• Clinical science
  • Physician

Fever

Summary

Fever is defined as an elevation of normal body temperature, which can vary based on a number of factors (e.g., the time of day, geographical location, degree of exertion). In general, fever is defined as a temperature > 38°C (100.4°F). Fever is a nonspecific symptom that may be caused by infectious and noninfectious conditions, including malignancies, systemic rheumatic diseases, and drug reactions. History and physical examination alone are often sufficient to diagnose uncomplicated infectious causes of fever (e.g., URI, gastroenteritis). Laboratory tests and imaging should be guided by the pretest probability of the differential diagnoses. Antipyretics and tepid sponging may be used to decrease body temperature, but treatment of the underlying cause is the main goal when managing febrile patients. Neutropenic fever is discussed elsewhere.

Acute management checklist

Emergency evaluation

Basic approach

  • Identify and treat sepsis, if present.
  • Identify and treat the underlying cause.
  • Provide supportive therapy (antipyretics, IV fluids, tepid sponging).

Red flags

Focused history

History of present illness

  • Onset
  • Duration
  • Characteristics (e.g., continuous vs. intermittent or nocturnal, high grade vs. low grade)

Recent exposures

  • Travel (see below)
  • Sick contacts
  • New medication or substance
  • Animals, including farm and wild animals

Associated symptoms

  • General
    • Chills, rigors
    • Night sweats
    • Unintentional weight loss
  • HEENT
  • Pulmonary
  • Gastrointestinal
  • Urogenital
  • Neurologic
    • Dizziness
    • Headache
    • Neck stiffness
    • Altered mental status
    • Photophobia
    • Seizures
    • Focal neurological deficits
  • Skin and soft tissue
  • Extremities
    • Myalgia
    • Arthralgia
    • Bone pain
    • Arthritis
    • Joint stiffness or change in range of motion

Past medical history, social history, and family history

  • Past medical history
  • Past surgical history
  • Medications
  • Indwelling devices/implants
  • Vaccination status (see immunization schedule)
  • Menstrual history
  • Sexual history
  • Allergies
  • Social history
    • Occupation
    • Pets
    • Alcohol
    • Drug use
    • Tobacco
  • Family history

Travel history

In addition to the focused history checklist above, the following history should be obtained from a returning traveler:

  • Dates of travel
  • Mode of travel
  • Places visited (incl. travel stops)
  • Pretravel vaccination status
  • Prophylactic medications
  • Accommodation
  • Activities (e.g., hikes, camping, swimming)
  • History of bites and use of repellants
  • Exposure to farm animals and livestock
  • Ingestion of food or water that is potentially contaminated
  • Recent tattoos or piercings
  • History of medical care received

In > 25% of returning travelers with fever, a specific cause of the fever cannot be identified. [1]

Consider early consultation of an infectious disease specialist for patients with fever who have recently traveled abroad.

Focused examination

General

HEENT

Cardiovascular

Pulmonary

Abdominal and pelvic

  • Auscultation of the abdomen
  • Percussion of the abdomen
  • Palpation of the abdomen (including the back)
  • Percussion over the costovertebral angles
  • Palpation of the spine
  • Digital rectal examination
  • Pelvic examination

DRE should be avoided in neutropenic patients because of the risk of rectal mucosal injury and bacteremia.

Neurologic

  • Orientation to person, place, and time
  • Sensitivity to light
  • Muscle strength, deep tendon reflexes, and sensory function
  • Nuchal rigidity

Lymph nodes

Skin and soft tissue

  • Evaluation for pallor and icterus
  • Skin appendages
  • Skin turgor
  • Indwelling devices
  • Rash
  • Signs of abnormal bleeding
  • Ulceration
  • Presence of ticks

Extremities

  • Capillary refill time
  • Joints
  • Edema

Focused diagnostics

The diagnostic evaluation should be guided by the pretest probability of the diagnoses under consideration. The following list includes all of the diagnostic tests that might be of use in diagnosing or ruling out possible etiologies in a patient with fever.

Laboratory studies

Routine

In patients with suspected SIRS or sepsis

  • Blood gas analysis
  • Serum lactate
  • Procalcitonin assay
  • ESR/CRP
  • Blood cultures (at least 2 sets)
  • Additional cultures from other sites as indicated
  • Chest x-ray

Cultures should be obtained before initiating empiric antibiotic therapy, if possible without delaying the administration of antibiotics.

In admitted patients with a new-onset fever, the minimum initial workup generally should consist of CBC with differential, serum lactate, urinalysis with microscopy, blood cultures (2 sets), and a CXR. Further testing should be guided by the suspected etiology of the fever.

Further diagnostic testing to consider based on suspected localization of symptoms

Labs Imaging and other interventions
HEENT
  • Rapid strep test
  • Throat culture
  • CT scan of the head, face, and/or neck with IV contrast
Pulmonary
  • Sputum culture
  • Legionella urinary antigen
  • Respiratory viral panel
  • S. pneumoniae urinary antigen
  • AFB smear microscopy
  • Procalcitonin
  • Chest x-ray
  • CT chest with IV contrast
  • Bronchoscopy
  • Thoracentesis
Cardiovascular
  • ECG
  • TTE and/or TEE
  • CTA chest

Abdominal

  • Abdominal ultrasound
  • X-ray abdomen
  • CT abdomen/pelvis with oral and IV contrast
  • Paracentesis

Urologic/pelvic

Neurologic/psychiatric
Skin and soft tissue/bone/lymphatic
  • Gram stain and culture of any exudate
  • CT with IV contrast
  • MRI
  • Skin biopsy
  • Bone biopsy

Rheumatologic

Hematologic
  • Bone marrow biopsy
Endocrine

Differential diagnoses by fever characteristics

The pattern of fever may help to determine a diagnosis, although it has limited value in comparison to more specific laboratory tests.

Type of fever Course Associated diseases
Continuous fever Temperature permanently over 38°C (100.4°F); daily fluctuations < 1°C (1.8°F) Viral and bacterial infections (e.g., typhoid fever, lobar pneumonia)
Remittent fever Temperature permanently over 38°C (100.4°F); daily fluctuations ≥ 1°C (1.8°F) Viral infections, acute bacterial endocarditis
Intermittent fever High spike and rapid defervescence Pyogenic infection, TB, juvenile idiopathic arthritis

Recurrent fever

Relapsing fever Days of fever followed by an afebrile
period of several days and then a relapse into additional days of fever, usually after 14–21 days
Tick-borne relapsing fever and louse-borne relapsing fever
Pel-Ebstein fever Fever lasting 1–2 weeks followed by an afebrile period of 1–2 weeks Hodgkin lymphoma
Periodical fever Fever that recurs over months or years in the absence of associated viral or bacterial infection or malignancy Periodic fever syndromes (e.g., familial Mediterranean fever, hyper-IgD syndrome)
Others Still disease, Crohn disease, Behcet disease, relapsing malaria (tertian malaria, quartan malaria), drug fever, factitious fever
Biphasic fever A fever that breaks and returns once more Dengue fever , leptospirosis
Undulant fever Temperature rises gradually and falls like a wave over days to weeks Brucellosis
Postoperative fever Has a highly variable course and many different causes; discussed in the learning card on perioperative management

References:[2][3][4][5][6][7][8][9][10][11][12][13][14]

Differential diagnoses by affected system

System
Infectious causes Noninfectious causes
HEENT
  • Trauma
  • Malignancy

Pulmonary

Cardiovascular

Abdominal

Urologic/Pelvic

Neurologic/psychiatric

Skin and soft tissue/bone/lymphatic
Rheumatologic

Hematologic

Endocrine

Malignancy involving any system may also cause fever.

Differential diagnoses by associated finding

Associated finding Differential diagnoses
Jaundice

Bradycardia

Rash
Eosinophilia
Leukopenia
Anemia

Differential diagnoses by risk factors

Risk factors Differential diagnoses
Recent international travel
HIV infection

Trauma/stress

Drug exposure
Inherited fever syndrome

Autoimmune disease

Antipyretics

Acetaminophen is the preferred antipyretic during pregnancy but should be avoided in patients with severe hepatic dysfunction.

NSAIDs are contraindicated in pregnancy and hemorrhagic fevers. They should be used with caution in breastfeeding patients and those with CAD.

Fever of unknown origin (FUO)

  • Definition: temperature elevation > 38.3°C (101°F) lasting ≥ 3 weeks without a definitive diagnosis despite thorough clinical investigation
  • Classification
    • Classical FUO
      • Criteria: according to the definition + present at ≥ 3 outpatient visits or ≥ 3 days in hospital
      • Causes: infection, autoimmune disease, and malignant neoplasm
    • Nosocomial FUO
      • Criteria: new temperature elevation ; > 38.3°C (101°F) in patients who have been admitted to the hospital at least 24 hours ago present at ≥ 3 days of evaluation
      • Causes: surgery, medications, intravascular devices, TVT, pulmonary embolism, Clostridium difficile enterocolitis, sinusitis
    • HIV-associated FUO
      • Criteria: according to the definition but lasting > 4 weeks for outpatients and > 3 days for inpatients with confirmed HIV infection
      • Causes: CMV, Pneumocystis pneumonia, Mycobacterium avium-intracellulare, Kaposi sarcoma, and lymphoma
    • Immune-deficient FUO (neutropenic fever)
      • Criteria: according to the definition + neutrophil count ≤ 500/μL
      • Causes: chemotherapy , bacterial infections, aspergillosis, candidiasis, herpes virus
      • Management
        • Even without a determinant source of infection, broad-spectrum antibiotics must be administered without delay to avoid sepsis and life-threatening complications.
        • First-line treatment: an anti-pseudomonal ß-lactam drug (cefepime, meropenem, or piperacillin-tazobactam) that covers both gram-negative and gram-positive bacteria
        • If fever persists, reassess for fungal or viral infection and adapt treatment accordingly.
  • Diagnostic approach
    • The patient history should be taken and physical examination should be performed several times as the inflammatory process develops.
    • The pattern of fever should be documented and analyzed.
    • History should include:
      • Contact with animals
      • Travel history
      • Diet history
      • Immunosuppression
      • Family history
      • Social and sexual history
      • Occupational history
      • Drugs and medications
    • Specific investigations should be guided by physical findings and clinical suspicion.
    • If there are no diagnostic clues, the following tests should be performed:
    • If there are no findings ; from the tests above, abdominal and chest CT should be performed.
  • Patients with a negative workup generally have a favorable prognosis, with resolution of fever over time.

Infections and cancer account for the majority of cases of FUO!

Severe febrile neutropenia is life-threatening because of an impaired neutrophil-mediated inflammatory response to bacterial infections. After drawing blood and urine cultures, immediate empiric antibiotic therapy should be initiated.

References:[15][16][17][18]

Inherited fever syndromes

Familial Mediterranean fever (FMF)

  • Description: A hereditary autoinflammatory disorder characterized by recurrent, self-limiting fever attacks, serositis, and often other inflamed tissue. Patients do not experience any symptoms between attacks.
  • Epidemiology: mostly limited to individuals of eastern Mediterranean descent ; most common inherited fever syndrome
  • Genetics: an autosomal-recessive mutation in the MEFV gene on chromosome 16
  • Clinical presentation: can vary greatly
    • All patients experience fever attacks lasting 1–3 days and recurs over weeks to months.
    • Most patients (95%) experience abdominal pain and arthralgia (75%).
    • Other manifestations
    • The disorder often goes undiagnosed in patients with mild to moderate symptoms.
    • Patients often have an appendectomy scar from a past episode of FMF that was mistaken for acute appendicitis.
  • Complication: AA amyloidosis
  • Therapy: Prevention of AA amyloidosis through inhibition of granulocyte function: colchicine, TNF inhibitors

Other hereditary fever syndromes

  • Hyper-IgD syndrome
  • TNFα reception-associated periodic syndrome

References:[19][20]