Cutaneous Cryptococcus

Cryptococcosis is an infection caused by the encapsulated yeast Cryptococcus neoformans and Cryptococcus gattii. It was first demonstrated by Busse and Buschke in 1894. Although the primary site of infection is most often the lungs, with strong tropism for the central nervous system, the disease frequently manifests with signs of extrapulmonary dissemination, involving the skin in approximately 10-15% of cases. C neoformans has a worldwide distribution, while C gattii is endemic to temperate, tropical, and subtropical climates. C neoformans is found worldwide in soil in association with bird excreta, especially pigeons, and from other wild and pet birds. C gattii is associated with the Eucalyptus camaldulensis tree native to Australia and has traditionally been identified in tropical and subtropical regions. However, it has also been associated with temperate climates. as well.[1, 2, 3, 4, 5]

Cryptococcus is classified into four serotypes, A, B, C or D. Serotype A and D were previously classified under the species C neoformans; however, serotype A has been proposed to be reclassified into a separate variety Cryptococcus neoformans var grubii.[6] Serotype B and C are classified as a separate species, C gattii. Strains of serotype D are more likely to be found in skin lesions. Either variant can cause disease, although more reported cases involve the neoformans variant. Infections with the neoformans variant are thought to be more common in immunocompromised patients, while infections with the gattii variant are more common in immunocompetent individuals. Infections can range from mild symptoms such as fever and cough to severe disseminated disease resulting in death. Host immune factors, in particular, cell-mediated immunity, are the primary determinant of outcome.

Infection most commonly begins in the lungs after inhalation of the airborne yeast, and it may remain localized in 90% of cases. Manifestations of the disease depend on the host response, inoculum size, and innate virulence of the organism. Primary cutaneous infection may result from direct inoculation of organisms into the skin by an infected object; however, this is rare. Cutaneous Cryptococcus infection should be presumed to be disseminated until proven otherwise, and a search for other sites of involvement must be immediately undertaken.

Disseminated disease results after hematogenous spread, with the CNS and skin being the most common secondary sites. In addition to meningitis, disseminated Cryptococcus infection can cause hepatitis, osteomyelitis, prostatitis, pyelonephritis, and peritonitis. Cutaneous signs may be the first indication of infection, preceding the diagnosis of disseminated disease by 2-8 months, making its recognition crucial to early treatment.

Dissemination occurs primarily in immunocompromised hosts, such as those with AIDS, lymphoreticular malignancy (eg, chronic lymphocytic leukemia, Hodgkin lymphoma[7] ), sarcoidosis, systemic lupus erythematosus, those on long-term immunosuppression or prednisone therapy for organ transplantation or connective-tissue disease.[8, 9, 10] In HIV-infected patients, Cryptococcus infection is typically seen when the CD4 count is less than 50-100 cells/µL and is an AIDS-defining illness. In a study of 40 HIV-negative patients with Cryptococcus infection, 65% had an associated underlying condition. Of these, 41% were on immunosuppressive drug treatment, 16% had systemic lupus erythematosus, 16% had malignancy, and 14% had diabetes mellitus.

Cryptococcus infection occurs primarily from the inhalation of infectious yeast from contaminated soil. Primary cutaneous infections occur through direct inoculation via trauma, while secondary cutaneous infection occurs through hematogenous spread. C neoformans is found worldwide in soil contaminated with bird excreta, especially pigeons and from other wild and pet birds.C gattii is associated with the E camaldulensis tree native to Australia and has traditionally been identified in tropical and subtropical regions. However, it has also been associated with temperate climates.[1, 2, 3, 4, 5] Immunosuppression (eg, HIV infection, leukemia/lymphoma, sarcoidosis, long-term immunosuppression or prednisone therapy for organ transplantation or connective-tissue disease) is a key factor in developing disseminated disease.

Frequency

United States

The incidence of Cryptococcus infection was reported to be very low prior to the AIDS epidemic (0.8 case per million population). However, in 1992, at the height of the AIDS epidemic, the incidence increased to 5 cases per 100,000 population. Since the use of antiretroviral therapy, the incidence has decreased to very low levels.[11]

Studies have reported an overall prevalence of 2.9% in patients with AIDS, based on cryptococcal antigen positivity. A CD4 count of 50 cells/µL or less was associated with an increased prevalence of cryptococcal antigen positivity.[12]

International

The burden of cryptococcal infection remains very high in sub-Saharan Africa. The prevalence varies greatly in AIDS patients, from 3% in the United Kingdom to greater than 12% in parts of Africa.[1, 13] Cases of cryptococcosis without meningeal involvement have been reported in HIV-positive patients in Africa.[14]

Lizarazo et al[15] published the results of a national survey on cryptococcosis in Colombia, based on survey data recorded over a 9-year period from 1997-2005. From 76 centers, 931 surveys were received (82.7% were males, 17.3% were females). In the data, 59.4% of respondents were aged 20-39 years, and 25 children younger than 16 years were included. Of the respondents, 78.1% had HIV infection. The mean annual incidence rate of cryptococcosis in the general population was 1 case in 2.4 million inhabitants, but in the AIDS patients, the rate was 1 case in 3000 persons.

The associated disease syndromes were as follows:

• Neurocryptococcosis - 891 cases (95.7%)

• Pulmonary disease - 27 cases (2.9%)

• Cutaneous lesions - 5 cases (0.5%)

• Ganglionar forms - 2 cases (0.2%)

• Oropharyngeal lesions - 2 cases (0.2%)

• Peritonitis - 1 case (0.1%)

• Liver lesion - 1 case (0.1%)

• Cellulitis - 1 case (0.1%)

• Urinary tract infection - 1 case (0.1%)

The most frequent clinical features were as follows:

• Headache (85.2%)

• Nausea and vomiting (59.1%)

• Fever (59%)

• Mental status changes (46.2%)

• Meningeal signs (33.4%)

• Cough (23.6%)

• Visual alterations or loss of vision (20.9%)

Laboratory data showed that direct examination of cerebrospinal fluid revealed a positive result in 92.8% cases and Cryptococcus was recovered in 90.3% of the cases. Cryptococcal antigen reactivity was 98.9% in cerebrospinal fluid and 93.7% in serum samples. From 788 isolates submitted, 95.9% were C neoformans var grubii serotype A, 0.3% were C neoformans var neoformans serotype D, 3.3% were C gattii serotype B, and 0.5% were C gattii serotype C.

In a Brazilian report of two general hospitals between 2005 and 2010, 11 patients were noted to have cryptococcus,[16] 81.8% of which were male. Researchers identified immunosuppression in 54.5% of patients, and all of them were taking corticosteroids for a variety of diseases.

Race

All races are equally affected.

Sex

For disseminated disease, the reported male-to-female ratio is 3:1. For primary cutaneous cryptococcosis in immunocompetent patients, the reported male to female ratio is 17:4.[17]

Age

Cryptococcus infection is most common in persons aged 30-60 years. Cryptococcus laurentii is a very rare human pathogen, but was noted in an immunocompetent 8-year-old child.[18] It occurred on the forearms and was successfully treated with fluconazole.

Primary cutaneous cryptococcosis in immunocompetent patients carries an excellent prognosis, with a cure rate of around 95% with adequate medical therapy.[17]

Lifelong treatment and surveillance may be required for immunosuppressed patients.

Untreated disseminated Cryptococcus infection has a mortality rate of nearly 100%.

A patient's presenting symptoms are determined by the site of initial and subsequent infection and by his or her immune status. Factors favoring primary cutaneous infection include a solitary lesion, lesions on uncovered parts, a history of primary inoculation, and regional lymph node involvement. Factors favoring secondary cutaneous infection include the presence of systemic involvement, lesions on covered parts, multicentric skin involvement, and deep dermal or subcutaneous lesions. Cryptococcal meningitis with skin involvement in a 20-year-old woman has been reported and indicates that immunosuppression is not necessary for cryptococcal infection to occur and that skin manifestations can give clues to meningitis.[19]

Several reports in 2011 have noted that C gattii can affect immunocompetent hosts, so this must be considered when examining otherwise-well patients.[20] C gattii type VGII resulted in primary infection after trauma in one patient.[21]

C laurentii in a renal transplant recipient resulted in primary cutaneous cryptococcosis.[22] An immunosuppressed psoriatic patient with palmopustular involvement experienced generalized Cryptococcus albidus infection manifesting as generalized hemorrhagic plaques.[23]

Primary cutaneous infection findings are as follows:

• History of trauma and direct inoculation

• Most often occurs in immunosuppressed patients but may also occur in immunocompetent patients

• Single lesion develops at the site of infection

• Solitary nodules that may ulcerate

• Cellulitis

• Ulcers

• Abscesses

• Panniculitis[24] (eg, primarily in renal transplant patients[25] )

• Sporotrichoid-pattern, capsule-deficient cutaneous cryptococcosis[26]

Disseminated cutaneous Cryptococcus infection findings are as follows:

• Occurs in 10-15% of patients with disseminated infection

• Cutaneous signs possibly preceding other symptoms of disseminated disease by 2-8 months

• Lesions mostly found on head and neck

• First present as painless papules or pustules, which then become nodules that may ulcerate (eg, pustular eruption in a cardiac transplant patient with cryptococcal meningitis and headache[27] )

• Numerous other cutaneous manifestations (eg, acneiform papules or pustules, warty or vegetating crusted plaques and ulcers, hard infiltrated plaques or nodules, subcutaneous swellings, abscesses, blisters, tumorlike masses, eczematous plaques, granulomas, vasculitic lesions resembling palpable purpura [especially in transplantation patients])

Primary pulmonary infection findings are as follows:

• May be limited to fever, cough, and pleuritic chest pain

• Can progress to acute respiratory distress syndrome

CNS Cryptococcus infection findings are as follows:

• Nuchal rigidity

• Headache

• Vertigo

• Nausea and vomiting

• Changes in consciousness

• Mental changes

• Nerve palsies

Immunosuppressive medications are as follows:

• Treatment with methotrexate and adalimumab[28]

• Corticosteroid therapy[29] (including cutaneous cryptococcosis secondary to C gattii)[30]

Other possible developments are as follows:

• Hepatitis

• Osteomyelitis

• Prostatitis

• Pyelonephritis

• Peritonitis

Primary cutaneous Cryptococcus infection findings

The patient may have solitary nodules that break down and ulcerate (eg, facial ulceration[31] ).

Cutaneous Cryptococcus infection has been reported to mimic leishmaniasis (ulcerated nodule on the face).[8]

Other signs include local lymphadenopathy, cellulitis, confluent erythematous plaques, ulcerated tumor mass, and abscesses.[32, 33, 34, 35]

Disseminated cutaneous Cryptococcus infection findings

Numerous manifestations may be seen, but seldom are they pathognomonic.

Lesions are most often found on the head, neck, mouth, and nose.

Xanthomalike lesions (crusted yellowish-brown plaques, which were accompanied by smaller papules with telangiectasia) histologically and clinically have been noted.[36]

The most common manifestations are molluscum contagiosum–like umbilicated papules of varying sizes (approximately 50% of patients with HIV infection), as seen in the image below, which may have a gelatinous quality and develop a central hemorrhagic crust.

Cellulitis is seen most commonly in transplantation patients. In one report, 72% of organ transplantation patients with cutaneous Cryptococcus infection presented with cellulitis. Of these, 94% had cellulitis on the extremities. A particularly high rate was found among patients treated with tacrolimus. Primary cryptococcal cellulitis caused by C neoformans var gattii has also been reported in an immunocompetent host.

Patients may have acneiform papules or pustules and/or warty or vegetating crusted plaques and ulcers.

Other signs include hard infiltrated plaques or nodules, subcutaneous swellings, abscesses, blisters, tumorlike masses, eczematous plaques, granulomas, and/or vasculitic lesions resembling palpable purpura (especially in transplantation patients).

Disseminated cryptococcosis initially presenting as cellulitis in a rheumatoid arthritis patient was noted by Lu et al.[37] Cryptococcal cellulitis should be suspected in any immunosuppressed patient with cellulitis that is unresponsive to antibiotics.

Hoang and Burruss[38] described localized cutaneous Cryptococcus albidus infection in a 14-year-old boy on etanercept therapy.

Dilhuydy et al[39] reported on a patient who had cutaneous cryptococcosis with alemtuzumab; this patient was being treated for chronic lymphocytic leukemia.

Van Grieken et al[40] described a case of primary cryptococcal cellulitis in a lung transplant recipient.

Cutaneous cryptococcosis can resemble molluscum.[41]

In a person with AIDs, cutaneous plasmablastic lymphoma with disseminated cryptococcosis has been reported,[42] stressing that persons with HIV cryptococcal disease can have other significant pathology.

The latex agglutination test is a sensitive and specific method for testing serum, cerebrospinal fluid, and urine. Lesional skin scrapings have also reportedly been used for testing. The test may yield false-positive results in the presence of a rheumatoid factor. Decreasing titers indicate regression of the disease. Patients who do not have AIDS but have single, localized skin lesions are often antigen negative.

Enzyme-linked immunosorbent assay is sensitive and specific for testing blood or cerebrospinal fluid. It is capable of detecting the presence of antigen earlier and at a lower concentration than other tests.

Direct preparations are performed on a drop of serum or exudate placed on a slide. The cells seen are large (5-15 µm), budding cells with capsules. Stain with periodic acid-Schiff, mucicarmine, or India ink (for capsule).

Since cutaneous manifestations are often indistinguishable from those caused by other infections, tissue culture and biopsy are necessary for diagnosis. The colony appears moist, shiny, and white on Sabouraud dextrose agar, but it may darken with aging. Results are urease-positive. It can pigment on Guizotia seed medium.

Chest radiography may demonstrate local or diffuse infiltrates, nodules, hilar lymphadenopathy, cavitation, or pleural effusions. The diffuse interstitial infiltrates may be difficult to distinguish from Pneumocystis jiroveci pneumonia.

Head CT scanning shows normal results in approximately half the patients with CNS infection. No signs are pathognomonic for Cryptococcus infection, but studies may show hydrocephalus, gyral enhancement, and single or multiple nodules that may or may not be enhancing.

MRI is thought to be a more sensitive study than CT scanning.

Because cutaneous disease should be presumed to be disseminated, an appropriate workup for systemic involvement is essential. This includes a thorough history and physical examination, chest radiography or CT scanning to evaluate pulmonary involvement, lumbar puncture, imaging of the CNS, and other studies as indicated.

Lumbar puncture may reveal an increased opening pressure (associated with a poor prognosis), low glucose level, increased protein level, and an elevated white blood cell count, with lymphocyte predominance.

Typically, the organism can be visualized on histologic sections as an oval, thick-walled spherule surrounded by a polysaccharide capsule. Special staining with methylene blue, Alcian blue, or mucicarmine may be performed to demonstrate the capsule.

Two patterns of involvement can be seen. The first is the gelatinous type, which shows numerous budding yeasts in a foamy stroma with little or no inflammation. The second is the granulomatous type, which shows fewer, smaller organisms and a granulomatous inflammatory infiltrate.

Sing and Ramdial[43] described five solitary cryptococcal inflammatory pseudotumors in 2 men and 3 women ranging in age from 19-43 years. All were HIV positive and had been treated for disseminated cutaneous and/or meningeal cryptococcosis with antifungal therapy 6-12 months earlier. The cryptococcal inflammatory pseudotumors were located in the soft tissues of the anterior chest wall, thigh, and arm. They showed the following:

• A storiform arrangement of plump spindle cells

• Spindle and polygonal cells arranged in a haphazard manner

• Background lymphocytes, plasma cells, and fibrosis

• Scattered giant cells and focal necrosis

• C neoformans yeasts on high-power examination, which were within and between vacuolated spindle and polygonal cells after routine and special staining

Cryptococcal inflammatory pseudotumors are part of a heterogeneous spectrum of reactive, infective, and neoplastic entities characterized by a clinical mass composed of a histologic proliferation of spindle cells in a background of inflammatory cells and collagen fibers.[43]

Disseminated infection should always be ruled out in patients with cutaneous cryptococcosis. CNS involvement is treated with intravenous amphotericin B combined with flucytosine, followed by oral fluconazole. In immunosuppressed patients, the initial treatments are similar; however, long-term maintenance therapy with fluconazole may be required. In immunocompromised patients with pulmonary infection, lumbar puncture should be performed to rule out meningitis. Patients with fungemia or dissemination (involvement of at least two noncontiguous sites or evidence of high fungal burden based on cryptococcal antigen titer ≥1:512) are treated as CNS disease. In immunocompetent patients, nondisseminated, non-CNS Cryptococcus infection can be treated with oral fluconazole for 3-6 months or with itraconazole for 6-12 months.

There have been no studies performed to evaluate the effectiveness of different treatment modalities for immunocompetent patients with primary cutaneous cryptococcosis. As per published case reports, fluconazole at a dose of 200-800 mg/day for a duration ranging from 2 weeks to 6 months or itraconazole at a dose of 100-400 mg/day for 3-6 months has been tried with good success rates. Success was achieved in 20 of 21 patients, with the only treatment failure reported with fluconazole at 400 mg/dat for 3 months.[17]

Patients with acute, disseminated disease should be treated in an inpatient setting.

Also, see the following related clinical guidelines:

• Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children[44]

• Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents[45]

• Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America[46]

Surgical excision or cryotherapy may play a role in primary cutaneous infections.[9]

Consultation with an infectious disease specialist should be obtained for all patients to evaluate for disseminated disease. As warranted, consultations should be obtained from a pulmonologist or neurologist, among others, depending on the extent of disease involvement.

Avoidance of areas that may be contaminated by pigeon droppings, especially for immunosuppressed persons, can reduce the likelihood of infection. Early detection of HIV and the initiation of antiretroviral therapy to prevent severe immunodeficiency remains the most effective intervention to decrease the burden of cryptococcal infection.

The duration of treatment and the combination of agents depend on the patient's immune status and whether the infection is disseminated.[17, 46]

Immunocompetent patients

In primary cutaneous cryptococcosis, as per published case reports, treat with fluconazole at a dose of 200-800 mg/day for a duration ranging from 2 weeks to 6 months or itraconazole at a dose of 100-400 mg/day for 3-6months.

For patients with nondisseminated, non-CNS Cryptococcus infection, treat with oral fluconazole for 3-6 months or with itraconazole for 6-12 months.

For non-CNS disseminated pulmonary Cryptococcus infection, treat as CNS disease.

Patients with fungemia or dissemination (involvement of at least two noncontiguous sites or evidence of high fungal burden based on cryptococcal antigen titer ≥1:512) are treated as CNS disease.

For CNS disease, use amphotericin B at 0.7-1 mg/kg/day plus flucytosine at 100 mg/kg/day for 6-10 weeks. Alternatively, use amphotericin B/flucytosine for 2 weeks, followed by fluconazole at 400 mg/day for 10 weeks. This is then followed by fluconazole for 6-12 months. Voriconazole is another possible treatment, but its use is not well reported for cutaneous cryptococcosis.

Immunocompromised patients

For non-CNS disseminated Cryptococcus infection, treat as described. Maintenance fluconazole therapy is recommended for life. Studies have shown that treatment can be discontinued after 1-2 years if the patient is receiving highly active antiretroviral therapy (HAART) and has had a CD4 count greater than 200/µL for at least 6 months, a nondetectable viral load, and a negative serum Cryptococcus antigen test result.

For CNS disease, use amphotericin B at 0.7-1 mg/kg/day plus flucytosine at 100-150 mg/kg/day for 2 weeks, fluconazole at 400 mg/day for at least 10 weeks, and then, in some cases, maintenance fluconazole for life. Studies have shown that treatment can be discontinued after 1-2 years if the patient is receiving HAART and has had a CD4 count greater than 200/µL for at least 6 months, a nondetectable viral load, and a negative serum Cryptococcus antigen test result.

Liposomal formulations of amphotericin B may be used as needed. Newer azoles, such as voriconazole, appear to have good activity against Cryptococcus and may be used more frequently in the future. Caspofungin lacks significant activity against Cryptococcus and is not recommended.

Class Summary

Antifungal agents are used in the management of infectious diseases caused by fungi.

Fluconazole (Diflucan)

Fluconazole is a synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. It has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Fluconazole is available as a tablet for oral administration, as powder for oral suspension, and as sterile solution for intravenous use. It has fewer adverse effects and better tissue distribution than older systemic imidazoles. Fluconazole is active against many yeast and dimorphic fungi. In general, it has poor activity against molds and filamentous fungi.

Itraconazole (Sporanox)

Itraconazole has fungistatic activity. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Amphotericin B deoxycholate (Amphocin)

Amphotericin B deoxycholate is produced from a strain of Streptomyces nodosus. Its antifungal activity results from its ability to insert itself into fungal cytoplasmic membrane at sites containing ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium). At low concentrations, its main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity; however, at higher concentrations, 40- to 105-nm pores are produced in the cytoplasmic membrane, leading to large losses of ions and other molecules. A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. The main fungicidal activity of amphotericin B may reside in its ability to cause auto-oxidation of cell membranes.

If therapy is supplemented by oral flucytosine, therapy can be used until the patient is afebrile and alert and spinal fluid cultures are negative for 6 weeks; then, the patient can begin fluconazole therapy.

Flucytosine (Ancobon)

Although the exact mode of action is unknown, flucytosine may act directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism, where it is converted to 5-fluorouracil after penetrating fungal cells. It inhibits RNA and protein synthesis. Flucytosine is active against candidal and cryptococcal species and generally used in combination with amphotericin B.

Use it in combination with another agent because acquired resistance develops frequently when administered alone. Flucytosine is well absorbed orally but should be administered intravenously to critically ill patients.