Time Recommended to Complete: 1 day
Frederick S. Southwick, M.D.
GUIDING QUESTIONS
1. Which region of the brain is primarily responsible for temperature regulation?
2. Does core temperature vary at different times of the day?
3. Is fever beneficial?
4. How and when should fever be treated?
5. How do acetylsalicylic acid (ASA) and acetaminophen act to reduce fever?
TEMPERATURE REGULATION
Body temperature is regulated by the anterior hypothalamus in combination with many other neural structures, including the brain stem, spinal cord, and sympathetic ganglia. The region of the hypothalamus near the optic chiasm is thought to be primarily responsible for maintaining the body’s core temperature. A distinct temperature set point is established, and when the body’s core temperature drops below that set point, the nervous system increases body metabolism and stimulates shivering and chills. When core temperature exceeds that set point, the nervous system increases peripheral blood flow and sweating occurs. “Normal” body temperature is 37°C, but it varies from individual to individual, following a normal distribution. Some individuals therefore have a lower set point, and others have a higher set point than the mean “normal” temperature. Furthermore, each individual’s core temperature varies during the day, being lower in the morning and increasing in the evening. Before deciding that a patient has a fever, the physician must be familiar with that patient’s normal set point and diurnal core temperature variation.
MECHANISMS UNDERLYING THE FEBRILE RESPONSE
Fever is a consequence of the anterior hypothalamus responding to inflammatory mediators. Among the mediators thought to stimulate a rise in the normal core temperature set point are interleukin 1 (IL-1), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interferon γ (IFN-γ). These cytokines are released primarily by monocytes and macrophages in response to invasion by various pathogens and by other inflammatory stimuli. Investigators speculate that these cytokines stimulate the circumventricular organs near the optic chiasm, activating phospholipase A2, which in turn stimulates the cyclooxygenase pathway to produce increased levels of prostaglandin E2. This small molecule crosses the blood–brain barrier and stimulates the neurons within the anterior hypothalamus and brain stem responsible for thermal regulation.
BENEFITS AND HARMFUL EFFECTS OF FEVER
In addition to serving as a warning sign for the onset of infection, fever is thought to be beneficial. The growth of some viruses, bacteria, fungi, and parasites are inhibited by a rise in temperature above 37°C. Fever has also been shown to enhance the ability of macrophages and neutrophils to kill foreign pathogens and to improve cell-mediated immune function.
Depending on the individual patient, fever may also have harmful effects. Patients with heart disease may suffer cardiac ischemia because of the increase in heart rate and the oxygen demands associated with fever. Patients with severe pulmonary disease may similarly be unable to compensate for the increased oxygen demands associated with fever. Elderly patients with limited mental capacity may develop confusion and lethargy in response to fever, complicating their care.
KEY POINTS
About Fever
1. Body temperature is regulated by the hypothalamus, and prostaglandin E2 acts on this region to stimulate fever.
2. Fever most commonly occurs in the evening as a consequence of the diurnal variation of body temperature.
3. Fever may be protective and should be reduced only in patients with ischemic heart disease or pulmonary disease, in elderly patients, and in children who have a history of febrile seizures.
4. Acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, and acetaminophen (agents that reduce prostaglandin E2 production) are the preferred medications for reducing fever and need to be administered on a regular schedule.
TREATMENT OF FEVER
The primary treatment for fever is to treat the underlying cause. The role of lowering body temperature while trying to determine the primary cause of fever remains controversial.
Based on current understanding of thermal regulation, direct cooling of the body by using ice, cold water, or a cooling blanket should be considered only in conjunction with medicines that reset the thermal set point. Otherwise, the central nervous system will respond to such measures by inducing chills and shivering, increasing the patient’s discomfort. Use of antipyretics is probably warranted in patients with heart disease and, pulmonary disease, and in elderly patients with mental dysfunction in association with fever.
The pharmacologic agents used to reset the thermal set point all inhibit prostaglandin synthetase activity and reduce prostaglandin E2 production. Acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen are all effective. In children, ASA should probably be avoided because of the increased risk of Reye’s syndrome (a deadly syndrome consisting of fatal hepatic and renal failure), and acetaminophen should be avoided in patients with serious underlying liver disease. Coronary artery vasoconstriction has been associated with NSAIDs, and therefore those drugs probably should not be used in patients with ischemic heart disease. To avoid repeated shifting of the thermal set point and recurrent shivering and chills, antipyretic agents must be administered on a regular schedule until the primary cause of fever has been treated.
MANAGEMENT OF NEW ONSET FEVER IN THE HOSPITALIZED PATIENT
One of the most common problems encountered by the infectious disease consultant is the evaluation of new onset fever in the patient who is being managed for another medical problem in the hospital. These patients often have multiple medical and surgical conditions and may appear severely ill.
In the postoperative patient, wound infection must first be excluded. All surgical wounds need to be carefully examined for purulent discharge, erythema, edema, and tenderness. In the immediate postoperative period (24-48 hours), Streptococcus pyogenes can cause septic shock and severe bacteremia with only minimal purulence at the operative site. A Gram stain of serous exudate usually demonstrates gram-positive cocci in chains. In the later postoperative period, Staphylococcus aureus, including MRSA, and nosocomial pathogens such as Pseudomonas, Klebsiella, and Escherichia coli are associated with wound infection. In chronically ill patients, decubiti need to be considered as a source of infection, and a full examination of the back and buttocks regions should be performed for tissue breakdown and purulent discharge. The organisms associated with deep decubiti include the same organisms as associated with late postoperative infection with the addition of anaerobes, including Bacteroides fragilis.
Appropriate antibiotic therapy is generally guided by culture and Gram stain. Empiric antibiotic therapy should include gram-positive and gram-negative coverage. In patients who have suffered bowel perforation, the development of intra-abdominal abscess is a common cause of fever, and an abdominal computerized tomography (CT) scan should be ordered to exclude this possibility.
Because most ICU patients are intubated, bacteria colonizing the nasopharynx can more readily gain entry to the bronchi and pulmonary parenchyma, causing bronchitis and pneumonia. Patients in the less acute wards are also at increased risk for aspiration pneumonia, because many are elderly, have suffered a stroke, or are receiving sedatives. As is outlined in more detail in Chapter 4, sputum Gram stain is critical for differentiating colonization from true infection. The presence of a single organism on Gram stain, combined with more than 10 neutrophils per high-power field, strongly suggests infection. Sputum culture identifies the offending organism and sensitivities to antibiotics. Other parameters that are helpful in differentiating colonization from true infection are chest X-ray (CXR) and arterial blood gases. The presence of a new infiltrate supports the diagnosis of pneumonia, as does a reduction in arterial PaO2.
Hospitalized patients usually have several IV catheters in place. These lines are always at risk of becoming infected, and line sepsis is a common cause of fever in hospitalized patients. At the onset of new fever, all IV and arterial lines should be examined for erythema, warmth, and exudate. Particularly in the patient who has developed shock, all lines should be removed and appropriate empiric antibiotic coverage instituted immediately (within 1 hour, see Chapter 2).
Staphylococcus aureus, Staphylococcus epidermidis, and gram-negative rods are the primary causes of line sepsis. Initial antibiotic coverage should include vancomycin and a third-generation cephalosporin. Empiric antibiotic coverage must be individualized to take into account the prevailing bacterial flora in each hospital unit and the history of antibiotic use in the patient. Patients who have been in the hospital for prolonged periods and who have received multiple antibiotics are at risk of candidemia, particularly if two or more peripheral site cultures have grown this organism. These patients should be empirically covered with fluconazole or an echinocandin (caspofungin, anidulafungin, or micafungin), pending blood culture results.
Another major infectious cause of fever in hospitalized patients is prolonged bladder catheterization. The bladder catheter bypasses the urethra, and despite the use of closed urinary collecting systems, nearly all patients with bladder catheters develop urinary tract infections within 30 days (see Chapter 9). Urinalysis and urine culture therefore need to be part of the fever workup in all patients with urinary catheters.
In patients with nasogastric tubes or those who have been intubated through the nasal passage, the ostia draining the air sinuses can become occluded. This condition can lead to sinusitis and fever. Fever workup in these patients therefore needs to include sinus films. If sinusitis is discovered, the tube must be removed from the nasal passage, and appropriate antibiotic coverage instituted (see Chapter 5).
Noninfectious causes of fever also need to be considered. As noted later in this chapter, pulmonary emboli may present with fever. Patients are usually receiving a large number of medications, and they are therefore at higher risk of developing drug fever. All medications should be reviewed, and when possible, medications should be discontinued or changed.
Another cause of persistent low-grade fever is undrained collections of blood. These collections can be identified by CT scan. Generally, they do not require drainage, but they take time to fully resorb.
Fever in the hospitalized patient requires a systematic diagnostic approach and the judicious use of antibiotics. Too often, patients are covered unnecessarily for prolonged periods, using broad-spectrum antibiotics. This condition leads to the selection of highly resistant bacterial pathogens, and it also predisposes the patient to candidemia and Clostridium difficile colitis.
KEY POINTS
About New Onset of Fever in the Hospitalized Patient
1. New onset of fever is extremely common in the hospitalized patient.
2. A systematic approach to diagnosis is critical.
3. Key sites of infection include the following:
a) Wounds (particularly in the early postoperative period), decubiti
b) Lungs (critical to differentiate colonization from infection)
c) IV and intra-arterial lines
d) Urinary tract (at high risk secondary to prolonged bladder catheterization)
e) Sinuses (in patients with nasotracheal tubes)
4. Noninfectious causes include pulmonary emboli, drug fever, and old hemorrhage.
5. Empiric antibiotics need to be streamlined based on culture results.
6. Prolonged broad-spectrum antibiotic coverage predisposes to colonization with highly resistant bacteria, fungemia, Clostridium difficile colitis, and drug allergies.
Empiric antibiotic coverage needs to be streamlined once culture data are available. Close communication between the hospital staff and the infectious disease consultant is critical to achieve the best care for the febrile inpatient.
FEVER OF UNDETERMINED ORIGIN
GUIDING QUESTIONS
1. What are the criteria used to define fever of undetermined origin (FUO)?
2. Which diseases are most commonly associated with FUO?
3. Which diseases are most commonly associated with FUO in the elderly patients?
4. Which basic diagnostic tests should be ordered in cases of FUO?
5. What is Sutton’s law, and how is this law applied to FUO?
6. Should empiric antibiotics be started in cases of FUO?
7. What is the prognosis in patients with FUO?
POTENTIAL SEVERITY
Fever of undetermined origin (FUO) is a chronic disorder that requires a thoughtful diagnostic approach by a highly experienced clinician.
Determining the cause of fever of undetermined origin remains one of the great challenges in infectious diseases. This problem requires a team approach in which all caregivers repeatedly share their daily findings and continually generate and test new hypotheses. The team should be led by an expert, that is, a physician with extensive expertise in infectious diseases and many years of clinical experience.
DEFINITION OF FUO
At the time the patient first visits the physician with complaints of fever, the cause is in many cases not apparent. Some physicians label these complaints as FUO. However, the name “fever of undetermined origin” carries with it specific criteria and should not be loosely applied. As first defined in 1961, FUO requires that the patient have
1. an illness that has lasted least 3 weeks,
2. fever of more than 38.3°C on several occasions, and
3. no diagnosis after routine workup for 3 days in hospital or after 3 or more outpatient visits.
A duration of 3 weeks or longer was chosen to eliminate self-limiting viral illnesses that are generally difficult to diagnose and that resolve within that period. A temperature of more than 38°C was chosen to eliminate those individuals at the far right of the normal temperature distribution curve who normally may have a slightly higher core temperature set point and an exaggerated diurnal temperature variation. Recognizing that, in the present era of managed care, most patients with FUO are now diagnosed and managed as outpatients, the third criterion has been modified to include outpatient diagnostic testing, as well as that conducted in hospital.
KEY POINTS
About the Definition of Fever of Unknown Origin
1. Fever must persist for more than 3 weeks to exclude self-limiting viral illnesses.
2. Temperature must be more than 38.3°C (101 °F) to exclude normal variations in core body temperature set point.
3. No diagnosis reached after 3 days of testing.
Before launching a complex and expensive series of diagnostic tests, the physician must carefully document that the patient fulfills the criteria for FUO. Most important is the documentation of true fever. The patient should be instructed to measure both 6-AM and 6-PM temperature to rule out an exaggerated circadian rhythm. Second, an electronic thermometer should always be used to exclude the possibility of factitious fever (discussed in the next subsection). The exact pattern of fever is generally not helpful in identifying the fever’s cause, although patients with daily fever are more likely to be diagnosed as compared to those with intermittent or periodic fever. In patients whose fever is repeatedly highest in the early morning, miliary tuberculosis, typhoid fever, and periarteritis nodosa should be strongly considered (see below).
CAUSES OF FUO
Many diseases can initially present with the primary manifestation of prolonged fever (Table 3.1). The possible causes can be classified into three major categories: infections, neoplasms, and autoimmune disorders. The miscellaneous causes are numerous and include drug fever, factitious fever, familial Mediterranean fever (FMF), pulmonary emboli, and thyroiditis.
Table 3.1. Causes of Fever of Unknown Origin
Major causes:
1. Infection
2. Neoplasm
3. Autoimmune disease
Miscellaneous causes:
1. Drug fever
2. Factitious fever
3. Familial Mediterranean fever
4. Pulmonary emboli
5. Subacute thyroiditis
CASE 3.1
A 19-year-old man, university sophomore, presented with a 3-week history of fevers to 40°C, fatigue, and anorexia. He was evaluated in the school infirmary and was given IV fluids for dehydration. He was treated empirically with penicillin and clarithromycin. Despite this treatment, his fevers persisted.
Epidemiology indicated no recent travel. A review of systems was negative, other than 1-2 loose bowel movements daily for the week before admission.
Vital signs included a temperature of 39.2°C, pulse of 88 per minute, respiration rate of 20 per minute, and blood pressure of 122/60 mmHg. The patient appeared mildly ill. His physical examination was completely normal, including absence of palpable lymph nodes, no skin rashes, no cardiac murmurs, a benign abdominal examination without organomegaly, and a normal joint and extremity examination.
Laboratory workup showed a WBC count of 11,600/mm3, with 93% polymorphonuclear leukocytes. Hematocrit was 35%; platelets, 228,000/mm3; blood urea nitrogen, 6 mg/dL; serum albumin, 3.0 g/dL; total protein, 6.2 g/dL; alkaline phosphatase (ALP), 327 IU/L; alanine transaminase (ALT), 107 IU/L; and erythrocyte sedimentation rate (ESR), 105 mm/h. Blood cultures were twice negative, and a chest X-ray (CXR) was within normal limits.
Because of the persistent fever and anorexia, the patient underwent an abdominal CT scan that demonstrated a hepatic abscess 9 cm in diameter in the right lower lobe of the liver. Echinococcal serum titer was negative. Cutaneous aspiration demonstrated thick pus, and culture grew S. aureus, methicillin-sensitive.
Comment
Other than a mildly elevated ALP level, no clinical clues indicative of liver abscess were seen. On further review of medical history, the patient reported having intermittent furunculosis. His skin was likely the initial portal of entry, resulting in transient bacteremia and seeding of the liver.
Infection
In patients under the age of 65 years, infection remains the most common cause of FUO (Table 3.2). Common infectious causes of FUO include abscesses, particularly abdominal abscesses that may persist for prolonged periods before being diagnosed. Improvements in imaging techniques have enhanced the ability to locate and drain occult pyogenic collections. Osteomyelitis—particularly of the vertebral bodies, mandible, and air sinuses—can also present as FUO. Bone scan is particularly helpful in identifying such infections.
Table 3.2. Infectious Causes of Fever of Unknown Origin
1. Abscesses
2. Osteomyelitis (vertebrae, mandible, sinuses)
3. Subacute bacterial endocarditis (murmur usually present, beware of previous antibiotics)
4. Biliary system infections (may have no right upper quadrant tenderness)
5. Urinary tract infections (in absence of related symptoms)
6. Tuberculosis (especially miliary disease)
7. Spirochetal infection (leptospirosis, Borrelia)
8. Brucellosis (animal exposure, unpasteurized cheese)
9. Rickettsial infection
10. Chlamydia
11. Epstein–Barr virus, cytomegalovirus
12. Fungal infection (Cryptococcus, histoplasmosis)
13. Parasites (malaria, toxoplasmosis, trypanosomiasis)
In earlier series, subacute bacterial endocarditis (SBE) was a major cause of FUO. However, improved culture techniques, including prolonged incubation of blood cultures to identify more fastidious slow-growing pathogens such as the HACEK organisms (see Chapter 7 on bacterial endocarditis), and drawing large volumes of blood for culture have improved the sensitivity of blood cultures and reduced the number of undiagnosed cases of SBE. Transesophageal cardiac echo has also improved identification of vegetations. As a result of those advances, SBE has become a less common cause of FUO in recent reports. In almost every case, patients with SBE have an audible murmur, emphasizing the importance of a careful physical examination during the initial evaluation of the patient with FUO.
The physician must also keep in mind that, if the patient has received antibiotics, the utility of blood cultures is markedly reduced. Administration of antibiotics temporarily sterilizes the bloodstream. Antibiotics must be discontinued for 7-10 days before blood cultures become positive.
Biliary system infections also can present as FUO. Such patients often have no right upper quadrant pain and no right upper quadrant tenderness. Subacute pyelonephritis can also present with a prolonged fever in the absence of dysuria, frequency, or flank pain.
In cases of FUO, miliary tuberculosis (TB) must always be considered, particularly if the patient is experiencing fever peaks in the early morning. This potentially lethal disease is most common in elderly and immunocompromised patients, particularly patients with HIV and patients on high-dose glucocorticoids or a TNF inhibitor. Bone marrow culture is particularly helpful in making this diagnosis. A CXR may demonstrate micronodular (“millet seed”) interstitial changes; however, this radiologic finding may be absent in elderly individuals. If appropriate antituberculosis therapy is not initiated promptly, these patients usually deteriorate over 2-3 weeks and die.
Leptospirosis can cause persistent fever and is difficult to diagnose. A combination of appropriate epidemiology (animal or contaminated soil or water exposure), conjunctival suffusion, aseptic meningitis, liver enzyme abnormalities, and renal dysfunction should alert the clinician to this possibility. Other spirochetal diseases reported to cause persistent fever include Lyme disease and relapsing fever. Animal exposure, particularly the skinning of wild boar, should raise the possibility of brucellosis. Brucellosis can also be contracted by eating unpasteurized cheese.
Rickettsial infections can also cause FUO. Epidemiology plays a critical role in alerting the clinician to this group of pathogens. A history of camping, hunting, or other outdoor activities in areas endemic for these infections should raise the possibility. Rickettsia are tick-borne; however, a history of tick bite is not always obtained.
Chlamydia is another intracellular pathogen that on occasion can cause prolonged fever. Chlamydia psittaci in particular can result in a mononucleosis-like syndrome. This organism is usually contracted from birds, including pigeons, members of the parrot family (parakeets, macaws, and cockatoos), finches (canaries, goldfinches), and poultry. Epstein–Barr virus and cytomegalovirus can both cause a mononucleosis syndrome resulting in sore throat, lymphadenopathy, splenomegaly, and prolonged fever.
In addition to bacteria and viruses, fungi can occasionally result in FUO, cryptococcosis and histoplasmosis being the two most common fungal diseases reported. Parasites can similarly cause prolonged fever. Malaria (nonfalciparum forms), toxoplasmosis, and trypanosomiasis are the most commonly reported parasitic diseases associated with FUO.
KEY POINTS
About Infectious Causes of Fever of Unknown Origin
1. Infection is the most common cause of fever of unknown region (FUO) in patients under 65 years of age.
2. Epidemiology (animal exposure, insect bites, outdoor camping, travel, and exposure to infected humans) is helpful.
3. Physical examination may provide useful clues, particularly inspection of skin, nail beds, and fundi and cardiac auscultation.
4. Abdominal abscess, miliary tuberculosis, and disseminated fungal infections can be fatal.
5. Prior antibiotic administration interferes with diagnosis.
Neoplasm
Neoplastic disorders represent the second major category of diseases associated with FUO (Table 3.3). In elderly patients, neoplasia is the most frequent cause, and in this category, lymphomas are the most commonly reported cause of fever.
Table 3.3. Neoplastic Causes of Fever of Unknown Origin
1. Lymphoma (especially Hodgkin, Pel–Ebstein fever)
2. Leukemia (aleukemic or preleukemic phase)
3. Hypernephroma (high sedimentation rate)
4. Hepatoma (generally not metastatic liver disease)
5. Atrial myxoma
Hodgkin lymphomas intermittently produce pyrogens: 1 week the patient may be afebrile, and the following week may bring hectic fevers. This fever pattern has been termed Pel–Ebstein fever, which when present, raises the possibility of Hodgkin lymphoma. Patients with non-Hodgkin lymphoma may also present with fever. In some cases, the fever can be high and mimic sepsis.
Patients with leukemia may also present with fever. Older patients in the aleukemic or the preleukemic phase of their disease may have little or no evidence of leukemia on peripheral smear. In earlier series, hypernephroma was noted to cause FUO; however, examination of a large series of patients with hypernephroma has demonstrated that this solid tumor is rarely associated with fever.
KEY POINTS
About Neoplastic Causes of Fever of Unknown Origin
1. Lymphoma is the most common neoplasia causing fever of unknown region (FUO).
2. Pel–Ebstein fever strongly suggests Hodgkin lymphoma.
3. Preleukemia can present as FUO in the elderly patients.
4. Primary hepatoma can be associated with FUO; however, metastatic liver disease usually does not cause fever.
5. Renal cell carcinoma occasionally causes FUO.
6. Atrial myxoma can mimic subacute bacterial endocarditis.
The solid tumor most frequently reported as a cause of FUO is primary hepatoma, but tumors that metastasize to liver rarely cause fever. Atrial myxoma is a rare disorder that is associated with fever, and it can mimic SBE. Small pieces of the atrial tumor can break off and embolize to the periphery, causing small infarcts similar to those observed in bacterial endocarditis.
CASE 3.2
A 27-year-old Asian man presented with a chief complaint of fevers of 2-week duration. Two weeks earlier, he had begun to experience fever associated with weakness, malaise, shoulder and neck weakness, and muscle tenderness. He also noted a sore throat. He was admitted to a hospital in Puerto Rico, where a CXR demonstrated diffuse pulmonary infiltrates and a sputum Gram stain showed gram-positive cocci. His WBC count was 16,000/mm3. He was treated with IV mezlocillin and gentamicin and later switched to ampicillin. He failed to improve, remaining febrile, and he came to the university hospital.
Epidemiology indicated no pets, no allergies, no consumption of unpasteurized milk or raw meat, no swimming in fresh water, no exposure to TB, and no history of gonococcus or syphilis.
Social history recorded occasional alcohol use, single status, and employment as a cook. Other than the trip to Puerto Rico, travel was unremarkable. No pets. No exposure to TB or other infectious diseases.
Medical history indicated that, at age 9, he had an acute febrile episode associated with a rash, severe joint swelling, and high fever. The illness spontaneously subsided.
The patient’s physical examination showed a temperature of 38.3°C and a clear chest. Liver edge was palpated 2 cm below the right costal margin, slightly tender. His left upper quadrant was also tender, and skin showed a macular rash over the chest where he had applied rubbing ointment.
Laboratory workup showed a peripheral WBC count of 20,400/mm3, with 94% polymorphonuclear; leukocytes, 4% lymphocytes, 2% macrophages. Platelet count was 354,000/mm3; hemoglobin, 12.9 g/dL; PaO2, 69 mmHg; PaCO2, 33 mmHg; HCO3, 24 mEq/L. A urinalysis was negative. Total bilirubin was 2.8 mg/dL; ALT, 108 IU/L; aspartate aminotransferase (AST) 98 IU/L; and γ-glutamyl transpeptidase (GGT), 42 IU/L. A CXR showed infiltrate in the left lower lobe of the lungs.
Ceftriaxone and erythromycin were started; however, this patient’s fevers persisted in the range 38.3°C to 40.6°C.
A subsequent laboratory analysis included an ESR above 100 mm/h, a peripheral WBC count of 35,000/mm3, and hemoglobin of 9.1 g/dL.
After 4 days of persistent fever, the patient was switched to a tetracycline antibiotic, followed by 3 days of naproxen. Additional tests at that time included a PPD skin test (4 mm) and an acid-fast bacilli stain of sputum (negative). Abdominal ultrasound and CT scans were negative, with the exception of consolidation seen in the left and right lung bases. A bronchoscopy was negative for Pneumocystis and Legionella; transbronchial biopsy was consistent with focal pneumonitis. A lumbar puncture showed glucose, 89 mg/100 mL; total protein, 11 mg/mL; and WBC count 0 in the cerebrospinal fluid. Thick and thin malaria smears were negative; stool samples for ova and parasites were thrice negative. Hepatitis B surface antibody was positive (Ab+), core was Ab+, and surface antigen was negative. He had a 1:185, antinuclear antibodies (ANAs) and rheumatoid factor were negative, and the rapid plasma reagin was also negative. Eight separate blood cultures were negative, and a monospot test was negative. Repeat transaminase values registered ALT 94 IU/L; AST 64 IU/L, ALP 403 IU/L, and GGT 180 IU/L.
The patient continued to have fevers. A liver biopsy demonstrated nonspecific inflammation. Weight loss continued, and the patient’s ESR and WBC remained elevated. After 8 days in the hospital, he developed a swollen left wrist and swollen right elbow. He was treated with high-dose oral salicyclates. Within 24 hours of initiation of therapy, he defervesced. Over the next 2 weeks, his symptoms completely resolved. Based on medical history, clinical presentation, and response to salicyclates, he was discharged with a diagnosis of Still’s disease.
Autoimmune Disease
Autoimmune disease is the third major category of diseases that cause FUO (Table 3.4). In early series of FUO cases, systemic lupus erythematosus(SLE) was a frequent cause. However, with improvements in antinuclear and anti-DNA markers, these sensitive tests readily identify cases of SLE. The diagnosis is now usually made within 3 weeks.
Table 3.4. Autoimmune Diseases That Cause Fever of Unknown Origin
1. Systemic lupus erythematosus
2. Still’s disease
3. Hypersensitivity angiitis
4. Polymyalgia rheumatica, combined with temporal arteritis
5. Polyarteritis nodosa
6. Mixed connective tissue disease
7. Subacute thyroiditis
Still’s disease (adult-onset juvenile rheumatoid arthritis) is one of the most frequent autoimmune diseases resulting in FUO in younger patients. Key clinical features of this disease include an evanescent macular rash, arthralgias, and a sore throat. Patients with Still’s disease often have high fevers associated with high peripheral white blood cell (WBC) counts, and this combination frequently causes the physician to begin antibiotic therapy for a presumed bacterial infection. However, the fever fails to subside after initiation of antibiotics. No specific test is available for Still’s disease. Serum ferritin levels are generally markedly elevated, as is the erythrocyte sedimentation rate (ESR).
In elderly patients, polymyalgia rheumatica is the most common autoimmune disorder to cause FUO. This disease results in proximal muscle weakness and a high ESR. Temporal headaches and visual complaints are present, as is temporal arteritis, a vasculitis commonly associated with polymyalgia rheumatica.
Other autoimmune diseases reported to cause FUO include polyarteritis nodosa, hypersensitivity angiitis, and mixed connective tissue disease. Subacute thyroiditis may present with prolonged fever. On examination, the thyroid is often tender and serum antithyroid antibodies are elevated. Recently, Kikuchi’s disease, also called histiocytic necrotizing lymphadenitis, has been reported to cause prolonged fever. This self-limiting autoimmune disorder occurs in young Asian females and is associated with generalized lymphadenopathy. Diagnosis is made by lymph node biopsy.
KEY POINTS
About Autoimmune Causes of Fever of Unknown Origin
1. Still’s disease is associated with high fevers, evanescent skin rash, leukocytosis, high serum ferritin, and elevated erythrocyte sedimentation rate (ESR). A diagnosis by exclusion.
2. Polymyalgia rheumatica and temporal arteritis are found in elderly patients and cause proximal muscle weakness, visual symptoms, and a high ESR.
3. Subacute thyroiditis should be considered if the thyroid is tender.
4. Kikuchi’s disease often presents with fever and lymphadenopathy.
Other Causes of FUO
In addition to the major categories, clinicians must also consider multiple miscellaneous disorders. The most common cause of fever in this group is drug fever. Table 3.5 lists the drugs that most commonly cause fever. The anti-seizure medication phenytoin (Dilantin) is probably the drug that most frequently causes allergic reactions, including fever. Quinidine sulfate, procaine amide, sulfonamides, and penicillins are other major offenders. When a patient presents with FUO, all medications should be discontinued or switched to exclude this possibility.
Table 3.5. Drugs That Cause Fever of Unknown Origin
In female patients with a medical background, factitious fever must always be considered. In earlier series, patients often manipulated the mercury thermometer to fool the physician; the advent of the electronic thermometer has made this maneuver impossible. Today, patients usually inject themselves with saliva or stool, causing polymicrobial bacteremia and fever. This disorder occurs almost exclusively in women. In the absence of any clear cause for fever, a history of health care training should raise the clinician’s suspicion, particularly if the patient takes great interest in her illness and has a medical textbook at the bedside. The diagnostic test of choice is often a search of the patient’s room, seeking a syringe used for self-injection.
Familial Mediterranean fever is another important but rare cause of FUO. As the name implies, this is a genetic disorder associated with recurrent serositis primarily of the abdominal cavity, but it can also result in pleuritis and pericarditis. A family history is critical in raising this possibility. The molecular basis for this disease is loss of pyrin, a protein important for the regulation of inflammasomes.
Given increasing prevalence of obesity and the sedentary lifestyle of our population, pulmonary emboli are an increasing concern. Also, patients who have been at prolonged bed rest are at increased risk of thrombus formation in the calves. When emboli are small, they may not result in respiratory complaints and may simply present as fever. In all patients at risk for thrombophlebitis who present with FUO, pulmonary emboli need to be excluded.
In recent years, a number of cases of subacute thyroiditis presenting as FUO have been reported. These patients often complain of neck pain and, on physical examination, have a tender and edematous thyroid reflecting ongoing inflammation. Laboratory studies reveal elevated thyroid hormones accompanied by a high C-reactive protein (CRP). This is a self-limited disease thought to be precipitated by a viral infection.
KEY POINTS
About Other Causes of Fever of Unknown Origin
1. Discontinue all medications of the patient with fever of unknown region (FUO).
2. Consider factitious fever in the female health care worker with a medical textbook at the bedside and recurrent polymicrobial bacteremia.
3. Familial Mediterranean fever is usually accompanied by a positive family history.
4. Pulmonary emboli can present with fever in the absence of respiratory symptoms.
5. No diagnosis is made in an increasing percentage of modern cases.
Finally, in a recent series, a high proportion of patients (15-51%) had no explanation for their FUO. In many of these cases, fever spontaneously resolved over 3 to 6 months without harmful consequences.
HISTORY OF FUO
History can play a critical role in narrowing the differential diagnosis and in deciding on the most appropriate diagnostic tests. A review of all symptoms associated with the illness needs to be periodically updated. Symptoms often are transient and are recalled by the patient only after repeated questioning. A patient’s medical history often provides useful clues. History of tuberculosis, tuberculosis exposure, or a positive PPD should be included. Family history must also be thoroughly reviewed to exclude genetic disorders, such as cyclic neutropenia and familial Mediterranean fever. Social history needs to include animal exposure (pets and other domestic or wild animals), home environment, and occupational exposure. Travel history should explore travel to areas endemic for malaria and other parasites, typhoid, coccidiomycosis, histoplasmosis, and tick-borne illnesses. A list of all medications, including over-the-counter and natural organic remedies, must be compiled to exclude the possibility of drug fever.
PHYSICAL EXAMINATION OF FUO
In addition to a careful history, careful repeat physical examination is frequently helpful. Particular attention should be paid to the skin examination, looking for embolic or vasculitic lesions or evidence of physical manipulation. Particular attention should be paid to the nail beds, where small emboli can become trapped in the distal capillaries of the fingers and toes, resulting in small splinter-shaped infarcts. Joint motion and the presence of effusions should be looked for. Careful eye examination should be repeated, looking for conjunctival petechiae, conjunctivitis, punctate corneal lesions, uveitis, optic nerve changes, and retinal or choroidal abnormalities. Thorough palpation of all lymph nodes needs to be repeatedly performed, documenting the consistency, size, and tenderness. Cardiac examination should be repeated daily, listening for cardiac murmurs and pericardial rubs. The abdomen also should be palpated daily to detect new masses, areas of localized tenderness, and hepato- or splenomegaly.
KEY POINTS
About the History in Fever of Unknown Origin
1. A review of symptoms should be repeated frequently.
2. Medical history of infectious diseases and family history should be carefully reviewed.
3. Epidemiology history should include animal exposure, outdoor camping, insect bites, and travel to developing countries or the Southwest United States and the Ohio River valley.
4. All medications must be reviewed.
KEY POINTS
About Physical Examination in Fever of Unknown Origin
1. Thoroughly examine skin for embolic lesions.
2. Palpate all lymph nodes.
3. Perform a complete joint examination.
4. Listen carefully for cardiac murmurs.
5. Abdominal examination should assess liver and spleen size and should palpate for masses and areas of tenderness.
LABORATORY STUDIES OF FUO
All patients with FUO should receive a series of basic diagnostic tests (Table 3.6). However, because each case is different, a series of yes-or-no branch points are not possible for guiding the subsequent diagnostic approach to FUO.
Table 3.6. Preliminary Tests Recommended for Fever of Unknown Origin
Complete history
Careful physical exam
Complete blood count with differential
HIV antibody and antigen test
Liver function tests, LDH, CPK
Antinuclear antibodies and rheumatoid factor
CRP or ESR
Urinalysis and urine culture
Blood cultures × 3
Serum protein electrophoresis
Tuberculin skin test or interferon γ release assay
Chest and abdominal CT scan
KEY POINTS
About Diagnostic Workup in Fever of Unknown Origin
1. Physicians usually err by overtesting.
2. Care team should be led by an expert with more than 10 years clinical experience.
3. A cookbook approach should be avoided.
4. Sutton’s law (“Go where the money is”) should be applied. Tests should be directed toward specific complaints and abnormalities found on preliminary testing.
5. An iterative approach to testing and analysis is most effective.
In recent years, rather than insufficient studies being the norm, clinicians have erred on the side of excessive and uninformative testing. Each patient’s diagnostic workup must be tailored to personal history and physical findings. A cookbook approach subjects the patient to undue costly testing and stress. An iterative rather than a shotgun approach to testing is the most effective course of action. “Tincture of time” and repeated history and physical examination often allow the physician to most effectively apply Sutton’s law.
Willy Sutton was a famous bank robber, who, when finally captured, was asked by newspaper reporters, “Willy, why do you rob banks?” Willy replied, “That’s where the money is.” Clinicians need to focus on diagnostic tests that are likely to have a high yield. They need to “go where the money is.”
In applying Sutton’s law, the clinician must review each new potential diagnostic clue and assess its significance in relationship to the patient’s other positive findings. This exercise requires a seasoned clinician with over 10 years of experience who has developed the pattern recognition and intuitive expertise to differentiate between those abnormalities that have the potential to lead to a definitive diagnosis and those that represent false clues that have the potential to waste both time and money.
Classes of Diagnostic Tests
SKIN TESTS
An intermediate-strength PPD should be performed in all patients with FUO who do not have a previously documented positive tuberculin test. Alternatively, a interferon γ release assay can be performed to assess latent tuberculosis. This assay has proved equivalent in both sensitivity and specificity to the PPD skin test (see Chapter 4). The use of skin tests to detect histoplasmosis and coccidiomycosis is not generally recommended.
CULTURES
Blood cultures should be a part of the initial workup of all patients with significant prolonged fever. Yield for SBE is usually maximized by drawing blood for three cultures (see Chapter 7). In general, no more than six blood cultures should be drawn during the entire course of the illness. However, they may be repeated periodically or if a significant change occurs in the fever pattern. Because of the possibility of fastidious slow-growing bacteria, all blood cultures should be held for 3 weeks.
Multiple urine samples should be obtained and cultured for tuberculosis in addition to more conventional bacteria. In patients with respiratory complaints or CXR abnormalities, sputum should be cultured, and in patients undergoing bone marrow biopsy, culture is an important component of the marrow analysis. All biopsy specimens need to be cultured. Aerobic, anaerobic, mycobacterial, and fungal cultures should be ordered on virtually all samples. Viral cultures or quantitative polymerase chain reaction may also be considered in specific cases in which cytomegalovirus or Epstein–Barr virus is suspected.
SMEARS
Peripheral blood smears with Giemsa and Wright stains are critical for making the diagnosis of malaria, trypanosomiasis, or relapsing fever. In addition to a peripheral WBC count, Wright stain with differential cell count is often helpful in determining the nature of the inflammatory response associated with fever, and it should be performed in all patients with FUO. Stool smears for ova and parasites are usually less helpful, because gastrointestinal parasites are seldom present as FUO.
OTHER PERIPHERAL BLOOD TESTS
Antibody titers can be considered when specific pathogens are part of the differential diagnosis. To prove active infection, rising antibody titers are required. A single titer simply demonstrates a history of exposure; a rising titer indicates recent infection. Therefore, two samples, separated by 3-4 weeks, need to be drawn. Antibody titers may be useful in cytomegalovirus, Epstein–Barr virus, Toxoplasma, Rickettsia, Chlamydia, and Brucella infections. In most cases of FUO, serologies have proved not to be helpful, and the ordering of large batteries of serologic titers should be discouraged. If liver functions are abnormal, hepatitis serology should also be ordered (see Chapter 8). An HIV antibody test should be performed in all patients with FUO, as part of preliminary testing.
Tests that should be considered to diagnose connective tissue disease in most cases of FUO are antibody titers to human tissue, including antinuclear antibodies, anti-DNA antibodies, rheumatoid factor, and immune complexes. An ESR and/or CRP assay should be performed in all cases of FUO. A very high ESR is seen in the polymyalgia rheumatica–temporal arteritis combination and in Still’s disease. A normal ESR virtually excludes these diagnoses, as well as SBE.
IMAGING STUDIES
Tests That Should Be Ordered in All Patients With FUO—As part of the preliminary workup, a chest CT scan should be ordered. Results to look for are mediastinal enlargement (suggestive of lymphoma), micronodular interstitial changes (“millet seed” pattern, suggestive of miliary tuberculosis), or nodular lesions or infiltrates (can be seen in many infectious diseases, connective tissue diseases, and neoplasms). Abdominal CT scan should also be performed to identify abdominal abscesses, mesenteric nodes, and tumors. Imaging of the chest and abdomen by CT have an approximately 10% yield in patients with FUO who lack specific localizing symptoms.
Tests That Should Be Ordered Depending on the Patient’s Symptoms and Signs—In patients who are suspected of having a chronic infection, radionuclide scans may be helpful in localizing the site. Gallium scan may be useful in patients with chronic infection because this agent accumulates in areas of inflammation; however, indium WBC scan tends to be more specific. The indium WBC scan also has a higher positive yield than abdominal CT scan does for identifying occult intra-abdominal infection.
Another tracer molecule that accumulates in areas of inflammation and in malignant tumors is 18F fluorodeoxyglucose. Unlike other scans, which require that the patient be scanned during a period of 24-36 hours, positron emission tomography with 18F fluorodeoxyglucose is completed within a few hours. This test has proved more sensitive and specific than gallium scan. A recent meta-analysis of nine studies suggests that this is a cost-effective test that should be ordered early in the course of FUO.
Air sinus films or sinus CT scan can be performed to exclude occult sinus infection and tooth abscess. In patients with a heart murmur and persistent fever, cardiac echo should be considered. Transesophageal echo is the test of choice; it has a greater than 90% sensitivity for detecting cardiac vegetations, and it is also helpful in detecting myocardial abscess and atrial myxoma.
Ultrasound of the lower abdomen may be helpful in cases in which pelvic lesions are suspected. Abdominal CT is not as sensitive in that region because of reflection artifacts generated by the pelvic bones. When other tests are unrevealing, upper gastrointestinal barium study with small bowel follow-through should be ordered to exclude regional enteritis. Barium enema should be considered in older patients; however, yield from this procedure is likely to be low in FUO. Radiographs of all joints should be ordered in any patient with persistent joint complaints to document anatomic defects.
Invasive Procedures—Laparoscopic guided biopsy improves the yield by allowing biopsies to be taken in areas where abnormalities in the external capsule are seen; however, this surgical procedure is rarely used.
Bone marrow biopsy is also recommended as a routine invasive test if all noninvasive studies are negative and has a yield of nearly 25%. A higher yield was found in patients with thrombocytopenia and/or anemia. Hematologic malignancies are most commonly identified, particularly malignant lymphoma and less commonly acute leukemia. Infectious diseases can also be identified, and the bone marrow should be cultured (see the earlier subsection titled “Cultures”), because disseminated tuberculosis, histoplasmosis, coccidiomycosis, and other fungal and mycobacterial infections often seed the bone marrow.
Use of other invasive procedures will depend on the diagnostic findings, history, and physical findings to that point. In elderly patients with a high ESR and persistent fever, temporal artery biopsy is generally recommended. It should be kept in mind that, because skip lesions are common in temporal arteritis, a long sample of the temporal artery should be obtained and multiple arterial sections examined.
In addition to a complete series of cultures, all biopsy specimens should undergo Brown–Brenn, Ziehl–Neelsen, methenamine silver, periodic acid Schiff, and Dieterle silver staining in addition to routine hematoxylin and eosin. Frozen sections should be obtained for immunofluorescence staining, and the remaining tissue block should be saved for additional future studies.
It should be emphasized that, when symptoms, signs, or a specific diagnostic abnormality is found, all other scheduled diagnostic tests should be delayed and Sutton’s law applied. For example, if an abnormal fluid collection is found on abdominal CT, then all other diagnostic procedures can be halted while a needle aspiration of the potential abscess is being performed. If the result proves to be positive, additional investigations are unnecessary. The “money” has been found.
Ordering tests for completeness’ sake is unnecessary. Clinicians need to apply Baye’s theorem and predict the pretest and posttest probability of the particular disease. When ordering a test, the clinician needs to ask, “If this test is positive or negative how will it change how I manage my patient?” If the answer is “It won’t,” then the test should not be ordered. When in doubt about performing additional tests, the wisest course of action is to wait. Over time, the patient’s fever may spontaneously resolve or new manifestations may develop, helping to identify the cause.
TREATMENT OF FUO
In the past, many clinicians discouraged the use of antipyretics in FUO, because these agents mask the pattern of fever. However, as noted earlier in this chapter, with rare exceptions, the pattern of fever has not proved to be helpful in determining the cause of FUO.
Fever is commonly associated with chills, sweating, fatigue, and loss of appetite. Therefore, once true fever has been documented, antipyretics can be administered in most cases of FUO to relieve some of the patient’s symptoms while the diagnostic workup is pursued. To avoid repeated shifting of the thermal set point and recurrent shivering and chills, ASA, NSAIDs, or acetaminophen must be administered at the proper time intervals to maintain therapeutic levels. Otherwise, these antipyretics will exacerbate rather than reduce the symptoms of fever.
As was discussed in Chapter 1, physicians often over-prescribe antibiotics. In cases of FUO, the temptation to institute an empiric trial of antibiotics is great. This temptation should be avoided. Antibiotics are contraindicated until a specific diagnosis is made. Use of an empiric antibiotic trial often delays diagnosis and is rarely curative. Because infections susceptible to conventional antibiotics represent a small percentage of the diseases that cause FUO, antibiotic treatment will have no effect in most cases. In cases of occult bacterial infection, empiric antibiotics may mask the manifestations of the infection and delay appropriate treatment. Most infections that cause FUO require prolonged antibiotic treatment and surgical drainage. In the absence of a specific diagnosis, clinicians have difficulty justifying a prolonged course of antibiotics, and therefore antibiotics are often discontinued after 1-2 weeks, allowing the infection to relapse.
When a connective tissue disorder appears to be the most likely explanation for FUO, empiric use of systemic glucocorticoids is often considered. These agents are very effective in treating temporal arteritis and polymyalgia rheumatica, they may be helpful in Still’s disease, and they are used to treat specific complications in lupus erythematosus. However, because these agents markedly reduce inflammation and impair host defense, administration of glucocorticoids can markedly exacerbate bacterial, mycobacterial, fungal, and parasitic infections. Therefore, before considering an empiric trial of glucocorticoids such as prednisone, dexamethasone, or methylprednisone, infection must be convincingly ruled out. The physician must also keep in mind the many potential side effects of prolonged glucocorticoid use (Cushingoid face, osteoporosis, aseptic necrosis of the hip, diabetes mellitus, and opportunistic infections) before committing the patient with FUO to a prolonged course of systemic steroid treatment.
KEY POINTS
About the Treatment of Fever of Unknown Origin
1. Once the pattern of fever has been documented, NSAIDs, acetylsalicyclic acid, or acetaminophen can be used to lower fever.
2. Empiric antibiotics are contraindicated.
3. Glucocorticoids should be used only when infection has been excluded.
PROGNOSIS
Delay in diagnosis worsens the outcome in cases of intra-abdominal abscess, miliary tuberculosis, disseminated fungal infections, and pulmonary emboli. However, if these diseases are carefully excluded, lack of a diagnosis after an extensive workup is associated with a 5-year mortality of only 3%. The prognosis is somewhat worse in elderly patients because of their increased risk of malignancy. Therefore, once the clinician has completed the FUO diagnostic battery described in this chapter and serious life-threatening diseases have been excluded, additional diagnostic study is not warranted. If fever persists for an additional 4-6 months, a complete series of diagnostic studies may then be repeated.
FUO IN THE HIV-INFECTED PATIENT
Primary HIV infection can present with prolonged fever, and in patients with the appropriate risk profile (see Chapter 16), a diagnosis of HIV needs to be considered. Serum markers are negative in the early stages of HIV infection; quantitative polymerase chain reaction for HIV is therefore the diagnostic test of choice.
In the later stages of HIV infection, fever is a common manifestation of opportunistic infection. In order of frequency, the most common causes of FUO in patients with AIDS are mycobacterial infections (Mycobacterium tuberculosis, Mycobacterium avium intracellulare, other atypical mycobacteria), other bacterial infections, cytomegalovirus, Pneumocystis, toxoplasmosis, and Cryptococcus, and histoplasmosis. In HIV patients coming from endemic areas, visceral leishmaniasis also needs to be considered. Noninfectious causes include non-Hodgkin lymphoma and drug fever. Additional tests warranted in the HIV patient include mycobacterial blood culture, cryptococcal serum antigen, and cytomegalovirus quantitative polymerase chain reaction. Disseminated histoplasmosis may be difficult to detect and, in our experience, is most readily diagnosed by bone marrow culture.
KEY POINTS
About Fever of Unknown Origin in HIV-Infected Patients
1. Can be a manifestation of primary HIV infection.
2. Often the first symptom of an opportunistic infection.
3. Mycobacteria are the most common infectious cause.
4. Cytomegalovirus is also common, as are Cryptococcus and Toxoplasma.
5. Non-Hodgkin lymphoma is the most common noninfectious cause.
FURTHER READING
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Bujak JS, Aptekar RG, Decker JL, Wolff SM. Juvenile rheumatoid arthritis presenting in the adult as fever of unknown origin. Medicine (Baltimore). 1973;52:431-444.
Dong MJ, Zhao K, Liu ZF, Wang GL, Yang SY, Zhou GJ. A meta-analysis of the value of fluorodeoxyglucose-PET/PET-CT in the evaluation of fever of unknown origin. Eur J Radiol. 2011; 80(3):834-844
Ghose MK, Shensa S, Lerner PI. Arteritis of the aged (giant cell arteritis) and fever of unexplained origin. Am J Med. 1976;60:429-436.
Hot A, Jaisson I, Girard C, et al. Yield of bone marrow examination in diagnosing the source of fever of unknown origin. Arch Intern Med. 2009;169(21):2018-2023.
Larson EB, Featherstone HJ, Petersdorf RG. Fever of undetermined origin: diagnosis and follow-up of 105 cases, 1970-1980. Medicine (Baltimore). 1982;61:269-292.
Marik PE. Fever in the ICU. Chest. 2000;117:855-869.
Mayo J, Collazos J, Martinez E. Fever of unknown origin in the setting of HIV infection: guidelines for a rational approach. AIDS Patient Care STDS. 1998;12:373-378.
Mueller PS, Terrell CL, Gertz MA. Fever of unknown origin caused by multiple myeloma: a report of 9 cases. Arch Intern Med. 2002;162:1305-1309.
Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore). 1961;40:1-30.
Vanderschueren S, Knockaert D, Adriaenssens T, et al. From prolonged febrile illness to fever of unknown origin: the challenge continues. Arch Intern Med. 2003;163:1033-1041.