Pediatrics

Septicemia in neonates at birth-5 days of age

OVERVIEW: What every practitioner needs to know

Early onset sepsis (EOS) is defined as infection that occurs within the first 7 days of life. The overall incidence in the United States is approximately 1 case/1000 live births. Although the incidence is low, it is an important cause of neonatal morbidity and mortality. Morbidity and mortality attributable to EOS ranges from 15% to 33%, with highest risk among preterm infants. The incidence and relative risk of infection varies inversely with gestational age.

Group B Streptococcus agalactiae (GBS) remains the most common early onset pathogen among term infants. Escherichia coli is the most common early onset pathogen among preterm infants. The most common sites of early onset infections are bloodstream infections, meningitis, and pneumonia.

Bacteremia is defined as at least one positive blood culture with a known pathogen. Bacteremia resulting in clinical septicemia is the most common early onset infection in the newborn.

Meningitis should be considered and a lumbar puncture should be considered as a part of the initial evaluation for sepsis in the first week of life. The incidence of meningitis is difficult to estimate because practice with regard to routine lumbar puncture varies across the country. Infants may also be too unstable tolerate a lumbar puncture prior to starting antibiotics. The reported incidence of meningitis may be underestimated because of dyssynchrony between positive CSF and negative blood cultures.

Urinary tract infections are uncommon in the immediate neonatal period in the absence of structural GU anomalies. Therefore, urine cultures are not considered a part of the evaluations for EOS.

Clinical Sepsis is defined as having clinical signs and symptoms consistent with infection and/or sepsis syndrome in the absence of positive blood, urine or CSF cultures.

Are you sure your patient has neonatal septicemia? What are the typical findings for this disease?

Signs and symptoms of early onset sepsis may be subtle and mimic other diseases. Presentation varies somewhat based on gestational age of the neonate. Up to 20% of infants are asymptomatic. Among neonates with symptoms, the most common symptoms are:

1. Respiratory distress

2. Apnea

3. Lethargy

4. Poor feeding

5. Temperature instability

6. Hypoglycemia / hyperglycemia

7. Hypotension

8. Jaundice

What other disease/condition shares some of these symptoms?

Clinical signs and symptoms of septicemia are non-specific and overlap with findings in other diseases. For example, metabolic derangements seen in the critically ill newborn with sepsis can be seen in other diseases. A careful evaluation and review of differential diagnosis is important to avoid delay of appropriate therapy. Disorders with signs and symptoms that mimic neonatal sepsis include the following. (In some cases, sepsis represents a complication of the underlying condition.)

Respiratory distress syndrome

Congenital heart disease (especially ductal dependent lesions)

Cardiomyopathy

Congenital pneumonia

Hypoglycemia

Metabolic acidosis

Severe anemia

Hemolytic anemia

Inborn error of metabolism

Congenital adrenal hyperplasia

What caused this disease to develop at this time?

Most early onset septicemia occurs after direct seeding of the blood from an ascending amniotic fluid infection and/or from aspiration of infected amniotic fluid.

Maternal risk factors for infection:

  • Maternal fever

  • Preterm labor

  • Premature rupture of membranes

  • Prolonged rupture of membranes

  • History of group B streptococcus (GBS) colonization

  • Clinical concern of maternal chorioamnionitis

Infant risk factors for infection:

  • Immature immune responses

  • Limited innate immunity

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Blood culture (the "Gold Standard") - The predictive value of a blood culture is affected by the number of colony-forming units (CFU) per ml of blood and therefore by the volume of blood. Sensitivity increases when the volume collected is at least 1 ml. The predictive value is decreased by previous antibiotic treatment of mother or infant. Cultures are typically positive within 48-72 hours.

Complete Blood Count - Normal values for white blood cell count cover a wide range and vary with postnatal age and gestational age. (See Figure 1and Figure 2). Modest positive and negative predictive values limit an abnormal white blood count as the sole reason for antibiotic therapy. Neutropenia has higher predictive value than leukocytosis. A ratio of immature/total neutrophil count of > 0.2 has a higher positive predictive value than the immature neutrophil count. Thrombocytopenia is common due to platelet consumption and/or peripheral destruction.

Figure 1.

Reference ranges for blood neutrophil concentrations during the first 72 hours after the birth of term and near-term (36 weeks gestation) neonates. A total of 12,149 values were obtained for the analysis. The 5th percentile, the mean, and the 95th percentile values are shown. Reprinted with permission Christensen 2009.

Figure 2.

Reference ranges for blood neutrophil concentrations during the first 72 hours after the birth of 28- to 36-week gestation preterm neonates. A total of 8896 values were obtained for the analysis. The 5th percentile, the mean, and the 95th percentile values are shown. Reprinted with permission Christensen 2009.

Cerebrospinal Fluid Culture -CSF cultures should be considered in all neonates being evaluated for sepsis. This procedure is underutilized in low birth weight infants because many are clinically unstable. In newborns, characteristic findings of elevated neutrophil counts and protein concentrations and decreased glucose concentrations are obscured by normal elevations of the first two and by the frequency of hypoglycemia. Blood contamination from superficial blood vessels is common, which may complicate interpretation of the WBC cell count. Nevertheless, extreme elevations in neutrophils (in the absence of grossly bloody taps) or decrease in CSF glucose concentrations (in the presence of normal blood glucose concentrations) are helpful. A gram stain and aerobic and anaerobic CSF cultures are especially important. Positive CSF cultures may occur in the presence of negative blood cultures.

Urine Culture - Urinary tract infection is unlikely within the first week of life. Therefore, urine cultures are not considered a cost-effective part of the EOS evaluation.

Respiratory Culture - These are of limited utility and low predictive value. It is difficult to differentiate infection from colonization. A respiratory culture may be useful in a patient with suspected viral infection.

Coagulation studies -Consumptive coagulopathy is common in overwhelming sepsis syndromes, especially with Gram-negative infections.

Blood gas and Pulse oximetry -Infants with suspected sepsis should be evaluated for impaired gas exchange. Metabolic acidosis is common.

Electrolytes, BUN and Creatinine- Hyponatremia and hyperkalemia may be seen. Metabolic acidosis is common. Infants with suspected sepsis should be evaluated for renal insufficiency.

Would imaging studies be helpful? If so, which ones?

Chest X-ray - Chest x-ray: high yield, low cost, and minimal radiation exposure. Pneumonia is common with early onset sepsis.

Cranial ultrasound - Portable and low cost. CNS imaging is suggested in any critically ill neonate or those with suspected meningitis.

MRI - This is high cost and low yield. It should be used selectively. Abnormalities may help guide counseling to family after discharge.

Confirming the diagnosis

Group B Streptococcus (GBS) remains the most common pathogen causing early onset sepsis in term neonates. In 2010 the CDC, in conjunction with ACOG, the AAP, and the American Society of Family Physicians, revised guidelines to prevent invasive GBS disease in pregnant women and their newborns, including a revised algorithm for the evaluation of infants at risk for GBS disease. The strength of the evidence is high and includes surveillance and clinical data since the previous guidelines were published in 2002. (See Figure 3 Algorithm to Prevent Secondary GBS Disease).

Figure 3.

Algorithm for secondary prevention of early-onset group B streptococcal (GBS) disease among newborns.

If you are able to confirm that the patient has sepsis, what treatment should be initiated?

Antibiotic therapy

Antibiotic therapy should be initiated immediately. Do not delay therapy while awaiting results of laboratory data. Patients with early onset sepsis frequently have multi-system organ dysfunction and require supportive therapy in addition to antimicrobial therapy. The choice of empiric antimicrobial therapy should be based on the most likely pathogen, gestational age, and known potential colonization patterns. The most appropriate agent can only be chosen after pathogen and antimicrobial resistance patterns are identified. Dosing should be based on published pharmacological references based on gestational age. Antibiotic concentrations should be monitored to ensure proper dosing. Dosing adjustments may be necessary for patients with renal insufficiency. Duration of therapy varies based on the extent of systemic disease.

Respiratory support

Apnea is a common complication with sepsis. Respiratory support may be necessary to support blood gas exchange (supplemental oxygen, NCPAP, mechanical ventilation). Patients should be evaluated for hypoxemia and for signs of pulmonary hypertension.

Fluid administration

Feeding intolerance is common. Also, infants with tachypnea and respiratory distress cannot maintain a coordinated suck and swallow. Renal insufficiency may require adjustments in fluid and electrolyte administration.

Hematologic support

Infants should be evaluated for thrombocytopenia and for disseminated intravascular coagulopathy (DIC).

Cardiovascular support

Hypotension is common. Inadequate tissue perfusion may result in metabolic acidosis. Inotropic and chronotropic agents may be useful to help stabilize cardiac output and blood pressure.

What about long-term treatment?

Typically, treatment is confined to the hospitalization. Long-term treatment would be necessary for infants who develop complications secondary to the infection.

What are the adverse effects associated with each treatment option?

The benefits of treatment outweigh the risk of not treating neonates with sepsis. Potential adverse effects are outlined below:

Antibiotic therapy

  • Toxicity secondary to inappropriate dosing

  • Prolonged broad spectrum antibiotic usage is associated with increased risk of colonization with Candida or resistant organisms.

  • Ototoxicity with appropriate drug concentrations is rare, but possible.

Fluid administration

  • Electrolyte disturbances

  • Fluid overload

  • Inadequate nutrition

Respiratory support

  • Chronic lung disease

  • Prolonged oxygen requirement

Hematologic support

  • Transfusion reaction

  • Risk associated with exposure to blood transfusion

Cardiovascular support

  • Tachycardia

  • Effect on cardiac output

What are the possible outcomes of Early Onset Sepsis?

What will you tell the family about prognosis?

The majority of infants with early onset sepsis survive. The risk for death varies inversely with gestational age, with preterm infants having a higher risk of death compared to term infants. Fulminant presentation and Gram-negative sepsis carry a higher risk of mortality. Most infection-related deaths occur within 48-72 hours.

What will you tell the family about risks/benefits of the available treatment options?

The benefits of therapy are greater than the associated risks. There are minimal long-term risks associated with antibiotic therapy.

What causes this disease and how frequent is it?

Epidemiology

The incidence varies based on gestational age and birth weight, with increased incidence among low birth weight infants. The overall incidence is 1 case per 1000 live births. The incidence among infants <1500 grams ranges between 15 to 19 cases per 1000 live births.

Mode of transmission (See Figure 4 Potential Routes of Perinatal Infection, Goldenberg 2000)

Figure 4.

Reprinted with permission from Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000;342(20):1500-7

Bacteria may reach the infant across the placenta (transplacental), from an ascending amniotic fluid infection, by transmission during birth (intrapartum), or from aspiration of infected amniotic fluid.

Distribution of pathogens (See Table I Distribution of Early Onset Pathogens Among ELBW Infants)

Table I.

This varies based on gestational age. The distribution of pathogens has changed for preterm infants over time.

Gram-positive organisms:

  • Streptococcus agalactiae (Group B Streptococcus; GBS) is most common among term infants.

  • Listeria monocytogenes

  • Streptococcus pneumoniae

  • Coagulase-negative Staphylococcus

Gram-negative organisms

  • E. coli is the most common pathogen among preterm infants.

  • Klebsiella

  • Haemophilus influenzae (usually non-typable)

Fungal

  • Candida species are rare but carry a high mortality rate

Predisposing factors

  • Maternal history of GBS colonization

  • Maternal risk factors for infection (preterm labor, premature and/or prolonged rupture of membranes, maternal fever)

  • Maternal chorioamnionitis

Early Onset Invasive Group B Streptococcus Disease

GBS is the most common cause of early onset sepsis among term infants. The disease typically occurs within the first 7 days of life. The incidence has declined dramatically over the past decade after recommendations for universal screening of all pregnant women by the CDC, AAP and ACOG. (See Figure 5 Trends in Early-onset and Late-onset Invasive GBS Disease between 1998-2008) At present, the incidence of early onset GBS infection is 0.28 cases per 1000 live births. Nevertheless, GBS remains an important infectious cause of neonatal morbidity among term and preterm infants. Seventy percent of affected infants are term. Overall mortality is approximately 1%-3%; however, rates are approximately 20% in preterm infants. Treatment of early onset disease does not affect the incidence of late onset disease. Among treated infants, 1%-3% of them will develop recurrent disease.

Figure 5.

Trends in invasive GBS disease in newborns before and after consensus guidelines and revised guidelines from the American Board of Pediatrics and American College of Obstetrics and Gynecology. Modified and reprinted with permission from Jordan HT, Farley MM, Craig A, et al. Revisiting the need for vaccine prevention of late-onset neonatal group B streptococcal disease. Pediatr Infect Dis J 2008;27:1057-64.

Clinical manifestations of early onset GBS infection:

  • Sepsis

  • Pneumonia

  • Meningitis (more common in late onset GBS disease)

Maternal risk factors

  • Approximately 10% to 30% of women are colonized with GBS in the vagina and/or rectum, with highest colonization rates among African American women.

  • Colonization can be transient or consistent during the pregnancy.

  • In the absence of intrapartum treatment, 1%-2% of infants born to colonized mothers develop invasive disease.

  • The risk of intrapartum transmission decreases if the mother receives treatment

Seroprevalence

Ten known serotypes of GBS disease; however, serotypes Ia, Ib, III, V cause majority of EOS disease in newborns

  • Majority of early onset invasive disease is caused by Serotype III

  • Meningitis most likely to be caused by Serotype III

How do these pathogens/genes/exposures cause the disease?

Bacteremia

Vertical Transmission

Colonization during delivery

Other clinical manifestations that might help with diagnosis and management

N/A

Are additional laboratory studies available; even some that are not widely available?

Various cytokines are known to be elevated in patients with sepsis; however, laboratory tests for these are not readily available. Used in combination with other clinical and laboratory variables, they improve the positive predictive value.

How can Early Onset Sepsis be prevented?

Strategies to prevent early onset sepsis in neonates focuses on reduction of maternal risk factors known to be associated with this disease process.

Guidelines to Prevent Invasive Group B Strep Disease

  • Universal screening of all pregnant women between 35-37 weeks gestation

  • Compliance with published guidelines from CDC for management of pregnant women with GBS colonization. Appropriate intrapartum treatment prior to delivery is associated with decreased perinatal transmission rates ( See Table II Guidelines for Intrapartum Antibiotic Prophylaxis)

  • Compliance with guidelines for the evaluation and management of neonates at risk for invasive GBS disease (See Figure 3 Algorithm for secondary prevention of GBS).

Table II.

Other important measures include active labor management, including timely administration of antibiotics to mothers with signs and symptoms of infection, prenatal care so that risk factors can be diagnosed and communicated prior to delivery, and quality improvement measures to monitor and track missed opportunities for intrapartum GBS prophylaxis due to inadequate communication or system failure.

Researchers continue to development and effective vaccine to decrease the overall burden of early onset GBS disease because it is known that vaccination decreases maternal colonization rates and increases transplacental anti-GBS antibody transfer to the fetus. There are ten known serotypes of GBS. Serotypes Ia, Ib, III and V cause 95% of the invasive GBS disease in neonates. The distribution of serotypes identified as colonizing strains differ from those known to cause invasive disease.

What is the evidence?

Stoll, BJ, Hansen, NI, Sánchez, PJ. "Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues". Pediatrics. vol. 127. 2011. pp. 817-26.

Schelonka, RL, Chai, MK, Yoder, BA. "Volume of blood required to detect common neonatal pathogens". J Pediatr. vol. 129. 1996. pp. 275-8.

DiGeronimo, RJ. "Lack of efficacy of the urine culture as part of the initial workup of suspected neonatal sepsis". Pediatr Infect Dis J. vol. 11. 1992. pp. 764-6.

Visser, VE, Hall, RT. "Urine culture in the evaluation of suspected neonatal sepsis". J Pediatr. vol. 94. 1979. pp. 635-8.

Garcia-Prats, JA, Cooper, TR, Schneider, VF. "Rapid detection of microorganisms in blood cultures of newborn infants utilizing an automated blood culture system". Pediatrics. vol. 105. 2000. pp. 523-7.

Kumar, Y, Qunibi, M, Neal, TJ, Yoxall, CW. "Time to positivity of neonatal blood cultures". Arch Dis Child Fetal Neonatal Ed. vol. 85. 2001. pp. F182-6.

Christensen, RD, Henry, E, Jopling, J, Wiedmeier, SE. "The CBC: reference ranges for neonates". Semin Perinatol. vol. 33. 2009. pp. 3-11.

Mouzinho, A, Rosenfeld, CR, Sánchez, PJ, Risser, R. "Revised reference ranges for circulating neutrophils in very-low-birth-weight neonates". Pediatrics. vol. 94. 1994. pp. 76-82.

Stoll, BJ, Hansen, N, Fanaroff, AA. "Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants". N Engl J Med. vol. 347. 2002. pp. 240-7.

Larry, KP. "Group B streptococcal infections". American Academy of Pediatrics. 2012. pp. 680-5.

Verani, JR, McGee, L, Schrag, SJ. "Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Center for Disease Control and Prevention (CDC)". MMWR Recomm Rep. vol. 59. 2010. pp. 1-36.

Ongoing controversies regarding etiology, diagnosis, treatment

Cytokines: Researchers continue to investigate various cytokines and their relationship to infection in the neonate. It appears that a combination of various inflammatory markers increase the positive predictive value when trying to diagnose infection. Measurement of most cytokines is not readily available in the clinical setting at present.

Immune modulators for treatment: Limited data are available at this time in the neonatal population.

IVIG or other monoclonal antibody preparations: Commercially available IVIG preparations have not improved outcomes in neonates with sepsis. The risks associated with transfusion outweigh the benefit in this population. Researchers are investigating the efficacy of type-specific antibody preparations, which have higher antibody titers to specific pathogens known to be associated with neonatal sepsis.

Development of rapid intrapartum testing for GBS using Nucleic Acid Amplification Test (NAAT): This technology would have the advantage of diagnosing colonization at the time of delivery; however, the technique is cumbersome and testing is not readily available at this time in most hospitals.

Vaccine development for GBS: A recent randomized controlled trial of a conjugate vaccine to serotype III showed delayed acquisition of the vaccine serotype in women not known to be colonized.

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