Invasive Candidiasis (IC) in Pediatric Intensive Care Unit (PICU) remains a serious hospital-acquired infection and is associated with increased morbidity, mortality and nosocomial costs.1 , 2 The burden of IC among different PICUs in the US and EU countries, as well as the Candida species involved, present significant variability.1
Candida spp. is the cause of approximately 10%–15% of bloodstream infections (BSIs) in PICU.1 In Europe, it was the third most frequent pathogen (15% of PICU infections), whereas in the United States, it was implicated in 9.5% of PICU BSIs based on the National Nosocomial Infections Surveillance System.
The incidence of IC among PICUs and time periods varies significantly. The comparison of the existing epidemiologic data is difficult, due to significant variability of the presenting definitions among studies (presented either as rates of PICU infections or incidence rates with different denominators). Among EU countries, the IC incidence in PICUs ranges between 3.5 and 7 cases/1000 admissions.1
As far as the species distribution in PICUs, both in EU countries, in the United States and other countries, Candida albicans prevails with a percentage of 37%–55%.1 , 3 , 4 Candida parapsilosis remains the second cause reaching 20% of the identified Candida spp. in PICUs globally. The remaining Candida spp. are identified in 10%–15% with Candida tropicalis, Candida glabrata, Candida krusei and Candida lusitaniae being the most frequent.1 , 2 Candida auris, a newly found species extremely resistant to azoles and to amphotericin B, has been isolated from children as well.5
RISK FACTORS FOR IC IN PICU
Several studies have tried to identify independent risk factors and to design prediction models of acquiring IC in PICU as a means of developing prevention and prompt intervention strategies, such as identifying high-risk patients that would benefit mostly from prophylactic antifungal treatment.1 , 4 , 6 The following risk factors have been reported: presence of central venous catheters (CVC), presence of endotracheal tubes, prolonged broad-spectrum antibiotics use, prolonged PICU hospitalization, parenteral nutrition, gastrointestinal injury-surgery, corrective surgery for congenital heart disease, prior Candida colonization at multiple sites and underlying malignancy.1 , 4 , 6 Among them, the presence of CVC as an independent factor increases 3-fold the risk for developing disseminated Candida infection in children; therefore, the Infectious Diseases Society of America (IDSA) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines propose the immediate removal of the catheter if possible.7 , 8
Identical strains between colonization and IC have been found in 62%–76% PICU patients implying that colonization could be an additional risk factor for IC.4 , 9 A probabilistic IC risk stratification was tested by identifying risk factors associated with Candida colonization and candidemia in critically ill PICU patients with severe sepsis for >5 days. Ninety percent of patients with IC sepsis presented a prior Candida colonization and 75% with the same species.9 In a nationwide study in Greece, more than 70% of PICU children with IC presented prior Candida colonization.3 The presence of colonization in the lower respiratory tract might be the most appropriate site to justify pre-emptive antifungal treatment. Candida spp. concordance between colonized site and blood culture was observed in 62.5%. Similarly, prior Candida colonization was observed in 81%, while 76.2% of the patients that developed IC were colonized with the same Candida spp.4
OUTCOME OF IC IN PICU
The true estimate of case fatality rates of IC among PICU patients is difficult to be estimated because of the complexity of these patients and the different mortality definitions used (crude mortality vs. case fatality rates). In a population-based study, it has been shown that the mortality of candidemia is higher in adults than in pediatric patients; however, data regarding PICU patients were not separately presented.10 In PICUs, the case fatality rates derived from very few studies ranges between 42% and 44%.3 , 4 More specifically, the 30-day mortality rates in PICU patients with IC in the United States was significantly higher than in controls (PICU patients without IC) (44% vs. 14%), respectively. Similarly, in Egypt, the crude mortality was 42.2%, and in Greece, the attributable mortality from candidemia in PICU was 18.2%.3 , 4 Data concerning species-specific mortality rates in children are limited; therefore, the true impact of different Candida species remains to be elucidated.11
CHALLENGES OF IC IN PICU
Prediction Models–Clinical Scores for IC in PICU
Few studies have attempted to identify the specific subset of PICU patients at higher risk of developing IC by designing prediction models and clinical scores. The first found that IC in PICU was significantly associated with pre-PICU hospitalization ≥15 days, parenteral nutrition, fever and thrombocytopenia at PICU admission.11 This model showed also species-specific differences, such as association of C. albicans IC with metabolic disease, surgery, fever at PICU admission and parenteral nutrition, while C. parapsilosis IC was associated with other specific risk factors, such as prior Candida colonization, tracheostomy and prior bacterial infection. The second study conducted in the United States developed a prediction model by combining specific factors (CVC, malignancy, vancomycin use for >3 days and agents with anaerobic activity for >3 days both in the prior 2 weeks) observing a predicted probability of candidemia that ranged from 10.7% to 46%. Unfortunately, a subsequent multicenter case–control study failed to validate this model.12
Diagnosis and Prevention of IC in PICU
Prompt diagnosis of IC is often difficult in PICU patients because of the lack of specific symptoms and the remaining gaps in the correct interpretation of the noninvasive diagnostic fungal tools in pediatrics.13 The beta-D-glucan optimal cut-off levels in children have not been defined, while fungal PCR still presents lack of standardization as well as increased time needed for the final results. In addition, Candida mannan antigen/antibody and the promising T2 approach studies in children are limited to support clear recommendations.13 , 14
One of the proven strategies to prevent and decrease the rates of IC both in adults and pediatrics has been the implementation of infection control and stewardship programs.15 The role of antifungal prophylaxis, as an additional preventive strategy, has been established in specific pediatric populations with higher incidence of candidemia, such as hematology–oncology patients or premature neonates, but not in PICU patients. The benefits of implementing antifungal prophylaxis might outweigh its risks only if the prevalence of invasive fungal infections (IFIs) in an ICU exceeds 10%.6 Current literature does not generally support the pre-emptive antifungal treatment of all children in PICU, although individualized risk–benefit assessment is warranted in high-risk PICU patients.
The use of oral amphotericin B has been proposed for prevention of Candida BSIs in ventilated PICU patients, while the ESCMID guidelines recommend the use of fluconazole prophylaxis in subset of adult ICU patients who recently had gastrointestinal surgery with recurrent anastomotic leakages.8 Thus, further data are needed to identify the optimal agent for antifungal prophylaxis in PICU patients.
There is an ongoing debate concerning the role of probiotic use as prophylactic measure in PICU. Because of the significant proportion of children with immunosuppressive conditions in PICUs, and the lack of evidence, the existing guidelines do not clearly support their use in PICU.
Treatment of IC in PICU
The lack of specific guidelines concerning the management of IC in PICU contributes to management variation observed among centers and makes interpretation of the results challenging. Optimal antifungal agent as well as optimal dosing especially for infants and young children with IC in PICU is unclear. Therefore, the treatment of IC in PICU should follow the fundamental principle of therapy in all patient groups, which is early identification and removal of the likely source of infection.7 , 8 As in most cases, vascular catheter is the most likely source, its prompt removal is recommended in both IDSA and ESCMID guidelines whenever feasible. Similarly, if the source is the urinary tract then indwelling urinary catheters should be removed. On the contrary in immunocompromised PICU patients or in patients who have undergone gastrointestinal surgery, the route of IC could be because of gut translocation.7
The optimal drug of choice has not been identified yet for this pediatric population. The choice should be based on local epidemiology (rate of azole resistance among non-albicans species), prior colonization, critical condition and prior exposure to azoles. Vogiatzi et al3 suggested that fungicidal agents such as polyenes and echinocandins would be preferable as a first-line treatment option in critically ill patients. The IDSA and the ESCMID guidelines do not have graded recommendations for the management of candidemia in critically ill children specifically, a fact that reflects the lack of evidence about this patient population. The guidelines recommend either fluconazole for patients who are mild to moderately ill and have not been exposed to azoles in the past (therefore low risk for fluconazole-resistant Candida spp.) and echinocandins or lipid-based polyenes for moderate to severely ill patients or with previous azole exposure.
- The burden of Candida infections in PICU remains significant accounting for 10%–15% of BSIs with mortality rates reaching 45%.
- Overall antifungal prophylaxis is not recommended in PICU patients; further studies are needed to stratify PICU patients according to their risk.
- The treatment management of IC in PICU should be based on early identification and removal of the likely source of infection (catheters). Treatment options remain fluconazole but echinocandins are now regarded also as first-line treatment because of broad spectrum of activity, antibiofilm activity and good safety profile.
1. Pana ZD, Roilides E, Warris A, et al. Epidemiology of invasive fungal disease in children. J Pediatric Infect Dis Soc. 2017;6(suppl_1):S3–S11.
2. Steinbach WJ, Roilides E, Berman D, et al; International Pediatric Fungal Network. Results from a prospective, international, epidemiologic study of invasive candidiasis
in children and neonates. Pediatr Infect Dis J. 2012;31:1252–1257.
3. Vogiatzi L, Ilia S, Sideri G, et al. Invasive candidiasis
in pediatric intensive care in Greece: a nationwide study. Intensive Care Med. 2013;39:2188–2195.
4. Hegazi M, Abdelkader A, Zaki M, et al. Characteristics and risk factors of candidemia in pediatric intensive care unit
of a tertiary care children’s hospital in Egypt. J Infect Dev Ctries. 2014;8:624–634.
5. Warris A. Candida auris, what do paediatricians need to know? Arch Dis Child. 2018;103:891–894.
6. Brissaud O, Guichoux J, Harambat J, et al. Invasive fungal disease in PICU: epidemiology and risk factors. Ann Intensive Care. 2012;2:6.
7. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62:e1–e50.
8. Hope WW, Castagnola E, Groll AH, et al; ESCMID Fungal Infection Study Group. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp. Clin Microbiol Infect. 2012;18(suppl 7):38–52.
9. Singhi S, Rao DS, Chakrabarti A. Candida colonization and candidemia in a pediatric intensive care unit
. Pediatr Crit Care Med. 2008;9:91–95.
10. Blyth CC, Chen SC, Slavin MA, et al; Australian Candidemia Study. Not just little adults: candidemia epidemiology, molecular characterization, and antifungal susceptibility in neonatal and pediatric patients. Pediatrics. 2009;123:1360–1368.
11. Jordan I, Balaguer M, López-Castilla JD, et al; ERICAP Study Group. Per-species risk factors and predictors of invasive Candida infections in patients admitted to pediatric intensive care units: development of ERICAP scoring systems. Pediatr Infect Dis J. 2014;33:e187–e193.
12. Fisher BT, Ross RK, Roilides E, et al. Failure to validate a multivariable clinical prediction model to identify pediatric intensive care unit
patients at high risk for Candidemia. J Pediatric Infect Dis Soc. 2016;5:458–461.
13. Huppler AR, Fisher BT, Lehrnbecher T, et al. Role of molecular biomarkers in the diagnosis of invasive fungal diseases in children. J Pediatric Infect Dis Soc. 2017;6(suppl_1):S32–S44.
14. Hamula CL, Hughes K, Fisher BT, et al. T2Candida provides rapid and accurate species identification in pediatric cases of Candidemia. Am J Clin Pathol. 2016;145:858–861.
15. Hamdy RF, Zaoutis TE, Seo SK. Antifungal stewardship considerations for adults and pediatrics. Virulence. 2017;8:658–672.