Coexisting of Primary Central Nervous System Lymphoma and Talaromyces marneffei Brain Abscess in an AIDS Patient, A Case Report and Review of the Literature

Background

Talaromyces marneffei is a dimorphic and opportunistic fungus that can cause multiple organ involvement in humans.¹ The geographical distribution of the diseases is South China and Southeast Asia.² Both residents and travellers are susceptible to Talaromyces marneffei. Furthermore, immunocompromised hosts, such as patients with acquired immunodeficiency syndrome (AIDS), are more prone to develop disseminated Talaromyces marneffei infection.²

The clinical features of disseminated Talaromyces marneffei infection may include fever, lymphadenopathy, hepatomegaly, splenomegaly, respiratory and gastrointestinal abnormalities, and skin lesions.³ The symptoms of Talaromyces marneffei infection are sometimes insidious and atypical, and latent Talaromyces marneffei infections do exist, both of which increase the difficulty of diagnosis. The mortality rate of Talaromyces marneffei infection can be as high as 81% if diagnosis and treatment are delayed.⁴ Talaromyces marneffei infection can present with multiple organ involvement; however, intracranial infection with Talaromyces marneffei has rarely been reported, accounting for 1.9% of all Talaromyces marneffei infections.⁵

The pathophysiology underlying the concurrence of lymphomas and opportunistic infections in HIV patients is thought to be multifactorial. On one hand, the impaired cell-mediated immunity predisposes to the proliferation of oncogenic viruses, such as Epstein-Barr virus (EBV), which is implicated in the pathogenesis of certain types of non-Hodgkin’s lymphoma (NHL). On the other hand, the same defect in immunity provides a fertile ground for opportunistic pathogens to thrive. What`s more, the treatments for lymphoma may exacerbate the risk of opportunistic infections by further suppressing immunity. Antiretroviral therapy plays a pivotal role in restoring immune function, which can mitigate the risk of both lymphoma and opportunistic infections.

Lymphoma can present with fever, enlargement of the lymph nodes and multisystem damage. Hence, clinicians have difficulty distinguishing lymphoma and Talaromyces marneffei infection due to their similar clinical characteristics. The presence of both diseases makes the illness more complex and difficult to diagnose and treat. Here, we report a rare case of a patient with AIDS who developed central nervous system lymphoma and disseminated Talaromyces marneffei infection. In addition, we systematically review the cases of the misdiagnosis of lymphoma and Talaromyces marneffei infection and the cases of brain mass of Talaromyces marneffei to improve clinical knowledge.

Case Presentation

A previously healthy 19-year-old male was admitted to our hospital with the complaint of fever and shaking of hands for a period of approximately 1 month. He was diagnosed with human immunodeficiency virus (HIV) after admission. He had moved to Beijing (north China) 10 years earlier from Yunnan (South China) and had last visited Yunnan 1 year before presentation.

Laboratory examination revealed a white blood cell count of 0.81× 10⁹/L, a haemoglobin content of 71 g/L, and a platelet count of 35× 10⁹/L. CD4+ T-cell counts are 2/µL. Blood culture, bone marrow culture and sputum culture all grew Talaromyces marneffei.Coronal T2-weighted MRI showed a high-signal-density mass in the left parietal lobe (Figure 1A). Chest CT examinations showed a hollow plaque in the lower left lung (Figure 1B). PET/CT scan revealed abnormal uptake in the lesions of the lung (SUVmax = 2.0), bones (SUVmax = 5.1), lymph node (SUVmax = 5.7) and brain (SUVmax = 5.2).

Figure 1 (A) Contrast enhanced Magnetic resonance imaging showed the left parietal lobe mass with ring enhancement; (B) computed tomography scan shows hollow shadows in left lung field.

The patient was started on anti-Talaromyces marneffei therapy with intravenous voriconazole (200 mg) twice a day for 1 month (Neither liposomal amphotericin B nor itraconazole were available in the hospital). One month after treatment, the size of the pulmonary hollow plaques had decreased on CT chest examinations. However, he still presented with recurrent neutropenia, and coronal T2-weighted MRI showed that the brain mass in the left parietal lobe had further enlarged.

Surgical incision of the brain mass showed a compact mass (Figure 2). Subsequently, microscopic morphology of Giemsa stain (Figure 3A) lectophenol cotton blue stain (Figure 3B) and culture in SDA (Figure 3C) of the brain mass showed the presence of Talaromyces marneffei. Furthermore, metagenomic next-generation sequencing (mNGS) of the brain mass was conducted, and Talaromyces marneffei (sequence number: 9) and EBV (sequence number: 6054) were identified. Besides the Talaromyces marneffei infection, histopathologic examination of the brain mass revealed B-cell non-Hodgkin lymphoma!Thus, the patient continued antifungal therapy with voriconazole (200 mg bid po). After the pathology results revealed lymphoma, the patient started chemotherapy with a high-dose methotrexate (5.4 g once ivgtt, 3.5g/m²) regimen. The neurological function of the patient remained stable after surgery. Furthermore, his fever, neutropenia and lymphadenopathy improved after receiving antifungal therapy and chemotherapy.

Figure 2 Excised brain mass during surgery.

Figure 3 (A) microscopic morphology of Talaromyces marneffei in brain mass (Giemsa stain). The white arrow indicates the presence of Talaromyces marneffei; (B)microscopic morphology of Talaromyces marneffei in brain mass culture (lectophenol cotton blue stain); (C) Results of 6 days culture on SDA medium showed the Talaromyces marneffei.

Discussion and Conclusion

We present a case report focusing on the misdiagnosis of Talaromyces marneffei abscess and lymphoma. This case report describes a young male patient with HIV infection presenting with fever and shaking of hands. Blood and sputum cultures revealed infection with Talaromyces marneffei. Following antifungal treatment, the pulmonary lesions improved, but the cerebral lesions worsened. Subsequent surgical resection of the brain lesion confirmed the presence of central nervous system lymphoma with concomitant Talaromyces marneffei infection, which was histopathologically verified. Ultimately, the addition of chemotherapy led to improvement in the cerebral symptoms and lesion.We performed a review of the medical literature relating to Talaromyces marneffei infection and lymphoma. We searched all articles listed in PubMed, Embase and Web of Science (until February 2023, reported in the last 15 years) using the combination of terms “marneffei” and “lymphoma”. A filter for English and Chinese language was then applied. A flow chart for the search strategy is provided in Figure S1. We included 4 published case reports.^6–9 In 2 cases, the coexistence of Talaromyces marneffei and lymphoma was confirmed, while in the other 2 cases, Talaromyces marneffei infection was initially misdiagnosed as lymphoma. No case outside China was found during the literature search. Two patients were diagnosed with disseminated Talaromyces marneffei infection. Three patients received voriconazole and two patients received amphotericin B. The characteristics of the included cases reported are shown in Table 1. We performed a review of the medical literature relating to brain abscesses of Talaromyces marneffei. The article search used the PubMed, Embase and Web of Science databases (until February 2023, reported in the last 15 years) databases. The search terms were “marneffei”. and “brain”, or “central nervous system”, or “intracranial”. A filter for English and Chinese language was then applied. Finally, a flow chart for the search strategy is provided in Figure S2. We found 5 published case reports describing brain abscesses with Talaromyces marneffei in this context.^10–14 No case outside China was found during the literature search. Two of the five patients were diagnosed with HIV infection. Three patients were treated with amphotericin B and itraconazole. Two patients received voriconazole. Table 2 summarizes the demographic and epidemiological characteristics of these 5 patients.

Table 1 Clinical Features of the Reported Misdiagnosis Cases of Talaromyces Marneffei infection and Lymphoma

Table 2 Clinical Features of the Cases of Brain Mass of Talaromyces Marneffei Infection

To our knowledge, this is the first report describing a brain mass combined with Talaromyces marneffei infection and lymphoma. As a travel-associated infection, Talaromyces marneffei infection is increasingly being recognized in nonendemic areas such as Japan, Australia, Belgium, France, Germany, the Netherlands, Oman, Sweden, Switzerland, Canada and the United States, among patients who have traveled to or lived in endemic regions.^15–17 Talaromyces marneffei can affect not only AIDS patients but also transplant recipients,^18–20 immunosuppressed patients, and those with underlying medical conditions, such as lymphoma. Contact with bamboo rats and hunting have been proposed as potential risk factors for Talaromyces marneffei infection, but there is no direct evidence.²¹ It is important to note that Talaromyces marneffei infection can present as a latent infection, and the disease can reactivate at any time in an immunocompromised host.²² Therefore, the clinician must take a detailed epidemiological history to identify any potential exposure to the fungus.

Disseminated Talaromyces marneffei is a potentially lethal condition that primarily affects the peripheral blood, lymph nodes, liver and spleen, bone marrow, lung, digestive tract. According to a study by Qiu et al, 11 out of 14 cases of Talaromyces marneffei infection showed lymphadenopathy, and 10 out of 14 cases presented hepatosplenomegaly.²³ Due to the varying clinical patterns of Talaromyces marneffei infection, the associated symptoms are not typical and can often lead to misdiagnosis.^24,25 In our case and the previously published cases, an increase in 18F-FDG uptake was detected in the affected lymph nodes, particularly when traditional imaging and culturing methods are not providing sufficient diagnostic information. In cases where Talaromyces marneffei lymphadenopathy presents with nonspecific symptoms, and both laboratory testing and imaging, as well as lymph node biopsy, fail to provide any etiological results, a missed epidemiological history may lead to a misdiagnosis of lymphoma. In febrile travelers with an unknown cause, Talaromyces marneffei infection should also be considered as a possible etiology, especially in HIV or immunocompromised patients.

The diffuse involvement of Talaromyces marneffei in the central nervous system (CNS) is a rare occurrence, and in HIV patients infected with Talaromyces marneffei in the CNS, the mortality is 81%.^26,27 A study in Guangxi province, South China, involving HIV/AIDS patients, found that 10 out of 159 patients had meningitis due to Talaromyces marneffei infection, and 9 out of 10 patients had intracranial lesions.²⁸ Another study reported that 4/10 patients had intracranial infection after discovering Talaromyces marneffei in the cerebrospinal fluid.²⁹ In recent years, there have also been sporadic reports of Talaromyces marneffei causing intracranial occupation. The common clinical manifestations of CNS fungal infections include chronic meningitis, meningoencephalitis, abscesses, and fungal ventriculitis.³⁰ In our case and the previously published cases included in the systematic review, patients showed neuroimaging findings in single or multiple sites, and 3 out of 6 cases demonstrated abnormal ring enhancement in contrast-enhanced brain MRI. The primary symptoms exhibited by these patients were fever and changes in mental status. Therefore, in patients presenting with symptoms of fever and neuropathy, who have either lived in or traveled to endemic regions, Talaromyces marneffei infection should be considered as a differential diagnosis.

In a study conducted in Guangdong Province (South China), approximately 9.36% of HIV-infected patients were found to develop disseminated Talaromyces marneffei infection.³¹ Out of these patients, 4/12 died during treatment, while 4/12 relapsed after treatment.²³ In other studies, the mortality rate for disseminated Talaromyces marneffei infection was found to be 20%. This indicates that disseminated Talaromyces marneffei has a high mortality and is prone to recurrence. Therefore, early identification and treatment of this infection are of crucial importance. The effective antifungal drugs for treating disseminated Talaromyces marneffei infection are amphotericin B and voriconazole.³² In addition, oral itraconazole is recommended for patients with CD4<100 and an epidemiological history to prevent Talaromyces marneffei infection. Because amphotericin B and itraconazole were not readily available at our hospital, the voriconazole regimen was adopted.

In our case, the mNGS analysis of the resected brain tissue revealed a significant increase in EBV, while the EBV DNA in the cerebrospinal fluid tested negative. Previous studies have established a strong link between EBV and the development of lymphoma.³³ The incidence of EBV infection is higher among patients with HIV-related diffuse large B-cell lymphoma as compared to the general population.^34,35 In this case, it is speculated that the intracranial lymphoma is primary central nervous system lymphoma (PCNSL), while the systemic lymphadenopathy could be due to Talaromyces marneffei infection, rather than lymphoma. PCNSL is a common type of lymphoma in in individuals infected with HIV,³⁶ and approximately 80% of HIV-associated PCNSLs are linked to EBV infection.³⁷ The current recommended therapy for HIV-associated EBV PCNSL is the high-dose methotrexate regimen, and thus, this therapy was employed in our case.^38,39 In addition, The mNGS technique played an important role in confirming the link of EBV and PCNSL, and mNGS technique in differential diagnosis are essential. In our case, the tissue mNGS of Talaromyces Marneffei could be affected by blood-borne infection, however culture of the brain tissue also grew Talaromyces Marneffei, which confirmed Talaromyces Marneffei brain abscess.

In clinical practice, dualism is often observed in AIDS, such as coinfection of different pathogens or combined infection with tumors. Previous reports have shown AIDS patients with Talaromyces marneffei combined with tuberculosis, or nontuberculous mycobacteria. In one study conducted in China, tumours complicated with Talaromyces marneffei infection accounted for 16/212 cases in HIV-infected patients.²⁸ Due to the dualism frequently observed in AIDS, the diagnosis of etiology can be challenging. Histopathology is crucial for identifying Talaromyces marneffei when traditional culture has not yielded any results. However, it is noteworthy that histopathological examination has only been conducted in 32.34% of confirmed Talaromyces marneffei cases.²⁴ Recent studies show that the use of mNGS has contributed to an increase in the diagnosis of Talaromyces marneffei cases.^40–42 However, some lymphomas can be challenging to detect accurately, and there may have been potential for misdiagnoses and missed suspicious cases, particularly among patients infected with HIV.

PCNSL is a rare form of non-Hodgkin lymphoma confined to the brain, spinal cord, leptomeninges, or eyes, without evidence of systemic disease. In HIV-negative patients, PCNSL usually presents as a solitary lesion, predominantly affecting the immunocompetent elderly population, although cases have been reported across a wide age range.⁴³ The pathogenesis of PCNSL in immunocompetent individuals is not fully understood, but it is thought to involve genetic mutations and aberrant responses to viral infections, such as EBV, albeit less commonly than in immunocompromised individuals.⁴⁴ Talaromyces marneffei is a well-recognized opportunistic infection in HIV-positive individuals, and is also an important emerging pathogen in HIV-negative patients who are immunocompromised due to other causes, such as autoimmune diseases, cancer, or immunosuppressive therapy.⁴⁵ The incidence of Talaromyces marneffei infection among HIV-negative individuals has been increasing, likely due to greater clinical awareness and improved diagnostic capabilities.

In conclusion, we have presented an exceptionally rare case of PCNSL complicated by a Talaromyces marneffei brain abscess in an HIV-infected patient. If someone has a history of travelling to endemic areas, Talaromyces marneffei infection must be considered as a differential diagnosis in cases of fever, lymphadenopathy, and multisite lesions. Physicians should consider endemic infections, including Talaromyces marneffei, when examining patients with lymphadenopathy who have a medical history of travelling to endemic regions. However, physicians should also be alert to the possibility of lymphoma, especially if the effects of anti-infection therapy are ineffective in AIDS patients with lymphadenopathy. Indeed, at times, both conditions can exist simultaneously in the same patient.