C-reactive protein. An ED perspective Greg Stevens May 2010

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1 C-reactive protein An ED perspective Greg Stevens May 2010

2 Basic Biology Is a short Pentraxin Penta 5, ragos berries 224 residue protein Da Gene 1q21-q23 q23

3 History Tillett WS, Francis T Jr. Serological reactions in pneumonia with non-protein somatic fraction of pneumococcus. J Exp Med Reacts with the pneumococcal C-polysaccharide

4 Acute phase proteins Defined as a protein which has a change in plasma concentration of at least 25% during inflammatory disorders CRP may have a 1000 fold increase

5

6 Acute phase proteins Complement system C3, C4, C9, factor B, C1 inhibitor, C4 binding protein, mannose-binding lectin Coagulation and fibrinolytic system Fibrinogen, plasminogen, TPA, urokinase, prot S, vitronectin,, plasminogen-activator activator inhibitor 1 Antiproteases α 1 -protease inhibitor, α 1 -antichymotrypsin, pancreatic secretory trypsin inhibitor, inter-α-trypsin trypsin inhibitor

7 Acute phase proteins Transport proteins ceruloplasmin, haptoglobin, hemopexin Participants in inflammatory response secreted phospholipase A2, lipopolysaccharide- binding protein, interleukin-1-receptor receptor antagonist, granulocyte colony-stimulating factor Others CRP, serum amyloid A, α1-acid glycoprotein, fibrinonectin,, ferritin, angiotensinogen

8 Negative Acute phase proteins albumin transferrin transthyretin α2-hs-glycoprotein α-fetoprotein thyroxine-binding globulin insulin-like like growth factor I factor XII

9 Other acute-phase phenomena Neuro-endocrine endocrine Fever, somnolence, anorexia Increased corticotropin-releasing releasing hormone, corticotropin, cortisol Increased vasopressin Decreased insulin-like like growth factor I Increased catecholamines Haematopoietic Anaemia of chronic disease Leucocytosis Thrombocytosis

10 Other acute-phase phenomena Metabolic Loss of muscle and negative nitrogen balance Decreased gluconeogenesis Osteoporosis Increased hepatic lipogenesis Increased lipolysis in adipose tissue Decreased lipoprotein lipase activity Cahexia Hepatic changes Changes in some non-protein plasma componenets

11 More biology stimulated imulated by Interleukin-6 binds to phosphocholine,, phospholipids in damaged cell walls, and also phagocytic cells induces inflammatory cytokines and tissue factor in monocytes also antiinflammatory effects prevents adhesion of neutrophils to endothelial cells, stimulates Il-1-receptor antagonist

12 What elevates acute phase proteins Substantial Moderate Small infection trauma surgery burns tissue infarction inflammatory conditions advanced cancer strenuous exercise heat stroke child birth psychological stress some psychiatric conditions

13 Statistical terms

14 Statistical terms Positive Likelihood Ratio Sensitivity / (1-Specifity) Negative Likelihood Ratio (1-Sensitivity) / Specificity Good test has LR+ > 10 and LR- < 0.1

15 Biomarkers for sepsis should shorten the time to and improve the diagnosis should facilitate the differentiation between infectious and non infectious causes should differentiate between viral and bacterial causes should reflect the effectiveness of treatment

16 Bacterial vs other pathology Simon et al 2004 Meta-analysis analysis of studies comparing Pro- calcitonin with CRP Hospitalised patients 12 studies 46 neonates, 638 children, and 702 adults 50% in ICU

17 Bacterial vs other pathology Sensitivity = 75% (95% CI, 62% 84%) Specificity = 67% (95% CI, 56% 77%) positive LR = 2.43 (95% CI, ) 2.92) negative LR = 0.42 (95% CI, ) 0.49) variation in CRP techniques and levels PCT actually performed better

18 Community acquired pneumonia Chalmers JD, Singanayagam A, Hill AT year prospective study 570 patients outcome 30 day mortality, need for ventilation / inotropes,, complications measured admission + day 4 CRP compared with 2 clinical scores CURB65 and Pneumonia severity index

19 Admission CRP and adverse outcomes CRP mg/l n 30 day mortality % ICU % Complication % < < <

20 Prediction of 30 day mortality PPV NPV Sensitivity Specificity CRP 100 mg/l CURB Pneumonia severity index Failure of CRP to fall by > 50% on day 4 associated with worse outcomes CURB65 = new onset confusion, urea > 7 mmol/l, RR 30/min, SBP < 90 mmhg or DBP 60 mmhg, age 65 yrs

21 BTS guideline All patients should have the following tests performed on admission: Oxygenation saturations and, where necessary, arterial blood gases in accordance with the BTS Guideline for Emergency Oxygen Use in Adult Patients [B+]. Chest radiograph to allow accurate diagnosis [B+]. Urea and electrolytes to inform severity assessment [B+]. C-reactive protein to aid diagnosis and as a baseline measure [B+]. Full blood count [B-]. Liver function tests [D].

22 BTS pneumonia managed in community General investigations are not necessary for the majority of patients with CAP who are managed in the community [C]. Pulse oximeters allow for simple assessment of oxygenation. General practitioners, particularly those working in out of hours and emergency assessment centres, should consider their use [D]. Pulse oximetry should be available in all locations where emergency oxygen is used [D].

23 Acute Abdominal Pain Chi et al patients with acute abdominal pain Assessment included CRP and WBC Outcome = admission vs discharge

24 Acute abdominal pain Sensitivity % Specificity % PPV % NPV % CRP > 50 mg/l WBC > CRP and WBC CRP or WBC Much higher amylase and bilirubin in admission group

25 Acute Appendicitis Hallan S and Asberg A 1997 Meta-analysis analysis of 22 studies, 3436 patients Sensitivity % 0.99% Specificity % 0.90% Some variation in cut off values

26 Acute Appendicitis Asfar S et al patients undergoing laparotomy 15 negative by histology 13 of these had normal (< 20 mg/l) CRP 2/15 had another significant cause warranting OT Sensitivity 93.6% Specificity 86.6%

27 Paediatric Hip Pain Levine et al 2003 Review of children with aspiration results CRP in first 24 hours CRP < 10 mg/l as cut off 133 children 39 had septic arthritis

28 Paediatric Hip Pain Sensitivity = 41-90% Specificity = 29-85% PPV = 34-53% NPV = 78-87% 87% i.e. with ve CRP, 13-22% still have septic arthritis!

29 Cardiovascular disease Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin JUPITER hs-crp (laser nephelometry sens to 0.04 mg/l) group normal cholesterol + hs-crp > 2 mg/l about 50% reduction in cardiovascular endpoints over average 1.9 years

30 Cardiovascular disease HOWEVER: prinicple investigator designed the test $$$$$ AstraZeneca share prices went up after NEJM article Subsequent studies have as yet not validated these findings

31 Why talk about CRP in ED I wanted to come here and show that use of CRP does not add value and if we stopped using it we could save up to $70000 per year at TDHB. I believe that a test should only be done if the result will lead to an alteration in patient care. The use or otherwise of CRP does cause an emotional response in some clinicians.

32 How did I do?

33 There are conditions where measurement of CRP adds value. Not sure this is always additional value to clinical assessment.

34 It is not specific and as such has minimal value without considered clinical correlation. Timing is probably important. Can mislead.

35 Should NOT be done on every patient presenting to ED. We do not currently have a better measure of acute inflammation.

36 Right patient Right condition Right time Only when it will change management

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