Physician's Information



Study Summary and Physician Referral Information

Purpose / Study Design

The purpose of our NIH-funded clinical trial is to determine whether moderate exercise will improve immune response to influenza immunization in adults > age 65. Adults will be randomly assigned to either an aerobic exercise group or a flexibility/strength group. Subjects will attend supervised exercise sessions, 3 times per week, for approximately one year. The subjects assigned to the flexibility/strength group will have the option of joining the aerobic exercise group after their year as a subject is completed. Influenza vaccine will be given at the beginning of the year (fall 2003) and at the end of the year (fall 2004). Blood samples will be collected prior to and at several time points after immunization to measure immune response to the vaccine (antibody titer, influenza-specific cytokine production, lymphocyte proliferation, and cytotoxic lymphocyte function). We will also examine the association between psychosocial factors and immune response.

Benefits of Exercise

Regular exercise has been associated with a decrease in the risk of developing heart disease, diabetes, osteoporosis, and other chronic diseases. However, the potential benefits of moderate exercise on immune responsiveness are unknown. With aging, immune responsiveness declines and the results from our previous studies suggest that exercise has a greater impact on immune function in older populations than in younger populations.

Physician Assistance with Subject Recruitment

Although physicians may recommend exercise for their patients, few patients adhere to an appropriate exercise program. Adherence improves when exercise is supervised and participants are given information regarding their progress. In our pilot study, 100% of subjects assigned to the exercise group adhered to the assigned exercise program and completed one year of supervised moderate-vigorous exercise. Although we don't expect 100% retention in our larger study, we are successfully using strategies that improve subject retention. If you have older patients that may benefit from regular exercise, please consider telling your patient about our study. We will make every effort to assist your patient in safely starting and adhering to a moderate exercise program.

Most persons over age 65 will be eligible as long as they can participate in exercise and are not suffering from immune disorders. The complete list of exclusion/inclusion criteria is provided under the Subject Inclusion/Exclusion Criteria section below. We especially need patients taking non-selective beta-adrenergic blockers () to test neuroendocrine/immune interaction. The subject recruitment period is September and early October 2003.

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Research Abstract
The goal of this study is to investigate the effects of a long-term exercise program on older adults, in terms of the immune response to influenza vaccination; and to examine exercise-associated alterations in psychological state as potential mediators of the exercise-induced modulation of immunity. We hypothesize that exercise will be associated with an enhanced immune response to the vaccine and improved psychosocial state. Older adults experience a greater incidence and severity of influenza infection as well as reduced vaccine efficacy. The elderly population experiences psychosocial changes that may have a negative impact on their immune response such as bereavement, isolation, loss of independence, stress associated with role as a caregiver, etc. Moderate exercise has been associated with reduced anxiety and depression, improved mood-state and esteem and enhanced antigen-specific immune response in an aged population. Exercise may directly alter immune responsiveness in older adults and/or indirectly modify psychosocial state with subsequent effects on immune response. Direct immunomodulatory effects of exercise may be mediated via neuroendocrine outflow. We hypothesize that the immunomodulatory effects of exercise are mediated by the binding of catecholamines released during exercise to lymphocyte beta2-adrenergic receptors. We propose to test this hypothesis by including a group of subjects treated with non-selective (beta 1, beta 2) adrenergic receptors antagonists. The broad approach used in the proposed experiments in terms of immune function, psychological, and physiological responses may provide a basis for further study into the mechanisms mediating these relationships. Exercise is often recommended for older adults without documentation of clinical benefits, and the findings from this study may have importance both from a basic research and clinical perspective, if exercise is associated with enhanced immunity and improved protection from infection.



Specific Aim 1
We will evaluate the effect of exercise and exercise-induced alteration of psychosocial state on the immune response to influenza vaccination in older adults (n=72, > age 65). We hypothesize that exercise will enhance immune response to the vaccine and improve psychosocial state. The exercise intervention consists of 12 months of moderate to vigorous intensity, supervised aerobic exercise. The flexibility/strength exercise will be performed at a very low intensity. The immune responses will be assessed pre/post-immunization and pre/post-intervention. Outcome measures of immune response are anti-influenza IgG1, IgG, influenza-specific peripheral blood mononuclear cell (PBMC) proliferation, influenza-specific cytokine production (interleukin (IL)-2, IL-10, interferon (IFN) ) and cytotoxic T lymphocyte (CTL) function. Assessment of psychosocial status (perceived stress, depression, social support, positive/negative affect, daily hassles/uplifts) will be conducted at several time points throughout the study.



Specific Aim 2
We will test the hypothesis that the immunomodulatory effects of exercise are mediated in part by the exercise-induced release of catecholamines. A subgroup of subjects (n = 32, > age 65) currently treated with non-selective (beta 1, beta 2) adrenergic receptor antagonists for blood pressure control will be used to test this hypothesis. The 12-month exercise intervention / control treatment and outcome measures are identical to Specific Aim 1. According to our hypothesis, subjects treated with beta-adrenergic receptor blockade in the exercise intervention group will not demonstrate enhanced immune response to the vaccine.



Numerous studies have documented that a bidirectional communication between the neuroendocrine system and immune system exists, and that behavior may influence immunity. However, fewer studies have been able to demonstrate, in a controlled trial, that a particular intervention results in changes in psychosocial state, and that the adaptations in psychosocial state are subsequently related to an alteration of immune function. To our knowledge, long-term exercise training has not been studied as an intervention strategy with the intent of altering psychological state and immunological response. Numerous studies in both young and older adults demonstrate exercise-associated improvements in psychological well-being. Psychosocial state also influences immunity and therefore it is plausible that exercise-induced improvements in psychosocial state may impact immunity. Exercise as a physiological stimulus, rather than psychological stimulus, may also influence immune response via the release of neuroendocrine factors such as catecholamines. The inclusion of subjects treated pharmacologically with non-selective beta adrenergic antagonists provides an opportunity to test a mechanism of exercise-induced immunomodulation. We believe that the study of these behavioral-neuroendocrine-immune interactions, and the use of interventions to enhance immunity, may have particular biological and clinical relevance for older adults, given that there is a progressive decline of immunity with age and an increased incidence of life events associated with stress and/or depression.



Overall plan and hypotheses

In this study, we will test hypothesis #1 that 12 months of moderate to vigorous aerobic exercise will increase: influenza-specific CTL function, influenza-specific lymphocyte proliferation, influenza -specific cytokine production (IL-2, IFN, IL-10 measured in supernatants by ELISA and with intracellular cytokine staining techniques), anti-influenza IgG and IgG1 titer, in individuals > 65 years of age. Half of the subjects will be randomly assigned to an aerobic exercise group and the other half will be assigned to a flexibility/strength control group. Subjects in the aerobic exercise group will attend supervised aerobic exercise (treadmill, bicycles, rowers etc) sessions three times per week for one year. Subjects in the control group will attend flexibility and strength exercise classes three times per week for one year. We plan to evaluate the relationship between exercise training and psychosocial factors in an effort to determine whether the immunomodulatory effects of exercise are related to improved psychological well being. We hypothesize that the exercise intervention will decrease perceived stress assessed by the Global Measure of Perceived Stress (PSS), and decrease depression assessed by the Geriatric Depression Scale. Other psychosocial factors may influence the depression and perceived stress, and therefore other psychosocial measures will be used to analyze potential contributions of these other factors. The additional psychosocial measurement scales are Social Provisions Scale, Positive Affect - Negative Affect Schedule (PANAS), Daily Hassles and Uplifts.

The second hypothesis to be tested is that the immunomodulatory effects of exercise are mediated by beta-adrenergic receptors. Inclusion of subjects that have been prescribed beta-adrenergic receptor antagonists will be used to test this hypothesis.



Subject Inclusion/Exclusion Criteria

Seventy-two subjects (36 male, 36 female), age > 65, not currently participating in moderate or vigorous exercise and an additional 32 subjects treated will non-selective beta-adrenergic receptor antagonists will be recruited from the local community to participate in the proposed research study. Subject inclusion and exclusion will be dependent on age, health status, medication use, exercise history, influenza vaccination history, and ability to perform aerobic exercise on a regular basis. The lower age limit of 65 is based upon research suggesting that immune response to vaccination may be impaired as age increases. We have not set an upper limit with respect to age. However, the upper age limit may be affected by the ability to perform the exercise intervention.

Health status will be determined during the initial screening by a detailed medical history, physical examination and maximal graded exercise test. Any subjects experiencing a disease or condition that may impair their ability to safely perform the exercise intervention will be excluded from the study (i.e., uncontrolled hypertension, orthopedic limitations, significant coronary artery disease, uncontrolled metabolic disease, severe chronic obstructive pulmonary disease, etc.). In addition to the medical history and physical examination, the maximal graded exercise test will also screen potential subjects for their ability to perform the exercise intervention. An abnormal response (e.g., >1 mm ST segment depression > 80 ms past the J point) may result in exclusion from the study, based on the decision of the medical director in concert with the subject's personal physician. Individuals suffering from any condition that may alter the immune variables of interest will be excluded from the study. These conditions include but are not limited to: cancer within the last 5 years, autoimmune disorders such as lupus, rheumatoid arthritis, myasthenia gravis, Crohn's disease, Graves' disease, Type I (insulin dependent) diabetes, fibromyalgia, chronic fatigue syndrome, transplant recipient currently treated with immunsuppressive medications, and subjects with exercise -induced asthma that is severe enough to require medication. Subjects with chronic disorders such as hypertension, heart disease, Type II diabetes or elevated plasma total cholesterol or LDL cholesterol, will be included in the study if the condition is controlled with medication and if the participant can safely perform the exercise intervention (to be determined by the medical director).

Medication use may also limit participation in the study. Subjects treated with medications known to alter immune response to immunization, such as glucocorticoids, will be excluded from the study. Prolonged treatment (> 1 week) with non-steroidal anti-inflammatory medications or prescribed COX-2 inhibitors also warrants exclusion from the study. Persons treated with prescribed medication for allergies will also be excluded from the study. The use of over the counter cold or allergy medications will be allowed if treatment duration is less than 5 days and use of these medications is reported during the weekly cold/flu symptom report. Subjects taking nutritional supplements (other than vitamins and minerals that meet but not exceed the RDA) will also be excluded from the study. Medications that may alter the potential psychosocial factors (antidepressant therapy) will lead to exclusion. Any potential subject treated pharmacologically with a prescription medication for depression or anxiety will be excluded from the study. Specific Aim 2 of the study includes subjects treated with non-selective beta adrenergic receptor antagonists for hypertension. Patients treated with any of the following medications at the dose listed for hypertension will be included in the study: propranolol 120-240 mg/day, timolol maleate 20-40 mg/day, nadolol 40-80 mg/day, pindolol 10-60 mg/day. These doses correspond to the typical prescribed dose for hypertension. The hypertension comparison group for subjects treated with non-selective beta adrenergic receptor antagonists are subjects treated with a prescription medication for hypertension. The prescription medication must belong to one of the following groups of medications: calcium channel blockers, peripheral vasodilators (nonadrenergic), angiotensin-converting enzyme (ACE) inhibitors, ACE inhibitors + diuretics, angiotensin II receptor antagonists, or diuretics. Subjects treated with selective beta blockers for hypertension will not be included in the hypertension comparison group.

Prior exercise history is another criterion for inclusion in the study. Subjects will be included in the study if in the past three years they did not exercise or if they engaged in low intensity exercise such as walking (< 40% of heart rate reserve) < 3 times per week. Finally, the ability to perform exercise on a regular basis may limit participation. Subjects will be excluded from the study if they plan to be out of the area for more than 3 weeks over the 12+ month intervention period or if they are unable to attend the exercise classes 3 times per week.
Although we cannot control for previous exposure to influenza virus, prior vaccination history will allow us to select individuals with a similar antigenic history. Therefore, subjects will be included in the study if they received a flu vaccine every year for the previous 5 years.



Preliminary Results

Exercise training study

From fall 2000 to spring 2002, we completed a pilot study with 28 adults > 65 years of age. Exercise subjects (EX) participated in moderate exercise, 3 times per week, from fall 2000 through fall 2001. The control subjects (CON) did not change their activity pattern during this same period of time. All subjects were immunized with the trivalent influenza vaccine in fall of 2000. The immune response to influenza vaccine was not different between EX and CON at the start of the study (fall 2000). However after one year of exercise, the immune response to the second influenza vaccine (fall 2001) was improved in EX compared to CON. The HI titer to Influenza Type A H1N1 and H3N2 was significantly greater in EX than CON (p < 0.05). The HI titer to Influenza Type B appeared to be greater in EX than CON although it did not meet statistical significant (p = 0.08).

Cross sectional comparison (to be published in Sept 2002 issue Journal of Gerontology: Medical Sciences)

Background. Decreases in immune responsiveness with age contribute to the increased incidence and severity of infectious disease among the elderly. The immune response to immunization is also decreased with advancing age. Lifestyle factors (exercise, diet) have been established to play an important role in immunosenescence and the practice of "healthy" behavior may minimize the age-associated decline of immune function. The objective of this study was to determine whether exercise, diet and psychosocial factors were associated with altered immune response to influenza vaccine.

Methods. Adults, age> 62, were categorized into one of three groups, active (> 20 min vigorous exercise, > 3x week), moderately active (regular exercise < intensity, frequency, duration of active), or sedentary (no exercise). Two weeks post-immunization, serum was frozen for antibody analysis, and peripheral blood mononuclear cells (PBMC) were cultured in vitro with influenza vaccine to elicit antigen-specific responses (proliferation and cytokine (IL-2, IFN-?, IL-10) production). Cytokines and antibody were measured by ELISA.

Results. The results demonstrated that anti-influenza IgG and IgM was greater in active as compared to moderately active or sedentary participants. PBMC proliferation was lowest in sedentary subjects. Perceived stress was a significant predictor of IL-2. Greater optimism and social activity were associated with greater IL-10. Daily multivitamin intake was significantly correlated with IL-2.

Conclusion. These results suggest that lifestyle factors including exercise may influence immune response to influenza immunization. The practice of regular, vigorous exercise was associated with enhanced immune response following influenza vaccination in older adults.



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