Fever of Unknown Origin
PK Agarwal*, A Gogia**
n 1868 Wundelich, a German clinician, published in monograph form a convincing demonstration of the value of measuring the body temperatures in various diseases.1 Thus the thermometer became the first instrument of precision to be used in medical practice. “Fever” came to be used to designate a certain form of forms of illnesses, but the challenge remained in the identification of the cause of this fever.
A uniform and clear definition of FUO is essential for the purposes of epidemiological study and for delineation of the clinical approach to these patients. Fever of unknown origin (FUO) identifies a syndrome of fever that does not resolve spontaneously, in which the cause remains elusive after an extensive diagnostic workup. Petersdorf and Beeson2 first coined the term fever of unknown origin in 1961 and explicitly defined it as (1) Temperature > 38.3ºC (101ºF) on several occasions (2) duration of fever of more than 3 weeks and (3) failure to reach to diagnosis despite one week of inpatient investigations. In 1991, DT Durrack and AC Street 3 suggested two changes to the earlier definition. Durrack and Street proposed four types of FUO. 1. Classic FUO - When temperature > 38ºC (101ºF) recorded on several occasions occurring for more than three weeks in spite of investigations on three OPD visits or three days of stay in hospital or one week of invasive ambulatory investigations is called classic FUO. 2. Nosocomial FUO - When temperature more than 38.3ºC (> 101°F) is recorded on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest or incubating on admission is called nosocomial FO. Three days of investigations including at least two days incubtion of cultures, is the minimum requirement for this diagnosis. Neutropenic FUO - When temperature of > 38.3ºC (101ºF) on several ocasion is observed in a patient whose neutrophil count is less than 500/microliter or is expected to fall to that level in 1 or 2 days is called neutropenic FUO. This diagnosis should be considered when investigation including at least two days of incubation of cultures. It is also called immunodeficient PUO.
HIV associated FUO - When temperature of > 38.3ºC (> 101ºF) on several occasions is found over a period of more than 4 weeks for our patient or more than three days for hospitalized patients with HIV infection is called HIV associated FUO. This diagnosis is considered if appropriate investigations over three days including two day of incubation of cultures reveals no source. The criterion of range of fever has been challenged. Timing and method of temperature monitoring is not mentioned in most studies. When taking into account all these limitations, fever may be defined as a morning temperature value of > 37.2ºC (99.0ºF) or temperature of > 37.8ºC (100ºF) at any other time during the day, when taken orally (Table 1).
PREVALENCE AND SPECTRUM OF DISEASE
The cuases of FUO have traditionally been grouped into four categories: infectious, malignant, inflammatory and undetermined.2,5-13 There are 11 series that include over 1000 patients that have reported the diagnostic entities that constitute FUO. Grouping all the patients collected from 1952 until 1994 reveals that the spectrum of disease includes infections in 28% and inflammatory diseases in 21%. Malignancies account for a smaller proportion (17%). A cause is never identified in a significant proportion (19%) of patients (Fig. 1). The most common infectious causes documented in the literature are tuberculosis and intra-abdominal abscesses.2,5,7,8,11,12 Most common malignancies are Hodgkin’s disease and non-Hodgkin’s lymphoma.2,5,7,8,11,12 Temporal arteritis accounts for 16-17% of all causes of FUO in the elderly.15,16
*Consultant; **PG Student, Department of Medicine, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi 110 060. Received : 6.11.2003; Accepted : 1.3.2004
Fig. 1 : The percentage of patients with fever of unknown origin by cause over the past 40 years.21 © JAPI • VOL. 52 • APRIL 2004
extra-intestinal amoebiasis. temporal artery. • Parasitic . < 3w for inpatients. inflammatory conditions. connective tissue disorders. Imaging. devices. 52 • APRIL 2004
www. travel. investigations. revision of treatment regimens. psittacosis. contacts.pyogenic (also amoebic) • Granulomatous . exposures. Brucella. toxoplasmosis. periappendiceal.
fever. outpatient temperature chart. cardiac valve disorder Fundi.extra-pulmonary and miliary tuberculosis. 3d. but cause documented in only 40-60%
HIV-related FUO < 38oC. bacterial cultures
CXR. skin. sedimentation rate. dental osteomyelitis. rickettsial and chlamydial . sinuses. lymphomas. skin. and liver for cultures and cytological tests. nails. perinephric. neoplasms and undetermined conditions. avoidance of empirical drug treatments Months Weeks
Depends on situation
Blood and lymphocyte count. Listeria. sinuses. stool examination.sinus. typical and atypical mycobacteria.japi. atypical mycobacteria infection. drains. skin testes
Nosocomial FUO > 38 C. eyes. vaccines. risk factors. cryptococcosis Drugs. biopsies of lung. polymyalgia rheumatica. habitual hyperthermia (5 cases) and drug-induced fever (3 cases).catheter-related endocarditis. CMV. spleen. Viral.
Patient location Leading causes
Operations and procedures. habitual hyperthermia Travel. lungs perianal area
Imaging. brain imaging Antimicrobial protocols. stag of infection. negative culures alter 48 in < 1000 PMN/cumm Hospital or clinic Majority due to infections. **Inlucidng factitious fever (7 cases). drug fever
Immuno-deficient FUO > 38 C. biopsies. devices. Kala azar. 1. pelvic and other sites . bacterial cultures
Time course of disease Tempo of investigation
Observation. lymph nodes. rectum or postate. toxoplamosis. contacts. Q
Table 2 : Final diagnosis in elderly compared with younger patients with fever of unknown origin16. > 2 visits or 3 d in hospital Community. clinic or hospital (HIV primary infection). meningococcemia.17 A list of them is given in Table 2. genitalia. Intravascular . Almost all causes belong to one of four general categories of disease: infections. medications. gonococcemia.
© JAPI • VOL. drug treatment Wound.18
Diagnosis Infections Abscess Endocarditis Tuberculosis Viral infections Other** Tumours Hematologic Solid Multi-system disease* Miscellaneous No diagnosis < 65 years n=152 33 (21%) 6 2 4 8 13 8 (5%) 3 5 27 (17%) 39 (26%) 45 (29%) > 65 years n=201 72 25 14 20 1 2 37 19 18 57 17 18 (35%)
(28%) (8%) (9%)
*Rheumatic disease. 3 wk. not present or incubating on admission Acute care hospital Nosocomial infections. fungal infection. splenic. bone marrow. vasculitis (including temporal arteritis). inflammatory disorder or connective tissue disorders. and sarcoidosis. postoperative complications. gall bladder. subphrenic. urine
Stage of chemotherapy. anatomic considerations. rat bite fever.infectious mononucleosis. perianal area
Mouth. serologic test. underlying immunosuppressive disorder Skin folds. oropharynx. 3d. good nutrition Weeks to months Days to weeks
CAUSES OF FUO
Of the many publications concerned with the etiology of FUO most have dealt with classic FUO rather than the other subclasses listed previously. family history. lungs. lower limb deep veins. retro peritoneal. HIV infection confirmed Community. lymph nodes. cancer. relapsing fever. clinic or hospital Infections. IV sites. animal and insect exposure.org
. abdomen. viral hepatitis. CXR. hepatic. cytomegalovirus. HIV. malaria. Infections • Abscess . undiagnosed. joints. drugs administered. subhepatic. immunizations.Table 1 : Summary of definitions and major features of the four subtyps of fever of unknown origin (FUO)4
Classic FUO Definition > 38 C.
femoral aneurysm. liver. Hodgkin’s and non-Hodgkin’s lymphoma. occupational exposures. petechiae.* endocarditis. Age 2. myelodysplasic syndrome. acute leukemia. sickle cell disease. pets. Final diagnoses are determined in a number of ways. Kawasaki’s syndrome. Roth’s spot Thyroid Enlargment. crest. clubbing
*Includes tuebrculosis. 1. adrenal insufficiency. cholesterol emboli. Neoplasia • Leukemias. sickle-cell disease vasoocclusive crisis. prostatic tenderness. polymer fume fever.Cirrhosis. histoplasmosis. idiopathic hypereosinophilic syndrome. shunt nephritis. GI tract.sarcoidosis.
The initial evaluation of the patient with PUO typically includes. factitious illness. reduced pulsation Ulceration. alcoholic hepatitis. lung especially when metasatic • Atrial myxomas • Central nervous system tumors 4.Anomalous thoracic duct. primary hyeprparathyroidism. extrinsic allergic alveolitis. Crohn’s disease • Tissue injury .Kala azar in Bihar. • Hepatic . postmyocardial infarction syndrome • Drug fever • Endocrinal . Hamman-Rich syndrome. 3. sarcoidosis and syphilis. Abscess fluctuance Testicular nodule Periarteritis nodosa Epididymal nodule Disseminated granulomatosis Deep venous Thrombosis or tenderness thrombophlebitis Petechiae. tenderness Heart Murmur Abdomen
Lower extremities Skin and nails
Infective endocarditis Enlarged iliac Lymphoma. 3. teflon embolisation. specific disease like pelvic inflammatory disease or male specific disease like prostatitis. Schnitzler’s syndrome. hemolytic anemia. periapical abscess Disseminated granulomatosis. habitual hyperthermia. tender tooth Diagnosis Sinusitis Temporal arteritis Diseminated histoplasmosis.2. familial Mediterranean fever. hypothalamic hypopituitarism. endocarditis. adenitis). aortic dissection. coccidioidomycosis. anhidrotic ectodermal dysplasia. silicone embolisation. encephalitis. The yield of physical examination is not recorded in most studies of FUO. mesenteric fibromatosis.Milk protein allergy. granulomatus hepatitis. including a comprehensive history. endocarditis hemorrhages. medications.20 The following table shows how a complete and meticulous physical examination can lead to a diagnosis. 52 • APRIL 2004
EVALUATION OF PATIENT OF FUO
In FUO. • Allergic . Residence present and past . • Nervous system . splinter Vasculitis. Thyroditis
Fundi or conjunctiva Choroid tubercle.Subacute (de Quervain’s) thyroiditis. • Carcinoma . lymph nodes.kidney. rheumatoid arthritis particularly Still’s disease. vasculitis (all types) • Granulomtous . Collagen vascular diseases • Collagen vascular diseases .
www. Sweet’s syndrome. familial disorders and previous illnesses. • Others . Fabry’s disease. thrombosis. Kikuchi’s syndrome. chronic active hepatitis. hyperimmunoglobulin D syndrome.autoimmune diseases are more common in female. FAPA syndrome (fever. Graucher’s disease. recurrent pulmonary embolism.
Table 3 : Examples of subtle physical findings having specific significance in patients with fever of unknown origin
Body site Head Temporal artery Oropharynx Physical finding Sinus tenderness Nodules.19.Complex partial status epilepticus. pancreas. splenomegaly disseminated granulomatosis Perirectal fluctuance.japi. Sex .Haematoma.org
. and familial Hibernian fever. subcutaneous nodules. lymph node infarction. repeated physical examination (Table 3) and a host of laboratory investigations. hyeprthyroidism. aphthous stomatitis. The yield may be high is suggested by two studies reporting that in pediatric patients about 60% had abnormal findings that contributed to a diagnosis. cerebrovascular accident. there is no diagnostic gold standard agaisnt which other diagnostic tests may be measured. Abscess tenderness. cyclic neutropenia. psychogenic fever. pharyngitis.rheumatic fever. systemic lupus erythematosus. brain tumour. Miscellaneous • Vascular . hypersensitivity penumonitis.pulmonary emboli.
© JAPI • VOL. comprehensive history and physcal examination. The specific findings that have led to a diagnosis in FUO are numerous and diverse. Thorough history is important and this should include information about alcohol intake.some diseases are more prevalent in a particular area . Vogt-Koyanagi-Harada syndrome. inflammatory pseudotumour Castleman’s disease. travel. malacolapkia. metal fume fever. Further in the history careful attention is to be paid to the host factors. Brewer’s yeast ingestion.
6. C-reactive protein No study MRI.org
.a) Human immunodeficiency virus. other animals. 16. pattern or duration of fever did not relate to diagnosis. A CT of the abdomen has a high diagnostic yield (19%)25 and carries a low risk. CSF) 7. previous surgeries including splenectomy. 14. Serology . Complete blood count and differential 2. cardiac valve disorder. Chest radiogrpah 8. Clinical features Fever has been characterized by magnitude and frequency and specific fever patterns have been ascribed to many of the causes of FUO. Family history of TB or rarely hereditary cause of fever like familial Mediterranean fever should be sought. Comperhensive history B. bilirubin. complement levels. the clinician should then proceed to imaging. Two fair317
www. contacts persons. pANCA. Erythrocyte sedimentation rate 3. Collagen makers .Indinium and 67Gallium scans Invasive proceduresBone marrow aspiration and biopsy (also imprint smear and culture/serology) Lymph node FNAC and biopsy Liver biopsy/thoracoscopy (where indicated) Splenic aspirate (where indicated)
CT guided FNAC of mass/lymph node Laparoscopy Bronchoscopy and transbronchial biopsy Further evaluation if any abnormalities detected in the above tests. joints pleura. Non-invasive test yield diagnosis in about 25% of cases of FUO.
Past infections are sometimes responsible for reactivation or other effects. Q .24 Laboratory Investigations While planning a diagnostic workup for a patient of FUO it will be useful to remember that most often the cause of FUO is a common disorder presenting in atypical rather than an exotic disease presenting in its typical form. 9. Work environment/home environment. These should include a CT of the abdomen and a Technetium based nuclear scan. and thus should be used to identify endocarditis as the cause of FUO.4. Routine blood chemistry (including lactate dehydrogenase.23. and liver enzymes) 5. 12. cytomegalovirus IgM antibody.g. When the initial investigations are not helpful in identifying a cause. Drug.antinuclear antibodies. b) PCR/NASBA for tuberculosis. 11.fever serology (if exposure factor exist). Radionuclide scans . Diagnostic workup of fever of unknown origin19 A.
Echocardiography in case of cardiac murmur. rheumatoid factors. underlying disease.22 Unfortunately in most cases series. Immunization and medications. heterophil antibody test (if consistent with mononucleosis . 8. CMV. 5. Blood film reviewed by the hematopathologist including malarial parasite and malarial serology. angiotensin converting enzyme. 52 • APRIL 2004
Table 4 : Recommendations for diagnostic testing in FUO21
Maneuver The Duke criteria Abdominal CT Effectiveness Specificity 99% Level of Recommendation evidence Fair Very high specificity in patients with FUO High diagnostic yield High Specificity poor sensitivity Tracer of choice in FUO Poor specificity and sensitivity No evidence to make recommendations for or agaisnt it High diagnostic yield and minimal toxicity Very low diagnostic yield High yield in preCT era
Tc99m nuclear scan
Diagnostic yield 19% Fair Sensitivity 71% Specificity 71% Specificity 93%-94% Fair Sensitivity 40%-75%
Gallium 67 Specificity 70%-78% scan Sensitivity 54%-67% ESR. Skin Testing-tuberculin skin test 10. 4. echocardio Liver biopsy Diagnostic yield 14%-17% Diagnostic yield 0%-20%
Bone marrow cultures Laparotomy/ Laparoscopy Empiric Therapy
13. The response of fever to naproxen sodium may be helpful in that the fever due to solid tumours and many rheumatological diseases (most notably Still’s Disease) usually subside promptly while fever due to other causes may persist. Laboraotry tests (Table 4) 1. Physical examination C. 15. Exposure to pets. ENA.japi. hepatitis. Blood (x3) and urine cultures (and other sterile compartment if clinically indicated e. Abdominal ultrasonography 9. 7. The Duke’s criteria have a very high specificity (99%) in patients with FUO and suspected infective endocarditis. Venous duplex scan of lower limbs. hepatitis serology (if abnormal liver enzyme test result). Urinalysis and microscopy 6. CT abdomen/chest
© JAPI • VOL. the height.like syndrome). Imaging studies have been used to localize abnormalities as a preamble to more definitive (invasive) testing. c ANCA.
Ledingham JGG.quality studies show that technetium-based scans have a high specificity but are insensitive. Pyrexia of unknown origin: changing spectrum of disease in two consecutive series. Clin Infect Dis 1992. Fever of unknown origin reexamined and redefined. Vandenbrouchke JP. Featherstone HJ.8-4. Knockaert DC. The short-term prognosis of neutropenic fever of unknown origin is excellent with over 90% to empirical antibiotic therapy.org
© JAPI • VOL. 12.8.28 The yield from biopsies in the operating theatre or under CT guidance is greater than that of bedside biopsy procedures.
8.2.11 Therefore. In Oxford textbook of medicine.68:884-87. Weatherhall DJ. Deal WB. IA : prospective multicentre study of 167 patients with FUO using fixed epidemiological criteria. London. Petersdorf RG.
10.16 Exploratory laparotomy in the absence of localizing features is unusual these days. van der Meer JW.japi. fever of undetermined origin: not what it used to be. 1871. 1970-1980.18 A temporal artery biopsy should be considered in elderly patients with FUO.28
Outcomes of patients with FUO are a function of the underlying cause. Barbad FJ.8.
9. Warrell DA (edit). Street AT. There is fair evidence to suggest that a liver biopsy has a high diagnostic yield (14%-17%)26. Current Clin Tropical Infec Dis 1991.15:968-73. Larson EB. Fever of unknown origin: analysis of 34 patients. Non-specific treatment is rarely curative and has the potential to delay diagnosis.292:56-64. J Med 1984. Petersdorf RG. Durrack DT.
5.i. Fever of unknown origin (FUO): report on 53 patients in a Dutch university hospital. Laparoscopy. 1995. Bobaers HJ. At the same time diagnostic delay adversely affect the prognosis in intra-abdominal infections.15:185-92. even though the diagnostic yield is moderate . military TB. Barbado FJ. Mortality is much less if an infection is identified as the cause of FUO (8%-22%). Fever of unknown origin. On the temperature in diseases. Fever of unexplained origin. Vanneste SB. Fever of 86 patients treated in community hospitals.21 Invasive procedures Diagnosis of fewer than half the cases of FUO has resulted from excisional biopsy. It is particularly helpful in cases where there is a history of prolonged low-grade fever with evening rise along with raised ESR. De Kleijn EM. In other situations empirical treatment with antiinflammatory agents.47:54-60. the best predictor of survival is disease category. Am J Med Sci 1986. Therapeutic trials In appropriate clinical settings. Most FUO patients undergo at least one of these procedures. needle biopsy.11 Most of these patients have spontaneous recovery (51%-100%) and only a small proportion have persistent fever (0%-30%). is a less traumatic alternative.10. Wunderlich CA. 3. or anti-neoplastic agents should be desisted. Fever of unknown origin in the 1980s: an update of the diagnostic spectrum. Smith JW. Beeson P.
7. The prognosis of patients with FUO in whom a cause cannot be identified is excellent. van der Meer JW. including laparoscopic liver biopsy.
MANAGEMENT OF FUO
A fundamental principle in the management of classic FUO is that therapy should be delayed until the cause of fever has been determined so that the therapy can be tailored to a specific diagnosis. interviewing the patient and investigations.50:182-88. corticosteroids. Kazanjian PH. In suspected temporal arteritis to prevent vascular complications like blindness empirical corticosteroids may be given. It is most helpful when other features point to abdominal disease and has had a yield of only 20% when such features are absent. 12-35% of patients will die from FUO-related causes. Medicine (Baltimore) 1982.61:269-92.27 with minimal toxicity. Postgrad Med 1971. 4. Medicine (Baltimore) 1961. Medicine (Baltimore) 1997. disseminated fungal infection and recurrent pulmonary embolism. antibiotics. Arch Intern Med 1992.2. New Syndenham Society. employing agents with limited spectrum of activity like antitubercular drugs may be accepted. 2.8. Fever of unknown origin: a survey on 133 patiens. Pena JM. 52% to 100% of patients with a final diagnosis of malignancy will die within five years.5. et al. 2.11:35-51. a positive tuberculin test with or without loss of appetite and weight.6 biopsies per final diagnosis achieved. Diagnosis of PUO may require repeated examination. Vanneste LJ.
www. Leg Doppler imaging should be considered the next step in identifying deep vein thrombosis as a potential reversible and easily treatable cause. 52 • APRIL 2004
. Overall. 11. Postgrad Med J 1992. 3rd edition Oxford Medical Publications.40:1-30. with malignancy incurring the highest mortality.
1. Neth J Med 1995. 6. aspirin. The 5-year mortality rate of undiagnosed FUO was only 3.e.152:51-55.28 The only biopsy that may often be rewarding in the absence of prior localizing information is temporal artery biopsy in elderly patients with a very high ESR. De Kleijn EM. report of 100 cases. Southwestern Internal Medicine Conference.101516.2%. Vazquez JJ. or laparotomy. Bone marrow cultures are of low yield (0%-20%) and are not recommended in immunocompetent patients with FUO. Fever of unknown origin (FUO). Durrack DT.76:392-400. Fever of undetermined origin: diagnosis and follow up of 105 cases. 13. Vazquez J. The prognosis of nosocomial fever of unknown origin varies according to underlying disese. therapeutic trials. Non-specific treatment is rarely curative and has the potential to delay diagnosis.