Neonatal Sepsis : Classification, Clinical Features, Diagnosis and Treatment

Introduction to Neonatal Sepsis

Neonatal sepsis is a life-threatening medical condition characterized by the presence of a systemic infection in a newborn infant, typically occurring within the first 28 days of life. This condition arises due to the invasion and proliferation of pathogenic microorganisms, including bacteria, viruses, or fungi, within the bloodstream and various body tissues. Neonatal sepsis poses a significant risk to the vulnerable neonatal population, often presenting with non-specific clinical symptoms such as temperature instability, feeding difficulties, respiratory distress, and lethargy. Prompt recognition and treatment are imperative, typically involving the administration of broad-spectrum antibiotics and supportive care in a hospital setting to mitigate the potentially severe consequences of this condition. The condition mainly strikes low-income households and the least developed countries. Let us go through the key aspects of neonatal sepsis in detail.

Objectives

• To understand the definition and significance of neonatal sepsis as a life-threatening medical condition affecting newborn infants.
• To explore the classification of neonatal sepsis, including early-onset and late-onset sepsis, and the key pathogens associated with each type.
• To examine the etiology of neonatal sepsis, focusing on bacterial and fungal pathogens, and regional variations in causative organisms.
• To provide insights into the diagnostic procedures for neonatal sepsis.
• To describe the treatment of neonatal sepsis, including supportive care measures and specific antibiotic therapies, while emphasizing the importance of prompt intervention.
• To examine the prognosis of neonatal sepsis, highlighting the factors that influence outcomes and the importance of early treatment.

Classification Of Neonatal Sepsis

Early-Onset Neonatal Sepsis (EOS):

EOS typically occurs within the first 72 hours of life, and it is often caused by pathogens that the baby is exposed to during birth. These organisms may originate from the maternal genital tract and can include Group B Streptococcus (GBS) and Escherichia coli (E. coli).

Risk Factors

• Maternal risk factors for EOS include the presence of foul-smelling amniotic fluid, premature rupture of membranes (when the amniotic sac breaks) 24 hours or more before delivery, multiple unclean vaginal examinations during labor, and prolonged or difficult labor lasting more than 24 hours.
• Fetal risk factors include low birth weight, prematurity (born before 37 weeks of gestation), and perinatal asphyxia (inadequate oxygen supply during birth), which can increase susceptibility to EOS.

Late-Onset Neonatal Sepsis (LOS)

LOS typically presents beyond the first week of life and is often associated with pathogens from the baby's environment. In cases of community-acquired LOS, Staphylococcus aureus and E. coli are commonly responsible, while hospital-acquired or nosocomial LOS is linked to bacteria such as Acinetobacter and Klebsiella.

LOS is of particular concern because it can lead to neonatal meningitis, a severe inflammation of the brain and spinal cord. As a result, a lumbar puncture (spinal tap) is performed in infants with suspected LOS to assess for signs of meningitis.

Risk factors for LOS include neonatal intensive care unit (NICU) admission, invasive medical procedures like IV cannulation, the use of mechanical ventilation, and the administration of stock solutions during parenteral therapy (intravenous nutrition and medication).

Community-Acquired Sepsis Risk Factors

Poor hygiene practices in the home setting can contribute to community-acquired sepsis. Inadequate cord care, bottle feeding instead of breastfeeding, and a lack of exclusive breastfeeding are all factors that can increase a newborn's risk of developing sepsis.

Preventive Measures:

• Exclusive breastfeeding is a powerful preventive measure against neonatal sepsis. Breast milk contains antibodies and other protective factors that help defend the baby against infections.
• Proper handwashing by caregivers is essential to prevent the transmission of infectious agents to newborns. It involves thorough handwashing with soap, following six essential steps for at least two minutes. Caregivers should also remove jewelry and roll up their sleeves before handwashing.

Common Causative Organisms:

In India, Acinetobacter and Klebsiella are frequently responsible for neonatal sepsis, especially in hospital settings.

Globally, Escherichia coli is the most prevalent pathogen causing neonatal sepsis. Group B Streptococcus (GBS) is particularly prevalent in the genitalia of mothers, making it a significant concern during childbirth.

Etiology

The etiology of neonatal sepsis, a critical condition affecting newborns, primarily involves bacterial pathogens, with bacterial sepsis being more common than fungal sepsis. 

• Globally, the most frequent bacterial culprit is Group B Streptococcus (Streptococcus agalactiae), followed by Escherichia coli as the second most common and Klebsiella as the third.
• In India, the etiological pattern slightly differs, with Klebsiella ranking as the most common pathogen causing neonatal sepsis, followed by Staphylococcus aureus as the second most prevalent and Escherichia coli as the third. 
• Fungal sepsis, although less common, is often caused by Candida species, with Candida albicans being the most frequent offender, followed by Candida parapsilosis.

Identifying the specific pathogen responsible for neonatal sepsis is crucial for tailoring effective treatment, typically involving antibiotics. These variations in etiology underscore the importance of region-specific approaches to managing neonatal sepsis and the need for vigilant monitoring and diagnostic measures to combat this life-threatening condition.

Clinical Features of Neonatal Sepsis

Severe neonatal sepsis can manifest as a variety of clinical symptoms that range in severity from moderate to severe. To improve outcomes and lower the risk of problems in infants who are affected, early identification and immediate antibiotic therapy are essential. The key clinical indicators of newborn sepsis are listed below:

• Poor Feeding- Poor Feeding is one of the initial indicators of newborn sepsis. Infants' established feeding habits may change, and they may show little interest in nursing or bottle feeding.
• Temperature Abnormalities: Neonatals with sepsis frequently suffer aberrant temperature patterns. The more typical condition is hypothermia, which is a low body temperature. A baby's skin could feel chilly.
• Metabolic Disturbances: In newborns, sepsis can result in metabolic abnormalities. This may include hypoglycemia (low blood sugar levels), metabolic acidosis (an increase in acid levels in the body), and elevated lactate levels.
• Systemic Manifestations: Neonatal sepsis can be associated with meningitis, which is inflammation of the membranes surrounding the brain and spinal cord. This can cause symptoms such as irritability, abnormal posturing, and seizures.
• Central Nervous System (CNS) Manifestations: Other CNS signs may include a shrill cry, irritability, and abnormal posturing. Seizures can also occur in some cases.
• Respiratory Manifestations: Infants with sepsis may exhibit rapid breathing (tachypnea) and hypoxia (low oxygen levels). Features of respiratory distress, such as retractions (visible sinking of the chest between the ribs) and grunting sounds, can be observed.
• Gastrointestinal (GI) Manifestations: Neonates with sepsis may have abdominal distension (swelling), feed intolerance (difficulty digesting food), and recurrent episodes of vomiting. In severe cases, they may develop symptoms resembling necrotizing colitis, a serious intestinal condition.
• Severe Sepsis, Septic Shock, and Multi-Organ Dysfunction: As sepsis progresses, it can lead to severe sepsis, septic shock, and multi-organ dysfunction. These conditions involve a cascade of physiological abnormalities that affect various organ systems, leading to life-threatening situations.
• Disseminated Intravascular Coagulation (DIC): Neonatal sepsis can cause disseminated intravascular coagulation, a disorder that affects blood clotting and can result in both bleeding and clotting problems.
• Sclerema: Generalized non-pitting edema (swelling) of the skin, known as sclerema, can occur in severe cases of neonatal sepsis. It may also be seen in neonates with severe hypothermia. Sclerema neonatorum has a high mortality rate and requires immediate medical attention and intensive care.

Diagnosis of Neonatal Sepsis

Diagnosing neonatal sepsis is crucial for timely treatment. Here are key points regarding its diagnosis:

Gold Standard Diagnosis: The gold standard for confirming neonatal sepsis is a blood culture. This involves isolating the causative organism from a blood sample. The sensitivity pattern obtained from the culture helps guide treatment. Blood culture results typically take 48-72 hours to be reported.

Risk-Based Screening: In addition to the sepsis screen, some hospitals may use risk-based screening based on clinical risk factors. Babies with risk factors such as maternal fever during labor, prolonged rupture of membranes, and signs of illness are more likely to undergo sepsis evaluation.

Lumbar Puncture Importance: A lumbar puncture (spinal tap) is an essential diagnostic tool when there is a suspicion of neonatal meningitis, which often accompanies late-onset sepsis. This procedure involves collecting cerebrospinal fluid (CSF) to check for signs of infection.

Screening Test: Due to the time it takes for blood culture results, a screening test known as the "Sepsis Screen" is often performed. It consists of four components:

• Absolute Neutrophil Count (ANC): For term neonates, reference charts like Manroe's or Mouzinho's (for very low birth weight neonates) are used to determine the ANC.
• Immature: Total Neutrophil Ratio (IT ratio): An IT ratio above 0.2 indicates a higher presence of immature neutrophils in circulation.
• Micro ESR (MESR): A quick bedside test where a measurement above 15mm suggests neonatal sepsis.
• C Reactive Protein (CRP): A CRP level above 1mg/dl is considered a positive indicator.

Positive Sepsis Screen: If two out of these four parameters are positive, the sepsis screen is considered positive. A positive sepsis screen has a very high negative predictive value, meaning that if it's positive, the likelihood of neonatal sepsis is high. While a positive sepsis screen raises suspicion for neonatal sepsis, it's not definitive proof. Clinicians rely on a combination of clinical signs, laboratory results, and risk factors to make a diagnosis. Sensitivity for neonatal sepsis in this case is 90-100%, but specificity is around 80%. The positive predictive value is 25%, while the negative predictive value is very high at 99-100%.

Negative Sepsis Screen: If the sepsis screen is negative, there is a reasonable assumption that the baby does not have neonatal sepsis. However, if there is a strong suspicion of sepsis, the screen can be repeated after 12-24 hours. Additionally, supportive tests such as monitoring for hypoglycemia, chest X-rays to check for pneumonia, and lumbar punctures (especially for late-onset sepsis or cases with neurological symptoms) can provide further diagnostic information. Infants with negative initial sepsis screens may still be at risk. Many hospitals practice serial monitoring, repeating tests and assessments to ensure timely detection if sepsis develops.

Early and accurate diagnosis of neonatal sepsis is crucial to initiate appropriate treatment promptly and improve outcomes for affected infants.

New Markers For Neonatal Sepsis

• Procalcitonin (PCT): Rises in bacterial infections; helps assess treatment.
• Presepsin: Indicates early infection; aids rapid diagnosis.
• CD64: High levels on neutrophils suggest bacterial infections.
• STREM-1: Elevated levels indicate sepsis presence.
• Cytokines and Chemokines: IL-6, IL-8, TNF-alpha - reflect inflammatory state and severity of sepsis.

Fungal Sepsis In Neonates

Fungal sepsis in neonates is most common among very low birth weight infants and those receiving intravenous fluids or broad-spectrum antibiotics. The primary culprits behind fungal sepsis are Candida albicans and Candida parapsilosis. 

Treatment typically involves fluconazole, with amphotericin B reserved for fungal meningitis cases. Prophylactic use of fluconazole for six weeks is recommended for all extremely low birth weight neonates in the ICU. It's crucial to monitor and manage fungal sepsis in these vulnerable newborns due to its association with serious complications.

Fungal sepsis in neonates can manifest with nonspecific symptoms such as poor feeding, lethargy, and respiratory distress. Diagnosing it early is challenging due to these vague clinical presentations. 

Prophylactic use of fluconazole in extremely low birth weight neonates is crucial because fungal sepsis can be challenging to diagnose and treat promptly. Prophylaxis helps reduce the risk of this serious infection in infants who are vulnerable.

Treatment of Neonatal Sepsis

The treatment of neonatal sepsis is a critical aspect of newborn care, aimed at combating potentially life-threatening infections in infants. Prompt and appropriate intervention is essential to ensure the well-being of these vulnerable infants. This brief overview will delve into the key principles and discuss in detail the considerations in the treatment of neonatal sepsis.

Supportive Care:

NICU Admission: Most neonates with sepsis require admission to the Neonatal Intensive Care Unit (NICU) for intensive monitoring and treatment.

IV Fluids: Intravenous fluids are administered to maintain hydration and electrolyte balance.

Temperature Management: To avoid any potential difficulties, it's crucial to keep the infant's body temperature between 36.5°C and 37°C.

Euglycemia- Blood sugar levels are continuously checked and kept within the usual range to prevent hypoglycemia.

Support for Oxygen: If necessary, oxygen is given to provide adequate oxygen saturation.

Blood Products: In cases of bleeding, blood products like platelets or fresh frozen plasma may be administered.

Specific Treatment:

Antibiotics: Oral antibiotics are not used for neonatal sepsis. Instead, broad-spectrum empirical antibiotics are administered intravenously as the first-line treatment.

Indications for antibiotic therapy: 

• Early Onset Sepsis (EOS):
  • Foul-Smelling Amniotic Fluid: If there is a history of foul-smelling amniotic fluid during labor or delivery, it is a strong indicator for antibiotic therapy, as it suggests possible infection in the amniotic sac.
  • Multiple Risk Factors: When the newborn exhibits three or more risk factors for EOS, such as maternal factors (e.g., maternal fever during labor), prolonged rupture of membranes, or an abnormal fetal heart rate, antibiotic treatment is initiated.
  • Clinical Features: If the neonate displays clinical features suggestive of neonatal sepsis, even with fewer than three risk factors, antibiotic therapy is recommended. Clinical signs may include poor feeding, abnormal temperature, and respiratory distress. Strong Clinical 
  • Suspicion: In cases of strong clinical suspicion of neonatal sepsis, even if the sepsis screen is negative and there are no risk factors, antibiotics may be initiated as a precaution. 

• Late Onset Sepsis (LOS):
  • Positive Sepsis Screen: A positive sepsis screen, which includes various laboratory parameters indicating infection, is a clear indication for antibiotic therapy in cases of LOS. Strong Clinical Suspicion: If there is a strong clinical suspicion of neonatal sepsis based on the baby's symptoms and physical examination, even if the sepsis screen is negative, antibiotics may be started.
  • The selection of antibiotics may change depending on the common pathogens in the area and how sensitively they respond to different medicines. Ampicillin and Gentamycin are two commonly used first-line antibiotics. An additional third-generation cephalosporin, such as Cefotaxime, is given when meningitis is suspected.
  • Antibiotic Treatment Duration: Indicators of newborn sepsis determine how long the treatment will last. According to the baby's clinical response and the findings of the culture, the course may be altered over the course of several days.

Differential Diagnosis

Non-Infectious Respiratory Disorders:

• Respiratory distress syndrome.
• Newborns with Transient Tachypnea (TTN)
• Meconium Aspiration Syndrome.

Structural heart defects, such as poor nutrition and cyanosis, can manifest as congenital heart diseases and resemble sepsis in their symptoms.

Hematological and metabolic disorders:

Hematological and Metabolic Disorders: A number of inborn metabolic abnormalities, such as hyperbilirubinemia and hypoglycemia, can resemble the signs of sepsis.

Non-Specific Clinical Conditions

• Hypothermia
• Hypoglycemia
• Distressing breathing
• Feeding intolerance
• Neurological conditions
• Seizures in newborns
• Intraventricular bleeding

Gastrointestinal Conditions:

• Necrotizing Enterocolitis (NEC) is a condition of the digestive system.
• GERD (Gastroesophageal Reflux Disease)

Drug Withdrawal Syndrome:

Neonatal Abstinence Syndrome (NAS) is a form of drug withdrawal.

Immune-Mediated Conditions:

Neonatal lupus erythematosus is one example of an immune-mediated disease.

Prognosis

The prognosis of newborn sepsis depends on how fast it is identified and treated. Many infants do well in recovery when given prompt treatment. Sepsis can, however, worsen and become life-threatening if it is not treated promptly. Early initiation of antibiotics and stabilization of the infant's condition increases the likelihood of a successful result. Babies at risk for complications including prematurity or low birth weight may have a more difficult course.

Neonatal sepsis brought on by E. coli can have a wide range of prognoses, from complete recovery to serious problems or even death. The prognosis of newborns with impacted conditions must be improved through early diagnosis, prompt treatment, and thorough care.

In a Neonatal Intensive Care Unit (NICU), careful observation and treatment are crucial. To increase the odds that the infant will make a full recovery, it is critical for medical professionals to identify the symptoms of sepsis and initiate treatment very once.

Complications

The majority of neonates who recover from sepsis don't experience any issues. However, a lot of newborns that survive have long-term health problems. More than one-third of infants who survive sepsis will have cognitive skill delays. Nearly half of neonatal sepsis survivors visit the hospital at least once after their recovery.

Meningitis, an infection of the membranes encasing the brain, can occur in some infants. This syndrome can cause dangerous symptoms and negative consequences in newborns, such as:

• Extreme laziness.
• Bulging of the fontanelle, the soft region between their skull bones.
• Hearing impairment.
• Developmental lags.
• A cerebral palsy.
• Seizures.
• Coma.

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