Published online December 1, 2006
PEDIATRICS Vol. 118 No. 6 December 2006, pp. 2359-2364 (doi:10.1542/peds.2006-1311)
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ARTICLE

Risk Factors for Progression to Invasive Fungal Infection in Preterm Neonates With Fungal Colonization

Paolo Manzoni, MDa, Daniele Farina, MDa, MariaLisa Leonessa, MDa, Elisa Antonielli d'Oulx, MDa, Paolo Galletto, MDa, Michael Mostert, MDb, Roberto Miniero, MD, PhDa and Giovanna Gomirato, MD, PhDa

a Neonatology and Hospital Neonatal Intensive Care Unit
b Department of Pediatric Sciences, Azienda Ospedaliera Regina Margherita-S Anna, Torino, Italy


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Colonization by Candida spp is a major risk factor for development of fungal sepsis, but little is known about the variables associated with progression to invasive disease in already colonized neonates. We investigated such variables in a large number of colonized preterm neonates in an NICU.

SETTING. This study was conducted in the Department of Neonatology and the NICU at Sant'Anna Hospital in Torino, Italy.

DESIGN AND PATIENTS A database search of clinical charts and weekly surveillance cultures was used to identify all neonates with birth weights <1500 g (very low birth weight) who were admitted to our NICU during 1998–2005 and were colonized (≥1 site) by Candida spp during their stay, as well as infants with invasive fungal infection. The association between a number of factors with progression to invasive fungal infection was evaluated. Those shown to be significantly associated by univariate analysis were cross-checked by logistic regression.

RESULTS. Colonization occurred in 201 infants (32.1% of very low birth weight admitted neonates), and invasive fungal infection occurred in 51 (8.1%) of them, with an overall progression rate of 0.25. At univariate analysis, 10 factors (namely low birth weight, low gestational age, use of third-generation cephalosporins, endotracheal intubation, duration of stay in the NICU, bacterial sepsis, colonization of central venous catheter, of endotracheal tube, of gastric aspirate, or in ≥3 [multiple] sites) were associated with an increased risk of progression, whereas prophylaxis with fluconazole was associated to a decreased risk. After logistic regression, only colonization of central venous catheter and colonization in multiple sites remained significantly associated with invasive fungal infection. Fluconazole prophylaxis remained an independent protective factor.

CONCLUSIONS. Central venous catheter colonization and multiple-site colonization are independent risk factors and predictors of progression to fungal sepsis in preterm very low birth weight neonates colonized by Candida spp during their stay in the NICU. Fluconazole prophylaxis is an independent protective factor. These findings can be used to improve the surveillance, prophylaxis, or preemptive measures in neonates at high risk.

Key Words: very low birth weight • preterm infant • Candida • infection • colonization • progression

Abbreviations: VLBW—very low birth weight • ELBW—extremely low birth weight • IFI— invasive fungal infection • RR—relative risk • CI—confidence interval • DOL—day of life • LOS—late-onset sepsis • CVC—central venous catheter • OR—odds ratio

Invasive fungal infection (IFI) by Candida spp has become an increasing problem over the last 20 years. Fungi are the third most frequent causal agent of late-onset sepsis (LOS) in preterm neonates,1–3 with an estimated incidence of 2.6% to 3.1% in very low (<1500 g) birth weight (VLBW)2,4 and 10% to 16% in extremely low (<1000 g) birth weight (ELBW) neonates in the NICU,5 with a crude mortality of 30% to 75%.1,5

Most factors associated with an increased risk of fungal colonization and infection6–10 are closely related to the clinical and demographic characteristics of preterm neonates and the long and invasive care they require through their lack of immunocompetence.

It is also clear that IFI is usually preceded by colonization by the same species,11,12 and colonization itself is a major IFI risk factor.6–13 Infants who develop candidemia are 6 times more likely to have been previously colonized by fungi than matched controls.12 Attention, however, has so far been directed to all neonates admitted to NICU, with no specific reference to those already colonized. As a result, it is not known whether the variables associated with the risk of progression to IFI are equally applicable to noncolonized and colonized neonates, nor whether other risk factors are specific for the latter only. The clinical significance of this issue is evident. More precise identification of neonates with a higher risk of IFI in NICU would be the prelude to the elaboration of more effective prophylactic and preemptive measures.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Design and Setting
This nested, case-control study was performed by reviewing the clinical and microbiologic records of all VLBW neonates admitted to our NICU from January 1, 1998, to December 31, 2005. All patients diagnosed with fungal colonization through weekly surveillance cultures during their stay in NICU were identified and considered eligible for the study. Fungal colonization was defined by a positive surveillance culture at any time during their stay in NICU or at base line.13 The cohort was thus defined as all neonates colonized with fungi at any time point; cases were colonized neonates with IFI and controls were colonized neonates without IFI.

The study was conducted at the Sant'Anna Hospital, Turin, Italy. This is a level III unit in the greater Turin area (1 500 000 inhabitants and 15 000 births per year), with a mean delivery rate of 4000 per year and 150 admissions to its NICU.

Population
The exclusion criteria were incomplete data or charts and/or incomplete weekly surveillance cultures (see "Fungal Isolation and Identification From Cultures").

The demographic, gestational, and perinatal data of the eligible neonates were examined, as well as their antenatal risk factors (specifically those associated with maternal and fetal diabetes); septic episodes; type and duration of nutrition, clinical, and microbiologic-culture results; laboratory data; and treatments and outcome. All diagnoses of IFI met the appropriate laboratory and clinical criteria.

Other causes that might have affected the frequency or relative weight of factors increasing or decreasing the risk of IFI were ruled out. The infection control policies were not significantly different in our Unit, nor in the hospital as a whole over the period, and we followed the criteria expressed in protocols produced and regularly checked by a dedicated control-of-nosocomial-infections committee. In addition, the quarterly surveillance reports issued by this committee never disclosed either an increase of fungal isolates that might have been related to problems in infection control, nor any episodic increase in Candida parapsilosis isolates (often related to the spread of hospital-acquired fungal infections). Finally, no changes occurred in the policies and protocols regarding the use of antenatal and neonatal antibiotics or steroids or neonatal H2 antagonists, nor in nutritional protocols and policy.

Fungal Isolation and Identification From Cultures
The following cultures were obtained: ear canal swab at birth; weekly cultures of surveillance (≥3 of the following: stool or rectal swab, gastric aspirate, nasopharyngeal or endotracheal secretions if intubated, and urine); cultures from surgical and mechanical devices when removed (endotracheal tubes and intravascular catheters, as well as drains and similar devices); and cultures from any site indicated by the physician and justified clinically (eg, skin, respiratory secretions, etc).

Baseline fungal colonization was defined as (a) ear canal swab at birth positive for fungi, or (b) isolation of fungi from any site during day of life (DOL) 1 to 2. Colonization in ≥3 sites was classed as "multiple." Each site was considered once only, even if repeatedly positive. Stool, gastric aspirates, and surgical and intravascular devices were collected in sterile containers; respiratory secretions were obtained with an infant mucus sterile extractor kit supplied with two 3.3-mm suction catheters (Vygon, Ecouen, France); skin, ear, and nasopharynx specimens were obtained on swabs (Labobasi SA, Novazzano, Switzerland); and blood draws for culture were submitted in dedicated specimens (BacT/Alert PF; BioMerieux Inc, Durham, NC). Urine samples were obtained by sterile urethral catheterization or suprapubic aspiration of the bladder; samples collected from indwelling catheters or from urine bags were not considered.

For the identification of fungi, all specimens were inoculated onto chromogen culture plates (Albicans ID; Biomerieux Inc, Durham, NC), which allow for rapid Candida albicans identification through the blue staining of the colonies after 48 hours of incubation at 37°C. Differently stained colonies were speciated through a miniaturized system of biochemical tests (Vitec Yeast; Biomerieux Inc). The surveillance and culture collection and analysis procedures and methods were not changed at any time during the period studied.

Definition of IFI
A microbiologically documented (proven) fungal infection was defined through a positive culture from either (a) blood, or (b) urine (collected by suprapubic sterile puncture or sterile bladder catheterization, with growth of >10 000 fungal organisms per mL), or (c) cerebrospinal fluid.

A positive culture from urine collected without sterile procedures (ie, by means of urine bags or indwelling catheters or with growth of <10000 fungal organisms per mL) was considered as fungal colonization of urine. These criteria conform to the guidelines in international consensus documents14–16 and the recommendations of the Italian Neonatology Society's Fungal Infections Task Force.17

Antifungal Prophylaxis With Fluconazole and Treatment of IFIs
We reported previously that since January 2001, as a Unit policy, all VLBW infants admitted to our Unit receive prophylactic fluconazole.18 The regimen is 6 mg/kg fluconazole (Diflucan; Pfizer Italia s.r.l., Latina/Roma, Italy) every 72 hours in the first week of life, then every 48 hours from the second week until DOL 30 for neonates with birth weight 1000 to 1500 g and DOL 45 for ELBW neonates, or until earlier discharge, or until the need for systemic antifungal therapy (mostly with liposomal amphotericin B) because of the onset of IFI. This schedule was partially modified during a 15-month period between 2004 and 2005, when approximately one third of the VLBW neonates received 3 mg/kg and another one third did not receive fluconazole; this was a result of the involvement of our NICU in a multicenter trial on fluconazole performed with a NICU network in Italy.

When IFI was presumed, fluconazole was suspended, and systemic antifungal therapy with drug(s) other than fluconazole was given empirically until the culture results were known.20 Fluconazole is administered starting from DOL 1 as a single dose intravenously or orally, depending on the availability of a venous line and/or on the tolerance of oral feeding. This schedule is drawn from the literature.13,19 No agent-related adverse effects or reactions were recorded, and there were no discontinuances in fluconazole prophylaxis. When diagnosing an episode, removal of central venous catheters (CVCs) was the standard policy for the management of central intravascular lines.

Statistical Analysis of Data
The association of all factors listed in Table 1 with IFI was determined by univariate analysis. The variables found having a significant association (P < .05) with an increased or decreased risk of IFI were subsequently examined in a multivariate logistic regression model to identify any independent associations using a backward conditional strategy: Those with the highest P values were removed, one by one, until all variables had P values of <.05.


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  		TABLE 1 Neonate Characteristics and Univariate Analysis for the Factors Associated With Progression to IFI in Colonized Neonates (n = 201)

 
Yates' corrected {chi}2 to compare proportions and relative risk (risk ratio) estimates, differences in risk to compare incidence rates among groups, and t test for continuous variables were used as appropriate and calculated with SPSS version 9.0 statistical software.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
During the study period, 689 infants were admitted to our NICU and survived >3 days. Sixty-one were discarded because of incomplete data or charts (n = 27) and incorrect or incomplete weekly surveillance cultures (n = 34). Colonization occurred in 201 (32.1%) of the remaining 628 neonates: Their demographics, clinical, management, colonization and outcome characteristics are illustrated in Table 1. The fungal species isolated as colonization were C albicans (168 patients); C parapsilosis (32 patients); Candida glabrata (16 patients); Candida krusei (8 patients); Candida tropicalis (3 patients); and Aspergillus fumigatus, Candida lusitaniae, and Candida guilliermondii (2 cases each). Thirty neonates were colonized by ≥2 species, with variable associations.

IFI occurred in 51 neonates (8.1%), with a progression rate of 0.25 (51 of 201). The 51 episodes of IFI occurred at a median age of 21 days and were caused by C albicans (42 patients); C parapsilosis (7 patients); C glabrata (4 patients); C krusei (2 patients); and Aspergillus fumigatus, C tropicalis, and C guilliermondii (1 patient each). Seven neonates were infected by 2 species: C albicans + C parapsilosis (4 patients), C albicans + C krusei (1 patient), C parapsilosis + C tropicalis (1 patient), and C albicans + C glabrata (1 patient).

The breakdown of IFI cases was as follows: 38 bloodstream infections, 8 urinary tract infections, 4 meningitis, and 1 detected at autopsy. The overall mortality (before hospital discharge, not attributable to fungi) in the 201 colonized neonates was 13.2% (compared with 9.8% in the neonates not colonized by fungi admitted to our NICU in the same period). Overall mortality was significantly lower (P = .01) in the colonized neonates who received fluconazole prophylaxis (5.8% vs 17.0%, respectively).

Univariate analysis (see Table 1) showed that among already colonized neonates, colonization of CVC, colonization in multiple sites, duration of stay in NICU in days, low birth weight, low gestational age, days on supplemental oxygen, positive culture from gastric aspirate, positive culture of endotracheal tube, intubation, presence of bacterial sepsis and use of third-generation cephalosporins were significantly (P < .05) associated with IFI, although fluconazole prophylaxis was significantly protective.

We also analyzed some sets of clusters: <750, 750 to 1000, 1001 to 1250, and 1251 to 1500 g for birth weight and <27, 28 to 32, and >33 weeks for gestational age. A significant association was only found for the 750- to 1000-g cluster (P = .03; 95% confidence interval [CI]: 1.058–11.324) and for <27 weeks' gestational age (P = .04; 95% CI: 1.095–9.880).

Logistic regression (see Table 2) indicated that only colonization of CVC (P < .001) and colonization in multiple sites (P = .001) retained significance as independent predictors of IFI in already colonized neonates. Fluconazole prophylaxis retained significance (P = .03) as an independent protective factor.


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  		TABLE 2 Multivariate Analysis Controlling for the Factors Significantly (P < .05) Associated at Univariate Analysis With Progression to IFI in the Colonized Neonates

 

   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Many factors were shown to be associated with increased risk of fungal infection in both multicenter and single-center studies,4–13 and related to the wide range of conditions reported as at risk for IFI, almost every preterm neonate during its stay in NICU seems destined to feature at least 1. Thus, the clinical usefulness of these variables in separating infants at high risk from those at low risk in a NICU is questionable, because most preterm neonates should be considered at high risk.

Colonization by Candida spp is very frequent in NICU subsets and is a necessary first step in the pathogenesis of systemic infection.6,7,9,21 Because most IFI arise endogenously22 and are usually preceded by colonization by the same species,11,12,23 identification of factors leading to dissemination and systemic fungal infection in already colonized infants could provide more specific tools to identify the preterm infants at high risk for IFI.

The main finding of the our study is the demonstration of 2 new risk factors independently related to progression to IFI in colonized VLBW neonates. Contrary to expectations, the data provided by our systematic surveillance cultures ruled out independent associations for most of the variables classed as risk factors for fungal sepsis in preterm neonates in NICUs in the literature.

Conditions and management choices such as low birth weight, low gestational age, use of third-generation cephalosporins, steroids and H2 blockers, intubation and mechanical ventilation, use of intravenous nutrition and medication, and thrombocytopenia were described as associated with IFI with odds ratios (ORs) varying from 2.0 to 10.6.4,12,20,24,25 Nevertheless, these relationships seem to lose significance when only colonized neonates are considered.

An important result of our study concerns the CVC, because its presence4,26 and duration27 are well-known, powerful risk factors for IFI. Some studies have even advocated antifungal prophylaxis in preterm infants only when they have a central line positioned.28 However, as with the other risk factors in the literature, the data from our colonized infants rule out the CVC itself as a risk factor, but in turn show that a colonized CVC gives the infant a tenfold higher risk of progression to invasive fungal disease compared with other colonized neonates. It is possible that it serves as a site for continued Candida growth and dissemination that is particularly difficult to eradicate. The importance of this finding is obvious, because it means that prevention of IFI may be better achieved by preventing colonization of CVC.

Based on our data, higher numbers of sites colonized give higher frequencies of progression to IFI, as already shown by Kaufman et al.13 In the same way, high predictivity of an increased number of sites or a high colonization index were described for adult patients with hematologic malignancies or admitted to a surgical ICU.29–32 Consistently, there is evidence that in the intestinal tract (ie, the site from where dissemination may occur for some patients) the higher the mucosal concentration of Candida, the greater the chance of translocation across the intestinal epithelium.21

Our single-center study shows that the characteristics of colonization are an important predictor of progression to IFI, thus underlining the usefulness of performing systematic culture surveillance in a NICU setting. Through careful monitoring of the colonization status of our preterm infants, we narrowed the dozens of hypothesized risk factors for IFI down to 2, allowing us an easier identification and a more accurate targeting of the preterm neonates at high risk of IFI in NICU. However, it is noteworthy that prophylactic fluconazole greatly reduces the risk and is the only independent protective factor identified in our study.

Fluconazole prevents colonization, hence IFI, when administered from the early days of life,13,19,33–35 but its efficacy in decreasing the rate of progression in already-colonized infants has only been assessed in 1 report.18 Although it may need to be present at the time of exposure to be most efficacious, our data suggest that fluconazole may work by preventing progression and limiting proliferation as well.

This information is important because other prophylactic drugs, such as oral nystatin, are ineffective against dissemination in a colonized patient.36 Clearly, this ability of fluconazole could lead to more selective identification of candidates for prophylaxis and should be studied further.


   CONCLUSIONS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The novel risk factors described in this article may lead to more effective and selected preventive strategies and may help the clinician in making an early diagnosis of dissemination when it occurs, as well as in considering empiric management (and not only prophylaxis) of those infants with the highest OR of progression to IFI.


   FOOTNOTES
 
Accepted Aug 29, 2006.

Address correspondence to Paolo Manzoni, MD, Neonatology and Hospital NICU, Azienda Ospedaliera Regina Margherita-S Anna, C Spezia 60, 10136 Torino, Italy. E-mail: paolomanzoni{at}hotmail.com

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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