Epidemiology, clinical manifestations, and diagnosis of Scedosporium and Lomentospora infections

INTRODUCTION — During the past few decades, opportunistic fungal pathogens have become increasingly recognized as a cause of infection in severely ill or immunocompromised patients [1,2]. Although Aspergillus species remain the most common mold to cause invasive infection, other mold infections are becoming more common [1-3]. Two of these, Scedosporium apiospermum and Lomentospora prolificans, are considered major human pathogens [4,5].

The epidemiology, clinical manifestations, and diagnosis of Scedosporium and Lomentospora infections will be reviewed here. The treatment of these infections is discussed elsewhere. (See "Treatment of Scedosporium and Lomentospora infections".)

MYCOLOGY

Scedosporium apiospermum complex — S. apiospermum [6] is the asexual form (anamorph) of Pseudallescheria boydii [7-10]. Colonies grow rapidly and have a cottony appearance on cornmeal agar; with age, the colonies become gray or brown in color (picture 1). The hyphal forms appear as branching septate hyphae with a single terminal conidia, which is uninucleate and cylindrical in shape (picture 2) [11].

When the sexual form of S. apiospermum is present in culture, the organism is identified as P. boydii. Dark, spherical structures, known as cleistothecia, characterize the sexual form of this organism (picture 3) [12].

S. apiospermum complex has been recognized to encompass several distinct species. Through the use of molecular phylogeny, the following species have been accepted as unique: Pseudallescheria apiosperma (anamorph S. apiospermum), Scedosporium aurantiacum, P. boydii (Scedosporium boydii), Scedosporium dehoogii, and Pseudallescheria minutispora [13]. Identification to the species level is of interest since the susceptibility patterns differ among members of the S. apiospermum complex. (See "Treatment of Scedosporium and Lomentospora infections", section on 'Scedosporium aurantiacum'.)

S. aurantiacum is a medically important Scedosporium species. It is part of the S. apiospermum species complex as a subset of clinical isolates previously phenotypically identified as S. apiospermum. It is present in the environment, and it has also been isolated from the human respiratory tract [14-16]. S. aurantiacum was distinguished from S. apiospermum by analysis of internal transcribed spacer-restriction fragment length polymorphism (ITS-RFLP) patterns and strain typing with polymerase chain reaction fingerprinting [14]. Phenotypic microarray further elucidated the difference between the two strains [15].

Lomentospora (formerly Scedosporium) prolificans — When first isolated as a human pathogen, L. prolificans was named Scedosporium inflatum due to its basally swollen, flask-shaped conidiogenous cells but was later named S. prolificans (picture 4) [17]. Due to its morphologic and molecular characteristics, this organism was subsequently assigned to the genus Lomentospora and reclassified as Lomentospora prolificans [18-21]. In contrast with S. apiospermum, no sexual form has been identified for L. prolificans [9].

Colony characteristics differ based upon which nutrient agar is used [17,22]. On Sabouraud dextrose medium, colonies are white and cottony with the reverse side appearing greenish-gray to dark green [17]; colonies on potato dextrose agar are flat and olive-gray to black in color [11]. Conidiogenous cells may form singly or in small clusters along the vegetative hyphae [12].

EPIDEMIOLOGY — Scedosporium and Lomentospora species are found ubiquitously in the environment, including in soil and polluted water [7-10,22,23]. Both S. apiospermum complex and L. prolificans have a global distribution including Europe, Australia, South America, and the United States [7,9,24-32]. More recently, Scedosporium spp have also been isolated from soil surveys from areas of human impact in Thailand [33] and Morocco [34].

Human infection often results from inhalation of spores from the environment into the lungs or paranasal sinuses or through direct inoculation, as in a skin puncture [31].

Nosocomial outbreaks of Scedosporium and Lomentospora infection in immunocompromised hosts have been linked to contaminated ambient air in hospitals [27,35-38]. One such outbreak occurred at a time of hospital renovation [27]. Another report involved six hematologic malignancy patients with neutropenia who were not in laminar airflow rooms or high-efficiency particulate-absorbing (HEPA) filtered rooms when they developed infection [36]. Lomentospora isolates from four patients and two air samples were identical by polymerase chain reaction fingerprinting. After the initiation of stricter infection control practices as well as positive-pressure and HEPA filtration for hospital rooms, no further environmental contamination or clinical cases were reported in the subsequent two years of follow-up.

With the increase in the population at risk for filamentous mold infections, Scedosporium and Lomentospora infections have been reported from various locations. Surveillance studies of invasive non-Aspergillus mold infections in transplant recipients in the United States showed the highest rates for Scedosporium infection were in the south compared with other regions [39].

A report from the MD Anderson Cancer Center in Houston, Texas, noted an increasing incidence of both S. apiospermum and L. prolificans, with cases of the latter seen only after the year 2000 [40].

A retrospective study from San Diego, California, reported that cases of L. prolificans made up slightly over one-third of non-Aspergillus invasive mold infections in the period studied [41].

In a population-based survey from Spain, Scedosporium was the second most commonly detected filamentous mold in clinical samples, after Aspergillus spp [42].

In a review of hospitalized patients spanning 20 years at one institution in Spain, Scedosporium/Lomentospora constituted the third most common mold infections after aspergillosis and mucormycosis, with a stable incidence for the study period [43]. Another institutional review found that S. apiospermum and S. boydii were the predominant species of Scedosporium in their area [44].

A retrospective clinical observation study conducted in France of Scedosporium/Lomentospora infections detected S. apiospermum and S. boydii more frequently than L. prolificans and underscored the importance of species-level identification regarding clinical presentation and outcome [45].

In Australia, Scedosporium has also been reported as the second most common etiologic agent of filamentous mold infections [46], with S. apiospermum (35 percent), L. prolificans (41 percent), and S. aurantiacum (24 percent) identified by molecular polymorphisms in the internal transcribed spacer regions of the rDNA gene [16].

A retrospective single-center study in Australia of lung transplant patients spanning 24 years (1995 to 2019) showed no Scedosporium/Lomentospora infections in the 1995 to 2013 time period. The first case was detected in 2014, with cases detected yearly thereafter [47].

Large retrospective reviews of Scedosporium spp and Lomentospora involving multiple countries have been conducted [5,48,49]. Despite regional differences in incidence, infections with these fungi are now being detected in more countries.

COLONIZATION — S. apiospermum is the second most common filamentous fungus isolated from the airways of cystic fibrosis patients [50-53] and may be a stimulus for inflammatory responses, similar to that seen in allergic bronchopulmonary aspergillosis (ABPA). The presence of bacterial and fungal co-colonizers, the use of antimicrobial agents, and ABPA have been reported as possible risk factors for airway colonization of cystic fibrosis patients by Scedosporium species [54,55]. S. aurantiacum, a member of the S. apiospermum complex, has also been recognized as a colonizer in cystic fibrosis patients in Australia, Germany, France, and Argentina. In the latter, Scedosporium spp was the third most commonly isolated fungal colonizer [54-57].

Airway colonization with Scedosporium and Lomentospora species is of particular concern in lung transplant recipients because of the risk of progression to invasive infection. Two small single-center retrospective studies reviewed the outcomes of solid organ transplant recipients with Scedosporium and Lomentospora colonization in the era of second-generation azoles [58,59]. For lung transplant recipients, including cystic fibrosis patients, colonization prior to transplantation was reported for the majority of patients, with S. apiospermum complex being the most frequent colonizer. These patients were given second-generation azoles before and after transplantation, along with other antifungal agents, and most did not progress to invasive infection [5,43,45,47-49,60,61].

In addition to colonization of the airways, L. prolificans has been cultured from the external auditory canal of individuals without apparent clinical disease [28].

CLINICAL MANIFESTATIONS — Scedosporium and Lomentospora species can cause localized infection in immunocompetent hosts following trauma or surgery, or severe disseminated disease in immunocompromised hosts. The two species are discussed separately below.

S. apiospermum infections — S. apiospermum complex is mainly associated with infections in immunocompromised hosts, although some localized infections have been described in immunocompetent hosts [5,43,45,48].

Respiratory tract — S. apiospermum infection frequently involves the respiratory tract in patients with chronic granulomatous disease [62], chronic glucocorticoid use [63], hematopoietic cell transplantation [30,64-68], hematologic malignancy, or solid organ transplantation [29,30,47,69-73].

The initial presentation typically includes fever, cough, sputum production, pleuritic chest pain, tachypnea, and malaise. Scedosporium infection may present as a localized pulmonary process or may disseminate from the lungs to multiple organs, including brain and skin [30,69,70].

Keratitis and endophthalmitis — Ophthalmologic Scedosporium infections can present as a localized corneal process or as endogenous endophthalmitis in the setting of disseminated disease.

Fungal keratitis caused by Scedosporium spp has been reported in immunocompetent hosts with or without a history of overt ocular injury [5,74-79]. Patients experience eye pain, photophobia, foreign body sensation, conjunctival or corneal erythema, tearing, and changes in visual acuity. Scedosporium corneal infections can lead to frank corneal ulceration, abrasion, perforation, infiltrate, and anterior chamber hypopyon. Corneal scrapings or biopsy provide the diagnosis. (See "Treatment of Scedosporium and Lomentospora infections".)

In contrast, endogenous endophthalmitis due to S. apiospermum occurs after hematogenous dissemination in immunocompromised hosts [5,69,80-87]. Presenting symptoms include eye pain, photosensitivity, and decreased visual acuity. Funduscopic examination reveals exudates and a hazy vitreous; a hemorrhagic necrotizing chorioretinitis has been noted at autopsy [88].

Central nervous system — S. apiospermum has been associated with brain abscesses in both immunocompetent [5,89,90] and immunocompromised patients [5,69,91,92].

S. apiospermum brain abscesses have been described in individuals surviving near-drowning episodes [48,90,93-96]. The portal of entry may be directly through the sinuses with contiguous spread or via hematogenous dissemination from the lungs. Patients are obtunded, febrile, and often have severe hypoxia related to the near-drowning event.

Brain abscesses from hematogenous dissemination of S. apiospermum have been described in immunocompromised patients, particularly in recipients of hematopoietic cell [91,97,98] and solid organ [5,45,48,69,85,86,99-101] transplants. A case of S. apiospermum brain abscess without dissemination following treatment with Bruton tyrosine-kinase inhibitor has been reported [102]. Neurologic findings with brain abscess include headache, confusion, disorientation, agitation, cognitive decline, progressive lethargy, hemiparesis, and seizures.

Skin, soft tissue, and bone — Skin lesions secondary to S. apiospermum often occur in the setting of disseminated infection [30,69,99,103-106]. Lesions may appear as nodules or as erythematous to purple papules or bullae, which may develop a necrotic center. Occasionally, a pattern of lymphangitic spread may be seen with multiple nodules and pustules.

Localized soft tissue infections [73,106,107] and osteomyelitis [89,108-110] due to S. apiospermum [24,111-117] have also been reported in the setting of trauma. The extremities are most often involved, although cases involving the spine or cranium have also been described. Cases may be long standing, as evidenced by a case of pseudoarthrosis due to S. apiospermum in a femoral nonunion fracture with ongoing issues 20 years after the original trauma [118].  

A retrospective review of 145 cases of osteoarticular infections in children and adults between 1970 and 2013 revealed that Scedosporium species were implicated in the majority of non-Aspergillus filamentous mold infections [119]. S. apiospermum constituted 33 percent of the cases, while L. prolificans constituted 16 percent. Immunocompromised patients accounted for 62 percent of the patients with non-Aspergillus osteoarticular infections.

Eumycetoma of the foot due to S. apiospermum complex has also been reported [120].

Disseminated infection — Disseminated disease is defined as the infection of two or more noncontiguous body sites and/or bloodstream infection [5,43,45,48,101,105,121,122]. Dissemination is known to readily occur, particularly in severely immunosuppressed patients, and can cause shock and multiorgan failure [70].

Other — S. apiospermum has also been implicated as a cause of sinusitis in immunocompromised hosts [69,123,124], lymphadenitis in an immunocompetent host [125], and mycotic aneurysm in a kidney transplant recipient [126]. Endocarditis due to S. apiospermum has been reported in an orthotopic heart transplant recipient [127]. A fatal case S. apiospermum fungemia in an immunocompetent patient with a left ventricular assist device (LVAD) and an implantable cardiac device has been reported, with the patient presenting with arrhythmia, followed by fever and LVAD dysfunction [128].

S. aurantiacum infections — As noted above, S. aurantiacum has been recognized as a medically important Scedosporium species that is part of the S. apiospermum species complex. Most cases of S. aurantiacum infection have been reported from Australia, where it has typically been associated with chronic lung disease [16]. A few invasive cases have been described, including: subcutaneous abscess in a patient with diabetes and lymphoma [129], scleritis and corneal ulcer following trauma [130], pulmonary infection in a lung cancer patient undergoing chemotherapy and radiation [131], and brain abscess in a near-drowning victim after a tsunami [132].

L. prolificans infections — The first described clinical case of L. prolificans infection was in 1984 in an immunocompetent six-year-old boy who developed osteomyelitis of the foot after penetrating trauma [17]. Since then, multiple cases with different clinical presentations have been reported in the literature [5,25,26,28,31,43,45,48,49,133].

Respiratory tract — Infection of the respiratory tract with L. prolificans has been reported mainly in patients with immunosuppression [5,26,29,30,47,49,133]. Underlying conditions have included malignancy (usually hematologic), solid organ or hematopoietic cell transplantation, chronic immunosuppressive therapy, chronic corticosteroid treatment, and AIDS. The usual presenting symptoms have included productive cough, dyspnea, and fever, and the organism was recovered from either sputum or bronchoalveolar lavage specimens. (See "Treatment of Scedosporium and Lomentospora infections".)

In a group of lung transplant recipients, L. prolificans was repeatedly cultured from bronchoalveolar lavage fluid, often together with S. apiospermum [29]. The majority of these patients had the following characteristics, which may have predisposed them to infection: bacterial or cytomegalovirus pneumonitis, rejection episodes requiring pulse corticosteroids, and structural changes in their airways. Eradication of L. prolificans was unsuccessful in the majority of patients.

In a retrospective review of lung transplant patients with Scedosporium/Lomentospora isolated from sputum or bronchoalveolar lavage, Scedosporium/Lomentospora was isolated a median 929 days post-transplantation (intraquartile range 263 to 2960 days). Patients who had Scedosporium/Lomentospora from the respiratory tract (representing either colonization or invasive fungal infection) were more likely to have received antifungal therapy in the past when compared with other patients [47].

Keratitis and endophthalmitis — L. prolificans has been implicated as an agent of fungal keratitis [134-137] and endophthalmitis [5,49,88,133,138-140]. Trauma or surgery often serves as the portal of entry for the fungus.

Keratitis may present as foreign body sensation, lacrimation, and discharge. The cases described are in patients who either had a retained contact lens (which led to breakdown in the corneal epithelium) or who had experienced scleral necrosis after pterygium surgery with adjunctive beta-irradiation. If the corneal epithelium is invaded by the fungus, aggressive surgical debridement and antifungal therapy is needed to avoid loss of visual acuity or enucleation.

Both exogenous and endogenous endophthalmitis have been reported, the latter in the setting of disseminated infection. Changes in visual acuity or other visual disturbances, often with eye pain, are reported, with fundoscopic examination revealing vitreous turbidity and white retinal infiltrates or exudates. Progressive visual loss is common.

Central nervous system — Central nervous system infection with L. prolificans has been reported and has an extremely high mortality rate [5,25,30,48,49,133,141-146]. Most cases have occurred in the setting of disseminated infection. Manifestations have included meningitis, meningoencephalitis, and cerebral abscesses. Clinical features include headache, altered mental status, meningeal signs, focal neurologic deficits, seizures, or acute neurologic deterioration.

Skin, soft tissue, and bone infections — Localized musculoskeletal infections, such as arthritis or osteomyelitis due to L. prolificans have been reported [17,28,31,48,49,119,133,147-149]. The most frequent predisposing event is trauma, either penetrating or nonpenetrating, to the affected extremity. Initial presentations include laceration or cellulitis at the site, with progression to joint effusion, inflammation, and tenderness; some patients also have low-grade fever. Those with bone involvement have symptoms and signs of inflammation as well as imaging studies consistent with osteomyelitis. Rare cases of vertebral osteomyelitis and/or spinal epidural abscess have been reported [150]. Back pain was a common presenting clinical feature, followed by a slowly progressive, chronic course.

Endocarditis — Cases of endocarditis due to L. prolificans have been reported in patients with pre-existing cardiac abnormalities and/or immunosuppression [145,151-154]. The mortality is high. A fatal case report of disseminated L. prolificans in a heart transplant recipient described Gram stains of blood cultures with yeast-like forms. Mold grew on both bacterial and fungal media, and histopathology demonstrated branched, septate hyphae in endocardium and epicardium. Fungal hyphae were also noted in central nervous system, lung, skin, and other organs [155].

Disseminated infection — The most commonly reported presentation of L. prolificans infection is disseminated infection [5,25-27,30,32,45,48,49,88,133,140-142,144,156-161]. Fungemia is more common with L. prolificans than with S. apiospermum complex [30]. In three case series, positive blood cultures were reported in 80 percent (24 of 30), 75 percent (12 of 16), and 100 percent (6 of 6) of L. prolificans cases, respectively [25,26,32].

Predisposing underlying risk factors for fungemia include neutropenia, hematopoietic cell transplant, solid organ transplant, malignancy, AIDS, and treatment with kinase inhibitors [26,30,160,162]. In a series of neutropenic patients with hematologic malignancies, the most frequent clinical manifestation of disseminated L. prolificans infection was fever [25]. Pulmonary symptoms, such as dyspnea, cough, and infiltrates on chest radiographs, were also common. Other symptoms and signs included skin lesions, altered mental status, visual changes, renal failure, and septic shock.

Disseminated infection is associated with very high mortality rates. (See "Treatment of Scedosporium and Lomentospora infections", section on 'Prognosis'.)

DIAGNOSIS

Approach to diagnosis — The approach to diagnosis is individualized based upon various patient-specific factors, including site and severity of infection, as well as the immune status of the host. Whenever possible, and especially for immunocompromised hosts and/or for patients with severe disease, clinicians should aggressively pursue a diagnosis when Scedosporium/Lomentospora infection is suspected.

Proven invasive mold infection is defined as [163-165]:

●Histopathologic examination revealing tissue invasion and a culture result positive for mold

OR

●Histopathologic examination revealing fungal elements plus identification by fungal DNA polymerase chain reaction (PCR) combined with sequencing to the genus/species level, even in the absence of a positive culture

OR

●Clinical or radiographic findings consistent with infection and a culture positive for mold obtained via sterile technique from a normally sterile site

Histopathologic examination is helpful for determining that an invasive mold infection is present, but it is not possible to establish the causative pathogen without culture because various hyaline molds have a similar appearance. For this reason, culture is an essential part of the diagnostic evaluation. Culture is also important for testing in vitro susceptibility since Scedosporium spp, particularly L. prolificans, can be resistant to multiple antifungal agents. (See "Treatment of Scedosporium and Lomentospora infections", section on 'Susceptibility testing' and "Antifungal susceptibility testing".)

A serum beta-D-glucan test, which detects a cell wall component of many fungi, and a serum galactomannan antigen, which is fairly specific for Aspergillus spp, can be helpful if a mold infection is suspected. (See "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay' and "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection'.)

Diagnostic techniques — Multiple diagnostic techniques can be used to aid with the diagnosis of Scedosporium/Lomentospora infections; these are summarized in the following table (table 1) and discussed in detail below [164-167].

Histopathology — Specimens from potentially sterile sources, including tissue biopsies, aspirates, and bronchoalveolar lavage, may be used for examination for invasive mold infection [168]. Periodic-acid Schiff or Gomori methenamine silver stains can be used for better visualization of fungi in tissue. Diagnosis of an invasive mold infection may be made when septate hyphae are identified in an area of inflammation, granulomas, or necrosis. Septate, hyaline (nonpigmented) branching hyphae at a 45º angle are consistent with Scedosporium/Lomentospora infection but are also seen with other hyaline molds, such as Aspergillus and Fusarium spp [12]. (See 'Differential diagnosis' below.)

One histologic feature that distinguishes Scedosporium/Lomentospora infection from Aspergillus infection in vivo is the presence of adventitious forms. These unicellular forms may invade the wall of blood vessels and allow sporulation of the fungus directly into the blood, resulting in positive blood cultures [2]. Although this feature is not characteristic of Aspergillus, it may be seen with other hyaline molds. The overall histologic similarity between these organisms therefore necessitates culture of specimens in order to definitively identify the infecting pathogen.

Culture — Definitive diagnosis of Scedosporium/Lomentospora infection can be established through culture but must be interpreted in its clinical context. Cultures of corneal scrapings or corneal biopsy [76], skin [69,99], soft tissue [106], bone [31,147,157], joint fluid [28], and brain abscesses [90,94] have yielded Scedosporium/Lomentospora in patients with localized and disseminated infection. Alternatively, a positive culture from the respiratory tract may simply represent colonization [50-52] and must be interpreted carefully. However, in a patient with suggestive clinical findings, isolation from the respiratory tract provides a probable diagnosis of scedosporiosis [26,29,30,62,64-67,69,72]. (See 'Colonization' above.)

The use of selective fungal media for patients with chronic respiratory diseases, including cystic fibrosis, yields an overall increase in filamentous fungi detection, including clinically significant species [169-171].

An international survey conducted in lung transplant centers showed heterogeneity in the management of patients colonized or infected with Scedosporium/Lomentospora. Most centers used two or more different types of media for lower respiratory tract specimens, though only 18 percent of centers used a Scedosporium-selective medium [60].

Though some of the fungi detected are due to colonization, the use of Scedosporium-selective media may be considered for patients at high risk for Scedosporium/Lomentospora infection or for patients being considered for lung transplant where colonization might be a risk factor for disease post-transplantation.

Blood cultures are also useful for detection of Scedosporium/Lomentospora in cases of disseminated disease. In a case series, 52 of 72 patients (72 percent) with disseminated L. prolificans infection had positive blood cultures [133]. Although Scedosporium/Lomentospora can be isolated in commercial broth enrichment media, specialized fungal media, such as the Myco-F-Lytic bottle or the lysis centrifugation method, are suggested when fungemia is suspected [172,173].

Molecular techniques — Molecular methods have been developed for the identification and differentiation of molds. PCR technology, either panfungal or species specific, and sequencing [53,172,174,175] provide rapid identification of molds and have been used for epidemiologic purposes, with DNA fingerprinting or whole-genome sequencing used to evaluate possible outbreaks of L. prolificans [36,175-178]. Some institutions have developed their own PCRs targeting internal transcribed spacer sequence polymorphisms for the identification of the different Scedosporium and Lomentospora species in clinical specimens [55,155,179-182]. Other molecular targets that further differentiate between species include regions of the beta-tubulin gene or the calmodulin gene [43,57,167,183,184]. Unfortunately, these tools are not widely available in most clinical laboratories at this time.

The definition of proven invasive mold infection has expanded to include identification by molecular methods of mold in formalin-fixed paraffin-embedded (FFPE) tissue [164,165].

Successful PCR amplification of fungal DNA from FFPE tissue varies between centers. Methodology factors that impact success include but are not limited to: specimen variables such as type of biopsy (open versus fine-needle aspiration); quantity and quality of tissue; amount of fungal burden in tissue; time since formalin-fixed, buffered, or unbuffered formalin; and PCR/sequencing variables such as avoidance of contamination with other fungal DNA, extraction efficiency, primer selection, sequencing target, amplification efficiency, and quality and availability of reference genomes and curated databases. These types of assays should only be performed in reference laboratories or in high-volume centers with laboratory-derived protocols that, pending the establishment of international standards, follow a set of commonly agreed upon rules [165].

Antigen detection — Beta-D-glucan is a cell-wall constituent of many fungi, including Scedosporium/Lomentospora [185]. Detection of beta-D-glucan in the serum of patients in certain at-risk populations with suspected invasive mycoses and/or fungemia, including Aspergillus, Candida, Fusarium, Trichosporon, and Acremonium can be a useful test [186-190]. The diagnostic accuracy of this test for Scedosporium infections is not yet known.

There are no commercially available Scedosporium/Lomentospora specific serologic assays, though some research laboratories have developed antibody-based assays that warrant further investigation [191,192].

MALDI-TOF — Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry has emerged as an additional tool for the rapid identification of molds [193-198]. MALDI-TOF is able to identify and discriminate among different Scedosporium and Lomentospora species. Some clinical laboratories have developed extensive fungal databases for this purpose, and commercial MALDI-TOF systems with fungal databases are available in some reference laboratories.

DIFFERENTIAL DIAGNOSIS — All hyaline molds, including Aspergillus, Scedosporium, Lomentospora, Fusarium, Acremonium, and Paecilomyces exhibit similar appearance in clinical specimens by microscopic examination [2,199]. Septated, nonpigmented hyphae and branching at 45º angles render them indistinguishable from one another, and correlation with culture results is needed for definitive identification [168]. Identification of mold in formalin-fixed paraffin-embedded tissue by polymerase chain reaction amplification and fungal DNA sequencing to genus and possibly species level has been accepted as definitive diagnosis of proven invasive fungal infection [164]. (See 'Culture' above.)

There is substantial overlap in the clinical manifestations that can occur with infections caused by any of the hyaline molds.

SUMMARY AND RECOMMENDATIONS

●During the past few decades, opportunistic fungal pathogens have become increasingly recognized as a cause of infection in severely ill or immunocompromised patients. Although Aspergillus species remain the most common mold to cause invasive infection, other molds are becoming more common. Two of these, Scedosporium apiospermum complex and Lomentospora prolificans, are considered major human pathogens. (See 'Introduction' above.)

●Scedosporium and Lomentospora species are commonly found in soil and polluted water and have a global distribution. (See 'Epidemiology' above.)

●Scedosporium and Lomentospora are mainly associated with infections in immunocompromised hosts, although some localized infections have been described in immunocompetent hosts. Reported infections caused by these pathogens include pneumonia, keratitis, endophthalmitis, central nervous system infections, soft tissue infections, and disseminated disease. (See 'Clinical manifestations' above.)

●The approach to diagnosis is individualized based upon various patient-specific factors, including site and severity of infection, as well as the immune status of the host (table 1). Whenever possible, and especially for immunocompromised hosts and/or for patients with severe disease, clinicians should aggressively pursue a diagnosis when Scedosporium or Lomentospora infection is suspected. (See 'Approach to diagnosis' above.)

●Histologically, Scedosporium and Lomentospora, with septated, nonpigmented hyphae branching at 45º angles, resemble the other hyaline molds such as Aspergillus and Fusarium. Definite diagnosis is made through culture. Culture is also important for testing in vitro susceptibility since these pathogens, particularly L. prolificans, can be resistant to multiple antifungal agents. For mold in formalin-fixed paraffin-embedded tissue, polymerase chain reaction amplification of fungal DNA combined with sequencing allows for definitive identification and proven diagnosis; however, susceptibility testing requires living mold in culture. (See 'Diagnosis' above.)