Deep fungal infections

Subcutaneous mycotic infections are caused by a heterogeneous group of fungi and are infections of implantation (inoculated directly into the skin through local trauma). The four most important infections are sporotrichosis, chromomycosis, phaeohyphomycosis, and mycetoma. Lobomycosis and rhinosporidiosis are significantly less common. As a group, these infections involve primarily the skin and subcutaneous tissues and rarely disseminate to produce systemic disease in the immunocompetent host. These organisms are ubiquitous in soil, plants, and trees.

Queiroz-Telles F, McGinnis MR, Salkin R, Graybill JR: Subcutaneous mycoses, Infect Dis Clin North Am 17:59–85, 2003.

Cutaneous sporotrichosis is more common than systemic sporotrichosis. Cutaneous sporotrichosis can be further divided into two forms: lymphangitic or lymphocutaneous disease, and fixed infection. The lymphocutaneous form accounts for approximately 80% of the cases. This classic form of sporotrichosis begins at the site of inoculation (most commonly, upper extremity) as a painless pink papule, pustule, or dermal nodule, which rapidly enlarges and ulcerates (Fig. 32-1A). Without treatment, the infection ascends along the lymphatics, producing secondary nodules and regional lymphadenopathy that may ulcerate (Fig. 32-1B). The fixed cutaneous variant (20%) is confined to the site of inoculation. The organism may rarely disseminate hematogenously to the joints, bone, meninges, or eye. Disseminated disease is most common in immunosuppressed patients, especially those with impaired cellular immunity (acquired immune deficiency syndrome [AIDS] patients). Pulmonary disease is usually due to inhalation and generally occurs in alcoholics, immunocompromised or debilitated patients. Both erythema nodosum and erythema multiforme have been reported as reactive eruptions to sporotrichosis.

Ramos-e-Silva M, Vasconcelos C, Carneiro S, Cestari T: Sporotrichosis, Clin Dermatol 25(2):181–187, 2007.

Itraconazole (100 to 200 mg/day) for 4 weeks after clinical cure is the treatment of choice for lymphocutaneous, fixed cutaneous, and disseminated cutaneous sporotrichosis, with a success rate of 90% to 100%. Terbinafine (1000 mg/day) is second-line treatment, and because potassium iodide (SSKI) is less costly than other agents, it is still recommended, especially in developing-world epidemics. Fluconazole (200 mg/day) and local hyperthermia have also been shown to be effective. Children may be safely treated with itraconazole.

Bustamante B, Campos PE: Sporotrichosis: a forgotten disease in the drug research agenda, Expert Rev Anti Infect Ther 2(1):85–94, 2004.

Chromomycosis is a chronic subcutaneous infection characterized by the appearance in tissue biopsies of an intermediate, vegetative, pigmented fungal form with a yeastlike appearance that is arrested between yeast and hyphal formation. These pigmented, thick-walled fungal elements are called Medlar bodies (Fig. 32-2). Medlar bodies, also called copper pennies or sclerotic bodies, are diagnostic of chromomycosis, differentiating it from phaeohyphomycosis. Tissue biopsies of phaeohyphomycosis are characterized by lightly pigmented filamentous hyphae.

Five fungal species account for most infections. The most frequent organism worldwide is Fonsecaea pedrosoi. Others organisms include Phialophora verrucosa, Fonsecaea compactum, Rhinocladiella aquaspersa, and Cladophialophora carrionii.

Minotto R, Bernardi CDV, Mallmann LF, et al: Chromoblastomycosis: a review of 100 cases in the state of Rio Grande do Sul, Brazil, J Am Acad Dermatol 44: 585–592, 2001.

Phaeohyphomycosis may occur in both immunocompetent and immunocompromised patients. Due to the increasing immunocompromised patient population, there has been an increased number of fungi in this class that cause disease. Phaeohyphomycosis has been attributed to >60 genera and >100 species. The most important genera include Scedosporium (Pseudallescheria), Alternaria, Bipolaris, Curvularia, Exophiala, Phialophora, and Wangiella.

Revankar SG, Patterson JE, Sutton DA, et al: Disseminated phaeohyphomycosis: review of an emerging mycosis, CID 34:467–476, 2002.

Chromomycosis is a chronic cutaneous and subcutaneous infection that is usually present for years with minimal discomfort. The inciting injury is often not remembered. The infection is most common on the lower extremity and 95% of cases occur in males. The typical patient is a barefoot, rural agricultural worker in the tropics. At the site of inoculation, red papules develop that eventually coalesce into a plaque. The plaque slowly enlarges and acquires a verrucous or warty surface. Satellite lesions can develop from extension of the infection through scratching. There may also be secondary bacterial infections of the lesion. If the lesion is not treated, it can evolve into a cauliflower-like mass, leading to lymphatic obstruction and elephantiasis-like edema of the lower extremity (Fig. 32-3). Neoplastic transformation to squamous cell carcinoma can occur. Diagnosis is made through potassium hydroxide (KOH) mounts from scrapings, biopsies of the lesions showing the organism and suppurative and granulomatous inflammation, and culture. Rare reports of hematogenous dissemination to the brain have been made. Chromomycosis is typically resistant to treatment. The treatment of choice for small lesions is surgical excision with a wide margin of normal skin. Chronic or extensive lesions should be treated with a combination of itraconazole therapy and surgical excision. Combination therapy with terbinafine, posaconazole, cryotherapy and local heat therapy also appear to be effective. Treatment is continued for months.

Madura foot is an indolent localized painless infection with three characteristic features. The first is the formation of nodules in the skin at the site of inoculation, usually a penetrating injury. The second feature is purulent drainage and fistula formation. The third and most characteristic feature is the presence of grains or granules that are visible in the purulent drainage. Seventy percent of cases involve the lower extremity, the foot in particular. Other sites of infection include the hand, head, back, and chest. Madura foot is a progressive infection leading to marked swelling and deformity in its latter stages (Fig. 32-4). Additionally, the lesions have a tendency to become painful in the latter stages, when bone involvement and deformity ravage the site. Eumycetomas are extremely difficult to manage and include medical, surgical, or a combination of both. Itraconazole and terbinafine are the most commonly used antifungal agents and are more effective than ketoconazole.

Blastomycosis, caused by the soil saprophyte Blastomyces dermatitidis, is endemic in North America, especially the southeastern and south central states bordering the Mississippi, Ohio, and St. Lawrence rivers (Kentucky, Arkansas, Mississippi, North Carolina, Tennessee, Louisiana, Illinois, and Wisconsin), and the Great Lakes region (Fig. 32-5). Sporadic cases have been reported in Colorado, Texas, Kansas, and Nebraska. The typical patient is a middle-aged male with occupational or recreational exposure to the soil.

McKinnell JA, Pappas PG: Blastomycosis: new insights into diagnosis, prevention, and treatment, Clin Chest Med 30(2):227–239, 2009.

The most characteristic cutaneous presentation is a single (or multiple) crusted, verrucous plaque on exposed skin (face, hands, arms) with color variation from gray to violet (Fig. 32-6). Microabscesses can form, and pus exudes when the crust is lifted off. As the plaque progresses, there is central clearing. Ulcerative lesions are a less common cutaneous presentation. Cutaneous involvement leads to the correct diagnosis in most cases.

Blastomycosis, unlike other deep fungal infections (cryptococcosis, histoplasmosis, coccidioidomycosis, mucormycosis, penicilliosis, and aspergillosis), behaves, less commonly, as an opportunistic infection in the immunosuppressed host. There are, however, several reports of disseminated blastomycosis in AIDS patients, organ transplant recipients, diabetics, and patients receiving glucocorticosteroids and chemotherapy.

Lemos LB, Baliga M, Guo M: Blastomycosis: the great pretender can also be an opportunist. Initial clinical diagnosis and underlying diseases in 123 patients, Ann Diagn Pathol 6:194–203, 2002.

Histoplasmosis is caused by Histoplasma capsulatum, an environmental saprophyte. It is endemic in the midwestern and south central United States, where 80% of the population is skin test–positive. It does occur in other parts of the world, but it is not found in Europe. Soil infected with excreta from chickens, pigeons, blackbirds, and bats is inhaled, leading to a pulmonary infection. Rarely, primary cutaneous disease is contracted from traumatic inoculation.

Wheat LJ, Kauffman CA: Histoplasmosis, Infect Dis Clin North Am 17:1–19, 2003.

Three different patterns of disseminated histoplasmosis are described: acute, subacute, and chronic. The acute syndrome generally occurs in immunosuppressed patients and is characterized by fever, hepatosplenomegaly, and pancytopenia, with 18% developing mucocutaneous ulcers. Chronic disseminated histoplasmosis is characterized by involvement of the bone marrow, gastrointestinal tract, spleen, adrenals, and central nervous system (CNS); 67% have painful ulcerations on the tongue, buccal mucosa, gingiva, or larynx (Fig. 32-7). The treatment of choice is itraconazole and, for severe diseases and immunosuppressed patients, amphotericin.

Coccidioidomycosis, also called San Joaquin Valley fever, is caused by Coccidioides immitis. It is a dimorphic fungus found in the soil of arid and semiarid regions. This organism is endemic in southern California, Arizona, New Mexico, southwestern Texas, northern Mexico, and Central and South America (Fig. 32-8). Over 100,000 people in the U.S. are infected annually, and the number of reported cases increased by as much as 144% throughout the 1990s. Incidence is affected by annual temperature, precipitation and natural events like earthquakes.

Crum NF, Lederman ER, Stafford CM, et al: Coccidioidomycosis: a descriptive survey of a reemerging disease. Clinical characteristics and current controversies, Medicine 83:149–175, 2004.

Primary pulmonary infection is asymptomatic in 50% of patients. In 40%, patients present with a mild flulike illness or pneumonia. Erythema nodosum is present in 5% of patients with acute coccidioidomycosis. Hematogenous dissemination occurs in 1% to 5% of patients. Risk factors for dissemination and fatal disease include male sex, pregnancy, immunocompromised status, and race (in order of decreasing risk by race: Filipino, black, and white). Among immunosuppressed patients, lymphocytopenia correlates closely with dissemination. Coccidioidomycosis is considered an AIDS-defining illness. The most common sites of extrapulmonary disease include the skin, lymph nodes, bones/joints, and central nervous system (meninges). Cutaneous lesions of disseminated coccidioidomycosis are protean. Warty papules, plaques, or nodules are the most characteristic (Fig. 32-9). Cellulitis, abscesses, and draining sinus tracts also may occur. Rarely, cutaneous lesions can be from primary cutaneous inoculation. Erythema nodosum is the most common reactive manifestation of coccidioidomycosis and indicates a robust cell-mediated immune response. Other reactive patterns include generalized morbilliform, papular, targetoid or urticarial exanthem, interstitial granulomatous dermatitis, and Sweet syndrome.

DiCaudo DJ: Coccidioidomycosis: a review and update, J Am Acad Dermatol 55(6):929–942, 2009.

The lung is the primary site of infection. However, respiratory complaints are the least common presenting symptom. Painful mucosal ulcerations involving the mouth and nose are the most common findings. Patients may also have enlarged cervical lymph nodes and verrucous, crusted, edematous facial lesions. Hematogenous dissemination may also cause disease in the adrenals, spleen, liver, gastrointestinal tract, and central nervous system (CNS).

Almeida OP, Jacks J: Paracoccidioidomycosis of the mouth: an emerging deep mycosis, Crit Rev Oral Biol Med 14:377–383, 2003.

Penicilliosis is endemic in southeast Asia and southern China, although there have been a few case reports in other Asian countries. The increase in HIV-infected individuals in these areas has led to the emergence of this organism as a cause of infection. Bamboo rats may serve as a reservoir.

Kullavanijaya P: Penicilliosis in AIDS, J Dermatol 28:667–670, 2001.

Several species of bacteria and fungi infect and proliferate and actually thrive within the cytoplasm of macrophages rather than being killed by the macrophage (Table 32-2).

Candida and Cryptococcus species are the most common fungal infections in HIV-infected patients. See Table 32-3 for other fungal pathogens and their most frequent clinical presentation.

Table 32-3. Fungal Pathogens in HIV Infection

ORGANISM	CLINICAL FEATURES
Candida albicans	Thrush, vaginal, and esophageal candidiasis
Cryptococcus neoformans	Pulmonary and disseminated disease, meningitis, skin, eye, prostate
Histoplasma capsulatum	Disseminated disease with fever, weight loss, and predilection for reticuloendothelial system, adrenal glands, and CNS
Coccidioides immitis	Disseminated and pulmonary disease. Predilection for skin, lymph nodes, bones/joints, and CNS
Blastomyces dermatitidis	Disseminated and pulmonary disease. Predilection for lung, skin, bone, CNS, and prostate
Aspergillus fumigatus	Disseminated and pulmonary disease
Penicillium marneffei	Disseminated disease with fever, anemia, weight loss Mucocutaneous lesions are common
Sporotrichosis schenckii	Disseminated disease. Sites of predilection: joints/bones, eyes, and meninges

Ampel NM: Emerging disease issues and fungal pathogens associated with HIV infection, Emerg Infect Dis 2:109–116, 1996.

Organ transplant recipients are at increased risk of localized and disseminated disease from dermatophytes, yeast (candidiasis, Malassezia, cryptococcosis, Trichosporon), dimorphic organisms, and nondermatophyte molds (aspergillosis, fusariosis, mucormycosis). Skin manifestations due to Candida spp., Aspergillus spp., dematiaceous fungi, and Pityrosporum typically occur shortly after transplantation. Cryptococcosis occurs 6 months or later after transplantation, and the endemic dimorphic fungi can cause disease any time following transplantation. Emerging mold pathogens in the transplant patients have included Aspergillus fumigatus species, Fusarium, Scedosporium, and Zygomycetes.

Virgili A, Zampino MR, Mantovani L: Fungal skin infections in organ transplant recipients, Am J Clin Dermatol 3:19–35, 2002.

Wingard JR: The changing face of invasive fungal infections in hematopoietic cell transplant recipients, Curr Opin Oncol 17:89–92, 2005.

Cryptococcosis is caused by Cryptococcus neoformans, a ubiquitous encapsulated yeast found worldwide in the soil. Several strains are associated with pigeon and other avian excreta, and another strain is associated with eucalyptus trees. During the pre-AIDS era (prior to 1980), cryptococcal infections were rare and about 50% occurred in patients with lymphoreticular malignancies. Cryptococcosis is rare in immunocompetent patients, and patients at risk are those with impaired cellular immunity (advanced HIV patients, organ transplants, lymphoreticular malignancies, patients receiving corticosteroid therapy). The incidence of cryptococcosis is inversely proportional to the CD4 lymphocyte count. The prevalence of cryptococcosis in patients infected with HIV has declined with aggressive antiretroviral therapy. The mortality rate of untreated disseminated disease is 70% to 80%.

Perfect JR, Casadevall A: Cryptococcosis, Infect Dis Clin North Am 16:837–874, 2002.

Infection occurs primarily from inhalation of the organism leading to a primary lung infection. Immunocompetent patients generally present with a mild pulmonary infection. Disseminated disease via the hematogenous route occurs in 10% to 15% of immunosuppressed patients, with a predilection for the meninges. It is the leading cause of fungal meningitis. Other organs involved include the skin (10% to 20%), eye, bone, and prostate. There are a few rare reports of primary inoculation cutaneous disease, which manifests itself as a solitary papule/nodule. However, cutaneous disease is generally indicative of disseminated disease and a poor prognosis.

Neuville S, Dromer F, Morin O, et al, for the French Cryptococcosis Study Group: Primary cutaneous cryptococcosis: a distinct clinical entity, CID 36:337–347, 2003.

Cryptococcosis is a great imitator of a wide variety of cutaneous diseases. These include molluscum contagiosum–like lesions (Fig. 32-10), Kaposi sarcoma–like lesions, pyoderma gangrenosum–like lesions, herpetiform lesions, cellulitis, ulcers, subcutaneous nodules, and palpable purpura. Lesions are most commonly found on the head, neck, and genitals, but can be found anywhere. Cutaneous lesions are found in 10% to 20% of HIV-infected patients. Histologic features are characteristic with periodic acid–Schiff stain with diastase demonstrating budding yeast surrounded by a clear space representing the capsule (Fig. 32-11).

Patients may have single or multiple lesions that begin as a well-circumscribed papule, which over several days enlarges into an ulcer with a necrotic base and surrounding erythematous halo (Fig. 32-12). The organism has a propensity to invade blood vessels, causing thrombosis and infarction. The skin lesions can be very destructive and extend into cartilage, bone, and fascial planes. Aspergillosis should be considered in the differential diagnosis of necrotizing lesions.

Patients with prolonged neutropenia, especially leukemia patients, are susceptible to infections with Fusarium. In this patient population, Fusarium species are the second most common pathogenic mold. Fusarium is a filamentous mold found in soil and plants. Inhalation into the lungs is the primary route of infection; however, primary cutaneous infection from indwelling catheters may occur. The lung is the usual site of infection; however, 75% of patients have hematogenous spread with a predilection for the skin and sinuses. The cutaneous lesions caused by Fusarium are similar to aspergillosis. The typical presentation is a painful erythematous nodule with central ulceration and necrosis. Cellulitis and onychomycosis have also been reported. Histologically, the two are identical (septate hyphae with acute angle branching). The treatment of choice is amphotericin B and the mortality rate is 50% to 80%.

Dignani MC, Anaissie E: Human fusariosis, Clin Microbiol Infect 10:67–75, 2004.

Mucormycosis is caused by rapidly growing molds from several genera, including Apophysomyces, Mucor, Rhizopus, Absidia, and Rhizomucor. These organisms are ubiquitous in decaying vegetation, fruit, and bread. Approximately one third of patients have diabetes, and diabetics in ketoacidosis are at especially high risk. Other reported associations include malnutrition, uremia, neutropenia, corticosteroid therapy, burns, antibiotic therapy, neonatal prematurity, deferoxamine therapy, and HIV-infected individuals with a history of intravenous drug use. The neutrophil is the predominant component of host defense.

Gonzalez CE, Rinaldi MG, Sugar AM: Zygomycosis, Infect Dis Clin North Am 16:895–914, 2002.

Rhino-orbital-cerebral mucormycosis is the most common form of mucormycosis. Other clinical variants include pulmonary, cutaneous, gastrointestinal, and disseminated. Most commonly, the organism is deposited in the nasal turbinates or lung through inhalation. The majority of patients with Rhino-orbital-cerebral mucormycosis are diabetics (often in ketoacidosis) or have leukemia. Patients present with fever, headache, facial edema, proptosis, facial pain, orbital cellulitis, and cranial nerve dysfunction. The patients may have loss of vision from retinal artery thrombosis. This form is often fatal. Treatment consists of rapid diagnosis with aggressive debridement and antifungal therapy.

Eucker J, Sezer O, Graf B, Possinger K: Mucormycoses, Mycoses 44:253–260, 2001.

The treatment of mucormycosis includes rapid diagnosis in conjunction with correction of any underlying diseases. Biopsy sample of necrotic tissue demonstrates thick, nonseptate hyphae branching at right angles. Culture is only positive in 30% of cases. Also indicated is administration of amphotericin B, and aggressive surgical debridement of necrotic tissue in order to minimize mortality. Emerging treatments include posaconazole, and adjuvant treatment with interferon gamma and granulocyte-macrophage– or granulocyte colony–stimulating factors.

Tarrand JJ, Lichterfeld M, Warraich I, et al: Diagnosis of invasive septate mold infections. A correlation of microbiological culture and histologic or cytologic examination, Am J Clin Pathol 119(6):854–858, 2003.

Patients on TNF-α agonists most commonly are at risk for histoplasmosis, candidiasis, and aspergillosis. There may be a different degree of risk with each of the agents—infliximab creating a higher risk than etanercept or adalimumab. In endemic areas, patients are also at risk for primary or reactivation of latent coccidioidomycosis. One recent series reported 13 cases of coccidiomycosis, with two patients dying of disseminated disease. Close monitoring of current and past residents of endemic areas in the form of baseline and serial chest x-ray and serology is indicated.

Tsiodras S, Samonis G, Boumpas DT, Kontoyiannis DP: Fungal infections complicating tumor necrosis factor alpha blockade therapy, Mayo Clin Proc 83(2):181–194, 2008.

Also known as the “lid lifter,” coccidioidomycosis sporulates easily in culture and is highly infectious. It is the only fungus on the Select Agent List of the Department of Health and Human Services.

Centers for Disease Control and Prevention: National Select Agent Registry, Available at: http://www.selectagents.gov/. Accessed July 25, 2010.