HIV andpsychoimmunology: evidence promising and ... - Europe PMC

Journal of the Royal Society of Medicine Volume 87 November 1994

HIV and psychoimmunology: evidence promising and forthcoming

David Miller MA(Hons) DClinPsychl

Kenneth H Nott PhiD2

Kavita Vedhara PhD2

'Department of

Public Health, Medicine and Epidemiology, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH and 2Department of Psychology, University of Newcastle Upon Tyne, Newcastle Upon Tyne NE1 7RU, UK

Keywords: HIV; psychoimmunology; stress; psychosocial factors

Introduction AIDS teaches us that immunoregulatory diseases are truly multifactorial'.

Promising evidence on the validity of what came to be called 'psychoimmunology' (PI) has been recorded since the time of Galen, who reputedly observed that women of a melancholic temperament were more prone to develop cancer than those of a sanguine nature2. Forthcoming evidence, on the other hand, has fallen far short of the ideal. Conclusive evidence of clear links between disease, immunity and psychological factors is very rare. Despite this, new findings are looked upon with an interest and enthusiasm that even the most circumspect of observers finds hard to disguise. A relatively recent editorial in The Lancet3, which reviewed evidence for, and questioned the clinical importance of, a link between emotion and immunity, concluded: The answer is that counselling in the acute phase of disease and psychological support in the chronic may be as important to outcome as many other therapeutic measures now undertaken. The relation between emotion and immunity may prove to be another strong argument for a return towards whole-person medicine.

The problem of making PI research convincing has involved moving from the purely correlational to the predictive, and then from the weakly predictive (i.e., based on unidimensional analyses) to the convincingly predictive (i.e., reflecting real life complexities). Indeed, the task of making PI respectable suffers from at least two major obstacles: (1) an incomplete understanding of the human immune system; and (2) problems of defining an adequate methodology by which to observe reliably that which we recognize incompletely. PI and clinical correlates The following types of investigations have characterized the PI literature: 1 Cross-sectional studies comparing psychosocial characteristics of patients and non-diseased controls4'5 2 Predictive studies in which characteristics of individuals with possible disease are assessed before diagnosis and then compared with post-diagnostic outcome6 3 Prospective studies associating pre-morbid psychosocial characteristics, stress factors and health habits with later

development of disease7

Correspondence to Dr David Miller

4 Longitudinal studies relating stress and/or psychosocial factors to disease progression and survival time89 5 Studies relating psychosocial factors to physiological and particularly immunological variables that are possibly related to the onset of disease or disease developmentl'

Experimental paradigms, like those described above, have shed light on the role of psychosocial factors in the development and reappearance of cancer. Overall, the data suggest that a susceptibility to cancer is linked to emotional inhibition; suppression of anger; low anxiety; self-images involving greater control, more conforming and less aggression; greater emotional repression; an attitude involving faith in external authority; and behaviour characterized by passiveness, helplessness and appeasement. Studies have also examined relationships between psychosocial factors and longer survival or absence of relapse after initial intervention following diagnosis of life-threatening disease. For example, long-term survivors with Hodgkin's disease, malignant melanoma (MM), or cancer of the breast, lung or colon have been found to have closer personal relationships, were less emotionally distressed, complained less and coped better with illness-related problems than short-term survivors, who experienced periods of high emotional distress involving a typically passive, stoically accepting and trying-to-forget response pattern". A classic prospective study of 61 women with early diagnosed breast cancer revealed that, at 5- and 8-year follow-up after mastectomy, patients whose initial reaction to their cancer diagnosis was denial or a fighting spirit were characterized by recurrence-free survival 2. Conversely, poorer results were found if patients had initially responded with stoic acceptance or feelings of hopelessness and helplessness. PI and HIV: evidence promising and forthcoming Thus, studies correlating psychological characteristics and immunological responses to stress with clinical disease vulnerability would appear to convey a serious implication for HIV. It is known that HIV leads to profound immunosuppression over time, and that stress is also immuno-modulatory. Thus, it has been proposed that the variability evident in disease progression may be mediated by the experience of stress. While evidence for the existence of stress in HIV is ubiquitous'3, our understanding of the immunological, virological and clinical mechanisms is still elementary. Thus, HIV related PI research is still in its formative stages, with the questions outweighing the answers. This research area will therefore be reviewed according to some of the more pertinent questions that have been listed by Solomon and Temoshok'4.

Paper read to Section of Hypnosis & Psychosomatic Medicine, 11 May 1992

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Do psychosocial factors influence susceptibility to HIV disease and progression? As regards disease susceptibility, it has frequently been suggested that many groups affected by HIV have a pre-morbid immune vulnerability associated with the effects of their prior experiences, and one of the earliest postulations was that gay men were immune deficient because of the immunosuppressive effects of semen, late nights and use of stimulant drugs'5. Similarly, intravenous drug users (IVDUs) often have a history of poorer health and intercurrent infections that may confer a greater susceptibility to HIV infection and disease. The co-factor theory of disease expression also lends support to the view that intercurrent infection associated with (or acquired from) a history of HIV risk behaviour increases susceptibility to HIV disease expression. For example, Ostrove et al. demonstrated that HSV1 (herpes simplex virus) can activate HIV in infected cells'6, and Thompson et al. have shown that co-infection with HIV and either CMV (cytomegalovirus) or human herpes virus type 6 (HHV6) leads to accelerated disease progression17. However, it should be noted that theorizing of this nature has led some to suggest that HIV may not be the pathogen responsible for AIDS'8. Instead, it has been argued that the observed immune deficiency is due to the direct effects of immunosuppressive behaviours described earlier. Endocrinological evidence on disease progression has demonstrated the influence of stress hormones on HIV activity. Hydrocortisone in vitro elicits HIV activity in infected blood'9. The amount of detected virus was greatly increased in 65% of the samples by administering hydrocortisone, and was only detectable in 15% of the sample after hydrocortisone administration. Conversely, an association has been demonstrated between infusions of met-enkephalin and increased T helper cell numbers20. These data, therefore, suggest that stress hormones (i.e., hydrocortisone) released in maladaptive stress responding are commensurate with greater viral replication, while products released in adaptive responding (i.e., met-enkephalin) are associated with enhanced immunity. How do psychosocial factors influence the course of HIV infection? The suggestive findings from the PI and clinical state research on cancer have been affirmed by some of the earliest work on AIDS. Temoshok et al.2' showed that longer-term survivors used more problem-solving help than non-survivors. Indeed, people with AIDS, for whom the outcome of illness appeared more certain than for those with AIDS related complex (ARC) or asymptomatic infection, were found to use strikingly higher numbers of coping strategies than people in the other groups. This seems similar to Greer's 'fighting spirit' in breast cancer non-relapsers. Also, selfattribution for the cause of AIDS was significantly correlated with higher total dysphoria in people with AIDS, while self-attribution for possible clinical improvement was significantly negatively correlated with total dysphoria with people with ARC. It is therefore important to differentiate attribution of cause from attribution for possible improvement in clinical state. Long-term survivors have been characterized as having more flexible coping strategies, thereby supporting the conclusions drawn by Temoshok et al.21. Marguth et al.23 similarly reported fewer stressful life events in long-term survivors. However,

work ofthis kind has predominated in individuals who are towards end stage HIV disease. Thus, it is not clear whether the psychological factors associated with resilience during AIDS or ARC can be extrapolated back to the earlier stages of infection. Temoshok's group, in a series of intensive studies24 on small numbers of people with AIDS, ARC and early HIV infection, assessed the interplay between immune functioning and emotion. Psychosocial factors associated with higher numbers of CD4+ cells included less profile of mood states (POMS) tension and anxiety, less depression/dejection and fatigue/inertia, and less anger/hostility. Absolute numbers of CD8+ cells were positively associated with more fitness and regular exercise, not doing unwanted favours, less POMS fatigue/inertia, and withdrawing to nurture the self. Levels of p24 antigen were elevated in the presence of more depression, less vigour, more fear, less self-rated sense of humour and less active coping. There were no significant associations between any immune parameters and serum cortisol. This investigation also found that subjects who showed greater galvanic skin response (GSR) and finger temperature responses had "superior" NK cell cytolytic capacity. At 3-year followup, autonomic reactivity predicted survival after disease, and NK cell activity was also marginally predictive of survival. Thus, it was hypothesized that an autonomically reactive temperament should be associated with greater and more frequent release of catecholamines and thus enhanced NK cell activity. This is consistent with the earlier-described research on repressive and passive cancer patients having a poorer prognosis. Other reports have suggested that psychoimmunologic relationships may vary according to the stage of HIV disease25'26. A prospective study of 100 symptomatic gay men assessed at two 6-month intervals showed that, at the first assessment, CD4+ absolute numbers were associated with more POMS tension/anxiety, trait anxiety, anger/hostility and loneliness. Also, greater reported emotional control was associated with more CD4+ cells and NK cells. At the second assessment, greater emotional control was associated with more NK cell activity, and greater loneliness was associated with higher levels of CD4+ cells. In addition to the supportive research described above, much evidence exists against stress having immunosuppressant effects in those with HIV. Kemeny et al.4 compared 45 bereaved and 45 matched non-bereaved HIV-infected men and found no differences between the bereaved and non-bereaved on any immune parameters, including mitogenic reactivity, levels of serum neopterin, and percentages of CD4+ and NK cells. Similarly, in examining the relationship between emotional distress, CD4+ counts and cortisol levels, no association between cortisol levels and CD4+ counts was found27. However, these data are indicative of a sample of HIV positive men experiencing minimal emotional distress. Thus, the absence of evidence indicating stress-related immune impairment may have been due to the absence of stress. Catan assessed immune function and reported stressors in IVDUs and revealed that neither stress nor distress were significantly associated with decline in CD4+ count over time28. No significant differences in means for stress were found between those who had less than three ARC symptoms and those who had more than three. There were, however, significant differences between the two groups on measures of distress (anxiety and


depression), although how this was related (if at all) to illness progression is not clear. Kessler et al29 assessed stressful life events over six 6-month recalls to the study centre. The researchers found no evidence of serious stressors having any meaningful effect on symptom onset, and concluded that people with HIV did not need to protect themselves from stress, or develop anti-stress skills to forestall progression to HIV disease. However, their analysis of HIV-related life-events was limited and they did not consider any intervening variables such as coping. The ways in which a disregard of such factors may contribute to an unjustified acceptance ofthe null hypothesis, however, has been recently described30. Similarly, a cross-sectional and longitudinal study of 124 HIV-positive gay men found that there was no consistent association between depression, distress, or stress and immune status as measured by CD4+ count, and that this absence of association endured over a 6-month period31. Why this pattern of results was obtained is unclear, although a recent model suggests that the choice of immunological marker may determine the chance of detecting stress-related immune dysfunction30. According to this model, the use of CD4+ counts is appropriate only after prolonged exposure to a stressor. A 6-month follow-up as seen in the Rabkin et al. study31 is presumably therefore not a long enough time in which to identify stress-related dysfunction through cell-counts. The inconsistencies that characterize this area are perhaps best exemplified by two groups examining the influence of social support in HIV progression. While one team32 concluded there was no relationship between social support and CD4+ counts or symptomatology, another reported a significant association between social support and CD4+ counts33. The causes of such disagreement are numerous (e.g., method of determining psychosocial factors, use of anti-viral treatment, time since infection, etc.) and reflect the tremendous hurdles that face the PI researcher when examining the role of emotional distress in progression. Do psychosocial factors influence the interplay of intercurrent infections? The last question to be asked here is whether psychological or psychosocial interventions appear to have any beneficial impact on immunological or clinical outcomes over time in HIV infection. Here, once again, the evidence is equivocal, with some suggestion that interventions aimed at mediating stress experiences in HIV-positive men may have no appreciable effects on psychoimmunological functioning. For example, training in relaxation and stress management for men with HIV failed to produce any impact on lymphocyte subset enumeration, NK cell activity or mitogen response3. However, there are plausible reasons for this failure: the interventions may have been insufficiently engaging, participants may have been unhappy at the ending of the group intervention, and the educational components aimed at sexual risk reduction may have been stress-provoking. In contrast, in HIV positive men co-infected with Epstein-Barr virus (EBV) and HHV-6, both aerobic exercise and cognitive behavioural stress management reduced antibody titres to EBV, while cognitive behavioural stress management reduced antibody titres to HHV-635. Cognitive-behavioural support activities to encourage adaptive coping strategies such as planning and

behavioural engagement, and to counter denial! avoidance strategies, have also been demonstrated to buffer immunological changes accompanying notification of HIV infection36. These findings mirror those obtained in cancer patients using the same interventions. It is important that these early outcome studies are built upon as soon as possible, and that other stress-management approaches, such as hypnosis and direct problem-solving activities, be tried. There is clearly a need to establish the nature of psychosocial correlates which have therapeutic consequences for individuals who are ill. What does it all mean?: conclusions and pointers There is still so much uncertainty about what these results mean and how they advance our understanding of PI, and still a reluctance to embrace intervention measures that are based on patchy results - understandably so. One ofthe problems in interpreting such research is that our expectations (and hopes) often overreach the certain knowledge we bring to this still new arena. This has nicely been explicated in a recent review37, and our limits are worth re-stating here: Uncertainties about immune measures and procedures Immunology is not an exact science. Normal limits for immune variability have not yet been defined; there is disagreement over the relative utility of cell percentages, subsets, absolute numbers or functional assays; there are untested assumptions involved in using and interpreting immune measures using peripheral blood; and we have, as yet, no way to approximate the systemic function of the immune system and all its constituent parts. Even if these issues were clear, selection of appropriate measures linked to disease outcome is a major challenge. Then there are the ubiquitous sources of variability, be it technical, interlaboratory, intra-laboratory or assay variability.

HIV-associated uncertainties The natural history of HIV infection and disease is still in its exploratory stage. Clinical biological (including psychological, neurological, and immunological) processes and changes are central to HIV disease, rather than secondary, and they have yet to be fully explicated. Time elapsed since infection is usually unknown, and latencies for disease expression are not yet certain. The role of intercurrent infections and diseases in HIV psychoimmunology is still unclear. Medication effects may confound findings in PI research. The role of behaviour for PI assessment (e.g., drinking, drug use, etc.) is unclear. Uncertainties about psychosocial measures Not all psychological measures fit all IIV populations; psychosocial instruments are truly bewildering in their variety, with normative data that may be only geographically and sub-geographically appropriate. Uncertainties about specific populations Much of the PI knowledge from HIV research is nontransferable, and there are serious doubts about the comparability of studies in different settings and populations: illness severity and type varies with geography (e.g., as with prevalence of toxoplasma in people with HIV) and populations being studied; drug users in Glasgow may require different approaches and initiatives to those required for urban Ugandan

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prostitutes or Romanian babies; and there is also the possibility that predisposition to emotional inhibition and susceptibility to disease expression are genetically determined and not causally related or predictably linked.

Uncertainties about analysis There are often confusions drawn in analysing what is going on. CD4+ counts are coincident, as are predictions based on correlations: they do not identify cause and effect, although statistical techniques can help to clarify these issues. In much of the research discussed, the multi-factorial functions under analysis are required to be assessed using statistics that may obscure the subtleties of immune functioning. On the other hand, our incomplete understanding may equally encourage the likelihood of Type 1 errors in small populations. Temoshok points out, however, that within-subject correlations, for example, may be a more appropriate method for obtaining realistic pictures of what is happening to individuals, which may be obscured by using between-subject or within-group correlations. Allied to this is the dilemma about interpreting results, especially across studies, where the identification of non-linear relationships may be effectively obscured. Until these limitations can substantially be overcome, the move from the possibly correlational to the possibly (then significantly) causal and predictive will be acknowledged, to use Temoshok's apt phrase, more in theory than in practice. Along with the development of more rigorous methodologies, however, is the clear need for an embracing theory to give a coherent structure for future work. The biopsychosocial model2 '8 represents just such an initiative. With the aid of such a schema for channelling PI enthusiasms, it may one day be possible that the current demonstrable limitations and constraints associated with the present empiricism may be overcome to enable our technology and designs to catch up with our instincts. References 1 Temoshok L. Psychoimmunology and AIDS. In: Bridge TP, Mirsky AF, Goodwin FK, eds. Neuropsychiatric and Substance Abuse Aspects of AIDS. New York: Raven Press, 1988 2 Greer S, Watson M. Towards a psychobiological model of cancer: psychological considerations. Soc Sci Med 1985;20(8):773-7 3 Editorial. Emotion and immunity. Lancet 1985;ii:133-4 4 Kemeny ME, Fahey JL, Schneider S, Taylor SE, Weiner H, Visscher B. Psychosocial co-factors in H1V infection: associations among bereavement, depression and immunity in HIV+ and HIV- homosexual men. Psychosom Med 1989;51:244-6 5 Greer S. Cancer and the mind. Br JPsychiatry 1983;143:535-43 6 Temoshok L. Biopsychosocial studies on cutaneous malignant melanoma: Psychosocial factors associated with prognostic indicators, progression, psychophysiology and tumour-host response. Soc Sci Med 1985;20:833-40 7 Cohen S, Tyrrell DAJ, Smith AP. Negative life events, perceived stress, negative affect and susceptibility to the common cold. J Personality Soc Psychol 1993;64:131-40 8 Lyketsos CG, Hoover DR, Guccione M, Senterfitt W, Dew MA, Wesch J, et al. Depressive symptoms as predictors of medical outcomes in HIV infection. IX International AIDS Conference, Berlin, 6-11 June 1993 9 Tross S, Holland J, Hirsch, D, Schiffman M, Gold J, Safat B. Psychological and social impact of AIDS spectrum disorders. Proceedings of the Second International Conference on AIDS, Paris, France, 1986 10 Herbert TB, Cohen S. Depression and Immunity: a meta-analytic review. Psychol Bull 1993;113:472-86 11 Weisman AD, Worden JW. Coping and vulnerability in cancer patients. Project Omegn II, USA: Massachusetts General Hospital and Harvard Medical School, 1977 12 Greer 5, Morris T, Pettingale KW. Psychological response to breast cancer: Effect on outcome. Lancet 1979;ii:785-7 13 Miller D. Stress, stress roduction and coping in HIV infection and disease. VIII International Conference on AIDS/Ill International STD Conference, Amsterdam, 19-24 July 1992 14 Solomon GF, Temoshok L. A psychoneuroimmunologic perspective

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(Accepted 13 December 1993)