Fever of unknown origin — definition, evaluation and management of prolonged fever in the elderly

Classical definition. Petersdorf and Beeson (1961), modified by Durack and Street (1991): a temperature >38.3 °C (101 °F) on several occasions, of more than 3 weeks' duration, remaining undiagnosed after appropriate investigation — three days of inpatient work-up, three outpatient visits, or one week of intelligent and invasive ambulatory investigation.

The four categories (Durack and Street). Classic FUO; nosocomial FUO (onset in hospital, not incubating on admission); neutropenic / immune-deficient FUO (neutrophils <500/mm³); and HIV-associated FUO. Each has a different differential and a different work-up — say which you are addressing.

Why the definition must be adapted in old age. Kane's: the febrile response may be blunted or absent in older people with bacterial infection, baseline body temperature is lower, and nursing-home residents may fail to show a diurnal rise. Fever in a long-term care resident is therefore redefined as a single oral temperature above 37.8 °C (100 °F), repeated oral temperatures above 37.2 °C (99 °F), or a rise of more than 1.1 °C (2 °F) above the patient's baseline. Applying the 38.3 °C threshold to a frail older patient will miss disease. A poor febrile response is itself a negative prognostic factor.

The causes are distributed differently in the elderly — the key examinable fact. Approximate shares in over-65s: infection 25–35%, connective tissue and inflammatory disease 25–30% (far higher than in the young, and giant cell arteritis with polymyalgia rheumatica is the single commonest identifiable cause), malignancy 15–20%, miscellaneous including drug fever 10%, and undiagnosed 10–20% (lower than in the young). The governing principle is that FUO in an older person is usually an atypical presentation of a common disease, not a rare disease.

Infective causes to hunt for. Tuberculosis, especially miliary and extrapulmonary — Kane's rule: "suspect tuberculosis when a patient is inexplicably failing". Infective endocarditis — nearly 50% of cases occur in older adults, on degenerative valves and prostheses, and blood cultures may be negative if antibiotics were given. Also intra-abdominal, hepatobiliary and pelvic abscess, complicated urinary infection and prostatic abscess, vertebral osteomyelitis and discitis, infected prosthetic joints and devices, dental and sinus sepsis, and — in India — enteric fever, brucellosis, melioidosis, kala-azar, scrub typhus and malaria.

Non-infective causes. Inflammatory: giant cell arteritis and polymyalgia rheumatica, adult-onset Still's disease, rheumatoid arthritis, ANCA-associated vasculitis, polyarteritis nodosa, sarcoidosis. Malignant: lymphoma is commonest, then renal cell carcinoma, hepatocellular carcinoma, myelodysplastic syndrome, leukaemia, atrial myxoma and metastatic disease. Miscellaneous: drug fever — very common with polypharmacy (antibiotics, allopurinol, anticonvulsants, antiarrhythmics, heparin); venous thromboembolism; subacute thyroiditis and apathetic thyrotoxicosis; gout and pseudogout; resolving haematoma; adrenal insufficiency; and factitious fever.

Step 1 — history and repeated examination. The highest-yield "investigation" is a meticulous, repeated daily physical examination. Take a full drug history including over-the-counter and AYUSH preparations and every recently started agent, plus travel, animal and rural exposure, dental work, prosthetic implants, prior TB, transfusions and immunosuppression. On examination, look specifically at: temporal arteries, a new or changing murmur, all lymph node groups, liver and spleen, skin, nails and splinter haemorrhages, joints, thyroid, prostate and pelvis, rectum, fundi (Roth spots) and every prosthesis or device site.

Step 2 — first-line investigations. CBC with differential and peripheral blood film, ESR and CRP, renal and liver function, electrolytes, LDH, creatine kinase, urinalysis and urine culture, three sets of blood cultures taken off antibiotics, chest radiograph, sputum for AFB and GeneXpert, HIV test, TSH, ANA and rheumatoid factor, serum and urine protein electrophoresis, and — in India — a blood film and rapid test for malaria plus dengue and scrub typhus serology in season.

Step 3 — second-line and targeted investigations. CT of chest, abdomen and pelvis; echocardiography (transthoracic, then transoesophageal if endocarditis is suspected); ultrasound of abdomen and of any tender area; temporal artery ultrasound or biopsy in anyone over 50 with an ESR above 50; bone marrow aspiration and trephine biopsy with culture (high yield for miliary TB, lymphoma and myelodysplasia); and FDG-PET/CT. Then tissue is the answer — lymph node, liver or bone biopsy sent for histology, culture and TB PCR; lumbar puncture if there are any CNS features; joint aspiration if any joint is involved.

Management principles. Avoid empirical "blind" antibiotics. They obscure cultures, cause C. difficile and resistance, and are themselves a common cause of drug fever. Empirical therapy is justified only for haemodynamic instability or sepsis, neutropenia, or a strong suspicion of a dangerous treatable condition. The great exception is giant cell arteritis — start high-dose corticosteroids immediately on suspicion, without waiting for the biopsy, to prevent blindness. A trial of anti-tuberculous therapy may be justified in a high-burden setting when miliary TB is strongly suspected and the patient is deteriorating, but only after a determined attempt at tissue diagnosis. Stop or substitute every non-essential drug — drug fever settles within 48–72 hours. Throughout, provide geriatric care in parallel: hydration and nutrition, delirium and pressure-injury prevention, early mobilisation, medication review, and an explicit discussion of goals of care. Knowing when to stop investigating a very frail patient, and to observe instead, is itself a legitimate management decision — a specific diagnosis is eventually reached in 70–90% of older patients, and undiagnosed FUO that settles spontaneously has a good prognosis.

FDG-PET/CT is now the recommended second-line imaging modality in FUO, with a diagnostic yield of roughly 50–60% and the highest utility when CRP or ESR are raised. Current EANM/SNMMI and European guidance place it before invasive biopsy in the algorithm, and it is particularly valuable in older adults because it detects large-vessel vasculitis, occult lymphoma and vertebral osteomyelitis — the three commonest occult causes in this age group — and it directs the biopsy when one is needed.

Molecular diagnostics and a reframed terminology. Metagenomic next-generation sequencing of plasma cell-free DNA and targeted NGS can now identify pathogens in culture-negative endocarditis and deep-seated infection, though cost and false-positive signals limit routine use. Separately, current practice increasingly uses the term "inflammation of unknown origin" (IUO) for the raised-CRP, no-fever presentation — an important reframing for geriatrics, because many older patients with occult giant cell arteritis, lymphoma or endocarditis never mount a fever at all and would be missed by a temperature-based definition.