Rare and Emerging Fungal Pulmonary Infections
Jay B. Varkey, M.D.; John R. Perfect, M.D.

Semin Respir Crit Care Med.  2008;29(2):121-131.  ©2008 Thieme Medical Publishers
Posted 05/30/2008

Abstract and Introduction

Abstract

The frequency and diversity of serious fungal infections are increasing. Persons who are severely immunocompromised are particularly vulnerable to infection from unusual molds and yeasts that are often found naturally in the environment. Clinical manifestations from these unusual fungal infections range from colonization of airways to chronic localized lesions to acute invasive or disseminated disease. When present, rare and emerging fungi are often isolated from the respiratory tract during a severely immunosup-pressed state, and diagnosis requires isolation and identification of the infecting organism. Histopathology is often required to differentiate tissue invasion from airway colonization. There are no diagnostic serologies, and radiological exams are not specific. Furthermore, many emerging opportunistic molds demonstrate in vitro resistance to the older azoles and amphotericin B. As a result, successful treatment may require adjunct surgical debridement and, when possible, reconstitution of the host immune system. Also, the newer triazoles such as voriconazole and posaconazole may be useful to treat some of these infections caused by rare and emerging molds.

Introduction

The human airway is continuously open to the nonsterile environment where fungal spores have the potential to reach lung tissue and produce disease. In the immunocompromised host, many fungi, including species of fungi typically considered nonpathogenic, have the potential to cause serious morbidity and mortality. Over the last several decades the advent of the human immunodeficiency virus (HIV) epidemic and the increasing use of immunosuppressive drugs for serious medical conditions have dramatically increased the number of persons who are severely immunocompromised. As a result, the incidence of invasive fungal infections of the lungs has risen substantially.[1] In addition, the range and diversity of fungi that cause disease have broadened. This is significant because, despite marked advances in antifungal therapy, infections caused by opportunistic fungal infections (rare and emerging) continue to be associated with high morbidity, high mortality, and poor patient outcomes. This results from a combination of drug-resistant strains, lack of robust clinical studies evaluating treatments, and severe underlying diseases in the patient.

Although Candida and Aspergillus species continue to be the fungal pathogens that most frequently cause invasive fungal disease in immunocompromised persons overall, infections due to previously uncommon hyaline and dematiaceous filamentous fungi are being reported with increasing frequency.[2,3] This article reviews a select group of hyaline molds, yeastlike fungi, and a diverse number of clinical diseases caused by dematiaceous fungi. The article also discusses the potential role of several new antifungal agents that may be useful to treat serious infections caused by rare and emerging fungal pathogens. However, despite progress made in developing new antifungal therapy, successful treatment of these unusual fungal infections remains rare and challenging. The first step is an accurate diagnosis, and in most cases, it will require obtaining specimens from lung tissue for culture and histopathology. Furthermore, for these rare fungi, we need expert mycology either from a visual identification or possibly from polymerase chain reaction (PCR) of tissue/cultures and sequencing information. With accurate diagnosis, rare fungal infections require treatments that may include adjunctive surgical debridement, reconstitution of the host immune system, and new and old antifungals singly or in combination, one case at a time.

Hyaline Molds: Hyalohyphomycosis

Hyalohyphomycosis is a broad term used to describe infections caused by an increasing number of heterogeneous fungi. When present in infected tissue like the lung, these molds appear as hyaline (colorless or lightly pigmented), septate, branching filamentous fungi that may be indistinguishable from Aspergillus.[3] Many of the hyaline molds exhibit decreased susceptibilities to several antifungal agents. This section reviews the microbiology, epidemiology, clinical manifestations, diagnosis, and treatment of five specific hyaline molds that may present as a fungal pulmonary infection and that are increasing in frequency and significance: Scedosporium, Fusarium, Paecilomyces, Acremonium, and Trichoderma.

Scedosporium

Scedosporium is a filamentous fungus that is found worldwide. Although it has been isolated from freshwater, it is commonly associated with soil, sewage, manure from farm animals, and stagnant or polluted water. The genus Scedosporium contains two medically significant species of emerging fungi: S. apiospermum and S. prolificans (formerly S. inflatum).

The teleomorph (sexual state) of S. apiospermum is called Pseudallescheria boydii. The organism was first isolated by Siebenmann in the 1800s from the ear of a child with chronic otitis externa.[4] The first complete description of the organism was published in 1922 by Shear.[5] Human infection with Pseudallescheria boydii can produce two distinct rare diseases: mycetoma and pseudallescheriasis (scedosporiosis). Mycetoma is a rare chronic progressive granulomatous infection of the skin and subcutaneous tissue that can develop from fungi as well as from filamentous bacteria. In the United States, P. boydii, is the pathogen most commonly recovered from mycetomas.[6] Mycetomas are typically marked by the triad of localized swelling, underlying sinus tracts, and production of pale (white to yellow) grains or granules (composed of aggregations of the causative organism) within the sinus tracts. Infection typically develops following inoculation of organisms, frequently through thorn punctures, wood splinters, or preexisting abrasions or trauma. Diagnosis is clinical -- direct microscopy and culture of grain obtained from a sinus tract confirms the causative organism. Treatment typically requires both antimicrobial agents (see below) and surgery.

Pseudallescheriasis, which includes all other infections caused by P. boydii, is typically seen in immunocompromised patients. However, localized pseudallescheriasis may be seen in both immunocompetent and immunocompromised patients. Localized infections of the eye and cutaneous, subcutaneous, bone, and osteoarticular tissue have been described and typically develop following traumatic implantation of the fungus from soil or water. Osteoarticular infection in immunocompetent patients often appears as a painful, swollen joint with overlying erythema after penetrating joint injury. Occasionally, weeks to years may pass between antecedent trauma and the development of septic arthritis.[7,8]

The most common site of pseudallescheriasis is the upper and lower respiratory tracts. Infection develops following inhalation of P. boydii into the lungs or paranasal sinuses. Colonization of bronchiectatic lungs or intermittently obstructed paranasal sinuses occurs more commonly than infection. However, the clinical manifestations of pseudallescheriasis respiratory infection are diverse. Pneumonia caused by P. boydii has been described following near-drowning in contaminated water. Masses of P. boydii hyphae (fungus balls) have been found in lung cavities.[9] In immunocompromised persons, an invasive pulmonary disease similar to invasive pulmonary aspergillosis can be seen. P. boydii has also been reported as a cause of allergic bronchopulmonary disease (similar to allergic bronchopulmonary aspergillosis),[10] pleural space infection, lung abscess, and invasive sinusitis. This fungus can colonize the airways of cystic fibrosis patients, and similar to Aspergillus in this unique group of patients, it is at times difficult to determine whether it is colonizing or producing disease.

Disseminated pseudallescheriasis, often with central nervous system (CNS) involvement, has been observed in persons with acquired immunodeficiency syndrome (AIDS) and in solid-organ transplant recipients. The neurotropic behavior of this fungus may be explained by its dependency on free iron, which, in contrast to serum, is present in the CNS.[11] Cerebral abscesses have also developed in immunocompetent hosts following near-drowning in polluted water, such as ponds, pig troughs, and roadside ditches.[12-14] Mortality with brain abscess has traditionally been noted to be greater than 75%,[15,16] but with the use of voriconazole this outcome may now be improved.

Definitive diagnosis of P. boydii infection requires isolating and identifying the fungus via culture. However, a positive culture does not necessarily indicate infection. In persons with underlying pulmonary diseases such as bronchiectasis, sarcoidosis, tuberculosis, and cystic fibrosis, P. boydii can colonize either the sinuses and/or airways without producing disease. New techniques in diagnosis, including molecular techniques such as polymerase chain reaction and counter immunoelectrophoresis, are under development[17] but are not routinely used in clinical practice.

Effective therapy of pseudallescheriasis has not yet been clearly established. Surgical debridement has been an important adjunct in treatment of pseudallescheriasis of soft tissue, bone, joint, pleura, and para-nasal sinuses, although it is generally not curative. P. boydii is generally considered resistant to amphotericin B, and clinical response has been poor.[3] Voriconazole has been approved by the US Food and Drug Administration (FDA) for patients with pseudallescheriasis refractory to or intolerant of other approved antifungal agents and is generally considered the drug of choice for disseminated disease[18] and probably pulmonary disease. Posaconazole, like voriconazole, has also been used to successfully treat a case of brain abscess secondary to P. boydii.[19] These new extended-spectrum azoles may be an improvement to prior drug regimens, and combination of drugs, including use of an echinocandin, needs to be an individualized decision made "at the bedside."

S. prolificans (formally S. inflatum) was first described as a human pathogen in 1984.[20] In immuno-competent hosts, S. prolificans typically causes bone and soft tissue infections associated with trauma. In immunocompromised hosts, S. prolificans can cause deep invasive and disseminated infections associated with high mortality rates. Deep invasive and disseminated infections are typically marked by skin lesions, myalgias, endophthalmitis, and pulmonary infiltrates. However, S. prolificans can colonize sputum in persons with AIDS, cystic fibrosis, and solid organ transplants. Diagnosis is most commonly made by culturing the fungus from infected sites. Histopathology demonstrating tissue invasion may be useful to differentiate infection from colonization. In fact, S. prolificans like Fusarium, Aspergillus terreus, Acremonium, and Paecilomyces can produce adventitial forms (conidia and other asexual structures in addition to hyphae) in tissue, and this may be recognized in histopathology.[21] This morphological feature may allow these fungi to transverse into the bloodstream and disseminate throughout the body much more easily than Zygomycetes and most other Aspergillus species.

S. prolificans is considered resistant to virtually all of the systemically active antifungal agents. Of the currently available antifungal agents, voriconazole appears most promising in vitro, with better activity than amphotericin B, itraconazole, or posaconazole, but still with very little direct inhibitory activity. The investigational azole, albaconazole (UR-9825) is more active than voriconazole in vitro and has shown antifungal potential against this fungus in one animal model.[22] Because of the ineffectiveness of current antifungal therapy, surgical resection, if available to the clinician, remains an important definitive therapy for infections cause by S. prolificans.[3]

Fusarium

Species in the genus Fusarium are common in soil and organic debris and are frequently the cause of diseases in plants. The most frequent species causing infection in humans are F. solani, F. oxysporum, and F. moniliforme.[23] In humans, the clinical manifestations are diverse and depend largely on the immune status of the host.

In the normal host, Fusarium may cause localized infections of the nails (onychomycosis) and cornea (keratitis). Fusarium is one of the more common causes of fungal keratitis. The proportion of fungal keratitis attributable to Fusarium varies depending on region and ranges from 25 to 62%.[24-26] In early 2006, an unexpected increase in the incidence of Fusarium keratitis was noted in Singapore and the United States, predominantly among contact lens wearers using ReNu with MoistureLoc (Bausch & Lomb, Rochester, NY) contact lens solution.[27] Given the association between Fusarium keratitis and ReNu MoistureLoc, Bausch & Lomb announced its decision to voluntarily recall and permanently remove this contact lens solution from the worldwide market on May 15, 2006.[28] Localized infections can also occur as a result of direct inoculation of Fusarium following trauma or instrumentation. Cases of endophthalmitis, cellulitis, osteomyelitis, arthritis, and peritonitis have been reported among patients undergoing peritoneal dialysis.[23,29-31] These fungi can colonize a central venous line; complications then occur as septic emboli accumulate in the lung.

Rare cases of disseminated fusariosis have been described in immunocompetent persons who sustain severe burns[32] or develop heat stroke.[33] More commonly, however, fusariosis occurs in persons with hematological malignancy and prolonged neutropenia. Disseminated infection typically manifests with fever and myalgias. Cutaneous lesions are present in 60 to 80% of disseminated fusariosis, and blood cultures are frequently positive. Skin lesions are often initially macular with a central area of pallor but later become raised, erythematous, nodular lesions with progressive central necrosis. Fusariosis can occasional present as sinusitis, pneumonia, endophthalmitis, or pyomyositis prior to dissemination.[31,34,35]

Definitive diagnosis of disseminated fusariosis requires recovering the fungus in culture. Fusarium can usually be cultured from tissue obtained from biopsy of suspicious skin or lung lesions. In addition, Fusarium can be cultured from blood in over 50% of the cases of disseminated fusariosis.[35] In culture, the characteristic feature of Fusarium is the production of sickle-shaped multiseptate macroconidia.[23]

Despite advances in antifungal therapy, the immune status of the host remains the single most important factor predicting outcome of disseminated fusariosis.[35,36] The optimal antifungal treatment for disseminated fusariosis has not been definitively established. Some Fusarium species appear to be resistant to amphotericin B in vitro. However, high-dose amphotericin B in lipid formulations has been used to successfully treat this infection, but breakthrough Fusarium infections have occurred. Lipid formulations of amphotericin B have been used to successfully treat disseminated fusariosis and may be superior to standard amphotericin deoxycholate.[1,3] In a retrospective study, voriconazole was used to successfully treat 45% (5/11) of cases of fusariosis.[37] In addition, the 90-day Kaplan-Meier estimate of proportional survival in this study was 0.716 -- these data are noteworthy given previously published mortality rates of 50 to 80%.[38-40] There are case reports of successful treatment of fusariosis with a combination of voriconazole and lipid formulations of amphotericin B.[41,42] Finally, in a recent retrospective study, posaconazole treatment achieved a successful outcome in 50% (10/20) of persons who had failed lipid formulations of amphotericin B.[43]

Acremonium

Acremonium species are hyaline molds that are ubiquitous in the environment and typically found in soil. Infections due to Acremonium present in a manner similar to those of Fusarium infections. Most infections occur following a penetrating injury, with the most common sites of infection being the extremities and the cornea.[44] Like Fusarium species, Acremonium species often present with hematogenously disseminated cutaneous lesions and fungemia in markedly immunocom-promised persons. Diagnosis of Acremonium infection is difficult. In advanced disease, blood cultures may be positive. Acremonium species grow slowly; to ensure detection of a positive sample, cultures must be kept for at least 2 weeks.[45] In lung specimens, it is necessary to distinguish between airway colonization and tissue disease.

The optimal treatment for invasive infections due to Acremonium species has not been established. The newer triazoles, such as voriconazole, appear to be active in vitro, and posaconazole has been reported to have successfully treated a severely neutropenic patient with diffuse bilateral pulmonary infection due to Acremonium strictum.[45]

Paecilomyces

Paecilomyces, first described by Bainier in 1907,[46] is a filamentous fungus found worldwide that typically inhabits moist soil and is associated with decaying plants and wood.[47,48] Paecilomyces contains several species; the most common species associated with human infection are Paecilomyces lilacinus and Paecilomyces variotii.

Paecilomyces is usually considered as a contaminant or colonizing fungal species; however, in immuno-compromised persons, infection can occur and produce disease in virtually any body site or organ system. P. variotii is most often associated with keratitis, endophthalmitis, sinusitis, and peritonitis in persons receiving peritoneal dialysis.[49,50] Cutaneous infections, onychomycosis, otitis media, catheter-related fungemia, endocarditis, and osteomyelitis have all been reported.

The earliest report of pulmonary infection from Paecilomyces was a case report of empyema caused by P. lilacinus in 1972.[51] Case reports of pneumonia caused by P. variotii have been described in patients with leukemia[52] and diabetes.[47] Paecilomyces has also been implicated as a cause of allergic alveolitis in individuals living in areas in proximity to decaying wood. Cell-mediated granulomatous inflammation of the pulmonary parenchyma without pneumonia has resulted from the chronic alveolitis.[53,54]

P. variotii is susceptible to amphotericin B, and infections have been treated successfully with this agent. However, the more common P. lilacinus responds poorly to amphotericin B. In vitro susceptibility testing has shown multiple strains of these fungi to be more susceptible to voriconazole and posaconazole. Voriconazole has been used to treat both severe cutaneous infections[55] and disseminated disease.[56]

Trichoderma

Trichoderma is a hyaline mold that is most commonly recovered from soil but has also been isolated from air. Trichoderma species are excellent examples of fungi previously labeled as nonpathogenic that have emerged as important opportunistic pathogens in immunocom-promised persons. Six species of the genus Trichoderma have been identified as human pathogens: T. longibrachiatum, T. harzianum, T. koningii, T. pseudokoningii, T. citrinovirde, and T. viride.[57] Among these species T. longibrachiatum is the most commonly recovered from cases of invasive infections.

Clinical manifestations of Trichoderma infection are diverse. Trichoderma infections typically appear as localized cutaneous lesions, peritonitis complicating peritoneal dialysis, and disseminated infection including the CNS. Pulmonary disease (fungus ball) has also been described. Pulmonary infection typically presents with nodular infiltrates. Outcomes are generally poor; however, one case report describes a nonfatal pulmonary infection caused by T. viride in a patient with leukemia.[57]

Most Trichoderma species show decreased susceptibilities to amphotericin B, itraconazole, fluconazole, and flucytosine. Voriconazole appears to be active against the few species that have been tested.[58,59] Surgical resection of localized infection is recommended whenever feasible.[57]

Yeastlike Fungi

Trichosporon

Trichosporon has been isolated from soil, water, and plants and can also be found colonizing human skin. After recent changes in taxonomy, six species of Trichosporon have been associated with human disease. Trichosporon cutaneum and Trichosporon asteroides are associated with superficial cutaneous infections. White piedra of the scalp is caused by Trichosporon ovoides, and a similar disease of the pubic hair is caused by Trichosporon inkin.

Deep invasive and disseminated infection can occur in highly immunocompromised persons and is typically caused by Trichosporon asahii and Trichosporon mucoides. The illness is acute and often manifested by fever and multiple red papular skin lesions. Trichosporonosis affects multiple organs, including the lungs; however, pneumonia is not a consistent feature of the illness. Chronic hepatic trichosporonosis mimics hepatic candidiasis and may be seen in persons with recovery of their neutrophil counts following chemotherapy.[2] Renal involvement is common and can be associated with hematuria and funguria. In persons with prosthetic heart valves, fungal prosthetic valve endocarditis has been described. Diagnosis of disseminated infection is often made by biopsy -- in the absence of visible arthroconidia, the mixture of hyphae, pseudohyphae, and budding yeasts seen on histopathology often resembles Candida. In severe cases of trichosporonosis, fungemia is detected.

Trichosporonosis is associated with high mortality rates. The minimum inhibitory concentration (MIC) obtained for the echinocandins is very high; these agents should not be used to treat trichosporonosis. Amphotericin B has been recommended, but in vitro resistance and clinical failures have been reported.[60] Trichosporon species are usually susceptible in vitro to fluconazole, itraconazole, voriconazole, and posaconazole.[61,62]

Geotrichum

Geotrichum species are widely distributed in nature and have been isolated from soil, water, air, sewage, plants, cereals, and dairy products.[63] One related species, Blastoschizomyces capitatus, is the most prominent fungus in this group to produce disseminated infections in immunocompromised hosts.[64] These species have also been found in normal human flora such as sputum and feces. Disseminated infection such as Geotrichum candidum occurs in immunocompromised persons and is typically marked by skin lesions and fungemia.[65] Blood cultures are usually positive. As with Trichosporon, a chronic disseminated form of Geotrichum infection, similar to chronic disseminated candidiasis, may be seen in persons with resolving neutropenia.[66] Bronchial and pulmonary infection have been reported but must be differentiated from colonization of the respiratory tract, which is probably a more common clinical situation.

The optimal approach to therapy is not yet defined. Although in vitro susceptibility testing has demonstrated decreased antifungal activity to amphotericin B, clinical results have been promising with or without flucytosine or high-dose fluconazole.[67] Voriconazole yields very low MICs against Geotrichum species and may represent first-line therapy.[68] In cases of fungemia, central venous catheters should probably be removed.

Endemic Mycoses

In the area of dimorphic fungi producing rare and emerging pulmonary infections there are three infections to consider. Pulmonary adiaspiromycosis is caused by Emmonsia crescens, which can produce adiospores at 37 to 40°C that resemble spherules. It produces pulmonary disease in small rodents and occasionally in humans. Infection can range from asymptomatic in its presentation to invasive/disseminated infection in immunocom-promised hosts. It has responded to treatment with several antifungal agents, but it is important to realize that in many patients there has been spontaneous recovery with no treatment. Thus it is important to judge host immunity and degree of symptoms prior to starting any antifungal therapy.[69,70]

The other two endemic mycoses considered rare and/or emerging are sporotrichosis and penicilliosis (Penicillium marneffei). Pulmonary sporotrichosis has a chronic, insidious presentation and favors immunosup-pressed hosts such as those with a history of alcohol abuse. The treatment is not clearly defined but it is likely to be a combination of polyene for initial treatment followed by an azole such as itraconazole, with or without surgery. These infections can be quite refractory to both medical and surgical intervention.[71] Penicillium marneffei primarily causes pulmonary disease in Southeast Asia and in particular with concomitant human immunodeficiency virus infection. It presents in a sub-acute manner and can respond to treatment with azoles or polyenes. Immune reconstitution with highly active antiretroviral therapy (HAART) is critical for success.[72]

Dematiaceous Molds: Phaeohyphomycosis

Phaeohyphomycosis is a loosely defined term used to group infections caused by molds (and a few yeasts) that produce dark cell walls. As with the agents of hyalohyphomycosis, the list of dematiaceous fungi is both long and taxonomically diverse. These organisms are characterized by the presence of a pale brown to dark melanin-like pigment in the cell wall. This group of fungi is found in soil, air, plants, and organic debris. The number of genera and species of fungi causing phaeohyphomycosis is quite large. This section focuses on the disease entities caused by these diverse organisms.

Mycetoma

Like the hyaline molds, dematiaceous molds are a cause of mycetomas: chronic granulomatous infection marked by sinus tracts and production of tissue grains. Although mycetomas caused by hyaline molds produce pale white/yellow grains, mycetomas that form from the dematiaceous molds are marked by dark black grain production. Among the black fungi causing dark-grained mycetoma, the most common are Madurella mycetomatis, M. grisea, Leptosphaeria senegalensis, Pyrenochaeta romeroi, and Exophiala jeanselmei. Diagnosis is clinical -- direct microscopy and culture of grain obtained from a sinus tract confirms the causative organism. Treatment typically requires surgical resection and antifungal treatment. In vitro, voriconazole has good activity against many of the agents of eumycetoma (fungal mycetoma).[73]

Chromoblastomycosis

Chromoblastomycosis (chromomycosis) is a chronic localized fungal infection of the skin and subcutaneous tissue that produces raised scaly lesions, usually of the lower extremities. Several dematiaceous fungi cause chromoblastomycosis. Fonsecaea pedrosoi is the most common causative organism, although disease is also caused by F. compacta, Cladosporium carrionii (syn., Cladophialophora carrionii), Phialaphora verrucosa, and Rhinocladiella aquaspersa. Most cases arise in tropical and subtropical regions. Microscopic examination of skin scrapings can provide rapid diagnosis because the characterisitic muriform cells (also called "copper penny" or sclerotic bodies) may be seen in potassium hydroxide preparations, especially those containing black dots.[74] Treatment typically requires antifungal therapy combined with either or both surgical resection and cryotherapy with liquid nitrogen.[74] Terbinafine has produced excellent results in the treatment of chromoblastomycosis.[75] The newer extended-spectrum triazoles may also be useful to treat chromoblastomycosis. In vitro susceptibility testing has shown that the minimum inhibitory concentrations for voriconazole for F. pedrosoi and F. compacta are lower than those observed with itraconazole.[73]

Subcutaneous Phaeohyphomycosis

The dematiaceous fungi that cause subcutaneous phaeohyphomycosis are diverse -- the most common pathogens are Exophiala jeanselmei, Wangiella dermatitidis, Bipolaris, Phialophora, and Exserohilum species. Subcutaneous phaeohyphomycosis typically begins as a single red nodule, usually on the extremities. In the immunocompetent person, an indolent, painless expansion in the skin and subcutaneous tissue occurs and can occasionally develop well-formed cysts.[76] In immunosuppressed patients local progression and extension can occur rapidly producing scaly, crusty skin lesions or ulcers. Diagnosis of subcutaneous phaeohyphomycosis is usually made after surgical excision or biopsy by the demonstration of pigmented hyphae histologically and by the isolation and identification of compatible etiologic fungi.[77] Management of subcutaneous phaeohyphomycosis usually involves surgical treatment with or without the use of an antifungal agent.[78]

Keratitis

Dematiaceous fungi are the third most common cause of fungal keratitis after Fusarium and Aspergillus.[79] Among the dematiaceous fungi causing keratitis, Curvularia, Bipolaris, and Exserohilum species are the most common causative organisms. Dematiaceous fungi are a particularly significant cause of fungal keratitis in tropical areas, and most cases are associated with trauma from fungus-contaminated plant material. Clinical features typically include redness, photophobia, and decreased visual acuity accompanied with a yellow-white infiltrate typically limited to the central cornea. Diagnosis is made by isolating and identifying the causative organisms by histopathology and culture of corneal scrapings. Most cases are treated with topical polyenes such as natamycin and amphotericin B. Severe cases may require adjunctive therapy with an oral azole. In persons failing medical therapy, surgery, including penetrating keratoplasty, may be necessary.[80]

Sinusitis

Sinusitis may be caused by a wide variety of fungi. Among the dematiaceous molds, Bipolaris, Curvularia, Exserohilum, and Alternaria species represent the most common causative species.[81] Disease can present as allergic sinusitis or as large fungus balls in the sinus cavities. Treatment typically requires surgical debridement. In cases of fungus balls, antifungal agents do not appear to be of additional benefit unless invasion of the surrounding mucosa or bone is demonstrated.[82,83] Along with Aspergillus species, the phaeohyphomycetes are the main etiologic agents for cases of allergic fungal sinusitis, and the management of this entity still lacks clear guidelines.

Allergic Bronchopulmonary Mycoses

This is a fairly recent concept, similar in presentation to allergic bronchopulmonary aspergillosis (ABPA), which is typically seen in patients with asthma or cystic fibrosis.[84] The most common fungi are Bipolaris and Curvularia species. Therapy is primarily systemic steroids, usually prednisone at 0.5 mg/kg/d for 2 weeks, followed by a slow taper over 2 to 3 months or longer, if necessary. Itraconazole has been used as a steroid sparing agent, but its efficacy is not clear, and routine use of itraconazole is not specifically recommended.

Pneumonia

Nonallergic pulmonary disease with the black molds usually occurs in immunocompromised patients and may be due to a wide variety of species commonly found in the environment (including Bipolaris, Ochroconis (Dactylaria), Fonsecaea, and Chaetomium species). However, cases in immunocompetent patients may also be seen.[85] It is extremely important to perform proper identification of the black mold from nonsterile sites like fluid from bronchoalveolar lavage (BAL). The growth of Cladosporium, species even in lung transplant recipients, is unlikely to be causing disease, but other black molds like Dactylaria would cause much more concern about potentially invasive lung disease or dissemination. Therapy usually consists of intravenous amphotericin B or oral itraconazole initially, followed by itraconazole for a more prolonged period. Experiences with voriconazole and posaconazole are anecdotal but recent experience would suggest that these agents would be satisfactory for most of these infections, and echinocandins might be used in combination for serious or refractory cases. Mortality rates are high in immunocompromised patients.

Central Nervous System Infection

Although rare, CNS infection is one of the best-described and frequently fatal syndromes produced by the dematiaceous molds. A retrospective analysis of 101 reported cases of CNS phaeohyphomycoses found that over half occurred in immunocompetent patients, with Cladophialophora bantiana the most common species isolated.[86] Disease is also caused by Ramichloridium mackenziei, Ochroconis gallopavum (Dactylaria gallopavum), Wangiella dermatitidis, Bipolaris spicifera, B. hawaiiensis, and Chaetomium species. CNS infection from dematiaceous molds typically presents with indolent headache, low-grade fever, and development of focal neurological signs. Often, it requires surgical intervention and the use of a combination of antifungal agents for successful management.

Disseminated Infection

This is the most uncommon manifestation of infection seen with dematiaceous fungi. There are case reports of several different dematiaceous molds that have caused disseminated disease, including Bipolaris species and Wangiella dermatitidis. In a recent review, most patients were immunocompromised, though occasional patients without known immunodeficiency or risk factors developed disseminated disease as well,[87] and infections have occurred with contaminated devices or biological products. In contrast to most invasive mold infections, blood cultures are positive in over half the cases of disseminated phaeohyphomycosis -- this is likely related to adventitial yeast forms in tissue. There are no specific antifungal regimens associated with improved survival in disseminated infection. Despite combination regimens including itraconazole, voriconazole, posaconazole, flucytosine, echinocandins, and amphotericin B being tried, the mortality rate for disseminated disease remains < 70%.[86,87] In a case report, posaconazole successfully cleared fungemia in a patient with no known immunosuppression and a 12-year history of relapsing phaeohyphomycosis who developed disseminated Exophiala spinifera during pregnancy.[88]

Conclusions

In this review, we attempted to provide insights into the major rare and emerging fungal pathogens that produce pulmonary disease. We did not emphasize signs, symptoms, and radiographic presentations because they are not particularly specific or helpful to the clinician. What is most important is that the clinician recognizes the host risk factors and immune status, and in unexplained pulmonary disease, there must be aggressive collection of pulmonary tissue for histopathology, culture, and possibly PCR identification. Proper identification of recovered fungi can allow prediction of disease-producing potential even when recovery is from nonsterile sites such as BAL fluid. On the other hand, the lung is exposed to a nonsterile environment, and some fungal spores cannot produce disease even in the "human petri dish" that some of our patients have become. For instance, even in lung transplant recipients, the frequent isolation from BALs of the very nonpathogenic species such as Penicillium, Rhinocladiella, and most Cladosporium species are rarely significant. However, if Cladophialophora bantiana or Dactylaria galloparum were grown from BAL, then searching for clinical disease is very important.

In Table 1 ,[85,89-99] we have listed several examples of some of the unusual fungi that have caused pulmonary disease. This list is not comprehensive, and it is likely that many more unusual fungi have and will continue to cause disease in the future, but this table helps one to appreciate that the combination of immune suppression and environmental exposure can produce the perfect condition for an unusual fungus to produce disease. In fact, the case of Fonsecaea pneumonia[89] illustrates another important principle. Rare fungi may be causing disease as a coinfection with another pathogen or even another fungus at the same or different site. The clinician must be aggressive in making the correct diagnosis, and then management is individualized. With several classes of antifungals, surgery and control of underlying disease, success in management can be achieved for these rare and emerging fungi, but we have to document that they are producing disease.


Table 1. Examples of Very Rare Fungal Pulmonary Disease Cases


Table 1: Examples of Very Rare Fungal Pulmonary Disease Cases




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    Reprint Address

    Jay B. Varkey, M.D., DUMC Box 3824, Duke University Medical Center, Durham, NC 27710 (e-mail: jay.varkey@duke.edu ).


    Jay B. Varkey, M.D.,1 and John R. Perfect, M.D.1

    1Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina.