Infect Dis Clin N Am 21 (2007) 937945

Fever of Unknown Origin in Older Persons

Dean C. Norman, MDa,b,*, Megan Bernadette Wong, BSb, Thomas T. Yoshikawa, MDa,b
University of California, Los Angeles David Geen School of Medicine, Los Angeles, CA, USA b VA Greater Los Angeles Healthcare System (11), 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
a

Infectious diseases in general in the aged are associated with higher morbidity and mortality rates. Decremental biologic changes with age aect host defenses and responses to infection, and the frequent presence of comorbidities also may adversely impact host defenses, especially in frail older persons [1]. Furthermore, the geriatric patient is more likely to be on multiple medications that in turn may diminish host defenses (eg, sedative hypnotics increase the risk of aspiration). Unfortunately, infections may present dierently in older persons than in younger populations, making early diagnosis dicult. Delays in diagnosis and the initiation of appropriate therapy for this already-compromised population contribute to the observed higher morbidity and mortality rates. Fever is the cardinal sign of infection, but this most important diagnostic clue may be blunted or absent in up to one third of infected geriatric patients. Conversely, the presence of fever has special signicance for the older population. A large study of febrile adults presenting to walk-in clinics or emergency departments determined that the presence of fever in the elderly was much more likely to be associated with a serious bacterial or viral infection compared with younger febrile patients [2]. Similarly, the presence of a leukocytosis and/or bandemia in a geriatric patient is also

* Corresponding author. US Department of Veteran Affairs, West Los Angeles Health Care Center, 11301 Wilshire Boulevard, Los Angeles, CA 90073. E-mail address: dean.norman@va.gov (D.C. Norman). 0891-5520/07/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.idc.2007.09.003

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more likely to be associated with a serious infection, whether or not a fever is present [3,4]. Fever of unknown origin (FUO) in the old diers signicantly from FUO in younger adults because the etiology is dierent. Moreover, it is important to aggressively determine the etiology of FUO in this older population because it is often treatable. Unfortunately, few FUO studies in adults distinctly separate data on patients 65 years and older. However, an extensive literature review of studies of adults with FUO estimated the overall prevalence of FUO in hospitalized patients to be 2.9% [5], and a prospective study of 167 hospitalized patients with FUO determined 28% of cases occurred in patients 65 years and older [6]. A more recent retrospective study of 165 adults hospitalized in a non-university hospital with FUO determined that 42.3% of the cases were 65 and older [7]. The traditional denition of FUO as a fever higher than 38.3 C (101 F) on several occasions over a period of at least 3 weeks and whose etiology remains undetermined after 1 week of intensive study in the hospital has been modied because of broad changes in medical practice. The move from inpatient to ambulatory care and the ready availability of a wide range of diagnostic tests and procedures available in the ambulatory-care setting allow for the eective and ecient evaluation of FUO as an outpatient. Newer denitions have removed the requirement for hospitalization and added obligatory diagnostic investigations after standardized history and physical examination fail to reveal the etiology a fever before it is identied as an FUO [8]. Even so, the traditional and newer denitions requiring a minimal temperature of 38.3 C may not be applicable to older patients. This is due to the blunted or absent febrile response to infection observed in this age group [911]. Numerous studies conrm that approximately 20% to 30% of infected geriatric patients will not mount a robust fever response to infection [913]. Examples include studies of bacteremia [14,15], endocarditis [1618], pneumonia [1923], tuberculosis [24], and meningitis [25], all of which demonstrate that infected older persons may present with diminished or no fever compared with younger adults. Of note, a more recent study of community-acquired bacterial meningitis did not conrm a dierence in fever response between old and young adults. However, 16% of meningitis cases occurring in 267 adults over 60 years old did not present with a temperature greater than 38 C [26]. On the basis of the above studies and additional studies done by Castle and colleagues [27,28] that looked at baseline temperatures and changes in temperatures with infection in a nursing home population, the denition of fever in older persons should be changed. As baseline temperatures were found to be lower in the frail nursing home patients studied, the present authors recommend the new denition to be a persistent oral or tympanic membrane temperature of 99 F (37.2 C) or greater, or persistent rectal temperature of 99.5 F (37.5 C) or greater [9]. A fever would also be considered to be present if there is a change of temperature over baseline

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of 2.4 F or more (1.3 C). The clinician caring for frail elderly patients should be aware that any acute change in functional status may herald the onset of an infectious disease and, if associated with a change in temperature, increases the likelihood that an infection is present [10]. FUO in older persons diers from FUO in younger individuals both in etiology and because a diagnosis can be made in a higher percentage of cases. A precise etiologic diagnosis can be made in substantial majority of cases (over 70%) of older persons with FUO, whereas up to 51% of adults of all ages with FUO remain undiagnosed despite extensive work-up [7,8,2931]. Table 1 summarizes these comparative data, including data from several decades, and supports the aggressive approach to investigating the etiology of FUO in older persons as many of the causative diseases are treatable. In many cases, FUO in older persons may represent atypical, nonclassic presentations of common infectious and noninfectious diseases [3234]. Similar to the frequency observed in young patients, infection is a common etiology of FUO in older persons and occurs in 15% to 35% of cases. There are dierences in etiology of these infections between young and old, and tuberculosis is much more likely to be a cause of FUO in older persons than in the young. Tuberculosis, endocarditis, intraabdominal sepsis, and HIV infection in older patients may present particular diagnostic challenges. As mentioned above, tuberculosis is a more common disease in the older patient with FUO than it is in younger patients with FUO, and it was

Table 1 Etiology of fever of unknown origin in older versus younger patients Olda n (%) Total patients Infections Viral Tuberculosis Abscess Endocarditis Other Noninfectious inammatory diseases Neoplasms Miscellaneous No diagnosis
a b

Younga n (%) 152 33 (21) 8 (5) 4 (3) 6 (4) 2 (1) 13 (9) 27(17)c 8 (5) 39 (26) 45 (29)

Old n (%) 61 9 (15) d d d d d 22 (36) 9 (15) 3 (5) 18 (30)

Young n (%) 83 24 (29) d d d d d 16 (19) 5 (6) 19 (23) 19 (23)

All agesb n (%) 220 54 (25) 7 (3) 4 (2) 6 (3) 5 (2) 32 (15) 52 (24) 31 (14) 17 (8) 66 (30)

204 72 (35) 1 (.05) 20 (10) 25 (12) 14 (7) 12 (6) 57 (28)c 38 (19) 17 (8) 18 (9)

Includes subjects from the 1970s to the 1980s. Includes cases from the late 1980s to the early 1990s. c In descending order of frequency: temporal arteritis, polymyalgia rheumatica, Wegeners granulomatosis, polyarteritis nodosa, rheumatoid arthritis, and sarcoidosis. Data from de Kleijn E, van der Meer J. Fever of unknown origin (FUO): report on 53 patients in a Dutch university hospital. Neth J Med 1995;47:5460.

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responsible for 50% of infections in the older age group in a recent review of FUO comparing old and young FUO patients [35]. A more recent prospective study of 94 FUO patients reported from Taiwan found that tuberculosis was the cause of FUO in 23% of cases overall and was more likely to be present in older FUO patients [36]. In another prospective comparison study of tuberculosis, elderly patients were signicantly less likely to have fever, hemoptysis, cough, and a positive response to 5TU puried protein derivative skin test, but were more likely to have disseminated disease [24]. Finally, in a large prevalence study of tuberculosis in nursing homes in Hong Kong, only 3 of 15 active tuberculosis cases had any classical symptoms, conrming again that atypical presentations of infectious diseases are especially likely to occur in frail older persons [37]. Infective endocarditis in the old, as compared with younger patients, is characterized by less severe clinical symptoms (eg, blunted or absent fever) and may present with vague, nonspecic constitutional symptoms such as lethargy, malaise, anorexia, and weight loss. Early use of transesophageal echocardiography facilitates timely diagnosis and may reduce diagnostic delays [17,18]. Obviously, any heart murmur in an older FUO patient should lead to the consideration that endocarditis is present; diagnostic echocardiography should be performed. Similar to endocarditis, intra-abdominal infections may present in a nonspecic manner. Even mild symptoms and ndings (minimal tenderness and distention) may indicate an intra-abdominal infection, and early imaging (ultrasound, abdominal computed tomography) should be considered in these cases [38,39]. HIV infection may occur in older persons, and it is estimated that over 10% of new cases of HIV infection occur in adults over age 50. HIV should eventually be considered if no other etiology of FUO is found, but should be considered earlier if the history of sexual activity becomes a potential diagnostic clue [40]. Noninfectious inammatory diseases such as temporal arteritis, rheumatoid arthritis, and polymyalgia rheumatica are common causes of FUO in the old, but are seen less frequently in younger adults with FUO (see Table 1). Noninfectious inammatory diseases are at least second to infection as a cause of FUO in several FUO studies and are responsible for 25% to 36% of FUO cases in older persons (see Table 1, [35]). Conversely, FUO will occur in approximately 10% of temporal arteritis cases. A new localized headache, temporal artery abnormality (decreased pulse, tenderness or nodules), asthenia, anorexia, or weight loss is a typical clinical feature of this disease [41]. An elevated erythrocyte sedimentation rate, especially if at or above 50 mm per hour Westergren or a high C-reactive protein, provide additional diagnostic clues that should lead to prompt conrmatory temporal artery biopsy. Polymyalgia rheumatica, typically characterized by pain involving neck and shoulder girdle, is also associated with a high erythrocyte sedimentation rate and commonly coexists with temporal arteritis [41]. Finally, malignancies, usually hematological in origin, account for a signicant percentage of cases of FUO in older persons (see Table 1, [29,31]).

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Although unintentional weight loss in an older patient might suggest the presence of a neoplasm, unintentional weight loss commonly occurs with a variety of aictions aecting older patients, including depression, dementia, chronic disease, or as an adverse drug reaction.

Diagnostic approach to the older patient with fever of unknown origin A complete history and physical examination are still an important part of the assessment of any older patient. Potential diagnostic clues to the etiology of an FUO should be elucidated to narrow the potential diagnoses and focus on further laboratory and imaging work-up. Any recent clinical changes should be explored even if the patient considers these symptoms to be part of getting old (eg, new onset or change in chest pain in an immobile patient should lead to the consideration of pulmonary embolism as a cause of FUO). Historical data should be obtained from a variety of sources, even if the patient appears to be cognitively intact. Family members, caregivers, and others where appropriate should be interviewed and all medical records reviewed. Records from allied health professionals should also be read because key information on functional status, nutrition, and skin integrity may be revealed. Nonspecic ndings such as weight loss, depression, or failure-to-thrive symptoms could indicate hyperthyroidismdan entity that has a very dierent presentation in the older patient compared with the younger adult and may also be a cause of FUO. The list of drugs capable of causing FUO is extensive, and it should be assumed that any drug or drug combination is capable of causing fever in older persons. Therefore, a detailed medication history that includes alcohol and illicit drug use, dietary supplements, and over-the-counter medications should be obtained. Noncompliance with medications is common in older persons, and reconciliation between what a patient is prescribed and what he or she is actually taking, including determining the actual dosage and frequency of administration, is necessary. The patient should be queried about pet and occupational exposure and given the easy availability of drugs for treatment of erectile dysfunction; a sexual activities history is mandatory. Late infections of implanted devices may occur in older persons, and inquiries should also be made about the presence of any implants such as articial heart valves, joint replacements, and vascular grafts. The physical examination should include a neurological examination and an assessment of cognitive function with the Mini-Mental State Examination or an equivalent test. As mentioned above, temporal arteritis is a possible cause of FUO in the older patient, and the temporal arteries should be carefully inspected and palpated for thickening, tenderness, and nodules. Occult dental or periodontal infection may be also be a cause of FUO, and the condition of the dentition should be determined, including the gentle tapping over of teeth to elicit pain. As noted above, intra-abdominal

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infection may present in a subtle, nonspecic fashion [38,39], and thus the entire abdomen should be carefully palpated. Digital rectal examination should be part of the physical examination to examine the prostate for bogginess, tenderness, or nodules that could indicate inammatory disease of the prostate as a potential etiology of FUO. Patients with limited mobility are susceptible to skin breakdown and should undergo a skin examination. The clinician caring for an older immobile FUO patient should do his or her own examination. The sacrum and heels should be examined carefully and, as small sacral ulcers may be missed in obese patients, obese patients should be turned over and the skin examined. The extremities should be observed for the presence of phlebitis, especially in hospitalized patients with intravenous catheters, and the lower extremities should be examined for the presence of deep venous thrombosis. Palpation of the muscles of the shoulder girdle for tenderness and or observation of pain on motion may indicate polymyalgia rheumatica. The physical examination should be repeated at intervals to ascertain whether new physical ndings develop over time (eg, a new heart murmur) [42].

Laboratory and imaging studies Patients with FUO by denition have already undergone a basic diagnostic assessment that minimally would include standard laboratory testing and imaging, as used as erythrocyte sedimentation rate, C-reactive protein, repeated blood cultures, and a chest radiograph. Additional testing would depend on clues derived from the history and physical examination. Before additional costly evaluation is undertaken, consideration should be given to rst eliminating nonessential drugs and, if necessary, even essential drugs should be discontinued one by one as deemed clinically appropriate. Usually the fever, if the drug is the cause, resolves within a few days of discontinuance [43]. If no diagnostic clues are elucidated, further testing would next include an abdominal ultrasound and, if negative, computed CT of the abdomen and chest. An ultrasound should be also performed directed at any prosthetic devices or implant that the FUO patient might have. Many older persons have systolic heart murmurs secondary to aortic valve sclerosis, and thus transthoracic followed by transesophageal echocardiography should be strongly considered in older FUO patients with any murmur, even if no other diagnostic clues point toward the possibility of endocarditis. Finally, one study determined that when potential diagnostic clues are found, nuclear medicine scans may be helpful in localizing inammation [44]. A recent FUO study found that a potential cause for the FUO could be found in 12 of 19 patients (67%) with nuclear scanning. Indium-111labeledgranulocyte scintigraphy was superior to uorine-18-uorodeoxyglucose (FDG) positron emission tomography (PET) because FDG-PET was

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associated with a much higher false-positive rate [45]. Another study demonstrated FDG-PET to be clinically helpful in 37% of FUO cases where no diagnostic clues were apparent [46]. Performing FDG-PET before abdominal and chest CT has been suggested by the authors of a recent prospective study on FUO [8]. Finally, in occasional cases when diagnostic clues include abnormal liver function tests or indicate blood cell abnormalities, liver and bone marrow biopsy, respectively, should be considered if other, less invasive tests are inconclusive.

Therapy of fever of unknown origin A trial of antibiotics should be discouraged in older FUO patients except where there is rapid clinical deterioration. An empiric trial of corticosteroids may be initiated even before obtaining a temporal artery biopsy when temporal arteritis is a strong consideration. Corticosteroids may be held in stable patients pending biopsy results. A prospective study of 61 FUO patients discharged from the hospital without an etiologic diagnosis and followed for a mean of 5.8 years found that fevers resolved in most patients. The age range of these study participants was between 16 years and 75 years, and a diagnosis was eventually made in 12 patients during the follow-up period; all were successfully treated. Although 10% of the cases died during the follow-up period, it was determined that only in two cases (3%) was death thought to have resulted from the disease causing the FUO [47]. A later retrospective study found that in 78% of 37 patients with FUO and no diagnosis, fever resolved after several months (only ve of these cases received a trial of antibiotics) [7]. A more recent prospective study found 41% of 51 patients with FUO and no diagnosis either spontaneously recovered or their fevers resolved with nonsteroidal anti-inammatory agents. Only one death occurred in the 12-month median follow-up period [8].

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