Neonatal Sepsis: Transmission, Diagnosis, and Treatment Overview

1. Neonatal sepsis early vs. late maternal vs. nosocomial vs. community acquired modes of vertical trasmission Overview of neonatal immune system Manifestations of neonatal sepsis Differential diagnosis Maternal screening for STD Diagnostic work up for neonatal sepsis Treatment duration Antibiotics (dose – interval)

2. Modes of transmission 1- transplacental 2- transvaginal 3- ascending 4- breast milk Chronology Early onset <7days→(sepsis- pneumonia) Late onset>7days→(meningitis- local infections ) Late late onset>1month Source Maternal (vertical) Hospital (nosocomial) Community

3. Early onset sepsis Presents during the first week, usually during the first 72h of life . The clinical presentation is respiratory distress and pneumonia. Three common pathogens are GBS – E coli – Listeria monocytogen. UTI is not common. Late onset sepsis Presentation is after the first week. Pathogens are the same as early onset sepsis. Presentation with meningitis is more common than early onset sepsis. Nosocomial infection The CDC-NNIS system defines a nosocomial infection as a localized or systemic condition (1) that results from an adverse reaction to the presence of an infectious agent or it’s toxin and (2) that was not present or incubating at the time of admission to the hospital. (a) Pathogens are different from early and late onset sepsis and include klebsiella – pseudomona – enterobacter – CONS – staphylococcus aureus – stenotrophomonas – acintobacter – candida – enterococcus…

5. Overview of neonatal immune system Immunoglobulin In premature infants, cord IgG levels are directly proportional to gestational age. Studies of type-specific IgG antibodies to GBS have shown that the ratio of cord to maternal serum concentrations is 1.0, 0.5, and 0.3 at term, 32 wk, and 28 wk of gestation, respectively. Complement Full-term newborn infants have slightly diminished classical pathway complement activity and moderately diminished alternative pathway activity. Premature infants have lower levels of complement components and less complement activity than full-term newborns do. Monocyte – macrophage system The number of circulating monocytes in neonatal blood is normal, but the mass or function of macrophages in the reticuloendothelial system is diminished, particularly in preterm infants. In both term and preterm infants, chemotaxis of monocytes is impaired. Natural killer cells neonatal NK cells have decreased cytotoxic activity and ADCC in comparison to adult cells. The diminished cytotoxicity against herpes simplex virus (HSV)-infected cells may predispose to disseminated HSV infection in newborn.

6. Neutrophils Quantitative and qualitative deficiencies of the phagocyte system contribute to the newborns' susceptibility to infection. Neutrophil migration (chemotaxis) is abnormal at birth in both term and preterm infants. Neonatal neutrophils have decreased adhesion, aggregation, and deformability, all of which may delay the response to infection. 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 is frequently observed in preterm infants and those with intrauterine growth restriction; it 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 colony-stimulating factor (GM-CSF) are cytokines that play important roles in the proliferation, differentiation, functional activation, and survival of phagocytes.

7. Placental transport of antibodies The transport of IgG is an active placental process, and the neonates serum IgG concentration at birth is 5% to 10% higher than that of the mother. Elevated levels of IgM or IgA in cord blood usually indicate that the infant has been exposed to antigen in utero and has synthesized antibody itself. The concentration of IgG falls postnatally (because of the catabolism of maternal IgG) and reaches a nadir (physiologic hypogammaglobulinemia) at approximately 3 to 4 months of age.

8. BACTERIAL SEPSIS Neonates with bacterial sepsis may have either nonspecific signs and symptoms or focal signs of infection , including temperature instability, hypotension, poor perfusion with pallor and mottled skin, metabolic acidosis, tachycardia or bradycardia, apnea, respiratory distress, grunting, cyanosis, irritability, lethargy, seizures, feeding intolerance, abdominal distention, jaundice, petechiae, purpura, and bleeding.

11. BACTERIAL SEPSIS The initial manifestation may involve only limited symptomatology and only 1 system, such as apnea alone or tachypnea with retractions or tachycardia, or it may be an acute catastrophic manifestation with multiorgan dysfunction. Infants should be reevaluated over time to determine whether the symptoms have progressed from mild to severe. Later complications of sepsis include respiratory failure, pulmonary hypertension, cardiac failure, shock, renal failure, liver dysfunction, cerebral edema or thrombosis, adrenal hemorrhage and/or insufficiency, bone marrow dysfunction (neutropenia, thrombocytopenia ,anemia), and disseminated intravascular coagulopathy (DIC).

12. BACTERIAL SEPSIS A variety of noninfectious conditions can occur together with neonatal infection or can make the diagnosis of infection more difficult. Respiratory distress syndrome (RDS) secondary to surfactant deficiencycan coexist with bacterial pneumonia. Because bacterial sepsis can be rapidly progressive, the physician must be alert to the signs and symptoms of possible infection and initiate diagnostic evaluation and empirical therapy in a timely manner. The differential diagnosis of many of the signs and symptoms that suggest infection is extensive; these noninfectious disorders must also be considered.

13. SIRS The clinical manifestations of infection depend on the virulence of the infecting organism and the body's inflammatory response. The term systemic inflammatory response syndrome (SIRS)is most frequently used to describe this unique process of infection and the subsequent systemic response. In addition to infection, SIRS may result from trauma, hemorrhagic shock, other causes of ischemia, and pancreatitis. Patients with SIRS have a spectrum of clinical symptoms that represent progressive stages of the pathologic process. In adults, SIRS is defined by the presence of 2 or more of the following: (1) fever or hypothermia, (2) tachycardia, (3) tachypnea, and (4) abnormal WBC count or an increase in immature forms.

14. TNF→ increased vascular permeability TNF + IL1→ fever + vasodilation Arachidonic acid metabolites →fever, tachypnea, V/Q abnormalities, lactic acidosis Nitric oxide →hypotention Myocardial depressant factors→ myocardial depression

15. SIRS In neonates and pediatric patients, SIRS is manifested as temperature instability, respiratory dysfunction (altered gas exchange, hypoxemia, acute respiratory distress syndrome [ARDS], cardiac dysfunction (tachycardia, delayed capillary refill, hypotension), and perfusion abnormalities (oliguria, metabolic acidosis). Increased vascular permeability results in capillary leak into peripheral tissues and the lungs, with resultant pulmonary and peripheral edema. DIC results in the more severely affected cases. The cascade of escalating tissue injury may lead to multisystem organ failure and death.

16. Sepsis signs in body systems

17. Jaundice Splenomegaly Pallor Petechia Purpura Bleeding Oliguria Irregular respiration High pitch cry Full fontanel

18. FEVER Only about 50% of infected newborn infants have a temperature higher than 37.8 (axillary). Fever in newborn infants does not always signify infection; it may be caused by increased ambient temperature, isolette or radiant warmer malfunction, dehydration, central nervous system (CNS) disorders, hyperthyroidism, familial dysautonomia, or ectodermal dysplasia.

19. RASH Cutaneous manifestations of infection include impetigo, cellulitis, mastitis, omphalitis, and subcutaneous abscesses. Ecthyma gangrenosum is indicative of infection with Pseudomonas species. The presence of small salmon-pink papules suggests L. monocytogenesinfection. A vesicular rash is consistent with herpesvirus infection.

20. Ecthyma gangrenosum

21. OMPHALITIS Omphalitis is a neonatal infection resulting from inadequate care of the umbilical cord, which continues to be a problem, particularly in developing countries. The umbilical stump is colonized by bacteria from the maternal genital tract and the environment. The necrotic tissue of the umbilical cord is an excellent medium for bacterial growth. Omphalitis may remain a localized infection or may spread to the abdominal wall, the peritoneum, the umbilical or portal vessels, or the liver. Abdominal wall cellulitis or necrotizing fasciitis with associated sepsis and a high mortality rate may develop in infants with omphalitis. Prompt diagnosis and treatment is necessary to avoid serious complications.

22. TETANUS Neonatal tetanus is a serious neonatal infection in developing countries. It results from unclean delivery and unhygienic management of the umbilical cord in an infant born to a mother who has not been immunized against tetanus. The surveillance case definition of neonatal tetanus requires the ability of a newborn to suck at birth and for the 1st few days of life, followed by an inability to suck starting between 3 and 10 days of age, difficulty swallowing, spasms, stiffness, seizures, and death. Bronchopneumonia, presumably resulting from aspiration, is a common complication and cause of death. Neonatal tetanus is a preventable disease. It can be prevented by immunizing mothers before or during pregnancy and by ensuring a clean delivery, sterile cutting of the umbilical cord, and proper cord care after birth.

23. Pneumonia Pneumonia Signs of pneumonia on physical examination, such as dullness to percussion, change in breath sounds, and the presence of rales or rhonchi, are very difficult to appreciate in a neonate. X-rays of the chest may reveal new infiltrates or an effusion, but if the neonate has underlying RDS or BPD, it is very difficult to determine whether the radiographic changes represent a new process or worsening of the underlying disease.

24. Bacterial pneumonia Afebrile pneumonia syndrome The progression of neonatal pneumonia can be variable. Fulminant infection is most commonly associated with pyogenic organisms such as GBS. Onset may be during the 1st hours or days of life, with the infant often manifesting rapidly progressive circulatory collapse and respiratory failure. With early-onset pneumonia, the clinical course and radiographs of the chest may be indistinguishable from severe RDS. In contrast to the rapid progression of pneumonia when caused by pyogenic organisms, older infants with community-acquired infection often have an indolent course. The onset is usually preceded by upper respiratory tract symptoms or conjunctivitis. A nonproductive cough ensues, and the degree of respiratory compromise is variable. Fever is usually absent, and radiographic examination of the chest shows focal or diffuse interstitial pneumonitis. This infection has been called the "afebrile pneumonia syndrome" and is generally caused by C. trachomatis, CMV, Ureaplasma urealyticum, or one of the respiratory viruses. Although Pneumocystiscariniiwas implicated in the original description of this syndrome, its etiologic role is now in doubt, except in newborns infected with HIV.

25. SCREENING Sexually transmitted infections (STls) that infect a pregnant woman are of particular concern to the fetus and newborn because of the possibility for intrauterine or perinatal transmission. All pregnant women and their partners should be queried about a history of STls. Women should also be counseled about the need for timely diagnosis and therapy for infections during pregnancy.

26. SCREENING The CDC recommends the following screening tests and appropriate treatment of infected mothers: (1) All pregnant women should be offered voluntary and confidential HIV testing at the 1st prenatal visit. For women at high risk of infection during pregnancy (multiple sexual partners or STls during pregnancy, intravenous drug use), repeat testing in the 3rd trimester is recommended. (2) A serologic test forsyphilis should be performed on all pregnant women at the 1st prenatal visit. Repeat screening early in the 3rd trimester and again at delivery is recommended for women who had positive serology in the 1st trimester and for those at high risk for infection during pregnancy. (3) A serologic test for hepatitis B surface antigen (HBsAg) should be performed at the 1st prenatal visit and repeated late in pregnancy in those who are initially negative but at high risk for infection. (4) A maternal genital culture for C. trachomatisshould be performed at the 1st prenatal visit. Young women (under 25 yr) and those at increased risk for infection (new or multiple partners during pregnancy) should be retested during the 3rd trimester. (5) A maternal genital culture for Neisseriagonorrhoeaeshould be performed at the 1st prenatal visit for women at risk and for those who live in areas with a high prevalence of gonorrhea. Repeat testing in the 3rd trimester is recommended for those at continued risk. (6) Evaluation for bacterial vaginosis should be considered at the 1st prenatal visit for asymptomatic women at high risk for preterm labor. (7) The CDC has recommended universal screening for rectovaginalGBS colonization of all pregnant women at 35-37 wk gestation and a screening-based approach to selective intrapartum antibiotic prophylaxis against GBS.

27. SCREENING 1-HIV 2- Syphilis 3- hepatitis B 4- C. trachomatis 5- Neisseriagonorrhoea 6- Bacterial vaginosis 7- GBS

28. Diagnostic workup Bacterial infection is diagnosed by isolating the etiologic agent from a normally sterile body site (blood, CSF, urine, joint fluid). Obtaining 2 blood culture specimens by venipuncture from different sites avoids confusion caused by skin contamination and increases the likelihood of bacterial detection. (size of sample=0.5-1cc) Samples should be obtained from an umbilical catheter only at the time of initial insertion.

29. Although the total WBC count and differential and the ratio of immature to total neutrophils have limitations in sensitivity and specificity, an immature-to-total neutrophil ratio of >0.2 suggests bacterial infection. Neutropenia is more common than neutrophilia in severe neonatal sepsis, but neutropenia also occurs in association with maternal hypertension, preeclampsia, and intrauterine growth restriction.

30. Thrombocytopenia is a nonspecific indicator of infection. Tests to demonstrate an inflammatory response include: C-reactive protein, procalcitonin, haptoglobin, GCSF - fibrinogen, inflammatory cytokines (including IL-6, IL-8,IL10 and TNF-a), and cell surface markers like CD64.

31. When the clinical findings suggest an acute infection and the site of infection is unclear, additional studies should be performed, including blood cultures, lumbar puncture, urine examination, and a chest x-ray. (Urine should be collected by catheterization or suprapubic aspiration;) urine culture for bacteria can be omitted in suspected early-onset infections because hematogenous spread to the urinary tract is rare at this point.

32. When the clinical findings suggest an acute infection, the examination of the “buffy coat” with Gram or methylene blue stain may demonstrate intracellular pathogens. Demonstration of bacteria and inflammatory cells in Gram-stained gastric aspirates on the 1st day of life may reflect maternal amnionitis, which is a risk factor for early-onset infection. Stains of endotracheal secretions in infants with early-onset pneumonia may demonstrate intracellular bacteria, and cultures may reveal either pathogens or upper respiratory tract flora. Careful examination of the placenta can be helpful in the diagnosis of both chronic and acute intrauterine Infections.

33. Diagnostic evaluation is indicated for asymptomatic infants born to mothers with chorioamnionitis. The probability of neonatal infection correlates with the degree of prematurity and bacterial contamination of the amniotic fluid. In an asymptomatic term infant whose mother has chorioamnionitis, 2 blood cultures should be performed and presumptive treatment initiated. Maternal chorioamnionitis= Fever + leukocytosis + uterine tenderness + foul smelling amniotic fluid

34. There is controversy over whether a lumbar puncture is necessary for all term infants with suspected early-onset sepsis.

35. LP indications 1- positive blood culture 2- seizure 3- drowsiness/unconsciousness 4- pneumonia 5- apnea

36. CSF normal values: Normal, un infected infants from 0-4 wk of age may have elevated CSF protein levels of 85 ± 45 mg/ dL, glucose of 45 ± 10 mg/ dL, and elevated CSF leukocyte counts of 11 ± 10 with the 90th percentile being 22. During the neonatal period presence of RBC in CSF (up to 800 in first day and 50 in the end of neonatal period ) can be considered a normal finding.

37. Gram stain of CSF yields a positive result in most patients with bacterial meningitis. The leukocyte count is usually elevated, with a predominance of neutrophils (>70-90%); the number is often >1,000 but may be <100 in infants with neutropenia or early in the disease. Microorganisms are recovered from most patients who have not been pretreated with antibiotics. Bacteria have also been isolated from CSF that did not have an abnormal number of cells (<25) or an abnormal protein level (<200 mg/dL), thus underscoring the importance of performing a culture and Gram stain on all CSF specimens. Contamination of CSF by bacteremia after traumatic lumbar puncture may occur rarely. Culture negative meningitis may be seen with antibiotic pretreatment, brain abscess, or infection with Mycobacterium hominis, U. urealyticum, Bactericides fragilis, enterovirus, or HSV. Head ultrasonography or, more often, CT with contrast enhancementmay be helpful in diagnosing ventriculitis and brain abscess.

38. Head circumference chart is mandatory in neonatal meningitis. All the neonates should be reexamined for CSF (analysis and culture) 3-4 days after starting the treatment, to find out whether the antibiotic treatment has been effective or not in eradication of infection. The antibiotic regimen may be changed accordingly if necessary. A final examination on CSF should be done as well near the end of therapy, before discontinuation of antibiotics. Therapy for meningitis is continued for a minimum of 2 weeks after sterilization of CSF cultures. This equates to 14 days of therapy for meningitis caused by gram positive organisms and a minimum of 21 days of therapy for meningitis caused by gram negative pathogens. (a) Treatment for candida meningitis is with amphotericin B and flucytosine for a period of 3 to 6 weeks. (a) Dexamethasone is not used in neonatal meningitis. Complications of neonatal meningitis: the acute complications include communicating and noncommunicating hydrocephalus, subdural effusion, ventriculitis, and blindness. (a)

39. Immature/total The I:T ratio has been investigated as an early predictor of sepsis. The maximal I:T ratio in uninfected neonates is 0.16 in the first 24hrs, decreasing to 0.12 by 60 hrs. the upper limit of normal for neonates of 32 weeks gestation or less is slightly higher, at 0.2. Prolonged induction with oxytocin Stressful labor Prolonged crying

40. IVIG Meta-analysis of studies of IVIG for the treatment of neonates with sepsis has shown a significant decrease in the mortality rate compared with standard therapies. Dose: 200mg/kg/dose over 2hr GCSF 10 mcg/kg sc 1-3doses

41. 1- CBC – diff – ESR – CRP – BC – PT – ABG – UA – UC – SC CSF analysis & culture – ETT culture – clot for electrolytes 2- CXR 3- antibiotics 4- IVIG if indicated 5- G- CSF if indicated 6- exchange transfusion if indicated 7- acyclovir if indicated 8- amphotericin – B if indicated 9- hyperglycemia management 10- duration of antibiotic 10days if started for a positive BC or 7days after improvement if AB is started based on clinical indication. 11- chart head circumference in meningitis to detect hydrocephalus. 12- repeat LP after 3-4 days of AB treatment to decide whether the current antibiotics are appropriate or should be changed. 13- always make sure of normal CSF profile before discontinuing the AB therapy ( repeat LP near the end of treatment period).

42. ESR First 2 weeks of life: 3 + age in days Beyond 2 weeks of life: the maximum rate varies between 10 and 20 mm per hour.

43. CRP Normal concentrations in neonates are 1mg/dl or lower. An increasing CRP value is usually detectable within 6 – 18 hours, and the peak CRP is seen at 8 – 60 hours after onset of the inflammatory process.

44. Is antibiotic therapy mandatory for all neonates who receive intravenous fluid?