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Association Between Burnout at Work and Leukocyte Adhesiveness/Aggregation

From the Occupational Health and Rehabilitation Institute, Ra’annana, and Sackler Faculty of Medicine (Y.L., S.M., Y.S., T.K., Y.R), Faculty of Management (A.S.), and Department of Cell Biology and Histology, Sackler Faculty of Medicine (M.A.), Tel-Aviv University, Tel-Aviv, Israel.

Address reprint requests to: Dr. Yehuda Lerman, Occupational Health Center, Kupat-Holim, 101 Arlozorov St., Tel-Aviv 62098, Israel.

	ABSTRACT

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OBJECTIVE: This study examined whether burnout at work is associated with leukocyte adhesiveness/aggregation (LAA), a phenomenon known to be affected by stress.

METHODS: The LAA levels of 179 employees (68 men and 111 women) of Tel Aviv University were determined when the employees underwent their annual routine medical checkup. Blood pressure and toxic chemical exposure were also measured, and background data were retrieved from medical records. Information on burnout and somatic complaints (known to be a general marker of stress) was collected through a self-report questionnaire.

RESULTS: Total burnout and each of its subcomponents, emotional exhaustion, chronic fatigue, and cognitive weariness, was significantly associated with LAA levels, even after controlling for age, sex, and educational level. Burnout and somatic complaints intercorrelated positively, but somatic complaints were not significantly associated with LAA levels before or after controlling for the above possible confounders.

CONCLUSIONS: Burnout was positively associated with LAA levels. This finding is consistent with the growing evidence of the negative impact of burnout on physical health. The lack of an association between somatic complaints and LAA levels reinforces the claim that burnout and stress are two different concepts.

Key Words: leukergy • burnout • somatic complaints • leukocyte adhesiveness/aggregation test • stress • exhaustion

Abbreviations: LAA = leukocyte adhesiveness/aggregation.

	INTRODUCTION

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Burnout has been defined as a process of gradual loss of emotional, cognitive, and physical energy that is reflected in symptoms of emotional exhaustion, cognitive weariness, and physical fatigue, respectively (1). This syndrome does not overlap with any other related concepts, such as stress and clinical syndromes of depression or anxiety (1, 2), and it is conceptually distinct from a temporary state of fatigue, which passes after a resting period. It is viewed as a gradual erosion of energetic resources that results from continuous exposure to job and life stresses that are regarded as antecedents of this phenomenon (3). The consequences of burnout include work-withdrawal behaviors; depersonalization, expressed as regarding one’s clients in a cynical and detached way; and reduced job performance (4). In several longitudinal studies, burnout was found to be associated with depressive and cardiac symptoms (5, 6) as well as with absenteeism and job changes (7). It was also found to be related to negative personal and occupational outcomes, including job dissatisfaction and poorer quality of life (8).

The past decade witnessed the emergence of growing evidence of the negative impact of burnout on physical health (9–13). Two studies found it to be associated with coronary vascular disease risk factors: Melamed et al. (11) found that burnout among healthy employees of a high-tech firm was highly correlated with reported tension arousal and that those workers who scored high on both burnout and tension also had elevated levels of coronary vascular disease risk factors (eg, total cholesterol, low-density lipoprotein, glucose, triglycerides, uric acid, and marginally significant electrocardiographic abnormalities), even after controlling for several possible confounders. In another study of healthy employees, burnout in men was found to be predictive of cholesterol changes, evidenced 2 to 3 years later, whereas in women, changes in serum lipids (cholesterol and triglycerides) were positively correlated with emotional burnout but negatively correlated with physical fatigue (14). In a recent study, chronic burnout was found in association with heightened somatic and physiological arousal. This was manifested by high levels of tension at work, postwork irritability, sleep disturbances, complaints of waking up exhausted, and higher cortisol levels during the working day (15).

The present study was designed to further explore the possible negative implications to health of burnout at work and to test its association with LAA, which is known to be affected by stress. In 1824, Dutrocher first suggested that increased leukocyte adherence to the endothelium is an important inflammatory response (16). Fleck (1895–1961) was the first to systematically investigate various aspects of LAA. He described the appearance of aggregates of leukocytes in the peripheral blood of patients and laboratory animals with various inflammatory conditions and coined the term "leukergy" for this aggregation phenomenon (17). Leukergy was recently found to be increased during stress (17), and stress has been shown to have a significant influence on the function of various components of the immune system (18). At least two humoral factors that are released during stress could contribute to the leukocyte adhesive phenomenon, namely, epinephrine and substance P (14). Shirin et al. (19) demonstrated a significant dissimilarity in the level of leukergy (p < .001) between groups with different levels of stress. The LAA test was shown to have a sensitivity of 0.8 in the detection of acute mental stress as compared with a sensitivity of 0.35 for white blood cell count. The specificities of both tests were similar (0.87 and 0.89, respectively).

Because burnout was shown to be a consequence of chronic stress, both at work and outside work (12), but different conceptually from stress, we examined whether LAA levels would also be positively associated with burnout levels. We further examined whether this association would be similar to or different than that between LAA levels and somatic complaints. We reasoned that such a comparison would be interesting because 1) somatic complaints are considered to be a general marker of stress (20, 21) and 2) somatic complaints include many important symptoms that appear in most popular measures of depression as well as in some popular measures of burnout.

	METHODS

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Subjects
Two hundred forty-seven employees of Tel-Aviv University attending mandatory annual routine medical checkups were invited to take part in the study, and 227 (91.9%) agreed. Some of the subjects may have been exposed to chemical substances at work.

Informed consent was obtained from all participants for both the LAA test and completion of the questionnaires. Of the initial sample (N = 227), 48 subjects were excluded, 29 because of chronic conditions that might affect LAA levels (eg, high blood pressure, Crohn’s disease, anemia, and antiinflammatory drug use) and 19 because of incomplete data or poorly prepared slides, leaving a final study population of 179 (68 men and 111 women). These included 69 postgraduate students, 48 laboratory technicians, 46 research associates, and 16 individuals with other occupations, both academic and blue collar.

Medical Data
These included blood pressure measurements and assessment of blood and urine levels of lead, mercury, and trichloroethane. The LAA level was determined by a slide test according to a procedure described by Berliner and Aronson (16). Briefly, several large drops of blood were placed on a slide, which was held for 2 to 3 seconds at a 45° angle so that the blood dripped down, leaving a fine film. The slides were then dried at room temperature, held at -18°C for 10 minutes, and later heated under hot air to cause hemolysis and diminish the background. Samples were fixed with absolute methanol, and the slides were then stained with hematoxylin.

The percentage of aggregated leukocytes on the slides was determined by counting 300 to 600 white blood cells at random under a microscope at 400x magnification. Cells were considered to be aggregated when three or more nuclei were placed less than one cell diameter apart. Slides were read in a blind manner.

One of the main difficulties in performing leukergy measurement is the assessment of the distance between the white blood cells because only the cells’ nuclei are stained. To avoid measurement bias, a pilot study was performed on 30 samples. The slides were assessed twice, once by one of the authors (Y.S.) and independently by an experienced laboratory technician. Good agreement (92%) between the results of the two readers was achieved. The LAA results obtained in this study were similar to those obtained in earlier studies (19, 22).

Psychological Measurements
All participants completed a self-administered questionnaire that included demographic data as well as items to assess somatic complaints and burnout. The somatic complaints scale consisted of 12 four-point items based on an index described by Caplan et al. (20) that measures the frequency of symptoms during the month before participation (eg, dizziness, shortness of breath, clammy hands, and headaches).

Burnout was measured by the Shirom-Melamed Burnout Questionnaire (11, 12, 15), which is comprised of two subscales, an emotional exhaustion and physical fatigue scale (eight items) (11) and a cognitive weariness scale (six items) (12). Sample items for emotional exhaustion and fatigue were "I feel physically exhausted" and "My batteries are dead." Sample items for cognitive weariness were "My head is not clear" and "I feel I am disorganized lately." Each item was scored on a seven-point scale, ranging from 1 (almost never) to 7 (almost always). The reliability coefficient (Cronbach’s ) for the burnout scale was 0.91. In earlier studies, burnout measured by either the first two or all of the above subscales was found to be positively associated with both episodic stress (12) and chronic work stress (1). In our recent pilot study of 56 workers (26.4% women, 73.6% men) aged 23 to 65 years (mean, 47.4 years), burnout was found to correlate, at a level of 0.68 (p <.0001), with vital exhaustion using Appels et al.’s (23) Maastricht Questionnaire. Vital exhaustion was found to be predictive of future myocardial infarction, independent of the classic risk factors (24–26).

Statistical Analysis
Pearson correlations were computed among LAA levels for each of the burnout symptoms (emotional exhaustion, chronic fatigue, cognitive weariness, total burnout score, and somatic complaints) and four possible confounders (age, sex, educational level, and seniority) related to burnout (1, 3, 4, 10). The next step in the analysis consisted of a series of multiple linear regressions in which LAA levels were the dependent variable. Included in the regression equations were age, sex, and educational level, whereas each of the four predictors, emotional exhaustion, chronic fatigue, cognitive weariness, and somatic complaints, was entered separately because of the high collinearity among them.

No sex differences in LAA levels have been reported in the literature. However, given that we had earlier found that burnout interacted with sex to effect plasma lipid levels (14), we tested the possibility of such an interaction for LAA levels as well. Because no such interaction was found in a preliminary run, neither for burnout, each of its subscales, nor somatic complaints, it was omitted in subsequent analyses.

	RESULTS

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The means, standard deviations, and correlation matrix for all study variables are presented in Table 1. As expected, the scores on all three symptoms of burnout, emotional exhaustion, chronic fatigue, and cognitive weariness, are highly intercorrelated. This provides empirical support to the theoretical construct of burnout (1). The total burnout score significantly and positively correlated (r = 0.19, p < .05) with LAA levels. Significant and positive correlations with LAA levels were obtained for each of the burnout symptoms (r = 0.17, p < .05). Somatic complaints, on the other hand, positively correlated with burnout (r = 0.58, p < .05) but not with LAA levels (r = 0.10). None of the demographic variables significantly correlated with either burnout or LAA levels.

	DISCUSSION

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The major finding in this investigation was that burnout, as manifested by symptoms of emotional exhaustion, physical fatigue, and cognitive weariness, is associated with increased LAA in healthy employees in different occupations. This finding is consistent with and contributes to other evidence that burnout at work may be a potential threat to physical health (9–15).

The LAA phenomenon, its various applications in clinical settings, and the mechanisms involved have been the subject of ongoing research by an extended group at Tel-Aviv University since 1950 (for a review, see Ref. 16). Whereas it was initially assumed that a similar mechanism of adhesion operates both between leukocytes as well as between leukocytes and the endothelium, our recent findings do not confirm this hypothesis (27). We did not find a correlation between the expression of leukocyte antigens connected with adhesiveness to the endothelium and the extent of LAA. On the other hand, a high correlation was noted between fibrinogen levels and LAA values (r = 0.65, p < .05). Hence, we suggest that the LAA phenomenon depends on the presence of plasma factors. Our studies showed a high correlation between severity of disease and level of LAA in rheumatic diseases (28), bowel diseases (29), and respiratory infections (30). Similar observations were made by other researchers concerning patients with myocardial infarctions (22) and a previous cerebral ischemic event (31), which suggests that the LAA state may be related to mechanical obstruction in blood capillaries (32).

Leukergy levels have been found to be raised by physical effort and by mental stress (16, 19). Indeed, a three-fold LAA ratio has been found in a highly stressed group compared with a control group (19). The contribution of the present study is evidence that increased LAA levels are also associated with burnout, which may be an outcome of chronic exposure to work and/or life stress. An additional finding here was a positive association between each of the symptoms of burnout, namely, emotional exhaustion, physical fatigue, and cognitive weariness, and LAA levels. This association was independent of age, sex, and educational level. This shows that LAA is associated with burnout as a whole and not with only one or two of its subcomponents. This finding further supports the validity of the burnout construct as a constellation of the above symptoms. Although the variance in LAA levels as explained by burnout and the above control variables is rather low (5%), given that none of the confounders and only burnout was significantly associated with LAA levels, this percentage of explained variance is relatively high compared with the 2% of variance in plasma lipid (cholesterol and triglyceride) levels explained by burnout (14).

It is interesting to note that no association was found between somatic complaints, known to be a general marker of stress (20, 21), and LAA levels. This lack of association occurred despite the fact that somatic symptoms were found to be associated with burnout, both here and in previous studies (9, 11). The differential association with LAA levels observed here for burnout and somatic complaints is congruent with our earlier claim that burnout does not overlap with the concept of stress (1, 11). Somatic complaints were previously found to be positively associated with blood pressure levels (33), but burnout was not (11). Burnout, on the other hand, was found to positively correlate with serum lipids levels (11, 14). Taken together, these findings suggest that somatic complaints and burnout may be linked to physiological outcomes through different pathways.

As indicated earlier (in Methods), scores on the Shirom-Melamed Burnout Questionnaire highly correlated with Appel’s vital exhaustion measure (r = 0.68, p < .0001). Appels and his associates (25, 26, 34) have found that vital exhaustion constitutes a risk for myocardial infraction that is independent of the classic risk factors, suggesting that different pathways of linkage may be involved. Burnout was found to be related to salivary cortisol levels; however, the direction of the association was inconsistent. It was positively associated with cortisol levels sampled during work (15) but negatively associated with cortisol response to awakening (35). Thus, the direction of the above association might depend on when and how the hypothalamic-pituitary-adrenal axis is assessed. Nevertheless, the association between burnout and cortisol level and the positive association found here between burnout and LAA are congruent with Goodkin and Appels’ (36) hypothesized behavioral-neuroendocrine-immunologic interactions in myocardial infarction. They speculated that "Stressor-associated neuroendocrine changes result in immunosuppression, leading to reactivation of latent, systemic infections and potentially to autoimmune reactions as well. The consequent release of pro-inflammatory cytokines exacerbates fatigue and induces a stimulus for cytokine production in brain. This cytokine production stimulates a chronically activated, over-compensated limbic-[hypothalamic-pituitary-adrenal] axis, resulting in a dampened response, continued exhaustion, and a potential ‘reverberating circuit’ between behavior, neuroendocrine change, cytokine release and coronary artery occlusion, culminating in myocardial infarction" (36). Such a hypothesis is consistent with the renewed interest in the possible link between chronic infections, inflammation, and atherosclerotic coronary artery disease (37–39). Thus, the nature of possible interactions between stress, burnout, and neuroendocrine-immunologic changes in increasing myocardial infarction risk warrants further exploration.

This study has several shortcomings that should be addressed. LAA tests performed by different researchers may yield different absolute values. Hence, the comparison of LAA levels is only valid in different groups within each study, including the present one, meaning that the magnitude of the effect observed here cannot be compared with that obtained in other studies. Additional studies are needed in which burnout is measured by other scales, such as the Maslach Burnout Inventory (40, 41) or the Burnout Measure (42) to examine whether the present findings are replicated. Furthermore, the study’s external validity should be considered. Essentially, there was no bias due to self-selection to participate in the study. This is because the annual medical checkup is mandatory and the response rate for study participation among those invited to the checkup was very high (92%). However, it is possible that employees suffering from advanced cases of burnout were no longer working in the organization, leaving us to study the more hardy ones who reported their levels of burnout at their periodic health examinations. This "healthy worker effect" militates against our hypothesis in that we are less likely to have highly burned-out respondents in our sample, which leaves us with, in effect, a truncated distribution on this predictor.

Further studies are needed to determine the specificity and changes over time of the LAA state. Possible effects of stress and exaggerated response to sympathetic stimuli like "needle shock" may be controlled by means of blood samples drawn through an intravenous catheter and concomitant determination of plasma biochemical measures of stress.

Yet another possible limitation of this study is the possibility that our results are attributable to the effects of an unmeasured variable on our criterion variable that is highly correlated with burnout. A prime candidate is chronic stress. Chronic stresses, like overload, lack of control, insufficient rewards, conflicts with superiors and peers, and job impoverishment, have been found to be associated with burnout (43) and have been proposed to represent causal factors of burnout (44). Future studies assessing chronic stresses, burnout, and cortisol are warranted to clarify the relationship among these variables.

Finally, the findings should alert physicians, especially occupational health providers, to the importance of paying attention to an employee’s complaints of emotional and psychological origins. If the results of the present study are replicated in further investigations, the term "burnout" may ultimately be carried over to the realm of life sciences, after having flourished mainly in organizational behavior and psychology (10).

Received for publication October 19, 1998.

Accepted for publication June 30, 1999.

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