Organ dysfunction in sepsis and necrotizing enterocolitis

Key points

Sepsis and necrotizing enterocolitis are common sources of morbidity and mortality in the premature infant population.
There is a lack of consensus on the definition of neonatal sepsis, confounded by the overlap between pathologic and non-pathologic variability in vital signs, physiology, and exam findings.
Improved outcomes in neonatal sepsis and sepsis-like illness will require prompt intervention guided by sensitive, multimodal detection of end-organ dysfunction.

Sepsis and sepsis-like illnesses, including necrotizing enterocolitis (NEC), remain among the most common causes of mortality in premature infants. Neonatal sepsis kills thousands of newborns every year, and survivors commonly suffer serious morbidities. ^, The risk of sepsis and NEC is not evenly distributed across the population of all infants, with incidences increasing as gestational age decreases. Among those born before 28 weeks’ gestation, the rate of sepsis can be as high as 30% to 40%. The host response to infection is designed to fight off pathogens but often does so at the expense of normal organ function. The immune response signals inflammatory cascades with checks and balances from anti-inflammatory pathways, mediated by the autonomic nervous system. Much, if not all, of the morbidity and mortality associated with sepsis is the result of organ dysfunction; thus, the diagnosis and treatment of neonatal sepsis must be calibrated to the presence and severity of organ dysfunction.

Despite this need, definitions of sepsis based on organ dysfunction, originally developed for adult and older pediatric patients, perform poorly in preterm neonates, confounded by the generally unstable physiology of prematurity. As a result, most clinical trials have relied on the blood culture result alone as an unequivocal, albeit limited, definition of neonatal sepsis. Currently, experts are working to develop a core outcome set for clinical trials of neonatal sepsis. In 2005, the International Pediatric Sepsis Consensus Conference defined sepsis syndromes and organ failure for pediatric patients. These definitions modified those for adult patients with systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and organ dysfunction for children in six age groups, including term neonates, but notably not including premature infants. Some have suggested modifications to the pediatric SIRS criteria for application to premature infants, ^, but one study evaluating the accuracy of the modified SIRS criteria for premature infants found them to only modestly improve sensitivity from about 40% to 50%. More work is needed to develop consensus definitions for sepsis to operationalize organ dysfunction in premature infants with immature organ systems. The Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Collaborative was founded to better define organ dysfunction in pediatric sepsis, yet their work excludes premature infants. Recognizing and treating organ dysfunction early in the course of neonatal sepsis is an important yet challenging goal, especially in premature infants. Therefore, this review will focus on the pathophysiology of organ dysfunction in neonatal sepsis and NEC, with an emphasis on questions and controversies yet to be answered.

Organ dysfunction severity

End-organ dysfunction occurs when homeostasis is disrupted and the organ is no longer able to adequately support the body. Dysfunction may arise from many sources, including hypoxia, ischemia, destruction of tissue by infectious organisms, or altered function induced by local or systemic inflammation. Although organized as distinct units of the body, organs function as a network, and the physiology of one system reflects and adapts to changes in others. ^, Although organ dysfunction is the proximal cause of sepsis-related mortality, early signs may be subtle and the time course of progression to overt failure depends on complex interactions between the pathogen, the host, and the treatment.

The pathogen

The causative organism plays an important role in modulating the severity of illness during a bloodstream infection. Our understanding of the pathophysiology of neonatal sepsis is limited by blood cultures with a substantial number of false-negative and false-positive results. ^, Studies of neonatal sepsis with bacteremia show that Gram-negative organisms cause mortality and serious organ dysfunction more often than sepsis caused by Gram-positive bacteria. Different pathogens trigger different immune responses because of their unique virulence factors, referred to as pathogen-associated molecular patterns (PAMPs). For example, lipopolysaccharide (LPS), an integral component of the cell membrane in Gram-negative bacteria, activates immune cells via host receptors, such as Toll-like receptors. There is significant variability in PAMPs and their interaction with human receptors, underlining the complex, diverse, and unique inter-individual differences in the clinical manifestation of sepsis episodes.

Furthermore, the chronologic age of the preterm infant at the time of infection impacts the profile of the most likely organism; Gram-negative organisms are more common in early-onset sepsis (within the first 3 days after birth) and Gram-positive organisms are more common in premature infants with late-onset sepsis. ^, Sepsis caused by fungus ^, and viruses can also lead to organ dysfunction and serious illness but compose a minority of infections.

Although we often focus on bloodstream infections as the cause of the sepsis syndrome in neonates, NEC presents with a similar but subtly distinct course of illness. The systemic inflammatory syndrome that frequently accompanies NEC in premature infants develops in part due to disruption of the normal interface between enterocytes and the microbial flora of the intestinal tract. ^, Toll-like receptors of the innate immune system mediate the initial inflammatory response to pathogenic intestinal microbes, and the disease progresses with an inflammatory cascade leading to sepsis and shock just as a bloodstream infection would. These two processes are not always distinct, as many bloodstream infections in premature infants probably arise from the translocation of intestinal bacteria into the bloodstream. Similarly, pneumonia, urinary tract infection, focal intestinal perforation, and other localized infections may also lead to a sepsis-like illness with organ dysfunction in premature infants. ^, ^,

The host

Virulence factors of the pathogen play a major part in the severity of illness, but host factors influence the sepsis trajectory, as well. The immune response depends on many variables, including the infant’s gestational and postnatal age. ^, Fatal or severe sepsis occurs in some cases because the neonatal immune response is less robust than that of an adult or child, leaving them more susceptible to systemic infection and organ dysfunction. ^, Sex is a biological risk factor with a slightly higher incidence of sepsis in males. Black or non-White race has been associated with higher neonatal sepsis risk, ^, likely due to the complex influence of socioeconomic and maternal health factors. Molecular studies have identified genetic polymorphisms associated with a higher risk of sepsis. Studies in adults have shown a specific tumor necrosis factor polymorphism to be a risk marker for worse outcomes in severe sepsis, but a small study was unable to confirm the association in neonates with sepsis.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here