Infections of the Neonatal Infant

Chapter 103 Infections of the Neonatal Infant



103.1 Pathogenesis and Epidemiology




Infections are a frequent and important cause of neonatal and infant morbidity and mortality. As many as 2% of fetuses are infected in utero, and up to 10% of infants have infections in the 1st mo of life. Neonatal infections are unique in several ways:











103.2 Modes of Transmission and Pathogenesis




Pathogenesis of Intrauterine Infection


Intrauterine infection is a result of clinical or subclinical maternal infection with a variety of agents (cytomegalovirus [CMV], Treponema pallidum, Toxoplasma gondii, rubella virus, varicella virus, parvovirus B19) and hematogenous transplacental transmission to the fetus. Transplacental infection may occur at any time during gestation, and signs and symptoms may be present at birth or may be delayed for months or years (Fig. 103-1). Infection may result in early spontaneous abortion, congenital malformation, intrauterine growth restriction, premature birth, stillbirth, acute or delayed disease in the neonatal period, or asymptomatic persistent infection with sequelae later in life. In some cases, no apparent effects are seen in the newborn infant.



The timing of infection during gestation affects the outcome. First-trimester infection may alter embryogenesis, with resulting congenital malformations (congenital rubella) (Chapter 239). Third-trimester infection often results in active infection at the time of delivery (toxoplasmosis, syphilis) (Chapters 282 and 210). Infections that occur late in gestation may lead to a delay in clinical manifestations until some time after birth (syphilis).


Maternal infection is a necessary prerequisite for transplacental infection. For some etiologic agents (rubella), maternal immunity is effective and antibody is protective for the fetus. For other agents (CMV), maternal antibody may ameliorate the outcome of infection or may have no effect (Chapter 247). Even without maternal antibody, transplacental transmission of infection to a fetus is variable because the placenta may function as an effective barrier.



Pathogenesis of Ascending Bacterial Infection


In most cases, the fetus or neonate is not exposed to potentially pathogenic bacteria until the membranes rupture and the infant passes through the birth canal and/or enters the extrauterine environment. The human birth canal is colonized with aerobic and anaerobic organisms that may result in ascending amniotic infection and/or colonization of the neonate at birth. Vertical transmission of bacterial agents that infect the amniotic fluid and/or vaginal canal may occur in utero or, more commonly, during labor and/or delivery (Fig. 103-2). Chorioamnionitis results from microbial invasion of amniotic fluid, often as a result of prolonged rupture of the chorioamniotic membrane. Amniotic infection may also occur with apparently intact membranes or with a relatively brief duration of membrane rupture. The term chorioamnionitis refers to the clinical syndrome of intrauterine infection, which includes maternal fever, with or without local or systemic signs of chorioamnionitis (uterine tenderness, foul-smelling vaginal discharge/amniotic fluid, maternal leukocytosis, maternal and/or fetal tachycardia). Chorioamnionitis may also be asymptomatic, diagnosed only by amniotic fluid analysis or pathologic examination of the placenta. The rate of histologic chorioamnionitis is inversely related to gestational age at birth (Fig. 103-3) and directly related to duration of membrane rupture. Rupture of membranes for longer than 24 hr was once considered prolonged because microscopic evidence of inflammation of the membranes is uniformly present when the duration of rupture exceeds 24 hr. At 18 hr of membrane rupture, however, the incidence of early-onset disease with group B streptococcus (GBS) increases significantly; 18 hr is the appropriate cutoff for increased risk of neonatal infection.




Bacterial colonization does not always result in disease. Factors influencing which colonized infant will experience disease are not well understood but include prematurity, underlying illness, invasive procedures, inoculum size, virulence of the infecting organism, genetic predisposition, the innate immune system, host response, and transplacental maternal antibodies (Fig. 103-4). Aspiration or ingestion of bacteria in amniotic fluid may lead to congenital pneumonia or systemic infection, with manifestations becoming apparent before delivery (fetal distress, tachycardia), at delivery (failure to breathe, respiratory distress, shock), or after a latent period of a few hours (respiratory distress, shock). Aspiration or ingestion of bacteria during the birth process may lead to infection after an interval of 1-2 days.



Resuscitation at birth, particularly if it involves endotracheal intubation, insertion of an umbilical vessel catheter, or both, is associated with an increased risk of bacterial infection. Explanations include the presence of infection at the time of birth or acquisition of infection during the invasive procedures associated with resuscitation.





103.3 Immunity




Decreased function of neutrophils and other cells involved in the response to infection has been demonstrated in both term and preterm infants. Preterm infants may also have low concentrations of immunoglobulins. Both preterm and term infants have quantitative and qualitative defects of the complement system. Despite these alterations in immune function, the rate of systemic infection in newborns is low. All newborns enter an unsterile environment, but infection develops in only a few.





Neutrophils


Quantitative and qualitative deficiencies of the phagocyte system contribute to the newborn’s susceptibility to infection. Neutrophil migration (chemotaxis) is abnormal at birth in both term and preterm infants. Neonatal neutrophils have decreases in adhesion, aggregation, and deformability, all of which may delay the response to infection. Abnormal expression of cell membrane adhesion molecules (the β2 integrins and selectins) and abnormalities in the neonatal neutrophil cytoskeleton contribute to abnormal chemotaxis. With adequate opsonization, phagocytosis and killing by neutrophils are comparable in newborn infants and adults. In the presence of infectious or noninfectious stress (respiratory distress syndrome), however, the ability of neonatal neutrophils to phagocytose gram-negative (but not gram-positive) bacteria is decreased. Impairment of the oxidative respiratory burst of neonatal neutrophils is a factor in the increased risk of sepsis, especially in preterm infants.


The number of circulating neutrophils is elevated after birth in both term and preterm infants, with a peak at 12 hr that returns to normal by 22 hr. Band neutrophils constitute less than 15% in normal newborns and may increase in newborns with infection and other stress responses, such as asphyxia.


Neutropenia, which is frequently observed in preterm infants and infants with intrauterine growth restriction, increases the risk for sepsis. The neutrophil storage pool in newborn infants is 20-30% of that in adults and is more likely to be depleted in the face of infection. Mortality is increased when sepsis is associated with severe sepsis-induced neutropenia and bone marrow depletion. Granulocyte colony–stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) are cytokines that play important roles in the proliferation, differentiation, functional activation, and survival of phagocytes. These cytokines stimulate myeloid progenitor cells, increase the bone marrow neutrophil storage pool, induce peripheral blood neutrophilia, and influence neutrophil function, including enhancement of bactericidal activity. Although these myeloid colony-stimulating factors influence neutrophil number and function, their clinical utility in the treatment and/or prevention of neonatal sepsis remains undetermined.





Cytokines/Inflammatory Mediators


The patient’s response to infection and clinical outcome involves a balance between pro-inflammatory and anti-inflammatory cytokines. Several adverse neonatal outcomes, including brain injury, necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia, may be mediated by the cytokine response to infection in the mother, fetus, or newborn. The mediators that have been studied in newborns include tumor necrosis factor-α (TNFα), interleukin 1 (IL-1), IL-4, IL-6, IL-8, IL-10, IL-12, platelet-activating factor, and the leukotrienes. The release of various inflammatory mediators in response to infection offers the potential opportunity to facilitate an early laboratory diagnosis of infection. Potential surrogate markers for bacterial sepsis, pneumonia, and NEC include TNFα, IL-6, and IL-8.


Innate immunity involves nonspecific cellular and humoral responses to an infectious agent without previous exposure. Recognition of pathogens is initiated by soluble components in plasma (including mannose-binding lectin) and by recognition of receptors on monocytes and other cells. Toll-like receptors play an important role in pathogen recognition. Genetic polymorphisms (mutations) of various proteins involved in the immune response may increase the risk and severity of neonatal infections. The neutrophil is another important cellular component of innate immunity. Neutrophil granules contain many enzymes; one protein, bactericidal/permeability-increasing protein (BPI), binds to the endotoxin in the cell wall of gram-negative bacteria. This protein facilitates opsonization and prevents the inflammatory response to endotoxin. BPI activity may be decreased in neonates.




103.4 Etiology of Fetal and Neonatal Infection




A number of agents may infect newborns in utero, intrapartum, or postpartum (Tables 103-1 and 103-2). Intrauterine transplacental infections of significance to the fetus and/or newborn include syphilis, rubella, CMV, toxoplasmosis, parvovirus B19, and varicella. Although HSV, HIV, hepatitis B virus (HBV), hepatitis C virus, and tuberculosis (TB) can each result in transplacental infection, the most common mode of transmission for these agents is intrapartum, during labor and delivery with passage through an infected birth canal (HIV, HSV, HBV), or postpartum, from contact with an infected mother or caretaker (TB) or with infected breast milk (HIV).




Any microorganism inhabiting the genitourinary or lower gastrointestinal tract may cause intrapartum and postpartum infection. The most common bacteria are GBS, enteric organisms, gonococci, and chlamydiae. The more common viruses are CMV, HSV, enteroviruses, and HIV.


Agents that commonly cause nosocomial infection are coagulase-negative staphylococci, gram-negative bacilli (E. coli, Klebsiella pneumoniae, Salmonella, Enterobacter, Citrobacter, Pseudomonas aeruginosa, Serratia), enterococci, S. aureus, and Candida. Viruses contributing to nosocomial neonatal infection include enteroviruses, CMV, hepatitis A, adenoviruses, influenza, respiratory syncytial virus (RSV), rhinovirus, parainfluenza, HSV, and rotavirus. Community-acquired pathogens such as Streptococcus pneumoniae may also cause infection in newborn infants after discharge from the hospital.


Congenital pneumonia may be caused by CMV, rubella virus, and T. pallidum and, less commonly, by the other agents producing transplacental infection (Table 103-3). Microorganisms causing pneumonia acquired during labor and delivery include GBS, gram-negative enteric aerobes, Listeria monocytogenes, genital Mycoplasma, Chlamydia trachomatis, CMV, HSV, and Candida species.



Bacteria responsible for most cases of nosocomial pneumonia typically include staphylococcal species, gram-negative enteric aerobes, and occasionally, Pseudomonas. Fungi are responsible for an increasing number of systemic infections acquired during prolonged hospitalization of preterm neonates. Respiratory viruses cause isolated cases and outbreaks of nosocomial pneumonia. These viruses, usually endemic during the winter months and acquired from infected hospital staff or visitors to the nursery, include RSV, parainfluenza virus, influenza viruses, and adenovirus. Respiratory viruses are the single most important cause of community-acquired pneumonia and are usually contracted from infected household contacts.


The most common bacterial causes of neonatal meningitis are GBS, E. coli, and L. monocytogenes. S. pneumoniae, other streptococci, non-typable Haemophilus influenzae, both coagulase-positive and coagulase-negative staphylococci, Klebsiella, Enterobacter, Pseudomonas, T. pallidum, and Mycobacterium tuberculosis may also produce meningitis.




103.5 Epidemiology of Early- and Late-Onset Neonatal Infections




The terms early-onset infection and late-onset infection refer to the different ages at onset of infection in the neonatal period (Table 103-4). Although these disorders were originally divided arbitrarily into infections occurring before and after 1 wk of life, it is more useful to separate early- and late-onset infections according to peripartum pathogenesis. Early-onset infections are acquired before or during delivery (vertical mother-to-child transmission). Late-onset infections develop after delivery from organisms acquired in the hospital or the community. The age at onset depends on the timing of exposure and virulence of the infecting organism. Very-late-onset infections (onset after 1 mo of life) may also occur, particularly in VLBW preterm infants or term infants requiring prolonged neonatal intensive care.



The incidence of neonatal bacterial sepsis varies from 1 to 4/1,000 live births in developed countries, with considerable fluctuation over time and with geographic variation. Studies suggest that term male infants have a higher incidence of sepsis than term females. This sex difference is less clear in preterm LBW infants. Attack rates of neonatal sepsis increase significantly in LBW infants in the presence of maternal chorioamnionitis, congenital immune defects, mutations of genes involved in the innate immune system, asplenia, galactosemia (E. coli), and malformations leading to high inocula of bacteria (obstructive uropathy).


A study from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network documented rates of early-onset sepsis among approximately 200,000 live births at Network centers. The overall rate of early-onset sepsis was 1.2 cases per 1000 live births with rates inversely related to birthweight (401-1500 g BW, 12.33/1000; 1501-2500 g BW, 1.96/1000; >2500 g BW, 0.71/1000) (Table 103-5).



Intrapartum antibiotics are used to reduce vertical transmission of GBS as well as to lessen neonatal morbidity after preterm rupture of membranes. With introduction of selective intrapartum antibiotic prophylaxis to prevent perinatal transmission of GBS, rates of early-onset neonatal GBS infection in the USA declined from 1.7/1,000 live births to 0.32/ 1,000, according to U.S. Centers for Disease Control and Prevention (CDC) surveillance data. Intrapartum chemoprophylaxis does not reduce the rates of late-onset GBS disease and has no effect on the rates of infection with non-GBS pathogens. Of concern is a possible increase in gram-negative infections (especially E. coli) in VLBW and possibly term infants in spite of a reduction in early GBS sepsis by intrapartum antibiotics.


The incidence of meningitis is 0.2-0.4/1,000 live births in newborn infants and is higher in preterm infants. Bacterial meningitis may be associated with sepsis or may occur as a local meningeal infection. One third of VLBW infants with late-onset meningitis have negative blood culture results. The discordance between results of blood and cerebrospinal fluid (CSF) cultures suggests that meningitis may be underdiagnosed among VLBW infants and emphasizes the need for culture of CSF in VLBW infants when late-onset sepsis is suspected and in all infants who have positive blood culture results.




Nosocomial Infections


Nosocomial (hospital-acquired) infections are responsible for significant morbidity and late mortality in hospitalized newborns. Many experts define nosocomial infections in newborns as infections occurring after 3 days of life that are not directly acquired from the mother’s genital tract. For the purposes of surveillance in the acute care setting, the CDC National Healthcare Safety Network (NHSN) defines health care–associated infections in newborns as those that result from passage through the birth canal as well as infections that occur from exogenous sources such as health care personnel, visitors, and equipment/devices in the health care environment. This surveillance definition includes any infection occurring after admission to the neonatal intensive care unit (NICU) that was not transplacentally acquired. Rates of nosocomial infection in healthy term infants who are either rooming-in with their mothers or staying in the well baby nursery are low (<1%). The majority of nosocomial infections occur in preterm or term infants who require intensive care. Risk factors for nosocomial infection in these infants include prematurity, LBW, invasive procedures, indwelling vascular catheters, parenteral nutrition with lipid emulsions, endotracheal tubes, ventricular shunts, alterations in the skin and/or mucous membrane barriers, frequent use of broad-spectrum antibiotics, and prolonged hospital stay. The most frequent nosocomial infections are bloodstream infections associated with an intravascular catheter and pneumonia, especially ventilator-associated pneumonia. Nonetheless, nosocomial sepsis may occur in the absence of a catheter or ventilator. In addition, infants receiving intensive care in the NICU are at risk to acquire community or hospital associated infections during seasonal epidemics (rotavirus, RSV, influenza).


Almost one quarter of VLBW infants (<1,500 g BW) experience nosocomial infections. Rates of infections increase with decreasing gestational age and birthweight. The NICHD Neonatal Research Network has reported rates of 43% for infants 401-750 g; 28% for those 751-1,000 g; 15% for those 1,001-1,250 g; and 7% for those 1,251-1,500 g. The CDC NHSN monitors device-associated nosocomial infection rates. Rates are inversely related to birthweight, and in level III NICUs, they range from 3.7 infections per 1,000 central line days for infants < 750 g to 2.0 infections per 1,000 central line days for those weighing > 2,500 g. The widespread differences in practice regarding the inclusion of lumbar puncture (LP) in the diagnostic evaluation of an infant with suspected sepsis make it more difficult to determine rates of late-onset meningitis.


Various bacterial and fungal agents colonize hospitalized infants, health care workers, and visitors. Pathogenic agents can be transmitted by direct contact or indirectly via contaminated equipment, intravenous fluids, medications, blood products, or enteral feedings. Colonization of the infant’s skin, umbilicus, and respiratory or gastrointestinal tract with pathogenic agents often precedes the development of infection. Antibiotic use interferes with colonization by normal flora, thereby facilitating colonization with more virulent pathogens.


Coagulase-negative staphylococci are the most frequent neonatal nosocomial pathogens. In a cohort of 6,215 VLBW infants in the NICHD Neonatal Research Network, gram-positive agents were associated with 70%, gram-negative with 18%, and fungi with 12% of cases of late-onset sepsis (Table 103-6). Coagulase-negative staphylococcus, the single most common organism, was isolated in 48% of these infections. The emergence of nosocomial bacterial pathogens resistant to multiple antibiotics is a growing concern. Among NICU patients, methicillin-resistant S. aureus, vancomycin-resistant enterococci, and multidrug-resistant gram-negative pathogens are particularly alarming. Organisms responsible for all categories of neonatal sepsis and meningitis may change with time (Table 103-7).


Table 103-6 DISTRIBUTION OF PATHOGENS ASSOCIATED WITH THE 1ST EPISODE OF LATE-ONSET SEPSIS IN VERY LOW BIRTHWEIGHT INFANTS*















































































ORGANISM N %
Gram-positive organisms: 922 70.2
Staphylococcus—coagulase negative 629 47.9
Staphylococcus aureus 103 7.8
Enterococcus spp. 43 3.3
Group B streptococci 30 2.3
Other 117 8.9
Gram-negative organisms: 231 17.6
Escherichia coli 64 4.9
Klebsiella 52 4.0
Pseudomonas 35 2.7
Enterobacter 33 2.5
Serratia 29 2.2
Other 18 1.4
Fungi: 160 12.2
Candida albicans 76 5.8
Candida parapsilosis 54 4.1
Other 30 2.3
TOTAL 1,313 100

* National Institute of Child Health and Human Development Neonatal Research Network, September 1, 1998, through August 31, 2000.


Patients with dual infections and patients with presumed coagulase-negative staphylococci (CONS) contaminants excluded. According to the definitions in text, 276 (44%) CONS were definite infections and 353 (56%) were possible infections.


From Stoll BJ, Hansen N, Fanaroff AA, et al: Late-onset sepsis in very low birthweight neonates: the experience of the NICHD Neonatal Research Network, Pediatrics 110:285–291, 2002.



Viral organisms may also cause nosocomial infection in the NICU; they include RSV, varicella, influenza, rotavirus, and enteroviruses. For viral as well as bacterial infections, nursery outbreaks may occur in addition to individual cases. Hospital infection control policies are essential to prevent and/or contain nursery infection outbreaks.


The mean age at onset of the 1st episode of late-onset nosocomial sepsis is 2-3 wk, independent of the infecting pathogen. Nosocomial infections increase the risk of adverse outcomes, including prolonged hospitalization and mortality.

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Jun 18, 2016 | Posted by in PEDIATRICS | Comments Off on Infections of the Neonatal Infant

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