Application of Flow Cytometry in the Diagnostics Pipeline of Primary Immunodeficiencies Underlying Disseminated Talaromyces marneffei Infection in HIV-Negative Children

Abstract

Talaromyces (Penicillium) marneffei is an AIDS-defining infection in Southeast Asia and is associated with high mortality. It is rare in non-immunosuppressed individuals, especially children. Little is known about host immune response and genetic susceptibility to this endemic fungus. Genetic defects in the interferon-gamma (IFN-γ)/STAT1 signaling pathway, CD40/CD40 ligand- and IL12/IL12-receptor-mediated crosstalk between phagocytes and T-cells, and STAT3-mediated Th17 differentiation have been reported in HIV-negative children with talaromycosis and other endemic mycoses such as histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis. There is a need to design a diagnostic algorithm to evaluate such patients. In this article, we review a cohort of pediatric patients with disseminated talaromycosis referred to the Asian Primary Immunodeficiency Network for genetic diagnosis of PID. Using these illustrative cases, we propose a diagnostics pipeline that begins with immunoglobulin pattern (IgG, IgA, IgM, and IgE) and enumeration of lymphocyte subpopulations (T-, B-, and NK-cells). The former could provide clues for hyper-IgM syndrome and hyper-IgE syndrome. Flow cytometric evaluation of CD40L expression should be performed for patients suspected to have X-linked hyper-IgM syndrome. Defects in interferon-mediated JAK-STAT signaling are evaluated by STAT1 phosphorylation studies by flow cytometry. STAT1 hyperphosphorylation in response to IFN-α or IFN-γ and delayed dephosphorylation is diagnostic for gain-of-function STAT1 disorder, while absent STAT1 phosphorylation in response to IFN-γ but normal response to IFN-α is suggestive of IFN-γ receptor deficiency. This simple and rapid diagnostic algorithm will be useful in guiding genetic studies for patients with disseminated talaromycosis requiring immunological investigations.

Clinical epidemiology and outcome of HIV‐associated talaromycosis in Guangdong, China, during 2011–2017

“…In highly endemic regions in northern Thailand, Vietnam and southern China (Guangdong, Guangxi and Hong Kong) [2][3][4][5][6], the prevalence of talaromycosis as an HIVassociated opportunistic infection (OI) is only lower than that of tuberculosis and cryptococcosis [2,3]. The incidence of talaromycosis is also increasing in the HIV-negative population due to the expanding use of immunosuppressive drugs and chemotherapy and the rising number of solid and bone marrow transplantations [7][8][9]. Evidence suggests that the endemic areas of talaromycosis are increasing due to improved mass transportation and global warming [10][11][12].…”

Unusual disseminated Talaromyces marneffei infection mimicking lymphoma in a non-immunosuppressed patient in East China: a case report and review of the literature

“…Infection has been widely suggested to be an indicator disease for differential diagnosis in HIV-infected patients [ 4 , 5 , 7 ]. In recent years, it has been reported that an increasing number and proportion of cases in non-HIV-infected patients who had some form of immunodeficiency (hypogammaglobulinemia, CD4 lymphopenia) or underlying diseases with immunocompromised condition, including hematologic malignancies or autoimmune diseases, were receiving treatments that could impair their cellular immunity, such as antineoplastic or corticosteroid agents [ 8 , 9 ]. However, some researchers have recommended that T. marneffei infection also occur in persons with normal immunity [ 4 , 8 , 10 – 12 ].…”

Calcineurin A Is Essential in the Regulation of Asexual Development, Stress Responses and Pathogenesis in Talaromyces marneffei

“…T. marneffei can cause a life-threatening systemic infection in immunocompromised individuals, especially HIV-positive patients (Woo et al, 2012). In recent years, T. marneffei has become a leading AIDS-defining diagnosis in Southern Asia, trailing only tuberculosis and cryptococcosis in incidence (Wu et al, 2008;Le et al, 2011;Hien et al, 2016;Lee et al, 2019). Furthermore, T. marneffei infection has recently been increasingly observed in HIV-negative adults with no reported immunosuppressive condition, but immunodeficiency is suspected to be the cause of these infections (Ramos-e-Silva et al, 2012;Kauffman et al, 2014).…”