The patient was a 2-month and 18-day old boy, who had experienced shortness of breath and feeding pause since birth. At the age of one and a half months, the shortness of breath became more obvious and the infant was cyanotic when feeding. The frequency of feeding pause and cough also increased, but no fever was noted. Nine days before admission, the patient was examined by chest computed tomography (CT) at a local hospital, with neoplastic lesions suspected in the right lung. Initially, the patient received oxygen therapy, amoxicillin-potassium clavulanate, and gamma globulin injection (400 mg/kg) because of an increased white blood cell (WBC) and C-reactive protein level (CRP). Four days later the patient was transferred to another hospital where he was treated with oxygen therapy and cefoperazone/sulbactam for 3 days. These treatments were not effective and the patient continued to experience shortness of breath and fever. He was transferred to our hospital with vital signs of T 38  C, P 172 beats/min, and R 42 breaths/min, as well as shortness of breath and signs of increased inspiratory load (e.g. three concave sign positive). As the condition progressed to respiratory distress and carbon dioxide retention, the infant was admitted to the pediatric intensive care unit (PICU) and received noninvasive ventilation immediately.
For routine blood tests performed in other hospitals, all WBC counts were found to exceed the normal range, with a minimal value of 15.26 x 10 9/L and a maximal value of 34.1 x 10 9/L. In our hospital, WBC ranged from 17.31 x 10 9/L to 26.63 x 10 9/L. The concentrations of CRP and procalcitonin (PCT) upon admission were 34.99 mg/L and 0.21 ng/mL. Similarly, the (1, 3)-beta-D-glucan test (G test) initially showed a significantly high value of 177.2 pg/mL (cutoff value is 100 pg/mL). Initially, no pathogen was found in the sputum (by smear microscopy), blood, sputum, or BALF cultures. Other tests were also normal including immunoglobulin level, lymphocyte count, tuberculosis infection test (T-SPOT.TB), and cytomegalovirus IgM antibody levels.
In the absence of evidence of pathogens, we can only choose empirical treatment. Despite this, the child was still short of breath and febrile. CT scans taken before treatment (Fig. 1A and B) showed inflammatory lesions in both lungs, along with a mass and incomplete expansion of the upper right lung. CT-guided lung puncture pathological examination was performed because of a suspected tumor. Pathological examination revealed granulomatous lesions in right lung tissue with a nodular structure and an infiltration of a large number of lymphocytes, plasma cells, neutrophils, and scattered multinucleated giant cells. Gram stain, AFB stain, Fite stain, and Silver stain excluded neoplastic lesions. Therefore, we performed fiberoptic bronchoscopy and BALF-mNGS examination. The location of the lesion was determined by chest imaging examination, and the most significant part of the lesion was selected for bronchoalveolar lavage. BALF of the child was collected according to Chinese Guidelines for Pediatric Flexible Bronchoscopy, the total "recovery time" should be >30%, and the "lavage time" should be controlled within 5 minutes. Nucleic acid was extracted from 5 mL of BALF followed by library construction and high-throughput sequencing performed with an Illumina Nextseq 550Dx sequencer. By sequence alignment, BALF mNGS identified A. fumigatus on day 10 (Fig. 2A) and day 28 (Fig. 2B). Prior to this, antibiotic treatment was ineffective. Combined with clinical manifestations, lung CT scan, lung puncture pathology, elevated G test value, all of which made us suspect a fungal infection. After Aspergillus was found, we immediately changed to targeted therapy with intravenous caspofungin, and the condition gradually improved, body temperature returned to normal and breathing improved. Two weeks later, it was changed to sequential oral therapy of voriconazole. The treatment process is outlined in (Fig. 3).
Aspergillus is a common pathogen in people with immunodeficiency, so we have also improved the genetic testing. We found compound heterozygous mutations in the neutrophil cytosolic factor 1 gene (NCF1), consisting of a heterozygous mutation of paternal NCF1, and a deletion mutation of the maternal NCF1 that resulted in a large deletion of chromosomal segments (copy-number variations) of the gene (Fig. 4). The patient was diagnosed with autosomal recessive cytochrome b-positive CGD type I.
The patient had oral voriconazole sequential therapy after discharge and remained in good condition through 3-months of follow-up. The CT scans showed inflammatory lesions in both lungs and incomplete expansion of the upper right lung, with significantly fewer lesions (Fig. 1C and D), without any symptoms of fever or shortness of breath.