Fever and the Inflammatory Response

Pathogenesis

The body temperature is regulated by elevation of the thermoregulatory set-point located in the organum vasculosum of the lamina terminalis (OVLT) in the anterior hypothalamus (thermoregulatory center). Of the three mechanisms associated with fever production (induction by pyrogens, defective heat loss [e.g., in ectodermal dysplasia], and heat production greater than heat loss [e.g., in malignant hyperthermia]), induction by pyrogens is the most common and is reviewed in the following paragraphs.

Pyrogen-induced fever is triggered by the direct interaction between endogenous pyrogens, that is, interleukins (IL-1, IL-6), tumor necrosis factor (TNF) and type-I and II interferons (IFNs), or by the direct action of exogenous pyrogens (i.e., microbial pathogens and their products), endogenous pyrogens, and the OVLT. In the systemic circulation, pyrogenic cytokines activate phospholipase A2 that ultimately leads to the production of prostaglandin E ₂ (PGE ₂ ). In the brain, PGE ₂ stimulates the OVLT, raising the hypothalamic temperature set-point, and then recognizes the body temperature to be low and triggers different events to increase the body temperature to a new set-point ( Fig 10.1 ). ^, Pyrogenic substances also lead to activation of peripheral mechanisms that stimulate the sympathetic chain and terminal adrenergic efferent nerves, leading to vasoconstriction (heat conservation) and muscle contraction (heat production) that contribute to the generation of fever. ^, Whereas neural pathways responsible for fever production may account for the rapid onset of fever, maintenance of fever appears to be driven by cytokine release. When cytokine production ceases, the hypothalamic set-point is reset downward, and the process of heat loss through vasodilation and sweating is initiated.

Etiology and Definitions

Self-limited viral (upper respiratory tract infections, gastroenteritis) and bacterial infections (acute otitis media, pharyngitis) are the most common causes of fever in children. Different clues can help identify the cause of fever, such as the child’s exposures and the fever pattern. On the other hand, the response of fever to an antipyretic drug does not help distinguish between viral from bacterial infections. The pattern of fever are defined as (see Chapter 15 ): sustained fever (fever that is persistent and does not vary by more than 0.5°C (33.4°F) daily); remittent fever (persistent fever that varies more than 0.5°C daily); intermittent fever (periods of normal temperature on different days and without a specific pattern); recurrent or relapsing fever (febrile periods separated by afebrile periods that tend to follow a pattern, i.e., malaria); biphasic fever (two distinct periods of fever within the same illness, i.e., enterovirus or dengue fever); and periodic fever (fever with regular periodicity separated by intervals of normothermia, most cases having a noninfectious etiology).

Clinical Aspects

The upper limit for fever, unless there is a component of hyperthermia, is 42°C (107.6°F), although it is unusual for the temperature to exceed 41°C (106°F). Normal body temperature, thus the designation of fever, varies with age and sex (see Chapter 15 — Fig. 15.1 ), physical activity, and time of the day. In infants <8 weeks of age, temperature oscillates during the day and can decrease to 36°C during nocturnal sleep or increase to 37.8°C during active periods. The typical circadian rhythm evident in older children and adults, with peak core temperature in the late afternoon or early evening and lowest temperature in the early morning, develops by 10 weeks of age. The site of temperature measurement is also important.

• Rectal temperature is the most accurate and the recommended method by the American Academy of Pediatrics to assess fever, defined as a rectal temperature of ≥38°C (100.4°F) in children <4 years of age, but is difficult to perform safely in extremely premature neonates and is contraindicated in neutropenic and immunocompromised patients due to safety concerns.

• Oral temperature is on average 0.5°C lower than rectal temperature and can be influenced by environmental factors (ingestion of liquids, open mouth breathing, mucositis); however, oral measurement provides a safe and accurate alternative in children ≥5 years of age and adults.

• Axillary readings generally have low sensitivity but are as reliable as rectal temperatures in newborns. Axillary readings are 0.5°C lower than oral readings and 0.5°C–1°C lower than rectal values in neonates and older children, respectively.

• Other methods are popular because of their convenience. In theory, the tympanic membrane is ideal for measuring core body temperature because the membrane is perfused by a tributary artery supplying the body’s thermoregulatory center. Numerous studies have shown that tympanic membrane thermometers give highly variable readings compared with oral or rectal readings obtained simultaneously. Forehead non-contact infrared thermometers are a practical emerging technique, but more studies are needed to ensure their accuracy compared with traditional methods. ^,

Other common accompanying features of fever in children are decreased activity and appetite as well as fussiness. Tachycardia is expected, with a 10 beats/min increase per 1°C rise in temperature.

Evaluation

The evaluation of the febrile child is discussed in Chapter 14, Chapter 15 . A careful history and physical examination can lead to the diagnosis of the febrile episode in most cases. However, for certain clinical scenarios, such as pneumonia or fever in very young infants, clinical and standard laboratory tools are insufficient to differentiate viral versus bacterial causes of fever. Host RNA immune responses are gaining increased interest for the discrimination of viral versus bacterial infections and to assess clinical disease severity. Further aspects are discussed in the following section (see “Inflammatory Response”).