Clinical features of central nervous system candidiasis due to Candida albicans in children: experience from a single center | BMC Infectious Diseases

General information

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 0 to 14 years, and 21 patients (63.6%) had an age of onset of 0 to 6 months. The median duration to diagnosis (from symptom onset to positive culture) was 35 days, and the median length of hospital stay was 40 days. Four patients were misdiagnosed with tuberculosis infection and received antituberculosis treatment. A total of 14 patients were discharged from the hospital after their conditions improved, and their average 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 past 5 years, including 7 patients with invasive infection involving multiple sites ( Additional File 1: Fig. .S1).

High risk factors

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

Clinical features

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

Lab tests

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 patients. The CSF cell count was 292 × 10⁶/L, on average, and was > 1000 × 10⁶/L in 7 patients. The CSF protein level increased significantly, while the glucose level decreased (Table 3). A total of 19 patients received β-D glucan analysis (G test) of CSF and peripheral blood samples: 52% of patients had a positive CSF G test. Ninety-seven percent of the patients had positive CSF cultures. One patient refused lumbar puncture due to previous spinal surgery and he was confirmed to have CNSC by clinical diagnosis and positive culture of pus in the knee joint. The first cultures of twenty patients were positive and became negative after treatment. Time to culture negative conversion ranged from 7 to 89 days, with an average of 15.5 (10.5, 22.5) days.

imaging test

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

complications

No infection-related complications (eg, septic shock) occurred in 33 patients during hospitalization. A total of 28 patients presented neurological complications, including hydrocephalus (16), ependymitis (12), subdural effusion (7), cerebral hemorrhage (5), cerebral infarction (4), cerebral herniation in the lower third ventricle (3), thrombosis sinus venosus (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).

types of disease

In this study, there were 26 cases of community-acquired infection and 7 cases of hospital-acquired infection, and all children older than 7 years 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 infections were the most common (6). High risk factors existed in all children with invasive infections involving multiple sites, who had a shorter mean time to diagnosis but a longer hospital stay (Table 4).

prognostic analysis

During follow-up, 4 patients were lost and were not included in the analysis of results. Finally, 29 patients were followed up. The shortest follow-up time was 1 year and the longest 9 years. During follow-up, the children’s version of the extended Glasgow Outcome Scale was used to rate 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 of children with CNSC was 31.0% and the disability rate was 48.2% (Fig. 5).

Results of drug susceptibility testing and antifungal drugs

In this study, 27 patients with positive CSF and/or peripheral blood fungal cultures had drug susceptibility test results. All strains were sensitive 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 initial treatment, 7 patients were treated with fluconazole alone for the entire course of the disease, and the remaining patients subsequently received voriconazole, flucytosine combined with amphotericin B, or fluconazole combined with flucytosine and/or amphotericin B according to their conditions and the effectiveness of the treatment. 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), glucocorticoids, 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 fistula, ventricular-abdominal shunt, lateral ventricular drainage.

WES results

WES was carried out for 16 children. Two patients had CARD9 mutations One patient was a 10-year-old boy with the following main manifestations: bone destruction, intermittent fever, irritability, blurred vision, and a history of recurrent onychomycosis. His culture of pus in the knee joint was positive for Candida albicans. Her 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 have a limp, which had not improved at 2-year follow-up. Detection of the gene 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 : Figure S2). The other child was a 13-year-old boy who presented mainly with intermittent fever accompanied by a cough. He had a history of recurrent thrush. CSF culture from him was positive for Candida albicans. The imaging manifestations of it 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 reported at both sites) [19]. However, his parents refused validation of the Sanger sequencing.