Changing the paradigm of defining,detecting, and diagnosing NEC: Perspectives on Bell’s stages and biomarkers for NEC

Better means to diagnose and define necrotizing enterocolitis are needed to guide clinical practice and research. Adequacy of Bell’s staging system for clinical practice and clarity of cases used in NEC clinical datasets has been a topic of controversy for some time. This article provides reasons why a better global definition for NEC is needed and offers a simple alternative bedside definition for preterm NEC called the “Two out of Three” rule. Some argue that biomarkers may fill knowledge gaps and provide greater precision in defining relevant features of a clinical disease like NEC. NEC biomarkers include markers of inflammation, intestinal dysfunction, hematologic changes, and clinical features. Development and reporting of NEC biomarkers should be guided by the FDA’s BEST Consensus resource, “Biomarkers, EndpointS, & other Tools” and consistently report metrics so that studies can be compared and results pooled. Current practice in the NICU would be enhanced by clinical tools that effectively inform the clinical team that a baby is at increasing risk of NEC. Ideally, these tools will incorporate both clinical information about the baby as well as molecular signals that are indicative of NEC. While meaningful biomarkers for NEC and clinical tools exist, translation into practice is mediocre.     

Mechanisms of nitric oxide-mediated intestinal barrier failure in necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is the leading intestinal emergency in premature infants. The underlying etiology of NEC remains elusive, but hypoxic conditions and early enteral feeding are consistently implicated as the main risk factors in the pathogenesis of NEC. We postulate that nitric oxide (NO) plays a key role as a molecular signaling "hub" in the generation of gut barrier failure in NEC. Clinical studies suggest that inflammatory cytokines and excessive NO production may contribute to the pathogenesis of NEC. One of the major challenges in defining the critical signaling pathways that lead to the development of NEC is the lack of specific biochemical markers that consistently delineate the early stages of NEC. Intestinal pathology and molecular markers derived from late-stage NEC represent end-stage findings and thus provide little insight into the early events that led to intestinal inflammation. Such markers may not represent viable therapeutic targets for the treatment or prevention of NEC. Therefore, novel strategies are needed to identify the patients at risk for NEC and define the clinically relevant molecules that characterize the early stages of NEC. This review will examine the mechanisms of NO-mediated gut barrier failure and propose novel genetic-based approaches for elucidating the critical molecular pathways in NEC.     

新生儿坏死性小肠结肠炎研究进展

坏死性小肠结肠炎（NEC）是由多种因素导致的新生儿,尤其是早产儿的灾难性疾病。严重的NEC病死率高,幸存者多面临短期及长期不良预后。与NEC有关的危险因素包括早产、非母乳喂养、消化道内微生物异常、缺血再灌注损伤等。高分辨腹腔超声检查有助于NEC的早期诊断。通过营养干预保护肠黏膜、干扰肠道损伤信号、改变肠道微生态环境及早期微量喂养有助于预防NEC。该病进展迅速,目前尚无有效措施,以支持治疗为主,严重者需外科治疗,雷公藤红素、脂多糖结合蛋白、粪便移植可能有助于治疗NEC,但仍有待于进一步研究。     

肠道微生态与早产儿坏死性小肠结肠炎的研究进展

坏死性小肠结肠炎（NEC）是早产儿常见的严重胃肠道疾病,其发病率及病死率与早产儿胎龄及出生体重呈负相关,可引起多种胃肠道并发症,并可对患儿神经系统发育造成不良影响。近年来研究发现肠道微生态失调在NEC发病中起重要作用,探究肠道微生态改变与NEC的相关性有助于NEC早期诊断及严重程度的预测。益生菌在降低早产儿NEC发病率和病死率中的作用已受到业界广泛关注,但其在临床应用中的有效性和安全性仍存在较大争议。本文主要就新生儿肠道微生态发育及其与早产儿NEC之间的关系,以及益生菌对NEC的预防作用作一综述。     

新生儿坏死性小肠结肠炎发病原因及预后研究进展

新生儿坏死性小肠结肠炎(neonatal necrotizing enterocolitis,NEC)是一种常见的胃肠道急症,属于新生儿期严重危及生命的疾病之一.其发病原因尚不完全明确,主要有早产、喂养不当、肠道感染和菌群失调、缺氧缺血及再灌注损伤等.疾病的临床分期、呼吸衰竭等严重并发症、治疗方法等多种因素均会影响NEC患儿的预后.该文就近期相关研究展开综述,为NEC的早期诊断、临床观察及治疗提供线索.     

前白蛋白对重症坏死性小肠结肠炎的诊断价值

目的 了解重症新生儿坏死性小肠结肠炎(NEC)的临床特点,探究前白蛋白(PA)对于重症NEC的诊断价值。方法 对40例NEC新生儿(Ⅱ期29例、Ⅱ期11例)的临床资料及血常规、血生化结果进行研究,采用多因素logistic回归分析以及ROC曲线判断PA在重症NEC诊断中的价值。结果 多因素logistic回归分析发现PA对于重症NEC(≥Ⅱ B期)的诊断具有参考价值。ROC曲线分析显示在重症NEC(≥Ⅱ B期)的诊断中,PA拥有较高的灵敏度(0.870)及特异度(0.647)。结论 PA对重症NEC(≥Ⅱ B期)具有较高的诊断价值。     

Use of the barium enema in the diagnosis of necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is associated with considerable morbidity and mortality in infants. The diagnosis relies heavily upon radiographic and clinical features. Failure to accurately diagnose NEC is associated with a risk of complications and death, however overdiagnosis also causes both morbidity and mortality as well as excessive medical costs. This report documents the use of barium enema to evaluate suspected clinical or radiographic NEC in 31 premature infants with ambiguous clinical and radiographic signs. The enema was normal in 26 infants and no treatment for NEC was given. Only one of these infants developed signs of NEC subsequent to the examination. Five infants had radiographic evidence of colitis including small ulcerations, spasm, intramural extravasation of barium and mucosal irregularity. Two of the five positive cases are pathologically documented. The barium enema can represent a significant improvement in the specificity of the diagnosis of NEC. Its greatest value is in the exclusion of NEC in ambiguous cases.     

Interdisciplinary treatment of necrotizing enterocolitis and spontaneous intestinal perforations in preterm infants

From January 1986 to December 1992, 13 patients with necrotizing enterocolitis (NEC) (Grade II-III; Bell) were treated. The incidence was highest in the very immature infants with birth weight < 1000 g: 6/148 (4%). From onset, NEC was associated with clinical symptoms such as abdominal distension, bloody stools, retained gastric contents and septicemia. Indications of inflammation were seen in only 6 out of 13 patients at the time of diagnosis. No complications were seen in 10 patients during the acute phase. Two infants developed a bowel perforation and another one a gangrene. Immediate surgery was performed. In three other infants, elective surgery was performed because of colonic strictures. Twelve (92%) patients survived NEC. Five other VLBW infants developed spontaneous perforations of the bowel. The clinical presentation, laboratory and radiological findings differed greatly from those with NEC. Four infants survived. A primarily conservative therapeutic regime with close cooperation between the surgeon and pediatrician may be an alternative to early surgical intervention in NEC.     

Urinary biomarkers in prenatally diagnosed unilateral hydronephrosis

The introduction of prenatal ultrasonography as a screening method entails an increasing number of infants diagnosed with prenatal hydronephrosis. Ureteropelvic junction obstruction accounts for 35% of prenatal hydronephrotic cases. Urinary tract obstruction that occurs during early kidney development affects renal morphogenesis, maturation and growth, and in the most severe cases this will ultimately cause renal insufficiency. A major challenge in the clinical management of these patients is to preserve renal function by selection of the 15%-20% who require early surgical intervention, leaving those for whom watchful waiting may be appropriate because of spontaneous resolution/stabilization without significant loss of renal function. Today, this requires medical surveillance, including repetitive invasive diuretic renograms relying on arbitrary threshold values, and therefore there is a need for non-arbitrary, non-invasive urinary biomarkers that may be used as predictors for renal structural changes and/or decreasing renal function, and thereby provide the surgeon with more clear indications for surgical intervention. In this review, we summarize the currently well-known facts about urinary biomarkers in ureteropelvic junction obstruction concerning renal function, and we also suggest potential novel urinary biomarkers.     

新生儿坏死性小肠结肠炎伴发败血症的危险因素研究

目的 探讨新生儿坏死性小肠结肠炎 （NEC） 伴发败血症的危险因素。方法 回顾性研究273例NEC患儿的临床资料,分析伴发败血症的危险因素。结果 NEC伴发败血症的几率为32.2% （88/273）。Ⅲ期NEC伴发败血症的几率高于Ⅱ期 （69.0% vs 15.9%,P < 0.05）。62.5%的败血症发生在NEC诊断后3d内,37.5%发生在3d后。伴发败血症的NEC患儿与未伴发者相比,出生胎龄更小,出生体重更低 （P < 0.05）。硬肿症 （OR：9.75,95% CI：2.84~33.52,P < 0.001）、Ⅲ期NEC （OR：12.94,95% CI：6.82~24.55,P < 0.001） 及胃肠减压 （OR：2.27,95% CI：1.14~4.5,P=0.02） 为NEC伴发败血症的独立危险因素。结论 硬肿症、Ⅲ期NEC及胃肠减压为NEC伴发败血症的独立危险因素。     

Early intestinal bacterial colonization and necrotizing enterocolitis in premature infants: the putative role of Clostridium

Necrotizing enterocolitis (NEC) is among the most severe conditions that can affect preterm infants. Although the etiology of NEC remains unknown, initial bacterial colonization could play a pivotal role in the development of NEC. To further explore the putative relationship between pathogen microorganisms and NEC, we conducted a prospective case-control study in 12 preterm infants with a new approach based on molecular techniques. Over an inclusion period of 24 mo, 12 neonates of <34 wk gestational age admitted to the neonatal unit were enrolled. The group included three cases of NEC, and nine control infants without evidence of NEC who were matched for gestational age and birth weight. Stool samples were collected at weekly intervals from all infants. PCR and temporal temperature gradient gel electrophoresis of 16S ribosomal DNA were used to detect the establishment of bacterial communities in the digestive tract. A salient feature of the bacteriological pattern was observed only in the three infants who later developed NEC: A band corresponding to the Clostridium perfringens subgroup could be detected in early samples, before diagnosis. There was no evidence for this specific band in any of the nine controls. To our knowledge, the current report is the first to demonstrate that the use of molecular techniques based on the study of bacterial 16S rRNA genes allowed the recognition of C. perfringens species in the first 2 wk of life of three infants who later displayed symptoms of NEC. A significant temporal relationship was thus established between early colonization by Clostridium and the later development of NEC. Compared with conventional bacteriological culturing methods, the use of this new molecular approach to analyze the gastrointestinal ecosystem should therefore allow a more complete and rapid assessment of intestinal flora. Although the current data do not constitute definitive proof that the identified bacterial species was a causative agent in the development of NEC, they outline the promise of this new technique based on molecular biology, and suggest that large-scale studies on a much wider population at high risk for NEC may be warranted.     

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??Objective??To investigate the value of serum intestinal fatty acid binding protein??I-FABP?? and serum amyloid A??SAA?? in the diagnosis of necrotizing enterocolitis??NEC??in the newborn. Methods??Fifty-six preterm infants with a confirmed diagnosis of NEC from October 2014 to October 2015 were recruited as case group??stage??26 cases??stage??/??30 cases??. Thirty children diagnosed with non-digestive diseases in the same period were recruited as the control group. Serum levels of I-FABP and SAA were determined by enzyme-linked immunosorbent assay.The diagnostic value of I-FABP and SAA for severe NEC was assessed using the receiver operating characteristic??ROC??curve. Results??Stage??/?? cases in the case group had significantly higher serum I-FABP levels and SAA levels than the control group and Stage??cases??P??0.05??. The area under the ROC curve for serum I-FABP was 0.80??95%CI??0.69-0.92????with the optimal cut-off point of 21.8 μg/L. Under this cut-off point??the sensitivity and specificity were 70.0%and 81.0%??respectively. The area under the ROC curve for SAA was 0.76??95%CI??0.63-0.89????with the optimal cut-off point of 1657.8 μg/L. Under this cut-off point??the sensitivity and specificity were 67.0% and 80.0%??respectively. Conclusion??In newborn infants with NEC??serum I-FABP and SAA l can be used as biomarkers for the diagnosis of severe NEC.     

Prenatal and neonatal intussusception

Intussusception found in the 1st month of life is rare and usually discussed as one entity, neonatal intussusception, but in fact, includes the intussusceptions occurring both prenatally and neonatally, of which the clinical presentations and results are different. Four full-term babies with prenatal intussusception presenting as intestinal atresia (IA) and three premature babies with neonatal intussusception mimicking necrotizing enterocolitis (NEC) are presented. Prenatal intussusception, as one of the causes of IA produces prominent signs of intestinal obstruction immediately after birth. Preoperative evaluation usually fails to yield a definitive diagnosis, but surgery is usually performed in time and is successful. In neonatal intussusception, full-term infants usually have a pathological lead point and the colon is almost always involved. A barium enema is thus useful in diagnosis. Premature babies, on the other hand, rarely have a colonic component, and the clinical features are insidious and similar to NEC. This results in diagnostic confusion that may lead to a dangerous delay in appropriate surgical correction. A high level of suspicion about this condition in cases diagnosed presumptively with NEC is important. Serial abdominal sonograms may be helpful in the early diagnosis of neonatal intussusception.     

Necrotizing enterocolitis of the neonate with Clostridium perfringens: diagnosis,clinical course,and role of alpha toxin

The severity of the clinical course in necrotizing enterocolitis (NEC) associated with Clostridium perfringens (Cp) may support the hypothesis of a specific disease. We conducted a case control study of infants diagnosed with NEC, who underwent surgical treatment over a 7-year period. Patient histories examined characteristics of the infants, bacterial infection as well as NEC’s severity, antibiotic treatment, and clinical course. Infants infected with NEC associated with Cp were compared with NEC patients without Cp. The alpha toxin from Cp type A was detected in most of the isolated strains. Cp was identified as a causative agent of NEC in nine cases. As compared with the control group (n = 32), the onset of disease was earlier in life, the clinical course more severe, and patients had a larger extent of gangrene. Portal venous gas was evident in 77% of all Cp cases, as compared to 25% in the control group. The mortality rate was 44% in the Cp group, and only 18.7% in the control group. Type A Clostridium perfringens was identified in six cases. In each isolate alpha toxin production was proven, but without any correlation to the severity of the clinical course, the extent of intestinal gangrene or mortality. In premature infants NEC in conjunction with Cp seems to be more severe than other NEC cases; it also entails higher mortality and morbidity. Alpha toxin concentrations do not correlate with the severity of the disease. Portal venous gas is highly suggestive for the diagnosis of Cp infection.     

粪便高迁移率蛋白B1在早期诊断和评估新生儿坏死性小肠结肠炎病情中的价值

目的探讨粪便高迁移率蛋白B1(HMGB1)在早期诊断和评估新生儿坏死性小肠结肠炎(NEC)病情严重程度中的价值。方法 2013年7月至2015年6月纳入有腹胀、呕吐或肉眼血便,疑似NEC新生儿;以及同期住院无腹胀、呕吐、血便等消化道症状的住院患儿,分别为NEC组和对照组。收集患儿入院后1、3、5、7 d粪便标本,采用酶联免疫吸附法测定HMGB1水平。结果最终纳入分析的有46例NEC患儿和15例对照组。NEC组中,29例在入院24 h内腹部平片证实为Ⅰ期,全部在入院后4 d内恶化为Ⅱ期,其中10例进一步恶化到Ⅲ期;17例在入院24 h内腹部平片证实为Ⅱ期,其中7例恶化为Ⅲ期;17例Ⅲ期NEC患儿中,11例手术治疗、6例放弃手术治疗,手术患儿中8例存活、3例死亡。NEC患儿入院后第1、3、5、7 d HMGB1水平均高于对照组,差异有统计学意义(P?0.05);随着NEC患儿病情由Ⅰ期恶化至Ⅲ期,粪便HMGB1含量逐渐增高,差异有统计学意义(P?0.05)。结论随着NEC患儿病情恶化,粪便HMGB1含量逐渐增高,HMGB 1对于早期诊断NEC,以及在评估NEC患儿病情严重程度方面具有一定的临床价值。     

Neonatal metrizamide gastrointestinal series in suspected necrotizing enterocolitis

The diagnosis of necrotizing enterocolitis (NEC) in neonates may be made by clinical presentation, roentgenographic findings, or a combination of both. Diagnosis leads to immediate treatment including nasogastric suction, parenteral antibiotics, plasma, and close monitoring of clinical, roentgenographic, and laboratory findings. Occasionally, neither the clinical nor plain roentgenographic appearance of an infant allows the diagnosis of NEC to be made or excluded with confidence. In such infants portable isotonic metrizamide gastrointestinal (GI) series were used to help make the decision of whether to begin treatment for NEC or to continue feeding the patient. Of 15 patients examined, two exhibited signs of NEC and were successfully treated medically without GI (tract) sequelae. Twelve neonates had normal results of metrizamide GI series and ten were immediately fed with no GI complication. One of these 12 infants had feedings withheld for several days as a result of a positive blood culture. One infant with severe cardiac and pulmonary disease had profound adynamic ileus and could not be fed. We have found the metrizamide GI series to be a useful study in neonates suspected of having NEC.     

The role of the intestinal microbiota in the pathogenesis of necrotizing enterocolitis

Development of necrotizing enterocolitis (NEC) requires a susceptible host, typically a premature infant or an infant with congenital heart disease, enteral feedings and bacterial colonization. Although there is little doubt that microbes are critically involved in the pathogenesis of NEC, the identity of specific causative pathogens remains elusive. Unlike established normal adult gut microbiota, which is quite complex, uniform, and stable, early postnatal bacterial populations are simple, diverse, and fluid. These properties complicate studies aimed at elucidating characteristics of the gut microbiome that may play a role in the pathogenesis of NEC. A broad variety of bacterial, viral, and fungal species have been implicated in both clinical and experimental NEC. Frequently, however, the same species have also been found in physiologically matched healthy individuals. Clustered outbreaks of NEC, in which the same strain of a suspected pathogen is detected in several patients suggest, but do not prove, a causative relationship between the specific pathogen and the disease. Studies in Cronobacter sakazakii, the best characterized NEC pathogen, have demonstrated that virulence is not a property of a bacterial species as a whole, but rather a characteristic of certain strains, which may explain why the same species can be pathogenic or non-pathogenic. The fact that a given microbe may be innocuous in a full-term, yet pathogenic in a pre-term infant has led to the idea of opportunistic pathogens in NEC. Progress in understanding the infectious nature of NEC may require identifying specific pathogenic strains and unambiguously establishing their virulence in animal models.     

Oral gentamicin therapy in the prevention of neonatal necrotizing enterocolitis. A controlled double-blind trial.

The value of prophylactic oral gentamicin sulfate therapy in the prevention of necrotizing enterocolitis (NEC) was evaluated in a group of 42 high-risk neonates over a four-month period in a randomized, double-blind controlled trial. Twenty babies in the treatment group received 2.5 mg/kg of gentamicin sulfate every six hours for one week after birth, and 22 babies received dextrose-and-water placebo in an equivalently small volume. None of the 20 gentamicin-treated babies developed NEC. Four of the control babies did. Two of these babies died, and their diagnosis was pathologically confirmed. This difference in the incidence of NEC between the treatment and control group was significant at the .05 level. These results support the prophylactic use of orally given gentamicin for selected babies at high risk for NEC, particularly those born prematurely and those who have a history of perinatal asphyxia or umbilical artery catheterization or both. Continued surveillance for changes in antimicrobial sensitivity patterns is recommended.     

Contrast enema diagnosis of necrotizing enterocolitis

Contrast enema was performed in a select group of 126 neonates with ambiguous diagnosis of necrotizing enterolcolitis (NEC). Enema findings were compared with that on plain abdominal radiographs (AXR) and the clinical outcome. Thirty-one of the 34 patients with a discharge diagnosis of NEC were interpreted to have a positive contrast enema, and 91 of the 92 patients without a discharge diagnosis of NEC were interpreted to have a negative contrast enema. The AXR was interpreted as positive in 57 patients and as negative or indeterminate in 69. Not a single case of perforation was produced. Judicious use of contrast enema can improve specificity of diagnosis in cases with discordant clinical and plain radiographic findings.Presented at the Annual Meeting of The Society of Gastrointestinal Radiologists, Carlsbad, California, February 17–21, 1991