Fever of Unknown Origin: Description, Causes and Risk Factors:
Fever of unknown origin means fever that does not resolve spontaneously in the period expected for self-limited infection and whose cause cannot be ascertained despite considerable diagnostic effort. In 1961, Petersdorf and Beeson introduced the definition that subsequently became standard—namely, illness of more than three weeks' duration, fever higher than 38·3°C (101°F) on several occasions, and diagnosis uncertain after one week of study in hospital.
Because hospital admission is so expensive and since thorough diagnostic testing now can be done in outpatient settings, the definition recently was modified to remove the requirement that hospital be the setting for a week of evaluation. The definition does not specifiy what constitutes this evaluation but the studies listed in panel 2 are, we suggest, the minimum. Recognition that the causes of unexplained fever in patients with impaired immunity may differ from those in classic FUO has prompted categories such as fever of unknown origin in cancer for FUO in HIV infection, groupings that help formulate a more relevant and economical differential diagnosis, as has also been done with FUO in elderly patients and children.
Extrapulmonary tuberculosis is the most frequent cause of fever of unknown origin. Drug-induced hyperthermia, as sole symptom of an adverse reaction to medication, 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.
The proportion of fever of unknown origin cases grouped in specific disease categories has changed little during the past four decades. Infection accounts for about one-third of cases, followed by neoplasia and collagen vascular diseases. The frequency of neoplasia declined in several recent series ostensibly due to improved diagnostic imaging, but in a contemporaneous series the proportion was 24%. In our hospital neoplasia, in particular lymphoma, remains an important cause of FUO.
The role of certain individual diseases has changed considerably. For example, rheumatic fever and systemic lupus erythematosus (SLE) were common in early series but are unusual today, probably because of the sharp decline in rheumatic fever in the developed world and the wide availability of accurate tests for SLE that permit early diagnosis. Infective endocarditis has decreased in frequency since the 1950s as blood culture techniques have improved, but new pathogens that are difficult to isolate (eg, Bartonella quintana) ensure that it will not disappear as a cause of fever of unknown origin. A few diagnoses in recent series were unknown four decades ago, including Lyme disease, acute HIV infection, Sweet's syndrome, and Bartonella endocarditis. Early series also failed to report drug fever as a cause of FUO.
Signs and Symptoms:
Fever of more than 101 °F (38.3 °C), either continuous or intermittent, for at least 3 weeks.
- Fever above 101 °F with no known cause, even after extensive diagnostic testing.
The diagnostic approach in FUO has not been uniformbut has always included a thorough history, carefulphysical examination, laboratory tests, and radiographicstudies. These modes of investigation interact so thecontribution of each to a diagnosis is difficult to assess,even when the method of diagnosis or yield of a specifictest is reported.The difficulty is reflected by theinterval between hospital admission and diagnosis, whichaveraged 19 days in two recent studies.The causes of fever of unknown origin are usually familiar diseases withuncommon presentations rather than rare disorders. Inseveral series of paediatricand adult cases the correctdiagnosis was possible from the history, physicalexamination, and routine laboratory tests. Conversely,failure to utilize findings correctly,delay in orderingappropriate tests,and misinterpretation of test resultshave all contributed to missed diagnoses. Specialized noninvasive tests such as serology seldom help except toconfirm a diagnosis suggested by other findings.
Minimum diagnostic evaluation to qualify as FUO:
- Repeated physical examination.
- Complete blood count, including differential and platelet count.
- Routine blood chemistry, including lactate dehydrogenase, bilirubin,and liver enzymes.
- Urinalysis, including microscopic examination.
- Chest radiograph.
- Erythrocyte sedimentation rate.
- Antinuclear antibodies.
- Rheumatoid factor.
- Angiotensin converting enzyme.
- Routine blood cultures 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.
Unless the patient is acutely ill, no therapy should be started before the cause has been found. This is because nonspecific therapy rarely is 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.
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.
Acetaminophen (Tylenol). In cases of infection, your doctor may also prescribe an antibiotic, antifungal, or antiviral drug, depending on the cause of the infection.
Complementary and Alternative Therapies:
General immune support with nutrition and herbs may alleviate fevers. Most natural medicine practitioners will treat fever as a sign that the body is trying to heal itself, rather than as an illness. In addition, most natural therapies attempt to support the body's own healing processes rather than suppress the fever. It is important to speak to your medical doctor about any natural therapies you may be considering. Prolonged fever can be dangerous, and some natural therapies and conventional medications can have dangerous interactions.
Nutrition and Supplements:
These nutritional tips may help improve immunity:
Eat antioxidant foods, including fruits (such as blueberries, cherries, and tomatoes), and vegetables (such as squash and bell peppers).
- Avoid refined foods, such as white breads, pastas, and sugar.
- Eat fewer red meats and more lean meats, cold water fish, tofu (soy) or beans for protein.
- Use healthy cooking oils, such as olive oil or vegetable oil.
- Reduce or eliminate transfatty acids, found in commercially baked goods, such as cookies, crackers, cakes, French fries, onion rings, donuts, processed foods, and margarine.
- Avoid coffee and other stimulants, alcohol, and tobacco.
- Drink 6 - 8 glasses of filtered water daily.
- Exercise at least 30 minutes daily, 5 days a week, although while experiencing intermittent fevers, your health care provider may suggest mostly rest and some gentle stretching rather than your typical exercise regimen.
You may address nutritional deficiencies with the following supplements:
A multivitamin daily, containing the antioxidant vitamins A, C, E, the B-complex vitamins, and trace minerals such as magnesium, calcium, zinc and selenium.
- Omega-3 fatty acids, such as fish oil, 1 - 2 capsules or 1 - 2 tablespoons of oil daily, to help decrease inflammation. Omega-3 fatty acids may increase the effect of blood thinning medications such as Coumadin; speak with your physician.
- Acidophilus (Lactobacillus acidophilus), 5 - 10 billion CFUs (colony forming units) a day, for maintenance of gastrointestinal and immune health. Some acidophilus products may need refrigeration -- read the label carefully.
- Vitamin C, 500 - 1,000 mg daily, as an antioxidant.
Herbs are generally a safe way to strengthen and tone the body's systems. As with any therapy, you should work with your health care provider to choose the safest and most effective herbal therapies before starting any treatment. You may use herbs as dried extracts (capsules, powders, teas), glycerites (glycerine extracts), or tinctures (alcohol extracts). Unless otherwise indicated, make teas with 1 tsp. herb per cup of hot water. Steep covered 5 - 10 minutes for leaf or flowers, and 10 - 20 minutes for roots. Drink 2 - 4 cups per day. You may use tinctures alone or in combination as noted.
The following herbs may help reduce fever and improve immune response:
Green tea (Camelia sinensis) standardized extract, 250 - 500 mg daily, for immunity. You may also prepare teas from the leaf of this herb.
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.
- Cat's claw (Uncaria tomentosa ) standardized extract, 20 mg 3 times a day, to improve immunity.
- Reishi mushroom (Ganoderma lucidum) standardized extract, 150 - 300 mg 2 - 3 times daily, for immunity. You may also take a tincture of this mushroom extract, 30 - 60 drops 2 - 3 times a day.
- Milk thistle (Silybum marianum ) seed standardized extract, 80 - 160 mg 2 - 3 times daily, for detoxification support.
- Andrographis (Andrographis paniculata ), 6 g daily as a tea, is often used to treat colds and sore throats and may also help reduce a fever in Traditional Chinese Medicine. One clinical study suggested 6 g a day for 7 days was effective with no side effects. Do not use andrographis if you have gallbladder disease, an autoimmune disease, or if you are pregnant or trying to become pregnant.