Fever

Pyrexia of unknown origin is defined as T ≥ 38.3°C on a few occasions for at least three weeks, accompanied by failure to reach a diagnosis after one week of inpatient investigation

Differential diagnosis

• Infection
  • Respiratory tract
    • Sinusitis
    • Upper respiratory tract infection
    • Community-acquired pneumonia
    • Tuberculosis
    • Pneumocystis jirovecii pneumonia
    • Influenza
  • Cardiac
    • Bacterial endocarditis
    • HACEK organisms are fastidious and may only grow on extended incubation
      • Haemophilus spp.
      • Aggregatibacter spp.
      • Cardiobacterium spp.
      • Eikenella corrodens
      • Kingella spp.
  • Gastrointestinal
    • Whipple’s disease – Tropheryma whippleii causing malabsorption, migratory arthritis
    • Typhoid and other enteric fevers – Salmonella from contaminated food causing abdominal pain, fever, rash “rose spots” with hepatosplenomegaly. Risk of perforation.
    • Viral hepatitis
  • Urinary tract
    • Simple / complicated urinary tract infection
    • Renal abscess
    • Renal carbuncle
  • Soft tissue
    • Septic arthritis
    • Gonococcal arthritis
    • Osteomyelitis
  • Meningoencephalitis
    • Bacterial meningitis
    • Tuberculous meningitis
    • Cryptococcal meningitis
    • Viral encephalitis
  • Systemic infections
    • Q fever – Coxiella burnetti, including Q fever endocarditis; especially in farmers
    • Brucellosis – fever, sweating, migratory myalgia and arthralgia; undercooked meat, unpasteurized milk
    • Leptospirosis – myalgia, cough, diarrhoea, pulmonary haemorrhage; exposure to contaminated water, soil or infected animal tissue
      • Severe disease with jaundice and renal failure – Weil’s disease
    • Cat scratch disease – Bartonella, primary inoculation lesion, generalized lymphadenopathy
    • Rocky Mountain spotted fever – Rickettsia, rash, myalgia, seizures; Americas in the summer
    • Scrub typhus – Orientia, rash, myalgia, intense headache, lymphadenopathy
    • Deep-seated abscess
    • Epstein-Barr virus – lymphadenopathy, fever, rash exacerbated by amoxicillin
    • Cytomegalovirus – diarrhoea, retinitis, pneumonia
    • Human immunodeficiency virus infection
    • Malaria
• Inflammatory
  • Adult-onset Still’s Disease
    • Fever, often spiking in the evenings
    • Arthralgia and arthritis, often of the wrists, knees and ankles
    • Maculopapular salmon-pink rash over trunk and proximal limbs
    • May have lymphadenopathy, hepatosplenomegaly
    • Yamaguchi or Fautrel’s criteria for diagnosis
  • Systemic lupus erythematosus
  • Rheumatoid arthritis
  • Mixed connective tissue disease
  • Temporal arteritis
  • Sarcoidosis
  • Polymyalgia rheumatica
  • Inflammatory bowel disease
  • Kikuchi disease
  • Systemic vasculitis
• Neoplastic
  • Renal cell carcinoma
  • Lymphoma
  • Leukaemia
  • Colon cancer
  • Pancreatic cancer
  • Hepatic metastases
  • Hepatoma
• Drug fever
  • Anti-epileptics
  • Antibiotics, especially beta-lactams, sulphonamides, nitrofurantoin, minocycline
  • Allopurinol
  • Anti-psychotics – neuroleptic malignant syndrome
  • Succinylcholine – Malignant hyperthermia secondary to ryanodine receptor mutation
  • Selective serotonin reuptake inhibitors, monoamine oxidase inhibitors – serotonin syndrome
• Familial Mediterranean fever
  • Autosomal recessive
  • Attacks of severe pain and fever, lasting 1 – 3 days
  • Pain secondary to serositis – pleuritic, peritonitis, synovitis
  • Entirely well in between attacks
  • Attacks respond very well to colchicine
• Deep vein thrombosis / pulmonary embolism
• Hyperthyroidism

History

• History of presenting complaint
  • Onset of fever
  • Maximal temperature
  • Associated symptoms
    • Altered mentation (if history is from a relative, etc.)
      • Confusion (encephalitis)
      • Neck stiffness (meningitis)
      • Headache (meningitis)
    • Respiratory tract
      • Runny nose, sore throat (URTI, Wegner’s, Churg-Strauss)
      • Facial tenderness (sinusitis)
      • Epistaxis (Wegner’s granulomatosis)
      • Cough – productive / non-productive, haemoptysis (pneumonia)
      • Shortness-of-breath (pneumonia, interstitial lung disease from CTD)
    • Cardiac
      • Janeway lesions / Osler nodes / splinter haemorrhages (infective endocarditis)
      • Chest pain (pericarditis)
      • Symptoms of CCF (acute infective endocarditis)
    • Gastrointestinal
      • Jaundice (hepatitis infection)
      • Diarrhoea (enteric fevers, CMV, HIV, Whipple’s disease)
    • Genitourinary tract
      • Dysuria
      • Renal angle tenderness
      • Genital ulcers (syphilis, Bechet’s)
      • Genital discharge
    • Musculoskeletal
      • Myalgia (non-specific)
      • Arthritis / arthralgia
      • Bone pain (osteomyelitis)
    • Lymphadenopathy (lymphoma, CMV, EBV, HIV, Kikuchi)
    • Inflammatory
      • Rash
      • Mouth ulcers (SLE)
      • Alopecia (SLE)
      • Dry eyes / dry mouth (Sjogren’s)
      • Arthropathy
      • Peripheral neuropathy (vasculitis)
      • Jaw claudication (GCA)
    • Neoplastic
      • Weight loss
      • Change in bowel habit
      • Breast lumps
  • Sick contacts
  • Travel history
  • Animal contact
  • Dietary habits – unpasteurized milk, raw meat
  • Sexual history
• Past medical history
  • Previous episodes of rheumatic fever
  • Tuberculosis
  • Infective endocarditis
  • Surgery – indwelling prosthetic devices
  • Malignancy
  • Any medical conditions requiring immunosuppression
  • Previous transfusions
• Drug history
  • Current medications
  • Illicit drug use (endocarditis)
• Family history – FMF