. Biol. (2013), http://dx.doi.org/10.1016/j.fgb.2013.08.014 2 D. Andes, A. Casadevall / Fungal Genetics and Biology xxx (2013) xxx–xxx ior circulation stroke in 10% of affected individuals. Histological there were no prior reports of meningitis. Prior to the current out- analysis of post-mortem specimens demonstrated that E. rostratum break clinical experience with this organism was very limited. In was angioinvasive and elicited an inflammatory response with immunocompetent individuals with breaks in tissue integrity E. neutrophil predominance (Bell and Khabbaz, 2013). The incubation rostratum has been reported to cause cutaneous and corneal infec- period for the onset of meningitis after MPA injection ranged from tions. Disseminated E. rostratum disease had been reported in a 1 to 120 days (mean 23 days), with the longest times being compa- handful of immunocompromised individuals (Douer et al., 1987). rable to those described for the earlier Exophiala outbreak. As the The paucity of human cases suggests that E. rostratum has low outbreak has evolved later cases tended to present more com- pathogenic potential for humans. monly with infection of local tissues and these included a large The infection risk varied with the lot and one specific lot was number of paraspinal and epidural infections with a significantly associated with more infections. This lot was older than the others smaller number of joint and bone infections. For patients with and the likelihood of infection increased with vial age and was paraspinal infections the media number of days from injection to greatest for vials older than 60 days (Kainer et al., 2012). This could MRI diagnosis was 52 days for those that received one injection reflect a higher fungal contamination burden and/or growth of fun- and 43 for those that received several (Kontoyiannis et al., 2013). gi in the vials with time, possibly potentiated by the steroid. In this It is noteworthy that the time between infection and disease for regard, Aspergillus spp. have been reported to grow faster in the the soft tissue infections was significantly longer than that ob- presence of hydrocortisone (Ng et al., 1994). served with the meningitis cases, which may reflect differences An interesting aspect of this epidemic is a large subset of indi- in local immunity between the CNS and soft tissues and/or tissue viduals who have remained asymptomatic despite being known damage leading to symptomatology. The patients ranged in age to be infected. For example, 21% of 172 patients from a center in from 16 to 92 years with a mean age of 64. Older age (> 60) was Michigan who were found to have MRI imaging evidence for an ab- associated with 4-fold higher risk of disease (11.8% vs 2.9%) sug- scess at the injection site and have remained free of symptoms gesting the possibility that senescent immune system were less (Malani et al., 2013). Whether this reflects the injection of cortico- likely to control infection, especially in the presence of high con- steroids at the site or an indolent infection that will in time become centrations of corticosteroid in tissue (Kainer et al., 2012). symptomatic is not known. This situation represents a clear dis- One praiseworthy aspect of this iatrogenic tragedy was the ra- tinction between infection and disease. The word infection is often pid recognition of the outbreak and the decisive action taken by used synonymously with disease but they have been proposed to public health authorities, which is apparent by the timeline of represent different states whereby infection is the acquisition of events. On September 21, 2012 several fungal meningitis cases the microbe by the host and disease is an outcome whereby the were reported to the Center for Disease Control (Atlanta, Ga) and interaction of the host and microbe has resulted in sufficient dam- by October 4, 2012 that agency had associated the cases with age to impair homeostasis and produce clinical symptoms (Casa- MPA injections originating from the New England Compounding devall and Pirofski, 2000). Center, two days later the manufacturer recalled all vials and by The ability of the rarely pathogenic E. rostratum to cause infec- October 19, 2012 more than 99% of exposed individuals had been tion and disease after MPA injection reflects its deposition in nor- contacted. The investigation identified three contaminated lots mally sterile tissue sites in conjunction with an that included 17,675 vials that had been distributed to 76 health immunosuppressive drug in the form of MPA. In this regard, E. care facilities in 23 states.