Social Support and the Development of Immune Function in Human Immunodeficiency Virus Infection

TORES THEORELL, MD, VANJA BLOMKVIST, BA, HANS JONSSON, MD, SAM SCHULMAN, MD, ERIK BERNTORP, MD, AND LENNART STIGENDAL, MD

A psychosocial investigation offered to all human immunodeficiency virus (HlV)-infected men with moderately severe or severe hemophilia in Sweden was made in 1986. Most of these men had been infected in the years 1980 to 1984 and told about their infections in 1985. Forty-nine subjects had answered questions in regard to sources of emotional support in their life situation. Based on the responses to these questions a score of "availability of attachment" (AVAT) was calculated, and two groups of patients were identified: one with high AVAT and one with low AVAT scores. The subjects were followed with regard to the state of their immune system, as reflected by CD4 counts, until 1990. The results indicated that a low AVAT score in 1985 was associated with a significantly more rapid progressive deterioration in CD4 count during subsequent years. The mechanism behind this association is unknown. Several possible confounders were not studied. However, if the association between a poor AVAT score and rapid CD4 deterioration after HIV infection is replicated in other samples, it could be important to the future clinical care of HIV-infected subjects. Key words: hemophilia, HIV infection, immune function, social support.

INTRODUCTION Recent studies in psychoneuroimmunology have shown that psychological depression may inhibit the function of the immune system and also that psychological reactions may both stimulate and inhibit production of immunoglobulins and immune cell activity (1-3). The significance of this to the progression of acquired immunodeficiency syndrome (AIDS) in subjects who have become infected with human immunodeficiency virus (HIV) is unknown. However, one study gave indications that psychological factors such as an optimistic attitude may protect infected subjects, which results in a slower onset of manifest AIDS (4). Another study showed that distress at diagnosis, denial, and low adherence with intervention were significant predictors of disease progression and that increase in denial postdiagnosis significantly correlated
with a rapid deterioration of the immune system (5).

relationship and the other showing no such relationship (6, 7). No published study has explored the relationship between psychosocial situation and immune system deterioration. In the present study, the main question to be explored was whether the HIVinfected patient's self-reported psychosocial situation is associated with the rate of subsequent deterioration of immune function. Our hypothesis in the present study was based on research regarding the importance of social support. There is evidence that social support in the form of close confidants who are available in difficult situations is important in regard to the mortality rate in general and the cardiovascular mortality rate in particular (8). Social support has also been shown to influence the patient's emotional state in chronic disease (9) and the response of immunoglobulin levels to psychosocial stress, such as increasing job strain (10). This
means that social support could also be important in

Two recent publications describe analyses of the relationship between depression and deterioration of the immune system, with one of them showing a clear

From the National Institute of Psychosocial Factors and Health (T.T., V.B.), Department of Occupational Medicine (T.T.), and Divisions of Coagulation Medicine at the Departments of Medicine (H.J., S.S.), Kaiolinska Hospital, Stockholm; Malmo General Hospital, Malmo (E.B.); and Sahlgrenska Hospital, Goteborg (L.S.). Address reprint requests to: Dr. Tores Theorell, MD, National Institute of Psychosocial Factors and Health, P.O. Box 230, Stockholm, 171 77 Sweden. Received for publication December 2, 1993; revision received May 3, 1994.

regard to the course of ADDS in HIV-infected subjects. The present study focused on the relationship between measures of social support and immune activity and its deterioration in subjects infected with HTV. Previous studies that explored psychological states and the progress of AIDS have been done on homosexual men. In the present study, the study population was composed of men with hemophilia who represent a different part of the male population.

STUDY GROUP AND METHODS

The basis of this study was an investigation of the psychosocial situation of hemophiliac patients in Sweden. It was based on

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SOCIAL SUPPORT AND IMMUNITY IN HIV INFECTION personal contacts with all known HTV-infected male subjects with hemophilia in Sweden. The material used for the present study was collected by questionnaires, which were distributed either when the subject visited the outpatient clinic for hemophiliac patients or in his home. There are three centers in Sweden: Stockholm, Malmo, and Goteborg. Approximately 300 hemophiliac patients with severe or moderately severe forms of the disease who require treatment with infusions of products from human blood attend these clinics at regular intervals. The psychosocial investigation started in 1986 when the number of living HIV-infected hemophiliac patients was 94. Most of these subjects had been informed about their HIV infection approximately 1 year before the psychosocial exploration, during the spring or early summer of 1985. Four subjects were told about it in the spring 1986. Of these, 31 were excluded by the personnel from participation in the study. This group included adolescents who had not been informed that they were infected, boys younger than age 12 years, and subjects who were judged to be too ill to be able to fill out questionnaires. Thus, 63 were available for this study. Fourteen of these 63 subjects refused participation. Accordingly, 49 subjects participated in some part of the psychosocial exploration, but only 48 of them (76% of the eligible subjects) filled out the questionnaire described subsequently. At the time of the interview, the 48 participants had an age range of 12 to 66 years (mean, 32.3; SD, 13.1). During follow-up, 11 of these subjects died (23%), and hence, only 37 remained for follow-up until 1990. Socioeconomically, Swedish hemophiliac patients are an unusually homogeneous group. This is due to the fact that Sweden is an advanced country with regard to hemophilia treatment; hence, by international standards, many patients have become relatively old. Because of their illness, these hemophiliac patients were not able to work in physically demanding jobs. Only three men were academically trained professionals. All the remaining participants were lower-level clerks. Eighty per cent of the older participants (46-66 years old) were married (or cohabiting). Sixty-four per cent of the participants in the middle-age range (3045 years old) were married (or cohabiting). A Swedish version (11) of an Australian questionnaire (12) was used to measure the social network and support. For the present study, the availability of attachment (AVAT) index from the social network-support questionnaire was used. This is the summation of scores from eight questions (each scored 0-1) regarding social and emotional support in difficult situations. This differs somewhat from several other measures of social support and network in the sense that the availability of close contacts and contacts that can be of emotional help in crisis situations is focused. Scores could range from 0 to 8. The psychometric properties of these patients have been presented elsewhere (11). The Cronbach alfa, in a random sample of middle-aged men in the Swedish population, was .80. The mean AVAT score in the present study was 6.5 with a SD of 1.9. This was very similar to the AVAT mean score in a sample (11) of middle-aged men (mean, 6.6; SD, 1.6) and higher (9) than in a sample of men undergoing chronic renal dialysis in Sweden. As in previous studies, the index has a positively skewed distribution. Thus, one half of the subjects reported a maximal score of availability of attachment. The study group was divided into low AVAT support and high AVAT support groups, with the good support subjects scoring the maximal 8 points. The mean age of both these groups was 32. Two boys aged 12 and 15 years belonged to the low AVAT group, and two boys aged 15 years belonged to the high AVAT group. These four youngest subjects were not asked to fill out the social support questionnaire, but their mothers did so. Separate analyses were made after exclusion of the four youngest subjects. All other subjects were at least 18 years old. Age was not significantly associated with AVAT (rho = .12, p = .39). CD4 counts were calculated as part of the routine checkup of all patients. Patients were already beginning to be examined with regard to CD4 counts during the latter half of 1984 when suspicion was raised that HIV infection might exist in blood products. The measurements had stabilized methodologically for all patients in 1985, and calculations according to this methodology have been used for the present article (13). Accordingly, one of the most interesting parts of the analysis of the follow-up of CD4 counts, from the years of infection and particularly from 1983, could not be performed. The mean CD4 counts did not differ between the three centers in the samples reported in this article. Morbidity was followed in medical records annually until the end of 1990. Sixteen significant signs of disease were recorded by physicians at the medical examinations, namely, infections, such as Pneumocystis pneumonia, other pneumonias, sepsis, urinary infections, and infections in the genitals, mouth, pharynx, and brain; tumors in and outside of the brain; neurological signs, such as neuropathies and overt neuropsychological symptoms; and diverse changes, such as skin changes, joint involvement, changes in lymph glands, eye involvement, gastrointestinal involvement, and other signs. Most of these, but not all, were associated with AIDS; a few, such as joint involvement, were primarily signs of complications of hemophilia. For the purpose of the present study, the number of observed conditions in this group was calculated for each year: 1987,1988,1989, and 1990. Body weight means were calculated and recorded for each year and subject.

RESULTS Two-way analyses of variance for the period 1985 to 1990 showed that the mean levels of CD4 counts were not significantly different between the AVAT groups for the whole study period but that the development over time between the groups differed significantly for AVAT. Thus, the difference between the groups increased over time (F interaction T group by time = 4.06, p = .002, A = 18 low AVAT, N = 19 high AVAT). Figure 1 shows the means and standard errors of the CD4 counts (the calculations were based on logarithmic levels, but the levels were presented after antilogarithmic back transformations and recorded as the number of cells X 109/liter) for the years 1985 to 1990 in subjects for whom there were data for each one of these years. To control for the possible effect of initial value, ratios were calculated between the CD4 counts for 1986, 1987, 1988, 1989, and 1990 and the initial level in 1985. A two-way analysis of variance was calculated on the basis of logarithmic transformations of these ratios. A strongly statistically significant decrease was observed (F time, 23.00; p = .0001) and a significant interaction (F interaction group by time, 4.54; p = .002). In the high AVAT group, the levels showed the following percentage change during successive years (1986-1990): +2%, - 9 % , -22%, -24%, and -37%,
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DISCUSSION

High AVAT

CD4

Fig. 1. Means and standard errors of means of number of CD4 cells (number of cells x lO9/liter) during the successive years 1985 to 1990 in low AVAT (score < 8, N = 18) and high AVAT (score = 8, N = 19) groups.

whereas the corresponding numbers for the low AVAT group were 0, -4%, -26%, -46%, and -64%. Exclusion of the four subjects younger than age 18 resulted in a low AVAT group composed of 16 patients and a high AVAT group with 17 subjects, both with a mean age of 35 years. Analysis of variance showed results similar to those in the total group. Thus, in the interaction analysis of CD4 levels between 1985 and 1990 in the two groups, a significant interaction was found (Fgroup by time = 4.09, p = .004) In the corresponding analyses of changes in CD4 level in relation to the initial one in 1985, there was also a significant interaction (F group by time = 3.92, p - .002). The number of symptoms increased significantly over the study years in both groups. There was no statistically significant difference in the number of symptoms between the AVAT groups [p = .29) and no significant interaction group by time (p = .25), although the means tended to be higher in the low AVAT group during the years from 1988 until 1990. Body weight increased between 1985 and 1990 in the low AVAT group. Subjects younger than age 20 in 1985 were excluded from this analysis; thus, 14 subjects remained in both groups. In the low AVAT group, the mean body weight increased successively from 64.1 kg in 1985 to 69.1 kg in 1990, whereas no such changes were observed in the high AVAT group (from 68.0 to 68.4 kg with very small fluctuations). The interaction between group and time was significant (F interaction group by time, 3.66; p = .004). Eight of 35 men in the low AVAT and three of 24 in the high AVAT group died during follow-up. This difference was not significant (chi-square, 1.57; p = .21).
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The present study showed that a low level of self-reported availability of attachment was associated with rapid deterioration of number of CD4 cells in hemophiliac patients with HIV infection. These findings paralleled the results of other groups (5-7) in the sense that psychological states and behavior have been shown to be associated with CD4 decline. No previously published study, however, focused on the psychosocial situation, although a low level of education has been shown to be almost significantly associated with a shorter time from infection to the onset of AIDS (7). It has been found (11) that poor social support is associated with low social class and depression. Hence, there is a possibility that a group of psychosocial factors associated with moods, may be important. It is important to identify factors that could be actively improved in clinical practice, and social support is such a factor. It should be pointed out, however, that it is impossible to disentangle different components in the psychosocial total situation: depression, socioeconomic status, and social support. A difference between the present study and previous studies of psychosocial factors and progression of AIDS in relation to HIV infection is that other studies have been performed on homosexual men. The present study deals with hemophiliac patients who constitute a group with other psychological and psychosocial conditions. Parallel findings in different populations may provide additional support for a link between psychosocial factors and immunological changes. The study was based on an exploration of psychosocial needs in the total population of HIV-infected hemophiliac patients in Sweden. Accordingly, it was not possible to distribute extensive questionnaires. In most cases, the subjects had been aware of their infections for a couple of years, and hence, their social support situation may have stabilized after a period of dramatic changes. It should be emphasized that the subjects who were approached were healthier than average HIV-infected men because a requirement was that the subject should be able to participate in an interview and to fill out a questionnaire. The exact year of HIV infection was not known in most cases. However, the HIV-infected population could be divided into those who became infected in the years 1980 to 1983, the majority, and those who became infected in 1985 (three of the participants in this study, two of whom were
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in the low AVAT and one of whom was in the high AVAT group). The similarity with regard to CD4 mean level and the mean number of predominantly AIDS-related symptoms favors the view that subjects in the two AVAT groups were similar with regard to the phase of HIV infection in 1985, which was the starting year of the present study. The CD4 count level in the infected group was already low in 1985 compared with that of a noninfected group of hemophiliac patients. During the same period, this group had a stable level of 0.87 cells X 109/liter 0.06 (standard error of the mean), which was statistically significantly higher than that in the study groups. In the low AVAT group, the mean level was 0.49; in the high AVAT group, the mean level was 0.46 in 1985. The corresponding mean levels in 1990 were 0.30 in the high group and 0.17 in the low AVAT group. The starting levels in 19C5 in the infected group were comparable to those observed in two other studies of HIV-infected men (6, 7) in which a similar delay between infection and disclosure of HIV status occurred. On the other hand, they were lower than the levels observed in a study (5) of men who had been HIV infected recently and who had the same levels as those in the noninfected hemophiliac patients in the present study. The difference in development of CD4 counts between the group with low and high AVAT scores in 1985, i.e., more pronounced deterioration during subsequent years of the levels in the low AVAT group despite no difference in mean CD4 starting level and mean age between these groups, indicates that the patient's perception of availability of attachment during this period may be valuable in the prediction of the development of the immune system during subsequent years. The relatively small size of the study groups and the lack of control over a number of potentially important confounders necessitates caution in the interpretation of these findings, which have to be repeated by other research groups. In particular, it should be pointed out that this study gives no clue as to a possible mechanism behind a lack of availability of attachment and the rapid progression of CD4 deterioration after HIV infection in hemophiliac patients. AVAT was not significantly associated with the mortality rate during follow-up. In a similar way, previous studies of depression and the development of AIDS in morbidity/mortality studies have not shown any clear relationship (5-7). Accordingly, we might conclude that self-reported social support is significant to the prediction of progresPsychosomatic Medicine 57:32-36 (1995)

sion of immune function, whereas the significance of social support in regard to the mortality rate remains to be established. In a study based on the same study group, we showed, on the other hand, that a self-oriented active-optimistic coping behavior is associated with prolonged survival (14). It should be pointed out finally that blood concentrations of cytokines that play an important role in the mediation of mood changes in different disorders are elevated during the early phases of HIV infection (15, 16). Accordingly, it is possible that some of the relationships that have been observed between depression and immune function may be secondary to biological processes. At present, it is not possible to predict the direction of these associations.

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T. THEORELL et al. 13. Bottiger B, Blomback M, Berntorp E, et al: Serology and lymphocytes subsets in relation to therapy and clinical symptoms in haemophiliacs. Eur J Haematol 41:459-466, 1988 14. Blomkvist V, Theorell T, Jonsson H, et al: Psychosocial self prognosis in relation to mortality and morbidity in hemophiliacs with HIV-infection. Psychother Psychosom 62:185-192, 1994 15. Folks TM, Justment J, Kinter A, et al: Cytokine-induced expression of HIV 1 in a chronically infected promonocyte cell line. Science 238:800-802, 1987 16. Molina JM, Schindler R, Ferriani R, et al: Production of cytokines by peripheral blood monocytes/macrophages infected with human immunodeficiency virus type 1 (HIV-1). J Infect Dis 161:888-893, 1990

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