Unexplained biological inflammation (persistently raised CRP without a clue)
BioMG follows French guidelines. Adapt it to the guidelines and the tests available where you practise.
First-line tests (adult)
Laboratory tests
- FBC with blood film
- CRP (repeat)
- Serum electrolytes
- Serum creatinine
- Serum calcium
- AST
- ALT
- GGT
- Alkaline phosphatase
- Bilirubin
- Serum ferritin
- TSH
- Rheumatoid factor
- Antinuclear antibodies (ANA)
- HIV serology
- Urine microscopy and culture
- Serum protein electrophoresis (age 60 or over with bone pain, fracture, anaemia, hypercalcaemia or renal failure)if needednon-French guidelinePatient aged 60 or over with persistent bone pain (especially lumbar) or unexplained fracture: NICE recommends FBC, serum calcium and protein electrophoresis to look for myeloma [2]. Lymphomas and myeloma are among the haematological causes of prolonged fever [3].
- ANCA (if ENT, pulmonary, renal or skin involvement suggestive of vasculitis)if needednon-French guidelineSigns suggestive of vasculitis (ENT, pulmonary, renal or skin): ANCA are part of the minimal set of tests for prolonged fever in adults [3].
- Blood cultures, at least 3 sets taken at intervals (if fever)if needednon-French guidelineFever (≥ 38.3 °C on several occasions) or heart murmur: at least 3 spaced sets of blood cultures are part of the minimal work-up for prolonged fever [3]. Without fever or other sign of systemic inflammatory response, they are not indicated [4].
- Tuberculin skin test (exposure, origin from a high-endemicity country, sweats, cough, weight loss)if neededContact, stay in or origin from a high-endemicity area, general or respiratory signs: the tuberculin skin test or IGRA is part of the minimal work-up for prolonged fever [3]. IGRA is reimbursed in community laboratories in France only for limited indications (including as an aid to the diagnosis of extrapulmonary tuberculosis in a multidisciplinary setting) [5].
Imaging
- Chest X-ray (PA and lateral)
- Abdominal ultrasound (or CT of chest, abdomen and pelvis): imaging, not a laboratory test.
Also consider
Do not order
- ESR: there is no erythrocyte sedimentation rate test in the NABM (version 105) [5]; at diagnosis of giant cell arteritis, CRP alone is enough, and fibrinogen is preferred to ESR, which varies with anaemia and gammopathies [6].
- Non-targeted tests outside the minimal set (for example tumour markers or multiple serologies “just to see”): outside the minimal protocol, other tests should not be used as screening tests [7]; request them according to clinical leads.
Child: prolonged fever (5 days or more) without a focus
- Fever for 5 days or more: look for signs of Kawasaki disease (bilateral non-purulent conjunctivitis, red cracked lips, strawberry tongue, swelling or redness of the hands and feet, rash, cervical lymphadenopathy); if suspected, same-day paediatric hospital opinion.
Laboratory tests
- FBC
- CRP
- Urine dipstick
- Urine microscopy and culture (if dipstick positive: leucocytes or nitrites)if needednon-French guidelinePositive urine dipstick: urinary tract infection is a frequent cause of prolonged fever in children [10]; urine tests are part of the work-up for fever without a source [11].
- Blood cultures (on the paediatrician's advice)if needednon-French guidelineWork-up conducted with a paediatrician: NICE places FBC, CRP, blood cultures and urine tests in the work-up of fever without a source with an “amber” sign, which includes fever of 5 days or more [11].
Also consider
- Sign of severity in a child? "Red" signs call for an urgent paediatric opinion: see the page "Fièvre aiguë de l'enfant et du nourrisson".
Do not order
- Battery of serologies and autoantibodies without direction: the causes are so varied that tests should first be guided by the clinical history [10].
Sources (12)
- Betrains A, Moreel L, Mulders-Manders CM, et al. Comparison of diagnostic spectrum between inflammation of unknown origin and fever of unknown origin: A systematic review and meta-analysis. Eur J Intern Med. 2024;124:115-121.
- National Institute for Health and Care Excellence. Suspected cancer: recognition and referral (NG12). Mise à jour du 15 avril 2026 : recommandation 1.10.4 (myélome).
- Wright WF, Betrains A, Schoenau V, et al. State-of-the-Art Review: Contemporary Ambulatory Approach to Adult Fever of Unknown Origin. Clin Infect Dis. 2026;82(6):909-926.
- Riley LK, Rupert J. Evaluation of Patients with Leukocytosis. Am Fam Physician. 2015;92(11):1004-1011.
- Assurance maladie. Nomenclature des actes de biologie médicale (NABM), version 105 : absence d'acte « vitesse de sédimentation » ; acte 4103 (IGRA).
- Groupe d'étude français des artérites des gros vaisseaux (GEFA), filière FAI²R. Protocole national de diagnostic et de soins (PNDS) : artérite à cellules géantes (Horton). Haute Autorité de santé, janvier 2024.
- Bleeker-Rovers CP, Vos FJ, de Kleijn EMHA, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007;86(1):26-38.
- Wright WF, Stelmash L, Betrains A, et al. Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel. Open Forum Infect Dis. 2024;11(7):ofae298.
- David A, Quinlan JD. Fever of Unknown Origin in Adults. Am Fam Physician. 2022;105(2):137-143.
- Chow A, Robinson JL. Fever of unknown origin in children: a systematic review. World J Pediatr. 2011;7(1):5-10.
- National Institute for Health and Care Excellence. Fever in under 5s: assessment and initial management (NG143). Publiée le 7 novembre 2019, mise à jour le 26 novembre 2021 ; recommandations 1.2.14, 1.2.25, 1.4.4, 1.5.10 et tableau 1 (feu tricolore).
- McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927-e999.