Fever of unknown origin
| Fever of unknown origin | |
|---|---|
| Classification and external resources | |
| Specialty | Lua error in Module:Wikidata at line 446: attempt to index field 'wikibase' (a nil value). |
| ICD-10 | R50 |
| ICD-9-CM | 780.6 |
| MedlinePlus | 003090 |
| Patient UK | Fever of unknown origin |
| MeSH | D005335 |
Fever of unknown origin (FUO), pyrexia of unknown origin (PUO) or febris e causa ignota (febris E.C.I.) refers to a condition in which the patient has an elevated temperature (fever) but despite investigations by a physician no explanation has been found.[1][2][3][4][5]
If the cause is found it is usually a diagnosis of exclusion, that is, by eliminating all possibilities until only one explanation remains, and taking this as the correct one.
Definition
In 1961 Petersdorf and Beeson suggested the following criteria:[1][2]
- Fever higher than 38.3 °C (101 °F) on several occasions
- Persisting without diagnosis for at least 3 weeks
- At least 1 week's investigation in hospital
A new definition which includes the outpatient setting (which reflects current medical practice) is broader, stipulating:
- 3 outpatient visits or
- 3 days in the hospital without elucidation of a cause or
- 1 week of "intelligent and invasive" ambulatory investigation.[2]
Presently FUO cases are codified in four subclasses.
Classic FUO
This refers to the original classification by Petersdorf and Beeson. Studies show there are five categories of conditions:
- infections (e.g. abscesses, endocarditis, tuberculosis, and complicated urinary tract infections),
- neoplasms (e.g. lymphomas, leukaemias),
- connective tissue diseases (e.g. temporal arteritis and polymyalgia rheumatica, Still's disease, systemic lupus erythematosus, and rheumatoid arthritis),
- miscellaneous disorders (e.g. alcoholic hepatitis, granulomatous conditions), and
- undiagnosed conditions.[1][3]
Nosocomial
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]
Immune-deficient
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]
Human immunodeficiency virus (HIV)-associated
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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]
African hantavirus (Sangassou virus)
In 2010, the first indigenous African hantavirus, Sangassou virus (SANGV) was isolated from an African wood mouse in a forest in Guinea, West Africa. A retrospective seroepidemiological analysis revealed the presence of Sangassou virus-specific neutralizing antibodies in the sera of patients suffering from fever of unknown origin.[6][7]
Causes
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 another important etiology to consider. An underestimated reason is factitious fever. Patients frequently are women that work, or have worked, in the medical field and have complex medical histories.[1][8] Bartonella infections are also known to cause fever of unknown origin.[9]
Here are the known causes of FUO.[10]
Infection
Neoplasm
Although most neoplasms can present with fever, malignant lymphoma is by far the most common diagnosis of FUO among the neoplasms.[11] In some cases the fever even precedes lymphadenopathy detectable by physical examination.[11]
Noninfectious inflammatory diseases
Miscellaneous conditions
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- ADEM (Acute disseminated encephalomyelitis)[11]
- Adrenal insufficiency[11]
- Aneurysm[11]
- Anomalous thoracic duct[11]
- Aortic dissection[10]
- Aortic-enteral fistula[11]
- Aseptic meningitis (Mollaret’s syndrome)[11]
- Atrial myxoma[11]
- Brewer’s yeast ingestion[11]
- Caroli disease[11]
- Cholesterol emboli[11]
- Complex partial status epilepticus[11]
- Cyclic neutropenia[11]
- Drug fever[10][11]
- Erdheim-Chester disease[11]
- Extrinsic allergic alveolitis[11]
- Factitious disease[10][11]
- Fire-eater’s lung[11]
- Fraudulent fever[11]
- Gaucher’s disease[11]
- Hamman-Rich syndrome (acute interstitial pneumonia)[11]
- Hashimoto’s encephalopathy[11]
- Hematomas[10][11]
- Hemoglobinopathies[10]
- Hypersensitivity pneumonitis[11]
- Hypertriglyceridemia[11]
- Hypothalamic hypopituitarism[11]
- Idiopathic normal-pressure hydrocephalus[11]
- Inflammatory pseudotumor[11]
- Kikuchi’s disease[10][11]
- Linear IgA dermatosis[11]
- Laennec's cirrhosis[10]
- Mesenteric fibromatosis[11]
- Metal fume fever[11]
- Milk protein allergy[11]
- Myotonic dystrophy[11]
- Nonbacterial osteitis[11]
- Organic dust toxic syndrome[11]
- Panniculitis[11]
- POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)[11]
- Polymer fume fever[11]
- Post–cardiac injury syndrome[11]
- Postmyocardial infarction syndrome[10]
- Primary biliary cirrhosis [11]
- Primary hyperparathyroidism[11]
- Recurrent pulmonary emboli[10]
- Pyoderma gangrenosum[11]
- Retroperitoneal fibrosis [11]
- Rosai-Dorfman disease[11]
- Sclerosing mesenteritis[11]
- Silicone embolization[11]
- Subacute thyroiditis (de Quervain's)[10][11]
- Sweet syndrome (acute febrile neutrophilic dermatosis)[11]
- Thrombosis[11]
- Tubulointerstitial nephritis and uveitis syndrome (TINU)[11]
- Tissue infarction/necrosis[10]
- Ulcerative colitis[11]
Inherited and Metabolic diseases
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- Adrenal insufficiency[10]
- Cyclic neutropenia[10]
- Deafness, urticaria, and amyloidosis[10]
- Fabry disease[10]
- Familial cold urticaria[10]
- Familial Mediterranean fever[10][11]
- Hyperimmunoglobulinemia D and periodic fever[10][11]
- Muckle-Wells syndrome[10]
- Tumor necrosis factor receptor–associated periodic syndrome (familial Hibernian fever)[10][11]
- Type V Hypertriglyceridemia[10]
Thermoregulatory disorders
| Thermoregulatory Disorders | Location |
|---|---|
| Central | <templatestyles src="Div col/styles.css"/> |
| Peripheral | <templatestyles src="Div col/styles.css"/> |
Habitual Hyperthermia
- Exaggerated Circadian rhythm[10]
Other
- “Afebrile” FUO [<38.3 °C (100.94 °F)][10]
Diagnosis
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.[12]
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]
Therapy
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 mostly delays diagnosis. An exception is made for neutropenic patients in which delay could lead to serious complications. 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 persons with pyrexia and hypoxia will be started on medication for possible Pneumocystis jirovecii infection. Therapy is adjusted after a diagnosis is made.[3]
Prognosis
Since there is a wide range of conditions associated with FUO, prognosis depends on the particular cause.[1] If after 6 to 12 months no diagnosis is found, the chances diminish of ever finding a specific cause.[3] However, under those circumstances prognosis is good.[2]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Mandell's Principles and Practices of Infection Diseases 6th Edition (2004) by Gerald L. Mandell MD, MACP, John E. Bennett MD, Raphael Dolin MD, ISBN 0-443-06643-4 · Hardback · 4016 Pages Churchill Livingstone
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Harrison's Principles of Internal Medicine 16th Edition, The McGraw-Hill Companies, ISBN 0-07-140235-7
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 The Oxford Textbook of Medicine Edited by David A. Warrell, Timothy M. Cox and John D. Firth with Edward J. Benz, Fourth Edition (2003), Oxford University Press, ISBN 0-19-262922-0
- ↑ Cecil Textbook of Medicine by Lee Goldman, Dennis Ausiello, 22nd Edition (2003), W.B. Saunders Company, ISBN 0-7216-9652-X
- ↑ Irwin and Rippe's Intensive Care Medicine by Irwin and Rippe, Fifth Edition (2003), Lippincott Williams & Wilkins, ISBN 0-7817-3548-3
- ↑ Klempa B, Koivogui L, Sylla O et al. Serological evidence of human hantavirus infections in Guinea, West Africa. J Infect Dis 2010; 201: 1031–1034.
- ↑ Strecker, Jan ter Meulen and Detlev H. KrügerAuste, et al. Sangassou virus, the first hantavirus isolate from Africa. Journal of Virology2012, 86(7):3819. doi:10.1128/JVI.05879-11
- ↑ Fever of Unknown Origin at Mount Sinai Hospital
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ 10.000 10.001 10.002 10.003 10.004 10.005 10.006 10.007 10.008 10.009 10.010 10.011 10.012 10.013 10.014 10.015 10.016 10.017 10.018 10.019 10.020 10.021 10.022 10.023 10.024 10.025 10.026 10.027 10.028 10.029 10.030 10.031 10.032 10.033 10.034 10.035 10.036 10.037 10.038 10.039 10.040 10.041 10.042 10.043 10.044 10.045 10.046 10.047 10.048 10.049 10.050 10.051 10.052 10.053 10.054 10.055 10.056 10.057 10.058 10.059 10.060 10.061 10.062 10.063 10.064 10.065 10.066 10.067 10.068 10.069 10.070 10.071 10.072 10.073 10.074 10.075 10.076 10.077 10.078 10.079 10.080 10.081 10.082 10.083 10.084 10.085 10.086 10.087 10.088 10.089 10.090 10.091 10.092 10.093 10.094 10.095 10.096 10.097 10.098 10.099 10.100 10.101 10.102 10.103 10.104 10.105 10.106 10.107 10.108 10.109 10.110 10.111 10.112 10.113 10.114 10.115 10.116 10.117 10.118 10.119 10.120 10.121 10.122 10.123 10.124 10.125 10.126 10.127 10.128 10.129 10.130 10.131 10.132 10.133 10.134 10.135 10.136 10.137 10.138 10.139 10.140 10.141 10.142 10.143 10.144 10.145 10.146 10.147 10.148 10.149 10.150 10.151 10.152 10.153 10.154 10.155 10.156 10.157 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ 11.000 11.001 11.002 11.003 11.004 11.005 11.006 11.007 11.008 11.009 11.010 11.011 11.012 11.013 11.014 11.015 11.016 11.017 11.018 11.019 11.020 11.021 11.022 11.023 11.024 11.025 11.026 11.027 11.028 11.029 11.030 11.031 11.032 11.033 11.034 11.035 11.036 11.037 11.038 11.039 11.040 11.041 11.042 11.043 11.044 11.045 11.046 11.047 11.048 11.049 11.050 11.051 11.052 11.053 11.054 11.055 11.056 11.057 11.058 11.059 11.060 11.061 11.062 11.063 11.064 11.065 11.066 11.067 11.068 11.069 11.070 11.071 11.072 11.073 11.074 11.075 11.076 11.077 11.078 11.079 11.080 11.081 11.082 11.083 11.084 11.085 11.086 11.087 11.088 11.089 11.090 11.091 11.092 11.093 11.094 11.095 11.096 11.097 11.098 11.099 11.100 11.101 11.102 11.103 11.104 11.105 11.106 11.107 11.108 11.109 11.110 11.111 11.112 11.113 11.114 11.115 11.116 11.117 11.118 11.119 11.120 11.121 11.122 11.123 11.124 11.125 11.126 11.127 11.128 11.129 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
