Fever of Unknown Origin (FUO)

Documented fever of >38.3C (101’F) for more than 3 weeks and no established diagnosis despite appropriate investigation for 1 week.

The definition has been shortened within investigation period of 3 inpatient days or at least three outpatient visits.

The definition of an FUO is subjective, but is basically the absence of an identified cause a fever, despite reasonable investigations in, and the persistence for a sufficient time to rule out self limiting fevers.

FUO is a common manifestation of multiple, disparate disease processes.

Classifications are based on the immune status of the host, where did the patient is hospitalized, and the patient’s travel history.

There is no universal agreement on the precise time cut off or diagnostic criteria for FUO.

Three major categories: infections, collagen-vascular disease and granulomatous disease and tumors.

Workup includes history, physical examination, CBC, chemical blood profile, urinalysis, multiple blood cultures, chest X-ray, CT scan of the abdomen and chest.

Infections constitute about one third of cases.

Tumors account for 7-13% of cases.

Shifts in the causes of FUO have occurred with a reduction in the current era of infectious causes, and a rise in the autoimmune or autoinflammatory conditions.

Infectious diseases remain the leading causes of FUO.

There is a suggested correlation between lower income geographic regions and the prevalence of infection.

FUO has been divided into classic, nosocomial, immunodeficiency related and travel associated cases.

Durack and Street proposed four groups: classic, nosocomial, neutropenic, and HIV-associated.

Classic Petersdorf/Beeson FUOs-36% infections, 19% malignancy related, collagen vascular diseases 19%, miscellaneous disorders such as drug fever 19%, and 7% not determined.

Recent FUOs more related to ICU patients with traumatic brain injuries, of other neurologic diseases, dementia, mechanically ventilated, some have central or peripheral intravenous catheters, some cases postoperative, multiple have had previous antibiotics.

PET scan useful in evaluating such patients.

Tuberculosis has been among the most common infections causing FUO and is more common in non-US series.

Approximately 38% of patients with Whipple’s disease present with fever, often with arthritis, diarrhea, and weight loss.

Typhoidal and non typhoidal salmonella can cause bacteremia and FUO.

Infective endocarditis and deep-seated infection such as abscesses and prostatitis can cause FUO.

Most viral infections are self-limited but can be associated with FUO.

Herpes viruses, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, and herpes human herpesvirus 7, infectious mononucleosis may be associated with FUO.

The endemic mycoses of histoplasmosis, blastomycosis, coccidiomycosis, and paracoccidiomycosis may be associated with FUO in both immunocompetent then immunocompromised hosts.

Opportunistic invasive mycoses such as aspergillosis, mucormycosis, and cryptococcosis can infect healthy individuals, but occur largely in immunocompromised persons and can manifest as FUO.

Investigations for opportunistic infections should be undertaken  for patients in whom fever develops during iatrogenic immuno suppressive therapy.

About half of human pathogens or vectorborne or zoonotic, and these infections can manifest as FUO.

Malignancies constitute approximately 2 to 25% of cases of FUO.

Cancers most frequently associated with FUO include renal cell, lymphomas, hepatocellulular, ovarian cancer, atrial myxoma and Cattleman’s disease.

Pyrogenic cytokines are the likely basis of most cancer related fevers.

Aitoimmune and auto inflammatory diseases account for 5 to 30% of FUO‘s.

Immune reconstitutionsyndrome is the cause of FUO.

An estimated 3 to 7% of febrile episodes in hospitalized patients are attributable to drugs.

Drug associated fever is seen with associated eosinophilia, relative bradycardia, and rash in 25%, 10%, and 5% of cases, respectively.

About 1/3 of drug associated fevers are due to antibiotics, most likely  beta-lactams.

Drug reaction with a eosinophilia and systemic  symptoms (DRESS), is characterized by a severe rash, fever, visceral involvement, lymphadenopathy, eosinophilia, and atypical lymphocytosis.

Hyperthermic drug syndromes: serotonin syndrome and neuroleptic malignant syndrome may be associated with FUO.

Nosocomial FUOs  includes vascular catheter associated infections UTIs, pneumonia, intra-abdominal infections, sinusitis, Clostridium difficile infection.

Many serious  ill patients have none infectious fevers including: neurogenic fevers due to cerebral injury, thrombobolic events, or drugs.

Postoperative fevers are common and are frequently self-limited when due to release of inflammatory cytokines in response to the physiological stresses of surgery.

Common causes of FUO after surgery include: anastomotic leaks, fistulas, hematomas, gout, thromboembolic events, mesh or graft related infections, Mycoplasma hominis infections after cardiac, orthopedic, or neurosurgical procedures.

Immunosuppressives an immunostimulatory treatments: biologic agents, monoclonal antibodies, checkpoint inhibitors, chimeric antigen receptors can be associated with FUO.

FUO can occur in patients with HIV due to acute retroviral syndrome, developing approximately two weeks after the initiation of infection.

In patients  with AIDS  opportunistic infections with multiple organs can cause FUO: mycobacteria, CMV, leishmaniasis, histoplasmosis, cryptococcus, toxoplasmosis, HHV-eight infection and lymphoma.

FUO is documented in 1.4% of organ transplant recipients, and more than half of the episodes are related to infections.

Fever is universal in patients with hematologic cancers who have received induction chemotherapy and before engraftment in recipients of hematopoietic cell transplant when they are at risk for prolonged and severe neutropenia.

Fever may develop in hemopoietic cell transplant recipients in the early post engraftment period, as a result of engraftment, infectious or non-infectious pulmonary syndromes, fungal infections, reactivation of herpes viruses such as CMV, EBV, and HHV-6, adenovirus infection, hyperacute GVHD, or other processes.

Fever occurs in approximately 92% of patients with CAR T-cell therapy.

The recognition of travel related infections as a cause of fever is considerable including malaria, leptospirosis, rikettsiosis, typhus,  measles, enteric fever, tuberculosis, influenza, coronavirus infections, and anabiotic resistant bacterial infections.


Evaluation of FUO begins with a history, examination and variable diagnostic testing.

Extensive laboratory evaluation should be discouraged.

Basic laboratory-CBC, metabolic panel, blood cultures, serologic testing for HIV, echocardiogram, CT of chest, abdomen, pelvis and other regions based on symptoms and examination, ESR, CRP, discontinuation of new and potentially offending medications.

Additional testing based on history, physical exam, epidemiology, exposures, imaging include serological or PCR testing for zoonotic or a tickborne illness, endemic mycoses, evaluation for hepatitis, tuberculosis, testing for rheumatologic and thyroid disorders and consideration of biopsy of a rash, temporal artery, lymph nodes, masses, or other lesions.

Additional warranty diagnostic methods include PET scanning and next generation sequencing.

PET/CT for FUO has a sensitivity ranging from 86 to 98% and specificities ranging from 52 to 85% with a diagnostic yield of more than 50%, a yield is at least 30% greater than that of conventional CT.

Management: antibiotics and anti-inflammatory therapy should be withheld unless the patient has neutropenia, is severely immunocompromised or has a rapidly deteriorating clinical status: Attempts  should be made to establish a diagnosis before instituting such therapies.

Many patients with FUO that remain undiagnosed have excellent prognosis and may have spontaneous remission.

Therapeutic anti-microbial trials predispose to resistance or suppress the growth of fastidious pathogens and in the case of self limited conditions, such as a virus, may result in false reassurance that the underlying cause a fever has been treated.











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