Curr Infect Dis Rep (2013) 15:440–449 DOI 10.1007/s11908-013-0352-2 SKIN, SOFT TISSUE, BONE, AND JOINT INFECTIONS (N SAFDAR, SECTION EDITOR) Cutaneous Manifestations of Endemic Mycoses Jeannina A. Smith & James Riddell IV & Carol A. Kauffman Published online: 6 August 2013 # Springer Science+Business Media New York 2013 Abstract All of the endemic mycoses have cutaneous and be accompanied by cutaneous and mucocutaneous manifesta- mucocutaneous manifestations that are most commonly seen tions. In the proper epidemiological setting, skin and mucous when patients have disseminated infection. Biopsy of skin membrane lesions can be highly suggestive of endemic fungal lesions is simple and safe and can assist in making a timely infections. Each of the endemic mycoses has a particular pat- diagnosis of disseminated infection. Primary cutaneous inoc- tern of cutaneous manifestations, but there is overlap in the ulation infection has been reported with all of the endemic appearance of the lesions. An accurate diagnosis can only be mycoses, but is rare. In this situation, a nodule or ulcer occurs made by histopathological examination and culture of biopsy at the inoculation site, is often accompanied by lymphangitis samples from these lesions, which are readily accessible and and regional lymphadenopathy, and systemic symptoms and can yield rapid confirmation of the diagnosis of an endemic signs as almost always absent. Mucosal lesions are common fungal infection. with disseminated histoplasmosis, but also have been de- Most cutaneous and mucous membrane manifestations scribed in patients who have disseminated blastomycosis of the endemic mycoses are noted in the presence of widely and coccidioidomycosis. Biopsy is essential to rule out cancer disseminated infection, but occasionallytheyaretheonlysiteof and allows a rapid diagnosis of the endemic fungal infection. active infection when the patient seeks medical care. Even though the only manifestation of infection is one or several skin or mucocutaneous lesions, the pathogenesis in almost all cases is Keywords Histoplasmosis . Blastomycosis . hematogenous dissemination from a primary pulmonary infec- Coccidioidomycosis . Cutaneous lesions . Histoplasma tion. Rarely, cutaneous lesions arise from direct inoculation in capsulatum . Blastomyces dermatitidis . Coccidioides species the absence of disseminated infection. In these cases, the path- ogenesis and clinical manifestations differ from those usually seen. We discuss the pathogenesis, clinical features, and diag- Introduction nostic aspects of the cutaneous and mucocutaneous manifesta- tions of the major endemic fungal infections of North America, Endemic fungal infections have protean manifestations and can histoplasmosis, blastomycosis, and coccidioidomycosis. present a diagnostic challenge. All of the endemic mycoses can J. A. Smith (*) Division of Infectious Diseases, University of Wisconsin School of Histoplasmosis Medicine, 1685 Highland Avenue, Centennial Building, 5th Floor, Madison, WI, USA Mycology and Pathogenesis e-mail: [email protected] J. Riddell IV Histoplasmosis is caused by the thermally dimorphic fungus, Division of Infectious Diseases, University of Michigan Medical Histoplasma capsulatum. The genus consists of two clinically Center, 1500 E. Medical Center Drive, 3120 Taubman Center, important varieties. H. capsulatum var. capsulatum (hereafter Ann Arbor, MI 48109-5378, USA termed simply H. capsulatum) occurs world-wide, but is en- e-mail: [email protected] demic in the Ohio River and Mississippi River valleys, Latin C. A. Kauffman America, and scattered foci in the Eastern US and mid-East. University of Michigan Medical Center, Ann Arbor, MI, USA The other variety, H. capsulatum var. duboisii (hereafter termed simply H. duboisii) is endemic in certain areas of C. A. Kauffman Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, Africa. Phylogenetic analysis has suggested that there are at USA least eight different phylogenetic species of Histoplasma, each Curr Infect Dis Rep (2013) 15:440–449 441 of which occupies distinct geographic areas of the world [1]. Cutaneous involvement is relatively uncommon with infection due to most phylogenetic species of H. capsulatum, with the exception of H. duboisii, which is characterized by frequent cutaneous and subcutaneous lesions [2, 3]. Histoplasma infections are acquired by inhalation into the lungs of the microconidia produced in the mold phase. The organism grows luxuriantly as a mold in soil and other organic matter enriched by bird and bat excreta. After ingestion by pulmonary macrophages, the conidia transform into the yeast phase, and local infection in the lung ensues. The organism is distributed hematogenously within macrophages, usually without any manifest symptoms, until the host develops spe- cific cell-mediated immunity allowing killing of the intracel- Fig.1 Papules seen in a patient who had HIV/AIDS and disseminated histoplasmosis lular organism. Cell-mediated immunity is vital to the contain- ment of H. capsulatum, and hosts who have defective cell- lesions, acneiform eruptions, exfoliative erythroderma, ab- mediated immunity, such as those who have HIV/AIDS, a scesses, and cellulitis (Figs. 1 and 2)[8–15]. hematological malignancy, have received a transplant, or have In the US, about 10 % of patients with AIDS and dissem- been treated with a tumor necrosis factor (TNF) antagonist, are at inated histoplasmosis have been noted to have cutaneous le- high risk of developing acute symptomatic disseminated infec- sions [16, 17]. In contrast, cutaneous manifestations appear to tion. Chronic progressive disseminated histoplasmosis occurs be more common in Latin America; one report from Brazil mostly in older adults who are not overtly immunosuppressed. noted that as many as 66 % of AIDS patients with disseminated Both forms of disseminated histoplasmosis commonly manifest histoplasmosis had skin lesions [17, 18]. The manifestations of cutaneous and mucocutaneous lesions. skin involvement in Brazil were particularly impressive, with On rare occasions, cutaneous histoplasmosis has been re- some patients manifesting large crusted papuloulcerative le- ported to develop by direct inoculation into the skin or in one sions. It has been speculated that the differences in the skin case, possibly the vulva during intercourse [4–7]. Cases of manifestations seen in Latin America compared with the US cutaneous inoculation have occurred in the microbiology lab- are due to the different phylogenetic species of H. capsulatum oratory setting and during autopsies. In general, inoculation (classes5and6inBrazilversusclass2intheUS)thatexistin histoplasmosis is rare, and patients with cutaneous or mucocu- these different geographic regions [1, 17]. taneous findings always should be presumed to have dissem- The differential diagnosis of cutaneous lesions of histoplas- inated disease unless a clear mechanism for infection second- mosis includes a diverse group of other skin conditions, includ- ary to inoculation can be established. ing malignancy, drug-induced eruptions, HIV prurigo, scabies, eosinophilic or bacterial folliculitis, and psoriasis vulgaris. Other infections, including tuberculosis, nontuberculous mycobacterial Clinical Manifestations Most infections with H. capsulatum are asymptomatic. Acute pulmonary infection is typically associated with cough and fever and is indistinguishable from many other acute respiratory infections. In patients who have inhaled a large number of conidia from a heavily contaminated focus or in those who are immunosuppressed, the manifestations of pul- monary histoplasmosis can be severe, with progression to acute respiratory distress syndrome (ARDS). Disseminated disease, involving the liver, spleen, bone marrow, the adrenals, and many other organs, occurs most frequently in immuno- compromised patients and in those with the chronic progres- sive form of histoplasmosis. Many different types of skin lesions have been noted in patients with disseminated histoplasmosis. Examples of skin Fig.2 One of several ulcerated skin lesions that had been present for more than a month in an elderly man who had progressive disseminated lesions that represent tissue invasion include polymorphic histoplasmosis (permission to reproduce this figure granted by Springer plaques, papules, pustules, nodules, ulcers, molluscum-like Science) 442 Curr Infect Dis Rep (2013) 15:440–449 infections, other endemic fungal infections, cryptococcosis, and leishmaniasis also are in the differential diagnosis [19]. It is important to differentiate erythema nodosum and ery- thema multiforme from the lesions described above. These have been described in patients with acute pulmonary histo- plasmosis and are thought to arise as an immunological reac- tion to the infection. They are seen mostly in young healthy individuals, who are handling the infection appropriately. Cutaneous lesions that arise from direct inoculation consist of a primary nodule or indurated ulcer that occurs at the site of inoculation within several weeks. Lymphadenopathy or lymphangitis can occur, but there is no evidence of infection elsewhere. In three of the four reported cases, the infection resolved without antifungal therapy [4, 5, 7]; one patient, who was on corticosteroids, required antifungal treatment [6]. Fig.4 Extensive heaped-up ulcerated mass encompassing the upper lip, Mucosal involvement is common in patients who have gingival mucosa, and palate due to histoplasmosis in a renal