Fever of Unknown Origin (FUO): Practice Essentials, Background, Etiology (original) (raw)

Overview

Practice Essentials

Key features of fever of unknown origin (FUO), also known as pyrexia of unknown origin (PUO), are as follows:

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Background

The syndrome of fever of unknown origin (FUO) was defined in 1961 by Petersdorf and Beeson as the following: (1) a temperature greater than 38.3°C (101°F) on several occasions, (2) more than 3 weeks' duration of illness, and (3) failure to reach a diagnosis despite 1 week of inpatient investigation. [3, 4] It is important to allow for flexibility in this definition, however. "Normal" core temperature in studies in developed nations has declined since the Industrial Revolution and may be inferred to peak at 99.9º F (37.7º C). [5, 6] The emergence of the human immunodeficiency virus (HIV) and the expanding use of immunomodulating therapies prompted Durack and Street to propose differentiating FUO into 4 categories: classical FUO (Petersdorf definition), hospital-acquired FUO, immunocompromised or neutropenic FUO, and HIV-related FUO. [7]

Emerging techniques such as molecular diagnostics, expanding use of immunocompromising therapies and organ transplantation, and the advent of globally mobile populations demand an evolving approach to defining and evaluating FUO. [7, 8, 9] Modern imaging techniques (eg, ultrasonography, computed tomography [CT] scanning, magnetic resonance imaging [MRI], positron emission tomography [PET]) enable early detection of abscesses and solid tumors that were once difficult to diagnose.

In a meta-analysis of 8 prospective studies of FUO from 1997 to 2021, neither structured nor nonstructured diagnostic approaches to FUO yielded a significant advantage. However, geographic prevalence and probabilities need to be factored into any protocol and contributes to improved success. [29]

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Etiology

A baseline definition of "fever" is important in determining whether a patient's report of an elevated temperature warrants a fever of unknown origin (FUO) workup. The common assumption that "fever" is a temperature over 100.4 F (38 C) is obsolete. Large reviews of nonsurgical patients indicate that average temperature in uninfected individuals has been on the decline since the 1800s and ranges from 95.8 to an upper limit of 99.9 degrees Fahrenheit in both outpatients and inpatients. This may reflect multiple conditions, such as better sanitation and hygiene leading to reduced chronic diseases such as tuberculosis and gingivitis and increases in indoor and air-conditioned activities. Older individuals tend toward cooler temperatures. Most temperatures are measured orally for both practical and physiologic purposes. A "normal" core (internal) body temperature ranges from 96º F (35.6º C) to 99.9ºF (38ºC) in healthy persons. Core temperature in the afternoon is about 1ºF higher later in the day and may be a bit higher in women. [5, 6]

The temperature of the sublingual fossa correlates most closely, and changes most consistently, with core body temperature, which is fairly constant; the rectum and axilla do not, especially during sepsis. It is important to recognize that the use of infrared non-contact thermometers in adults may be fraught with error due to variations in user technique, known variations in detection range of these instruments, and environmental temperatures. The tympanic membrane correlates with core body temperature and is nearest to the hypothalamic center that regulates temperature, but accuracy is affected by user technique and whether the ear canal is obstructed (eg, by wax); cold weather also cools the tympanic membrane. [10] Both temporal artery and forehead thermometers are likely to underestimate core body temperature and should be verified with sublingual or other method if fever is suspected. In the author's 12-month institutional experience with entrance screening during the COVID-19 pandemic, infrared forehead thermometry results were highly variable and of low yield in detected infected individuals. [11, 12, 13]

For the purposes of this article, the term FUO refers to the classic category, which focuses on the adult population. The definition of FUO in the pediatric age group varies, with a time frame ranging from 1-3 weeks in the literature. In this age group, infections lead the differential diagnoses, followed by collagen vascular diseases; malignancy typically is not heralded by fever alone in children. [14] This article excludes FUO in the setting of impaired immunity such as HIV disease, solid-organ and bone marrow transplantation, and neutropenia. Disease-specific diagnostic algorithms in these conditions are described elsewhere. Regardless of age group, most clinicians define FUO as a persisting conundrum with few or no objective clues.

Realistically, it is difficult to define a set time frame or defined list of examinations to be performed before declaring "FUO." The duration of unsuccessful diagnosis varies widely because the diagnostic approach to fever is highly dependent upon the tools accessible in a given healthcare setting, including socioeconomic, and other disparities in healthcare. Similarly, local geography and epidemiology factor into diagnostics.

How aggressive and prolonged the evaluation must be before declaring failure also is subjective and dependent on the setting. Reflecting this, Fusco et al found only 6 series out of 18 publications from across the globe predefined a minimum diagnostic workup. "In general, complete blood count, routine haematochemical tests, inflammatory indexes, including C-reactive protein and/or Erythrocyte Sedimentation Rate, urine analysis, blood and urine cultures, chest x-ray and abdominal and pelvic ultrasonography, were included." [2]

Thus, declaring a case an FUO realistically depends on the standard-of-care approach to fever in a given geographic area or population.

Causes of FUO may differ geographically based on regional exposures, economic development, and available diagnostic tools. For example, in developing countries, the baseline incidence of infection may be higher, whereas noninfectious inflammatory and malignant conditions are more common in developed countries.

This article addresses FUO as approached from the lens of practitioners in developed countries; however, causes that may present from developing countries should not be missed and may be increasing with travel. Fusco et al observed the correlation of infections causing FUO in lower-medium income countries, versus neoplasias and non-infectious inflammatory diseases in higher-income nations in a systematic review of 18 case series. The majority of papers originated from countries considered high (6 countries) and upper-medium (8 countries) income. Four papers originated from Europe, 8 from Asia, and 6 from the Middle East. The final etiologies across the board were infections (nearly 40%), inflammatory diseases (20%), neoplasia (11%), and other (6.5%). [2]

The list of etiologic possibilities is extensive, and it is helpful to break the differential diagnoses into broader categories, such as infection, noninfectious inflammatory conditions, malignancies, and miscellaneous.

A prospective review of FUO in 290 subjects between 1990 and 1999 found noninfectious inflammatory diseases in 35.2% of cases, infections in 29.7%, miscellaneous causes in 19.8%, and malignancies in 15.1%. Most were diagnosed within 3 visits or 3 hospital days. This differs from prior estimates, in which infections dominated, followed by malignancies, collagen vascular diseases, and numerous miscellaneous conditions. With the increasing use of immunomodulators used to treat an expanding range of conditions, infections may yet regain their lead as the cause of FUO. Interestingly, the rate of unknown causes is higher in this report than in prior estimates, with 33.8% remaining undiagnosed beyond 7 days. The short time frame may overestimate the number of undiagnosed cases. Evaluations in the past may not have proceeded as quickly, and, even now, newer tests may require transport to specialty laboratories, and diagnosis still may take longer than 7 days. [15]

The causes of FUO often are common conditions presenting atypically. Listed below are the most common, less common, and least common in their respective categories, but by no means the only causes.

Noninfectious Inflammatory Causes of FUO (Connective Tissue Diseases, Vasculitides, and Granulomatous Disorders)

The most common noninfectious inflammatory causes of FUO include the following:

Less-common noninfectious inflammatory causes of FUO include the following:

The least common noninfectious inflammatory causes of FUO include the following:

Infectious Causes of FUO

The most common infectious causes of FUO include the following:

Less common infectious causes of FUO include the following:

The least common infectious causes of FUO are listed below.

Organ-based infectious causes of FUO are as follows:

Geographic and travel-related considerations for FUO are listed below.

Tickborne infections, as follows:

Regional infections, as follows:

Malignant and Neoplastic Causes of FUO

Malignant and neoplastic causes of FUO are as follows:

Miscellaneous Causes of FUO

Miscellaneous Causes of FUO are as follows:

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Patient Education

For patient education information, see Fever in Adults and Fever in Children.

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Prognosis

Despite extensive differential diagnoses, patients with fever of unknown origin (FUO) that remains undiagnosed after an intensive and rational diagnostic evaluation generally have a reassuringly benign long-term course.

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Author

Sandra G Gompf, MD, FACP, FIDSA Professor of Infectious Disease and International Medicine, University of South Florida Morsani College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley Veterans Hospital

Sandra G Gompf, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Michele Davis, MD Fellow in Infectious Disease, University of South Florida Morsani College of Medicine; Co-Investigator, Florida Department of Health-Hillsborough County

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Charles V Sanders, MD Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine in New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center

Charles V Sanders, MD is a member of the following medical societies: Alliance for the Prudent Use of Antibiotics, Alpha Omega Alpha, American Association for Physician Leadership, American Association for the Advancement of Science, American Association of University Professors, American Clinical and Climatological Association, American College of Physicians, American Federation for Medical Research, American Geriatrics Society, American Lung Association, American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal Disease Association, Association for Professionals in Infection Control and Epidemiology, Association of American Medical Colleges, Association of American Physicians, Association of Professors of Medicine, Infectious Disease Society for Obstetrics and Gynecology, Infectious Diseases Society of America, Louisiana State Medical Society, Orleans Parish Medical Society, Royal Society of Medicine, Sigma Xi, The Scientific Research Honor Society, Society of General Internal Medicine, Southeastern Clinical Club, Southern Medical Association, Southern Society for Clinical Investigation, Southwestern Association of Clinical Microbiology, The Foundation for AIDS Research

Disclosure: Receives royalties from Baxter International for: Takeda-receives royalties; UpToDate-receives royalties.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Kirk M Chan-Tack, MD Medical Officer, Division of Antiviral Products, Center for Drug Evaluation and Research, Food and Drug Administration

Disclosure: Nothing to disclose.

John Bartlett, MD † Professor Emeritus, Johns Hopkins University School of Medicine

John Bartlett, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Clinical Pharmacology, American College of Physicians, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, American Thoracic Society, American Venereal Disease Association, Association of American Physicians, Infectious Diseases Society of America, Society of Critical Care Medicine

Disclosure: Nothing to disclose.