Although previous studies have reported some risk factors for IC in children and adults,[11,16–18,21,22] there are very few reports that evaluated the risk factors associated with death due to IC in the pediatric population. Here, we present a series of 94 pediatric patients with IC, evaluating the mortality rate and the involved risk factors.
Consistent with the current literature that reports mortality rates between 10% and 35% for pediatric patients with IC, we found a mortality rate of 14% (13/83), which reinforces the severe outcomes associated with these infections.[8,11,16,23,24] Most episodes of death (92.3%: 12/13) were recorded in the ICU, as already reported for adults and children; however, as previously reported for the adults,[8,25–27] there was a statistical difference between admission and non-admission to ICU as a risk factor for death associated with IC (P < .01).
Our analysis demonstrated that patients with thrombocytopenia had a higher mortality rate than those with normal platelet counts (P < .01). Though thrombocytopenia has previously been described as a risk factor for candidemia and IC in children and newborns, no specificity for the diagnosis or death has been found.[28–31] Although some crucial effects of platelets, such as the ability to attract cells of the immune system, activate the complement system, and release microbicidal proteins, have already been clarified, their involvement in the pathogenesis of IC and, therefore, the real significance of thrombocytopenia as a risk factor for infection and death remains unclear.
Regarding the pathological conditions prior to IC, it was noted that patients with heart diseases and renal insufficiency were associated with increased mortality (P < .01 and .03, respectively). Recently, some publications have demonstrated an association between renal insufficiency and death in pediatric patients with IC.[16,32] However, this is the first report that describes the association between heart diseases and increased mortality. We found that 9/13 (69.2%) patients who succumbed to IC had heart disease. Previous studies have also reported IC-related mortality rates of 15% and 21% in adults and pediatric patients with heart disease, respectively. Based on all these findings, it is accepted that heart disease (especially congenital heart disease) is a risk factor for death in patients with IC. Therefore, greater efforts are required to prevent infections in patients in the ICU, especially after surgery.[33,34]
We found that the use of mechanical ventilation (P < .01) and dialysis (P = .03) were associated with increased mortality, in agreement with our previous publications.[16,26]
Although C. albicans is predominant in adult and pediatric populations, some authors describe the emergence and even inversion of this scenario by other non-albicans species.[17,35,36] We report a predominance of non-albicans species (71.2%) with Candida parapsilosis being the most common (35.1%), followed by C. albicans (28.8%) and Candida tropicalis (23.4%). The distribution of Candida spp. is important, as some species seem to be associated with relatively better outcomes. Some authors have reported that IC cases linked to C. parapsilosis are less aggressive than others linked to C. albicans[17,22];however, we did not find any difference in the mortality rates associated with C. albicans and non-albicans species. Our results are consistent with recent literature reports that describe C. parapsilosis and C. tropicalis among the most common non-albicans species in Latin America, Southern Europe, India, and Pakistan, while in the United States and Europe, Candida glabrata stands out among non-albicans species.
Our results indicate that biofilm formation is associated with increased mortality (P = .02). Biofilm is a community of microorganisms that are irreversibly attached to living or nonliving surfaces, producing extracellular polymeric substances that provide a structural matrix. The ability of Candida isolates to form biofilms varies by species and is considered an important virulence factor that could contribute to the development of antifungal resistance and persistence of infections. However, the clinical significance of in vitro biofilm production by Candida spp. remains unclear. The in vitro detection of biofilm by laboratory techniques does not necessarily indicate the in vivo production.[38,40,41] We tested 23 isolates for biofilm production, of which 15 (65.2%) were found to be producers. The biofilm producer species included C. tropicalis (7; 46.6%), C. parapsilosis (6; 40%), Candida krusei (1; 6.7%), and C. fabianii (1; 6.7%). Although C. albicans is recognized as the main biofilm-producing species, other studies have demonstrated higher production by the non-albicans species, especially C. parapsilosis and C. tropicalis.[39–41]
Multivariate analysis showed that factors independently associated with death in pediatric IC included male sex (OR 5.849; CI 1.186–28.83; P = .03), thrombocytopenia (OR 6.399; CI 1.254–32.66; P = .03), and heart disease (OR 11.55; CI 2.532–52.66; P < .01). Infectious diseases rarely affect men and women equally, and evidence suggests that physiological sex differences are behind the differences in prevalence and mortality in many infectious diseases. Some invasive fungal infections endemic to Brazil, such as paracoccidioidomycosis, cryptococcosis, aspergillosis, mucormycosis, and episodes of IC (including candidemia), have been found to be prevalent among men; in addition, male sex is a risk factor for IC in neonates.[19,27,43,44] However, for the first time, we have shown that male sex is a risk factor for death in pediatric IC patients in a population with homogeneous distribution between men and women.
Our study had a few limitations. It was a retrospective study performed in a single pediatric tertiary hospital; our epidemiology findings cannot be applied to all other health centers. Although the diagnosis of invasive candidiasis was judicious, some cases may have been erroneously classified, and some cases were lost during the study. Due to the great diversity of factors that could be evaluated in relation to the risk of IC-related death, not all were considered in the statistical analysis of this study, including prematurity and low birth weight. In addition, not all isolates of Candida sp. could be investigated with respect to biofilm production capacity, which precludes deep reflections of this finding in relation to the risk of death for the IC patient, although the results from the data on hand indicate a statistically significant finding.
In this study, variables were selected based on the previous evidence on risk factors for IC and mortality by IC, in addition to biological knowledge. However, if we consider the uncertainties generated by the statistical analyses in the scientific context in view of the current knowledge, it would be possible to come up with new approaches. For example, using the Bonferroni correction considering the multiple comparisons made in this study, the significance criterion would change to P = .002 and P = .005 for the univariate and multivariate analysis, respectively, to maintain the overall type I (alpha) error probability previously considered (0.05). In this context, only heart disease would be the possible risk factor for death by IC; however, these types of correction increase the probability of type II (beta) error. Therefore, it is important that further studies on the subject in other clinical settings be developed in order to reinforce if the variables found in this study would also be determinant in death by IC.
In conclusion, data from this study emphasizes that mortality among pediatric patients with IC is around 15%. While we found that the mortality rates are not dependent on the Candida species, they could be directly related to biofilm formation. Additionally, we have identified for the first time that heart disease and male sex are possible risk factors for IC-related death in pediatric patients.
Editage provided English editing of the manuscript.
Fábio Araújo Motta and Libera Maria Dalla Costa designed the study.
Luiza Souza Rodrigues and Libera Maria Dalla Costa submitted the research to the Ethics and Research Committee for approval.
Fábio Araújo Motta performed clinical evaluations and selected patients for the study.
Gledson Luiz Picharski performed the statistical analyses.
Thaís Muniz Vasconcelos, Marinei Campos Riccieri, and Luiza Souza Rodrigues collected the demographic, clinical, and laboratory data.
Luiza Souza Rodrigues and Fábio Araújo Motta wrote the manuscript, and all authors made contributions. All authors reviewed and approved the final manuscript.
Conceptualization: Fabio Araujo Motta, Libera Maria Dalla-Costa.
Data curation: Gledson Luiz Picharski, Libera Maria Dalla-Costa.
Formal analysis: Gledson Luiz Picharski.
Investigation: Fabio Araujo Motta.
Methodology: Luiza Souza Rodrigues, Thaís Muniz Vasconcelos, Marinei Campos Riccieri.
Project administration: Luiza Souza Rodrigues, Fabio Araujo Motta, Libera Maria Dalla-Costa.
Supervision: Fabio Araujo Motta.
Validation: Gledson Luiz Picharski.
Writing – original draft: Luiza Souza Rodrigues, Libera Maria Dalla-Costa.
Writing – review & editing: Fabio Araujo Motta, Libera Maria Dalla-Costa.
Luiza Souza Rodrigues orcid: 0000-0002-9774-8650.
. Sardi JC, Scorzoni L, Bernardi T, et al. Candida
species: current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options. J Med Microbiol 2013;62(pt 1):10–24.
. Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis
: a persistent public health problem. Clin Microbiol Rev 2007;20:133–63.
. Guinea J. Global trends in the distribution of Candida
species causing candidemia. Clin Microbiol Infect 2014;20(suppl):5–10.
. Colombo AL, Júnior JNA, Guinea J. Emerging multidrug-resistant Candida
species. Curr Opin Infect Dis 2017;30:528–38.
. Jeffery-Smith A, Taori SK, Schelenz S, et al. Candida
auris: a review of the literature. Clin Microbiol Rev 2017;31: pii: e00029-17.
. Colombo AL, Guimarães T, Camargo LF, et al. Brazilian guidelines for the management of candidiasis - a joint meeting report of three medical societies: Sociedade Brasileira de Infectologia, Sociedade Paulista de Infectologia and Sociedade Brasileira de Medicina Tropical. Braz J Infect Dis 2013;17:283–312.
. Lehrnbecher T, Groll AH. Invasive fungal infections in the pediatric
population. Expert Rev Anti Infect Ther 2011;9:275–8.
. Steinbach WJ. Pediatric invasive Candidiasis
: epidemiology and diagnosis in children. J Fungi (Basel) 2016;2:5.
. Yapar N. Epidemiology and risk factors for invasive candidiasis
. Ther Clin Risk Manag 2014;10:95–105.
. Motta FA, Dalla-Costa LM, Muro MD, et al. Risk factors for candidemia mortality
in hospitalized children. J Pediatr (Rio J) 2017;93:165–71.
. Pana ZD, Roilides E, Warris A, et al. Epidemiology of invasive fungal disease in children. J Pediatric
Infect Dis Soc 2017;6(suppl):S3–11.
. Paim J, Travassos C, Almeida C, et al. The Brazilian health system: history, advances, and challenges. Lancet 2011;377:1778–97.
. Christensen GD, Simpson WA, Bisno AL, et al. Adherence of slime-producing strains of Staphylococcus epidermidis to smooth surfaces. Infect Immun 1982;37:318–26.
. Sida H, Shah P, Pethani J, et al. Study of biofilm formation as a virulence marker in Candida
species isolated from various clinical specimens. Int J Med Sci Public Health 2016;5:842–6.
. Hassan A, Usman J, Kaleem F, et al. Evaluation of different detection methods of biofilm formation in the clinical isolates. Braz J Infect Dis 2011;15:305–11.
. Motta AL, Almeida GM, Almeida Júnior JN, et al. Candidemia epidemiology and susceptibility profile in the largest Brazilian teaching hospital complex. Braz J Infect Dis 2010;14:441–8.
. Brissaud O, Guichoux J, Harambat J, et al. Invasive fungal disease in PICU: epidemiology and risk factors. Ann Intensive Care 2012;2:6.
. Zaoutis TE, Greves HM, Lautenbach E, et al. Risk factors for disseminated candidiasis in children with candidemia. Pediatr Infect Dis J 2004;23:635–41.
. Benjamin DK, Stoll BJ, Fanaroff AA, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality
rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics 2006;117:84–92.
. Cox DR. The regression analysis of binary sequences. J R Stat Soc 1958;20:215–42.
. Lai MY, Hsu JF, Chu SM, et al. Breakthrough candidemia in children: clinical and microbiological characteristics, therapeutic strategies and impact on outcomes. Future Microbiol 2017;12:695–705.
. Zaoutis T. Candidemia in children. Curr Med Res Opin 2010;26:1761–8.
. Tsai MH, Hsu JF, Chu SM, et al. Clinical and microbiological characteristics, and impact of therapeutic strategies on the outcomes of children with candidemia. Sci Rep 2017;7:1083.
. Leroy O, Gangneux JP, Montravers P, et al. Epidemiology, management, and risk factors for death of invasive Candida
infections in critical care: a multicenter, prospective, observational study in France (2005-2006). Crit Care Med 2009;37:1612–8.
. Akbar DH, Tahawi AT. Candidemia at a University Hospital: epidemiology, risk factors and predictors of mortality
. Ann Saudi Med 2001;21:178–82.
. Celebi S, Hacimustafaoglu M, Ozdemir O, et al. Nosocomial candidaemia in children: results of a 9-year study. Mycoses 2008;51:248–57.
. Doi AM, Pignatari AC, Edmond MB, et al. Epidemiology and microbiologic characterization of nosocomial candidemia from a Brazilian National Surveillance Program. PLoS One 2016;11:e0146909.
. King J, Pana ZD, Lehrnbecher T, et al. Recognition and clinical presentation of invasive fungal disease in neonates and children. J Pediatric
Infect Dis Soc 2017;6(suppl):S12–21.
. Liu M, Huang S, Guo L, et al. Clinical features and risk factors for blood stream infections of. Exp Ther Med 2015;10:1139–44.
. Kelly MS, Benjamin DK, Smith PB. The epidemiology and diagnosis of invasive candidiasis
among premature infants. Clin Perinatol 2015;42:105–17. viii–ix.
. Speth C, Rambach G, Lass-Flörl C. Platelet immunology in fungal infections. Thromb Haemost 2014;112:632–9.
. Santolaya ME, Alvarado T, Queiroz-Telles F, et al. Active surveillance of candidemia in children from Latin America: a key requirement for improving disease outcome. Pediatr Infect Dis J 2014;33:e40–4.
. Ascher SB, Smith PB, Clark RH, et al. Sepsis in young infants with congenital heart disease. Early Hum Dev 2012;88(suppl):S92–7.
. Yang Y, Guo F, Kang Y, et al. Epidemiology, clinical characteristics, and risk factors for mortality
of early- and late-onset invasive candidiasis
in intensive care units in China. Medicine (Baltimore) 2017;96:e7830.
. Blyth CC, Chen SC, Slavin MA, et al. Not just little adults: candidemia epidemiology, molecular characterization, and antifungal susceptibility in neonatal and pediatric
patients. Pediatrics 2009;123:1360–8.
. Kang SJ, Kim SE, Kim UJ, et al. Clinical characteristics and risk factors for mortality
in adult patients with persistent candidemia. J Infect 2017;75:246–53.
. Pappas PG, Lionakis MS, Arendrup MC, et al. Invasive candidiasis
. Nat Rev Dis Primers 2018;4:18026.
. Cavalheiro M, Teixeira MC. Biofilms: threats, challenges, and promising strategies. Front Med (Lausanne) 2018;5:28.
. Li WS, Chen YC, Kuo SF, et al. The impact of biofilm formation on the persistence of candidemia. Front Microbiol 2018;9:1196.
. Pongrácz J, Benedek K, Juhász E, et al. In vitro biofilm production of Candida
bloodstream isolates: any association with clinical characteristics? J Med Microbiol 2016;65:272–7.
. Tumbarello M, Fiori B, Trecarichi EM, et al. Risk factors and outcomes of candidemia caused by biofilm-forming isolates in a tertiary care hospital. PLoS One 2012;7:e33705.
. Guerra-Silveira F, Abad-Franch F. Sex bias in infectious disease epidemiology: patterns and processes. PLoS One 2013;8:e62390.
. Strollo S, Lionakis MS, Adjemian J, et al. Epidemiology of hospitalizations associated with invasive candidiasis
, United States, 2002-2012. Emerg Infect Dis 2016;23:7–13.
. Bitar D, Lortholary O, Le Strat Y, et al. Population-based analysis of invasive fungal infections, France, 2001–2010. Emerg Infect Dis 2014;20:1149–55.
. Wasserstein RL, Schirm AL, Lazar NA. Moving to a world beyond “p < 0.05”. Am Stat 2019;73(suppl):1–9.
Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
Candida; intensive care unit; invasive candidiasis; mortality; pediatric