Pyrexia Of Unknown Origin Harrison
Enrique Vasquez
Fever of unknown origin (FUO) refers to a condition in which the patient has an elevated temperature (fever) but, despite investigations by one or more qualified physicians, no explanation is found.[1][2][3]
Worldwide, infection is the leading cause of FUO with prevalence varying by country and geographic region.[4] Extrapulmonary tuberculosis is the most frequent cause of FUO.[2]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 (i.e. pulmonary embolism, deep venous thrombosis) occasionally shows fever. Although infrequent, its potentially lethal consequences warrant evaluation of this cause. Endocarditis, although uncommon, is possible. Bartonella infections are also known to cause fever of unknown origin.[5]
Endemic mycoses such as histoplasmosis, blastomycosis, coccidiomycosis 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 (such as fevers, chills, night sweats, unexplained weight loss).[4] The endemic mycotic infection talaromycosis primarily affects those who are immunocompromised.[4] Invasive opportunistic mycoses may also occur in immunocompromised people; these include aspergillosis, mucormycosis, Cryptococcus neoformans.[4]
Cancer can also cause 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).[4] The cancer types most associated with fever of unknown origin include renal cell carcinoma, lymphoma, liver cancer, ovarian cancer atrial myxoma and Castleman disease.[4]
In those with HIV currently being treated with antiretroviral therapy and with a low or undetectable viral load; 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.[4] 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.[4]
Immune reconstitution inflammatory syndrome is a common cause of FUO when a previously suppressed immune system is re-activated. 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 as after microbiological control of infection (in cases of immune suppressing pathogens such as HIV) but the syndrome may also present after organ transplant, in the post-partum state, with formerly neutropenic hosts or withdrawing anti-TNF therapy.[4]
Auto-inflammatory and auto-immune disorders account for approximately 5-32% of fevers of unknown origin.[4] These can be classified as purely auto-inflammatory disorders (disorders of innate immunity, with dysregulated interleukin 1 beta and/or IL-18 responses), purely auto-immune disorders (in which the adaptive immunity is dysregulated, with a dysregulated type 1 interferon response) or disorders with mixed features.[4] Rheumatoid arthritis or adult-onset Still's disease have mixed features and are common causes of FUO.[4]
Although most neoplasms can present with fever, malignant lymphoma is by far the most common diagnosis of FUO among the neoplasms.[7] In some cases the fever even precedes lymphadenopathy detectable by physical examination.[7]
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.[1][3]
Other investigations may be needed. Ultrasound may show cholelithiasis, 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.[1][3]
Positron emission tomography using radioactively labelled fluorodeoxyglucose (FDG) has been reported to have a sensitivity of 84% and a specificity of 86% for localizing the source of fever of unknown origin.[8]
Despite all this, diagnosis may only be suggested by the therapy chosen. When a patient recovers after discontinuing medication it likely was drug fever, when antibiotics or antimycotics work it probably was infection. Empirical therapeutic trials should be used in those patients in which other techniques have failed.[1]
Nosocomial FUO refers to pyrexia in patients that have been admitted to hospital for at least 24 hours. This is commonly related to hospital-associated factors such as surgery, use of a urinary catheter, intravascular devices (i.e. "drip", pulmonary artery catheter), drugs (antibiotic-induced Clostridium difficile colitis, drug fever), and/or immobilization (decubitus ulcers). Sinusitis in the intensive care unit is associated with nasogastric and orotracheal tubes.[1][2][3] Other conditions that should be considered are deep-vein thrombophlebitis, pulmonary embolism, transfusion reactions, acalculous cholecystitis, thyroiditis, alcohol/drug withdrawal, adrenal insufficiency, and pancreatitis.[2]
HIV-infected patients are a subgroup of the immunodeficient FUO, and frequently have fever. The primary phase shows fever since it has a mononucleosis-like illness. In advanced stages of infection fever mostly is the result of a superimposed infections.[1][2][3]
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 for neutropenic (low white blood cell count) patients or patients who are severely immunocompromised in which delay could lead to serious complications.[4] 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.[1][2][3]
Since there is a wide range of conditions associated with FUO, prognosis depends on the particular cause.[1] If after six to twelve months no diagnosis is found, the chances of ever finding a specific cause diminish.[3] Under those circumstances, the prognosis is good.[2]
The syndrome of fever of unknown origin (FUO) was defined in 1961 by Petersdorf and Beeson as the following: (1) a temperature greater than 38.3C (101F) on several occasions, (2) more than 3 weeks' duration of illness, and (3) failure to reach a diagnosis despite 1 week of inpatient investigation. [3, 4] It is important to allow for flexibility in this definition, however. "Normal" core temperature in studies in developed nations has declined since the Industrial Revolution and may be inferred to peak at 99.9 F (37.7 C). [5, 6] The emergence of the human immunodeficiency virus (HIV) and the expanding use of immunomodulating therapies prompted Durack and Street to propose differentiating FUO into 4 categories: classical FUO (Petersdorf definition), hospital-acquired FUO, immunocompromised or neutropenic FUO, and HIV-related FUO. [7]
Emerging techniques such as molecular diagnostics, expanding use of immunocompromising therapies and organ transplantation, and the advent of globally mobile populations demand an evolving approach to defining and evaluating FUO. [7, 8, 9] Modern imaging techniques (eg, ultrasonography, computed tomography [CT] scanning, magnetic resonance imaging [MRI], positron emission tomography [PET]) enable early detection of abscesses and solid tumors that were once difficult to diagnose.
In a meta-analysis of 8 prospective studies of FUO from 1997 to 2021, neither structured nor nonstructured diagnostic approaches to FUO yielded a significant advantage. However, geographic prevalence and probabilities need to be factored into any protocol and contributes to improved success. [29]
A baseline definition of "fever" is important in determining whether a patient's report of an elevated temperature warrants a fever of unknown origin (FUO) workup. The common assumption that "fever" is a temperature over 100.4 F (38 C) is obsolete. Large reviews of nonsurgical patients indicate that average temperature in uninfected individuals has been on the decline since the 1800s and ranges from 95.8 to an upper limit of 99.9 degrees Fahrenheit in both outpatients and inpatients. This may reflect multiple conditions, such as better sanitation and hygiene leading to reduced chronic diseases such as tuberculosis and gingivitis and increases in indoor and air-conditioned activities. Older individuals tend toward cooler temperatures. Most temperatures are measured orally for both practical and physiologic purposes. A "normal" core (internal) body temperature ranges from 96 F (35.6 C) to 99.9F (38C) in healthy persons. Core temperature in the afternoon is about 1F higher later in the day and may be a bit higher in women. [5, 6]
The temperature of the sublingual fossa correlates most closely, and changes most consistently, with core body temperature, which is fairly constant; the rectum and axilla do not, especially during sepsis. It is important to recognize that the use of infrared non-contact thermometers in adults may be fraught with error due to variations in user technique, known variations in detection range of these instruments, and environmental temperatures. The tympanic membrane correlates with core body temperature and is nearest to the hypothalamic center that regulates temperature, but accuracy is affected by user technique and whether the ear canal is obstructed (eg, by wax); cold weather also cools the tympanic membrane. [10] Both temporal artery and forehead thermometers are likely to underestimate core body temperature and should be verified with sublingual or other method if fever is suspected. In the author's 12-month institutional experience with entrance screening during the COVID-19 pandemic, infrared forehead thermometry results were highly variable and of low yield in detected infected individuals. [11, 12, 13]
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