22 June 2018
Defining NEC: beginning to shed light in a dark room.
Associate Professor of Pediatrics – Neonatology
Associate Professor of Microbiology and Immunology
University of Iowa
“The beginning of wisdom is to call things by their right names.”
– Old Chinese Proverb
We’re still at a loss to answer “What is NEC?”
Necrotizing enterocolitis (NEC) is one of the oldest diagnoses in the field of neonatology and yet remains one of its biggest scourges. NEC was first described and became part of the medical landscape in the 1950s and ’60s, which is the same time frame during which neonatology was born. In fact, the first dedicated NICU didn’t even open in the United States until 1965. The incidence pattern of NEC is quite unique. The tiniest and most premature infants are most likely to develop NEC; however, it doesn’t develop at birth when these small humans are so fragile and are tenuously clinging to life, but weeks later when these same infants appear healthy and are thriving. Then, when NEC strikes, it is typically with little warning and often ends in death or long-term impairment for survivors. Over the past 50+ years, neonatologists, researchers, and all the caregivers that look after these tiniest of patients have made amazing strides in helping them breathe, grow, have fewer debilitating side effects of their preterm birth, and yet in general, we are applying the same treatments to infants who develop NEC today that our colleagues did in the 1970s. So why have we made so little progress in one of neonatology’s original diagnoses? In part, this is because we still are at a loss to answer the question “What is NEC?”.
NEC is a medical condition that typically occurs in premature or otherwise unwell newborns where a portion of the bowel dies. But tissue death can occur from a multitude of reasons such as lack of oxygen, overwhelming inflammation, microbial invasion, or from disruption of common processes that occur in normal intestinal cells (like apoptosis and autophagy). Since we define NEC by visual or radiologic presence of tissue necrosis, the tissue death we diagnose as NEC is likely the end result of multiple different disease processes. An example of this was the realization in the 1990’s that, despite the fact that they both occur in premature infants and often require surgical intervention, spontaneous intestinal perforations were different diseases than NEC. However, while neonatologists and pediatric surgeons understand that NEC and spontaneous intestinal perforations are distinct entities, to date there remain no biomarkers or blood tests that separate the two.
So, when a surgeon operates on a preterm infant for an intestinal perforation, they still have to rely on their eyes, experience, and the report from a pathologist to make a final diagnosis. Because of this, databases of NEC patients often contain infants who had spontaneous perforations and vice versa. Similar problems exist for term infants who develop NEC. Term NEC remains an important, but small, subset of the already small group of infants who develop NEC. These infants are more likely to have congenital heart disease, a difficult delivery, or an intestinal malformation such as gastroschisis that have decreased blood flow to the intestine and which may help initiate their NEC. This is different from the classic preterm NEC which we believe is mainly an inflammatory phenomenon. However, again, as we have no biomarkers or diagnostic tests, it is difficult to distinguish these infants from infants who develop more “classic” preterm NEC.
Why is the room dark?
When I explain the problem to non-medical friends and family, I liken the problem to standing in a dark room. You want to fix the problem and turn on the lights, but you don’t know why the room is dark. Did the light bulbs burn out? Were they broken? Did the power go out? Or did you suddenly become blind? Without understanding why the room is dark, it is extremely difficult to begin to address the fix. So how can we help move the needle forward? The first is we must as a field remain committed to continue basic science research in understanding the immature intestine. Without these studies, new insights and novel hypotheses about NEC will never be generated. However, the second is that we as a field must start to all talk the same language and have coordinated international definitions of what NEC is and is not (or at least come to agreement on how to name clinical subsets of NEC).
“…we as a field must start to all talk the same language and have coordinated international definitions of what NEC is and is not..”
The definition of NEC has historically utilized Bell’s criteria to define the disease. These criteria were developed 40 years ago to help group infants by surgical severity but do little to help us define non-surgical or pre-surgical disease or to discriminate between different causes or subsets of NEC. Several manuscripts have recently been published (with several more currently under development)* that attempt to help define what NEC is and isn’t (PMID 29275814, 28046187, 27866661, 25078862, and 23730536). In general, these authors are attempting to use gestational age, laboratory values, and other physiologic data to attempt to cohort infants with NEC into better defined categories. Since we don’t have a quantitative marker (blood, stool, etc) to use to help us define the disease, the next best thing is to utilize timing and physiologic criteria that help us best define the disease processes. For example, since classic NEC seen in preterm infants is rare in the first two weeks of life while spontaneous perforations tend to cluster in the first week to 10 days of life, we can use this time frame to help us better classify infants who present with intestinal pathology. By rethinking how we define NEC in terms of its presentation and physiology, we can begin to shed light in the dark room that we currently define as NEC.
* Dr McElroy is a member of the Necrotizing Enterocolitis Workgroup of the International Neonatal Consortium. The group is currently developing a White Paper and Dr McElroy is a co-author of the section ‘Refining the diagnosis of necrotizing enterocolitis’. He has worked on this with Phillip V. Gordon, who will speak about a subset approach to NEC and NEC data at the SIGNEC meeting in October.
Dr McElroy’s presentations to SIGNEC meetings have included ‘Paneth cells and their potential role in the development of NEC’. For more information on his research, please visit the website of the Steven McElroy Laboratory.
You can also follow him on Twitter at @mcelroylabiowa
Fighting the phantom menace of necrotizing enterocolitis
David J. Hackam, MD, PhD
Chief of Pediatric Surgery and Surgeon-in-Chief
Johns Hopkins Children’s Center
Misty Good, MD, MS
Assistant Professor of Pediatrics
St Louis Children’s Hospital
Dr Minesh Khashu
Special Interest Group in Necrotizing Enterocolitis