Fever, an elevation in core body temperature above the daily range for an individual, is a characteristic feature of most infections but is also found in a number of noninfectious diseases such as autoimmune and autoinflammatory diseases. Definitions of normal body temperature, the pathophysiology of fever, the role of cytokines, and the treatment of fever in adults will be reviewed here. Fever of unknown origin in adults, drug fever, and the treatment of fever in infants and children are discussed separately.
Normal body temperature ranges from approximately 35.3 to 37.7°C (95.5 to 99.9°F), with an average of 36.7°C (98.0°F) when measured orally, as suggested by studies in both outpatients and hospitalized individuals:
●In a study that included 35,488 individuals who underwent 243,506 oral temperature measurements during routine outpatient visits, the mean temperature was 36.6°C (97.9°F), with a 99 percent range 35.3 to 37.7°C (95.5 to 99.9°F) [
1]. The mean age of participants was 52.9 years, 64 percent were female, and 41 were percent non-White.
●In another study that included 42,622 medical inpatients without known infection, malignancy, or immunocompromising condition who underwent 495,866 oral temperature measurements during the first week of hospitalization, the mean temperature was 36.7°C (98.0°F), with a 99 percent range 35.4 to 37.7°C (95.8 to 99.9°F). The mean age of participants was 61 years, 50 percent were female, 25 were percent Black, and mean body mass index was 30 [
2].
In both studies, older age was associated with lower temperatures, as was lower body mass index. Higher temperatures were recorded in females compared with males. Temperatures also vary by underlying conditions. Hypothyroidism has been associated with lower temperatures and cancer with higher temperatures [
1]. Pregnancy and endocrinologic dysfunction also affect body temperature.
個體每日體溫波動 －
正常體溫在一天中會發生變化，由位於下視丘前部的體溫調節中樞控制。通常情況下，清晨至傍晚的體溫日增幅約為0.5°C (0.9°F)。然而，對於一些從發燒疾病中恢復的人來說，這種日增幅可高達1.0°C (1.8°F)。研究表明，早晨口腔溫度高於37.2°C (98.9°F) 或下午體溫高於37.7°C (99.9°F) 可視為發熱。
一項針對148名年齡在18至40歲之間的健康個體進行口腔溫度測量的詳細研究，使用了超過700次測量數據[ 3 ]。此組的口腔溫度範圍為35.6°C (96.0°F)至38.2°C (100.8°F)，平均值為36.8±0.4°C (98.2±0.7°F)。口腔溫度在早上6點較低，在下午4點至6點較高。早上6點的最高正常口腔溫度為37.2°C (98.9°F)，下午4點的最高正常口腔溫度為37.7°C (99.9°F)，這兩個值均處於健康人群口腔溫度的第99百分位。
在月經期女性中，排卵前兩週晨起體溫通常較低，排卵後體溫升高約0.6°C（1.0°F），並維持在該水平直至月經來潮。雖然黃體期（排卵後）女性體溫較高已被充分證實，但其體溫晝夜節律的振幅與男性相同[ 4 ]。
雖然已有關於體溫季節性變化的描述，但這可能反映的是代謝變化，並非普遍現象。餐後體溫會升高，但這並非發燒。幼兒時期，體溫的日變化似乎已趨於穩定。
在發燒疾病期間，每日清晨最低溫度和傍晚最高溫度之間的溫差保持不變，但會向上移動到更高的水平。
人類的晝夜節律以及調節體溫日間波動的基因已被研究。通常情況下，人體能夠維持相對穩定的體溫，因為下丘腦體溫調節中樞能夠平衡肌肉和肝臟代謝活動產生的過剩熱量與皮膚和肺部散發的熱量。然而，當面臨極端環境時，如果沒有衣物和防護環境的幫助，人類就無法維持體溫的狹窄日間波動[ 5 ]。
Individual daily variation — Normal body temperature varies over the course of the day, controlled in the thermoregulatory center located in the anterior hypothalamus. The normal early morning to late afternoon daily increase is typically 0.5°C (0.9°F). However, in some individuals recovering from a febrile illness, this daily variation can be as high as 1.0°C (1.8°F). Studies suggest that a morning oral temperature >37.2°C (98.9°F) or an afternoon temperature of >37.7°C (99.9°F) could be considered a fever.
A detailed study of the range of oral temperature readings in 148 healthy individuals aged 18 to 40 years was reported using over 700 measurements [
3]. Oral temperatures in the cohort ranged from 35.6°C (96.0°F) to 38.2°C (100.8°F) with a mean of 36.8±0.4°C (98.2±0.7°F). Low levels occurred at 6 AM and higher levels at 4 to 6 PM. The maximum normal oral temperature at 6 AM was 37.2°C (98.9°F), and the maximum level at 4 PM was 37.7°C (99.9°F), both values defining the 99th percentile for healthy subjects.
In menstruating women, the morning temperature is generally lower during the two weeks prior to ovulation, rising by approximately 0.6°C (1.0°F) with ovulation and remaining at that level until menses occur. Although it is well established that females in the luteal (postovulatory) phase have higher body temperature, the amplitude of the circadian rhythm for body temperature is the same as in males [
4].
Seasonal variation in body temperature has been described, but this may reflect a metabolic change and is not a common observation. Elevation in body temperature occurs during the postprandial state, but this is not fever. The daily temperature variation appears to be fixed in early childhood.
During a febrile illness, the daily low early morning and high evening temperature difference is maintained but shifted upwards to higher levels.
The circadian rhythms in humans and the genes that regulate daily oscillations in body temperature have been studied. The body is normally able to maintain a fairly steady temperature because the hypothalamic thermoregulatory center balances the excess heat production, derived from metabolic activity in muscle and the liver, with heat dissipation from the skin and lungs. However, when faced with environmental extremes, humans cannot maintain the narrow daily variation of body temperature without the aid of clothing and protective environments [
5].
測量方法 －
週邊體溫監測方法（鼓膜、顳動脈、腋窩和口腔測溫）不如中心方法（肺動脈導管、膀胱、食道和直腸測溫）準確[ 6 ]，但中心方法不如周邊方法實用。
直腸溫度通常比口溫高0.6°C（1.0°F）。口腔溫度偏低可能是由於患者張口呼吸所致，這對於呼吸道感染和呼吸急促的患者尤其重要。鼓膜溫度接近核心體溫。
Methods of measurement — Peripheral methods of monitoring temperature (tympanic membrane, temporal artery, axillary, and oral thermometry) are not as accurate as central methods (pulmonary artery catheter, urinary bladder, esophageal, and rectal thermometry) [
6], but central methods are less practical than peripheral methods.
Rectal temperatures are generally 0.6°C (1.0°F) higher than oral readings. Oral readings are lower probably because of mouth breathing, which is particularly important in patients with respiratory infections and rapid breathing. Tympanic membrane temperature readings are close to core temperature.
發熱、高熱和體溫過高
發燒、高熱和體溫過高並不是同義詞。
FEVER, HYPERPYREXIA, AND HYPERTHERMIA
Fever, hyperpyrexia, and hyperthermia are not synonymous terms.
發燒 － 發燒是指核心體溫高於個體每日正常範圍。由於正常體溫因人而異、受一天中不同時間以及測量方法的影響，因此沒有統一的發熱閾值。根據記錄正常體溫晝夜變化的研究，早晨口腔溫度高於37.2°C (98.9°F) 或下午口腔溫度高於37.7°C (99.9°F) 可視為發燒。然而，在實踐中，通常採用高於37.8°C (100.0°F) [ 7 ] 或高於38°C (100.4°F) [ 8 ] 的通用閾值。眾所周知，老年人的基礎體溫低於年輕人，且老年人發燒的能力也較弱 [ 9 ]。因此，即使體溫低於這些閾值，老年患者仍可能出現發燒（以及潛在的嚴重感染）。 （請參閱上文「正常體溫」。）
發熱是由下視丘調節的。就像家中的恆溫器調節室溫一樣，下視丘控制核心體溫的方式也類似。例如，發燒時，下視丘體溫調節中樞的設定溫度會升高，從攝氏37度上升到攝氏39度。換句話說，發熱時，下視丘的「設定點」會從「正常體溫」設定值升高到發熱水平，這與家用恆溫器調高溫度以提高室內環境溫度的方式類似。下視丘中前列腺素E2 (PGE2) 水準升高似乎是觸發設定點升高的因素。一旦下視丘設定點升高，就會活化血管運動中樞的神經元，啟動血管收縮，並活化溫度感受神經元，降低其放電頻率，增加週邊的產熱。
血管收縮會使手腳產生明顯的冰冷感。血液從週邊轉移到內臟器官，從而減少了皮膚的熱量散失，使患者感到寒冷。對於大多數發燒而言，這足以使核心體溫升高1到2攝氏度。
同時，脂肪組織產熱有助於提高核心體溫，這被稱為「非顫抖性產熱」。新生兒體內存在大量產熱性極強的棕色脂肪，但會在新生兒期迅速減少。目前尚不清楚成年後體內還有多少棕色脂肪可以作為產熱來源。
脂肪或肌肉中的產熱是透過解偶聯蛋白來實現的，解偶聯蛋白會釋放三磷酸腺苷（ATP）和熱量。熱量保存和產熱的共同作用是發燒的主要原因。此外，肝臟的產熱也會增加。
顫抖可能是為了增加肌肉產熱而啟動的，但大多數發燒並不需要顫抖。顫抖似乎發生在體溫迅速升高以達到新的發熱閾值時。
在人類中，行為本能有助於透過減少體表面積來提高體溫。人們會尋找溫暖的房間，增加衣物，並減少活動。保暖（血管收縮）、產熱（顫抖、非顫抖性產熱、代謝活動增加）和行為改變等過程會持續進行，直到流經下丘腦神經元的血液溫度與新的設定值相符。一旦達到這個臨界點，下丘腦就會將體溫維持在發熱水平，就像在正常體溫下一樣。事實上，研究表明，發燒時平衡散熱和產熱的機制與非發燒狀態下的機制相同。
當下視丘體溫調節閾值下調時，血管舒張和出汗會加速散熱。下視丘體溫調節閾值下調可能是由於致熱原濃度降低或使用退燒藥所致。此時也會觸發行為改變，例如脫掉保暖衣物或被褥。出汗和血管舒張會持續散熱，直到供應下視丘的血液溫度達到較低的設定值。
在一些罕見病例中，由於局部創傷、出血、腫瘤或下丘腦自身功能障礙，下丘腦的體溫調節閾值升高。有時會用「下視丘性發燒」來描述下視丘功能異常所引起的體溫升高。然而，大多數下視丘損傷患者表現為體溫過低而非過高。這些患者對輕微的環境溫度變化反應遲鈍；在這種情況下，即使環境溫度略有下降，核心體溫也會下降，而正常的下視丘功能可以使核心體溫維持數小時。對於極少數疑似由下視丘損傷引起的核心體溫升高患者，診斷依賴其他下視丘功能異常的證實，例如下視丘釋放因子的產生、對寒冷的異常反應以及晝夜體溫和荷爾蒙節律的缺失。
Fever —
Fever is an elevation in core body temperature above the daily range for an individual. There is no universal threshold for fever, as normal body temperature varies by individual, time of day, and method of measurement. Based on studies documenting diurnal variations in normal body temperature, a morning oral temperature >37.2°C (98.9°F) or an afternoon temperature of >37.7°C (99.9°F) could be considered a fever. However, in practice, a general threshold of temperature >37.8°C (100.0°F) [
7] or >38°C (100.4°F) [
8] is often used. It is well established that baseline temperature in older adults is lower than in younger adults, and the ability to develop fever in older adults is impaired [
9]. Thus, temperatures lower than those thresholds may still reflect fever (and potentially severe infection) in older adult patients. (See
'Normal body temperature' above.)
Fever is regulated at the level of the hypothalamus. The thermostat device, which regulates the temperature in a home, is comparable to the way the hypothalamus controls core body temperature. The thermostat setting in the hypothalamic thermoregulatory center shifts upwards during a fever, for example, from 37 to 39°C. In other words, during fever, the "set-point" in the hypothalamus shifts upward from the "normothermia" setting to febrile levels, similar to the way the home thermostat is reset to a higher level in order to raise the ambient temperature in a room. Elevated levels of prostaglandin E2 (PGE2) in the hypothalamus appear to be the trigger for raising the set-point. Once the hypothalamic set-point is raised, this activates neurons in the vasomotor center to commence vasoconstriction and warm-sensing neurons to slow their firing rate and increase heat production in the periphery.
The vasoconstriction produces a noticeable cold sensation in the hands and feet. Blood is shunted away from the periphery to the internal organs, essentially decreasing heat loss from the skin, and the patient feels cold. For most fevers, this is sufficient to raise core body temperature 1 or even 2°C.
At the same time, thermogenesis in fat contributes to increasing core temperature. This is termed "nonshivering thermogenesis." At birth, highly thermogenic brown fat is present but rapidly decreases within the neonatal period. It is unclear how much brown fat remains as a source of heat production in the adult.
Thermogenesis in either the fat or muscle takes place by uncoupling proteins, which release adenosine triphosphate (ATP) and heat. The combination of heat conservation and thermogenesis accounts for the majority of fever. There is also increased heat production from the liver.
Shivering may be initiated in order to increase heat production from the muscles, but shivering is not required for most fevers. Shivering appears to take place when there is a rapid rise to match the new febrile set-point.
In humans, behavioral instincts assist in raising body temperature with reduction of exposed surfaces. Subjects seek warm rooms, add extra clothing, and reduce activity. The processes of heat conservation (vasoconstriction), heat production (shivering, nonshivering thermogenesis, increased metabolic activity), and behavioral changes continue until the temperature of the blood bathing the hypothalamic neurons matches the new setting. When that point is reached, the hypothalamus now maintains the new setting at the febrile level temperature, just as it does at the normothermic level. In fact, studies have shown that the mechanisms of balancing heat loss and heat production in fever are the same as in the afebrile state.
When the hypothalamic set-point is reset downward, the processes of heat loss are accelerated through vasodilation and sweating. The resetting of the set-point downward can be due to either a reduction in the concentration of pyrogens or the use of antipyretics. Behavioral changes are also triggered at this time and removal of insulating clothing or bedding takes place. Loss of heat by sweating and vasodilation continue until the temperature of the blood supplying the hypothalamus matches the lower setting.
In some rare patients, the hypothalamic set-point is elevated owing to local trauma, hemorrhage, tumor, or intrinsic hypothalamic malfunction. The term "hypothalamic fever" is sometimes used to describe elevated temperature caused by abnormal hypothalamic function. However, the majority of patients with hypothalamic damage have hypo- not hyperthermia. These patients do not respond properly to minor environmental temperature changes; in this condition, core temperature falls upon exposure to slight drops in temperature, whereas normal hypothalamic function can maintain core temperature for a few hours. In those very few patients in whom elevated core temperature is suspected to be due to hypothalamic damage, the diagnosis depends upon the demonstration of other abnormal hypothalamic functions, such as production of hypothalamic releasing factors, abnormal response to cold, and absence of circadian temperature and hormonal rhythms.
高熱 － 高熱是指體溫異常高（>41.5°C），常見於嚴重感染患者，但也可能發生在中樞神經系統（CNS）出血的患者身上。Hyperpyrexia — Hyperpyrexia is the term for an extraordinarily high fever (>41.5°C), which can be observed in patients with severe infections but can also occur in patients with central nervous system (CNS) hemorrhages.
體溫過高 － 雖然絕大多數體溫升高的患者表現為發燒，但也有一些情況下體溫升高代表體溫過高。這些情況包括中暑綜合症、某些代謝性疾病以及乾擾體溫調節的藥物的作用。與發燒不同，體溫過高時體溫調節中樞的設定值保持不變（即維持在正常體溫水平），而體溫卻不受控制地升高，並超過了散熱能力。外源性熱暴露和內源性產熱是導致體溫過高並危及生命的兩種機制。 （請參閱 「成人非勞力性（經典型）中暑」。）
區分發熱和體溫過高至關重要。體溫過高可能迅速致命，其治療方法也與發燒不同。儘管人體有生理和行為機制來調節體溫，但仍容易出現產熱過多的情況。例如，穿著過厚的保暖衣物會導致核心體溫升高。體溫過高最常見於在高溫環境下工作或運動的人群，因為他們產熱速度超過了周邊散熱機制的散熱速度。脫水是導致體溫過高的主要原因之一。
某些代謝性疾病，例如甲狀腺功能亢進，可導致核心體溫輕度升高。有些藥物（例如阿托品）會幹擾體溫調節，透過抑制出汗或血管舒張來達到治療目的，從而導致核心體溫升高。這些症候群屬於高熱症，因為它們發生在下視丘體溫調節正常的情況下。娛樂性藥物「搖頭丸」（3,4-亞甲基二氧基甲基安非他命）會引起高熱症，這是由於解偶聯蛋白3抑制了散熱（血管收縮）和產熱所致。
高熱的診斷通常是基於既往熱暴露史或服用某些幹擾正常體溫調節的藥物。目前尚無快速區分發熱引起的體溫升高和高熱的方法。高熱發作前的直接情況通常在確定其病因方面起著重要作用。然而，身體檢查可以幫助臨床醫生診斷某些類型的高熱；例如，中暑患者和服用抑制出汗藥物的患者皮膚發熱但乾燥。退燒藥無法降低高熱患者的體溫，而對於發燒甚至「高熱」患者，服用足量阿斯匹靈或對乙醯氨基酚後，體溫通常會下降。
當某些麻醉劑導致易感個體氧化磷酸化迅速解偶聯時，也可能出現高熱[ 10 ]。這種情況被稱為惡性高熱，通常是致命的。另一種高熱形式是由服用某些抗精神病藥物的患者引起的，被稱為「抗精神病藥物惡性症候群」[ 11,12 ]。 （請參閱 「成人非勞累性（經典型）中暑」和 「抗精神病藥物惡性症候群」。）
另一個可能導致高熱的原因是血清素綜合徵，任何能增強血清素能神經傳遞的藥物組合都可能導致此綜合徵（表1）。此症候群通常與同時服用兩种血清素能藥物有關，但對於血清素特別敏感的個體，即使只服用一种血清素能藥物或增加血清素能藥物的劑量，也可能發生該綜合徵。
Hyperthermia — Although the vast majority of patients with elevated body temperature have fever, there are a few instances in which an elevated temperature represents hyperthermia. These include heat stroke syndromes, certain metabolic diseases, and the effects of pharmacologic agents that interfere with thermoregulation. In contradistinction to fever, the setting of the thermoregulatory center during hyperthermia remains unchanged (ie, at normothermic levels), while body temperature increases in an uncontrolled fashion and overrides the ability to lose heat. Exogenous heat exposure and endogenous heat production are two mechanisms by which hyperthermia can result in dangerously high internal temperatures. (See
"Nonexertional (classic) heat stroke in adults".)
It is important to make the distinction between fever and hyperthermia. Hyperthermia can be rapidly fatal, and its treatment differs from that of fever. Despite physiologic and behavioral control of body temperature, excessive heat production can easily occur. As an example, overinsulating clothing can result in elevated core temperature. Hyperthermia is most often observed in persons who work or exercise in hot environments and produce heat faster than the peripheral mechanisms can lose it. Hypohydration is a major cause of hyperthermia.
Certain metabolic diseases such as hyperthyroidism can result in mild elevations of core temperature. The effects of some pharmacologic agents (
atropine) that interfere with thermoregulation by blocking sweating or vasodilation can also raise core temperature. These syndromes represent hyperthermia because they take place in the presence of a normal hypothalamic set-point. The recreational drug "ecstasy" (3,4-methylenedioxymethamphetamine) produces hyperthermia, which is due to a loss in heat dissipation (vasoconstriction) and heat production via uncoupling protein 3.
A diagnosis of hyperthermia is often made because of a preceding history of heat exposure or use of certain drugs that interfere with normal thermoregulation. There is no rapid way to differentiate elevated core temperature due to fever from hyperthermia. The immediate events prior to the onset of hyperthermia usually play an important role in determining its cause. However, physical examination can assist the clinician in some forms of hyperthermia; for example, the skin is hot but dry in heat stroke syndromes and in patients taking drugs that block sweating. Antipyretics do not reduce the elevated temperature in hyperthermia whereas there is usually some decrease in body temperature in patients with fever or even "hyperpyrexia" after adequate doses of either
aspirin or
acetaminophen.
Hyperthermia can also occur when certain anesthetics produce a rapid uncoupling of oxidative phosphorylation in susceptible individuals [
10]. This is known as malignant hyperthermia and is often fatal. Another form of hyperthermia results in patients taking certain neuroleptic drugs and is called "neuroleptic malignant syndrome" [
11,12]. (See
"Nonexertional (classic) heat stroke in adults" and
"Neuroleptic malignant syndrome".)
Another possible cause of hyperthermia is the serotonin syndrome, which may result from any combination of drugs that has the net effect of increasing serotonergic neurotransmission (
table 1). The syndrome is classically associated with the simultaneous administration of two serotonergic agents, but it can occur after initiation of a single serotonergic drug or increasing the dose of a serotonergic drug in individuals who are particularly sensitive to serotonin.
發燒的發病機制
致熱原 － 致熱原一詞用來描述任何能引起發熱的物質。致熱原可分為外源性和內源性。內源性致熱原屬於一類稱為細胞激素的生物活性蛋白質。更準確地說，能引起發燒的細胞激素稱為致熱細胞激素。
PATHOGENESIS OF FEVERPyrogens — The term pyrogen is used to describe any substance that causes fever. Pyrogens are either exogenous or endogenous. Endogenous pyrogens belong to the class of biologically active proteins called cytokines. Fever-producing cytokines are more precisely termed pyrogenic cytokines.
外源性致熱原 － 外源性致熱原來自宿主外部，主要包括微生物或其產物，如毒素。外源性致熱原的經典例子是所有革蘭氏陰性菌產生的脂多醣內毒素。內毒素不僅是強效致熱原，還能誘導革蘭氏陰性菌感染中觀察到的各種病理變化[ 13 ]。內毒素屬於一類稱為Toll樣受體（TLR）配體的微生物產物。 TLR起源於昆蟲，其在巨噬細胞上的哺乳動物同源物能夠結合多種細菌和真菌的微生物產物，從而激活細胞。因此，TLR對細菌的辨識解釋了感染如何引起發燒。如下文所述，哺乳動物細胞上的TLR活化巨噬細胞會導致發燒細胞因子的產生[ 14 ]。
另一類強效致熱原是由革蘭氏陽性菌產生的細菌物質。中毒性休克症候群毒素 (TSST-1) 與從中毒性休克症候群 (TSS) 患者中分離出的金黃色葡萄球菌菌株相關 [ 15,16 ]。 TSST-1 和其他金黃色葡萄球菌腸毒素以及 A 型鏈球菌外毒素既可作為直接毒素發揮作用，也可作為「超抗原」發揮作用 [ 17,18 ]。超抗原似乎透過與主要組織相容性複合體 (MHC) II 和多種 T 細胞亞群相互作用 [ 19,20 ] 來釋放致熱細胞因子，從而在嚴重革蘭氏陽性菌感染的發病機制中發揮作用。與革蘭氏陰性菌的內毒素類似，葡萄球菌和鏈球菌產生的毒素在亞微克/公斤劑量下靜脈注射到實驗動物體內時，可引起發燒。值得注意的是，內毒素在人體內是一種高度致熱分子，因為2至3奈克/公斤的劑量即可使志願者出現發燒和全身不適症狀[ 21 ]。
Exogenous pyrogens —
Exogenous pyrogens, derived from outside the host, are mainly microbes or their products, such as toxins. The classic example of an exogenous pyrogen is the lipopolysaccharide endotoxin produced by all gram-negative bacteria. Endotoxins are potent substances not only as pyrogens but also as inducers of various pathologic changes observed in gram-negative infections [
13]. Endotoxins belong to a classification of microbial products termed Toll-like receptor (TLR) ligands. TLR evolved with insects, and the mammalian homologues on macrophages bind microbial products from several bacteria and fungi and result in activation of the cell. Therefore, TLR recognition of bacteria explains how infections cause fever. As discussed below, the activation of macrophages via the TLR on mammalian cells results in the production of fever-producing cytokines [
14].
Another group of bacterial substances that are potent pyrogens is produced by gram-positive organisms. The toxic shock syndrome toxin (TSST-1) is associated with strains of Staphylococcus aureus isolated from patients with toxic shock syndrome (TSS) [
15,16]. TSST-1 and other enterotoxins from S. aureus and exotoxins from group A Streptococcus act both as direct toxins but also serve as "superantigens" [
17,18]. Superantigens appear to play a role in the pathogenesis of severe gram-positive infections by interacting with the major histocompatibility complex (MHC) II and a number of T cell subsets [
19,20] to release pyrogenic cytokines. Like the endotoxins from gram-negative bacteria, the toxins produced by staphylococci and streptococci produce fever in experimental animals when injected intravenously in the submicrogram/kg range. Of considerable importance is the fact that endotoxin is a highly pyrogenic molecule in humans since 2 to 3 ng/kg produces fever and generalized symptoms of malaise in volunteers [
21].
致熱細胞因子 － 致熱細胞激素是TLR活化後產生的特異性細胞因子，會引起發燒[ 3 ]。細胞激素是分子量10至20,000道爾頓的小分子蛋白質，可調節免疫、發炎和造血過程（表2）。例如，疫苗接種引起的免疫反應過程中淋巴球增殖的刺激是由多種細胞激素共同作用的結果，包括白血球介素（IL）-2、IL-4和IL-6。粒細胞集落刺激因子（G-CSF）可刺激骨髓中的粒細胞生成（請參閱 「重組造血生長因子簡介」）。在眾多細胞激素（超過70種）中，只有少數幾種是透過直接作用於下視丘體溫調節中樞而引起發燒的。
從歷史角度來看，「細胞激素生物學」領域始於1940年代對活化白血球產物引起發燒原因的實驗室研究。這些致熱分子稱為「內源性致熱原」[ 22 ]。從活化白血球中純化出的內源性致熱原不僅能引起發熱，還具有廣泛的生物活性，影響所有器官系統。細胞激素在疾病期間會影響器官功能，但除非受到感染或創傷，否則細胞激素似乎不參與正常的生理功能，包括體溫調節或內分泌功能。
已知有多種致熱細胞因子，包括白細胞介素-1 (IL-1)、白細胞介素-6 (IL-6)、腫瘤壞死因子 (TNF) 和睫狀神經營養因子 [ 23,24 ]。可能還有其他致熱細胞因子。幹擾素 (IFN)-α 也可被視為一種致熱細胞因子，因為它會引起發熱。事實上，重組 IL-1、IL-6 或 TNF 都已註射到人體，並引起發燒。 IL-1 的致熱性尤其強，皮下或靜脈注射劑量低至 10 ng/kg 即可引起發燒 [ 23 ]。 IL-6 也具有致熱性，但需要微克/公斤 (μg/kg) 而非奈克/公斤 (ng/kg) 的劑量才能在人體中引起發燒。儘管如此，幾乎所有發燒性疾病中都存在大量的 IL-6 循環，而由 IL-1 或 IL-1 與 TNF 聯合誘導的 IL-6 很可能是臨床上最常檢測到的發燒的原因。缺乏IL-6基因的小鼠在細菌感染期間不會發燒。因此，在大多數發炎和感染性疾病中，IL-1和TNF（即使濃度很低）也會誘導大量IL-6的產生，而IL-6很可能是活化下視丘中樞以控制體溫的關鍵因素。因此，除了來自微生物的外源性致熱原外，內源性致熱細胞因子也會導致發燒。每種細胞激素都由一個獨立的基因編碼，並且已證實每種致熱細胞因子不僅能在實驗動物中引起發熱，而且注射到人體後也能引起發熱。
多種外源性致熱原可透過活化Toll樣受體（TLR）誘導致熱細胞因子的合成與釋放。大多數外源性致熱物質來自細菌或真菌。病毒可藉由感染細胞誘導致熱細胞因子的產生。此外，發燒也可能是多種非感染性疾病的症狀。發炎、創傷或抗原-抗體複合物可誘導白血球介素-1（IL-1）、腫瘤壞死因子（TNF）和白血球介素-6（IL-6）的產生，這三種細胞因子中的任何一種或全部均可觸發下丘腦，使體溫調節閾值升高至發燒水平[ 25 ]。致熱細胞因子的細胞來源主要是單核細胞、嗜中性球和淋巴球，但許多其他細胞在受到刺激時也能合成這些分子。
Pyrogenic cytokines — Pyrogenic cytokines are specific cytokines produced upon activation of TLR that cause fever [
3]. Cytokines are small proteins (molecular weight 10 to 20,000 Daltons) that regulate immune, inflammatory, and hematopoietic processes (
table 2). As an example, stimulation of lymphocyte proliferation during an immune response to vaccination is the result of various cytokines including interleukin (IL)-2, IL-4, and IL-6. A cytokine called granulocyte colony-stimulating factor (G-CSF) stimulates granulocytopoiesis in the bone marrow (see
"Introduction to recombinant hematopoietic growth factors"). Of the many cytokines (over 70), only few cause fever by directly acting on the hypothalamic thermoregulatory center.
From a historical point of view, the field of "cytokine biology" began with laboratory investigations into the cause of fever by products of activated leukocytes in the 1940s. These fever-producing molecules were called "endogenous pyrogens" [
22]. When endogenous pyrogens were purified from activated leukocytes, they were shown to cause fever as well as possess a broad range of biologic activities, affecting all organ systems. Cytokines can affect organ function during disease, but unless challenged by infection or trauma, cytokines do not seem to play a role in normal physiologic functions, including temperature regulation or endocrine functions.
There are several pyrogenic cytokines, namely IL-1, IL-6, tumor necrosis factor (TNF), and ciliary neurotrophic factor [
23,24]. Others likely exist. Interferon (IFN)-alpha can also be considered a pyrogenic cytokine since it produces fever. In fact, recombinant IL-1, IL-6, or TNF have each been injected into humans and have produced fever. IL-1 is particularly pyrogenic, resulting in fever at doses as low as 10 ng/kg (either subcutaneously or intravenously) [
23]. IL-6 is also pyrogenic but microgram/kg rather than nanogram/kg doses of IL-6 are needed to produce fever in humans. Nevertheless, large amounts of IL-6 circulate in nearly all febrile diseases and IL-6 induced by IL-1 or the combination of IL-1 plus TNF likely accounts for the clinical fever most often measured. Mice without the gene for IL-6 do not develop fever during bacterial infection. Thus, in most inflammatory and infectious diseases, IL-1 and TNF (even at low concentrations) induce large amounts of IL-6, and it is the IL-6 that likely triggers the hypothalamic centers for control of body temperature. Thus, in addition to exogenous pyrogens from microbial sources, endogenous pyrogenic cytokines cause fever. Each cytokine is coded by a separate gene and each pyrogenic cytokine has been shown to cause fever not only in laboratory animals but also when injected into humans.
A wide spectrum of exogenous pyrogens induces the synthesis and release of pyrogenic cytokines via activation of the TLRs. Most exogenous pyrogenic substances are from bacterial or fungal sources. Viruses induce pyrogenic cytokines by infecting cells. Additionally, fever can also be a symptom of a variety of noninfectious diseases. Inflammation, trauma, or antigen-antibody complexes induce the production of IL-1, TNF, and IL-6, and each or all three cytokines trigger the hypothalamus to raise the set-point to febrile levels [
25]. The cellular sources of pyrogenic cytokines are primarily monocytes, neutrophils, and lymphocytes, although many different cells can synthesize these molecules when stimulated.
Elevation of the hypothalamic set-point by cytokines — During fever, hypothalamic tissue and third cerebral ventricle levels of prostaglandin E2 (PGE2) are elevated [
26-28]. The highest concentrations of PGE2 are near the circumventricular vascular organs (organ vasculosum lamina terminalis), which are networks of fenestrated capillaries surrounding the hypothalamic regulatory centers [
29]. Destruction of these organs reduces the ability of pyrogens to produce fever. However, most studies in animals have not been able to show that pyrogenic cytokines pass from the circulation into the brain substance itself [
23]. Thus, it appears that both exogenous and endogenous pyrogens interact with the endothelium of these capillaries, which is probably the first step in initiating fever.
The interaction of pyrogens with the hypothalamic circumventricular vascular endothelium is the first step in raising the set-point to febrile levels. The following Algorithm illustrates the key events in the production of fever (
figure 1). As shown, several cells have the potential to produce pyrogenic cytokines. Pyrogenic cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) are then released from the cell and enter the systemic circulation. Although the systemic effects of these circulating cytokines initiate fever by their ability to induce the synthesis of PGE2, they also induce PGE2 in peripheral tissues [
23]. The increase in PGE2 in the periphery accounts for the nonspecific myalgias and arthralgias that often accompany fever. However, it is the induction of PGE2 in the brain that starts the process of raising the hypothalamic set-point for core temperature.
There are four receptors for PGE2, and each signals the cell in different ways. Studies in mice demonstrated that the third PGE2 receptor (EP-3) is essential for the production of fever; mice deficient in the gene for this receptor do not develop fever following the injection of IL-1 or endotoxin [
30]. Deletion of the other PGE2 receptor genes leaves the fever mechanism intact. Although PGE2 is essential for fever, PGE2 is not a neurotransmitter. However, release of PGE2 from the brain side of the hypothalamic endothelium triggers the PGE2 receptor on glial cells, and this results in the rapid release of cyclic adenosine monophosphate (cAMP), which is a neurotransmitter [
23].
As shown in the following Algorithm, release of cAMP from the glial cells activates neuronal endings from the thermoregulatory center that extend into the area (
figure 1). The elevation of cAMP is thought to account for changes in the hypothalamic set-point either directly or indirectly by inducing the release of monoamine neurotransmitters. Receptors for endotoxin share many similarities to those of IL-1, and, hence, activation of endotoxin receptors on the hypothalamic endothelium also results in PGE2 production and fever [
31].
細胞激素升高下視丘溫度設定點 － 發燒期間，下視丘組織和第三腦室中前列腺素E2 (PGE2) 的水平升高[ 26-28 ]。 PGE2濃度最高的地方是腦室周圍血管器官（終板血管器官），這些器官是由圍繞下視丘調節中心的有孔毛細血管網所組成[ 29 ]。破壞這些器官會降低致熱原引起發熱的能力。然而，大多數動物研究未能證實致熱細胞因子能夠從血液循環進入腦實質[ 23 ]。因此，外源性和內源性致熱原似乎都會與這些微血管的內皮細胞相互作用，這可能是引發發燒的第一步。
致熱原與下視丘室週血管內皮的相互作用是提高體溫設定點至發燒程度的第一步。下圖（圖1）展示了發熱產生過程中的關鍵事件。如圖所示，多種細胞具有產生致熱細胞因子的能力。致熱細胞因子，例如白細胞介素（IL）-1、IL-6和腫瘤壞死因子（TNF），隨後從細胞中釋放並進入體循環。雖然這些循環細胞因子會透過誘導PGE2的合成而引發發燒，但它們也能在周圍組織中誘導PGE2的產生[ 23 ]。周圍組織中PGE2的增加是導致發燒常伴隨的非特異性肌痛和關節痛的原因。然而，正是大腦中PGE2的誘導啟動了提高下視丘核心體溫設定點的過程。
PGE2有四種受體，每種受體以不同的方式向細胞發出訊號。小鼠研究表明，第三種PGE2受體（EP-3）對於發燒的產生至關重要；缺乏該受體基因的小鼠在註射IL-1或內毒素後不會出現發燒[ 30 ]。其他PGE2受體基因的缺失並不影響發燒機制。儘管PGE2對於發燒至關重要，但它本身並非神經傳導物質。然而，下視丘內皮細胞腦側釋放的PGE2會活化神經膠質細胞上的PGE2受體，進而導致環磷酸腺苷（cAMP）的快速釋放，而cAMP是一種神經傳導物質[ 23 ]。
如以下演算法所示，神經膠質細胞釋放的 cAMP 活化了從體溫調節中樞延伸至該區域的神經元末梢（圖 1）。 cAMP 水平升高被認為可直接或間接地透過誘導單胺類神經傳導物質的釋放來改變下丘腦的體溫設定點。內毒素受體與 IL-1 受體有許多相似之處，因此，活化下視丘內皮細胞上的內毒素受體也會導致 PGE2 的產生和發熱 [ 31 ]。
中樞神經系統細胞激素的產生 － 多種病毒性疾病會在大腦中引起活動性感染。神經膠質細胞，特別是小膠質細胞，以及可能還有神經元細胞，會合成IL-1、TNF和IL-6[ 32 ]。睫狀神經營養因子也由神經元和神經細胞合成。這些在大腦內產生的細胞激素似乎在發熱過程中發揮作用。當細胞激素直接注射到實驗動物的大腦中時，引起發燒所需的劑量比靜脈注射低幾個數量級。因此，中樞神經系統（CNS）產生的這些細胞因子似乎可以提高下丘腦的體溫調節閾值，從而繞過參與循環細胞因子引起的發燒的腦室周圍器官。中樞神經系統局部產生的細胞激素可能解釋了上述中樞神經系統出血引起的高熱。
Production of cytokines in the central nervous system — Several viral diseases produce active infection in the brain. Glial cells, but particularly microglia and possibly neuronal cells, synthesize IL-1, TNF, and IL-6 [
32]. Ciliary neurotrophic factor is also synthesized by neural as well as neuronal cells. These cytokines produced within the brain itself appear to play a role in the production of fever. When a cytokine is injected directly into the brain of experimental animals, the dose required to cause fever is several orders of magnitude lower compared with intravenous injection. Thus, it appears that central nervous system (CNS) production of these cytokines can raise the hypothalamic set-point, bypassing the circumventricular organs involved in the fever that results from circulating cytokines. Local production of cytokines in the CNS may account for the hyperpyrexia of CNS hemorrhage noted above.
抗細胞激素療法是否會透過抑制發燒來掩蓋感染？ —— 越來越多的自體免疫疾病或自體發炎性疾病患者正在接受生物製劑治療。這些藥物多為抗細胞激素療法，如IL-1受體拮抗劑（如阿那白滯素）、TNF-α抑制劑、IL-6受體抑制劑、抗IL-12抗體或抗IL-23抗體。抗細胞激素療法的一個顯著缺點是會降低宿主對感染的防禦能力[ 33 ]。例如，使用英夫利西單抗或阿達木單抗等TNF-α中和抗體後，已有結核分枝桿菌播散等機會性感染的報告[ 34,35 ]。 TNF-α可溶性受體依那西普也與機會性感染有關，但與中和抗體相比，其相關性較低[ 35,36 ]。在幾乎所有與抗細胞激素療法相關的感染病例報告中，發燒都是首發症狀之一。然而，這些患者的發燒症狀很可能會像使用高劑量糖皮質激素一樣被抑制。 患者即使接受抗細胞激素藥物治療仍出現發燒，可能是由於其他可引起發燒的細胞激素（例如IL-1、TNF-α、IL-6、幹擾素等）不受特定抗細胞激素藥物的影響[ 14 ]。例如，在接受抗TNF-α治療類風濕性關節炎的葡萄球菌皮膚感染患者中，會產生三種致熱細胞因子：TNF-α、IL-1和IL-6，但只有TNF-α會被抗TNF-α抗體阻斷。在這種情況下，患者可能僅表現為低熱或無發燒，這會幹擾活動性感染的診斷。另一種解釋是，微生物產物能夠透過下視丘Toll樣受體直接誘導腦內PGE2的產生。對於因類風濕性關節炎接受抗 TNF-α 治療的葡萄球菌皮膚感染患者，葡萄球菌產物可能到達下視丘內皮細胞的 TLR，並觸發 COX-2 表現。
抗細胞激素藥物可顯著降低自體免疫疾病和自體發炎性疾病的發燒。一些自體免疫疾病和大多數自體發炎性疾病以反覆發燒為主要臨床表現。自體發炎性疾病是指單核細胞而非淋巴球在病理過程中發揮作用的疾病。自體發炎性疾病包括成人和青少年史蒂爾病、家族性地中海熱、高免疫球蛋白D症候群、家族性寒冷誘發自體發炎症候群、新生兒發病的多系統自體發炎性疾病、布勞症候群、施尼茨勒氏症候群、穆克爾-韋爾斯症候群和TNF受體相關週期性症候群。這些疾病的特徵是反覆發燒、嗜中性球增多和漿膜發炎。使用IL-1受體拮抗劑、caspase-1抑制劑或抗IL-1β中和抗體阻斷IL-1可顯著降低這些疾病相關的發燒[ 37-42 ]。成人史蒂爾氏症患者每日出現高熱，每日服用潑尼松無效，但單次注射IL-1受體拮抗劑後體溫迅速下降（圖2）[ 37 ]。雖然自體發炎性疾病的發燒是由IL-1β介導的，但患者對退燒藥物也有反應。
Do anticytokine therapies mask infection by preventing fever? —
An increasing number of patients with autoimmune or autoinflammatory diseases are being treated with biologic agents. These are mostly anticytokine therapies, such as IL-1 receptor antagonists (eg,
anakinra), TNF-alpha inhibitors, IL-6 receptor inhibitors, anti-IL-12 antibodies, or anti-IL-23 antibodies. Anticytokine therapies have the distinct drawback of lowering host defense against infection [
33]. In the case of neutralizing antibodies to TNF-alpha by
infliximab or
adalimumab, opportunistic infections such as Mycobacterium tuberculosis with dissemination have been reported [
34,35]. The soluble receptor for TNF-alpha,
etanercept, is also associated with opportunistic infections, but less so compared with the neutralizing antibodies [
35,36]. In nearly all reports of infections associated with the use of anticytokine therapies, fever is one of the presenting signs. However, it is likely that fever in these patients is blunted in much the same way as with high-dose glucocorticoids. (See
"Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and
"Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)
The ability of a patient to present with fever despite being treated with an anticytokine agent can be due to the other cytokines that can cause fever (eg, IL-1, TNF-alpha, IL-6, interferons, and others) that are not affected by a specific anticytokine agent [
14]. For example, in a patient with staphylococcal skin infection being treated with anti-TNF-alpha for rheumatoid arthritis, the three pyrogenic cytokines, TNF-alpha, IL-1, and IL-6, are produced, but only TNF-alpha is blocked by the anti-TNF-alpha antibody. In that case, the patient may manifest a low-grade fever or no fever, which confounds the diagnosis of an active infection. Another explanation is that microbial products are capable of inducing brain PGE2 directly via hypothalamic toll-like receptors. In the case of the patient with staphylococcal skin infection being treated with anti-TNF-alpha for rheumatoid arthritis, staphylococcal products may reach the TLRs of the hypothalamic endothelium and trigger COX-2 expression.
Anticytokine agents dramatically reduce fever in autoimmune and autoinflammatory diseases. Some autoimmune diseases and most autoinflammatory diseases have recurrent fever as a prominent presenting sign. The autoinflammatory diseases are diseases in which the monocyte rather than the lymphocyte plays a pathologic role. The autoinflammatory diseases include adult and juvenile Still's disease, familial Mediterranean fever, hyper immunoglobulin (Ig) D syndrome, familial cold-induced autoinflammatory syndrome, neonatal onset multisystem autoinflammatory disease, Blau's syndrome, Schnitzler's syndrome, Muckle-Wells syndrome, and TNF receptor-associated periodic syndrome. They are characterized by recurrent fevers, neutrophilia, and serosal inflammation. The fever associated with these diseases is dramatically reduced by blocking IL-1 with the IL-1 receptor antagonist, caspase-1 inhibitors, or anti-IL-1beta neutralizing antibodies [
37-42]. The febrile course of a patient with spiking daily fevers due to Still's disease in adults are unaffected by daily
prednisone but rapidly falls with a single dose of the IL-1 receptor antagonist (
figure 2) [
37]. Although the fever in autoinflammatory diseases is mediated by IL-1beta, patients also respond to antipyretics.
