ORIGINAL ARTICLE

Risk Factors for Candidemia in Pediatric IntensiveCare Unit Patients

Hasan Ağın & Ilker Devrim & Rana İşgüder &

Utku Karaarslan & Esra Kanık & İlker Günay &

Miray Kışla & Sultan Aydın & Gamze Gülfidan

Received: 19 September 2012 /Accepted: 6 January 2014# Dr. K C Chaudhuri Foundation 2014

AbstractObjectıve To determine the risk factors for developing candi-da infections in pediatric intensive care unit (PICU).Methods The present study was conducted as a case–con-trol study and included the population of patients whowere admitted to PICU during the period of March 2010–March 2011.Results During the study period, a total of 57 patients in PICUhad candidemia, 4 cases were excluded due to their PICU stayless than 48 h and one due to the insufficient data. The mostcommonly isolated Candida species was C. albicans, followedby C. parapsilosis. The median duration of hospitalization inPICU was higher (22.0 d) in candidemia patients compared tocontrol group (13.5 d) (p=0.037). The patients withcandidemia had higher rates of presence of mechanical venti-lation, presence of central venous catheter, and being undertotal parenteral nutrition; compared to the control group.Conclusıons The longer PICU durations, mechanical ventila-tion, central venous catheter, total parenteral nutrition were theassociated factors. Although trials for predicitive models orscoring systems for development of candidemia have been

performed; more future studies were required for practicalusage in clinics settings in order to prevent candidemia.

Keywords Pediatric intensive care unit . Candida . Riskfactors

Introduction

Infections with Candida species are one of the most leadingcauses of nosocomial bloodstream infections [1]. They arealso important in children, being one of the most frequentcauses of healthcare associated infections [2]. Candida infec-tions are not only associated with prolonged hospital stay andincreased cost of care; but also cause mortality in children [3].Several risk factors were reported for candidemia. One of theimportant risk factors for candida infections is intensive careunit stay [4, 5]. This is related with patient’s critical underlyingproblems, immune system malfunction and invasive proce-dures performed for monitoring and treatment [6]. Pediatricintensive care unit (PICU) patients with candidemia are athighest risk of death [7]. The studies concerning the riskfactors for developing candidemia in PICU are limited whencompared to adult group [3]. The reported risk factors forcandidemia in PICU include endotracheal intubation, pres-ence of central venous and arterial catheters (CVC) [8–10],parenteral nutrition [4, 11], prolonged ICU stay, previousbroad-spectrum antibiotics [4], immunodeficiency [10], neu-tropenia, malignancies [4], prolonged use of antimicrobialagents [12] and vancomycin [9], mechanical ventilation [6],bone marrow transplantation and prior colonization withCandida spp. [6, 10, 11, 13].

In the present study; the authors aimed to determine the riskfactors for developing candida infections in the PICU of a

H. Ağın :R. İşgüder :U. Karaarslan : E. KanıkDepartment of Intensıve Care, Dr. Behcet Uz Children’s Hospital,Izmir, Turkey

I. Devrim (*)Pediatric Infectious Disease Unit, Dr. Behcet Uz Children’s Hospital,Izmir 35100, Turkeye-mail: ilkerdevrim2003@yahoo.com

İ. Günay :M. Kışla : S. AydınDepartment of Pedıatrıcs, Dr. Behcet Uz Children’s Hospital,Izmir, Turkey

G. GülfidanDepartment of Clinical Microbiology, Dr. Behcet Uz Children’sHospital, Izmir, Turkey

Indian J PediatrDOI 10.1007/s12098-014-1343-5

tertiary level hospital in Turkey with a retrospective case–control study setting.

Material and Methods

Dr. Behçet Uz Children’s Hospital, Izmir, Turkey is a400-bed pediatric teaching hospital with annual outpatientvisits exceeding 465,000 in 2007 and approximately 20,000hospitalization per year. The PICU of Dr. Behçet UzChildren’s Hospital is 12-bed unit in which annual admissionis about 600 patient.

This retrospective case–control study included the patientswho were admitted to PICU during the period ofMarch 2010–March 2011. All patients admitted were identified using bothhospital and unit-specific databases. The neonates (babiesyounger than 28 d of life) were not included.

Inclusion Criteria

1. The patients with candidemia who were followed-up inPICU.

2. Candidemia was defined by isolation of Candida speciesfrom the blood samples of the patients hospitalized in thePICU for at least 48 h.

3. Presence of fever and signs of infection while bloodculture samples were obtained.

4. For the patients with one or more positive culture forcandida; the time of the first isolated culture was acceptedas the date for enroling into the study.

Exclusion Criteria

1. Patients who had been in PICU less than 48 h beforecandida isolation were excluded from the study group.

2. Patients with insufficient data in his or her files were alsoexcluded.

Selection of Control Group

Patients for the control group were selected using both hospi-tal and unit-specific databases. The control group was ran-domly selected among the children who were at the same ageand gender and had been in PICU at the same time period withthe case. Duration of PICU stay for a study case was calcu-lated from the date of admission to the date of candida isola-tion. Duration of stay for the matched control was from thedate of admission, to the date of candida isolation from thematched study case. Furthermore the patients in the controlgroup who had developed candida infections during the studyperiod were excluded from the study.

The investigators recorded the data including age, sex, typeof ICU, duration of hospitalization prior to infection, date ofinfection, the underlying disease and co-morbidities, indica-tions for admission. Possible risk factors such as antimicrobialtherapy, total parenteral nutrition, mechanical ventilation, in-sertion of central venous catheters, co-infection with othermicroorganisms were recorded. Also antimicrobial treatmentregiments were also recorded. The co-morbidities of the pa-tients such as malignancy, primary immunodeficiency, neu-tropenia (absolute neutrophil count, <1,500 mm3) and dura-tion of neutropenia were recorded.

SPSS, version 13.0 (inc USA) was used for statistical anal-yses. Distribution of numeric variables were tested by bothgraphical methods and Shapiro-Wilk test. The difference be-tweenmeans of numeric variables are tested by Student-t test orMann Whitney U test, where appropriate. The difference be-tween proportions were tested by continuity corrected Chi-Square or Fisher’sexact test. Risk factors and characteristicfactors with statistical significance by uni-variate methods wereentered into a multivariable conditional logistic regressionmodel. A stepwise approach was used to determine which ofthe studied factors or variables were most strongly associatedwith candida infections. The remaining variables were evalu-ated for associations with the candida infections with logisticregression. Avalue of p< 0.05was considered to be significant.

The study was approved by local ethics committee of theDr. Behçet Uz Children’s Hospital.

Results

During the study period, a total of 57 cases in PICU had beenreported as candidemia. Among them, 4 cases were excludeddue to their PICU stay less than 48 h and one due to theinsufficient data. The most commonly isolated Candida spe-cies was C. albicans (57.7 % of isolates), followed byC. parapsilosis (32.7 %). The other non-albicans species wereC. famata (3.8 %); C. dubliensis (1.9 %), C. Lusitansae(1.9 %) and C. kefyr (1.9 %). Fifty-two patients from PICUswere recruited as the control group.

Risk Factors

The median age of the patients were 7.5 y. The medianduration of “time passed from admission to PICU to thedetection of candidemia” was higher (22.0 d) in candidemiapatients compared to the PICU duration in the control group(13.5 d) (p= 0.037). Most of the patients with candidemia hadunderlying disease (92.3 %), while 69.2 % of the controlpatients had associated underlying disease and the differencewas significantly higher in candida group (p = 0.006). Theassociated chronic diseases were congenital heart disease,neurometabolic diseases, cardiomyopathies and etc.

Indian J Pediatr

The patients with candidemia had higher rates ofmechanical ventilation (p= 0.032), presence of central venouscatheter (p = 0.001), and total parenteral nutrition (p < 0.001)(Table 1).

Logistic regression analyses: Among the variables; signif-icant variables were entered into a multivariable conditionallogistic regression model (Table 2). The factors with increasedrisk of candida infections included associated underlying dis-ease (OR 4.9; 95 % CI 1.3–17.8), TPN administration(OR 3.7; 95 % CI 1.5–9.4), central venous catheterization(OR 3.3; 95 % CI, 1.3–8.3) (Table 2).

Discussion

The incidence of candidiasis has been rising dramatical-ly in the last two decades. Bloodstream infections dueto Candida spp. have become an important cause of

morbidity and mortality in hospitalized patients [1]. Inthe present study, C. albicans and C.parapsilosis werethe most frequent Candida spp. that was isolated fromPICU patients. This was the case in previous studies[12, 14, 15]. In some recent series C. parapsilosis werethe most common candida [16] whereas older reportssuggested the other non-albicans candida species couldbe dominant in different clinical settings [17].

In the present study; longer PICU stay (22.0 vs. 13.5 d) wasobserved in patient who had developed candidemia compar-ing to the control patients. There are a number of studies thathas demonstrated increased risk with longer PICU stay [9, 18,19]. On the other hand, longer PICU stay would increase theimpact of other risk factors such as possible requirement ofCVC, total parenteral nutrition (TPN) etc. which could in-crease the candidemia incidence even when present alone.

The authors have found that CVC had increased 3,3times of development of candidemia supported by previous

Table 1 Risk factors for development of candidemia in PICU

Candidemia cases Control group Odds ratio P value(% 95 CI)

Median intensive care stay duration 22 d 13.5 d N/A 0.037

Associated underlying disease 48 (92.3 %) 36 (69.2 %) 5.3 (1.6–17.3) 0.006

Mechanical ventilation 42 (80.8 %) 31 (59.6 %) 2.8 (1.1–6.8) 0.032

Presence of central venous catheterization 31 (59.6 %) 13 (25.0 %) 4.4 (1.9–10.2) 0.001

Total parenteral nutrition 40 (76.9 %) 21 (40.4 %) 4.9 (2.1–11.5) <0.001

Presence of urinary catheters 23 (45.1 %) 15 (28.8 %) 1.9 (0.8–4.4) 0.15

Previous gram negative bacteremia 5 (9.6 %) 4 (9.6 %) 1.2 (0.3–5) 1

Presence of congenital immune disorders 2 (3.8 %) 2 (3.8 %) 1 (0.1–7.3) 1

3rd generation cephalosporine therapy 37 (71.2 %) 27 (51.9 %) 0.4 (0.2–1) 0.07

Carpabenem therapy 22 (42.3 %) 24 (46.2 %) 0.8 (0.4–1.8) 0.84

Glycopeptide therapy 22 (42.3 %) 27 (51.9 %) 0.7 (0.3–1.4) 0.43

Ciprofloxacilin therapy 2 (3.8 %) 2 (3.8 %) 1 (0.1–7.3) 1.000

Requirement for mechanical ventilation in thefirst day of admission to PICU

21 (40.4 %) 13 (25.5 %) 2 (0.9–4.6) 0.14

Presence of cardiopulmonary arrest 5 (9.6 %) 7 (13.7 %) 0.7 (0.2–2.3) 0.75

Presence of hypoxia 8 (15. 4 %) 5 (10.2 %) 1.7 (0.5–5.6) 0.55

Table 2 Risk factors for the development of Candida infection through the multivariable logistic regression analysis

Logistic regression predicting candidemia in patients hospitalized in pediatric intensive care unit

Risk factors B S.E. Wald Sig Odds ratio(OR) 95 % CI

Lower Upper

Underlying disease 1.59 0.65 5.9 0.015 4.9 1.3 17.8

Central venous catheterization 1.21 0.46 6.7 0.01 3.3 1.3 8.3

Total parenteral nutrition 1.3 0.47 8.0 0.005 3.7 1.5 9.4

Constant −0.553 0.33 2.7 0.57

The variables listed in Table 1 were included in the model. Significant variables are shown

Indian J Pediatr

studies reporting CVC as an important risk factor [3, 9, 20]. Athree fold increase in the occurrence of disseminated infectionwas also reported [8] with the presence of central venousline. In the present study, the rate of candidemia due toC. parapsilosis was high; which was not suprising sinceC. parapsilosis has been reported to be associated withCVC infections [21]. This may be due to the ability toproduce large amounts of biofilm by C. parapsilosis onthe surface of catheters [22]. There is also a high fre-quency of candida parapsilosis colonization in the hands[23, 24]. However, a recent study reported no significantincrease in C. parapsilosis group with CVC compared tothe other candida species[25] showing the problematicfeature of C. parapsilosis.

Hyperalimentation (TPN) rate was also significantly higherin the present candidemic patients and increases the risk 3,7times. Receiving TPN was reported as an independent riskfactor in multiple reports [3, 18, 20, 25]. Intravenous hyper-alimentation requires CVC and generally used for patients inICU or patients with co-morbid diseases. However, candidaspecies, especially C. parapsilosis were reported to causecandidemia in pediatric patients even receiving total parenteralnutrition at home settings [26].

Although the rates of mechanical ventilation was signifi-cantly higher in candidemic patients, the authors could notfind any relationship for developing candidemia in logisticregression model. Mechanical ventilation, was reported to beone of the independent risk factors, especially when it isprolonged [9, 20]. The present results could be due to notanalysing the relationship of the duration of mechanical ven-tilation and developing of candidemia.

Antimicrobial therapy was thought to be a risk fac-tor since prolonged use compromises the normal intes-tinal flora and weakens colonization resistance [27, 28].This may be responsible from overcolonization by en-dogenous organisms such as Candida species [29].However, in the present study the authors could notfind such a relationship associated with previous broadspectrum antimicrobial usage or 3rd generation cepha-losporin usage (p>0.05). In the present study, glyco-peptides; carpabenems or ciprofloxacilins were also notfound to be associated with candidemia (p>0.05). Inauthors opinion this could be due to the patients beingtreated with more broad spectrum antibiotics if theirhospitalizations were prolonged.

In conclusion, several risk factors for candidemia inPICU had been investigated in this article. Among them,longer PICU stay, presence of central venous cathetersand total parenteral nutrition were associated risk factors.Although trials for predictive models or scoring systemsfor development of candidemia have been performed;further prospective studies were required for risk factorsfor special candida species.

Contribution Dr. Ilker Devrim will act as guarantor for this paper.

Conflict of Interest None.

Role of Funding Source None.

References

1. Pfaller MA, Diekema DJ, Jones RN, Sader HS, Fluit AC, Hollis RJ,et al. SENTRY Participant Group. International surveillance ofbloodstream infections due to Candida species: Frequency of occur-rence and in vitro susceptibilities to fluconazole, ravuconazole, andvoriconazole of isolates collected from 1997 through 1999 in theSENTRY antimicrobial surveillance program. J Clin Microbiol.2001;39:3254–9.

2. Wisplinghoff H, Seifert H, Tallent SM, Bischoff T, Wenzel RP,Edmond MB. Nosocomial bloodstream infections in pediatric pa-tients in United States hospitals: Epidemiology, clinical features andsusceptibilities. Pediatr Infect Dis J. 2003;22:686–91.

3. Zaoutis TE, Prasad PA, Localio AR, Coffin SE, Bell LM, Walsh TJ,et al. Risk factors and predictors for candidemia in pediatric intensivecare unit patients: Implications for prevention. Clin Infect Dis.2010;51:e38–45.

4. Arslankoylu AE, Kuyucu N, Yilmaz BS, Erdogan S. Symptomaticand asymptomatic candidiasis in a pediatric intensive care unit. Ital JPediatr. 2011;37:56.

5. Singhi S, Deep A. Invasive candidiasis in pediatric intensive careunits. Indian J Pediatr. 2009;76:1033–44.

6. Filioti J, Spiroglou K, Panteliadis CP, Roilides E. Invasive candidi-asis in pediatric intensive care patients: Epidemiology, risk factors,management, and outcome. Intensive Care Med. 2007;33:1272–83.

7. Zaoutis TE, Coffin SE, Chu JH, Heydon K, Zhao H, Greves HM,et al. Risk factors for mortality in children with candidemia. PediatrInfect Dis J. 2005;24:736–9.

8. Zaoutis TE, Greves HM, Lautenbach E, Bilker WB, Coffin SE. Riskfactors for disseminated candidiasis in children with candidemia.Pediatr Infect Dis J. 2004;23:635–41.

9. Zaoutis T. Candidemia in children. Curr Med Res Opin. 2010;26:1761–8.

10. Smith MJ. Catheter-relatedbloodstreaminfections in children. Am JInfect Control. 2008;36(S173):e1–3.

11. Galal N, Badawy A, Khalaf-Allah O, Youssef A. Identification of T-lymphocyte function in healthy vs. septicpreterms and its relation tocandidal infections in the hospital setting. Indian J Pediatr. 2012;79:348–52.

12. Garcia-San Miguel L, Cobo J, Martos I, Otheo E, Muriel A, PintadoV, et al. Risk factors for candidemia in pediatric patients with con-genital heart disease. Infect Control Hosp Epidemiol. 2006;27:576–80.

13. Singhi S, Rao DS, Chakrabarti A. Candida colonization andcandidemia in a pediatric intensive care unit. Pediatr Crit CareMed. 2008;9:91–5.

14. Belet N, Ciftçi E, Aysev D, Güriz H, Uysal Z, Taçyildiz N, et al.Invasive Candida infections in children: The clinical characteristicsand species distribution and antifungal susceptibility of Candida spp.Turk J Pediatr. 2011;53:489–98.

15. Kuzucu C, Durmaz R, Otlu B, Aktas E, Gulcan H, Cizmeci Z. Speciesdistribution, antifungal susceptibility and clonal relatedness ofCandida isolates from patients in neonatal and pediatric intensive careunits at a medical center in Turkey. New Microbiol. 2008;31:401–8.

16. Pemán J, Cantón E, Linares-Sicilia MJ, Roselló EM, Borrell N, Ruiz-Pérez-de-Pipaon MT, et al. Epidemiology and antifungal

Indian J Pediatr

susceptibility of bloodstream fungal isolates in pediatric patients: ASpanish multicenter prospective survey. J Clin Microbiol. 2011;49:4158–63.

17. Singhi SC, Reddy TC, Chakrabarti A. Oral itraconazole in treatmentof candidemia in a pediatric intensive care unit. Indian J Pediatr.2004;71:973–7.

18. Çelebi S, Hacımustafaoğlu M, Özdemir Ö, Özkaya G. Nosocomialcandidaemia in children: Results of a 9-year study. Mycoses.2007;51:248–57.

19. Blyth CC, Chen SC, Slavin MA, Serena C, Nguyen Q, Marriott D,et al. Not just little adults: Candidemia epidemiology, molecularcharacterization, and antifungal susceptibility in neonatal and pediat-ric patients. Pediatrics. 2009;123:1360–8.

20. Nucci M, Anaissie E. Should vascular catheters be removed from allpatients with candidemia?An evidence-based review. Clin Infect Dis.2002;34:591–9.

21. Ayala-Gaytán JJ, Alemán-Bocanegra MC, Guajardo-Lara CE.Valdovinos-Chávez SB [Catheter-associated bloodstream infections.Review of five-year surveillance among hospitalized patients]. RevMed Inst Mex Seguro Soc. 2010;48:145–50.

22. Levin AS, Costa SF, Mussi NS, Basso M, Sinto SI, MachadoC, et al. Candida parapsilosis fungemia associated with im-plantable and semi-implantable central venous catheters and

the hands of healthcare workers. Diagn Microbiol Infect Dis.1998;30:243–9.

23. Dotis J, Prasad PA, Zaoutis T, Roilides E. Epidemiology, risk factorsand outcome of candida parapsilosis bloodstream infection in chil-dren. Pediatr Infect Dis J. 2012;31:557–60.

24. Bonassoli LA, Bertoli M, Svidzinski TI. High frequency of Candidaparapsilosis on the hands of healthy hosts. J Hosp Infect. 2005;59:159–62.

25. Yapar N, Pullukcu H, Avkan-Oguz V, Sayin-Kutlu S, Ertugrul B, SacarS, et al. Evaluation of species distribution and risk factors of candidemia:A multicenter case–control study. Med Mycol. 2011;49:26–31.

26. Cano MV, Perz JF, Craig AS, Liu M, Lyon GM, Brandt ME, et al.Candidemia in pediatric outpatients receiving home total parenteralnutrition. Med Mycol. 2005;43:219–25.

27. Vollaard EJ, Clasener HA. Colonization resistance. AntimicrobAgents Chemother. 1994;38:409–14.

28. van der Waaij D. Colonization resistance of the digestive tract:clinical consequences and implications. J Antimicrob Chemother.1982;10:263–70.

29. Samonis G, Gikas A, Anaissie EJ, Vrenzos G, Maraki S, Tselentis Y,et al. Prospective evaluation of effects of broad-spectrum antibioticson gastrointestinal yeast colonization of humans. Antimicrob AgentsChemother. 1993;37:51–3.

Indian J Pediatr