Are You Confident of the Diagnosis?
What you should be alert for in the history
Cryptococcosis is an invasive mycosis that occurs worldwide causing significant morbidity and mortality. Cutaneous cryptococcosis is a condition that is classified as a primary or secondary infection. Primary cutaneous cryptococcosis is a distinct infection that is usually a result of direct inoculation of Cryptococcus spp into injured skin through trauma or laboratory accidents. Infection tends to be localized but can spread to deeper layers of tissue and muscle. Secondary skin infection is a result of cryptococcal dissemination; this tends to occur in immunocompromised hosts. Primary infection is significantly less common than secondary infection.
Characteristic findings on physical examination
In primary cutaneous cryptococcal infection, there tends to be a single lesion where initial inoculation occurs. These lesions can present as a whitlow, nodule, ulceration, cellulitis, or phlegmon. Infection can spread to deeper layers of tissue and eventually disseminate to regional lymph nodes and blood; dissemination is more likely to occur in immunocompromised hosts.
Cryptococcus can cause almost any type of skin lesion. Secondary cutaneous cryptococcosis can manifest in several ways, such as nodules, papules, maculopapules, vesicles, bullae, pustules, acneiform lesions, purpura, ulcers, granulomas, abscesses, plaques, draining sinuses, cellulitis, and necrotizing infection (Figure 1, Figure 2). Often, multiple lesions are seen in disseminated infection. In patients with human immunodeficiency virus (HIV) disease, cutaneous cryptococcosis can be indistinguishable from mollluscum contagiosum; the skin lesions appear as skin-colored papules with central umbilication (Figure 1).
In transplant recipients, cutaneous cryptococcosis has been reported to present as necrotizing skin and soft tissue infections that were indistinguishable in appearance from bacterial or other fungal infections.
Expected results of diagnostic studies
Skin biopsy is the diagnostic test of choice to confirm cutaneous infection; biopsy should be ample enough for pathologic and microbiologic evaluation. Cryptococcus spp readily grow on routine agar media and can be identified by morphology and biochemical tests. India ink is commonly used to identify Cryptococcus spp; this test is used directly on clinical specimens and will highlight the thick polysaccharide capsule of the yeast (Figure 3).
Experience is necessary to distinguish yeasts from lymphocytes. Histopathology will reveal spherical, encapsulated yeast, with the capsule being the most predominant feature. Using routine stains such as hematoxylin and eosin (H&E), the yeasts are surrounded by empty spaces that reflect the capsule. The capsule can be identified with stains such as mucicarmine and Alcian blue (Figure 4). Melanin production allows for staining with the Fontana-Masson stain. There also may be evidence of budding, which is narrow-based. Gomori’s methenamine silver stain identifies the budding yeast in tissue.
All patients with cutaneous cryptococcal infection should also have fungal blood cultures and a serum cryptococcal antigen test performed. These tests are important to determine if disseminated infection has occurred and will alter the management of these patients. If the serum cryptococcal antigen is positive, a lumbar puncture should be performed to rule out cryptococcal meningitis even in the absence of symptoms since findings may be very subtle.
Because cutaneous cryptococcosis can mimic several other infections or even squamous or basal cell carcinomas, confirmatory testing with skin biopsy is essential for the diagnosis. Transplant recipients on immunosuppressive therapy, as well as patients receiving immunomodulating agents such as tumor necrosis factor (TNF)-alpha inhibitors or monoclonal antibodies, are at particular risk of invasive fungal infections.
In HIV-infected patients, cutaneous cryptococcosis often manifests with characteristic papules with central umbilication. These lesions may be difficult to distinguish from molluscum contagiosum; hence, skin biopsy is important to ascertain which entity is causing disease and for appropriate therapy. Both conditions can occur in HIV-infected individuals; these patients tend to have severely depressed T-cell counts.
Who is at Risk for Developing this Disease?
For primary cutaneous cryptococcosis, infection tends to occur after direct inoculation of traumatized skin and/or soft tissue. A review of 28 cases of primary cutaneous cryptococcosis in France noted that risk factors associated with development of disease included living in rural areas, older age, as well as occupations that predisposed individuals to skin injury and concomitant contamination.
Secondary cutaneous cryptococcosis is commonly a result of disseminated cryptococcal infection. The majority of individuals who develop disseminated disease tend to have severe immunodeficiency, especially in regard to T-cell immunity. Such individuals include HIV-positive patients with low CD4 cell counts (<100), solid organ transplant recipients on immunosuppressive therapy, patients on chronic systemic corticosteroid or monoclonal antibody therapy, or other immunosuppressive states such as malignancies, sarcoidosis, cirrhosis, renal failure, connective tissue disorders, and innate immunodeficiencies such as CD4+ T-cell lymphopenia, hyper-IgM, and hyper-IgE syndromes.
Patients with disseminated cryptococcosis or meningoencephalitis should be tested for HIV infection. Some strains of C neoformans are dermotrophic. Patients receiving tacrolimus have a higher ratio of skin and soft tissue infections to central nervous system (CNS) infections compared with other immunosuppressive treatment regimens.
What is the Cause of the Disease?
Although the Cryptococcus genus comprises several species, C neoformans is the predominant species that causes disease in humans. C neoformans is an encapsulated yeast; it has been recovered worldwide, and its environmental niches include soil, bird excreta, and other decaying organic matter (eg, rotting trees). C neoformans is further classified into two varieties based on capsular structure (serotypes): C neoformans var grubii (serotype A), and C neoformans var neoformans (serotype D).
The majority of infection worldwide is attributable to C neoformans var grubii; however, for primary cutaneous disease, C neoformans var neoformans has been recovered more frequently. Some strains of C neoformans have been described as being more dermatotrophic in animal models.
C gattii is another species that has been identified as a human pathogen, although far less common than C neoformans. This species has two serotypes (B and C) and has been ecologically linked to eucalyptus trees. C gattii infection occurs predominantly in tropical and subtropical areas where eucalyptus trees are more common. However, outbreaks of C gattii infection in apparently immunocompetent humans and animals on Vancouver Island, British Columbia and surrounding areas within Canada and the northwest United States have occurred in the past decade; the ecologic niche for this strain may be linked to trees that are endogenous to the area. Recent studies from this outbreak suggest that a recombinant strain in nature became more virulent than its parent.
The most common portal of entry for Cryptococcus spp is through inhalation of aerosolized yeast or spores into the alveoli. Immunocompetent hosts are generally able to contain infection by cell-mediated immunity; also, infection can remain dormant for years in lymph nodes or lung parenchyma. However, in hosts with cell-mediated immunodeficiency, initial infection in the lungs can rapidly disseminate. C neoformans has a predilection for invading the CNS; the most common manifestation of cryptococcosis is meningoencephalitis. Other areas of disseminated disease include skin, prostate, bone, eyes, and urinary tract.
In primary cutaneous cryptococcosis, direct inoculation of traumatized skin is hypothesized as the cause of infection. Typically, traumatized skin wounds have been exposed to material contaminated with cryptococcus, such as soil or bird excreta.
Systemic Implications and Complications
In hosts with impaired cell-mediated immunity, Cryptococcus spp have the propensity to disseminate from the initial portal of entry or from sites of latent infection. The most common site of dissemination is to the CNS; followed by the lungs and skin. Hence, cutaneous cryptococcal infection represents secondary infection via hematogenous seeding. It is imperative that a serum cryptococcal antigen test be performed when cutaneous cryptococcal disease is suspected or confirmed in these immunocompromised hosts. If the serum cryptococcal antigen test is positive, a lumbar puncture must be done to assess for CNS infection; patients with CNS cryptococcal infection may not manifest with symptoms typical of meningoencephalitis.
Although primary cutaneous cryptococcal infection tends to be uncommon in immunocompromised hosts, obtaining a serum cryptococcal antigen would be advised to ensure that dissemination has not occurred.
Primary cutaneous infection without evidence of dissemination:
–Preferred: fluconazole 400mg daily for 3 to 6 months
–Alternative: amphotericin B formulations, itraconazole
Disseminated cutaneous infection, immunocompromised host: if other organ systems are involved (CNS, lungs), or cryptococcemia. Disseminated infection should follow the treatment recommendations of cryptococcal meningitis. (Infection confined to the lungs responds well to fluconazole.):
–Induction therapy (2 weeks):
1. HIV-positive: amphotericin B deoxycholate (0.7 to 1.0mg/kg/day) OR lipid formulations of amphotericin B PLUS flucytosine (100mg/kg/day in 4 divided doses)
2. Organ transplantation: liposomal amphotericin B (3 to 4mg/kg/day) OR amphotericin B lipid complex (5mg/kg/day) PLUS flucytosine (100mg/kg/day in 4 divided doses)
–Consolidation therapy (8 weeks):
1. HIV-positive: fluconazole 400mg daily
2. Organ transplantation: fluconazole 400 to 800 mg daily
–Maintenance therapy (6 months to 1 year):
1. HIV-positive: fluconazole 200mg daily; can be discontinued if on effective antiretroviral therapy; CD4 greater than 100 for more than 3 months; HIV viral load undetectable or very low for more than 3 months; and has received at least 1 year of antifungal therapy
2. Organ transplantation: fluconazole 200 to 400mg daily; may require life-long therapy if unable to decrease amount of immunosuppressive agents
Primary cutaneous infection: may be helpful, especially in rapidly expanding infection
Disseminated cutaneous infection: usually not needed, unless there is evidence of deep soft tissue infection not responding to antifungal therapy, or necrotizing fasciitis
Optimal Therapeutic Approach for this Disease
Optimal therapy for cutaneous cryptococcosis depends on several factors. The most important determinant of therapy is whether there is evidence of disseminated cryptococcal infection. Along with fungal blood cultures, the serum cryptococcal antigen test is an excellent tool to detect hematogenous dissemination of infection. If the serum cryptococcal antigen is positive, a lumbar puncture must be performed to assess for CNS disease given the predilection of cryptococcus to infect this particular organ system.
For primary cutaneous cryptococcosis without evidence of dissemination, an azole antifungal is the preferred therapy; of the azoles, fluconazole is the antifungal agent of choice. Although medical therapy alone may be successful, surgical debridement may be necessary. In a study of 28 cases of primary cutaneous cryptococcal infection, more than half of the cases received some form of surgical intervention. For patients who are unable to tolerate azole therapy, amphotericin B formulations can be used; however, due to toxicities, it is not the preferred treatment of choice.
Patients with secondary cutaneous cryptococcosis tend to have impaired immunity, commonly due to cell-mediated dysfunction. As such, cutaneous infection is often evidence of disseminated disease. If there is evidence of disseminated disease in patients with secondary cutaneous cryptococcosis, initial therapy should be with amphotericin B, followed by fluconazole (see therapeutic ladder above).
Control of host immunity, the site of infection, management of antifungal drug toxicity, and the status of underlying disease are the most important factors for management of cryptococcosis. For treatment of both primary and secondary cutaneous cryptococcal infection, consultation with an infectious disease specialist is recommended.
Fluconazole is 100% bioavailable, so it can be administered orally; this is the preferable mode of administration since patients may require several weeks to months of therapy. Fluconazole is generally well tolerated; the major side effects are gastrointestinal (GI) upset (e.g. nausea, vomiting, abdominal pain, and diarrhea), transaminitis, rash, and headache. Because fluconazole can contribute to QT prolongation, it should be used with caution in patients who may be predisposed to QT prolongation. A baseline EKG should be done to assess for cardiac arrhythmias.
Finally, fluconazole is an inhibitor of the cytochrome P450 system and can alter the metabolism of other medications that are metabolized through this pathway. Patient’s medication lists should be thoroughly reviewed prior to using fluconazole therapy; this is especially important for patients who are on immunomodulating agents after solid organ transplantation.
All formulations of amphotericin B are administered via the intravenous route. Amphotericin B deoxycholate is associated with several side effects, including infusion-related symptoms (fever, chills, rigors, headache, GI upset), renal toxicity, electrolyte imbalance, hepatotoxicity, cardiac arrhythmias, and bone marrow suppression. The lipid formulations of amphotericin B are less likely to cause these toxicities, especially renal insufficiency, but there is still risk and renal function must be monitored closely.
Because amphotericin B can cause irreversible nephrotoxicity, careful review of the patient’s medications should be done; other potential nephrotoxic agents that are not essential should be withheld while on amphotericin B. Frequent monitoring of electrolytes and renal function should be performed while on therapy; aggressive electrolyte supplementation is important to ensure that the patient is not at risk for cardiac disturbances.
Toxicities of flucytosine include rash, nausea, vomiting, diarrhea, abdominal pain and bone marrow suppression.
Unusual Clinical Scenarios to Consider in Patient Management
Immune reconstitution inflammatory syndrome (IRIS) causing increased symptoms of cryptococcosis has been described predominately as a complication of antiretroviral therapy for HIV. IRIS also occurs as a complication of solid-organ transplantation, even in normal hosts whose immune status has improved. Manifestations of IRIS are caused by exuberant tissue inflammation and include fever, lymphadenopathy, meningitis, and cerebral abscesses. Cultures are usually negative, and there are no specific tests for it. The diagnosis is clinical.
IRIS is important to recognize since the management differs from persistence or relapse of infection, which are also in the differential diagnosis. Severe manifestations of IRIS can be fatal. There is no need to change antifungal therapy, and minor manifestations will resolve in days to weeks. Corticosteroid therapy along with concurrent antifungals should be administered for moderate to severe IRIS.
A detailed history for exposure to birds, including pets and work-related, should be performed for individuals on immunomodulating agents, such as TNF-alpha inhibitors, as well as HIV-infected and organ transplant patients. Exposure to birds such as turkeys, chickens, pigeons, and parrots have been linked to cases of cryptococcosis in such individuals, and care should be taken to avoid such exposure.
Finally, patients with infection due to C. gattii may not respond to therapy with fluconazole; prolonged treatment with Amphotericin B agents should be considered in these patients.
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