Uncommon Fungi and Related Species

Scedosporium Apiospermum ( Pseudallescheria Boydii ) Species Complex

In humans, infection with Scedosporium apiospermum, Scedosporium boydii (formerly Pseudallescheria boydii ) and Scedosporium aurantiacum (collectively, the S. apiospermum species complex) can produce two distinct diseases: mycetoma and scedosporiosis (pseudallescheriasis). Mycetoma is a chronic subcutaneous infection characterized by the production of grains (see Chapter 261 ), whereas scedosporiosis includes all other infections caused by Scedosporium spp. The most common sites of Scedosporium infections are lung, bone, joints, and the central nervous system (CNS). Sinusitis, keratitis, endophthalmitis, skin and soft tissue infections, prostatitis, and endocarditis have also been described. These fungi are found in soil and fresh water, especially stagnant or polluted water, throughout the world. Disease is acquired after inhalation of this organism into the lungs or paranasal sinuses or after traumatic inoculation through the skin. There are more than a dozen reported cases of Scedosporium -related pneumonia after near drowning in contaminated water. Although colonization is more common than infection with this organism, an invasive pulmonary disease similar to invasive pulmonary aspergillosis occurs, usually in immunocompromised patients. Local trauma is the most common cause of eye, soft tissue, and osteoarticular infections in previously healthy persons. CNS infection is seen in both immunocompromised and healthy individuals. Infections in immunocompetent patients usually have subacute to chronic courses, whereas those in immunocompromised patients are frequently acute and severe.

Scedosporium can colonize bronchiectatic lungs, including those of patients with cystic fibrosis, or intermittently obstructed paranasal sinuses. Masses of hyphae (fungus balls) have been found in lung cavities. Scedosporium has also been reported as a cause of allergic bronchopulmonary disease (similar to allergic bronchopulmonary aspergillosis), pleural space infection, lung abscess, pneumonia (including aspiration pneumonia), and invasive sinusitis. As with invasive pulmonary aspergillosis, invasive pulmonary scedosporiosis most commonly occurs in patients with prolonged neutropenia, those receiving prolonged high-dose corticosteroid therapy, or those who have undergone allogeneic bone marrow transplantation. Invasive pulmonary disease with associated dissemination appears common and has also occurred in patients with acquired immunodeficiency syndrome (AIDS) and after solid-organ transplantation. Pulmonary disease in severely immunocompromised patients usually manifests with fever, cough, pleuritic pain, and often hemoptysis. Chest radiography may show areas of nodularity, alveolar infiltrates, consolidation, or cavitation. The classic signs of invasive pulmonary aspergillosis, the halo or air crescent signs, may also be seen in invasive pulmonary scedosporiosis. Disseminated disease that manifests with only painful cutaneous nodules or endophthalmitis has also been described in immunocompromised patients. Invasive pulmonary disease with extension to the vertebrae has been described in a patient without apparent immunocompromise.

Localized disease—including infections of the eye, bone, cutaneous tissue, subcutaneous tissue ( Fig. 268.1 ), and osteoarticular tissue—may be seen both with and without immunocompromise. Infection is commonly initiated through traumatic implantation of the fungus from soil or water. Surgery, intravenous drug injection, and repeated corticosteroid injections have less frequently been associated with localized infections. Osteoarticular infection in immunocompetent patients often manifests as a painful, swollen joint with overlying erythema after penetrating injury. In occasional patients, weeks to even years may pass between antecedent trauma and the development of septic arthritis.

Brain abscesses may result from a known or unsuspected lung lesion in immunocompromised patients, including those with AIDS. CNS infection appears to be disproportionately prevalent among patients infected with Scedosporium spp., in comparison with many other mycoses. For example, of 23 solid-organ transplant recipients with Scedosporium spp. infections, 11 (48%) had CNS involvement. Cerebral abscesses are usually multiple; in immunocompetent hosts, they are often reported in association with near drownings in polluted water, such as ponds, pig troughs, and roadside ditches. CNS infection from contiguous spread of sinusitis and after penetrating trauma has also been described. Indolent, severe neutrophilic meningitis has been reported occasionally, usually in patients with intravenous drug abuse or human immunodeficiency virus (HIV) infection. Cerebrospinal fluid culture and smear have yielded negative results; the diagnosis was made at autopsy. The first described human case of Scedosporium spp. was meningitis that was probably iatrogenic after lumbar puncture for the administration of anesthesia.

Isolation of Scedosporium spp. from normally sterile sites is diagnostic. Only rarely are Scedosporium spp. cultured from blood. Growth of the organism from sputum, bronchoalveolar lavage, draining wounds, or paranasal sinus aspirates is less convincing evidence of infection, unless it is accompanied by hyphae on smear or biopsy. Histologically, Scedosporium spp. resemble Aspergillus spp., with dichotomously branching septate hyphae seen in tissue, although branching off to the side at a 60- to 70-degree angle, instead of Y-shaped dichotomous branching, is more common in scedosporiosis. Air-containing spaces, such as a paranasal sinus, can permit sporulation. In addition to hyphae and conidia, distinctive coremia or an ascocarp may indicate Scedosporium as the mold. In neutropenic patients, blood vessel invasion and thrombosis are usual. The fungus grows well in standard mycologic media. After a few days, the mold colony takes on a tan color and has sporulating structures that are quite different from those of Aspergillus. Cultures can produce either asexual conidia or the sexual reproductive structure, cleistothecia. Identification is usually by DNA sequencing, but matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is being used increasingly for identification of the mold.

Effective therapy of scedosporiosis remains elusive. In vitro and clinical resistance to amphotericin B, as well as breakthrough infections, have been reported repeatedly. Surgical débridement has been an important adjunct in treatment of soft tissue, bone, joint, and pleural and paranasal sinuses, although it is not curative by itself. Intraarticular instillation of amphotericin B may have contributed to success of treatment in a few patients. The rate of mortality with brain abscess has traditionally been noted to exceed 75%. Susceptibility to azoles and echinocandins in vitro has proven variable. Voriconazole has the best activity in vitro and is often considered the drug of choice, but reducing the level of immunosuppression is vital. Response to posaconazole was achieved in a single reported case of brain abscess. Voriconazole is approved by the US Food and Drug Administration (FDA) for patients with Scedosporium spp. infection refractory to other approved antifungal agents and for patients who cannot tolerate those agents. This indication was based on success reported in 15 of 24 patients treated with this agent (including 6 of 10 with CNS infection). Because of poor response to the only approved agent, amphotericin B, most experts believe that voriconazole is the drug of choice in the treatment of scedosporiosis .

Lomentospora (Formerly Scedosporium ) Prolificans

Lomentospora prolificans (formerly Scedosporium prolificans or Scedosporium inflatum ), a fungus found in soil, was first described in 1984 as an agent of human disease. Since that time at least 161 additional cases have been reported. Infection can occur in both immunocompromised and immunocompetent patients. Patients with intact immunity most frequently have focal infections (usually osteoarticular) associated with trauma, whereas immunocompromised persons most frequently have disseminated disease, associated with malignancy. In one review, only 34 of 162 patients (21%) were noted to have no underlying disease; 72 of the 162 patients (44%) had disseminated infection.

In immunocompetent patients, infection is usually localized and associated with trauma, including surgery. These cases have included infections of bone and joints ( Fig. 268.2 ), eye, or wounds and onychomycosis. Immunocompromised patients, commonly those undergoing cytoreductive chemotherapy or bone marrow transplantation, present with fungemia and fever with neutropenia. Skin lesions, myalgia, endophthalmitis, endocarditis, and pulmonary infiltrates have been described in this setting. Skin lesions have been described as a papular rash, later becoming necrotic. Disseminated disease without neutropenia has been described in patients who have undergone lung and kidney transplantation. Fatal localized CNS infection was reported in a child with acute leukemia who had received six intrathecal chemotherapeutic injections. L. prolificans has also been recovered from the external ear and sputum of patients without apparent disease. Sputum colonization has been observed in patients with AIDS and cystic fibrosis and in those who have undergone liver or lung transplantation.

Diagnosis is most commonly established by the recovery of the organism from culture of infected sites, including skin biopsy samples. Disseminated disease in immunocompromised patients is usually diagnosed through blood culture. Identification of L. prolificans is based chiefly on DNA sequencing or the morphologic characteristics of the asexual structures produced by the mold in culture.

No antifungal therapy currently available is effective in treating these infections. L. prolificans appears to be intrinsically resistant to most antifungals. Successful therapy of joint infections has, however, been reported with the use of surgical débridement with or without intraarticular amphotericin B. Disseminated infection is usually resistant to antifungal agents and carries a high mortality rate. Survival was reported in one patient with disseminated disease and neutropenia who received granulocyte colony-stimulating factor (G-CSF) and amphotericin B, followed by itraconazole. In one animal model, liposomal amphotericin B with the addition of G-CSF improved survival. Of the currently available antifungal agents, voriconazole appears most promising in vitro, with better activity than amphotericin B, itraconazole, or posaconazole. Unfortunately, current dosing regimens of voriconazole are not associated with serum concentrations at which the drug appears to be effective in vitro. One report described a 44% response rate (16 of 36 patients) with voriconazole. The investigational azole, albaconazole (UR-9825), appears more active than voriconazole in vitro and has shown potential in one animal model. Because of the in vitro and in vivo resistance of L. prolificans to currently available agents, the effect of combining agents has been examined. In laboratory studies, synergy has been shown through the use of combinations of amphotericin B with pentamidine and of terbinafine with voriconazole, itraconazole, or miconazole. Clinical support for this in vitro synergy is limited, although anecdotal experiences have been reported with voriconazole and terbinafine.

Dark-Walled Fungi and Agents of Phaeohyphomycosis

Phaeohyphomycosis is a loosely defined term used to group infections caused by molds (and a few yeasts) that produce dark cell walls. Also described as dematiaceous, these are a diverse group of fungi found in the soil and air and growing on plants and in organic debris. The number of genera and species of fungi causing phaeohyphomycosis is quite large. Frequent changes in species names have compounded the difficulty in comparing similar cases from the literature. Chromoblastomycosis (see Chapter 260 ) and mycetoma (see Chapter 261 ) are distinct infections that include dark-walled fungi as etiologic agents that are generally not included in this loose classification ( Table 268.1 ). The syndromes most commonly produced by the dark-walled fungi include cutaneous and subcutaneous disease (other than chromomycosis or mycetoma), brain abscesses, and sinusitis. Fungemia and disseminated disease have more commonly been described in immunocompromised individuals. Meningitis, pneumonia, prosthetic valve endocarditis, contamination of saline-filled breast implants, infections in peritoneal dialysis and central venous catheters, osteomyelitis, and septic arthritis have also been reported. For most clinical purposes, it is preferable to describe disease by the type of infection and species name, such as “ Cladophialophora bantiana brain abscess,” and to reserve the term phaeohyphomycosis for cases in which no culture data exist or in which recovered fungi have not yet been identified.

Subcutaneous phaeohyphomycosis typically begins as a single red nodule, usually on the extremities. In an immunocompetent person, an indolent, painless expansion in the skin and subcutaneous tissue occurs, sometimes with cyst formation ( Fig. 268.3 ). More rapid local progression and, in rare cases, extension to the brain can occur in immunosuppressed patients. A history of minor trauma is often present, or a splinter is found in the resected lesion. The fungi causing subcutaneous phaeohyphomycosis are extraordinarily diverse, but species of Exophiala, Exserohilum, Phialophora, and Curvularia (which includes most clinical species formerly in the genus Bipolaris ) are particularly common.

Brain abscess is one of the best-described syndromes produced by the dark-walled fungi. Disease manifests with headache of indolent onset, low-grade or no fever, and development of focal neurologic signs. There is rarely a history of exposure to dust or mold, no obvious pulmonary portal, and no evidence of dissemination outside the CNS. Affected male patients have outnumbered female patients 3 : 1, the median age of diagnosis is 38 years, and most patients have been immunocompetent. Abscesses may be single or multiple and, on computed tomography or magnetic resonance imaging, are well localized within the cerebral cortex ( Fig. 268.4 ). Purulent meningitis, with or without brain abscess, may also be observed ( Fig. 268.5 ). Hematoxylin and eosin (H&E) staining reveals abscesses to have purulent centers with surrounding granulomatous reaction, and organisms appear as septate hyphae with golden brown cell walls. As in other forms of infections with the dark-walled fungi, hyphae are commonly irregular in diameter, and yeastlike cells are seen with some species. The species most commonly causing these infections is C. bantiana (previously named Xylohypha bantiana, Cladosporium bantianum, and Cladosporium trichoides ), but disease is also caused by Rhinocladiella (formerly Ramichloridium ) mackenziei, Ochroconis gallopava (formerly known as Dactylaria constricta var. gallopava ), Exophiala (Wangiella) dermatitidis, Curvularia (formerly Bipolaris ) spicifera, Curvularia (formerly Bipolaris ) hawaiiensis, Chaetomium spp., and, even more rarely, other phaeohyphomycetes. R. mackenziei infections are reported chiefly from the Middle East and India, and E. dermatitidis cases predominate in the Far East. Fonsecaea monophora (formerly classified with Fonsecaea pedrosoi ) has been recognized as an etiologic agent of CNS phaeohyphomycosis.

Iatrogenic meningitis and other infections related to epidural injections of corticosteroids have been reported in two recent outbreaks traced to environmental contamination at compounding pharmacies. The first report that involved infection with E. dermatitidis resulted in four cases of meningitis and one case of sacroiliitis in 2002. The second and more recent outbreak included meningitis due to Exserohilum rostratum. Between September and December of 2012, 590 cases of infection and 37 deaths were confirmed among the 13,534 people potentially exposed to the contaminated lots of methylprednisolone. Early cases usually presented with meningitis, some with stroke from invasion of arteries in the basilar meninges. Later cases more often presented as more localized disease, depending on the site injected with steroid. Lumbar injections were most common, leading to epidural abscess with increased lumbar pain and some with cauda equina syndrome. Indolent septic arthritis occurred in the sacroiliac joint or rarely in injected peripheral joints. Although hyphae were commonly found in surgical specimens, cultures were only positive for E. rostratum in 14% and polymerase chain reaction in 29%. Amphotericin B seemed the most effective treatment but was followed by several months of voriconazole therapy. The optimal course of treatment and prevention of relapse is not yet known.

Twenty-one surgical site infections with Bipolaris (currently Curvularia ) spp. were reported after cardiothoracic surgery in 10 hospitals during 2008–2013. Most infections were in the mediastinum or sternal wound. Delayed wound closure was the most frequent predisposing factor.

Allergic fungal sinusitis may be caused by a wide variety of fungi, although the dark-walled fungi (usually Bipolaris, Exserohilum, Curvularia, or Alternaria spp.) and Aspergillus spp. are the most common causes. By definition, disease is allergic and confined to the lumen of the paranasal sinuses. Patients present with an indolent onset of sinus pain or painless proptosis. A history of seasonal or allergic rhinitis is common, and there may be a history of nasal polyps. On computed tomography or magnetic resonance imaging, one or more paranasal sinuses appear full of fluid, with outward pressure on the thinner bony sinus walls, such as the lamina papyracea, medial maxillary wall, or midline sphenoidal septum. Maxillary and ethmoid sinuses are usually involved, but sphenoid and frontal sinuses may be diseased ( Fig. 268.6 ). Surgical débridement of the paranasal sinus removes dark, inspissated mucus; histopathologic examination reveals that this mucus has eosinophils with Charcot-Leyden crystals (degenerated eosinophils) and scattered septate hyphae. The walls of the hyphae may not appear as dark as those seen in brain abscess. Irregular diameter and bulbous swellings may help distinguish these hyphae from Aspergillus, but culture is essential for diagnosis. The most serious sequela of allergic fungal sinusitis is brain invasion, which, when it occurs, usually does so in immunocompromised hosts ( Fig. 268.7 ). Extension from the ethmoid or frontal sinus into the frontal lobe of the brain can be clinically silent. Erosion into the frontal lobe, clivus, pterygoid space, or middle fossa occurs but is rare. Sudden blindness can result from compression of the optic nerve posterior to the orbital fissure. Compression of the orbit by lateral bulging of the lamina papyracea does not decrease visual acuity but does cause proptosis.

Diagnosis of these infections requires observation of the fungi invading tissue or recovery of the fungi in culture from an otherwise sterile site. Typical pathology is necessary for the diagnosis of allergic fungal sinusitis. In disease outside the CNS, these organisms may not always appear dark walled on standard histopathologic stains. Cell wall melanin may be visible as a brownish-yellow color on H&E stain ( Fig. 268.8 ). If melanin is not evident on fresh preparations of H&E stain, it can be stained by the Fontana-Masson method, which better enables diagnosis, especially if culture results are negative or if culture is not performed. Fontana-Masson stain is, however, not 100% specific for the dark-walled fungi because the cell walls of some Aspergillus and other fungi with hyaline hyphae have been shown to stain dark with this method.

Surgical débridement is essential to the cure of most of the infections caused by the dark-walled fungi. Good surgical curettage often suffices in treating allergic sinusitis if the cranial cavity has not been invaded. Amphotericin B is probably the drug of choice for life-threatening infection, including CNS infection. Itraconazole has been used frequently with success in infections that are not life threatening. To help prevent further recurrence in patients who have recurrent allergic fungal sinusitis, long-term itraconazole therapy may be used after repeated surgical drainage. In vitro, in response to most of these fungi, voriconazole commonly produces minimal inhibitory concentrations (MICs) that are similar to or lower than those seen with itraconazole, which makes this new drug a potentially useful therapeutic agent. Posaconazole and caspofungin have also been shown to have in vitro activity against many of these fungi. Posaconazole has been reported to produce a good clinical response in single cases of CNS and disseminated infection caused by R. mackenziei and Exophiala spinifera, respectively. Response of a skin and soft tissue infection to terbinafine, after poor response to amphotericin B and itraconazole, has also been reported.

Fusarium Spp

Species in the genus Fusarium are common in soil and organic debris and are frequently the cause of disease in plants. Current taxonomy divides the species causing infections in humans into seven species complexes, called Fusarium solani, Fusarium oxysporum, Fusarium fujikuroi, Fusarium dimerum, Fusarium chlamydosporum, Fusarium incaratum-equiseti, and the complex including Fusarium sporotrichioides. The first three species complexes in the list are those most commonly encountered clinically. Acremonium falciforme has been moved to the F. solani spp. complex and renamed Fusarium falciforme. The most common manifestations of fusariosis are keratitis and onychomycosis. Infection of soft tissue, including mycetoma, can occur after traumatic inoculation in the healthy host. Inhalation into the lung or paranasal sinus or minor trauma to the skin can lead to fusariosis in immunocompromised patients.

Rare cases of dissemination have been described in the clinical setting of severe burns, trauma, and heat stroke. Most commonly, however, fusariosis occurs in patients with acute leukemia (70%–80% of cases) and prolonged neutropenia (>90% of cases). In one review of 43 patients, the median duration of neutropenia was more than 3 weeks. Fusariosis is also increasingly reported in patients receiving allogeneic hematopoietic stem cell transplants. The portal of entry in most of these cases of disseminated infection is not known. Inhalation, ingestion, and entry through skin trauma have been suggested. Sinusitis has preceded dissemination in a few reports. Hematogenous spread has been attributed to indwelling intravascular catheters. Onychomycosis with paronychia has appeared to be a source of disseminated infection in some patients. Water has been suggested as a source of these infections; the fungus was found in one hospital water supply system and in several water sources at a dialysis center.

Infection commonly manifests with fever and myalgia unresponsive to broad-spectrum antibacterial antibiotics during periods of profound neutropenia. Disseminated fusariosis has been recognized in patients who have been receiving empirical or prophylactic antifungal therapy. Skin lesions occur in 60% to 80% of infections, usually appearing as multiple papules or deep-set, painful nodules ( Fig. 268.9 ). They may initially be flat (macular) with a central pallor, but later they become raised, erythematous, and necrotic ( Fig. 268.10 ). Lesions are most common on the extremities but have been reported on the trunk and face as well. In profoundly neutropenic patients, this infection can progress rapidly to death, in a manner similar to that in invasive aspergillosis. Skin lesions, denoting dissemination, can occur within a day of the onset of fever. In patients whose neutrophil levels recover, the infection can progress slowly over weeks until death or can become controlled and eventually cured.

Recovery of the fungus from blood and skin lesion biopsy are the two most common and effective ways to diagnose this infection. In contrast to aspergillosis, in which blood culture results are nearly always negative, fusariosis is accompanied by positive blood culture results about 50% of the time (48 of 98 patients in one review ). The septate hyphae of Fusarium spp. have both acute and right-angle branching and usually appear similar to those of Aspergillus on histopathology. Hyphae are often difficult to visualize with routine H&E staining but are easily identified when tissue is stained with Gomori methenamine silver or periodic acid–Schiff. Fusarium, unlike Aspergillus, can sporulate in deep tissue by a process called adventitious sporulation. Identification of these spores along with hyphae can suggest the diagnosis. Conidia (spores) in tissue do not resemble the banana-shaped, septate conidia in culture but are ellipsoidal, spherical, or cylindrical and not septated. They may be seen free or attached to the end of a hypha. Gram stain of a blood culture may also show these spores. The spore-bearing structure, called a phialide, may appear as a flat, truncated hyphal end if the spore has become detached. In culture, the characteristic feature of Fusarium is the production of sickle (banana)-shaped multiseptate macroconidia. Identification beyond the genus level is best done by molecular methods, with multilocus sequence typing currently favored. MALDI-TOF MS has the promise of rapid identification of Fusarium isolates, although not necessarily to the species level. Patients with fusariosis may have positive beta- d -glucan tests and Aspergillus galactomannan assays in serum.

The optimal treatment for disseminated fusariosis has not been established. Overall mortality with this infection has been reported to range from 50% to 80%. Survival is almost always associated with the recovery from neutropenia, although corticosteroid use also impairs response to therapy. In an analysis of responders versus nonresponders in one study of 43 patients, investigators noted associations with malignancy in remission (100% vs. 10%), adequate neutrophil counts (100% vs. 0%), and lack of significant (grade II or greater) graft-versus-host disease (0% vs. 66%). Removal of indwelling venous catheters has been associated with improvement and thus should be considered in all cases of fungemia. Surgical débridement of soft tissue infections resulting from trauma is helpful. Currently, voriconazole or a lipid formulation of amphotericin B is favored for deep infections. Natamycin 5% ophthalmic suspension is used for keratitis (see Chapter 113 ). Echinocandins are not recommended for deep infections, although terbinafine, posaconazole, and combination regimens have been reported as useful. Animal models have shown liposomal amphotericin B, posaconazole, and voriconazole to be potentially useful. On the basis of successful therapy in 9 of 21 patients (43%) who received voriconazole, the FDA approved this agent for second-line use in fusariosis. Successful therapy in 10 of 21 patients (48%) with posaconazole has also been reported. Unfortunately, cases of breakthrough infection in patients receiving voriconazole or posaconazole have been reported. The addition of colony-stimulating factors (G-CSF or granulocyte-macrophage colony-stimulating factor) or granulocyte transfusions to specific antifungal therapy have also been reported, but the benefit of these adjunctive therapies is also not proven.

Other Opportunistic Molds

In immunocompromised hosts, virtually any of the normally nonpathogenic fungi may cause disease. In addition to more common infections caused by Aspergillus and Fusarium spp., other rare light-colored (hyaline) molds, including species of Paecilomyces, Acremonium, and Trichoderma, have been described as causing clinical disease more frequently than do other rare fungi. Some authorities have grouped diseases caused by molds with light-colored cell walls into a group, termed the hyalohyphomycoses . As with the dark-walled fungi, description of these infections by the causative organisms is preferable to minimize confusion. Paecilomyces has been reported to cause keratitis, endophthalmitis, and cutaneous and subcutaneous infections, as well as catheter-related fungemia, sinusitis, and disseminated infection. Like Fusarium, both Paecilomyces and Acremonium organisms have been reported to form reproductive structures in vivo in a process called adventitious sporulation. This is believed to account for the much higher frequency of recovery in blood culture observed in infections involving these three genera. Also like Fusarium, both are typically associated with poor response to amphotericin B and the older azoles, although resistance varies among species. Paecilomyces varioti is susceptible to amphotericin B, and infections have been treated successfully with this agent. Paecilomyces lilacinus, now named Purpureocillium lilacinum, responds poorly to amphotericin B and, in vitro, is resistant to this agent, caspofungin, and the older azoles. In vitro testing has shown multiple strains of these fungi to be more susceptible to voriconazole and posaconazole, but clinical treatment results are limited to case reports and small case series. Scopulariopsis spp. are common in the soil, air, and decaying organic debris. Isolates identified as forming ascospores are placed in the genus Microascus, the teleomorph of Scopulariopsis. Onychomycosis, keratitis, and deeply invasive or disseminated infections have been reported. Hyphae are septated and branch at acute angles. Bulbous swelling of hyphal segments may be seen, a feature usually encountered in agents of phaeohyphomycosis.