Raised ESR and CRP

A raised erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) is a laboratory marker of the acute phase response, indicating inflammation, infection, tissue injury or malignancy, but it is non-specific. Its value is in directing the search for a cause, estimating severity, and following the response to treatment, and it should be interpreted with the clinical picture.

Clinical relevance. A raised marker is a very common finding in primary and secondary care. Most results are explained by infection or known inflammatory disease, but a markedly raised ESR (over 100 mm/hour) is associated with a serious cause (infection, malignancy, vasculitis or myeloma) in most patients.

Physiology. CRP is a pentraxin produced by the liver within 6 to 8 hours of stimulation by interleukin 6, rising 10 to 1000 fold, peaking at 36 to 50 hours, and falling with a half life of about 19 hours. ESR measures the rate at which red cells sediment in a column of blood (Westergren method, mm in the first hour) and depends on fibrinogen, immunoglobulins and other acute phase proteins that reduce red cell repulsion. ESR rises over 24 to 48 hours and falls slowly over days to weeks.

Classification by level.

• CRP (assay dependent): normal under 5 to 10 mg/L; mild rise 10 to 50 mg/L (viral infection, minor inflammation, obesity, smoking); moderate 50 to 100 mg/L; high over 100 mg/L (bacterial infection, severe inflammation, major tissue injury); over 200 mg/L suggests severe bacterial infection, systemic vasculitis or major trauma.
• ESR: age adjusted upper limit of about age divided by 2 in men, and (age plus 10) divided by 2 in women; mild rise up to 50 mm/hour; marked rise 50 to 100; extreme rise over 100 mm/hour.

Classification by pattern.

• Both raised: infection, active inflammatory disease, malignancy, tissue injury.
• ESR raised with normal CRP: anaemia, pregnancy, older age, renal disease, hypergammaglobulinaemia, myeloma and macroglobulinaemia, systemic lupus erythematosus (CRP often modest), hypothyroidism, obesity, and technical causes.
• CRP raised with normal ESR: early infection (CRP rises first), polycythaemia, sickle cell disease, spherocytosis, hypofibrinogenaemia, severe leucocytosis, and some drugs.

Key distinctions. CRP reflects current inflammation and changes within hours, so it is preferred for acute illness and monitoring antibiotic response. ESR changes slowly and is influenced by red cell and protein factors, and its main uses are in polymyalgia rheumatica, giant cell arteritis, and screening in myeloma.

History.

• Fever, rigors, night sweats, weight loss, malaise, fatigue, anorexia, and duration.
• Localising symptoms: cough, sputum, dyspnoea, chest pain, abdominal pain, change in bowel habit, dysuria, headache, jaw claudication, scalp tenderness, visual symptoms, neck and shoulder girdle stiffness, back pain, bone pain, joint swelling, morning stiffness (over 45 minutes), rash, oral ulcers, red eyes and Raynaud phenomenon.
• Exposures: recent infection, surgery, trauma, dental work, intravenous drug use, travel, tuberculosis contacts, animals, unpasteurised dairy, sexual history, and occupational exposures.
• Drugs (recent vaccination, hormonal therapy, corticosteroids, antibiotics) and history of cancer, autoimmune disease, kidney disease, thyroid disease, and inflammatory bowel disease.
• Family history of autoinflammatory disease or autoimmune disease.

Examination.

• Vital signs including temperature, weight and body mass index. General appearance, pallor, clubbing, lymph nodes, skin (rash, purpura, nodules, ulcers), mouth, eyes, joints (swelling, effusion, range of movement), muscles, temporal arteries (tenderness, thickening, reduced pulse), and thyroid.
• Chest, cardiovascular (new murmur, splinter haemorrhages, Osler nodes), abdomen (masses, organomegaly, tenderness), spine (percussion tenderness), prostate and breast where indicated, and neurological examination.
• Stool, urine dipstick, and fundoscopy.

Red flags.

• Jaw claudication, new headache, scalp tenderness, visual loss or double vision in a patient over 50 years (giant cell arteritis).
• Fever with back pain, spinal tenderness or neurological symptoms (spinal infection), or a new murmur (endocarditis).
• Unexplained weight loss, drenching night sweats, lymphadenopathy, hepatosplenomegaly, or a mass (lymphoma or solid cancer).
• Bone pain with anaemia, hypercalcaemia or kidney impairment (myeloma).
• ESR over 100 mm/hour or CRP over 100 mg/L without an obvious cause.
• Fever in a patient who is immunosuppressed, neutropenic, has a prosthetic valve or joint, or is injecting drugs.
• Shock, hypotension, confusion, or other signs of sepsis.
• Haemoptysis, chronic cough, or tuberculosis exposure.
• Rapidly progressive kidney failure, haematuria or purpura (vasculitis).

Special groups. Older adults have a higher baseline ESR and may not mount fever. Children need paediatric thresholds, and a raised ESR with fever for 5 days or more raises the possibility of Kawasaki disease. Pregnancy raises ESR (up to 70 mm/hour) and mildly raises CRP. Patients on tocilizumab or high dose corticosteroids can have falsely normal CRP.

Infection.

• Bacterial: pneumonia, urinary tract infection, pyelonephritis, cellulitis, abscess, endocarditis, osteomyelitis, septic arthritis, spinal infection, intra-abdominal infection (appendicitis, diverticulitis, cholecystitis), meningitis, sepsis, tuberculosis, brucellosis, Q fever.
• Viral: influenza, Epstein-Barr virus, cytomegalovirus, hepatitis, HIV, parvovirus.
• Fungal and parasitic infections.

Inflammatory and autoimmune.

• Vasculitis: polymyalgia rheumatica, giant cell arteritis, Takayasu arteritis, ANCA associated vasculitis, polyarteritis nodosa, Kawasaki disease, Behcet disease.
• Arthritis and connective tissue disease: rheumatoid arthritis, systemic lupus erythematosus, spondyloarthritis, psoriatic arthritis, adult onset Still disease, juvenile idiopathic arthritis, systemic sclerosis, myositis.
• Other: sarcoidosis, inflammatory bowel disease, gout and pseudogout, familial Mediterranean fever, and other autoinflammatory disease.

Malignancy. Multiple myeloma, Waldenstrom macroglobulinaemia, lymphoma, leukaemia, renal cell carcinoma, hepatocellular carcinoma, lung, colon, breast and pancreatic cancer, and metastatic disease. Tissue injury and thrombosis. Myocardial infarction, pulmonary embolism, deep vein thrombosis, pancreatitis, burns, trauma, fracture, surgery, and rhabdomyolysis.

Other causes. Chronic kidney disease and nephrotic syndrome, anaemia, pregnancy, age and female sex, obesity, diabetes, smoking, hypothyroidism, subacute thyroiditis, hypergammaglobulinaemia, dialysis, drugs (oral contraceptives, hormone therapy), periodontal disease, and technical or laboratory error.

Step 1. Confirm the result and decide whether the pattern is explained. Repeat the test in 1 to 4 weeks if the patient is well and the rise is mild. Check CRP with ESR when evaluating suspected inflammatory disease.

Step 2. First line tests: full blood count with differential and blood film (rouleaux, left shift, atypical cells, anaemia), urea, creatinine, electrolytes, calcium, albumin, globulin, liver tests, glucose, urinalysis with microscopy, urine protein to creatinine ratio, lactate dehydrogenase, thyroid function, ferritin, and creatine kinase.

Step 3. Directed tests.

• Suspected infection: blood cultures before antibiotics, urine and sputum culture, chest radiograph, HIV, hepatitis B and C, interferon gamma release assay or tuberculin test, echocardiography for endocarditis, and procalcitonin (a level under 0.25 micrograms/L makes bacterial infection less likely, and over 0.5 micrograms/L suggests it).
• Suspected inflammatory disease: antinuclear antibody, rheumatoid factor, anti-cyclic citrullinated peptide, ANCA, complement, immunoglobulins, anti-double stranded DNA, and angiotensin converting enzyme where sarcoid is suspected.
• Suspected myeloma: serum protein electrophoresis, serum free light chains, immunoglobulins, urine Bence Jones protein, and a skeletal survey or low dose whole body CT.
• Suspected giant cell arteritis: temporal artery ultrasound (halo sign) or biopsy, ideally within 2 weeks of starting corticosteroids.
• Suspected malignancy: CT of the chest, abdomen and pelvis, mammography, endoscopy, prostate specific antigen as appropriate, lymph node biopsy, and bone marrow examination.
• Persistent unexplained raised markers with fever or weight loss: PET CT and referral.

Interpretation. CRP over 100 mg/L usually indicates bacterial infection, vasculitis or major tissue injury.

ESR over 100 mm/hour has a serious cause in most patients (infection, malignancy, myeloma, giant cell arteritis). A normal ESR and CRP together make active inflammation unlikely but do not exclude it (giant cell arteritis can have a normal ESR in up to 10% of patients). A raised ESR with normal CRP suggests anaemia, myeloma or lupus.

Limitations. Both markers are non-specific and influenced by age, sex, pregnancy, obesity, anaemia, kidney disease, drugs and technical factors. CRP can be low in lupus, ulcerative colitis, and in patients treated with interleukin 6 inhibitors. ESR is falsely low in polycythaemia, sickle cell disease, heart failure and hypofibrinogenaemia, and is falsely high in anaemia and with delayed processing.

General principles. There is no treatment for the marker. Treat the cause, avoid empirical corticosteroids or antibiotics before samples are taken unless the patient is acutely unwell, and decide on urgency from the clinical picture.

Suspected sepsis. Take blood cultures and give antibiotics within 1 hour: ceftriaxone 2 g IV once every 24 hours (maximum 4 g daily; monitor for rash, diarrhoea and biliary sludge; no routine renal adjustment), widened to cover resistant organisms by the likely source and local resistance patterns.

Add fluids (isotonic crystalloid 30 mL/kg for hypotension or lactate of 4 mmol/L or more) and source control.

Suspected giant cell arteritis. Start corticosteroids immediately without waiting for biopsy.

• Prednisolone 40 to 60 mg orally once daily in the morning (1 mg/kg, maximum 60 mg) for 2 to 4 weeks, then reduce slowly over 12 to 18 months, adjusted to symptoms and CRP.
• Add a proton pump inhibitor (omeprazole 20 mg once daily), calcium and vitamin D, and bone protection.

With visual symptoms, use methylprednisolone 500 mg to 1 g IV once daily for 3 days then oral prednisolone 60 mg, with urgent ophthalmology review. Monitor blood pressure, glucose, mood, bone density and infection. Aspirin 75 mg once daily is considered in the absence of bleeding risk when ischaemic events are a concern.

Refer urgently to rheumatology, and consider tocilizumab 162 mg subcutaneously once weekly as a steroid sparing agent under specialist care.

Suspected polymyalgia rheumatica. After excluding other causes:

• prednisolone 15 mg orally once daily for 3 weeks, then 12.5 mg for 3 weeks, then 10 mg for 4 to 6 weeks, then reduce by 1 mg every 4 to 8 weeks
• monitor symptoms and CRP, glucose, blood pressure and bone health
• give calcium with vitamin D

Refer when response is incomplete, relapses occur, or atypical features are present.

Suspected spinal or deep infection or endocarditis.

In a stable patient take at least 3 sets of blood cultures before antibiotics, obtain MRI or echocardiography, and give antibiotics after cultures; in an unstable patient give empirical antibiotics immediately (ceftriaxone 2 g IV every 24 hours plus flucloxacillin 2 g IV every 6 hours, maximum 12 g daily; or vancomycin 25 mg/kg IV loading dose, maximum 3 g, then dosing by levels where MRSA is likely).

Suspected myeloma with hypercalcaemia or kidney injury. Isotonic saline 3 to 4 L daily to produce urine output over 100 mL/hour, avoid nephrotoxic drugs, and give zoledronic acid 4 mg IV over 15 minutes for hypercalcaemia (reduce for creatinine clearance under 60 mL/min; check dentition and calcium; monitor creatinine). Urgent haematology referral and dexamethasone 40 mg orally once daily for 4 days under specialist direction.

Persistent mild rise in a well patient. Reassure after a clinical review and limited tests, repeat in 4 to 6 weeks, and investigate further for progression or new symptoms. Treat obesity, smoking and periodontal disease, and review drugs.

Monitoring. In inpatients, CRP every 24 to 48 hours with the clinical response (a falling CRP by over 50% in 48 to 72 hours suggests response to antibiotics, and a persistent rise suggests undrained collection or wrong antibiotic). ESR and CRP every 4 to 8 weeks in polymyalgia rheumatica and giant cell arteritis alongside symptoms, and with every dose reduction. Do not treat the number alone.

Referral and escalation. Rheumatology for suspected vasculitis, giant cell arteritis, polymyalgia rheumatica or connective tissue disease. Haematology for suspected myeloma or lymphoma. Infectious diseases for fever of unknown origin, endocarditis, tuberculosis or bone infection. Oncology for malignancy. Urgent specialist input for ESR over 100 mm/hour without a cause.

Admission criteria. Sepsis or haemodynamic instability, suspected giant cell arteritis with visual symptoms, suspected spinal or endovascular infection, neutropenic or immunosuppressed fever, suspected myeloma with hypercalcaemia or kidney injury, severe pain, and any patient who needs urgent investigation that cannot be arranged as an outpatient.

Discharge and safety netting. Discharge when the cause is identified and treatment is started, or the patient is well, with a plan to repeat tests in 1 to 4 weeks. Patients return for fever, weight loss, night sweats, jaw pain, visual change, new headache, bone pain, breathlessness, or worsening symptoms.