The clinical presentation of patients with Scedosporium infection encompasses numerous forms. A broad classification recognizes three distinct clinical entities [1] [2] [13]:

1. Localized disease after trauma - This type, unlike other forms, is more commonly seen in immunocompetent individuals who develop an infection after skin trauma that allows the fungus to invade local tissues. As a result, several forms may develop. Mycetoma is a chronic, suppurative inflammation of subcutaneous and bone tissue and is one of the most common clinical presentations of Scedosporidium. In most cases, a small, hard, painless nodule develops on the lower limbs, most commonly the feet, which ulcerates over time and releases purulent fluid. If untreated, significant morbidity due to further involvement of adjacent tissues can occur [2]. Arthritis is another clinical subtype that often presents with minimal or no symptoms; the knee and elbow joints may be infected by Scedosporidium and cause chronic inflammation. Endophthalmitis, osteomyelitis, otomycosis and lymphocutaneous syndrome are amongst other recognized forms of localized disease.
2. Colonization of cavities - Sinusitis, otitis, pulmonary fungus ball and allergic bronchopulmonary Scedosporium pneumonia (ABSP) occur as a result of Scedosporium inhalation into the upper respiratory tract and its subsequent invasion into local cavities. These syndromes may be either asymptomatic or symptomatic, in which case typical features such as epistaxis, facial edema, pallor, earache that may progress to tympanic membrane rupture and asthma-like symptoms may be reported, respectively [2].
3. Systemic invasive disease, most commonly in the form of pneumonia, is a severe and life-threatening infection that occurs as a result of local fungal invasion and cough, hemoptysis, weight loss, fatigue, dyspnea and respiratory failure are its reported symptoms [2]. Apart from respiratory infection, disseminated disease, endocarditis and CNS infection [14], can also be caused by Scedosporium.

In all patients, a thorough patient history that may identify previous trauma or an underlying disease that predisposes to opportunistic infections and a meticulous physical examination should be performed, followed by imaging procedures including plain radiography or computed tomography (CT) in the setting of a soft-tissue or pulmonary infection. Although Scedosporium is rarely encountered in clinical practice, its under -recognition must be taken into consideration, especially in the frequent presence of competing flora such as Aspergillus and Candida which often leads to misinterpretation of microbiological findings [2]. Nevertheless, it is imperative to obtain a valid sample for investigation, whether it is bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), blood or sample of the skin. Culture is a reliable method to identify Scedosporium, although direct microscopy and staining, as well as histopathological examination, are also mentioned as possible diagnostic procedures [2]. PCR, however, is a rapid diagnostic test that can provide results much faster than culture and had equal specificity, which is why it should be performed whenever possible. It is of essential to determine the organism responsible for the symptoms, because antimicrobial therapy may significantly differ from one species to the another.

In the case of localized infection after trauma, surgical debridement is by far the most important therapeutic modality, while administration of antifungal drugs is the mainstay of managing symptomatic colonization and systemic infections [5]. Reports have shown that Scedosporium sp. are universally resistant to amphotericin B, fluconazole, ketoconazole and even to itraconazole and miconazole [5] [10]. These results significantly limit the number of options regarding antifungal therapy, leading to the selection of voriconazole as first-line therapy according to current guidelines [5]. 6 mg/kg either PO or V q12g on the first day, followed by 4 mg/kg either PO or IV q12h is the recommended regimen [5]. As an alternative therapy, posaconazole in doses of 400 mg PO q12h taken during meals is suggested [5]. For this reason, it is necessary to perform susceptibility testing after identification of Scedosporium in patient samples, so that optimal therapy can be given.

The outcome of infection significantly depends on the status of the immune system of the individual, the severity of infection and the site of involvement [4]. Unfortunately, S. prolificans is normally resistant to available antifungal agents, and mortality rates in isolated reports range between 70-100% for S. apiospermum and S. prolificans, respectively [8]. For these reasons, an early identification of the microorganism is essential in order to initiate therapy as soon as possible.

Scedosporidium sp. is an emerging cause of infection in immunocompromised hosts. Two principal species responsible for the infection have been described - S. apiospermum and S. prolificans. Under the microscope, these filamentous fungi show greyish-white, fast growing colonies and a greyish-black reverse, while their mycelium is colorless [2]. The natural habitat for Scerosporodium sp. is yet to be determined, but it was isolated from soil, plants, mud and various poorly aerated areas with low oxygen concentrations,and also from various animals such as horses, dogs and cats and animal excretions (bats, chickens and bird feces) [1] [2]. Additionally, studies that have described nosocomial outbreaks show that contaminated air-conditioning systems and buildings under construction may also be a source of this filamentous fungus [6].

Infection by Scedosporium is reported in countries where levels of humidity are high, including Canada, United States, Germany, France, the Netherlands, Spain [1], and also Australia, where the percentage of less common mold infections was surprisingly high [7]. Incidence rates in single-center studies have shown a slight increase in the number of cases, rising from 0.82 per 100,000 in the 1990s to 1.33 cases per 100,000 patient-inpatient days at the beginning of the 21st century [8]. The opportunistic nature of S. apiospermum is shown by the fact that it is a well-known cause of death in transplant recipients, with an established incidence rate of 1 in 1000 patients [2]. As reports state that the majority of infections were acquired by inhalation and the respiratory route, preexisting lung disease, such as cystic fibrosis (CF) has shown to be a significant risk factor for Scedosporium infection [9]. In fact, between 10-20% of CF patients yield positive sputum samples for this filamentous fungus [3]. Severe pulmonary infections were also recognized in a very small number of individuals who experienced near-drowning accidents after aspirating polluted water and sewage [2].

The pathogenesis model in the case of Scedosporidium infection is not completely clear. The first step of invasion is colonization of the human host, either by inoculation of the skin after breaks due to trauma or inhalation and colonization of the upper respiratory tract. In either setting, the main defense system against filamentous fungi are polymorphonuclear leukocytes and monocytes, collectively known as macrophages, involving both oxidative and non-oxidative reactions [10]. It was established that cytokines such as interleukin-15 (IL-15) play an important role in the mobilization of immune cells [11]. However, studies have determined that alveolar macrophages phagocytose and eliminate Scedsporidium hyphae much less efficiently than other filamentous fungi, for e.g. Aspergillus, suggesting that other factors play a role in limiting the potency of the immune system to eliminate this fungus [10]. So far, the most prominent candidate is alpha-glucan, a glycogen-like polysaccharide located on the Scedosporidium hyphae, which was shown to be one of the key elements in induction of cytokines and phagocytosis [12]. One of the main reasons why immunocompromised individuals are at a much higher risk for this infection, especially those suffering from neutropenia, is the insufficient activity of the monocyte-macrophage system, leading to a favorable environment for the fungus to grow, replicate, invade local tissues and disseminate through hematogenous routes to distant sites [2].

Management of the underlying condition that causes immunosuppression can be considered as a preventive strategy [5]. This may not be easy, however, since bone marrow and solid organ recipients must be on intensive immunosuppressive therapy, which is why antifungal prophylaxis was recommended by some authors, but infections have developed despite adequate prophylactic administration of antifungal therapy, thus questioning this strategy in reducing incidence of Scedosporium infections [13]. Due to the extensive presence of these filamentous fungi in nature and the fact that their natural habitat is unknown, prevention of their inhalation or inoculation onto the skin is currently impossible.

The two Scedosporium species - Sp. prolificans and Sp. apiospermum (also known as the asexual form of Pseudallescheria boydii), are rare but emerging causes of infection in various countries of the world including Europe, North America and Australia [1]. Scedosporium sp. are considered to be opportunists, meaning that they almost exclusively cause infections in immunocompromised individuals, most frequently those receiving heavy corticosteroid therapy for bone marrow or solid organ transplant [2]. Patients suffering from cystic fibrosis (CF) were shown to be at a particular risk for this infection, as Scedosporium was found in up to 10-20% of sputum samples in certain reports [3]. The pathogenesis model somewhat varies depending on the type of infection, but various host factors, as well as the degree of fungal virulence determine the course of the disease [4]. On the basis of its acquisition, there are three main forms - localized disease after trauma (such as mycetoma, arthritis and osteomyelitis, which can occur in immunocompetent individuals as well); colonization of cavities (sinusitis, otitis and pulmonary colonization that may be either symptomatic or asymptomatic); and systemic disease (pneumonia, endocarditis, meningitis and disseminated disease) that may be life-threatening if not recognized early on [1] [2]. Because of a diverse clinical presentation that may involve virtually any organ or site on the body, a proper microbiological workup that includes identification of the underlying microorganism is vital. Various tests have been proposed (cultivation, serology), but because of its similarity to several other fungal organisms, the most reliable method for detection of Scedosporium in patient samples is detection of DNA through polymerase chain reaction (PCR) testing [2]. Treatment principles somewhat vary depending on the type of infection. Surgical debridement is recommended in subcutaneous and localized infections, while antifungal therapy is the mainstay of cavity colonization and systemic infections. One of the main issues in treating Scedsporidium is a very high rate of antifungal resistance and current guidelines suggest voriconazole as first-line therapy because all other agents are ineffective[5]. The prognosis of patients is determined by the severity of infection, status of the immune system and treatment efficacy, but it is essential to recognize and confirm this microorganism early, as systemic infections are quite commonly life-threatening and fatal, especially those involving the central nervous system [2].

Scedosporium infection is a rare but sometimes life-threatening disease and is caused by two fungi - Scedosporidium apiospermum and S. prolificans, microorganisms that are ubiquitously present in nature. They are not only found in soil, polluted waters, plants, but also in the excretory products of various animals.They are considered opportunistic pathogens as they primarily cause disease in individuals who have a disease which weakens their immune system. Use of immunosuppressive therapy in bone marrow or solid organ recipients, chemotherapy for cancer and human immunodeficiency virus (HIV) infection are some clinical circumstances in which patients are predisposed to this infection. Studies show that Scedosporium is rarely encountered in medical practice, but countries all over the world including Spain, Germany, United States, Canada and Australia have reported patients in whom this infection was confirmed. Scedosporium may present in myriad forms and three main entities have been described: local infection after previous skin trauma that allowed inoculation of fungi into the subcutaneous tissue; colonization of sinuses or the lungs that may be either asymptomatic or symptomatic; and systemic disease in the form of pneumonia (lung infection), endocarditis (infection of the heart valves), meningitis (infection of the central nervous system) or disseminated infection. Local infection of the skin and subcutaneous tissues may be seen in otherwise healthy and immunocompetent individuals, whereas colonization of the respiratory tract and subsequent infection of internal organs is restricted to immunocompromised patients. For this reason, the appearance of the disease is closely related to the status of the patient's immune system. To make the diagnosis, it is necessary to obtain a sample from the patient that is suitable for microbiological investigation (blood, cerebrospinal fluid, piece of skin, or sputum) and various tests are used for confirmation. Treatment principles are surgical debridement in the case of local infection and administration of antifungal drugs in other types of infection. Unfortunately, Scedosporium species are resistant to the majority of drugs currently used in therapy and voriconazole is currently one of the few agents that is effective against this fungus. With early therapy, the prognosis of patients is very good, but mortality rates in severe infections are very high, rising up to 100% in central nervous system infection, which is why early recognition of the disease is essential in reducing the burden of this infection.

1. Idigoras P, Pérez-Trallero E, Piñeiro L, et al. Disseminated infection and colonization by Scedosporium prolificans: a review of 18 cases, 1990-1999. Clin Infect Dis. 2001;32(11):E158-165.
2. Guarro J, Kantarcioglu AS, Horré R, et al. Scedosporium apiospermum: Changing clinical spectrum of a therapy-refractory opportunist. Med Mycol. 2006;44:295-327.
3. Cimon B, Carrère J, Vinatier JF, Chazalette JP, Chabasse D, Bouchara JP. Clinical significance of Scedosporium apiospermum in patients with cystic fibrosis. Eur J Clin Microbiol Infect Dis. 2000;19(1):53-56.
4. Berenguer J, Rodríguez-Tudela JL, Richard C, et al. Deep infections caused by Scedosporium prolificans. A report on 16 cases in Spain and a review of the literature. Scedosporium Prolificans Spanish Study Group.Medicine (Baltimore). 1997;76(4):256-265.
5. Gilbert DN, Chambers HF, Eliopoulos GN, Saag MS. The Sanford Guide to Antimicrobial Therapy 2015. 45th ed. Antimicrobial Therapy, Inc, Sperryville, VA; 2015.
6. Alvarez, M, Lopez-Ponga B, Rayon C, Gala J, Roson Porto MC, Gonzalez M, et al. Nosocomial outbreak caused by Scedosporium prolificans (inflatum): four fatal cases in leukemic patients. J. Clin. Microbiol. 1995;33:3290-3295.
7. Slavin, MA. The epidemiology of candidaemia and mould infections in Australia. J. Antimicrob. Chemother. 2002;49(1):3-6.
8. Lamaris GA., Chamilos G, Lewis RE, Safdar A, Raad II, Kontoyiannis DP. Scedosporium infection in a tertiary care cancer center: a review of 25 cases from 1989-2006. Clin. Infect. Dis. 2006;43:1580-1584.
9. Williamson ECM, Speers D, Arthur IH, Harnett G, Ryan G, Inglis TJJ. Molecular Epidemiology of Scedosporium apiospermum Infection Determined by PCR Amplification of Ribosomal Intergenic Spacer Sequences in Patients with Chronic Lung Disease. J Clin Microbiol. 2001;39(1):47-50.
10. Gil-Lamaignere C, Maloukou A, Rodriguez-Tudela JL, Roilides E. Human phagocytic cell responses to Scedosporium prolificans. Med Mycol. 2001;39(2):169-175.
11. Winn RM, Gil-Lamaignere C, Roilides E, Simitsopoulou M, Lyman CA, Maloukou A, Walsh TJ. Effects of interleukin-15 on antifungal responses of human polymorphonuclear leukocytes against Fusarium spp. and Scedosporium spp.Cytokine. 2005;31(1):1-8.
12. Bittencourt VC Figueiredo RT, da Silva RB, Mourão-Sá DS, Fernandez PL, Sassaki GL. An alpha-glucan of Pseudallescheria boydii is involved in fungal phagocytosis and Toll-like receptor activation. J. Biol. Chem. 2006;281:22614-22623.
13. Sayah DM, Schwartz BS, Kukreja J, Singer JP, Golden JA, Leard LE. Scedosporium prolificans pericarditis and mycotic aortic aneurysm in a lung transplant recipient receiving voriconazole prophylaxis. Transplant Infectious Disease. 2013;15(2):E70–E74.
14. Larbcharoensub N, Chongtrakool P, Wirojtananugoon C, et al. Treatment of a brain abscess caused by Scedosporium apiospermum and Phaeoacremonium parasiticum in a renal transplant recipient. Southeast Asian J Trop Med Public Health. 2013;44:484-489.