Invasive Talaromyces marneffei Fungemia in an HIV-Negative Patient with T-Prolymphocytic Leukaemia: A Case Report and Review of Emerging Risks

Background

Talaromyces marneffei (T. marneffei, formerly known as Penicillium marneffei) is a thermally dimorphic fungus that can cause a severe opportunistic infection known as talaromycosis (TSM), a disseminated systemic mycosis.¹ The first case of natural human infection was reported in 1973.² This fungus is primarily endemic to the tropical regions of Southeast and South Asia, including eastern India, Thailand, Vietnam, Laos, Myanmar, and the southern provinces of China, such as Guangdong, Guangxi, Yunnan, and Fujian. With the yearly increase in population mobility, cases have also been reported in other provinces.^1,3–8 While talaromycosis is classically an AIDS-defining infection in human immunodeficiency virus (HIV) patients with advanced immunosuppression, it is increasingly recognized in HIV-negative individuals with other immune deficits.^9–12 Immunosuppressive chemotherapy, targeted agents such as Janus kinase (JAK) inhibitors, and prolonged neutropenia represent key risk factors.^12,13 Among the general population with acute leukemia, the incidence of invasive fungal infections (IFIs) can reach 10–25% in acute myeloid leukemia (AML) and approximately 6.5% in acute lymphoblastic leukemia (ALL).¹⁴ However, these fungal infections are predominantly caused by Candida albicans, Aspergillus species, and others, with T. marneffei accounting for only a very small proportion.^14–17

Nevertheless, sporadic cases in hematologic malignancy patients have been documented since the early 2000s. These include patients with non-Hodgkin lymphomas (NHL), plasma cell neoplasms (PCN), myeloid malignancies, and rare hematologic disorders.¹⁸ Overall, the incidence remains low relative to more common invasive fungi – but it appears to be rising with the advent of newer immunosuppressive cancer therapies.¹²

T. marneffei primarily invades the reticuloendothelial system (RES) of human monocytes and macrophages, and is characterized by either localized or disseminated infections.¹⁹ Localized infections are relatively rare and typically involve a single organ, such as the lungs, leading to localized symptoms. Disseminated infections, on the other hand, may affect multiple systems and organs throughout the body, presenting with symptoms such as fever, anemia, weight loss, fatigue, hepatosplenomegaly, lymphadenopathy, cough, and gastrointestinal discomfort. In some cases, involvement of the central nervous system (CNS) may also occur.^3,12,20,21 Disseminated talaromycosis may be complicated by secondary bacterial infections, often resulting in delayed diagnosis and increased mortality.²²

We report a case of T. marneffei fungemia combined with cytomegalovirus infection in an HIV-negative patient diagnosed with T-prolymphocytic leukaemia (T-PLL). Additionally, we provide a literature review summarizing T. marneffei infections in patients with hematologic malignancies, aiming to raise awareness of this rare infection in non-HIV-infected individuals with blood disorders.

Case Presentation

A 55-year-old female patient presented with a 7-month history of T-prolymphocytic leukaemia, diagnosed through histopathological examination of bone marrow and cervical lymph node, with molecular confirmation via next-generation sequencing, was admitted to our hospital due to thrombocytopenia with nasal bleeding for one day. Although alemtuzumab (anti-CD52 monoclonal antibody) is considered the first-line therapy for T-PLL in international guidelines, it is not currently approved for clinical use in our country. Therefore, a pragmatic, individualized approach was adopted. The patient initially received two cycles of chemotherapy at a referring hospital: First Cycle: CHOP regimen: Cyclophosphamide 1.2 g, Epirubicin 100 mg, Vincristine 2 mg, Intraperitoneal injection of methotrexate, cytarabine, and dexamethasone; Second Cycle: Chidamide 20 mg twice a week, Cyclophosphamide 0.5 g on days 1–2, Vincristine 1 mg, Liposomal Doxorubicin 10 mg on day 1, 20 mg on day 2, along with prednisone 30 mg/d from days 1–5. Following disease progression and hematologic intolerance, she was switched to low-dose chemotherapy with gemcitabine (0.4 g) and targeted therapy with chidamide (10 mg qd) and golidocitinib (150 mg qd).

The patient developed Grade IV thrombocytopenia (platelet count: 16 × 10⁹/L; reference range: 125–350 × 10⁹/L), accompanied by left nasal bleeding, scattered ecchymoses on the skin, and dense petechiae on both lower limbs. Grade IV neutropenia (neutrophil count: 0.40 × 10⁹/L; reference range: 1.8–6.3 × 10⁹/L) and fever (up to 39°C) were noted. Retrospective review of the medical records showed that T-cell counts/subpopulations and serum immunoglobulin levels were not assessed at the time of admission, limiting further characterization of the patient’s cellular and humoral immune status. Blood cultures and infectious markers were obtained, and empirical therapy was initiated, including antipyretics (compound paracetamol), imipenem-cilastatin for antibacterial coverage, fluconazole for antifungal prophylaxis, transfusion of single-donor platelets, granulocyte colony-stimulating factor, intravenous immunoglobulin (IVIG), and temporary suspension of anti-tumor therapy.

Physical examination showed abdominal distension; there was suspected rebound tenderness at McBurney’s point in the right lower quadrant, tympanic sounds on percussion, and suspected positive shifting dullness. Notable bilateral lower limb edema was observed. The patient experienced a persistent fever for three days. Laboratory tests revealed significantly elevated inflammatory markers: C-reactive protein (CRP) at 6.17 mg/L (reference range: 0–5 mg/L), procalcitonin (PCT) at 0.066 ng/mL (reference range: <0.046 ng/mL), and interleukin-6 (IL-6) at 113.00 pg/mL (reference range: <7 pg/mL). One week prior to the fever, a comprehensive metagenomic sequencing test was conducted, detecting cytomegalovirus (CMV: 3664 reads), human herpesvirus type 6B (HHV-6B: 439 reads), and Epstein-Barr virus (EBV: 276 reads). CMV DNA quantification by PCR revealed an initial viral load of 4.43 × 10⁴ copies/mL (reference range: < 4.00 × 10² copies/mL). Oral valacyclovir was initiated as an antiviral treatment. However, a follow-up test after one week showed a significant increase in CMV DNA levels to 2.42 × 10⁵ copies/mL, suggesting treatment failure or resistance. CMV reactivation was considered a potential contributing factor to the patient’s immunosuppression and vulnerability to invasive fungal infection.

Microbiological Identification

Blood cultures from central and peripheral venous access became positive under aerobic conditions after 86.7 and 88 hours, respectively. Gram staining and Fungal fluorescence staining showed septate hyphae with an antler-shaped morphology resembling molds (Figure 1A and B). Upon reviewing the patient’s peripheral blood smear stained with Wright’s stain, an elongated oval or sausage-shaped yeast-like fungal organism was observed, characterized by a transparent septum between the cells (Figure 1C). After dual-phase cultivation on Sabouraud dextrose agar (SDA) medium, the culture showed rapid growth at 25°C within four days, forming filamentous, yellow, velvety colonies that produced a characteristic diffusible red pigment (Figure 2A). At 37°C, colonies were yeast-like after four days, slow-growing and non-pigmented (Figure 2B). Lactophenol cotton blue staining revealed typical penicillate conidiophores with a rosette or broom-like arrangement and smooth, oval-shaped conidia under culture conditions of 25°C (Figure 2C), while at 37°C, microscopy showed round to oval yeast-like cells and elongated cells with septa and blunt ends (Figure 2D). Based on morphological characteristics observed through microscopic examination and culture, the isolate was highly suspected to be T. marneffei. The fungal isolate was sent to Shanghai Bioengineering Co., Ltd. for ITS sequencing and species identification to further confirm the diagnosis. The isolate was definitively identified as T. marneffei. The ITS region of the fungal isolate was amplified and sequenced using the primers ITS1 and ITS4, and the obtained sequence has been deposited in GenBank under the accession number PX498444.

Figure 1 Morphology of fungal elements in blood culture smears observed under light and fluorescence microscopy using Gram and fungal fluorescent staining showed septate hyphae with an antler-shaped morphology. (A) Gram-stained smears under light microscopy, ×1000. (B) Fluorescent-stained smears under fluorescence microscopy, ×1000. (C) Wright’s stained peripheral blood smear revealed an elongated oval or sausage-shaped yeast-like fungal organism, with a transparent septum separating the cells (×1000). The red circle highlights Talaromyces marneffei yeast cells.

Figure 2 Colony and Microscopic Morphology of Talaromyces marneffei on Sabouraud Dextrose Agar under Different Incubation Conditions. (A) Blood culture of T. marneffei in the mold phase at 25°C for 4 days, showing characteristic red pigment production. (B) Blood culture of T. marneffei in the yeast phase at 37°C for 4 days. (C) Lactophenol cotton blue staining revealed typical penicillate conidiophores with a broom-like arrangement and smooth, oval-shaped conidia incubated at 25°C for 4 days (×1000). (D) Round to oval yeast-like cells and elongated cells with septa and blunt ends observed at 37°C for 4 days (×1000).

Antifungal Treatment

The treatment of talaromycosis in HIV-negative patients generally follows the same principles as in HIV/AIDS populations, involving an initial intensive phase with amphotericin B, followed by a prolonged consolidation phase with an azole antifungal such as itraconazole or voriconazole.²³ Given the diagnosis of T. marneffei fungemia, and considering its nature as a deep-seated invasive fungal infection commonly occurring in severely immunocompromised individuals with notable mortality risk, amphotericin B is considered the first-line treatment. However, in our case, liposomal amphotericin B was not available at our hospital at the time of diagnosis. Moreover, given the patient’s profound immunosuppression, hematologic fragility, and the potential toxicity profile of amphotericin B, an alternative approach was deemed necessary. After thorough multidisciplinary discussion and shared decision-making with the patient’s family, voriconazole was selected as the initial antifungal agent. The patient received intravenous voriconazole (0.2 g q12h) for 2 weeks during hospitalization, followed by oral administration for an additional 2 weeks after discharge. The patient’s body temperature remained consistently normal following two week of antifungal treatment (Figure 3), and repeat blood cultures returned negative. At the time of discharge, the patient was diagnosed with stage IVB T-PLL, involving multiple lymph nodes, liver, spleen, and bone marrow, with associated malignant ascites. Following two cycles of low-dose chemotherapy (gemcitabine) combined with targeted therapy (chidamide) and corticosteroids, partial clinical and biochemical improvement was observed, including reduced transaminase levels, LDH, and improvement in abdominal distension. However, laboratory indicators such as thrombocytopenia and hepatosplenomegaly on imaging remained, suggesting persistent disease activity. The patient was discharged in a clinically stabilized but non-remission state, with arrangements for continued outpatient follow-up and supportive care.

Figure 3 Hospitalization treatment timeline and changes in body temperature.

Discussion

Invasive T. marneffei infection has traditionally been regarded as an AIDS-related opportunistic disease. However, as this and other recent cases highlight, the infection increasingly affects HIV-negative patients with hematological malignancies.^12,13,24 Profound immune suppression, especially cell-mediated immunity deficits, and the use of targeted therapies are critical contributors to this shift in epidemiology. Notably, Chan et al reported four cases in two years in Hong Kong among patients receiving targeted therapies for hematologic malignancies.²⁵ This suggests an emerging epidemiologic pattern: patients on anti-CD20 monoclonal antibodies or kinase inhibitors in endemic regions may be at heightened risk.

We report a case of a patient with T-prolymphocytic leukaemia who developed T. marneffei bloodstream infection after receiving two cycles of treatment, followed by targeted therapy with chidamide, golidocitinib, and treatment with methylprednisolone.

Given the increasing use of such therapies, clinicians in or near endemic areas should be aware of talaromycosis as an opportunistic infection in hematology patients.

Summary of Reported Cases

To further analyze the characteristics of T. marneffei infection in patients with hematologic malignancies undergoing immunosuppressive therapy, we have summarized the relevant literature identified through a PubMed search using the keywords “Talaromycosis”, “Penicillium”, “marneffei”, and “penicilliosis”. Each case includes patient demographics, underlying malignancy with therapies, presenting infection sites, antifungal treatments, and outcomes (Table 1).

Table 1 Key Features of Reported Talaromyces marneffei Infections in Patients with Hematological Malignancies

In the context of hematologic malignancies, T. marneffei behaves not as a localized fungal infection but as a true systemic mycosis. Dissemination via the bloodstream is frequent, with potential involvement of the bone marrow, lungs, gastrointestinal tract, and skin. This systemic nature makes talaromycosis a diagnostic challenge and a clinical emergency. In our case and others reviewed, fungemia was not only a marker of severity but also a key diagnostic clue. Prompt recognition of this systemic pattern is critical to improve outcomes.

Comparison with Published Cases in Hematologic Malignancies

Our patient, an HIV-negative woman with T-PLL, represents one of the few reported cases of T. marneffei fungemia in this rare subtype of leukemia. Previous literature¹² includes reports of disseminated T. marneffei infections in patients with chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia, myelofibrosis, and acute myeloid leukemia. Common features across these cases include: 1) Prolonged neutropenia or lymphopenia, often due to chemotherapy or targeted agents (eg, rituximab, fludarabine, JAK inhibitors). 2) Geographic exposure to endemic regions in Southeast Asia or southern China. 3) Delayed diagnosis, frequently due to overlapping clinical presentations with malignancy progression or other opportunistic infections.

A key similarity between our case and those reported by Chan et al 12 is the occurrence of infection during or shortly after administration of novel immunosuppressive agents, particularly kinase inhibitors like ruxolitinib or golidocitinib. These therapies impair macrophage and T-cell-mediated responses, which are crucial for host defense against T. marneffei. Specifically, chidamide, a histone deacetylase inhibitor (HDACi), suppresses Th1 and Th17 differentiation and impairs macrophage function. Similarly, golidocitinib (a JAK1/2 inhibitor) interferes with cytokine signaling pathways, such as IFN-γ and IL-17, that are critical for the immune response against fungal infections. In our case, the use of chidamide and golidocitinib likely synergistically contributed to profound immunosuppression and increased susceptibility to T. marneffei fungemia.

Table 1 shows that disseminated fungemia was associated with a higher risk of mortality, especially when antifungal therapy was delayed or inadequate. Notably, a CLL patient developed T. marneffei fungemia and marrow infiltration but eventually died from other opportunistic infections despite initial antifungal response.²⁵ Conversely, early antifungal treatment, as seen in the marginal zone lymphoma case,¹³ was associated with complete remission and no recurrence at 3-year follow-up.

Diagnostic Challenges and Mycological Clues

Clinically, talaromycosis in this population may masquerade as progressive hematologic malignancy, tuberculosis, or bacterial sepsis. Fever, lymphadenopathy, pulmonary infiltrates, and cytopenias are common but nonspecific. Our patient’s rapidly worsening cytopenias and fever were initially attributed to chemotherapy-related toxicity and viral reactivations (CMV, EBV, HHV-6B), delaying suspicion for fungal infection.

The gold standard is fungal culture or histopathology from clinical specimens. Blood cultures are often positive in disseminated talaromycosis. In the reviewed cases, T. marneffei was isolated from blood in at least five patients (including those with fungemia and marrow involvement). Microbiological diagnosis is also essential. In our case, fungal culture yielded characteristic morphology: a red pigment-producing mold phase at 25°C and a yeast-like form at 37°C. This dual-phase morphology is a hallmark of T. marneffei, as noted in nearly all reviewed cases.

In summary, a multimodal approach is recommended when talaromycosis is in the differential. Clinicians should obtain biopsies of accessible lesions (such as lymph nodes, skin, etc.) for histopathology and culture, perform blood cultures, and consider a bone marrow biopsy if no other site is yielding a diagnosis.

Therapeutic Considerations

Amphotericin B (AmB) remains the recommended induction therapy, followed by itraconazole for consolidation.²³ However, it is worth noting that a recent randomized trial in HIV patients compared high-dose itraconazole as primary therapy to AmB, finding that itraconazole was not inferior for mild-to-moderate cases, while AmB was superior for severe disease.²⁹ In malignancy patients, most experts still advocate using AmB for induction, given the high mortality if treatment fails. That said, in cases where AmB is contraindicated (eg, renal failure or infusion reactions), an azole (voriconazole or high-dose itraconazole) can be used as an alternative initial. In several reviewed cases¹³—including ours—voriconazole monotherapy was successfully used, particularly when AmB was unavailable or contraindicated. Our patient’s clinical stability and rapid defervescence support this alternative, especially in resource-limited settings.

In disseminated T. marneffei infection, prolonged antifungal therapy is crucial, particularly for immunocompromised patients. Current guidelines recommend a minimum of 12 weeks of treatment for severe cases, especially in those with hematologic malignancies. Treatment duration may vary depending on clinical response, relapse risk, and patient factors. Our literature review (Table 1) shows antifungal durations ranging from 2 weeks to over 21 months. Delayed diagnosis and poor initial response can lead to worse outcomes, as seen in cases like Waldenström’s macroglobulinemia.²² Early initiation of appropriate therapy, as in the marginal zone lymphoma case, was associated with complete remission and no recurrence at 3-year follow-up.¹³

Managing talaromycosis does not preclude treating the cancer–delaying chemotherapy could allow the infection to worsen, while delaying antifungals could allow the fungus to proliferate. In practice, physicians have carefully employed combined therapy or staged therapy. In the NSMM myeloma case, antifungal treatment was initiated first (to address the acute infection), and once the patient stabilized and fungal burden decreased, definitive chemotherapy for myeloma was administered, leading to long-term remission.⁹ The timing requires judgment – often, antifungal induction is given for a few weeks. Cancer therapy can resume once clear improvement is seen (with careful monitoring and secondary prophylaxis to prevent fungal relapse). This coordinated approach maximizes patient outcomes.

Conclusion

This case expands the spectrum of hematologic malignancies associated with T. marneffei and confirms its capacity to cause infections in non-HIV patients receiving targeted therapies. Literature review highlights emerging patterns in risk factors (notably kinase inhibitors), the nonspecific clinical presentation, and the critical role of early mycological diagnosis. Voriconazole appears to be an effective treatment option when amphotericin B is unavailable. Greater awareness among hematologists and infectious disease specialists is necessary to enhance recognition and improve outcomes.