Anaphylaxis Prediction During Peanut Oral Food Challenge

                 Fight or Flight Response 

 

The Concept of Fight or Flight 

The concept of physiological changes that occur in the individual was first highlighted by the French physiologist Claude Bernard in 1878 who described the physiological balance of the internal environment of the individual as the milieu intérieur. In the first half of the twentieth century, Walter B. Cannon (Walter B. Cannon, 1915) was the first physiologist to introduce the concept of homeostasis for the first time and described the role of the adrenal medulla and the release of adrenaline (also called epinephrine) in the readiness of the individual to face unwelcomed situations. Cannon proposed that the environmental impact on the individual represents a stressful stimulus that provokes the activity of the adrenal medulla and the release of adrenaline. Consequently, adrenaline causes the heart rate to rise, bronchi to dilate, and the blood flow to shift from the skin and digestive system to the heart and brain. Moreover, the blood glucose rises to provide energy to the organs. Therefore, Cannon conceived the physiological changes during ‘stress’ as preparedness to ‘fight or run’ that later, in due course, became the well-known term fight and flight (McCarty, 2016). 

 

What is Stress? 

 The ever-changing daily demands, obligations, and duties of the life of the 21st century make continuous challenges to individuals. These challenges should be responded to at the expense of strong physical and psychological efforts; hence strain is created. The psycho-somatic response to strain ensures a homeostatic balance between the individuals’ resources and the demand. As long as the resources-demands balance is maintained the individual continues to be healthy. When the challenges become too strong and/or too prolonged to exceed the resources, coping failure occurs and maladaptation incurs. The state of incurred maladaptation is called stress that when not resolved may lead to physical and/or mental illness. The influence of stress varies according to the individual’s perception of the stressors, the outcome prediction and anticipation, and the ability to control stress. Moreover, the promptness and efficiency of gaining balance in face of the challenge and maladaptation as well as the duration allowed for stress to influence the individual's potentials to participate in the development of stress-related illness. When stress overwhelms the resources and is sustained for a long time without being resolved, chronicity is incurred, hence the name Chronic stress.  

As stress is recognized as disruption of the individual balance, chronic stress is defined as a devastating psychological state due to prolonged exposure to internal (e.g., chronic disease) or external (e.g., loss of a beloved) state or condition (Cuthbert, 2014). Chronic stress affects emotions and cognition. The duration of chronicity could be weeks or months according to the type of stress and the durability of the individual. Finally, the influencing state or condition should be adaptable to either escaping or avoidance (Ross et al., 2017). One of the most important features of chronic stress is that the resulting outcome (affect, cognition, psychological behavior, or physical) caused by the continuous and prolonged stress persists in the absence of the actual or anticipated threat experienced by stress exposure (Timmers et al., 2019).   

The Physiological Aspect of Fight or Flight Response  

The Neuro-Endocrine Pathway 

To understand how the body and the psycho become ready for a fight or flight response, it is worth understanding how the human body interacts with the environmental stressors leading to an adaptive neuro-hormonal response. The environmental stressors are perceived by the amygdala and hippocampus that consequently trigger the hypothalamic-pituitary-adrenal axis (HPA). Activation of the HPA initiates a hormonal cascade system leading to the final secretion of adrenal glucocorticoids (AGC) hormones. The AGC prompts a feedback loop by acting on specific receptors on the amygdala and hippocampus that send projections to the hypothalamus and prefrontal cortex (PFC)- collectively known as the limbic system. The feedback loop of AGC to the limbic system integrates the environmental stress with the stored memory recalling the experience, the physiological state such as hunger-satiety center, and the higher centers in the PFC influencing the decision-making process. Furthermore, the limbic system can alter the emotional, cognitive, and behavioral state of the individual according to the challenges of the surrounding environment.  

The hypothalamic-pituitary-adrenal axis 

The neural array of a stress response is localized in the paraventricular nucleus of the hypothalamus, the anterior lobe of the pituitary gland, and the gland of the adrenal medulla – collectively known and the hypothalamic-pituitary-adrenal axis (HPA). In the time of stress, the hypothalamic neurons release corticotropin-releasing factor (CRF). CRF reaches the anterior pituitary gland through the hypophysial portal blood supply. CRF binds to specific receptors on the pituitary gland leading to the release of the adrenocorticotropic hormone (ACTH). ACTH is released into the systemic blood circulation to the adrenal cortex. ACTH acts on the adrenal cortex stimulating the synthesis of glucocorticoids. The synthesized glucocorticoids are released into the circulation to act on intracellular receptors of the target organs (Smith & Vale, 2006). Because HPA is an adaptive system, a feedback loop, mediated by cerebral glucocorticoid receptors, allows control of the magnitude of HPA activation to cope with the severity of the stress/threat. Similarly, CRF is modulated by CRF-binding proteins in the systemic circulation and pituitary gland (Chen et al., 2005; Harlé et al., 2018). The exact mechanism by the glucocorticoids affect the activity of the HPA is not well understood. Two mechanisms are proposed. The first mechanism involves genomic changes leading to the de-activation of the HPA axis. The second mechanism involves a nongenomic molecular feedback pathway(Herman et al., 2020). The hypothalamic neurons are controlled by afferent neuronal inputs from the brain stem, the limbic system, and extra-hypothalamic nuclei (Lightman et al., 2020). The input of the different afferent cerebral neurons integrates to relay information about the external and internal environment to the hypothalamus. Consequently, CRF is expressed and released and the HPA axis is activated. 

The sympathetic nervous system 

The rise of the adrenaline during the fight or flight response has several consequences on the physiological function of the organs of the individuals. These changes are related to the readiness of the individual to challenge threatening situations. The physiological changes mediated by the sympathetic nervous system ensure the supply of oxygen and glucose to the vital organs (brain, heart, lungs, and muscles). Oxygen and glucose represent the vital energy supply that is needed for fight or flight response. During threatening situations, survival needs the utmost level of energy to cope with the threat. 

  By the effect of adrenaline, the heart rate increases, and the coronary vessels dilate resulting in an increase in the blood flow and oxygen supply to the cardiac muscle. Adrenaline causes vasoconstriction of the blood vessels to the skin and digestive system and vasodilates the blood vessels to the heart and brain, thus shifting the blood and oxygen to the more vital organs for survival. Moreover, the blood supply to the muscles increases several folds. To increase the level of oxygen in the circulation, adrenaline causes bronchodilation with an increase in the respiratory rate. Therefore, the oxygen blood supply is ensured. Furthermore, adrenaline enhances the synthesis of glucose by conversion of glycogen to glucose leading to elevation of blood glucose level that is necessary for energy production.  

Amygdala and hippocampus 

Amygdala and hippocampus as well as projections to PFC participate in learning through fear as the individual interacts with the environment adaptively to maintain the balance between the resources and challenges. The fear learning model is demonstrated by Pavlov conditioning and extinction paradigms to acknowledge the concept of chronic stress. Non-stressful stimulus induces fear behavior when accompanied by unconditioned stressful stimulus (conditioning). On the opposite, unlearning (extinction) of the fear occurs when the non-stressful conditioning stress is presented without the unconditioned stressful stimulus several times. If the brain processes failed to extinguish the negative conditioned learning when the stressful stimulus does not exist i.e., failure of extinction, post-traumatic stress disorder (PTSD) develops. Therefore, the brain-body crosstalk e.g., failure in extinction learning, impacts the mental health of the individual to a great extent. 

The amygdala and hippocampus are complex brain structures that play a pivotal role in the adaptability to stress. The role of the amygdala and hippocampus in chronic stress disorders has been demonstrated by the structural and neurohormonal changes that are associated with stress-related mental disorders, delayed or impaired stress recovery, and deficiency of fear extinction. Amygdala processes the cortical and thalamic signals to handle stress and related behavior. Amygdala-hippocampus mutual signaling as well as projections to stress-related key brain structures including PFC, nucleus accumbens (NAcc), and hindbrain influence mental brain functions such as cognition, motivation, and memory. Both amygdala and hippocampus express different types of receptors such as the gamma-aminobutyric acid (GABA) receptors and dopamine and somatostatin receptors that respond to AGC hormone release. Therefore, the body and the brain mutual signaling is established allowing the individual to respond both physically and mentally to stress. 

The basolateral neurons of the amygdala are responsible for receiving the actual and anticipated stress signals from the environment. The received signals stimulate the GABAergic receptors expressed on the surface of the basolateral neurons leading to behavioral changes corresponding to the received stress signals. Actual stress signals lead to fear emotions and anticipated stress signals can cause anxiety manifestations. The intracellular mechanisms controlling the GABA-A subunit expressed in the amygdala are responsible for the wide differences of vulnerability to the same stress between the individuals. The excited GABAergic basolateral neurons of the amygdala modulated the release of AGC through stimulatory signals to the HPA initiating the hormonal cascade system. The rise of AGC, through a feedback loop, controls the expression of the GABAergic receptors as well as the excitability of these receptors. Therefore, brain-body crosstalk is established to adapt to stress. The previously gained experience shifts the response to stress from goal-directed to habitual-directed.  

The hippocampus is the salient cerebral structure for learning and memory. Morphological changes have been noticed in relation to stress and stress-related anxiety and depression behaviors. Moreover, cognition and memory are reduced as well. The hippocampus neurons express adrenal steroid receptors that respond to AGC released by the HPA axis. The release of AGC at the time of stress has a structural neuroplasticity effect on the hippocampus. Therefore, brain-body crosstalk is established at the level of hippocampus excitability. As a result of hippocampus excitability potentiation, object recognition memory, and prolonged depression develops depending on the behavioral arousal state. Moreover, the neuroplasticity of the hippocampus that develops as a result of AGC release influences two types of memories: spatial memory and contextual memory.  

Stress and Physical Morbidities 

Cardiovascular Morbidity 

A large body of evidence suggests the undeniable role of chronic stress as a significant risk factor for the development of cardiovascular morbidity. Accumulating evidence concluded that long-term exposure to stressors (psychological stressors) is highly associated with the increased incidence of cardiac stroke, myocardial ischemia and infarction, and coronary artery disease. The risk of myocardial infarction and/or stroke is reported to increase by 60% among participants diagnosed clinically as PTSD (Gilsanz et al., 2017; Sumner et al., 2015). The correlation between chronic stress and the development of cardiovascular disorders can be explained by aversive behavioral changes including an increase in a high-fat diet that cause obesity and metabolic disorders. A metabolic syndrome is a group of disorders occurring together including obesity, hypertension, insulin resistance (leading to hyperglycemia), and hyperlipidemia. Recent studies concluded a strong relationship between chronic stress and the risk of metabolic syndrome and consequently the cardiovascular disorders. Moreover, hyperglycemia is shown to be related to chronic stress leading to increased pro-inflammation and enhancement of oxidative stress.  

Blood vessel dysfunction has been demonstrated to be associated with chronic stress. Chronic stress impairs vascular reactivity with reduced vascular dilation and enhanced vasoconstriction. Takotsubo syndrome (also known as the broken heart syndrome) is an acute coronary disorder resulting from chronic and intense emotional or physical stress. The observed impaired reactivity of the coronary vasculature resembles that in the conventional coronary artery disease mediated by an increase of adrenaline (sympathetic activity) release (Wittstein, 2016). Moreover, psychological stress was reported to reduce coronary blood flow precipitating acute myocardial infarction and arrhythmias (Ma et al., 2016). 

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 Homeostasis  

Living Organism Survival 

Fight or Flight 

Fight or Flight Response Model  

Since the theme fight or flight was coined by Cannon in 1915 (Walter B. Cannon, 1915), the theme was expanded to encompass the response to the living organism to a stressful situation that threatens the existence of living organisms. Several studies examined the response of the animals, plants, and humans in a different threatening situation and the theme of fight or flight have been identified clearly. Observation of fight and flight in plants has been identified. In coniferous forests, trees exhibit a "fight or flight" response to a threatening situation such as drought. The fight involves directing the available resources toward growth, pest defense, and drought-resistant xylem. Flight involves directing available resources toward reproduction and increasing the offspring production at the expense of the survival of the parent trees (Lauder et al., 2019). 

Fight or flight response has been observed in insects as well. Research on beetles (horned passalus beetles) revealed that the response of the beetles to the environmental threat, predators, varies from no action and complete surrender to sending alarms (flight) and very aggressive behavior (fight). Moreover, parasitized with the nematode, Chondronema passali, the defense is ameliorated rendering them more prone to surrender to the predators and fall as victims to the environmental threat (Ebot-Ojong et al., 2019). Gene expression was concluded to take part in determining the preferred response of the organism reflecting the role of inheritance in the fight or flight response preferences (Oster et al., 2015). 

Therefore, fight and flight influence the survival of the organism by enabling them to deal effectively with the threats that the environment may have including predators, illness, lack of resources, and weather changes. The study of the predator-prey relationship in the wild revealed that moose, for example, was not easy and simple prey for the wolves. Old wolves were found with broken ribs in the wild. This was explained by the observation that adult moose had survival tactics to attack wolves by the backside and throw them aggressively against the bulk of the old tree. On the contrary, the small moose was found to be easy prey to the wolves (Frail, 2012). Therefore, fight or flight helps animals, the prey, to survive the natural threat and give offspring as well. Another observation came from songbirds. Increased nest predation risk leaves the songbirds adults with two survival options either to stay in the nest for observation of the fledglings at the expense of reduced feeding and delay in fledge growth (fight) or to leave the risky nests with short wings and inability to fly (flight). Those who leave the nest (flight) were observed to compensate by improving flight performance, selecting a potential safe habitat with heavy woody vegetation (Mouton et al., 2020). Nature has its way. This slogan is translated by the physiologist, Cannon, and later, by the ecologists as fight or flight response of the living organisms to survive the overwhelming environmental threat.  

Fight, Flight, or Freeze Model 

The stress response was revolving around the effect of the autonomic nervous system and the related brain centers including the thalamus, hypothalamus, amygdala, and the hippocampus (the limbic system) as well as projections to other centers in the brain such as the prefrontal cortex. The autonomic stress response was coined by Cannon (Cannon, 1922) by the theme fight or flight. The theme was widely used in several contexts including the health service provision, workplace, social reaction to the crisis, and military situations. In the medical field, for example, the theme coined by Cannon has shaped the expectation of the healthcare providers from the patients and their expectations of themselves (Bracha et al., 2004). Advanced studies on lab animals and humans revealed that the stress response is more complicated than to be simply expressed by the dualism, fight or flight. Four separate response-related behavior have been identified and presumed to occur in a certain order. Gary (1987) presumed that stress response occur sequentially with the ‘freeze response’ comes first, followed by giving a trial to flee (flight) when the possibility is available, the fight comes next when fleeing is restricted, and finally the newly observed term tonic immobility or fright (Gray, 1987).  

The freezing response, also called freezing, was first recognized in lab animals. Freezing reflects a high level of attention and vigilance toward the threat. Freezing includes watchfulness, observation, and assessment of the situation. The freezing response is usually associated with fear leading to a ‘stop, look, and listen’ response (Bracha et al., 2004). Standing still increases the chance of the prey surviving the predator attack which usually detects motion rather than color (Anggreini et al., 2019). The second newly developed term is ‘tonic immobility or ‘fright’. Tonic immobility is the last resort for the victim or prey. It reflects the complete helplessness of the victim of prey. The tonic-immobility response is known as the absence of responsiveness and the victim enters a state of catatonic-like or imitating-death-like posturing. The victims produce no sound and in a suspended paralytic state (Scaer, 2014).  

Although the concept of the fight, flight, or freeze has been widely used in the framework of the studies that examine the response of the living organism to environmental threat, most of the studies has been animal-derived and do not reflect the complex response in humans (Katz et al., 2021). In humans, cognition, emotions, and experience intervene between the threat and its damaging consequences including risk assessment, situation evaluation, asking for help, and taking a risk (Blanchard et al., 2001; Harrison et al., 2015; Perkins et al., 2010). Moreover, women who were victims of sexual assault showed different types of survival responses. Apart from a fight (resistance, pushing, or threatening) and flight (passing out) response, surrendering, dissociation, begging, crying, or imploring were observed as well (Feinstein et al., 2011; Kaysen et al., 2005).  

Tend and befriend Model  

Cannon’s theme, fight or flight, describes the physiological response of the body to stress/threat through the activity of the autonomic nervous system. However, other response models have been described involving the psychosocial attitude of the individual. Taylor et al (2000) postulated that the response of the individual to trauma is more complicated and multidimensional than the simple Cannon’s theme (fight or flight). The built-in social tendencies motivate the individuals to engage in activities (response) to protect in-danger others or seek social contact for support and security (Taylor et al., 2000). Such affiliation under stress is termed tend-and-befriend response. The tend-and-befriend response was observed more in females. The gender difference can be explained by the social norms of the community and the unique neuroendocrine network of the females (Anggreini et al., 2019; Baumgartner & Strayer, 2008; Rodrigues et al., 2020). Affiliation to social engagement as a buffering strategy to stress was observed also in males (von Dawans et al., 2012). 

It has been concluded that human response to stress for survival encompasses multiple dimensions including physiological reactions (increase of heart and respiratory rate, hot flushes, and enhancement of muscle twitches), subjective emotions such as fear, anger, or disgust, and cognitive responses such as risk assessment or dissociation (Bovin & Marx, 2011). 

Fight or flight is Born with Us   

The fight or flight response can be observed in the preschool children reflexing that the response is not acquired by human experience. Rather, fight and flight in a ‘built-in’ mechanism of the human being. Fight or flight response can be noticed among preschool children as a consequence of peer conflicts. Preschool children tend to fight, flight, standoff, and mediate in response to peer conflicts. However, the response judgment is subject to the observer's evaluation and interpretation of the child's behavior. Therefore, studies on children reveal that fight or flight response to threatening situations is inherited behavior acquired during early childhood (Baumgartner & Strayer, 2008). However, fight or flight is not always the case with children. It was found that the response to threatening situations differs by the gender of the child. While boys tend to respond by fight or flight, girls tend to respond by tender-and-befriend strategy. The word 'tend' refers to tending to one’s offspring, and 'befriend' refers to seeking out social support during times of stress (Taylor et al., 2000). It was proposed that females tend to respond by the tend-and-befriend coping strategy to the mothers' frightening behavior rather than fight-or-flight response that was shown to be more adopted by male children (David & Lyons-Ruth, 2005). 

Fight and flight in the Working Place 

Moreover, fight or flight can be useful in determining the response of the employees in the company to certain adverse situations including toxic leadership. Understanding the coping strategy adopted by the employees in response to toxic leadership allows the organization to intervene accordingly to increase the productivity of the employees. Coping is an unconscious and involuntary adaptive process aiming at intervening between the stressful situation and the harmful consequences including physiological, psychological, or emotional outcomes. Fight, flight or freeze is considered as a coping mechanism to stress (Warszewska-Makuch, 2019). 

Conflict in the workplace is a frequent problem that faces managers and employees. According to some authors, conflict arises from interest incompatibility. The common causes of conflict in the workplace include information diversity and ambiguity leading to different interpretations by the employees. Moreover, lack of resources especially time is considered a major cause of conflict in the workplace. Other causes include personal goals, needs, ambitions, communication style, and mistaken assumptions to name a few (Park, 2012). Resolution of conflict in the workplace among professionals or between the manager and employees excludes confrontation (fight) as an option. Instead, negotiation, moderation, and prevention (flight) are adopted to resolve conflicts (Clohisy et al., 2017; Park, 2012; Zimmermann, 2003). 

To cope with the stress caused by the toxic leadership, the employees were observed to adopt several coping strategies to intervene between the stressors and the outcome. Common coping strategies reported in toxic threatening situations included assertively challenging the leader, seeking social support, ruminating, taking leave, and leaving the organization. These coping strategies can be interpreted as fight, flight, or freeze response (Webster et al., 2016).  

Moreover, gender differences have been noticed during economic negotiation as men were found to achieve better economic negotiation outcomes than the female counterparts. However, considering the context of negotiation including experience, available information, and delegation situations, the difference between males and females as regards economic negotiation was shown to be reduced (Mazei et al., 2015). A more recent meta-analysis study concluded that although males tend more than females to initiate a negotiation, the apparent difference is markedly reduced when the situation is appropriate, less ambiguous, and the negotiation is compatible with the female practice and experience (Kugler et al., 2018). Therefore, negotiation is preferred by men irrespective of the context of the negotiation; negotiation is the war filed for men, and whatever the context men tend to ‘fight’ rather than ‘flight’. On the other hand, women prefer to involve in the negotiation when the context is more certain and under control- flight tendency (Castaño et al., 2019).                                                        

Fear and Anger  

 Fear and anger are two negative emotions that were presumed to provoke destructive and counterproductive consequences. Fear arises from situations of uncertainty and lack of control while anger, on the contrary, is associated with certainty and strong control over the threatening situation. Fear and anger were found to prompt for change, thus motivate people to behave differently to modulate the unfavorable situation. The change that can be taken by the individual in threatening life situations means the anticipatory action that may change the life situation to be less harmful e.g., negotiation with the authority or self to be more qualified to deal with the situation without being harmed e.g., physical training to win potential street assault. Therefore, fear and anger can be proactive rather than reactive.  

It was postulated that anger prompts for action to rectify a perceived wrong or confront with the offending blame. It was suggested that anger is responsible for generating counterproductive workplace behavior. Therefore, anger is largely suggested to be associated with ‘fight’. On the other hand, fear was reported to motivate the individual to avoid unsafe physical and/or psychological situations. This reaction was shown as a counterproductive behavior as well. The fear experience was found to be associated with quitting work, low performance, and the tendency for falsified leaves. Therefore, fear leads to ‘fright’. 

However, the negative consequences of fear and anger based on fight or flight response were challenged by many authors (Lebel, 2017). Fear and anger prompt the individual for action. The situation, the degree of threat, and the capacity of the individual to control are presumed to impose the type of action whether reactive and destructive or proactive and constructive. Fear and anger are high-activation negative unpleasant emotions. The provoked fear and anger energizes the individual so that the potential physical and psychological resources become ready for an overwhelming action, fight, or flight (Lebel, 2017).  

Fear is a principal emotion that elicits during encountering a threat and anticipation of an aversive environmental situation. In the animal kingdom, fear is the emotion that activates a defense system for survival and procreation (Mobbs et al., 2020). Fear allows the individual to achieve the avoidance goals either by escape (flight) or defend (fight) according to the situation and the option availability (Qi et al., 2018). Therefore, fear is defined as the principal emotion that is associated with the initiation of the appropriate defensive mechanism to maintain the life of the living organism including man (Maack et al., 2015). 

The threat and resources of the individual determine the choices of the individual to face threat either fight, when survival is the issue, flight if it is available, or freeze, taking no action, to avoid the exposure to threat (Maack et al., 2015). In a recent study examining the effect of online fear messages e.g., from terrorists, fear may be expected to elicit withdrawal reaction. However, a recent study showed that receiving online threat messages from terrorists elicited variable responses ranging from submission to the demands of the terrorists (flight) to hidden support to combat the terrorist threat (fight). Therefore, fear was concluded to play a pivotal role in determining the response to the threat more than other persuasive variables (Iyer et al., 2015). Similarly, the response of the individuals during the time of crisis was shown to be determined by fear emotions. Although people tend to escape the place of danger, this decision was not always wise. People may come across another danger e.g., crowdedness and pushing to reach a safe place. Fear usually arises during crises leading to public panic. This panic may lead people to think to flight, flee the source of threat rather than facing it, fight. It is the autocratical communication and the dispatch of the proper information that would direct people to encounter the threat in a more reasonable and safe way, fight, rather than flighting, especially when fleeing carries potential dangers and untoward consequences (Wester, 201).

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