Peripheral immune profile of children with Talaromyces marneffei infections: a retrospective analysis of 21 cases

Abstract

Background Talaromyces marneffei (T. marneffei) is an opportunistic pathogen that infects immunodeficient children. The aim of the study is to determine the clinical features and peripheral immune state of Talaromyces marneffei (T. marneffei) infections in children for early detection and diagnosis. Methods We retrospectively reviewed 21 pediatric patients who were diagnosed with T. marneffei infections and were followed up in the Guangzhou Women and Children’s Medical Center from January 2010 to January 2020. For each patient, we collected and analyzed clinical characteristics, peripheral immunological results, genetic tests, complications and prognosis. Results Common clinical features of the patients included fever (20/21, 95.24%), cough (17/21, 80.95%) and hepatomegaly (17/21, 80.95%). Severe complications included septic shock (12/21, 57.14%), hemophagocytic lymphohistiocytosis (HLH) (11/21, 52.38%), acute respiratory distress syndrome (ARDS) (10/21, 47.62%), multiple organ dysfunction syndrome (MODS) (9/21, 42.86%), and disseminated intravascular coagulation (DIC) (7/21, 33.33%). Eleven children (11/21, 52.38%) eventually died of T. marneffei infections. All patients were HIV negative. Seven cases revealed reduced antibody levels, especially IgG. Higher levels of IgE were detected in 9 cases with an obvious increase in two patients. Ten patients showed decreased complement C3 levels, some of whom had low C4 levels. Three patients displayed decreased absolute T lymphocyte counts, including the CD 4+ and CD 8+ subsets. A reduction in NK cells was present in most patients. No patient had positive nitro blue tetrazolium (NBT) test results. Nine patients were screened for common genetic mutations. Of the cases, one case had no disease-specific gene mutation. Four children had confirmed hyperimmunoglobulin M syndrome (HIGM) with CD40LG variation, one case had severe combined immunodeficiency (SCID), and one case had hyper-IgE syndrome (HIES). One patient was identified as having a heterozygous mutation in STAT3 gene; however, he showed no typical clinical manifestations of HIES at his age. One patient had a mutated COPA gene with uncertain pathogenic potential. Another patient was diagnosed with HIES that depended on her clinical features and the National Institutes of Health (NIH) scoring system. Conclusions T. marneffei infections in HIV-negative children induced severe systemic complications and poor prognosis. Children with T. marneffei infections commonly exhibited abnormal immunoglobulin levels in peripheral blood, particularly decreased IgG or increased IgE levels, further suggesting possible underlying PIDs in these patients.

Diagnosis by metagenomic next-generation sequencing of a Talaromyces marneffei bloodstream infection in an HIV-negative child: A case report

“…The exact basis for patient susceptible to TM due to immunodeficiency caused by the CD40LG mutation is unknown. In our case, the IgG levels of the child decreased, which was consistent with changes in immunoglobulins common to children infected with TM ( 25 ). In addition, we also found a lower percentage of NK cells in the patient, which may be due to increased activation-induced cell death and decreased production of NK cells through defective CD40L-CD40 interaction ( 24 ).…”

Talaromyces marneffei Infections in 8 Chinese Children with Inborn Errors of Immunity

“…The reported TM-infected children with CARD9 , IFNGR1 , or RELB mutations, also exhibited decreased NK cells [ 32 , 39 – 41 ]. Zeng et al [ 21 ] reported reduced NK cells in 62% of the TM-infected patients. In Guo’s study, 81.8% of the children with TM-infections exhibited decreased NK cells [ 48 ].…”

“…In our study, 5 patients died during the follow-ups (62.5%). Zeng et al [ 21 ] reported 11 in 21 children (52.38%) died of TM infections. In Guo’s study, they enrolled 11 TM-infected HIV-negative children and four of them (36.36%) died during 1-year follow-ups [ 48 ].…”

“…Actually, some HIV-negative adults with TM infections were detected with anti-IFN- γ autoantibodies, belonging to a kind of adult-onset IEIs [ 19 , 20 ]. Most recently-reported children patients are also HIV-negative, and more infected children were revealed to have IEIs, such as hyperimmunoglobulin M syndrome (HIGM) [ 21 ], hyper-IgE syndrome (HIES) [ 22 , 23 ], and STAT1 gain-of-function (GOF) disorder [ 24 ]. However, the reported spectrum of IEIs with TM infections is very limited.…”

Characteristics of Talaromyces marneffei infection associated with inborn errors of immunity

“…Compared to HIV-positive patients, IEI patients require a longer duration of antifungal therapy. Some patients died of serious complications such as MODS, ARDS, HLH, septic shock, and DIC [25,26]. The treatment regimen recommended by international guidelines for management HIV patients with T. marneffei is Amphotericin B in the induction period for 2 weeks, followed by oral itraconazole for 10 weeks [1,13,27].…”