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EBMG

Prolonged Fever in the Adult

Essentials

  • Prolonged fever in an adult refers to a fever that is ≥ 38.3°C at times and has lasted for more than 3 weeks, and routine investigations have not revealed any cause for it.
  • Diagnose common infections (pneumonia, sinusitis, urinary tract infection) before ordering a large number of tests.
  • Decide on the urgency of tests according to the patient's general condition, risk factors (immunosuppression) and local signs.
  • Repeat history and physical examination before repeating tests.
  • Unwarranted use of antimicrobials can hinder or delay proper diagnosis.
  • The most common diseases that cause prolonged fever are infections, autoimmune diseases and cancers.

Diagnostic strategy

  1. Exclude the following common diseases before further investigations:
    • Pneumonia (chest x-ray and auscultation)
      • Chest x-ray may also show tuberculosis, sarcoidosis, alveolitis, pulmonary infarction or pulmonary neoplasm.
    • Urinary tract infection (urine test and culture)
      • Urine test may even also suggest epidemic nephropathy, other nephritis or renal tumour.
    • Maxillary sinusitis (ultrasound or x-ray).
  2. Important questions on the history include
    • Occurrence (measuring!) and duration of fever
    • Travelling, place (country) of birth, living
    • Past diseases, particularly tuberculosis and valvular defects
    • Unprotected sex contacts, use of intravenous illicit drugs
    • Dental interventions in the previous months
    • Rheumatic diseases in close relatives
    • Organ transplants, prosthetic joints
    • Drug therapy, including over-the-counter drugs
    • Alcohol use and smoking
    • Systematic review of organ systems for symptoms
      • Arthralgias, other local or generalized aches, abdominal symptoms, urinary symptoms, pain in the throat or on the neck, skin eruptions
  3. Clinical examination and findings
    • Enlarged lymph nodes
    • Condition of the dentition
    • Heart murmurs
    • Abnormal findings in lung auscultation
    • Abdominal palpation in order to detect pain or masses
    • Condition of the skin both on the trunk and on the extremities
  4. Diagnostic clues and possible aetiologies
    • See table T1.
  5. Tests
    • Primary investigations
      • Urine test and culture
      • CRP and ESR
      • Basic blood count with platelet count
      • ALT and ALP
      • Throat culture
      • HIV test
      • Antinuclear antibodies, rheumatoid factor and anti-CCP antibody assays possibly in this phase already
      • Option: serum sample to be frozen for eventual serology
      • ECG
      • Chest x-ray
      • Maxillary sinus ultrasound or x-ray
    • Secondary investigations
      • Tests for antibodies selected according to history and symptoms
        • E.g. Yersinia, tularaemia, Borrelia burgdorferi, nephropathia epidemica, Karelian fever, mononucleosis, hepatitides (for the diagnostics, see Viral Hepatitis)
        • Antinuclear antibodies, rheumatoid factor and anti-CCP antibody assay if not investigated in the primary phase
      • Thyroid function tests
      • Blood bacterial culture
      • Combination of nucleic acid testing for faecal pathogenes and their culture
      • Abdominal ultrasonography or CT scan
      • Echocardiography
      • Bone marrow aspiration
  6. Consider your tactics before continuing with investigations
    • See table T2.
  7. Browse a list of causes for fever to see what may have escaped your notice.

Prolonged fever in the adult - diagnostic clues

CluePossible causes 1)
Infection parameters (ESR, CRP) are normalChronic fatigue syndrome, minor temperature elevation after an infectious disease, drug fever, self-induced fever
Already cured viral or bacterial infectionMild temperature elevation after an infectious disease is a functional disorder. Stress and fatique may contribute to the disorder.
ErythemaDrug fever, vasculitis
Throat or neck painSubacute thyreoiditis Subacute Thyroiditis, retropharyngeal abscess*, mononucleosis Mononucleosis
ConfusionIn elderly confusion is associated with the fever itself, in younger patients remember encephalitis* Encephalitis and any possible septic infection* Sepsis
Known valvular defect or murmur suggesting oneEndocarditis* Infective Endocarditis
GI symptomsCrohn's disease Ulcerative Colitis, ulcerative colitis, periappendicular abscess*, other peritoneal abscesses*, yersiniosis Yersiniosis
Weight loss and recurrent feverMalignancies; HIV and other chronic infections
Abnormal urinary findingsUTI, epidemic nephritis* Epidemic Nephropathy, other nephritis, renal cancer, endocarditis
Fever in a returning travellerSee Fever in a Returning Traveller. Always consider the possibility of malaria.
FarmerFarmer's lung* Allergic Alveolitis
Suppurative mosquito bite or ulcerTularaemia Tularaemia
Lymph nodes felt on palpationMononucleosis Mononucleosis, lymphoma Lymphomas
Psychotropic medicationNeuroleptic malignant syndrome*, serotonin syndrome* Neuroleptic Malignant Syndrome (Nms)
Long-term antimicrobial medicationDrug fever, Clostridioides difficile
Immunosuppression patientSee Infections in Immunosuppressed and Cancer Patients
HeadacheTemporal arteritis* Giant Cell (Temporal) Arteritis
MyalgiaPolymyalgia rheumatica Polymyalgia Rheumatica (may be associated with the fever itself)
Bone painsMyeloma Multiple Myeloma (Mm), metastasis
Back painAnkylosing spondylitis, several infections
Back pain on tappingInfectious focus
Recurring feverEndocarditis, deep infection foci*
Discrepancy between findings and historySelf-induced fever
  1. The diagnosis of diseases marked with asterisk must not be delayed.
Diagnostic tactics in prolonged fever
RightWrong
Take history again.Repeat laboratory and radiologic investigations
Repeat the physical examination (eyes, nasopharynx, touch per rectum, auscultation).Start drug therapy or increase dosage
Read the patient record again.Suggest a surgical intervention
Focus further investigations according to the clues provided by the history and clinical findings.
Make a consultation.
Take time to reflect upon the case.
Atypical presentations of common diseases are more probable than typical presentations of rare diseases.

Causes of prolonged fever (aetiological grouping)

Fever of unknown origin (FUO)

  • The diagnosis Febris e causa ignota (fever of unknown origin, FUO) is used when a fever ≥ 38.3°C has lasted longer than 3 weeks.
  • An aetiological diagnosis should be pursued intensively in order to exclude a serious disease, preferably in the hospital.
  • In some patients, the cause of prolonged fever remains unclear despite comprehensive investigations.
  • If the temperature elevation is very mild, the patient is feeling well and the laboratory tests are normal, the patient usually will not benefit from an assessment by the specialized care.

    References

    • Wright WF, Betz JF, Auwaerter PG. Prospective Studies Comparing Structured vs Nonstructured Diagnostic Protocol Evaluations Among Patients With Fever of Unknown Origin: A Systematic Review and Meta-analysis. JAMA Netw Open 2022;5(6):e2215000. [PubMed]
    • Wright WF, Simner PJ, Carroll KC, et al. Progress Report: Next-Generation Sequencing, Multiplex Polymerase Chain Reaction, and Broad-Range Molecular Assays as Diagnostic Tools for Fever of Unknown Origin Investigations in Adults. Clin Infect Dis 2022;74(5):924-932. [PubMed]

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