Physician Awareness Form
Instructions:
1) Please fill in your name on the top of the first
page.
2) Please ask your physician to complete the first
page of this form and return it to us:
Marian L. Kohut, Ph.D.
235 Forker Building
Iowa State University
Ames, IA 50011
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PHYSICIAN'S AWARENESS FORM
, has expressed an interest in taking part in
A patient of yours,
a research project that may include participation in a supervised, moderate exercise program at the
ISU exercise clinic. The medical director of the research project (board certified M.D.) will perform a
physical examination on each potential subject, and supervise a maximal graded exercise test prior
to participation in the exercise program. The maximal graded exercise test will screen subjects for the
ability to perform the exercise intervention aspect of the study. A complete list of inclusion/exclusion
criteria is attached, please refer to "Subject Inclusion/Exclusion criteria". The purpose of this form
is to make you, the physician, aware that the above individual wishes to participate in this
study and gain your input as to the suitability of this patient for this study.
The goal of this study is to investigate the effects of a long-term moderate exercise program in
older adults on the immune response to influenza vaccination; and to examine exercise-associated
alterations in psychological state and neuroendocrine outflow as potential mediators of the exerciseinduced modulation of immune response. A brief description of this study is attached, please refer to
"Research Plan". A complete description of the study is also available if desired. Please list your
address below if you would like a copy of the complete study description. Please note that this
study has been approved by the Human Subjects Committee of Iowa State University and has met
NIH criteria for Human Research.
In order to allow this patient to participate in this study, please be kind enough to
answer the following questions:
1.
Does this individual have any physical limitations/conditions that you feel warrants the
complete exclusion of exercise for your patient (yes/no)?
2.
Does this individual have any physical limitations/conditions which you feel warrants
limiting or modifying their participation (yes/no)?
If yes, please explain:
3.
Additional Comments:
If you would like a copy of the study description mailed to you, please list your email or mailing
address in the space provided.
If you have any questions or concerns pertaining to this form and/or your patient's participation in
this study, please feel free to contact me at 294-8364. Thank you for your assistance.
Please mail this form in the enclosed return envelope.
Marian L. Kohut, Ph.D. (Principal investigator)
235 Forker Building, ISU
Ames, IA 50011
mkohut@iastate.edu
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SUPPLEMENTAL INFORMATION
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 (β1, β2) 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 (β1, β2) 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
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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 Clinic 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
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RESEARCH PLAN
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 (7,8,9,10,11), and enhanced antigen-specific immune response in an aged population (6).
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 (β1β2) 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.
A.1 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 high intensity, supervised aerobic exercise. Control subjects will
participate in flexibility exercise at a very low intensity. The immune responses will be assessed
pre/post-immunization and pre/ post-intervention. Outcome measures of immune response are antiinfluenza IgG1, IgG, influenza-specific peripheral blood mononuclear cell (PBMC) proliferation,
influenza-specific cytokine production (interleukin (IL)-2, IL-10, interferon (IFN)γ) 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.
A.2 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 (β1β2) adrenergic receptor antagonists for blood pressure control
will be used to test this hypothesis. The 12-month exercise intervention or 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.
A.3 Model
Exercise
Psychosocial alteration
(direct effect)
Immune response to vaccine
Beta adrenergic receptor mediated response
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