Fever of unknown origin


Fever of unknown origin refers to a condition in which the patient has an elevated temperature for which no cause can be found despite investigations by one or more qualified physicians. If the cause is found, it is usually a diagnosis of exclusion, eliminating all possibilities until only the correct explanation remains.
In the West, the classical medical definition of the FUO required a clinician-verified measurement of temperature of ≥38.3 at any site on several occasions over 3 weeks, though in the recent years the threshold of ≥38.0 has been becoming increasingly more prevalent.

Causes

Worldwide, infection is the leading cause of FUO, with prevalence varying by country and geographic region. Extrapulmonary tuberculosis is the most frequent cause of FUO.
Drug-induced hyperthermia, as the sole symptom of an adverse drug reaction, should always be considered. Disseminated granulomatoses such as tuberculosis, histoplasmosis, coccidioidomycosis, blastomycosis, and sarcoidosis are associated with FUO. Lymphomas are the most common cause of FUO in adults. Thromboembolic disease 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.
Human herpes viruses are a common cause of fever of unknown origin with one study showing Cytomegalovirus, Epstein–Barr virus, human herpesvirus 6, human herpesvirus 7 being present in 15%, 10%, 14% and 4.8% respectively with 10% of people presenting with co-infection. 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 and leukopenia, and younger adults and adolescents more likely to have splenomegaly, pharyngitis and lymphadenopathy.
Endemic mycoses such as histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis 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 as B symptoms. The endemic mycotic infection talaromycosis primarily affects those who are immunocompromised. Invasive opportunistic mycoses may also occur in immunocompromised people; these include aspergillosis, mucormycosis, Cryptococcus neoformans.
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. The cancer types most associated with fever of unknown origin include renal cell carcinoma, lymphoma, liver cancer, ovarian cancer atrial myxoma and Castleman disease.
In those with HIV currently being treated with antiretroviral 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 with AIDS, with high viral loads, viral replication, and immune compromise; cancers and opportunistic infection are the most common cause of FUO. Approximately 2 weeks after initial HIV infection, with viral loads being high, an acute retroviral syndrome can present with fevers, rash and mono-like symptoms.
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, but the syndrome may also present after organ transplant, in the post-partum state, with formerly neutropenic hosts, or after withdrawing anti-TNF therapy.
Auto-inflammatory and auto-immune disorders account for approximately 5-32% of fevers of unknown origin. These can be classified as purely auto-inflammatory disorders, purely auto-immune disorders or disorders with mixed features. Rheumatoid arthritis or adult-onset Still's disease have mixed features and are common causes of FUO.

Infection

Infection cause
Localized pyogenic infections
Intravascular infections
Systemic bacterial infections
Mycobacterial infections
  • M. avium/M. intracellulare infections
  • Other atypical mycobacterial infections
  • Tuberculosis
Other bacterial infections
Rickettsial infections
Chlamydial infections
Viral infections
Fungal infections
Parasitic infections

Neoplasm

Although most neoplasms can present with fever, malignant lymphoma is by far the most common diagnosis of FUO among neoplasms. In some cases, the fever even precedes lymphadenopathy detectable by physical examination.
Neoplasm causeDisease name
Hematologic malignancies
Solid tumors
Benign

Noninfectious inflammatory diseases

Noninfectious inflammatory diseasesDisease name
Systemic rheumatic and autoimmune diseases
Vasculitis
Granulomatous diseases
Autoinflammatory
syndromes

Miscellaneous conditions