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Physiologic Temperature Variation

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The first historical reference of fever was observed on a Sumerian pictogram in the sixth century bc with the first robust scientific study to address normal temperature variation performed by Carl Reinhold Wunderlich in the nineteenth century. Over 1 million temperature measurements were obtained on approximately 25,000 subjects establishing a normal value for the healthy human as 37°C.1 It is now clear that “normal” temperature represents a range of values rather than a single value. Furthermore, diurnal variation in temperature exists such that the lowest body temperature occurs in the early morning (approximately 4 am) and the highest in the early evening (approximately 4 pm). Significant elevations of core body temperature can also occur from endogenous or exogenous factors. Among the exogenous factors that can influence this rate, ambient temperature and humidity are most important.

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Fever Syndromes and Definition of Fever of Unknown Origin

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Fever in a child is an everyday occurrence in an office-based pediatric setting and accounts for 19–30% of all physician encounters.2 Prolonged fevers account for only a minority of these visits.

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The term fever of unknown origin (FUO) was first coined in 1961 by Petersdorf and Beeson and directed the evaluation of the adult patient.3 They introduced the concept that FUO be defined as a temperature higher than 38.3°C on several occasions and lasting longer than 3 weeks, with a diagnosis that remains uncertain after 1 week of investigation. The classic spectrum of disease they outlined included “no diagnosis,” infections, inflammatory diseases, and malignancies. Deep vein thrombosis and temporal arthritis in the elderly were important considerations. Conventional bias at that time held that most adult patients presenting with FUO had serious, potentially life-threatening disease. The traditional approach for evaluation of FUO in the adult patient involved a staged evaluation culminating in tissue diagnosis.

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In the first observational survey of children with FUO, Pizzo et al. in 1975 described 100 children with fever greater than 38.5°C for longer than 2 weeks and identified infections as the most commonly established diagnoses.4 Pizzo's experience suggested that an aggressive staged approach to diagnosis was not necessary in most pediatric cases as most patients had reversible or treatable disease, usually an infection. They emphasized that most children recovered and prognosis was usually good. Diagnoses that were age-based were described and infectious diseases predominated. A small percent of those younger than 6 years had malignancy (neuroblastoma or leukemia) or rheumatoid disease (juvenile arthritis). Similarly, children older than age 6 years on occasion had an oncologic or rheumatologic diagnosis (leukemia, lymphoma, systemic lupus erythematosus). An organized approach in such cases was felt to be essential to identify those children with prolonged fever related to treatable infection or noninfectious disease to avoid morbidity and occasional mortality.

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From a practical standpoint, we often use the term “prolonged fever” interchangeably with FUO. This term implies (1) ...

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