Download PDF

Fever of Unknown Origin¶

Chapter 22 | Part 2: Cardinal Manifestations and Presentation of Diseases · Part 2 – Cardinal Manifestations & Presentation · Chapter 22

Key Clinical Points¶

FUO is defined as fever ≥38.3°C (≥101°F) on at least two occasions, illness duration ≥3 weeks, and no known immunocompromised state.
In Western cohorts, noninfectious inflammatory diseases (NIIDs) are the most common cause; in non-Western cohorts, infections (especially tuberculosis) predominate.
The 'FUO paradox' describes how the proportion of undiagnosed cases remains high despite advanced diagnostics because easier cases are identified before 3 weeks.
Drug fever must be ruled out by stopping all medications for ≥72 hours before attributing fever to other causes.
VEXAS syndrome is a new adult-onset multisystem autoinflammatory syndrome (UBA1 mutation) characterized by myeloid precursor vacuoles and recurrent inflammation.
Potentially Diagnostic Clues (PDCs) are essential for narrowing the differential; 18F-FDG-PET/CT has a diagnostic yield of approximately 50%.
Infections like endocarditis, diverticulitis, and osteomyelitis remain common; Q fever and Whipple's disease should be considered in specific clinical contexts.
Neoplasms: Malignant lymphoma is the most common malignancy causing FUO.
Noninfectious inflammatory diseases (NIIDs) include adult-onset Still's disease, various vasculitides, SLE, and sarcoidosis.
A second opinion from an expert center is recommended if no diagnosis is found after standard workup.

DEFINITION & OVERVIEW¶

• General Definition: Clinicians commonly refer to any febrile illness without an initially obvious etiology as fever of unknown origin (FUO).

Definition Criteria¶

• Harrison's Definition: - Fever ≥38.3°C (≥101°F) on at least two occasions. - Illness duration of at least 3 weeks. - No known immunocompromised state.

Inflammation of Unknown Origin (IUO)¶

• Definition: Presence of elevated inflammatory parameters (CRP or ESR) on multiple occasions for a period of at least 3 weeks in an immunocompetent patient with normal body temperature, for which a final explanation is lacking despite history-taking, physical examination, and the obligatory tests. - Clinical Note: IUO and FUO share the same causes and workup; the term FUO is used to refer to both conditions in this chapter.

Historical Evolution¶

• 1960s Context: Defined by Petersdorf and Beeson (1961) as ≥3 weeks duration, fever ≥38.3°C on 2 occasions, and no diagnosis after 1 week of inpatient evaluation. - Evolutionary Changes: ◦ Decreased cases of intraabdominal abscesses/tumors due to CT/ultrasound. ◦ Decreased endocarditis cases due to improved blood cultures/echocardiography. ◦ Increased identification of new entities like acute HIV and autoinflammatory diseases.

EPIDEMIOLOGY¶

• Prevalence: Largely unknown; varies by geography and healthcare setting. - Diagnostic Probability: Higher when using older time-based criteria vs. newer criteria including a standard basic workup.

Etiology Distribution by Geography¶

• Non-Western Cohorts: Infections are the most common cause. - Risk of infection is >4x higher in Southern Asia and 3x higher in Far East Asia compared to Europe. - Up to 50% of infections outside Western nations are caused by Mycobacterium tuberculosis. - Western Cohorts: Noninfectious inflammatory diseases (NIIDs) are the most common cause. - Approximately 1/3 of Western patients have a diagnosis falling under NIIDs (autoimmune, autoinflammatory, granulomatous, or vasculitides). - The FUO Paradox: The proportion of undiagnosed cases remains high because easier cases are diagnosed before 3 weeks, leaving only complex cases for the 'FUO' category.

ETIOLOGY & PATHOPHYSIOLOGY¶

• General Principle: Patients with FUO most often suffer from an atypical presentation of a more common disease, rather than a rare disease.

Infectious Causes¶

• Common Infections: Endocarditis, diverticulitis, vertebral osteomyelitis, and extrapulmonary tuberculosis. - Specific Considerations: ◦ Q fever (Coxiella burnetii): Test via IFA if patient is in rural area or has heart valve/vascular history. ◦ Whipple's disease (Tropheryma whipplei): PCR on stool and blood for CNS, GI, or joint symptoms. ◦ Culture-negative endocarditis: Consider HACEK organisms, Coxiella burnetii, T. whipplei, or Bartonella species. ◦ Marantic endocarditis: Sterile thrombotic disease (paraneoplastic, SLE, or antiphospholipid syndrome). - Table 2 (Infections): Includes Bacterial (nonspecific/specific), Fungal, Parasitic, and Viral categories.

Noninfectious Inflammatory Diseases¶

• Common NIIDs: Adult-onset Still's disease, large-vessel vasculitis, polymyalgia rheumatica, SLE, and sarcoidosis. - Autoinflammatory Syndromes: Often diagnosed by clinical criteria; e.g., Familial Mediterranean fever (geographic), Schnitzler's syndrome (urticaria, bone pain, monoclonal gammopathy). - VEXAS Syndrome: ◦ Definition: Vacuoles, E1 enzyme, X-linked autoinflammatory syndrome. ◦ Characteristics: Adult-onset multisystem autoinflammatory syndrome; predominantly in middle-aged to elderly males; features include recurrent inflammation, arthritis, and myelodysplastic syndrome. ◦ Pathophysiology: Somatic mosaicism for mutations in UBA1. ◦ Diagnostic Clue: Presence of vacuoles in myeloid precursors on bone marrow biopsy. - Table 3 (Noninfectious): Includes systemic rheumatic/autoimmune, vasculitis, granulomatous, and autoinflammatory categories.

Neoplasms¶

• Hematologic: Malignant lymphoma is the most common diagnosis of FUO among neoplasms; may precede detectable lymphadenopathy. - Solid Tumors: Most common are breast, colon, hepatocellular, lung, pancreatic, and renal cell carcinomas.

Miscellaneous Causes¶

• Drug Fever: Rule out by stopping all medications for ≥72 hours. - Benign Hyperthermia: No increase in CRP/ESR; may be postinfectious (e.g., EBV, Q-fever). - Factitious/Fraudulent Fever: ◦ Factitious: Patient induces fever. ◦ Fraudulent: Patient manipulates the thermometer. - Table 5 (Miscellaneous): Includes a wide range of conditions including ADEM, various syndromes, and environmental exposures.

Thermoregulatory Disorders¶

• Central: Brain tumor, cerebrovascular accident, encephalitis, hypothalamic dysfunction. - Peripheral: Anhidrotic ectodermal dysplasia, benign hyperthermia, exercise-induced hyperthermia, heat stroke, hyperthyroidism, paroxysmal sympathetic hyperactivity, pheochromocytoma.

CLINICAL FEATURES¶

• General Observation: Most cases resolve or develop distinguishing features before a final diagnosis is made. - Physical Examination: ◦ Focus: Eyes, lymph nodes, temporal arteries, liver, spleen, skin, and mucous membranes. ◦ Timing: Perform during an inflammatory episode; abnormalities may be absent between episodes. ◦ Pre-test Step: Stop antibiotics/glucocorticoids before testing to ensure accurate cultures and clear imaging. - Fever Patterns: ◦ Recurrent inflammation: Defined as repeated episodes of fever/inflammation with ≥2 weeks of remission. Lower chance of finding an infection. ◦ Duration: Symptoms >12 months associated with lower chance of diagnosis (less likely to be infection/malignancy). ◦ Imaging: Normal PET/CT correlates with a lower chance of final diagnosis.

Specific Syndromes¶

• VEXAS: Recurrent skin lesions, chondritis, lung disease, venous thrombosis, arthritis, and myelodysplastic syndrome. - Schnitzler's: Urticaria, bone pain, and monoclonal gammopathy.

DIFFERENTIAL DIAGNOSIS¶

• Core Principle: Most FUO cases are atypical presentations of common diseases. - Geographic Influence: Distribution is heavily influenced by local epidemiology (e.g., higher infection rates in non-Western regions).

DIAGNOSTIC APPROACH¶

Initial Assessment & Preparation
Perform comprehensive history and physical examination.
Pre-test Step: Stop all medications (e.g., antibiotics, corticosteroids) for ≥72 hours before attributing fever to a specific cause or performing definitive tests.
Obligatory Investigations
Laboratory: CBC with differential, ESR, CRP, electrolytes, renal/liver function, ferritin, ANA, RF, protein electrophoresis, urinalysis.
Cultures: 3 blood cultures, urine culture.
Imaging: Chest X-ray, abdominal ultrasound (preferred over CT due to cost/radiation).
Other: TST/IGRA.
Decision Pathway based on Potentially Diagnostic Clues (PDCs)
Identify PDCs (all localizing signs, symptoms, and abnormalities).
If PDCs are present:
Proceed to guided diagnostic tests → Diagnosis reached OR → Proceed to 18F-FDG-PET/CT.
If PDCs are absent or misleading:
Perform cryoglobulin and fundoscopy → Proceed to 18F-FDG-PET/CT.
Post-Imaging Analysis (18F-FDG-PET/CT)
If 18F-FDG-PET/CT is abnormal:
Confirm abnormality (e.g., culture) → Diagnosis reached OR No diagnosis.
If 18F-FDG-PET/CT is normal:
Repeat history and physical examination → Proceed to PDC-driven invasive looking → Diagnosis reached OR No diagnosis.
Final Management Step
Stable condition: Follow up in 3 months with repeat imaging.
Deteriorating condition: Perform more aggressive clinical trials and further diagnostic tests.

Imaging Modalities¶

• 18F-FDG-PET/CT: Preferred over conventional scintigraphy; approximately 50% diagnostic yield. - Standard Imaging: Abdominal ultrasound and chest X-ray are preferred initial steps due to lower cost and radiation.

MANAGEMENT & TREATMENT¶

Pre-diagnostic Management
Stop all medications for ≥72 hours before attributing fever to a specific cause (to rule out drug fever).
Treatment Principles
Treatment should be tailored based on the identified diagnosis.
Follow-up Protocol
Stable patients: Follow up in 3 months with repeat imaging.
Deteriorating patients: Initiate more aggressive clinical trials and additional diagnostic tests.

PROGNOSIS & COMPLICATIONS¶

• Diagnostic Delay: Longer duration of symptoms (>12 months) correlates with a lower probability of finding an infection or malignancy. - Clinical Stability: Deteriorating patients require more aggressive intervention.

SPECIAL CONSIDERATIONS¶

• Geographic Variation: - Non-Western: High prevalence of infections (especially TB). - Western: Higher proportion of NIIDs. - Immunocompromised State: Standard FUO definition excludes known immunocompromised states; these patients require different diagnostic considerations.

KEY PEARLS & CLINICAL TRAPS¶

• PDCs: The cornerstone of the workup; they guide specific testing and narrow the differential. - Drug Fever Rule: Must wait ≥72 hours after stopping meds to rule out drug-induced fever. - VEXAS Syndrome: Look for myeloid precursor vacuoles in bone marrow if a patient has recurring inflammation and is over age 40. - FUO Paradox: Acknowledges that many 'easy' cases are caught early, leaving only complex/hard-to-diagnose cases as FUO.

Reference Tables¶

TABLE 22-1 Etiology of FUO: Pooled Results of Large Studies Published in the Past 20 Years (2003–2023)¶

Harrison's 22e, p.149

GEOGRAPHIC AREA	NO. OF COHORTS (INCLUSION PERIOD)	NO. OF PATIENTS	INFECTIONS, MEDIAN % (RANGE)	NONINFECTIOUS INFLAMMATORY DISEASES, MEDIAN % (RANGE)	MALIGNANCY, MEDIAN % (RANGE)	MISCELLANEOUS, MEDIAN % (RANGE)	NO DIAGNOSIS, MEDIAN % (RANGE)
Western Europe	12 (1995–2020)	2100	15.5 (4–36)	25 (17–33)	11 (3–30)	7.5 (0–16)	39.5 (26–54)
	15 (1984–2019)	1615	42 (26–74)	23 (12–38)	14 (4–19)	5 (2–18)
Middle East	3 (2009–2010)a	1289	66 (42–79)	15 (7–17)	7 (1–30)	1 (0–12)	8 (2–12)
	39 (1994–2021)a	7191	42 (3–58)	19 (7–57)	13 (6–23)	6.5 (0–15)

TABLE 22-2 Reported Causes of Fever of Unknown Origin (FUO) a Infections Bacterial, nonspecific Abdominal abscess…¶

Harrison's 22e, p.151

Infections
Bacterial, nonspecific	Abdominal abscess, adnexitis, aortitis, apical granuloma, appendicitis, bacterial translocation, bronchiectasis, cholangitis, cholecystitis, diverticulitis, endocarditis, endometritis, epididymitis, epidural abscess, infected joint prosthesis, infected vascular catheter, infected vascular prosthesis, infectious arthritis, infective myonecrosis, intracranial abscess, liver abscess, lung abscess, malakoplakia, mastitis, mastoiditis, mediastinitis, muscle abscess, mycotic aneurysm, osteomyelitis, pelvic inflammatory disease, prostatitis, pyelonephritis, pylephlebitis, pyomyoma, renal abscess, septic arthritis, septic phlebitis, sinusitis, spondylodiscitis, xanthogranulomatous urinary tract infection
Fungal	Aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, Malassezia furfur infection, mucormycosis, paracoccidioidomycosis, Penicillium spp., Pneumocystis jirovecii pneumonia, sporotrichosis, Talaromyces infection
Viral	Colorado tick fever, coxsackievirus infection, cytomegalovirus infection, chikungunya, dengue, Epstein-Barr virus infection, hantavirus infection, hepatitis (A, B, C, D, E), herpes simplex, HIV infection, human herpesvirus 6 infection, parvovirus infection, West Nile virus infection
Noninfectious Inflammatory Diseases
Vasculitis	Allergic vasculitis, antineutrophil cytoplastic antibody (ANCA) vasculitis, Cogan’s syndrome, eosinophilic granulomatosis with polyangiitis, giant cell vasculitis/polymyalgia rheumatica, granulomatosis with polyangiitis, hypersensitivity vasculitis, IgA vasculitis, Kawasaki disease, polyarteritis nodosa, Takayasu arteritis, urticarial vasculitis
Autoinflammatory syndromes	Blau syndrome, CAPSb (cryopyrin-associated periodic syndromes), Crohn’s disease, DIRA (deficiency of the interleukin 1 receptor antagonist), deficiency of adenosine deaminase 2 (DADA2), familial Mediterranean fever, hyper-IgD syndrome (HIDS, due to mevalonate kinase deficiency), juvenile idiopathic arthritis, macrophage activation syndrome, NLRP12-related disease, PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis), recurrent idiopathic pericarditis, SAPHO (synovitis, acne, pustulosis, hyperostosis, osteomyelitis), Schnitzler’s syndrome, Still’s disease, TRAPS (tumor necrosis factor receptor– associated periodic syndrome), VEXAS (vacuoles, E1 enzyme, X-linked autoinflammatory syndrome)
Neoplasms
Solid tumors	Most solid tumors and metastases can cause fever. Those most common causing FUO are breast, colon, hepatocellular, lung, pancreatic, and renal cell carcinomas.
Miscellaneous Causes
	ADEM (acute disseminated encephalomyelitis), adrenal insufficiency, alcoholic steatohepatitis, allergic purpura, aneurysms, anal fistula, anti- NMDA encephalitis, antisynthetase syndrome, anomalous thoracic duct, aortic dissection, aortic-enteral fistula, aseptic meningitis (Mollaret’s syndrome), atrial myxoma, brewer’s yeast ingestion, calcium pyrophosphate deposition, Caroli’s disease, cholesterol emboli, cirrhosis, complex partial status epilepticus, crowned dense syndrome, cyclic neutropenia, cryptogenic organizing pneumonia, drug fever, Erdheim-Chester disease, extrinsic allergic alveolitis, Fabry’s disease, factitious disease, fire-eater’s lung, fraudulent fever, Dressler’s syndrome, ganglioneuroma, extrinsic allergic alveolitis, Gaucher’s disease, hemolytic uremic syndrome, Hamman-Rich syndrome (acute interstitial pneumonia), Hashimoto’s encephalopathy, hematoma, heparin-induced thrombocytopenia, histiocytic necrotizing lymphadenitis, hypersensitivity pneumonitis, hypertriglyceridemia, hypogammaglobulinemia/subclass deficiency, hypothalamic hypopituitarism, idiopathic inflammatory myopathy, idiopathic normal-pressure hydrocephalus, IgG4 disease, inflammatory pseudotumor, interstitial nephritis, Kikuchi’s disease, limbic encephalitis, linear IgA dermatosis, mesenteric fibromatosis, metal fume fever, microaspiration, milk protein allergy, Mollaret’s meningitis, myotonic dystrophy, nonbacterial osteitis, obstructive suppurative pancreatic ductitis, organic dust toxic syndrome, panniculitis, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), obstructive sleep apnea syndrome, organizing pneumonia, polymer fume fever, post–cardiac injury syndrome, primary biliary cirrhosis, primary hyperparathyroidism, pseudomembranous colitis, pulmonary embolism, pulmonary nodular lymphoid hyperplasia, pyoderma gangrenosum, recurrent large bowel ischemia, retroperitoneal fibrosis, Rosai-Dorfman disease, sclerosing mesenteritis, silicone embolization, subacute thyroiditis (de Quervain’s), Sweet’s syndrome (acute febrile neutrophilic dermatosis), thrombosis, TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) tubulointerstitial nephritis and uveitis syndrome (TINU), ulcerative colitis, XIAP deficiency (X-linked inhibitor of apoptosis deficiency)
Thermoregulatory Disorders
Peripheral	Anhidrotic ectodermal dysplasia, benign hyperthermia, exercise-induced hyperthermia, heat stroke, hyperthyroidism, paroxysmal sympathetic hyperactivity, pheochromocytoma