Fever of unknown origin

Introduction

In 1868 Carl Reinhold, a German physician and Wunderlich demonstrated the value of measuring body temperature between various diseases¹. Later, Sir William Osler published the first edition of Principles and Practices of Medicine in 1892 that included temperature curves for disorders common to that time, such as malaria, recurrent fever, scarlet fever and typhoid fever². The focus on fevers grew later, especially after the report by Alt and Barker from Peter Bent Brigham Hospital in Boston, in whom the cause of prolonged fevers lasted > 10 days³. RG Petersdorf and PB Beeson¹ collected data on 100 consecutive cases to develop the first set of diagnostic criteria for fever of unknown origin^1,2,4.

This study differed from previous reports^3,5–8 because it was prospective, including a complete patient follow-up, excluding patients with clear fever explanation. RG Petersdorf and E Larson⁹ conducted a second study analyzing 105 patients, emphasizing the examination of the patient and the search for diagnostic clues. In response to the evolution of medical trends and the advent of acquired immunodeficiency syndrome, DT Durack and AC Street² proposed modifications in 1991 that subdivided fever of unknown origin into four different categories: classic, nosocomial, neutropenic and related to the human immunodeficiency virus³.

In 1997, EM De Kleijn et al.⁴ suggested a modification of this definition with the addition of standardized research, which, if it was not unsuccessful, meant that the 1991 categorization scheme could be used. In 2007, the same study group proposed a structured diagnostic protocol to facilitate clinical care and research¹⁰. Clinical research, including diagnostic advances, in recent decades, is now enough to define a new standard classification system. Updating research on this heterogeneous disorder can allow an easier comparison of studies and be more consistent with contemporary medical practices.

Unknown origin fever classification and temperature criterion of the patient. Among the most convincing reasons for reviewing this syndrome is based on the fundamental description of what a fever comprises^1,2,4,11. Petersdorf used a temperature threshold of 38.3°C (100.9°F) in an attempt to eliminate the usual hyperthermia entity^1,9. Although this is still poorly defined or understood, it usually refers to a persistently high baseline body temperature or the exaggeration of the variation in daytime temperature in the second half of the female menstrual cycle, up to 38.0°C (100.4°F) in the absence of high inflammatory parameters^12–16. While RG Petersdorf and E Larson⁹ excluded these patients from their cohort, others incorporated it as a diagnosis, representing between 2.5 and 5.5% of patients^13–16, four having 38.0°C as a threshold for fever of unknown origin is considered the highest standard level of normality for rectal or tympanic body temperature measurements¹⁷. In a series of cases, we found 127 cases of fever of dark origin that met the criteria of 38.3°C and more¹⁸. A recent study by M Protsiv et al.¹¹ that analyzed 677,423 human body temperature measurements from three different cohort populations spanning 157 years provides additional support to lower the temperature threshold to improve sensitivity. These researchers reported that average body temperatures in American men and women, after adjusting for age, height and weight, have decreased by 0.03°C per decade of birth since the 1890s. Analyzing the veterans of the Civil War Union Army 1862-1930, the National Health and Nutrition Examination Survey I surveyed 1971-1975, and the cohort of the Stanford Integrated Translational Research Database 2007-2017, the researchers reported that these studies showed an average normal body temperature of 97.9°F (36.6°C)¹¹.

The researchers postulated that chronic undiagnosed infections of the previous era, such as tuberculosis, syphilis, and other causes of chronic inflammation and possible physiological changes in the modern population, which are generally higher and heavier than in previous times, could contribute to these findings⁵. Duration criterion: almost all fevers in the initial evaluation are of unknown origin until they are associated with a diagnosis. RG Petersdorf and PB Beeson and RG Petersdorf and E Larson^1,9 developed the categorization to refer to a particular subset of prolonged fevers that challenged diagnosis after a reasonable analysis during 1 week of hospitalization.

The definition of duration of 3 weeks proposed by Petersdorf and PB Beeson and RG Petersdorf and E Larson^1,9 allowed the resolution of many self-limiting infectious diseases (for example, viral infections). However, prolonged fevers may still not have an apparent source after a contemporary study carried out well before 3 weeks^2,4,10,16,19. Although some authors have proposed shortening the definition of duration to 2 weeks^20,21, the consensus is that the duration of 3 weeks should remain a key component of the definition. On the other hand, commonly used tests, such as blood cultures and computed tomography (CT) images, can now more quickly facilitate frequent diagnoses such as bacteremia, endocarditis or abdominal abscesses. With the exception of abdominal CT and early emission tomography of 18fluoro-desoxi-glucose-positrons (2-deoxy-2-[fluorine-18]fluoro-D-glucose-positron emission tomography/CT)¹⁰, routine laboratory diagnostic tests or basic imaging tests used in the absence of possible diagnostic clues have low performance in finding a final explanation^4,16. Despite advances in many medical fields in the last 50 years, studies of fever of unknown origin consist mainly of a series of uncontrolled cases and without prospective comparative trials. There are few resources for the substantial research necessary to address a challenging and heterogeneous condition²². An additional reason to facilitate more research is that many patients remain undiagnosed. Recent series have reported between 8.5 and 51.0%²². Finally, as for the treatment of fever, regardless of its known origin or not; it is certainly symptomatic because of the discomfort it causes, and thus, the physical means are still those that are initially recommended with baths with warm water (never use ice), with which the body loses heat by evaporation and can lower body temperature to 1ºC. Of course, some antipyretic can be used after physical means if the fever is persistently high. Not using ice is that a medium is counterproductive since it causes contraction of the skin vessels, and then heat is not lost, but on the contrary, it raises body temperature further²³.

Conclusion

The ever of unknown origin at present is a challenge for physicians, surgeons, and healthy staff. The fever duration for at least 3 weeks has been termed a fever of unknown origin if unexplained after preliminary investigations.

The fever has been 38.3°C or higher. The new technologies in medicine and the advances in diagnosis and management, and diagnostic testing over the last decades have prompted a needed update to the definition and approaches.

Funding

The authors declare that they have not received funding for this study.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical disclosures

Protection of humans and animals. The authors declare that no experiments on humans or animals have been performed for this research.

Confidentiality of data. The authors declare that no patient data appear in this article.

Right to privacy and informed consent. The authors declare that no patient data appear in this article.

Use of artificial intelligence to generate texts. The authors declare that they have not used any type of generative artificial intelligence in the writing of this manuscript or for the creation of figures, graphs, tables, or their corresponding captions or legends.