Continuing Education Activity

Trichosporon species are pathogenic yeast that colonizes and proliferates in different parts of the human body, including the gastrointestinal tract, respiratory tract, and skin. These organisms can cause superficial and invasive infections. Invasive Trichosporon infections are common in immunosuppressed patients, such as those with hematological malignancies. Unfortunately, invasive trichosporonosis can be difficult to diagnose and treat, and the global incidence is increasing. This activity reviews the evaluation and management of patients with trichosporonosis and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Objectives:

• Describe the clinical features of trichosporonosis.
• Identify the risk factors for invasive trichosporonosis.
• Summarize the current treatment options for trichosporonosis.
• Outline the significance of care coordination among the interprofessional team to improve the outcome for patients with trichosporonosis.

Introduction

Trichosporon spp. are yeast-like anamorphic organisms that belong to the basidiomycetes yeasts. Trichosporon species are broadly spread in nature but mostly found in areas where warm and tropical temperatures prevail. These organisms are usually found in substrates like soil; water areas like rivers, lakes, and even seawater; decomposing wood; air; foods like cheese; scarab beetles, and feces from birds, pigeons, bats, and cattle. In humans, they are occasionally found as part of gastrointestinal and oral cavity microbiota and can transiently colonize the respiratory tract, skin, and vagina.[1][2][3][4]

Beigel first described the genus Trichosporon in 1865 upon discovering that it can cause a benign hair shaft infection. The absence of simple methods to distinguish among the species in the clinical microbiology laboratory led to multiple members of the genus Trichosporon being categorized together under the name T. beigelii. However, modern molecular techniques led to the discovery of several strains that are part of other fungi groups and the strain categorization of Trichosporon spp. species.  Currently, more than 50 different subspecies and around 16 different strains cause human disease.

Although most Trichosporon spp. has been cultivated in laboratories, the fungus is now an agent of opportunistic infections, mostly seen in immunocompromised patients.

Etiology

Invasive trichosporonosis has been mainly documented in patients with hematological malignancies and other medical conditions associated with immunosuppression, whereas superficial infections and allergic pneumonia are found predominantly in immunocompetent hosts.

In 2005, Girmenia et al. did a very large retrospective study about invasive trichosporonosis, focusing on patients with hematological conditions. Data collected over 20 years in a multicenter study of 287 cases of trichosporonosis showed that 74.7% of the patients had a bloodstream infection of Trichosporon, while 50.6% developed a disseminated infection.

Risk factors for severe disease include:

• Chemotherapy
• Malignancy
• State of immunosuppression
• Neutropenia
• End-stage renal disease
• Severe burns[5][6][5]
• Cystic fibrosis[7]

Epidemiology

Geographical distribution of infections due to Trichosporon species varies, but data collected between 1997 and 2005 during the ARTEMIS DISK Surveillance Study found that infections with Trichosporon are predominantly found with equal frequencies in tropical and temperate areas such as South America, the Middle East, India, Southeast Asia, Africa, Europe, Japan, and parts of southeastern USA.[8][9][10]

Most cases of white piedra have been reported in children and young adults, particularly females. Different studies have come to a mutual consensus, where colonization from Trichosporon in admitted patients to the hospital wards can be from 1% to 3%. In the outpatient setting, asymptomatic volunteers had skin colonization at higher rates, 12.4%. The mode of transmission of superficial Trichosporon spp. infections is not clear, but the main reported risk factors include close contact, poor hygienic habits such as bathing in stagnant waters, long hair, and humidity. Sexual transmission has been reported in cases of pubic white piedra, which a report from a clinic in Houston, Texas reported as more common in black men. The disease presented with genital symptoms in young men 40% of the time. A Danish study reported rectal colonization rates of 13% among men who have sex with men and 2.5% among heterosexual men who attended a sexually transmitted diseases clinic.

In invasive infection, epidemiology is quite different. Most cases are seen in patients with neutropenia plus malignancies, either hematological or from a solid organ. Actually, disseminated trichosporonosis has been reported, right after candida, as the second most common yeast infection in patients with hematological malignancies, reaching a mortality rate of 80% despite antifungal therapy.

Another group that is at increased risk are neonates with low birth weight, premature neonates with AIDS, patients on steroids or with intravascular catheters, patients who had heart valve surgery or liver transplant, and patients with kidney failure who are on dialysis.[11]

Pathophysiology

Trichosporon spp. can cause two types of infection: superficial and systemic, and both presentations can lead to hypersensitivity pneumonia.

Superficial Infection

Commonly known as white piedra ("piedra" is a Spanish word for "stone"), this is a condition that affects the hair shafts and starts to grow beneath the cuticle until a nodule is formed, weakening the hair shaft and leading it to break. The main characteristic of this disease is rough and hard hair. Nonetheless, once the nodule is identified, removal of this is very easy, preventing the evolution of the disease. It has been suggested that strains of Corynebacterium can enhance the growth of Trichosporon spp. and may play a synergistic role in white piedra. This disease can affect any part of the body with hair.

Invasive Infection

Invasive infection occurs in three forms: disseminated disease (which is the most common presentation), disease localized to major organs, and infections that do not affect the tissues but are related to catheters. Trichosporon spp has virulence factors that allow its growth and permit the establishment of the disease and its dissemination within the host. It has the ability to adhere to and form biofilms on implanted devices. Another important virulence factor is the ability to produce and secrete enzymes for scavenging nutrients from the environment. Most invasive Trichosporon spp infections probably start with the colonization of mucosal or cutaneous surfaces, with a break in the integrity of the surface subsequently seeding the bloodstream. Such breaks may be secondary to chemotherapy-induced epithelial damage or intravascular catheters. Antibiotics may also increase the incidence and extent of colonization and may play a role in increasing the risk of human infections. 

Histopathology

Microscopically, these are seen as yeast cells which then produce hyaline hyphae that cutoff at the septa and those hyphal elements act as arthroconidia. Pseudohyphae and blastoconidia are also observed but no teleomorphic states. 

History and Physical

Superficial Infection

Patients with white piedra are usually asymptomatic and only seek medical attention because of the grossly visible nodules on the affected hair. Occasionally, the patient complains of pruritus or pain at the involved site. The nodules are usually soft, pasty, and ivory-colored. They are about 0.5 millimeters in size but can coalesce to blanket several millimeters of the hair shaft. Genital and facial hair is more often involved than the scalp and torso hair.

Invasive Infection

Typically, the patient has an acute febrile illness, not responding to empirical broad-spectrum antibiotics or even to empirical antifungal agents that becomes septic and progresses rapidly to multiorgan failure. In the vast majority of cases, fungemia is present (more than 70%). The crude mortality rate can vary from 30% to as high as 77% in published cases.

The cutaneous manifestations of disseminated trichosporonosis include erythematous papules on the trunk and extremities that can sometimes form bullae. In cases of central nervous system infection, the predominant symptoms are headache, nausea, vomiting, and fever. A patient with dyspnea could suggest that pulmonary involvement is present and can include a productive cough and even bloody sputum. Diffuse infiltrates are seen in the chest x-ray with an alveolar pattern. Other findings, such as reticulonodular infiltrates, lobar infiltrates, and cavitation, also can be detected. Patients that have disseminated trichosporonosis with the involvement of the kidneys may have proteinuria, microscopic hematuria, and renal failure. 

Trichosporonosis has also been documented to cause peritonitis, pacemaker lead endocarditis, and pneumonia. Other rare manifestations include sinusitis in an immunocompetent patient, fungemia, and urinary tract infection in patients with diabetes mellitus, and nosocomial infection in patients with severe burns.[12][13][14][15][16][17][7]

Evaluation

The diagnosis of white piedra is based on clinical findings and confirmed by microscopy and culture. Complete blood count, renal and liver function, and urinalysis are usually performed.

In deep infections, identification of Trichosporon spp. depends on biochemical characteristics and cell morphology. Trichosporon spp. should be a diagnosis under suspicion if the following characteristics are present: the organism produces urease, yeast-like, and forms arthroconidia. Diagnosis is usually confirmed by positive blood culture. A dermatophyte test medium that contains cycloheximide should not be used for culture because cycloheximide inhibits its growth. The colonies are raised, waxy appearing, and have radial furrows and irregular folds. Supplementary tests can help confirm the diagnosis, as well as carbohydrate and nitrate assimilation and temperature studies. Trichosporon species assimilate L-arabinose but not melibiose. It grows at 37 degrees C.

Urine cultures may be the first to grow Trichosporon in the setting of disseminated disease. A serum cryptococcal antigen latex agglutination test is occasionally positive in disseminated trichosporonosis.

Some investigational rapid molecular diagnostic methods such as DNA-based microarrays, polymerase chain reaction, and pyrosequencing are emerging methods for faster diagnosis. 

Depending on the organ involved, imaging studies may be necessary. A chest x-ray and a CT scan of the chest, abdomen, and pelvis are done in those with invasive disease. An echocardiogram is performed in patients with suspected endocarditis. If lung involvement is suspected, bronchoscopy with lavage is recommended.

Treatment / Management

Complete removal of the nodule and infected hair is the treatment for white piedra. The first-line antifungal regimen is topical 2% miconazole or 2% ketoconazole four times a day for two weeks. For patients that refuse to shave, the addition of 100 milligrams of oral itraconazole once a day for a course of three to four weeks has been effective. For patients allergic to azoles, 6% precipitated sulfur in white petrolatum or 2% selenium sulfide foam is the treatment of choice.[18][19]

Although data is limited, voriconazole has been shown to be the most active drug against trichosporonosis and should be the first-line treatment for patients that are neutropenic and have disseminated disease. As a second line, one can use itraconazole and fluconazole; they have moderate susceptibility based on their elevated minimum inhibitory concentrations. Most experts recommend combination therapy consisting of amphotericin and voriconazole/5-flucytosine.

Another alternative is amphotericin B and should be used in unresponsive and resistant trichosporonosis along with voriconazole or micafungin. Lastly, it is important to remember that echinocandins have no effect when treating this fungal infection. Regardless of the antifungal options, a cure for invasive trichosporonosis depends on the duration of neutropenia and source control by surgical intervention.

Differential Diagnosis

Trichosporonosis resembles other invasive fungal infections such as invasive candidiasis, aspergillosis, and cryptococcosis. It also is important to consider that, in the immunocompromised patient, Trichosporon infection can coexist with other fungal, bacterial, or viral infections. Therefore, the differentiation between these organisms will then mainly rely on laboratory testing instead of a clinical scenario.

Diagnosis is usually confirmed by positive blood culture. In a study, using Grocott's method, Trichosporon can be easily differentiated from Candida with periodic acid methenamine silver (PAS) as Trichosporon will clearly enhance. Other stains that strongly react with Trichosporon are colloidal iron and alcian blue.

Histopathological staining patterns and electron microscopic findings also can facilitate the diagnosis of trichosporonosis. One main difference in electron microscopy is the variance of their hypha and granules. Candida shows equal pseudohyphae with fine granules, and Trichosporon presents with different sizes and silver granules.

Prognosis

In general terms, the resolution of a superficial infection has a very good prognosis. Most patients are asymptomatic or have only mild symptoms. Although relapses are common, the removal of the affected hair is usually curative. White piedra is not a risk factor for invasive Trichosporon infections.

The prognosis of invasive infection is dependent on the underlying condition or immune state of the patient, with the mortality rate being high in several published cases. The cure of disseminated infection has been seen in patients who were either not neutropenic at the time of diagnosis or who recovered from their neutropenia quickly. Mortality rates of 40% to 60% have been reported in patients with severe invasive disease.

Patients with localized disease, such as wound infections and cellulitis due to T. asahii, have been cured with surgical debridement and prolonged antifungal therapy.

Complications

Recurrent episodes of Trichoporonosis infection affecting the central nervous system, in transplant recipients, have been reported implying the need for long-term treatment in some patients.[20] 

Resistance to therapy with Amphotericin B has been documented with T. beigelii and thus, has the potential to cause a fatal outcome.[21]

Pearls and Other Issues

• Trichosporon spp. are basidiomycetous, yeast-like, anamorphic organisms that are widely distributed in nature and found predominantly in tropical and temperate areas.
• Hematologic malignancies, neutropenia, HIV/AIDS, end-stage renal disease, corticosteroid use, solid tumors, intravascular devices, prosthetic heart valves, and hemochromatosis are all considered risk factors for invasive Trichosporon infection.
• First-line treatment of Trichosporon is with azoles, either topical (ketoconazole) for superficial infections or oral/parenteral (voriconazole) for disseminated infections. Voriconazole, isavuconazole, and posaconazole show excellent in vitro activity against Trichosporon.
• Echinocandins are not effective against Trichosporon. The echinocandins caspofungin and micafungin showed poor in vitro activity against Trichosporon when used alone.

Enhancing Healthcare Team Outcomes

The management of trichosporonosis is with an interprofessional team that includes a dermatologist, infectious disease expert, pharmacist, and hematologist. Complete removal of the nodule and infected hair is the treatment for white piedra. Topical antifungal drugs may help but those with allergies to azoles, other options include selenium sulfide. In neutropenic patients, voriconazole, itraconazole, and fluconazole have all been used with partial success. 

Another alternative is amphotericin B and should be used in unresponsive and resistant trichosporonosis along with voriconazole or micafungin. The pharmacist should educate the patient on the potential benefits of the antifungal agents and their adverse effects. Nurses who look after these patients should monitor for signs of progression as some patients with invasive disease may not respond to the medications. Every attempt should be made to reverse the state of immunosuppression or neutropenia.

Lastly, it is important to remember that echinocandins have no effect when treating this fungal infection. Regardless of the antifungal options, a cure for invasive trichosporonosis depends on the duration of neutropenia and source control by surgical intervention.

An interprofessional team approach is vital in order to improve patient outcomes. All clinicians who look after these patients should communicate with each other so that the patient is not deprived of the current standard of care.