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Higher Abnormal Leukocyte and Lymphocyte Counts 20 Years After Exposure to Severe Stress: Research and Clinical Implications

From the Center for Outcomes Measurement and Performance Assessment, Merck–Medco Managed Care, L.L.C., Montvale, New Jersey (J.A.B.); and Outcomes Research Department, Catholic Health Initiatives, Louisville, Kentucky (J.C.).

Address reprint requests to: Joseph A. Boscarino, PhD, MPH, Center for Outcomes Measurement and Performance Assessment, Merck–Medco Managed Care, L.L.C., 100 Summit Ave., Mail Stop R2–22, Montvale, NJ 07645-1753. Email: Joseph_Boscarino{at}Merck.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
OBJECTIVES: Research suggests that individuals with posttraumatic stress disorder (PTSD) are more likely to develop medical conditions and other stress-related psychiatric disorders. Given these findings and others suggesting that PTSD victims may have altered neuroendocrine and immune systems, the hypothesis that Vietnam veterans with PTSD have abnormally high leukocyte and lymphocyte counts was tested.

METHODS: The leukocyte and lymphocyte status of male Vietnam "theater" veterans with current partial posttraumatic stress (N = 286), anxiety (N = 274), and depression disorders (N = 192) were compared with those of Vietnam veterans without these disorders 20 years after military service (N = 2179–2272), controlling for intelligence, race, age, income, education, type of enlistment, Vietnam volunteer status, region of birth, cigarette smoking, illicit drug use, body mass index, and alcohol consumption. Abnormal values were defined using standard laboratory reference ranges. Adjusted mean differences also were compared.

RESULTS: Based on the results of two-tailed tests, PTSD-positive veterans are more likely to have adjusted leukocyte (OR = 1.83, p = .04) and T-cell (OR = 1.82, p = .045) counts above the normal range and higher mean adjusted leukocyte (p = .042), lymphocyte (p = .01), T-cell (p = .008), and CD4 cell (p = .027) counts. Those with anxiety disorders have adjusted lymphocyte (OR = 1.68, p = .048) and T-cell (OR = 2.06, p = .011) counts above range. They also have test results indicating reactive delayed cutaneous hypersensitivity (OR = 1.77, p = .006), which suggests the presence of highly sensitized T-cell lymphocytes. Finally, depressed veterans are less likely to have B-cell counts above the reference range (OR = 0.55, p = .006). Results of one-tailed tests further suggest that PTSD-positive men also have abnormally high CD4 and CD8 T-cell lymphocyte counts as well (p < .05).

CONCLUSIONS: Our findings suggest that chronic, primarily combat-related PTSD is associated with clinically elevated leukocyte and total T-cell counts. Those with current anxiety also have some of these abnormalities in addition to highly sensitized T-cell lymphocytes. Additional research is needed to specify the mechanisms involved here and to investigate the health risks associated with these findings.

Key Words: posttraumatic stress disorder • immunesystem • leukocytes • T-cell lymphocytes • cell-mediated immunity • Vietnamveterans

Abbreviations: PTSD = posttraumatic stress disorder; WBC = white bloodcell; HPA = hypothalamic-pituitary-adrenocortical; SAM =sympathetic-adrenomedullary; DIS = Diagnostic Interview Schedule; CMI = cell-mediated immunity; CI = confidence interval; OR = odds ratio; ANCOVA = analysis of covariance; ANS =autonomic nervous system.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
The fact that exposure to severe stress is associated with the onset of certain psychiatric disorders has been established (1–9). However, recent studies of disaster survivors (1), Vietnam combat veterans (2), and other populations exposed to severe environmental stressors (3) suggest that these victims also have higher rates of medical morbidity (10). Recently, studies have reported that veterans with PTSD have lower circulating cortisol and/or higher circulating catecholamine levels (11–16). Some of these findings also have been replicated in other populations, including Holocaust survivors (17). In addition, other studies have documented alterations in immune functioning after exposure to acute stress (18–24). Thus, there is evidence that exposure to environmental stressors can alter human neuroendocrine system functions and that these alterations may affect the immune system and perhaps lead to disease.

Although many other neuroendocrine substances are involved in immune functions (18), given the reduced cortisol levels often found among PTSD victims, it is possible that an elevation in leukocyte activity could occur, because cortisol is known to act as an immunosuppressant under certain conditions (25–28). To date, one study has confirmed that even though PTSD victims have reduced natural killer cell cytotoxicity, they have significantly increased WBC counts (29). Furthermore, a recent meta-analytic review of five studies of the immune system also suggested a consistent increase in WBC counts in humans after exposure to different acute and chronic stressors (22). Moreover, it has been suggested that constant HPA axis activation, such as seems to occur among chronic PTSD victims (10, 16), alters -5 adrenal androgens, which in turn may result in a predominance of Type 2 helper T-cells (27, 30, 31). Thus, in this study, we assessed whether PTSD-positive veterans with chronic PTSD show elevations in leukocytes, total lymphocytes, and lymphocyte subsets counts, because there is some evidence suggesting that these alterations are possible.

Although complex physiologic processes seem to be involved in the disease pathogenesis associated with severe stress exposures, one pathway or shared mechanism often cited involves long-term alterations in the SAM and HPA stress axes (25, 26, 32). In particular, it is thought that disturbances in these systems could result in disease pathogenesis, in part because of alterations in immune system functions associated with specific neuroendocrine secretions (25, 26, 32–34).

Research clearly documents that the vast majority of Vietnam veterans with PTSD had this as a result of combat exposures in Vietnam (7, 16, 35). Currently, the best estimates are that more than 30% developed PTSD in their lifetime because of combat in Vietnam and that about 15% have this disorder (7). Therefore, the long-term immunologic consequences of severe stress exposures among Vietnam veterans, if they exist, should be detectable in large sample of veterans years after this exposure. As noted below, although we report results for veterans with "current" partial PTSD, these men tend to be chronic PTSD suffers, because they developed PTSD as a result of combat experiences in Vietnam. Thus, our study focused on chronic, as opposed to acute stress outcomes, even though we measured current PTSD.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
Sample
Subjects for this study were from the Vietnam Experience Study, which is based on a random sample of all male US Army veterans who served during the Vietnam War (6, 35–37). Altogether, 48,513 records were randomly selected from 4.9 million US Army records for this period. From these, two groups, "theater" veterans, who served in Vietnam, and "era" veterans, who did not, were randomly selected among all veterans known not to be deceased and were traced. From these two samples, 87% of theater veterans (7924) and 84% of the era veterans (7364) were located and interviewed by telephone. Among those interviewed by telephone, a random subsample was selected for personal interviews and medical examinations. Altogether, 75% of the theater veterans selected in this second subsample (2490) and 63% of the era veterans (1972) participated in this study phase. Only the results for Vietnam theater veterans are presented in the current study. The reasons for this were that PTSD was rare among the era veterans studied (lifetime PTSD = <2%), and including them would introduce additional biases and confounding factors, further complicating our study. Psychological testing and physical examinations were administered at one medical facility (Lovelace Medical Foundation, Albuquerque, NM) between June 1985 and September 1986. Because participation rates differed between theater and era veterans, a detailed analysis was conducted using original military records and telephone interview data. Statistical comparisons indicated that the nonresponse rates did not appear to bias most study results examined in the Vietnam Experience Study (2).

Examinations, Medical Histories, and Psychiatric Evaluations
The examination schedule required that veterans spend 4 days on site, with the first day including informed consent and study orientation. The second day included medical histories, examinations, and laboratory specimen collection. The third day included psychological and neuropsychological testing. On the fourth day, individual veterans met with an internist and a psychologist to discuss their examination results and were then released.

Psychiatric evaluations in the Vietnam Experience Study included the DIS (38), a standardized questionnaire designed to assess the presence of psychiatric conditions that is based on DSM-III (39). Studies of the reliability and validity of the main DIS classifications have been published, and these classifications are considered to be acceptable (40, 41). The DIS was administered by psychology technicians under the supervision of licensed clinical psychologists. Only "lifetime" and "1-month" PTSD were assessed in the original Vietnam Experience Study. For reasons explained below, in our study we used a "current partial" PTSD diagnosis category. PTSD was defined as current if the veteran met at least one of the diagnostic criteria for PTSD in the past year (ie, a reexperiencing symptom, numbing symptom, or two or more autonomic arousal symptoms) and ever met the full (all three) diagnostic criteria for either combat- or noncombat-related PTSD in his lifetime (36). In addition, because anxiety and depression often are associated clinical features of PTSD (9, 10, 35), we also present immune results for anxiety and depression in this report. These latter disorders also were based on DIS and DSM-III criteria. As with PTSD, we defined anxiety and depression as current if the veteran met at least one of the diagnostic criteria for anxiety or depression in the past year and ever met the full diagnostic criteria for these disorders in his lifetime. Thus, the current partial PTSD, anxiety, and depression categories used in our study indicate that a veteran had a history of the particular disorder and that he had experienced one or more major symptoms for that disorder in the past year.

We used a 1-year partial diagnosis in our study for several reasons. First, the DIS instrument used in our study included only lifetime and 1-month prevalence categories (36, 37), both of which were unsuitable for our analysis. Lifetime was thought to be a poor time frame in which to expect an association between PTSD and current immune status. Conversely, although the 1-month current prevalence period seemed to be a good time frame and also implied the necessary chronicity, this exposure did not provide a sufficient number of PTSD cases (N = 54) for our analysis, because we needed to control for covariates and to model rare outcomes (42, 43). Even use of analysis of variance is limited here because of extremely unequal cell sizes (44). Finally, the original 1-month prevalence category used was for combat-related PTSD and did not include noncombat-related cases. Consequently, the 1-year partial category seemed to be a reasonable alternative, especially since analyses using these categories produced similar results to those using the full diagnostic criteria in previous studies (16, 35). Second, the 1-year diagnostic categories we used were correlated with the 1-month diagnostic categories (p < .0001), with coefficients of 0.40, 0.62, and 0.60 for PTSD, anxiety, and depression, respectively. In summary, given our statistical needs and available evidence, we thought that use of 1-year partial diagnoses was a reasonable methodological alternative. In the Discussion, we note the study biases that may have resulted from this measurement approach. Also, we stress that even though we assessed current PTSD here, for Vietnam veterans this normally indicates chronic PTSD, because these veterans generally acquired this disorder shortly after military service (7, 36). Finally, the DIS was administered after the medical examinations and laboratory tests, and era veterans and theater veterans were brought in together for testing in small groups. (The DIS, however, was administered individually.) Furthermore, all men were instructed not to reveal information about their military experiences unless asked as part of their evaluations. Finally, all study technicians and testers were blinded to the individual’s cohort status.

Laboratory Methods
In this article, we present laboratory results for total WBC (leukocyte), total lymphocyte, and lymphocyte subset counts. Lymphocyte subpopulations were characterized in the following manner. Peripheral blood mononuclear cells were stained with fluorescein-tagged monoclonal antibodies, and the percentage of mononuclear cells that were fluorescent was determined by analysis in a flow cytometer. Antibodies used were OKT3 for T lymphocytes, OKT4A for CD4 (helper/inducer) T lymphocytes, OKT8 for CD8 (cytotoxic/suppressor) T lymphocytes, and CCB1 for B lymphocytes. Delayed cutaneous hypersensitivity was assessed with the CMI multitest, an anergy test that includes seven antigens (tetanus, diphtheria, Streptococcus group C, old tuberculin, Candida albicans, Trichophyton, and Proteus mirabilis). Trained technicians applied the seven antigens to each subject’s forearm using a preloaded applicator, with induration results for each antigen measured at 48 hours. Subjects were defined as highly reactive (N = 188) if their indurations to all seven antigens were 2 mm or more (2). We also report the adjusted mean number of reactive (nonanergic) responses to the seven antigens, defined as 2 mm or more for each response (2).

All collected blood specimens were placed in a cooler or refrigerator and maintained at 2 to 8°C until processed. Generally, all specimens were processed within 24 hours of collection. All laboratory determinations were monitored using standard quality-control procedures and were under the supervision of board-certified clinical pathologists (37, 45). Laboratory testing was performed at the Clinical and Research Division, Department of Laboratories, Lovelace Medical Foundation, Albuquerque, New Mexico. Additional information on the laboratory procedures used is available elsewhere (2, 16, 37, 45).

Study Control Variables
Twelve covariates were used as control variables to adjust immune results for potential bias or confounding. Age was based on the veteran’s age at the time of the interview and was used as a continuous variable. Income was based on the total annual household income reported and was coded using a 6-point ordinal scale representing lower to higher income. Race was based on the veteran’s reported race and was categorized as white (82.5%), black (11.5%), Hispanic (4.3%), and other (1.7%). For this analysis, black, Hispanic, and other were combined into one category, and this variable was used as a dichotomous covariate (white vs. nonwhite). Education was based on total years of education at the time of interview and was used as a continuous variable. Region of birth was taken from the military record and included five categories: non-U.S., Midwest, Northeast, South, and West. Intelligence was based on results of the General Technical Examination taken at induction into the military, which is considered to be a good measure of mental aptitude (6). For this analysis, results of the General Technical Examination were categorized in quartiles and used as an indicator variable. Enlistment status was based on whether the veteran enlisted or was drafted; this information was taken from the military record. Vietnam volunteer status was based on whether the veteran reported volunteering for service in Vietnam. Biometric variables controlled included the following. Body mass index was used as a continuous variable and was calculated as the subject’s weight divided by his height squared. Cigarette smoking was categorized as an indicator variable and was classified as follows: smoked no cigarettes in the past month, smoked one to 16 cigarettes per day, smoked 17 to 24 cigarettes per day, smoked 25 to 35 cigarettes per day, or smoked more than 35 cigarettes per day in the past month. Alcohol consumption was based on the number of drinks consumed during the past month and was used as a log-transformed continuous variable (46). Current illicit drug use was based on drug use in the past 12 months and was used as an indicator variable as follows: no illicit drugs used in the past 12 months, marijuana only used at least once per week in the past 12 months, and "hard" drugs (eg, heroin, barbiturates, and amphetamines) used at least once per week in the past 12 months. Cigarette smoking, alcohol consumption, and illicit drug use were based on self-reports. Controlling for socioeconomic status variables and others, such as cigarette smoking, is important because Vietnam combat veterans are reported to come from lower socioeconomic groups and other high-risk groups (47), factors often associated with poorer health and riskier health behaviors (48, 49). Controlling for current cigarette smoking is especially important in this case, because this factor is known to be related to WBC counts (50, 51).

The 12 covariates discussed above were retained in the final multivariate models because they were found to have an impact on immune status and because there were good reasons to suspect that these could be potential effect modifiers or confounders. Current prescriptive medication use also was evaluated but was dropped because it was not found to be consistently associated with immune status.

Statistical Methods
Statistical analyses for our study were performed using SPSS for Windows, version 7.5 (52), and Stata, release 5 (53). Ninety-five percent (95%) CIs are provided for the 12 control variables, stratified by PTSD status. Significant differences for variables by PTSD status are approximated by nonoverlapping CIs. Detailed bivariate (2 x 2) cross-tabular results also are provided for immune status variables above the clinical reference ranges, by PTSD, anxiety, and depression, together with their crude (unadjusted) ORs. The unadjusted results are presented for comparison only. For this study, high abnormal leukocyte and lymphocyte values were defined using laboratory reference range standards (2). As noted, the CMI test results reported here were based on reactive antigen responses to all seven antigens (defined as having intradermal indurations 2 mm at 48 hours).

The adjusted ORs for current psychiatric disorders by immune status, which were adjusted for the variables discussed using logistic regression, are presented with their 95% CIs. All logistic regressions were based on maximum likelihood estimation methods (43). Finally, ANCOVA was used to assess the mean adjusted differences for the eight immune status results by psychiatric status, using the 12 covariates discussed (54). Unless otherwise stated, all p values are based on two-tailed tests. However, because we hypothesized an increase in leukocytes, we also discuss some of our results based on the one-tailed test.

Hypotheses
On the basis of previous reports of immune responses associated with severe stress exposures, we hypothesized that PTSD-positive veterans have abnormal immune functioning in the form of clinically higher WBC and lymphocyte counts. Because of the clinical overlap between anxiety and PTSD (9), similar associations were expected for anxiety disorders but not for depression.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
Table 1 shows the profile of our control variables by current partial PTSD status. As shown, PTSD-positive veterans were less likely than PTSD-negative veterans to have household incomes greater than $29,000 per year (35.8 vs. 45.2%) and to have higher aptitude test results at induction (mean score = 99.5 vs. 105.3). However, they are more likely to have volunteered for Vietnam service (30.0 vs. 21.1%) and to be current smokers (57.0 vs. 45.0%).

Table 3 shows the mean results for leukocyte and lymphocyte counts by current psychiatric status adjusted for the covariates discussed. As shown, PTSD-positive veterans have higher mean WBC (p = .042), total lymphocyte, (p = .010), T-cell (p = .008), and CD4 cell (p = .027) counts. In comparison, no significant adjusted mean results are found for anxiety or depression.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

As shown, theater veterans with current partial PTSD are more likely than era veterans to have higher adjusted mean WBC (p = .042), total lymphocyte, (p = .010), T-cell (p = .008), and CD4 cell (p = .027) counts. Furthermore, they tend to have abnormally high WBC (>11,000/mm3; OR = 1.83, 95% CI = 1.03–3.25, p = .040) and T-cell (>2640/mm3; OR = 1.82, 95% CI = 1.01–3.26, p = .045) counts. In addition, abnormal CD8 cell counts (>1220/mm3) also approach the significance level for two-tailed tests (OR = 1.80, 95% CI = 0.97–3.35, p = .062). In short, PTSD-positive veterans tend to have higher circulating total leukocyte and leukocyte subset counts in clinical ranges that are often suggestive of disease in medicine (60).¹The results for current partial anxiety are similar. Men with this disorder tend to have abnormally high total lymphocyte (>3000/mm3; OR = 1.68, 95% CI = 1.01–2.77, p = .048) and T-cell (>2640/mm3; OR = 2.06, 95% CI = 1.18–3.61, p = .011) counts. They also have reactive CMI test results (OR = 1.77, 95% CI = 1.17–2.67, p = .006), suggesting sensitized T-cell lymphocytes (55). The results for current partial depression show that this disorder is protective against abnormal B-cell counts (>370/mm3; OR = 0.55, 95% CI = 0.36–0.84, p = .006) for some reason. To date, one study has confirmed that even though PTSD victims have reduced natural killer cell cytotoxicity, they have significantly increased WBC counts (29). In addition, as noted, a recent meta-analytic review of five immune studies also suggested a consistent increase in WBC counts after human exposures to different acute and chronic stressors (22).

This study has some limitations. First, most of our data are not longitudinal; thus, our findings may be confounded by factors that could have affected the PTSD-positive veterans since discharge. Second, because the overall response rate for theater veterans was 65.3% (87% x 75% = 65.3%) (see sample discussion), the results reported could be distorted by nonresponse bias, although previous analyses failed to detect this (2). Third, although we validated the utility of our 1-year current partial diagnostic categories in other studies (16, 35) and these were correlated with the original 1-month categories, our categories were not based on standard DIS diagnostic nomenclature. Consequently, generalization of our findings may be limited. Fourth, the overall effect sizes found were generally moderate, with significant adjusted ORs between 1.68 and 2.06. Fifth, because only men were included in our study, our findings may not apply to women. Sixth, as noted, we principally studied cases of chronic PTSD, because the men studied often developed their disorders shortly after military service (36). Thus, our findings may not apply to acute stress cases. Finally, the immune-neuroendocrine processes briefly described seem to be very complex (18, 25, 26, 61). For example, one study reported that leukocyte counts were associated with a host of factors, including triglyceride levels, platelet counts, prothrombin time, race, use of ß-blockers, and other factors (62), suggesting the need for true prospective studies to sort all of these factors out.

Given these limitations, we still think our findings have some implications. First, they suggest that theater veterans with current PTSD may have higher circulating leukocytes. Second, they suggest that veterans with current anxiety disorders may also have some of these immune characteristics. In addition, the finding that men with current anxiety are more likely to have highly sensitized T-cell lymphocytes needs further study, because this could be related to autoimmune-related diseases. It is worth noting that leukocyte proliferation and stimulation are currently being implicated in a number of autoimmune-related diseases, including diabetes and multiple sclerosis (63, 64), although the pathophysiologic mechanisms involved here seem very complex (63–65). Taken together, our findings suggest that neuroendocrine-immunologic research should be a priority, especially since mononuclear leukocytes and endothelial-dependent mechanisms have been implicated in a broad spectrum of diseases ranging from atherosclerosis to rheumatoid arthritis (10). Also, now that elevated WBC counts have been linked to coronary heart disease (66–68), our findings may be important given the increasing age of the veteran population studied.

Socioeconomic status often has been linked to both disease morbidity and mortality in many epidemiologic investigations (48), even though the causal pathway of this "risk factor" remains a mystery (48). If environmental stress exposures are concentrated in communities of lower socioeconomic status, as suggested by US crime reports, in part specific psychobiological models of stress may help explain the inverse associations often found between socioeconomic status and specific diseases, such as coronary heart disease (69). As noted elsewhere (10), we think our research and that of others is beginning to suggest that traditional biological models of disease need to be better integrated with psychosocial ones. As a consequence of this, viable links between the medical, behavioral, and social sciences may be possible and science further advanced.

	ACKNOWLEDGMENTS

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Support for this research was provided in part by the National Institute of Mental Health, Grant MH-19105, and the Sisters of Charity of Nazareth Health System (Louisville, KY). In addition, the authors express their appreciation to the Centers for Disease Control and Prevention for making this study possible. A version of this paper was presented a the 29th Annual Meeting of the Society for Epidemiologic Research, Boston, Massachusetts, June 1996.

	NOTES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
It should be noted that comparison of the unadjusted mean immune findings for the 1-year partial disorder categories with the unadjusted mean immune results for the full 1-month categories originally used reveals similar results. For example, generally, these results were in the same direction and of similar magnitude. As expected, however, the associated p values tend not to be significant here because of the unequal cell sizes involved, which also precludes the use of ANCOVA to make adjusted comparisons (44). It also should be noted that unadjusted comparisons should be evaluated with caution, because there are significant risk factor differences between PTSD-positive and PTSD-negative veterans that could affect these results (see Table 1).

Received for publication March 18, 1998.

Revision received December 23, 1998.

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