34: Stress & Disease

Human history is replete with stories of the connection between stress and disease. A story about John Hunter (1728–1793), a surgeon and medical educator at St. George’s Hospital in London, is that he stated publicly, “My life is at the mercy of any rogue who chooses to provoke me,” and soon afterward died following a contentious meeting with hospital administrators.

A review of coroners’ records in Los Angeles in 1994 revealed a marked increase in deaths, including sudden death, related to atherosclerotic cardiovascular disease on the day of the 1994 Northridge earthquake. In 1999 during a 7.3 magnitude earthquake in Taiwan, patients on Holter monitors showed heart rate variability derangement due to withdrawal of parasympathetic activity and increase in sympathetic arousal. In the quarterfinal of the 1996 European football championships between the French and Dutch teams, a draw at the end of overtime resulted in a sudden death penalty shoot out, which was won by the French. An analysis of mortality in the total population of Dutch men and women aged 45 years or more revealed a relative risk of death from acute myocardial infarction (MI) or stroke of 1.51 among the men on the day of the match, compared with the 5 days on either side. There was no such effect on French men. This gave new meaning to the term “sudden death penalty.”

The psychological sequelae of exposure to life-threatening stressors are also problematic and disruptive to people’s lives. The terrorist attacks on the World Trade Center and the Pentagon on September 11, 2001, were witnessed directly by an estimated 100,000 people and vicariously by millions of Americans and others worldwide. In the period of time between October 16 and November 15, 2001, it is estimated that 7.5% of Manhattan residents south of 110th street were suffering from posttraumatic stress disorder (PTSD) and 9.7% were suffering from depression. In a representative sample of the American population surveyed 3–5 days following the attacks, 44% reported one or more substantial symptoms consistent with acute stress disorder (ASD), and 90% had one or more symptoms to some degree. Refugees and prisoners of war who have been exposed to torture are also likely to develop symptoms of PTSD, anxiety, and depression.

Less dramatically, research since the late 1960s has demonstrated correlations between significant changes in individuals’ lives and the subsequent onset of various types of physical and psychological illness. A consistent relationship has even been found between daily hassles and the onset of illness.

The interrelationship between mental stress and physical disease is complex and multifactorial. As a result, the study of stress and disease embraces a wide range of behavioral, emotional, cognitive, physiologic, hormonal, biochemical, cellular, environmental, and even spiritual interconnections, not easily understood or encapsulated in the controlled clinical trial.

It has been estimated that up to 70% of visits to primary care physicians are for problems related to stress and lifestyle. Most clinicians, however, have not been trained to extend their diagnostic workup and treatment interventions into the psychosocial context of these illnesses. Yet, adequate treatment and prevention require that providers regard their patients’ illnesses and suffering in the context of their life struggles. This perspective allows the clinician to intervene at multiple points along the continuum from mind to molecule. The biopsychosocial model of medicine, originally proposed by Engel, regards illness as multidetermined—by biochemical alterations on the molecular level and by psychological and social events on the molar level. This model encourages clinicians to move conceptually up and down the hierarchy from patients’ genetic susceptibilities and pathophysiologic processes to their unique life circumstances, stressors, and psychological meanings by which they construct their reality, to understand fully the origins of disease and the most appropriate therapies.

This chapter offers a framework for clinicians to think broadly and clinically about the stress–illness connection and suggests some approaches to assessing and treating stress-related illness. It offers a brief background of the research base for this perspective; provides a conceptual framework to guide diagnosis and treatment; suggests methods for communicating with patients about stress; and offers some options for stress assessment, prevention, and intervention.

This case is a common occurrence in primary care medicine, and the patient’s chronic complaints pull for efforts by the new physician to ease her symptoms, especially with pain medication. Many physicians might regard this as a “difficult patient” (see Chapter 4). This physician astutely refrains from developing a treatment plan until after a complete history and physical, scheduled for the next visit. He provides a pain medication refill to meet the patient’s immediate needs and elicits her agreement to return for the subsequent evaluation. That next visit will offer an opportunity, in addition to the physical examination, to explore the psychological and social stress pathways that contribute to the patient’s symptom constellation. We will return to this case later, but first we will review the history and meaning of “stress,” its research background, and the rich array of assessment and intervention tools available for the physician to help this patient steer a new course to health.

The concept of stress was borrowed by physiology and psychology from physics, where it generally refers to a force acting against some resistance. In materials science, stress is what is imposed on a material by the outer world; strain is the reaction of the material to the stress.

Hans Selye is generally credited with introducing the concept of stress into physiology. He defined stress loosely as “the rate of wear and tear in the body” and more rigorously as “the state manifested by a specific syndrome which consists of all the nonspecifically induced changes within a biologic system.” In this specific syndrome, termed by Selye the general adaptation syndrome (GAS), glucocorticoids are secreted by the adrenal cortex in response to adaptational demands placed on the organism by such disparate stressors as heat, cold, starvation, and other environmental insults—hence the expression “nonspecifically induced changes.”

A distinction is usually made between “stress” and “stressors.” Although stress is sometimes loosely used to refer to the environmental sources of threat to the organism, the term stressor is more appropriate in reference to these agents, whereas “stress” refers to the organism’s response.

More recent definitions of stress in humans emanate from a transactional model that takes into account the interactions between persons and their environment. In this view, stress occurs when a situational demand presents a call for action that the individual perceives as exceeding available resources. I have proposed the following working definition: “Stress is a process of interchange between an organism and its environment that involves self-generated or environmentally induced changes that, once they are perceived by the organism as exceeding available resources (internal or external), disrupt homeostatic processes in the organism–environment system.” This definition includes the traditional notion of stress as originating with an external demand (environmentally induced change) that exceeds the coping resources of the organism. It also includes, however, those expectations of events that arise from within, that are seen as essential to one’s life project, and that cannot be accommodated by the environment (exceeding external resources). The disruption of homeostasis in the organism–environment system can have its primary manifestation as a pathological end-state in the organism (illness or tissue damage) or as a destructive alteration of the environment (domestic violence as a stress response).

Psychoneuroimmunology

Psychoneuroimmunology (PNI) involves the study of the interactions of consciousness, the central nervous system (CNS), and the immune system (involving the body’s defense against infection and aberrant cell division). The compelling evidence of these studies is that the CNS influences immune function and that, conversely, the immune system can influence the CNS. The brain is normally part of the immunoregulatory network. Specifically, stimulation of the hypothalamic–pituitary–adrenal (HPA) axis leads to downregulation of immune system function in response to stress (see Figure 34-1). Stressful thoughts and emotions may reach the hypothalamus by axons projecting from the limbic system (primarily the amygdala) or from the forebrain. Corticotropin-releasing factor (CRF), produced in the hypothalamus under conditions of stress, acts on the anterior pituitary to release adrenocorticotropin hormone (ACTH), which in turn stimulates the production of corticosteroids in the adrenal cortex. Under conditions of acute stress, corticosteroids have immunosuppressive effects on the lymphoreticular system and marked antiallergic and anti-inflammatory effects.

In addition, CRF leads to release of catecholamines, which themselves may produce changes in lymphocyte, monocyte, and leukocyte functions. Opiates are also elevated with stress, and they are generally reported to be immunosuppressive. Finally, growth hormone and prolactin, which are immunoenhancing factors, are initially elevated at the onset of acute stress, but under conditions of prolonged stress their secretion is inhibited. Thus, the combined effect of elevated corticosteroids, catecholamines, and opiates, along with inhibition of growth hormone and prolactin, is to dysregulate the immune system.

Recent evidence indicates that chronic psychological stress can lead to increased production of proinflammatory cytokines, particularly interleukin-6 (IL-6), which is also triggered by infection and trauma. Proinflammatory cytokines have been implicated in a range of diseases in older adults that can be traced to inflammation, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain lymphoproliferative diseases or cancers (including multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia), depression, Alzheimer disease, and periodontal disease. IL-6 promotes the production of C-reactive protein, which is an important risk factor for MI. Depression and anxiety also enhance the production of proinflammatory cytokines, which is a possible mediator of the association of these disorders with increased morbidity and mortality (see Chapters 25 and 26). A recent study has shown that depressed subjects, compared with nondepressed controls, showed an impaired ability to regulate inflammation triggered by acute stress.

Another recent development in stress research involves the concept of “allostatic load,” which is the wear and tear on organisms that results from chronic overactivity or underactivity of allostatic systems. Allostasis refers to the body’s ability to produce hormones (e.g., cortisol) and other mediators (e.g., cytokines) that help it to adapt to novel situations or challenges. These systems, which include the autonomic nervous system (Figure 34-2), HPA axis (Figure 34-1), and the cardiovascular, metabolic, and immune systems, protect the body by responding to internal and external stress in an attempt to achieve stability through change.

Activation of allostatic systems in response to a stressor includes the release of catecholamines from nerves and the adrenal medulla, as well as the stimulation of cortisol release from the adrenal cortex via the HPA system described above. Four types of allostatic load can result from prolonged stress: (1) Repeated elevations of blood pressure over weeks or months accelerates atherosclerosis, increasing the risk of MI. (2) When adaptation to repeated stressors is lacking, there may be prolonged exposure to stress hormones. (3) There may be an inability to shut off allostatic responses after stress is terminated, leading to conditions such as hypertension or decreased bone mineral density. (4) Inadequate responses in some allostatic systems, such as cortisol secretion, may lead to compensatory increases in other systems, such as proinflammatory cytokines (which are downregulated by cortisol).

Stress, Food, & Inflammation

Inflammation is a common link for diseases high in mortality risk, including cardiovascular disease, cancer, and diabetes. Stress and depression, as well as dietary intake, can promote inflammation through proinflammatory cytokine production. Diet influences cytokine-induced inflammation by means of the balance between omega-3 (n-3) polyunsaturated fatty acids (PUFA) and omega-6 (n-6) PUFA, with n-6 (refined vegetable oils) promoting the production of proinflammatory cytokines and n-3 (fish, fish oil, walnuts, flax seed) mitigating their production. The link between depression and inflammation interacts with dietary balance, with higher n-6/n-3 ratios showing a relationship with depression. In epidemiologic studies, greater fish consumption has been associated with a lower prevalence of depression. A diet with higher n-6/n-3 ratio can also increase vulnerability to inflammatory responses to stress. Stress, in turn, promotes unhealthy food choices that promote inflammation, with higher stress associated with decreased fruit and vegetable consumption and increased consumption of sweets and fast food. Higher stress is also associated with higher peaks in postprandial lipidemia and delayed gastric clearing of these compounds, both associated with atherogenesis.

Effect of Psychological Interventions on the Immune System

In a series of studies on asymptomatic men following notification of human immunodeficiency virus (HIV) seropositivity, a 10-week program of cognitive behavioral stress management and aerobic exercise training programs buffered distress responses and immune alterations. The same intervention had positive effects on mood and immune function in gay men whose disease had become symptomatic. Meta-analyses of the placebo effect have shown positive effects in various inflammatory and immune-related diseases, including asthma, cancer symptoms (pain and appetite), Crohn disease, chronic fatigue, duodenal ulcer, irritable bowel syndrome, and multiple sclerosis (relapse frequency). A meta-analytic review showed that three classes of interventions could reliably alter immune function. Hypnosis with immune suggestions showed a positive influence on total salivary immunoglobulin A (IgA) concentration and neutrophil adherence, along with a modest suppression of intermediate-type hypersensitivity erythema. These effects were mediated through relaxation. Some studies have shown differential delayed skin sensitivity reactions on the right and left arm of subjects depending on which arm was suggested under hypnosis to show no changes. Conditioning interventions, in which a neutral stimulus is initially paired with an immune-modulating stimulus and later elicits the immune changes on its own, were able to enhance natural killer (NK) cell cytotoxicity. Disclosure interventions, which encourage patients to write essays about previously inhibited stressful experiences, have shown some success in reducing antibody titers to Epstein–Barr virus and enhancing the body’s control over latent herpes simplex virus production.

Stressful Life Events

In 1967, Holmes and Rahe published a scale of 43 life events, along with a method of quantifying life changes according to the amount of readjustment they require for the average person. This scale allowed greater quantitative precision in life change and illness studies and provided a pivotal methodological leap that broke through the circularity in which the stressful life changes had been measured in terms of illness outcome, rather than in terms of the inherent magnitude of the stressor. Questionnaires based on this and similar scales have gathered data on several populations globally. Retrospective studies have shown a relationship between recent life change and a host of pathological outcomes, such as sudden cardiac death, onset of MI, occurrence of fractures, pregnancy and birth complications, aggravation of chronic illness, tuberculosis, multiple sclerosis, diabetes, onset of leukemia in children, and onset of mental disorders such as depression and schizophrenia. Prospective studies, particularly those conducted on US Navy populations while deployed at sea, predicted future illness based on life change scores prior to deployment and subsequently verified the accuracy of those predictions by inspection of medical records.

Recent attention has focused on individual and situational variables that may mediate the relationship between life change and illness. Among the psychological variables that seem to mediate the stress response are locus of control (including the extent to which individuals prefer control in their lives and how much control they perceive they have over specific life events), need for stimulation, openness to change, stimulus screening, self-actualization, the use of denial, the presence of social supports, and emotional self-disclosure. In one study of Illinois Bell executives during the divestiture of AT&T, those executives who experienced high levels of stressors while remaining healthy differed from those with high stressors and high illness on a dimension of “hardiness.” This personal characteristic consists of “the 3 Cs”: a strong commitment to self, work, family, and other important values; a sense of control over one’s life; and the ability to see change as a challenge rather than a threat. More recently researchers suggest a “fourth C”: coherence, a belief that one’s internal and external environments are predictable and that things will work out as well as can be expected.

More recent studies of resilience (a concept related to hardiness) have focused on the neurochemical and hormonal feedback systems that dampen or switch off the stress response (HPA axis and sympathetic nervous system response described above). Among these resilience chemicals are DHEA (dehydroepiandrosterone), which lessens the effects of cortisol, and neuropeptide Y, which counters the effects of CRF at the anterior pituitary. These stress inhibitory mechanisms may be more prevalent in people who show a greater resiliency or hardiness in response to stressful events. Yet to be examined is the question of whether levels of these feedback chemicals are modifiable in response to stress management training or other psychological interventions.

Technostress

Increased use of mobile phones, smartphones, and the Internet has established new norms for work and connectivity in industrialized countries. Although allowing broader and more rapid access to information than ever before in human history, as well as increasing flexibility for work location and hours among many workers, these technologies also exact a toll on human health. In a recent Swedish study of young adults, high mobile phone use was a predictor of stress, sleep disturbance, and depression at a 1-year follow-up. Increased use of social media to interact frequently with friends near and far presents a paradox. On the one hand these media facilitate engagement with social support networks, which are a well-established stress buffer. Chatting and instant messaging are among the high-frequency activities of those in Generation Y (born after 1980). On the other hand, these media also lead to communication overload, the taxing of working memory through multitasking, distractibility, and guilt induced by the social expectation of immediacy of response and constant availability.

Stress in America Survey

The Stress in America survey published by the American Psychological Association (APA) revealed that those who serve as caregivers—providing care to both the aging and chronically ill—for their family members report higher levels of stress, poorer health, and a greater tendency to engage in unhealthy behaviors to alleviate that stress than the population at large. According to estimates from the National Alliance for Caregiving, 65.7 million Americans served as caregivers for an ill or disabled relative in the past year. In the APA survey, 55% of caregivers (median age 49 years) felt overwhelmed by the amount of care required by chronically ill or aging family members. Caregivers were more likely than those in the general population to report that they are doing a poor or fair job of managing stress and getting enough sleep. Mean stress level of caregivers (on a scale of 1–10) was 6.5 compared to 5.2 for the general public. Caregivers reported being poorer in health than the rest of the nation, with greater rates of high cholesterol, high blood pressure, overweight/obesity, and depression. Other survey findings were that caregivers were more likely than the general population to have chronic illness, to lie awake at night, to have poor nutrition, to skip a meal, and to get sick five or more times a year.

Work-Related Stress and Burnout

The demands of the workplace in industrialized societies are a persistent and intense stressor. Job strain is defined as a combination of high job demands and low perceived control. In a prospective study of healthy young adults (Cardiovascular Risk in Young Finns study), job strain was associated with increased carotid atherosclerosis among the men, but not the women.

In another prospective study, the degree of job stress over time increased the risk of the metabolic syndrome in a linear fashion. Subjects with lower grades of employment suffered disproportionately from the effects of stress as a risk factor for the metabolic syndrome, with men showing more susceptibility than women. Burnout is a syndrome associated with unrelenting stress and has been studied extensively as a phenomenon in a variety of work settings and professions, including physicians. It includes symptoms of emotional exhaustion, depersonalization, and a decreased sense of personal accomplishment. In a prospective study, burnout was associated with an increased risk of type 2 diabetes in apparently healthy individuals.

In Japan, the concept of karoshi, or death from overwork, has received government attention in recent decades. Rapid growth in industrialization following World War II led to production efficiencies placing pressure on Japanese workers, who often worked overtime without additional compensation. A new phenomenon of sudden death among high-level businessmen who were previously healthy brought attention to these stressful work environments. In 2008 in a well-publicized case a company was ordered to pay 200 million yen to a man who overworked until he fell into a coma. Among statistics published by the Japanese Ministry of Health, Labor, and Welfare in 2007 for the previous year, 189 workers had died from overwork, many from heart attacks and strokes, and 208 more had become severely ill.

The Role of Acute and Chronic Stress in Cardiac Disease

Acute stress activates the sympathetic nervous system (Figure 34-2), which leads to increases in heart rate and blood pressure, coronary vasoconstriction, and decreased myocardial electrical stability. Several behavioral and emotional events have been implicated as probable triggers of acute coronary syndromes (MI and sudden cardiac death) in vulnerable individuals, especially events within a 1-to 2-hour period before the onset of symptoms.

Behavioral triggers include physical exertion (more common in men than women), sexual activity, sleep disturbance, and heavy consumption of alcohol. Well-studied emotional triggers include earthquakes, sporting events, war, high-pressure deadlines at work, and anger. In one study, the relative risk of acute MI in the 2 hours following an anger episode was 2.3, and in comparison with a control period 24 hours earlier it was 4.0. This effect was independent of age, sex, cardiovascular risk factors, and use of beta-blockers. The risk of anger triggering an MI was inversely related to socioeconomic status. In a large-scale study, the relative risk of anger triggering an MI was 9.0 compared to usual levels of anger, but when limiting the analysis to patients who had no premonitory symptoms the relative risk increased to 15.7.

Examination of the stored electrocardiograms of 200 New York area patients with implantable cardioverter-defibrillators showed differences in ventricular tachyarrhythmias triggering cardioverter-defibrillator therapy before and after the World Trade Center attack of September 11, 2001. There was a 2.3-fold increase in ventricular tachyarrhythmias during the month after 9/11, relative to other months between May 2001 and October 2002. Similar to the data from the 1996 European football championships mentioned above, in a study examining daily cardiovascular disease events in Munich during the 2006 World Cup, cardiovascular emergencies increased 2.7 times in men and 1.8 times in women on the days when Germany was participating in the quarterfinals and semifinals. On these days, MI and major arrhythmia admissions increased three times compared with the same day in previous years. The highest incidence of cardiac events occurred during the first 2 hours of the games.

In addition to promoting unhealthy behaviors, chronic stress activates and reactivates the sympathetic nervous system. Repeated sympathetic stimulation increases heart rate and blood pressure, and autonomic nervous system dysregulation leads to decreased heart rate variability and baroreflex dysfunction, which has been associated with cardiovascular disease events. Depression increases levels of inflammatory markers, including fibrinogen, C-reactive protein, IL-6, and tumor necrosis factor. Chronic stressors also activate the HPA axis producing hypercortisolemia, which in turn promotes central obesity and insulin resistance, risk factors for cardiovascular disease.

Chronic work stress, defined as high demands and low control, was associated with cardiovascular disease events in a study of 10,308 middle-aged London-based civil servants, with work stress contributing a relative risk of 1.68. Associations were found between work stress and negative behaviors, such as low physical activity and poor diet, and pathophysiologic consequences, such as decreased heart rate variability and an increase in morning cortisol.

In the Caregiver Health Effects study, 400 caregivers showed a 63% higher mortality rate than noncaregiving control subjects over a 4-year period. The increased mortality was particularly evident in caregivers who already had known cardiovascular disease. In a series of physiologically oriented studies, the San Diego Caregiver study examined possible pathways between caregiving and cardiovascular disease. Distressed caregivers had an increased risk for developing hypertension when followed over a 6-year period. Caregivers also had increased levels of D-dimer (a circulating procoagulant factor), more sleep disruption, and higher levels of circulating inflammatory cytokines.

Personality Influences on Cardiovascular Disease

Recent research has examined the relationship between coronary heart disease and a personality constellation that includes hostility, anger, cynicism, suspiciousness, and excessive self-involvement. Hostility is conceptualized as comprising three elements: the emotion of anger; its expression; and cognitions of cynical mistrust. Using well-validated measures of the cognitive aspect of hostility, studies have linked higher hostility scores with subsequent coronary events like hospitalizations for angina, nonfatal MI, stroke, and congestive heart failure. Higher hostility has also been associated with coronary risk factors, such as increased plasma homocysteine levels, triglycerides, body mass index, waist-to-hip ratio, glucose levels, alcohol consumption, and smoking. In a study of middle-aged women, each 1-point increase in hostility scores predicted a significantly higher intimal–medial thickening in the carotid arteries.

Gender Differences

Females have been noted to respond to stress with a “tend-and-befriend” way of coping, in contrast with the “fight-or-flight” model that may be more characteristic of males. When confronted with stress, females tend to engage in nurturing activities that protect themselves and their offspring and that enhance social support, which has been identified as a powerful stress buffer. In particular, there may be links between estrogen and a blunting of oxytocin, which is implicated in the fight-or-flight response. The “tend-and-befriend” response may also lower blood pressure.

Positive Cognitive Styles

Evidence is accumulating from a variety of studies that optimism, perceptions of personal control, and a sense of meaning are protective of physical health. These cognitive resources assume special significance in helping people cope with intensely stressful events. Even unrealistically optimistic expectations appear to slow down the progression of disease in men infected with HIV. In a study of healthy older adults, a sense of coherence (one indicator of resilience) moderated the association between anticipation of moving and reduced NK cell lysis, with a low sense of coherence associated with poorest levels of NK cell lysis. In a recent study of the cognitive and psychological sequelae of the 2011 Japanese earthquake and tsunami among survivors in the primary disaster area, posttraumatic stress had a major impact on self-perceived quality of life 3 months after the disaster. The study authors concluded that reducing negative cognitions would have a greater impact than positive re-appraisals on lowering depression and anxiety in this early stage of response. It was expected that positive re-appraisals leading to posttraumatic growth (PTG) would occur over longer time frames. Similar to the time course of recovery from other disasters, it was expected that PTG would include enhanced relationships with others, a sense of new possibilities, self-perceived personal strength, a sense of purpose in life, the concept of ikigai (meaningfulness), and a deepened spirituality.

Religion and Spirituality

Several studies have shown a relationship between religious or spiritual practice and health outcomes. “Religion” can be considered a collection of beliefs and practices that are external expressions of spiritual experience. These expressions can be organizationally based or private, but are usually grounded in a collective tradition. “Spirituality” can be considered an orientation toward or experiences with the transcendent, existential, or sacred dimensions of life. That which is transcendent or sacred is considered as something beyond oneself, whether it be conceptualized as a divine being, higher power, nature, spirit, or the ultimate ground of being. It is possible for people to engage in religious activities independent of having spiritual experiences, just as some people consider themselves intensely spiritual without being religious. Some consider their religious practice to be a pathway toward spirituality.

Types of studies on the religion–health connection have included cross-sectional as well as prospective and retrospective studies where participation in religious or spiritual practice is correlated with some health outcome measure, as well as intervention studies in which subjects were randomized into treatment and control groups. Correlational studies of religious or spiritual involvement and health outcomes have shown a positive association with longer life; less cardiovascular disease; less hypertension; more engagement in health-promoting behaviors; decreased risk of depression, anxiety, substance abuse, and suicide; better coping with illness; and better health-related quality of life. Among the intervention studies the best evidence for efficacy with health outcomes has been with religiously oriented cognitive therapy, meditation, 12-step fellowships, forgiveness therapy, and intercessory prayer. These studies need further replication with better designed controls.

Both religion and spirituality represent a heterogeneous group of belief systems, religious practices, and spiritual experiences. Most of the research linking religious or spiritual practice to health outcomes does not account for this heterogeneity, and thus the generalizability of results is limited. Nevertheless, the growing accumulation of evidence of positive health correlates of religion and spirituality warrants not only more sophisticated research but the attention of clinicians seeking to improve the health of patients.

In allowing the patient to disclose her psychological and social stressors, the physician was able to gain relevant information within a biopsychosocial perspective of patient care. Relevant stressors potentially contributing to this patient’s medical symptoms included caregiving for a disabled partner, having to assume a parenting role of grandchildren, and a self-expectation of a way of loving her partner that allowed no escape for her from an uncontrollable situation. In allowing the patient’s emotional self-disclosure, there was an immediate effect on mitigating migraine symptoms. Going forward from this interview, it was important for the physician to have a pathway to navigate and orchestrate the various biological, psychological, and social interventions relevant to this patient’s condition.

The etiology of illness and its waxing and waning course are multifactorial. Any given illness episode is determined by many circumstances. The complex pathway by which stress influences the outcome of illness is subject to the ongoing accumulation of data and elaboration of heuristic and clinical models. A model of stress that can aid diagnosis, prevention, and intervention is shown in Figure 34-3. Adapted from an optical model first proposed by Rahe and Arthur (1978), it depicts stressors as light rays filtered through successive lenses representing the individual’s perception (threat appraisal), coping, physiologic processes, and arousal reduction activities, and then projected onto illness outcome screens. Each lens either augments or diminishes the intensity of light (heavy bold lines or dotted lines, respectively) on its pathway to illness outcome, and represents a potential focal point for the clinician’s diagnosis of a stress influence or risk factor for patient illness. Each lens also represents a potential focus of preventive health care or intervention.

Perception refers to the person’s appraisal of the threat involved in various stressors. Several personal variables that may affect the degree of perceived threat are shown in Figure 34-3. For example, the degree of a person’s openness to change or the extent to which he or she values change influences whether a particular life change, such as a child leaving home, is perceived as a threat to the self or an opportunity for growth. The degree of control individuals prefer to have in their lives, as well as the amount of control they perceive they have over specific stressors, also influence their perception of threat. Thus, a parent with a high need to control an adolescent child’s outside activities experiences more stress when the child struggles toward emancipation than does a parent who has less of a need for control and who trusts the child’s judgment.

Coping refers to methods an individual uses to mitigate the influence of stressors perceived as threatening. One approach to coping is “exposure management,” or attempts to increase or decrease the amount and intensity of stressors encountered. Thus, an overworked, overcommitted manager might attempt to mitigate stress by withdrawing from some commitments, by reducing work hours, and by delegating more responsibility to subordinates. Social supports are an important stress buffer, and successful coping with stressors may involve both developing confiding relationships and increasing the amount of one’s self-disclosure about the effect of stressors in one’s life. There is some evidence that emotional self-disclosure about stressors enhances immune functioning. In the aftermath of the September 11, 2001 attacks, it is estimated that 98% of Americans coped by talking with others, 90% by turning to religious or spiritual practices, 60% by participating in group activities to memorialize the events, and 36% by making donations. “Stimulus screening” involves techniques to focus attention on relevant stimuli and to regulate the overall flow of stimulation to one’s optimal level of functioning.

Two major classes of physiologic response to stressors that lead to target organ pathology are autonomic hyperreactivity and immunosuppression. Both are cortically mediated through the individual’s perceptions and methods of coping. Hyperreactivity in the presence of stress, sometimes called the defense reaction, has been shown to be a factor in disease processes specific to vulnerable organ systems in persons with established disease. Thus, exaggerated pressor responses in hypertensives, increased electromyelogram responses in those suffering from tension headaches and chronic back pain, disturbances in glucose metabolism in insulin-dependent diabetics, and bronchoconstrictive responses in asthmatics are all examples of hyperreactivity in the presence of a definable stressor. In the case of hypertension, hyperreactivity is present in normotensives at risk for the disorder and in some studies has predicted future blood pressure levels. Other examples are increased levels of serum cholesterol seen in studies of tax accountants in the 2 weeks prior to April 15 and of fighter pilots landing on aircraft carriers compared with pilots on long commercial airline flights.

One of the adaptive functions of sympathetic activation (Figure 34-2) is to prepare the organism for large-muscle movement to either attack or flee a threat. In the twenty-first century human society, these somatomotor responses are often voluntarily suppressed or sublimated, leading to delayed elimination of released glucose and fatty acids and often bringing more powerful and prolonged increases in blood pressure. In addition, the relative absence of skeletal muscle exertion in affluent societies (without compensatory aerobic exercise) prevents the activation of endorphins that normally accompanies muscle exertion. Because these endorphins dampen mental arousal and sympathetic activity, in the absence of skeletal muscle exertion these arousal and activation states are prolonged.

Immunosuppression, as discussed previously, occurs through the mechanisms of increased levels of circulating corticosteroids, catecholamines, and opioids and decreased levels of growth hormone and prolactin under conditions of chronic or prolonged stress. Sometimes referred to as the defeat reaction, this response pattern occurs when patients are exposed to long-term stressful situations that tend to overwhelm ordinary coping mechanisms, thus leading to despair or deep sorrow in situations that appear to be beyond all hope and rescue. Rather than working directly on target organ systems as in the case of hyperreactivity, downregulation of the immune system in the defeat reaction increases vulnerability to external invasive organisms and endogenous neoplasms.

Several arousal reduction strategies are available to individuals to mitigate physiologic activation and disruption of homeostatic processes in conditions of stress. These include both health-enhancing and health-degrading activities. Among the health-enhancing arousal-reduction strategies are exercise, which expends accumulated corticosteroids and dampens sympathetic activation through the release of endorphins, and various approaches to stimulating the parasympathetic nervous system (Figure 34-2). This latter category includes relaxation exercises, abdominal breathing, self-hypnosis, meditation, soothing music, massage, and contact with nature (see Chapter 9).

Health-degrading activities, which may be attempts at physiologic arousal reduction but that actually magnify the stress response and lead to target organ disease, include substance abuse, tobacco use, and eating disorders. Intensification of all of these behaviors may coincide with stressful life episodes. An example is the mediating role of increased alcohol intake in the relationship between occupational stress and hypertension seen in studies of air traffic controllers.

Various illness outcomes of stress include biomedical disease manifested in specific organ systems, such as cardiovascular, immune, and neurologic disorders; emotional and cognitive disorders, such as depression, anxiety, and somatization; and behavioral disorders, such as violence, performance impairment, absenteeism, and overuse of health care resources. These stress outcomes are the usual focus of medical and mental health intervention, but the larger model of the stress pathway provides primary care clinicians with potent opportunities for comprehensive preventive health care.

Each organ system has a unique susceptibility to stress. The following is a brief overview of some of the stress and treatment implications in specific diseases.

Cardiovascular

Cardiovascular disease is the leading cause of mortality in the United States. As reviewed above, stress contributes to all expressions of heart disease, including coronary artery disease, congestive heart failure, and sudden cardiac death. Because a third of sudden cardiac deaths and MIs cannot be fully explained by the severity of the standard cardiac risk factors—family history, hypertension, dyslipidemia, diabetes, or tobacco use—stress may explain some of this variance. As mentioned above, there is a connection between hostility and cardiac disease. It has been shown that hostility contributes independently of other risk factors to the pathogenesis of heart disease through lipid accumulation, increased blood pressure, and heart rate and platelet physiology.

Mind–body therapies show promise in the treatment of coronary artery disease. A meta-analysis of the use of psychoeducational interventions (health education and stress management) as a component of cardiac rehabilitation showed an overall 34% reduction in mortality, a 29% reduction in recurrent MI, and positive effects on dietary and exercise habits, weight, smoking, cholesterol, and blood pressure.

Immune

Clinical expressions of immune deficiencies are in part the result of stress. They range from the common cold to some forms of cancer. Although research on the relationship between stress and cancer is still inconclusive, there is some evidence that stress and surgical excision of the primary tumor can promote tumor metastasis by suppression of cell-mediated immunity. The perioperative period is a particularly important window during which psychological or pharmacological interventions to prevent or reduce stress may offer a reduced risk of metastasis. Other immune-mediated diseases, such as rheumatoid arthritis and systemic lupus erythematosus, may show a pattern of exacerbation brought on by stress.

HIV

More rapid disease progression in people infected with HIV has been associated with greater concealment of homosexual identity, more cumulative stressful life events, and less cumulative social support over a 5-year period. Alternatively, more deliberate cognitive processing about the death of a close friend or partner has been associated with greater likelihood of finding positive meaning in the loss, less rapid decline in CD4+ cell levels, and lower rates of AIDS-related mortality over a 9-year period in HIV-seropositive men.

Neurologic

All forms of stroke show a circadian expression in their presentation, with peaks during the early morning hours when catecholamines are highest. Dizziness, vertigo, and other balance disorders often have stress as a causative or contributing factor. One of the most common neurologic expressions of stress in clinical practice is headache. Both tension headache and migraine headache are substantially influenced by patient stressors. Meta-analysis has shown behavioral interventions (relaxation training and skin temperature biofeedback) to be as effective as medication in treatment of migraine headaches. Hypnosis with hand-warming imagery is an effective method to reverse the progression of migraine headache, especially early in the prodromal stage (see Chapter 5).

Gastrointestinal

Peptic ulcer disease may have an association with stress. Gastric hyperacidity and excess pepsin production are hallmarks of the sympathetic arousal that occurs during stress. Inflammatory bowel syndrome (IBS), which is characterized by abdominal pain with altered bowel habits (constipation or diarrhea) in the absence of a definable lesion or structural abnormality, frequently correlates with periods of emotional stress. The human “defense reaction” (fight-or-flight response) promotes activation of the cardiovascular system along with inhibition of gastric motility. The role of stress in promoting proinflammatory cytokines is a probable mechanism in the etiology of this disorder. Inflammation is also associated with depression, which is frequently a comorbidity with IBS.

Musculoskeletal

Some forms of arthritis show stress-related exacerbations. Complex syndromes such as fibromyalgia seem to have a psychosocial trigger. Temporomandibular joint (TMJ) dysfunction and its related pain syndrome are frequently associated with mental stress. Chronic pain tends to correlate with stress in a person’s life. Persistent pain and psychological symptoms frequently seen after motor vehicle accidents (MVA) may involve the impact of acute stress interacting with past experience, post-MVA behavior, and cognitive/psychological consequences to alter activity in brain pathways that process pain.

Pulmonary

Asthma and chronic obstructive pulmonary disease appear to be worsened by stress. Conversely, one of the more powerful, self-regulatory, stress-control techniques is relaxed abdominal breathing. Asthmatics who participate in stress reduction programs have shown improved physical activity and decreased medical visits. Hypnosis has helped some asthmatics decrease their use of bronchodilators (see Chapter 5).

Reproductive & Genitourinary

The neurohormonal, vascular, and immunologic effects of stress significantly impact the reproductive and genitourinary systems. Changes in estrogen and testosterone levels can show marked association with environmental and psychological stressors. Amenorrhea frequently occurs during stressful times in the lives of women. Fertility also can be affected by stress. Dysmenorrhea, dyspareunia, endometriosis, and impotence all have substantial stress and strain connections.

Dermatological

A variety of skin lesions and rashes have been associated with the stress response. Stress-induced vasomotor changes may aggravate inflammatory dermatoses. Vasodilation is considered to be responsible for the thermal aggravation often expressed as pruritus. This lowering of the itch threshold by vasodilation may account for the pruritus seen with many dermatological syndromes. Emotional stress, fear, and pain are all accompanied by substantial drops in skin temperature of the fingers.

Wound Healing

Psychological stress has measurable negative consequences for production of proinflammatory cytokines, and stress-related delays in wound healing have ranged from 24% to 40% with effect sizes between 0.30 and 0.74. These effects on wound healing are consistent with other studies that have shown that greater fear or distress prior to surgery is associated with poorer outcomes, including longer hospital stays, more postoperative complications, and higher rates of rehospitalization.

Frailty in the Elderly

Elevated serum levels of the proinflammatory cytokine IL-6 have predicted future disability in older adults. These cytokines slow muscle repair after injury and accelerate muscle wasting. IL-6 and C-reactive protein play a pathogenic role in several diseases associated with disability among the elderly, including osteoporosis, arthritis, and congestive heart failure.

Given the multivariate, multiple-pathway nature of the stress response, clinical diagnosis of stress assumes a multifactorial approach. Traditional medical diagnosis and treatment occur at the point of illness manifestation in target organ systems. From the broader perspective of stress medicine, however, each of the lenses in the optical model (see Figure 34-3) is a potential focus of diagnosis.

The Medical Interview

The richest source of data concerning stressors, perception, coping, and arousal reduction strategies is the medical interview (see Chapter 1). Having the stress model in mind allows the clinician to inquire about current and recent life stressors and to make note of significant clusters of stressors that precede illness onset. A careful history should uncover whether life stressors are temporally related to the onset of chronic disease and to periods of disease exacerbation.

During the interview, the clinician can ask patients about their beliefs, expectations, self-perceptions, and needs that influence how stressors are perceived. For example, asking patients how much control they prefer in their lives and how much control they perceive that they have over specific life events can determine whether there is congruence or incongruence between preferred control and perceived control. Incongruence tends to amplify the effect of stressors. It is also helpful to ask patients how they view their own resources (internal and external) for coping with stressors, since the more the perceived threats exceed the perceived personal resources, the greater the stress involved.

Patients’ approaches to coping with stressors should also be probed in the interview. The presence or absence of social supports as well as the ability of patients to access these supports through self-disclosure are critical data for facilitating stress management. The perceptual and coping styles uncovered in the interview have implications for management of the patient’s health, both in prevention and intervention.

It is also important to assess patients’ approaches to arousal reduction and to ascertain the balance of health-enhancing and health-degrading strategies. The following questions can be helpful in this regard: “What are the signs indicating that you are experiencing stress?” “What are your physical symptoms?” “What happens in your emotional life?” “How do you act differently when you are stressed?” Methods used to mitigate this arousal can then be ascertained: “When you notice these signs of stress, what do you do to reduce the intensity of the physical symptoms?” It is also important to elicit the short-and long-term outcomes of these strategies: “How does this strategy work for you?” “How does it affect the way you feel immediately? … several hours later? … the next day?” Sometimes it is helpful to ask about specific arousal reduction techniques: “Do you practice a form of meditation or relaxation exercise?” “Do you get regular physical exercise?” When questioning patients about substance use or tobacco use, it is helpful to ask whether their use is associated with periods of stress.

Self-Report Questionnaire

A multitude of self-report questionnaires and inventories have been developed for research purposes that measure stressors and many of the variables listed in Figure 34-3 related to perception and coping. Given the limitations of physician and support staff time, it is recommended that any questionnaire be simple, brief, and provide data that can be used by the clinician in counseling patients in the area of stress management. An example of such an instrument is the Life Stress Inventory shown in ^fel_ch34apa. Borrowing from the life event scaling studies and the critical role that perceived control plays in mediating stress, this inventory asks patients in an open-ended way to list the major events (and expected nonevents), changes, and stressors that have occurred during the previous year. They are asked to check those stressors that are current, ongoing problems. In addition, patients are asked to rate each stressor on a scale of 1–10, indicating the extent of perceived control they had over these events. The provider can take the mean of the control ratings and place that number (1–10) in the “control score” blank. This instrument provides both qualitative and quantitative data on the nature of patients’ stressors, those that are a current source of struggle, and patients’ perceived control over these events. The higher the external control score, the more at risk the patient is for adverse consequences of stress. Examining with patients those stressors that seem under their control can allow the clinician to suggest lifestyle changes in those areas. In some instances, patients can be counseled to adjust their perceptions of no control in the direction of greater control. For example, a patient who perceives that she/he has no control over her/his work hours can be helped to see areas in which limits can actually be set. In other cases, patients can be led to consider changing their expectations and accepting areas that are truly beyond their control.

Stress Management in the Intensive Care Unit

The immune system of many patients in the intensive care unit (ICU) is suppressed due to trauma, sepsis, or profound physiologic and psychological stress. Increases in cortisol levels have been found to correlate with severity of injury in minor and moderate trauma immediately after injury and hours later. Sepsis often begins as a local process of inflammation involving cytokine upregulation. These cytokines eventually, however, may move into circulation, leading to inflammatory processes systemically. Psychological stressors reported by ICU patients include pain, sleep deprivation (due to noise, disturbances by health care staff, and pain), and fear or anxiety (which may manifest in the extreme as delirium, confusion, and other unreal experiences), each of which is associated with decreased immune functioning. The implications for the ICU team are that intervening to reduce these psychosocial stressors may help prevent nosocomial infection. Feelings of anxiety and isolation can be buffered by a nurse providing a nurturing presence. Anxiety can be decreased through the use of benzodiazepines, which may also aid sleep. Nurses can attempt to minimize noise levels as much as possible and decrease the number of times patients are disturbed. Although many analgesic drugs used in the ICU can suppress immune function, alternative approaches to reducing pain should be attempted, since pain itself is immunosuppressive.

Stress Management in Primary Care

The model of stress, shown in Figure 34-3, offers the clinician various foci for illness prevention and intervention, just as it does for diagnosis. The clinician familiar with this model should be able to tailor specific psychological, social, behavioral, and pharmacological strategies to the unique needs of individual patients. This is preferable to referring the patient for “stress management,” since this generic term does not address the multiplicity of stress-related variables and pathways discussed earlier.

Communicating with Patients about Stress

A primary component of stress prevention and treatment involves the way stress is discussed with patients. Avoiding the implication that “it’s all in your head” is of great importance. Equally important is avoiding the message that “you are responsible for your illness,” which implies greater personal control over somatic processes than is realistic. Here the risk is inducing guilt in patients who become ill and who feel they have failed at being a “better person.” Avoiding negative emphases, for example, “Your hectic pace is going to kill you,” in favor of a positive framing of the health benefits of stress management is more likely to have a positive influence (see Chapter 5). For example, the clinician can express optimism about the patient’s ability to influence health as follows: “Fortunately there are many avenues available for examining and changing your habits of thought and ways of responding to life challenges. I’d like to give you an overview of some strategies that we can discuss now and in future appointments.” Showing the patient a model such as that in Figure 34-3 can be helpful as part of this discussion.

It is also important to frame beneficial lifestyle changes as the patient’s choice. Rather than using the stress model to assume more responsibility for patients’ lives, the primary care provider can act as a consultant and coach, clearly giving feedback to patients about the patterns of stress revealed by the diagnostic workup and offering concrete strategies for health promotion along with likely consequences for adherence and nonadherence (see Chapters 19 and 20).

Counseling about Perception & Coping

The perception and coping variables listed in Figure 34-3 represent potential topics for primary care counseling with patients. Depending on the clinician’s expertise, inclination, and time, this could be done during a portion of several primary care visits. For example, a parent who is feeling stressed because of a teenager’s oppositional behavior could be invited to reflect on how much parental control is needed and coached on ways of setting realistic limits. With an accountant feeling overwhelmed about a recent promotion to senior management, the clinician could elicit the patient’s recollections of previous adaptations to challenging life changes to help him become cognizant of his own resources.

Referring a parent of a child with recently diagnosed leukemia to a support group of other parents is an example of a coping strategy. Encouraging a widower to confide feelings of sadness to close friends is an example of helping a patient improve his use of social supports. Referring a teacher with a chronically explosive temper for short-term anger management therapy would potentially reduce a cardiac risk factor.

Counseling patients about time management offers a rich opportunity for clinicians to raise questions concerning the patients’ values and missed opportunities for personal renewal. For example, the clinician can ask the patient to reflect on those important but nonurgent activities that can contribute to personal well-being (e.g., time spent playing with a child), but which are consistently postponed in favor of more urgent but less important tasks (e.g., keeping track of the performance of stocks). A list of potential nonpharmacological strategies related to perception and coping that can be suggested to patients is shown in Table 34-1.

Arousal Reduction Strategies

For patients showing a high degree of autonomic hyperreactivity, the clinician can provide or suggest several arousal reduction strategies that can work synergistically with perception and coping skills, as well as with pharmacological interventions. These strategies are listed in Table 34-2. Mindfulness meditation in particular is an effective method of stress reduction that not only activates the parasympathetic response, but builds a mental habit of staying present to the task at hand while assuming a nonjudgmental stance toward the progression of one’s thoughts and emotions (see Chapter 7). Referring patients to introductory books on mindfulness meditation, such as those listed at the end of this chapter, or encouraging them to take a meditation class, can provide them with a powerful stress management resource. One study showed that 16 weeks of transcendental meditation improved components of the metabolic syndrome (blood pressure, insulin resistance, and heart rate variability) among patients with stable coronary heart disease.

Referral for Psychotherapy

The clinician may choose to refer patients for psychotherapy or to educational groups to achieve some of the desired outcomes in the areas of perception, coping, and arousal reduction techniques. These referrals are more effectively targeted to the unique needs of patients if the clinician uses the multifactorial model in Figure 34-3. This model can also aid the primary care clinician in communicating with the psychotherapist about possible foci for treatment. Psychotherapy may be more effective than primary care counseling for altering dysfunctional belief systems (e.g., a perception of no control in one’s life) or coping habits (e.g., excessive need for achievement) that amplify stress. In addition, it may offer focused training in the acquisition of arousal reduction skills such as meditation and self-hypnosis.

The relationship between stress and disease is well established, although the specific pathways are complex and multifactorial. Clinicians increasingly are asked to examine the cost-effectiveness of the time spent with their patients with a view to improving outcomes within the constraints of available financial and human resources. Attention to the function of stress in patients’ illnesses creates the potential for improving treatment outcomes and preventing or delaying the onset of costly target organ disease or the exacerbation of chronic illness. Applying a multidimensional stress model that includes patients’ perceptions, coping strategies, physiologic arousal mechanisms, and arousal reduction strategies offers the health care professional multiple opportunities for influencing the ecology of disease.

PsychoNeuroImmunology Research Society.

http://www.pnirs.org/. Accessed January 2014.

Center for Mindfulness in Medicine, Health Care, and Society.

http://www.umassmed.edu/cfm/. Accessed January 2014.