Talaromycosis
Also known as: Talaromyces marneffei Infection, Penicilliosis, Penicillium marneffei Infection
Talaromycosis is a systemic infection caused by the thermally dimorphic fungus Talaromyces marneffei (formerly Penicillium marneffei), endemic in South East Asia, southern China, and north east India. It is a leading cause of death in people with advanced HIV disease in endemic regions, and a growing cause of disease in people with anti interferon gamma autoantibodies, other immune defects, and transplant. It causes fever, weight loss, anaemia, hepatosplenomegaly, lymphadenopathy, and umbilicated skin papules, and mortality is near total when untreated.
| Feature | Description |
|---|---|
| Dimorphism | The only thermally dimorphic Talaromyces species |
| Mould phase | At 25 to 30 degrees Celsius, colonies that are flat and woolly, white or green, and produce a characteristic red diffusible pigment in the agar; hyaline septate hyphae with biverticillate penicilli bearing chains of conidia |
| Yeast phase | At 37 degrees Celsius and in tissue, oval to round yeasts 2 to 6 micrometres that divide by fission with a central transverse septum (no budding), inside macrophages (or free); no pigment is produced |
| Culture | 3 to 14 days; the colour change with red pigment is a helpful clue; mould phase is hazardous |
| Identification | Dimorphism, microscopy, sequencing, and mass spectrometry |
| Aspect | Details |
|---|---|
| Geography | Thailand (northern), Vietnam, Myanmar, Laos, Cambodia, Malaysia, Indonesia, southern China (Guangxi, Guangdong, Hong Kong), Taiwan, and north east India (Manipur); imported cases in travellers and migrants in Europe and North America |
| Reservoir | Bamboo rats (Rhizomys, Cannomys, and Spalax) and soil; the exact route of infection is not known, and human infection follows inhalation of conidia |
| Seasonality | Peaks in the rainy season |
| Hosts | Advanced HIV (CD4 below 100 cells per microlitre, and most cases below 50); anti interferon gamma autoantibodies (adult onset immunodeficiency, mostly in Asian adults); inherited defects (STAT1 gain of function, CD40LG, IL12RB1, CARD9, STAT3); transplant, haematological malignancy, corticosteroids, and biologics |
| Burden | Estimated as the third most frequent opportunistic infection in HIV in Thailand and Vietnam; high mortality |
Inhaled conidia are taken up by alveolar macrophages and survive in them in yeast form. Control depends on a T helper 1 response with interferon gamma, interleukin 12, and tumour necrosis factor, so disease in HIV and anti interferon gamma autoantibody disease follow loss of these. The fungus spreads in the reticuloendothelial system (liver, spleen, bone marrow, nodes), the lungs, skin, and gut.
| Feature | Details |
|---|---|
| Systemic | Fever, weight loss, fatigue, anaemia, hepatomegaly, splenomegaly, and generalised lymphadenopathy |
| Skin | Papules with central umbilication and necrosis (resembling molluscum contagiosum), on the face, upper trunk, and arms, in about 70 percent of those with HIV; also pustules, ulcers, abscesses, and subcutaneous nodules |
| Respiratory | Cough, dyspnoea, and chest radiograph with diffuse reticulonodular infiltrates, nodules, and cavities; pleural effusion |
| Gastrointestinal | Diarrhoea, abdominal pain, and ileocolonic ulcers; hepatic involvement with raised alkaline phosphatase |
| Bone and joint | Lytic lesions and arthritis, with osteomyelitis |
| Others | Central nervous system disease, oral and genital ulcers, and endocarditis, rarely |
| Haemophagocytic lymphohistiocytosis | In severe disease |
| Anti interferon gamma autoantibody disease | Prolonged or relapsing disease with lymphadenopathy and skin lesions (Sweet like), with coexisting infections by nontuberculous mycobacteria, Salmonella, and Burkholderia |
| Immune reconstitution inflammatory syndrome | Within weeks of antiretroviral therapy, with fever and enlarging lesions |
| Imported disease | Fever and skin lesions in a returned traveller with HIV |
| Condition | Points that separate it |
|---|---|
| Histoplasmosis | Narrow based budding yeasts 2 to 4 micrometres, no central septum, and a positive antigen |
| Cryptococcosis | Capsule, India ink, and cryptococcal antigen |
| Tuberculosis and disseminated Mycobacterium avium complex | Acid fast bacilli and cultures |
| Molluscum contagiosum and skin lesions of cryptococcosis and histoplasmosis | Skin scraping microscopy |
| Leishmaniasis | Amastigotes with kinetoplasts |
| Emergomycosis | Culture, sequencing, and geography |
| Bacterial sepsis and lymphoma | Cultures and biopsy |
| Pneumocystis pneumonia | Polymerase chain reaction and beta D glucan |
| Test | Details |
|---|---|
| Microscopy | Wright or Giemsa stain of skin scrapings, lymph node aspirates, bone marrow, and blood films, and methenamine silver or periodic acid Schiff on tissue, show oval yeasts with a central septum; sensitivity is about 70 to 100 percent and the result is available within hours, which makes it the fastest test |
| Culture | Blood (positive in about 70 percent), bone marrow (up to 100 percent), skin, lymph node, and sputum, in 3 to 14 days; the red pigment and dimorphism confirm |
| Antigen | The Mp1p galactomannan enzyme immunoassay in serum, plasma, or urine, with about 86 percent sensitivity and high specificity, and is a new rapid test |
| Biomarkers | Beta D glucan is positive; galactomannan is positive in some, through cross reaction |
| Molecular tests | Polymerase chain reaction on blood and tissue |
| Serology | Anti Mp1p antibody is not routine |
| Other tests | CD4 count, HIV test, anti interferon gamma autoantibody assay, liver tests, imaging |
| Situation | Regimen |
|---|---|
| Standard induction in HIV | Amphotericin B deoxycholate 0.7 mg per kg intravenously once daily for 2 weeks (the preferred regimen supported by a randomised trial, with lower mortality than itraconazole alone at 2 weeks and 6 months), then itraconazole 200 mg twice daily for 10 weeks |
| Liposomal amphotericin B | 3 to 5 mg per kg intravenously once daily for 2 weeks (preferred where available), then itraconazole 400 mg per day for 10 weeks |
| Mild disease | Itraconazole 200 mg twice daily for 12 weeks, in patients who are not severely ill, and where amphotericin B is not available |
| Voriconazole | An alternative when amphotericin B is unavailable or not tolerated: 6 mg per kg intravenously every 12 hours on day 1, then 4 mg per kg every 12 hours for at least 1 week, then 200 mg orally every 12 hours for 12 weeks, with level monitoring |
| Secondary prophylaxis | Itraconazole 200 mg once daily after the 12 week course until the CD4 count is above 100 cells per microlitre for at least 6 months with antiretroviral therapy |
| Antiretroviral therapy | Begin within 1 to 2 weeks of antifungal therapy (an early start was safe in a randomised trial), with the immune reconstitution inflammatory syndrome managed by continuing both therapies and adding corticosteroids for severe cases |
| Anti interferon gamma autoantibody disease | Prolonged amphotericin B induction and then itraconazole at 200 mg twice daily for 12 weeks, then long term suppression for 1 to 2 years or more, with immunomodulation (rituximab, cyclophosphamide, or plasma exchange) for refractory cases; relapse is common |
| Other immune defects | Antifungal therapy follows the HIV regimen, with correction of the underlying defect and reduction of immunosuppression |
| Pregnancy | Amphotericin B |
| Monitoring | Clinical response, blood culture clearance, liver tests, itraconazole levels (at least 1 microgram per mL), amphotericin B toxicity, and antigen |
| Primary prophylaxis | Itraconazole 200 mg once daily in HIV with CD4 below 100 cells per microlitre in endemic regions (reduced disease and mortality in a trial from northern Thailand), where antiretroviral therapy is delayed |
Untreated disease is almost always fatal. With induction therapy mortality is 10 to 30 percent (lowest with prompt diagnosis and amphotericin B, higher in those with delayed diagnosis, shock, and respiratory failure), and the commonest cause of death is delayed diagnosis. Relapse occurs in 10 to 20 percent without secondary prophylaxis. In anti interferon gamma autoantibody disease, relapse is frequent and long term suppression is needed.
Antiretroviral therapy and early HIV diagnosis, primary itraconazole prophylaxis in advanced HIV in endemic regions where the CD4 count is below 100, secondary prophylaxis after treatment, and avoidance of soil disturbance and rodent contact (especially during the rainy season) in people with advanced HIV who live in or travel to endemic regions.
