Advertisement

Clinical Characteristics of HIV-Associated Talaromyces marneffei Infection of Intestine in Southern China

  • Author Footnotes
    1 Zhiman Xie and Jingzhen Lai contributed equally to this manuscript.
    Zhiman Xie
    Footnotes
    1 Zhiman Xie and Jingzhen Lai contributed equally to this manuscript.
    Affiliations
    No. 4th People's Hospital of Nanning and the Affiliated Nanning Infectious Diseases Hospital of Guangxi Medical University, Guangxi Medical University, No. 1, Second Lane, Changgang Road, Nanning, Guangxi 530023, China
    Search for articles by this author
  • Author Footnotes
    1 Zhiman Xie and Jingzhen Lai contributed equally to this manuscript.
    Jingzhen Lai
    Footnotes
    1 Zhiman Xie and Jingzhen Lai contributed equally to this manuscript.
    Affiliations
    Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Medical University, No. 22 Shuangyong Road, Nanning, Guangxi 530021, China

    Guangxi Biobank, Life Sciences Institute, Guangxi Medical University, No. 22 Shuangyong Road, Nanning, Guangxi 530021, China
    Search for articles by this author
  • Renping Peng
    Affiliations
    No. 4th People's Hospital of Nanning and the Affiliated Nanning Infectious Diseases Hospital of Guangxi Medical University, Guangxi Medical University, No. 1, Second Lane, Changgang Road, Nanning, Guangxi 530023, China
    Search for articles by this author
  • Minhong Mou
    Affiliations
    No. 4th People's Hospital of Nanning and the Affiliated Nanning Infectious Diseases Hospital of Guangxi Medical University, Guangxi Medical University, No. 1, Second Lane, Changgang Road, Nanning, Guangxi 530023, China
    Search for articles by this author
  • Hao Liang
    Correspondence
    Correspondence author:
    Affiliations
    Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Medical University, No. 22 Shuangyong Road, Nanning, Guangxi 530021, China

    Guangxi Biobank, Life Sciences Institute, Guangxi Medical University, No. 22 Shuangyong Road, Nanning, Guangxi 530021, China
    Search for articles by this author
  • Chuanyi Ning
    Correspondence
    Correspondence author:
    Affiliations
    Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Medical University, No. 22 Shuangyong Road, Nanning, Guangxi 530021, China

    Nursing college, Guangxi Medical University, No. 8 Shuangyong Road, Nanning, Guangxi 530021, China
    Search for articles by this author
  • Author Footnotes
    1 Zhiman Xie and Jingzhen Lai contributed equally to this manuscript.
Open AccessPublished:April 06, 2022DOI:https://doi.org/10.1016/j.ijid.2022.03.057

      Hightlights

      • We first report 31 patients infected with HIV with intestinal TM infection in China.
      • Early antifungal therapy can effectively improve intestinal talaromycosis.
      • Patients with HIV with unexplained intestinal symptoms with CD4<50 need to screen TM.

      ABSTRACT

      Intestinal Talaromyces marneffei (TM) infection among patients with HIV/AIDS is rare. Herein, we report 31 cases of intestinal TM infection in Guangxi. Most patients exhibited fever, lymphadenectasis in the abdominal cavity, and chronic intestinal symptoms. CD4+ T-cell counts <50 cells/μL were reported in 28 patients. TM was cultured from the blood of 23 patients and from the marrow of 7 patients, whereas TM-like fungal spores in the cytoplasm of tissues with erosion, ulceration, and/or polyps were found in all 31 patients. We suggest that intestinal TM infection should be considered among patients infected with HIV with extremely low CD4+ T-cell counts (<50 cells/μL) who are manifesting fever, chronic gastrointestinal symptoms, and endoscopic evidence of erosion and/or ulceration.

      Keywords

      Introduction

      Talaromycosis is an invasive mycosis that is endemic to Southeast Asia and South China and is caused by Talaromyces marneffei (TM). It primarily affects individuals infected with HIV with advanced conditions and individuals with other immunocompromising conditions (
      • Narayanasamy S
      • Dat VQ
      • Thanh NT
      • Ly VT
      • Chan JF
      • Yuen KY
      • et al.
      A global call for talaromycosis to be recognised as a neglected tropical disease.
      ). Despite a mortality rate of up to 50%, which is a higher mortality rate than that of most HIV-related complications (
      • Hu Y
      • Zhang J
      • Li X
      • Yang Y
      • Zhang Y
      • Ma J
      • et al.
      Penicillium marneffei infection: an emerging disease in mainland China.
      ,
      • Jiang J
      • Meng S
      • Huang S
      • Ruan Y
      • Lu X
      • Li JZ
      • et al.
      Effects of Talaromyces marneffei infection on mortality of HIV/AIDS patients in southern China: a retrospective cohort study. Clinical microbiology and infection: the official publication of the European Society of.
      ), TM has received little attention from regional and global researchers. Diagnostic and treatment modalities remain extremely limited. Common manifestations of disseminated TM infection include fever, weight loss, skin lesions, and gastrointestinal abnormalities (
      • Cao C
      • Xi L
      • Chaturvedi V.
      Talaromycosis (Penicilliosis) Due to Talaromyces (Penicillium) marneffei: Insights into the Clinical Trends of a Major Fungal Disease 60 Years After the Discovery of the Pathogen.
      ). Approximately 1.9% of all talaromycosis cases are intestinal infections (
      • Zhou Y
      • Liu Y
      • Wen Y.
      Gastrointestinal manifestations of Talaromyces marneffei infection in an HIV-infected patient rapidly verified by metagenomic next-generation sequencing: a case report.
      ). However, the clinical features of intestinal TM infection have rarely been reported in detail. Here, we report the clinical characteristics of 31 patients infected with HIV with disseminated intestinal TM infection who were diagnosed by identifying TM in intestinal biopsies by microscopy.

      Methods

      A retrospective survey was performed to identify cases of patients with HIV/AIDS with intestinal TM infection in No. 4th People's Hospital of Nanning between 2011 and May 2021. Intestinal talaromycosis was confirmed by identifying TM spores in intestinal biopsies. Clinical characteristics, treatment regimen, and outcomes were reported in the current study. The G test was used to detect the levels of the fungal cell wall component (1,3)-β-D-glucan, which indicates deep mycosis.

      Case series

      Clinical characteristics

      Of the 31 included patients, 77.42% were male, and the median age was 42 years. Most patients presented with abdominal pain (38.71%), fever (38.71%), and diarrhea (25.81%) that prompted their hospital visit (Table 1). On physical examination, intestinal symptoms were present in 29 patients, including abdominal pain in 19 patients, diarrhea in 9 patients, and abdominal distension in 11 patients. Fever was the main extraintestinal symptom. Splenomegaly, hepatomegaly, or hepatosplenomegaly was reported in 16 patients. Enlargement of lymph nodes in the abdominal cavity was found in 15 patients by ultrasonography. Blood tests (Figure 1a–j and Supplementary Table 2) showed that a low CD4+ T-cell count was present in all 31 patients. Anemia and abnormal platelets were detected in 28 and 16 patients, respectively. High aspartate aminotransferase levels were present in 19 patients, and high alanine aminotransferase levels were present in 7 patients. The G test was performed in 28 patients, and positivity was reported in 25 patients. TM was cultured from the blood of 23 patients and from the marrow of 7 patients. Endoscopy revealed that erosion and ulceration were scattered in the large intestines of 27 patients, and polyps were found in 6 patients (Supplementary Table 1). The erosion was elevated or flat, with some visible fusion (Figure 1k–l). The ulceration was peripherally swollen, which indicated proliferative swelling or hyperemia edema (Figure 1m–n). Biopsies of tissues with erosion, ulceration, and/or polyps showed TM-like fungal spores in the cytoplasm of cells in all 31 patients. Most of the spores were small, round, or oval. Sometimes the transverse septum was seen in the spores. D-PAS staining was clearly visible (Figure 1o).
      Table 1Clinical characteristics of HIV/AIDS patients co-infected with intestinal Talaromyces Marneffei
      Sex
       Male (%)24 (77.42)
       Female (%)7 (22.58)
      Age (years) (median, IQR)42 (35, 52)
      Main presenting symptoms
       Abdominal pain (%)12 (38.71)
       Fever (%)12 (38.71)
       Diarrhea (%)8 (25.81)
       Abdominal distension (%)5 (16.13)
       Cough (%)3 (9.68)
      Main clinical manifestation
       Abdominal pain (%)19 (61.29)
       Hepatomegaly and/or splenomegaly (%)16 (51.61)
       Fever (%)16 (51.61)
       Abdominal distension (%)11 (35.48)
       Diarrhea (%)9 (29.03)
       Nausea (%)6 (19.35)
       Emesis (%)3 (9.68)
      Enlargement of lymph nodes in the abdominal cavity (%)15 (48.39)
      Diagnostic methods
       Talaromyces Culture from blood (%)23 (23/30,)
       Talaromyces Culture from marrow (%)7(7/9, 77.78)
       Found Talaromyces spores by biopsies (%)31 (100.00)
       PAS+ (%)23 (23/23, 100.00)
       DPAS+ (%)23 (23/23, 100.00)
      Endoscopy
       Erosion /ulceration (%)27 (27/30, 90.00)
       Polyps (%)9 (9/30, 30.00)
      ART initiated before admission12 (12/29, 41.38)
      ART duration (months) (median, IQR) (n=10)41 (0.875, 63.25)
      Anti-fungal treatment
       Amphotericin B, followed by Itraconazole (%)17 (54.84)
       Itraconazole only (%)11 (35.48)
       Fluconazole, followed by Itraconazole (%)3 (9.68)
      Duration of hospitalization (days) (median, IQR)19 (12, 25)
      Outcome
       Lost to follow up (%)16 (51.61)
       Cured (%)12 (38.71)
       Died (%)3 (9.68)
      Follow up time (months) (median, IQR)41.5 (23.75, 52)
      Figure 1
      Figure 1Results of blood tests, endoscopy, and histopathologic biopsies. a) CD4+T cell count of the patients; b) white blood cell (WBC) count of the patients; c) red blood cell (RBC) count of the patients; d) hemoglobin (HB) level of the patients; e) platelet (PLT) level of the patients; f) total bilirubin (TBil) level of the patients; g) direct bilirubin (DBil) level of the patients; h) aspartate aminotransferase (AST) level of the patients; i) alanine aminotransferase (ALT) level of the patients; j) (1,3)-β-D glucan level of the patients; Red dotted line in b-i) showed the threshold of the normal range of different indicators, while the red background in b-i) showed the normal range of different indicators. k-n) were shot by endoscopy. k) showed erosive erosion; l) showed simple erosions, some were partial fused; m) showed ulceration with obvious proliferative and bulging lesions around; n) showed ulceration with obvious hyperemia and edema of mucosa around; o) pathological section stained with D-PAS (× 400) showed many round or oval spores with transverse septum.

      Outcomes

      Twelve patients received antiretroviral therapy (ART) before admission, and the median ART duration was 41 months. The median duration of hospitalization was 19 days. All patients received antifungal therapy during hospitalization or after hospital discharge, including fluconazole, amphotericin B, and itraconazole (Supplementary Table 1). After their discharge, 12 patients were followed up for a median duration of 41.5 months, whereas 16 of them were lost to follow-up. Most of the patients who were followed up improved or were cured after receiving therapy, except three who died during hospitalization or after against-advice discharge.

      Discussion

      We described a rare TM infection in the intestine of HIV-infected patients. Although gastrointestinal symptoms are common in talaromycosis, TM in the intestine identified via histopathology or cultured from intestinal tissue is rare. To the best of our knowledge, this is the first report of a large number of histopathologically confirmed intestinal TM infection cases among patients with HIV. Patients with HIV with intestinal TM infection exhibited fever, lymphadenectasis in the abdominal cavity, and chronic intestinal symptoms of abdominal pain, diarrhea, and abdominal distension. Fever, diarrhea, and abdominal pain are the top three symptoms of intestinal talaromycosis (
      • Zhao YK
      • Liu JY
      • Liu JH
      • Lu S
      • Wu HH
      • Luo DQ.
      Recurrent Talaromyces marneffei Infection Presenting with Intestinal Obstruction in a Patient with Systemic Lupus Erythematosus.
      ). The patient had no intestinal symptoms that distinguished this condition from other intestinal diseases. Hepatosplenomegaly is a common but nonspecific symptom in talaromycosis, but abdominal lymph node enlargement may be an indirect indication of possible intestinal lesions. Blood tests confirmed poor immunity, common anemia, and abnormally high AST levels in these patients. The extremely low CD4 cell count (<50 cells/mm3) directly indicates that the patients have very poor immunity and are vulnerable to pathogens. The prevalence of anemia in TM-HIV coinfection was 95.6% (
      • Ying RS
      • Le T
      • Cai WP
      • Li YR
      • Luo CB
      • Cao Y
      • et al.
      Clinical epidemiology and outcome of HIV-associated talaromycosis in Guangdong, China, during 2011-2017.
      ), which is close to what we reported. Elevated AST level usually indicates impaired liver function and poor prognosis in TM infection (
      • Wei HY
      • Liang WJ
      • Li B
      • Wei LY
      • Jiang AQ
      • Chen WD
      • et al.
      Clinical characteristics and risk factors of Talaromyces marneffei infection in human immunodeficiency virus-negative patients: A retrospective observational study.
      ,
      • Ying RS
      • Le T
      • Cai WP
      • Li YR
      • Luo CB
      • Cao Y
      • et al.
      Clinical epidemiology and outcome of HIV-associated talaromycosis in Guangdong, China, during 2011-2017.
      ). TM cultures from blood, marrow, or feces are not always positive. However, erosion and ulceration are the most common intestinal lesions. TM can be identified from biopsies of intestinal tissue with erosion and ulceration. Early antifungal therapy with amphotericin B and itraconazole can effectively treat talaromycosis and improve patient survival (
      • Le T
      • Kinh NV
      • Cuc NTK
      • Tung NLN
      • Lam NT
      • Thuy PTT
      • et al.
      A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis.
      ). In conclusion, patients with HIV with unexplained intestinal symptoms with CD4 <50 cells/mm3 should be considered to have intestinal talaromycosis.

      Funding source

      This work was supported by the National Natural Science Foundation of China (grant numbers 81760602 and 81803295), Guangxi Natural Science Foundation (grant number 2018GXNSFAA138031), the Research Basic Ability Enhancement Project of Young and Middle-Aged Teachers in Guangxi Universities in 2021 (grant number 2021KY0081), and Nanning Scientific Research and Technology Development Program (grant number 20193008).

      Ethical approval

      The study was approved by the Ethical Committee of No. 4th People's Hospital of Nanning. Written informed consents were obtained from all included patients.

      Conflict of interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      References

        • Cao C
        • Xi L
        • Chaturvedi V.
        Talaromycosis (Penicilliosis) Due to Talaromyces (Penicillium) marneffei: Insights into the Clinical Trends of a Major Fungal Disease 60 Years After the Discovery of the Pathogen.
        Mycopathologia. 2019; 184: 709-720https://doi.org/10.1007/s11046-019-00410-2
        • Hu Y
        • Zhang J
        • Li X
        • Yang Y
        • Zhang Y
        • Ma J
        • et al.
        Penicillium marneffei infection: an emerging disease in mainland China.
        Mycopathologia. 2013; 175: 57-67https://doi.org/10.1007/s11046-012-9577-0
        • Jiang J
        • Meng S
        • Huang S
        • Ruan Y
        • Lu X
        • Li JZ
        • et al.
        Effects of Talaromyces marneffei infection on mortality of HIV/AIDS patients in southern China: a retrospective cohort study. Clinical microbiology and infection: the official publication of the European Society of.
        Clinical Microbiology and Infectious Diseases. 2019; 25: 233-241https://doi.org/10.1016/j.cmi.2018.04.018
        • Le T
        • Kinh NV
        • Cuc NTK
        • Tung NLN
        • Lam NT
        • Thuy PTT
        • et al.
        A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis.
        The New England journal of medicine. 2017; 376: 2329-2340https://doi.org/10.1056/NEJMoa1613306
        • Narayanasamy S
        • Dat VQ
        • Thanh NT
        • Ly VT
        • Chan JF
        • Yuen KY
        • et al.
        A global call for talaromycosis to be recognised as a neglected tropical disease.
        The Lancet Global health. 2021; 9: e1618-e1e22https://doi.org/10.1016/S2214-109X(21)00350-8
        • Wei HY
        • Liang WJ
        • Li B
        • Wei LY
        • Jiang AQ
        • Chen WD
        • et al.
        Clinical characteristics and risk factors of Talaromyces marneffei infection in human immunodeficiency virus-negative patients: A retrospective observational study.
        World journal of emergency medicine. 2021; 12: 281-286https://doi.org/10.5847/wjem.j.1920-8642.2021.04.005
        • Ying RS
        • Le T
        • Cai WP
        • Li YR
        • Luo CB
        • Cao Y
        • et al.
        Clinical epidemiology and outcome of HIV-associated talaromycosis in Guangdong, China, during 2011-2017.
        HIV medicine. 2020; 21: 729-738https://doi.org/10.1111/hiv.13024
        • Zhao YK
        • Liu JY
        • Liu JH
        • Lu S
        • Wu HH
        • Luo DQ.
        Recurrent Talaromyces marneffei Infection Presenting with Intestinal Obstruction in a Patient with Systemic Lupus Erythematosus.
        Mycopathologia. 2020; 185: 717-726https://doi.org/10.1007/s11046-020-00469-2
        • Zhou Y
        • Liu Y
        • Wen Y.
        Gastrointestinal manifestations of Talaromyces marneffei infection in an HIV-infected patient rapidly verified by metagenomic next-generation sequencing: a case report.
        BMC infectious diseases. 2021; 21: 376https://doi.org/10.1186/s12879-021-06063-1