Disseminated Talaromyces marneffei Infection With STAT3-Hyper-IgE Syndrome: A Case Series and Literature Review

Abstract

Background: Little is known about the clinical characteristics of talaromycosis with hyper-immunoglobulin E syndrome (HIES).

Methods: We conducted a multicenter retrospective study, which included 7 hospitals from 2016 to 2022. Five consecutive cases of human immunodeficiency virus (HIV)-negative patients with systemic Talaromyces marneffei infections due to STAT3-HIES were identified. A systematic literature review of original articles published in English identified an additional 7 cases. Clinical characteristics and laboratory parameters were collected.

Results: Forty-two percent (5/12) of patients were young adults. The main symptoms of 10 patients were similar: fever (75%), cough (75%) and dyspnea (33%), but two patients mainly had gastrointestinal symptoms. Most patients had a history of infections since infancy. T marneffei was cultured from the bronchoalveolar lavage fluid (50%) and 25% of patients were next-generation sequencing positive. Eight patients had significantly elevated serum immunoglobulin E, increased B cells and decreased natural killer cells. There were ten different STAT3 mutations, three of which were reported for the first time in this study. Chest computed tomography examinations showed multiple exudations with cavities in the lungs. Voriconazole combined with thymosin was effective. Despite given antifungal agents, most had poor outcomes and the case fatality rate was as high as 25%.

Conclusions: STAT3-HIES is most likely a susceptibility factor for T marneffei infections among HIV-negative patients, which has a high case fatality rate. Increased awareness among clinicians is necessary to help in early diagnosis.

Keywords: STAT3 mutation; Talaromyces marneffei; hyper-IgE syndrome; immunodeficiency.

Figure 1.

Chest computed tomography (CT) and etiological diagnosis of Talaromyces marneffei. A, Pathology of the lymph node (A1). A large number of epithelioid granulomas can be seen in the lymph nodes, including many multicellular giant cells and some caseous necrosis (hematoxylin and eosin staining, ×200 magnification). Periodic acid-Schiff staining (×600 magnification) revealed multiple fungal yeast cells in the cytoplasm of multicellular giant cells, as indicated by the arrows. A2 describes the isolation of T marneffei from bronchoalveolar lavage fluid (BALF) at 35°C (①), 25°C (②). The specific morphological features of T marneffei were detected by an oil immersion lens (③). A typical symmetrical bipolar broom-like branch can be seen under high magnification. B, CT scan showing multiple cystic thick-walled cavities in both lungs. The fluid plane of the cavity is visible, and the lungs had scattered patches of tree bud–like blurred shadows (case 2).

Figure 2.

Pathogenetic diagnosis of hyper–immunoglobulin E syndrome. A, STAT3 gene mutation (V637 M) in case 2 and the family members. B, STAT3 gene mutation (c.1673G > A, p. G558D) in case 5 and the family members. C, STAT3 gene mutation (A595G) in case 1 and the family members. D, STAT3 gene mutation (c.1138_1139 + 1del p.?) in case 3 and the family members.

Figure 3.

Mutations in STAT3. The mutations in STAT3, as visualized by Oviz-Bio (https://academic.oup.com/nar/article/48/W1/W415/5835823) and showing the single-nucleotide variants (SNVs) and InDels with positions and functional annotations on 3 layers: genome (DNA), cDNA, and protein. The top panel specifies the positions and content changes of the variants, with shapes and colors indicating the different types of variants. The bottom panel gives the protein domains annotated by the following databases: SuperFamily (https://supfam.mrc-lmb.cam.ac.uk/SUPERFAMILY/publications.html), Gene3D (https://pubmed.ncbi.nlm.nih.gov/22139938/), CDD (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943070/), and Pfam (https://academic.oup.com/nar/article/49/D1/D412/5943818).