DISCUSSION
The present study describes 28 episodes of IFD in 27 children out of 471 patients at risk in a PHOU during 14 years. The global prevalence of IFD was 5.9% and the rate of cases per 1 000 admissions decreased throughout the study. IFD prevalence was higher in children with AML (23.1%) and in those requiring allogeneic HSCT (16.9%). Prevalence of yeast and mold infections was 1.1% and 4.9%, respectively. Yeast infections decreased over time, whereas all IFD cases in the last two periods were mold infections and they were mostly probable and possible disease. Mold infections occurred in older high-risk children, with numerous host factors and mostly receiving AFP. A rising activity in the PHOU and the increasing complexity in patients’ pathologies did not produce an increase in mortality rates.
The global prevalence of IFD in children with cancer and HSCT recipients ranges from 5-7.2%1,11. The wide variety of immune dysfunctions related to underlying conditions, institutional variations in diagnostic and supportive care practices and inconsistencies in diagnostic criteria make determining this prevalence very challenging1,3,11-16. Our study´s prevalence in different cohorts was similar to that reported recently by Bartlettet al 13. Other studies have also shown that AML and high-risk ALL have an exceptionally high risk for IFD2,10,16-18. In the same line, the risk of IFD after allogeneic HSCT is considerably higher than after autologous HSCT2,13,19.
Several patients in our study, especially those with mold infections, had numerous host factors for developing an IFD. It is known that IFD in children rarely occurs in the presence of an isolated host factor2. Notably, we detected 20 episodes of breakthrough IFD in children receiving AFP, all of which were bronchopulmonary mold infections. The AFP consisted of a mold-active agent in 80% of them (mostly micafungin), and fluconazole in 20%. In agreement with international guidelines, micafungin and liposomal amphotericin B are considered the first choices for AFP in our institution protocols; broad-spectrum triazoles are alternatives for AFP, considering the high incidence of drug interactions and potential adverse effects9,10,20. Non-Aspergillus molds are being diagnosed with increased frequency in patients receiving anAspergillus -active AFP1,2.
We identified five episodes of proven bloodstream candidemias; all of them took place during the first study period in children with a central venous catheter (CVC), and 60% were non-C. albicans species. These findings are consistent with recent reports, which describe a decrease in yeast infections in the past decade, attributed to the extended use of AFP, improved environmental strategies and infection control measures during line emplacement. As a consequence, mold infections have replaced IC as the most frequent IFD12,13,15,17,20,21. The predominance of non-C. albicans in children has been attributed to the affinity of C. parapsilosis for CVC2,11,13,20.
Twenty-three episodes were bronchopulmonary mold infections, two of which were associated with rhino-sinusitis. The diagnosis of mold IFD in children is challenging, as only 30-50% of cases meet the criteria for a proven or probable disease11,13,16,18. In our study, pulmonary infiltrates and consolidations were the most frequent radiological signs whereas the halo sign and cavities appeared in 17.4% and 8.7% of cases. Other studies have shown that radiological findings in pediatric IFD are unspecific and adult hallmarks are less common, with the halo sign appearing in less than 15% of images and the air crescent sign being very rarely observed7,10-12,15,17.
According to EORTC classification3, a proven mold IFD diagnosis requires a sample obtained from sterile material, which is generally unfeasible to pediatric patients. The diagnosis of a probable IFD requires either a direct microbiological test from a non-sterile specimen –such as bronchoalveolar lavage (BAL)-, or a positive biomarker result -such as galactomannan (GM) in plasma, serum, BAL or cerebrospinal fluid. BAL has positioned itself as a safe technique, useful for culture, GM and PCR testing22,23. The detection of Aspergillus by PCR in serum, plasma or BAL requires two or more positive tests to support the diagnosis of probable IFD3. The threshold of the promising (1-3)-β-D-glucan (BDG) may vary according to the age, etiology, specimens and manufacturers, and it is not currently recommended to provide evidence of an invasive mold disease3,8,10,20,24. In our study, only one child met the criteria for proven mold IFD, based on necropsy findings, and eight children were classified as probable IFD based on seric GM (5/8 cases) or GM in BAL (3/8). The remaining 14 children were possible IFD cases, including four children with a single positive PCR in BAL and two with positive serum BDG. The exposure to mold-active AFP reduces the sensitivity of GM assay and it may be a reason for the high proportion of possible IFD3,8,10,17,22. A better comprehension of the role of these novel mycological biomarkers is needed to guide clinical decision-making in children.
The prompt initiation of empiric antifungal therapy is critical for treating children with a suspected IFD10. A pre-emptive treatment is a safe strategy to avoid overuse of antifungals17,25 and it is the standard strategy used in our institution. In our study, yeast infections were mostly treated with caspofungin or voriconazole, mold infections with liposomal amphotericin B or voriconazole, and 25% of patients received a combination of antifungals as first or second-line therapy. Antifungal agents in pediatrics are limited and no specific antifungal drug regimen is superior in terms of mortality, whereas combination therapy may increase adverse events10,15,17.26. Echinocandins are the first-line agents for candidemia in children and adults, but liposomal amphotericin B and voriconazole may be a suitable option if additional mold coverage is desired20,27-30. Antifungal agents and treatment duration in our study followed pediatric guidelines10,17,22,28,31. The high variability in days of therapy may be explained because the length of treatment is not well defined and depends on clinical response, degree of immunosuppression and recovery from predisposing factors17.
In our study, six patients (21.4%) died during antifungal treatment, all diagnosed with mold infections. Despite the rising activity in the PHOU at HGUGM and an increase in the complexity of pathologies, mortality rates did not increased. Mortality in the second period was higher but no differences in the comparison between groups were found. The overall case-fatality rate attributable to IFD is very variable, reaching 10-25% in yeast infections and 20-50% in mold infections1,13,16,17. Patients who died without completing treatment can explain the shorter duration of treatment in period 2. A multidisciplinary management between experts in pediatric oncologic and infectious diseases that maintain a high level of suspicion of IFD in children with numerous host factors allowing for a prompt diagnosis can explain the lower number of proven infections in the third period and the stable mortality rates within the study period.
This study has several limitations. It is a retrospective study and data are limited to the information available in medical records. It is a single-center study with a relatively small sample size; however, the study is probably representative considering that it was done in a tertiary hospital during a long study period. A high level of suspicion in patients with several risk factors could have led to an over-diagnosis of the cases of possible IFD.
In conclusion, this study offers a good picture of IFD in children receiving chemotherapy or undergoing HSCT and may improve the current knowledge of IFD in these patients. We observed a decrease in yeast infections during the study time. The rising activity and complexity in our PHOU did not produce an increase in the prevalence of IFD or mortality rates. Local epidemiology knowledge of IFD is essential to implement appropriate therapeutic interventions early and improve survival in these children.