Neonatal Sepsis

Introduction

Sepsis continues to be among the leading cause of neonatal deaths contributing to 33% of neonatal deaths in India¹, despite the fact that the field of neonatology has grown by leaps and bounds in the past decade. It is extremely important to arrive at an early diagnosis of sepsis to prevent morbidity and mortality. However, progress in this area has been far from satisfactory, and newer methods are being studied in the quest for a fool-proof system.

Classification of Neonatal Sepsis:

Sepsis can be classified into early-onset sepsis (EOS) where clinical manifestations appear within 72 hours of birth or late-onset sepsis (LOS) symptoms develop after 72 hours of life.

Risk factors associated with EOS are low birth weight (<2500 grams) or prematurity, fever in the mother with bacterial infection within 2 weeks before delivery, foul-smelling and/or meconium stained liquor, rupture of membranes >24 hours, single unclean or >3 sterile vaginal examinations, prolonged labor (total duration of 1st and 2nd stage of labor >24 hrs) and Apgar score <4 at 1 minute.

In the Presence of Foul-smelling liquor or three of the above-mentioned risk factors, antibiotics to be started, for Infants with two risk factors septic screen to be done and treatment are decided based on the results^2,3

Late onset sepsis (LOS):

Pathogensis

Early-onset sepsis (EOS) is acquired either in-utero or during the passage through the birth canal during delivery. Ascending infection following the rupture of membranes is also an important source for EOS. Late-onset sepsis by contrast (LOS) is acquired after birth from the hospital environment or from the community.

In India, unlike in the West, gram-negative organisms are the commonest cause for neonatal sepsis of which Klebsiella is the most common pathogen isolated among both intramural and extramural births followed by Staphylococcus aureus.⁴ Hence antibiotic policies should be individualized according to institutional antibiogram characteristics.

Clinical Features

The clinical signs in neonatal sepsis are usually non-specific, warranting a very high degree of suspicion these include subtle presentations like lethargy, refusal of feeds, temperature instability, bradycardia or tachycardia, respiratory difficulty, poor perfusion with pallor to fulminant signs like DIC, pulmonary hemorrhage, seizures, cerebral edema, respiratory failure, cardiac failure, shock, and adrenal insufficiency.

Investigations

Septic screen:
Consist of total leukocyte counts, absolute neutrophil counts, micro-ESR, immature neutrophils, and CRP are the components of the septic screen and if 2 of the above-mentioned parameters are positive antibiotics are to be given after sending blood culture. Septic screens are to be used to rule out sepsis rather than ruling in sepsis since it has low specificity but a higher negative predictive value.

Even though blood culture is the gold standard in the diagnosis of neonatal sepsis for quick and accurate diagnosis newer methods are being tested. Some of the recent developments are physiomarkers and biomarkers.

I. PHYSIOMARKERS:

Heart Rate Characteristics (HRC) and Heart Rate Variability (HRV):

Normal newborns have a beat-to-beat variability in their heart rate and are controlled by various neural inputs. Studies in neonatal sepsis have shown 2 main differences in HRC:

• Decreased beat-to-beat variability
• Transient decelerations in heart rate.

The Heart Rate Characteristics index (HRCi) is a statistically derived number, which can predict the deterioration of the patient in the next 24 hours. An increase in HRCi predicts an increased risk of clinical deterioration.⁵

II. BIOMARKERS

1. ACUTE PHASE REACTANTS:

a) CRP:

CRP is the commonest biomarker used in neonatal sepsis. It increases by around 6-18 hours of exposure, and peaks after 48 hours. CRP has a half-life of 18 hours and hence falls with the resolution of acute-phase reaction. CRP is highly specific, however, sensitivity is low^6,7. Serial CRP monitoring increases its utility and can also be used in deciding the response as well as the duration of antimicrobial therapy.

b) Procalcitonin:

This is another acute-phase reactant which is produced by 2-4 hours of exposure, and peaks by 24-48 hours. The half-life is 25-30 hours. However, there is a physiologic rise of procalcitonin in newborns in the first 2 days of life, which makes it less helpful in EOS⁸. The sensitivity and specificity of procalcitonin is around 80%, with a particular use in LOS.

Other acute phase reactant proteins such as a-1 antitrypsin, haptoglobin, lactoferrin, fibronectin are also being studied.

2. PRO-INFLAMMATORY CYTOKINES:

a) Interleukin-6:

Peaks by 2-3 hours of exposure, and falls back to baseline after 6-8 hours. Half-life is less than 20 mins. Acute phase reactants like CRP and fibrinogen are induced mainly by IL-6.

IL-6 can also be measured in cord blood of babies with the risk of sepsis. It is an early marker of sepsis and has high sensitivity and specificity in both EOS and LOS. The disadvantage is that the short half-life causes many false-negative results.⁹

b) Interleukin-8:

Has similar kinetics like IL-6. IL-8 can also be used in the detection of EOS from cord blood.

c) Tumor Necrosis Factor Alpha:

This is a very early pro-inflammatory cytokine that stimulates the production of IL-6. However, it has a lower sensitivity and specificity in diagnosing sepsis.

3. Cell Surface Markers:

Measured by flow cytometry. Highly sensitive and specific, and the expression begins minutes after exposure. Useful in both EOS and LOS. Requires only about 0.05 ml of blood. However, the cost of sophisticated equipment is a barrier in its routine use.

1. CD11ß:

   Can be detected within 5 minutes of exposure. Very high sensitivity and specificity. More useful in EOS than in LOS.

2. CD 64:

   Has very high sensitivity and Negative Predictive Value of >95%. When combined with CRP or IL-6, sensitivity reaches 100%, and specificity of >80%.

3. HLA-DR:

   May be used as a prognostic test, rather than a diagnostic test.

III) Molecular Microbiology:

Genomics, Proteomics, and Nucleic Acid-Based Molecular Techniques:
Helps in the identification of the organism. Various techniques available are:

• Whole-cell Mass Spectrophotometry (WC-MS)

• Amplification and sequencing of 16S ribosomal nucleic acid.

• Inter an inhibitor protein (IAIP)

• Real-time PCR(10)

Treatment

1. Supportive Therapy: Thermoneutral environment, adequate nutrition, proper oxygenation, volume expansion, and inotropic support if needed.
2. Antibiotics: Should be based on institutional antibiogram and sensitivity patterns. Narrow spectrum antibiotics to be used and every unit must have antibiotic stewardship policy
3. Adjunctive therapy: Many therapies like exchange transfusion, GM-CSF, IVIG, Ig M Enriched IVIG, and Pentoxyphiline have been tried none of them has proven benefits.