Fever Of Unknown Cause

Ferri: Ferri's Clinical Advisor 2008, 10th ed. Copyright © 2008 Mosby, An Imprint of Elsevier Fever of Undetermined Origin

ETSUKO AOKI, M.D., Ph.D. BASIC INFORMATION DEFINITION

Fever of undetermined origin (FUO) was defined by Petersdorf and Beeson in 1961 as an illness characterized by temperatures >101° F on several occasions for >3 wk with no known cause despite extensive workup. •

Persistence for >2 wk separates an FUO from an insignificant viral illness.

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Traditionally, diagnosis made only after a 1-wk inpatient workup. In contemporary practice, much of the workup is performed as an outpatient.

SYNONYMS

Fever of unknown origin ICD-9CM CODES 780.6 Pyrexia of undetermined origin EPIDEMIOLOGY & DEMOGRAPHICS

The incidence of undiagnosed FUO dropped to <10% in the 1950s but increased to approximately 30% in the 1990s. CLINICAL PRESENTATION

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Fever (101° F or more) >3 wk.

ETIOLOGY

(Most common etiologies italicized) •

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Infection (25%) ○ Abscess: abdominal, pelvic ○

HIV infection

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Nosocomial (febrile for 3 days in hospital): UTI, pneumonia, line-related bacteremia, Clostridium difficile diarrhea, or sinusitis

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Bacterial endocarditis (especially caused by difficult-to-isolate organisms)

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Biliary tract infection

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Osteomyelitis, vertebral and mandibular

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Tuberculosis

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Less common infections: Q fever, leptospirosis, psittacosis, tularemia, secondary syphilis, gonococcemia, chronic meningococcemia, Whipple's disease, yersiniosis, and fungal infections

Malignancy (15%): lymphoma and leukemia, renal cell carcinoma, other solid

malignancies •

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Collagen-vascular disease (24%) ○ Systemic lupus erythematosus ○

Juvenile rheumatoid arthritis (younger patients)

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Hypersensitivity vasculitis

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Temporal arteritis (elderly patients)

Others (8%) ○ Drug-induced fever ○

Inflammatory bowel disease

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Sarcoidosis

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Granulomatous hepatitis

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Deep venous thrombosis

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Alcoholic hepatitis

DIAGNOSIS DIFFERENTIAL DIAGNOSIS

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Factitious fever (Munchausen's syndrome)

WORKUP

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Accurate history and careful physical examination is essential.

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Laboratory tests and imaging dependent on historical clues, physical findings.

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When in doubt, perform another complete history and physical examination.

HISTORICAL CLUES

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Fever duration, tempo; inciting factors

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Rash, myalgia, weight loss, pain

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Sick contacts

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Past medical history: tuberculosis, HIV, malignancies, surgeries

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Medications

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Family history: tuberculosis, malignancies, familial Mediterranean fever

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Social history: daily routine, rural vs. urban, pets and animal contacts, arthropod bites, recent and remote travel, socioeconomic status, occupation, military service, sexual history

PHYSICAL FINDINGS

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HEENT: sinus tenderness, dental abscesses, funduscopic lesions

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Neck: adenopathy, palpable thyroid

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Lungs: auscultate for rales

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Heart: murmur

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Abdomen: organomegaly

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Rectal: prostate tenderness

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Pelvic: cervical motion tenderness, fundal or adnexal masses/pain; inguinal adenopathy

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Extremities: clubbing, splinter hemorrhages; tenderness/fluctuance at IV access site

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Musculoskeletal: joint effusions

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Skin: rashes, wounds

LABORATORY TESTS

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Most FUO workups will include ○ Blood cultures ○

CBC

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Urinalysis

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Transaminases

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PPD testing

Consider ○ HIV antibody testing ○

Lumbar puncture

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Thyroid function testing

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Stool culture and C. difficile assay

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Bone marrow biopsy

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Skin biopsy

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ANA

May need to repeat tests at regular intervals until diagnosis is established. IMAGING STUDIES

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Most workups eventually include ○ Chest x-ray ○

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Abdominal CT scan

Further imaging based on historical clues and physical findings

TREATMENT ACUTE GENERAL Rx

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Antibiotics and other treatment indicated only after definitive or highly probable diagnosis is established, unless patient is severely ill or septic.

DISPOSITION

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Diagnoses are found in majority of cases of FUO. In some cases, a diagnosis will not be made for years. At a 5-year follow-up, mortality among patients with undiagnosed FUO was only 3.2% in one study.

REFERRAL

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To an infectious disease specialist, hematologist, or rheumatologist if no diagnosis after thoughtful workup

PEARLS & CONSIDERATIONS COMMENTS

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Due to improvements in imaging and laboratory tests, fewer cases of FUO are attributed to infectious causes and more are diagnosed as secondary to tumors and collagen-vascular diseases.

FEVER AND JAUNDICE ICD-9CM # 789.6 FEVER 782.4 JAUNDICE

Cholecystitis. Hepatic abscess (pyogenic, amebic). Ascending cholangitis. Pancreatitis. Malaria. Neoplasm (hepatic pancreatic, biliary tract, metastatic). Mononucleosis. Viral hepatitis. Sepsis. Babesiosis. HIV (cryptosporidium). Biliary ascariasis.

Toxic shock syndrome. Yersinia infection, leptospirosis, Yellow fever, Dengue fever, relapsing fever. Email to Colleague Print Version

FEVER AND RASH ICD-9CM # 782.1 EXANTHEM 57.9

EXANTHEM VIRAL

789.6 FEVER

Drug hypersensitivity: penicillin, sulfonamides, thiazides, anticonvulsants, allopurinol. Viral infection: measles, rubella, varicella, erythema infectiosum, roseola, enterovirus infection, viral hepatitis, infectious mononucleosis, acute HIV. Other infections: meningococcemia, staphylococcemia, scarlet fever, typhoid fever, Pseudomonas bacteremia, Rocky Mountain spotted fever, Lyme disease, secondary syphilis, bacterial endocarditis, babesiosis, brucellosis, listeriosis. Serum sickness. Erythema multiforme. Erythema marginatum. Erythema nodosum. SLE. Dermatomyositis. Allergic vasculitis. Pityriasis rosea. Herpes zoster. Email to Colleague Print Version

FEVER IN RETURNING TRAVELERS AND IMMIGRANTS[25] ICD-9CM # CODE VARIES WITH SPECIFIC DISORDER Differential Diagnosis of Some Selected Systemic Febrile Illnesses to Consider in Returned Travelers and Immigrants.[*] * Diagnoses for which particular symptoms are indicative are in italics. Exposure to regions of the world that are most likely to be significant to the diagnosis are presented in (parentheses). Vectors, risk behaviors, and sources associated with acquisition are presented in [brackets]. Special clinical characteristics are listed within {braces}.

COMMON

Acute respiratory tract infection (worldwide). Gastroenteritis (worldwide) [foodborne, waterborne, fecal-oral]. Enteric fever, including typhoid (worldwide) [food, water]. Urinary tract infection (worldwide) [sexual contact]. Drug reactions [antibiotics, prophylactic agents, other] {rash frequent}. Malaria (tropics, limited areas of temperate zones) [mosquitoes]. Arboviruses (Africa; tropics) [mosquitoes, ticks, mites]. Dengue (Asia, Caribbean, Africa) [mosquitoes]. Viral hepatitis (worldwide). Hepatitis A (worldwide) [food, fecal-oral]. Hepatitis B (worldwide, especially Asia, sub-Saharan Africa) [sexual contact] {long incubation period}. Hepatitis C (worldwide) [blood or sexual contact]. Hepatitis E (Asia, North Africa, Mexico, ?others) [food, water]. Tuberculosis (worldwide) [airborne, milk] {long period to symptomatic infection}. Sexually transmitted diseases (worldwide) [sexual contact]. LESS COMMON

Filariasis (Asia, Africa, South America) [biting insects] {long incubation period, eosinophilia}. Measles (developing world) [airborne] {in susceptible individual}. Amebic abscess (worldwide) [food]. Brucellosis (worldwide) [milk, cheese, food, animal contact]. Listeriosis (worldwide) [foodborne] {meningitis}. Leptospirosis (worldwide) [animal contact, open fresh water] {jaundice, meningitis}. Strongyloidiasis (warm and tropical areas) [soil contact] {eosinophilia}. Toxoplasmosis (worldwide) [undercooked meat]. RARE

Relapsing fever (western Americas, Asia, northern Africa) [ticks lice]. Hemorrhagic fevers (worldwide) [arthropod and nonarthropod transmitted]. Yellow fever (tropics) [mosquitoes] {hepatitis}. Hemorrhagic fever with renal syndrome (Europe, Asia, North America) [rodent urine] {renal impairment}. Hantavirus pulmonary syndrome (western North America, ?other) [rodent urine] {respiratory distress syndrome}. Lassa fever (Africa) [rodent excreta, person to person] {high mortality rate} Other—chikungunya, Rift Valley, Ebola-Marburg, etc. (various) [insect bites, rodent excreta, aerosols, person to person] {often severe}. Rickettsial infections {Rashes and eschars}. Leishmaniasis, visceral (Middle East, Mediterranean, Africa, Asia, South America) [biting flies] {long incubation period}. Acute schistosomiasis (Africa, Asia, South America, Caribbean) [fresh water]. Chagas' disease (South and Central America) [reduviid bug bites] {often asymptomatic}. African trypanosomiasis (Africa) [tsetse fly bite] {neurologic syndromes, sleeping sickness}. Bartonellosis (South America) [sandfly bite; cb] {skin nodules}. HIV infection/AIDS (worldwide) [sexual and blood contact]. Trichinosis (worldwide) [undercooked meat] {eosinophilia}. Plague (temperate and tropical plains) [animal exposures and fleas]. Tularemia (worldwide) [animal contact, fleas, aerosols] {ulcers, lymph nodes}. Anthrax (worldwide) [animal, animal product contact] {ulcers}. Lyme disease (North America, Europe) [tick bites] {arthritis, meningitis, cardiac abnormalities}.

Fever of Unknown Origin Fever of unknown origin (FUO) is defined as a temperature of at least 101_F for at least 3 weeks without discovery of the cause (Merck Manual, 2002). In children, over 50% of fevers are due to upper respiratory or viral illness; in adults, one should be more suspicious of malignancy. History The history should include the timing and degree of the fever. Recent travel or exposure to illnesses or certain animals is often very helpful. Travel outside the United States can be particularly problematic, and one should consider such diseases as malaria, typhoid, tuberculosis, Mycobacterium avium complex, or HIV. Brucellosis and histoplasmosis should be considered if there is animal exposure. Weight loss might indicate a malignant process or might be due to anorexia caused by the fever. As usual, a thorough medicine history, past medical history, and family history might alert the practitioner to a possible cause. Any recent infection should be investigated first because it may not have been adequately treated. A history of frequent infections could raise the index of suspicion regarding an immunocompromised condition, such as HIV, leukemia, or lymphoma. It is important to inquire about sexual practices. Physical Examination The physical should include examination of the skin for lesions, redness, increased temperature, or edema, which might indicate infection or an inflammatory process. Examine the lymph nodes. If there is lymphadenopathy in a particular area, it might lead you to the point of infection. If it is generalized, consider lymphoma, leukemia, or HIV. A cardiac assessment is important especially listening for a murmur or friction rub. Pericarditis or endocarditis has a variety of causes and may present as unexplained fever, shortness of breath, precordial pain/tenderness, and tachycardia. The lung assessment is crucial because over 50% of FUO in children are caused by an upper respiratory illness. Observe the skin and nail beds for cyanosis. The abdomen should be palpated for tenderness or masses: smoldering cases of appendicitis, cholecystitis, pancreatitis, or hepatitis might cause a lingering fever.

INFECTION

Any infection, viral or bacterial, can cause prolonged fever. Patients usually have some other complaint that alerts you to the cause of the fever. If bacterial, it can be treated with antibiotics, which should resolve the symptoms. Viral illnesses are more problematic because supportive measures are generally all that can be provided. Be watchful for a secondary bacterial infection to develop with some prolonged viral illnesses. Signs and Symptoms. The signs and symptoms are highly variable depending on the source of the infection. Expected are the typical symptoms that accompany a fever, such as headache, malaise, anorexia, and possibly chills. A thorough review of systems is necessary to detect the underlying source of the fever, if not completely obvious by other complaints. Diagnostic Studies. Although the diagnostics vary with the underlying cause, ordering a CBC with differential, urinalysis, and chest x-ray is a good place to start with any complaint of FUO. Blood cultures may be necessary as well as cultures of bodily fluids. In babies, a lumbar puncture is recommended to rule out meningitis. Rising antibody titers for typhoid, brucellosis, and other viral infections may be helpful. Ultrasound or CT scan of the abdomen will identify abscesses or other infections in the abdomen, including diverticulitis, peritonitis, cholecystitis, possibly pancreatitis, or appendicitis. A CT scan of the chest can detect cardiac vegetation, which might suggest pericarditis or endocarditis as a cause for the fever.

MALIGNANCY Many malignancies can cause fever, but lymphoma and leukemia should be at the top of the differential list. Acute leukemia is more common in children, and the chronic leukemias are more common in middle-aged to elderly adults. Hodgkin’s lymphoma is more prevalent in children and young adults, whereas non-Hodgkin’s lymphoma is more 390 Advanced Assessment and Differential Diagnosis by Body Regions and Systems common in middle-aged to elderly adults. Burkitt’s lymphoma is more common in HIV patients. Signs and Symptoms. With leukemia, common symptoms include unexplained fever, easy bruising or bleeding, fatigue, bone or joint pain, and enlarged liver or spleen. With lymphoma, common symptoms include fatigue, fever, night sweats, lymphadenopathy, and weight loss. Diagnostic Studies. A CBC is the first and easiest laboratory test to perform. The abnormalities in the CBC vary some with the type of leukemia—acute or chronic, lymphocytic or myelocytic—but in general there is a proliferation of immature white cells (blasts), anemia, and low platelet count. In lymphoma, there is a leukocytosis, lymphocytopenia, and possibly thrombocytosis. A hypochromic, microcytic anemia is often present. A bone marrow biopsy confirms the diagnosis in both leukemia and lymphoma. Diffuse Connective Tissue Disorders The connective tissue disorders include rheumatoid arthritis, Sjögren’s syndrome, Behçet’s syndrome, vasculitis, systemic and discoid lupus erythematosus, polymyositis, polymyalgia rheumatica, temporal arteritis, and polyarteritis. Although fever can be present in any of the connective tissue disorders, muscle and joint pain are more common presenting symptoms. The specific signs, symptoms, and diagnostics for each of these diseases are beyond the scope of this text. Immunodeficiency Disorders Immunodeficiency disorders are numerous and are characterized as primary or secondary, with the secondary being more common than the primary disorders. The primary disorders are classified into B-cell deficiencies (antibody), T-cell deficiencies (cellular), phagocytic disorders, and complement disorders. The secondary immunodeficiencies are

classified by cause and include hereditary and metabolic diseases (chromosome abnormalities, uremia, DM, malnutrition, nephritic syndrome, myotonic dystrophy, and sickle cell disease), infectious diseases (rubella; cytomegalovirus; viral exanthemas; mono; and severe bacterial, viral, or fungal infections), infiltrative and hematologic diseases (histocytosis, sarcoidosis, lymphoma, leukemia, myeloma, and aplastic anemia), those caused by surgery and trauma (burns, splenectomy, and anesthesia), and those caused by immunosuppressive agents (radiation, chemotherapy, corticosteroids, and other immunosuppressive drugs). Specific signs, symptoms, and diagnostics are beyond the scope of this text. Some of these are discussed in other chapters. Drug Reaction The most likely drugs to cause fever are the chemotherapeutic agents used to treat cancer, mainly as a result of leukopenia. The medical history should be all that is needed, along with a CBC to make this diagnosis. Allergic reactions to any drug, particularly the antibiotics, can cause fever as well as rash. The history is usually all that is necessary to identify the cause of the fever.

Unexplained Weight Loss

History Malignancy and diabetes should top the list of differential diagnoses for unexplained weight loss. A thorough history and review of systems will alert the practitioner to other Nonspecific Complaints 391 complaints that could give clues to the cause, such as cough, hemoptysis, shortness of breath, nausea, vomiting, diarrhea, steatorrhea, hematemesis, melena, fatigue/weakness/ lethargy, changing or new moles, persistent pain, enlarged lymph nodes, abnormal menstrual bleeding, breast discharge, and chronic headaches. A thorough medicine history is critical especially in the elderly or those with chronic diseases who are on a multitude of medicines. A psychosocial history is critical, especially in the elderly client who may not be eating due to the inability to shop for groceries because of financial or transportation problems, inability to prepare meals resulting from a functional limitation, poorly fitting dentures or no dentures, or loss of appetite owing to depression or medications. Inquire about smoking and EtOH intake because both of these can increase the risk for both weight loss and malignancies. Physical Examination Patients with unexplained weight loss that is due to malignancy may look cachectic, pale, and lethargic or they may look well depending on the amount and cause of the weight loss. Weights over the past year should be plotted out to see how much weight has been lost over a period of time. A slow weight decrease in the elderly is not uncommon and may simply be due to a lack of appetite, to institutional food, or to disinterest in food resulting from a decreased sense of taste and/or smell. A full physical exam is necessary, paying particular attention to any masses, tenderness, swelling, or lymphadenopathy.

MALIGNANCY Depending on the stage of the malignancy, any are capable of causing weight loss, either as a primary or secondary symptom. However, the most common malignancies to cause weight loss are GI, lung, hematologic, and musculoskeletal. Signs and Symptoms. The signs and symptoms will vary with the source of the malignancy, and many are asymptomatic except for the complaint of weight loss. Diagnostic Studies. Ordering a CBC and blood chemistries is a good place to start, as well as a chest x-ray and Hemoccult cards, depending on the age and medical history. The results of these and the history should assist the practitioner in narrowing down the search. Other diagnostics such as CT or MRI should be ordered as needed. Depression and Anxiety

See Chapter 16 for a detailed discussion. Eating Disorders See Chapter 16 for a detailed discussion.

FUNCTIONAL AND FINANCIAL MALNUTRITION Depending on the patient population, malnutrition may be a possibility. It is common in the very poor and in the elderly owing to the inability to purchase, prepare, and consume the proper, varied diet. Eating disorders, depending on the severity, may result in malnutrition. In developing countries, malnutrition is a huge problem, but it is not common in the United States except in the elderly and very poor populations. 392 Advanced Assessment and Differential Diagnosis by Body Regions and Systems Signs and Symptoms. Aside from the weight loss, other signs of malnutrition include dry skin and hair, pale conjunctivae, cheilosis, glossitis, bruising, lethargy, decreased vibratory sensation, decreased DTRs, bone demineralization, liver or heart enlargement, muscle wasting, lower extremity edema, and growth failure. Diagnostic Studies. Malnutrition has a variety of consequences that can involve several body systems. A complete metabolic profile, CBC, and thyroid studies are recommended. Electrolyte imbalance is common especially if the malnutrition is brought on by anorexia or bulimia, and it can be life threatening. Kidney and liver functions may be affected as well. Depending on the chronicity of the problem, dual energy x-ray absorptiometry should be considered because bone health may be at risk. In severe cases, heart failure may ensue and an echocardiogram or more invasive cardiac testing may be needed to evaluate cardiac functioning. Drug Reaction There are few drugs that actually cause weight loss (thyroid replacement in greater than therapeutic doses, SSRIs, neuroleptics), but many drugs cause anorexia with weight loss as a secondary side effect. Because drug side effects vary greatly between patients, it is not possible to supply an exhaustive list of drugs that cause anorexia. A few that seem to be most problematic are digitalis, many psychotropic medications, chemotherapeutic agents mostly as a result of nausea, stimulants such as pseudoephredrine or other drugs used to treat obesity, and drugs used to treat attention deficit/hyperactivity disorder. A complete medication history including over-the-counter medications may allow the practitioner to identify the cause of the weight loss. If a drug is suspected, it should be changed if possible. For patients on multiple drugs, the suspected agents should be discontinued or substituted one at a time in order to determine the offending agent.

MALABSORPTION Malabsorption falls into two main categories: impaired digestion and impaired absorption, and there are many diseases that fall into each category. Diseases that fall under impaired digestion include gastrectomy, barosurgery, chronic pancreatitis, chronic liver failure, biliary obstruction, lactose intolerance, diverticula, and Zollinger-Ellison syndrome. Diseases that fall into the impaired absorption category include intestinal infections, alcohol, celiac disease, tropical sprue, Whipple’s disease, amyloidosis, ischemic or infarcted bowel, Crohn’s disease, volvulus, and intussusception. Signs and Symptoms. The signs and symptoms vary according to the underlying problem, but common symptoms include weight loss, flatulence, abdominal bloating, edema in the lower extremities resulting from protein deficiency, muscle weakness, possibly diarrhea or steatorrhea, dehydration, glossitis, and bruising. A variety of abnormal findings can be associated with malabsorption syndromes, including iron, folic acid or B12 deficiency anemia; calcium deficiency; vitamins A, B, C, and D deficiencies; and niacin deficiency. A combination of

weight loss, diarrhea, and anemia should raise the possibility of malabsorption. Nonspecific Complaints 393 Diagnostic Studies. There are as many diagnostics as there are causes of malabsorption. Measurement of fat in the stool is the most valuable diagnostic for diagnosing malabsorption, and a 3- to 4-day stool collection is advised. Stool specimens for ova and parasites and culture and sensitivity will help to rule out infectious causes. Absorption tests, flat plate of the abdomen, upper GI with small bowel follow-through, endoscopy, and small bowel biopsy may be necessary for definitive diagnosis. Hyperthyroidism See p. 388.

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SUGGESTED READINGS

Beers, M., Berkow, R., & Burs, M. (Eds.). (1999). Merck Manual of Medical Therapeutics (17th ed). Rahway, NJ: Merck & Co., Inc. Tierney, L.M., McPhee, S.J., & Papadakis, M.A. (Eds.). (2003). CURRENT Medical Diagnosis & Treatment. New York: Lange Medical Books/McGraw Hill. 394 Advanced Assessment and Differential Diagnosis by Body Regions and Systems