Rare and Emerging Fungal Pulmonary Infections

Jay B. Varkey, MD; John R. Perfect, MD

Disclosures

Semin Respir Crit Care Med. 2008;29(2):121-131. 

In This Article

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.[12,13,14] 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%.[24,25,26] 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.[23,29,30,31] 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%.[38,39,40] 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]

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