Prolonged and recurrent fever

Prolonged fever is fever of 14 days or more in an adult where the evaluation is still at an early stage (fewer than 3 outpatient visits, fewer than 3 days of hospital assessment, or under 1 week of structured ambulatory work up). Recurrent fever is fever that returns in discrete episodes separated by fever free intervals. Once structured evaluation fails to give a diagnosis, the label changes to fever of unknown origin.

Clinical relevance. Most prolonged fevers have a common cause that was missed or presented atypically, such as tuberculosis, endocarditis, abscess, brucellosis, enteric fever, drug fever, lymphoma, giant cell arteritis or adult onset Still disease. Every patient needs a documented fever chart, because patient reported fever and non fever causes of sweating or malaise are common.

Fever patterns.

• Continuous or remittent: fever throughout the day with little or only partial daily fall.
• Intermittent or hectic: a return to normal each day, with wide swings.
• Quotidian (daily), tertian (every 48 hours) and quartan (every 72 hours): the interval between spikes.
• Relapsing: days of fever alternating with fever free days.
• Undulant: weeks of fever followed by weeks of remission.
• Biphasic: a fever, a break, then a second fever.
• Periodic: episodes at regular intervals with complete health between.

Recurrent versus periodic fever. Recurrent fever has irregular episodes, most often from relapsing infection, repeated exposure or a focus that intermittently seeds. Periodic fever recurs at regular or semi regular intervals, with stereotyped features, and points to an autoinflammatory syndrome or cyclic neutropenia.

Mechanism. Infection, inflammatory cytokine release, tumour necrosis, tissue destruction, drug hypersensitivity, and inflammasome activation in autoinflammatory disease all raise the hypothalamic set point through interleukin 1 and 6.

History.

• Fever record: dates, duration, maximum temperature by thermometer, pattern, relation to time of day, antipyretic response, episodes and gaps, tests and treatments already given.
• Systemic symptoms: weight loss, night sweats, anorexia, fatigue, rash, joint pain, muscle pain, headache, jaw claudication, visual disturbance, eye pain, oral ulcers, dental pain, sinus symptoms, cough, haemoptysis, abdominal pain, diarrhoea, urinary symptoms, back pain, bone pain, lumps.
• Exposure: travel and residence (malaria, leishmaniasis, schistosomiasis, tuberculosis, endemic fungi), animals, unpasteurised dairy, ticks and lice, cat scratches, rodents, sexual and injecting risk, household tuberculosis, occupation.
• Drugs: every prescribed, over the counter and herbal agent, with start dates (drug fever typically starts after 7 to 10 days of exposure, with eosinophilia or rash in a minority).
• Past history: cancer, immunosuppression, surgery, prostheses, valve disease, previous tuberculosis, inflammatory bowel disease.
• Family history of recurrent fever, amyloidosis, ancestry.
• Previous antibiotic or steroid use, which can mask or partly treat disease.

Examination (repeated daily).

• Temperature chart: record every 4 hours with one method in hospital, with the clinician observing the measurement when factitious fever is a question.
• Skin: rash, nodules, petechiae, splinter haemorrhages, Osler nodes, Janeway lesions, eschar, erythema nodosum, livedo, heliotrope rash.
• Head and neck: temporal artery tenderness or absent pulse, scalp tenderness, fundi (Roth spots, choroidal tubercles, uveitis), conjunctivae, mouth ulcers, dental abscess, sinus tenderness, thyroid tenderness, lymph nodes.
• Heart: new or changing murmur. Chest. Abdomen: hepatomegaly, splenomegaly, mass, renal angle tenderness. Rectal examination and prostate, perianal abscess. Genitalia and testes.
• Joints, bone tenderness, spine percussion, sacroiliac joints, calves, muscles.
• Neurology: meningism, focal signs, neuropathy.

Red flags.

• Haemodynamic instability, neutropenia, new murmur, meningism, new neurological deficit.
• Headache with jaw claudication, scalp tenderness or visual symptoms (giant cell arteritis).
• Progressive weight loss, lymphadenopathy, hepatosplenomegaly, pancytopenia, very high ferritin or LDH.
• HIV, immunosuppression, exposure to tuberculosis, travel to endemic regions.
• Injecting drug use, prosthetic valve or joint, indwelling device.
• Persistent back pain with fever, sacral or vertebral tenderness.

Infective: localised. Infective endocarditis (including culture negative endocarditis: Coxiella, Bartonella, Brucella, HACEK organisms, Tropheryma), intra-abdominal, pelvic, hepatic or subphrenic abscess, cholangitis, liver abscess, osteomyelitis and discitis, prostatitis and prostatic abscess, dental abscess, sinusitis, mastoiditis, empyema, infected prosthetic material and vascular grafts, septic thrombophlebitis, perinephric abscess.

Infective: systemic.

• Mycobacterial: tuberculosis (pulmonary, miliary, abdominal, extrapulmonary), nontuberculous mycobacteria.
• Bacterial: brucellosis, typhoid and paratyphoid fever, Q fever, Bartonella (cat scratch disease), leptospirosis, melioidosis, syphilis, Lyme disease, rickettsiae, relapsing fever, Whipple disease, rat bite fever.
• Viral: HIV, Epstein-Barr virus, cytomegalovirus, hepatitis B and C.
• Parasitic: malaria, visceral leishmaniasis, African trypanosomiasis, toxoplasmosis, amoebiasis, schistosomiasis.
• Fungal: histoplasmosis, cryptococcosis, coccidioidomycosis, talaromycosis (HIV).

Neoplastic. Hodgkin and non Hodgkin lymphoma (including angioimmunoblastic T cell lymphoma), leukaemia, myelodysplasia, renal cell carcinoma, hepatocellular carcinoma and hepatic metastases, colon and pancreatic cancer, atrial myxoma, central nervous system tumours, Castleman disease, haemophagocytic lymphohistiocytosis.

Noninfectious inflammatory. Adult onset Still disease, systemic lupus erythematosus, giant cell arteritis and Takayasu arteritis, polyarteritis nodosa, ANCA associated vasculitis, polymyalgia rheumatica, rheumatoid arthritis, sarcoidosis, inflammatory bowel disease, Behcet disease, gout and pseudogout, IgG4 related disease, Kikuchi disease, antiphospholipid syndrome, autoimmune hepatitis, subacute thyroiditis, relapsing polychondritis, cryoglobulinaemia, reactive arthritis.

Autoinflammatory and periodic fevers.

• Familial Mediterranean fever: episodes lasting 1 to 3 days with serositis (peritonitis, pleuritis), arthritis and an erysipelas like rash; people of Eastern Mediterranean ancestry (Turkish, Armenian, Arab, Sephardic Jewish).
• TNF receptor associated periodic syndrome: episodes lasting over a week with migratory myalgia, rash, periorbital oedema and conjunctivitis.
• Mevalonate kinase deficiency (hyper IgD syndrome): childhood onset, abdominal pain, diarrhoea, lymphadenopathy and oral ulcers.
• Cryopyrin associated periodic syndromes: urticarial rash, sensorineural hearing loss and arthralgia.
• PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis): children, 3 to 6 days every 3 to 6 weeks.
• Others: Behcet disease, Schnitzler syndrome (urticarial rash with monoclonal IgM), cyclic neutropenia (21 day cycles).

Relapsing and undulating infections. Borrelia relapsing fever, Plasmodium vivax and ovale relapse, brucellosis, rat bite fever, chronic meningococcaemia, recurrent cholangitis, recurrent urinary tract infection or prostatitis, recurrent abscess, Hodgkin lymphoma (Pel-Ebstein fever).

Miscellaneous. Drug fever, deep vein thrombosis and recurrent pulmonary emboli, haematoma, factitious fever, thyrotoxicosis, adrenal insufficiency, phaeochromocytoma, central (hypothalamic) fever, granulomatous hepatitis, alcoholic hepatitis, haemolytic anaemia, fat embolism, Crohn disease, hereditary conditions.

1. Verify the fever with a supervised temperature chart. Repeat the history and examination completely. Many diagnoses are found by this step.
2. Review every drug. If clinically safe, stop non essential drugs (fever from drug hypersensitivity resolves within 72 to 96 hours of stopping the culprit).
3. First tier tests: full blood count with film (blasts, atypical lymphocytes, parasites, left shift, eosinophilia, cytopenia), ESR, C reactive protein, ferritin (over 1,000 microgram/L suggests Still disease or haemophagocytic lymphohistiocytosis; over 10,000 microgram/L is strongly suggestive of haemophagocytic lymphohistiocytosis), lactate dehydrogenase, urea, creatinine, electrolytes, liver function tests with alkaline phosphatase and gamma glutamyl transferase, creatine kinase, urinalysis and urine culture, at least 3 sets of blood cultures before any antibiotic (prolonged incubation is no longer routinely needed with modern systems), HIV test, hepatitis B and C serology, malaria films and rapid test when exposure exists, chest radiograph, antinuclear antibody, rheumatoid factor, complement, serum protein electrophoresis.
4. Infection directed: tuberculosis (interferon gamma release assay or tuberculin skin test, with induration of 10 mm or more positive, 5 mm or more in HIV or immunosuppression; sputum or other specimen for Xpert MTB/RIF Ultra and culture; urine lipoarabinomannan antigen in advanced HIV with CD4 under 200 cells/microlitre), brucella serology and culture, Bartonella and Coxiella serology, Epstein-Barr and cytomegalovirus testing, syphilis serology, leptospira testing, rickettsial serology, typhoid cultures, Borrelia thick and thin films during fever, and Leishmania serology or rK39 rapid test when relevant.
5. Imaging: CT of chest, abdomen and pelvis with contrast when no focus is found; abdominal ultrasound; echocardiography (transoesophageal if transthoracic is negative and endocarditis remains likely); dental panoramic radiograph; sinus CT; MRI spine for back pain. Fluorodeoxyglucose positron emission tomography with CT is helpful when the first tier is non diagnostic and contributes in about half; it is particularly useful for large vessel vasculitis, occult infection and lymphoma.
6. Tissue: temporal artery ultrasound or biopsy when giant cell arteritis is suspected (biopsy within 2 weeks of starting steroid); bone marrow aspirate and trephine with culture and microscopy for cytopenia or suspected tuberculosis, leishmaniasis, haemophagocytosis or lymphoma; excisional lymph node biopsy for lymphadenopathy; liver biopsy for granulomatous hepatitis; skin or muscle biopsy when there is a rash or myositis.
7. Recurrent fever: chart each episode, take blood during an attack (C reactive protein, serum amyloid A, ferritin, blood count) and between attacks (normalisation supports periodic fever). Genetic testing for MEFV, MVK, TNFRSF1A and NLRP3 when features fit; urinary mevalonic acid in an attack; absolute neutrophil count twice weekly for 6 weeks for cyclic neutropenia; blood film during febrile paroxysms for Borrelia; malaria films serially.

Limits. Blood cultures are negative in culture negative endocarditis and after antibiotics. Interferon gamma release assays and skin tests miss active tuberculosis in HIV and advanced disease. Normal ESR makes giant cell arteritis unlikely but does not exclude it. Genetic tests can be normal in true autoinflammatory disease. Imaging should be targeted to avoid incidental findings.

Principle. Stable patients are best observed and investigated without empirical antibiotics or corticosteroids, because both mask or delay diagnosis. Treat immediately only when the patient is septic, neutropenic, has suspected endocarditis, meningitis or a time critical diagnosis, or has threatened vision (giant cell arteritis).

Symptom control. Paracetamol 1 g orally every 6 hours (maximum 4 g daily; 3 g in frail patients or under 50 kg). Ibuprofen 400 mg every 8 hours with food (maximum 2.4 g daily), avoided in kidney disease and peptic ulcer. Fluids and nutrition.

Cause directed treatment.

• Giant cell arteritis: prednisolone 40 to 60 mg orally daily started at once without waiting for biopsy; for visual symptoms or neurological events, methylprednisolone 500 mg to 1 g intravenously daily for 3 days. Add a proton pump inhibitor, bone protection and low dose aspirin 75 mg daily; tocilizumab 162 mg subcutaneously weekly is a steroid sparing option.
• Adult onset Still disease: NSAID, prednisolone 0.5 to 1 mg/kg orally daily, anakinra 100 mg subcutaneously daily, or methotrexate 7.5 to 25 mg weekly; screen for macrophage activation syndrome (ferritin, triglycerides, fibrinogen, cytopenia).
• Familial Mediterranean fever: colchicine 1 to 2 mg orally daily (maximum 3 mg); reduce in renal impairment and avoid combination with clarithromycin, cyclosporine or strong P glycoprotein inhibitors. It prevents amyloidosis. Add anakinra 100 mg subcutaneously daily for colchicine resistant disease.
• PFAPA (children): single dose prednisolone 1 mg/kg orally at the start of an episode.
• Cryopyrin associated periodic syndromes: canakinumab 150 mg subcutaneously every 8 weeks (adults) or anakinra. TNF receptor associated periodic syndrome: anakinra or etanercept.
• Tuberculosis: isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg (maximum 2 g) and ethambutol 15 mg/kg orally daily for 2 months, then isoniazid and rifampicin for 4 months in pulmonary and most extrapulmonary disease (9 to 12 months for bone, joint and central nervous system disease), with pyridoxine 10 to 25 mg daily and liver function monitoring.
• Brucellosis: doxycycline 100 mg orally twice daily with rifampicin 600 to 900 mg orally daily for 6 weeks, or doxycycline for 6 weeks with gentamicin 5 mg/kg intravenously daily for the first 7 days.
• Relapsing fever: louse borne, doxycycline 200 mg orally once (or erythromycin 500 mg once); tick borne, doxycycline 100 mg twice daily for 7 to 10 days. Jarisch-Herxheimer reaction occurs within 1 to 4 hours and needs monitoring and supportive care.
• Q fever endocarditis: doxycycline 100 mg twice daily with hydroxychloroquine 200 mg three times daily for at least 18 months. Other culture negative endocarditis needs specialist regimens.
• Endocarditis and deep abscess: culture directed therapy with drainage.
• Haemophagocytic lymphohistiocytosis: urgent haematology; dexamethasone 10 mg/m2 daily with etoposide 150 mg/m2 twice weekly in the first 2 weeks, with treatment of the trigger.
• Lymphoma and malignancy: oncology referral after tissue diagnosis.
• Drug fever: stop the drug. Fever settles in 72 to 96 hours.
• Empirical antituberculous therapy: reserve for patients who are deteriorating, are HIV positive or live in high burden regions where tuberculosis is likely and diagnosis is delayed. Use the four drug regimen with the doses given for tuberculosis and review at 2 weeks for response.
• NSAID response (naproxen 250 to 375 mg orally twice daily for 3 days) can distinguish neoplastic fever, but evidence is limited and it does not exclude infection.

Monitoring. Daily temperature chart, review at 1 week, repeat examination for new signs, repeat blood count, CRP, ferritin and cultures as clinically needed, and revisit negative tests and the history.

Referral and escalation. Infectious diseases for tuberculosis, brucellosis, tropical infection and suspected endocarditis; rheumatology for vasculitis, Still disease and autoinflammatory syndromes; haematology for cytopenia, haemophagocytic lymphohistiocytosis and lymphoma; oncology after tissue diagnosis. Urgent specialist input for visual symptoms, haemodynamic instability or suspected haemophagocytic lymphohistiocytosis.

Admission. Fever with instability, neutropenia, suspected endocarditis or meningitis, haemophagocytic lymphohistiocytosis, visual symptoms, need for invasive diagnostic tests, or patients who cannot be followed reliably.

Safety netting. Return for rigors, confusion, severe headache, visual loss, breathlessness, chest pain, new rash, bleeding, reduced urine, or weight loss.

Special groups. Older adults: giant cell arteritis, polymyalgia rheumatica, tuberculosis, endocarditis, abscess and drugs are commonest. HIV: tuberculosis, Mycobacterium avium complex (CD4 under 50 cells/microlitre), cytomegalovirus, cryptococcosis, histoplasmosis, Pneumocystis, lymphoma and immune reconstitution syndrome. Children: PFAPA, Kawasaki disease, juvenile idiopathic arthritis, Epstein-Barr virus, tuberculosis and malignancy.

Pregnancy: listeriosis, toxoplasmosis, malaria and tuberculosis; avoid radiation based imaging where possible and use ultrasound or MRI. Returning travellers: malaria, typhoid, brucellosis, visceral leishmaniasis, schistosomiasis and tuberculosis.