C-Reactive Protein

C-reactive protein (CRP) is a pentameric acute phase protein of the pentraxin family, made by hepatocytes under the control of interleukin-6, with a contribution from interleukin-1 and tumour necrosis factor. It binds phosphocholine on microbes and damaged cells and activates complement. Measured by immunoturbidimetry or nephelometry, it is reported in mg/L.

CRP rises within 6 to 8 hours of an inflammatory stimulus, doubles about every 8 hours, and peaks at 36 to 50 hours. The plasma half life is about 19 hours and is constant across conditions, so the level is a direct reflection of the rate of production. This kinetic profile makes it more responsive than the erythrocyte sedimentation rate, which changes over days.

CRP is the most widely used marker of inflammation and infection. A high sensitivity assay (hs-CRP) detects levels down to 0.1 to 0.3 mg/L and is used to assess low grade vascular inflammation.

In hospital practice, CRP is measured in a large share of emergency admissions. A value over 100 mg/L is present in a minority of admissions and is associated with a high rate of bacterial infection.

Indications. Fever, suspected bacterial infection, sepsis, postoperative surveillance, neonatal sepsis, monitoring of rheumatoid arthritis, polymyalgia rheumatica, giant cell arteritis, vasculitis and Crohn disease, assessment of pancreatitis severity, differentiating infection from flare in lupus, cardiovascular risk stratification (hs-CRP), and monitoring of response to antibiotics.

Specimen. Serum or heparin plasma. No fasting is needed. Stable for 3 days at 2 to 8 °C. Haemolysis and lipaemia have little effect.

Reference range. Under 5 mg/L (under 10 mg/L by some methods). Values rise with age, obesity, smoking and in the third trimester.

Magnitude and likely cause.

• Under 10 mg/L: normal, or minor inflammation.
• 10 to 40 mg/L: mild rise from viral infection, obesity, smoking, pregnancy, tissue injury, or autoimmune disease.
• 40 to 100 mg/L: moderate rise from bacterial infection, active inflammatory disease, or major tissue injury.
• Over 100 mg/L: severe bacterial infection, systemic vasculitis, major trauma, or large volume tissue necrosis.
• Over 200 mg/L: sepsis, severe pneumonia, abscess, empyema, pancreatitis with necrosis, or active systemic vasculitis.

Magnitude overlaps between bacterial and viral infection, and the value is an aid, not a discriminator. A value under 20 mg/L in a patient with lower respiratory tract symptoms makes pneumonia unlikely, and a value over 100 mg/L makes it likely.

High sensitivity CRP for vascular risk. In a clinically well patient with no acute illness, sampled twice at least 2 weeks apart: under 1 mg/L low risk, 1 to 3 mg/L moderate risk, over 3 mg/L high risk. A value over 10 mg/L is attributed to acute inflammation, and the test is repeated.

Serial monitoring.

• Falling by half within 48 hours: effective therapy.
• Persistent or rising level after 48 to 72 hours of antibiotics: inadequate cover, undrained collection or alternative diagnosis.
• Postoperative course: CRP peaks on day 2 or 3, then falls. A second rise or a value over 150 mg/L after day 4 suggests anastomotic leak, abscess, wound infection or thromboembolism.
• Neonates: two normal values 24 hours apart, 8 to 24 hours after onset, make bacterial sepsis unlikely.

Causes of raised CRP.

• Infection: bacterial (pneumonia, pyelonephritis, cellulitis, meningitis, abscess, endocarditis, intra-abdominal sepsis), tuberculosis, fungal, some viral (adenovirus, influenza, COVID-19), and malaria.
• Inflammatory and autoimmune: rheumatoid arthritis, polymyalgia rheumatica, giant cell arteritis, vasculitis, adult onset Still disease, Crohn disease, familial Mediterranean fever, gout and pseudogout.
• Tissue injury and necrosis: myocardial infarction, pulmonary embolism, surgery, trauma, burns, pancreatitis.
• Malignancy: lymphoma, renal cell carcinoma, and advanced solid tumours.
• Chronic low grade: obesity, smoking, diabetes, depression, periodontal disease, sleep apnoea.

Causes of disproportionately low CRP. Systemic lupus erythematosus (unless serositis or infection is present), ulcerative colitis, scleroderma, dermatomyositis, severe liver failure, interleukin-6 receptor blockade (tocilizumab and sarilumab suppress CRP for weeks and can mask infection), and early infection in the first 6 hours.

Critical values and findings needing immediate action. Triggers vary by laboratory.

• CRP over 200 mg/L with fever, hypotension, tachycardia or altered consciousness.
• A rising CRP in a neutropenic or immunosuppressed patient.
• CRP over 100 mg/L in a postoperative patient on day 4 or later, or any second rise.
• CRP over 50 mg/L in a neonate with temperature instability or apnoea.
• High CRP in a patient on tocilizumab, since the true inflammatory burden is higher than the value shows.

Interferences and pitfalls.

• A normal value does not exclude infection in the first 6 to 12 hours or in localised or immunosuppressed disease.
• Rheumatoid factor and heterophile antibodies rarely interfere with the assay.
• Very high CRP can show a prozone effect with some assays, with a falsely low result. Dilution corrects this.
• Corticosteroids and interleukin-6 blockers lower CRP, and non-steroidal anti-inflammatory drugs have little effect.
• Liver disease lowers synthesis and values.
• Renal failure does not alter clearance, but chronic inflammation is common.
• hs-CRP is not interpreted during acute illness, and it must not be used as a screening test for coronary disease in the general population.

Special groups.

• Neonates: CRP responds slowly, and serial samples are needed. Pre-term infants and those with early onset sepsis may have a normal first value.
• Children: viral illness can produce values of 20 to 80 mg/L, and values over 100 mg/L raise concern for bacterial infection, Kawasaki disease or multisystem inflammatory syndrome.
• Pregnancy: levels rise modestly in the third trimester and in labour.
• Older adults: atypical infection may give a modest rise, and a value over 30 mg/L has higher significance.
• Obesity: baseline values of 3 to 10 mg/L are common.
• Regions: tuberculosis, typhoid, malaria and brucellosis cause marked rises.

Follow up tests. Full blood count with differential, blood cultures, procalcitonin, lactate, urinalysis and culture, chest radiograph, imaging for collections, erythrocyte sedimentation rate, ferritin, rheumatoid factor, antinuclear antibodies, ANCA, complement, urea and electrolytes, liver function tests, serum amyloid A, and interleukin-6 in selected cases.