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Infectious Diseases and Microbiology: Fever of Unknown Origin
Basics
Description
Fever of unknown origin (FUO) describes persistent fever that lasts longer than expected for a typical acute febrile illness and is meant to exclude self-limited infections, conditions identified on basic initial testing, and benign fevers below 38.3°C. Current criteria, revised from the 1961 Petersdorf and Beeson definition, require illness duration of at least three weeks, documented temperatures above 38.3°C on multiple occasions, and no diagnosis despite a thorough evaluation. Durack and Street proposed FUO subtypes reflecting differing causes and workups: classical FUO, immune-deficient FUO, healthcare-associated FUO, and HIV-related FUO. Using this framework, immune-deficient patients, hospitalized patients who were afebrile before admission, and patients with HIV may meet FUO criteria after three to five inpatient days of evaluation with 48 hours of negative cultures.
Approach to the Patient
FUO is clinically difficult for both patients and clinicians, and management centers on identifying a cause, reaching a diagnosis efficiently and safely with appropriate testing, and initiating targeted therapy once a diagnosis is established or, when necessary, performing a therapeutic trial. Evaluation should be individualized to avoid both excessive testing for unlikely causes and missed evaluation of likely ones, so rigid algorithms are discouraged. Key aims are to confirm true fever and define its pattern, assess illness tempo and severity, look for localizing symptoms, place the illness in context of comorbidities and medications, and identify exposure risks such as travel, occupational and sexual history, animal contact, vaccination status, and intravenous drug use. Minimum baseline evaluation should include detailed history, repeated physical examination, complete blood count with smear, differential and platelets, routine chemistries including liver enzymes, LDH and bilirubin, urinalysis with microscopy and culture, chest radiograph, ESR and CRP, ANA, rheumatoid factor and anti-CCP, three sets of blood cultures obtained off antibiotics, tuberculosis testing with TST or IGRA, CT abdomen and pelvis, and infectious serologies guided by the clinical scenario.
Special Populations
Geriatric Considerations
Consider polymyalgia rheumatica and recognize that the distribution of undiagnosed etiologies differs in older adults.
Pediatric Considerations
Herpesviruses HHV-6/7/8 are common in infants and children. Ultrasound is preferred over CT to limit radiation and because pediatric imaging resolution is favorable. Connective tissue disease and neoplasia are uncommon under 12 months, Kawasaki disease is common under 5 years, Still’s disease often affects children and young adults, and arthritis in children should be treated as a marker of potentially serious disease. Periodic fever and other entities to consider include hyper-IgD syndrome, cyclic neutropenia, and nephroma.
Pregnancy Considerations
Pregnancy increases venous thromboembolism risk. Consider septic pelvic thrombophlebitis after obstetric surgery, sexually transmitted infections including HIV and syphilis, and pyometra.
Epidemiology
True FUO is uncommon. Reported etiologic frequencies vary by population, geography, institution, age, local disease prevalence, and practice patterns. Over time, the proportion of infectious and malignant causes has decreased while the proportion of undiagnosed cases has increased.
Diagnosis
FUO evaluation relies on iterative history-taking, repeated examinations, laboratory studies, and imaging.
History
History should cover alcohol use, medications, occupational and sexual exposures, pets, travel, family conditions, and prior illnesses. Although fever patterns are described for many disorders, truly distinctive patterns are rare in practice; classic patterns such as malaria are uncommon in many settings, and patterns considered characteristic for other diseases, such as Pel–Ebstein fever in lymphoma, are infrequently observed.
Physical Examination
Repeated comprehensive examination is central and should specifically assess the oropharynx for dental abscess, thyroid for thyroiditis, temporal regions for arteritis, cardiac auscultation for murmurs suggesting endocarditis or atrial myxoma, skin for vasculitis and Whipple disease clues, all wounds and vascular access sites with dressings removed for inspection, regional lymph nodes, and the genitoperineal region, sometimes requiring rectal or vaginal examination. Relative bradycardia can be a clue but is nonspecific and occurs in diverse conditions including brucellosis, drug fever, factitious fever, hepatitis A, Legionella infection, leptospirosis, malignancy, psittacosis, subacute necrotizing lymphadenitis, and typhoid fever. Fever from solid tumors and many connective tissue diseases may abate with NSAIDs, whereas fever from other causes may not. Symptoms such as sweats, chills, and weight loss do not reliably distinguish etiologies. Clues suggesting factitious fever include lack of tachycardia or tachypnea, temperatures exceeding 41°C, absent diurnal variation, and lack of sweating after defervescence.
Diagnostic Tests and Interpretation
Laboratory Studies
Noninvasive tests yield a diagnosis in roughly one-quarter of cases and include serologies for infectious and rheumatologic disease, biochemical markers such as ferritin for Still’s disease, and genetic markers such as those used for familial Mediterranean fever.
Imaging
Imaging is primarily used to localize targets for further evaluation. Abdominal CT has improved diagnostic yield when followed by invasive sampling, though false negatives can occur even with solid-organ abscesses. MRI is preferred when spinal or paraspinal pathology is suspected. Nuclear imaging with gallium-67 or indium-111 labeled leukocytes can sometimes help when infection or malignancy is suspected, but limitations include false-negative gallium scans in secondarily infected lesions, poor detection of splenic abscess due to background uptake, and low positive predictive value with indium studies. FDG PET/CT can help establish malignant, inflammatory, or infectious diagnoses in at least one-third of cases. If imaging and serologies are unrevealing, invasive investigations such as liver and bone marrow biopsy should be considered, and fewer than half of diagnoses are ultimately made via biopsy or laparotomy. Temporal artery biopsy is often high yield in older adults with markedly elevated ESR even without obvious local symptoms. Disseminated tuberculosis is a highly treatable lethal cause of FUO and warrants aggressive pursuit; TST and IGRA can be negative in up to half of cases, sputum smears are only intermittently positive, and confirmation often requires biopsy of lymph node, bone marrow, or liver. Excisional lymph node biopsy is helpful when nodes are enlarged, though inguinal nodes are commonly palpable and usually not diagnostically useful.
Differential Diagnosis
The major etiologic categories and approximate frequencies include infections, malignancies, connective tissue or inflammatory disorders, miscellaneous causes, and undiagnosed cases. Unusual presentations of common diseases and conditions that are difficult to confirm account for more FUO cases than truly rare diseases, and thinking in terms of FUO subtype helps prioritize causes.
Classical FUO
Common infectious drivers remain tuberculosis, bacterial endocarditis, and intraabdominal collections. Systemic bacterial causes include bartonellosis, brucellosis, Campylobacter infection, cat-scratch disease or bacillary angiomatosis, ehrlichiosis, gonococcemia, HACEK organisms, Legionella infection, leptospirosis, listeriosis, Lyme disease, meningococcemia, rat-bite fever, relapsing fever due to Borrelia recurrentis, salmonellosis including typhoid, syphilis, tularemia, and yersiniosis, along with chlamydial, fungal, parasitic, and viral infections. Localized infections include intravascular infections such as endocarditis, aortitis, catheter infections, septic jugular phlebitis, and vascular graft infection; intraabdominal infections such as appendicitis, cholangitis, cholecystitis, diverticulitis, and diverse abscesses (subphrenic, hepatic, splenic, pancreatic, perinephric, pelvic), mesenteric lymphadenitis, pelvic inflammatory disease, and pyometra; prosthesis-related infections involving joint prostheses, pacemakers, defibrillators, shunts, and vascular access; and other focal infections including dental, intracranial, pulmonary, mastoid, middle ear, sinus, prostatic, and wound infections. Common noninfectious causes include malignancies such as renal cell carcinoma, hepatocellular carcinoma, Hodgkin and non-Hodgkin lymphoma, colon cancer, leukemia, malignant histiocytosis, pancreatic cancer, and sarcoma; benign tumors such as atrial myxoma; inflammatory disorders such as adult Still’s disease, Behçet syndrome, and cryoglobulinemia; and miscellaneous conditions including neuroleptic malignant syndrome, hematoma, recurrent pulmonary embolism, aortic dissection, post–myocardial infarction fever syndromes, subacute thyroiditis, hyperthyroidism, adrenal insufficiency, drug fever, factitious fever, gout, pseudogout, hypersensitivity pneumonitis, stroke, familial Mediterranean fever, and pheochromocytoma.
Healthcare-Associated FUO
Infectious causes include intravascular catheter infection, septic thrombophlebitis, prosthetic device infection, deep postoperative wound infections and intraabdominal collections, C. difficile colitis that may present with ileus rather than diarrhea in severe disease, septic pelvic thrombophlebitis after obstetric or gynecologic surgery, acalculous cholecystitis, and ICU-associated sinusitis related to nasogastric tubes and endotracheal intubation. Miscellaneous causes include venous thromboembolism, drug fever often without rash or eosinophilia and commonly triggered by antimicrobials and multiple other medication classes, factitious fever, and postoperative inflammatory fever without a defined diagnosis.
Immune-Deficient FUO
Most cases are infectious, with pathogen identification in a large fraction, and the likely infections depend on the type and duration of immunodeficiency. Persistent fever can reflect progressive or relapsed malignancy in hematology-oncology patients, inflammatory causes such as graft-versus-host disease, or miscellaneous etiologies including venous thromboembolism, drug fever, and adrenal insufficiency.
HIV-Related FUO
Most cases are infectious, though FUO has decreased in the antiretroviral era due to fewer opportunistic infections, and likely etiologies depend strongly on CD4 count. Scenarios include HIV seroconversion illness, opportunistic infections such as mycobacterial disease, Pneumocystis jirovecii, cytomegalovirus, toxoplasmosis, histoplasmosis, and leishmaniasis, inflammatory syndromes such as immune reconstitution, Castleman disease, and hemophagocytic lymphohistiocytosis, malignancies such as lymphoma and Kaposi sarcoma, and drug fever.
Treatment
Medications
Management is determined by the underlying cause. If TST or IGRA is positive or if granulomatous disease with possible anergy is suspected, a therapeutic trial for tuberculosis is recommended and may be continued for up to six weeks; persistent fever beyond this period suggests an alternate diagnosis. Glucocorticoids and NSAIDs can suppress fever and obscure diagnosis while allowing infection to progress and should be avoided unless infection has largely been excluded. In severely immune-deficient patients, empiric antimicrobial therapy is often necessary because infections are common and associated with high mortality.
Ongoing Care and Follow-Up
Hospitalized patients with FUO require close monitoring for evolving symptoms or new physical findings that may provide diagnostic direction.
Basics
Description
Fever of unknown origin (FUO) describes persistent fever that lasts longer than expected for a typical acute febrile illness and is meant to exclude self-limited infections, conditions identified on basic initial testing, and benign fevers below 38.3°C. Current criteria, revised from the 1961 Petersdorf and Beeson definition, require illness duration of at least three weeks, documented temperatures above 38.3°C on multiple occasions, and no diagnosis despite a thorough evaluation. Durack and Street proposed FUO subtypes reflecting differing causes and workups: classical FUO, immune-deficient FUO, healthcare-associated FUO, and HIV-related FUO. Using this framework, immune-deficient patients, hospitalized patients who were afebrile before admission, and patients with HIV may meet FUO criteria after three to five inpatient days of evaluation with 48 hours of negative cultures.
Approach to the Patient
FUO is clinically difficult for both patients and clinicians, and management centers on identifying a cause, reaching a diagnosis efficiently and safely with appropriate testing, and initiating targeted therapy once a diagnosis is established or, when necessary, performing a therapeutic trial. Evaluation should be individualized to avoid both excessive testing for unlikely causes and missed evaluation of likely ones, so rigid algorithms are discouraged. Key aims are to confirm true fever and define its pattern, assess illness tempo and severity, look for localizing symptoms, place the illness in context of comorbidities and medications, and identify exposure risks such as travel, occupational and sexual history, animal contact, vaccination status, and intravenous drug use. Minimum baseline evaluation should include detailed history, repeated physical examination, complete blood count with smear, differential and platelets, routine chemistries including liver enzymes, LDH and bilirubin, urinalysis with microscopy and culture, chest radiograph, ESR and CRP, ANA, rheumatoid factor and anti-CCP, three sets of blood cultures obtained off antibiotics, tuberculosis testing with TST or IGRA, CT abdomen and pelvis, and infectious serologies guided by the clinical scenario.
Special Populations
Geriatric Considerations
Consider polymyalgia rheumatica and recognize that the distribution of undiagnosed etiologies differs in older adults.
Pediatric Considerations
Herpesviruses HHV-6/7/8 are common in infants and children. Ultrasound is preferred over CT to limit radiation and because pediatric imaging resolution is favorable. Connective tissue disease and neoplasia are uncommon under 12 months, Kawasaki disease is common under 5 years, Still’s disease often affects children and young adults, and arthritis in children should be treated as a marker of potentially serious disease. Periodic fever and other entities to consider include hyper-IgD syndrome, cyclic neutropenia, and nephroma.
Pregnancy Considerations
Pregnancy increases venous thromboembolism risk. Consider septic pelvic thrombophlebitis after obstetric surgery, sexually transmitted infections including HIV and syphilis, and pyometra.
Epidemiology
True FUO is uncommon. Reported etiologic frequencies vary by population, geography, institution, age, local disease prevalence, and practice patterns. Over time, the proportion of infectious and malignant causes has decreased while the proportion of undiagnosed cases has increased.
Diagnosis
FUO evaluation relies on iterative history-taking, repeated examinations, laboratory studies, and imaging.
History
History should cover alcohol use, medications, occupational and sexual exposures, pets, travel, family conditions, and prior illnesses. Although fever patterns are described for many disorders, truly distinctive patterns are rare in practice; classic patterns such as malaria are uncommon in many settings, and patterns considered characteristic for other diseases, such as Pel–Ebstein fever in lymphoma, are infrequently observed.
Physical Examination
Repeated comprehensive examination is central and should specifically assess the oropharynx for dental abscess, thyroid for thyroiditis, temporal regions for arteritis, cardiac auscultation for murmurs suggesting endocarditis or atrial myxoma, skin for vasculitis and Whipple disease clues, all wounds and vascular access sites with dressings removed for inspection, regional lymph nodes, and the genitoperineal region, sometimes requiring rectal or vaginal examination. Relative bradycardia can be a clue but is nonspecific and occurs in diverse conditions including brucellosis, drug fever, factitious fever, hepatitis A, Legionella infection, leptospirosis, malignancy, psittacosis, subacute necrotizing lymphadenitis, and typhoid fever. Fever from solid tumors and many connective tissue diseases may abate with NSAIDs, whereas fever from other causes may not. Symptoms such as sweats, chills, and weight loss do not reliably distinguish etiologies. Clues suggesting factitious fever include lack of tachycardia or tachypnea, temperatures exceeding 41°C, absent diurnal variation, and lack of sweating after defervescence.
Diagnostic Tests and Interpretation
Laboratory Studies
Noninvasive tests yield a diagnosis in roughly one-quarter of cases and include serologies for infectious and rheumatologic disease, biochemical markers such as ferritin for Still’s disease, and genetic markers such as those used for familial Mediterranean fever.
Imaging
Imaging is primarily used to localize targets for further evaluation. Abdominal CT has improved diagnostic yield when followed by invasive sampling, though false negatives can occur even with solid-organ abscesses. MRI is preferred when spinal or paraspinal pathology is suspected. Nuclear imaging with gallium-67 or indium-111 labeled leukocytes can sometimes help when infection or malignancy is suspected, but limitations include false-negative gallium scans in secondarily infected lesions, poor detection of splenic abscess due to background uptake, and low positive predictive value with indium studies. FDG PET/CT can help establish malignant, inflammatory, or infectious diagnoses in at least one-third of cases. If imaging and serologies are unrevealing, invasive investigations such as liver and bone marrow biopsy should be considered, and fewer than half of diagnoses are ultimately made via biopsy or laparotomy. Temporal artery biopsy is often high yield in older adults with markedly elevated ESR even without obvious local symptoms. Disseminated tuberculosis is a highly treatable lethal cause of FUO and warrants aggressive pursuit; TST and IGRA can be negative in up to half of cases, sputum smears are only intermittently positive, and confirmation often requires biopsy of lymph node, bone marrow, or liver. Excisional lymph node biopsy is helpful when nodes are enlarged, though inguinal nodes are commonly palpable and usually not diagnostically useful.
Differential Diagnosis
The major etiologic categories and approximate frequencies include infections, malignancies, connective tissue or inflammatory disorders, miscellaneous causes, and undiagnosed cases. Unusual presentations of common diseases and conditions that are difficult to confirm account for more FUO cases than truly rare diseases, and thinking in terms of FUO subtype helps prioritize causes.
Classical FUO
Common infectious drivers remain tuberculosis, bacterial endocarditis, and intraabdominal collections. Systemic bacterial causes include bartonellosis, brucellosis, Campylobacter infection, cat-scratch disease or bacillary angiomatosis, ehrlichiosis, gonococcemia, HACEK organisms, Legionella infection, leptospirosis, listeriosis, Lyme disease, meningococcemia, rat-bite fever, relapsing fever due to Borrelia recurrentis, salmonellosis including typhoid, syphilis, tularemia, and yersiniosis, along with chlamydial, fungal, parasitic, and viral infections. Localized infections include intravascular infections such as endocarditis, aortitis, catheter infections, septic jugular phlebitis, and vascular graft infection; intraabdominal infections such as appendicitis, cholangitis, cholecystitis, diverticulitis, and diverse abscesses (subphrenic, hepatic, splenic, pancreatic, perinephric, pelvic), mesenteric lymphadenitis, pelvic inflammatory disease, and pyometra; prosthesis-related infections involving joint prostheses, pacemakers, defibrillators, shunts, and vascular access; and other focal infections including dental, intracranial, pulmonary, mastoid, middle ear, sinus, prostatic, and wound infections. Common noninfectious causes include malignancies such as renal cell carcinoma, hepatocellular carcinoma, Hodgkin and non-Hodgkin lymphoma, colon cancer, leukemia, malignant histiocytosis, pancreatic cancer, and sarcoma; benign tumors such as atrial myxoma; inflammatory disorders such as adult Still’s disease, Behçet syndrome, and cryoglobulinemia; and miscellaneous conditions including neuroleptic malignant syndrome, hematoma, recurrent pulmonary embolism, aortic dissection, post–myocardial infarction fever syndromes, subacute thyroiditis, hyperthyroidism, adrenal insufficiency, drug fever, factitious fever, gout, pseudogout, hypersensitivity pneumonitis, stroke, familial Mediterranean fever, and pheochromocytoma.
Healthcare-Associated FUO
Infectious causes include intravascular catheter infection, septic thrombophlebitis, prosthetic device infection, deep postoperative wound infections and intraabdominal collections, C. difficile colitis that may present with ileus rather than diarrhea in severe disease, septic pelvic thrombophlebitis after obstetric or gynecologic surgery, acalculous cholecystitis, and ICU-associated sinusitis related to nasogastric tubes and endotracheal intubation. Miscellaneous causes include venous thromboembolism, drug fever often without rash or eosinophilia and commonly triggered by antimicrobials and multiple other medication classes, factitious fever, and postoperative inflammatory fever without a defined diagnosis.
Immune-Deficient FUO
Most cases are infectious, with pathogen identification in a large fraction, and the likely infections depend on the type and duration of immunodeficiency. Persistent fever can reflect progressive or relapsed malignancy in hematology-oncology patients, inflammatory causes such as graft-versus-host disease, or miscellaneous etiologies including venous thromboembolism, drug fever, and adrenal insufficiency.
HIV-Related FUO
Most cases are infectious, though FUO has decreased in the antiretroviral era due to fewer opportunistic infections, and likely etiologies depend strongly on CD4 count. Scenarios include HIV seroconversion illness, opportunistic infections such as mycobacterial disease, Pneumocystis jirovecii, cytomegalovirus, toxoplasmosis, histoplasmosis, and leishmaniasis, inflammatory syndromes such as immune reconstitution, Castleman disease, and hemophagocytic lymphohistiocytosis, malignancies such as lymphoma and Kaposi sarcoma, and drug fever.
Treatment
Medications
Management is determined by the underlying cause. If TST or IGRA is positive or if granulomatous disease with possible anergy is suspected, a therapeutic trial for tuberculosis is recommended and may be continued for up to six weeks; persistent fever beyond this period suggests an alternate diagnosis. Glucocorticoids and NSAIDs can suppress fever and obscure diagnosis while allowing infection to progress and should be avoided unless infection has largely been excluded. In severely immune-deficient patients, empiric antimicrobial therapy is often necessary because infections are common and associated with high mortality.
Ongoing Care and Follow-Up
Hospitalized patients with FUO require close monitoring for evolving symptoms or new physical findings that may provide diagnostic direction.
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