Fever of Unknown Origin

Russell E. Lewis

2026-03-01

Fever of Unknown Origin (FUO)

Prof. Russell E. Lewis
Department of Molecular Medicine
University of Padua

russelledward.lewis@unipd.it
https://github.com/Russlewisbo

slides available at: www.padovaid.com

Objectives

• Recognize leading infectious causes of FUO in key patient groups
• Identify fever patterns and clinical histories that may direct diagnosis
• Differentiate FUO risks and possible spectrum of pathogens in immunocompromised hosts

Today we’ll explore the fascinating history of fever, understand the modern definition of FUO, review its epidemiology across different patient populations, and learn systematic approaches to diagnosis and management. We’ll pay particular attention to how fever patterns can guide clinical thinking and how immunocompromised patients present unique diagnostic challenges.

The history of fever

• 10th Century BCE Persian Physician Akhawayni defined a system for fever curves in Hidāyat al-Muta’allimīn fī al-Tibb (The Student’s Handbook of Medicine)
• Hippocratic physicians proposed that body temperature, and physiologic harmony in general, involved a delicate balance among four corporal humors—blood, phlegm, black bile, and yellow bile.
  • Fever was due to excess of yellow bile (many infections caused jaundice)
• Galen: many types of fever developed from putrefaction of humors.
• Middle ages: demonic possession
• 18th century (Harvey’s discovery of circulation)- friction of blood flow through body causing fermentation and putrefaction in intestines
• Claude Bernard in the 19th century- metabolic processes in the body

The history of fever reflects humanity’s struggle to understand bodily temperature. From ancient humoral theory through Renaissance advances to modern medicine, our conceptualization has evolved from supernatural and chemical explanations to physiologic understanding.

Febris - Roman Goddess of Fever

The legend of Febris was said to center around the haunting marshes of Camagna in Southern Italy where like clockwork every year, the people would become deathly ill with a mysterious disease. She was so feared by the Romans that the suffering population had created a cult to Febris. They went so far as to wear protective amulets and build her temples in order to worship her to win her favour.

Early thermometers

A typical design of a thermoscope is a tube in which a liquid rises and falls as the temperature changes. The Sanctorius thermoscope. Source: Professor Francis Ring, the University of Leeds

Fever in modern medicine

• Wunderlich’s pioneering studies of thermometry reported normal temperature at 37°C

• Since the 19th century, humans have become gradually colder - 0.05° to 0.5°C per decade!

  • Current normal range is 36.3 to 36.5°C
  • Less manual labor, less chronic inflammation-infection, poor dental health, increased body mass

• Mackowiak (1992): mean oral temperature 36.8 ± 0.4°C; only 8% had 37°C

• Fever now defined as: early-morning temperature ≥37.2°C or anytime ≥ 37.8°C

Carl Reinhold Wunderlich

(Mackowiak and Worden, 1994)

Thermal homeostasis

The hypothalamus acts as the body’s thermostat, continuously comparing core temperature against a defended setpoint (~37°C). Afferent thermal signals arrive from both peripheral cutaneous receptors and central thermosensors in the preoptic area of the anterior hypothalamus. When core temperature fa of bodylls below the setpoint, efferent pathways activate heat-conserving and heat-generating responses: cutaneous vasoconstriction reduces radiative heat loss, and shivering thermogenesis in skeletal muscle increases metabolic heat production. When temperature exceeds the setpoint, the balance shifts to heat dissipation: cutaneous vasodilation increases convective and radiative losses, and eccrine sweating provides evaporative cooling. Understanding this tightly regulated system is essential for interpreting fever: a true febrile response represents a deliberate upward resetting of this setpoint by pyrogenic mediators—not a failure of thermoregulation. (Sajadi and Mackowiak, 2020)

Diurinal pattern of body temperature

Physiologic variables affecting body temperature

• Age and sex differences
  • Women ~0.5°C higher at ovulation
  • Infants have higher baseline temperatures
• Circadian rhythm
  • Zenith: late afternoon (peak)
  • Nadir: early morning (trough)
• Other factors
  • Exercise and physical exertion
  • Medications (antipyretics, corticosteroids)
  • Digestion and recent meals
  • Chronic disease and metabolic conditions

Understanding normal temperature variation is crucial when evaluating a patient for FUO. A temperature of 37.5°C in a patient’s early morning measurement may be pathologic, while 38.2°C in the evening may be within normal diurnal variation for that individual.

Fever vs. Hyperthermia

Feature	Fever	Hyperthermia
Set point	Elevated	Normal
Mechanism	Regulated response	Unregulated heat generation
Cause	Pyrogens (LPS, IL-1, TNF)	Heat exposure, drugs, malignant hyperthermia
Pathophysiology	Altered hypothalamic setpoint	Failure of heat dissipation
Sweating	Absent initially (shivering); later excessive	May be absent
Treatment response	Antipyretics effective	Antipyretics ineffective; cooling required
Examples	Infection, NIID, malignancy	Heat stroke, neuroleptic malignant syndrome

This distinction is critical clinically. A patient with heat stroke will not respond to antipyretics because the problem is not a resetting of the hypothalamic setpoint, but rather failure of thermoregulation itself. Conversely, fever in infection responds to antipyretics because the elevated temperature is the body’s intentional response to pathogens. NIID- Non-infectious inflammatory disease

Infection-associated fever - The febrile response

When pathogens are recognized by the innate immune system, LPS from gram-negative bacteria and other PAMPs activate macrophages to release pyrogenic cytokines IL-1, TNF-α, and IL-6. These circulate to the hypothalamus, where they stimulate production of PGE₂ in the preoptic area (POA), which directly resets the thermoregulatory setpoint upward. The anterior hypothalamus then interprets the new setpoint as the desired temperature and initiates heat-generating mechanisms (shivering, vasoconstriction, behavior changes) until core temperature matches this new higher setpoint.

(Wright and Auwaerter, 2020)

Sequelae of fever - Benefits of fever

• Phylogenetic conservation suggests fever is beneficial - appears in ectotherms and endotherms
• Microbial metabolism - most pathogenic bacteria are mesophiles (optimal growth at 35-37°C)
  • Even modest temperature elevations slow replication
• Iron sequestration - fever triggers hepatic synthesis of hepcidin and lactoferrin
  • Sequesters free iron necessary for bacterial replication
• Enhanced immune function
  • Increased neutrophil migration
  • Augmented antibody production
  • Enhanced T-cell proliferation

Rather than viewing fever as purely pathologic, modern immunology reveals it as an important component of the inflammatory response to infection. This is why antipyretics in certain infections (like pneumococcal pneumonia) may actually worsen outcomes.

Acute phase proteins

Category	Proteins
↑ Complement system	C3, C4, C9, Factor B, C1 inhibitor, C4b-binding protein, Mannose-binding lectin
↑ Coagulation / fibrinolysis	Fibrinogen, Plasminogen, tPA, Urokinase, Protein S, Vitronectin, PAI-1
↑ Antiproteases	α₁-Protease inhibitor, α₁-Antichymotrypsin, Pancreatic trypsin inhibitor, Inter-α-trypsin inhibitors
↑ Transport proteins	Ceruloplasmin, Haptoglobin, Hemopexin
↑ Inflammatory mediators	Secreted PLA₂, LPS-binding protein, IL-1 receptor antagonist, G-CSF
↑ Others	CRP, Serum amyloid A, α₁-Acid glycoprotein, Fibronectin, Ferritin, Angiotensinogen
↓ Negative acute-phase	Albumin, Transferrin, Transthyretin, α₂-HS glycoprotein, Alpha-fetoprotein, Thyroxine-binding globulin, IGF-I, Factor XII

(Gabay and Kushner, 1999)

Acute phase phenomena

Category	Phenomena
Neuroendocrine	Fever, somnolence, anorexia; ↑ CRH, corticotropin & cortisol; ↑ arginine vasopressin; ↓ IGF-I; ↑ adrenal catecholamines
Hematopoietic	Anemia of chronic disease; leukocytosis; thrombocytosis
Metabolic	Muscle loss & negative nitrogen balance; ↓ gluconeogenesis; osteoporosis; ↑ hepatic lipogenesis; ↑ adipose lipolysis; ↓ lipoprotein lipase activity; cachexia
Hepatic	↑ Metallothionein, iNOS, heme oxygenase, MnSOD, TIMP-1; ↓ phosphoenolpyruvate carboxykinase activity
Nonprotein plasma	Hypozincemia, hypoferremia, hypercupremia; ↑ plasma retinol & glutathione

The acute phase response is orchestrated by IL-1, IL-6, and TNF-α. The dramatic rise in inflammatory markers like ESR and CRP, along with changes in protein synthesis (increased fibrinogen, ceruloplasmin; decreased albumin), reflects the body’s comprehensive metabolic mobilization against infection or inflammation.

(Gabay and Kushner, 1999)

Epidemiology of FUO - Definitions

Category	Key causes / definition
Classic FUO	Infection (TB, endocarditis, occult abscess, zoonoses, enteric fever, syphilis, histoplasmosis), malignancy, autoimmune/autoinflammatory, miscellaneous; includes virally suppressed HIV (CD4 >200)
Nosocomial FUO	FUO arising in hospitalized patients
ICU	Bacteremia, pneumonia, C. difficile, fungemia, catheter infections, PE, acalculous cholecystitis, drug fever, stroke/intracranial hemorrhage
Non-ICU	Similar to ICU causes; patient not critically ill
Immunodeficiency-associated FUO	Highly variable; depends on type and degree of immunodeficiency
Organ-transplant recipients	Viruses, donor-derived infections, Strongyloides hyperinfection, opportunistic fungi, rejection, GVHD, HLH, ureaplasma hyperammonemia
Neutropenia	Febrile >5 days despite empirical antibiotics; influenced by neutropenia duration, GVHD prophylaxis, antimicrobial agents
HCT recipients	Pre-engraftment: neutropenic causes; early post-engraftment: herpesvirus, adenovirus, hyperacute GVHD, pneumonia; late: relapsed cancer, immune reconstitution
HIV/AIDS (no ART)	Acute retroviral syndrome, mycobacteria, endemic mycoses, toxoplasmosis, cryptococcosis, HHV-8–associated diseases, lymphoma
Travel-associated FUO	Malaria, enteric fever, leptospirosis, viral hemorrhagic fevers, typhus, undifferentiated tropical febrile illness

(Haidar and Singh, 2022)

Different definitions exist for FUO depending on clinical context. The classic definition applies to outpatient or minimally hospitalized patients with prolonged fever. The newer categories - nosocomial, neutropenic, and HIV-associated FUO - reflect that different populations have different diagnostic considerations and thresholds for investigation.

Fever therapy to treat neurosyphilis

• Treponema pallidum is uniquely sensitive to increased temperatures

• Fever therapy involved purposely infecting the patient with Plasmodium vivax with control of the infection with anti- malarians while maintaining the fever it causes to the detriment of other, ongoing, and then-incurable infections such as late-stage syphilis

• This type of pyrotherapy was most famously used by psychiatrist Julius Wagner-Jauregg, who won the Nobel Prize for Medicine in 1927 for his elaboration of the procedure in treating neurosyphilis

Classic FUO

• Definition:
  • Temperature of > 38.3°C > 3 weeks
  • Fever >2 separate outpatient visits with diagnostic investigations or
  • Fever >2 visits in hospital of 3 days with diagnostic investigations
    • However,… these definitions are largely subjective
• Leading causes:
  • Infections (geography dependent)
  • Inflammatory conditions (age dependent)
  • Cancer (age dependent)
  • Undiagnosed/unknown

Frequency of the 5 main etiologic categories of FUO

Infectious causes decrease in patients above age 65 years

Classic FUO - Infectious Etiology

• Chronic or relapsing infections
  • Occult abscess (intra-abdominal, hepatic, splenic, renal, perirectal)
  • Endocarditis (both native and prosthetic valve)
  • Tuberculosis (pulmonary and extrapulmonary)
  • Complicated urinary tract infections (pyelonephritis, prostatitis)
  • Osteomyelitis (especially vertebral)
  • Other: brucellosis, leptospirosis, syphilis, bartonellosis

Rare and miscellaneous causes of fever

Category	Examples
Autoinflammatory / periodic fevers	Adult-onset Still’s disease, Behçet’s syndrome, Familial Mediterranean fever, Familial Hibernian fever, Periodic fever, Schnitzler’s syndrome
Vascular / cardiac	Aortic dissection, Aortitis, Atrial myxoma, Giant coronary aneurysm, Pericarditis, Postpericardiotomy syndrome, Polyarteritis nodosa, Pulmonary emboli, Veno-occlusive disease
Hematologic / oncologic	Castleman’s disease, Cyclic neutropenia, Hemoglobinopathies, Hemolytic anemias, Hemophagocytic syndrome, Histiocytosis X, Immunoblastic lymphadenopathy, Lymphomatoid granulomatosis, Myeloproliferative syndromes, Paroxysmal hemoglobinurias, Rosai-Dorfman disease, TTP
Granulomatous / lymphoproliferative	Allergic alveolitis, Granulomatous hepatitis, Granulomatous peritonitis, Kikuchi-Fujimoto disease, Lofgren syndrome, Retroperitoneal fibrosis, Sarcoidosis, Subacute necrotizing lymphadenitis
Autoimmune / rheumatologic	Autoimmune cholangitis, Erythema multiforme, Inflammatory bowel disease, Serum sickness, Sjögren’s syndrome, Wegener’s granulomatosis
Endocrine / metabolic	Addison’s disease, Fabry’s disease, Parathyroid apoplexy, Pheochromocytoma, Thyroiditis & thyrotoxicosis, Vitamin B₁₂ deficiency
GI / hepatic	Alcoholic hepatitis, Cirrhotic fever, Pancreatitis
Infectious	Bartonellosis, Carcinomatous meningitis, Chronic meningitis, Hantavirus, Human picornavirus, Hypereosinophilic syndrome, Infected urachal cyst, Sinusitis, Whipple’s disease
Other	Drug fever & hypersensitivities, Factitious fever, Metal fume fever, Resorbing hematoma

Uncommon and rare causes of FUO

Category	Examples
Infections	Bartonellosis, hantavirus, coccidioidomycosis, histoplasmosis, blastomycosis, cysticercosis
NIID	Addison disease, Behçet syndrome, SLE, vasculitis, inflammatory bowel disease, GPA, sarcoidosis, Sjögren syndrome, thyroiditis, adult-onset Still disease
Malignancy	Atrial myxoma, lymphoma, leukemia, pheochromocytoma, Schnitzler syndrome
Other	Cirrhotic fever, drug fever, factitious fever, vitamin B₁₂ deficiency, pulmonary embolism

This table emphasizes that the differential for FUO is vast. The key to narrowing the differential is careful history-taking, physical examination, and judicious use of targeted investigations rather than indiscriminate laboratory testing.

Classic FUO in infants and children

• Respiratory tract infections - viral, atypical organisms
• Other infections:
  • UTIs (especially important in young girls)
  • Brucellosis, tuberculosis, bartonellosis
• Systemic inflammatory conditions:
  • Kawasaki disease (critical, age < 5 years)
  • Inflammatory bowel diseases
  • Still’s disease (juvenile rheumatoid arthritis)
• Note: Connective tissue diseases and cancers are generally rare in children
• Important: Joint involvement is a sign of serious disorder - consider endocarditis, leukemia, connective tissue disease

Classic FUO in elderly patients

• In developed countries: connective tissue diseases > infections
  • Temporal arteritis (critical diagnosis - risk of blindness)
  • Polymyalgia rheumatica
  • Other vasculitides
• Diagnostic challenge: symptoms are subacute and non-specific, easily attributed to aging
• Infections still need to be considered:
  • Intra-abdominal abscess
  • Complicated UTIs (often without pyuria)
  • Tuberculosis (may be reactivation)
  • Endocarditis (prosthetic valves more common in elderly)
• Malignancy: solid tumors and hematologic malignancies increase with age

The elderly warrant special mention because temporal arteritis is a medical emergency masquerading as FUO. An elevated ESR alone is not sufficient - clinical suspicion and a low threshold for temporal artery biopsy can be vision-saving.

Fever in returning travelers

Diagnosis	Maclean et al (n = 587)	Doherty et al (n = 195)
Malaria	32%	42%
Respiratory tract infection	11%	2.6%
Dysentery	4.5%	5.1%
Urinary tract infection / pyelonephritis	4%	2.6%
Dengue fever	2%	6.2%
Enteric fever	2%	1.5%
Hepatitis	6%	3%
Tuberculosis	1%	2%
Rickettsial infection	1%	0.5%
Amebic liver abscess	1%	0%
Acute HIV infection	0.3%	1%
Other miscellaneous infections	4.3%	9.2%
Miscellaneous noninfectious causes	6%	1%
Undiagnosed	25%	24.6%

In the returning traveller with FUO, the incubation period and geographic exposures are paramount. Malaria, dengue, typhoid, leptospirosis, and rickettsial infections should be high on the differential based on travel history and season. Serologic testing and blood cultures are essential early investigations (Wright and Mackowiak, 2015).

Nosocomial (Health-Care Associated) FUO

• Leading causes:
  • Drug fever (especially to antibiotics, anti-epileptic medications)
  • Post-operative complications (e.g., occult abscess, anastomotic leak)
  • Decubitus ulcers with superimposed infection
  • Septic thrombophlebitis (peripherally inserted central catheters)
  • Recurrent pulmonary emboli
  • Myocardial infarction
  • Hematologic malignancy (newly diagnosed during hospitalization)
  • Blood transfusion reaction
  • Reactions to contrast media used in radiologic procedures
  • Clostridium difficile colitis

Fever in post-operative patients

• Epidemiology: > 1/3 of patients manifest fever in first 5 days post-surgery
• Infectious vs. non-infectious: < 10% of febrile patients have an identified source or positive cultures
• Pathophysiology: Fever may represent a physiological response to surgically-induced tissue injury
  • Release of pyrogenic cytokines and interleukins
  • Not necessarily indicative of infection
• Clinical pearl: Early fever (post-op day 1-3) is usually non-infectious; later fever (day 5+) warrants infection investigation

FUO in ICU patients

• Early fevers are common and often non-infectious
  • Associated with good prognosis
  • Related to inflammatory response to critical illness
• Prolonged fever carries a poorer prognosis
• Common complications:
  • Sinusitis (from mechanical ventilation, supine positioning, feeding tubes)
  • Ventilator-associated pneumonia
  • Catheter-related bloodstream infections
• Other causes similar to nosocomial FUO
  • Abscess, drug fever, septic thrombophlebitis, pulmonary emboli

FUO in stroke patients

• Non-infective fevers are common in stroke patients
  • Occur earlier after stroke than infection
  • Related to hypothalamic injury and cytokine release
• Infection-related complications:
  • UTI (from urinary catheterization)
  • Aspiration pneumonia
  • DVT/PE
• Clinical challenge: Distinguishing fever from infarct-related inflammation vs. infection can be difficult; broad-spectrum antibiotics are often given empirically

FUO in neutropenic patients

• ANC = Total WBC x (% Segs + % Bands)

• Definition of neutropenia:

  • ANC < 500 cells/mm³
  • “Profound” neutropenia: ANC < 100 cells/mm³

• Frequency of fever during chemotherapy-induced neutropenia:

  • 10-50% of patients with solid tumors
  • 80% of those with hematologic malignancies during ≥1 chemotherapy cycle
  • Most patients will have NO infectious etiology documented

• Critical finding: Signs of inflammation are notoriously absent other than fever

  • No exudate, no fluctuance, no purulent drainage
  • Makes clinical diagnosis extremely difficult

This is one of the most challenging patient populations. The absence of typical signs of infection makes physical examination findings less frequent, and a single positive blood culture in a neutropenic patient must be treated as bacteremia until proven otherwise. Prompt empiric broad-spectrum antibiotics (before cultures return) are standard of care.

Clinical manifestations of infection related to absolute neutrophil count

Sign/Symptom	Type of Infection	% with ANC<100	% with ANC>1000
Fever	Overall	98	76
Bacteremia	Overall	43	13
Fluctuance	Anorectal	8	67
Exudate	Skin	5	92
Purulent sputum	Pneumonia	8	84
Pyuria	UTI	11	97

(Sickles et al., 1975)

This table powerfully illustrates why clinical signs fail in severe neutropenia. A profoundly neutropenic patient with anorectal infection has only 8% chance of fluctuance - the classic finding that would alert us to a perirectal abscess. Yet such abscesses are common sources of bacteremia in this population.

Possible causes of fever in neutropenic patients not responding to broad-spectrum antibiotics

Cause	Approx. frequency in high-risk patients
Fungal infections susceptible to empirical therapy	40%
Bacterial infections (cryptic foci, biofilms, resistant organisms)	10%
GVHD after hematopoietic stem cell transplantation	10%
Fungal infections resistant to empirical antifungal therapy	5%
Toxoplasma gondii, mycobacteria, or fastidious pathogens (Legionella, Mycoplasma, Chlamydia pneumoniae, Bartonella)	5%
Viral infections (herpesviruses, CMV, EBV, HHV-6, VZV, HSV, parainfluenza, RSV, influenza)	5%
Undefined (drug fever, chemotherapy toxicity, antitumor responses, undefined pathogens)	25%

When neutropenic patients fail to defervescence on appropriate empiric antibiotics, fungal infection (especially invasive aspergillosis) and CMV must move high on the differential. Invasive fungal infection carries mortality rates exceeding 50% even with treatment if there is significant delay in diagnosis.

(Corey and Boeckh, 2002)

Cell-mediated immunity - Th1 pathway

(Playfair and Bancroft, 2013)

Cell-mediated immunity - Th2 pathway

(Playfair and Bancroft, 2013)

Cell-mediated immunity -
Drug allergy (Type IV hypersensitivity)

Drug fever is a type IV hypersensitivity reaction mediated by T cells. It typically appears 1-3 weeks after starting a medication and resolves within 48-72 hours of drug discontinuation. Antibiotics are the most common culprits, but NSAIDs, anticonvulsants, and many other drugs can cause fever. The diagnosis is clinical - there are no specific tests, but re-challenge with the drug should reproduce the fever (though this is rarely done in practice).

(Playfair and Bancroft, 2013)

Infections in immunocompromised hosts:
A summary in one slide!

The degree and type of immunosuppression determines which infections are most likely. CD4 count <200 in HIV predisposes to PCP and toxoplasmosis. Neutropenia predisposes to bacterial and fungal infections. T-cell defects (from chemotherapy, calcineurin inhibitors) predispose to opportunistic infections like CMV and fungal infections. Understanding the specific immune defect is critical for generating an appropriate differential diagnosis.

HIV-related FUO

• Primary infection phase characterized by mononucleosis-like illness
  • Fever is common
  • May be undiagnosed if it precedes seroconversion (acute retroviral syndrome)
• Later phases of untreated HIV
  • Episodes of fever become common
  • Often signify superimposed illness - e.g., opportunistic infections
  • Infections may manifest atypically
• HAART era impact
  • Once highly-active antiretroviral therapy (HAART) is started
  • Effective suppression of HIV viral load
  • Frequency of FUO falls markedly
  • CD4⁺ recovery allows control of opportunistic infections

Etiology of fever in HIV-Associated FUO (n=70)

Etiology	No. (%)
Infection	63 (88%)
DMAC	22 (31%)
Pneumocystis jirovecii pneumonia	10 (13%)
CMV	8 (11%)
Histoplasmosis	5 (7%)
Viral (not CMV)	5 (7%)
Bacterial	4 (5%)
Mycobacterium tuberculosis	4 (5%)
Fungal (not histoplasmosis)	2 (3%)
Parasitic	2 (3%)
Mycobacterium genavense	1 (1%)
Neoplasia	6 (8%)
Lymphoma	5 (7%)
Kaposi sarcoma	1 (1%)
Miscellaneous	3 (4%)
Drug fever	2 (3%)
Castleman disease	1 (1%)

DMAC- disseminated Mycobacterium avium complex

(Wright and Mackowiak, 2015)

Naproxen (NSAID) fever suppression test for “tumor fever”

• Indications for trial:
  • Temperature > 37.8°C at least once daily for ≥2 weeks
  • Lack of evidence of infection (physical exam, labs, imaging)
  • Absence of drug fever, transfusion reaction, or allergic mechanisms
  • Lack of response to ≥7 days of empiric antibiotics
• Procedure:
  • Naproxen 500 mg BID × 3-5 days
• Positive result:
  • Prompt complete defervescence (lysis of fever)
  • Sustained normal temperature while receiving naproxen
  • Fever recurrence when drug discontinued
• Note: Not universally used; sensitivity/specificity debated

Diagnosis of FUO

General diagnostic evaluation of FUO

Step	Investigation
History & Exam	Comprehensive history; repeated physical exams
Laboratory	CBC, comprehensive metabolic panel, urinalysis with microscopy
Inflammatory Markers	ESR, C-reactive protein
Autoimmune Screening	ANA, rheumatoid factor
Imaging - First Line	Chest radiograph, CT abdomen/pelvis
Cultures	Blood cultures (3 specimens without antimicrobials), urine culture
Serologies	CMV IgM/PCR, heterophil antibody (EBV) in young adults
Tuberculosis	Tuberculin skin test, interferon-gamma release assay
Advanced Imaging	MRI, PET-CT, duplex ultrasound lower extremities
Invasive Procedures	Biopsy (lymph node, liver, bone marrow) if indicated

The history and physical examination must guide which investigations to pursue, otherwise the patient will undergo excessive and often unnecessary testing with false positives leading to misdirected therapy.
(Wright and Mackowiak, 2015)

Patient history

• Helps guide choice of initial laboratory investigations - this is the most important step

• Travel history: where, when, duration, exposures to animals, arthropod vectors, contaminated water

• Exposure to animals and work environment: pet birds (psittacosis), cats (toxoplasmosis, bartonellosis), tick exposure (Lyme, Q fever)

• Recent contact with ill persons or family history of FUO (e.g., familial Mediterranean fever)

• Complete medication list: including OTC drugs, supplements, recent antimicrobials

• Prior history of FUO - may be recurrence of same diagnosis

• Previously diagnosed conditions: malignancy, rheumatic fever, valve disease that predisposes to endocarditis

A 45-year-old history of fever in a farmer with exposure to birth products of cattle should immediately suggest Q fever. A history of fever in a Southwest US resident with respiratory symptoms should suggest coccidioidomycosis. The history is the most efficient diagnostic tool - proper use can narrow a vast differential to a manageable few diagnoses.

Verification of fever and pattern of fever

• Verification of fever: Often overlooked step
  • In some series, up to 30% referred for FUO where determined to NOT have fever
  • Request fever log or have patient take temperatures at home
• Fever patterns - use of patterns to narrow differential:
  • Continuous, remittent, intermittent, hectic (Charcot’s), quotidian, quartan, biphasic (saddleback), Pel-Ebstein
• Factors affecting fever pattern:
  • Hydration status, ambient temperature
  • Accuracy of temperature measurements (different sites)
  • Antipyretics and corticosteroids suppress fever
  • Blood transfusions and other medical interventions

Continuous sustained fever

• Continuous fever with slight remission not exceeding 2°C

  • Lobar and gram-negative pneumonia
  • Rickettsiosis
  • Typhoid fever
  • CNS disorders
  • Tularemia
  • Falciparum (malignant tertian) malaria

(Mackowiak et al., 1997)

Intermittent (quotidian) fever

• Intermittent fever with wide fluctuations, usually normal or low in the morning and peaking between 4:00 and 8:00 PM
  • Localized pyogenic infections and bacterial endocarditis with chills and leukocytosis
  • Malaria may present with daily (quotidian), every 3rd day (tertian), or every 4th day (quartan) patterns
  • Double quotidian pattern (two daily spikes) seen with:
    • Salmonellosis
    • Miliary tuberculosis
    • Double malarial infections (>1 species)
    • Gonococcal and meningococcal endocarditis

(Mackowiak et al., 1997)

Malaria fever - Paroxysmal patterns

Febrile paroxysms may occur every other day for P. vivax, P. ovale, and P. falciparum (tertian fever) and every third day for P. malariae (quartan fever).

Paroxysms occurring at regular intervals are more common in P. vivax or P. ovale than P. falciparum. With improvements in early diagnosis and treatment, this traditional description of cyclic fever is seen infrequently.

The regular paroxysmal pattern of malaria fever historically served as a diagnostic clue, but modern rapid diagnostic tests have made fever pattern analysis less clinically relevant. Still, recognizing the tertian and quartan patterns can be helpful in settings with limited diagnostic capacity.

Saddle-back (biphasic) fever

• Several days of fever, distinct reduction in fever for ~1 day, then several days of higher fever
  • Dengue and yellow fever
  • Colorado tick fever
  • Rift valley fever
  • Influenza and other viral infections

(Mackowiak et al., 1997)

Intermittent hectic (Charcot’s) fever

• Sporadic episodes of fever with periods of normal temperature and recurrence
  • Frequently seen in cholangitis associated with cholelithiasis
  • Classic teaching: jaundice, fever, right upper quadrant pain (Charcot’s triad)
  • Often associated with leukocytosis and toxic appearance

(Mackowiak et al., 1997)

Undulating (Pel-Ebstein) fever

• Weekly or longer periods of fever and equally long afebrile periods, with repetition of the cycle
  • Hodgkin’s disease (classic association)
  • Brucellosis due to Brucella melitensis
  • Occasionally tuberculosis

While Pel-Ebstein fever was historically associated with Hodgkin lymphoma, modern cases are rarely encountered in developed countries due to earlier diagnosis. However, it remains a useful pattern to recognize in resource-limited settings where lymphoma diagnosis may be delayed.

(Mackowiak et al., 1997)

Typus Inversus

• Reversal of diurnal pattern with highest temperatures in early morning hours rather than late afternoon/evening
  • Miliary TB
  • Salmonelloses
  • Hepatic abscess
  • Bacterial endocarditis

Typus inversus is an unusual pattern but when present strongly suggests one of the listed diagnoses. Its presence should prompt investigation for disseminated TB or endocarditis.(Mackowiak et al., 1997)

Typhoid fever - Step-ladder fever

The classic teaching of typhoid’s step-ladder fever (progressively higher fever each day for 3-4 days until reaching a plateau) is less commonly observed in modern cases, possibly due to partial treatment with antipyretics or other antimicrobials before diagnosis. However, when present, it is highly suggestive of enteric fever. Note the relative bradycardia-a suggestive sign of Typhoid fever.

Jarisch-Herxheimer reaction

• Definition: Sharply increased elevation of temperature with rigors, chills, and constitutional symptoms occurring within hours of starting antibiotic therapy

• Mechanism: Lysis of spirochetes (or other organisms) releases endotoxin triggering acute inflammatory response

• Organisms associated:

  • Primary or secondary syphilis
  • Leptospirosis
  • Tick-borne relapsing fever (Borrelia)
  • Tetracycline or chloramphenicol therapy for acute brucellosis

• Clinical significance: Can be severe enough to cause hemodynamic compromise; does not indicate treatment failure

Recognizing the Jarisch-Herxheimer reaction prevents inappropriate termination of antibiotic therapy. Patients and clinicians should be counseled to expect transient clinical deterioration with initiation of treatment for spirochetal diseases.

Physical examination

• Some signs are subtle and may require repeated exams to be appreciated
• Vigorous search for lymphadenopathy (consideration for biopsy)
• Careful examination of fundi, oropharynx, temporal arteries, abdomen, spleen, joints, skin, nails, genitalia

Body site	Physical finding	Diagnosis
Head	Sinus tenderness	Sinusitis
Temporal artery	Nodules, reduced pulsations	Temporal arteritis
Oropharynx	Ulceration; tender tooth	Disseminated histoplasmosis, periapical abscess
Fundi / conjunctivae	Choroid tubercle, petechiae, Roth’s spot	Disseminated granulomatosis, endocarditis
Thyroid	Enlargement, tenderness	Thyroiditis
Heart	Murmur	Infective or marantic endocarditis
Abdomen	Enlarged iliac lymph nodes, splenomegaly	Lymphoma, endocarditis, disseminated granulomatosis
Rectum	Perirectal / prostatic fluctuance, tenderness	Abscess
Genitalia	Testicular nodule; epididymal nodule	Periarteritis nodosa; disseminated granulomatosis
Lower extremities	Deep venous tenderness	Thrombosis / thrombophlebitis
Skin and nails	Petechiae, splinter hemorrhages, subcutaneous nodules, clubbing	Vasculitis, endocarditis

(Wright and Mackowiak, 2015)

Laboratory investigations

“The cause of FUO is more frequently a common disease presenting in an atypical fashion than a rare disease presenting in a typical fashion.”

• Multiple diagnostic algorithms exist in literature

• Must be selectively applied or will result in excessive unfocused diagnostic testing

  • False positives lead to misdiagnosis
  • Misguided treatment plans

• “Sutton’s Law” - pursue most likely diagnosis first based on history and epidemiology

• History and physical exam (most important) should guide choice and sequence of tests

Shotgun laboratory approach to FUO is expensive, time-consuming, and counterproductive. A focused history-driven approach is far more efficient. This principle of parsimony - explaining the patient’s illness with the fewest assumptions - remains central to good diagnostics.

Examples of potential diagnostic clues (1/3)

Etiology	Historical clues	Physical clues
Anaplasmosis	Ixodes tick bite; outdoor activity in North Central / Eastern US	Fever, headache, arthralgia, myalgia, pneumonitis, thrombocytopenia, lymphopenia, ↑ liver enzymes
Babesiosis	Ixodes tick bite; outdoor activity in Northeastern US	Arthralgias, myalgias, relative bradycardia, hepatosplenomegaly, anemia, thrombocytopenia, ↑ liver enzymes
Bartonellosis	Travel to Andes (Oroya fever; B. bacilliformis); homelessness (B. quintana); scratch from infected kitten/cat (B. henselae)	Conjunctivitis, retro-orbital pain, anterior tibial bone pain, macular rash, nodular plaque lesions, regional lymphadenopathy
Blastomycosis	Contact with soil near Mississippi/Ohio River valleys, Saint Lawrence River, or Great Lakes; exposure to infected dogs	Arthritis, atypical pneumonia, pulmonary nodules, ARDS, verrucous/nodular/ulcerative skin lesions, prostatitis
Brucellosis	Contact with/consumption of products from infected goats, pigs, camels, yaks, buffalo, cows; abattoir work	Arthralgias, hepatosplenomegaly, suppurative musculoskeletal lesions, sacroiliitis, spondylitis, uveitis, hepatitis, pancytopenia
Coccidioidomycosis	Exposure to soil or dust in the southwestern US	Arthralgias, pneumonia, pulmonary cavities, pulmonary nodules, erythema multiforme, erythema nodosum
Ehrlichiosis	Amblyomma, Dermacentor, or Ixodes tick bite; outdoor activity in midwestern / southeastern US	Pneumonitis, hepatitis, thrombocytopenia, lymphopenia

Examples of potential diagnostic clues (2/3)

Etiology	Historical clues	Physical clues
Enteric fever (Salmonella Typhi)	Recent travel to endemic country; consumption of potentially contaminated food or water	Headache, arthritis, abdominal pain, relative bradycardia, hepatosplenomegaly, leukopenia
Histoplasmosis	Exposure to bat/blackbird excreta in roosts, chicken houses, or caves; Ohio and Mississippi River valleys	Headache, pneumonia, pulmonary cavities, mucosal ulcers, adenopathy, erythema nodosum, erythema multiforme, hepatitis, anemia, leukopenia, thrombocytopenia
Leptospirosis	Occupational exposure in sewers, rice/sugar cane fields, abattoirs; recreational water sports; contact with contaminated water or infected dogs	Bitemporal/frontal headache, calf and lumbar muscle tenderness, conjunctival suffusion, hepatic and renal failure, hemorrhagic pneumonitis
Leishmaniasis (visceral)	Recent travel to sand fly–endemic areas	Hepatosplenomegaly, lymphadenopathy, hyperpigmentation of face/hands/feet/abdomen (kala azar)
Malaria	Recent travel to endemic areas in Asia, Africa, or Central/South America	Fever, headaches, nausea, vomiting, diarrhea, hepatosplenomegaly, anemia
Psittacosis (Chlamydia psittaci)	Contact with birds, especially psittacine birds	Fever, pharyngitis, hepatosplenomegaly, pneumonia, blanching maculopapular eruptions, erythema multiforme, erythema marginatum, erythema nodosum

Examples of potential diagnostic clues (3/3)

Etiology	Historical clues	Physical clues
Q fever (Coxiella burnetii)	Farm, veterinary, or abattoir work; unpasteurized milk; contact with infected sheep, goats, or cattle	Atypical pneumonia, hepatitis, hepatomegaly, relative bradycardia, splenomegaly
Rat-bite fever (Streptobacillus moniliformis)	Recent bite/scratch from rat, mouse, or squirrel; ingestion of food/water contaminated with rat excrement	Headaches, myalgias, polyarthritis, maculopapular/morbilliform/petechial/vesicular/pustular rash over palms, soles, and extremities
Relapsing fever (Borrelia recurrentis)	Poverty/crowding/poor sanitation (louse-borne); camping in the Grand Canyon (tick-borne)	High fever with rigors, headache, delirium, arthralgias, myalgias, hepatosplenomegaly
Rocky Mountain spotted fever	Outdoor activity in South Atlantic or southeastern US; Dermacentor tick bites	Headache, petechial rash on extremities, palms, and soles
Tuberculosis	Contact with TB; immigration from endemic country; homeless shelter or healthcare facility exposure	Night sweats, weight loss, atypical pneumonia, cavitary pulmonary lesions
Tularemia	Bites from Amblyomma or Dermacentor ticks, deer flies, or mosquitoes; direct contact with rabbits, squirrels, deer, raccoons, cattle, sheep, or swine	Ulcerated skin lesion at bite site, pneumonia, relative bradycardia, lymphadenopathy, conjunctivitis
Whipple’s disease (Tropheryma whipplei)	Potential association with exposure to sewage	Chronic diarrhea, arthralgia, weight loss, malabsorption, malnutrition

Each finding or cluster of findings can point toward specific diagnoses. A patient with fever and a pulsatile abdominal mass should get abdominal imaging for AAA. A patient with fever and new cardiac murmur should get echocardiography. A patient with fever and temporal headache in someone over 50 should get ESR/CRP and consideration for temporal artery biopsy.

(Wright and Mackowiak, 2015)

Bone marrow biopsy

• Diagnostic yield: ~25% in two case series; especially valuable for:
  • Granulomatous infections (TB, histoplasmosis, sarcoidosis)
  • Hematologic malignancies (leukemia, lymphoma)
  • Patients with abnormal CBC (anemia, thrombocytopenia, leukopenia)
• Organisms identified:
  • Mycobacterium tuberculosis
  • Fungi (Histoplasma, Cryptococcus, Coccidioides)
  • Intracellular bacteria (Brucella, Bartonella)
• Consider: When fever pattern and presentation suggest granulomatous disease or hematologic malignancy

Imaging studies

Generally low diagnostic yield without localizing symptoms

• CT of abdomen and chest

• Ultrasound of gallbladder and hepatobiliary systems

• CT pulmonary angiogram (for pulmonary embolis)

• MRI for CNS, spleen, lymph nodes, aorta (vasculitis)

• Indium 111-tagged white blood cell scan (becoming less common)

• Gallium-67 scan (largely replaced by PET-CT)

• PET-CT: Superior sensitivity for inflammatory and malignant processes

¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography

PET-CT has revolutionized the diagnostic approach to FUO. Overall sensitivities range from 86-98% and specificities from 52-85%, depending on the etiology. It is particularly useful for detecting focal sites of infection or inflammation that might be missed on conventional imaging.Key clinical applications: - Should be performed early in workup - Most helpful for: abscesses, osteomyelitis, vasculitis, adult-onset Still disease, Crohn disease, subacute thyroiditis - Can identify sites for targeted biopsy

(Kouijzer et al., 2018)

Invasive diagnostic procedures

• Biopsy techniques:
  • Excisional biopsy (lymph node)
  • Needle biopsy (liver, kidney, muscle)
  • Laparotomy or laparoscopy for direct visualization
• Diagnostic yield:
  • Biopsy yields diagnosis in < 50% of cases
  • Average 2-3 biopsies needed to establish diagnosis
• Indications:
  • Abnormal imaging or physical exam findings
  • Lymphadenopathy suitable for lymph node biopsy
  • Suspected granulomatous disease
  • Persistent fever despite extensive workup

Treatment Section

A fundamental principle in classic FUO:

Therapy should be withheld until the cause of fever is determined

This is easier said than done in clinical practice, but the principle remains sound. Non-specific treatment with antipyretics, antibiotics, or corticosteroids rarely “cures” FUO and often delays the correct diagnosis, leading to prolonged suffering and inappropriate therapy.

Diagnostic summary and approach

Step 1

Perform a comprehensive history and complete physical examination.

Step 2

PDCs identified?

YES →

NO

Step 3

Order CBC, CMP, ESR, CRP, ferritin, TSH, RF, ANA, HIV-1/2 serology, hepatitis A, B, and E, urinalysis with microscopy, tuberculosis skin test or TB whole-blood interferon-γ releasing assay, blood cultures ×3, venous duplex imaging of the lower extremities, CT of chest and abdomen/pelvis, and echocardiography (TTE/TEE).

Step 4

Any positive first-tier testing?

YES →

NO

Step 5

Any PDCs by repeat history and physical examination?

YES →

NO

Step 6

Order 18FDG-PET/CT scan imaging (if not already performed).

Positive →

Negative Result

Step 7

If there are still no new PDCs, re-evaluate the patient history and physical examination periodically. Continue to monitor for any new PDCs and apply appropriate noninvasive and/or invasive diagnostic testing based upon any new findings. At this stage, empiric use of nonsteroidal anti-inflammatory agents or immunosuppressant therapy such as corticosteroids could be entertained after discussing risks and benefits with the patient.

Step 2 — If YES

Apply appropriate invasive or noninvasive diagnostic studies for investigation.

Step 4 — If YES

Apply second-tier testing such as specialized imaging (MRI, nuclear imaging, or 18FDG-PET scans) or appropriate biopsy methods for culture and histologic analysis.

Step 5 — If YES

Apply appropriate invasive and noninvasive diagnostic studies for investigation.

Step 6 — Positive Result

Apply appropriate invasive and noninvasive diagnostic studies for investigation.

Adapted from Cunha et al. © 2020 JHU/AAM

(Wright and Auwaerter, 2020)

When is immediate treatment indicated?

• Suspected temporal arteritis
  • Empirical corticosteroids to prevent vascular complications (blindness, stroke)
  • Do not wait for biopsy confirmation if clinical suspicion high
• Febrile neutropenia or severe immunocompromise
  • High prevalence of serious bacterial infections
  • Broad-spectrum antimicrobial therapy with anti-pseudomonas coverage after appropriate cultures obtained
  • No delay for culture results
• Select cases with strong clinical suspicion:
  • Anti-mycobacterial therapy in suspected TB (especially if respiratory symptoms)
  • Targeted therapy based on epidemiology and presentation

These exceptions to the “do not treat before diagnosis” rule are important. Temporal arteritis is a true medical emergency where delaying treatment risks permanent vision loss. Similarly, in neutropenic patients, the high mortality of untreated bacteremia necessitates empiric therapy. In contrast, empiric antibiotics in immunocompetent patients with FUO are generally unhelpful.

Prognosis

• Determined by: The underlying cause of fever and nature of underlying disease(s)

• Poor prognosis: Elderly patients with malignant neoplasms

• Diagnostic delay worsens prognosis in:

  • Intra-abdominal infections (perforation, sepsis)
  • Miliary tuberculosis
  • Disseminated fungal infections
  • Recurrent pulmonary emboli

• Favorable outlook: Patients with undiagnosed FUO after extensive evaluation

  • Most experience resolution of fever within 4 weeks without sequelae
  • 5-year mortality rate: 3.2% for undiagnosed FUO
  • Superior to patients with diagnosed malignancy as the underlying cause

This prognosis for undiagnosed FUO is reassuring and often not communicated to patients. Many are left feeling that an undiagnosed fever indicates a serious overlooked condition, when in fact the natural history suggests spontaneous resolution in most cases. Of course, continued surveillance is appropriate.

References

Corey L, Boeckh M. Persistent fever in patients with neutropenia. New England Journal of Medicine 2002;346:222–4.

Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. New England Journal of Medicine 1999;340:448–54.

Haidar G, Singh N. Fever of Unknown Origin. New England Journal of Medicine 2022;386:463–77.

Kouijzer IJE, Vos FJ, Rijnders BJA, Aarntzen EAHG, Bleeker-Rovers CP. The value of \(^{18}\)F-FDG PET/CT in diagnosing infectious endocarditis. European Journal of Nuclear Medicine and Molecular Imaging 2018;45:1085–99.

Mackowiak PA, Wasserman SS, Levine MM. Concepts of fever: Recent advances and lingering dogma. Clinical Infectious Diseases 1997;25:996–1003.

Mackowiak PA, Worden G. Carl Reinhold August Wunderlich and the evolution of clinical thermometry. Clinical Infectious Diseases 1994;18:458–67.

Playfair JHL, Bancroft GJ. Infection and Immunity. 4th ed. Oxford University Press; 2013.

Sajadi MM, Mackowiak PA. Chapter 57: Temperature Regulation and the Pathogenesis of Fever. Mandell’s principles and practice of infectious diseases. 9th ed., Elsevier; 2020.

Sickles EA, Young VM, Greene WH, Wiernik PH. Clinical presentation of infection in granulocytopenic patients. Archives of Internal Medicine 1975;135:715–9.

Wright WF, Auwaerter PG. Chapter 58: Fever of Unknown Origin. Mandell’s principles and practice of infectious diseases. 9th ed., Elsevier; 2020.

Wright WF, Mackowiak PA. Fever of Unknown Origin. Mandell’s principles and practice of infectious diseases. 8th ed., Elsevier; 2015.