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Clinics in Dermatology (2005) 23, 565 – 571 Cutaneous infections due to opportunistic molds: uncommon presentations Irina Vennewald*, Uwe Wollina, MD Institute of Laboratory Medicine, Academic Teaching Hospital Dresden-Friedrichstadt, 01067 Dresden, Germany Department of Dermatology, Academic Teaching Hospital Dresden-Friedrichstadt, 01067 Dresden, Germany Abstract Molds are quite more often suspected as pathogens by the public than by the medical care community. Molds may, however, cause serious medical problems, and mold infections can develop incognito. Among the mycoses caused by opportunistic molds, alternariosis and fusariosis together with aspergillosis are of particular importance. They are more common than other groups with pathological characteristics. The aim of our presentation is to demonstrate the important role of common molds as causative agents in skin and ear infections. The clinical picture, etiology and pathogenesis, diagnosis and treatment, and course and prognosis of cutaneous infections will be given. The spectrum of clinical symptoms ranges from eczemalike lesions to chronic erythematous, verrucous lesions of the skin or multiple acute infiltrations of the dermis, occasionally forming abscesses. The mycologic direct preparation of the specimens, particularly with optical brighteners, and a histological examination of a skin biopsy are strongly recommended. The outbreak of cutaneous infections is triggered by weakened host defense mechanisms. A review of the literature regarding immunosuppressed and immunocompetent patients will be given. D 2005 Elsevier Inc. All rights reserved. Introduction The problem of pathogenicity of molds in dermatology has been known for some time. Whenever molds are found on the skin, the question arises as to whether they represent a contamination, a saprophytic colonization, or a clinically relevant infection. The mycologic direct preparation of the specimens, particularly with optical brighteners, signifi- T Corresponding author. Mykologisches Labor, Institut fqr Klinische Chemie und Labormedizin, Akademisches Lehrkrankenhaus DresdenFriedrichstadt, 01067 Dresden, Germany. Tel.: +49 351 480 3861; fax: +49 351 480 3236. E-mail address: [email protected] (I. Vennewald). 0738-081X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2005.01.003 cantly improves the immediate diagnosis of dermatomycosis.1,2 Histological examination of a skin biopsy is strongly recommended. The complete review Atlas of Clinical Fungi 3 and other very informative references offer great support for diagnosis and risk assessment of fungi.4- 6 The aim of our presentation is to demonstrate the important role of common molds as causative agents in skin and ear infections. Among the mycoses caused by opportunistic molds, alternariosis and fusariosis are of particular importance. They are more common than other groups with pathological characteristics. In addition, they show many unusual traits. These two groups of mycosis are described in detail in the following sections. 566 I. Vennewald, U. Wollina Alternariosis Definition Alternariosis is a form of phaeohyphomycosis caused by cosmopolitan opportunistic molds of the genus Alternaria. Causative organism (fungi) and epidemiology The organism lives in soil, on organic detritus, and as saprophytes and parasites of various plants. Only six species are described as human pathogens in the Atlas of Clinical Fungi: Alternaria alternata, A chlamydospora, A dianthicola, A infectoria, A tenuissima, and A longipes. The infections are not contagious. Etiology and pathogenesis A main predisposing factor of alternariosis is hypercorticism, which may be endogenous (Cushing disease) or therapeutically induced. Three forms of alternariosis can be distinguished: 1. 2. 3. exogenous, superficial form caused dermatopathy; exogenous, unilocular form of traumatic origin; endogenous, multilocular, disseminated form. Clinical manifestation The spectrum of clinical symptoms ranges from localized epidermal eczemalike lesions to extremely chronic solitary verrucous lesions of the skin to multiple acute infiltrations of the dermis, which occasionally form abscesses.7 Exogenous, superficial form caused by dermatopathy Clinical symptoms result from seborrheic eczemalike alteration of the skin, particularly after treatment with steroids or antibiotics. The skin shows erythema and desquamation or red papules with a granular surface, which are usually painless. In particular, erosion and ulceration can develop after treatment with corticosteroids. The localization is mostly paranasal and on the cheeks.7-9 Histological examination of the skin biopsy shows hyperkeratosis, parakeratosis, and fungal elements in the epidermis. With progressive-type disease, microabcesses with fungal hyphae may be observed. Exogenous, unilocular form of traumatic origin This form of infection is associated with a penetrating injury by a foreign body or trauma. The infection follows a traumatic introduction of the fungus into the skin, such as by cuts or wounds caused by thorns or wood splinters. This form is found in healthy patients. The skin lesion appears as a livid-red plaque with superficial central ulceration. Without adequate treatment, this kind of plaque can develop into a crust-ulcerous lesion of remarkable size.7,10 -14 The outbreak of mycosis can be as late as 10 to 40 years after the initial inoculation and might be triggered by a weakening of host defense mechanisms. The skin lesions are found on bare parts of body, legs, and arms. Usually, patients who work outdoors such as farmers, gardeners, and car drivers are affected. This relationship with outdoor profession cannot be seen in the other forms of alternariosis. Histological examination of the skin biopsies of these patients reveals epidermal acantholysis and parakeratosis. A subepidermal abscess contains neutrophils. The corium shows granulation tissue (granuloma) containing histiocytes, plasma cells, and giant cells of foreign-body types. After periodic acid–Schiff and Grocott-Gömöri methenamine-silver stains, septate hyphae can be found within the granuloma, microabscesses, and giant cells. Endogenous, multilocular form This form most probably originates from metastatic invasion of disseminated alternariosis.7,14 -22 Underlying conditions may be the following: 1. 2. 3. hypercorticism caused by Cushing disease; neutropenia as a result of a malignant condition; organ transplantation and its treatment. The entry of Alternaria species can be paranasal sinusitis, pneumonia, or wound infection after surgery. Outbreak or significant worsening of alternariosis has been described after corticosteroid therapy. In addition, most of these patients suffer from steroid-induced diabetes mellitus. Skin manifestations appear with multiple erythematous and partially necrotic papules approximately 1 cm in diameter. Papulonodular lesions approximately 3 to 4 cm in diameter or cutaneous nodules can also be observed. These manifestations are usually painless.14,17,18,20 In general, the patients are in otherwise good condition, afebrile, and have no other signs of infection. The lesions are often found simultaneously on the trunk, neck, and limbs. Histological examination of a skin biopsy reveals an epidermis of normal conformation and various dermal granulomas, as well as an occasionally occurring central abscess. Mixed infiltrates consisting of macrophages, plasma cells, and neutrophils can be seen. No foreign body reaction is observed. Special stains for fungi, periodic acid– Schiff and Grocott-Gfmfri methenamine-silver, show occasional septate hyphae and many round bodies in the granuloma center.15 -19 The skin lesions of patients with bone marrow aplasia may reveal a dense dermal infiltration by septate hyphae without inflammation. Macroconidia of Alternaria, single or in short chains, are occasionally present.20 Diagnosis Laboratory diagnosis includes direct microscopy, culture, and, in selected cases, histopathology. Diagnosis is usually obtained by skin biopsy, a sterile skin needle puncture, or swabs from skin lesions, wound fluids, or ulcers. Cutaneous infections due to opportunistic molds: uncommon presentations Mycology Direct microscopic examination after 15% to 30% KOH preparation of skin samples shows numerous dark brown septate hyphae, partially branched and sometimes few Alternaria conidia. Skin samples are cultured on Sabouraud glucose agar with and without cycloheximide at room temperature and 378C. After 3 days of incubation, the culture of the skin samples forms white-brown mold colonies. No growth can be observed on cycloheximide-containing media. Morphological identification is obtained on malt agar within 48 hours. Very good growth and production of typical brown conidia in chains can be found at 308C to 338C. Course and prognosis Usually, the course of alternariosis is asymptomatic. Often, the patients do not realize the skin lesions because they are painless and without pruritus. The course of disease lasts many weeks or months. The prognosis is good. Spontaneous remissions of patients with dermatopathic form have been published when the underlying condition improves and steroid therapy can be stopped. Fungal spread from primary cutaneous lesions has not been described. 2. 3. 567 a unilocular form of exogenous traumatic origin25,26; an endogenous multilocular form that most probably originates from metastatic invasion of disseminated fusariosis.27-38 The port of entry for Fusarium infection is unclear. The fungus may enter through skin lesions. A toenail lesion has been suspected as the port of entry by several authors.23,24,33,37,38 Onyxes due to Fusarium are not uncommon, in particular, in patients who underwent chemotherapy or bone marrow transplantation. Airborne infection is also possible, as Fusarium was isolated from bronchoalveolar lavage fluid or sputum. Sinusitis can be a starting point for infection. The following diseases can be associated with Fusarium infections: burns, diabetes mellitus, cancer, or AIDS. Patients who underwent bone marrow transplantation are most susceptible to Fusarium infection. Fusarium is the second most frequent fungal agent after Aspergillus.37 Corticosteroid therapy is not a risk factor for Fusarium infections. Prolonged aplasia and pancytopenia increase the risk of Fusarium infection. Skin (60-80%) and blood (4050%) are the sites most frequently involved.30,37,38 Clinical manifestations Treatment Surgical excision is the method of choice. If the excision is not complete, a relapse will occur after a short remission. In some cases, cure has resulted from debridement combined with antifungal therapy. Alternaria species are susceptible to antifungal drugs such as ketoconazole, itraconazole, voriconazole, and sertaconazole. Superficial form The patients are usually in good general health and develop skin lesions attributed to Fusarium species despite the lack of clinical evidence of a systemic immunodeficient state or a skin damage. 1. Fusariosis Definition Fusariosis is a form of hyalohyphomycosis caused by cosmopolitan opportunistic molds of the genus Fusarium. Causative organism (fungi) and epidemiology Fusarium species are opportunistic molds and are present in soil and on plants. Only 13 species are known to be human pathogens; those most often isolated from the cutaneous lesions are Fusarium solani, F oxysporum, F verticillioides, and F proliferatum. The infections are not contagious. Etiology and pathogenesis The fusariosis can be devised into three forms: 1. a superficial form of patients with good health status23,24; a. interdigital intertrigo, b. paronychia. 2. Interdigital intertrigo of the feet. Sometimes intertrigo is associated with alteration of the toenails. Some patients complain about focal hyperhidrosis.23 The patients have normal immune status and a history of infection extending several years. The patients often went barefoot. The affected skin is macerated, eroded, and painful. Paronychia of fingers shows acute and pustulous lesions, erythema with dry desquamation, or erythema with onychomycosis. The lesions are painful and have a history of 5 to 12 months. Housewives seem to be the special risk group.24 Often, patients are initially treated with topical corticosteroids, which cause the clinical symptoms to become worse. Histological examination of biopsy fragments stained with hematoxylin-eosin shows hyperkeratosis, zonal parakeratosis, slight spongiosis, and epidermal acanthosis. In the superficial dermis, perivascular lymphohistiocytic infiltration with occasional eosinophilic granulocytes can be seen. In the stratum corneum, numerous septate hyphae or spores are found with periodic acid–Schiff staining and GrocottGömöri methenamine-silver staining. 568 Exogenous, unilocular form of traumatic origin This form may take an acute or chronic course of fusariosis in patients of normal health status. The acute infection develops a few weeks after an injury caused a foreign body (thorns, fish barb, or wood splinters). Despite surgical and antibiotic treatment, an erythematous lesion of 4-cm diameter with progressive induration develops around the wound. Straw-colored fluid is discharged. After minimal covered trauma, chronic infection can develop as long as 1 year later. The skin shows abscess formation with fluctuation. Predominant localization of such a lesion is on bare limbs.25,26 Histological studies show fibrous tissues with ill-defined granulomatous inflammation (granuloma with central necrosis). Elongated and septate hyphae can be found in the lesion. I. Vennewald, U. Wollina Fusarium infection in immunosuppressed patients can develop into an acute invasive form with lethal consequences when not treated properly with systemic antifungal drugs. Retrospective studies confirm that Fusarium infection mainly affects severely immunosuppressed patients such as those with hematologic malignancy.31,37,38 The prognosis in similar groups of patients is clearly better than that for invasive aspergillosis. This suggests of a lower pathogenicity of Fusarium. Because the prognosis is closely correlated with neutrophil recovery, promising therapeutic results obtained with the use of colony-stimulating factors should be further evaluated. Treatment Cure can be achieved by surgical excision with debridement and skin grafting in conjunction with antifungal drugs. Fusarium species are susceptible to amphotericin B, voriconazole, sertoconazole, and terbinafine. Endogenous, multilocular form, probably originates from metastatic invasion of disseminated fusariosis Painful erythematous maculae or papules with progressive central infarction occur surrounded by an erythema. The lesions are often found simultaneously on the trunk, face, limbs, balls of the toes, or on the finger pad.27,30 -35,38 In skin biopsies, fungal hyphae are seen predominantly in capillaries and small vessels, infiltrating surrounding tissue structures and causing edema, epidermolysis, and focal necrosis. Sometimes, fungal hyphae are present in the connective tissue without an inflammatory reaction.30,33 -35,38 The term otomycosis is used to describe mold or yeast infections of the external auditory canal. Diagnosis Causative organism (fungi) and epidemiology Laboratory diagnosis includes direct microscopy, culture, and, in selected cases, histopathology. Molds and yeasts are common in the auditory canals of healthy people, but the percentage of isolated Aspergillus and Candida species is very low.39 Many authors have reported only Aspergillus isolates of patients with otomycosis.40 - 48,50 The predominance of thermophile Aspergillus and Candida species is related to the inflammatory processes of the ear. Etiologic agents causing fungal infection in the ear were reported to be in two thirds of cases molds and in one third yeasts.51 The molds mostly isolated from the ear are listed in Table 1.40,41,49 -52 The Aspergillus species represent 95% of the molds isolates with a predominance of Aspergillus niger, followed by Aspergillus fumigatus and Aspergillus flavus. The infections are not contagious. Mycology Direct microscopic, mycologic examination of skin fragments, macerated in 15% to 30% KOH, reveals hyaline septate hyphae of irregular diameters, which are sometimes contorted and much larger than those of dermatophytes. Skin samples are cultured on Sabouraud glucose agar with and without cycloheximide at room temperature and 378C. After 3 to 5 days of incubation, the culture of the skin samples forms pink, yellow, or purple mold colonies. No growth can be observed on cycloheximide-containing media. Morphological identification can be obtained on malt and oatmeal agar within 1 week. Microscopic examination shows that the colonies consist mainly of sickle-shaped macroconidia. Chlamydospores were mostly observed in older cultures after exposure to daylight. The Fusarium colonies need the day-night rhythm for the building of fruiting bodies. Course and prognosis The prognosis of immunocompetent patients is good, although with topical treatment, the course of disease lasts many weeks or months. Otomycosis Definition Table 1 Spectrum of molds isolated from the external and middle ear Aspergillus Aspergillus Aspergillus Aspergillus Aspergillus Aspergillus Aspergillus niger fumigatus flavus terreus candidus hollandicus alliaceus Aspergillus janus Aspergillus versicolor Aspergillus nidulans Paecilomyces variotii Mucor species Penicillium species Cutaneous infections due to opportunistic molds: uncommon presentations Etiology and pathogenesis Whenever fungi are found in the ear, the question arises whether they represent colonization or clinically relevant infection. Persisting discharge with maceration of the meatal epithelium may support fungal colonization of the external ear in patients with otitis media. The demonstration of conidiophores (Aspergillus heads) in the auditory canal is consistent with the hypothesis that mucous discharge serves as a nutrient. Clinically relevant infections are accompanied by inflammation.51 The reason for this discharge lies in the chronic hyperplastic inflammation of the mucous membrane in the middle ear. This results in a disturbance of the continuous drainage of fluids from the middle ear cavity to the auditory tube, perforation of the tympanic membrane, and relapsing otorrhea. The persisting tympanum perforation is an entrance to the middle ear. A primary infection may arise from the oropharynx via the auditory tube. Infection by molds, in contrast to bacteria and yeasts, is only possible after perforation of the eardrum.51,53 Clinical manifestation Fungal infection of the ear occurs in three primary types: (1) chronic colonization, (2) acute invasive, and (3) chronic invasive. The patients can be classified by their clinical history into two groups: 1. The larger otomycosis group is represented by patients with chronic otitis media and persisting perforation of the tympanic membrane with otorrhea with or without cholesteatoma. Most of these patients (86%) are not neutropenic or otherwise immunocompromised and have been experiencing chronic otitis media for many years. These patients had longterm relapsing otorrhea and had been treated repeatedly with antibiotics without achieving remissions. They show chronic fungal colonization of the auditory canal.51 Usually, the patients complain about the following symptoms: ! ! ! ! persisting white or colorless otorrhea with tympanum perforation; edema, erythema of tympanic membrane residuum, ear pain, pruritus; whitish, cottonlike, or greasy debris in the external auditory canal, sometimes on the tympanic membrane or in the residual space (after excision of cholesteatoma); increasing hearing loss. A small part of affected patients (7%) have individual immunosuppression as the result of an underlying disease or 569 its treatment. They can develop fatal acute invasive or chronic invasive form of fungal infection.44,46 -51 2. The rest of the patients (7%) have some kind of immunodisturbance and are experiencing generalized skin diseases such as psoriasis or atopic dermatitis rather than chronic otitis media.51 These patients were treated with topical steroids for many years. They had clinical signs of otitis externa only. Clinical symptoms are seborrheic eczemalike skin lesions with erythema and scaling or red papules with a granular surface and fungal elements in the epidermis. Lesions are itching in most cases. Usually, these patients have a fungal colonization of the external ear. Diagnosis Laboratory diagnosis includes direct microscopy, culture, and, in selected cases, histopathology. The samples from the auditory canal contain debris and secretion. From the external ear, skin biopsies or swabs of pustules can be used for mycologic culture. Surgical material from the tympanic membrane, the residual space, and middle ear cavity may be used for histopathology. Mycology One part of the samples has to be smeared on a microslide with a drop of 15% to 30% KOH-containing optical brighteners.1,2,51 After an incubation period of 2 to 24 hours, the slide is examined by fluorescence microscopy at 330 to 390 nm. In addition, Giemsa and Gram stains may be performed. Tightly packed septate hyphae are common in specimens of debris from the auditory canal. In Giemsastained specimens from the auditory canal, numerous hyperkeratotic (sometimes parakeratotic) epithelial cells, some leukocytes, and hyphae of molds can be found. The specimens should be inoculated directly into two Sabouraud glucose agar tubes or plates for fungal culture. One tube per plate is incubated at 378C and the other at room temperature (228C) for 14 days. The molds have to be subcultured on Czapek or malt agar. All investigations have to be performed under safety conditions (class 2) to minimize contamination with airborne germs.51 Histopathology Surgical specimens of patients suspected of having mastoiditis or cholesteatoma should be examined histologically. Special stains for fungi should be performed, including periodic acid–Schiff, Grocott-Gfmfri methenamine-silver, and optical brighteners. Histological studies demonstrate different fungal growth in the ear of affected patients.45-51 1. Chronic colonization of epithelium of auditory canal and cholesteatoma. Fungal hyphae mostly of Asper- 570 gillus are observed between the horny lamellae of cholesteatoma and in the stratum corneum of meatal epithelium of immunocompetent patients. No inflammatory cellular response accompanied Aspergillus hyphae.45,51,52 2. Acute invasive and chronic invasive otomycosis. These forms are often associated with fungal infections of middle and inner ears. Histological sections of a fragment from a tympanic membrane or a residuum space of immunocompromised patients show the matrix of cholesteatoma or epithelium of an auditory canal with granulocytes and numerous fungal hyphae. An invasive growth of mycelium in the blood vessels or bones can be observed in patients with individual immunosuppression or neutropenia.46 -51 Course and prognosis The prognosis of immunocompetent patients is good. Fungal infection in immunosuppressed patients can develop into acute invasive or chronic invasive forms of otomycosis with lethal consequence when not treated properly. Treatment The patients with chronic colonization should be treated with intense debridement and cleansing in combination with topical clotrimazole, imidazole, ciclopiroxolamine, amphotericin B, or nystatin. The treatment of immunocompromised patients is based on the application of combined systemic and topical antifungal drugs after the surgical debridement of infected tissue.51,54,55 Conclusions Diagnosis of mold infections does not only need the laboratory that is experienced in mycology but the medical doctor who thinks about mold infection and performs diagnosis with all the clinical skill needed. Many of falsenegative and false-positive bmold infectionsQ could be avoided by careful patient’s history, clinical investigation, and common sense in the interpretation of laboratory data. Close communication between the dermatologist and the mycologist in the laboratory is recommendable. References 1. Monod M, Baudraz-Rosselet F, Ramelet AA, et al. Direct mycological examination in dermatology: a comparison of different methods. Dermatologica 1989;179:183 - 6. 2. Rqchel R, Schaffrinski M, Seshan KR, et al. 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