Cutaneous Manifestations of Endemic Mycoses

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)

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 pathogenesis and clinical manifestations differ from those usually seen. We discuss the pathogenesis, clinical features, and diag- Introduction nostic aspects of the cutaneous and mucocutaneous manifestations 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 specific 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 pulmonary 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 immunocompromised patients and in those with the chronic progressive 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 erythema multiforme from the lesions described above. These have been described in patients with acute pulmonary histoplasmosis and are thought to arise as an immunological reaction 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 transplant chronic progressive disseminated histoplasmosis and is a use- recipient ful clinical clue to the diagnosis (Fig. 3)[20•]. Mucous membrane lesions are also seen with acute disseminated infection, typically present, but occasionally, oral lesions are the only especially among patients with HIV/AIDS; one report from clinical finding of histoplasmosis (Fig. 4). In general, these Latin America noted mucous membrane involvement in near- patients should be considered to have disseminated infection ly 60 % of patients [21•]. with spread to the mucous membranes via the hematogenous A variety of mucous membrane lesions have been de- route. However, there are patients in whom an appropriate scribed in histoplasmosis [21•, 22–26]. These include painful search for other systemic involvement is nonrevealing, and the oral and nasal ulcerations and erosions, nodules, and heaped- question has been raised as to whether these patients have up lesions that can be large and destructive on the buccal truly localized infection of the oropharyngeal tissues [20•, 26]. mucosa, tongue, lips and gingiva; nasal sepal and palatal H. duboisii is characterized by a variety of cutaneous perforations have been reported. The main differential diag- manifestations. Most nonimmunocompromised hosts have nosis is cancer. Other signs of disseminated disease are cutaneous and osteoarticular manifestations with no evidence of dissemination to the viscera. Although uncommon, H. duboisii infection has been reported in African patients with HIV/AIDS, and in this population, dissemination to many organs, in addition to cutaneous and osteoarticular involvement, is common [2, 3, 27]. Cutaneous manifestations include papules, which appear similar to molluscum contagiosum, ulcers, subcutaneous nodules, and draining sinus tracts from underlying infected bone or lymph nodes (Fig. 5).

Fig.3 Tongue ulcer that progressively increased in size over a year in a Fig.5 Molluscum-like lesions in an African child who had disseminated patient with progressive disseminated histoplasmosis. Courtesy of Dr. infection with H. duboisii. Courtesy of Dr. Bertrand Dupont (permission Andrew Thompson to reproduce this figure granted by Springer Science) Curr Infect Dis Rep (2013) 15:440–449 443

Diagnosis

Cutaneous and mucous membrane lesions afford easily accessible locations for biopsy. A full-thickness punch biopsy is the diagnostic method of choice for evaluation of cutaneous involvement with H. capsulatum or H. duboisii.Onhistopath- ological examination, necrotizing granulomas are usually seen. H. capsulatum appears as tiny (2–4 μm) intracellular yeasts (Fig. 6). The yeast forms of H. duboisii are larger (8–15 μm) and thick-walled, and can appear as short chains in tissues (Fig. 7). They often appear lemon-shaped with one bud that leaves a “scar” when it detaches [28]. Because of its small size, H. capsulatum is especially difficult to appreciate on routine hematoxylin and eosin-stain sections, but methenamine silver or periodic acid-Schiff (PAS) stains will reveal the Fig.7 Aspirate from a bone lesion in a patient with African histoplasmosis showing large, 8–15 micrometer, thick-walled yeasts in a short chain tiny yeasts. PCR on tissue specimens has been useful in some typical of H. duboisii (KOH preparation). Courtesy of Dr. Bertrand Dupont cases, but has to be performed at reference laboratories and is (permission to reproduce this figure granted by Springer Science) not standardized [29, 30]. Skin biopsy specimens should be plated onto Sabouraud’s Blastomycosis dextrose agar and incubated at 25 °C to allow growth of the mold phase of H. capsulatum. Once growth occurs, the or- Mycology and Pathogenesis ganism can be identified easily with the use of a commercially available DNA probe [20•]. Although definitive, growth in Blastomycosis is caused by the thermally dimorphic fungus, B. culture is slow, usually taking several weeks. dermatitidis. In North America, it is endemic in the Great Lakes An enzyme immunoassay (EIA) that detects Histoplasma regions of both the US and Canada, the Mississippi River polysaccharide cell wall antigens and that can be performed in Valley, and along the St. Lawrence Seaway. It is hyperendemic serum and urine is very useful for the rapid diagnosis of in several focal areas in northern Wisconsin and Michigan [32]. disseminated histoplasmosis [31]. Cross-reactivity is common Infection is acquired from inhalation of the conidia pro- with Blastomyces dermatitidis and several other fungi, includ- duced in the mold phase, which flourishes in moist soil rich in ing H. duboisii, although it has been noted that sensitivity is organic debris. After inhalation, the mold converts to the yeast low for H. duboisii. Antibody assays using immunodiffusion phase and multiplies in the lungs [33]. Hematogenous dissem- and complement fixation techniques are available at reference ination is probably common, almost always asymptomatic, laboratories and are helpful in the diagnosis of histoplasmosis, and occurs before the development of specific cell-mediated but they are less useful in immunocompromised hosts, who immunity. Skin lesions are almost always a manifestation of frequently fail to mount an antibody response. disseminated infection. Cutaneous inoculation blastomycosis has been reported in a small number of cases [34]. The diagnosis of inoculation blastomycosis should be made only if a source for direct inoculation can be identified, a localized lesion has developed at the site, and no evidence of systemic infection can be found. Several cases have been reported in laboratory technicians working with B. dermatitidis and in pathologists performing autopsies on animals or patients with blastomycosis. Other cases involved patients who were injured with items contaminated with soil or had bites from infected animals, including a pet kinkajou [35–37].

Clinical Manifestations

Most patients infected with B. dermatitidis remain asymptom- Fig.6 Typical 2–4-μm budding yeasts of H. capsulatum stained with atic or have minimal pulmonary symptoms. Both immuno- methenamine silver stain competent and immunosuppressed patients can develop 444 Curr Infect Dis Rep (2013) 15:440–449 severe pulmonary infection progressing to ARDS, presum- ably because they encounter a large burden of organisms in the environment. Patients who are immunosuppressed, particularly those who have HIV/AIDS, a hematological malignancy, have received a transplant, or are receiving anti-TNF agents, have more severe disease [38–41]. The skin is the most common extrapulmonary site of blastomycosis. Earlier reports cited as many as 80 % of patients with disseminated disease presenting with cutaneous involvement, but in several recent reports, only about 20 % of cases have been noted to have skin lesions [42, 43]. As many as 50 % of patients who present with skin lesions have cleared their pulmonary infiltrates and have no abnormal findings noted on chest radiography; others have concomitant pulmo- Fig.9 Nodular scaling lesion on the eyelid, a not uncommon site for dissemination of blastomycosis. Courtesy of Dr. Gunner Deery nary and skin lesions noted at presentation [44]. The cutaneous findings of blastomycosis include crusted although some patients have had fever. Work-up reveals no verrucous lesions with punctate areas of purulence, plaque- other manifestations of blastomycosis. In a review of 22 like lesions, painful ulcers with raised borders, and tender patients, only 5 had what would be described now as effective subcutaneous nodules (Figs. 8 and 9). Lesions typically occur antifungal therapy, and they all were treated with ketoconazole on the exposed areas of the head and extremities, but can or itraconazole for 1–6 months. In patients seen in the pre- occur anywhere on the body [45, 46]. Over time, the lesions azole era, their infection resolved with no therapy, potassium gradually enlarge and can become quite disfiguring (Fig. 10). iodide treatment, or local debridement; one patient was given Skin lesions also occur over areas of osteomyelitis, appearing intravenous amphotericin B for 5 days [34]. as draining sinus tracts. Typically patients have one to a few B. dermatitidis involves the mucous membranes much less lesions, but hundreds of lesions can occur. commonly than H. capsulatum. Oral, nasal, and pharyngeal The differential diagnosis of skin lesions seen in blastomy- lesions have been seen in blastomycosis [48–50]. The lesions, cosis includes pyoderma gangrenosum, keratoacanthoma, especially those that present as a nodule on the larynx, closely squamous cell or basal cell carcinomas, as well as bromide mimic squamous cell carcinoma. or iodide ingestion and cutaneous tuberculosis. Although much less commonly seen with blastomycosis than with the other endemic mycoses, erythema nodosum can occur during thecourseofacutepulmonaryblastomycosis[47]. The usual presentation of localized inoculation blastomycosis is development of a papule, pustule, or ulcer within several weeks at the site of inoculation. Local spread to lymph nodes is common, and systemic symptoms are infrequent

Fig.8 Typical verrucous skin lesion with multiple punctate areas of Fig.10 Extensive lesion on the neck and face that had enlarged over a 3- purulent drainage in a patient with disseminated blastomycosis month period in a patient who had disseminated blastomycosis Curr Infect Dis Rep (2013) 15:440–449 445

Diagnosis

Histopathological examination of skin lesions classically reveals pseudoepitheliomatous hyperplasia with mixed purulent and granulomatous inflammation (Fig. 11). The yeast form of B. dermatitidis is distinctive; it is 8–15 μmand appears as a broad-based budding yeast with a doubly refractile cell wall. It is best seen with methenamine silver or PAS stains, but can sometimes be visualized in hematoxylin and eosin stained tissues (Fig. 12)[51]. The yeast can also be seen in purulent exudate from skin lesions using a calcofluor stain or lactophenol cotton blue/KOH preparation. Skin biopsy specimens should be plated onto Sabouraud’s dextrose agar and incubated at 25 °C to allow growth of the Fig.12 Cutaneous lesion of blastomycosis showing extensive neutrophilic response and several large, 8–15 micrometer, thick-walled yeast mold phase of B. dermatitidis.Oncegrowthoccurs,aspecific structures (without budding) (hematoxylin and eosin stain) DNA probe allows rapid confirmation of the identity of the mold. PCR has been shown to be useful in some patients [52]. posadasii in the remaining endemic areas [55]. There is recent Antigen testing using an EIA that detects B. dermatitidis evidence that climate change may be expanding the ecological cell wall polysaccharide in urine and serum can aid in the niche for Coccidioides species, as cases as far north as Wash- diagnosis of blastomycosis. It is most often positive when ington have been reported [56]. disseminated disease is present. The antigen assay cross- There has been a recent increase in cases of coccid- reacts extensively with Histoplasma antigens [53, 54]. Serol- ioidomycosis in the US. A report from the Centers for Disease ogy has not been standardized for blastomycosis and in gen- Control and Prevention demonstrated an increase in the inci- eral, is not useful for diagnosis. dence of coccidioidomycosis from 5.3 per 100,000 population in the endemic area in 1998 to 42.6 per 100,000 in 2011 [57]. In some highly endemic areas of California almost 100 % of the Coccidioidomycosis population has serological evidence of exposure to Coccidioides species [58]. Mycology and Pathogenesis Infection is acquired through inhalation of arthroconidia formed in the mold phase in the environment. In the lung, the Coccidioidomycosis is caused by the dimorphic fungi organism transforms into spherules, which are packed with Coccidioides immitis and C. posadasii, which are endemic in endospores. Rupture of the spherules allows local and hematog- the Lower Sonoran life zone in the arid portions of the south- enous dissemination of the endospores, which perpetuates spread western United States and in selected areas in Central and until the host is able to handle the infection [55]. In the vast South America. C. immitis occurs in California and C. majority of cases, the initial infection is asymptomatic. Symp- tomatic dissemination occurs more commonly in persons who are dark-skinned, especially African-American individuals, and in those who have impaired cell-mediated immunity [59, 60]. The skin is a major site for dissemination in coccidioidomycosis. Very few cases of primary inoculation coccidioidomycosis have been described [61–64]. Most of the reports describe individuals who developed cutaneous infections at the site of puncture wounds sustained at autopsy or in a laboratory setting, but other sources have included inoculation from cactus barbs and bites from infected animals. Unless proven to be due to inoculation, all cases of cutaneous coccidioidomycosis should be thought of as a manifestation of disseminated disease.

Clinical Manifestations Fig.11 As seen on high power microscopy of a biopsy from a cutaneous lesion in a patient with blastomycosis showing pseudoepitheliomatous hyperplasia and mixed granulomatous and pyogenic reaction in the dermis Pulmonary coccidioidomycosis is a common cause of com- (hematoxylin and eosin stain) munity-acquired pneumonia in the endemic area, but has no 446 Curr Infect Dis Rep (2013) 15:440–449 specific features that distinguish it from the usual bacterial often in young women, manifest within a few days to weeks of pneumonias. It is likely that most patients are not diagnosed pulmonary symptoms, and are generally a good prognostic sign with acute pulmonary coccidioidomycosis and recover without that the person is developing immunity against Coccidioides. therapy. Patients who are immunosuppressed, particularly those Mucocutaneous lesions are not uncommon with dissemi- who have HIV/AIDS, a hematological malignancy, have re- nated coccidioidomycosis [70–72]. Ulcerations of the oral ceived a transplant, or are receiving anti-TNF agents, have more mucosa and tongue are among the most common manifesta- severe disease [59, 65]. Disseminated coccidioidomycosis fre- tions, but nasal lesions that can be destructive have been quently involves the skin, osteoarticular structures, and the noted. Mucosal lesions of the airway, sometimes large enough meninges, but dissemination to many organs is common. to cause obstruction, have been described. The skin is the most common extrapulmonary site of infection and may be the first and only clinical manifestation Diagnosis of disseminated disease [66, 67]. However, it has been noted that as many as 90 % of patients who have skin lesions also Histopathological examinationofbiopsymaterialfromskin have dissemination to other organs [60]. In a recent large lesions is very useful for the diagnosis of coccidioidomycosis. series, 36 % of patients presented with a single cutaneous The usual findings include granulomas that contain large (10– lesion, 28 % with two to five lesions, and 36 % with more 80 μm), thick-walled, refractile spherules that may or may not than five lesions [68]. The cutaneous findings associated with contain many 2–4-μm endospores. Collapsed spherules from coccidioidomycosis are diverse and include papules, macules, which the endospores have been released are often seen pustules, nodules, ulcers, verrucous plaques, abscesses, and (Fig. 14). Neutrophilic infiltrates surrounding the spherules atrophic scars (Fig. 13)[64, 69]. Lesions can occur anywhere are frequent, and in some patients, large numbers of eosinophils on the body, but have a predilection for the scalp and face. The are noted in involved tissues [69, 73]. The distinctive spherules differential diagnosis of cutaneous lesions due to coccidioido- also can be seen when aspirates from abscesses or draining mycosis includes other endemic fungal infections, cryptococ- cutaneous lesions are examined with calcofluor white [74]. cosis, tuberculosis, sarcoidosis, leishmaniasis, and basal cell Biopsy material from skin lesions should be sent to the or squamous cell carcinomas. laboratory for culture; the laboratory should be notified that Patients who have inoculation coccidioidomycosis develop coccidioidomycosis is a possibility so that they can take special a papular or ulcerated lesion 1–3 weeks later at the site of the precautions with this highly contagious organism. The mold injury [62]. Lymphangitis and regional lymphadenopathy are phase of Coccidioides species grows readily on standard agar common, and rarely osteomyelitis can occur. Patients de- plates used to culture bacteria, as well as on Sabouraud’s scribed before azoles were available received no treatment or dextrose agar. Unless certified to be able to handle bioterrorism surgical debridement and the infection resolved within weeks agents, the laboratory will have to send a suspicious mold to a to months. Therapy with either fluconazole or itraconazole is reference laboratory for identification. now used to hasten resolution of the infection [63]. Serological assays for antibody performed in reference lab- Early in the course of acute pulmonary infection with oratories that are experienced in the diagnosis of coccidioido- Coccidioides species, patients may experience an evanescent, mycosis can be very helpful in the diagnosis of disseminated often pruritic, erythematous rash [64]. Erythema nodosum and infection [75]. Complement fixation antibodies also provide erythema multiforme are noted in as many as 25 % of patients with acute pulmonary coccidioidomycosis. They occur most

Fig.14 Biopsy of a lesion in a patient with coccidioidomycosis showing Fig.13 Draining skin lesion overlying osteomyelitis in a man who had several large 10–80 micrometer empty spherules that have released their disseminated coccidioidomycosis endospores (methenamine silver stain) Curr Infect Dis Rep (2013) 15:440–449 447 prognostic value in that patients who are developing effective 2. Loulegue P, Bastides F, Baudouin V, et al. Literature review and case immunity generally have a fall in antibody titer, and a rising histories of Histoplasma capsulatum var. duboisii infections in HIV- infected patients. Emerging Infect Dis. 2007;13:1647–52. titer portends a poorer outcome. However, antibody assays are 3. Antinori S, Magni C, Nebuloni M, et al. Histoplasmosis among problematic in immunocompromised patients, who often can- human immunodeficiency virus-infected people in Europe. Report not mount an antibody response. Indeed, one study demon- of 4 cases and review of the literature. Medicine (Baltimore). – strated that single initial serological tests were positive in only 2006;85:22 36. 4. Tosh FE, Balhuizen J, Yates JL, Brasher CA. Primary cutaneous 21 % of solid organ transplant recipients with disseminated histoplasmosis: report of a case. Arch Intern Med. 1964;114:118–9. coccidioidomycosis; repeated testing and testing for several 5. Tesh RB, Schneidau JD. Primary cutaneous histoplasmosis. N Engl J different antibodies were necessary to increase the sensitivity Med. 1966;275:597–9. [76]. 6. Cott GR, Smith TW, Hinthorn DR, Liu C. Primary cutaneous histoplasmosis in immunosuppressed patient. JAMA. 1979;242:456–7. Antigen tests for the galactomannan in the cell wall of 7. Sills M, Schwartz A, Weg JG. Conjugal histoplasmosis: a conse- Coccidioides species have been reported to be useful in acute quence of progressive dissemination in the index case after steroid infection. Cross-reactivity with antigens of H. capsulatum therapy. Ann Intern Med. 1973;79:221–4. occurs, and the Histoplasma antigen test was found to be 8. Rosado-Odom VM, Daoud J, Johnson R, et al. Cutaneous presentation of progressive disseminated histoplasmosis nine years after renal positive in 11 of 14 patients in one study [77]. transplantation. Transpl Infect Dis. 2013;15:e64–9. 9. McGuinn ML, Lawrence ME, Proia L, Segreti J. Progressive disseminated histoplasmosis presenting as cellulitis in a renal transplant recipient. Transplant Proc. 2005;37:4313–4. Treatment/Conclusions 10. Farr B, Beacham BE, Atuk NO. Cutaneous histoplasmosis after renal transplantation. South Med J. 1981;74:635–7. Specific treatment recommendations are not discussed in this 11. Srivastava B, King B, Galan A. An unusual clinical and histologic review. Almost all patients with cutaneous or mucocutaneous presentation of disseminated cutaneous histoplasmosis. J Am Acad Dermatol. 2011;65:e146–8. lesions due to endemic fungi have disseminated infection, and 12. Scheinfeld N. Diffuse ulcerations due to disseminated histoplasmosis they should be treated as recommended in the Infectious in a patient with HIV. J Drugs Dermatol. 2003;2:189–91. Diseases Society of America (IDSA) guidelines for the man- 13. Rosenberg JD, Scheinfeld NS. Cutaneous histoplasmosis in patients – agement of disseminated infection due to the specific organ- with acquired immunodeficiency syndrome. Cutis. 2003;72:439 45. •• •• •• 14. Ramdial KP, Mosam A, Dlova NC, et al. Disseminated cutaneous ism [78 , 79 , 80 ]. Only rarely are cutaneous infections histoplasmosis in patients infected with human immunodeficiency truly localized and related to direct inoculation. In such cir- virus. J Cutan Pathol. 2001;29:215–25. cumstances, clinicians must be certain that there is no other 15. Chang P, Rodas C. Skin lesions in histoplasmosis. Clin Dermatol. – site of infection; only then, can these infections be treated with 2012;30:592 8. – 16. Baddley JW, Sankara IR, Rodriquez JM, et al. Histoplasmosis in short course (1 3 months) of an azole antifungal agent. HIV-infected patients in a southern regional medical center: poor prognosis in the era of highly active antiretroviral therapy. Diagn – Compliance with Ethics Guidelines Microbiol Infect Dis. 2008;62:151 6. 17. Karimi K, Wheat JL, Connolly P, et al. Differences in histoplasmosis Conflict of Interest Jeannina A. Smith, James Riddell IV, Carol A. in patients with acquired immunodeficiency syndrome in United – Kauffman declare that they have no conflict of interest States and Brazil. J Infect Dis. 2002;186:1655 60. 18. Gutierrez ME, Canton A, Sosa N, et al. Disseminated histoplasmosis in patients with AIDS in Panama: a review of 104 cases. Clin Infect Human and Animal Rights and Informed Consent This article does Dis. 2005;40:1199–202. not contain any studies with human or animal subjects performed by any 19. Thompson GR, La Valle CE, Everett ED. Unusual manifestations of of the authors. histoplasmosis. Diagn Microbiol Infect Dis. 2004;50:33–41. 20. • Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20:115–32. This is an excellent update on the diagnosis, and management of histoplasmosis. 21. • Cunha VS, Zampese MS, Aquino VR, et al. Mucocutaneous man- References ifestations of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome: particular aspects in a Latin-American – Papers of particular interest, have beenhighlighted as: population. Clin Exp Dermatol. 2007;32:250 5. This is an excellent update on the diagnosis, and management of blastomycosis. • Of importance 22. Hernández SL, López de Blanc SA, Sambuelli RH, et al. Oral •• Of major importance histoplasmosis associated with HIV infection: a comparative study. J Oral Pathol Med. 2004;33:445–50. 23. Ferreira OG, Cardoso SV, Borges AS, et al. Oral histoplasmosis in Brazil. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;93:654–9. 24. Ceccato F, Gongora V, Zunino A, et al. Unusual manifestation of 1. Kasuga T, White TJ, Koenig G, et al. Phylogeography of the fungal histoplasmosis in connective tissue diseases. Clin Rheumatol. 2007; pathogen Histoplasma capsulatum. Mol Ecol. 2003;12:3383–401. 26:1717–9. 448 Curr Infect Dis Rep (2013) 15:440–449

25. Alcure ML, Di Hipólito O, de Almeida OP, et al. Oral histoplasmosis 52. Sidamonidze K, Peck MK, Perez M, et al. Real-time PCR assay for in an HIV-negative patient. Oral Surg Oral Med Oral Pathol Oral identification of Blastomyces dermatitidis in culture and in tissue. J Radiol Endodontol. 2006;101:e33–6. Clin Microbiol. 2013;50:1783–6. 26. Mignogna MD, Fedele S, Lo Russo L, et al. A case of oral localized 53. Bariola JR, Hage CA, Durkin M, et al. Detection of Blastomyces histoplasmosis in an immunocompetent patient. Eur J Clin Microbiol dermatitidis antigen in patients with newly diagnosed blastomycosis. Infect Dis. 2001;20:753–5. Diagn Microbiol Infect Dis. 2011;69:187–91. 27. Manfredi R, Mazzoni A, Nanetti A, Chido F. Histoplasma capsulati 54. Durkin M, Witt J, Lemonte B, et al. Antigen assay with the potential to and duboisii in Europe: the impact of the HIV pandemic, travel, and aid in the diagnosis of blastomycosis. J Clin Microbiol. 2004;42:4873–5. immigration. Eur J Epidemiol. 1994;10:675–81. 55. Chiller TM, Galgiani JN, Stevens DA. Coccidioidomycosis. Infect 28. Kauffman CA. Histoplasmosis. In: Kauffman CA, Pappas PG, Sobel Dis Clin North Am. 2003;17:41–57. JD, Dismukes WE, editors. Essentials of clinical mycology. 2nd ed. 56. Marsden-Haug N, Goldoft M, Ralston C, et al. Coccidioidomycosis New York: Springer; 2011. p. 321–35. acquired in Washington state. Clin Infect Dis. 2013;56:847–50. 29. Koepsell SA, Hinrichs SV,Iwen PC. Applying a real-time PCR assay 57. Centers for Disease Control and Prevention. Increase in reported for Histoplasma capsulatum to clinically relevant formalin-fixed coccidioidomycosis—United States, 1998–2011. MMWR. 2013; paraffin-embedded human tissue. J Clin Microbiol. 2012;50:3395–7. 62:217. 30. Bialek R, Feucht A, Aepinus C, et al. Evaluation of two nested PCR 58. Borchers AT, Gershwin ME. The immune response in coccidioido- assays for detection of Histoplasma capsulatum DNA in human mycosis. Autoimmun Rev. 2010;10:94–102. tissue. J Clin Microbiol. 2002;40:1644–7. 59. Blair JE, Logan JL. Coccidioidomycosis in solid organ transplanta- 31. Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tion. Clin Infect Dis. 2001;33:1536–44. tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011;53:448–54. 60. Crum NF, Lederman ER, Stafford CM, et al. Coccidioidomycosis: a 32. Baumgardner DJ, Buggy BP, Mattson BJ, et al. Epidemiology of descriptive survey of a reemerging disease. Clinical characteristics blastomycosis in a region of high endemicity in north central Wis- and current controversies. Medicine (Baltimore). 2004;83:149–75. consin. Clin Infect Dis. 1992;15:629–35. 61. Wilson JW, Smith CE, Plunkett OA. Primary cutaneous coccidioi- 33. Gauthier GM, Klein BS. Insights into fungal morphogenesis and domycosis—the criteria for diagnosis and a report of a case. Calif immune evasion. Microbe. 2008;3:416–23. Med. 1953;79:233–9. 34. Gray NA, Baddour LM. Cutaneous inoculation blastomycosis. Clin 62. Chang A, Tung RC, McGillis TS. Primary cutaneous coccidioido- Infect Dis. 2002;34:e44–9. mycosis. J Am Acad Dermatol. 2003;49:944–9. 35. Harris JR, Blaney DD, Lindsley MD, et al. Blastomycosis in man 63. Gaidici A, Saubolle MA. Transmission of coccidioidomycosis to a after kinkajou bite. Emerg Infect Dis. 2011;17:268–70. human via a cat. J Clin Microbiol. 2009;47:505–6. 36. Gnann JW, Bressler GS, Bodet II, et al. Human blastomycosis after a 64. Blair JE. State-of-the-art treatment of coccidioidomycosis, skin and dog bite. Ann Intern Med. 1983;98:48–9. soft-tissue infections. Ann N Y Acad Sci. 2007;1111:411–21. 37. Larson DM, Eckman MR, Alber RL, et al. Primary cutaneous 65. Masannat FY,Ampel NM. Coccidioidomycosis in patients with HIV- (inoculation) blastomycosis: an occupational hazard to pathologists. 1 infection in the era of potent antiretroviral therapy. Clin Infect Dis. Am J Clin Pathol. 1983;79:253–5. 2010;50:1–7. 38. Gauthier GM, Safdar N, Klein BS, et al. Blastomycosis in solid organ 66. Stevens DA. Coccidioidomycosis. N Engl J Med. 1995;332:1077–82. transplant recipients. Transpl Infect Dis. 2007;9:310–7. 67. Schwarts RA, Lamberts RJ. Isolated nodular cutaneous coccidioido- 39. Pappas PG, Threlkeld MG, Bedsole GD, et al. Blastomycosis in im- mycosis. The initial manifestation of disseminated disease. J Am munocompromised patients. Medicine (Baltimore). 1993;72:311–25. Acad Dermatol. 1981;4:38–46. 40. Lemos LB, Baliga M, Guo M. Acute respiratory distress syndrome 68. Carpenter JB, Feldman JS, Leyva WH, DiCaudo DJ. Clinical and and blastomycosis: presentation of nine cases and review of the pathologic characteristics of disseminated cutaneous coccidioidomy- literature. Ann Diagn Pathol. 2001;5:1–9. cosis. J Am Acad Dermatol. 2010;62:831–7. 41. Saccente M, Woods GL. Clinical and laboratory update on blasto- 69. Quimby SR, Connolly SM, Winkelmann RK, Smilack JD. Clinico- mycosis. Clin Microbiol Rev. 2010;23:367–81. pathologic spectrum of specific cutaneous lesions of disseminated 42. Crampton TL, Light RB, Berg GM, et al. Epidemiology and clinical coccidioidomycosis. J Am Acad Dermatol. 1992;26:79–85. spectrum of blastomycosis diagnosed at Manitoba hospitals. Clin 70. Rodriguez RA, Konia T. Coccidioidomycosis of the tongue. Arch Infect Dis. 2002;34:1310–6. Pathol Lab Med. 2005;129:e4–6. 43. Mason AR, Cortes GY, Cook J, et al. Cutaneous blastomycosis: a 71. Polesky AP, Kirsch CM, Snyder LS, et al. Airway coccidioidomy- diagnostic challenge. Int J Dermatol. 2008;47:824–30. cosis: report of cases and review. Clin Infect Dis. 1999;28:1273–80. 44. Clinton TS, Timko AL. Cutaneous blastomycosis without evidence 72. Boyle JO, Coulthard SW, Mandel RM. Laryngeal involvement in of pulmonary involvement. Milit Med. 2003;168:651–3. disseminated coccidioidomycosis. Arch Otolaryngol Head Neck 45. Bartley GB. Blastomycosis of the eyelid. Ophthalmology. 1995; Surg. 1991;117:433–8. 102:2021–3. 73. Echols RM, Palmer DL, Long GW. Tissue eosinophilia in human 46. Saucier J, Gauthier G. Verrucous lesions and ectropion in an immu- coccidioidomycosis. Rev Infect Dis. 1982;4:656–64. nocompetent individual. Clin Infect Dis. 2012;55:1426–8. 74. Ampel NM. Coccidioidomycosis. In: Kauffman CA, Pappas PG, 47. Miller DD, Davies SF, Sarosi GA. Erythema nodosum and blasto- Sobel JD, Dismukes WE, editors. Essentials of clinical mycology. mycosis. Arch Intern Med. 1982;142:1839. 2nd ed. New York: Springer; 2011. p. 349–66. 48. Rose HD, Gingrass DJ. Localized oral blastomycosis mimicking 75. Mendoza N, Blair JE. The utility of diagnostic testing for active actinomycosis. Oral Surg Oral Med Oral Pathol. 1982;54:12–4. coccidioidomycosis in solid organ transplant recipients. Am J Transpl. 49. Gerwin KM, Myer CM. Intranasal blastomycosis. Am J Otolaryngol. 2013;13:1034–9. 1981;2:267–73. 76. Pappagianis D. Serologic studies in coccidioidomycosis. Semin 50. Reder PA, Neel HB. Blastomycosis in otolaryngology: review of a Respir Infect. 2001;16:242–50. large series. Laryngoscope. 1993;103:53–8. 77. Kuberski T, Myers R, Wheat LJ, et al. Diagnosis of coccidioidomy- 51. Smith JA, Kauffman CA. Blastomycosis. Proc Am Thorac Soc. cosis by antigen detection using cross-reaction with a Histoplasma 2010;7:173–80. antigen. Clin Infect Dis. 2007;44:e50–4. Curr Infect Dis Rep (2013) 15:440–449 449

78. •• Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice Infectious Diseases Society of America. Clin Infect Dis. 2008; guideline for the management of patients with histoplasmosis: 2007 46:1801–12. These are the updated guidelines from the IDSA and update by the Infectious Diseases Society of America. Clin Infect Dis. are very helpful in the evaluation and management of patients with 2007;45:807–25. These are the updated guidelines from the IDSA and suspected blastomycosis. are very helpful in the evaluation and management of patients with 80. •• Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin suspected Histoplasma. Infect Dis. 2005;41:1217–23. These are the current guidelines from 79. •• Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice the IDSA for the evaluation and management of patients with guidelines for the management of blastomycosis: 2008 update by the suspected coccidioidomycosis. Updated guidelines expected shortly.