Fever of Unknown Origin (FUO)

2. recite the common causes of FUO.

3. recite the common sites of infection that lead to an FUO due to an infectious process.

Reading: 

Lecture: Dr. Neal R. Chamberlain

References: Arnow, PM., JP Flaherty. 1997. Fever of Unknown Origin. Lancet. 350: 575-580

Hirschmann, V. 1996. Fever of Unknown Origin in Adults. Clinical Infectious Diseases. 24: 291-302.

Definition
Peterdorf and Beeson in 1961 defined FUO as:

1. illness of greater than 3 week's duration.
2. fever higher than 101^oF (38.3^oC) on several occasions.
3. no diagnosis established despite 1 week of intensive evaluation.

Etiologies
As mentioned before over 200 different conditions can cause FUO. However, FUO can be placed into various groups depending on the cause. Infections are still the most common cause of FUO. Understanding the common causes of FUO aid in developing a diagnosis. The causes of FUO are usually familiar diseases with uncommon presentations rather than rarer disorders. In several studies the correct diagnosis was possible from the history, physical examination, and routine laboratory tests. Conversely, failure to utilize findings correctly, delay in ordering appropriate tests, and misinterpretation of test results have all resulted in missed diagnoses.

Common causes:

• Infections cause 30-40% of the cases of FUO. Most common cause.
• Neoplasms cause 20-30% of the cases of FUO.
• Rheumatologic diseases cause 10-20% of the cases of FUO.
• Miscellaneous conditions cause 15-20% of the cases of FUO.
• 5-15% of FUO's remain undiagnosed. Usually these FUO's resolve on their own. Most of these patients have a relatively good prognosis.

Diagnosis

History- A thorough history is very important. This history should include information concerning alcohol consumption, medications, occupational history, pets, travel, familial disorders, and previous illnesses. Examples of diseases for which clues are provided include:

• Amoebiasis- leading to liver abscess, foreign travel has usually occurred in the recent past
• Mediterranean fever- family history is very helpful
• Psittacosis- patient has mentioned contact with parakeets.
• Metastatic cancer- patient mentions previous cancer or cancer treatment.
• Drug fever- patient mentions the use of various medications.
• Prior inflammatory processes in the abdomen can lead to intraabdominal abscesses- patient with Crohn's disease or prior episode with cholecystitis, diverticulitis, or appendicitis.

Physical Examination- The findings on physical examination can be numerous and diverse. Examples include lymphadenopathy (any number of diseases), enlargement of the thyroid (thyroiditis), periodontal disease or loose teeth (undiagnosed dental abscess), thickened temporal artery (temporal arteritis), cardiac murmur that changes with position (atrial myxoma), and widespread hyperpigmentation (Whipple's disease)

Whipple's Disease is due to a bacteria called Tropheryma whippelii (Tw)- is a gram-positive bacterium, which has only recently  been cultured and has been propagated in deactivated macrophages. Polymerase chain reaction (PCR) has been used to identify Tw  DNA in the intestinal tissue, peripheral blood, and cerebrospinal fluid of infected people. Whipple's disease, was named after the pathologist George Hoyt Whipple, who described it for the first time in 1907. The symptoms of this disease are malabsorption, weight loss, arthralgia, fevers, and abdominal pain. Any organ system can be affected, including the heart,  lungs, skin, joints, and central nervous system. This disease can be fatal if not adequately treated with antibiotics. Fatality is most often related to a relapse in the nervous system which may occur months or years after successful treatment with antibiotics.

Clinical features- Fever periodicity, peaks, duration, and frequency does not usually help in diagnosis. Relative bradycardia can be helpful however a number of entities can cause this: typhoid fever, legionnaire's disease, psittacosis, leptospirosis, drug fever, brucellosis, subacute necrotising lymphadenitis, neoplasm, and factitious fever. The response of fever to treatment with naproxoen sodium maybe useful in that fever due to solid tumors and many rheumatological diseases (most notable Still's disease) usually subside promptly while fever due to other causes may persist. FUO of very long duration (months) is not likely to be due to an infection.

Laboratory Tests- Non-invasive lab tests help in providing a diagnosis in about 25% of the cases of FUO. The following is a suggested panel for evaluating a patient with FUO
 

Comprehensive History Repeated Physical Examinations

Complete blood count, including differential and platelet count Routine blood chemistry, including lactate dehydrogenase, bilirubin, and liver enzymes. Urinalysis, including microscopic examination Antinuclear antibodies Rheumatoid factor Angiotensin converting enzyme Routine blood cultures (X3) while not receiving antibiotics. Cytomegalovirus IgM antibodies or virus detection in blood. Heterophile antibody test in children and young adults. Tuberculin skin test. CT of abdomen or radionuclide scan. HIV antibodies or virus detection assay. Further evaluation of any abnormalities detected by above tests.

Invasive procedures- diagnosis in less than 50% of the cases of FUO has resulted from excisional biopsy, needle biopsy, or laparotomy. Most patients with FUO undergo at least one of these procedures. Usually, better biopsies are obtained in the surgical suite or under CT guidance than that of bedside biopsy procedures. Temporal artery biopsy in an elderly FUO patient with a high ESR is essential in the diagnosis of giant cell arteritis. This biopsy can turn up positive even in the absence of localized symptoms.

Laparoscopy is useful when CT reveals abnormalities in the abdomen. This procedure is less traumatic and can be used to obtain liver biopsy.

Prognosis- The patient's prognosis is dependent on the underlying disease process and by how soon a diagnosis is obtained. Outcomes are worse for neoplasms. Delays in diagnosis have contributed in death in patients with intraabdominal infection (especially splenic abscess), miliary TB, disseminated fungal infection, and in recurrent pulmonary emboli. Patients with FUO that remain undiagnosed after extensive and timely evaluation generally have favorable outcomes with the fever resolving in 4-5 weeks without sequelae. Some undiagnosed patients have clinical features that resemble polymyalgia rhematica, vasculitis, or other inflammatory disease but do not meet the accepted criteria. In these cases treatment with corticosteroid yields favorable responses.

Selected Infectious Causes of FUO- The following causes of FUO focus on clinical and laboratory tests that are likely to be of help in diagnosis of some of the infectious causes of FUO.

Endocarditis- Many cases do not present with detectable heart murmurs, Osler's nodes, or Janeway's lesions. Microbiological confirmation can be difficult because of slow growing pathogens. Cultures requiring over a week of growth include the HACEK group (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella). Routine blood cultures are not kept for more than 48-72 hours unless the physician tells the lab to culture for slow growing pathogens. The blood cultures can also be negative due to prior antibiotic therapy. Organisms that fail to grow in routine media also result in culture negative blood cultures; Chlamydia spp., Coxiella burnetii, or Bartonella spp.. Echocardiography can be very helpful in diagnosis of endocarditis. Transthoracic echocardiography can detect vegetations in about 75% of these cases. Transesophageal echocardiography can detect vegetations in about 90% of these cases.

Intraabdominal Abscesses-  which include hepatic, diveticular, splenic, subphrenic, pancreatic, biliary tract, psoas muscle, and pelvic infections. A diverse number of signs and symptoms can be useful in diagnosing intraabdominal abscesses as a cause of FUO. Abdominal pain, nausea, vomiting, or diarrhea are common in liver or intraperitoneal abscess or chronic cholecystitis. Tenderness on examination is reported in most cases of liver, splenic, or intraperitoneal abscess. Elderly patients usually have a more subacute course with few signs and symptoms. Certain antecedent conditions predispose patients to FUO (e.g. Crohn's disease can predispose a patient to intraperitoneal or retroperitoneal abscesses and/or infective endocarditis. Biliary disease and pancreatitis can predispose a patient to abscesses of the spleen, liver and pancreas.).

Liver abscesses usually are the result of an infection elsewhere in the body. The organisms reach the liver via the bloodstream or the biliary ducts. Therefore, previous or concurrent gallbladder or bile duct diseases, especially obstruction; intraabdominal infections such as diverticulitis or appendicitis; hepatic trauma resulting in a hematoma that later becomes infected; prior systemic bacteremia; and travel to areas where amoebiasis is endemic may predispose a pation to liver abscesses.

Splenic abscesses also tend to occur in patients with preceding or simultaneous infection elsewhere (e.g. illicit intravenous drug users) that spreads contiguously or hematogenously to the spleen. Splenic abscesses are more likely to occur in immunodeficient patients (chemotherapy, AIDS, etc.) and patients with splenic abnormalities (due to trauma, sickle-cell and other hemolytic anemias).

Subphrenic abscesses are usually a complication of previous abdominal surgery involving the stomach, duodenum, biliary tract, or spleen. Pancreatic abscesses most commonly occur a few weeks after an attack of acute pancreatitis. FUO has been observed in patients with cholecystitis; with cholangitis which can cause recurrent episodes of fever (Charcot's intermittent fever) due to periodic bile duct obstruction; and with empyema of the gallbladder, usually associated with cholelithiasis.

FUO has occured from psoas muscle abscesses following gastrointestinal tract perforations, including those from Crohn's disease, as a complication of spinal osteomyelitis, or due to hematogenous spread of an infection to the muscle.

Pelvic abscesses usually result from complications of colonic diverticulitis, appendicitis, Pelvic Inflammatory Disease (PID), or intraabdominal surgery. Inflammation can extend to involve the rectum or urinary tract with diarrhea and tenesmus or urinary frequency, dysuria, and urgency being prominent.

Abdominal ultrasonography and CT are very helpful and can usually detect these intraabdominal abscesses.

Urinary Tract Infections- The urinary tract is a very frequent site of infection. Symptoms may be very mild or nonexistant in the elderly. Ascension of the infection from the bladder to the kidneys can result in severe complications and FUO's. Pyleonephritis can result in an FUO even when the patient is receiving proper antimicrobial therapy. Oftentimes the pyelonephritis is complicated by a perinephric abscess, urinary tract obstruction, or intrarenal suppuration (focal bacterial nephritis, intrarenal abscess). Urine cultures maybe negative when obstruction is present or when perinephric abscesses are present. Perinephric abscesses occur frequently in diabetics and in patients with preceding urinary tract surgery, infections, obstruction, or stones. Patients greater than 50 years of age can develop prostatic abscesses which result in FUO. Rectal exam reveals elargement of the prostate without fluctuance, tenderness, or bogginess.

Oral Cavity and Upper Respiratory Tract Infections- Many times infections can be present without impressive localizing features (edema, erythema, pain, warm to the touch). Dental abscesses can cause FUO manifesting as intermittent febrile episodes that may following eating. Usually patients have no dental symptoms but some patients may complain of painful loose teeth or discomfort while chewing. A large number of these patients have abnormalities on careful examination that may include; severe periodontal disease, discolored, dead teeth; visible or palpable abscesses. Rarely, does antimicrobial therapy alone resolve these infections. Dental extraction is usually necessary.

Otitis media and sinusitis have also caused FUO's but are rare causes.

Bone and Blood Vessel Infections- Most cases of osteomyelitis involving the vertebrae or infected joint prostheses have only local discomfort. However, this discomfort is minimal and its significance is oftentimes not appreciated. Septic phlebitis is more likely to occur in illicit intravenous drug use, indwelling catheters, and cardiac pacing wires. Arterial vessels can become infected leading to native arterial aneurysms (most common causes include Staphylcoccus aureus  and Salmonella spp.), infections of vascular grafts, and traumatic ateriovenous fistulas.

Systemic causes-

Bacterial causes; Salmonellosis, brucellosis, chronic meningococcemia, Whipple's disease, yersiniosis, tularemia (hunters), syphilis, disseminated gonococcal infection, Q fever (farmers, veterinarians), psittacosis (bird fanciers), borreliosis, leptospirosis (wind surfers, outdoorsman), Cat-scratch disease, and meliodosis (Southeast Asia). The most common systemic bacterial infection has been tuberculosis. Unfortunately, the tuberculin skin test is frequently negative in miliary and peritoneal forms of tuberculosis, and the chest radiograph is normal in about 50% of most types of extrapulmonary tuberculosis. Patients may be ill for several weeks before the "millet seed" appearance of a chest radiograph appears in miliary tuberculosis.

Fungal causes: Usually of the hosts with systemic fungal infections causing FUO have seriously impaired immune systems. The following are usually seen as systemic causes of FUO in the immunosuppressed patient: candidiasis, aspergillosis, and cryptococcosis. Patients with normal immune function can develop FUO with systemic infictions due to Histoplasma capsulatum and Coccidiodes immitis but this is rare.

Viral causes: The most common cause of viral FUO is Cytomegalovirus which causes atypical lymphocytosis and elevated hepatic enzyme levels. Even patients with normal immune systems can have prolonged fevers (about 25% of patients are febrile for greater than 3 weeks). Other viruses to consider are EBV and HIV.

Parasitic: Usually the patient has a history of foreign travel. Tropical and subtropical regions are endemic for various parasitic infections that can become and FUO. Malaria, amebiasis, trypanosomiasis, leishmaniasis, and fasciolitis are some of the parasitic infections that can cause long term fevers. In temperate regions of the world (U.S.) toxoplasmosis, babesiosis, and Pneumocytis carinii infections in immunocompromised (AIDS) patients can cause FUO.

The other causes of FUO are best covered by others and are not a primary concern of this course.

Depends on the infectious process. It oftentimes requires removal of the abscess(es) and/or antimicrobial agents.