Talaromyces marneffei: Infectious substances pathogen safety data sheet
Section I – Infectious agent
Name
Talaromyces marneffei
Agent type
Fungus
Taxonomy
Family
Trichocomaceae
Genus
Talaromyces
Species
Talaromyces marneffei
Synonym or cross-reference
Formerly Penicillium marneffeiFootnote 1. T. marneffei causes a disease known as talaromycosis, penicilliosis, or penicilliosis marneffeiFootnote 2Footnote 3.
Characteristics
Brief description
T. marneffei has a DNA genome that is approximately 28.5 Mb in length, and is organized into multiple chromosomesFootnote 4Footnote 5. It's mitochondrial genome is 35kbFootnote 6. T. marneffei is thermally dimorphic; it grows as a multicellular mould at 25°C and unicellular yeast like from at 37°CFootnote 3Footnote 7. Optimal temperature for mould growth ranged from 17 to 28°C. The temperature capable of supporting yeast transition begins at 32°C, while morphogenesis optimally occurs at 37°C. A temperature of 40°C and higher inhibits fungal growth. Fungal growth can happen in a broad pH range from 4.0-10.0Footnote 8Footnote 9. The mycelial form appears as short, septate, branching hyphae that bear conidia, and sausage-shaped cellsFootnote 6Footnote 10. Conidia swell and elongate to form hyphae by apical extensionFootnote 6Footnote 10. The mould form usually produces a soluble red pigment when cultured on Sabouraud agarFootnote 10. Intracellular T. marneffei yeast are oval or spherical shaped and measure 2-3 μm in diameterFootnote 6; extracellular yeast cells are elongated, measuring up to 13 μm in length, and have a central dividing septumFootnote 6.
Properties
Following host entry, usually via inhalation, T. marneffei conidia are engulfed by host macrophagesFootnote 3. T. marneffei undergo a morphogenic transformation to a yeast-like form and replicate within host cells by fissionFootnote 6. T. marneffei produce virulence factors such as melanin and Mp1p to dampen host innate immune responseFootnote 11Footnote 12. CD4 T cells play an important role in host resistance to T. marneffei infectionFootnote 13. T. marneffei is the only thermally dimorphic species known to be pathogenic to mammalsFootnote 8Footnote 14. Glyceraldehyde-3-phosphate dehydrogenase is an important adhesion factor for conidial attachment in T. marneffeiFootnote 15. Additionally, it has been found recently that T. marneffei escapes macrophage killing through TUT 1-mediated alternative splicing of NCOR2/SMRTFootnote 16.
Section II – Hazard identification
Pathogenicity and toxicity
In healthy hosts, T. marneffei infection us usually localized to lungs and spleenFootnote 10Footnote 11, and the host immune response is often sufficient to clear T. marneffei infection within 2-3 weeksFootnote 6Footnote 13. T. marneffei can cause local or disseminated infections in humansFootnote 12. Local infection cases typically exhibit localized symptoms and signs, and rarely involve systemic symptomsFootnote 17. Localized infections are uncommon, but cases have been reported, tonsils being an exampleFootnote 18Footnote 19. Symptoms of disseminated infections in HIV-negative children include cough, hepatosplenomegaly, lymph node enlargement, rash, rales, wheezing, hoarseness, hemoptysis, anemia, and thrushFootnote 14.
In immunocompromised hosts, T. marneffei causes disseminated mycosis, primarily affecting the respiratory tract, reticuloendothelial system, and skinFootnote 3Footnote 6. T. marneffei disseminates to other parts of the body via the circulatory and lymphatic systems, where it causes infection in the liver, spleen, kidney, bones, joints, and pericardium. Approximately 60-70% of patients develop papular skin lesions, the face and neck being the most common sites (100%), as well as chest (39%), arms (52%), and legs (30%)Footnote 3Footnote 6Footnote 15. The papular lesions usually have necrotic centersFootnote 6. T. marneffei has been associated with arthritis, osteomyelitis, and, in rare cases, pneumoniaFootnote 3Footnote 6Footnote 16Footnote 20.
In T. marneffei-infected HIV patients, higher mortality rates are associated with delayed diagnosis and treatmentFootnote 20Footnote 21. As talaromycosis is usually fatal if untreatedFootnote 22Footnote 23. In treated patients, the talaromycosis mortality rates is estimated to be 6-33%Footnote 24Footnote 25Footnote 26. A study reported relapse in 15% of HIV patients that clinically and microbiologically responded to amphotericin B treatmentFootnote 27; most relapses occurred within 6 months after completing treatmentFootnote 27Footnote 28, and in rare cases several years laterFootnote 29.
Epidemiology
Endemic in Southeast Asia, southern China, and parts of IndiaFootnote 3. T. marneffei causes disease primarily in immunocompromised individuals. In the 1980s and 1990s, talaromycosis was considered to be an AIDS-indicating opportunistic infection, where the increase in prevalence of T. marneffei infection in endemic regions correlated with an increase in HIV infectionFootnote 20Footnote 23Footnote 25Footnote 27. During this time, a large portion of reported talaromycosis cases occurred in individuals with HIV infectionsFootnote 20. By 2022, over 288,000 talaromycosis cases have been reported in 34 countries, which account for a prevalence of 3.6% along people living in with HIVFootnote 30Footnote 31Footnote 32Footnote 33. Approximately, 16% of individuals with HIV who live in T. marneffei-endemic area are co-infected with T. marneffeiFootnote 34. The number of T. marneffei cases has rapidly increased and ranked 3rd as the most common HIV-associated opportunistic infections, accounting for up to 16% of HIV hospital admissions, and the leading cause of death among patients with advanced HIV in Thailand, Vietnam and Southern ChinaFootnote 35Footnote 36Footnote 37Footnote 38.
Recently, the widespread use of antiretroviral therapies in T. marneffei endemic regions led to a to a decrease in the proportion of T. marneffei cases affecting individuals with HIVFootnote 39, and an increasing number of T. marneffei cases in individuals with other immunosuppressive conditionsFootnote 26. Talaromycosis mortality rates are higher in HIV-negative patients compared to HIV- positive patients due to physical awareness and timely diagnosis for the latterFootnote 40Footnote 41.
T. marneffei is rare in immunocompromised individuals, with only 4-well documented cases among non-HIV, non-endemic populationsFootnote 42. One reported case discusses a 75-year-old Navy veteran, who served in Vietnam. He was treated with several medications, started to progress, soon after stopping the medication, the patients symptoms recurred and ultimately the patient expiredFootnote 42.
In some endemic regions, higher incidence of T. marneffei infection is reported during the rainy seasonFootnote 43. Incidence of T. marneffei infection in Thailand is estimated to be 0.3 cases per 100,000 people per yearFootnote 44. Talaromycosis has a high mortality rate, killing up to one in three diagnosed individualsFootnote 45Footnote 46. Sporadic travel-related cases of T. marneffei have occurred in individuals who reside in non-endemic regionsFootnote 25.
Immunocompromised individuals have greater susceptibility for T. marneffei infectionFootnote 3. This includes individuals with HIV infection, especially those with low CD4 T-cell counts;Footnote 20Footnote 47Footnote 48 Sweet's syndromeFootnote 41; primary immune deficiency disorders (e.g., severe combined immunodeficiency)Footnote 49; organ transplant recipientsFootnote 50Footnote 51; adults with autoantibodies to interferon-gammaFootnote 41Footnote 51; and individuals taking immunosuppressive drugsFootnote 52.
T. marneffei- associated mycosis has been reported in dogsFootnote 53. Clinical signs in dogs include skin dermatitis, rhinitis, and inflammation of the ear canalFootnote 54; the lungs are rarely involvedFootnote 55. T. marneffei DNA has been found in the nasal cavities of 13% of healthy dogsFootnote 56.
Host range
Natural host(s)
Humans, bamboo ratsFootnote 3, Egyptian mongooseFootnote 55, and dogsFootnote 51.
Other host(s)
Caenorhabditis elegansFootnote 57, rabbitsFootnote 58, and moths (Galleria mellonella) have been experimentally infectedFootnote 59. An immunocompromised macaque was inadvertently infected in a laboratory settingFootnote 60.
Infectious dose
Unknown.
Incubation period
One to three weeks in acute diseaseFootnote 25Footnote 31; reactivation can occur years after exposureFootnote 25Footnote 29.
Communicability
T. marneffei appears to be transmitted to humans via inhalation of airborne conidiaFootnote 3Footnote 20Footnote 25, and through spores from soil. It then spreads to the reticuloendothelial system, skin, and other organ systems through the hematogenous routeFootnote 61. One case of human-to-human transmission via organ transplantation has been describedFootnote 62.
Section III – Dissemination
Reservoir
Bamboo rats (Rhizomys siensis, R. sumatranesis, Cannomys badius)Footnote 3Footnote 6. T. marneffei is shed in rat fecesFootnote 63.
Zoonosis
No direct evidence of rat-to human transmission, although samples of blood, skin, pus from subcutaneous abscesses, lymph node biopsies and bronchoalveolar lavage pellet samples isolated from human and bamboo rats have had similar or identical genotypeFootnote 64.
Vectors
None.
Section IV – Stability and viability
Drug susceptibility/resistance
T. marneffei is susceptible to azoles (e.g., itraconazole, ketoconazole, miconazole, isavuconazole, posaconazole, voriconazoleFootnote 27Footnote 65; 5-fluorocytosineFootnote 27, and amphotericin BFootnote 6.
Some T. marneffei stains were found to be resistant to fluconazoleFootnote 6Footnote 60Footnote 66. The yeast form is resistant to anidulafunginFootnote 67.
Susceptibility to disinfectants
Other fungi in the Trichocomaceae family are susceptible to sodium hypochlorite (1%), phenolics, formaldehyde, and glutaraldehydeFootnote 68.
Physical inactivation
Other fungi in the Trichomaceae family are inactivated by moist heat treatment at 121°C for 30 minutesFootnote 69.
Survival outside host
T. marneffei can survive for more than 2 weeks in sterile soilFootnote 70. Other conidia-producing fungi in the Trichomaceae family can survive for more than 30 days on fabrics and plasticsFootnote 71.
Section V – First aid/medical
Surveillance
Diagnosis is accomplished through the monitoring of clinical symptoms. While T. marneffei can be identified in clinical specimens using culture-based methods, this approach can take days to weeksFootnote 6. Presumptive diagnosis can be made based on microscopic examination of intracellular T. marneffei yeast in stained tissue or bone marrow samplesFootnote 25. Enzyme-linked immunosorbent assays (ELISA) for T. marneffei antigen detection in urine or blood samples have been developedFootnote 72Footnote 73. T. marneffei antigen has also been detected in clinical specimens using polymerase chain reaction (PCR)Footnote 74Footnote 75, and MALDI-TOFFootnote 73. Very recently a diagnosis of T. marneffei was established by blood metagenomic next-generation sequencing (mNGS) using blood of an HIV-negative patient with a CD40LG mutationFootnote 76.
Note: The specific recommendations for surveillance in the laboratory should come from the medical surveillance program, which is based on a local risk assessment of the pathogens and activities being undertaken, as well as an overarching risk assessment of the biosafety program as a whole. More information on medical surveillance is available in the Canadian Biosafety Handbook.
First aid/treatment
A common treatment regime includes amphotericin B deoxycholate (0.7-1mh/kg) daily for 2 weeks, followed by itraconazole (400mg/day) for 10 weeksFootnote 2Footnote 44.
Note: The specific recommendations for first aid/treatment in the laboratory should come from the post-exposure response plan, which is developed as part of the medical surveillance program. More information on the post-exposure response plan can be found in the Canadian Biosafety Handbook.
Immunization
No human vaccine is currently availableFootnote 77. It was demonstrated that production of murine specific IgM and IgG antibody responses to a highly immunogenic secreted cell wall mannoprotein, Mp1p, using both recombinant protein and DNA immunization strategiesFootnote 8Footnote 77. Hexane extract (AMA50CH), from a marine-derived actinomycete, was capable of neutralizing T. marneffei in vitro and purified proteins from two medicinal plants (Andrographis paniculata and Rhinacanthus nasutus) have been shown to have the capacity to kill T. marneffei in vitroFootnote 78Footnote 79Footnote 80. Additionally, it was demonstrated that galactose exerts growth-inhibitory effects on clinical T. marneffei isolatesFootnote 80Footnote 81. This is significant as T. marneffei in the presence of galactose, may lead to the creation of avirulent strains of T. marneffei, which may be important for the development of vaccines against T. marneffeiFootnote 80.
Note: More information on the medical surveillance program can be found in the Canadian Biosafety Handbook, and by consulting the Canadian Immunization Guide.
Prophylaxis
Prophylaxis treatment with itraconazole for HIV patients with prior T. marneffei infection can be undertaken to prevent relapses of T. marneffei infectionFootnote 44Footnote 82.
Note: More information on prophylaxis as part of the medical surveillance program can be found in the Canadian Biosafety Handbook.
Section VI – Laboratory hazard
Laboratory-acquired infections
An HIV-infected man became ill after visiting a laboratory that contained T. marneffei specimens; inhalation was the presumed exposure routeFootnote 83. A researcher conducting T. marneffei experiments in rodents developed T. marneffei infection after an accidental autoinoculationFootnote 84.
Note: Please consult the Canadian Biosafety Standard and Canadian Biosafety Handbook for additional details on requirements for reporting exposure incidents.
Sources/specimens
Bone marrow aspirate, blood, urine, stool, sputum, cerebrospinal fluid, lymph node biopsy specimen, skin scrapings or biopsy specimen, other tissue biopsy specimens (e.g., kidney, lung, spleen, liver, intestine)Footnote 10.
Primary hazards
Exposure to T. marneffei via inhalation of airborne infectious material, or autoinoculation with infectious material.
Special hazards
None.
Section VII – Exposure controls/personal protection
Risk group classification
T. marneffei is considered to be a Risk Group 2 Human pathogen and a Risk Group 1 Animal pathogenFootnote 85Footnote 86.
Containment requirements
Containment Level 2 facilities, equipment, and operational practices outlined in the Canadian Biosafety Standard for work involving infectious or potentially infectious materials, animals, or cultures.
Protective clothing
The applicable Containment Level 2 requirements for personal protective equipment and clothing outlined in the Canadian Biosafety Standard are to be followed. The personal protective equipment could include the use of a labcoat and dedicated footwear (e.g., boots, shoes) or additional protective footwear (e.g., boot or shoe covers) where floors may be contaminated (e.g., animal cubicles, post mortem rooms), gloves when direct skin contact with infected materials or animals is unavoidable, and eye protection where there is a known or potential risk of exposure to splashes.
Note: A local risk assessment will identify the appropriate hand, foot, head, body, eye/face, and respiratory protection, and the personal protective equipment requirements for the containment zone and work activities must be documented.
Other precautions
A biological safety cabinet (BSC) or other primary containment devices to be used for activities with open vessels, based on the risks associated with the inherent characteristics of the regulated material, the potential to produce infectious aerosols or aerosolized toxins, the handling of high concentrations of regulated materials, or the handling of large volumes of regulated materials.
Use of needles and syringes are to be strictly limited. Bending, shearing, re-capping, or removing needles from syringes are to be avoided, and if necessary, performed only as specified in standard operating procedures (SOPs). Additional precautions are required with work involving animals or large-scale activities.
For diagnostic laboratories handling primary specimens that may contain T. marneffei the following resources may be consulted:
Section VIII – Handling and storage
Spills
Allow aerosols to settle. Wearing personal protective equipment, gently cover the spill with absorbent paper towel and apply suitable disinfectant, starting at the perimeter and working towards the centre. Allow sufficient contact time with disinfectant before clean up (Canadian Biosafety Handbook).
Disposal
All materials/substances that have come in contact with the regulated materials to be completely decontaminated before they are removed from the containment zone or standard operating procedures (SOPs) to be in place to safely and securely move or transport waste out of the containment zone to a designated decontamination area / third party. This can be achieved by using decontamination technologies and processes that have been demonstrated to be effective against the regulated material, such as chemical disinfectants, autoclaving, irradiation, incineration, an effluent treatment system, or gaseous decontamination (Canadian Biosafety Handbook).
Storage
The applicable Containment Level 2 requirements for storage outlined in the Canadian Biosafety Standard are to be followed. Primary containers of regulated materials removed from the containment zone to be labelled, leakproof, impact resistant, and kept either in locked storage equipment or within an area with limited access.
Section IX – Regulatory and other information
Canadian regulatory information
Controlled activities with Talaromyces marneffei require a Pathogen and Toxin licence issued by the Public Health Agency of Canada.
The following is a non-exhaustive list of applicable designations, regulations, or legislations:
- Human Pathogens and Toxins Act and Human Pathogens and Toxins Regulations
- Transportation of Dangerous Goods Act and Transportation of Dangerous Goods Regulations
Last file update
May, 2024
Prepared by
Centre for Biosecurity, Public Health Agency of Canada.
Disclaimer
The scientific information, opinions, and recommendations contained in this Pathogen Safety Data Sheet have been developed based on or compiled from trusted sources available at the time of publication. Newly discovered hazards are frequent and this information may not be completely up to date. The Government of Canada accepts no responsibility for the accuracy, sufficiency, or reliability or for any loss or injury resulting from the use of the information.
Persons in Canada are responsible for complying with the relevant laws, including regulations, guidelines and standards applicable to the import, transport, and use of pathogens in Canada set by relevant regulatory authorities, including the Public Health Agency of Canada, Health Canada, Canadian Food Inspection Agency, Environment and Climate Change Canada, and Transport Canada. The risk classification and related regulatory requirements referenced in this Pathogen Safety Data Sheet, such as those found in the Canadian Biosafety Standard, may be incomplete and are specific to the Canadian context. Other jurisdictions will have their own requirements.
Copyright © Public Health Agency of Canada, 2024, Canada
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