**4. Fever, hypothermia, and other disruptions to the human body temperature circadian rhythm**

Numerous studies had been carried out to demonstrate how disruption in the circadian rhythm of body temperature can affect human health. Perhaps the most extreme situations are those where fever or hypothermia completely obliterate the circadian rhythm balance. To better understand the clinical implications of these disruptions, we need to define fever and hypothermia. It had been known for a long time that a pyrogen (such as bacteria, viruses, toxins, and others) triggers "fever" by causing the release of prostaglandin E2, which acts on the preoptic area of the hypothalamus (a.k.a., the mammalian thermostat) to make it raise the temperature set point [61]. A higher temperature set-point results in a systemic body response attempting to raise the peripheral body temperature via active heat generation and by heat retention. Fever (pyrexia) in humans is associated with high inflammatory states such as sepsis and trauma [62]. Elevation of body temperature promotes the activation and trafficking of immune cells— in the case of T-lymphocytes, cell mobilization is achieved via a thermal sensory pathway involving alpha4 integrins and heat shock protein 90 [63]. On the other hand, hypothermia is a state of lower-than-normal hypothalamic setpoint. It occurs in settings such as severe debility due to illness leading to the inability to raise the body temperature; brain injury involving the preoptic area including age-related microvascular brain damage, stroke, and traumatic brain injury; congenital malformation of the preoptic area; seizure disorders, and likely others [64]. Hypothermia is associated with the inability to mount a strong inflammatory reaction and this is the reason why induced hypothermia had been used in some patients of cardiac arrest, where inflammation needs to be suppressed in order to allow time for the cardiac tissues to recover from the ischemic injury [65].

Deviations from normothermia among critically ill patients had been extensively studied. These deviations manifest in most such patients and appear to carry a prognostic value. For instance, a study by Sunden-Cullberg et al. [66] demonstrated that the ability among critically ill septic patients to mount fever while in the emergency department, i.e., before their admission to the ICU, was associated with lower in-hospital mortality and shorter hospital length of stay. On the other hand, Kiekkas et al. [67] showed that among the 239 ICU patients without cerebral damage such as stroke or neurosurgery in their study, fever was not associated with mortality but there was statistically significant increase in mortality with each 1°C increase in sustained maximal body temperature, indicating too much of a good thing (fever and the associated heightened immunity levels) can be harmful. Further, Peres Bota et al. [68] studied 439 ICU patients, not excluding any patients such as those with cerebral damage or those undergoing hypothermia protocols e.g., following cardiac arrest. These researchers found that both fever and hypothermia were associated with increased morbidity and mortality but those with hypothermia had a worse survival rate than the febrile patients. A potential confounding factor there was the fact that the hypothermic patients were significantly older compared with the patients with fever and it is common sense that older age is associate with less favorable clinical outcomes. In the case of patients with cerebral injury, studying 251 hospitalized subjects Schwartz et al. [69] demonstrated worse outcomes for patients with persistent fever and intracerebral hemorrhage, while Bao et al. [70] found similar results among their 355 patents with traumatic brain injury.

Regarding alterations in the body temperature circadian rhythms, these had been shown to occur in a variety of ways among the critically ill, including erratic acrophases, bathyphases, amplitudes, even complete abolishment of the cycling pattern [71–74]. Specifically, Tweedie et al. [71] showed that among the 15 intensive care unit (ICU) patients in their study, the acrophases varied by several hours from day to day both between patients and within the same individual patients over the study period of at least 8 ICU days per patient. Nuttall et al. [72] evaluated 149 ICU patients and reported that nearly all lacked a circadian rhythmicity of body temperature with the bathyphases distributed randomly throughout each 24-hour period. Paul et al. [73] studied 48 ICU patients and demonstrated major disturbance and often complete abolishment of the circadian rhythm as given by body temperature, melatonin and cortisol levels, blood pressure, heart rate, and spontaneous motor activity, all of which are known to be cycling with a 24-hour period in healthy individuals. Pina et al. [74] evaluated 8 patients managed in the burn ICU for 30 days and demonstrated the lack of circadian rhythm based on body temperature, melatonin, and cortisol levels for all patients during the entire hospitalization, although the authors noted a trend toward normalization of the body temperature diurnal cycle for some of the patients during the later stages of hospitalization. The latter two studies described above were prospective in design, thus providing more frequent data points, which may correspond to higher reliability but the overall conclusion based on all research findings is that critical illness is associated with major disturbance in the circadian rhythm of human body temperature.

The clinical prognostication value of human body temperature circadian rhythm variations is remarkable as well. Blume et al. [75] demonstrated that among their 18 patients with severe brain injury leading to loss of consciousness, preservation of the body temperature diurnal cycling was associated with increased chance for recovering from their comatose state. Further, Tweedie et al. [71] found that among their 15 ICU patients, there was a bigger circadian rhythm amplitude during periods of unconsciousness compared with when patients were conscious and the amplitudes were also bigger among the patients who died compared to those who survived. In a larger study of 248 patients with severe trauma admitted to the ICU and excluding any patients who had undergone targeted hypothermia protocol following cardiac arrest, Culver et al. [76] found that disruption in the body temperature circadian rhythm with mesor <36.9°C and amplitude >0.6°C were associated with higher 28-day-all-cause mortality. They also showed that the association was more pronounced among patients with head trauma compared with those with non-head trauma. Among the general ICU patient population comprising of 21 patients, Gazendam et al. [77] documented an acrophase shift in 81% of the studied patients and also found that the severity of illness, as given by the APACHE III (Acute Physiology and Chronic Health Evaluation) score, was predictive of the magnitude of circadian misplacement. Importantly, it was demonstrated by Drewry et al. [78] how in the ICU setting one can monitor the diurnal body temperature oscillations and look for specific disruptions in the rhythm that had been associated with the early development of sepsis, thus providing an early sepsis warning before the traditional sepsis criterial are met, which in turn would allow for an earlier intervention with antibiotics. Given all the clinical data, it is fair to conclude that disruption of the circadian rhythm and deviation from normothermia among the critically ill likely facilitates a mal-adaptive and hyperactive (in the case of fever) or hypoactive (in the case of hypothermia) inflammatory responses that can lead to organismal failure and death.

The importance of the circadian rhythm has also been demonstrated in noncritically ill hospitalized patients. For instance, our group [79] found that among the 16,245 hospitalized patients included in the study, the circadian rhythm was disrupted

#### *Human Body Temperature Circadian Rhythm in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.1003852*

in 80%. Further, we reported an age-dependent shift in the circadian pattern, with the body temperature bathyphase of older people shifted to 12 pm in the afternoon (compared with 8 am for young adults) but with the acrophase among the old remaining at 8 pm, similar to the younger patient cohort. (**Figure 4**, adopted with modifications and permission from Geneva et al. [79]). After considering other theories, we had concluded that the most likely explanation for the circadian body temperature disruption during hospitalization was the disturbance in the patients' day-night light cycles caused by frequent awaking at night for procedures, vital signs measurements, and the associated exposure to light during the night. Several other studies with human subjects have also supported the role of diurnal light levels in resetting the human circadian clock [80–84]. Similar to the ICU patients, body temperature measurements from non-critically ill patients appear to carry prognostic value as demonstrated by Obermeyer et al. [11]. The authors studied the body temperature of over 35,000 hospitalized patients, who were not diagnosed with infection and did not receive antibiotics; they showed that after adjustment for age and comorbidities that could affect body temperature (e.g., hypothyroidism is associated with lower body temperature, active cancer is associated with higher body temperature), there was correlation between deviation from the expected normothermia range and the one-year mortality.

On the outpatient basis, the disruption of the natural circadian rhythm emerged as an important player in disease pathogenesis via epidemiologic studies in the 1990s that linked it to the development of cancers among night shift workers. Specifically, higher levels of breast cancer were noted among Norwegian radio and telegraph operators [85]. Further research also demonstrated increased incidence of colorectal and prostate cancers as well as metabolic and gastrointestinal disorders among people working night shifts [86–88]. In this population of workers, various circadian rhythm

#### **Figure 4.**

*Diurnal body temperature variation of hospitalized patients classified by age. Adapted with modifications and with permission from Geneva et al. [79] Figure 2A.*

markers such as melatonin and cortisol blood levels as well as the diurnal cycling of body temperature were shown to be disturbed [89–92]. The situation was further aggravated by the realization that these circadian abnormalities persist for years after retirement from night shift work jobs [92, 93]. It should be mentioned that not all research had been supportive of these associations; namely a recent meta-analysis by Dun et al. [94] evaluated 57 observational studies and concluded that there was no association between any exposure to night shift work during subjects' lifetime and increased risk for several common solid cancers, albeit there were several major caveats regarding the data heterogeneity. Notwithstanding the meta-analysis results, researchers theorized that light exposure at night facilitates the carcinogenesis via disruption of the natural melatonin cycle in humans. Melatonin is believed to have a second function, in addition to neuro-hormonal signaling, where it acts as a scavenger of reactive oxygen species [95]. As melatonin production occurs at night and it is suppressed by light, exposure to light during night shift-work leads to less melatonin production and supposedly accumulation of oxygen radicals, which constitute a known risk for the development of malignancies [96]. In support of this theory, it was demonstrated that women with complete blindness (no light perception) had significantly lower prevalence of breast cancer compared with blind women with preserved light perception [97]. Research with mice had provided more specific evidence, where melatonin knockout animals prone to breast cancer development (p53(R270H/+)WAPCre conditional mutant mice) suffer from faster tumor growth in shift work simulation experiments as compared to animals with the same breast cancer predisposition but with normal melatonin production [98]. Over the years, sufficient evidence had accumulated from epidemiological studies and animal model research to prompt the Agency for Research on Cancer to classify shift work involving circadian rhythm disruption as likely carcinogenic [99]. This is a good place to point out that in the current era of technological advance, a large portion of Earth's population is living in conditions akin to night shift workers' due to the extensive use of digital devices (cell phones, tablets, TV, etc.) late into the night, thus leading to the so called social jetlag and likely circadian misalignment [100, 101].

It is well established that a weakened immune system is a predisposition to the growth of malignancies, with cancer immunotherapy currently being a hot area of research [102]. As such, the above-described associations between circadian rhythm disruption and cancer may stem from the effect of circadian rhythm abnormality on the immune system, which was previously reviewed by Logan et al. [103], Comas et al. [104], and Coiffard et al. [105]. While most research had been done in animal models, human studies did show that disruption of the circadian rhythm (induced with a sleep desynchronization protocol) negatively affects the human transcriptome [106]. Namely, the authors found a reduction in the normal diurnally-guided rhythmic transcription from a baseline of 6.4% to 1.0%. Many of the genes affected by this transcription reduction are known to play important roles in immune pathways, including cytokine and NFκB signaling [106, 107]. The effect of the circadian rhythmicity on one's immunity could also explain the observation from mice animal models where disease severity was higher if a pulmonary infection with Streptococcus *pneumoniae* was induced during the resting phase of the animals (when their body temperature is lower) compared with infecting them during their active phase (when their body temperature is higher) [108].

In addition to associations with cancer and immunologic dysfunction, night shift-work-related circadian rhythm disturbance had been linked to cardiovascular risk factors such as decrease in insulin sensitivity and decrease in leptin (the satiety hormone) blood levels [109–114]. Other published reports have demonstrated links

#### *Human Body Temperature Circadian Rhythm in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.1003852*

to cognitive and psychiatric disorders as reviewed by Karatsoreos et al. [115]. These include decreased reaction time, increased error rate, and temporal lobe atrophy among flight attendants serving on frequent trans-Atlantic flights leading to jet-laginduced circadian rhythm desynchronization [116]; correlation between the intensity of major depression attacks with the size of delays in the circadian pacemaker as regards the timing of sleep onset [117]; reduction in the self-reported mood and wellbeing level among healthy volunteers who were subjected to a sleep-wake circadian rhythm disruption experimental protocol [118]. Even the gut microbiota was shown to be altered upon disruption of the circadian rhythm based on light-dark cycling in animal models using mice [119] and Drosophila [120]. It should be noted that the experimental findings detailed in this paragraph do not directly link disruption in the body temperature circadian rhythm to the identified behavioral or physical health conditions and deficits. Still, body temperature is the most easily measured indicator of circadian rhythm preservation or disruption. As such, its application in the design of experimental paradigms and tests for the effects of medical interventions is expected to be of great benefit to future research, which is the focus of the next chapter section.
