Fever of unknown origin | |
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Other names | Pyrexia of unknown origin, febris e causa ignota |
Types | Various |
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 qualified physicians. [1] [2] [3] If the cause is found, it is usually a diagnosis of exclusion, eliminating all possibilities until only the correct explanation remains.
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]
Human herpes viruses are a common cause of fever of unknown origin with one study showing Cytomegalovirus, 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). [4] 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. [4]
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 (such as fevers, chills, night sweats, and 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 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]
Neoplasm cause | Disease name |
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Hematologic malignancies |
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Solid tumors | |
Benign |
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Thermoregulatory disorders | Location |
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Central | |
Peripheral |
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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]
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. [4]
In 1961 Petersdorf and Beeson suggested the following criteria: [1] [2]
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 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 Clostridioides 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]
Immunodeficiency can be seen in patients receiving chemotherapy or in hematologic malignancies. Fever is concomitant with neutropenia (neutrophil <500/uL) or impaired cell-mediated immunity. The lack of immune response masks a potentially dangerous course. Infection is the most common cause. [1] [2] [3]
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]
HIV-infected people with pyrexia and hypoxia will be started on medication for possible Pneumocystis jirovecii infection. Therapy is adjusted after a diagnosis is made. [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]
Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord can cause the myelin and axon to be damaged resulting in symptoms such as paralysis and sensory loss. Myelitis is classified to several categories depending on the area or the cause of the lesion; however, any inflammatory attack on the spinal cord is often referred to as transverse myelitis.
Neutropenia is an abnormally low concentration of neutrophils in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria, bacterial fragments and immunoglobulin-bound viruses in the blood. People with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening.
Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.
Histoplasmosis is a fungal infection caused by Histoplasma capsulatum. Symptoms of this infection vary greatly, but the disease affects primarily the lungs. Occasionally, other organs are affected; called disseminated histoplasmosis, it can be fatal if left untreated.
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID.
AIDS-related lymphoma describes lymphomas occurring in patients with acquired immunodeficiency syndrome (AIDS).
Cryptococcosis is a potentially fatal fungal infection of mainly the lungs, presenting as a pneumonia, and brain, where it appears as a meningitis. Cough, difficulty breathing, chest pain and fever are seen when the lungs are infected. When the brain is infected, symptoms include headache, fever, neck pain, nausea and vomiting, light sensitivity and confusion or changes in behavior. It can also affect other parts of the body including skin, where it may appear as several fluid-filled nodules with dead tissue.
Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type is lymphadenitis, producing swollen or enlarged lymph nodes. In clinical practice, the distinction between lymphadenopathy and lymphadenitis is rarely made and the words are usually treated as synonymous. Inflammation of the lymphatic vessels is known as lymphangitis. Infectious lymphadenitis affecting lymph nodes in the neck is often called scrofula.
Harrison's Principles of Internal Medicine is an American textbook of internal medicine. First published in 1950, it is in its 21st edition and comes in two volumes. Although it is aimed at all members of the medical profession, it is mainly used by internists and junior doctors in this field, as well as medical students. It is widely regarded as one of the most authoritative books on internal medicine and has been described as the "most recognized book in all of medicine."
This is a list of AIDS-related topics, many of which were originally taken from the public domain U.S. Department of Health Glossary of HIV/AIDS-Related Terms, 4th Edition.
WHO Disease Staging System for HIV Infection and Disease in Adults and Adolescents was first produced in 1990 by the World Health Organization and updated in September 2005. It is an approach for use in resource limited settings and is widely used in Africa and Asia and has been a useful research tool in studies of progression to symptomatic HIV disease.
Pneumonitis describes general inflammation of lung tissue. Possible causative agents include radiation therapy of the chest, exposure to medications used during chemo-therapy, the inhalation of debris, aspiration, herbicides or fluorocarbons and some systemic diseases. If unresolved, continued inflammation can result in irreparable damage such as pulmonary fibrosis.
Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of HIV/AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse.
Meningoencephalitis, also known as herpes meningoencephalitis, is a medical condition that simultaneously resembles both meningitis, which is an infection or inflammation of the meninges, and encephalitis, which is an infection or inflammation of the brain tissue.
Mycobacterium avium-intracellulare infection (MAI) is an atypical mycobacterial infection, i.e. one with nontuberculous mycobacteria or NTM, caused by Mycobacterium avium complex (MAC), which is made of two Mycobacterium species, M. avium and M. intracellulare. This infection causes respiratory illness in birds, pigs, and humans, especially in immunocompromised people. In the later stages of AIDS, it can be very severe. It usually first presents as a persistent cough. It is typically treated with a series of three antibiotics for a period of at least six months.
Aspergillosis is a fungal infection of usually the lungs, caused by the genus Aspergillus, a common mould that is breathed in frequently from the air, but does not usually affect most people. It generally occurs in people with lung diseases such as asthma, cystic fibrosis or tuberculosis, or those who are immunocompromised such as those who have had a stem cell or organ transplant or those who take medications such as steroids and some cancer treatments which suppress the immune system. Rarely, it can affect skin.
Diffuse infiltrative lymphocytosis syndrome (DILS) is a rare multi-system complication of HIV believed to occur secondary to an abnormal persistence of the initial CD8+ T cell expansion that regularly occurs in an HIV infection. This persistent CD8+ T cell expansion occurs in the setting of a low CD4+/CD8+ T cell ratio and ultimately invades and destroys tissues and organs resulting in the various complications of DILS. DILS classically presents with bilateral salivary gland enlargement (parotitis), cervical lymphadenopathy, and sicca symptoms such as xerophthalmia and xerostomia, but it may also involve the lungs, nervous system, kidneys, liver, digestive tract, and muscles. Once suspected, current diagnostic workups include (1) confirming HIV infection, (2) confirming six or greater months of characteristic signs and symptoms, (3) confirming organ infiltration by CD8+ T cells, and (4) exclusion of other autoimmune conditions. Once the diagnosis of DILS is confirmed, management includes highly active antiretroviral therapy (HAART) and as-needed steroids. With proper treatment, the overall prognosis of DILS is favorable.
The stages of HIV infection are acute infection, latency, and AIDS. Acute infection lasts for several weeks and may include symptoms such as fever, swollen lymph nodes, inflammation of the throat, rash, muscle pain, malaise, and mouth and esophageal sores. The latency stage involves few or no symptoms and can last anywhere from two weeks to twenty years or more, depending on the individual. AIDS, the final stage of HIV infection, is defined by low CD4+ T cell counts, various opportunistic infections, cancers, and other conditions.
Eosinophilic myocarditis is inflammation in the heart muscle that is caused by the infiltration and destructive activity of a type of white blood cell, the eosinophil. Typically, the disorder is associated with hypereosinophilia, i.e. an eosinophil blood cell count greater than 1,500 per microliter. It is distinguished from non-eosinophilic myocarditis, which is heart inflammation caused by other types of white blood cells, i.e. lymphocytes and monocytes, as well as the respective descendants of these cells, NK cells and macrophages. This distinction is important because the eosinophil-based disorder is due to a particular set of underlying diseases and its preferred treatments differ from those for non-eosinophilic myocarditis.
Epstein–Barr virus–associated lymphoproliferative diseases are a group of disorders in which one or more types of lymphoid cells, i.e. B cells, T cells, NK cells, and histiocytic-dendritic cells, are infected with the Epstein–Barr virus (EBV). This causes the infected cells to divide excessively, and is associated with the development of various non-cancerous, pre-cancerous, and cancerous lymphoproliferative disorders (LPDs). These LPDs include the well-known disorder occurring during the initial infection with the EBV, infectious mononucleosis, and the large number of subsequent disorders that may occur thereafter. The virus is usually involved in the development and/or progression of these LPDs although in some cases it may be an "innocent" bystander, i.e. present in, but not contributing to, the disease.