| Fever of unknown origin | |
|---|---|
| Other names | Pyrexia of unknown origin,febris e causa ignota |
| Duration | ≥3 weeks |
| Types | Various |
| Causes | Infections, malignancies, non-infectious inflammatory diseases, others |
| Diagnostic method | Clinician-verified temperature at or above 38.3Celsius at any measurement site on several occasions over at least 3 weeks. |
| Differential diagnosis | Factitious fever,malingering |
| Frequency | 2–3 % of all medical admissions[1] |
Fever of unknown origin (FUO) refers to a condition in which the patient has an elevated temperature (fever) for which no cause can be found despite investigations by one or more qualifiedphysicians.[2][3][4] If the cause is found, it is usually adiagnosis of exclusion, eliminating all possibilities until only the correct explanation remains.
Inthe West, the classical medical definition of the FUO required a clinician-verified measurement of temperature of ≥38.3 at any site on several (varied) occasions over 3 weeks,[5][6][7] though in the recent years the threshold of ≥38.0 has been becoming increasingly more prevalent.[8]
Worldwide, infection is the leading cause of FUO, with prevalence varying by country and geographic region.[9] Extrapulmonary tuberculosis is the most frequent cause of FUO.[3]Drug-induced hyperthermia, as the sole symptom of anadverse drug reaction, should always be considered. Disseminated granulomatoses such astuberculosis,histoplasmosis,coccidioidomycosis,blastomycosis, andsarcoidosis are associated with FUO.Lymphomas are the most common cause of FUO in adults. Thromboembolic disease (i.e.,pulmonary embolism,deep venous thrombosis) occasionally causes a fever. Although infrequent, its potentially lethal consequences warrant evaluation of this cause.Infective endocarditis, although uncommon, is possible.Bartonella infections are also known to cause fever of unknown origin.[10]
Human herpes viruses are a common cause of fever of unknown origin with one study showingCytomegalovirus,Epstein–Barr virus, human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7) being present in 15%, 10%, 14% and 4.8% respectively with 10% of people presenting with co-infection (infection with two or more human herpes viruses).[9]Infectious mononucleosis, most commonly caused by EBV, may present as a fever of unknown origin. Other symptoms of infectious mononucleosis vary with age with middle-aged adults and the elderly more likely to have a longer duration of fever andleukopenia, and younger adults and adolescents more likely to havesplenomegaly,pharyngitis andlymphadenopathy.[9]
Endemic mycoses such as histoplasmosis, blastomycosis, coccidioidomycosis, andparacoccidioidomycosis can cause a fever of unknown origin in immunocompromised as well as immunocompetent people. These endemic mycoses may also present with pulmonary symptoms or extra-pulmonary symptoms such asB symptoms (such as fevers, chills, night sweats, and unexplained weight loss).[9] The endemic mycotic infectiontalaromycosis primarily affects those who are immunocompromised.[9] Invasive opportunistic mycoses may also occur in immunocompromised people; these includeaspergillosis,mucormycosis,Cryptococcus neoformans.[9]
Cancer can also cause a fever of unknown origin. This is thought to be due to release of pyrogenic cytokines from cancer cells as well as due to spontaneous tumor necrosis (sometimes with secondary infections).[9] The cancer types most associated with fever of unknown origin includerenal cell carcinoma,lymphoma,liver cancer,ovarian canceratrial myxoma andCastleman disease.[9]
In those withHIV currently being treated withantiretroviral therapy and with a low or undetectable viral load, the causes of fever of unknown origin are usually not associated with HIV infection. But in those withAIDS, with high viral loads, viral replication, and immune compromise; cancers and opportunistic infection are the most common cause of FUO.[9] Approximately 2 weeks after initial HIV infection, with viral loads being high, anacute retroviral syndrome can present with fevers, rash and mono-like symptoms.[9]
Immune reconstitution inflammatory syndrome is a common cause of FUO when a previously suppressed immune system is reactivated. The newly active immune system often has an exaggerated response against opportunistic pathogens, leading to a fever and other inflammatory symptoms. Immune reconstitution syndrome commonly presents after microbiological control of infection (in cases of immunosuppressing pathogens such as HIV), but the syndrome may also present after organ transplant, in the post-partum state, with formerly neutropenic hosts, or after withdrawinganti-TNF therapy.[9]
Auto-inflammatory and auto-immune disorders account for approximately 5-32% of fevers of unknown origin.[9] These can be classified as purely auto-inflammatory disorders (disorders of innate immunity, with dysregulatedinterleukin 1 beta and/orIL-18 responses), purely auto-immune disorders (in which the adaptive immunity is dysregulated, with a dysregulatedtype 1 interferon response) or disorders with mixed features.[9]Rheumatoid arthritis oradult-onset Still's disease have mixed features and are common causes of FUO.[9]
Although most neoplasms can present with fever, malignant lymphoma is by far the most common diagnosis of FUO among neoplasms.[12] In some cases, the fever even precedes lymphadenopathy detectable by physical examination.[12]
| Thermoregulatory disorders | Location |
|---|---|
| Central | |
| Peripheral |
A comprehensive and meticulous history (i.e. illness of family members, recent visit to the tropics, medication), repeated physical examination (i.e.skin rash,eschar,lymphadenopathy,heart murmur) and myriad laboratory tests (serological, blood culture, immunological) are the cornerstone of finding the cause.[2][4]
Other investigations may be needed. Ultrasound may showcholelithiasis,echocardiography may be needed in suspected endocarditis and a CT-scan may show infection or malignancy of internal organs. Another technique is Gallium-67 scanning which seems to visualize chronic infections more effectively. Invasive techniques (biopsy and laparotomy for pathological and bacteriological examination) may be required before a definite diagnosis is possible.[2][4]
Positron emission tomography using radioactively labelledfluorodeoxyglucose (FDG) has been reported to have asensitivity of 84% and aspecificity of 86% for localizing the source of fever of unknown origin.[13]
Despite all this, diagnosis may only be suggested by the therapy chosen. When a patient recovers after discontinuing medication, it likely wasdrug fever; when antibiotics or antimycotics work, it probably was infection. Empirical therapeutic trials should be used in those patients in whom other techniques have failed.[2]
There is no universal agreement with regards to time criteria or other diagnostic criteria to diagnose a fever of unknown origin, and various definitions have been used.[9]
In 1961 Petersdorf and Beeson suggested the following criteria:[2][3]
A new definition, which includes the outpatient setting (which reflects current medical practice), is broader, stipulating:
Presently, FUO cases are codified in four subclasses.
This refers to the original classification by Petersdorf and Beeson. Studies show there are five categories of conditions:[citation needed]
Nosocomial FUO refers topyrexia in patients who have been admitted to the hospital for at least 24 hours. This is commonly related to hospital-associated factors such as surgery, use of aurinary catheter, intravascular devices (i.e., "drip",pulmonary artery catheter), drugs (antibiotic-inducedClostridioides difficile colitis,drug fever), and/or immobilization (decubitus ulcers).Sinusitis in theintensive care unit is associated with nasogastric and orotracheal tubes.[2][3][4] Other conditions that should be considered are deep-vein thrombophlebitis,pulmonary embolism,transfusion reactions, acalculous cholecystitis,thyroiditis, alcohol/drug withdrawal,adrenal insufficiency, andpancreatitis.[3]
Immunodeficiency can be seen in patients receivingchemotherapy or in hematologic malignancies. Fever is concomitant withneutropenia (neutrophil <500/uL) or impaired cell-mediated immunity. The lack of immune response masks a potentially dangerous course. Infection is the most common cause.[2][3][4]
HIV-infected patients are a subgroup of the immunodeficient FUO, and frequently have fever. The primary phase shows fever since it has amononucleosis-like illness. In advanced stages of infection, fever is mostly the result of a superimposed infection.[2][3][4]
A specific disorder, reported especially in theJapanese literature, also known under the names functional hyperthermia and psychogenic hyperthermia. Like otherfunctional disorders, it is reported to primarily affect teenagers.[14] Such fever (actuallyhyperthermia) is reported not to react toNSAIDs, but drugs affecting thecentral nervous system: powerfulanxiolytics (such asdiazepam)[15] andbeta-blockers, cause quickdefervescence.[15][16][17][18][19]
Unless the patient is acutely ill, no therapy should be started before the cause has been found. This is because non-specific therapy is rarely effective and may delay the diagnosis. An exception is made forneutropenic (low white blood cell count) patients or patients who are severely immunocompromised, in which delay could lead to serious complications.[9] After blood cultures are taken, this condition is aggressively treated with broad-spectrum antibiotics. Antibiotics are adjusted according to the results of the cultures taken.[2][3][4]
HIV-infected people with pyrexia andhypoxia will be started on medication for possiblePneumocystis jirovecii infection. Therapy is adjusted after a diagnosis is made.[4]
Since a wide range of conditions are associated with FUO, prognosis depends on the particular cause.[2] If, after six to twelve months, no diagnosis is found, the chances of ever finding a specific cause diminish.[4] Under those circumstances, the prognosis is good.[3]