NEONATAL SEPSIS NEONATAL INFECTION

Neonatal sepsis (neonatal infection, early-onset neonatal sepsis, late-onset neonatal sepsis, early-onset sepsis syndrome, late-onset sepsis syndrome)
Neonatal sepsis may be categorized as early or late onset. Eighty-five percent of newborns with early-onset infection present within 24 hours, 5% present at 24-48 hours, and a smaller percentage of patients present between 48 hours and 6 days of life. Onset is most rapid in premature neonates. Early-onset sepsis syndrome is associated with acquisition of microorganisms from the mother. Transplacental infection or an ascending infection from the cervix may be caused by organisms that colonize in the mother's genitourinary tract. The infant may acquire the microbe by passage through a colonized birth canal at delivery. The microorganisms most commonly associated with early-onset infection include group B Streptococcus (GBS), Escherichia coli, Haemophilus influenzae, and Listeria monocytogenes.

Late-onset sepsis syndrome occurs at 7-90 days of life and is acquired from the caregiving environment. Organisms that have been implicated in causing late-onset sepsis syndrome include coagulase-negative staphylococci, Staphylococcus aureus, E coli, Klebsiella, Pseudomonas, Enterobacter, Candida, GBS, Serratia, Acinetobacter, and anaerobes. The infant's skin, respiratory tract, conjunctivae, gastrointestinal tract, and umbilicus may become colonized from the environment, leading to the possibility of late-onset sepsis from invasive microorganisms. Vectors for such colonization may include vascular or urinary catheters, other indwelling lines, or contact from caregivers with bacterial colonization.

Pneumonia is more common in early-onset sepsis, whereas meningitis and/or bacteremia are more common in late-onset sepsis. Premature and ill infants have an increased susceptibility to sepsis and subtle nonspecific initial presentations; therefore, they require much vigilance so that sepsis can be identified and treated effectively.

Pathophysiology: The infectious agents associated with neonatal sepsis have changed over the past 50 years. S aureus and E coli were the most common infectious hazards for neonates in the 1950s in the United States. GBS then replaced S aureus as the most common gram-positive agent, causing early-onset sepsis during the next decades. During the 1990s, GBS and E coli continued to be associated with neonatal infection; however, coagulase-negative S aureus is now observed more frequently. Additional organisms, such as L monocytogenes, Chlamydia pneumonia, Haemophilus influenzae, Enterobacter aerogenes, and species of Bacteroides and Clostridium have also been identified in neonatal sepsis.

Meningoencephalitis and neonatal sepsis syndrome can also be caused by infection with adenovirus, enterovirus, or coxsackievirus. Additionally, sexually transmitted diseases and viral diseases, such as gonorrhea, syphilis, herpes simplex virus (HSV), cytomegalovirus (CMV), hepatitis, HIV, rubella, toxoplasmosis, Trichomonas vaginalis, and Candida species, have all been implicated in neonatal infection. Bacterial organisms with increased antibiotic resistance have also emerged and have further complicated the management of neonatal sepsis. The colonization patterns in nurseries and personnel are reflected in the organisms currently associated with nosocomial infection. Infants with lower birth weight and infants who are less mature in today's neonatal intensive care units (NICUs) have increased susceptibility to these organisms.

Staphylococcus epidermidis, or coagulase-negative Staphylococcus is increasingly seen as a cause of nosocomial or late-onset sepsis, especially in the premature infant. It is considered the leading cause of late-onset infections for this population. Its prevalence is related to its preference for the plastic mediums found in cannulas and shunts, which increases its introduction via umbilical catheters and other indwelling lines. The bacterial capsule polysaccharide adheres well to the plastic polymers of the catheters. The adherence creates a capsule between microbe and catheter, which prevents C3 deposition and phagocytosis. Also, proteins found in the organism [AtlE and SSP-1] enhance attachment to the surface of the catheter.

Biofilms are formed at the site from the aggregation of organisms that have multiplied with the protection provided by the adherence to the catheter. Slimes are produced at the site from the extracellular material formed by the organism, which provides a barrier to the host defense, as well as antibiotic action. Therefore, it can be seen that slime production increases the difficulty to treat coagulase-negative staphylococcal septicemia. The toxins formed by this organism have been associated with necrotizing enterocolitis. Coagulase-negative Staphylococcus is a frequent contaminate of blood and cerebrospinal fluid (CSF) cultures; therefore, it can be a false indicator of coagulase-negative staphylococcal septicemia.

The neonate is unable to respond effectively to infectious hazards because of deficits in the physiological response to infectious agents. The neonatal neutrophil or polymorphonuclear (PMN) cell, which is vital for effective killing of bacteria, is defective in chemotaxis and killing capacity. Decreased adherence to the endothelial lining of blood vessels reduces their ability to marginate and leave the intravascular area to migrate into the tissues. Once in the tissues, they may fail to deaggregate in response to chemotactic factors. Also, neonatal PMNs are less deformable; therefore, they are less able to move through the extracellular matrix of tissues to reach the site of inflammation and infection. The limited ability of neonatal PMNs for phagocytosis and killing of bacteria is impaired when the infant is clinically ill. Lastly, neutrophil reserves are depleted easily because of the diminished response of the bone marrow, especially in the premature infant.

Neonatal monocyte concentration and function are at adult levels; however, macrophage chemotaxis is impaired and continues to exhibit decreased function into early childhood. Macrophages are decreased in the lungs and probably also in the liver and spleen. The chemotactic and bacteriocidal activity and the antigen presentation by these cells are not fully competent. Cytokine production by macrophages is decreased, which may be associated with a corresponding decrease in T-cell production.

T cells are found in early gestation in fetal circulation and increase in number from birth to about age 6 months; however, these cells represent an immature transitory population. Neonates are deficient in T cells with the memory cell surface phenotype; however, the number of these T cells increases with maturity as the neonate is exposed to antigenic stimuli. These antigenically naive cells do not proliferate as readily as adult T cells when activated. Also, neonatal T cells do not effectively produce the cytokines that assist with B-cell stimulation and differentiation and with bone marrow stimulation of granulocyte/monocyte proliferation. A delay occurs in the formation of antigen specific memory function following primary infection. The cytotoxic function of neonatal T cells is 50-100% as effective as adult T cells.

The fetus has some preimmune immunoglobulin present; however, preimmune immunoglobulin is relatively limited in fetuses compared to adults. The infant receives immunoglobulin G (IgG) prenatally after 16 weeks of gestation; however, the infant born prematurely has less IgG due to the shorter period of placental transmission of immunoglobulin.

Additionally, if the mother is immunosuppressed, it is possible that less IgG can be transmitted to the infant. The neonate is capable of synthesizing immunoglobulin M (IgM) in utero at 10 weeks of gestation; however, IgM levels are generally low at birth, unless the infant was exposed to an infectious agent during the pregnancy, thereby stimulating increased IgM production. IgG and immunoglobulin E (IgE) may be synthesized in utero; however, only traces are found in cord blood at delivery. The neonate may receive immunoglobulin A (IgA) from breastfeeding but does not secrete IgA until 2-5 weeks after birth. Response to bacterial polysaccharide antigen is diminished and remains so during the first 2 years of life.

Natural killer (NK) cells are found in greater concentration in the peripheral blood of neonates than in that of adults; however, certain antigen expressivity by the cells' membranes is diminished, thereby reducing cytolytic activity. This decreased response has been observed with infection by herpes group viruses in the neonate.

The fetus is capable of complement protein production as early as 6 weeks gestational age; however, wide variability exists among individual neonates in the concentration of the components of the complement system. Some infants who were studied had comparable concentrations to adults. Deficiencies appear to be greater for neonates in the alternative pathway than in the classic pathway. The terminal activity for complement that leads to killing of organisms, especially gram-negative bacteria, is inefficient. This deficiency is more marked in preterm infants. Mature complement activity is not reached until infants are aged 6-10 months. Fibronectin, a serum protein that assists with neutrophil adherence and has opsonic properties, is found in lower concentrations in neonates. Therefore, neonatal sera have reduced opsonic efficiency against GBS, E coli, and S pneumoniae.

The physical and chemical barriers to infection in the human body are present in the newborn but are functionally deficient. Skin and mucus membranes are broken down easily in the premature infant. Neonates who are ill and/or premature are additionally at risk because of the invasive procedures that breach their physical barriers to infection. Because of the interdependence of the immune response, these individual deficiencies of the various components of immune activity in the neonate conspire to create a hazardous situation for the neonate exposed to infectious threats.

Frequency:
• In the US: The incidence of culture-proven sepsis is approximately 2 in 1000 live births. Of the 7-13% of neonates who are evaluated for neonatal sepsis, only 3-8% have culture-proven sepsis. The early signs of sepsis in the newborn are nonspecific; therefore, many newborns undergo diagnostic studies and the initiation of treatment before the diagnosis has been determined. Additionally, because the American Academy of Pediatrics (AAP), American Academy of Obstetrics and Gynecology (AAOG), and Centers for Disease Control and Prevention (CDC) all have recommended sepsis screening and/or treatment for various risk factors related to GBS diseases, many asymptomatic neonates now require evaluation. Because the mortality rate of untreated sepsis can be as high as 50%, most clinicians believe that the hazard of untreated sepsis is too great to wait for confirmation by positive cultures; therefore, most clinicians initiate treatment while awaiting culture results.

Mortality/Morbidity: The mortality rate in neonatal sepsis may be as high as 50% for infants who are not treated. Infection is a major cause of fatality during the first month of life, contributing to 13-15% of all neonatal deaths. Neonatal meningitis, a serious morbidity of neonatal sepsis, occurs in 2-4 cases per 10,000 live births and significantly contributes to the mortality rate in neonatal sepsis; it is responsible for 4% of all neonatal deaths.

Race: Black infants have an increased incidence of GBS disease and late-onset sepsis. This is observed even after controlling for risk factors of low birth weight and decreased maternal age.

Sex: The incidence of bacterial sepsis and meningitis, especially for gram-negative enteric bacilli, is higher in males than in females.

Age: Studies have shown that premature infants have an increased incidence of sepsis. The incidence of sepsis is significantly higher in infants with very low birth weight (<1000 g), at 26 per 1000 live births, than in infants with a birth weight of 1000-2000 g, at 8-9 per 1000 live births. The risk for death or meningitis from sepsis is higher in infants with low birth weight than in full-term neonates.