Clinical characteristics of central nervous system candidiasis due to Candida albicans in children: a single-center experience

Based on the inclusion and exclusion criteria, this study included 33 children with CNSC, including 22 males and 11 females (Table 1). The age of onset was from 0 to 14 years old, and 21 patients (63.6%) had an age of onset from 0 to 6 months old. The median duration for diagnosis (from onset of symptoms to positive culture) was 35 days, and the average length of hospital stay was 40 days. Four patients were misdiagnosed as tuberculosis infection and received antituberculosis treatment. A total of 14 patients were discharged from the hospital after their conditions improved, and their average length of hospital stay was 69 days. There were 19 patients admitted in the first 5 years of the study period, including 4 patients with invasive infection involving multiple sites, and 14 patients admitted in the latter 5 years, including 7 patients with invasive infection involving multiple sites (Additional file 1: Fig. S1).

A total of 29 patients had high-risk factors, including preterm birth, low birth weight, perinatal asphyxia, surgery within 3 months before onset, admission to the ICU, tracheal intubation, application of broad-spectrum antibiotics, and neutropenia (Fig. 1). High-risk factors were present in all children younger than 1 year old, and the proportion (50%) of patients with high-risk factors was significantly lower in children aged 1 year or older. Four patients who had no clear disease history were all older children. Notably, among children aged 7 years or older, 1 had intrauterine hypoxia but normal growth and development, 1 had neutropenia that improved after treatment, 1 had a history of recurrent thrush, and 1 had a history of recurrent onychomycosis. The latter 2 patients did not receive regular treatment.

The main clinical manifestations of the patients included fever, convulsions, headache, vomiting, and enlarged head circumference. The main positive signs included changes in mental reactions (lethargy, irritability, and dysphoria), positive meningeal irritation signs, positive pathological signs, bulging fontanelle/high fontanelle tension, abnormal muscle strength/dystonia. Fever occurred in 75.7% of the patients, and the positivity rate for neurological examinations was 81.8% (Table 2).

The white blood cell count was 10.32 × 10⁹/L, on average, and was < 4 × 10⁹/L in 2 patients. C-reactive protein (CRP) was normal in 87.8% of the patients. The CSF cell count was 292 × 10⁶/L, on average, and was > 1000 × 10⁶/L in 7 patients. The protein level in CSF significantly increased, while the glucose level decreased (Table 3). A total of 19 patients received β-D glucan assay (G test) of CSF and peripheral blood samples: 52% of the patients had positive G test of CSF. Ninety-seven percent of the patients had positive CSF cultures. One patient refused lumbar puncture due to past spinal surgery and was confirmed to have CNSC by clinical diagnosis and positive knee joint pus culture. The first cultures for twenty patients were positive and became negative after treatment. The time to negative culture conversion was 7–89 days, with an average of 15.5 (10.5, 22.5) days.

In this study, intracranial CNSC lesions were classified into meningoencephalitis, brain abscess, primary granuloma, and vascular complication. Imaging examinations were performed for 32 patients, showing varying degrees of intracranial diseases, including meningeal enhancement, granuloma, hydrocephalus, ependymitis, subdural effusion, intracranial artery stenosis, brain atrophy, and cerebral haemorrhage (Fig. 2). Seven patients presented meningoencephalitis, 1 patient presented primary granuloma (Fig. 3), 3 patients younger than 6 months old presented vascular complications (Fig. 4), and the remaining 21 patients presented combinations of the above 4 types.

No infection-related complications (e.g., septic shock) occurred in 33 patients during hospitalization. A total of 28 patients had neurological complications, including hydrocephalus (16), ependymitis (12), subdural effusion (7), cerebral haemorrhage (5), cerebral infarction (4), cerebral herniation in the lower third ventricle (3), cerebral venous sinus thrombosis (1), hearing impairment (4), symptomatic epilepsy (2), and optic nerve block (1). Fourteen children were treated with amphotericin B, including 2 with electrolyte imbalance and 2 with renal dysfunction. Five children were treated with amphotericin B liposomes, including 1 with electrolyte imbalance. Venous catheterization was performed in 13 patients. Five patients had catheter-related complications, including phlebitis (4) and venous thrombosis (2).

In this study, there were 26 cases of community-acquired infection and 7 cases of hospital-acquired infection, and all children over 7 years old had community-acquired infections (Additional file 1: Table S1). Twenty-two patients had CNS infections alone, and 11 patients had CNS infections combined with invasive infections involving multiple sites (Additional file 1: Table S2, Fig. S1). In children with invasive infections involving multiple sites, CNS infections combined with bloodstream infection were most common (6). High-risk factors existed in all children with invasive infections involving multiple sites, who had a shorter average diagnosis time but a longer length of hospital stay (Table 4).

During the follow-up, 4 patients were lost to follow-up, who were not included in the outcome analysis. Ultimately, 29 patients were followed up. The shortest follow-up time was 1 year, and the longest was 9 years. During follow-up, the children’s version of the extended Glasgow Outcome Scale was used for scoring prognosis. The results showed 9 cases of death (8 points), 7 cases of severe disability (5–6 points), 7 cases of moderate disability (3–4 points), and 6 cases of good recovery (1–2 points). The mortality rate for children with CNSC was 31.0%, and the disability rate was 48.2% (Fig. 5).

In this study, 27 patients with positive CSF and/or peripheral blood fungal cultures had drug susceptibility test results. All strains were susceptible to fluconazole, and 2 strains had intermediate susceptibility to voriconazole (their voriconazole MICs were both 0.25 µg/mL, and fluconazole MICs were both 2 µg/mL). The amphotericin B MIC of 26 strains was ≤ 0.5 µg/mL, and only 1 strain was 2 µg/mL (Additional file 1: Table S3).

All patients received initial treatment after a confirmed positive fungal culture: 2 received triad treatment with fluconazole, flucytosine, and amphotericin B, 5 received flucytosine combined with amphotericin B, and 26 received fluconazole (Additional file 1: Table S4). Among the patients who received fluconazole as the initial treatment, 7 patients were treated with fluconazole alone for the whole disease course, and the remaining patients later received voriconazole, flucytosine combined with amphotericin B, or fluconazole combined with flucytosine and/or amphotericin B based on their conditions and treatment efficacy. Nineteen patients received intravenous antifungal therapy for 4 weeks, and 14 patients received intravenous antifungal therapy for less than 4 weeks. Other medical treatment regimens included intravenous immunoglobulin (IVIG), glucocorticoid, interferon, and granulocyte colony-stimulating factor (G-CSF) (Additional file 1: Table S5). In addition, due to the high proportion of children with hydrocephalus or subdural effusion, 15 patients received surgical treatment, including Ommaya reservoir implantation, third ventriculostomy, midbrain aqueduct fistulation, ventricular-abdominal shunt, lateral ventricular drainage.

WES was conducted for 16 children. Two patients had CARD9 mutations. One patient was a 10-year-old boy, with the following major manifestations: bone destruction, intermittent fever, irritability, blurred vision and history of recurrent onychomycosis. His knee joint pus culture was positive for Candida albicans. His head imaging manifestations were meningoencephalitis and vasculitis. The patient was diagnosed with IC (CNS, spine, right knee joint). Although his condition improved after 48 days of hospitalization, he continued to suffer from lameness, which had not improved at 2 years of follow-up. The gene detection indicated CARD9 compound heterozygous mutations (NM_052813, c.246C>A, p.S82R, from his father, and c.1497delT, p.F499Lfs*? from his mother, which are mutation sites that have never been reported before) (Additional file 1: Fig. S2). The other child was a 13-year-old boy who mainly presented intermittent fever accompanied by coughing. He had a history of recurrent thrush. His CSF culture was positive for Candida albicans. His imaging manifestations were meningoencephalitis. The patient was diagnosed with CNSC, which improved after 45 days of hospitalization. The patient had no sequelae at 4 years of follow-up. Gene detection revealed 2 CARD9 mutation sites (NM_052813, c.191_192insTGCT, p.L65Afs*58, het, and c.820dupG, p.D274Gfs*60, het; pathogenic mutations on both sites have been reported) [19]. However, his parents refused Sanger sequencing validation.