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

https://doi.org/10.1053/j.sempedsurg.2017.11.002Get rights and content

Abstract

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.

Introduction

The field of necrotizing enterocolitis (NEC) research and the diagnosis of NEC itself has existed for more than 60 years.1, 2 It has preceded and transcended all the different forms of continuous positive ventilation, and it has been transformed in the era of surfactants.3 The field has also seen the emergence of clinical cohort studies (versus case-series), randomized controlled trials, long-term outcome studies and meta-analytics. In short, the field of NEC is older than neonatology itself. For much of that time, the field has relied on the opinion of the surgeon who created Bell’s criteria to characterize the severity of disease in the pre-surfactant era.4 Bell’s three stages were originally designed to help the bedside clinician determine when surgery was prudent. However, during the age when cohort studies were emerging, Bell’s staging became popular as the means to define NEC cohorts. It has been refined successfully only once5 yet still informs many of the dataset definitions that are in use for billing6 and quality improvement.7 After the advent of surfactant and improved survival of premature newborns, it was determined that the lowest stage contained too many patients with confounding, non-NEC diagnoses.

The challenge today lies in the evolution of neonatal patient populations and our ability to refine large datasets, such that these populations now represent distinct and often novel patient groups.8, 9 Term infants versus preterm infants experience different NEC outcomes and precedent risk factors.10, 11 Infants with severe congenital anomalies, even if they have a common endpoint disease like NEC, also have dramatically different presentations and outcomes compared to gestational age-matched cohorts with NEC. Finally, there are non-NEC diseases that lurk within our datasets and literature (such as spontaneous intestinal perforations; SIP), which can fatally sabotage our understanding of NEC.8 Recent success in NEC prevention12 and recognition of NEC subsets (where more stringent definitions are being used),13 demonstrate that we must refine our global NEC definition if we are to progress in our understanding of the disease.14

The success and clinical utility of emerging biomarkers, applied diagnostics like ultrasound and quality initiatives (e.g., bundles and checklists) that aim to reduce NEC are highly dependent on a refined and more precise definition. Each modality promises improved capacity to pinpoint the timing, accuracy, and potentially the sub-cohort categorization of NEC. New technologies and approaches make it imperative that we create a more adaptive definition. Finally, it remains crucial that any new definition be operative at the bedside. Whether in London or Kampala, a clinician must have the ability to make the diagnosis of NEC with reasonable accuracy every time. Promising preventive strategies are emerging, including breast milk feeding, antibiotic stewardship, and probiotics whose success will only be fully realized through dissemination and adoption of more rigorous risk assessment and diagnostic definitions.15, 16, 17 As NEC decreases globally we must have the ability to capture confirmed cases in our datasets, correctly, or risk an ever greater pool of non-NEC versus true cases of NEC.14 The purpose of this review is to (1) offer a better definition of NEC based on newer and novel markers and radiographic imaging, and (2) define adequate biomarkers which may be used to help guide clinical decision-making.

Section snippets

Survey of experts about adequacy of current NEC definitions

During the 2017 NEC Symposium, participants at a “Defining NEC” workshop were asked questions about the adequacy of current definitions used to define NEC. Prior to the conference, a waiver of consent was obtained from the University of Virginia Social and Behavioral Sciences Institutional Review Board (project #2017-0125-00). Workshop participants were self-selected stakeholders in NEC so initial survey questions were used to identify bias. Respondents to the survey included 20 physicians (4

Assessing risk for NEC and diagnostic uncertainty

To address the unmet need of reducing or eliminating NEC will require both the development of new tools to assist in defining NEC objectively and a deeper understanding of NEC-associated pathophysiology. Diagnostic uncertainty is a challenge in numerous suspected cases of NEC that do not present clinical signs of definitive disease. For example, reliance on pneumatosis or perforation by Bell’s Stage II and III, respectively, typically indicates that the disease is both established and has

Implications for future work

To move the field forward, both precise definitions for NEC and clear criteria for conducting and reporting studies for NEC prognostics (including biomarkers) are needed. We have presented one alternative to Bell’s staging called the “Two out of Three” rule that incorporates items available to the neonatologist and pediatric surgeon to distinguish between preterm NEC and other confounding types of acquired neonatal intestinal diseases (e.g., term NEC and SIP). One of the outcomes of the NEC

Acknowledgment

Dr. Gephart acknowledges support from the Robert Wood Johnson Foundation Nurse Faculty Scholars Program (72114) and the Agency for Healthcare Research and Quality (K08HS022908). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or Robert Wood Johnson Foundation. The Necrotizing Enterocolitis Symposium: A Transdisciplinary Approach to Improved NEC Outcomes was supported by a Eugene

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