Basics
Description
- Fever is an elevation of core body temperature caused by an increase in the bodys thermoregulatory set point.
- Prostaglandin E2 (PGE2) synthesis in the anterior hypothalamus controls the thermostat, and is the target of antipyretics.
- Core temperature is regulated to 37 °C ± 2 °C.
- Autonomic discharge from hypothalamus can raise core temperature through shivering and dermal vasoconstriction.
- Normal circadian variation in core temperature occurs with nadir in early morning and peaks in late afternoon.
- Fever is not synonymous with hyperthermia or hyperpyrexia.
- Hyperthermia is an elevated temperature with normal thermostat set point; caused by excessive endogenous heat production or endogenous production (e.g., malignant hyperthermia or heat stroke).
- Hyperpyrexia is extreme fever >41.5 °C usually from CNS hemorrhages.
- Both exogenous and endogenous factors can raise the body's set thermoregulatory point:
- Endogenous pyrogens include PGE2, IL-1, IL-6, TNF, IFN-γ.
- Exogenous pyrogens include lipopolysaccharide (LPS) endotoxin and other TLR ligands, and toxic shock syndrome toxin (TSST-1) and other MHC II ligands.
- Patients on anticytokine medications or glucocorticoids have impaired fever response.
- Fever of unknown origin (FUO):
- Fever >38.3 °C for at least 3 wk as an outpatient and 3 days of inpatient evaluation or 3 outpatient visits without determining etiology.
Etiology
- Infectious processes:
- CNS, chest and lung, gastrointestinal, genitourinary, skin, soft tissue and bone, vascular and endocardial
- Iatrogenic: Catheters, implants, hardware, recent surgical sites.
- 1 ° CNS processes such as CVA, trauma, seizures
- Neoplastic fevers
- Drug fever:
- Most drugs can cause elevated temperatures by a wide variety of mechanisms
- Toxidromes (e.g., adrenergic, anticholinergic, dopaminergic, salicylate overdose, serotonin toxicity)
- Hypersensitivity:
- Allergic reaction
- Serum sickness
- Jarisch-Herxheimer reaction
- Local phlebitis from irritant drugs
- Severe withdrawal:
- Systemic rheumatologic and inflammatory diseases (e.g., familial Mediterranean fever, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, temporal arteritis)
- Endocrine:
- Hyperthyroidism, pheochromocytoma
- Miscellaneous:
- Alcoholic cirrhosis
- Acute inhalation exposures (e.g., metal fume fever)
- Cotton fever:
- Febrile reaction from an injected contaminant when IV drug abusers strain drug through cotton
- Sickle cell disease
- Hemolytic anemia
- Pulmonary embolus
- Common causes of FUO:
- Infectious:
- Abdominal and pelvic abscesses
- Cardiac (endocarditis, pericarditis)
- Cat scratch disease
- Cytomegalovirus
- Epstein-Barr virus
- TB (miliary, renal, or meningitic)
- Typhoid enteric fevers
- Visceral leishmaniasis
- Neoplastic:
- Colon adenocarcinoma
- Hepatocellular carcinoma and metastases
- Myeloproliferative disorders
- Leukemia and lymphoma
- Renal cell carcinoma
Diagnosis
Signs and Symptoms
History
- Chills, shivering, and rigors:
- Rigors may suggest bacteremia
- Weight loss:
- Suggestive of neoplastic, chronic infectious, or endocrine disorders
- Night sweats:
- Suggestive of neoplastic, chronic inflammatory disease, or TB
- Specific fever patterns:
- Daily morning temperature spikes:
- Miliary TB, typhoid fever, polyarteritis nodosa
- Relapsing fevers: Febrile episode with alternating afebrile intervals:
- Seen in malaria, Borrelia infections, rat-bite fever, and lymphoma
- Remittent fever: Temperature falls daily but does not return to normal:
- Seen in TB and viral diseases
- Intermittent fevers: Exaggerated circadian rhythm:
- Seen in systemic infections, malignancy, and drug fever
- Double quotidian fever:
- Common pattern of 2 temperature spikes in 24 hr
- In FUO, consider miliary TB, visceral leishmaniasis, and malarial infections
- High-risk features:
- Anticytokine therapy (e.g., TNF-α monoclonal antibodies, calcineurin inhibitors)
- Glucocorticoid use
- Immunosuppressed states
- Incomplete vaccination status
- IV drug use
- Pregnancy and peripartum patients
- Rash
- Recent chemotherapy
- Recent travel
- Splenectomy
Physical Exam
- Elevated core temperature:
- Temperature >38 °C (100.4 °F) rectally or 37.5 °C (99.5 °F) orally
- Lower thresholds in patients older than 65 yr, as the febrile response is not as strong
- Diaphoresis:
- Absence of diaphoresis with severe hyperthermia suggests anticholinergic poisoning or heat stroke.
- Tachycardia:
- For each degree of elevation in temperature in Fahrenheit, there should be a 10 bpm increase in pulse.
- Relative bradycardia (Faget sign):
- Associated with malaria, typhoid fever, CNS disorders, lymphoma, drug fever, brucellosis, ornithosis, Legionnaire disease, Lyme disease, and factitious fevers
- Muscle rigidity, clonus, and hyper-reflexia:
- Associated with specific toxidromes and medical conditions
- Changes in mental status:
- Toxic-metabolic encephalopathy vs. primary CNS disorder
- Rash:
- Lesion type, distribution, and progression can offer important clues to diagnosis.
- Petechia, purpura, vesicles, mucosal, or palm and sole involvement require special note
- Signs of hyperthyroidism:
Essential Workup
- Core temperature is most acutely measured rectally.
- Careful history and physical exam (PE) necessary to determine need for further diagnostic testing:
- History should elicit any sick contacts, previous infections, occupational exposures, recent travel, medications, animal or tick exposure, and immunization status.
Diagnosis Tests & Interpretation
Lab
- CBC:
- Important in determining neutropenia in patients with risk factors
- Neutrophilia and bandemia suggestive of bacterial infection
- Lymphocytosis suggestive of typhoid, TB, brucellosis, and viral disease
- Atypical lymphocytosis seen in mononucleosis, cytomegalovirus, HIV, rubella, varicella, measles, and viral hepatitis
- Monocytosis suggestive of TB, brucellosis, viral illness, and lymphoma
- Lactate:
- Initial and repeat measurements useful for screening for sepsis, risk stratification, and management decisions
- Urinalysis and urine culture
- Blood cultures:
- Obtain for all systemically ill patients, and patients at risk for bacteremia
- Thick and thin blood smears and malaria antigen testing in at-risk individuals for parasitic and intraerythrocytic infections
- Stool culture and Clostridium difficile assay for suspected individuals.
- Heterophile antibody testing in select patients.
- Erythrocyte sedimentation rate and C-reactive protein generally not useful:
- Very high values suggestive of endocarditis, osteomyelitis, TB, and rheumatologic conditions.
- Decreased immunocompetence, increased risk of systemic spread, increased exposure to health care settings, may have comorbid conditions.
- If institutionalized consider the infectious implications of multiple potential sick contacts.
Imaging
- CXR:
- In patients with PE finding of cardiopulmonary disease and patients with unclear fever source
- CT or MRI may be indicated if lumbar puncture or osteomyelitis is considered, respectively.
Differential Diagnosis
- The differential diagnosis is very broad as listed above, but is generally categorized as infectious vs. noninfectious, and by immunocompetency.
Treatment
Pre-Hospital
- No specific field interventions required
- Monitoring and IV access should be obtained in the field for unstable patients or patients with altered mental status.
Initial Stabilization/Therapy
- ABCs for unstable patients.
- Initiate early broad-spectrum antibiotics for patients with suspected sepsis or unstable vital signs, particularly those who are at high risk for serious bacterial infection.
Ed Treatment/Procedures
- Antipyretics:
- Generally either acetaminophen or NSAIDs
- Inhibit the cyclooxygenase enzyme, thereby blocking synthesis of prostaglandins.
- Empiric antibiotics for neutropenic patients:
- Combination therapy:
- Extended spectrum β-lactam (ceftazidime, piperacillin) with an aminoglycoside
- Monotherapy:
- Cefepime
- Ceftazidime
- Imipenem
- Empiric antibiotics for asplenic patients for encapsulated bacteria
- Empiric antiviral therapy for patients with encephalitis and potential disseminated viral infections (e.g., recent organ or bone marrow transplant patients, AIDS patients)
- External cooling mechanism rarely indicated
Medication
- Antipyretics:
- Acetaminophen: 650-1,000 mg PO/PR q4-6h; do not exceed 4 g/24h
- Aspirin: 650 mg PO q4h; do not exceed 4 g/24h
- Ibuprofen: 800 mg PO q6h
- Antibiotics:
- Cefepime: 2 g IV q12
- Ceftazidime: 2 g IV q8
- Gentamicin or tobramycin (D): 2 mg/kg IV load then 1.7 mg/kg q8h + piperacillin/tazobactam (B) 3.375 g IV q4h or ticarcillin/clavulanate (B) 3.1 g IV q4h
- Imipenem/cilastatin: 500-1,000 mg IV q8h
- Meropenem (B): 1 g IV q8h
- Ciprofloxacin: 750 mg PO BID + amoxicillin/clavulanate (B) 875 mg PO BID
- Antivirals:
- Herpes simplex virus and varicella-zoster virus (VZV):
- Acyclovir 10-15 mg/kg IV q8h
- Influenza A and B:
- Oseltamivir 75 mg PO q12h
Follow-Up
Disposition
Admission Criteria
- Patients with unstable vital signs require ICU admission.
- When identified, the underlying source of the fever usually determines the disposition.
- Certain high-risk groups who have fever without an identifiable source:
- Neutropenic patients
- Immunosuppressed or immunocompromised patients
- Asplenic patients
- IV drug abusers
- Lower thresholds for admission in patients older than 60 yr and diabetics
Discharge Criteria
Immunocompetent patients with stable vital signs and an identified source of fever or a high suspicion of a nonthreatening viral infection may be safely discharged.
Issues for Referral
The suspected etiology of the fever determines the referral to a primary care physician or a specialist.
Followup Recommendations
Appropriate outpatient treatment and follow-up for further outpatient assessment of the suspected etiology.
Pearls and Pitfalls
- Screening lactates for sepsis.
- Early, empiric, and broad-spectrum antibiotic coverage for all septic patients.
- Consider all potential sources of infection.
- Careful consideration for the immunosuppressed, elderly, and IV drug users.
Additional Reading
- Cunha BA. Fever of unknown origin: Focused diagnostic approach based on clinical clues from the history, physical examination, and laboratory tests. Infect Dis Clin North Am. 2007;21:1137-1187.
- Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56-e93.
- Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal of 98.6 degrees F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA. 1992;268(12):1578-1580.
Codes
ICD9
- 780.60 Fever, unspecified
- 780.61 Fever presenting with conditions classified elsewhere
ICD10
- R50.2 Drug induced fever
- R50.9 Fever, unspecified
- R50.81 Fever presenting with conditions classified elsewhere
SNOMED
- 386661006 fever (finding)
- 7520000 Pyrexia of unknown origin (finding)
- 95908009 Drug fever (finding)