FEVER OF UNKNOWN ORIGIN (FUO) – Definition, Etiology, Diagnosis and Investigations
Syn: Pyrexia of Unknown Origin (PUO) FUO is the term used to denote fever that does not resolve spontaneously in the period expected for self limited infections and whose cause could not be ascertained even after reasonable investigations.
FUO was defined by Petersdorf and Beeson in 1961 as temperature > 38.3oC (101oF), lasting for more than 3 weeks and failure to reach a diagnosis, even after 1 week of inpatient investigations. A subsequent definition in 2003 stated that failure to get a diagnosis after 3 days of inpatient investigations or three outpatient visits should qualify for the term FUO.
A. Infections: 30–50% is caused by infections. These include the following:
1. Occult tuberculosis: Extrapulmonary tuberculosis affecting the lymph nodes, intestines, mesentery, vertebrae, joints, liver, pleura, pericardium, and genital organs may remain latent without any local symptoms; but causing fever. The local lesion may become evident only after several weeks or months.
2. Intra-abdominal infections: Renal, retroperitoneal paraspinal, subdiaphragmatic, and pelvic abscesses may remain silent and cause diagnostic problems. Complicated urinary tract infection and infections of the biliary tree may also present as FUO.
3. Other infections: Infective endocarditis, brucellosis osteomyelitis, dental and sinus infections, enteric fever with atypical presentation, malaria, amebiasis, syphilis, leprosy, leshmaniasis and prostatis may present as FUO.
4. Viral infections: Infectious mononucleosis and cytomegalovirus infection may present as FUO.
5. Fungal infections: Examples are histoplasmosis and cryptococcosis.
B. Malignancy: These form about 20% Leading malignancies presenting as FUO are:
1. Leukemias, lymphomas and multiple myeloma 2. Solid tumours like renal cell carcinoma, liver, colon stomach and pancreatic cancers.
C. Connective Tissue Diseases (About 15%): SLE, rheumatoid arthritis, rheumatic fever, polyarteritis nodosa, temporal arteritis, polymyalgia rheumatica, Wegener’s granulomatosis, adult Still’s disease and others.
D. Miscellaneous (About 20%): Inflammatory bowel disease, cirrhosis of the liver, granulomatous hepatitis, sarcoidosis, atrial myxoma, thyroiditis, thyrotoxicosis, drug reactions, hemolytic anemias, hematomas, deep vein thrombosis ( DVT) and pulmonary embolism.
Undiagnosed: About 15 % may remain undiagnosed.
Factitious fever: This is elevation of temperature, self induced by patients with psychological problems – mostly young women working in health profession. They may induce disease or may devise methods to make the thermometer record higher temperature even when they are normal.
Nosocomial FUO: This term denotes fever above 38.3oC, (101o F) lasting for more than 72 hours, developing in a patient who is afebrile on admission to hospital. Most common causes are pneumonia, urinary tract infection, catheter related infections, Clostridium difficile colitis, Cytomegalovirus infection, sinusitis, septic thrombophlebitis and pulmonary embolism.
Neutropenic FUO: This is fever more than 38.3Oc (101o F) lasting for more than 72 hours in a patient with absolute neutrophil count less than 500/cmm or expected to reach that level in 1-2 days. Most commonly this is produced by bacterial infections – bacteremias, pneumonia and soft tissue infections. Infection of the perianal area is also common. If neutropenia is prolonged, fungal and viral infections also supervene.
Human immunodeficiency virus (HIV) associated FUO: Fever is a common accompaniment of HIV infection when it leads to immunodeficiency. The most common infective agents are Mycobacterium tuberculosis, Mycobacterium avium complex, Pneumocystis carinii, disseminated cryptococcosis, toxoplasmosis and nocardiosis. Uncomplicated HIV infection itself can be the cause of prolonged fever.
Careful attention to history and a complete physical examination, repeated when necessary may reveal the etiology in many. Enquire about possible recent exposure to sexually transmitted disease, injected illicit drug use, which may predispose to hepatitis B and C, HIV, and infective endocarditis. Travel history may give a clue. Occupational history may be significant and give evidence of exposure to birds (psittacosis) or animals (toxoplasmosis, brucellosis). Examination ocular fungi may reveal etiological clues – Roth spots in infective endocarditis, choroid tubercles in miliary tuberculosis and CMV retinitis. It is important to reassess the patient clinically at regular intervals. Look carefully for skin rash, skin nodules, conjunctival petechiae, clubbing and splinter hemorrhage. Digital rectal examination may suggest the cause occasionally – perianal disease suggests inflammatory bowel disease, local sepsis and abscess, rectal carcinoma, prostatitis, prostatic malignancy.
Even though the first clinical examination may be negative, repetition at weekly intervals or (shorter) will bring out diagnostic clues and therefore this is an important diagnostic procedure.
Investigations: Investigations must be individualized based on the most probable suspected diagnosis. Differential diagnosis will depend upon the geographical area, age of the patient and co-morbid conditions. In general non invasive investigations should be done first before resorting to invasive investigations such as biopsy, endoscopy and others.
A complete blood count and erythrocyte sedimentation rate (ESR) is to be done in all cases. ESR above 80 mm/hr is seen in tuberculosis, malignancy, connective tissue diseases and temporal arteritis. A peripheral smear is to be examined for abnormal cells, malaria parasite and atypical lymphocytes.
Mid stream urine is to be collected for microscopy and culture. Bacterial counts is above 105 organisms/mL indicate urinary tract infection.
Isolation of Infective Agent
Blood culture should be done routinely in all fevers persisting more than a week. Many a times repeated blood cultures may have to be done to isolate the organism e.g. infective endocarditis.
Polymerase chain reaction (PCR) is very valuable in detecting the nuclear or cytoplasmic components of infecting organisms early in the disease. It is specific and reliable, but false positive results may occur.
Rise in serum uric acid level may suggest rapid cell turnover occurring in malignancies like lymphomas. Rise in alkaline phosphatase, especially the hepatic isoenzymes should indicate liver cell involvement.
Mantoux test: This is a commonly done test to detect allergy to tuberculoprotein. Positive Mantoux test indicates the possibility of tuberculous infection – past or active. In active tuberculosis, the Mantoux test is generally hyperactive, but it may be misleadingly negative in miliary tuberculosis and immunocompromised persons. The specificity of this test is only moderate.
X-ray imaging: This is the most time honoured, almost universally available, relatively cheap and non- invasive imaging modality which is very helpful in the diagnosis of lesions in the chest e.g. pneumonia and tuberculosis, paranasal sinuses, bones and joints and others. Plain skiagram and specialized procedures are available to delineate almost all organ system.
Ultrasound imaging: The morphology of several organ systems in the body can be imaged by ultra sound using appropriate probes and computer techniques. Abdominal organs, genitourinary tract, uterus and any other part can be studied in detail. This modality has become a very useful and commonly used investigation to detect organomegaly in the abdomen, detection of fluid in the abdomen and the plural cavities, pericardium, cardiac structures and almost all other organs in some form or other. Examination of the abdomen may detect abnormalities in the liver (tumour, abscess), biliary system, kidneys, retroperitoneal nodes, pus and fluid collations, ascites and organomegaly.
Echocardiography is useful in detecting cardiac vegetations, atrial myxoma, and other cadiac abnormalities. Therefore this is a very valuable investigation to rule out or confirm a diagnosis of infective endocarditis. In infective endocarditis, trans-esophageal probes have to be used if the conventional transthoracic probes are not fully informative.
Limited skeletal survey is useful in suspected multiple myeloma.
Other imaging modalities: These include CT scanning, MRI scanning, PET scanning and their further modifications appropriate to the organ and the disease to be studied.
Isotope bone scan is useful in detecting malignancy, osteomyelitis and septic arthritis.
Selected Serological Tests
A. Infections: Example typhoid, leptospirosis, brucellosis, dengue fever, Ebstein Barr virus , cytomegalovirus, chlamydiae, mycoplasma, Q fever, amebiasis, leshmaniasis, toxoplasmosis and others.
Detection of specific antibodies against infecting organisms or their products, e.g. Widal rection detects antibodies against Salmonella. Antistreptolysin-O (ASO) titre estimates the antibody to the toxin of streptococcus.
Specific serological tests are available for diagnosis of connective tissue diseases, e.g. rheumatoid factor, in rheumatoid disease, antinuclear antibodies (ANA) in systemic lupus erythematosus which all can mimic infective fevers. Nonspecific tests such as erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) indicate the presence of an inflammatory process, non-specifically. Once the infection is identified, serial determination of ESR or CRP helps to assess progress.
B. Diseases of connective tissue and vasculitis: Antinuclear antibody (ANA), anti ds DNA, anti neturophil cytoplasmic antibody (ANCA).
Selection of further investigations needs careful consideration of the likely benefit and the cost involved. Gastrointestinal endoscopy with biopsy is indicated if symptoms or findings on imaging studies suggest diseases of the abdominal hollow viscera such as inflammatory bowel disease, intestinal tuberculosis or cancer.
Bronchoscopy and bronchoalveolar lavage for culture of organisms and cytology for malignant and other pathognomic abnormalities may be considered in selected cases.
Role of biopsy in the diagnosis of FUO: All biopsy procedures are invasive and associated with at least moderate or serious risks to life and health, even though, small. Therefore biopsy procedure should be reserved for cases where diagnosis is not arrived at by simpler procedures. Biopsy specimen can be obtained either by open biopsy or fine needle aspiration cytology (FNAC). Biopsy specimen should also be sent for culture of the organisms and sensitivity studies as well.
Liver biopsy: This procedure may help to diagnose miliary tuberculosis, sarcoidosis, lymphoma, and histoplasmosis if the lesions are generalized and tumours or localized inflammation such as granulomas if they are large enough. Guidance with ultrasound helps to reach the target precisely. Yield is generally low if liver function test and liver imaging are normal.
Bone marrow aspiration and biopsy: This is most useful in diagnosing hematological disordes such as leukemias, myeloma and anemias. Among infections visceral leishmaniasis is diagnosed by bone marrow examination. Typhoid, brucellosis, tuberculosis and other infections can be diagnosed by bone marrow culture and this is done when blood culture is negative.
Lymph node biopsy – This is useful when nodes are enlarged, as in lymphomas, tuberculosis, secondary malignant deposits, and others. In generalized lymphadenopathy it is better to take a node which is moderately enlarged. Since the inguinal nodes are likely to show nonspecific changes, they are preferably avoided.