Introduction

Cerebral phaeohyphomycosis is a rare but severe infection due to melanized fungi. Along with Cladophialophora bantiana, Rhinocladiella mackenziei is one of the main fungi responsible for this disease [1]. There are no definite risk factors for this pathogen, and, notably, no immunodeficiency found in most of the afflicted patients [2]. On 2% malt agar, R. mackenziei grows as green olive to brown lanose colonies. The microscopic aspect is characterized by the presence of short conidiophores arising from melanized septate hyphae. In addition, hyaline denticled–conidiogenous cells producing pale brown ellipsoidal conidia in sympodial succession are observed. Prognosis of cerebral phaeohyphomycosis is dreadful, with only a handful of nonlethal cases reported [3–6]. Other members of the Rhinocladiella genus are involved in human diseases, such as chromoblastomycosis [7]. Diagnosis has become more accessible and accurate with the advent of polymerase chain reaction (PCR) techniques and DNA sequencing, which allowed to pin down the precise taxonomy of black fungi [8].

While other pathogens involved in cerebral phaeohyphomycosis seem to be found worldwide [1], R. mackenziei has classically been reported as being geographically restricted to the Middle East. However, in the last decade, cases were reported in a broader area [4,9,10]. The aim of this report is to underline the extension of the endemic areas for R. mackenziei by reporting the first 2 cases of R. mackenziei cerebral phaeohyphomycosis in patients from Morocco.

Case presentation

Case discussion

Phaeohyphomycosis is a neglected fungal disease. R. mackenziei is one of the responsible pathogens, with the particularity of being considered geographically restricted. Here, we report, to our knowledge, the first 2 cases from Morocco natives.

Risk factors for R. mackenziei infection remain unclear. Although some cases occurred in immunocompromised hosts such as solid organ transplant recipients or patients with hematological malignancies, other cases were reported in patients with few comorbidities [1]. Little is known about the reservoir of R. mackenziei and the route of contamination, and it was never isolated from the environment [14].

So far, most of the cases found in the literature originated from the Middle East (24/36, 67%; Fig 1, S1 Table). However, recently, an increasing number of cases have been reported from other countries at risk, notably Pakistan, India, Iran [15], and, now, Morocco, which still concurs with the hypothesis of an organism fitted for an arid climate. Similar organisms have been isolated from air biofilters, dry, and/or acidic soil [16]. An analysis of the literature allows formulating new hypotheses about the pathogenesis of R. mackenziei cerebral phaeohyphomycosis. Reading the case from Cristini and colleagues [10], with a 20-year gap between the patient’s stay in Afghanistan and the disease, one can assume the possibility of a latent in vivo reservoir, which ultimately reactivates under particular circumstances. Many patients in the literature have a travel history to areas with arid climates. If we hypothesize a prolonged carrier state, the geographical area at risk could be even broader than what previously thought: Turkey, Kenya, Egypt, and Somalia might also be at risk, for example (Fig 1).

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Fig 1. Geographical distribution of Rhinocladiella mackenziei cerebral phaeohyphomycosis (N = 36).

In black, countries with confirmed cases. In dark gray, countries with possible contamination. In light gray, countries where diagnoses were made but unlikely to be at risk for contamination (probable imported cases). If several countries were possibly incriminated, priority was given to the country with other confirmed cases if present; else, every country was considered as “possible contamination.” Articles used in this figure are reported in S1 Table. Map template can be found at https://www.freeworldmaps.net/powerpoint/.

https://doi.org/10.1371/journal.pntd.0009563.g001

Shortly, we can recommend extensive surgery as the cornerstone for treatment. Posaconazole is probably the optimal associated antifungal for R. mackenziei, based on our one surviving patient and success of others with this triazole [3,10]. These conclusions are limited by the scarce available clinical evidence, but concordant with in vitro [17] and animal data [18].

This study has limitations. First, this was not an exhaustive collection of all imported French cases of R. mackenziei infections, exposing to selection bias. Moreover, the Necker-Enfants Malades Hospital is associated with the NRCMA and may have a different case mix than other centers. Second, this is a retrospective study, limiting the conclusions that can be made about exposure to the pathogen and route of contamination. Third, the small number of cases obviously limits the generalizability of our findings.

In conclusion, the area at risk of R. mackenziei cerebral abscess is extending to new countries and now also includes North Africa with Morocco. Clinicians should be aware of this emerging disease and take a detailed travel history in patients with atypical and undocumented brain abscess.

Supporting information

Acknowledgments

We thank Ophélie Deouard and Dr. Philippe Lesprit for the risks taken in identifying the strains.