On November 12th, 2020, a 2-year-old boy with one-month chronic cough was admitted to Tianjin Children’s Hospital. His cough was mild with less sputum. No obvious wheezing, dyspnea or fever was observed. Oral antitussive medicine was taken at home but did not work. Afterwards, the patient was sent to local hospital to take a two-day intravenous administration of cefotaxime sodium. Peripheral blood test revealed a clear increase of white blood cell count (WBC23.9 × 10
9/L) with eosinophilia (58.91%, AEC14.1 × 10
9/L) and neutropenia (3.32%, absolute neutrophil count 0.8 × 10
9/L). The patient was admitted for further diagnosis and treatment by Department of Immunology. The parents claimed that the boy had BCG lymphadenitis (self-healing) previously and has been suffering from upper respiratory infections four to five times a year when peripheral blood tests indicated a decrease in granulocytes. His family history included a deceased elder brother who had BCG lymphadenitis (incision and drainage) and died of cyanosis at the age of 11 months. His test results revealed that C-reactive protein (CRP), hemoglobin and platelet approached the normal limits, while neutrophil (7%, normal range 45–77%, ANC 1.27 × 10
9/L) decreased and eosinophil (46%, normal range 0.5-5%, AEC 10.58 × 10
9/L) elevated notably. Biochemical indicators were basically normal with a slight increase in lactate dehydrogenase (LDH) 490U/L (normal range 120–300). IgA (0.05 g/L, normal range 0.2-1.0 g/L), IgG (0.07 g/L, normal range 4.53–9.16 g/L) and IgE (< 0.1 IU/ml, normal range 0-100 IU/ml) all decreased whereas IgM was in normal range (0.7 g/L, normal range 0.19–1.46 g/L). Lung computed tomography (CT) scan showed multiple diffuse ground-glass opacities and patchy consolidation in both lungs (Fig.
1a). The admission diagnosis was severe pneumonia with neutropenia and eosinophilia, and PID was suspected. The initial anti-infective therapy included cefoperazone-sulbactam, trimethoprim-sulfamethoxazole (SMZCo) and voriconazole. The patient also received a 2 g/Kg intravenous immunoglobulin (IVIG) replacement, an anti-inflammatory of 2 mg/kg/d prednisone and oxygen inhalation with respiratory management. Lymphocyte subsets showed CD19
+ 44.1% (normal range 17–41%), CD3
+ 52.5% (normal range 39–73%), CD3
+CD8
+ 21.28% (normal range 11–32%), CD3
+CD4
+ 30.3% (normal range 25–50%) and CD16
+CD56
+ 2.03% (normal range 3–16%). Blood pathogen tests on EBV-DNA, CMVPP65, (1,3)-β-d-glucan test, glactomannan (GM), tuberculosis, cryptococcus capsular antigen, antibody test for parasites including schistosoma, paragonimus, cysticercus, trichinella spiralis, liver fluke, sparganum and hydatid were all negative. Peripheral blood was tested again after three days, showing a normal level of WBC (5.78 × 10
9/L) and eosinophils (0.2%, AEC 0.01 × 10
9/L). Cefoperazone sulbactam was discontinued and the dosage of prednisone was reduced quickly. No significant improvement was observed on lung CT after five days in hospital (Fig.
1b). The fiberoptic bronchoscopy was performed. Cytology results of the BALF were neutrophil 8%, eosinophil 5%, lymphocyte 6%, macrophage 78% and epithelium 3%. mNGS of the BALF showed Pneumocystis jirovecii (PJ) infection. Voriconazole was discontinued, caspofungin was used together with SMZCo to treat PJP. When prednisone was reduced to 15 mg/d, the count of WBC (17.76 × 10
9/L) and eosinophils (36%, AEC 6.39 × 10
9/L) rebounded. After we adjusted the dosage of prednisone and reduced it gradually, AEC maintained in a normal range (Fig.
2). The child was discharged 15 days after the initial treatment and continued to take SMZCo and prednisone. One month after discharge, he was hospitalized again for IVIG replacement therapy. The lung CT scan was notably improved (Fig.
1c). With the informed consent from the patient’s family, venous blood was collected from four members of the family and sent to Beijing Genomics Institute (BGI) for whole exome sequencing (WES) test. The results revealed a large deletion in the 1st to 5th exon of CD40L gene in the patient, and thus XHIGM was confirmed. Sanger sequencing was used to verify the CD40L gene fragment in peripheral blood DNA of the other family members, which indicated a heterozygous mutation for his mother and elder sister (Fig.
3). His father’s genotype is normal. The patient underwent a successful HSCT two months after diagnosis in another hospital. The donor was the sibling sister, and HLA matching was 9/10. After HSCT, the peripheral blood test showed WBC5.13 × 10
9/L, ANC2.81 × 10
9/L, AEC0.1 × 10
9/L, which were all within normal range. In addition to the normal IgE (5 IU/mL, normal range 0-165IU/mL), IgG was pronouncedly elevated to a normal level (1020 mg/dl, normal range 500-1300 mg/dl) with slight decreases of IgA (6.67 mg/dl, normal range 22-220 mg/dl) and IgM (10.4 mg/dl, normal range 43-163 mg/dl). The patient was in a good condition after three months follow-up with 99.93% donor chimerism. Mycophenolate mofetil and cyclosporine were used for graft-versus-host disease (GvHD) prophylaxis.