An 8-month-old Chinese boy was referred to this tertiary hospital on 29 December, 2021 for fever and cough, 6-days in duration. On admission vital signs were body temperature 37.3 C, blood pressure 82/54 mmHg, pulse 132 beats per minute, respiratory rate 32 breaths per minute, and poor spirit. The superficial lymph nodes were palpable in the neck and behind the ear, a few moist rales were heard over both lungs. The child's abdomen was soft, liver and spleen were not palpable, and the neurological examination was normal. With only a fever, the child was sent to a local hospital for blood tests. Results of those test were white blood cell (WBC) 24.62*10 9/L, neutrophil percentage (N%) 44.1%, and C-reactive protein (CRP) 32.4 mg/L. Antibacterial treatment for 5-days produced no improvement and the child was referred again to our hospital. The parents indicated that the patient had normal psychomotor development and physical growth, but had recurrent episodes of respiratory infections from delivery until now.
Upon admission, routine blood test results were WBC 21.5*10 9/L, N% 40.6%,CRP 47.98 mg/L, procalcitonin (PCT) 0.28 ng/ml, (1, 3)-beta-D-glucan test (G test), purified protein derivative (PPD) test, and T-spot test for tuberculosis were negative. Serological tests for HIV, cytomegalovirus (CMV), herpes virus, and rubella virus were negative. A chest computed tomography (CT) scan showed lung inflammation and a small amount of liquid in the right pleural cavity, foliar consolidation in the upper left lung, and multiple calcified nodules in bilateral axillary fossa, with multiple enlarged lymph nodes in the bilateral supraclavicular fossa. Echocardiographic showed no dilation of the coronary arteries. Brain magnetic resonance imaging (MRI) and abdominal ultrasound results were normal. Lymphocyte counts, as measured by flow cytometry, were CD3+ cells (total T lymphocytes) 58.57% (peripheral blood reference range 49.1-83.6%); CD19+ cells (total B lymphocytes) 35.4% (higher than normal 6.5-27.0%); CD3+CD4+ T helper cells (Th) 50.06% (28.2-62.8%); CD3+CD8+ T cells (Ts) 6.8% (10.2-40.1%); Th/Ts 7.36% (0.7-2.8%); and NK (natural killer) cells 4.23% (7-40%). The IgG, IgA, and IgM concentrations were; 0.49 g/L (reference 2.32-14.11 g/L), 0.07 g/L (reference 0.0-0.83 g/L), and 0.94 g/L (reference 0.0-1.45 g/L), respectively. The patient received antibacterial (cefoperazone sulbactam, imipenem cilastatin) treatment and supportive care, including human gamma globulin. The child's condition did not improve. Temperature exceeded 39 C, with WBC 16.5*10 9/L, N% 52.0%, and CRP 62.38 mg/L.
After 8-days of administration and a poor response to antibiotic therapy, blood was collected for mNGS (Figure 1). Fourteen hours later TM was identified by mNGS. Microbiological blood culture confirmed TM infection on the 9th day of hospitalization, and with the quick mNGS results (Figure 2), intravenous amphotericin B (0.1-0.5 mg/kg/day, with gradual increase every 2 days) and oral itraconazole (4 mg/kg/dose bid) were administered. The patient's condition improved dramatically. On the 13th day of hospitalization, the patient's fever was <38 C. He was discharged from the hospital on December 30, 2022 when his body temperature had remained normal for 1 week. This was the 30th day of hospitalization.
The patient was young and HIV- negative. However, his lymphocyte counts and immunoglobulin levels were abnormal and therefore congenital immunodeficiency was not excluded. Blood exon sequencing was performed to identify possible CD40LG gene variations. Analysis demonstrated the proband to be a hemizygous intron variant (c.346+1G>T) of the CD40LG gene (NM_000074), which was inherited from his mother, who was heterozygous. The father had the wild-type sequence (Figure 3). The patient was diagnosed with TM-BSI and a CD40LG mutation.
For follow up, the patient has returned to the hospital for outpatient examination. His general condition remains normal without any apparent abnormalities. Oral itraconazole treatment has continued.