FEVER OF

UNKNOWN ORIGIN
Ryan Olmedo
1st Year Resident
MHARSMC IM Dept.
 DEFINITIONS
FEVER OF UNKNOWN ORIGIN – any febrile illness without an initially obvious etiology
- reserved for prolonged febrile illnesses without an established etiology despite intensive
evaluation and diagnostic testing
- illness of > 3 weeks’ duration with fever of ≥38.3°C (101°F) on 2 occasions and an uncertain
diagnosis despite 1 week of inpatient evaluation

INFLAMMATION OF UNKNOWN ORIGIN – same definition as FUO, except for the body
temperature criterion
- presence of elevated inflammatory parameters 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, PE and the obligatory tests listed
 CRITERIA FOR FUO
1. Fever ≥ 38.3°C (101°F) on at least 2 occasions
2. Illness duration of ≥ 3 weeks
3. No known immunocompromised state
4. Diagnosis that remains uncertain after a thorough history-taking, physical
examination, and the following obligatory examinations: ESR, CRP, PLATELET
COUNT, LEUKOCYTE COUNT AND DIFFERENTIAL, HEMOGLOBIN,
ELECTROLYTES, CREATININE, TOTAL PROTEIN, ALKALINE
PHOSPHATASE, ALT, AST, LDH, CREATINE KINASE, FERRITIN,
ANTINUCLEAR ANTIBODIES, RHEUMATOID FACTOR, PROTEIN
ELECTROPHORESIS, URINALYSIS, BLOOD CULTURES (3), URINE
CULTURE, CHEST XRAY, ULTRASOUND OF ABDOMEN, TST OR IGRA
ETIOLOGY AND
EPIDEMIOLOGY
● INFECTIONS: remain the most common cause of FUO
○ Mycobacterium tuberculosis: up to half of all infections in patients with FUO outside Western
nations , less common in Western Europe and USA
● NON-INFECTIOUS INFLAMMATORY DISEASES: most common cause of
FUO in Western cohorts (more than 1/3 of FUOs in Western patients)
○ INCLUDES autoimmune, autoinflammatory and granulomatous diseases, as well as vasculitides
 WESTERN COHORTS
● FUOs remain unexplained in more than 1/3 of cases
○ WHY? Only cases that are most difficult to diagnose continue to meet the criteria for FUO and most
patients with FUO without a diagnosis currently do well

○ Less aggressive diagnostic approach used in clinically stable patients once diseases with immediate
therapeutic or prognostic consequences have been ruled out
● RECURRENT FEVER – repeated episodes of fever interspersed with fever-free
intervals of at least 2 weeks and apparent remission of the underlying disease
○ ETIOLOGY is diagnosed in <50% of cases
DIFFERENTIAL
DIAGNOSIS
● NOTE: FUO is far more often caused by an atypical presentation of a rather common
disease than by a very rare disease
 SPECIAL CONSIDERATIONS: INFECTIOUS
ETIOLOGIES
● Q FEVER –serologic testing should be done by immunofluorescence assay when the
patient lives in a rural area or has a history of heart valve disease, an aortic aneurysm,
or a vascular prosthesis
● WHIPPLE’S DISEASE – PCR testing should be performed in patients with
unexplained symptoms localized to the CNS, GIT or joints
● HISTORY OF TRAVEL OR RESIDENCE IN TROPICS – malaria,
lesihmaniasis, histoplasmosis, coccidioidomycosis
 SPECIAL CONSIDERATIONS:
ENDOCARDITIS
● ETIOLOGIES OF CULTURE-NEGATIVE ENDOCARDITIS – nutritionally
variant bacteria, HACEK bacteria (Haemophilus parainfluenzae, H. paraphrophilus,
Aggregibacter actinomycetemcomitans, A. aphrophilus, A. paraphrophilus,
Cardiobacterium hominis, C. valvarum, Eikenella corrodens, Kingella kingae),
Coxiella burnetti, Tropheryma whipplei, Bartonella
● MARANTIC ENDOCARDITIS – sterile thrombotic disease occurring as a
paraneoplastic phenomenon related to adenocarcinomas
● STERILE ENDOCARDITIS – can be found in SLE and APAS
 SPECIAL CONSIDERATIONS: NIIDs

● HEREDITARY AUTOINFLAMMATORY SYNDROMES – very rare except

familial Mediterranean fever in specific geographic regions, presenting in young
patients
● SCHNITZLER SYNDROME – presents at any age, uncommon, diagnosed easily in
a patient with FUO presenting with urticaria, bone pain, monoclonal gammopathy
 SPECIAL CONSIDERATIONS: NEOPLASMS
● MALIGNANT LYMPHOMA – most common FUO diagnosis among the
neoplasms
○ Fever may precede lymphadenopathy detectable by physical examination
OTHER CONSIDERATIONS
● DRUG-INDUCED FEVER – includes DRESS (drug reaction with eosinophilia and
systemic symptoms)
○ accompanied by eosinophilia, lymphadenopathy (may be extensive)

○ CAUSES: allopurinol, carbamazepine, lamotrigine, phenytoin, sulfasalazine, furosemide,

antimicrobials (sulfonamides, minocycline, vancomycin, beta lactams, isoniazid), cardiovascular drugs
(quinidine), antiretrovirals (nevirapine)
● EXERCISE INDUCED HYPERTHERMIA – elevated body temperature
associated with moderate to strenuous exercise lasting from half an hour up to several
hours without an increase in CRP level or ESR
● FACTITIOUS FEVER – fever artificially induced by the patient
○ Consider in all patients but more common in young women in health-care professions
● FRAUDULENT FEVER – normothermic patient that manipulates the thermometer
○ NOTE: dissociation between pulse rate and temperature

○ Simultaneous measurements at different body sites

 SPECIAL CONSIDERATIONS: ELDERLY
POPULATIONS
● MOST FREQUENT: giant cell arteritis, polymyalgia rheumatica
● TUBERCULOSIS: most common infectious cause
APPROACH TO
PATIENT WITH
FUO
FIRST STAGE DIAGNOSTIC TESTS
 IMPORTANT CONCEPTS
● POTENTIALLY DIAGNOSTIC CLUES – all localizing signs, symptoms and
abnormalities potentially pointing toward a diagnosis
○ HISTORY: fever pattern and duration, previous medical history, present and recent drug use, family
history, sexual history, country of origin, recent and remote travel, unusual environmental exposures,
animal contacts

○ PHYSICAL EXAMINATION: special attention to eyes, lymph nodes, temporal arteries, liver, spleen,
sites of previous surgery, entire skin surface, mucous membranes
● IMPORTANT: antibiotic and glucocorticoid treatment stopped before further
diagnostic tests are initiated
 CONSIDERATIONS: OBLIGATORY TESTS
● ABDOMINAL ULTRASOUND – relatively low cost, lack of radiation burden,
absence of side effects
● UTILITY OF CHEST XRAYS – may separate cases caused by easily diagnosed
diseases from those that are not
● CRYOGLOBULIN INVESTIGATION – valuable screening test in patients with
FUO given the absence of specific symptoms in many patients and the relatively low
cost of the test
● CULTURES – multiple samples taken and cultured long enough to ensure ample
growth time for any fastidious organisms (HACEK)
○ SPECIALIZED MEDIA: Histoplasma, Legionella

○ REPEAT CULTURES – indicated when previous culture samples were collected during antibiotic
treatment or within 1 week after its discontinuation
● MICROBIOLOGIC EXAMINATION OF CSF – indicated for FUOs with
headache for organisms like HSV Type 2, Cryptococcus neoformans, Mycobacterium
tuberculosis
○ CNS TUBERCULOSIS – elevated CSF protein, lowered glucose concentrations, mononuclear
pleocytosis

■ PROTEIN – 100-500mg/dL

■ GLUCOSE <45 mg/dL in 80% of cases

■ CSF CELL COUNT – 100-500 cells/µL

● TUBERCULIN SKIN TESTS, INTERFERON GAMMA RELEASE ASSAYS –
may have false-negative results in patients with miliary tuberculosis, malnutrition,
immunosuppression
○ MILIARY TUBERCULOSIS – may manifest as granulomatous disease in liver or bone marrow
biopsy samples

■ HIGHEST DIAGNOSTIC YIELD: liver biopsy for Acid-fast smear, culture, PCR

■ CONSIDER biopsies of bone marrow, lymph nodes, other involved organs

● TESTS THAT SHOULD NOT BE USED FOR SCREENING – low diagnostic
yields in the absence of PDCs
○ Echocardiography

○ Sinus radiography

○ Radiologic or endoscopic evaluation of the GIT

● FUNDOSCOPY – useful in the early stages of the diagnostic workup in patients
without PDCs or with misleading PDCs to exclude retinal vasculitis
● PET/CT SCAN or RADIOLABELED LEUKOCYTE SCINTIGRAPHY –
performed when the first-stage diagnostic tests do not lead to a diagnosis especially
when the ESR or the CRP level is elevated
APPROACH TO
RECURRENT
FEVER
● IMPORTANT: Repeat history, physical examination and laboratory tests during a
symptomatic phase
● PET/CT SCAN OR SCINTIGRAPHY – performed only during a febrile episode or
when inflammatory parameters are abnormal
● RECURRENT FEVER > 2 YRS - unlikely infectious or malignant
○ Test for infections or malignancies indicated when there are PDCs for infections, vasculitis syndromes
or malignancy or when patient’s condition is clinically deteriorating
FLUORODEOXYG
LUCOSE PET
SCANS
 PRINCIPLE OF 18F-FDG PET/CT SCANS
● FDG – accumulates in tissues with high rate of glycolysis (malignant cells, activated
leukocytes – acute and chronic inflammatory processes)
● ADVANTAGES: higher resolution, greater sensitivity in chronic low-grade
infections, high degree of accuracy in the central skeleton, increase vascular uptake
in vasculitis
● USES: may be used to guide additional diagnostics (biopsies) to yield final diagnosis
● PITFALLS: does not differentiate between infection, sterile inflammation and
malignancy, may obscure pathologic foci in the brain, heart, bowel, kidneys and
bladder, relatively expensive, limited availability
● PET and PET/CT
○ SENSITIVITY ~85%

○ SPECIFICITY ~50%

○ TOTAL DIAGNOSTIC YIELD ~50% (PET/CT) and ~40% (PET)

● Correct timing of PET/CT increases diagnostic yield
○ Fever at time of scan

○ Elevated inflammatory markers

● GLUCOCORTICOIDS: eradicates pathologic FDG uptake in many diseases
CONVENTIONAL
SCINTIGRAPHIC
IMAGING
● 67Ga-citrate scintigraphy
● 111In- or 99mTc-labeled leukocyte scintigraphy
● SENSITIVITY and SPECIFICITY lower than PET/CT
● DIAGNOSTIC YIELD
○ Gallium scintigraphy - 21-54% (correct localization in 1/3 of patients)

○ Leukocyte scintigraphy – 8-31% (correct localization in 1/5 of patients)

LATER STAGE
DIAGNOSTIC
TESTS
● LYMPH NODE BIOPSIES – necessary if lymphadenopathy is found, even when
the affected lymph nodes are hard to reach or when previous biopsies were
inconclusive
● SKIN BIOPSY – undertaken in the case of skin lesions
● SCREENING CHEST AND ABDOMINAL CT – used as screening procedure at a
later stage despite negative PET/CT due to their noninvasive nature and high
sensitivity
○ DIAGNOSTIC YIELD ~20%

○ SPECIFICITY of chest CT ~80% and abdominal CT ~63-80%

● BONE MARROW ASPIRATION – seldom useful in absence of PDCs for bone
marrow disorders and with FDG-PET/CT being highly sensitive for lymphoma,
carcinoma and osteomyelitis
● TEMPORAL ARTERY BIOPSY – recommended for patients ≥55 years of age in a
later stage of diagnosis
● LIVER BIOPSY – should not be used for screening purposes in patients with FUO
except in those with PDCs for liver disease or miliary tuberculosis
 SECOND OPINION IN AN EXPERT CENTER
● In 57.3% of patients with unexplained FUO, a diagnosis could be found in an expert
center
○ Of all the patients who remained without a diagnosis even after the second opinion, 10.9% became
fever-free upon empirical treatment

○ TOTAL BENEFICIAL OUTCOME of 68.2% of patients

TREATMENT
FOR FUOs
 EMPIRICAL THERAPIES
● NOTE: Start empirical therapies only when a patient’s condition is rapidly
deteriorating after the aforementioned diagnostic tests have failed to provide a
definite diagnosis
● EMPIRICAL THERAPIES
○ Antibiotics and Antituberculous Therapy

○ Colchicine

○ NSAIDs

○ Glucocorticoids

○ IL-1 Inhibition
 ANTIBIOTICS AND ANTITUBERCULOUS
THERAPY
● INDICATIONS FOR EMPIRIC ANTIBIOTICS: hemodynamic instability,
neutropenia
● INDICATIONS FOR ANTITUBERCULOUS THERAPY
○ Positive TST/IGRA

○ Granulomatous disease that is unlikely to be sarcoidosis

● PITFALLS: irrevocably diminishes ability to culture fastidious bacteria or
mycobacteria
 COLCHICINE
● INDICATIONS: patients with features compatible with Familial Mediterranean
Fever, especially when the patients originate from a high-prevalence region
● PREVENTION UTILITY: highly effective in preventing attacks of FMF  most
patients show remarkable improvement in the frequency and severity of subsequent
febrile episodes within weeks to months
● TREATMENT UTILITY: not always effective once an attack is under way
 NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS
● INDICATIONS: supportive treatment in cases in which fever persists and the source
remains elusive after completion of later-stage investigations
○ Ex: Adult-onset Still’s disease
● WHEN TO USE EMPIRICALLY: cases where infectious diseases and malignant
lymphoma have been largely ruled out and inflammatory disease is probable and
likely debilitating or threatening
 GLUCOCORTICOIDS
● INDICATIONS: useful in cases of Giant cell arteritis and Polymyalgia rheumatica
● DISADVANTAGES OF EMPIRICAL USE: decreases chances of arriving at a
diagnosis for which more specific and life-saving treatment might be more
appropriate
● WHEN TO USE EMPIRICALLY: cases where infectious diseases and malignant
lymphoma have been largely ruled out and inflammatory disease is probable and
likely debilitating or threatening
 INTERLEUKIN 1 INHIBITORS
● IL-1: key cytokine in local and systemic inflammation and the febrile response
● ANAKINRA – recombinant form of the IL-1 receptor antagonist
○ Blocks activity of both IL-1α and IL-1β

○ INDICATIONS: autoinflammatory syndromes (FMF, cryopyrin-associated periodic syndrome, TNFR-

associated periodic syndrome, mevalonate kinase deficiency [hyper IgD syndrome], Schnitzler
syndrome, adult-onset Still’s disease)

○ CONSIDER in patients whose FUO has not been diagnosed after later-stage diagnostic tests
● ADVANTAGES: provide improved control without the metabolic, immunologic and
gastrointestinal side effects of glucocorticoid administration
 PROGNOSIS
● Favorable in patients in whom FUO remains unexplained
● OVERALL – FUO-related mortality rates have continuously declined over recent
decades and is dependent on the underlying disease
● Majority of fevers are caused by treatable diseases
 REFERENCES
● Loscalzo, Kasper, Longo, Fauci, Hauser, Jameson. (2022). Harrison’s Principles of
Internal Medicine (21st Edition, Vol. 1). McGraw-Hill Education.