Meditation and Exercise for Prevention of Acute Respiratory Infection

ABSTRACT

Background Preliminary evidence suggests that meditation and exercise may work through
interacting psychological and physiological pathways to influence the immune system and
reduce infectious respiratory disease.

Methods In this study, women and men aged 50 and older will be randomized to: 1) an 8-week
behavioral training program in mindfulness meditation, 2) an intensity, duration and
location-matched 8-week exercise training program, or 3) a waiting list control group.
Sample size will be N=150 enrolled, with N=50 in each group. The main patient-oriented
outcome will be severity-adjusted total days of acute respiratory infection (ARI) illness,
as self-reported on the Wisconsin Upper Respiratory Symptom Survey (WURSS-24), a validated
questionnaire outcome measure. Nucleic acid based viral identification will verify all
symptomatic infections, and the cytokine IL-8 and nasal neutrophil from nasal wash will
serve as biomarkers of illness severity. Biomarkers of immune function will include antibody
response to influenza immunization (serum IgG, mucosal IgA) and cytokines IFN-γ and IL-10
from cultured ex vivo lymphocytes. Questionnaire measures assessing perceived stress,
positive and negative emotion, optimism, and anxiety will be analyzed as potential mediators
of immunomodulation and illness prevention.

Timeframe / logistics This will be a 2-year project, with 2 cohorts conducted during a
single cold season. The first cohort of N=60 will be randomized and begin interventions in
September 2009. The second cohort of N=90 will be randomized and begin interventions in
January 2010. Tri-valent influenza vaccination will occur on week 6 of behavioral
interventions in both cohorts. Blood for antibody titer and ex vivo cytokine assay will be
drawn at baseline, at the end of the 8-week session, and once again 3 months later. Nasal
swab for IgA will be done at the same times. Participants will be followed with telephone
contact every 2 weeks, with monthly questionnaire instruments, and with daily
self-assessments during ARI illness episodes.

Analysis ANOVA-based models will assess effects of meditation and exercise on immune markers
and ARI illness. Psychological measures will be assessed as potential mediators of effects
of meditation and exercise on ARI illness. Generalized estimating equations, random-effects
pattern-mixture models, and hierarchical linear models will be used to assess longitudinal
effects, interactions, and covariate mediation.

Section 2. Specific Aims

2.1. Background Acute respiratory infection (ARI) is a leading cause of morbidity and
mortality. Influenza is the most pathogenic of the many viruses involved, and hence merits
special attention. Protective and ameliorative immune mechanisms are poorly understood, but
are associated with various indicators of mental as well as physical health.

A broad literature suggests that regular exercise affects the immune system, positively
influences mental health, and protects against ARI illness. A separate and smaller body of
evidence suggests that mindfulness meditation may lead to lower stress levels and better
mental and physical health. Published evidence from our own study suggests that meditation
may enhance antibody (serum IgG) response to influenza vaccination (flu shot) [1].

2.2. Methods & Aims The proposed randomized controlled trial (RCT) will test for effects of
meditation and exercise on incidence and severity of ARI illness during an 8-month
observation period. Participants (N=150) will be randomized to 1) an 8-week training program
in mindfulness meditation, 2)an attention, duration and location-matched program in moderate
intensity exercise, or 3) a waiting list control group. Each ARI illness episode will be
assessed by a validated questionnaire outcomes instrument, verified with nucleic acid based
multiplex viral identification system, and assessed for inflammation with IL-8 assay and
neutrophil count from nasal wash. Immunological measures will include antibody response to
flu shot (both serum IgG and mucosal IgA) and cytokine indicators of TH1 (IFN-γ) and TH2
(IL-10) immune response, as measured in stimulated ex vivo lymphocyte cell culture.
Psychological domains to be assessed include perceived stress, positive and negative
emotion, anxiety, and optimism. Immune biomarkers and psychological domains will be assessed
as consequences of behavioral interventions, and as predictors of ARI illness. Finally, we
will attempt to disentangle the mediating effects of psychological health on immune
mechanisms and ARI illness. For example, one hypothesis is that meditation influences the
immune system through reduction of stress-related immune dampening mechanisms. That
hypothesis would receive support if perceived stress and ARI illness were lowest in the
meditation group, and if perceived stress associated more strongly with immune biomarkers
and ARI measures than did measures of other psychological domains. We expect that both
exercise and meditation will improve psychological health, influence immune biomarkers, and
reduce ARI illness burden. However, current evidence is not sufficient to estimate the
relative magnitude of these effects, nor to confidently predict whether cellular and/or
antibody-mediated immune mechanisms will be implicated.

2.3 Null hypotheses - 2.3.1 Compared to control, an 8-week training program in mindfulness
meditation will not lead to statistically significant reductions in number of
severity-weighted days of ARI illness. 2.3.2 Compared to control, a matched 8-week exercise
training program will not lead to significant reductions in ARI illness. 2.3.3 Meditation
training will not enhance either antibody response to flu shot (serum IgG, mucosal IgA), or
cytokine expression linked to TH1 and TH2 cell-mediated immune pathways (IFN-γ, IL-10).
2.3.4 Exercise training will not enhance either antibody response to flu shot or cytokine
expression from cultured lymphocytes. 2.3.5 Mindfulness meditation training will not lead to
improvements in measures of psychological health (perceived stress, positive and negative
emotion/affectivity, anxiety, optimism). 2.3.6 Exercise training will not improve these
psychological measures. 2.3.7 Immune biomarkers will not predict ARI outcomes. 2.3.8
Psychological measures will not predict ARI outcomes. 2.3.9 The effects of meditation and
exercise on psychological measures, immune biomarkers, and ARI illness will not be
distinguishable from each other. 2.3.10 Observed effects of meditation and exercise on ARI
outcomes will not be explained by either psychological measures or biomarkers of immune
mechanisms.

2.4 Justification Influenza and other acute viral infections are responsible for tremendous
health burden. Antibody-mediated immunity, responding to vaccination or natural exposure, is
only partially effective in conferring protection. Current evidence suggests that
cell-mediated immune mechanisms are important in this process. Both antibody-mediated and
cell-mediated immune mechanisms have been linked to psychological domains, and appear to
decline with aging. Preliminary evidence suggests that both mindfulness meditation and
moderate intensity exercise may be at least partially effective in modifying immune response
and reducing infectious illness burden. No studies have compared these 2 quite different
behavioral intervention techniques. This proposed research would provide new knowledge
regarding effects of meditation and exercise training on ARI illness, and immunological and
psychological pathways involved.

Inclusion Criteria: 1) Aged 50 years or older at study entry. 2) Literacy in English
language sufficient for understanding the study protocol and completing questionnaires. 3)
Must answer "Yes" to either "Have you had at least 2 colds in the last 12 months?" and/or
"On average do you get at least 1 cold per year?" 4) Self-reported ability and willingness
to follow through with either exercise or meditation training, or neither, according to
randomized allocation. 5) Successful completion of tasks during run-in period, including 2
in-person appointments, 2 phone contacts, and 1 set of homework questionnaires. 6) A score
of 14 or lower on the PHQ-9 depression screen, self-reported both at entrance to run-in
trial and again just prior to enrollment in the main study. 7) A score of 24 points or
higher on the Folstein mini-mental status exam, administered by research personnel at
entrance to run-in trial and again just prior to consent and enrollment in the main study.

Exclusion Criteria: 1) Physical or medical condition prohibiting adherence to study
protocol. Prospective participants must meet the American Heart Association guidelines225
for suitability for an exercise program. Prospective participants will be advised (but not
required) to seek their physicians' advice before enrollment. 2) Current or recent use of
meditative practice, or previous meditation training. Assessed by answering "Yes" to any
of the following questions: Do you meditate on a regular basis? In the last year, have you
meditated at least weekly for 2 or more months in a row? Have you ever been trained in
meditation? Have you ever been involved in a mindfulness class or mindfulness practice? 3)
Potential participants must not engage in moderate exercise more than twice per week or
vigorous exercise more than once per week, as assessed by the following questions adapted
from the BRFSS classification226 system: On average, how many times per week do you engage
in moderate recreational activities such as walking, tennis doubles, ballroom dancing,
weight training, or similar activities that last at least 20 minutes per occasion? A) Less
than 1 time per week; B) 1 time per week; C) 2 times per week; D) 3 times per week; E) >4
times per week. How many times per week do you engage in vigorous sport and recreational
activities such as jogging, swimming, cycling, singles tennis, aerobic dance or other
similar activities lasting at least 20 minutes per occasion? A) Less than 1 time per week;
B) 1 time per week; C) 2 times per week; D) 3 or more times per week. 4) Immune deficiency
or auto-immune disease (eg. HIV/AIDS, lupus, rheumatoid arthritis, multiple sclerosis,
inflammatory bowel disease; Co-Investigator Dr. Muller will advise in questionable cases).
5) Current use or forecasted need for immunoactive drugs (eg. steroids,
immunosuppressants, chemotherapy); nonsteroidal antiinflammatories will be allowed. 6)
Current use or forecasted need for antibiotic or antiviral medications (eg. prophylactic
or suppressive therapy for chronic urinary tract infection, recurrent herpes, or other
chronic infections. 7) Malignant disease (prospective participants' physicians to advise.
Dr. Barrett to make final decision in questionable cases). 8) Function-impairing
psychopathology (prospective participants' psychiatrist or psychologist to advise). 9)
Influenza vaccination (flu shots) within 6 months prior to enrollment. 10) True egg
allergy or true allergic reaction to prior flu shot, either of which would have to include
at least one of the following: a) large rash or swelling (more than 12 inches in
diameter), b) any swelling in throat, c) any difficulty breathing, d) reaction with
hospitalization, or e) anaphylaxis. Reactions that would NOT exclude people: a) local pain
or swelling, b) fever, c) malaise, feeling lousy, or d) cold, flu or other infectious
illness.