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Invasive Fungal Infections in Neonates in Canada

Epidemiology and Outcomes

Ting, Joseph Y., MBBS, MPH*; Roberts, Ashley, MD, MEd*; Synnes, Anne, MDCM, MHSc*; Canning, Roderick, MD, FRCPC; Bodani, Jaya, MD; Monterossa, Luis, MD§; Shah, Prakesh S., MD, MSc¶,‖ for the Canadian Neonatal Network Investigators

The Pediatric Infectious Disease Journal: November 2018 - Volume 37 - Issue 11 - p 1154–1159
doi: 10.1097/INF.0000000000001968
Maternal-Neonatal Reports

Background: Neonatal fungemia is associated with adverse neonatal outcomes and higher overall healthcare expenditure. Our objective is to review the epidemiology of invasive fungal infections (IFIs) in neonates in Canada.

Methods: A retrospective cohort study using data collected by the Canadian Neonatal Network (CNN) was conducted. Using a nested matched cohort study design, risk factors and outcomes of neonates born <33 weeks gestation (n = 39,305) during 2003–2013 were compared between neonates diagnosed with an IFI during their stay to infection-free controls.

Results: Overall incidence of IFI among all admitted neonates was 0.22% (n = 286), while the incidence of IFI in the group of neonates born <33 weeks gestation was 0.64%. Of the isolates, 170 (59%) had Candida albicans and 59 (21%) had Candida parapsilosis. Risk factors for IFI were lower gestation, male sex, Apgar score <7 at 5 minutes, higher severity of illness score, maternal diabetes and vaginal birth. Neonates with IFI had higher odds of mortality [adjusted odds ratio (aOR): 1.60; 95% confidence interval (CI): 1.06–2.43], necrotizing enterocolitis (aOR: 2.97; 95% CI: 1.76–5.01) and severe retinopathy of prematurity (aOR: 2.15; 95% CI: 1.26–3.67).

Conclusions: The overall incidence of IFI in neonates was low in Canada in comparison to other large population cohort studies; however, the mortality and morbidity remained high.

From the *Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada

Department of Pediatrics The Moncton Hospital, Moncton, New Brunswick, Canada

Department of Pediatrics, Regina General Hospital, Regina, Saskatchewan, Canada

§Department of Pediatrics, Saint John Regional Hospital, Saint John, New Brunswick, Canada

Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada

Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada

**The Canadian Neonatal Network Investigators are listed in the Appendix.

Accepted for publication December 22, 2017.

Organizational support was provided by the Maternal-Infant Care Research Centre (MiCare) at Mount Sinai Hospital in Toronto, ON, Canada. MiCare is supported by a team grant from the Canadian Institutes of Health Research (CIHR, FRN87518) and in-kind support from Mount Sinai Hospital. Dr. Shah holds an Applied Research Chair in Reproductive and Child Health Services and Policy Research awarded by the CIHR (APR-126340). The funding agencies had no role in the design and conduct of the study; collection, analysis and interpretation of the data; the writing of the report; and the decision to submit the manuscript for publication.

The authors have no conflicts of interest to disclose.

J. Y. T. conceptualized and designed the study, contributed to the interpretation of data, drafted the initial manuscript, and approved the final manuscript as submitted. A.R., A.S., R.C., J.B. and L.M. contributed to the concept, design and interpretation of data, critically reviewed and revised the draft manuscript for intellectual content and approved the final submitted version of the article. P.S.S. conceptualized, designed and supervised the study, contributed to the interpretation of data, critically reviewed and revised the manuscript for intellectual content and approved the final manuscript as submitted. All authors agree to be accountable for all aspects of the work presented, including the accuracy and integrity of the findings reported.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Prakesh S. Shah, MD, MSc, Department of Pediatrics, University of Toronto, 19-231F, 600 University Ave, Toronto, ON M5G 1X5, Canada. E-mail: Prakeshkumar.Shah@sinaihealthsystem.ca.

Invasive fungal infections (IFIs) continue to be an important cause of mortality and morbidity among preterm infants.1 While representing approximately 10% of nosocomial bloodstream infections in neonates, fungemia is also associated with an increased risk of bronchopulmonary dysplasia, retinopathy of prematurity (ROP), impaired neurodevelopment and higher overall healthcare expenditure.2–4 The rate of mortality secondary to fungemia has been reported to be 30%, whereas composite outcomes of death/neurodevelopmental impairments have been observed in 70% of extremely-low-birth-weight survivors.1 , 5 , 6 A previous study of 150 neonatal intensive care units (NICUs) revealed that fungal meningitis accounted for the deaths of 41% of infants with culture-positive Candida meningitis and 71% of infants with blood and cerebrospinal fluid (CSF) cultures both positive for Candida.7

The high rates of fungemia reported in the 1980s and 1990s have declined substantially over the past decade.6 In very low birth weight (VLBW) infants, fungemia rates range between 1.0% and 7.5% from recent studies, which vary between centers and inclusion criteria.8–10 Risk factors associated with fungemia in neonates include preterm birth, cephalosporin or carbapenem use within 7 days before blood culture retrieval, fungal colonization, parenteral nutrition, delayed initiation of enteral feeds, use of histamine-2 blockers, prolonged intubation, abdominal surgery and increased length of stay.11–13 Common NICU interventions, including antibiotics and dexamethasone, further stimulate the gastrointestinal colonization and dissemination of Candida albicans.14 , 15 Among infants diagnosed with candidemia, 5%–25% develop meningitis,5 , 16 and of those, up to two-thirds may present no evidence of candidemia at the time of diagnosis.5 , 7

Based on the high incidences of IFIs reported in very preterm or VLBW neonates, several studies suggest the administration of prophylactic fluconazole as the preferred therapeutic approach; however, the results of such studies need to be interpreted and applied cautiously.17 Nonetheless, universal antifungal prophylaxis has not been widely adopted in Canadian NICUs, with only 2.9% of infants <33 weeks gestational age (GA) receiving prophylactic antifungal agents during their hospitalization in recent years, according to Canadian Neonatal Network (CNN) surveillance (unpublished data, Canadian Neonatal Network 2016 Annual Report http://www.canadianneonatalnetwork.org/). We speculate that low administration of prophylactic agents may be because of the perception of already low fungemia rates in Canadian NICUs. In the present study, we aimed to evaluate the incidence, risk factors, microbiology and outcomes associated with IFI among infants in Canadian NICUs to help inform clinicians about the need for universal antifungal prophylaxis.

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MATERIALS AND METHODS

Study Design and Population

A retrospective cohort study using data collected by the CNN was conducted. Information from 85% of tertiary level NICU admissions across 29 units was captured during the study period. All infants with GAs ranging from 22 to 42 weeks, admitted between January 1, 2003 and December 31, 2013, were reviewed. Data were abstracted from infant medical records according to standardized definitions and transmitted to the CNN coordinating center in Toronto. Infants with missing information on demographics or IFI diagnoses were excluded.

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Outcomes

Cases of IFI were defined as infants with positive growth of fungus in their blood culture or CSF samples during their hospital stay. Necrotizing enterocolitis (NEC) was classified according to modified Bell staging criteria.18 , 19 Severe ROP was defined as ROP stages 3–5 in either eye.20 Bronchopulmonary dysplasia was described operationally as the receipt of oxygen at 36 weeks’ postmenstrual age or at discharge, whichever came first.21

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Statistical Analysis

The study population was summarized using descriptive statistical methods. The incidences of IFI and case fatality rate (CFR) were calculated for various GAs or birth weight (BW) groups. The change in the incidence of IFI over time from 2003 to 2013 for each GA or BW group and the distribution of IFI across GA was calculated and presented graphically. To examine the association between IFI and major neonatal adverse outcomes, and the risk factors that were independent of GA and BW, a 1:3 nested matched cohort study was conducted for very preterm (<33 weeks GA) neonates. The nested matched cohort was identified to match the cases of IFI by GA in weeks, BW (±50 g) and major congenital anomalies (yes/no) using SAS %MATCH macro with OPTIMAL method. The selection of infants without IFI was random. Patient characteristics were compared between case and matched cohort groups using the χ2 and Student t test for categorical and continuous variables, respectively. Multivariable conditional logistic regression models were applied to compare major neonatal adverse outcomes between the case and matched cohort groups, and adjusted for gender, Apgar score at 5 minutes, maternal diabetes, prolonged rupture of membranes and mode of delivery, which are known clinical risk factors for IFI. All data management and statistical analyses were performed using SAS V.9.3 (SAS Institute, Cary, NC). A 2-sided significance level of 0.05 was used.

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Ethics Approval

Data collection and transmission from each site were approved by either local research ethics boards or hospital quality improvement committees. Specific approval for this study was obtained from the Children’s and Women’s Research Ethics Board at the University of British Columbia (H14-02528) and the Executive Committee of the CNN.

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RESULTS

Epidemiology of IFI in Canada

Of 130,026 eligible neonates, 286 infants (0.22%) developed IFIs. Thirty-five infants developed fungal meningitis, 6 of whom (17% of those with fungal meningitis) did not have concomitant positive fungal isolates from blood cultures (Table 1). Four neonates had both early-onset (0–2 days) and late onset (>2 days) IFI. The annual IFI rate ranged from 0.12% to 0.28% during the study period, with higher incidences among infants with lower GA and lower BW in each individual year (Fig. 1). The IFI incidence rates at each GA in completed weeks are shown in Figure 2, which generally decline with increasing GA. The median IFI rate for each NICU varied between 0% and 2.4% among infants with a GA <33 weeks (Figure 1, Supplemental Digital Content, http://links.lww.com/INF/D155).

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

IFI rates and corresponding case fatality rates (CFRs) during the study period are reported in Table 1, which are stratified by GA subgroups. The incidences were highest among those born at extremely low GA (<29 weeks) or with extremely low BW (<1000 g), and most cases were of late-onset IFI (developed after 2 days of age). The overall CFR among all admitted neonates with IFI was 30% (95% confidence interval: 25%–36%), which was substantially higher compared with the remaining neonates who did not develop IFI (CFR: 3.1%; 95% confidence interval: 3.0%–3.2%; P < 0.001). There were no significant differences in CFRs between the subgroups that developed IFIs (Table 1).

Candida spp. were the most common pathogens isolated, with Candida albicans and Candida parapsilosis responsible for 170 (59.4%) and 59 (20.6%) of cases, respectively. Six cases of Candida lusitaniae (2.1%) were isolated, and another 6 cases (2.1%) of Candida glabrata were diagnosed (Table 1, Supplemental Digital Content, http://links.lww.com/INF/D156).

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Nested Matched Cohort Study

Characteristics and outcomes of infants born at <33 weeks GA were compared between neonates without IFI (n = 756) and those who were identified with an IFI (n = 252; 3 appropriate controls could not be identified for 1 neonate). Infants with IFIs were more likely to be male, born through vaginal delivery and to mothers with maternal diabetes, and have score for neonatal acute physiology II >20 and Apgar <7 at 5-minute scores (Table 2). Compared with neonates without IFI, those with an IFI had higher odds of mortality, NEC (stage II or above) and ROP (grade III or above) (Table 3).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

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DISCUSSION

In this large, multicenter, national retrospective cohort, the IFI rate among all admitted neonates was extremely low at approximately 1 in every 500 admitted neonates; however, the incidence was higher among lower GA and lower BW groups. CFR was approximately 1 in 3 for all categories of patient characteristics and IFI subtypes. Compared with those without IFI, preterm neonates of <33 weeks GA who had an IFI were associated with higher odds of mortality, NEC and severe ROP. C. albicans and C. parapsilosis were responsible for 80% of IFI cases.

Our reported IFI incidences of 0.12%–0.28% of IFI throughout the study period, including 0.64% among infants <33 weeks GA, 0.90% among the VLBW group and 1.78% among the ELBW group, were lower in comparison to other large population cohort studies including those from the National Epidemiology of Mycosis Survey study group,22 Pediatrix Medical Group,23 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from United States,24 though similar to the National prospective surveillance study from United Kingdom.8 Our CFRs of 30.8%–36.2% are not different to the 27.6%–48.0% reported mortality rates associated with Candida bloodstream infections in other cohorts.4 , 5 , 25 We speculate that our country’s lower overall rates of late-onset sepsis and antibiotic utilization may be responsible for our observed trends, considering that antibiotic utilization is a major risk factor for developing IFI.1 , 26 It is well known that antibacterial therapy increases the density of Candida colonization by reducing the competitive pressure exerted by commensal bacteria.1 , 27

In our study, risk factors identified for IFI were lower gestation, male sex, higher illness severity, maternal diabetes and birth via vaginal route. Neonates born at lower GA and BW have immature gastrointestinal tracts and skin, impaired immune function, frequent sepsis evaluations and exposure to antibiotics and increased need for central venous catheterization. All of these factors contribute to the pathogenesis of IFIs.1 Moreover, preterm infants are more likely to require postnatal rescue steroids, which alter the number and function of T-lymphocytes and inhibit phagocytosis of Candida spp.14 , 28 Studies have shown that risk of vaginal Candida colonization in pregnant women is much higher in women with diabetes29 and birth via vaginal route increases the likelihood for colonization by pathogens of the Candida species,11 which were reflected in our findings.

IFI is associated with substantial adverse neonatal outcomes, with at least one-fifth of cases developing ophthalmologic, visceral or cardiac complications.30 In our cohort, infants with IFI had increased odds of mortality, NEC and severe ROP. Meta-analyses have shown that systemic fungal infections are associated with the development of all degrees of retinopathy in VLBW infants, which could be related to the increased production of inflammatory cytokines, resulting in damage to the developing blood vessels in the retina.2 , 31 NEC and other gastrointestinal pathologies are known to be associated with candidiasis among premature infants, which is likely because of translocation of the pathogen across the colonized gastrointestinal tract.10 , 15 Moreover, infants with NEC often receive broad-spectrum intravenous antibiotics for varying periods of time, which by itself, also raises the risk of IFI.1 , 19

In the literature, most infant cases of IFIs are caused by relatively few species.1 In the 10-year population study of neonatal and pediatric candidemia in England and Wales, C. albicans and C. parapsilosis account for most infections in all age groups. In our cohort, C. albicans and C. parapsilosis accounted for 4 of 5 cases of IFI, a pattern similar to other published studies.10 , 32 , 33 Unlike the concerning rising trend of candidemia caused by species with inherent or potential resistance to fluconazole in adult populations, C. krusei and C. glabrata accounted only for a relatively small proportion, if any, of our cases, which is comparable to other neonatal cohorts.10 , 11 , 32 Less than 5% of our isolates were identified as C. lusitaniae, which may bring additional challenges to treatment because of their resistance to amphotericin B, a commonly used broad-spectrum antifungal agent.34

The main strength of our study is the inclusion of a large number of infants from a national neonatal network that captured the majority of tertiary level NICU admissions over a decade period. This enabled us to conduct a comprehensive analysis of IFI rates to determine whether prophylactic antifungal therapy should be revisited in Canada. However, our study has some limitations. First, data on the duration and type of antibiotics received before the development of IFI were not available. This is important information to achieve a better understanding of the chronology of IFI, as well as specific antibiotic risk categories for the development of IFI. Second, information on the insertion of a central catheter in situ at the time of development of IFI was not captured, which may have played a critical role in its pathogenesis.5 , 10 , 22 , 24 Third, we did not use an active surveillance study design to capture details of risk factors at the time of identification of infection; therefore, this prevents us from providing more conclusive results. There could be different approaches to the initiation and choice of antifungals across the whole study period and between sites, which might potentially affect the development of IFI. Neither did we capture the susceptibility of organisms to the antifungal agents. Also, we cannot rule out a minority of infants with fungi grown at sterile sites other than blood or CSF, as quoted in another study.24 We did not include positive urine growth of fungi as cases of invasive infection because of lack of standardized definitions of urinary tract infection in neonatal populations.35 Including these infants may underestimate the case-fatality. Also, CNN started collecting the data of NEC and spontaneously intestinal perforation (SIP) separately since 2010. Thus, neonates with SIP would not be included in our analysis during 2010–2013. However, for admissions between 2003 and 2009, we might include neonates who had SIP in the group classified as NEC. Finally, there is the possibility of ascertainment bias in our study, particularly among neonates who presented with significant systemic compromise and could not provide proper samples for evaluation of an IFI. However, this is probably unlikely given the fact that >85% of neonates born and admitted to NICUs were included in our population.

Research studies have focused on the utilization of antifungal prophylaxis and early empirical antifungal therapy to improve neonatal outcomes.12 , 36 Fluconazole prophylaxis is considered to be effective and safe in reducing invasive Candidiasis and Candida colonization in premature infants and has no impact on resistance.37 A recent Cochrane Review revealed a statistically significant reduction in the incidence of IFI, but not the risk of death before hospital discharge among VLBW infants receiving antifungal prophylaxis.17 Such findings should be interpreted and applied cautiously because the average incidence of IFI in the control groups (16%) of these trials was much higher than that generally reported in large cohort studies.17 Fluconazole prophylaxis may have value in reducing adverse neonatal outcomes in NICUs reporting IFI rates of 25%–43% among VLBW infants.17 In a recent cost analysis of fluconazole prophylaxis for the prevention of neonatal invasive candidiasis, it was identified that a rate of ≥2.8% among high-risk patients in a unit was considered to be the threshold for its cost-effectiveness in terms of initial hospitalization cost.38 While there have been wide variations in the practice of antifungal prophylaxis among neonatologists in the United States,39 most Canadian neonatal centers do not practice routine antifungal prophylaxis. Our own surveillance showed that only 2.9% of infants <33 weeks GA received antifungal prophylaxis in the recent years (unpublished data, Canadian Neonatal Network 2016 Annual Report http://www.canadianneonatalnetwork.org/). Studies revealed fungemia can also be reduced through adopting clinical practices that (1) minimize the unnecessary use of broad-spectrum antibacterials via antimicrobial stewardship programs, (2) reduce the use and duration of central venous catheters and (3) improve the molecular or fungal antigen-based diagnostics to rapidly identify fungal pathogens and avoid delay in initiation of antifungal therapy.1 , 35 , 40 Targeted antifungal prophylaxis at high risk group may be considered10 , 38 (like ELBW infants born at threshold of viability requiring prolonged parenteral nutrition via central catheter), though this largely depends on the local incidence rate and microbiology data.

In summary, we found the overall incidence of IFI in neonates was low in Canada in comparison to other large population cohort studies; however, the mortality and morbidity remained high.

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ACKNOWLEDGMENTS

The authors gratefully acknowledge all site investigators of the Canadian Neonatal Network (CNN). We would also like to thank the data abstractors of the CNN, as well as the staff at the Maternal-Infant Care Research Centre at Mount Sinai Hospital, Toronto, ON, for providing organizational support for this project. Specifically, we extend our thanks to Philip Ye, MSc, for statistical support, and Natasha Musrap, PhD, for editorial assistance.

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APPENDIX

Investigators of the Canadian Neonatal Network: Prakesh S. Shah, MD, MSc (Director, Canadian Neonatal Network and site investigator), Mount Sinai Hospital, Toronto, ON, Canada; Adele Harrison, MD, MB ChB, Victoria General Hospital, Victoria, BC, Canada; Anne Synnes, MDCM, MHSC, and Joseph Y. Ting, MD, B.C. Women’s Hospital and Health Centre, Vancouver, BC, Canada; Zenon Cieslak, MD, Royal Columbian Hospital, New Westminster, BC, Canada; Rebecca Sherlock, MD, Surrey Memorial Hospital, Surrey, BC, Canada; Wendy Yee, MD, Foothills Medical Centre, Calgary, AB, Canada; Khalid Aziz, MBBS, MA, MEd, and Jennifer Toye, MD, Royal Alexandra Hospital, Edmonton, AB, Canada; Carlos Fajardo, MD, Alberta Children’s Hospital, Calgary, AB, Canada; Zarin Kalapesi, MD, Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, MD, MBBS, and Sibasis Daspal, MD, Royal University Hospital, Saskatoon, Saskatchewan, Canada; Mary Seshia, MB ChB, Winnipeg Health Sciences Centre, Winnipeg, MB, Canada; Ruben Alvaro, MD, St. Boniface General Hospital, Winnipeg, MB, Canada; Amit Mukerji, MD, Hamilton Health Sciences Centre, Hamilton, ON, Canada; Orlando da Silva, MD, MSc, London Health Sciences Centre, London, ON, Canada; Chuks Nwaesei, MD, Windsor Regional Hospital, Windsor, ON, Canada; Kyong-Soon Lee, MD, MSc, Hospital for Sick Children, Toronto, ON, Canada; Michael Dunn, MD, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Brigitte Lemyre, MD, Children’s Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, ON, Canada; Kimberly Dow, MD, Kingston General Hospital, Kingston, ON, Canada; Victoria Bizgu, MD, Jewish General Hospital, Montréal, QC, Canada; Keith Barrington, MB ChB, Hôpital Sainte-Justine, Montréal, QC, Canada; Christine Drolet, MD, and Bruno Piedboeuf, MD, Centre Hospitalier Universitaire de Québec, Sainte Foy, QC, Canada; Martine Claveau, MSc, LLM, NNP, and Marc Beltempo, MD, McGill University Health Centre, Montréal, QC, Canada; Valerie Bertelle, MD, and Edith Masse, MD, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Roderick Canning, MD, Moncton Hospital, Moncton, NB, Canada; Hala Makary, MD, Dr. Everett Chalmers Hospital, Fredericton, NB, Canada; Cecil Ojah, MBBS, and Luis Monterrosa, MD, Saint John Regional Hospital, Saint John, NB, Canada; Akhil Deshpandey, MBBS, MRCPI, Janeway Children’s Health and Rehabilitation Centre, St. John’s, Newfoundland; Jehier Afifi, MB BCh, MSc, IWK Health Centre, Halifax, NS, Canada; Andrzej Kajetanowicz, MD, Cape Breton Regional Hospital, Sydney, NS, Canada; Shoo K. Lee, MBBS, PhD (Chairman, Canadian Neonatal Network), Mount Sinai Hospital, Toronto, ON, Canada.

Keywords:

preterm infants; mortality; morbidity; candidemia; antifungal prophylaxis

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