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Fever

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Fever - A Comprehensive Overview

Definition

Fever (pyrexia) is an abnormal elevation of core body temperature resulting from a raised hypothalamic temperature set point. It is generally defined as a rectal temperature >38°C (100.4°F). Temperatures above 41.1°C (106°F) carry serious risk of end-organ damage, and above 43°C, heat stroke and death become common.
  • Costanzo Physiology 7th Ed.

Pathophysiology

The mechanism of fever is a cascade involving exogenous stimuli, immune cells, cytokines, and the hypothalamus:
Pathogenesis of fever - from endotoxin to cytokines to raised hypothalamic set point
Step-by-step cascade:
  1. Pyrogenic stimulus (endotoxin/LPS, viral antigens, inflammation, immune complexes) activates monocytes, macrophages, and Kupffer cells.
  2. These cells release endogenous pyrogens (EP) - cytokines including IL-1β, IL-6, TNF-α, IFN-β, and IFN-γ.
  3. LPS also signals via vagal afferents to the preoptic anterior hypothalamus, activating COX-2 to generate prostaglandin E2 (PGE2). A slower second wave of PGE2 is produced locally in the brain by IL-1β.
  4. PGE2 acts on EP1-EP4 receptors in the preoptic hypothalamus, raising the temperature set point - the hypothalamus now treats normal body temperature as "too low."
  5. The body activates heat-conservation mechanisms: vasoconstriction, shivering, and reduced sweating to raise temperature to the new set point.
  6. Fever results.
  • Ganong's Review of Medical Physiology 26th Ed. | Bradley and Daroff's Neurology in Clinical Practice
Note on mechanism update: Classical teaching attributed fever purely to circulating cytokines, but current evidence suggests the initial brain signal travels via vagal afferents with norepinephrine activating COX-2 in the preoptic area - not circulating cytokines alone. Circulating IL-1β acts in a slower, secondary phase.

Causes of Fever

Fever is one of the most common presenting symptoms in medicine and has a wide differential:

Infectious (most common)

  • Bacterial: pneumonia, UTI, cellulitis, septicemia, TB, endocarditis, abscess
  • Viral: influenza, EBV, CMV, HIV, enteroviruses
  • Fungal: histoplasmosis, cryptococcosis (especially in immunocompromised)
  • Parasitic: malaria (cyclical fever from red cell rupture releasing pyrogens/cytokines)

Non-Infectious Inflammatory

  • Autoimmune: SLE, rheumatoid arthritis, Still's disease, vasculitis
  • Granulomatous: sarcoidosis
  • Inflammatory bowel disease
  • Familial Mediterranean fever, polymyalgia rheumatica

Malignant

  • Hematologic: lymphoma, leukemia, myelodysplastic syndrome
  • Solid tumors: renal cell carcinoma, hepatocellular carcinoma, colon cancer, metastatic carcinoma

Drug-Induced Hyperthermia

  • Malignant hyperthermia (inhalation anesthetics - ryanodine receptor mutation)
  • Neuroleptic malignant syndrome (NMS - antipsychotics)
  • Serotonin syndrome
  • Anticholinergic poisoning

Surgical / Post-operative Fever

Common causes include atelectasis, pneumonia, UTI, transfusion reactions, line sepsis, and surgical site infection. - Goldman-Cecil Medicine

Fever of Unknown Origin (FUO)

Classic definition: Fever >38.3°C on several occasions, lasting >3 weeks, with no diagnosis after 1 week of inpatient investigation (modified to 3 days in hospital or 3 outpatient visits in modern practice).
Fever of Unknown Origin - categorized into infectious, noninfectious inflammatory, malignant, and other causes
FUO causes fall into four categories (see diagram above):
CategoryExamples
InfectiousOccult abscess, TB (miliary), endocarditis, osteomyelitis, zoonoses
Noninfectious inflammatoryStill's disease, SLE, RA, sarcoidosis, vasculitis, IBD, Familial Mediterranean fever
MalignantLymphoma, leukemia, renal cell carcinoma, HCC, atrial myxoma
OtherDrug fever, factitious fever, undiagnosed
Most common etiology: infectious causes dominate, with no final diagnosis found in a significant proportion of cases. Most common viral causes: EBV and CMV.
  • Frameworks for Internal Medicine

Antipyretics - Mechanism of Action

DrugMechanism
Aspirin / NSAIDsInhibit cyclooxygenase (COX) -> block PGE2 synthesis in hypothalamus -> lower set point
Paracetamol (Acetaminophen)Also inhibits COX (primarily central) -> reduces hypothalamic PGE2
IbuprofenCOX inhibitor; commonly used in children (children's ibuprofen effective in reducing fever to ~38°C)
When antipyretics lower the set point, the hypothalamus "sees" the body temperature as too high and activates heat-dissipating mechanisms: vasodilation and sweating.
  • Costanzo Physiology 7th Ed.

Biological Role of Fever

Fever is not simply harmful - it has evolved adaptive functions:
  • Many microorganisms have a narrow optimal growth temperature; elevated temperature inhibits their growth
  • Antibody production increases at elevated temperatures
  • Before antibiotics, induced hyperthermia was used to treat neurosyphilis (beneficial)
  • Fever also benefits patients with anthrax, pneumococcal pneumonia, leprosy, and certain viral/fungal/rickettsial infections
  • Some tumors grow more slowly at higher temperatures
However, prolonged temperatures >41°C cause brain damage, and >43°C heat stroke with high mortality.
  • Ganong's Review of Medical Physiology 26th Ed.

Dangerous Related Syndromes

SyndromeKey Feature
Heat strokeCore temp rise with impaired heat dissipation; hyperthermia, hypotension, tachycardia, decreased consciousness, seizures
Malignant hyperthermiaTriggered by inhalation anesthetics; ryanodine receptor mutation -> massive Ca²⁺ release from sarcoplasmic reticulum -> skeletal muscle contracture + extreme heat production
Neuroleptic malignant syndrome (NMS)Antipsychotics; diffuse muscle rigidity, akinesia, fever, decreased consciousness, autonomic dysfunction
Serotonin syndromeSerotonergic excess; hyperthermia with clonus, agitation

Key Clinical Points

  • Always exclude acute infection before attributing fever to non-infectious causes (especially in immunosuppressed patients on steroids or biologics)
  • In SLE, fever may represent disease flare or opportunistic infection (PCP, cryptococcal meningitis, Listeria, herpes zoster)
  • In pediatrics, key developments include Hib and conjugated pneumococcal vaccines, which have significantly changed the approach to febrile children
  • Empirical antibiotics breed resistance; use culture-guided therapy when possible
  • Hydration, nutrition, and general supportive care are often neglected but important in prolonged fever

Infectious and treatment

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Infectious Causes of Fever & Treatment

Overview: Approach to the Febrile Patient

Most acute, undifferentiated febrile illnesses resolve spontaneously within 1-2 weeks without a specific diagnosis. However, a systematic approach is needed to identify serious bacterial infections that require prompt treatment.
Key principle: Empiric antibiotics should be avoided as a default. Most causes of pharyngitis in adults are viral; bacterial pneumonia is effectively excluded by normal vital signs and a normal chest exam. Culture-guided therapy is preferred whenever possible to avoid antimicrobial resistance.
  • Goldman-Cecil Medicine, International Edition

Infectious Causes of Fever - By Syndrome

1. Fever + Rash

A careful history must establish:
  • Immunocompromising conditions
  • Travel history
  • Animal/insect exposures
  • New medications (drug fever is common)
  • Sexual history
Rash TypeKey Differential
Petechial / purpuricMeningococcemia, Rocky Mountain spotted fever (RMSF), dengue, endocarditis
MaculopapularViral exanthem, drug reaction, secondary syphilis, EBV/CMV, rubella
VesicularVaricella-zoster, HSV, hand-foot-mouth disease
ErythrodermaToxic shock syndrome (Staph/Strep), scarlet fever

2. Fever + Lymphadenopathy

From Goldman-Cecil Medicine - Table 259-4:
Regional LymphadenopathyGeneralized Lymphadenopathy
Cervical: Streptococci, TB, viral URTIEBV (infectious mononucleosis)
Peripheral: Bartonella henselae (cat scratch), HerpesvirusesCMV
SporotrichosisHIV
Lymphoma, metastatic cancerSarcoidosis
Syphilis (secondary), Toxoplasmosis, Viral hepatitis

3. Fever + Musculoskeletal Complaints

  • Localized tenderness/swelling/erythema: Suggests septic arthritis, osteomyelitis, or spinal epidural abscess (due to S. aureus in Western countries; M. tuberculosis in endemic areas for vertebral disease/psoas abscess)
  • Polyarthritis: Disseminated gonococcal infection, chikungunya, dengue, parvovirus B19, Hepatitis B/C, Lyme disease
  • Deep muscle myositis: Clostridial, streptococcal, or mixed aerobic-anaerobic infections
  • Rhabdomyolysis: Legionellosis, various viral infections
  • Diffuse myositis: Leptospirosis, toxoplasmosis

4. Fever in the Hospital (Nosocomial Fever)

In ICU patients, ~80% of febrile episodes are infectious.
Common Infectious Causes (from Goldman-Cecil Table 259-1):
Common InfectiousLess Common Infectious
Clostridioides difficile enterocolitisBiliary tract disease
Pneumonia (HAP/VAP)Endometritis
Surgical wound infectionIntra-abdominal abscess
Urinary tract infectionMediastinitis
Vascular catheter infectionSinusitis
Common Non-Infectious Causes (hospital setting): Drug-induced fever, hematoma, transfusion reaction, venous thromboembolism, post-op state, MI, pancreatitis, organ infarction.
Note: C. difficile can cause fever and a leukemoid reaction even with little or no diarrhea.

5. Postoperative Fever

TimingLikely Cause
Within 24 hoursS. pyogenes or Clostridium species
3+ days (with catheter)Urinary tract infection
Day 5-7Surgical wound infection (more common after GI procedures)
Any timeC. difficile, drug fever, atelectasis, acalculous cholecystitis, DVT/PE

Infectious Causes of FUO - Detailed Breakdown

Intra-abdominal Abscess

  • Most common infectious cause of FUO in the industrialized world
  • Common sites: liver, spleen, intraperitoneal cavity
  • Also: dental, renal, perinephric abscesses
  • Usually preceded by biliary disease, diverticulitis, appendicitis, or Crohn's disease
  • CT abdomen/pelvis has high diagnostic yield and should be performed early
  • Elderly patients may have subtle signs - leading to protracted course
  • Treatment: Antibiotics + percutaneous drainage (image-guided); open surgery reserved for select cases

Tuberculosis

  • Forms most likely to present as FUO:
    • Extrapulmonary (especially hepatic TB) without clear localizing features
    • Miliary TB without characteristic CXR pattern
    • Pulmonary TB in immunocompromised (CXR may be normal in HIV)
  • Investigations: Interferon-γ release assay (IGRA) or tuberculin skin test, sputum smear/culture/PCR, BAL, tissue biopsy (lung, liver, bone marrow)
  • Treatment: Standard 4-drug RIPE regimen (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol)

Endocarditis

  • Culture-negative endocarditis - consider after prior antibiotic use, or fastidious organisms (HACEK group, Bartonella, Coxiella burnetii/Q fever, Brucella, fungi)
  • Classic presentation: Fever, night sweats, weight loss + new murmur
  • Treatment: Prolonged IV antibiotics (4-6 weeks); surgery for hemodynamic compromise or failure to clear bacteremia

Osteomyelitis

  • Most common site in FUO: vertebral osteomyelitis (usually starts as discitis with symmetrical involvement of adjacent vertebrae)
  • Causes: S. aureus (most common), TB in endemic areas
  • Antibiotics not helpful for chronic osteomyelitis in isolation - surgical debridement often required

Viral Causes (most common: EBV and CMV)

  • EBV (infectious mononucleosis): fever, pharyngitis, lymphadenopathy, hepatosplenomegaly
  • CMV: similar syndrome but more heterophile-negative
  • HIV: acute retroviral syndrome - fever, rash, lymphadenopathy, pharyngitis
  • Treatment: largely supportive; antivirals for specific indications (CMV in immunocompromised, HIV with ART)

Zoonoses

  • Cat scratch disease (Bartonella henselae): tender regional lymphadenopathy after cat scratch
  • Leptospirosis: freshwater exposure, fever, conjunctival suffusion, AKI, liver injury, thrombocytopenia, hyponatremia - treated with doxycycline or penicillin
  • Q fever (Coxiella burnetii): livestock/animal contact - treated with doxycycline
  • Brucellosis: animal/dairy exposure

Diagnostic Workup

Initial Evaluation for FUO (Goldman-Cecil Table 259-7)

TestRationale
CBC with differentialLeukocytosis, eosinophilia, cytopenias
Comprehensive metabolic panelLiver, kidney function
Urinalysis + sedimentUTI, glomerulonephritis
ESR + CRPInflammation marker
Blood cultures x3 (spaced >74 hrs apart)Bacteremia, endocarditis
HIV Ag/Ab (4th generation)HIV
CMV IgM/IgG + EBV heterophile AbViral causes
TB IGRATuberculosis
LDHLymphoma, hemolysis
TSHThyroiditis
Rheumatoid factor, ANAAutoimmune
Chest X-rayPulmonary TB, lymphoma, pneumonia
Hepatitis A/B/E serologies (if LFTs abnormal)Viral hepatitis
Lower limb Doppler USDVT
EchocardiographyEndocarditis
CT chest/abdomen/pelvisAbscesses, lymphoma, TB

Treatment Principles

Antipyretics

  • Paracetamol (Acetaminophen) and Ibuprofen are first-line for symptomatic fever relief
  • Both inhibit COX → reduce hypothalamic PGE2 → lower set point → vasodilation + sweating
  • They do NOT treat the underlying infection

Antimicrobial Therapy

General principles:
  1. Cultures before antibiotics - always obtain blood cultures (and other relevant cultures) before starting antibiotics
  2. Narrow spectrum when possible - broad-spectrum empirical antibiotics breed resistance
  3. Shorter courses are generally better (Ann Intern Med 2019)
  4. De-escalate once culture and sensitivity results are available
Empirical antibiotic selection for common settings:
ScenarioEmpirical Antibiotic Choice
Community-acquired infection (non-severe)Amoxicillin-clavulanate / fluoroquinolone
Intra-abdominal infectionPiperacillin/tazobactam OR 3rd/4th-gen cephalosporin + metronidazole
ESBL-producing EnterobacteriaceaeCarbapenem (drug of choice)
MRSAVancomycin
VRELinezolid or daptomycin
Suspected Candida (severe/Candida glabrata)Micafungin (echinocandin)
HAP/VAPAntipseudomonal beta-lactam ± anti-MRSA agent
  • Fischer's Mastery of Surgery 8th Ed. | Goldman-Cecil Medicine

Antimicrobial Stewardship

Key elements of hospital stewardship programs include:
  • Leadership commitment and dedicated resources
  • Prospective audit and feedback / preauthorization
  • Tracking resistance patterns and antibiotic use
  • Regular reporting to prescribers and hospital leadership
  • Education on adverse reactions, resistance, and optimal prescribing
  • Goldman-Cecil Medicine (CDC Core Elements)

Source Control

For abscesses and loculated infections:
  • Image-guided percutaneous drainage is now standard (lower morbidity than open surgery)
  • May serve as bridge to definitive surgical repair
  • IV antibiotics alone may suffice for small intrahepatic abscesses (<3 cm)
  • MDR organisms warrant early infectious disease consultation

Red Flags Requiring Urgent Evaluation

  • Fever >41°C (hyperpyrexia - consider CNS hemorrhage or medication-induced)
  • Fever + petechial rash → meningococcemia until proven otherwise
  • Fever + stiff neck + photophobia → bacterial meningitis (LP urgently)
  • Fever + new murmur → endocarditis
  • Fever + immunocompromised state → broad differential including opportunistic infections
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