Meditation or Exercise to Prevent Acute Respiratory Infection (MEPARI)

Bruce Barrett MD PhDAssociate Professor of Family Medicine

U.W. School of Medicine & Public Health

WREN Conference

September 20, 2012

(Cold and Flu)

Acute Respiratory Infection?

Can we prevent

Research Question:

Mindfulness meditation may reduce stress, & thereby prevent or ameliorate cold-n-flu

http://theantiagingspecialist.com/destructive-stress-and-aging

HYPOTHSIS

#1

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Exercise may stimulate the immune system, and thereby prevent or ameliorate cold-n-flu

HYPOTHSIS

#2

Acute respiratory infection = ARI• Influenza ARI is associated with ≥ 30,000 deaths and

500,000 hospitalizations in the U.S yearly• Non-influenza ARI accounts for ≥ 20 million doctor

visits and 40 million lost school/work days• Economic impact of non-influenza ARI ≥ $40 billion,

making non-influenza ARI one of the top 10 most expensive illnesses

A. E. Fiore et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm.Rep. 59 (RR-8):1-62, 2010.

N. A. Molinari, et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 25 (27):5086-5096, 2007.

A. M. Fendrick, A. S. Monto, B. Nightengale, and M. Sarnes. The economic burden of non-influenza-related viral respiratory tract infection in the United States. Archives of Internal Medicine. 163 (4):487-494, 2003.

Rhinovirus

Coronavirus

Parainfluenza virus

Adenonvirus

Unknow n

Influenza virusRespiratory syncytial virus

Enteroviruses

A. S. Monto. Epidemiology of viral respiratory infections. American Journal of Medicine. 112:Suppl-12S, 2002.

Metapneumovirus reported 2004, Bocavirus in 2006

J. V. Williams et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. New England Journal of Medicine. 350 (5):443-450, 2004.T. P. Sloots, etal. Evidence of human coronavirus HKU1 and human bocavirus in Australian children.

J.Clin.Virol. 35 (1):99-102, 2006.

Mean annual incidence of respiratory infections

0

1

2

3

4

5

6

7

<1 1 to2

3 to4

5 to9

10 to14

15 to19

20 to24

25 to29

30 to39

40 to49

50 to59

>60

Age

male

female

A. S. Monto. Epidemiology of viral respiratory infections. American Journal of Medicine. 112:Suppl-12S, 2002.

Flu shots prevent flu – Somewhat

• Seasonal influenza vaccination is generally accepted as cost-effective for preventing influenza

illness• Seroprotection rates range from 60-80% in healthy

younger adults to 40-60% in the elderly• Actual preventive effectiveness is probably lower

AC Voordouw et al. Annual revaccination against influenza and mortality risk in community-dwelling elderly persons. JAMA 2004;292:2089-95.

Advisory Committee on Immunization Practices CfDCaP. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2006;55:1-41.

M. J. Postma, et al. Pharmacoeconomics of influenza vaccination in the elderly: reviewing the available evidence. Drugs & Aging 17 (3):217-227, 2000.

Q. Can we prevent non-influenza ARI?A: Maybe, sometimes, don’t know

• Contact avoidance• Hand-washing• Enhance physical health• Exercise• Nutrition• Enhance mental health• Stress reduction• Self-care• Relationships

• Immunization is impractical because too many viruses

• Immune enhancing drugs, herbs (echinacea) and supplements (vitamins) are unproven

Stress & immunity to colds & flu

• Stressed people have more frequent and more severe cold and flu illness episodes

• Stress negatively influences several immune system processes

• S. Cohen et al. Psychological stress, cytokine production, and severity of upper respiratory illness. Psychosomatic Medicine 61 (2):175-180, 1999.

• E. Fondell et al. Physical activity, stress, and self-reported upper respiratory tract infection. Med.Sci.Sports Exerc. 43 (2):272-279, 2011.

• N. P. Walsh, et al. Position statement. Part two: Maintaining immune health. Exerc.Immunol.Rev. 17:64-103, 2011.

Stress hits at multiple levels

http://ecohealthwellness.com

Mindfulness based stress reduction

Pioneered by Jon Kabat-Zinn PhD Center for Mindfulness in Medicine, Health CareUniversity of Massachusetts Medical School

Standardized 8 week course

Incorporates aspects of meditation & yoga

Aims to enhance awareness of body & mind

Attention to sensation, thought, emotions

2.5 hours in class each week

45 minutes daily practice

MBSR

Mindfulness training reduces stress

• Reasonable evidence exists suggesting that MBSR training can reduce self-reported stress and other negative emotions

• Not much evidence regarding actual illness

Carmody J,.Baer RA. Relationships between mindfulness practice and levels of mindfulness, medical and psychological symptoms and well-being in a mindfulness-based stress reduction program. J.Behav.Med. 2008;31:23-33.Mars TS,.Abbey H. Mindfulness meditation practise as a healthcare intervention: A systematic review. International Journal of Osteopathic Medicine 2010;13:56-66.

Regular exercise may prevent ARI• Observational and experimental studies suggest that regular

exercise may protect people from ARI illness. [1]• The largest RCT (n=115; 1-year f/u), designed for other purposes,

reduced chance of ARI from 48% to 30% (p=0.03) [2]• An observational cohort study (n=1002) reported 32 to 46% lower

incidence, duration and severity of ARI illness among most active vs. least active people [3]

1. S.A. Martin, B.Pence, and J. Woods. Exercise and respiratory tract viral infections. Exerc.Sport Sci.Rev. 37 (4):157-164, 2009.

2. J. Chubak et al. Moderate-intensity exercise reduces the incidence of colds among postmenopausal women. Am J Med 2006;119:937-42.

3. D.C. Nieman et al. Upper respiratory tract infection is reduced in physically fit and active adults. Br.J.Sports Med. 2010.

“Ergo, sufficient evidence exists to justify formal testing of the hypotheses that training in meditation or exercise might reduce incidence, duration and severity of ARI illness”

MEPARI trial

• Meditation or

• Exercise to

• Prevent• Acute• Respiratory• Infection

MEPARI • OBJECTIVE• To evaluate potential preventive

effects of mindfulness meditation or sustained moderate intensity exercise on incidence, duration and severity of acute respiratory infection

Department of

Family Medicine

MEPARI = randomized controlled trial

Community recruited adults aged 50 years or older were randomized to 1 of 3 conditions:

8-week training in mindfulness meditation

matched 8-week training in moderate intensity sustained exercise

wait-list observational control

Mindfulness based stress reduction

Pioneered by Jon Kabat-Zinn PhD Center for Mindfulness in Medicine, Health CareUniversity of Massachusetts Medical School

Standardized 8 week course

Incorporates aspects of meditation & yoga

Aims to enhance awareness of body & mind

Attention to sensation, thought, emotions

2.5 hours in class each week

45 minutes daily practice

MBSR

Exercise

• Duration (8 weeks)• Attention (weekly 2½ hour

group sessions)• Intensity (daily 45 minute

at-home practice)• Location (UW Research Park)

• Aimed at sustained moderate intensity exercise

• Jogging, fast walking, biking, swimming, etc

• Goal of 12 to16 points on Borg’s Rating of Perceived Exertion

Matched to MBSR by:

Borg GV,.Linderholm H. Perceived exertion and pulse rate during graded exercise in various age groups. Acta Medica Scandinavica 1967;472:194-206

Randomized using statistical algorithm

Sampling frameworkInclusion• age ≥ 50 years• willingness to do any of the

3 randomized assignments• self-report either ≥ 2 colds

in the last 12 months or an average of ≥ 1 cold per year

• ability to complete protocol, including short run-in trial

Exclusion• previous training or current

practice in meditation• moderate exercise ≥ 2X/week

or vigorous exercise ≥ 1X/wk• immunodeficiency,

immunoactive drugs, autoimmune or malignant ds.

• contraindication to flu shot

Recruitment via community advertising with telephone screening and in-person informed consent and enrollment

Human subjects monitoring

• I.R.B. - University of Wisconsin Institutional Review Board Human Subjects Committee

• D.S.M.C. - Data and Safety Monitoring Committee• No specific potential adverse outcomes were

designated for monitoring

2-week Run-in Trial

• 2 phone contacts• 1 set of homework questionnaires• 2 in-person appointments, consisting of:

a) consent and instructions for run-in b) exit of run-in and consent for main trial

ARI illness defined• Beginning of ARI illness is when participant first answers “Yes” to

either: “Do you think you are coming down with a cold?” OR “Do you think that you have a cold?” AND

• Must have ≥ 1 of: nasal congestion, nasal discharge, sneezing, or sore throat AND ≥ 2 points on the Jackson scale* AND

• Both participant and research assistant say it’s not allergy AND• Symptoms must last at least 2 days in a row • Last moment of ARI illness episode is defined as when participant

last rates their ARI illness severity above zero using “How sick do you feel today?” AND repeats the subsequent “Not sick” assessment for 2 days in row

G.G. Jackson, H. F. Dowling, and R. L. Muldoon. Present concepts of the common cold. Am J Public Health 52 (6):940-945, 1962

ARI illness assessed

• Duration of ARI illness episode assessed in hours and minutes, then converted to decimalized days

• During ARI illness episode each participant fills out WURSS-24 instrument every day

• Items summed to give daily severity score (Y axis)• Primary outcome of global severity defined as area

under the time severity curve (AUC)• Trapezoidal approximation used to calculate AUC

B. Barrett, et al. Validation of a short form Wisconsin Upper Respiratory Symptom Survey (WURSS-21). Health and Quality of Life Outcomes 7 (76), 2009

Do not havethis symptom Very mild Mild Moderate Severe

0 1 2 3 4 5 6 7

Runny nose O O O O O O O O

Plugged nose O O O O O O O O

Sneezing O O O O O O O O

Sore throat O O O O O O O O

Scratchy throat O O O O O O O O

Cough O O O O O O O O

Hoarseness O O O O O O O O

Head congestion O O O O O O O O

Chest congestion O O O O O O O O

Feeling tired O O O O O O O O

Headache O O O O O O O O

Body aches O O O O O O O O

Fever O O O O O O O O

: Over the last 24 hours, how much has your cold interfered with your ability to: Not

at allVerymildly Mildly Moderately Severely

0 1 2 3 4 5 6 7

Think clearly O O O O O O O O

Sleep well O O O O O O O O

Breathe easily O O O O O O O O

Walk, climb stairs, exercise O O O O O O O O

Accomplish daily activities O O O O O O O O

Work outside the home O O O O O O O O

Work inside the home O O O O O O O O

Interact with others O O O O O O O O

Live your personal life O O O O O O O O

Please rate the average severity of your cold symptoms over the last 24 hours for each symptom:

WURSS 21

WURSS has been “validated”

• B. Barrett, R. Brown, and M. Mundt. Comparison of anchor-based and distributional approaches in estimating important difference in common cold. Quality of Life Research 17 (1):75-85, 2008.

• B. Barrett, R. Brown, R. Voland, R. Maberry, and R. Turner. Relations among questionnaire and laboratory measures of rhinovirus infection.

European Respiratory Journal 28 (2):358-363, 2006.• B. Barrett, et al. The Wisconsin Upper Respiratory Symptom Survey:

Development of an instrument to measure the common cold. Journal of Family Practice 51 (3):265-273, 2002.

• B. Barrett, et al. The Wisconsin Upper Respiratory Symptom Survey is responsive, reliable, and valid. Journal of Clinical Epidemiology 58 (6):609-617, 2005.

• B. Barrett, et al.. Validation of a short form Wisconsin Upper Respiratory Symptom Survey (WURSS-21). Health and Quality of Life Outcomes 7 (76), 2009.

Hypothesis-testing & Power

• From the NIH-accepted protocol:• “Null hypotheses will be rejected if interventions are superior

to control at a p ≤ 0.025, using one-sided alternative testing.”• “Power calculations are based on 2-way contrasts between: 1)

meditation vs. control and 2) exercise vs. control.”• “One-sided testing is supported by previous published

research, which is overwhelmingly in the direction of positive results.”

• Decisions vetted by several statisticians & methodologists at the University of Wisconsin and at NIH

Because of limited power, MEPARI best described as preliminary trial

(phase 2?)

Biweekly phone monitoring

• Participants given Jackson and WURSS questionnaires at enrollment and were reminded with each study contact to begin documenting ARI symptoms as soon as they felt they might be getting a cold

• Contacted by phone every 2 weeks if they had not called in

• As soon as ARI criteria met, arrangements made for lab visit to collect nasal wash specimen

Biomarkers of ARI illness

• Nasal wash specimens analyzed for:• Viral nucleic acid using multiplex PCR• Neutrophils (cell count per high power field)

considered marker of nasal inflammation• Interleukin-8 (pg/mL). IL-8 is cytokine considered

as marker of immune response

Lee WM, et al. High-throughput, sensitive, and accurate multiplex PCR-microsphere flow cytometry system for large-scale comprehensive detection of respiratory viruses. J.Clin.Microbiol. 2007;45:2626-34

ELISA - Human IL-8 BD OptEIA Set, BD Biosciences Pharmingen, San Diego, CA

NIH NCCAM ARRA funding

• National Center for Complementary & Alternative Medicine (NCCAM)

• National Institutes of Health (NIH)• American Recovery & Reinvestment Act (ARRA)

of 2009 “Economic Stimulus” funding• Original proposal was for 4 to 5 year project• ARRA required data collection over 1 year, and

full project finished within 2 years• Aimed for Employment as well as Science• Medical research “soft money” = New jobs

Many people involved in MEPARI• Shari Barlow, Michele Gassman, Lori Wilson, Kati Krome,

Tola Ewers • Chidi Obasi MD MSPH, Becky West PhD APRN, also

several undergrad students • Exercise & Mindfulness trainers/coordinators• Nursing & Lab personnel at UW Hospitals• Grant management, Personnel, UW support• Principal Investigator: Bruce Barrett MD PhD, Co-

Investigators: Chris Coe PhD, Mary Hayney PharmD, Dave Rakel MD, Daniel Muller MD PhD, Roger Brown PhD, Zhengjun Zhang PhD, Ann Ward PhD, Aleksandra Zgierska MD PhD, James Gern MD, Richard Davidson PhD

2009-2010 cold/flu season

ARRA required data collection take no more than 1 year

Logistical limitations required two cohorts:

Cohort 1 – September to May

Cohort 2 – January to May

Exercise Meditation# Control P-value

Sample (n) Ex47E vbg51 f51

Exercise Mindfulness Control p-value

Age (years) mean (SD)

59.0 (6.6) 60.0 (6.5) 58.8 (6.8) 0.63

Female n (%) 39 (83.0) 42 (82.4) 41 (80.4) 0.94

Non smokers n (%) 43 (91.5) 48 (94.1) 48 (94.1) 0.84

Race φ Black n (%) 3 (6.4) 1(1.9) 2 (3.9) 0.52

White n (%) 43 (91.5) 49 (92.5) 48 (94.1) 0.88

Other n (%)

1 (2.13) 3(5.7) 1 (2.0) 0.50

Ethnicity Non-Hispanic n (%)

47 (100) 51 (100) 49 (96.1) 0.14

BMI mean (SD) 29.0 (6.9) 29.0 (6.0) 29.8 (6.8) 0.77

Participant Characteristics of N=149 MEPARI trial finishers

Error bars represent 95% confidence intervals

Figure 2 - MEPARI Trial Main Results

MEPARI Main Outcomes

P-values come from unadjusted intervention-to-control contrasts, using 2 sample T-test for continuous means (SAS 9.2; SAS Institute, Carey, NC, USA) and proportional difference for binomials (StatXact-5 Cytel Software Corporation).

Zero-inflated Poisson regression

• People can have or not have ARI episodes (binomial; logistic)• ARI episodes vary in duration & severity (continuous; linear)• Zero-inflated models (ZIM) are a mixed model approach taking

into account both frequency and magnitude of ARI illness• Each primary contrast (MM vs CTL and EX vs CTL) is tested

within a ZIM model for each main outcome (duration, severity)• Adjusting for pre-specified covariates, both total days of illness

(p=0.033) and global severity (p=0.010) appeared lower for meditation, but not for exercise (p=0.47 and 0.31, respectively)

Count Predictors (Linear sub-model) Predictors of excess zero (Logistic sub-model)

Estimate(S.E) P-value Estimate(S.E) P-value

Group 1 0.83(0.45) 0.032Group 1 EX -0.16(0.32) 0.31

Group 2 MM -0.74(0.32) 0.010* Group 2 0.60(0.42) 0.079

Cohort -0.46(0.26) 0.040 Cohort 0.16(0.40) 0.34

AGE 0.026(0.025) 0.15 AGE 0.05(0.028) 0.038

Smoking status -0.028(0.34) 0.47 Smoking status -2.51(1.1) 0.012*

Education -0.038(0.15) 0.40 Education -0.041(0.21) 0.42

BMI 0.025(0.024) 0.15 BMI -0.038(0.031) 0.11

SF-12 Physical -0.021(0.016) 0.097 SF-12 Physical 0.018(0.024) 0.23

SF-12 Mental 0.004(0.019) 0.42 SF-12 Mental 0.015(0.029) 0.31

Gender -0.003(0.26) 0.5 Gender 0.062(0.45) 0.45

Intercept Intercept

AUCT 5.51(2.27) 0.008 AUCT#1 -3.76(3.36) 0.13

Zero-inflated Poisson regression model for Global severity (AUC)

Count Predictors (Linear sub-model) Predictors of excess zero (Logistic sub-model)Estimate(S.E) P-value

Estimate(S.E) P-value

Group 1 EX -0.013(0.20) 0.47 Group 1 MM 0.82(0.45) 0.034

Group 2 MM -0.43(0.23) 0.033 Group 2 EX 0.50(0.42) 0.12Cohort -0.26(0.20) 0.10 Cohort 0.084(0.39) 0.42Age 0.013(0.017) 0.22 Age 0.049(0.028) 0.041

Smoking status -0.35(0.22) 0.059 Smoking status -2.53(1.11) 0.011*

Education 0.023(0.10) 0.41 Education -0.087(0.21) 0.34

BMI 0.010(0.014) 0.24 BMI -0.038(0.031) 0.11

SF-12 Physical -0.004(0.012) 0.37 SF-12 Physical 0.015(0.024) 0.26

SF-12 Mental 0.007(0.013) 0.30 SF-12 Mental 0.016(0.029) 0.29

Gender -0.023(0.18) 0.45 Gender 0.021(0.45) 0.48

Intercept InterceptTOTDAYS 1.71(1.81) 0.17 TOTDAYS#1 -3.24(3.34) 0.17

Zero-inflated Poisson regression model for Duration (total days of ARI)

MEPARI Secondary Outcomes

Exercise Meditation Control

Exercise 9 weeks 3 months 9 weeks 3 months 9 weeks 3 months Met Minutes/week **2222

(1815, 2628)**1805

(1356, 2253)1037

(694, 1381)1122

(804, 1440)1224

(810, 1638)1050

(688, 1412)

Mindfulness 4.59 (4.36, 4.82) 4.82 (4.59, 5.05) 4.55 (4.37, 4.73) 4.73 (4.54, 4.91) 4.60 (4.40, 4.81) 4.59 (4.37, 4.82)

Indicators of good health - positive change indicates improvementPhysical Health 51.8 (49.3, 54.2) 52.0 (49.4, 54.6) 49.8 (47.2, 52.3) 50.5 (48.0, 53.1) 51.1 (48.5, 53.6) 50.6 (47.8, 53.6)

Mental health *53.0 (50.9, 55.1) 49.7 (46.7, 52.7) *52.6 (50.5, 54.7) *50.5 (48.1, 53.0) 49.0 (46.4, 51.5) 46.3 (43.5, 49.0)

Social Support 43.4 (41.1, 45.7) 43.6 (41.3, 45.9) 42.4 (39.8, 44.9) 44.5 (42.4, 46.5) 44.0 (42.1, 45.9) 44.0 (42.1, 46.0)

Indicators of poor health - negative change indicates improvementPerceived Stress 9.5 (7.8, 11.2) 10.0 (8.2, 11.7) 11.2 (9.7, 12.8) 11.4 (9.5, 13.4) 10.5 (8.6, 12.3) 11.4 (9.5, 13.2)

Negative emotion 14.0 (12.8, 15.2) 14.4 (13.1, 15.7) 15.0 (13.7, 16.2) 15.0 (13.3, 16.7) 14.6 (13.3, 15.9) 14.9 (13.8, 16.0)

Anxiety 30.2 (27.6, 32.8) 29.1 (26.6, 31.7) 30.7 (28.0, 33.4) 29.7 (26.9, 32.5) 31.2 (28.4, 33.9) 30.4 (27.9, 32.9)

* p-value <0.05 and **p<0.01 for comparison of intervention means vs. control means at each time period

Limitations

• First trial of its kind• Underpowered• Participants not blinded to intervention• Outcomes mostly self-reported• Logistics required 2 cohorts of differing lengths• No clear mechanistic pathways

Immune system

http://www.microbiologybytes.com

Highly complex

Widely distributed

“Innate” immunitypoorly understood

(Adaptive immunity better understood)

Conclusions:

Mind-body behavioral trainings such as mindfulness meditation or moderate intensity sustained exercise may reduce incidence, duration and severity of cold/flu illness

If these results are confirmed in future studies there may be important implications for both:

1) health-related policy & practice, and 2) scientific understanding of mechanisms of

health maintenance and disease prevention

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