8/24/15  

1  

Karen Knuth, ARNP, MN, NNP-BC Seattle Children’s Hospital

� � Introduction and background information � Immunity � Risk factors � Types of infections � Signs and symptoms � Diagnosis � Treatment � Prevention � Practice

� �  A clinical syndrome in an infant 28 days of life or

younger with � Signs of illness and/or the identification of bacteria

in blood

� Early Onset: within < 72h and up to six days for GBS � Late Onset: after three days up to > 7 days of life

Definition �

� 1 – 5 to 1 – 8/1000 live births � Inversely related to gestational age

� Preterm infants as high as 13 – 27/100 <1500g � Lower in term infants: 1 – 2/1000 livebirths

� Early Onset � Decreased since GBS prophylaxis

� Late Onset �  10 – 32% of all incidences

Incidence

Incidence of early- and late-onset invasive group B streptococcal (GBS) disease: Active Bacterial Core surveillance areas, 1990-2010*, and activities for prevention of GBS disease

� � Mortality rates 13-25% � Higher in preterm infants and early

onset disease

Mortality

8/24/15  

2  

�

� Early � Late � Nosocomial

Pathophysiolgy �

Early Onset � ≤ 3 days � 0.3 - 0.4% neonates � Usually symptomatic

with respiratory component

� Acquired during intrapartum period � Mother’s genital tract � Membranes ruptured � Transplacental � Chorioamnionitis: 4%

� Areas colonized: skin, nasopharynx, oropharynx, conjunctiva, and umbillical cord

� Sudden onset and fulminant course �  Septic shock � High mortality rate

� Meningitis: 25%

� Late Onset

� 3-5 days, but more so >7 days

� Less associations with o.b. complications

� Usually have a focus � Many with meningitis � Caused by bacteria

from genital tract and human or equipment contact after birth

� Horizontally transmitted organisms

� Unclear why some infants get sick and some don’t – immunity?

� Nosocomial

� A.k.a. hospital acquired or horizontal

� Occurs in high-risk newborns

� Pathogenesis related to �  underlying disease �  Condition of infant �  The NICU bug

environment �  Invasive monitoring, etc

� Ie: breaks in skin and intestine � Allow passage of

organisms � Can easily overwhelm

infant � Increased risk of

meningitis

� Immunity

Specific

� a.k.a. humoral �  specific mechanisms

� T cell: cell mediated � B-Cell: humoral or

antibody mediated � Operate more

effectively with prior exposure

Non-Specific

� Physical barriers � Chemical barriers � Phagocytosis � Inflammatory response

and � Amping systems

(complement) � Function without prior

exposure to antigen

� � Antibodies are the immunoglobulins produced in response

to specific antigens. � Types:

�  IgM – not passed via placenta, early, fetus can make �  IgG – crosses placenta in 3rd trimester only, protects the first

few months �  IgA – found in secretions: saliva, lungs, colostrum, EBM… �  IgD �  IgE

Humoral

8/24/15  

3  

� �  ↑ Blood supply to the area �  ↑ capillar permiability � Leukocytes and macrophages migrated out of the

capillaries into surrounding tissues.

� Endotoxins

� Can lead to septic shock

Inflammatory Response �

Neonatal Immunodeficiencies

Infants and especially preterm infant have increased susceptibility to infection due to:

�  Decreased antibody levels �  Antigens �  Antibodies �  B-cells �  T-cells

�  Decreased opsonic activity �  Ciculating antibody �  Maternal complement �  Depressed complement

�  Neutrophil response �  Storage pool �  Limited stem cell

proliferation �  Function abnormal

� � Prematurity (<37wks) and low birth weight � Rupture of membranes � Maternal fever or infection around delivery � Abnormal amniotic fluid � Resuscitation at birth , Apgar <5 � Multiple gestation � Invasive procedures � Infants with galactosemia, immune defects, or asplenia � Iron therapy � Other factors

Risk Factors �

� Males affected 4x more than females � Blacks >whites � Low socioeconomic (low birth weight) � Being in a NICU:

� staff, visitors, poor handwashing – all spread microorganisms

Other risk factors

� Types & Sources

� Bacterial

� Viral

� Fungal

� Blood � CSF � Urine � Respiratory � Skin � Bone � Soft tissues

8/24/15  

4  

� Gram Positive Organisms � GBS � Listeria � Enterococcus - rare � Staphylococcus

�  Staph aureus �  Staph epi �  MRSA – Methicillin Resistant Staphylococcus Aureus

Bacteria �

� GBS + E Coli : Most common causes of early onset sepsis �  10 – 40% of women colonized in the vaginal/rectal area � Late onset: contact from colonized persons �  In the USA

�  Early: 1.8/1000 live births down to probably 0.25/1000 live births �  Late: 4- 5 wks of age. 0.3-0.4 /1000 live births (no change) �  Late, Late: >3 mos of age. Common 28 wks g.a.

�  Fatality 2-3% term without meningitis, early up to 30% preterm � CDC guidelines 2010

�  http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5910a1.htm?s_cid=rr5910a1_w

GBS – group beta strep

� � Early: generalized sepsis (80-85%), pneumonia (10%), or

meningitis (7%) �  90% within 24h �  IAP less likely to have severe disease or bacteremia

�  Inhibit growth of BGS in blood and SCSF � Late: bacteremia (65%), meningitis (25-30%), and focal

infections. �  Can also present as bone/joint infections, cellulitis/adenitis

� Late Late: bacteremia, most common <28wks g.a. at birth or focal sites of infection (CNS, soft tissues, bones/joints, catheters)

�  After 6 mos first sign of immunodeficiency (HIV)

GBS - Clinical

� � Preterm delivery < 37 weeks � Premature ROM at any gestation � PROM > 18 hours �  Intrapartum fever > 38° C or 100.4°F during labor � GBS bacteriuria (>10 cFu/mL) � Previous GBS disease in an older sibling � Chorioamnionitis

�  25-30% of moms will be identified using risk factors � Risk factor (versus culture) analysis will only detect 50%

of GBS

Risk Factors for GBS �

Chorioamnionitis

� a.k.a. “intraamniotic infection” � Culture and/or pathology � Clinical diagnosis

� Maternal fever >38 deg C /100.4 deg F PLUS ONE OR TWO OF THE FOLLOWING:

� Maternal leukocytosis (greater than 15,000 cells/mm3) � Maternal tachycardia (greater than 100 beats/minute) �  Fetal tachycardia (greater than 160 beats/minute) � Uterine tenderness �  Foul odor of the amniotic fluid

� Treatment and surveillance protocols vary

8/24/15  

5  

� Gram negative organisms � E Coli (most common cause in the neonatal period) � Pseudomonas aeruginosa � H. Influenza � N. Gonorrhea � Klebsiella � Enterobacter � Citrobacter

Bacteria

� � Transmission – 3 modes

� 1. congenital � 2. intrapartum (5-7 days) � 3. post natal (nosocomial infection, breast milk or blood transfusion)

Viral �

�  T toxoplasmosis

�  O other (syphillis, Hep B, coxsackie, Parvovirus B-19

Epstein-Barr, varicella, HPV, HIV….)

�  R rubella

�  C CMV �  H HSV

Viral

� TORCH?

� Hydrops fetalis � Microcephaly �  Seizures � Cataracts � Hearing loss � CHD � Hepatosplenomegaly �  Jaundice � Rash �  thrombocytopenia

� May have similar clinical presentations (rash, ocular findings)

� Goal is to investigate, diagnose and appropriately treat IF there is an infection

� � Mothers screened for Hep B, Rubella and syphilis � Sometimes screened for toxoplasmosis, HPV, and/or

varicella � Prenatal screening for syphilis is also known as

treponema pallidum, VDRL, RPR, or serology � Rubella “blueberry muffin” rash (thrombocytopenia) � CMV – most common congenital viral infection � HSV – � Congenital Varicella Syndrome

TORCH

8/24/15  

6  

� � 40,000 infants in US annually � 0.5-2% all births � 90% asymptomatic (hearing loss , learning) � 5-20% with primary CMV very symptomatic � Small, microcephalic, preterm birth, sick “fulminant

presentation” �  30% mortality �  Survivors have long term outcomes (MR, vision and/

or hearing loss), brain calcifications � Diagnosis: urine and saliva � Treatment: specific problems, gancyclovir (viral load)

CMV �

� Transmitted via infected genital tract � Grater with primary HSV acquired during

pregnancy vs reactivation of previous infection � Most normal at birth but can get very sick, very fast � Presentation:

�  SEM (skin, eyes, mouth) � CNS disease � Disseminated (multi-organ)

� May or may not have skin lesions

HSV

� HSV

�

� Asymptomatic at birth � Most newborns immunized prior to discharged from

hospital � Vaccine within hours of birth if hepatitis B status

unkown or Hep B positive � HBIG within 7 days if Hep B positive

Hepatitis B

� Viral

� HIV

�  treatment is Zidovudine (AZT)

� RSV - Respiratory Syncytial Virus �  Diagnosed by nasal washing;

rapid screening �  Can be severe; no real

treatment – supportive care �  Synagis® (palivizumab) is a

humanized monoclonal antibody

�  Given only in fall/winter �  Qualify for coverage �  Treat the symptoms –

secretions, temperature, hypoventilation, hypoxemia

� Don’t forget about enteroviruses

� Varicella Zoster � Or Parvovirus B-19

� � “ this baby just doesn’t look right” � “ I have this feeling” � “his/her color is off”

� Usually non-specific, must consider many other things that could be causing the problems, but must always consider infection

Signs & Symptoms

8/24/15  

7  

� Signs & Symptoms

CNS � Temperature instability:

hypo or hyperthermia � Hypotonia � Lethargy � Irritability � Seizures � Buldging fontanels � Change in behavior

Cardiovascular

� Color: pale, mottled or grey

� Perfusion poor � Pulses weak/thready � Prolonged cap refill � Heart rate: increased

decreased � Blod pressure:

hypotension � bradycardia

� Signs & Symptoms cont’d

Respiratory

� Cyanosis � Increased A/B/C or D’s � Apnea

�  within 24h of birth or new onset after 1 week of life

� Tachy or bradypnea � Increased work of

breathing � Respiratory failure

Gastrointestinal

� Poor feeding � Increased gastric

residuals � Abdominal distension ±

loops � Emesis � Diarrhea � Watery or bloody stools

� Signs & Symptoms cont’d

Skin

� Pallor � Mottling � Rashes � Pustules � Petechiae � Omphalitis � Conjunctivitis � Jaundice � Sclerema

Physiologic

� Hypo or hyperglycemia � Electrolyte anomalies � Hyperlipidemia � Metabolic acidosis

� � Jaundice – 35% � Respiratory distress – 33% � Hepatomegaly – 33% � Anorexia – 30% � Vomiting – 25% � Lethargy – 20% � Cyanosis – 20% � Apnea – 20% � Abd distension – 17% � Irritability – 15% � Diarrhea – 11%

Findings Associated with Neeonatal Sepsis

� � Cultures & Gram stains

� Viral studies

� CBC � Neutrophils

� Acute-phase reactants � CRP � ESR � Others (cytokines, procalcitonin)

� Miscellaneous tests: CXR, ultrasound (yeast sepsis)

Evaluation / Diagnosis

8/24/15  

8  

� � Blood

�  Sterile specimen, clean skin well with antimicrobial � Prior to antibiotics � Can confirm 99% of common infections by 48h

�  5 days total

� Maternal antibiotics at birth may make the sample sterile or have less organisms – grow slower �  Use adjunct tests and clinical presentation to support

dianosis

�  0.5 – 2 mls blood � Can have false positives and false negatives

Cultures � � Urine

�  Sterile specimen is best: bladder tap, > 6 days of life � Catheter specimen after cleanse with antimicrobial � Bag not appropriate or accurate � Urinalysis

� CSF � When neurologic signs and symptoms � Late onset sepsis - mostly � Positive blood culture � Practice site specific

Cultures

� � Sputum

� Late onset sepsis – peumonia in intubated infants especially

� Stool:

� Skin: �  surface for bacteria and viral, ie: groin MRSA,

herpes virus, nares RSV

Cultures, cont’d �

Gram Stain

� Quick results to help determine organism � Based on cell wall differences in bacteria � Classified as gram negative and gram positive � Can change treatment based on findings or confirm

suspicions on causes of illness � Takes a few days to definatively identify the organism � Can do this on blood, urine, stool, amniotic fluid etc.

� WBCs with organisms may indicate colonization with bacteria – not 100% for infection

Gram Stain

Gram Pos Cocci Gram Negative Cocci

Staphlococcus – Gm Pos bacteria Clusters Staph Aureous – coag positive Staph Epidermidis – coag negative Pairs and Chains Group A Group B Group D – Enterococcus, Strep pneumoniae

Streptococcus – Gm Negative Bacteria Gram negative cocco bacilli – Haemophilus influenzae Nisseria - N. Gohorrhoeae - N. Menigititens Doiplococci

Gram Positive Rods Gram Negative Rods

Listeria Monocytogenes – Bacillus

Anaerobes: Clostridium – rods C difficile, Listeria Diptheria

Enterobacteriaceae Family - Rods

Escherichia Coli Klebsiella Proteus Salmonella Pseudomonas Anaerobe Bacteriodes Fragillis (penicillin resistant)

8/24/15  

9  

� � CBC with differential

� May need to follow serial CBCs

� What to look at for signs of infection �  Immature to total neutrophil count (I/T) � Left shift – elevated I/T ratio > 0.2 � WBC count:

�  Elevated (>20,000/mm3) or depressed (<5,000/mm3) �  Both associated with sepsis �  Ie; a second CBC may be more normal

CBC

� � Absolute neutrophil count (ANC)

� ANC of 500-1000 intermediate risk � ANC <500 increased risk

� Platelets: normal 150,00 to 400,000/mm3 � Thrombocytopenia (low) < 100,000 � Possibly associated with bacterial sepsis or viral

infection �  Severe: DIC (disseminated intravascular coagulation)

CBC cont’d � � Main defense against invading organisms

� Made in the liver initially, then bone marrow � Granulocytes

� Neutrophils, eosinophils, and basophils � Agranulocytes

� Lymphocytes and monocytes

� Elevated: infection, leukemia, or leukemoid reaction

� Decreased: viral or bacterial infections, maternal hypertension

Leukocytes

� � Concentrations vary, especially in the first 2-3 days

after birth � Peak at ~ 12 h, back to baseline about 72h

� Neutrophilia: Increased �  Inflammation, malignancies, corticosteroids

� Neutropenia: Decreased �  Infection, impaired bone marrow production, or

abnormal distribution � More predictive of sepsis than neutrophila �  Short life – stores can be rapidly depleted � Can be associated with other things, PIH for example –

resolves in 3 – 5 days

Neutrophils

8/24/15  

10  

� � Immature neutrophils � Number circulating increased in term and preterm � One part of sepsis evaluation � Normal values: <10% � Elevations not specific to infection

�  ‘left shift’ � Indicate the marrow is releasing more immature cells …

left shift indicates an elevated I/T ratio (>0.2) � Things that induce a stress response can cause the bone

marrow to produce more immature neutrophils

Bands

� � A complex, multifunctional group made of complement components, coagulation proteins, protease inhibitors, C-reacive protein (CRP) and others that rise in concentration in the serum in resonse to a tissue injury

� CRP: increases in the presence of inflammation

� Not specific to infection � A strong negative predictor of infection � Need a series of values (2-3) � Useful for determining length of treatment � Normal values: <1 g/dL or < 10g/L � Obtained at 24 and 48h

Acute Phase Reactants �

� ESR – erythrocyte sedimentation rate � May be elevated but only well into illness

� Cytokines �  IL-1, IL-6, IL-8, and TNF

�  Produced by monocytes and macrophages �  Mediators to systemic response to infection �  Combined use of IL-8 and CRP - decreased unnecessary

antibiotic treatment

� Procalcitonin: released when bacterial toxins present

Acute Phase Reactants

8/24/15  

11  

� � Abnormal values for:

� Glucose � Bilirubin � Sodium

� CXR: respiratory symptoms � Placenta and fetal membrane studies

Miscellaneous Tests �

� Obtained by lumbar puncture/spinal tap to screen for meningitis

� 1/3 of all infants with sepsis also have meningitis – usually later onset

� If a baby has a positive blood culture they need CSF analysis

� Bacterial meningitis does happen without a positive blood culture

� Different policies/practices with CSF collection � Sample analyzed for protein, glucose, culture and gram

stain, and cell count - WBCs (±differential), RBCs

Lumbar Puncture: CSF (cerebral spinal fluid)

� � Respiratory: support respirations and ensure

adequate tissue oxygenation

� Cardiovascular: watch for signs of shock � Support blood pressure with volume boluses,

blood transfusions if anemic, andvasopressors � Monitor volume status: in/outs

� Hematologic: watch for DIC � Neutropenia: GCSF � IVIG

Treatment: General �

� CNS: � Watch for seizures, treat as appropirate � Monitor temp � Treat fever/pain with acetominophen

� GI/Nutrition: � NPO – septic ileus � Gavage feeds �  IV fluids – TPN; may not metabolize lipids

� Metabolic: � Monitor and treat hypo/hyperglycemia � Monitor and treat metabolic acidosis

Treatment: General

� � Combination of a penicillin & aminoglycoside

� Ampicillin � •Effective coverage for gram + H. flu. E. coli,

Proteus & Listeria � Gentamicin

� •Coverage against gram neg (plus Pseudomonas) � Synergistic effect with ampicillin against

GBS, E.coli, listeria & enterococus

Treatment: Antimicrobials – Initial therapy

� � Different organisms

� Still broad spectrum until identified � Different antibiotics

� Vancomycin � Cefotaxime (Claforan) � Zosyn

� May include a fungicidal if extreme preterm infant

Treatment: Late onset

8/24/15  

12  

� Treatment-Viral

� RSV- supportive, Isolation precautions, Synagis prophylaxis �  Treatment: Ribavirin – contraversial, expensive, old

�  Influenza – supportive, isolation, vaccinations � Varicella – acyclovir, VZIG � Enterovirus – suppotive, isolation � HIV – assymptomatic during first few months of life

�  Most treatment aimed at antiviral treament during pregnancy

�  Testing early, routine/scheduled – blood smears �  No breastfeeding

� Hepatitis: A, B, C �  Hep B immuniation of neonates

� � Candida - albicans, parapsilosis, glabrata, tropicalis,

guilliermondii � Can be acquired prenatally, during birth, or

postnatally � Diaper dermatitis: Nystatin ointment � Thrush: Nystatin suspension, fluconazole, gentian

violet �  Systemic: Amphotericin �  Fluconazole prophylaxis for VLBW early preterms � Malasseia fur fur

Treatment - Fungal

� � Prophylaxis

� GBS � Vaccines: ie: Synagis for RSV � Antivirals

� Handwashing � Asceptic techniques / standard precautions

� Barriers, protective equipment, cleaning surfaces, disposal of tissues and contaminents

� Getting central lines out more quickly

Prevention �

� Leukopenia: a decreased number of all the white blood cells �  leukopenia<5,000

� Leukophilia: an increased number of all the white blood cells �  leukophilia>11,000

� Neutropenia: a decrease in just the neutrophil line of the total WBC (leukocytes)

� Neutrophilia signifies an increase in the neutrophil line.

� To determine if the patient has neutropenia or neutrophilia you calculate the Absolute Neutrophil Count (ANC).

Practice

� � ANC: multiply the percentage (%) of all the

neutrophils (mature & immature cells) by the WBC/mm3 �  (% neutrophils + % immature) x WBC

�  If ANC between 500-1000: patients are likely to be at intermediate risk for developing infection.

�  If ANC <500: patient at increased risk of developing infection.

Absolute Neutrophil Count �

ANC: (% neutrophils + % immature) x WBC

CBC �  WBC: 17.6 �  Hct: 43.5 �  Platlets: 257k

�  Segs: 48 �  Bands: 28 �  Lymphs: 17 �  Metamylocytes: 1 �  Mylocytes: 0 �  Promylocytes: 0

ANC

� Segs = Neutrophils

� (48 + 1) x 17.6 � 0.49 x 17 600 � 8624

� Low risk infection

8/24/15  

13  

� � immature neutrophils cells / total neutrophil cells (mature + Immature)

�  (% Bands + Metas + myelos) / (% Bands + Metas + myelos + neutrophils)

� Values vary in literature between >0.15 to >0.3 � Use the value from your institution � Better measure than just looking at the band count � Can be affected by stress

‘Immature’ to ‘Total’ Neutrophil Ratio

�

I:T Ratio

(% Bands + Metas + Myelos) _________________________________________________________________________________________________________________________________________________________________

(% bands + metas + myelos + neutrophils)

CBC I:T

� % bands+ metas + myelos / % bands + metas + myelos + neuts

�  0.28 + 0.1 / 0.48 + 0.28 + 0.1

�  0.29 / 0.77

�  0.377 � High I:T ratio

�  WBC: 17.6 �  Hct: 43.5 �  Platlets: 257k

�  Segs: 48 �  Bands: 28 �  Lymphs: 17 �  Metamylocytes: 1 �  Mylocytes: 0 �  Promylocytes: 0