RESULTS
From January 2006 to December 2019, a total of 471 children at risk for an IFD were followed at the PHOU. Twenty-six children had one episode of IFD and one child had two episodes, corresponding to 28 episodes overall. The median age at diagnosis was 10 years (IQR 5-15 years) and 50% were males. The global prevalence of IFD was 5.9%, and differed according to the underlying condition: 23.1% (6/26) for AML, 12.1% (8/66) for ALL and 1.8% (6/333) for SOT. The prevalence in those who required a HSCT was 13.3% (12/90), being 16.9% (11/65) for allogeneic and 4% (1/25) for autologous HSCT. Twenty-three were mold and five were yeast infections, with a prevalence of 4.9% and 1.1%, respectively.
There was a global ratio of 4.1 cases of IFD per 1 000 admissions in the PHOU and declined by 25% between the first and last study periods (Table 1). In contrast, there was a rising activity in the PHOU, with a 64% increase in the number of admissions and 277% in the HSCT carried out. In the last period, children had more IFD host factors (p =0.028), high-risk underlying disorders (p =0.012) and were more commonly receiving AFP (p =0.012). All yeast infections took place during the first period (55.6% of cases in period 1), whereas all IFD episodes in the second and third periods were mold infections (p =0.002).
Most episodes (71.4%) occurred in children at high-risk for IFD (Table 2). Fourteen (50%) corresponded to children with blood malignancies (ALL n=8; AML n=6); eight (28.6%) occurred in children with non-malignant blood disorders (sickle cell disease n=4, aplastic anemia n=2, Fanconi anemia n=1, β-thalassemia major n=1), and six (21.4%) were children with SOT (neuroblastoma n=3, osteosarcoma n=2, sarcoma n=1). Twelve episodes (42.9%) occurred following an HSCT (11 allogeneic; 1 autologous). Twenty children (71.4%) were receiving AFP, including 19/20 high-risk children and 1/3 low-risk children; all the episodes in children with AFP were mold infections. Agents used for AFP were micafungin (65%), fluconazole (20%), posaconazole (10%), and itraconazole (5%).
The most common IFD host factors were blood malignancies (50%), prolonged use of corticosteroids (50%), allogeneic HSCT (39.3%) and prolonged neutropenia (39.1%) (Table 3). The median time between HSCT and IFD was 43 days (IQR 14 - 253 days), and the median time of prolonged neutropenia was 16 days (IQR 12.5 - 23 days). More than a third of the patients (39.3%) had three or four IFD host factors and 7.1% had five or more.
In 11 episodes (39.3%), a clinically relevant pathogen was identified by culture or polymerase chain reaction (PCR): five culture-positive yeast infections (Candid albicans n=2; C. parapsilosisn=2; C. kefyr n=1), one culture-positive mold infection (Aspergillus ustus ) and five PCR-positive mold infections (Aspergillus spp n=3; Cunninghamella spp n=1;Myriangiales spp n=1). All yeast and only one mold infection met the criteria for proven IFD (100% vs . 4.3%, p=0.001; Table 4). According to EORTC criteria, the final diagnosis was proven IFD in six episodes (21.4%), probable in eight (28.6%), and possible in 14 (50%).
The most common site of IFD were mold bronchopulmonary infections (n=23; 82.1%), followed by bloodstream yeast infections (n=5; 17.9%) and mold rhino-sinusitis (n=2; 7.1%, in patients with bronchopulmonary disease) (Table 4). Children with mold infections were older than those with yeast infections (median age 126 months vs. 21 months;p =0.045), had more IFD host factors (median 3 vs. 1;p =0.001), underlying high-risk disorders (87% vs. 0%;p =0.001) and were receiving AFP more frequently (87% vs.0%; p =0.001). There was a non-significant trend towards higher mortality in mold than yeast infections (26.1% vs. 0%,p= 0.553). Table 5 shows the radiological and microbiological findings of mold IFD.
Liposomal amphotericin B and voriconazole were the first options for IFD treatment in 85.7% and 25% of cases, respectively, used in combination in 14.2% of cases. Two-thirds of the children required a salvage treatment (67.9%), mostly based on voriconazole (68.4%), and one-tenth needed a third-line option (10.7%). The median duration of treatment was 43 days (IQR 19.5-69 days).
Regarding outcomes, eight patients (28.6%) entered the Pediatric Intensive Care Unit (PICU), four (14.3%) needed mechanical ventilation and three (10.7%), inotropic support. Any case required surgical intervention and one patient required thoracic drainage. Six patients (21.4%) died during the IFD episode, all of which had mold infections, although death was attributed to the IFD in only one of them. Table 6 compares the characteristics between surviving and non-surviving children.