The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam or etoricoxib (10 mg/kg for both) and, 30 minutes later, treated with icv CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ~0.4°C from 10 min post-infusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ~70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ~50% in both); all these changes were all completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg; icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways, and that the activation of COX-2 is required for the development of this response.

Fever and hypothermia represent two populations of sepsis patients and are associated with outside temperature

Background Fever and hypothermia have been observed in septic patients. Their influence on prognosis is subject to ongoing debates. Methods We did a secondary analysis of a large clinical dataset from a quality improvement trial. A binary logistic regression model was calculated to assess the association of the thermal response with outcome and a multinomial regression model to assess factors associated with fever or hypothermia. Results With 6542 analyzable cases we observed a bimodal temperature response characterized by fever or hypothermia, normothermia was rare. Hypothermia and high fever were both associated with higher lactate values. Hypothermia was associated with higher mortality, but this association was reduced after adjustment for other risk factors. Age, community-acquired sepsis, lower BMI and lower outside temperatures were associated with hypothermia while bacteremia and higher procalcitonin values were associated with high fever. Conclusions Septic patients show either a hypothermic or a fever response. Whether hypothermia is a maladaptive response, as indicated by the higher mortality in hypothermic patients, or an adaptive response in patients with limited metabolic reserves under colder environmental conditions, remains an open question. Trial registration The original trial whose dataset was analyzed was registered at ClinicalTrials.gov (NCT01187134) on August 23, 2010, the first patient was included on July 1, 2011.

Individual factors including age, BMI and heritable factors underlie temperature variation in sickness and in health: an observational, multi-cohort study

Background Ageing affects immunity, potentially altering fever response to infection. We assess effects of biological variables on basal temperature, and during COVID-19 infection, proposing an updated temperature threshold for older adults ≥65 years. Methods Participants were from four cohorts: 1089 unaffected adult TwinsUK volunteers; 520 adults with emergency admission to a London hospital with RT-PCR confirmed SARS-CoV-2 infection; 757 adults with emergency admission to a Birmingham hospital with RT-PCR confirmed SARS-CoV-2 infection and 3972 adult community-based COVID Symptom Study participants self-reporting a positive RT-PCR test. Heritability was assessed using saturated and univariate ACE models; mixed-effect and multivariable linear regression examined associations between temperature, age, sex and BMI; multivariable logistic regression examined associations between fever (≥37.8°C) and age; receiver operating characteristic (ROC) analysis was used to identify temperature threshold for adults ≥ 65 years. Results Among unaffected volunteers, lower BMI (p=0.001), and increasing age (p<0.001) associated with lower basal temperature. Basal temperature showed a heritability of 47% 95% Confidence Interval 18-57%). In COVID-19+ participants, increasing age was associated with lower temperatures in Birmingham and community-based cohorts (p<0.001). For each additional year of age, participants were 1% less likely to demonstrate a fever ≥37.8°C (OR 0.99; p<0.001). Combining healthy and COVID-19+ participants, a temperature of 37.4°C in adults ≥65 years had similar sensitivity and specificity to 37.8°C in adults <65 years for discriminating infection. Conclusions Ageing affects temperature in health and acute infection, with significant heritability, indicating genetic factors contribute to temperature regulation. Our observations suggest a lower threshold (37.4°C/97.3°F) for identifying fever in older adults ≥65 years.

How Does the Social Grouping of Animals in Nature Protect Against Sickness? A Perspective

Sickness behavior is broadly represented in vertebrates, usually in association with the fever response in response to acute infections. The reactions to sickness behavior in a group member or potential group member in humans is quite variable, depending upon circumstances. In animals, the reactions to sickness behavior in a group member or potential group member evoke a specific response that reflects the species-specific lifestyle. Groups of animals can employ varied strategies to reduce or address exposure to sickness. Most of these have scarcely been studied in nature from a disease perspective: (1) adjusting exposure to sick conspecifics or contaminated areas; (2) caring for a sick group member; (3) peripheralization and agonistic behaviors to strange non-group conspecifics; and (4) using special strategies at parturition when newborn are healthy but vulnerable. Unexplored in this regard is infanticide, where newborn that are born with very little immunity until they receive antibody-rich colostrum, could be a target of maternal infanticide if they manifest signs of sickness and could be infectious to littermates. The strategies used by different species are highly specific and dependent upon the particular circumstances. What is needed is a more general awareness and consideration of the possibilities that avoiding or adapting to sickness behavior may be driving some social behaviors of animals in nature.

The Therapeutic Effect of Traditional Chinese Medicine on Inflammatory Diseases Caused by Virus, Especially on Those Caused by COVID-19

Inflammasomes are large multimolecular complexes best recognized because of their ability to control activation of caspase-1, which in turn regulates the maturation of interleukin-18 (IL-18) and interleukin-1 β (IL-1β). IL-1β was originally identified as a pro-inflammatory cytokine, capable of inducing local and systemic inflammation as well as a fever response reaction in response to infection or injury. Excessive production of IL-1β is related to inflammatory and autoimmune diseases. Both coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are characterized by excessive inflammatory response. For SARS, there is no correlation between viral load and worsening symptoms. However, there is no specific medicine which is available to treat the disease. As an important part of medical practice, TCM showed an obvious therapeutic effect in SARS-CoV-infected patients. In this article, we summarize the current applications of TCM in the treatment of COVID-19 patients. Herein, we also offer an insight into the underlying mechanisms of the therapeutic effects of TCM, as well as introduce new naturally occurring compounds with anti-coronavirus activity, in order to provide a new and potential drug development strategy for the treatment of COVID-19.

99 Heritability of Temperature and the Effects of Ageing on Temperature Regulation: An Observational Multi-Cohort Study

Introduction Ageing affects homeostasis and immunosenescence, resulting in aberrant fever and immune responses to infection in older adults. This study assesses heritability of basal temperature and explores effects of ageing on basal temperature and temperature in response to SARS-CoV-2 infection. Methods Observational study using multiple cohorts. Participants: (a) Twin volunteers: 1089 healthy adults enrolled in Twins-UK, mean age 59 (17); tympanic temperature measurements; (b) Community-based: 3972 adults using the COVID Symptom Study mobile application, age 43 (13); self-reported test-positive for SARS-CoV-2 infection; self-reported temperature measurements; (c) Hospitalised: cohorts of 520 and 757 adult patients with emergency admission to two teaching hospitals between 01/03/2020–04/05/2020, age 62 (17) and 68 (17) respectively; RT-PCR-confirmed SARS-CoV-2 infection. Analysis (a) heritability analysed using saturated and ACE univariate models; linear mixed-effect model for associations between basal temperature and age, sex and BMI. (b&c) multivariable linear regression for associations between temperature and age, sex and BMI; multivariable logistic regression for associations between fever(>/= 37.8°C) and age, sex and BMI. Results Basal temperature in twins demonstrated 50% heritability (95%CI[42–57%]). In healthy twin, community-based and hospitalised cohorts, increasing age is associated with lower temperatures, and increasing BMI with higher temperatures: (a) Twins (age:p < 0.001; BMI:p = 0.002); (b) Community-based (age: p < 0.001; BMI: p < 0.001); (c) Hospitalised (1st hospital: age: p = 0.106; BMI: p = 0.033; 2nd hospital: age: p < 0.001; BMI: p = 0.010). Increasing age was negatively and BMI positively associated with fever (1st hospital: Age: OR = 0.99, p = 0.033; BMI: OR = 1.00, p = 0.045; 2nd hospital: Age: OR = 0.99, p = 0.010; BMI: OR 1.02, p = 0.038). Conclusions Heritability of basal temperature suggests a genetic component to thermoregulation. Associations observed between increasing age and lower temperatures and higher BMI and higher temperatures are important in understanding effects of ageing and obesity on basal temperature and the fever response. In older adults, findings have important implications for defining fever thresholds and diagnosing infections, including SARS-CoV-2.

Altered Febrile Responses in Older Adults: A Systematic Review

Human and animal studies support generalizations that older adults are less able than younger adults to mount an effective febrile response. Beyond difficulties this presents for assessing signs and symptoms of infection, concern exists that older adults may lack fever’s protective immuno-stimulant benefits. Fever is a systemic physiological host response to a pyrogen resulting in release of proinflammatory cytokines that produce a regulated elevation of thermoregulatory set-point. Heat is generated, by shivering and molecular activity, and conserved, by vasomotor activity, elevating and maintaining body temperature at the higher set-point level. Because immunological, vasomotor, and kinetic activities raise body temperature, age-associated alterations have been hypothesized to explain blunted febrile responses in older adults. Purpose: A systematic review was done to 1) determine factors underlying presumed origins and alterations in older adults’ febrile responses. 2) assess for gaps and controversies in emerging research that could inform care decisions. Comparisons of disciplinary assumptions, perspectives, and cross-disciplinary interpretations sought relevance to interdisciplinary care. Methods: Search of literature databases: Medline (OVID), and CINAHL (EBSCO). PubMed, and included relevant animal and human research findings since 2000 from physiology, gerontology, immunology, infectious disease, clinical medicine, and nursing. Findings: Altered innate immunity in sepsis shows early hyper-reactive response, prolonged inflammatory activity, and fever response contributing to cardiovascular and neurological morbidity, not temperature elevation. Morbidly was attributed to disease not age. Conclusions: Hazards of blunted febrile temperatures include undetected infections and possible loss of immune benefits. Significant evidence of age-related diminished febrile temperature’s immune consequences shown with animal models.