Makindo Medical Notes

Related Subjects: | Fever in a Traveller | Malaria Falciparum | Malaria Non Falciparum | Viral Haemorrhagic Fevers (VHF) | Lassa Fever | Dengue | Marburg Virus Disease | AIDS/HIV | Yellow Fever | Ebola Virus | Leptospirosis | Crimean-Congo Haemorrhagic Fever | African Trypanosomiasis (Sleeping Sickness) | American Trypanosomiasis (Chagas Disease) | Incubation Periods | Notifiable Diseases UK

A case to consider multiple expert opinions, as the differential diagnoses for FUO are broad and not all prolonged fevers are infectious in origin. The current definition: a documented fever persisting for over 2 weeks with no clear diagnosis despite thorough and intelligent investigation.

About

• Original Definition (1960s, Petersdorf and Beeson): Fever >38.3°C lasting more than 3 weeks with no obvious cause despite 1 week of inpatient investigation (pre-CT/MRI era).
• Current Definition: Fever of more than 2 weeks’ duration with no clear diagnosis despite detailed and directed investigations.
• Fever arises from cytokines and interferons resetting the hypothalamic temperature set point. It usually provides some evolutionary benefit against infection. However, patients on steroids, the elderly, or those who are immunocompromised may not develop a fever even with severe infection.
• Any pyrogen (microbial toxin, microbial particle, or cytokine) can initiate the process.

Definition

• Current: Fever >2 weeks with no diagnosis after thorough testing.
• Original: Fever >38°C for >3 weeks with no diagnosis after initial hospital investigations.

Differential Diagnoses

• Infections: Tuberculosis, endocarditis, urinary or respiratory tract infections.
• Abscesses: Pelvic, abdominal, renal, epidural, spinal, or subdiaphragmatic.
• Parasitic and Tropical: Malaria, amoebiasis, leishmaniasis, trypanosomiasis.
• Other Infectious Causes: Toxoplasmosis, EBV/CMV, brucellosis, Lyme disease, Whipple’s disease, HIV, rickettsial infections (typhus, Q fever).
• Rheumatological/Inflammatory: SLE, giant cell arteritis (GCA), polymyalgia rheumatica (PMR), rheumatoid arthritis, adult-onset Still’s disease, vasculitides.
• Genetic: Familial Mediterranean fever.
• Malignancies: Lymphoma, leukemia, renal cell carcinoma, other solid tumors.
• Others: Drug-induced fever, atrial myxoma, thyrotoxicosis.

Key Approaches

• Obtain a very focused, detailed history: travel, drug use (including IV drugs), occupational exposures, sexual history.
• Perform a comprehensive examination: thorough skin check (front and back), oral and dental exam, perineal, rectal, and pelvic exams where appropriate.
• Use imaging to evaluate areas not easily examined clinically.
• Look for infection, malignancy, and connective tissue diseases as primary categories.
• Repeat investigations and examinations regularly until the cause is found.
• Seek early advice from specialists (cardiologists, hematologists, rheumatologists, microbiologists) when indicated.

Investigations

• Basic Labs: FBC with differential, ESR, CRP, LFTs, U&Es, TFTs.
• Serology: EBV, CMV, HIV, Bartonella, Toxoplasma, Brucella, Lyme disease, Q fever, leptospirosis, salmonella, chlamydia.
• Microbiology: Blood, urine, stool cultures (x3), wound swabs as indicated.
• Imaging: Chest X-ray, abdominal/pelvic ultrasound, CT, MRI as needed. Bone scans or WBC-labeled scans for osteomyelitis or abscesses.
• Additional Tests: Tuberculin skin test, rheumatoid factor, ANA, ANCA, vasculitis panels.
• Specialized Imaging/Procedures: Echocardiogram (for endocarditis or myxoma), repeated malaria blood films, HIV/Hepatitis/Syphilis testing.
• Biopsies: Liver biopsy (for TB, lymphoma, granulomatous disease), bone marrow biopsy (myelodysplasia, hematological malignancies, TB, brucellosis, enteric fever, visceral leishmaniasis), temporal artery biopsy (GCA) if age >50 years.

List of Causes

Category	Details
Common Infections (30-40%)	UTI, chest infections, endocarditis (may need transesophageal echo). Obtain blood cultures before antibiotics.
Malaria	Consider if travel to endemic areas. Falciparum malaria can be rapidly fatal. Send blood films, take travel history.
TB	Miliary or extrapulmonary. Imaging and tests (CXR, IGRA tests) may be needed.
Abscess	Splenic, perirenal, pelvic, spinal, etc. Often requires ultrasound, CT, or MRI. WBC-labeled scans may help.
Other Infections	HIV, osteomyelitis, typhoid, brucellosis, Lyme, syphilis, EBV, CMV, Bartonella (cat scratch), toxoplasmosis.
Cancers (20%)	Lymphoma, leukemia, renal cell carcinoma. Look for abnormal blood tests, imaging findings, and ESR elevation.
Inflammatory/Connective Tissue (10-20%)	Giant cell arteritis (very high ESR), Still’s, SLE, vasculitis, rheumatoid arthritis. Check CRP/ESR, ANA, ANCA.
Miscellaneous	Atrial myxoma, familial Mediterranean fever, thyrotoxicosis, Crohn’s disease, sarcoidosis, occult hematoma.
Idiopathic	No diagnosis despite prolonged, extensive testing.
Drugs	Drug-induced fever. Obtain a thorough drug history.
Fraudulent	Factitious fever. Patient appears well, often with very high recorded temperatures but no objective findings. Normal ESR/CRP. Measure fresh urine temperature to confirm.

Management

• Avoid blind treatment if possible. Broad-spectrum antibiotics prior to referral often complicate the picture.
• Obtain a second opinion from senior colleagues or specialists. Re-evaluate history and examinations frequently.
• If the patient is stable (not septic or deteriorating), consider suspending unnecessary medications and observe carefully to identify evolving clues.
• For stable outpatients, careful follow-up is appropriate. Intensive inpatient evaluation is warranted if condition worsens.