Systemic mycoses can be classified according to whether the causative agent is a systemic fungal pathogen (Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum [variants capsulati and duboisii], and Paracoccidioides brasiliensis) or one of an increasing number of opportunistic fungal pathogens normally found in the environment. These fungi are thermally dimorphic microorganisms with 2 phases. Transition from the mycelial to yeast phase is normally associated with a change in temperature from 25°C to 37°C. With the exception of C immitis, which forms spherules with endospores, the natural phase of each of these fungi is a mold, while the histic form is a yeast.1–4

All these fungi are essentially pulmonary pathogens and inhalation of conidia is the most likely route of entry to the respiratory tract. Skin manifestations generally require disseminated infection but can occasionally be due to traumatic implantation of material contaminated with the fungi. The majority of deep-seated mycoses usually occur in certain regions of North America, South America, Central America, and Africa. These infections and their corresponding skin manifestations have become the most frequent opportunistic infection among the increasingly large populations of individuals with severe immune deficiencies, including AIDS. Skin manifestations are important for 2 reasons. First, they may preempt other clinical manifestations, including pulmonary or neurologic conditions, and so their detection can enable early treatment. Second, a skin biopsy can be readily taken with minimally invasive procedures. The biopsy samples enable microbiological culture and histopathologic study, which are sometimes necessary for correct diagnosis. The diagnostic yield for such procedures is high. The present article should therefore be useful for younger dermatologists and for all those interested in the study of mycosis. We have focused on 3 types of infection—histoplasmosis, coccidioidomycosis, and cryptococcosis—as these are the most prevalent. They are also the infections for which we have most information and experience.

We have conducted a thorough review of the literature on epidemiologic, clinical, diagnostic, and therapeutic information pertaining to endemic systemic mycoses (histoplasmosis, coccidioidomycosis, and cryptococcosis) in adult patients infected with the human immunodeficiency virus (HIV)/AIDS, from the first reports of cases until the end of 2011. We have also included data and images from our own experience.

The cryptococcus can usually be identified by laboratory analysis of blood, bone marrow, CSF, and samples from the eye, respiratory tract, skin and mucosae, urine, and other tissues. From any patient who is positive for the cryptococcal antigen, in whom encapsulated yeasts are detected in direct examination or histology, or in whom C neoformans is isolated from any other body site, it is recommended to obtain, immediately inspect, and culture samples from the CSF, blood, urine, and serum. This process will enable the assessment of the severity of infection and the optimal induction of treatment.5,45

The India ink test can be performed with any body fluid. Yeasts measuring 2 to 5μm are observed to be surrounded by a mucoid capsule that remains unstained (Fig. 13). This test is quick (taking less than a minute) and very specific though sensitivity is low as only 50% of cases are positive.46

Figure 13.

Cryptococcus neoformans. India ink staining reveals a thick capsule (original magnification, ×40).

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Tissue sections can be stained to facilitate visualization of the fungus. The most useful stains are PAS, Grocott, Papanicolaou, and Gram. For diagnosis of clinical samples, the fungus can be also be inspected by fluorescence microscopy with calcofluor-white staining or phase contrast microscopy.5

Any tissue or body fluid can be cultured. The fungi grow in temperatures ranging from 25°C to 37°C and the yeast colonies can be white, yellow, or light-coffee colored. A cryptococcal species is definitively identified be means of the carbohydrate utilization test and production of pigment on Niger agar (Gyzotia abissinica).47

With the introduction of highly active antiretroviral therapy (HAART), the incidence of many opportunistic infections has decreased in HIV-infected patients. At the same time though, these agents have brought new problems, such as immune reconstitution inflammatory syndrome (IRIS), an adverse effect of HAART-induced reconstitution of the antigen-specific immune response that is manifest as the clinical onset of preexisting subclinical infections or the vigorous onset of autoimmune and neoplastic diseases.48–50

Cases of skin manifestations of histoplasmosis have been reported. In most cases, the patients presented with generalized papular or crusty lesions (Fig. 14) and, in 1 case in particular the patient had a nodular lesion on the face, with accompanying fever and lymphadenitis. Histology of samples from skin and lymph nodes showed giant cell granulomas with necrosis and yeast cells. H capsulatum was cultured from blood samples and this microorganism was also isolated from skin and the lungs. The treatment is the same antifungal therapy as described above.51

Figure 14.

Crusted lesions and umbilicated lesions (different phases of development) caused by Histoplasma capsulatum in a patient with immune reconstitution inflammatory syndrome in different phases of development.

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The exact incidence of C neoformans-related IRIS is not known even though this microorganism is always detected in series and case reports of patients with IRIS. In most cases, the cause is reactivation of previously treated infections, suggesting that the condition is an immune response to inadequately treated disease or an inflammatory reaction to certain residual antigens. IRIS presents mostly in the form of meningitis, although cases presenting as lymphadenitis and mediastinitis have also been reported.

Skin manifestations are uncommon, but when present they appear as large single or multiple masses or large ulcers. In some cases, surgery is required to excise the nodular lesions while HAART continues.52

There have been no reports of IRIS in patients with HIV/AIDS and coccidioidomycosis.

Dermatologists should be prepared to detect rare diseases and atypical presentations of the most common infections—skin infections in particular—in patients with a compromised immune system, including those with HIV infection/AIDS. The impairment and dysregulation of immunity caused by HIV makes patients are susceptible to a wide range of skin infections. Lesions may show less inflammation than is usual or be more generalized, disfiguring, and destructive. Lesions can also be atypical when HIV-infected patients develop lesions caused by simultaneous infection of more than a single pathogen.53

Histoplasmosis is a common opportunistic infection in HIV-infected patients who live in endemic areas. Mortality can be as high as 80% according to some reports. Although uncommon in Europe, and particularly in Spain, some cases are still seen mainly because of the increasing number of immigrants and visitors from endemic countries such as eastern United States of America, Latin America, sub-Saharan Africa, east Asia, and Oceania.53 When HIV-infected individuals seek our care, histoplasmosis is present in disseminated form in 95%.54 The skin lesions arise as a result of hematogenous spread and onset generally occurs after the CD4+ cell count has fallen below 150 cells/μL.

Different strains of H capsulatum have been identified, in relation to whether the patient has AIDS or not. Reyes-Montes et al.55 isolated the following chain types from H capsulatum in Mexican patients with AIDS: EH-316, EH-317, EH-318, EH-319, EH-323, and EH-325. In contrast, EH-46 and EH-53 were isolated from patients without AIDS.

Whether or not sex is a risk factor for disease is still under debate. Some authors report that histoplasmosis affects men and women in equal measure whereas others have found predominance among men. There is little information about the incidence of histoplasmosis between different ethnic groups or races. However, many authors seem to agree that the features of the skin lesions may differ with race and endemic status of the region.

The first cases of disseminated histoplasmosis with skin involvement were reported by Bayes et al.56–59 Subsequently, other investigators reported further cases.60,61 After reviewing the literature, we found that the most common sites for lesions, in decreasing order, were the face and scalp, legs, shoulders and back, trunk, neck, and abdomen9,16,17,57–62 (Fig. 15). However, Bonifaz and Chang63 found that lesions occur mainly on the face and trunk. Cutaneous lesions are present in 38% to 85% of cases, according to whether patients are originally from South America or Africa, suggesting that genetic differences are present in these 2 variants. It has been suggested that dermotropic strains of H capsulatum may be responsible for the higher frequency of skin lesions in patients with AIDS. H capsulatum has been found in endoneural macrophages and in Schwann cells in cutaneous nerves. It is thought that a large number of these microorganisms invade the dermis, with secondary nerve infection then occurring although affected nerves do not show necrosis or cell proliferation. The presence of fungal elements in cutaneous nerves could be the main indicator of recurrent disease or dissemination. Mucosal lesions such as papules, nodules, and ulcers may occur in the gastrointestinal tract.

Figure 15.

Most frequent sites for skin lesions in patients with disseminated histoplasmosis.

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Bonifaz and Chang63 found papules, nodules and hyperkeratotic plaques, some ulcers, and purpuric lesions in all their patients. This clinical presentation occurs frequently and had been reported previously in populations in Latin America.12,64 Samples taken by curettage of these lesions lead to confirmation of the diagnosis of mycosis in almost all cases.64

Of note is that primary prophylaxis (itraconazole, 200mg/d) is administered to HIV-positive patients with a CD4+ count less than 150 cells/μL. A mortality rate of 43.5% has been reported in patients with disease that has become disseminated despite treatment,8 whereas in a recent European review this figure was 15% in the initial phases of treatment and 57% during follow-up.65

Coccidioidomycosis is a systemic mycosis found in America. The disseminated form is most common in men and in patients with AIDS and with dark skin. The course of infection may be acute, subacute, or chronic. In the subacute and chronic forms, most symptoms are localized to the skin, subcutaneous tissue, osteoarticular system, lymph nodes, and the CNS.

The primary pulmonary form manifests as pneumonia (in 44%) and miliary involvement may be present (in 19%). Cavitation or coccidioidomas may also be present (in 19%).21,22,66 In approximately 0.2% of patients with primary pulmonary coccidioidomycosis, the lesions spread predominantly to the skin, CNS, and osteoarticular system. The disseminated form generally follows an acute course, reaching various organs and systems and rapidly leading to death if diagnosis and treatment are delayed. The first report of HIV-associated coccidioidomycosis in Spain appeared in 1997.67 Approximately 10% to 20% of HIV-positive patients with systemic infection have cutaneous lesions, which provide a defining characteristic of AIDS and are a sign of poor prognosis. Early detection of these lesions can lead to early start of ART and so improve the prognosis.66

The large number of clinical forms and possible complications make it difficult to indicate specific treatment regimens for every situation. Recently, in cases refractory to treatment, voriconazole and posaconazole have been suggested for their broad spectrum of action, but outcomes have not been very satisfactory.68

Although vaccines against coccidioidomycoses have been under investigation for years, none as yet has proven effective. Vaccines based on total RNA extracted from spherules have been shown to be ineffective. However, in recent studies, recombinant antigens have shown promising results in animal models.18,42

Surgical resection of the lesion is indicated in cases of nodules in the lungs and at other sites when patients do not respond to antifungal therapy. Detection of a mass or abscess in the brain requires drainage or surgical resection. Debridement of cutaneous lesions to eliminate necrotic material is an important auxiliary measure. Patients should be treated in an outpatient setting, with follow-up at 3 and 6 months, then annually for a further 12 years.32

The virulence of the Cryptococcus genus is related to protease and oxidase production as well as the antiphagocytic properties of the capsular polysaccharide. The most plausible explanation for infection is the small diameter of the basidiospores (1.2–1.8μm), which allows them to accumulate in the alveoli, where the encapsulated yeasts are transformed at a temperature of 37°C. In most cases, inhalation of Cryptococcus species causes asymptomatic and self-limiting pulmonary infection, and yeasts can remain latent in the pulmonary environment or die. If an immunocompromised state develops subsequently, they may become reactivated and cause disease.69 Several studies have shown that C neoformans molecular type VNI is predominant in HIV-positive patients whereas C gattii molecular type VGII is predominant in HIV-negative ones (P<.001). Only 3 out of 37 cases in HIV-positive patients (8.1%) were caused by C gattii molecular type VGII, whereas 5 of 21 cases in HIV-negative patients (23.8%) were caused by C neoformans molecular type VNI.70–72

Before ART became available, cryptococcosis had become a major opportunistic infection and the leading cause of death in HIV-infected patients with CD4+ counts below 100cells/μL.5,43 In Spain, cryptococcosis was the most common fungal infection in these patients as of 2006.73

Skin infection in cryptococcosis occurs in 10% to 20% of cases, almost always secondary to systemic infection and so is considered a “sentinel sign” of disseminated disease. Necrotizing infections in soft tissues (cellulitis and necrotizing fascitis) and lesions that resemble pyoderma gangrenosum and keloid scars have occasionally been reported. Mortality is high (80%).74,75

Primary cutaneous cryptococcosis is a very rare condition, defined in the literature by the identification of C neoformans in a skin biopsy or culture in absence of disseminated disease. The sporotrichotic pattern is an extremely uncommon presentation. The patients in the cases we reviewed were immunocompromised but were not infected with HIV.76

The use of primary prophylaxis is still under discussion. In a metaanalysis of primary prophylaxis with fluconazole or itraconazole in HIV-infected patients with CD4+ counts below 300 cells/μL, the incidence of cryptococcosis decreased but mortality was unaffected. In patients with HAART-induced immune reconstitution, fluconazole or itraconazole can be interrupted provided the CD4+ count has remained stable above 100 cells/μL over the last 12 months.77,78

Systemic mycoses are mainly pulmonary diseases caused by dimorphic pathogenic fungi. If the inoculum is large or the individual's immune system is compromised, primary infection is possible and may be acute, self-limiting, or subclinical. Most skin manifestations correspond to disseminated disease, and so systemic treatment is required. Given that other skin lesions may also develop in the course of these diseases, it is recommended to take an extensive medical history and perform additional imaging tests, accompanied by histopathologic study and culture.

The authors declare that they have no conflicts of interest.