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39-Year-Old Woman With Fever and Weight Loss
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39-Year-Old Woman With Fever and Weight Loss ANNA M. KEANE, MD,* AND MARY J. KASTEN, MD†
A
39-year-old woman presented to our institution with a 4-month history of weight loss, nausea, malaise, and daily fever (temperature, 38.3°C-39.5°C). Her medical history was remarkable for type 2 diabetes mellitus and hypothyroidism. Her medications included levothyroxine and insulin. Born in Mexico, she lived in Texas with her husband and 2 children and was employed as a clerical worker. She did not smoke, drink alcohol, or use recreational drugs. She had not traveled to foreign countries and had no exposure to tuberculosis (TB) or contact with animals or ill people. Family history was noncontributory. Our patient’s fever occurred nightly and was first noted after an elective laparoscopic sterilization, performed at another institution. There were no complications during the procedure, and she was able to walk well the next day. At her 2-week postoperative visit at her local institution, she reported daily fever and described symptoms of nausea, fatigue, and pain on the left side of her abdomen. She denied any change in bowel habit or in respiratory, urinary, or other focal symptoms. Examination revealed lower abdominal tenderness, without guarding, but was otherwise normal. 1. Which one of the following is the most likely cause for the patient’s fever 2 weeks after laparoscopic sterilization? a Inflammation due to the trauma of surgery b. Perioperative drugs c. Nosocomial pneumonia d. Intra-abdominal abscess e. Deep venous thrombosis and pulmonary embolism (PE) Postoperative fever is common and can be due to many infectious and noninfectious causes. Immediate postoperative fever can be secondary to the normal inflammatory response to trauma or it can be caused by the drugs used during the operation, eg, antibioti cs or anestheticagents. However, fever due to inflammation of surgery, which is less common with laparoscopic than with open procedures, would have been unlikely to l ast 2 weeks , and fever caused by intraoperative drugs would be transient. Nosocomial respiratory tract infections are frequent with prolonged intubation and immobility, but the patient had no such history. Deep abdominal abscesses frequently cause persistent postoperative fever. Studies have shown that the incidence of abscesses after pelvic surgery is similar with open and laparoscopic techniques.1 The persistence of abdominal pain–associated fever 2 weeks after pelvic surgery is highly suggestive of an abscess. Mayo Clin Proc.
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Deep venous thrombosis and PE can also cause postoperative fever. However, these diagnoses were unlikely in our patient because studies show minimal risk of thromboembolism after laparascopic sterilization (as low as 0.05%) when patients have minimal tissue damage and early mobilization.2 Computed tomography of the chest, abdomen, and pelvis revealed no evidence of PE or other abnormalities. An exploratory laparotomy was performed at the patient’s local institution. No abscess or other cause for her fever was found. Further investigations at her local hospital yielded the following results (reference ranges provided parenthetically): an elevated erythrocyte sedimentation rate of 70 mm/h (0-29 mm/h); normochromic, normocytic anemia (hemoglobin, 9.5 g/dL [12.0-15.5 g/dL]); elevated liver enzymes, including aspartate aminotransferase (84 U/L [843 U/L]), alanine aminotransferase (78 U/L [7-45 U/L]), and alkaline phosphatase (300 U/L [37-98 U/L]); and elevated triglycerides (1005 mg/dL [<150 mg/dL]). Findings on upper and lower gastrointestinal endoscopy with biopsies were normal. Transesophageal echocardiography revealed normal valves. A set of blood cultures and a urine culture yielded no growth. Cerebrospinal fluid (CSF) culture and analysis were negative for infection or malignancy. Serologic studies were negative for hepatitis and human immunodeficiency virus; the tuberculin skin test (purified protein derivative standard [PPD]) was also negative. Four months later, the patient presented to our institution with a fever of unknown origin (FUO) for further evaluation. In addition to ongoing high fever, she reported a 3-week history of gradually progressive, diffuse myalgia with generalized weakness and associated joint stiffness. She had lost 20 kg during the past 4 months. She reported intermittent nausea and a poor appetite but denied any other symptoms. Her medications had remained unchanged and she had not used over-the-counter drugs. On initial examination she appeared very frail. Cardiovascular, respiratory, and breast examinations were unremarkable. There was no splenomegaly or lymphadenopathy and only moderate nontender hepatomegaly. Findings *Visiting resident, St. Vincent's University Hospital, Dublin, Ireland. †Adviser to resident and Consultant in General Internal Medicine, Mayo Clinic, Rochester, MN. See end of article for correct answers to questions. Individual reprints of this article are not available. Address correspondence to Mary J. Kasten, MD, Division of General Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]). © 2008 Mayo Foundation for Medical Education and Research
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on neurologic examination were entirely normal, apart from diffuse muscle weakness, most severe in the lower extremities. On previous examination, nontender nodular erthyematous patches had been observed; on this examination, they were fading and were noted in the pretibial areas bilaterally. We noted mild edema of her lower extremities but no evidence of arthritis. 2. Which one of the following broad categories is least likely to account for the patient’s symptoms? a. Infection b. Noninfectious inflammatory disease c. Drug-induced fever d. An endocrine or metabolic disorder e. Malignancy In many studies, infection has been found to be the most common cause of FUO (up to 59% of cases). Most of these studies were performed in areas with a high incidence of TB, or during a time when infections were more common and more challenging to diagnose.3 A negative PPD occurs in approximately 25% of patients with active TB.4 Our patient was born in Mexico where TB is endemic. Subacute bacterial endocarditis is the classic infectious cause of an FUO. Importantly, the transesophageal echocardiogram was negative for vegetations, but 3 sets of blood cultures were obtained to complete the investigation. Therefore, infection, particularly TB, remained in our differential diagnoses as a cause of her FUO. Noninfectious inflammatory diseases include rheumatologic, vasculitic, and granulomatous diseases. A recent multicenter study found this broad category to account for most (22%) diagnoses.3 The constellation of fever, weight loss, myalgia, joint stiffness, rash, and elevated erythrocyte sedimentation rate in a middle-aged woman is suggestive of a rheumatologic disorder or connective tissue disease. Her elevated liver enzymes also raised the possibility of granulomatous hepatitis. A noninfectious inflammatory illness was strongly suspected at her initial presentation to our institution. Drug-induced fever is often overlooked. Medications commonly implicated in drug-induced fever include antihypertensives, diuretics, oral contraceptives, and antibiotics. It is important to ask about nonprescription drugs as well as “natural remedies.” All nonessential drugs should be discontinued.4,5 Because our patient had been receiving long-term levothyroxine and insulin with no new pharmacotherapy, we thought that drug-induced fever was the least likely category to account for her current illness. Endocrine and metabolic disorders are unusual causes of FUO; however, hyperthyroidism, pheochromocytoma, and hypertriglyceridemia can all cause fever and occasionally present as an FUO.3 Our patient’s markedly elevated triglyc352
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eride levels could have caused pancreatitis and fever. Thus, a metabolic disorder remained in the differential diagoses. Lymphoma and leukemia are the most common malignancies to present as an FUO. We thought a bone marrow biopsy and aspiration was warranted given her weight loss and anemia. Extensive additional laboratory testing (Table) was conducted; results on urinalysis were normal, multiple blood cultures showed no growth, and a blood smear suggested a leukoerythroblastic picture. Bone marrow aspirates showed reactive changes only, with no evidence of granulomas or malignancy. On repeated computed tomography of the abdomen and pelvis, fatty infiltration of the liver and substantial diffuse subcutaneous edema extending down to the musculature and subcutaneous tissue of the lower limbs were revealed. No masses or lymphadenopathy were noted. At this point, our patient was so weak that she was unable to walk without assistance. Her fever persisted, and she continued to lose weight. 3. Which one of the following management strategies would be most appropriate for this patient? a. Empiric antibiotics b. Empiric antituberculous medications c. Empiric corticosteroid therapy d. Further observation e. Admittance to the hospital, so that the search for a cause of her FUO could continue Therapeutic trials of antibiotics, antituberculous agents, and corticosteroids are often tempting. However, these should be withheld in cases of FUO unless clinical deterioration is clear and could lead to loss of life and/or until a comprehensive investigation has been completed.5 Response to any of these therapies is not diagnostic of disease. Antituberculous medications are empirically given at times when clinical suspicion is high, especially when pathology reveals granulomatous changes and culture results are negative or pending. Clinical suspicion was not sufficiently high for our patient to warrant antituberculous medications. Empiric corticosteroid therapy is similarly inappropriate at this point in the evaluation. If the fever were secondary to an underlying rheumatologic disorder or hematologic malignancy, corticosteroids could mask and delay diagnosis. Provided that the general condition of the patient is good and that a careful initial work-up has been unrevealing, the observation or “wait-and-see” strategy would be the recommended management. One reason for this strategy is the rather low likelihood of establishing a final diagnosis in this situation.5 Most patients will either improve or develop additional clues to their illness that will help guide further investigation.
March 2008;83(3):351-354
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TABLE. Laboratory Results of 39-Year-Old Woman With Fever and Weight Lossa Laboratory test
Result (reference range)
Hemoglobin (g/dL) White blood cell (× 109/L) Platelets (× 109/L) Differential (%) Neutrophils Lymphocytes Monocytes Metamyelocytes Myelocytes Thyroid-stimulating hormone (mIU/L) C-reactive protein (mg/dL) Calcium (mg/dL) Erythrocyte sedimentation rate (mm/h) Albumin (g/dL) Bilirubin (mg/dL) Alanine aminotransferase (U/L) Alkaline phosphatase (U/L) Creatine kinase (U/L) Aldolase (U/L) Lactate dehydrogenase (U/L) Amylase (U/L) Creatinine (mg/dL)
8.6 (12.0-15.5) 8.6 (3.5-10.5) 287 (150-450) 80 (42-75) 6 (16-52) 5(1-11) 2 (0-1) 2 (0-0.5) 3.0 (0.3-5.0) 12.7 (<0.8) 8.0 (8.9-10.1) 52 (0-29) 1.5 (3.5-5.0) 1.3 (0.1-1.0) 526 (7-45) 297 (37-98) 22 (38-176) 19.6 (<7.7) 516 (122-222) 41 (26-102) 0.5 (0.6-1.1)
Given the severity of our patient’s illness, simple observation was not an option, and she was admitted to the hospital for continued evaluation. 4. Which one of the following would most likely lead to a diagnosis? a. Antinuclear antibody titer for connective tissue disease b. Liver biopsy c. Repeated CSF analysis d. Screening for occult cancer with cancer antigen (CA) 125 e. Temporal artery biopsy The antinuclear antibody titer, although sensitive, is not diagnostic for the presence of connective tissue disease. In one study, only 35% of symptomatic patients with a high antinuclear antibody titer actually had a final diagnosis of connective tissue disease.6 The diagnostic yield from liver biopsy has been found to be as high as 16%, even in the absence of potential diagnostic clues.3 Obtaining tissue is often valuable in the work-up of FUO. Liver biopsy was thought to be the test most likely to be diagnostic in our patient, given her hepatomegaly, elevated liver enzymes, and evidence on computed tomography of fatty infiltration. Repeating the lumbar puncture would be indicated if there were symptoms suggestive of infection or malignancy in the central nervous system. The lack of headache, cognitive complaints, or neurologic signs in our patient greatly diminished the likelihood that a CSF examin ation would be helpful. Levels of CA 125 can be elevated in ovarian, endometrial, and pancreatic cancer; however, a finding of elevated Mayo Clin Proc.
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CA 125 levels is very nonspecific. A recent study that screened more than 10,000 healthy women found that more than 4% had a benign elevation of CA 125 levels.7 This test should be reserved for monitoring confirmed cases of malignancy and detecting recurrent disease. Temporal arteritis accounts for up to 17% of cases of FUO in elderly people.8 Thus, temporal artery biopsy is reasonable to consider early in elderly patients with an FUO, but not in a patient younger than 50 years. Liver biopsy was performed and revealed fatty infiltration (grade 2 of 3) and periportal fibrosis (grade 1 of 4). Staining was negative for malignancy. No granulomas were seen. Thus, liver biopsy was not diagnostic. Other clues remaining unexplained were the subcutaneous edema, profound weakness of the lower extremities, and the lower limb rash, which had by this time resolved. Magnetic resonance imaging of the lower extremities showed diffuse subcutaneous edema with increased signal intensity throughout all visualized musculature. 5. Which one of the following tests is most likely to lead to a diagnosis at this stage? a. Skin biopsy of the lower extremities b. Indium-labeled granulocyte scan (nuclear imaging) c. Positron emission tomography (PET) d. Electromyelography (EMG) e. Muscle biopsy of the lower extremities In the presence of skin abnormalities, skin biopsy has a diagnostic yield in FUO of up to 35%.9 Because her rash had resolved, obtaining skin without underlying muscle was unlikely to give definitive results. The role of nuclear imaging in the evaluation of FUO varies from study to study. Although indium-labeled granulocyte scans and gallium scans can be helpful to localize inflammation, infection, or malignancy, these tests are limited by the difficulty in proving that an abnormal finding is in fact the cause of the fever5 and by the necessity of obtaining a tissue sample once an abnormality has been localized. Positron emission tomography has been compared with conventional nuclear imaging with variable results. Some studies have found PET to be superior to indium or gallium scanning, in particular for identifying vasculitic disease.5 However, other studies reported PET to have less specificity than indium-labeled granulocyte scans (46% vs 92%).9,10 Positron emission scanning can be helpful but will not give diagnostic results. In view of our patient’s myalgia and weakness, we thought EMG might reveal myositis and could be helpful in localizing an abnormality, although we knew that it would not be diagnostic. Myopathy, most extensive in the left gastrocnemius muscle, was revealed on EMG.
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Muscle biopsy using the other investigations (magnetic resonance imaging and EMG) to target the optimal biopsy site is most likely to be diagnostic. Biopsy of the left calf was performed, and pathology revealed subcutaneous panniculitis-like T-cell lymphoma, γδ type, with underlying muscular atrophy. This disease, an uncommon mature type of T-cell lymphoma, initially can mimic a benign panniculitis. Median age of onset is 40 years. The disease is usually characterized by the development of subcutaneous inflammatory nodules, most frequently on the trunk and extremities. It is associated with fever, weight loss, night sweats, and fatigue. Lymphomatous dissemination to lymph nodes and other organs, most notably the bone marrow, is uncommon and occurs late.11 Involvement of the overlying dermis is variable (20%-81%) and usually minimal.12 Untreated, median survival is less than 2 years. Therapeutic options include rad iation therapy, immunosuppressive agents, chemotherapy (cyclophosphamide, hydroxydaunomycin [doxorubicin], vincristine [Oncovin], and prednisone [CHOP]), and stem cell transplant. Immediately after diagnosis, our patient began receiving CHOP chemotherapy. She wished to continue this therapy closer to her home and did so under the care of a hematologist in her home city. DISCUSSION Fever of unknown origin is defined as a temperature of 38.3°C or higher on several occasions during a period of at least 3 weeks, the cause of which remains undetermined after an initial evaluation. Patients with FUO remain a diagnostic challenge. The approach to the patient with FUO includes obtaining a detailed history, conducting a careful physical examination, and running an appropriate series of diagnostic tests. A detailed history is paramount. Physicians should make particular note of recent travel, the work environment, high-risk behaviors, exposure to animals, or contact with ill people. They should ascertain whether patients have any history of malignancy, rheumatic fever, or inflammatory disorders. Finally, they should obtain a full medication list and a detailed family history. A complete physical examination with careful attention to the skin, mucous membranes, fundoscopy, cardiac examination, and assessment for lymphadenopathy and organomegaly can also reveal potential diagnostic clues. The fever should be formally confirmed and documented. If a diagnosis is not reached, the physical examination should be repeated periodically. Any nonessential medications should be discontinued to rule out drug-induced fever. The minimal initial work-up should usually include a complete blood cell count and 354
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differential; a blood film reviewed by a pathologist; assays for electrolytes, liver enzymes, and lactate dehydrogenase; serology for hepatitis and human immunodeficiency virus; urinalysis, microscopy, and urine culture; 3 sets of blood cultures; a chest radiograph; and a PPD. Antinuclear antibody and rheumatoid factor testing should be considered but results must be interpreted cautiously because of false positives. Heterophile antibodies and cytomegalovirus IgM should be obtained if the illness is suggestive of mononucleosis. To avoid both unnecessary exposure of the patient to medical intervention and unnecessary cost, testing should not be undertaken without good clinical indication. Secondary investigations that should be considered and selected according to potential diagnostic clues include abdominal ultrasononography or computed tomography, additional antibody testing, liver biopsy, temporal artery biopsy, skin and muscle biopsy, echocardiography, bone marrow aspiration, lower extremity Doppler ultrasonography, nuclear imaging, small bowel biopsy, and endoscopy. Despite enormous strides in our diagnostic capabilities, FUO remains a challenging problem, mostly because of the vast potential diagnoses. REFERENCES 1. Chung RS, Rowland DY, Li P, Diaz J. A meta-analysis of randomized controlled trials of laparoscopic versus conventional appendectomy. Am J Surg. 1999;177(3):250-256. 2. Hughes G, Liston WA. Comparison between laparoscopic sterilization and tubal ligation. Br Med J. 1975;3(5984):637-639. 3. Bleeker-Rovers PC, Vos FJ, de Kleijn EM, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007;86(1):26-38. 4. Diagnostic Standards and Classification of Tuberculosis in Adults and Children: this official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999: this statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med. 2000;161(4, pt 1):1376-1395. 5. Knockaert DC, Vanderschueren S, Blockmans D. Fever of unknown origin in adults: 40 years on. J Intern Med. 2003;253(3):263-295. 6. Vaile JH, Dyke L, Kherani R, Johnston C, Higgins T, Russell AS. Is high titre ANA specific for connective tissue disease? Clin Exp Rheumatol. 2000; 18(4):433-438. 7. Jacobs IJ, Skates SJ, MacDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet. 1999;353(9160):1207-1210. 8. Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in elderly patients. J Am Geriatr Soc. 1993;41(11):1187-1192. 9. de Kleijn EM, van Lier HJ, van der Meer JW, the Netherlands FUO Study Group. Fever of unknown origin (FUO): II, diagnostic procedures in a prospective multicenter study of 167 patients. Medicine (Baltimore). 1997;76 (6):401-414. 10. Kjaer A, Lebech AM, Eigtved A, Hojgaard L. Fever of unknown origin: prospective comparison of diagnostic value of 18F-FDG PET and 111Ingranulocyte scintigraphy. Eur J Nucl Med Mol Imaging. 2004 May 31;31(5): 622-626. Epub 2004 Jan 17. 11. Török L, Gurbity TP, Kirschner A, Krenács L. Panniculitis-like T-cell lymphoma clinically manifested as alopecia. Br J Dermatol. 2002;147(4):785-788. 12. Go RS, Wester SM. Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature. Cancer. 2004;101(6):1404-1413.
Correct answers: 1. d, 2. c, 3. e, 4. b, 5. e
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39-Year-Old Woman With Fever and Weight Loss ANNA M. KEANE, MD,* AND MARY J. KASTEN, MD†
A
39-year-old woman presented to our institution with a 4-month history of weight loss, nausea, malaise, and daily fever (temperature, 38.3°C-39.5°C). Her medical history was remarkable for type 2 diabetes mellitus and hypothyroidism. Her medications included levothyroxine and insulin. Born in Mexico, she lived in Texas with her husband and 2 children and was employed as a clerical worker. She did not smoke, drink alcohol, or use recreational drugs. She had not traveled to foreign countries and had no exposure to tuberculosis (TB) or contact with animals or ill people. Family history was noncontributory. Our patient’s fever occurred nightly and was first noted after an elective laparoscopic sterilization, performed at another institution. There were no complications during the procedure, and she was able to walk well the next day. At her 2-week postoperative visit at her local institution, she reported daily fever and described symptoms of nausea, fatigue, and pain on the left side of her abdomen. She denied any change in bowel habit or in respiratory, urinary, or other focal symptoms. Examination revealed lower abdominal tenderness, without guarding, but was otherwise normal. 1. Which one of the following is the most likely cause for the patient’s fever 2 weeks after laparoscopic sterilization? a Inflammation due to the trauma of surgery b. Perioperative drugs c. Nosocomial pneumonia d. Intra-abdominal abscess e. Deep venous thrombosis and pulmonary embolism (PE) Postoperative fever is common and can be due to many infectious and noninfectious causes. Immediate postoperative fever can be secondary to the normal inflammatory response to trauma or it can be caused by the drugs used during the operation, eg, antibioti cs or anestheticagents. However, fever due to inflammation of surgery, which is less common with laparoscopic than with open procedures, would have been unlikely to l ast 2 weeks , and fever caused by intraoperative drugs would be transient. Nosocomial respiratory tract infections are frequent with prolonged intubation and immobility, but the patient had no such history. Deep abdominal abscesses frequently cause persistent postoperative fever. Studies have shown that the incidence of abscesses after pelvic surgery is similar with open and laparoscopic techniques.1 The persistence of abdominal pain–associated fever 2 weeks after pelvic surgery is highly suggestive of an abscess. Mayo Clin Proc.
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Deep venous thrombosis and PE can also cause postoperative fever. However, these diagnoses were unlikely in our patient because studies show minimal risk of thromboembolism after laparascopic sterilization (as low as 0.05%) when patients have minimal tissue damage and early mobilization.2 Computed tomography of the chest, abdomen, and pelvis revealed no evidence of PE or other abnormalities. An exploratory laparotomy was performed at the patient’s local institution. No abscess or other cause for her fever was found. Further investigations at her local hospital yielded the following results (reference ranges provided parenthetically): an elevated erythrocyte sedimentation rate of 70 mm/h (0-29 mm/h); normochromic, normocytic anemia (hemoglobin, 9.5 g/dL [12.0-15.5 g/dL]); elevated liver enzymes, including aspartate aminotransferase (84 U/L [843 U/L]), alanine aminotransferase (78 U/L [7-45 U/L]), and alkaline phosphatase (300 U/L [37-98 U/L]); and elevated triglycerides (1005 mg/dL [<150 mg/dL]). Findings on upper and lower gastrointestinal endoscopy with biopsies were normal. Transesophageal echocardiography revealed normal valves. A set of blood cultures and a urine culture yielded no growth. Cerebrospinal fluid (CSF) culture and analysis were negative for infection or malignancy. Serologic studies were negative for hepatitis and human immunodeficiency virus; the tuberculin skin test (purified protein derivative standard [PPD]) was also negative. Four months later, the patient presented to our institution with a fever of unknown origin (FUO) for further evaluation. In addition to ongoing high fever, she reported a 3-week history of gradually progressive, diffuse myalgia with generalized weakness and associated joint stiffness. She had lost 20 kg during the past 4 months. She reported intermittent nausea and a poor appetite but denied any other symptoms. Her medications had remained unchanged and she had not used over-the-counter drugs. On initial examination she appeared very frail. Cardiovascular, respiratory, and breast examinations were unremarkable. There was no splenomegaly or lymphadenopathy and only moderate nontender hepatomegaly. Findings *Visiting resident, St. Vincent's University Hospital, Dublin, Ireland. †Adviser to resident and Consultant in General Internal Medicine, Mayo Clinic, Rochester, MN. See end of article for correct answers to questions. Individual reprints of this article are not available. Address correspondence to Mary J. Kasten, MD, Division of General Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]). © 2008 Mayo Foundation for Medical Education and Research
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on neurologic examination were entirely normal, apart from diffuse muscle weakness, most severe in the lower extremities. On previous examination, nontender nodular erthyematous patches had been observed; on this examination, they were fading and were noted in the pretibial areas bilaterally. We noted mild edema of her lower extremities but no evidence of arthritis. 2. Which one of the following broad categories is least likely to account for the patient’s symptoms? a. Infection b. Noninfectious inflammatory disease c. Drug-induced fever d. An endocrine or metabolic disorder e. Malignancy In many studies, infection has been found to be the most common cause of FUO (up to 59% of cases). Most of these studies were performed in areas with a high incidence of TB, or during a time when infections were more common and more challenging to diagnose.3 A negative PPD occurs in approximately 25% of patients with active TB.4 Our patient was born in Mexico where TB is endemic. Subacute bacterial endocarditis is the classic infectious cause of an FUO. Importantly, the transesophageal echocardiogram was negative for vegetations, but 3 sets of blood cultures were obtained to complete the investigation. Therefore, infection, particularly TB, remained in our differential diagnoses as a cause of her FUO. Noninfectious inflammatory diseases include rheumatologic, vasculitic, and granulomatous diseases. A recent multicenter study found this broad category to account for most (22%) diagnoses.3 The constellation of fever, weight loss, myalgia, joint stiffness, rash, and elevated erythrocyte sedimentation rate in a middle-aged woman is suggestive of a rheumatologic disorder or connective tissue disease. Her elevated liver enzymes also raised the possibility of granulomatous hepatitis. A noninfectious inflammatory illness was strongly suspected at her initial presentation to our institution. Drug-induced fever is often overlooked. Medications commonly implicated in drug-induced fever include antihypertensives, diuretics, oral contraceptives, and antibiotics. It is important to ask about nonprescription drugs as well as “natural remedies.” All nonessential drugs should be discontinued.4,5 Because our patient had been receiving long-term levothyroxine and insulin with no new pharmacotherapy, we thought that drug-induced fever was the least likely category to account for her current illness. Endocrine and metabolic disorders are unusual causes of FUO; however, hyperthyroidism, pheochromocytoma, and hypertriglyceridemia can all cause fever and occasionally present as an FUO.3 Our patient’s markedly elevated triglyc352
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eride levels could have caused pancreatitis and fever. Thus, a metabolic disorder remained in the differential diagoses. Lymphoma and leukemia are the most common malignancies to present as an FUO. We thought a bone marrow biopsy and aspiration was warranted given her weight loss and anemia. Extensive additional laboratory testing (Table) was conducted; results on urinalysis were normal, multiple blood cultures showed no growth, and a blood smear suggested a leukoerythroblastic picture. Bone marrow aspirates showed reactive changes only, with no evidence of granulomas or malignancy. On repeated computed tomography of the abdomen and pelvis, fatty infiltration of the liver and substantial diffuse subcutaneous edema extending down to the musculature and subcutaneous tissue of the lower limbs were revealed. No masses or lymphadenopathy were noted. At this point, our patient was so weak that she was unable to walk without assistance. Her fever persisted, and she continued to lose weight. 3. Which one of the following management strategies would be most appropriate for this patient? a. Empiric antibiotics b. Empiric antituberculous medications c. Empiric corticosteroid therapy d. Further observation e. Admittance to the hospital, so that the search for a cause of her FUO could continue Therapeutic trials of antibiotics, antituberculous agents, and corticosteroids are often tempting. However, these should be withheld in cases of FUO unless clinical deterioration is clear and could lead to loss of life and/or until a comprehensive investigation has been completed.5 Response to any of these therapies is not diagnostic of disease. Antituberculous medications are empirically given at times when clinical suspicion is high, especially when pathology reveals granulomatous changes and culture results are negative or pending. Clinical suspicion was not sufficiently high for our patient to warrant antituberculous medications. Empiric corticosteroid therapy is similarly inappropriate at this point in the evaluation. If the fever were secondary to an underlying rheumatologic disorder or hematologic malignancy, corticosteroids could mask and delay diagnosis. Provided that the general condition of the patient is good and that a careful initial work-up has been unrevealing, the observation or “wait-and-see” strategy would be the recommended management. One reason for this strategy is the rather low likelihood of establishing a final diagnosis in this situation.5 Most patients will either improve or develop additional clues to their illness that will help guide further investigation.
March 2008;83(3):351-354
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TABLE. Laboratory Results of 39-Year-Old Woman With Fever and Weight Lossa Laboratory test
Result (reference range)
Hemoglobin (g/dL) White blood cell (× 109/L) Platelets (× 109/L) Differential (%) Neutrophils Lymphocytes Monocytes Metamyelocytes Myelocytes Thyroid-stimulating hormone (mIU/L) C-reactive protein (mg/dL) Calcium (mg/dL) Erythrocyte sedimentation rate (mm/h) Albumin (g/dL) Bilirubin (mg/dL) Alanine aminotransferase (U/L) Alkaline phosphatase (U/L) Creatine kinase (U/L) Aldolase (U/L) Lactate dehydrogenase (U/L) Amylase (U/L) Creatinine (mg/dL)
8.6 (12.0-15.5) 8.6 (3.5-10.5) 287 (150-450) 80 (42-75) 6 (16-52) 5(1-11) 2 (0-1) 2 (0-0.5) 3.0 (0.3-5.0) 12.7 (<0.8) 8.0 (8.9-10.1) 52 (0-29) 1.5 (3.5-5.0) 1.3 (0.1-1.0) 526 (7-45) 297 (37-98) 22 (38-176) 19.6 (<7.7) 516 (122-222) 41 (26-102) 0.5 (0.6-1.1)
Given the severity of our patient’s illness, simple observation was not an option, and she was admitted to the hospital for continued evaluation. 4. Which one of the following would most likely lead to a diagnosis? a. Antinuclear antibody titer for connective tissue disease b. Liver biopsy c. Repeated CSF analysis d. Screening for occult cancer with cancer antigen (CA) 125 e. Temporal artery biopsy The antinuclear antibody titer, although sensitive, is not diagnostic for the presence of connective tissue disease. In one study, only 35% of symptomatic patients with a high antinuclear antibody titer actually had a final diagnosis of connective tissue disease.6 The diagnostic yield from liver biopsy has been found to be as high as 16%, even in the absence of potential diagnostic clues.3 Obtaining tissue is often valuable in the work-up of FUO. Liver biopsy was thought to be the test most likely to be diagnostic in our patient, given her hepatomegaly, elevated liver enzymes, and evidence on computed tomography of fatty infiltration. Repeating the lumbar puncture would be indicated if there were symptoms suggestive of infection or malignancy in the central nervous system. The lack of headache, cognitive complaints, or neurologic signs in our patient greatly diminished the likelihood that a CSF examin ation would be helpful. Levels of CA 125 can be elevated in ovarian, endometrial, and pancreatic cancer; however, a finding of elevated Mayo Clin Proc.
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CA 125 levels is very nonspecific. A recent study that screened more than 10,000 healthy women found that more than 4% had a benign elevation of CA 125 levels.7 This test should be reserved for monitoring confirmed cases of malignancy and detecting recurrent disease. Temporal arteritis accounts for up to 17% of cases of FUO in elderly people.8 Thus, temporal artery biopsy is reasonable to consider early in elderly patients with an FUO, but not in a patient younger than 50 years. Liver biopsy was performed and revealed fatty infiltration (grade 2 of 3) and periportal fibrosis (grade 1 of 4). Staining was negative for malignancy. No granulomas were seen. Thus, liver biopsy was not diagnostic. Other clues remaining unexplained were the subcutaneous edema, profound weakness of the lower extremities, and the lower limb rash, which had by this time resolved. Magnetic resonance imaging of the lower extremities showed diffuse subcutaneous edema with increased signal intensity throughout all visualized musculature. 5. Which one of the following tests is most likely to lead to a diagnosis at this stage? a. Skin biopsy of the lower extremities b. Indium-labeled granulocyte scan (nuclear imaging) c. Positron emission tomography (PET) d. Electromyelography (EMG) e. Muscle biopsy of the lower extremities In the presence of skin abnormalities, skin biopsy has a diagnostic yield in FUO of up to 35%.9 Because her rash had resolved, obtaining skin without underlying muscle was unlikely to give definitive results. The role of nuclear imaging in the evaluation of FUO varies from study to study. Although indium-labeled granulocyte scans and gallium scans can be helpful to localize inflammation, infection, or malignancy, these tests are limited by the difficulty in proving that an abnormal finding is in fact the cause of the fever5 and by the necessity of obtaining a tissue sample once an abnormality has been localized. Positron emission tomography has been compared with conventional nuclear imaging with variable results. Some studies have found PET to be superior to indium or gallium scanning, in particular for identifying vasculitic disease.5 However, other studies reported PET to have less specificity than indium-labeled granulocyte scans (46% vs 92%).9,10 Positron emission scanning can be helpful but will not give diagnostic results. In view of our patient’s myalgia and weakness, we thought EMG might reveal myositis and could be helpful in localizing an abnormality, although we knew that it would not be diagnostic. Myopathy, most extensive in the left gastrocnemius muscle, was revealed on EMG.
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Muscle biopsy using the other investigations (magnetic resonance imaging and EMG) to target the optimal biopsy site is most likely to be diagnostic. Biopsy of the left calf was performed, and pathology revealed subcutaneous panniculitis-like T-cell lymphoma, γδ type, with underlying muscular atrophy. This disease, an uncommon mature type of T-cell lymphoma, initially can mimic a benign panniculitis. Median age of onset is 40 years. The disease is usually characterized by the development of subcutaneous inflammatory nodules, most frequently on the trunk and extremities. It is associated with fever, weight loss, night sweats, and fatigue. Lymphomatous dissemination to lymph nodes and other organs, most notably the bone marrow, is uncommon and occurs late.11 Involvement of the overlying dermis is variable (20%-81%) and usually minimal.12 Untreated, median survival is less than 2 years. Therapeutic options include rad iation therapy, immunosuppressive agents, chemotherapy (cyclophosphamide, hydroxydaunomycin [doxorubicin], vincristine [Oncovin], and prednisone [CHOP]), and stem cell transplant. Immediately after diagnosis, our patient began receiving CHOP chemotherapy. She wished to continue this therapy closer to her home and did so under the care of a hematologist in her home city. DISCUSSION Fever of unknown origin is defined as a temperature of 38.3°C or higher on several occasions during a period of at least 3 weeks, the cause of which remains undetermined after an initial evaluation. Patients with FUO remain a diagnostic challenge. The approach to the patient with FUO includes obtaining a detailed history, conducting a careful physical examination, and running an appropriate series of diagnostic tests. A detailed history is paramount. Physicians should make particular note of recent travel, the work environment, high-risk behaviors, exposure to animals, or contact with ill people. They should ascertain whether patients have any history of malignancy, rheumatic fever, or inflammatory disorders. Finally, they should obtain a full medication list and a detailed family history. A complete physical examination with careful attention to the skin, mucous membranes, fundoscopy, cardiac examination, and assessment for lymphadenopathy and organomegaly can also reveal potential diagnostic clues. The fever should be formally confirmed and documented. If a diagnosis is not reached, the physical examination should be repeated periodically. Any nonessential medications should be discontinued to rule out drug-induced fever. The minimal initial work-up should usually include a complete blood cell count and 354
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differential; a blood film reviewed by a pathologist; assays for electrolytes, liver enzymes, and lactate dehydrogenase; serology for hepatitis and human immunodeficiency virus; urinalysis, microscopy, and urine culture; 3 sets of blood cultures; a chest radiograph; and a PPD. Antinuclear antibody and rheumatoid factor testing should be considered but results must be interpreted cautiously because of false positives. Heterophile antibodies and cytomegalovirus IgM should be obtained if the illness is suggestive of mononucleosis. To avoid both unnecessary exposure of the patient to medical intervention and unnecessary cost, testing should not be undertaken without good clinical indication. Secondary investigations that should be considered and selected according to potential diagnostic clues include abdominal ultrasononography or computed tomography, additional antibody testing, liver biopsy, temporal artery biopsy, skin and muscle biopsy, echocardiography, bone marrow aspiration, lower extremity Doppler ultrasonography, nuclear imaging, small bowel biopsy, and endoscopy. Despite enormous strides in our diagnostic capabilities, FUO remains a challenging problem, mostly because of the vast potential diagnoses. REFERENCES 1. Chung RS, Rowland DY, Li P, Diaz J. A meta-analysis of randomized controlled trials of laparoscopic versus conventional appendectomy. Am J Surg. 1999;177(3):250-256. 2. Hughes G, Liston WA. Comparison between laparoscopic sterilization and tubal ligation. Br Med J. 1975;3(5984):637-639. 3. Bleeker-Rovers PC, Vos FJ, de Kleijn EM, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007;86(1):26-38. 4. Diagnostic Standards and Classification of Tuberculosis in Adults and Children: this official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999: this statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med. 2000;161(4, pt 1):1376-1395. 5. Knockaert DC, Vanderschueren S, Blockmans D. Fever of unknown origin in adults: 40 years on. J Intern Med. 2003;253(3):263-295. 6. Vaile JH, Dyke L, Kherani R, Johnston C, Higgins T, Russell AS. Is high titre ANA specific for connective tissue disease? Clin Exp Rheumatol. 2000; 18(4):433-438. 7. Jacobs IJ, Skates SJ, MacDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet. 1999;353(9160):1207-1210. 8. Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in elderly patients. J Am Geriatr Soc. 1993;41(11):1187-1192. 9. de Kleijn EM, van Lier HJ, van der Meer JW, the Netherlands FUO Study Group. Fever of unknown origin (FUO): II, diagnostic procedures in a prospective multicenter study of 167 patients. Medicine (Baltimore). 1997;76 (6):401-414. 10. Kjaer A, Lebech AM, Eigtved A, Hojgaard L. Fever of unknown origin: prospective comparison of diagnostic value of 18F-FDG PET and 111Ingranulocyte scintigraphy. Eur J Nucl Med Mol Imaging. 2004 May 31;31(5): 622-626. Epub 2004 Jan 17. 11. Török L, Gurbity TP, Kirschner A, Krenács L. Panniculitis-like T-cell lymphoma clinically manifested as alopecia. Br J Dermatol. 2002;147(4):785-788. 12. Go RS, Wester SM. Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature. Cancer. 2004;101(6):1404-1413.
Correct answers: 1. d, 2. c, 3. e, 4. b, 5. e
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