130: Sepsis

Neonatal sepsis is a clinical syndrome of systemic illness accompanied by bacteremia occurring in the first month of life

The overall incidence of primary sepsis is 1–5 per 1000 live births. The incidence is much higher for very low birthweight (VLBW) infants (birthweight <1500 g), with early-onset sepsis rate of 2% and late-onset nosocomial sepsis rate of 36% according to data from the National Institute of Child Health and Human Development Neonatal Research Network (NICHD-NRN). The mortality rate is high (13–25%); higher rates are seen in premature infants and in those with early fulminant disease.

Neonatal sepsis can be classified into 2 relatively distinct syndromes based on the age of presentation: early-onset and late-onset sepsis.

1. Presents in the first 3–5 days of life and is usually a multisystem fulminant illness with prominent respiratory symptoms. Typically, the infant has acquired the organism during the antepartum or intrapartum period from the maternal genital tract. Several infectious agents, notably treponemes, viruses, Listeria, and probably Candida, can be acquired transplacentally via hematogenous routes. Acquisition of other organisms is associated with the birth process. With rupture of membranes, vaginal flora or various bacterial pathogens may ascend to reach the amniotic fluid and the fetus. Chorioamnionitis develops, leading to fetal colonization and infection. Aspiration of infected amniotic fluid by the fetus or neonate may play a role in the resultant respiratory symptoms. Finally, the infant may be exposed to vaginal flora as it passes through the birth canal. The primary sites of colonization tend to be the skin, nasopharynx, oropharynx, conjunctiva, and umbilical cord. Trauma to these mucosal surfaces may lead to infection. Early-onset disease is characterized by a sudden onset and fulminant course that can progress rapidly to septic shock and death.

2. Late-onset sepsis (LOS). May occur as early as 5 days of age. LOS is usually more insidious but it can be fulminant at times. It is usually not associated with early obstetric complications. In addition to bacteremia, these infants may have an identifiable focus, most often meningitis in addition to sepsis. Bacteria responsible for LOS and meningitis include those acquired after birth from the maternal genital tract (vertical transmission) as well as organisms acquired after birth from human contact or from contaminated equipment/environment (nosocomial). Therefore, horizontal transmission appears to play a significant role in late-onset disease. The reasons for the delay in development of clinical illness, the predilection for central nervous system (CNS) disease, and the less severe systemic and cardiorespiratory symptoms are unclear. Transplacental transfer of maternal antibodies to the mother's own vaginal flora may play a role in determining which exposed infants become infected, especially in the case of group B streptococcal infections. In case of nosocomial spread, the pathogenesis is related to the underlying illness and debilitation of the infant, the flora in the neonatal intensive care (NICU) environment, and invasive monitoring and other techniques used in the NICU. Breaks in the natural barrier function of the skin and intestine allow opportunistic organisms to invade and overwhelm the neonate. Infants, especially the premature, have an increased susceptibility to infection because of underlying illnesses and immature immune defenses that are less efficient at localizing and clearing bacterial invasion.

3. Microbiology. The principal pathogens involved in EOS have tended to change with time. Before 1965, Staphylococcus aureus and Escherichia coli used to be the most commonly isolated organisms. In the late 1960s, group B Streptococcus (GBS) emerged as the most common microorganism. Currently, most centers continue to report GBS as the most common microorganism, even though the incidence has decreased considerably after the widespread adoption of universal antenatal screening for GBS colonization at 35–37 weeks' gestation and intrapartum prophylaxis with penicillin or ampicillin for colonized women. The incidence of EOS secondary to GBS decreased from 1.7 per 1000 live births in 1993 to 0.28 per 1000 in 2008 (>80% reduction). The second most common bacteria are gram-negative enteric organisms, especially E. coli. An increase in the incidence of E. coli has been noted in EOS in VLBW infants to the extent that E. coli is currently the predominant microorganism in this group of patients. This increase was noted in late 1990s and early 2000s and appears to be stabilizing. Recent data from NICHD-NRN suggest that widespread use of intrapartum antibiotic prophylaxis to reduce vertical transmission of GBS has not resulted in a further increase in non-GBS EOS among the larger cohort of infants of all birthweights or among VLBW infants beyond what was noted previously. GBS and E. coli account for two-thirds of all cases of EOS. Other pathogens causing EOS include Listeria monocytogenes, Staphylococcus, enterococci, anaerobes, Haemophilus influenzae, and Streptococcus pneumoniae. The pathogens that cause LOS or nosocomial sepsis tend to vary in each nursery; however, coagulase-negative staphylococci (CoNS), especially Staphylococcus epidermidis, are the most predominant. Other microorganisms causing LOS include Gram-negative rods (including Pseudomonas, Klebsiella, Serratia, and Proteus), S. aureus, GBS, and fungal microorganisms.

1. Prematurity (<37 weeks' gestation) is the single most significant factor correlated with sepsis. The risk increases in proportion to the decrease in birthweight and gestational age.

2. Rupture of membranes (ROM) ≥18 hours. The risk for proven sepsis increases 10-fold.

3. Maternal peripartum infection. Infections such as chorioamnionitis, urinary tract infection (UTI) especially GBS bacteriuria, rectovaginal colonization with GBS, and perineal colonization with E. coli are well-recognized risk factors for EOS. Chorioamnionitis is a major risk factor for neonatal sepsis. The essential criterion for the clinical diagnosis of chorioamnionitis is maternal fever. Other criteria are relatively insensitive. When defining intra-amniotic infection (chorioamnionitis) for clinical research studies, the diagnosis is typically based on the presence of maternal fever of >38°C (100.4°F) and at least 2 of the following criteria: maternal leukocytosis (>15,000 cells/mm³), maternal tachycardia (>100 beats/min), fetal tachycardia (>160 beats/min), uterine tenderness, and/or foul odor of the amniotic fluid.

4. Previous delivery of a neonate with GBS disease.

5. Fetal and intrapartum distress. Infants who had intrapartum fetal tachycardia, meconium-stained amniotic fluid, were born by traumatic delivery, or were severely depressed at birth and required intubation and resuscitation are either infected in utero or at significant risk for EOS.

6. Multiple gestation.

7. Invasive procedures. Invasive monitoring (fetal scalp electrodes), intravascular catheterization (percutaneously inserted central catheters [PICC] and umbilical catheters), and respiratory (endotracheal intubation) or metabolic support (total parenteral nutrition) are important risk factors for LOS. Continuous positive airway pressure has been associated with an increased risk of Gram-negative infections in VLBW infants.

8. Metabolic factors. Hypoxia, acidosis, inherited metabolic disorders (eg, galactosemia predisposing to E. coli sepsis), and immune defects (eg, asplenia) are factors that predispose as well as increase the severity of sepsis.

9. Other factors. Males are 4 times more affected than females, and the possibility of a sex-linked genetic basis for host susceptibility is postulated. Bottle-feeding (as opposed to breast-feeding) may predispose to infection. Persons of black African descent have been found to have an independent risk factor for GBS sepsis (both EOS and LOS). Reasons for the disproportionately high disease burden among black populations cannot be fully explained by prematurity or socioeconomic status. NICU staff and family members are often vectors for the spread of microorganisms, primarily as a result of improper or lack of hand washing.

Because the initial diagnosis of sepsis is, by necessity, a clinical one, it is crucial to begin treatment before the results of cultures are available. Clinical signs and symptoms of sepsis are nonspecific, and the differential diagnosis is broad. Some signs are subtle or insidious, and therefore a high index of suspicion is required to identify and evaluate infected neonates. Clinical signs and symptoms most often mentioned include the following:

1. Temperature irregularity. Hypothermia is more common than fever as a presenting sign for bacterial sepsis in premature infants. Hyperthermia is more common in full-term infants beyond the first 24 hours of life and if viral agents (eg, herpes) are involved.

2. Change in behavior. Lethargy, irritability, or change in tone.

3. Skin. Poor peripheral perfusion, cyanosis, mottling, pallor, petechiae, rashes, sclerema, or jaundice singularly or in combinations are known signs of sepsis.

4. Feeding problems. Feeding intolerance, vomiting, diarrhea, or abdominal distention with or without visible bowel loops.

5. Cardiopulmonary. Tachypnea, respiratory distress (grunting, flaring, and retractions), apnea within the first 24 hours of birth or of new onset (especially after 1 week of age), tachycardia, and hypotension singularly or in combinations should suggest sepsis. Hypotension tends to be a late sign.

   Reduced variability and transient decelerations in heart rate (HR) may be present in the hours to days before diagnosis of LOS. These abnormal HR characteristics (HRC) in response to systemic infection and inflammation have been characterized mathematically, and the resulting HRC index can be computed in real time and displayed continuously at the bedside. Preliminary studies suggest that monitoring the HRC index in high-risk premature infants may result in improved outcomes and decreased mortality (through early warning with diagnosing early sepsis and prompt treatment with antibiotics).

6. Metabolic. Metabolic findings include hypoglycemia, hyperglycemia, or metabolic acidosis.

7. Focal infections. These may precede or accompany LOS. Look for cellulitis, impetigo, soft tissue abscesses, omphalitis, conjunctivitis, otitis media, meningitis, or osteomyelitis

1. Differential diagnosis. Because signs and symptoms of neonatal sepsis are nonspecific, noninfectious etiologies need to be considered. If the infant is presenting with respiratory symptoms, respiratory distress syndrome, transient tachypnea of the newborn, meconium aspiration, and aspiration pneumonia are considered. If the infant is showing CNS symptoms, then intracranial hemorrhage, drug withdrawal, and inborn errors of metabolism are considered. Patients with feeding intolerance and bloody stool may have necrotizing enterocolitis, gastrointestinal perforation, or obstruction. Some nonbacterial infections such as disseminated herpes simplex virus can be indistinguishable from bacterial sepsis and should be considered in the differential diagnosis, especially if the infant has fever.

2. Laboratory studies

   1. Cultures. Blood and other normally sterile body fluids (urine, spinal fluid, and tracheal aspirate) should be obtained for culture. Body surface cultures are not recommended.

      1. Blood cultures. Computer-assisted automated blood culture systems identify up to 94–96% of all microorganisms by 48 hours of incubation. Results may vary because of a number of factors, including maternal antibiotics administered before birth, organisms that are difficult to grow and isolate (ie, anaerobes), and sampling error with small sample volumes (the minimum volume for blood culture is 1 mL). One blood culture is typically obtained in cases of EOS and 2 blood cultures (1 from PICC and 1 peripheral) in cases of LOS. In many clinical situations, infants are treated for “presumed” sepsis despite negative cultures, with apparent clinical benefit (see Chapter 73). Positive bacterial cultures confirm the diagnosis of sepsis.

      2. Lumbar puncture (LP). Some controversy currently exists regarding whether an LP is needed in asymptomatic newborns being worked up for early-onset presumptive sepsis. Many institutions perform LPs only on infants who are clinically ill, infants who have CNS symptoms such as apnea or seizures, or in cases of documented positive blood cultures or if the decision is made to extend antibiotics beyond 48–72 hours for presumptive clinical sepsis. This practice is consistent with a recent report from the American Academy of Pediatrics (AAP) Committee on the Fetus and the Newborn that LP should be part of the routine evaluation for LOS. Meningitis is likely to happen without sepsis in VLBW infants, and therefore LP should be considered strongly in this group.

      3. Urine cultures. In neonates <24 hours of age, a sterile urine specimen is not necessary, given that the occurrence of UTIs is exceedingly rare in this age group. If indicated, urine for culture must be obtained by either a suprapubic tap (see Chapter 25) or catheterized specimen (see Chapter 26). Bag urine samples should not be used to diagnose UTI.

      4. Tracheal cultures. Should be obtained in intubated neonates with a clinical picture suggestive of pneumonia; if the mother developed chorioamnionitis with overwhelming EOS of the newborn; or when the quality and volume of tracheal secretions change substantially. Tracheal aspirates done after several days of intubation are of limited value.

   2. Gram stain of various fluids. Gram staining is especially helpful for the study of cerebrospinal fluid (CSF). Gram-stained smears and cultures of amniotic fluid are helpful in diagnosing chorioamnionitis. A Gram stain of fluid obtained from the endotracheal tube can alert one of an inflammatory process.

   3. Other laboratory tests

      1. Complete blood count with differential. These values alone are very nonspecific. There are reference values for total white blood cell (WBC) count, and absolute neutrophil counts are a function of postnatal age in hours (see Chapter 73, particularly Tables 73–1, and 73–2). Neutropenia may be a significant finding with an ominous prognosis when associated with sepsis. However, neutropenia has been described commonly as an incidental finding in otherwise healthy growing VLBW infants. The presence of immature forms is more specific but still rather insensitive. Ratios of bands to segmented forms >0.3 and of bands to total polymorphonuclear cells >0.1 have good predictive value, if present. The diagnostic yield of WBC count improves when testing is done after 4 hours of age. A variety of conditions other than sepsis can alter neutrophil counts and ratios, including maternal hypertension and fever, neonatal asphyxia, maternal intrapartum oxytocin, hypoglycemia, stressful labor, meconium aspiration syndrome, pneumothorax, and even prolonged crying. Serial WBC counts obtained several hours apart may be helpful in establishing a trend.

      2. Decreased platelet count. This is usually a late sign and very nonspecific.

      3. Acute-phase reactants (APRs). A complex multifunctional group comprising complement components, coagulation proteins, protease inhibitors, C-reactive protein (CRP), and others that rise in concentration in the serum in response to inflammation. The inflammation may be secondary to infection, trauma, or other processes of cellular destruction. An elevated APR does not distinguish between infectious and noninfectious causes of inflammation. Except for CRP, most of APRs are not commercially available for routine testing.

         1. CRP is an APR that increases the most in the presence of inflammation caused by infection or tissue injury. The highest concentrations of CRP are reported in patients with bacterial infections, whereas moderate elevations typify chronic inflammatory conditions. Synthesis of acute-phase proteins by hepatocytes is modulated by cytokines. Interleukin-1b (IL-1b), IL-6, IL-8, and tumor necrosis factor (TNF) are the most important regulators of CRP synthesis. CRP secretion starts within 4–6 hours after the inflammatory stimulus and peaks at ∼36–48 hours. The biologic half-life of CRP is 19 hours, with a 50% reduction daily after the acute-phase stimulus resolves. Serial CRP measurements demonstrate high sensitivity and negative predictive value but low specificity for infection. A single normal value cannot rule out infection because the sampling may have preceded the rise in CRP. Serial determinations, therefore, are recommended. CRP elevations in noninfected neonates have been seen with fetal hypoxia, respiratory distress syndrome (RDS), meconium aspiration, after trauma/surgery, and after immunizations. A false-positive rate of 8% has been found in healthy neonates. Nonetheless, CRP is a valuable adjunct in the diagnosis of sepsis (ruling it out when serial CRPs are low), monitoring the response to treatment as well as guiding duration of treatment.

         2. Cytokines IL-6, IL-8, and TNF are produced primarily by activated monocytes and macrophages and are major mediators of the systemic response to infection. Studies have shown that combining cytokines with CRP may be better than using CRP alone. IL-6, IL-8, and procalcitonin may be better than CRP in the diagnosis and follow-up of neonatal sepsis secondary to coagulase-negative staphylococci (CoNS).

         3. Procalcitonin (PCT) is a propeptide of calcitonin that increases markedly with sepsis. It may not be useful to screen for early sepsis because it normally rises in the first 48 hours of life. However, PCT appears to be a sensitive marker for LOS and may be superior to CRP. PCT became commercially available recently.

         4. Neutrophil surface antigen CD11 and CD64 are promising markers of early infection that correlate well with CRP but peak earlier.

3. Imaging and other studies

   1. Chest radiograph. A chest radiograph should be obtained in cases with respiratory symptoms, although it is often impossible to distinguish GBS or Listeria pneumonia from uncomplicated RDS. One distinguishing feature is the presence of pleural effusion, which occurs in 67% of cases of pneumonia.

   2. Urinary tract imaging. Imaging with renal ultrasound examination, renal scan, and possibly voiding cystourethrogram should be considered when UTI accompanies sepsis.

4. Other studies. Examination of the placenta and fetal membranes may disclose evidence of chorioamnionitis and thus an increased potential for neonatal infection.

Isolation precautions for all infectious diseases, including maternal and neonatal precautions, breast-feeding, and visiting issues, can be found in Appendix F. (See Chapter 73 for AAP recommendations for management of neonates with suspected or proven early-onset bacterial sepsis.)

1. Prevention

   1. GBS prophylaxis. Because of the widespread use of intrapartum antibiotic prophylaxis, EOS secondary to GBS has been reduced by 80%. Approximately 10–30% of pregnant women are colonized with GBS in the vaginal or rectal area. Consensus guidelines regarding management of GBS were published by the Centers for Disease Control and Prevention in 1996 and were later revised in 2002 and in 2010. These guidelines are supported by the AAP and the American College of Obstetricians and Gynecologists. The guidelines recommended that all pregnant women should be screened at 35–37 weeks' gestation for vaginal and rectal GBS colonization. At the time of labor or rupture of membranes, intrapartum chemoprophylaxis should be given to all pregnant women identified as GBS carriers. Women with GBS isolated from the urine (>10,000 colony-forming U/mL) during their current pregnancy should receive intrapartum chemoprophylaxis because such women usually are heavily colonized with GBS and are at increased risk of delivering an infant with EOS. Women who have previously given birth to an infant with invasive GBS disease should receive intrapartum chemoprophylaxis as well. Penicillin is the drug of choice, but ampicillin is an acceptable alternative. Cefazolin, and less commonly vancomycin, may be used for penicillin-allergic women. The risk-based approach is no longer acceptable except for circumstances in which screening results are not available before labor and delivery. In these circumstances, intrapartum antibiotic prophylaxis should be given to women <37 weeks' gestation, those with ROM ≥18 hours, and women who have a fever ≥38° C (100.4° F). The new guidelines recognize the availability of commercial nucleic acid amplification tests (NAAT) such as polymerase chain reaction for rapid detection of GBS. If available, NAAT intrapartum rectovaginal testing can be performed on women with unknown GBS status and no intrapartum GBS risk factors. Antibiotic prophylaxis should be given if the NAAT testing returns positive or an intrapartum risk factor develops regardless of NAAT results. In addition, the guidelines specifically addressed threatened preterm labor (PTL) and preterm premature rupture of membranes (pPROM) with detailed algorithms. Briefly, women with threatened PTL or pPROM should be screened for GBS colonization on admission unless a GBS culture was obtained within the preceding 5 weeks. In both of these situations, women should receive GBS prophylaxis (typically for 48 hours) unless the screening results are negative. The new recommendations also provided clarification on optimal GBS culturing methods. Finally, the guidelines provided specific recommendations for management of neonates born to mothers who are GBS colonized, have risk factors for sepsis, or were exposed to chorioamnionitis (Figure 130–1).

   2. Prevention of nosocomial sepsis in premature infants in NICU. A subset of nosocomial sepsis is central line–associated bloodstream infections (CLABSIs). Although primary prevention of CLABSI relies on minimizing the use of central lines, novel technologies such as antiseptic and antimicrobial impregnated catheters in addition to meticulous care during PICC insertion and maintenance are key factors in preventing CLABSIs. Hand hygiene is the single most important strategy for avoiding transmission of contagions in the NICU. Fresh maternal milk contains a number of substances responsible for innate immune and humoral responses against pathogens; therefore, promotion of breast-feeding is a key step in the prevention of NICU infections. Medical stewardship of antibiotics, steroids, and H2 blockers is mandatory; indiscriminate use of these agents has been associated with increased nosocomial sepsis. Enhancement of the enteric microbiome composition with the possible use of probiotics may restore gut immune function and help prevent necrotizing enterocolitis and sepsis. Use of bioactive substances with known anti-infective properties such as lactoferrin may be helpful. A recently published multicenter study conducted in Italy showed that oral bovine lactoferrin was beneficial in preventing LOS in VLBW infants during their stay in NICU, regardless of the type of nutrition. Finally, specific and targeted pharmacologic prophylactic interventions have been used with some success. For example, specific antifungal prophylaxis with fluconazole has been associated with 85% reduction in invasive fungal infection. However, the use of pagibaximab, a recombinant monoclonal antibody targeting staphylococcal species, does not appear to offer protection against gram-positive CLABSIs in NICU.

2. Empiric antibiotic therapy. Treatment is most often begun before a definite causative agent is identified. For EOS, it usually consists of ampicillin and gentamicin. This empirical regimen covers the most commonly encountered microorganism; namely GBS and E. coli, and has proved to be efficacious over the years. In nosocomial sepsis, the flora of the NICU must be considered; however, staphylococcal coverage with vancomycin plus an aminoglycoside such as gentamicin or amikacin is usually begun. Third-generation cephalosporins should be avoided as an empirical therapy for EOS or nosocomial sepsis because they are associated with increased risk for antibiotic resistance and invasive fungal infections. The empirical treatment for suspected LOS in a neonate admitted from the community is ampicillin and gentamicin; cefotaxime can be added only when there is a concern for meningitis. Dosages are presented in Chapter 148.

3. Continuing therapy. Based on culture and sensitivity results, clinical course, and other serial laboratory studies (eg, CRP). Monitoring for antibiotic toxicity is important, as well as monitoring levels of aminoglycosides and vancomycin. When GBS is documented as the causative agent, penicillin G is the drug of choice; however, an aminoglycoside is often added because of documented synergism in vitro.

4. Complications and supportive therapy

   1. Respiratory. Ensure adequate oxygenation with blood gas monitoring, and initiate oxygen therapy or ventilator support if needed.

   2. Cardiovascular. Support blood pressure and perfusion to prevent shock. Use volume expanders such as normal saline, and monitor the intake and output of fluids. Inotropes such as dopamine or dobutamine may be needed (see Chapter 65).

   3. Hematologic

      1. Disseminated intravascular coagulation (DIC). With DIC, one may observe generalized bleeding at puncture sites, the gastrointestinal tract, or CNS. In the skin, large-vessel thrombosis may cause gangrene. Laboratory parameters consistent with DIC include thrombocytopenia, increased prothrombin time, and increased partial thromboplastin time. There is an increase in fibrin split products or d-dimers. Treatment options include fresh-frozen plasma, 10 mL/kg; vitamin K (see Chapter 148); platelet infusion; and possible exchange transfusion (see Chapter 30).

      2. Neutropenia. Multiple factors contribute to the increased susceptibility of neonates to infection, including developmental quantitative and qualitative neutrophil defects. Colony-stimulating factors (CSFs) comprise a group of cytokines that are central to the hematopoiesis of blood cells, as well as to the maintenance of homeostasis and overall immune competence. Granulocyte CSF (G-CSF) and granulocyte-macrophage-CSF (GM-CSF) have been used in neonates with established sepsis associated with neutropenia, in neutropenic infants without sepsis, and prophylactically in neonates at risk for sepsis. Limited data suggest that CSFs administration may reduce mortality when systemic infection is accompanied by severe neutropenia. A recent randomized control trial that enrolled 280 small for gestational age extremely preterm infants and used early GM-CSF prophylactically showed no reduction in sepsis or improvement in survival in the treated group. Intravenous immunoglobulin does not appear useful either as a prophylactic or as an adjunct to antibiotic therapy in serious neonatal infection.

   4. Central nervous system. Implement seizure control measures using phenobarbital, and monitor for the syndrome of inappropriate antidiuretic hormone (decreased urine output, hyponatremia, decreased serum osmolarity, and increased urine specific gravity and osmolarity).

   5. Metabolic. Monitor for and treat hypoglycemia or hyperglycemia. Metabolic acidosis may accompany sepsis and is treated with bicarbonate and fluid replacement.

5. Future developments. Intensive research continues in the development of vaccines (especially for GBS) as well as synthetic monoclonal antibodies to the specific pathogens causing neonatal sepsis (ie, antistaphylococcal antibodies). Research is also ongoing into blocking some of the body's own inflammatory mediators that result in significant tissue injury, including endotoxin inhibitors, cytokine inhibitors, nitric oxide synthetase inhibitors, and neutrophil adhesion inhibitors. Finally, recent trials are showing probiotics and lactoferrin to be promising agents in the prevention of LOS and necrotizing enterocolitis.

With early diagnosis and treatment, most infants will recover and not have any long-term problems. However, the mortality rate is still significant. For early-onset disease, the mortality rate is 5–10%, and for late-onset disease, the rate is 2–6%. For VLBW infants with early-onset disease, the fatality rate is higher (16% based on recent report from NICHD NRN). E. coli sepsis is associated with higher mortality compared with GBS.