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Phaeohyphomycosis:

PHAEOHYPHOMYCOSIS (PHM)1

PHM is an infection of humans and other animals caused by a number of phaeoid (melanized) fungi, characterized by the development of dark-colored hyphae and other types of fungal elements, depending on species, in invaded tissues. The term PHM encompasses distinct mycotic infections regardless of the site of the lesion, the pattern of tissue response, granuloma or abscess, or the taxonomic classification of the etiologic agents.

With the increasing number of immunocompromised patients, the number of genera and species of fungi causing PHM has been growing. As of 1998, the phaeoid fungi, verified as causing PHM, comprised 109 species classified in 60 genera. Certainly, this number has increased over the past decade. The most common etiologic agents are Exophiala jeanselmei and Wangiella (Exophiala) dermatitidis, followed by such phaeoid fungus species as Alternaria alternata, Bipolaris spicifera, Curvularia lunata, Exophiala moniliae, E. spinifera, Exserohilum rostratum, Phaeoacremonium parasiticum, Phialemonium obovatum, and Phialophora repens.  Deep-seated cases of PHM have been caused by more than 40 species classified in at least 27 genera. In particular, 44% of cerebral PHM infections are caused by Cladophialophora bantiana

Clinical and Pathologic Manifestations:

PHM is a cosmopolitan disease. Patients are usually adults, and about half of them seem to be immunologically compromised by associated underlying diseases such as diabetes mellitus, tuberculosis, leprosy, acquired immunodeficiency syndrome (AIDS), lymphoma, and leukemia. Some patients appear to be locally compromised because of the application of topical corticosteroids. PHM lesions may occur anywhere in the body, often in exposed parts, especially the upper arms. Frequently, but not exclusively, inoculation of the agent is by wounds made by contaminated materials.

The most common and typical lesions are cutaneous or subcutaneous cysts or abscesses, frequently caused by E. jeanselmei. The primary lesion occurs as a single, discrete, asymptomatic small nodule. This is palpable under the smooth and slightly elevated skin. The nodule gradually evolves to become an encapsulated, fluctuant abscess with a liquefied center. The overlying epidermis is hardly affected, and formation of a sinus tract or ulceration is rarely observed. Occasionally, a granulomatous, slightly elevated plaque may appear when the main site of the lesion is in the epidermis and dermis. Less frequently, it is manifested as a small verrucous nodule or plaque consisting of coalesced nodules, which resembles the clinical appearance of CBM.

Lymph node involvement and dissemination are rare. However, PHM may occur in the central nervous system or other internal organs, such as the liver, lungs, or pancreas. It may appear as a hematogenous metastasis from cutaneous or subcutaneous infections, or without any visible lesions. Human infections caused by W. dermatitidis have been equally distributed between cutaneous and subcutaneous infections, and systemic involvement. Wangiella dermatitidis should be regarded as a dermotropic and neurotropic pathogen. Because of this, its designation as a paradigm for phaeohyphomycosis is appropriate.

Cyst or abscess formation is mainly confined to the dermis and adjacent subcutaneous tissue. Three stages have been described: (1) a tuberculoid phase, (2) a stellate abscess, and (3) a fluctuant abscess. In the primary lesion, a hypercellular tubercle composed mainly of epithelioid cells and foreign body giant cells is formed. Scattered foci of necrosis follow, accompanied by acute and chronic cellular infiltrations, and stellate abscesses develop. The stellate abscesses coalesce to transform themselves into a fluctuant abscess.

A thick wall surrounds the abscess. The inner layer is made up of a combination of epithelioid cells, macrophages, giant cells of foreign body and Langhans' types, and neutrophils. The middle layer is composed predominantly of vascularized scar tissue surrounded by an outer layer of hyaline fibrous tissue. The center of the abscess contains necrotic debris mixed with polymorphonuclear leukocytes. Foreign plant material, as in CBM, may be present. The granulomatous lesions in the middle to upper dermis mainly consist of epithelioid cells and giant cells that are covered by the necrotic epidermis. Pseudoepitheliomatous hyperplasia, hyperkeratosis, parakeratosis, and acanthosis overlying the upper dermal granuloma are recognized in PHM. These appear clinically as verrucous plaques resembling CBM.

Treatment and Prognosis:

Successful treatment of cutaneous and subcutaneous PHM is achieved by simple surgical excision. However, cases of systemic and disseminated PHM are serious and have a high mortality rate. Antifungal chemotherapy is not easy because of the huge variety of etiologic agents. Amphotericin B or flucytosine or combination therapy with these agents, and treatment with fluconazole, itraconazole, ketoconazole, or terbinafine has been reported with mixed results. clinical responses are well correlated with in vitro susceptibility test results; however, resistance does not preclude clinical response.

As in cases of CBM, new antifungal agents may prove important in the treatment of PHM. Most fungi causing PHM are sensitive in vitro to the triazole, voriconazole, as well as itraconazole, an imidazole antifungal agent.  Many agents of PHM that cause superficial infections are susceptible to terbinafine in addition to the echinocandins. In contrast, the pathogenic agents of PHM appear less sensitive to fluconazole in vitro.

Local heat therapy, using a pocket warmer or an electric pad, may also be applied to cutaneous and subcutaneous PHM, even though some of the etiologic fungi possess considerable thermotolerance.

Prevention and Control:

Prevention and control are not practical for PHM. Owing to the cosmopolitan, ubiquitous nature of the fungi causing PHM, it is not feasible to attempt their eradication.

 

1.Matsumoto, T., C. R. Cooper, Jr. and P. J. Szaniszlo.  Chromoblastomycosis and Phaeohyphomycosis. p.569-572..  In: R. L. Guerrant, D. H. Walker and P. F. Weller (ed.) Infectious Diseases: Principles, Pathogens, and Practice, Third Edition, (2011). Saunders Elsevier, Oxford, U.K.

 

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About our research:
     The Szaniszlo Lab's research is primarily in the elucidation of the mechanisms of fungal cell development, specifically that of the fungus, Wangiella dermatitidis (Wd).  Wangiella is used as a model to identify cell-wall virulence factors among dematiaceous (melanized) fungal pathogen of humans.  Specific emphasis is placed on the cell-wall because it is a boundary between host and pathogen, an ultimate determinant of morphology, known to represent a virulence factor, and is a potential target for the design of antifungal drugs.  Particular focus is on the systems leading to chitin localization and melanin enrichments of cell walls in the polarized and nonpolarized vegetative phenotypes known to be expressed by this polymorphic fungus under conditions of human infection.

Thus, the lab's current research is designed to provide insights about how the five chitin synthase (WdCHS) structural genes of Wangiella contribute to its pathogenicity and virulence. The specific aims of the laboratory are

  1. To study the WdCHS genes, establish how their expression is regulated, and identify factors that control the time, place and function of their products, with a focus on the mechanisms involved in the very high expression of WdCHS3 and WdCHS5, two genes with no homologs in Saccharomyces cerevisiae or Candida albicans, at 37C and under other conditions that influence growth, development and differentiation during infections.
  2. To establish the individual and collective importance of the five WdChsp isozymes and their chitin products to yeast, isotropic and hyphal growth, and their contributions, if any, to pathogenicity and virulence as augmented by melanin and periods of isotropic enlargement, and with a focus on the potential for WdChs3p and WdChs5p to be particularly vulnerable antifungal targets.
  3. To continue to extend the concepts revealed with this model phaeohyphomycotic fungus to a limited number of other dematiaceous pathogens of humans

What is Wangiella dermatitidis?
     Wangiella dermatitidis (aka Exophiala dermatitidis) is a dematiacious fungus known for causing a variety of infections known collectively as "phaeohyphomycosis".   It is a monotypic species in the form-class Deuteromycetes.  What distinguishes it as a dematiacious fungus is the black pigment seen on the walls of its vegetative and reproductive structures -- the hyphae and spores. Wangiella is also a polymorphic organism, taking on a variety of cell types, which include the typical budding yeast cell, isodiametric cell, moniliforme hyphae, true hyphae, and conidia (McIntosh, 1996).  It grows as a yeast in rich liquid medium, but has been shown to convert to other forms by changing growth conditions (de Hoog et al., 1994).

     Phaeohyphomycosis include several human syndromes which include black-grained mycetoma, chromoblastomycosis, tinea nigra, black piedra, keratitis, and onychomycosis.

How do I get around this site?
   The Szaniszlo Lab website is navigable by clicking on one of the text selections on the black region to the left of the page.  You will notice that the selections will highlight when you move the cursor over them.  With your mouse pointer over the selection, click on the text to jump to that page.  The choices are Introduction, People, Publications, Protocols, Images, Courses, Links, and Search.  If your browser is having trouble with the selections on the left, you can still make your selections using the same text selections at the bottom of every page.  You can return to the Szaniszlo Lab's main page at any time by clicking on "the Szaniszlo Lab"  at the top right hand corner of any page.

Help! I'm know nothing  about science!  Can you translate any of this to me?
    

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This page updated on:
Tuesday, July 26, 2011 04:13:12 PM

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