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Rhinocladiella mackenziei is a pigmented fungus and is a common cause of human cerebral phaehyphomycosis. Rhinocladiella mackenziei was believed to be endemic solely to the Middle East, due to the first cases of infection being limited to the region. However, cases of R. mackenziei infection are increasingly reported from regions outside the Middle East.

History and taxonomy
Rhinocladiella mackenziei was first brought to attention in 1993, when C.K. Campbell and Al-Hedaithy investigated eight similar cases of human phaeohyphomycosis caused by an unknown fungal agent, with all eight cases originating from the Middle East. All eight patients had abscess formation and six of the patients had aspirated pus with branching hyphae. C.K. Campbell and Al-Hedaithy considered different genera for the un-named fungus, including Zasmidium, Leptodontidium, Ramichloridium, and Rhinocladiella. Due to the fungus' morphological similarity to other species in the Ramichloridium genera, it was placed under Ramichloridium and given the name Ramichloridium mackenziei, even though unlike Ramichloridium species, this fungus did not produce well differentiated conidia. In previous publications, Naim-Ur-Rahman placed the fungus in the genus Cladosporium, while Al-Hedaithy et al (1988) gave it the name Fonsecaea pedrosoi.

However, a study analyzing morphological features, characteristics of conidiogenous cells, and molecular data of several Ramichloridium-like species found that Ramichloridium mackenziei in fact belonged in the genus Rhinocladiella. It was found that Ramichloridium species produce conidia from well differentiated unbranched conidiogenous cells. Rhinocladiella, on the other hand, produces conidia from poorly differentiated unbranched conidiogenous cells resemblant of R. mackenziei.

Rhinocladiella mackenziei was compared most closely to Rhinocladiella obovoidea, which De-Hoog classified as a Ramichloridium, due to the similar sized conidia and the production of few conidia per axis. Rhinocladiella and Ramichloridium were separated mainly by the level of differentiation of their conidia produced by vegetative hyphae, with Rhinocladiella having less differentiated conidia. However, Rhinocladiella and Ramichloridium were further separated into different orders, Chaetothyriales and Capnodiales, respectively. Rhinocladiella was classified under the order Chaetothyriales.

While Rhinocladiella mackenziei is compared to Pleurothecium obovoideum, there are morphologic differences and classification differences between the two. Unlike P. obovoideum, the cylindrical, spore-bearing, tooth-like projections known as "denticles" are less prominent in R. mackenziei. Also, Rhinocladiella mackenziei is classified in the order Chaetothyriales while P. ovoideum is treated in the order Chaetosphaeriales.

Growth and morphology
Grown on a glucose peptone agar at 30°C, the fungus can grow in diameter to a length of 5mm in one week. In colony, its forms a center that is dome-like with submerged margins, has a fuzzy texture, with dark brown to black pigment and a black reverse. Some strains develop little or no spores when first isolated but produce many conidia in subsequent subcultures. The conidia are poorly differentiated compared to the vegetative mycelium and have a protruding hilum. The fungus produces few brown conidia from poorly differentiated conidiogenous cells. Under a microscope, the fungus appears smooth, with septate hyphae that are pigmented brown. The conidia appear oval and are characterized by brown pigmentation. Rhinocladiella mackenziei is not known to reproduce sexually.

In a study comparing colonial growth rates of the fungus, it was found that after 17 days of growth at 30°C, the colonies ranged in diameter from 15, 13, 11, and 8 mm. At 37°C, diameters ranged from 12, 13, and 20 mm. The fungus grew the least at 25°C, with diameters averaging 2-4 mm. The fungus did grow at 42°C.

Physiology
The brown pigment produced by the fungus acts as a virulence factor by allowing it to evade a human host's immune system and cross the blood-brain barrier. Furthermore, it protects the fungal cell wall from hydrolysis, binds to free radicals and hypochlorite produced by phagocytic cells, blocking them from acting upon the fungal pathogen, as well as binds to anti-fungal drugs, preventing them from acting on the fungus.

Habitat and ecology
Rhinocladiella mackenziei is an environmental mold, however, its specific ecological niche is as of yet unknown. The species within Rhinocladiella are commonly found in temperate and tropical regions, with most cases of human infection being reported from the Middle East and surrounding regions.

Etiology
The fungus was believed to be solely endemic to the Middle East since the first cases of human infection were limited to Saudia Arabia, Kuwait, and Qatar. However, in 2010, a case was reported on the Indian subcontinent, the first known Rhinocladiella mackenziei infection occuring outside of the Middle East. Additionally, a woman was diagnosed in Afghanistan, and a male was diagnosed in Iran. Cases of infection have also been reported in immigrants in the US and UK.

Disease
Rhinocladiella mackenziei is an opportunistic fungus that infects the brain of human hosts, causing cerebral phaeohyphomycosis which is characterized by the formation of an abscess in the brain. Though cerebral phaeophyphomycosis is a rare disease, it often ends in fatality. In cultures taken from infected patients, the fungus appears as aspirated pus that contains brown-walled septate hyphae. Infections occur in individuals regardless of their immunocompetence, with the majority of cases occurring in previously healthy hosts. In humans, R. mackenziei infection is restricted to the central nervous system, most commonly causing headaches and seizures. Other symptoms include fever and neurological deficits.

Rhinocladiella mackenziei infection was diagnosed in conjunction with Primary Central Nervous System Lymphoma (PCNSL) in a 50 years old male patient in Somalia. Both the cerebrum and cerebellum were affected. PCNSL was presented as a large B-cell lymphoma with a high proliferation rate and R. mackenziei infection caused brain abscess formation. Since several segments of the CNS were impacted, the patient was given a combination of amphotericin B and voriconazole, which did not reduced the size of the cerebral abcess. The fungus did not respond to anti-fungal treatments, rendering the growth of the mycosis to be uncontrolled, eventually killing the patient. The combination of R. mackenziei infection and PCNSL in one individual presents a possible linkage of disease agents, with the fungal infection first causing inflammation and proliferation of lymphocytes, eventually leading to the development of PCNSL.

The first case of Rhinocladiella mackenziei infection reported in Iran was diagnosed in a 54 years old male who never traveled outside of Iran. Examination of the aspirate revealed fungal septate hyphae that were pigmented. The fungus caused the formation of granulomas that contained neutrophils, epithelioid cells, and giant cells. Granulomas and giant cells contained septate hyphae characteristic of R. mackenziei. ITS rDNA region of fungal hyphae was sequenced and matched in GenBank as belonging to R. mackenziei.

Treatment
Surgical excision of the fungal lesion and anti-fungal antibiotics have been sought as treatments, however, they are met with poor results. The fungus was found to be unresponsive to the drug Amphotericin B both in vivo and in vitro. However, it was found to be susceptible to itraconazole, posaconazole, and isavuconazole. The drug posaconazole was shown to be especially effective in vitro against R. mackenziei infection.