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Journal of Clinical Microbiology, April 2005, p. 1495-1504, Vol. 43, No. 4
0095-1137/05/$08.00+0     doi:10.1128/JCM.43.4.1495-1504.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

MINIREVIEW

Unusual Fungal and Pseudofungal Infections of Humans

M. A. Pfaller1,2* and D. J. Diekema1,3

Departments of Pathology,1 Medicine, College of Medicine,3 Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa2


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INTRODUCTION
 
The spectrum of mycotic disease continues to expand well beyond the familiar entities of candidiasis and aspergillosis (73, 99). The field of medical mycology has become a challenging study of infections caused by a wide and taxonomically diverse array of opportunistic fungi (73). Previously we reviewed some of the less-common "emerging" opportunistic fungal pathogens with an emphasis on resistance to new and established antifungal therapies (73). In this article, we discuss several exotic and unusual infections that historically have been considered fungal or pseudofungal infections based on their clinical and histopathologic presentation but have been difficult to classify because they grow poorly or not at all on artificial media. In one instance, recent molecular evidence has indicated that an organism previously considered to be a fungus (Rhinosporidium seeberi) is in fact a protistan parasite (29, 37). We also discuss a nonreplicative pulmonary infection (adiaspiromycosis), two subcutaneous mycoses (entomophthoromycosis and lobomycosis), two algal infections (chlorellosis and protothecosis), and an infection due to the oomycete Pythium insidiosum. The diagnosis of these rare infections is based largely on detection of characteristic structures observed on histopathologic examination of tissue. A listing of the infections, the etiologic agents, and the typical morphology in tissue is provided in Table 1 and Fig. 1 and 2 .


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  		TABLE 1. Morphologic features of fungal and pseudofungal infections of unusual or uncertain etiologya



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  		FIG. 1. Examples of unusual fungal infections. (A) Pulmonary adiaspiromycosis. The hematoxylin-eosin stain defines three layers in the wall of the adiaconidium. Each adioconidium has evoked a fibrogranulomatous response. Magnification, x30.4. Reprinted from reference 15 with permission of the publisher. (B) Entomophthoromycosis. The hematoxylin- and eosin-stained section of tissue shows broad septate hyphae surrounded by an eosinophilic sheath (Splenodore-Hoeppli phenomenon). Copyright 1987 American Society of Clinical Pathologists. Reprinted from reference 14 with permission. Panels C and D show lobomycosis caused by Lacazia loboi, which forms a single chain with individual cells joined by tubelike bridges. (C) Organism revealed by Gridley staining. Magnification, x304. Copyright 1987 American Society of Clinical Pathologists. Reprinted from reference 14 with permission. (D) Organism revealed by GMS. Reproduced from the DoctorFungus website (www.doctorfungus.org) with permission.



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  		FIG. 2. Examples of unusual pseudofungal infections. (A) Chlorellosis. Chlorella sp. stained by GMS and showing intracellular chloroplasts and doubly contoured cell wall. Reprinted from reference 15 with permission of the publisher. (B) Protothecosis. Prototheca wickerhamii. Single and endosporulating algal cells that are readily demonstrated with the PAS stain are shown. A classic morula form is present. Magnification, x740. (C) Pythiosis. Pythium insidiosum invading an arterial wall. GMS reveals infrequently septate, weakly stained hyphae, and hyphal fragments resemble those of Zygomycetes. Magnification, x118.4. Reprinted from reference 15 with permission of the publisher. (D) Rhinosporidiosis: mature sporangium of Rhinosporidium seeberi showing the zonal arrangement of immature, maturing, and fully mature sporangiospores. Magnification, x355.2. Copyright 1987 American Society of Clinical Pathologists. Reprinted from reference 14 with permission.


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UNUSUAL FUNGAL INFECTIONS
 
Adiaspiromycosis. Adiaspiromycosis (also known as adiaspirosis or haplomycosis) of humans is a rare, self-limited pulmonary infection caused by inhalation of the asexual conidia of the saprophytic soil fungus Emmonsia crescens (formerly Chrysosporium parvum var. crescens) (72, 86). E. crescens grows as a mold in nature and in culture at room temperature. The hyphae are hyaline, septate, and branched, with small (2 to 4 µm) aleurioconidia borne on conidiophores arising at right angles to the vegetative hyphae. When introduced into the lungs or upon incubation in vitro at 40°C, the conidia transform into spherical adiaconidia, which subsequently undergo massive enlargement but show no evidence of replication (e.g., no budding or endospore formation).

The mature adiaconidia are thick walled (20 to 70 µm) spherules that measure 200 to 400 µm or more in diameter (Table 1). The walls of the spherule are refractile and when stained with hematoxylin-eosin (H&E) appear to be comprised of two layers: a narrow, outer, eosinophilic layer containing periodic fenestrations and a broad, hyaline, inner layer composed predominantly of chitin (Fig. 1A) (27, 102). The conidial walls stain with Gomori's methenamine silver (GMS), periodic acid-Schiff (PAS), and the Gridley fungus stains but not with Mayer's mucicarmine (Table 2). In human lung tissue, the adiaconidia are usually empty but may contain small eosinophilic globules along the inner surface of the walls (102).


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  		TABLE 2. Comparative morphologic features of fungi and pseudofungal organisms that appear as large spherules in tissuea

Human adiaspiromycosis is uncommon (27), but it has been reported from South and Central America, Israel, Europe, and the United States (24, 27, 66, 95, 102). Both pulmonary and disseminated adiaspiromycosis have been found in patients with AIDS (24, 95). Rodents may serve as a zoonotic reservoir for the disease, although the fungus causing disease in rodents, Emmonsia parva (formerly Chrysosporium parvum var. parvum), rarely infects humans (24, 26, 72, 86). E. crescens is found in nature predominantly in temperate zones, and the likely mode of human infection is accidental inhalation of fungal conidia aerosolized from contaminated soil.

Three forms of human adiaspiromycosis are recognized: (i) solitary granuloma, (ii) localized granulomatous disease, and (iii) diffuse, disseminated granulomatous disease (27, 95). The severity of the disease depends upon the number of spores inhaled (27). Most cases of documented adiaspiromycosis have been asymptomatic. In the case of a limited inoculum, the disease remains localized, and pulmonary nodules may be detected radiographically or incidentally at autopsy or in surgical specimens of lung removed for another reason (95). Patients with the disseminated granulomatous form of pulmonary adiaspiromycosis may experience fever, cough, and progressive dyspnea due to compression and displacement of distal airways and alveolar parenchyma by the expanding granulomas (27, 95). Fungal replication in the lungs does not occur; however, other organs may be involved (rarely), including the skin (42), peritoneum (23), and bone (24). Extrapulmonary dissemination causing extensive osteomyelitis and bone marrow involvement was found in a patient with AIDS (24).

Adiaspiromycosis is diagnosed by histopathologic examination of affected tissue and identification of the characteristic adiaconidia (27, 95, 102). The organism is not easily cultured and is not readily observed in sputum, and serological and skin tests are unreliable and not widely available (27, 95). Histologically, each adiaconidium is surrounded by an epithelioid and giant-cell granulomatous response, which is further encompassed by a dense capsule of fibrous tissue (Fig. 1A) (102). Importantly, all of the granulomas are at similar stages of development, reflecting a one-time exposure without subsequent replication within the lung.

Adiaconidia should not be confused with the spherules of Coccidioides immitis or Rhinosporidium seeberi, two other organisms that produce large spherules in tissue (Table 2) (102). In contrast to those of C. immitis, the adiaconidia of E. crescens are much larger, have a thicker wall, and do not contain endospores (Fig. 1A). The sporangia of R. seeberi are distinguished from those of both C. immitis and E. crescens by the zonation of the internal sporangiospores and by the presence of distinctive eosinophilic globules contained within the mature sporangiospores (Table 2 and Fig. 2D). No other fungus of medical importance has walls as thick as those of the adiaconidia of E. crescens.

Human pulmonary adiaspiromycosis is self-limited, and specific antifungal therapy is usually not necessary (27). Surgical intervention with limited resection may be required if the condition progresses. The organism appears to be susceptible to azole antifungal agents (68), and treatment with ketoconazole (55, 84), fluconazole (95), and amphotericin B (24, 66, 95) has been used with success in severe or progressive infection in immunocompromised individuals.

Entomophthoromycosis. Entomophthoromycosis is caused by zygomycetes of the order Entomophthorales: Conidiobolus coronatus, Conidiobolus incongruous, and Basidiobolus ranarum (previously Basidiobolus haptosporus). These fungi cause a chronic subcutaneous form of zygomycosis that occurs sporadically as a result of traumatic implantation of the fungus that is present in plant debris in tropical environments. The predilection for host and anatomic site of infection is species specific: B. ranarum causes subcutaneous infection of the proximal limbs in children, whereas Conidiobolus spp. infection is localized to the facial area predominately in adults (14, 31, 78, 96).

The appearance of the agents of entomophthoromycosis in tissue differs from that of the mucoraceous zygomycetes. The hyphal elements are sparse, often fragmentary, and surrounded by intensely eosinophilic Splendori-Hoeppli material (Fig. 1B) (14). The inflammatory response is granulomatous, containing eosinophils, lymphocytes, plasma cells and macrophages (Table 1). Septations within the hyphae are infrequent; however, they are more prominent than those seen with the Mucorales. In contrast to those of the Mucorales, the hyphae of the Entomophthorales are rarely angioinvasive.

Both types of entomophthoromycosis are seen most commonly in Africa and to a lesser extent in India (16, 31, 62, 78, 96). Infection due to Basidiobolus spp. has also been reported from the Middle East, Asia, and Europe (62, 78, 96), whereas that due to Conidiobolus spp. has been reported from Latin America as well (16, 31). Cases of basidiobolomycosis and conidiobolomycosis in the United States are extremely rare and appear to be more acutely invasive than those seen more commonly in the tropics (25, 40, 53, 91, 97, 98).

Both basidiobolomycosis and conidiobolomycosis are rare diseases without known predisposing factors such as acidosis or immunodeficiency. Infection due to B. ranarum is thought to occur following traumatic implantation of the fungus into the subcutaneous tissues of the thighs, buttocks, and trunk. This form of zygomycosis occurs mainly in children (80% under the age of 20 years) with a male/female ratio of 3:1 (6, 19, 32). Infections with Conidiobolus spp. occur following inhalation of the fungal spores, which then invade the tissues of the nasal cavity, the paranasal sinuses and facial soft tissues. There is a 10:1 male/female ratio, and the disease is seen predominantly in young adults (31, 78). Infection among children is rare.

Basidiobolomycosis is characterized by disk-shaped rubbery, movable masses that may be quite large and are localized to the shoulder, pelvis, hips, and thighs (14, 32). The masses may expand locally and eventually ulcerate. Gastrointestinal basidiobolomycosis is extremely rare, with only 15 cases reported worldwide (46, 53, 70, 101, 106, 107). Notably, all seven cases of gastrointestinal basidiobolomycosis reported from the United States have occurred in adults residing in Arizona. Potential risk factors include prior ranitidine use and longer residence in Arizona (53). This suggests ingestion and environmental exposure as important factors in this unusual mycosis. Widespread fatal systemic dissemination was recently reported for a previously healthy woman, with involvement of brain, pancreas, kidney, stomach, lung, and spleen (5).

Infection with Conidiobolus spp. is often confined to the rhinofacial area and usually does not come to medical attention until there is noticeable swelling of the upper lip or face (16, 31). The swelling is firm and painless and may progress slowly to involve the nasal bridge and the upper and lower face, including the orbit. The facial deformity can be quite impressive; however, due to the lack of angioinvasion, intracranial extension or dissemination is rare. As with basidiobolomycosis, cases of conidiobolomycosis originating in the United States are rare but appear to be more acutely invasive than those seen in the tropics (25, 40, 91, 97, 98). In particular, conidiobolomycosis in immunocompromised patients is more deeply invasive and can cause endocarditis and widespread fatal dissemination (40, 97, 98).

Entomophthoromycosis requires biopsy for diagnosis, despite the characteristic clinical features of the infections. The histopathologic picture is the same for both organisms and is marked by focal clusters of inflammation and typical zygomycotic hyphae often surrounded by eosinophilic Splendori-Hoeppli material (Table 1). The organisms can be cultured from clinical material on standard mycologic medium. Cultures should be inoculated soon after tissue procurement, since the organisms do not survive at 4°C. In contrast to the Mucoraceae, the Entomophthorales grow as waxy and folded colonies consisting of hyphae with rare septae and sporophores bearing single-celled round spores. At maturity the spores are forcibly ejected into the surrounding environment. B. ranarum produces abundant zygospores with thick walls and a prominent beak-like appendage.

Both types of infection may be treated with itraconazole (30). Alternatively, potassium iodide, amphotericin B, fluconazole, or terbinafine or combinations of these drugs have been used (28, 31, 33, 53). The role of new and investigational azoles (e.g., posaconazole, which is active against some Mucorales) in treatment of entomophthoromycosis is not known. Facial reconstructive surgery may be necessary in the case of conidiobolomycosis, as the extensive fibrosis remains after eradication of the fungus. In the case of gastrointestinal basidiobolomycosis, it is recommended that patients undergo resection of all affected bowel and debridement of other involved tissues, followed by ≥3 months of antifungal therapy with itraconazole (53).

Lobomycosis. Lobomycosis is a chronic mycosis of the skin caused by the fungus Lacazia loboi (formerly Loboa loboi) (89). The disease is seen primarily in the South and Central American tropics. Natural infection occurs only in humans and dolphins, although it has been reproduced by injecting infected tissue into hamsters and armadillos (79). There is also one well-documented case of experimental inoculation in a human volunteer who developed a single lesion 3 months after intradermal injection of infected tissue (7). The organism has never been cultured in vitro.

L. loboi is globose, thick-walled, and yeast-like in appearance (9). The cells are 6 to 12 µm in diameter and have a hyaline double refractile cell wall. The organism reproduces by sequential budding, leading to the production of chains of cells linked to one another by a tubular connection, or isthmus (Fig. 1C and D). Some of the cells may have secondary buds, giving rise to branched or radiating chains of cells (9, 80). The globose budding cells of L. loboi may resemble the "mariners wheel" form of Paracoccidioides brasiliensis in tissue; however, the consistent diameter and chain-like arrangement of the yeast cells of L. loboi distinguish it from P. brasiliensis (9). L. loboi is usually intracellular, although extracellular forms may be seen.

Lobomycosis is endemic in the tropical regions of Central and South America and has been reported in central and western Brazil, Bolivia, Colombia, Costa Rica, Ecuador, Guyana, French Guiana, Mexico, Panama, Peru, Surinam, and Venezuela (8, 9, 80, 89). Isolated cases have been reported from Holland (88), and a single case recently was reported in the United States with a patient with a history of travel to Venezuela (9).

Although a plant reservoir has not been identified, L. loboi is believed to be a saprophyte of soil or vegetation. Lobomycosis predominates in tropical regions with thick vegetation, such as the Amazon rain forests, and among agricultural workers, hunters, fishermen, and miners (8, 80). Cutaneous trauma is believed to be the mode of infection.

Given the fact that lobomycosis occurs in marine and freshwater dolphins (17, 21, 60, 88), an aquatic habitat is likely as well. Infection among dolphins has been reported in Florida, the Texas coast, the Spanish-French coast, the south Brazilian coast, and the Surinam River estuary (10, 17, 21, 60, 89). Possible dolphin-to-human transmission has been reported for a handler of an affected dolphin (88), but there is no evidence of human-to-human transmission.

Lobomycosis occurs primarily in men, although it may also be seen in women who are involved in farming and jungle clearing. Farmers, miners, hunters, and rubber plant workers have an increased incidence of disease (8, 80). There is no apparent racial or ethnic predilection, and lobomycosis affects all age groups, with the peak age of onset being 20 to 40 years (80).

Lobomycosis is characterized by slowly developing cutaneous nodules of various sizes and shapes that tend to arise on traumatized areas of skin, such as the face, ears, arms, legs, and feet. Local cutaneous spread may occur through autoinoculation. The dermal lesions are polymorphic, ranging from macules, papules, keloidal nodules, and plaques to verrucous and ulcerated lesions, all of which may be present in a single patient. The nodular keloid-like lesion is the most common (8). The disease is characterized by a long dormancy period of months to years, and the increase in the number and size of lesions may progress slowly over a period of 40 to 50 years (8, 9, 80). The disease does not involve mucous membranes or internal organs; however, it has been found to affect regional lymph nodes in 10 to 25% of cases (3). Squamous cell carcinoma has been described developing in old scar lesions of lobomycosis (4). There are no systemic manifestations of the disease, and aside from occasional pruritis and hypesthesia or anesthesia of the affected area, patients are asymptomatic (80).

Diagnosis is based on demonstrating the presence of the characteristic yeast cells in lesion exudates or tissue sections (8, 9, 80, 89). Biopsy reveals a dispersed granulomatous infiltrate with giant cells, macrophages, epithelioid cells, and numerous round yeast cells in chains of 6 to 10 (Table 1 and Fig. 1C and D) (8, 64). The epidermis is usually atrophic but may show pseudoepitheliomatous hyperplasia or ulceration. L. loboi is mostly intracellular within giant cells and macrophages. Fibrosis is infrequent, and there is no necrosis (8).

L. loboi stains intensely with both GMS and PAS stains. The cell wall of L. loboi contains constitutive melanin that is readily detectable by use of the Fontana-Masson histologic stain (89, 90). H&E stain reveals the thick doubly contoured hyaline cell wall and one or more hematoxylinophilic nuclei (64). Asteroid bodies in giant cells are present in approximately 25% of biopsies of lobomycosis (79).

Despite a gross appearance that resembles a keloid, microscopically the lesions of lobomycosis are not fibrotic, whereas keloids exhibit marked fibrosis (64). Conversely, keloids lack granulomas and fungal elements. The morphology and pattern of budding of L. loboi are distinctive and should not be confused with that of P. brasiliensis (multiple buds, variable size, melanin negative), Blastomyces dermatitidis and Histoplasma capsulatum var. duboisii (no chains of cells), or Sporothrix schenckeii and H. capsulatum var. capsulatum (both smaller, 2 to 8 µm versus 5 to 12 µm) (8, 64, 89, 90). These fungi will also grow in culture, whereas L. loboi has never been cultured in vitro (80, 89).

There is no effective medical treatment for lobomycosis, although clofazimine has been reported to be partially effective in some cases (8). Early lesions are managed by surgical excision with wide margins (4). More-widespread disease usually recurs when treated surgically and does not respond to antifungal therapy due to the slow generation time of L. loboi (77).


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UNUSUAL PSEUDOFUNGAL INFECTIONS
 
Although not caused by true fungi, the infections discussed in this section have historically been included with the mycoses due to their clinical and histopathologic presentations. Medical treatment of these infections is problematic. Successful therapy usually involves surgical excision coupled with administration of antifungal agents.

Chlorellosis. Chlorellosis is caused by a unicellular green alga of the genus Chlorella. In contrast to Prototheca, another alga that causes human infection (Table 1), Chlorella contains chloroplasts that give the lesions of chlorellosis a distinct green color (34, 63, 81). A single human infection has been reported thus far (41).

Chlorella spp. are unicellular, ovoid, spherical, or polygonal, 4 to 5 µm in diameter, and reproduce asexually by internal septation and cytoplasmic cleavage (endosporulation), producing up to 20 daughter cells (sporangiospores) within the parent cell (sporangium) (Table 1) (34, 83). The organisms contain numerous green chloroplasts, which appear as cytoplasmic granules and stain intensely with GMS, PAS, and Gridley fungal stains (Fig. 2A) (83). Upon maturation, the outer wall of the sporangium ruptures, releasing the sporangiospores, each of which goes on to produce sporangiospores of its own.

The single human case of chlorellosis took place in Nebraska and resulted from exposure of a surgical wound to river water (41). The wound drained a greenish-yellow exudate, and infected tissues contained endosporulating organisms ranging from 6 to 9 µm in diameter. The organisms contained multiple, strongly PAS-, GMS-, and Gridley fungus-positive cytoplasmic granules, which with electron microscopy were shown to be chloroplasts. The organisms did not stain with immunofluorescence conjugates specific for Prototheca wickerhamii and Prototheca zopfii. The infection was cured by surgical debridement over a 10-month period.

Infections in domestic (sheep and cattle) and wild (beaver, gazelle, and camel) animals range from lymph node and deep organ involvement to cutaneous and subcutaneous lesions, presumably related to exposure to water containing the organism (34, 44, 50, 81, 87). Fresh lesions in liver, lymph nodes, and subcutaneous tissue are green in color on gross examination, and smears reveal organisms that contain green refractile granules (chloroplasts) (14, 83).

Infections due to Chlorella spp. may be diagnosed by culture and by histopathologic examination of infected tissue (14, 83). The organisms grow readily on solid media and produce characteristic bright green colonies (14). Wet mounts of wound exudates or touch preparations of infected tissue reveal ovoid, endosporulating cells with typical green cytoplasmic granules representing chloroplasts (Table 1). The organisms in tissue stain intensely with GMS and PAS but not H&E stains. They are easily distinguished from Prototheca by the intracellular chloroplasts (Fig. 2A and B).

Treatment of the only human case of chlorellosis consisted of debridement, irrigation, and gauze packing and removal to ensure drainage and granulation (41). Medical treatment with amphotericin B plus tetracycline has proven efficacious in the treatment of protothecosis and may be useful for chlorellosis should surgical excision prove inadequate.

Protothecosis. Protothecosis is an uncommon infection of humans and animals caused by an achlorophyllous algae of the genus Prototheca. Two species, P. wickerhamii and P. zopfii, are known to cause infection, though the majority of human infections are due to P. wickerhamii (47, 49). These organisms belong to the same family as the green algae of the genus Chlorella.

The protothecae are unicellular, oval or spherical organisms that reproduce asexually by internal septation and irregular cleavage to produce between 2 and 20 sporangiospores within a hyaline sporangium. The sporangiospores are arranged in a characteristic "morula" configuration and upon rupture of the sporangium are released to develop in turn into additional endosporulating forms (Fig. 2B). The cells measure 3 to 30 µm in diameter and differ from those of Chlorella in the lack of chloroplasts (Table 1). Protothecae differ from fungi by the lack of glucosamine in their cell walls. The two species of Prototheca that cause human disease are readily stained with PAS, GMS, and the Gridley fungus stain and are gram positive (76). They differ from one another in size: P. wickerhamii measures 3 to 15 µm in diameter, whereas P. zopfii measures 7 to 30 µm in diameter.

Prototheca spp. are ubiquitous in nature, where they can be isolated from grass, soil, water, and both wild and domesticated animals (39, 63, 74). They have also been found colonizing the human skin, fingernails, respiratory tract, and digestive system (39, 104). Prototheca infection is generally introduced via traumatic inoculation and has been reported on all continents except Antarctica (63). In the United States, protothecosis is reported most often in the Southeast (93, 105).

Three forms of human protothecosis are described: (i) cutaneous, (ii) olecranon bursitis, and (iii) disseminated (47, 49, 93). At least half of protothecosis cases are simple cutaneous infections (47, 49). The majority of these infections occur in individuals who are compromised by immunosuppressive therapy, AIDS, malnutrition, renal or hepatic disease, cancer, or autoimmune disorders (11, 49, 93, 104, 105). Lesions usually arise in areas exposed to traumatic implantation and present in an indolent fashion as nodules, papules, or an eczematoid eruption.

In contrast, individuals presenting with olecranon bursitis are usually not immunocompromised but report penetrating or nonpenetrating trauma to the affected elbow (20, 65, 76). Signs and symptoms appear gradually several weeks following the trauma and include mild induration of the bursa accompanied by tenderness, erythema, and production of a variable amount of serosanguinous fluid.

Disseminated protothecosis is rare and almost always occurs in individuals with severe immunocompromise from cancer treatment, a prior solid organ transplant, or AIDS (36, 43, 48, 54, 93, 104). The organs most commonly affected in disseminated infection are skin, subcutaneous tissue, and spleen (93). Central venous catheter-related algaemia has been reported with accompanying fever, chills, and sepsis syndrome (48, 93). One patient with visceral protothecosis has been described who presented with signs and symptoms of cholangitis (13). The patient had multiple peritoneal nodules that resembled metastatic cancer but were in fact manifestations of protothecosis.

Prototheca spp. grow readily on a variety of synthetic media at 30 to 37°C (22). Colonies are creamy, white, and yeast-like in appearance and consistency. A wet mount of the culture material may be stained with lactophenol cotton blue to reveal the characteristic endosporulating sporangia (so-called morula form) (76). The organisms are quite metabolically active and may be identified using one of several commercially available yeast identification systems to determine the carbohydrate assimilation profile (22, 69).

Histopathologic examination of infected tissue may be accomplished using the PAS, GMS, or Gridley fungus stain to visualize the endosporulating sporangia (morula form) of Prototheca spp. (Fig. 2B) (76). In addition to the size differences noted previously (Table 1), the two species of Prototheca differ in that P. wickerhamii tends to form symmetrical morula forms, whereas these forms are rare with P. zopfii, which exhibits more random internal segmentation (76). The inflammatory response in protothecosis is predominantly granulomatous but can consist of lymphocytes, plasma cells, eosinophils, neutrophils, macrophages, epithelioid cells, and giant cells.

Treatment of cutaneous protothecosis with a variety of topical and systemic antibacterial, antifungal, and antiprotozoal agents has met with variable success (47, 49). Surgical excision is recommended for small localized lesions. Amphotericin B and the azoles (itraconazole, fluconazole, and ketoconazole) appear to be the most effective medical treatment (11, 49, 67, 71, 93). Cure of olecranon bursitis generally requires bursectomy (47, 49). Repeated drainage has failed; however, drainage coupled with local instillation of amphotericin B has been curative (20, 76). Treatment of disseminated protothecosis is best accomplished with amphotericin B, although the optimal dose and duration of therapy are uncertain (49, 93).

Pythiosis insidiosi. Pythiosis is a pseudofungal infection of humans and animals caused by the oomycete Pythium insidiosum (59, 75). Although described as an aquatic fungus, this organism is not a true fungus. It belongs to the kingdom Stramenopila, phylum Oomycota, class Oomycetes, and family Pythiaceae (1).

P. insidiosum grows in culture as white colonies with submerged vegetative hyphae and short aerial hyphae (56). A plant pathogen, P. insidiosum requires water cultures containing the appropriate leaves to produce zoosporangia and zoospores in vitro (18, 58). In nature, it produces biflagellate zoospores that attach and penetrate the leaves of various grasses and water lilies. The zoospores have a tropism for skin and hair, as well as water lilies and grass leaves (58). If zoospores contact injured tissue, they encyst, form germ tubes that produce hyphae, and cause invasive disease.

In tissue, P. insidiosum exists as hyaline, pausi-septate, thin-walled hyphae or hyphal fragments that branch infrequently (56). The hyphae are 5 to 7 µm wide with nonparallel walls and superficially resemble those of Zygomycetes (Table 1 and Fig. 2C). Similar to the Zygomycetes, P. insidiosum is angioinvasive and stains weakly with GMS and other fungal stains (56). In contrast to true fungi, the cell walls of P. insidiosum are composed of cellulose rather than glucan, mannan, and chitin.

P. insidiosum grows in aquatic to wet environments in tropical and subtropical regions, and pythiosis has been reported from Thailand, the United States, Australia, New Zealand, Malaysia, and Haiti (75). The risk of this infection is high for those who are exposed to water in rice fields without wearing boots.

Human disease due to P. insidiosum can be classified into three forms (75): ocular, cutaneous, and arterial. The ocular form of pythiosis is manifest as keratitis that can be severe and result in corneal perforation. The cutaneous and subcutaneous form most often presents as a periorbital cellulitis or mass with progressive local invasion of soft tissue (85, 94). The arterial form is the most serious and is largely limited to farmers in Thailand who also suffer from thalassemia (56, 75, 82, 92, 100). The disease process is marked by pain, swelling, and chronic ulcers of the lower extremities with progressive ischemia, necrosis, and thrombosis of major arteries due to hyphal invasion. Limb gangrene, aneurysm formation of the femoral, popliteal, and iliac arteries and the aorta, and ultimately fatal hemorrhage is common (41% overall mortality) despite aggressive medical and surgical intervention (75). The importance of thalassemia in this process in unknown, since this is a very common condition in Thailand. Additional reported sites of infection with P. insidiosum include head and neck arteries in a 14-year-old Thai boy (92) and pleuropericarditis and pneumonia in a 12-year-old child with leukemia (35). The latter child was of Pakistani ancestry but was born and lived in the United States.

In animals (cats, dogs, horses, and cattle), pythiosis is an osseous, subcutaneous, or pulmonary infection. Equine pythiosis is marked by chronic ulcerated lesions with numerous yellow coral-like bodies ("kunkers") on the limbs, chest, and abdomen (58, 59). Dogs and horses may also present with intestinal obstruction due to pythium granuloma in the duodenum or jejunum (51, 56).

The organism may be isolated from fresh clinical material seeded onto mycologic medium, such as Sabouraud's glucose agar (56). Demonstration of biflagellate zoospores may be accomplished using water cultures with grass or water lily bait at 37°C for 1 h (12).

Immunodiagnosis using an immunodiffusion or a fluorescent-antibody assay to detect antibodies to P. insidiosum has been useful (75, 85). Likewise, the presence of the organism in tissue may be confirmed by staining with specific fluorescent-antibody conjugates (57).

Histopathologic examination of infected tissue shows a necrotizing arteritis and thrombosis (Table 1). Vascular invasion by sparsely septate, irregularly branched hyphae is seen (56). The infectious process spreads along the vessel walls proximally, and the organism may be visualized in the arterial wall or in the outer part of the thrombus using GMS or PAS stains. Eventually the acute perivascular inflammatory reaction is replaced by granulomas containing sparse hyphae and hyphal fragments (56, 100).

Treatment of ocular pythiosis involves keratoplasty coupled with both topical (amphotericin B, natamycin, miconazole, and ketoconazole) and systemic (amphotericin B, ketoconazole, and itraconazole) antifungal agents (75). Despite these efforts, enucleation or evisceration is usually necessary. In contrast, treatment of cutaneous and subcutaneous infection with surgical debridement and antifungal therapy is generally successful (75). One notable case in the United States of deep facial infection in a child demonstrated that pharmacological cure with itraconazole plus terbinafine is feasible (85).

Given the serious nature of arterial pythiosis, prompt recognition and aggressive medical and surgical therapy are warranted. Surgical debridement, amputation, and aneurismectomy may be necessary to limit the extent of the infection and prevent fatal hemorrhage (75). Antifungal therapy with amphotericin B, itraconazole, and terbinafine, sequentially or in combination, has been used with some success (35, 75, 85). One patient with life-threatening arteritic infection with P. insidiosum was treated successfully with aneurismectomy and the use of P. insidiosum vaccine immunotherapy after failing medical treatment with amphotericin B, iodides, and ketoconazole (92). The vaccine employed in this case was a modified therapeutic vaccine that had been used successfully in treating equine pythiosis.

Rhinosporidiosis. Rhinosporidiosis is a granulomatous disease of humans and animals that is characterized by the development of mucosal polyps that primarily affect the nasopharynx and ocular conjunctiva of infected individuals (2, 52, 103). The condition is caused by Rhinosporidium seeberi, an organism with a confusing taxonomic history. R. seeberi has been considered to be a protozoan and a fungus and most recently has been placed in a novel clade of aquatic protistan parasites, the Mezomycetozoa (29, 37). Since R. seeberi will not grow in synthetic media nor in human or animal cell lines, this reclassification was based on sequence analysis of the 18S small-subunit ribosomal DNA of this organism. This analysis, performed in two independent laboratories, placed R. seeberi among the Mesomycetozoa (formerly DRIP clade; Dermocystidium, Rosette agent, Ichthyophonus, and Psorospermium), a clade of fish parasites that form a branch of the evolutionary tree near the animal-fungus divergence (29, 37).

Two developmental forms of R. seeberi are seen in tissue (Table 1): the large endosporulating spherical form, or sporangia, and the smaller trophocyte (103). The sporangium is considered to represent the mature form of the organism and measures 100 to 350 µm in diameter with a thin (3 to 5 µm thick) wall that is composed of an inner hyaline layer and an outer eosinophilic layer. Within the sporangium are numerous endospores (sporangiospores) arranged in a characteristic zonal formation with the small, flattened, immature uninucleate sporangiospores (1 to 2 µm) forming a crescent-shaped mass at the periphery of one wall of the sporangium and larger maturing and mature sporangiospores arranged sequentially toward the center (Fig. 2D) (103). When fully mature, the sporangiospores range in size from 5 to 10 µm in diameter and contain numerous refractile cytoplasmic globules. This zonal arrangement of immature, maturing, and fully mature sporangiospores within the sporangium is pathognomonic of R. seeberi and distinguishes it from other spherical endosporulating organisms in tissue (Table 2).

The mature sporangia have been estimated to contain as many as 12,000 sporangiospores that are discharged through a pore in the sporangium. The trophocyte form is thought to develop directly from sporangiospores that have been liberated from the sporangium. The trophocytes range in size from 10 to 100 µm in diameter and have refractile eosinophilic walls (2 to 3 µm thick), granular cytoplasm, and a round pale nucleus with a prominent nucleolus (103).

Approximately 90% of all known cases of rhinosporidiosis occur in India and Sri Lanka, where the prevalence is estimated at 1.4% (61). The disease has also been reported from the Americas, Europe, and Africa (2, 52). The natural habitat and extent of distribution of R. seeberi is unknown, although studies have linked infection to swimming or bathing in freshwater ponds, lakes, or rivers (45). There is no evidence that rhinosporidiosis is contagious.

Rhinosporidiosis occurs primarily in young men, 20 to 40 years old, and manifests as slow-growing polypoid or tumor-like masses, usually of the nasal mucosa or conjunctiva (52). Lesions may also be seen in the paranasal sinuses, larynx, and external genitalia. Limited systemic dissemination has been reported but is rare (38). In most patients the disease remains localized, and symptoms are primarily nasal obstruction and epistaxis (52).

Rhinosporidiosis is diagnosed by histopathologic examination of the affected tissue. The distinctive appearance of the trophocytes and sporangia in routine H&E-stained sections is diagnostic (Table 1). The walls of both the sporangia and sporangiospores stain with both GMS and PAS fungal stains (103). In addition, the walls of the sporangiospores and the inner wall of the sporangium stain positively with Mayer's mucicarmine (Table 2). Although other organisms that occur in tissue in the form of large spherules may be mistaken for R. seeberi (i.e., C. immitis and E. crescens [adiaspores]), they usually can be differentiated one from another by consideration of the tissue involved and the morphological and staining characteristics of the spherule and the endospores (Table 2).

The only effective treatment for rhinosporidiosis is surgical excision of the lesions. Recurrences are common, especially in mucosal sites, such as the oropharynx and the paranasal sinuses, where complete excision is often difficult to achieve (2, 52).


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FOOTNOTES
 
* Corresponding author. Mailing address: Medical Microbiology Division, C606 GH, Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 384-9566. Fax: (319) 356-4916. E-mail: michael-pfaller{at}uiowa.edu. Back


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Journal of Clinical Microbiology, April 2005, p. 1495-1504, Vol. 43, No. 4
0095-1137/05/$08.00+0     doi:10.1128/JCM.43.4.1495-1504.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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