Demographic characteristics and clinical manifestations
The age of disease onset of six children ranged from 8 months to 8 years (4.2 ± 3.8 years). There were five males (83.3%) and one female (16.7%). Respiratory system infection was the first manifestation in all cases; all cases (100%) had cough and hepatosplenomegaly, and most patients (83.3%) had a fever. Out of the six cases, lymph node enlargement was noted in three cases (50%), and two cases (33.3%) had a rash. Rales could be heard in two cases (33.3%), and wheezing and hoarseness were present in one patient (16.6%). Furthermore, hemoptysis and anemia occurred in one case (16.6%), and one case (16.6%) had thrush.
Of all the cases, 66.7% had underlying diseases (three patients had malnutrition, and one had severe combined immune deficiency [SCID]). Specifically, P1 had a history of tuberculosis of the spleen, varicella, and recurrent respiratory infections (RRTIs), and P2 had a previous diagnosis of an axillary abscess, RRTI, and Salmonella typhimurium infection. The most common coinfecting pathogen was Pneumocystis carinii, which occurred in two cases (33.3%), followed by one case (16.6%) of Aspergillus. The duration from symptom onset to diagnosis ranged from 1 to 3 months in all six children.
The diagnosis of TM infection relied on a variety of samples and detection methods, including a sputum smear and culture (16.7%), lung tissue (16.7%) and lymph node tissue (16.7%) biopsy, blood culture (33.3%), BALF culture (16.7%), bone marrow culture (16.7%), and BALF (16.7%) and blood (16.7%) mNGS, individually or in combination (Table 1 and Fig. 1).
Pathogenic variants were detected through whole-exon gene sequencing of the six children. Of these, five children (83.3%, P1–P5) had confirmed PID. P6, with a hemizygote variation at the related site of the CD40LG gene, had uncertain pathogenicity. Additionally, three cases (50%) had STAT1 variations, one case (16.7%) had a large intragenic deletion variation of the CD40LG gene, and one case (16.7%) had a hemizygous variation of IL2RG.
Table 1
Demographic characteristics and clinical data of children with Talaromyces marneffei infection
Patient | Sex | Age (years) | Time from onset to diagnosis | Clinical manifestation | Family history | Base diseases | Medical history | Mutant gene | Concurrent opportunistic pathogens | Pathogenic confirmed specimens |
P1 | Female | 8 | 1 month | Fever, cough, enlarged lymph nodes, enlarged liver and spleen, rash | None | Mild malnutrition | Splenic tuberculosis, varicella, RRTI | STAT1 | None | Lung tissue biopsy culture |
P2 | Male | 1.2 | 3 months | Fever, cough, enlarged liver and spleen | None | Mild malnutrition | Axillary abscess, RRTI, Salmonella typhimurium infection | CD40LG | None | Blood culture |
P3 | Male | 8.7 | 2 months | Fever, cough, hemoptysis, enlarged lymph nodes, enlarged liver and spleen | None | Moderate malnutrition | None | STAT1 | None | Lymph node biopsy tissue culture, BALF mNGS |
P4 | Male | 1.3 | 1 month | Wet cough, wheezing, hoarseness, shortness of breath, wet rales, enlarged liver and spleen | None | None | None | STAT1 | Aspergillus, Pneumocystis jirovecii | BALF mNGS, BALF smear microscopic exam |
P5 | Male | 0.67 | 20 days | Fever, cough, anemia, rash, enlarged liver and spleen, hematuria | Brother died of TM infection | SCID | None | IL2RG | Pneumocystis jirovecii | Blood culture, sputum culture, medullo culture |
P6 | Male | 6 | 20 days | Fever, cough, enlarged cervical lymph nodes, thrush, enlarged liver and spleen, moist rales, hemophagocytic lymphohistiocytosis | None | None | None | Uncertain | None | Blood smear, blood culture, lymph node biopsy, BALF, blood mNGS |
- negative, + positive; SCID: Severe combined immune deficiency; RRTI: Recurrent respiratory tract infection; BALF: Bronchoalveolar lavage fluid; mNGS: Next-generation metagenome sequencing; TM: Talaromyces marneffe |
Laboratory Examination
We detected elevated (1,3)-β-D-glucan (G experimental) in three cases (50%, P1, P2, P3). Additionally, the IgG titer was increased in three cases (50%), while two cases (33%, P2, P5) had decreased IgA, two cases (33%, P2, P5) had decreased IgM, and complement C3 and C4 levels were normal. Six children (100%) had decreased NK cell ratios. P5 was diagnosed with SCID and had significantly decreased total T, CD4 + T, CD8 + T, and NK cells (Table 2).
Table 2
Results of laboratory examinations of children with T. marneffei infection
| P1 | P2 | P3 | P4 | P5 | P6 |
G experimental (0–70.0 pg/ml) | 74.51 | 815.8 | 115.93 | < 37.5 | < 37.5 | Unchecked |
IgA (g/L) | 2.83 (0.51–2.97) | 0.09 (0.19–2.22) | 3.70 (0.51–2.97) | 1.3 (0.41–2.97) | 0.01 (0.19–2.22) | 0.94 (0.41–2.97) |
IgG (g/L) | 34.76 (5.28–21.9) | 21.83 (2.86–16.8) | 24.36 (5.28–21.9) | 14.06 (5.28–21.9) | 2.32 (2.86–16.8) | 7.75 (5.28–21.9) |
IgM (g/L) | 1.22 (0.48–2.26) | 0.38 (0.43~) | 1.09 (0.48–2.26) | 1.64 (0.48–2.26) | 0.02 (0.43 ~ 1.63) | 0.64 (0.48–2.26) |
IgE (IU/L) | 9.57 | 0.1 | 13.8 | 2.12 | Unchecked | Unchecked |
C3 (g/L) | 1.2 (0.7–2.06) | 1.64 (0.7–2.06) | 1.55 (0.7–2.06) | 1.38 (0.7–2.06) | 0.77 (0.7–2.06) | 0.78 (0.7–2.06) |
C4 (g/L) | 0.12 (0.11 ~ 0.61) | 0.26 (0.11 ~ 0.61) | 0.44 (0.11 ~ 0.61) | 0.31 (0.11–0.61) | 0.22 (0.11 ~ 0.61) | 0.15 (0.11–0.61) |
Total T-lymphocytes (%) | 67.25 (56–86) | 80.87 (56–86) | 76.74 (57.1–73.43) | 55.68 (53.88–72.87) | 6.03 (55.32–73.11) | 52.29 (60.05–74.08) |
CD4 + T cells (%) | 42.06 (33–58) | 54.88 (33–58) | 33.77 (33–58) | 49.1 (33–58) | 1.63 (33–58) | 27.32 (33–58) |
CD8 + T cells (%) | 19.28 (13–39) | 23.18 (13–39) | 25.48 (13–39) | 20.97 (13–39) | 4.46 (13–39) | 23.47 (13–39) |
NK cells (%) | 3.52 (5–26) | 1.96 (5–26) | 3.45 (5–26) | 1.3 (5–26) | 1.87 (5–26) | 2.07 (5–26) |
B cells (%) | 27.12 (5–22) | 15.40 (5–22) | 14.06 (5–22) | 25.42 (5–22) | 91.46 (5–22) | 41.85 (5–22) |
ANC: Absolute neutrophil count |
Chest Computed Tomography And Tracheoscopic Manifestations
Computed tomography (CT) scan revealed mediastinal lymphadenectasis (66.6%, P1, P3, P4, P6), nodular shadow (50%, P1, P3, P4), consolidation of the lung (33.3%, P1, P5), interstitial lung disease (16.7%, P2), mediastinal pneumoperitoneum (16.7%, P5), pleural effusion (16.7%, P2), and the pulmonary cavity (16.7%, P1). Furthermore, five cases (83.3%, P1–P4, P6) had a white secretion attached under the tracheoscopy, and two patients (33.3%, P3 and P4) had a bean curd residue-like tracheal secretion (Fig. 2).
Antifungal Therapy And Outcome
Antifungal therapy and outcome
Two cases (P2, P5) did not complete follow-up, and four cases (66.7%, P1, P3, P4, P6) improved. Two patients (33.3%, P1, P2) relapsed after 6 months and 9 months of antifungal treatment, respectively. The average duration of antifungal treatment in the children was 17.7 months (6–51 months). The plasma concentrations of voriconazole or itraconazole were detected to determine the appropriate dosing in all cases. Three children (50%, P1, P5, P6) were treated with amphotericin B, voriconazole, and itraconazole, respectively. P1 received voriconazole (100-175mg twice daily) for 6 months, and her cough recurred after withdrawal after 5 months. CT scan indicated that her pulmonary lesions had worsened, and recurrence was considered. Finally, amphotericin B was administered intravenously for 1 month, and itraconazole (5mg/kg twice a day) was taken orally for 44 months. Of note, this girl had been on antifungal therapy for more than 4 years. P5, in the initial stage of his disease, was administered amphotericin B intravenously and oral voriconazole (50mg twice daily) for 1 week. When his symptoms improved, itraconazole (5-6mg/kg twice a day) was administered orally for 6 months. His parents requested automatic discharge, so he did not complete follow-up. Moreover, P6 received amphotericin B and voriconazole injections for 1 month and 18 days, respectively; after his symptoms improved, itraconazole (3-4mg/kg twice daily) was taken orally for 12 months, and he continues to receive antifungal treatment.
Three children (50%, P2, P3, P4) were treated with voriconazole and itraconazole. P2, who had not clinically improved after receiving voriconazole for 10 days, changed to itraconazole intravenously for 2 weeks, then oral itraconazole (3-4mg/kg twice daily) for 12 months. Additionally, intermittent antifungal therapy was provided for 1 year, during which time there was recurrence. This patient did complete follow-up. For P3, voriconazole was administered intravenously for 10 days. After his symptoms improved, itraconazole(5mg/kg twice a day)was taken orally for 12 months, and antifungal drugs were administered for more than 1 year. For P4, voriconazole was given intravenously for 3 days, change to oral itraconazole was prescribed with the dosage of 5mg/kg three times daily for three days, followed by twice daily, then maintained at 6.5mg/kg twice daily based on the concentration of itraconazole. After 2 weeks, his symptoms improved significantly. Notably, itraconazole had been administered for nearly 1 year (Table 3).
Table 3
Treatment administered to children with Talaromyces marneffei infections
Patient | Antifungal therapy | Treatment of combined infection and underlying diseases | Antifungal course (month) | Outcome |
P1 | voriconazole + amphotericin B + itraconazole | None | 51 | Improved |
P2 | voriconazole + itraconazole | None | 12 | No follow-up |
P3 | voriconazole + itraconazole | None | 12 | Improved |
P4 | voriconazole + itraconazole | Compound sulfamethoxazole | 12 | Improved |
P5 | amphotericin B + voriconazole + itraconazole | Regular intravenous Immunoglobulin, Compound sulfamethoxazole | 6 | No follow-up |
P6 | amphotericin B + voriconazole + itraconazole | Compound sulfamethoxazole, hemophagocytic lymphohistiocytosis treatment | 12 | Improved |