Diagnostic accuracy of a dynamically increased red blood cell distribution width in very low birth weight infants with serious bacterial infection

Infections account for 40% of neonatal deaths worldwide each year [1]. Preterm infants weighing less than 1500 g, called very low birth weight (VLBW) infants, represent a more vulnerable group of newborns. Almost 25% of VLBW infants experience more than one episode of nosocomial infection [2]. Efforts to address neonatal infections are critical to achieving survival goals in newborns [3], early recognition of infection and timely responses are vital to reduce morbidity and mortality among neonates. Currently, in the clinical work, cultures are the gold standard for laboratory diagnosis of bacterial infection even though they lack sensitivity in neonates [4]. Despite serving as predictors of sepsis in neonates, C-reactive protein, IL-6 and procalcitonin have some limitations and are not available in some centers [5].

Previous studies have demonstrated that red blood cell distribution width (RDW) could be a laboratory indicator of infection or inflammation [6]. RDW is a routinely reported hematology parameter as part of the complete blood count [7] which can be automatically measured by modern hematological analyzers. Recently, increasing evidence has proven that RDW may be a frequent predictor for inflammatory diseases in adults, such as pancreatitis and hepatitis [8, 9]. To date, most previous studies that have investigated the relationship between RDW and infection have utilized a single RDW measurement at initial presentation. Recent evidence suggests that RDW can be considered as a dynamic variable with rapid changes associated with acute disease states, and dynamic change of RDW from baseline can provide more prognostic information than the baseline RDW value alone [10, 11]. However, there are few studies reportingthe use of RDW in neonates for monitoring and determining infant’s serious bacterial infection (SBI; including urinary tract infection [UTI], bacterial meningitis, and/or bacteremia).

Also, little is known about the potential impact of changes in RDW from baseline on diagnosis value in infants with SBI. Thus, this study was designed to test the hypothesis that the combination of elevated RDW at baseline and a dynamic increase in RDW from baseline can reflect SBI states and provide more diagnostic information than the baseline or dynamically increased RDW value alone.

The present study is a retrospective clinical investigation of the diagnosis value of increased RDW in infants with SBI. This study found that the combination of elevated RDW at baseline and dynamically increased RDW from baseline could reflect infection disease states and provide more diagnostic information than the baseline or dynamically increased RDW value alone. Specifically, patients in group 4, who had increased RDW at baseline (RDW > 17%) and dynamic increase during hospitalization (ΔRDW > 2%), exhibited the highest risk of SBI, whereas patients in groups 2 and 3, who had increased RDW level at baseline (RDW > 17%) or ΔRDW> 2%, had a lower risk of SBI. Group 1 served as the reference. This significant association between an increase in RDW and SBI remained unaltered even after adjusting for various confounding variables.

In our study, the comparison of predictive accuracy of baseline RDW, ΔRDW, and the combination of the two showed that the combination parameter had superior performance in prediction of SBI. This finding was consistent with a recent study, which showed a significant increase in RDW levels in infants with gram-negative sepsis. A RDW cut-off of > 19.50% was associated with prediction of late-onset Gram-negative sepsis (P < 0.001), with a sensitivity of 87% and a specificity of 81% [13]. Another study reported that high RDW became a risk indicator for critical newborns [14]. Moreover, one study reported that increased RDW values were associated with the severity of sepsis in neonates [15]. However, Ju XF et al. showed that continuous increase in RDW level, rather than the level of RDW at baseline, was more beneficial in predicting in-hospital death of elderly patients with septic shock [16]. Our present study found that not only elevated baseline RDW but also increased ΔRDW were associated with SBI. In clinical settings, elevated baseline RDW in preterm infants is caused by or associated with intrauterine infection, which is a major cause of premature delivery [17]. Despite the lack of obvious symptoms of system infection, preterm infants are more susceptible to serious infections [18]. It is vital to initiate timely antimicrobial therapy during a bacterial infection episode, therefore we should clarify the noble prediction value of the RDW during the entire hospital stay.

The reason why patients with SBI have a higher RDW remains poorly understood. Some potential mechanisms by which infection causes RDW elevation have been reported. RDW represents the size variance in circulating erythrocytes, so in any physiologic process that upregulates erythropoiesis or causes an increased release of immature red block cells into circulation, RDW becomes elevated [19, 20]. One study found that RDW could measure the efficiency of biological control, therefore, it may be a predictor of the function of organism [21]. Inflammation not only disrupts the survival of erythrocytes but also deforms red block cell membranes [22, 23]. Taken together, increased systemic inflammation is the major theorized mechanism that results in an increase in RDW [23, 24].

To the best of our knowledge, this study is the first to report that the combination of an increase in RDW at baseline and dynamic increase during hospitalization plays a potential role in predicting newborns developing SBI. However, this study has several limitations. First, we arbitrarily determined the median of RDW value as a measurement and defined ΔRDW as an increase in RDW. It remains unclear whether changes in RDW during hospital stay could represent the pathophysiologic changes. The range of RDW value in normal or pathological conditions has not yet been determined [6], and increased RDW indicates that the inflammatory system is active in patients [12]. Therefore, we investigated the clinical outcomes of the patients with SBI by the RDW at baseline and ΔRDW. Second, this study is conducted base on a public database, therefore, it is unknown whether use of erythropoietin, iron or vitamin B12, and reticulocyte count, could have affected RDW values. Moreover, RDW is a red blood cell index that is rapidly and automatically calculated by all modern hematological analyzers such as Sysmex XE-2100 analyzer, Sysmex-XT-2000i counter (Sysmex, Kobe, Japan), and ADVIA 2120i instrument (Siemens, Munich, Germany) [13, 25, 26]. The reference interval of RDW varies with the instrumental used [25, 26]. The information of the hematological analyzers was not recorded in MIMIC-III, different instruments and measurement techniques used to obtain RDW might have limited interpretation and direct application of the results in other medical institutions. Third, standard deviation RDW (RDW-SD) was not considered in this study. Finally, this is an observational study, which may have a bias or a lack of randomly distributed exposure, and confusion causality. Further research should be undertaken to investigate the predictive value of RDW at baseline and dynamic change.

Our results imply that an increase in RDW from baseline through the hospitalization is significantly associated with SBI. Therefore, a combination of an increased baseline RDW value and a dynamically increased RDW could be a promising independent diagnostic indicator in infants with SBI. This study provides support for future investigations considering changes of RDW and the associated stratification of critically ill infants at risk for infection.