Neonatal Candidiasis

Full study article found here.

The incidence of candidiasis has increased in neonatal intensive care units, and invasive candidiasis is associated with significant morbidity and mortality. However, few data exist on outcomes directly attributable to neonatal candidiasis.

Methods. We estimated the incidence of systemic candidiasis in hospitalized neonates within the United States and determined the attributable mortality, length of hospital stay, and associated costs. We used the 2003 Kid's Inpatient Database from the Healthcare Cost and Utilization Project. Systemic candidiasis and comorbidities were defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Neonates with uncomplicated births and neonates who died within the first 3 days of life were excluded. We used propensity score methods to balance covariates between the neonates with and neonates without candidiasis. Attributable outcomes were calculated between propensity score–matched neonates with and neonates without candidiasis. Because of the known confounding effect of birth weight, we performed separate propensity score analyses for extremely low birth weight (ELBW) neonates (i.e., neonates weighing <1000>

Results. The overall incidence of invasive candidiasis in neonates is 15 cases per 10,000 neonatal admissions (95% confidence interval [CI], 13–16 cases per 10,000 neonatal admissions). ELBW neonates with invasive candidiasis were 2 times more likely to die (odds ratio, 2.2; 95% CI, 1.4–3.5) than propensity-matched ELBW neonates without candidiasis. The propensity score–adjusted mortality rate attributable to candidiasis among ELBW neonates was 11.9%. Candidiasis in ELBW infants was not associated with an increase in length of hospital stay but was associated with a mean increase in total charges of $39,045 (95% CI, $1374–$76,715). Among infants with a birth weight 1000 g, those who had candidiasis did not experience a significant increase in mortality, compared with infants without candidiasis. However, the propensity score–adjusted length of stay and charges attributable to candidiasis among neonates with a birth weight 1000 g were 16 days (95% CI, 8–24 days) and $122,302 (95% CI, $80,457–$164,148), respectively.

Conclusions. Invasive candidiasis is associated with a significantly increased risk of death and excess hospital charges in ELBW neonates and with excess hospital stay and excess hospital charges in neonates with a birth weight 1000 g.

Candida species are the leading cause of invasive fungal infection in the neonatal intensive care unit (NICU) and are the third most common blood culture isolates recovered from cases of late-onset sepsis in the NICU. Candidiasis is frequently associated with dissemination and resultant end-organ damage. The incidence of neonatal candidiasis (candidemia and/or disseminated candidiasis) in extremely low birth weight (ELBW) infants (defined as infants with a birth weight <1000>1500 g.

Neonatal candidiasis is associated with significant morbidity and mortality, and previous epidemiologic outcome studies of neonatal candidiasis have reported crude mortality rates of 30%–60%, with ELBW infants experiencing the highest mortality rates. Determining the health impact of infection due to Candida species on premature neonates is an important, yet difficult, task. Attributable outcomes in premature neonates are difficult to determine because of the potential confounding effect of comorbid conditions related to prematurity that predispose individuals both to candidiasis and to poor outcomes. Although the high crude mortality rates associated with candidiasis are well documented, the proportion of neonatal mortality and other health care–related outcomes that is attributable specifically to candidiasis is unknown. Therefore, we conducted a retrospective cohort study of neonatal candidiasis and used propensity score analyses to determine the outcomes attributable to neonatal candidiasis with use of a nationally representative database of hospital discharges, prepared by the Agency for Healthcare Research and Quality.

We found that the mortality rate attributable to neonatal candidiasis in ELBW infants was 11.9%, whereas there was no significant increase in mortality rate among non-ELBW infants with candidiasis. We also found that candidiasis in ELBW infants had no effect on LOS and hospital charges but that, in non-ELBW infants, candidiasis was associated with a statistically significant increase in LOS and charges. Finally, we found that candidiasis is a disease that is seen almost exclusively in ELBW infants

Our estimate of a 26% crude mortality rate associated with candidiasis in ELBW infants is similar to prospective data collected by the National Institute of Child Health and Human Development–sponsored Neonatal Research Network (32%) and is almost identical to the findings of a previous retrospective study. Comparing our attributable mortality findings among ELBW infants with findings from previous studies is more difficult, because these studies included non-ELBW patients. In a prospective registry study of infants with birth weights <1500>

Our finding that candidiasis in ELBW infants had a relatively small effect on LOS and hospital charges may be attributable to censoring as a result of death, because more patients in the candidiasis group died and, therefore, had a shorter LOS than would otherwise have been the case, and LOS is directly related to hospital charges. In addition, the LOS of ELBW infants is likely to be driven by issues of gestational age and other issues of prematurity and not by neonatal candidiasis. This hypothesis is supported by the finding that, among non-ELBW infants, neonatal candidiasis was associated with significant increases in LOS and hospital charges; therefore, it was more likely for candidiasis to prolong the LOS of neonates who otherwise would not have remained hospitalized on the basis of gestational age.

Our incidence estimate for neonatal candidiasis among ELBW neonates is lower than estimates reported in previous studies. In a recent study that involved 128 NICUs participating in the National Nosocomial Infections Surveillance system, the incidence of candidiasis among ELBW infants between 2000 and 2004 was 5%. The lower incidence reported in our study may be attributable to the lower sensitivity of ICD-9-CM codes for the diagnosis of candidiasis. Our incidence estimate for candidiasis among non-ELBW neonates is low and is consistent with previous reports.

Use of these national administrative databases offers the unique advantage of allowing for the generation of nationwide estimates of candidiasis rates. Administrative data are limited, however, with specific regard to the possibility of miscoded or inaccurate information. Although 112.5 is the only ICD-9-CM code that explicitly describes systemic disease and has been used in a previous study of candidiasis that used administrative data, we are unaware of any analysis that has determined the sensitivity and specificity of this particular ICD-9-CM code for detecting cases, compared with, for example, a thorough review of all medical charts. In our review of the medical records of neonates with documented candidiasis at our center, we identified an additional code used for patients with candidiasis, 112.89, which resulted in improved sensitivity and positive predictive value. The addition of this code did not alter the association between candidiasis and death in ELBW infants. We believe that the coding practices for candidiasis at the other institutions are unlikely to be significantly different, given the rarity of the disease, as well as the unambiguous case definition of a patient with a blood or tissue culture that grows Candida species (compared with “sepsis,” which is not defined by the result of a definitive test). Our finding of high specificity and low sensitivity is consistent with the findings of previous studies that have used ICD-9-CM codes to identify cases in administrative databases; although high in specificity (i.e., resulting in few instances in which patients did not, in fact, receive a diagnosis of the condition), this method may be low in sensitivity (i.e., the administrative diagnosis may fail to detect all true cases).

Any analysis of a potential cause-and-effect relationship between candidiasis and clinical outcome would be strengthened by more information than this study and its datasets can provide regarding the temporal sequence of events and the severity of illness before the development of candidiasis. As with all observational studies, propensity analyses cannot completely control for the effect of confounding, because they can only adjust for factors that were measured in the cohort, and residual confounding, therefore, remains a possibility. Overall, the propensity-score matching served as an adequate and robust method for controlling a large number of factors, as shown by the lack of statistically significant differences among almost all of the observed variables. Finally, our sensitivity analysis revealed that an omitted confounding factor would have to be very common and be associated with a 5-fold higher risk of death in the candidiasis group than in the noncandidiasis group for the significant result to disappear, which is an unlikely scenario.

In summary, the attributable mortality of candidiasis among ELBW infants is substantial, whereas non-ELBW infants do not seem to experience excess mortality as a result of candidiasis but do have increased use of health care resources. Our results suggest that, in this population, 1 life would be saved for every 8 ELBW infants in whom candidiasis can be prevented. One single-center, randomized clinical trial has supported the use of antifungal prophylaxis for the prevention of candidiasis in ELBW infants; however, the incidence of candidiasis at that center was extremely high. Given the overall low incidence of candidiasis among ELBW infants, validation of clinical prediction rules that identify subsets of ELBW infants at particularly high risk for candidiasis, with subsequent intervention studies focused on this subgroup of infants, is critically needed. Previous investigators have suggested that preventative strategies should be targeted to populations with a baseline rate of candidiasis of >10%. We hope that these findings will be useful in the design and implementation of future interventions.