Meditation and Exercise for Prevention of Acute Respiratory Infection
Meditation and Exercise for Prevention of Acute Respiratory Infection
The overarching goal of this project is to determine whether mind-body practices such as
 meditation or exercise can reduce the public health burden of acute respiratory infection. A
 major secondary goal is to determine whether mindfulness meditation or moderately strenuous
 exercise can enhance immune processes such as antibody response to influenza vaccination (flu
 shots). Finally, we want to investigate the influence of stress, optimism, anxiety and
 positive and negative emotion on immunity and resistance to 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.