The incidence of systemic fungal infections in people with HIV infection in high-income countries has decreased over time with improved testing for HIV infection, earlier diagnosis and the availability of antiretroviral therapy (ART) (5). While systemic infections with Cryptococcus neoformans and Pneumocystis jirovecii are well-recognised opportunistic infections in people with HIV infection, other endemic fungi are also important pathogens in different geographic and epidemiological contexts.
Talaromyocosis (formerly Penicilliosis)
Talaromycosis (formerly Penicilliosis), is a life-threatening mycosis caused by the fungus Talaromyces marneffei (formerly Penicillium marneffei). This systemic mycosis is endemic in Southeast Asia, Hong Kong, north-east India and the southern parts of China (5, 6). While initially thought to be a rare human pathogen (6), it has increasingly been recognised as a major cause of HIV-associated death in areas such as Thailand, Myanmar, Hong Kong and Vietnam (6-9). Infection is thought to occur via inhalation (similar to other systemic opportunistic mycoses) (10), although delayed presentations (in keeping with latency and subsequent disease reactivation) have been described (11). The bamboo rat is the only non-human host frequently found to have a high prevalence of infection. Isolates from bamboo rats have been found to be closely related by genotype to those that cause human disease (12), although their role as a potential disease vector is not clear. A recent case-control study from Vietnam identified exposure to tropical plants and to farm animals as risk factors for infection (13). Similarly, patients living in or travelling to highland regions in Southern Vietnam were at increased risk. The incubation period is estimated to be 1 to 3 weeks in acute disease, although disease reactivation can occur years after exposure (5).
Clinical Presentation
Most episodes of Talaromycosis occur in patients with CD4+ T cell counts <100/μL (5, 10). The clinical presentation is typically subacute and may be nonspecific with fever, weight loss, cough, hepatosplenomegaly and lymphadenopathy. However, perhaps the most distinctive clinical feature that may hint at the diagnosis is the presence of characteristic papulonecrotic skin lesions, which are present in 60-70% of patients (5). These lesions often have central necrotic umbilication and may resemble molluscum contagiosum. They are usually distributed on the upper parts of the body (face, upper extremities and trunk). Umbilicated papules may also be present on the oral mucosa in disseminated disease (10). Diagnosis can be more challenging when skin lesions are not present.
Laboratory findings are non-specific and may include anaemia, thrombocytopenia, and elevated liver enzymes (8, 9). Reported mortality rates vary from around 10-30% in treated patients, depending on the context, time of diagnosis, and access to ART (6, 14-16). Immune reconstitution inflammatory syndrome (IRIS) reactions have been reported in patients starting ART (as ‘unmasking’ IRIS) (5).
Diagnosis
Diagnosis is made by fungal culture or histopathologic examination of body fluid or tissue from a normally sterile site. Microscopy may reveal yeast-like organisms in smears from skin lesions, biopsy specimens, blood cultures or bone marrow aspirates. Culture can be slow and polymerase chain reaction (PCR)-based assays are currently not sufficiently sensitive for clinical use (5). The galactomannan assay may be a useful diagnostic tool in some settings, particularly in patients with fungemia (17). Serological assays have shown some promise (18), but are not widely used in clinical practice.
Management
Treatment of Talaromycosis is usually specialised and therapy depends on the severity of the disease. As HIV-infected patients with Talaromycosis usually have advanced immunodeficiency, initiation of ART is an important consideration. There are no data to guide the optimal timing of ART initiation (with regards to the risk of an IRIS). However, extrapolating from recommendations for other opportunistic infections such as tuberculosis, early initiation of ART is advisable for patients with very low CD4+ T cell counts (≤50/μL), while initiation may be delayed for 2 weeks where the CD4+ T cell count is >50/μL (19). Amphotericin B and itraconazole are effective drug therapy for Talaromycosis but fluconazole is not. In a recent randomised controlled trial in Vietnam, Amphotericin B deoxycholate (0.7 to 1.0 mg per kg for 14 days) was found to be superior to itraconazole (600mg for 3 days followed by 400mg per day for 11 days) as initial induction therapy with regards to 6-month mortality and clinical response (20). Induction therapy is usually followed by maintenance therapy with itraconazole 400mg daily for 10 weeks, and then secondary prophylaxis with itraconazole 200mg daily until CD4+ T cell counts are >100/μL for at least 6 months (5, 19). Primary prophylaxis with itraconazole 200mg daily may be considered for patients with CD4+ T cell counts <200/μL who reside in endemic areas (21); however, the strategy has not been widely adopted. Liposomal amphotericin B and Voriconazole are effective alternative drugs but are not widely available in many endemic settings.
Histoplasmosis
Histoplasmosis is caused by infection with the thermally dimorphic fungus Histoplasma capsulatum. Although rarely seen in Australia, it remains an important HIV-associated opportunistic infection in other parts of the world. The mould form has a wide distribution, especially in rich, moist soils containing bird droppings or bat guano (22). While widely distributed, the majority of cases occur in central-eastern USA and Latin America (5). The usual route of acquisition is inhalation from contaminated environments when soil disruption aerosolises microconidia or mycelial fragments.
Clinical presentation
In immunocompetent adults, infection is either asymptomatic or takes the form of a self-limiting flu-like illness. In advanced HIV infection, however (typically when CD4+ T cell counts are <150/μL), histoplasmosis presents as a disseminated disease with fever, fatigue and weight loss (23). All organs can be involved, and symptoms can be nonspecific. Diffuse radiological infiltrates, often with a miliary reticulonodular pattern, may be seen on chest imaging. Abdominal symptoms of pain, diarrhoea and gastrointestinal bleeding, associated with colonic ulceration, may occur. Laboratory test findings may be nonspecific and include elevated lactate dehydrogenase, liver enzymes and ferritin (5). As with Talaromycosis, skin lesions may occur and onset may vary from a septic shock-like syndrome to a subacute presentation occurring over months. A history of potential environmental exposure, such as exposure to bat guano in caves, can sometimes provide a diagnostic clue when taking a patient history (24). IRIS-type presentations have also been described (25)
Diagnosis
Diagnosis can be made on microscopy (with special staining when the diagnosis is suspected) and culture of normally sterile tissue or body fluids. These may include blood, biopsy specimens or bone marrow aspirates. Laboratory precautions should be taken, and the laboratory informed in advance when the diagnosis is suspected. Urine antigen testing is reportedly a sensitive test for histoplasmosis (26), and may be accessible in Australia as a ‘send-away’ test to the USA (24). Acute and convalescent serology may also be performed, but may not be as useful in the context of HIV infection due to impaired antibody responses (27).
Management
Treatment involves an acute phase of induction therapy, followed by long-term maintenance therapy. In a randomised controlled trial (28), liposomal amphotericin B (3mg/kg daily) was more effective than standard IV amphotericin B deoxycholate (0.7 mg/kg daily). For moderate to severe cases, treatment with intravenous liposomal amphotericin B is recommended for 2 weeks or until clinical improvement. This is followed by treatment with oral itraconazole 200mg tds, and then 200mg bd for ≥ 12 months (19). Non-severe cases may be treated with itraconazole alone. Consideration should be given to potential drug interactions with antiretroviral drugs and therapeutic drug monitoring may be of value (5). Long term suppressive therapy with itraconazole 200mg should be given to patients with severe disseminated infection, central nervous system (CNS) infection or following relapse. This may be safely discontinued when certain criteria are met, including completion of at least one year of maintenance therapy, ART for 6 months, antigen levels that are low or negative, blood cultures that are negative, and a CD4+ T cell count of >150/μL (29).
Primary prophylaxis with itraconazole may be considered in certain endemic settings (21), and additionally activities associated with increased risk, such as working with soil or environments which may be contaminated with bird droppings or bat guano, should be avoided (19).
Coccidioidomycosis
Coccidioidomycosis, also known as ‘San Joaquin Valley fever’ or ‘Valley fever’, is caused by Coccidioides immitis, a soil-dwelling fungus. It is geographically restricted to certain arid and semi-arid areas of the Americas (30). Infection occurs via inhalation of soil or dust containing the fungus, and among immunocompetent individuals, the majority of those infected are asymptomatic. The remainder of cases may have a self-limiting pulmonary syndrome that resembles community-acquired pneumonia (31). Immunocompromised individuals, including those with HIV infection, may develop a number of different clinical syndromes including focal pneumonia, diffuse ‘reticulonodular’ pneumonia (resembling Pneumocystis jirovecci pneumonia) or extra-thoracic involvement including meningitis (19). Response to treatment can be poor, particularly in cases of severe disease, with high rates of mortality. Expert advice and specialised care should be sought in all cases.
Diagnosis is most often made on the basis of a positive serological test in the context of a compatible clinical syndrome. Culture of body fluids or tissues is also a useful diagnostic tool, and Coccidioides species may be detected on histological examination of biopsy samples, though this is less common (31). Laboratory staff should be informed if the diagnosis is suspected so that additional precautions may be taken.
There is no proven benefit to primary prophylaxis, and no absolute ways to avoid risk of infection (most infections occur without any definable exposure). Most immunodeficient HIV patients warrant treatment, regardless of severity, although there are limited published data to guide choice of therapy (31). In addition to ART, antifungal therapy with either fluconazole or itraconazole are typically used and treatment continued for at least 6 months. In more severe forms of disease, combination therapy with an amphotericin B formulation and a triazole antifungal is often preferred (19).