Excerpt from Neonatal Sepsis

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Background

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, with acquisition of 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, GI 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 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 effectively identified and treated.

Pathophysiology

The infectious agents associated with neonatal sepsis have changed over the past 50 years. S aureus and E coli were the most common bacterial infectious hazards for neonates during the 1950s in the United States. Over the ensuing decades, GBS replaced S aureus as the most common gram-positive organism that caused early-onset sepsis. During the 1990s, GBS and E coli continued to be associated with neonatal infection; however, coagulase-negative S aureus is now more frequently observed. Additional organisms, such as L monocytogenes, Chlamydia pneumoniae, H 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 (eg, gonorrhea, syphilis, herpes simplex virus [HSV], cytomegalovirus [CMV], hepatitis, human immunodeficiency virus [HIV], rubella, toxoplasmosis, Trichomonas vaginalis, 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. In neonatal ICUs (NICUs), infants with lower birth weight and infants who are less mature have an increased susceptibility to these organisms.

Staphylococcus epidermidis, a coagulase-negative Staphylococcus, is increasingly seen as a cause of nosocomial or late-onset sepsis, especially in the premature infant, in whom it is considered the leading cause of late-onset infections. Its prevalence is likely related to several intrinsic properties of the organism that allow it to readily adhere to the plastic mediums found in intravascular catheters and intraventricular shunts. The bacterial capsule polysaccharide adheres well to the plastic polymers of the catheters. Also, proteins found in the organism (AtlE and SSP-1) enhance attachment to the surface of the catheter. The adherence creates a capsule between microbe and catheter, preventing C3 deposition and phagocytosis.

Biofilms are formed on indwelling catheters by 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, making coagulase-negative staphylococcal septicemia more difficult to treat. The toxins formed by this organism have also been associated with necrotizing enterocolitis. In addition to being a cause of neonatal sepsis, the ubiquitous nature of coagulase-negative Staphylococcus as part of the normal skin flora makes it a frequent contaminant of blood and cerebrospinal fluid (CSF) cultures; therefore, a culture growing coagulase-negative Staphylococcus may represent a contaminated sample rather than true coagulase-negative staphylococcal septicemia.

In addition to the specific microbial factors mentioned above, a number of host factors predispose the newborn infant to sepsis. These factors are especially prominent in the premature infant and involve all levels of host defense, including cellular immunity, humoral immunity, and barrier function.

Cellular immunity

The neonatal neutrophil or polymorphonuclear (PMN) cell, which is vital for effective killing of bacteria, is deficient in chemotaxis and killing capacity. Decreased adherence to the endothelial lining of blood vessels reduces their ability to marginate and leave the intravascular space to migrate into the tissues. Once in the tissues, they may fail to degranulate 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 further impaired when the infant is clinically ill. Lastly, neutrophil reserves are easily depleted because of the diminished response of the bone marrow, especially in the premature infant.

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

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

Natural killer (NK) cells are found in small numbers in the peripheral blood of neonates. These cells are also functionally immature in that they produce far lower levels of interferon-gamma upon primary stimulation than do adult NK cells. This combination of findings may contribute to the severity of HSV infections in the neonatal period.

Humoral immunity

The fetus has some preformed immunoglobulin present, primarily acquired through nonspecific placental transfer from the mother. Most of this transfer occurs in late gestation, such that lower levels are found with increasing prematurity. The neonate's ability to generate immunoglobulin in response to antigenic stimulation is intact; however, the magnitude of the response is initially decreased, rapidly rising with increasing postnatal age.

The neonate is also capable of synthesizing immunoglobulin M (IgM) in utero at 10 weeks' 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. Immunoglobulin G (IgG) and immunoglobulin E (IgE) may be synthesized in utero; however, only traces are found in cord blood at delivery, as most of the IgG is acquired from the mother during late gestation. 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.

Complement protein production can be detected as early as 6 weeks' gestation; however, the concentration of the various components of the complement system widely varies among individual neonates. Although some infants have had complement levels comparable with those in adults, deficiencies appear to be greater in the alternative pathway than in the classic pathway. The terminal cytotoxic components of the complement cascade that leads to killing of organisms, especially gram-negative bacteria, are deficient. This deficiency is more marked in preterm infants. Mature complement activity is not reached until infants are aged 6-10 months. Neonatal sera have reduced opsonic efficiency against GBS, E coli, and S pneumoniae because of decreased levels of fibronectin, a serum protein that assists with neutrophil adherence and has opsonic properties.

Barrier function

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

United States

The incidence of culture-proven sepsis is approximately 2 per 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 presence of sepsis has been proven. Additionally, because the American Academy of Pediatrics (AAP),¹ American Academy of Obstetrics and Gynecology (AAOG), and Centers for Disease Control and Prevention (CDC)² 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 based on positive culture results; 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. In the preterm infant, inflammatory mediators associated with neonatal sepsis may contribute to brain injury and poor neurodevelopmental outcomes.

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

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.

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