Novel Markers of Serious Bacterial Infections in Children

1. Novel Markers of Serious Bacterial Infections in Children Marc Francis FRCPC R4 PEM Fellow Year 1

2. Case • PP • 32 day old male • PMHx • Term baby • Uncomplicated pregnancy • Uncomplicated delivery • Mother GBS+ and rec’d antibiotics during labour • Discharged home after <48hrs in hospital

3. Case • HPI • Previously well breastfed infant • 3 day hx of nasal congestion • In last 48hrs mother noted tactile fever at home • More lethargic and not breastfeeding as well • Concerned he has “caught a cold”

4. Case • Exam • Vitals • HR 150, RR 50, sat 95%, Temp 38.2 rectally • Generally • Sleeping comfortably and looks well • Irritable with the exam • CVS • Normal HS, pulses strong, cap refill <2sec • Resp • Mild tachypnea, no distress, no indrawing, clear throughout

5. Case • Exam con’t • Abd • Soft and non-tender, BS normal • Derm • No rash • Neuro • PEARL, Fontanelle soft, Tone normal, grasp +, • Moro +, poor suck

6. Informal survey Options: • Reassure the parents and send the child home • Further investigations including CBC, BC, urine R+M/C&S , CXray • Full septic work-up and admission to teams pending cultures

7. The issue • Fever is one of the most frequent reasons for ED visits for children <3yo • 20% of these children will have no identifiable source of fever after Hx and PE1 • The vast majority of these children will have benign viral illness • This age group is however at risk for clinically undetectable serious bacterial infections (SBI)

8. The Issue • Febrile infant <3yo • 2-3% of these children have occult bacteremia2 • 2-8% have UTI depending on age and gender3 • ~3% will have occult pneumonia4 • Meningitis • Bone and Joint infections • Bacterial enteritis • Deep soft tissue abscess

9. The issue • Neonatal sepsis • Occurs in about 1-8/1000 live births5 • Hampered by vague, nonspecific or nonexistent clinical manifestations • Often fail to induce elevations in temperature and WBC

10. The Issue • Antibiotic therapy is necessary for children with SBI • The majority of these kids do not have SBI • Unnecessary investigations • Cost • Time • Discomfort • Expectant antibiotic therapy • Antibiotic resistance • Resource allocation • Parental anxiety

11. I have a dream….

12. Well appearing child with fever or worrisome history Test X Low probability Mod probability High probability Send home with No investigations Further investigations and work-up Full septic work-up Admission and antibiotics My Dream……

13. Cheap Bedside availability Rapid results Minimally invasive Highly Sensitive Highly Specific Useful in all age ranges Able to differentiate infection from inflammation Maximum diagnostic sensitivity and negative predictive value “Test X”

14. Failed attempts to date……

15. PROS Cheap Bedside test Minimally invasive Some of us are good at it…. CONS Difficult for those that don’t see large volumes of pediatrics Lacks the necessary sensitivity and specificity in detecting occult SBI History and Physical exam

16. PROS Gold standard of diagnosis Allows for antibiotic sensitivities CONS Invasive Average time to detection of + cultures is 15-16hrs6 Blood Cultures

17. PROS Readily available Rapid results CONS Low predictive value Sensitivity of ~50% Specificity of <85% Results in unnecessary treatment in 85-95% of cases7 WBC ≥ 15,000

18. PROS Readily available Rapid Results More accurate test than WBC in detecting occult bacteremia CONS Overall sensitivity and specificity similar to WBC count7 Absolute Neutrophil Count

19. Novel markers of inflammation

20. ESR • Erythrocyte sedimentation rate • The rate at which RBCs fall through plasma • Depends on the plasma concentration of fibrinogen • An indirect marker of the acute phase response that accompanies inflammation

21. ESR Advantages • Familiarity • Simplicity • Abundant literature complied over the past seven decades

22. ESR disadvantages • ESR is an indirect measurement of acute phase response • Influenced by size, shape and number of RBCs • Imprecise and misleading • ESR changes slowly if patient’s condition improves or worsens • Normal values are higher among women than men8 • Elevated in Obesity • Considerable overlap between diseased and healthy individuals

23. C-reactive Protein

24. CRP • Discovered in 1930 by Tillett and Francis9 • Polysaccharide first discovered in patients with S. pneumoniae • Synthesized in the liver • Activates the classical complement pathway • The C-reactive component was not identified in healthy individuals • Quickly disappeared as patients recovered

25. CRP • The principle protein produced in the acute phase of inflammation • Binds potentially toxic substances released from damaged tissues and clears them from the blood • With onset of inflammation10 • CRP synthesis increases within 4-6hrs • Doubles every 8hrs • Peaks at 36-50hrs • With resolution of inflammation or tissue destruction11 • Declines rapidly due to short half-life of 4-7hrs

26. Major Components of the Acute Phase Response

27. CRP in the Health Region • 0.5mL of whole blood in pediatrics • Cost is $5.34 • Reference interval • 0.0 – 8.0mg/L • Sent to Diagnostic and Scientific Centre (DSC) • Run once daily including Sat/Sun • Expected turnaround time of 24hrs • No STAT runs

28. CRP • Most clinical studies from Europe • In general CRP elevations in SBI tend to be in the range of 150-350mg/L 12 • In viral infections it tends to be much lower <20-40mg/L 13 • However this is not absolute with CRP values >100 seen in 14,15 • Adenovirus • Measles and mumps • CMV • Influenza • EBV

29. Neonatal Sepsis CRP crosses the placenta in exceedingly low quantities 16 Despite immature immune systems endogenous CRP synthesis occurs 17 Elevated in non-infectious conditions 18 Meconium aspiration, RDS, IVH Complicated by nonspecific 3d rise related to stress of delivery 8% false positive rate reported in healthy neonates 19 CRP

30. Prospective cohort study • N = 77 patients • Inclusion criteria • Febrile children presenting to ED • 1mth – 36mth old • Temp ≥ 39°C • Clinically undetectable source of fever

31. WBC, ANC and CRP concentrations were measured at arrival • All pts received • Blood cultures • Urine R+M and C+S • Further work-up as required • Main outcome was the presence of laboratory or radiographically proven SBI • Bacteremia • Meningitis • UTI • Pneumonia • Septic arthritis • Osteomyelitis

32. Results • 77 patient enrolled • 14(18%) had SBI • 6 UTI • 4 pneumonia • 4 occult bacteremia • 63 had no SBI

33. In multivariate logistic regression only CRP remained an independent predictor of SBI • CRP cutoff point of 70mg/L maximized sensitivity and specificity

34. Conclusions • Sensitivity of 79% (49.0, 94.2) • Specificity 91% (79.8, 96.0) • Better predictor than WBC or ANC • CRP <50mg/L effectively ruled out SBI

35. CRP Advantages • Direct measurement of acute phase response in inflammation • As the patient’s condition worsens or improves the CRP concentration changes rapidly • Appears to be higher in significant bacterial infections • Probably one of the better diagnostic test for neonatal sepsis

36. CRP Disadvantages • Range of abnormal values is large • Some individuals have baseline levels as high as 10mg/L • Unable to differentiate inflammatory responses from infection • Dependant on the duration of fever • More reliable if fever >12hrs • Elevated in minor bacterial and certain viral infections • Lacks the sensitivity required in the ED setting

37. Who is the new kid on the block?

38. Procalcitonin

39. Procalcitonin • The prohormone of calcitonin • Found in blood • Thought to be released by Macrophages and Monocytes • Normal physiologic action is unknown!!! • Described as an innovative parameter of infection in 1993 • Serum levels are very low (<0.5ng/mL) in healthy individuals • In severe infections can reach up to 1000ng/ML

40. Procalcitonin • Concentration increases to high levels in bacterial infections • Remains low in viral infections and inflammatory disease states • Extremely useful marker in sepsis20 • Correlates positively with the severity of illness • Follows the course of illness and resolves as the patient improves • Differentiates SIRS from Sepsis

41. Procalcitonin: • Rapid induction starting at 3hrs • Peak at 6hrs • Half-life of 25-30hrs • CRP levels showed no increase in levels at the 6hr mark

42. Could this be my dream come true???

43. Show me the evidence…..

44. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections Ped Inf Disease Journal Vol 18(10) 1999 • Prospective observational study • N=360 children • Inclusion Criteria • Age 1mth – 15yrs • Temp >38.5°C • Responsible pathogen was identified • No known chronic disease states • PCT concentration was determined at admission and treating MDs were blinded to the results

45. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections Ped Inf Disease Journal Vol 18(10) 1999 • Patients were retrospectively assigned to 3 groups 1) Invasive bacterial infections (n=46) • 23 culture + meningitis • 23 culture + septicemia 2) Localized bacterial infections (n=78) • Negative blood cultures • Bacterium detected in a specimen 3) Viral infections (n=236) • No bacterial cause identified • Immunofluorescence or culture • Large increase in antibody titer 2 weeks apart

46. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections Ped Inf Disease Journal Vol 18(10) 1999

47. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections Ped Inf Disease Journal Vol 18(10) 1999 • Better than CRP or IL-6 at discriminating between all three groups • Still overlap between the groups

48. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections Ped Inf Disease Journal Vol 18(10) 1999

49. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections Ped Inf Disease Journal Vol 18(10) 1999 • ROC plots for PCT, CRP and IL-6, for discrimination between bacterial (Groups 1 + 2) and viral (Group 3) infections. • PCT area under ROC curve, 0.94; 95% confidence interval, (0.90 to 0.96) • PCT was found to be significantly more discriminating than either CRP or IL-6 (P < 0.0001).

50. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections Ped Inf Disease Journal Vol 18(10) 1999 • Conclusions • PCT cutoff of 1ug/mL was 83% sensitive and 93% specific for differentiating viral from bacterial infections • Very suitable for use in the Peds ED • Better marker than CRP, IL-6, IFN-α for distinguishing viral from bacterial infections in the ED • Useful indicator of the severity of bacterial infection