Psychoneuroimmunoendocrinology describes the unity of mental, neurological, hormonal and immunological functions with its many potential applications. PNIE addresses the impact of cognitive images of the mind (whatever its elusive definition) on the central nervous system and consequent interactions with endocrine and immune systems. It encompasses many arenas, including biofeedback and voluntary controls, impacts of thought and belief on physiology, past and present effects of stress on mental, emotional and physical function, placebo effects, effects of social relationships on health and disease, and impacts of "energy medicine" on personal function and that of others. This column highlights the impact of cogent studies from these arenas on the understanding of holistic medicine in the new millennium.

Asthma and programmed Buteyko breathing
Buteyko breathing teaches subjects how to reduce the depth and rate of respiration. Thirty-nine patients (age 12-70) meeting criteria for asthma were recruited from the community and, after stratification for severity based on daily use of salbutamol or comparable bronchodilators, were randomly assigned to receive general asthma education and relaxation techniques including abdominal breathing, or to a series of Buteyko breathing training sessions. Medication continued to be used as needed. Patients recorded symptoms and medication use in a diary. At baseline, and at 3 months, flow volume loops were completed with and without bronchodilator, and patients completed a quality of life questionnaire. At each evaluation, indices of resting ventilation were determined. End-tidal CO2, FEV1, and peak expiratory flow did not change in either group. Use of beta-agonist agents fell 904 v. 57 µg/day in Buteyko and educational groups, respectively (p=.002), inhaled steroid use fell 49% and 0%, respectively (p=.06), and minute volume decreased more in the Buteyko group (p=.004); quality of life scores were also significantly better in the Buteyko group.
Bowler SD et al. Buteyko breathing techniques in asthma: a blinded randomised controlled trial. Med J Aust 1998 Dec 7-21; 169(11-12):575-8.

COMMENT: In spite of no change in FEV1, CO2 and expiratory flow rate, minute volume improved and quality of life indices improved. This technique is a matter of programming better quality respiratory patterns with controlled practice. The feedback of better results strengthens the intentions and motivation in a positive feedback loop which achieves far more than mere education. The added component is experiential, always a very effective tool in teaching. When one experiences something, it is far better grounded than something which is only experienced cognitively.

Asthma and yoga
Forty-six asthmatic patients age 11-18 engaged in the practice of yoga for 90 minutes in the a.m. and 60 minutes in the p.m. for 40 days. The yoga exercises included krigas (cleansing practices), asanas (body postures) and pranayama (breathing practices). The following changes occurred: FEV1 increased from 67.9% of predicted to 75.8% (p<.01); MVV (maximum ventilatory volume) improved from 70.9 to 85.8 L/min (p<.01); and MMFR (maximum mid-expiratory flow rate) increased from 94.5 to 121.1 L/min (NS). Physical fitness index (step test) increased from 324 to 343 (p<.01). After 2 years of followup (n=26) subjective responses termed "good" totaled 15, "fair" 9 and "poor" 2. Fourteen were totally asymptomatic and drug use decreased.
Jain SC et al. Effect of yoga training on exercise tolerance in adolescents with childhood asthma. J Asthma 1991; 28(6):437-42.

COMMENT: The practice of yoga in most of its forms involves physical, mental, and sometimes, emotional focus. Some of the results of yoga are similar to those experienced with biofeedback. Like biofeedback, yoga may address a specific disease process, but has generic benefits in nearly everyone who takes up the practice. One-third of the subjects in this study became asymptomatic within two years. And for those who succeed with incorporation of yoga practice, the benefit is permanent: i.e. the very function of the involved organ system is changed, as opposed to medication use in which the changed functions (lung in this case) require continued use of the medications.

Asthma and relaxation-biofeedback
Nine asthmatic patients were treated with 16 sessions of relaxation (progressive relaxation, desensitization) and EMG biofeedback and compared with nine who received a complex placebo. General condition was significantly better in the biofeedback group (p<.03). Frontalis muscle relaxation compared to controls was significantly better (p<.05). Respiration following a challenge with methacholine, which stimulates bronchospasm, was improved and subjective evaluation of life management was dramatically improved compared to placebo (p<.001).
Lehrer PM et al. Relaxation decreases large-airway but not small-airway asthma. J Psychosom Res 1986; 30(1):13-25

COMMENT: Subjective and objective measure of improvement were significantly and markedly better in the biofeedback group in this study. The autonomic nervous system plays a role in asthma, and the response to stress is involved in the opinion of many authorities. Biofeedback and relaxation techniques alter the level at which the subject responds to a given challenge. Another way of saying this is that the individual can face the same challenges but not pay such a high price in doing so. The response of the autonomic nervous system with its attendant synthesis of catecholamines is attenuated and less frenzied and intense. No responsiveness would be death, and excessive responsiveness spells disease. A muted responsiveness is equated to less disease and longevity. There is no reason why these techniques could not be taught in every school of healing in the country, other than the typical territoriality and institutional inertia.

Asthma and emotional expression
Research has demonstrated that writing about emotionally traumatic experiences has a surprisingly beneficial effect on symptom reports, well-being, and health care use in healthy individuals. A volunteer sample of 61 patients with asthma received the intervention; 58 completed the study. Patients were randomly assigned to write for 20 minutes daily for 3 consecutive days, either about the most stressful event of their lives or about emotionally neutral topics – their plans for the day. Asthma patients were evaluated with spirometry. Assessments were conducted at baseline and at 2 weeks, 2 months and 4 months after writing and were done in blinded fashion. Of evaluable patients 4 months after treatment, asthma patients in the experimental group showed improvements in lung function (the mean percentage of predicted FEV1 improved from 64% at baseline to 76% (p<.001) v. controls who showed no change. Forty-seven percent of completing experimental patients had clinically relevant improvement v. 24% of controls (p=.001). The authors conclude that patients with mild/moderately severe asthma who wrote about stressful life experiences had clinically relevant changes in health status at 4 months compared with those in the control group. These gains were beyond those attributable to the standard medical care that all participants were receiving.
Smyth JM et al. Effects of writing about stressful experiences on symptom reduction in patients with asthma or rheumatoid arthritis: a randomized trial. JAMA 1999 Apr 14; 281(14):1304-9

COMMENT: Improvement in immune status, previously shown by those writing about their traumas, were shown in healthy subjects. Release of feelings is highly therapeutic. This study, repeating the approach of James Pennebaker, emphasizes the importance of emotional factors in disease control. The improvements gained in these patients would have been very welcome results of the use of any new pharmaceutical. Yet one expects that not only the cost, but also the tendency for the results to be more permanent, would favor this approach over the pharmaceutical one.

Infections and stress
This is a review of the studies linking stress experience with immune responsiveness and susceptibility to infections. Immune function is mediated by the release of cytokines, nonantibody messenger molecules from a variety of immune and endothelial cells. Cytokine release stimulates the inflammatory response, induced by hormonal changes elicited following activation of the hypothalamic-pituitary-adrenal – the sympathetic-adrenal medullary axis. This leaves room for doubt about conclusions of in vitro studies in which the stress hormonal influences are not present. Stress experience inhibits NK cell responsiveness, T-cell responses, and antibody responses in vivo and in vitro. Some studies show little effect on actual disease incidence, but these are mainly done in healthy populations of young volunteers whose immune systems have much greater levels of reserve. Wound healing is compromised by stress, adding to post-surgical expense. Susceptibility to cold viruses is consistently found to be much greater in stressed populations, and most studies in HIV patients link stress with a diminished prognosis. Lifestyle changes, including broadening social involvements (social and spiritual groups, having a confidant, interaction with friends), and maintaining proper diet, exercise and sleep patterns enhances greater resistance and immune responsiveness. Stress is also associated in the literature with prolongation of recovery from infectious disease.
Glaser R, Rabin B, Chesney M et al. Stress-Induced Immunomodulation. Implications for Infectious Diseases? JAMA 1999 Jun 23/30; 281(24):2268-70

COMMENT: Several well-known researchers joined to publish this review. Practitioners taking a holistic worldview of medical practice will usually find better outcomes utilizing a multidisciplinary approach. In every epidemic and pandemic, the more susceptible in the population succumb to the viral or bacterial vector, and the more resistant do not become ill. A prominent factor in that resistance is the ability to manage stress at low cost. Relaxation training, biofeedback, meditation, yoga and similar practices have all been shown to improve immunity. These authorities in this review confirm that stress, at least when not well managed, is imminently related to susceptibility to infectious disease.

Colds and stress
Two-hundred thirty-five adults from 94 families were followed for six months. High and low stress groups were identified by median splits of scores on the Life Events Inventory, the Daily Hassles Scale and the General Health Questionnaire administered at baseline and repeated during and after the six-month trial. The high stress group had a mean of 2.7 episodes of respiratory infection v. 1.56 in the low stress group (p<.0005), and 29.4 symptomatic days v. 15.4 in the low stress group (p=.005).
Graham NM et al. Stress and acute respiratory infection. Am J Epidemiol 1986 Sep; 124(3):389-401

COMMENT: This prospective study confirmed that the highly stressed tend to succumb to the ubiquitous viruses and bacteria that inhabit our environment. The comparison of symptomatic days – twice as many in the highly stressed group compared to low and medium stress subjects
is a powerful conclusion. Yet how many times does the medical practitioner raise the issue of stress for her/his patients who present with repetitive episodes of infection. A holistic look at all the factors which influence susceptibility – nutrition, supplements, exercise, attitudes, and the amount of stress – will improve the probability that patients will learn how to prevent rather than merely cope with these episodes of respiratory illness.

More colds and stress
In a study of 79 married couples, hassles and upsetting events including marital fights based on journaling, showed a strong pattern of predicting colds and upper respiratory infections with a 3-4 day lag period. The impact of increased undesirable events did not reach significance but decreased desirable events significantly predicted susceptibility (p=.05).
Stone AA et al. Changes in daily event frequency precede episodes of physical symptoms. J Human Stress 1987 Sum; 13(2):70-74

COMMENT: There is high stress in marital discord. Arguments and fights take a high toll and reduce immune resistance. And again, how often does this question get included in the practitioner’s history of an episode? Patients will probably learn more through popular magazine health advice columns than they will in medical offices.

More yet on colds and stress
Three-hundred ninety-four healthy volunteers, after completing psychological tests determining stress levels, were deliberately exposed either to rhinoviruses or placebo nasal spray: 90% of those in the highly stressed group succumbed to respiratory infection compared to 74% of the least stressed (p<.005); and 47% of the high stressed succumbed to colds compared to 27% of the least stressed (p<.02).
Cohen S et al. Psychological stress and susceptibility to the common cold. N Engl J Med 1991 Aug 29; 325(9):606-12

COMMENT: This goes beyond the observational study to a clinical situation involving deliberate exposure to rhinoviruses, commonly implicated in many upper respiratory infections. The last comparison is probably the most significant: susceptibility to the rhinovirus exposure was 75% greater in the subjects determined to be highly stressed at the time the experiment took place. Perhaps we should worry less about being sneezed on by an infected person and more about whether we are appropriately managing our stress.

Influenza and stress
Two-hundred forty-six family members in 55 families kept logs of daily stresses; instruments used were the Family Adaptability and Cohesion Evaluation Scores, Family APGAR and the Schedule of Recent Stressful Events. Those experiencing URI symptoms were assessed with viral pharyngeal throat cultures and comparison of acute and 2-week post-viral serum antibody titers using a 4-fold rise as the threshold. The risk for infection was significantly inversely related to family cohesion (p=.02) and adaptability scores (p=.002).
Clover RD et al. Family functioning and stress as predictors of influenza B infection. J Fam Pract 1989 May; 28(5):535-39

COMMENT: The psychological and energetic climate in the family plays a mediating role in predicting susceptibility. The skills in entraining an atmosphere of cohesion and adaptability with the family setting can be learned when they have not been incorporated from parental example in the family of origin. Total health includes the learning of these types of skills. Future multidisciplinary clinics will recognize these needs as legitimate health concerns and provide the opportunities for families to acquire and learn what is necessary.

Upper respiratory bacterial infections
Stressful daily events disrupting family and personal life, as documented in personal logs, were 4-5 times as likely to precede colds and streptococcal infections than to follow them, in a study of 100 URIs in members of 16 families. Significant stress preceded 36% of streptococcal illnesses, 20% of asymptomatic streptococcal infections and 10% of non-streptococcal upper respiratory illnesses.
Meyer RJ, Haggerty RJ. Streptococcal infections in families. Pediatrics 1962 Apr; 29(4):539-49

COMMENT: This older and still valid study shows the same relationships between stress and streptococcal infections that obtains in regard to stress and viral respiratory infections. These authors also showed in other studies that positive bacterial throat cultures are surprisingly often found in asymptomatic persons. We need to treat the strep and stress together.

Upper respiratory infection/stress
Thirty percent of well children spontaneously harbor group A streptococci; 75% of children harboring Mycoplasma pneumonia are clinically well; and 42% harbor pneumococci; 58 children from a day care complex, mean age 4.3 years, were observed 5 days/week for signs and symptoms of respiratory infection and cultures for bacteria, Mycoplasma and viruses were obtained twice weekly and at the onset of illness. Stress was assessed by a modification of the Holmes-Rahe Schedule of Recent Experiences and family assessment was obtained through the 30-item Family Routine Inventory. The magnitude of life change was strongly related to the duration of experienced illnesses (p<.01). Life change and the adherence to regular family routines were related to the severity of illness (both p<.05). Neither life change events nor family routine experience were related to the growth of pathogens in health or disease.
Boyce WT et al. Influence of Life Events and Family Routines on Childhood Respiratory Tract Illness. Pediatrics 1977 Oct; 60(4 pt 2):609-15

COMMENT: In this study, pathogens are less related to severity and duration of illness than are family routines and stress changes. Unusual family schedules, unexpected interruptions in routines and stresses requiring greater amounts of adaptation were important in determining illness duration and severity. Many times astute family members already know something about these relationships and will offer their input if asked questions such as “Do you have any sense of anything that has reduced the resistance of (this person) to this infection?”

Robert Anderson is a retired family physician. In mid-career, his practice took on a more holistic nature as decades passed. He has authored five major books, Stress Power! (1978), Wellness Medicine (1987), The Complete Self-Care Guide to Holistic Medicine (1999) (co-author), The Scientific Basis for Holistic Medicine, (5th edition) available from American Health Press, nhf@msn.com, and Clinician's Guide to Holistic Medicine (McGraw Hill, 2001). Anderson served as the founding president of the American Board of Holistic Medicine, is a past president of the American Holistic Medical Association, former Assistant Clinical Professor of Family Medicine at the University of Washington, and currently Adjunct Instructor in Family Medicine at Bastyr University.

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