The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study.

The Swedish OCTO and NONA immune longitudinal studies were able to identify and confirm an immune risk profile (IRP) predictive of an increased 2-year mortality in very old individuals, 86-94 years of age. The IRP, was associated with persistent cytomegalovirus infection and characterized by inverted CD4/CD8 ratio and related to expansion of terminally differentiated effector memory T cells (TEMRA phenotype). In the present HEXA immune longitudinal study, we have examined a younger group of elderly individuals (n = 424, 66 years of age) in a population-based sample in the community of Jönköping, Sweden, to examine the relevance of findings previously demonstrated in the very old. Immunological monitoring that was conducted included T cell subsets and CMV-IgG and CMV-IgM serology. The result showed a prevalence of 15 % of individuals with an inverted CD4/CD8 ratio, which was associated with seropositivity to cytomegalovirus and increases in the level of TEMRA cells. The proportion of individuals with an inverted CD4/CD8 ratio was significantly higher in men whereas the numbers of CD3+CD4+ cells were significantly higher in women. In conclusion, these findings are very similar to those previously found by us in the Swedish longitudinal studies, suggesting that an immune profile previously identified in the very old also exists in the present sample of hexagenerians. Therefore, it will be important to examine clinical parameters, including morbidity and mortality, to assess whether the immune profile also is a risk profile associated with higher mortality in this sample of hexagenerians.

Human immunosenescence: does it have an infectious component?

The rate of acceleration of the frequency of death due to cardiovascular disease or cancer increases with age from middle age up to around 75-80 years, plateauing thereafter. Mortality due to infectious disease, however, does not plateau, but continues to accelerate indefinitely. The elderly are particularly susceptible to novel infectious agents such as SARS, as well as to previously encountered pathogens. Why is this? The elderly commonly possess oligoclonal expansions of T cells, especially of CD8 cells, which, surprisingly, are associated with cytomegalovirus (CMV) seropositivity. This in turn is associated with many of the same phenotypic and functional alterations to T cell immunity that have been suggested as biomarkers of immune system aging. We suggest that, in fact, CMV, not age per se, is the prime driving force behind many or most of the oligoclonal expansions and altered phenotypes and functions of CD8 cells in the elderly. Thus, the manner in which CMV and the host immune system interact (over which period? on which genetic background? with which co-infections?) is critical in determining the "age" of adaptive immunity and hence human longevity. In this respect, immunosenescence is infectious.

Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection.

OBJECTIVES: The nature of the immune response in coronary artery disease (CAD) is not fully defined. One pathogen that has been linked to atherogenesis, cytomegalovirus (CMV), is known to exert strong and long-lasting effects on peripheral T cells. In the present study, we investigated the effect of prior CMV infection on the immune system in CAD patients. SUBJECTS: Patients with stable angina and angiographically verified CAD (n=43) and clinically healthy controls (n=69) were included. METHODS: The expression of CD57 and CD28 on peripheral CD4+ and CD8+ T cells was evaluated with three-colour flow cytometry. The findings were related to serological markers of inflammation, T-cell activation and CMV seropositivity. RESULTS: An expansion of CD8+ T cells expressing CD57 but lacking CD28 was seen in the patient group. The numbers of CD8+ CD57+ and CD8+ CD28-T-cell subsets were independently related to CMV seropositivity (P<0.001) but also to CAD per se (P<0.05). Serum concentrations of C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were elevated in the patients but not related to CMV or CD8+ T-cell subsets. CONCLUSION: A pronounced shift in peripheral T-cell homeostasis was observed in CAD patients. Primarily CMV infection but also CAD per se contributed to the expansion of CD8+ T-cell subsets. The T-cell changes were not related to a systemic inflammatory response but should rather be considered as markers of a chronic antigen exposure and/or immunosenescence in CAD.

Low serum beta-carotene reflects immune activation in patients with coronary artery disease.

BACKGROUND AND AIM: Low serum levels of antioxidant vitamins are associated with coronary artery disease (CAD). An immunomodulatory effect of antioxidants has been proposed. The aim of the study was to investigate whether an increased immune response in CAD patients was associated with suppressed circulating levels of antioxidant vitamins. METHODS AND RESULTS: Forty-four men with stable angina and angiographically verified CAD were included as well as 69 healthy controls. T cell subsets in peripheral blood were quantified by 3-colour flow cytometry. C-reactive protein (CRP), soluble interleukin-2 receptor (sIL-2R) and the lipophilic antioxidants alpha-tocopherol, beta-carotene and lycopene were determined in serum. Compared with controls, patients had signs of an enhanced inflammatory activity assessed by significantly increased levels of CRP, sIL-2R and CD4+CD25+T cell subsets. Patients also had significantly lower beta-carotene and lycopene levels whereas a-tocopherol levels did not differ. The increased inflammatory/immune parameters in patients showed a significant inverse relationship to serum beta-carotene but not to lycopene or alpha-tocopherol. CONCLUSIONS: Low serum beta-carotene in CAD patients reflects activation of the immune system. Inflammation should be considered as an important confounding factor when analysing data on beta-carotene and CAD.

Plasma cytokine profiles in elderly humans.

It is known that as we age, immune dysregulation often occurs, leading to failing health, and increased susceptibility to a number of different diseases. In this study we have investigated plasma cytokine profiles in order to identify immune markers of ageing. Plasma samples were obtained from 138 participants of the Swedish longitudinal NONA study (aged 86, 90 and 94 years) and 18 healthy Swedish volunteers (aged between 32 and 59 years). Our results show significantly increased levels of the pro-inflammatory cytokine interleukin-6 (P<0.0001) and soluble intercellular adhesion molecule-1 (P<0.0001) in the elderly group. The anti-inflammatory cytokine interleukin-10 did not alter with age whereas active (naturally processed) transforming growth factor-beta levels were significantly (P<0.0001) increased in the elderly group. No difference was observed between males and females. These data suggest that there are measurable changes in cytokine profiles with ageing with increased levels of potentially harmful molecules, which may contribute to immune alterations and declining health in the elderly population.

Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study.

Results from the previous times (Times 1-3) of the Swedish longitudinal OCTO immune study indicated that a combination of high CD8 and low CD4 percentages and poor T-cell proliferation in PBL was associated with a higher 2-year mortality in a sample of very old Swedish individuals. The combination of immune parameters was closely related to an inverted CD4/CD8 ratio. In the present study at Time 4 (T4) results are reported from the final follow-up of this longitudinal study, 8 years after it was initiated in 1989. An additional goal at this time point was to examine the immune system alterations in the very old in relation to evidence of lymphocyte activation and cytomegalovirus antibody status. In the present study immune system changes were identified that suggest a loss of T-cell homeostasis, as reflected by a decrease in the number of CD4 cells and a very significant increase in the number of CD8 cells in individuals with an inverted CD4/CD8 ratio. When considered over the duration of the OCTO study the inversion occurred in a high percentage (32%) of the individuals included in the original sample and was associated with non-survival. At T4 the changes were apparent in a number of the T-cell subsets, but particularly in the CD8+CD28-and CD57+ subsets. T-cell activation was significantly associated with the inversion of the CD4/CD8 ratio. In this very old sample the subset alterations were associated with evidence of cytomegalovirus (CMV) infection.

Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study.

Results from a previous longitudinal study indicated that a combination of high CD8 and low CD4 percentages and poor T cell proliferation in peripheral blood lymphocytes was associated with higher mortality in a subgroup of a sample of very old Swedish individuals. The present study examined whether those results could be confirmed at a subsequent 2-year time interval by investigating if additional individuals from the same original sample had developed the immune profile associated with higher mortality. Subgroups were formed by cluster analysis and similar to our previous results, this follow-up study identified a subgroup of subjects (n = 18) with an immune profile which again included high CD8, low CD4 percentages and poor mitogen response and was associated with higher mortality. Over the 2-year period 12 additional individuals: (1) Developed this immune profile; and (2) Could be identified by changes in their CD4:CD8 ratios which progressively decreased over the study period. These results confirm our original study and indicate that in this very old sample, over a subsequent 2 year period, additional individuals moved into the cluster at risk for higher mortality.

Metabolic control, quality of life, and negative life events: a longitudinal study of well-controlled and poorly regulated patients with type 1 diabetes after changeover to insulin pen treatment.

In a previous study of a group of 74 patients with Type I diabetes, quality of life was found to be consistently enhanced a year after transition to multiple injection therapy with the insulin pen, whereas metabolic control (HbA1C) only improved moderately. The aim of the present investigation was to examine quality of life, recent life events, and metabolic control longitudinally in this original study group over a 5-year period beginning 1 year after transition to the insulin pen. Multiple analysis of variance with a repeated-measures design was used to analyze the data longitudinally and compare metabolic control in subgroups of well-controlled and poorly regulated patients during the study period. For the group as a whole, quality of life was found to change only moderately, whereas metabolic control deteriorated significantly across time following transition to the insulin pen. The two subgroups exhibited distinct differences, however, in quality of life, recent life events, and metabolic control patterns. These findings are discussed in terms of the clinical suitability of a multiple injection regimen.

Pen injection and change in metabolic control and quality of life in insulin dependent diabetes mellitus.

A second follow-up of metabolic control and quality of life in insulin dependent diabetes mellitus (IDDM) patients who had switched 3 years before from syringe to multiple pen injection treatment, was carried out. A total of 73 consecutive outpatients were enrolled in the initial follow-up study in 1988, 1 year after their changeover to insulin pen, with their metabolic control and quality of life examined. The present study concerns the reexamination of 65 of them in 1990. Their HbA(1c) level was recorded yearly, already from 1987, on. After an enhancement of metabolic control in 1988, exhibited primarily by patients with fewer syringe injections before pen treatment, control up to 1990 was found to have regressed to about baseline level or to have gradually declined. Patients who perceived their ability to self-test blood glucose to have decreased exhibited the least satisfactory course of metabolic control. This is seen to indicate that maintaining self-testing in multiple injection insulin treatment is a very real challenge to this regimen.

Immune parameters in a longitudinal study of a very old population of Swedish people: a comparison between survivors and nonsurvivors.

As a part of an ongoing longitudinal investigation, this study examined relationships between survival and selected immune system parameters in a sample (n = 102) of very old individuals (86-92 years at the time of initial immune system data collection). Analyses were performed comparing initial time-point measurements from those individuals who were alive (n = 75) and those who were deceased (n = 27) two years after initial data collection. Immune system measurements consisted of determination of peripheral blood lymphocytes and lymphocyte subsets, as well as T-cell responses to activation by Concanavalin A. Cluster analysis identified a subgroup associated with nonsurvival which indicated characteristics that included: poor T-cell proliferative responses, high CD8 percentages, and low CD4 and CD19 percentages. This multivariate analysis suggested that combinations of immune system parameters predict two-year survival otherwise not apparent when single immune system parameters were evaluated in the elderly.

Recent life events, gender differences, and the control of insulin-dependent diabetes mellitus. A 2-year follow-up study.

In an earlier study of patients with insulin-dependent diabetes mellitus (IDDM), males who reported predominantly negative life events over the previous year and had a poorer social support situation showed poorer HbA1C values than those who reported fewer or no negative life events. For the females it was found that the greater the number of life events reported, especially positive ones, the greater the change for the better was HbA1C over the event year studied. The present study aimed at following up, during the next event year period, various gender-specific patterns obtained in the previous study. For the males, negative life events and HbA1C values were found to be positively related this second event year as well. In addition, more negative life events were reported by those males who, in the previous study, were defined as high-negative eventers. In contrast, for the females, no significant correlations were obtained between life events and HbA1C values for the second event year. The results are discussed in terms of possible differences in psychosocial environment and coping strategies between males and females.

Change in quality of life along with type 1 diabetes.

The aim of this study was to recurrently follow quality of life in type 1 diabetes patients who have switched from syringe to multiple pen injection treatment. The insulin pen is a simpler automatically preset device for self-injection. Seventy-three consecutive outpatients were initially examined in 1988, 66 of whom were re-examined in 1990. Quality of life was defined as perceived well-being and life satisfaction, globally as well as within key domains and functions. Various status and retrospective change ratings were repeatedly performed by patients and significant others. For a great majority, quality of life status was fairly stable between 1988 and 1990. Nine subjects with recent incidences of severe socio-medical complications accounted for a great deal (41%) of the decline in composite quality of life status recorded. Future-orientation and the conduct of the multiple regimen declined in the major fairly stable patient group as well. Contrary to the change-in-status outcome referred to, the direct retrospective change ratings in 1990 indicated a certain continuing consistent improvement over the last 2 years. It was minor, though, in comparison with the preceding enhancement attributed to the pen. In spite of the divergent mean outcome, the disparate change parameters correlated. The self-rated life quality trends were corroborated by ratings by significant others. To a certain extent, the mean change bias may reflect coping strategies released by and adopted against the strain of the illness. Probably, these primarily coloured the more sensitive direct retrospective change ratings. Some bias may also be due to a lack of sensitivity of the status ratings. However, the differential change assessments may also tease out and illustrate two separate, equally valid, patient perspectives, one on their current situation and another one on how it has changed. The diabetes illness appears reasonably stable in a majority of the subjects over the study interval. There seem to be some remaining satisfactory quality of life effects of the pen therapy. The study underscores the benefit of undertaking combined retro-/prospective and sufficiently longitudinal analyses with simultaneous dual rating operations, to get the most nuanced overview.

Type II diabetes and quality of life: a review of the literature.

In this review, an attempt was made to describe how non-insulin-dependent diabetes mellitus (NIDDM, type II diabetes) affects the life of the ill person. Patients are affected by and cope with this complex disease in different ways, depending on its severity and complications. Influences on well-being therefore also vary--from none to major deterioration. A substantial proportion of patients are primarily affected with fatigue, anxiety, and depression. Deteriorations in cognitive function have also been documented, although diverging evidence exists. Some negative social circumstances have also been noted. Social support, particularly specific support, appears to be helpful, although self-efficacy and health practices seem to be as important. Resistance to compliance with diabetes regimens together with reactions to the demands for increased levels of physical activity are often seen. Systematic focused studies examining how patients and significant others perceive the impact of the disease in retrospect are still awaited. There is a great need for more research on type II diabetes; broad prospective longitudinal follow-up studies monitoring natural disease progression, as well as examining the predictive significance of quality of life, would be welcome.

Age-related changes in immune parameters in a very old population of Swedish people: a longitudinal study.

This study used a longitudinal design to examine age-related changes in a well-defined sample of Swedish people ranging from 86 to 92 years of age at baseline. The longitudinal design encompassed three measurement occasions with 1 year intermeasurement intervals. The results were analyzed by multivariate analyses of variance (MANOVA), which is useful for comparing individuals over time. Healthy middle-aged subjects (39 years SD +/- 5.8) served as controls. The proliferative responses to Concanavalin A (Con A), a T-cell mitogen, indicated significant lower levels in responses of the old when the two groups were compared. The MANOVA revealed no significant change in mitogen responses over measurement occasions in the old sample as compared with the young. However, when cell types and lymphocyte subpopulations were examined, significant differences were found between the two age groups in many of these parameters and for some (lymphocyte percentages and numbers, CD3 numbers) the MANOVA indicated significant decreases over the measurement occasions in the very old. The results also consistently indicated significant intraindividual correlations in cell types, lymphocyte subpopulations, and mitogen responses over time.

Coping behaviour and degree of discrepancy between retrospective and prospective self-ratings of change in quality of life in type 1 diabetes mellitus.

Quality of life and metabolic control were examined in 74 adults with Type 1 diabetes mellitus in 1988. Sixty-six of the persons were followed up in 1990 with the aim of studying more closely the subgroup that showed a 'major' discrepancy between 'retrospective' and 'prospective' quality of life change ratings. 'Prospective' quality of life change was defined as the difference in assessed quality of life status between 1990 and 1988. 'Retrospective' quality of life change was assessed directly by subjects in 1990 covering the same time period. Data on quality of life, well-being, sociodemographics and metabolic control were collected on both occasions. Recent life-change events and long-term complications were also recorded in 1990. Subjects with 'major' discrepancy reported greater retrospective quality of life improvement, higher quality of life, and greater well-being, as well as lesser occurrence of negative and greater occurrence of positive recent life-change events, than did those with 'minor' discrepancy, despite their exhibiting poorer metabolic control and a higher prevalence of incipient nephropathy. The results are discussed in terms of possible coping and defence strategies.

Quality of life: status and change (QLsc) reliability, validity and sensitivity of a generic assessment approach tailored for diabetes.

The aim was to review the psychometric properties of a generic strategy for assessing status and change in quality of life (QLsc) partly tailored for patients with insulin-dependent diabetes mellitus. Quality of life was defined as perceived well-being and life satisfaction, globally as well as within key domains and functions. The strategy has been developed iteratively and, thereby, proven psychometrically satisfactory across groups and settings. Seventy-three consecutive outpatients were examined in 1988, after a period on multiple injection treatment by insulin pen; 66 were re-examined in 1990. In 1988 and 1990, perceived well-being and life domain status were self-rated. Life domain changes attributed to pen treatment were rated retrospectively in 1988 and subsequent general changes over 2 years rated similarly in 1990. Shortened parallel ratings were performed by significant others. Series of cross-sectional and longitudinal analyses yielded convincing reliability, validity and sensitivity evidence of various kinds for all ratings, irrespective of rater-self or significant other. As expected, a consistent correlational pattern emerged between status self-ratings, suggesting 'the better/worse off' in one sense, the 'better/worse off' in other senses assessed. Moreover, congruent change linkages, suggesting 'the greater change for the better/worse' according to the one type, the 'greater change for the better/worse' according to the other one, were also salient. Fourteen persons with less congruence in the disparate, but parallel change rating parameters appeared to be in a critical disease phase, applying reaction formation or denial like defence mechanisms. In conclusion, the entire cohesive strategy also functioned well in the current setting. It may probably be applied in search for other vulnerable sub-groups and in analyses of coping strategies. It offers rich analytic options especially in evaluational contexts. The study outcome may stimulate development of methodology within this field.

Background factors, long-term complications, quality of life and metabolic control in insulin dependent diabetes.

Sixty-six of 74 adults with Insulin Dependent Diabetes Mellitus (IDDM) examined earlier (1988), were followed up two years later (1990) with the aim of studying the influence of sociodemographic factors, long-term complications and quality of life on metabolic control. It was found that both non-cohabitance and a major discrepancy between quality of life change ratings made prospectively (difference in current QOL ratings made 1990 vs 1988) and retrospectively (assessed in 1990 and covering the same period) were associated with poorer metabolic control, and also that perceived somatic health was linked with better metabolic control. A majority of the persons with a major discrepancy in their quality of life ratings, seen as suggestive of difficulties in their realistically assessing their own life situation, was also found to be non-cohabitant and/or to have incipient nephropathy, indicating these persons to constitute a risk group. In addition, well-regulated subjects were found to rate their bodily health as higher than they did their quality of life, whereas for poorly regulated persons the opposite was the case. The results were seen as pointing to the need of paying special attention clinically to the group of persons characterized here by a major discrepancy in their quality of life change ratings and also as emphasizing the fact that living with IDDM is a balancing act for the individual between satisfying bodily demands to be well-regulated and living in such a way as to perceive quality of life.

Recent life events, gender, and the control of diabetes mellitus.

Sixty-six outpatients with insulin-dependent diabetes mellitus (IDDM) filled in a life event questionnaire reflecting positive and negative life events perceived to have occurred over the past year. The difference in glycosylated hemoglobin (HbA1C) measures obtained before and after the 1-year period in question (Delta-HbA1C) served as a proxy measure of change in metabolic control. Among males, those reporting predominantly negative life events showed poorer metabolic control than those reporting few negative life events or none. Among females, the greater the number of events reported, especially positive ones, the greater the change for the better in HbA1C over the event year studied. These results suggest that life events may be significant to metabolic control in insulin-dependent diabetes. This only becomes apparent, however, when the two genders are analyzed separately, as various relationships found in one sex may be lacking or even opposite to the other sex. The findings also suggest the importance to the diabetic of learning of life events both the relative lack and preponderance of positive as well as negative events.

Background, quality of life and metabolic control in patients with insulin-dependent diabetes mellitus.

The interference of background characteristics with quality of life and metabolic control in patients with insulin-dependent diabetes mellitus (IDDM) were examined. Seventy-three consecutive outpatients who switched from syringe injections to multiple pen-injection treatment comprised the study group. Perceived status as well as retrospective changes in quality of life, attributed to the new treatment modality, were assessed at follow-up after 9-13 months. Data on metabolic control (HbA1C) were collected at base-line and follow-up. Sub-group comparisons in life quality and metabolic control were performed with regard to differences in sex, age, cohabitation, onset and duration of IDDM. Most of the background characteristics had no or just minor significance for status and change in the life quality and metabolic control of the patients. Cohabitation, however, was linked to a better life quality status pertaining to different domains and a tendency to better metabolic control. In addition, females reported a slightly better health status and a more healthy life style (i.e. eating, drinking and smoking habits) than did males. Extra treatment attention may therefore be justified for non-cohabiting males.