Laboratory tests - C-reactive protein

What it is

A pentameric acute phase protein of the pentraxin family, synthesised by hepatocytes under IL-6 control
Function: binds phosphocholine exposed on damaged host cell membranes and on certain pathogen surfaces (pneumococcal C-polysaccharide - hence the name)
- -> activates the CLASSICAL complement pathway (via C1q)
- -> opsonisation and phagocytosis by binding Fc-gamma receptors
- -> clearance of apoptotic cells and nuclear debris
*An innate immune opsonin, not merely a marker*

Normal <5 mg/L; median in healthy adults ~1 mg/L
*Rises within 4-6 h, DOUBLES every ~8 h, peaks at 36-50 h*
Half-life ~19 h and constant - so the level depends only on the rate of synthesis; it falls fast once the stimulus stops
Can rise 1,000-fold (to >500 mg/L)
Modestly higher with age, obesity, smoking, diabetes and in women on oestrogen

Tissue injury or infection -> macrophage/adipocyte IL-6 (and IL-1, TNF) -> hepatocyte CRP transcription
*IL-6 is the dominant driver* - which explains the drug interactions that matter:
- *TOCILIZUMAB and sarilumab (IL-6 receptor blockers) SUPPRESS CRP COMPLETELY - a normal CRP in a patient on tocilizumab is meaningless and dangerously falsely reassuring in sepsis*
- JAK inhibitors and high-dose corticosteroids also suppress it
CRP is NOT affected by: anaemia, polycythaemia, immunoglobulin levels, or red cell morphology - unlike ESR
Hepatic failure blunts the response (synthesis is hepatic)

	CRP	ESR
Measures	The protein directly	Red cell sedimentation - a surrogate for fibrinogen and immunoglobulin
Rise	Within 4-6 h	24-48 h
Fall	Rapid (t1/2 ~19 h)	Slow - days to weeks
Affected by anaemia/polycythaemia	No	Yes (anaemia raises it, polycythaemia lowers it)
Affected by paraproteins/immunoglobulins	No	Yes - markedly
Affected by age/sex/pregnancy	Minimally	Yes (rule of thumb: upper limit = age/2 for men, (age+10)/2 for women)
Best for	Acute change, monitoring response	Chronic/indolent disease; myeloma; PMR/GCA

CRP (mg/L)	Typical
<5	Normal
5-40	Mild inflammation, viral infection, most autoimmune flares, malignancy
40-200	Bacterial infection, active inflammatory disease, trauma, surgery
>200	*Serious bacterial infection, abscess, vasculitis, severe tissue injury*

No threshold reliably separates viral from bacterial infection - but a very high CRP makes serious bacterial infection more likely

*SLE flare: CRP is characteristically LOW or normal despite a very high ESR*
- *A HIGH CRP in lupus means INFECTION or SEROSITIS, not lupus activity - the single most useful CRP fact in rheumatology*
- (Type I interferon suppresses hepatic CRP production)
Scleroderma and Sjogren - similarly modest CRP
Polymyalgia rheumatica / giant cell arteritis - both markedly raised, though ~4-20% of GCA has a normal ESR - never exclude GCA on inflammatory markers alone
Ulcerative colitis - CRP rises less than in Crohn disease for equivalent activity
*Normal CRP does NOT exclude: early infection (<6 h), localised/walled-off infection, endocarditis in some cases, osteomyelitis, deep abscess in the immunosuppressed, or any patient on tocilizumab or high-dose steroid*

Cardiovascular risk stratification: <1 low, 1-3 intermediate, >3 high
JUPITER: rosuvastatin benefited patients with LDL <3.4 mmol/L but hs-CRP >2 mg/L
Canakinumab (IL-1beta) reduced cardiovascular events in CANTOS - proof that inflammation is causal in atherosclerosis, not just a marker
Not recommended for routine risk assessment in Australia - it is not in the Australian absolute cardiovascular disease risk calculator

Serial measurements beat single values - the TREND is the information
- A falling CRP on antibiotics supports response; a plateau or rise at 48-72 h suggests the wrong drug, the wrong bug, or an undrained collection
Use it to shorten antibiotic courses - CRP-guided de-escalation reduces antibiotic days without harm
Use it to monitor: RA, vasculitis, IBD, PMR/GCA, osteomyelitis, endocarditis, post-operative sepsis
*Do NOT use it*
- To exclude serious infection in an unwell patient - treat the patient
- In a patient on tocilizumab, sarilumab, a JAK inhibitor or high-dose steroid - it will be normal regardless
- As a screening test in an asymptomatic person - a mildly raised CRP with no symptoms generates cascade investigation with very low yield
- To monitor SLE

Full history and examination, infection screen (cultures, echocardiogram, dental, sinus), CT chest/abdomen/pelvis
Malignancy screen (lymphoma, renal cell carcinoma - classically raise CRP)
Vasculitis and connective tissue screen; consider temporal artery ultrasound/biopsy or PET-CT for large-vessel vasculitis if age >50
Consider an autoinflammatory syndrome in recurrent fevers from childhood (FMF, TRAPS, CAPS) - serum amyloid A, genetic testing; risk of AA amyloidosis
Serum electrophoresis (a raised ESR with a normal CRP points to a paraprotein)

Bacterial infection, abscess, endocarditis, osteomyelitis
Rheumatoid arthritis, vasculitis (GCA, ANCA-associated), PMR, adult-onset Still disease, IBD
Malignancy - lymphoma, renal cell carcinoma, myeloma (CRP is a prognostic marker in myeloma via IL-6)
Tissue injury - trauma, surgery, burns, myocardial infarction, pancreatitis, venous thromboembolism
Obesity, metabolic syndrome, T2DM, smoking - chronic low-grade elevation
Cardiovascular risk - hs-CRP; JUPITER, CANTOS
*Low or normal despite active disease: SLE, scleroderma, Sjogren, ulcerative colitis, hepatic failure, and on IL-6 blockade or high-dose corticosteroid*
AA amyloidosis - the consequence of sustained elevation over years

Rises and falls faster than any other routine inflammatory marker - the reason it is the monitoring test of choice in acute illness
Persistently raised CRP over years -> serum amyloid A is co-induced -> *AA (secondary) amyloidosis* in chronic inflammatory disease
- This is an argument for treating inflammation to target, not just to symptom control
In chronic disease, a CRP that never normalises on treatment predicts structural damage (erosions in RA, strictures in Crohn)
hs-CRP predicts cardiovascular events independently of lipids, and the residual inflammatory risk it identifies is now a therapeutic target (colchicine, canakinumab)

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