Rapid diagnosis of Talaromyces marneffei infection by metagenomic next-generation sequencing technology in a Chinese cohort of inborn errors of immunity

Abstract

Talaromyces marneffei (T. marneffei) is an opportunistic pathogen. Patients with inborn errors of immunity (IEI) have been increasingly diagnosed with T. marneffei in recent years. The disseminated infection of T. marneffei can be life-threatening without timely and effective antifungal therapy. Rapid and accurate pathogenic microbiological diagnosis is particularly critical for these patients. A total of 505 patients with IEI were admitted to our hospital between January 2019 and June 2022, among whom T. marneffei was detected in 6 patients by metagenomic next-generation sequencing (mNGS), and their clinical and immunological characteristics were summarized. We performed a systematic literature review on T. marneffei infections with published immunodeficiency-related gene mutations. All patients in our cohort were confirmed to have genetic mutations in IL12RB1, IFNGR1, STAT1, STAT3, and CD40LG. T. marneffei was detected in both the blood and lymph nodes of P1 with IL12RB1 mutations, and the clinical manifestations were serious and included recurrent fever, weight loss, severe anemia, splenomegaly and lymphadenopathy, all requiring long-term antifungal therapy. These six patients received antifungal treatment, which relieved symptoms and improved imaging findings. Five patients survived, while one patient died of sepsis after hematopoietic stem cell transplantation. The application of mNGS methods for pathogen detection in IEI patients and comparison with traditional diagnosis methods were investigated. Traditional diagnostic methods and mNGS tests were performed simultaneously in 232 patients with IEI. Compared to the traditional methods, the sensitivity and specificity of mNGS in diagnosing T. marneffei infection were 100% and 98.7%, respectively. The reporting time for T. marneffei detection was approximately 26 hours by mNGS, 3-14 days by culture, and 6-11 days by histopathology. T. marneffei infection was first reported in IEI patients with IL12RB1 gene mutation, which expanded the IEI lineage susceptible to T. marneffei. For IEI patients with T. marneffei infection, we highlight the application of mNGS in pathogenic detection. mNGS is recommended as a front-line diagnostic test for rapidly identifying pathogens in complex and severe infections.

Characteristics of Talaromyces marneffei infection associated with inborn errors of immunity

“…We report an international retrospective study of talaromycosis in IEI patients, reporting the genetic, immunological, and clinical characteristics of disease. The diseases of talaromycosis with IEI are common in severe combined immunode ciency (IL-2R, ADA) and combined immunode ciency (RELB, CD40L, STAT3), antibody de ciencies (CVID caused by NFKB2 de ciency), intrinsic and innate immunity defects (IL12RB1 de ciency, IFNGR1 de ciency, CARD9, and STAT1-GOF), and autoin ammatory disorders (COPA gene defect), in which XHIM, STAT1-GOF, and HIEs (STAT3-LOF) are the most susceptible diseases for development of IEI-associated talaromycosis [4,11,12].…”

“…Infections commonly occur in Indonesia and southern China, especially Guangdong, Guangxi, Hong Kong, and Taiwan [1]. T. marneffei causes aggressive infections in immunocompromised patients, especially in patients with HIV diagnosis, anti-IFN-γ autoantibody positivity (AIGA), autoimmune disease, glucocorticoid administration and/or immunosuppression therapy, malignancies, and IEI [3,4]. Diagnosis of talaromycosis is often delayed, or talaromycosis is misdiagnosed as tuberculosis [5].…”

“…At the same time, macrophages harboring T. marneffei can promote T cell activation to achieve successful clearance of T. marneffei. In recent years, cases of IEI with talaromycosis have increased [4,7]. Due to the low incidences of each gene defect, few data are available to describe the clinical spectrum of IEI with talaromycosis.…”

Case report: Acute Talaromyces marneffei mediastinitis in an HIV-negative patient

“…Recent studies have shown that some infected individuals thought to be non-immunosuppressed carry neutralizing anti-IFN-γ autoantibodies and associated HLA alleles (Guo et al, 2020). Additionally some HIV-negative patients have been shown to carry immune-related genetic mutations such as CD40L, STAT1, STAT3 and CARD9 (You et al, 2021;Liu et al, 2022). For this reason, in spite of the fact that there was no evidence suggesting this patient suffered from immune diseases, her immunocompetency remains undetermined.…”

“…T. marneffei infections in humans are overwhelming in immunocompromised individuals, however a number of cases in apparent immunocompetent individuals have been described (Duong, 1996;Qiu et al, 2015;Pruksaphon et al, 2022). Increasingly these HIV-negative patients are found to have a variety of other immunocompromising conditions (You et al, 2021;Liu et al, 2022). Clinically, talaromycosis is usually referred to as an easily misdiagnosed, intractable and high-mortality disease, for its uncertain pathogenesis, non-specific symptoms, various imaging manifestations and complicated treatment with serious side effects.…”