The incidence of NEC is extremely high in preterm infants,20 and is associated with an increase in mortality. Most of the survivors often experience a variety of serious short-term and long-term complications, such as intestinal stenosis, short bowel syndrome, and neurological sequelae.21,22 Although the literature is limited, the direct hospital cost of NEC has been estimated to be anywhere from 1.4 to over 10 times higher in very low birth weight (VLBW) infants with NEC than in VLBW infants without NEC. The increased cost stems from longer hospital stays and additional medical interventions (e.g., surgery, central line placement, and increased total parenteral nutrition time), as well as the increased risk of morbidities associated with NEC. NEC has a significant negative impact on healthcare utilization and costs. Therefore, a method to reduce the NEC rate will not only prevent the associated mortality and morbidity and improve the neonatal prognosis, but also reduce healthcare and social costs.
The uncertainty in the course of NEC is due to the absence of a definitive etiology and pathogenesis; moreover, it manifests in a variety of ways. The signs and symptoms of NEC may be concealed and nonspecific, making it difficult to diagnose preterm neonates with NEC earlier. Due to a deficiency in available diagnostic skills and tools, and the accelerated progression of the disease, some infants, particularly the premature infants, do not receive timely treatment. In practice, the diagnosis and treatment of NEC involves duplicate blood testing and abdominal X-ray, the use of broad-spectrum antibiotics, and fasting or decreased enteral feeding. Consequently, many infants may develop secondary anemia, further disturbing the gut microbiome and resulting in retarded growth and development. Thus, it is crucial to develop strategies to identify infants who are less susceptible to NEC to avoid excessive treatment.23 Furthermore, in order to decrease healthcare utilization and costs which are associated with NEC, identifying preterm infants with NEC accurately and rapidly is very important. For the sake of reducing the burden of NEC in preterm neonates, the prediction and early diagnosis of this catastrophic disease are of utmost necessity.
The current clinical practice to diagnose NEC depends on nonspecific systemic symptoms including inflammation, local abdominal signs, and specific radiographs to determine the presence of gastrointestinal inflammation. However, all of these symptoms are non-specific for NEC, thus, confusing it with the differential diagnosis of other conditions, such as neonatal sepsis, other gastrointestinal diseases, and feeding intolerance. When NEC is suspected, the modified Bell’s staging criteria should be applied, which allows rapid clinical decision-making. The features of the Bell’s staging criteria represent clinical, laboratory, and radiologic signs, most of which are non-specific and may be less sensitive,23 and there are numerous shortcomings in the current use of Bell’s staging criteria.6,20 The criteria should not be used as a prognosticating diagnostic tool, but only if NEC had already occurred. The ideal diagnostic biomarker should be both highly sensitive, so as not to miss potential cases, and specific to avoid over-treating infants who are not likely to progress to NEC. Moreover, it should be reliable and have accurate predictive value. Other useful features include affordability, reproducibility, and availability.24 Some researchers have investigated biomarkers as possible tools to predict NEC, such as interleukin-6,25 intestinal fatty acid-binding protein,26 and serum amyloid A.27 However, the majority of these are not available for routine laboratory tests performed at most medical institutions because of medical costs and the complex methodology required. On the contrary, complete blood counts are simple, easy, and convenient to determine.
The increase in neutrophil count and decrease in lymphocyte count is a response to microbial infection. The increase in neutrophils results from reduced apoptosis of neutrophils and rapid mobilization of neutrophils from a marginated pool within the bone marrow.28–30 Neutrophils are important in removing pathogens, but neutrophil infiltration and activation also result in major tissue injury associated with acute and chronic inflammatory disorders.31 Although neutrophils play a vital role in host defense, they can also cause severe morbidity and mortality. The lymphocyte count decreases due to the migration of activated lymphocytes to inflamed tissues and increased apoptosis of lymphocytes.29,32 It is an indicator of immunosuppression and plays a role in the septic patients’ mortality.33,34 Zahorec previously introduced the NLR as a simple, rapid, and cost-effective method to determine inflammation in critically ill patients.35 In addition, a previous study showed that this ratio could be utilized as a predictor of disease severity in adult patients.36 Recent studies found that NLR had a higher sensitivity and specificity for infectious diseases diagnosis.37,38 For example, Sen et al. showed that NLR preoperatively could be a promising predictor of bacteremia and postoperative sepsis in patients requiring percutaneous nephrolithotomy.39 In China, there are several similar results, where Yang et al. found that the NLR was significantly higher in the death group than in the control group within 205 adult bloodstream infection patients.40 In summary, NLR could be utilized to indicate the status of the inflammatory response and the level of physical stress in a timely and accurate manner.40 In addition, NLR could be used as a predictive marker for patients with infections.
In our study, a statistically significant positive correlation was found between the NLR and preterm NEC when NLR values were ≥ 1.60 and < 3.20. In the univariate analysis, NLR was significantly correlated with preterm NEC (OR, 1.40; 95% CI, 1.00–1.90; P = 0.042). Moreover, CRP and PE may also be associated with preterm NEC. After adjusting for these potential confounders in the multivariate logistic regression analysis, we still found a significant correlation between NLR and preterm NEC. NLR values of ≥ 1.60 and < 3.20 were determined as the predictive cutoff values for the preterm NEC group (OR, 0.20; 95% CI, 0.10–0.40; P < 0.001), which is associated with a decreased risk of NEC in preterm infants. In addition, NLR (< 1.60 or ≥ 3.20) may be used as a diagnostic tool for preterm NEC. This ratio may be applied in clinical practice and can be used during routine diagnostic processes for preterm NEC in NICUs.
The present study has some limitations. The inherent bias due to the retrospective design of the study should be mentioned. Moreover, the sample number of this study was small and only from a single center, which may also restrict the accuracy and generalizability of the results.