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Psychosomatics. Author manuscript; available in PMC 2017 July 01. Published in final edited form as: Psychosomatics. 2016 ; 57(4): 423–430. doi:10.1016/j.psym.2016.02.015.
The Association between Post-Traumatic Stress Disorder and Markers of Inflammation and Immune Activation in HIV-Infected individuals with Controlled Viremia
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Peter Siyahhan Julnesa, Sungyoung Auhb, Rebecca Krakorac, Keenan Withersd, Diana Norad, Lindsay Matthewsc, Sally Steinbacha,e, Joseph Snowd, Bryan Smitha, Avindra Natha, Caryn Morsec, and Suad Kapetanovicd,f aSection
of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
bNational
Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
cCritical
Care Medicine Department, National Institutes of Health, Bethesda, MD, USA
dNational
Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
eClinical
Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702
fDepartment
Author Manuscript
of Psychiatry and The Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Abstract Introduction—Post-traumatic stress disorder (PTSD) may be associated with chronic immune dysregulation and a pro-inflammatory state. Among HIV-infected individuals, PTSD is associated with greater morbidity and mortality, but the association with immune dysfunction has not been evaluated. This study explores the association between PTSD and selected markers of inflammation and immune activation in a cohort of HIV-infected, virally-suppressed individuals. Methods—HIV-infected adults who were virologically controlled on anti-retroviral medications were recruited through a screening protocol for studies of HIV-related neurocognitive disorders.
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Corresponding author: Peter Siyahhan Julnes, [email protected], National Institutes of Health, Bldg. 10 Rm. 7C103 MSC 1430, Bethesda, Maryland 20892. Disclaimers: All authors contributed to this article as part of their official duties. This research was supported by the Intramural Research Training Award program at the National Institutes of Health; by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke; the authors have no relevant financial or non-financial relationships to disclose. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institute of Health, under Contract No HHSN261200800001E. (SS) The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This data was presented in part in a poster session at the Annual Meeting of the Academy of Psychosomatic Medicine, in New Orleans, in November 2015. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Each participant underwent blood draws, urine toxicology screen, and completed the Client Diagnostic Questionnaire (CDQ), a semi-structured psychiatric interview. Results—Of 114 eligible volunteers; 72 (63%) were male, 77 (68%) African American, and 34 (30%) participants met criteria for PTSD. Participants with PTSD were more likely to be current smokers (79%) than those without (60%) (p=0.05). The PTSD cohort had significantly higher total white blood cell counts (5318 and 6404 cells/uL, p=0.03), absolute neutrophil count (2767 and 3577 cells/uL, p=0.02), CD8% (43 and 48, p=0.05) and memory CD8% (70 and 78%, p=0.04); lower naïve CD8% (30 and 22%, p=0.04), and higher rate of high-sensitivity C-reactive protein >3 mg/L (29 and 20, p=0.03). Discussion—A high prevalence of PTSD was identified in this cohort of HIV-infected adults who were virally-suppressed. These results suggest that PTSD may be associated with immune dysregulation even among ART-adherent HIV-infected individuals.
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Keywords immunophenotyping; antiretroviral therapy; Client Diagnostic Questionnaire; neuropsychoimmunology; PLWH
BACKGROUND
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Post-traumatic stress disorder (PTSD) is a highly prevalent comorbidity among adults with human immunodeficiency virus (HIV) infection, with the prevalence rates ranging from 23% to 42% (1–3). Such high prevalence stands in sharp contrast to the 9.7% prevalence of PTSD in the general US population reported in large epidemiologic surveys (4, 5), but is less surprising considering that more than half of HIV-infected individuals report experiencing at least one severe traumatic event in their lifetime. (1, 2).
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Evidence suggests that PTSD and, to a smaller extent, a history of psychological trauma without PTSD, may be associated with alterations in immune responsiveness and a proinflammatory state. Psychological trauma survivors tend to have significantly lower percentages of naïve CD8+ T cells, increased proportions of CD3+ central and effector memory T cells, and a major reduction in the proportion of regulatory T cells compared to non-traumatized individuals (6, 7). This effect is relatively more pronounced among trauma survivors with current PTSD than among trauma survivors without current PTSD (6, 7), and the severity of PTSD symptoms correlates with the degree of T cell activation (6). In vitro experiments with peripheral blood mononuclear cells harvested from trauma survivors either with or without current PTSD, and controls without trauma or PTSD, demonstrated decreased leukocyte glucocorticoid receptor density in both groups of trauma survivors and decreased dexamethasone-induced inhibition of T-cell proliferation only from individuals with current PTSD, suggesting that PTSD may be associated with a qualitatively different effect on immune regulation compared to trauma exposure alone (8). In a prospective lifecourse study, a history of childhood maltreatment was predictive of serum high-sensitivity C-reactive protein (hsCRP) levels >3mg/mL (a marker of a pro-inflammatory state and increased cardiovascular disease risk) 20 years later, even after controlling for key health behaviors, including smoking (9). These reported associations of PTSD and trauma history
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with compromised immune responsiveness and pro-inflammatory state may explain why individuals suffering from PTSD are more likely to have infections, autoimmune disorders, and other inflammatory diseases than those without PTSD (6, 7).
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To date, the effect of PTSD on circulating markers of immune activation or inflammation has not been evaluated in HIV-infected individuals. Growing evidence suggests that even a history of psychological trauma alone is independently associated with a number of unfavorable clinical and behavioral outcomes among HIV-infected individuals. This includes increased AIDS-related mortality, opportunistic infections (10), increased HIV viral load, as well as ART non-adherence and unprotected sex, even after controlling for psychosocial factors and comorbidities (i.e., coping style, self-efficacy, social support, trust in the medical system, recent stressors, mental health and substance abuse) (11). Given the high prevalence of PTSD among HIV-infected individuals, and the importance of immune regulation to HIV disease outcomes, it is important to know if the reported associations between PTSD and alterations in T-cell compartments and inflammation also exist among HIV-infected individuals with co-morbid PTSD.
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The hypothetical effect of PTSD on immune and inflammatory markers might be caused by the neuroendocrine or neuroimmune mechanisms suggested by the studies described above (6,7,8). Alternatively, given the reported associations between psychological trauma and ART non-adherence among HIV-infected individuals (11), this effect may be caused by or mediated through ART non-adherence. This project is a cross-sectional exploratory analysis of selected immune and inflammatory biomarkers in a cohort of HIV-infected adults screened for both trauma and PTSD. To minimize the potential confounding effect of ART non-adherence on the association between PTSD and the biomarkers, this analysis was restricted to virally-suppressed HIV-infected individuals.
METHODS Study Sample and Procedures Participants were recruited through a natural history screening study of HIV-associated neurocognitive disorders (HAND). The objective of the natural history study is to determine the eligibility of HIV-infected individuals for participation in other Neuro-HIV studies at the NIH Clinical Center. The Institutional Review Board of the National Institute of Allergy and Infectious Diseases approved the study. Written informed consent was obtained from all participants.
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Eligible HIV-infected participants were 18–61 years old, had at a least seventh grade educational level by self-report and were able to speak, read, and understand English. Volunteers were excluded if they had a history of central nervous system (CNS) infection, other CNS condition associated with cognitive impairment (e.g. untreated sleep apnea), a history of head injury with loss of consciousness >30 minutes, current substance abuse that in the opinion of the investigator would impede participation in study procedures or interpretation of results, or severe or untreated psychiatric illness. Participants taking psychotropic medications were eligible for participation if on a stable treatment regimen for at least 6 months.
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All participants underwent a screening assessment that included a detailed history and physical examination, a blood draw for safety and research studies, and a semi-structured psychiatric interview. This analysis was restricted to HIV-infected participants receiving ART with controlled viremia (HIV viral load 3 mg/L (p=0.03). The mean hsCRP as a continuous variable was not significantly different by PTSD status (p=0.12). Adjusted Analyses
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Immune markers that differed by PTSD status with a p-value 3 vs. =3 by PTSD status was examined using a logistic regression with current smoking as an independent variable. After adjusting for current smoking status, the PTSD group had a significantly larger mean WBC count (p=0.03), ANC (p=0.02) and memory CD8+ T cell % (p=0.02); and lower mean naïve CD8+ T cell % (p=0.02) compared to the group without PTSD. The likelihood of having hsCRP >3 mg/L was 2.5 times higher in the PTSD group compared to the group without PTSD (95% confidence interval (1.65, 5.66), p=0.04). There was no significant difference in continuous hsCRP (p=0.06), CD8% (p=0.08), or CD8+CD27+ (p=0.13) between the two groups.
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In the post-hoc analysis using smokers only (Table 4), the differences by PTSD status remained significant in total WBC (p=0.05), ANC (p=0.02), CD8% (p=0.05), memory CD8+ T cell % (p=0.04), and naïve CD8+ T cell % (p=0.04). However, among smokers only, there was no significant difference between the two cohorts in proportions of participants with CRP >3 mg/L (p=0.18).
DISCUSSION
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6This project was an exploratory analysis of the association between current active PTSD symptoms and selected markers of inflammation and immune activation in a cohort of virally-suppressed HIV-infected adults receiving ART. Consistent with previous studies with HIV-infected populations (1–3), there was a high prevalence of PTSD in this cohort, with 30% screening positive. Additionally, PTSD was associated with significantly higher mean total WBC counts, ANC, CD8% and memory CD8%; lower naïve CD8%, and higher rates of hsCRP >3 mg/L. These data suggests that previously observed associations between PTSD and immune dysregulation and inflammation also apply to HIV-infected individuals, even in the setting of suppressed HIV viremia on ART. Mechanisms underlying the association between PTSD and immune outcomes are not well understood. Proposed mechanisms include chronically elevated stress and stress hormone (e.g. cortisol) level or chronically increased sympathetic arousal and elevated circulating norepinephrine levels. Additionally, as in other populations, PTSD may affect health behaviors and lead to poor decision making and subsequent adverse health outcomes (1, 8, 10). The present analysis included only HIV-infected individuals with ART-suppressed viremia, thus minimizing the potential confounding effect of poor health behaviors, and possibly highlighting the role of neuro-endocrine or neuro-autonomic pathways.
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The observed associations between PTSD and immune and inflammatory markers remained significant after controlling for smoking status. However, in the sensitivity analysis restricted to smokers only, the association between hsCRP >3 and PTSD was no longer significant. This suggests a robust effect of smoking on hsCRP relative to that associated with PTSD, contradicting the reports of long-term effect of childhood trauma on hsCRP (9), possibly because the prevalence of smoking was lower in that study (i.e., ~1/3 vs. ~2/3 in the present analysis) and the sensitivity analysis for smoking status was not indicated. Alternatively, the long-term effects of childhood trauma on hsCRP may be mediated through pathways that do not necessarily involve active symptoms of PTSD.
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The PTSD group had significantly higher proportions of CD8+ and memory CD8+, and lower proportions of naïve CD8+ T-cells, a pattern that is associated with compromised immune responsiveness and increased susceptibility to novel pathogens. The elevated WBC and ANC in the PTSD cohort are consistent with such immune dysregulation. These differences may or may not be biologically important. Yet, statistically significant associations between PTSD and markers of immune dysregulation have been previously reported in HIV-uninfected populations (6, 7, 15, 16), and they may have additional clinical implications in the context of HIV infection. Indeed, a history of psychological trauma has been associated with detrimental HIV clinical outcomes such as increased AIDS-related
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mortality and opportunistic infections (10), and the findings from the present study suggest that such associations could be mediated though alterations in immune regulation and inflammation, even under circumstance of controlled viremia. This clinical concern is further augmented in light of the markedly high prevalence of PTSD in HIV-infected populations.
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Taken together, these findings may be of high clinical relevance as they suggest that a substantial proportion of HIV-infected individuals are actively struggling with a psychiatric condition that not only causes significant distress and functional impairment, but also may be associated with factors that interfere with optimal immune reconstitution in the context of viremia suppression. Clinically, this means that HIV-infected patients should be carefully screened for the history of psychological trauma and symptoms of PTSD, and referred for appropriate mental health care as indicated. Recent literature review of the HIV and trauma syndemic recommends implementing a “trauma-informed model of care” in clinical facilities caring for HIV-infected patients, outlines key characteristics of the model, and provides general guidelines for its implementation (1). Future randomized controlled trials, evaluating specific mental-health interventions for virally-suppressed HIV-infected persons with co-morbid PTSD, could provide important information about potential impact of such interventions on the biological and clinical outcomes.
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Future research should investigate additional markers of altered immunity or inflammatory processes associated with PTSD in ART-adherent HIV-infected individuals. Levels of immune cell products (i.e., cytokines, chemokines) from plasma and cerebrospinal fluid should be evaluated in relation to PTSD status. In addition, future studies should evaluate the role of clinical interventions in optimizing immune outcomes in HIV-infected patients with PTSD, and mechanistic studies may help identify novel therapeutic targets to achieve that objective.
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This study has several limitations. First, the cross-sectional design precludes inferences about direction or causality of the observed associations. Second, statistical adjustments were not made for multiple comparisons in this exploratory study, and thus p-values < 0.05 were reported as significant. This approach was used to allow maximum sensitivity in identifying signals of potential effects of PTSD on immune and inflammatory outcomes in this relatively small cohort. Although exploratory, these findings are bolstered by the congruent findings reported by other groups examining biomarkers of PTSD in non-HIV populations (7, 15, 16). To minimize impact of multiple comparisons, future confirmatory studies should focus only on the few identified candidate biomarkers, and be sufficiently statistically powered to allow controlling for multiple comparisons, ideally in a prospective, longitudinal design. Third, although the CDQ is validated for adult HIV-infected populations (12), it is still a screening tool and is not diagnostic. Ideally, PTSD would be diagnosed or ruled out in a comprehensive psychiatric interview; however the structured interview of the CDQ provides strong reproducibility which is essential in a research setting. Forth, the relatively homogenous nature of the study population limits the generalizability of the findings to other socio-demographic groups. On the other hand, this study sample was sociodemographically representative of the HIV epidemic in the US, making the findings relevant in the context of HIV/AIDS epidemic in the US. Lastly, cross-study comparisons in PTSD
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are limited by the evolving understanding of PTSD and the subsequent changes in diagnostic criteria (e.g. International Classification of Diseases [ICD], and in the DSM-IV-TR and DSM-5) (17, 18). In conclusion, current active symptoms of PTSD were detected in almost one-third of this sample of HIV-infected adults with ART-controlled viremia. Previously reported associations between PTSD and immune dysregulation or inflammation may also apply to viremia-controlled HIV-infected individuals. The consequences of this association may be especially costly in the context of HIV-infection and may need to be addressed as more is understood about PTSD and HIV disease.
Acknowledgments Author Manuscript
The authors would like to extend a special thanks to Cheryl Chairez, Angela Summers, Talia Shirazi, the OP8 Clinic staff, and all research participants.
References
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1. Brezing C, Ferrara M, Freudenreich O. The syndemic illness of HIV and trauma: implications for a trauma-informed model of care. Psychosomatics. 2015; 56(2):107–18. Epub 2015/01/20. [PubMed: 25597836] 2. Brief DJ, Bollinger AR, Vielhauer MJ, Berger-Greenstein JA, Morgan EE, Brady SM, et al. Understanding the interface of HIV, trauma, post-traumatic stress disorder, and substance use and its implications for health outcomes. AIDS Care. 2004; 16(Suppl 1):S97–120. Epub 2005/03/02. [PubMed: 15736824] 3. Malee KM, Mellins CA, Huo Y, Tassiopoulos K, Smith R, Sirois PA, et al. Prevalence, incidence, and persistence of psychiatric and substance use disorders among mothers living with HIV. J Acquir Immune Defic Syndr. 2014; 65(5):526–34. Epub 2014/04/25. [PubMed: 24759063] 4. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005; 62(6):593–602. Epub 2005/06/09. [PubMed: 15939837] 5. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005; 62(6):617–27. Epub 2005/06/09. [PubMed: 15939839] 6. Lemieux A, Coe CL, Carnes M. Symptom severity predicts degree of T cell activation in adult women following childhood maltreatment. Brain Behav Immun. 2008; 22(6):994–1003. Epub 2008/04/09. [PubMed: 18396007] 7. Sommershof A, Aichinger H, Engler H, Adenauer H, Catani C, Boneberg EM, et al. Substantial reduction of naive and regulatory T cells following traumatic stress. Brain Behav Immun. 2009; 23(8):1117–24. Epub 2009/07/22. [PubMed: 19619638] 8. de Kloet CSVE, Bikker A, Meulman E, Geuze E, Kavelaars A, Westenberg HG, Heijnen CJ. Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder. Mol Psychiatry. 2007; 12(5):443–53. [PubMed: 17245326] 9. Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104(4):1319–24. Epub 2007/01/19. [PubMed: 17229839] 10. Leserman J. Role of depression, stress, and trauma in HIV disease progression. Psychosom Med. 2008; 70(5):539–45. Epub 2008/06/04. [PubMed: 18519880] 11. Pence BWMM, Carter TJ, Leserman J, Thielman NM, Raper JL, Proeschold-Bell RJ, Reif S, Whetten K. Childhood trauma and health outcomes in HIV-infected patients: an exploration of causal pathways. J Acquir Immune Defic Syndr. 2012; 59(4):409–16. [PubMed: 22107822]
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12. Aidala AHJ, Mellins CA, Dodds S, Whetten K, Martin D, Gillis L, Ko P. Development and validation of the Client Diagnostic Questionnaire (CDQ): A mental health screening tool for use in HIV/AIDS service settings. Psychol Health Med. 2004; 9:362–80. 13. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA. 1999; 282(18):1737–44. Epub 1999/11/24. [PubMed: 10568646] 14. American Psychiatric Association. Electronic DSM-IV-TR plus. Washington, D.C: American Psychiatric Association; 2000. 15. Boscarino JA, Chang J. Higher abnormal leukocyte and lymphocyte counts 20 years after exposure to severe stress: research and clinical implications. Psychosom Med. 1999; 61(3):378–86. Epub 1999/06/15. [PubMed: 10367620] 16. Vidovic A, Gotovac K, Vilibic M, Sabioncello A, Jovanovic T, Rabatic S, et al. Repeated assessments of endocrine- and immune-related changes in posttraumatic stress disorder. Neuroimmunomodulation. 2011; 18(4):199–211. Epub 2011/02/22. [PubMed: 21335985] 17. Stein DJ, McLaughlin KA, Koenen KC, Atwoli L, Friedman MJ, Hill ED, et al. DSM-5 and ICD-11 definitions of posttraumatic stress disorder: investigating “narrow” and “broad” approaches. Depression and anxiety. 2014; 31(6):494–505. Epub 2014/06/05. [PubMed: 24894802] 18. Van Ameringen M, Mancini C, Patterson B. The impact of changing diagnostic criteria in posttraumatic stress disorder in a Canadian epidemiologic sample. The Journal of clinical psychiatry. 2011; 72(8):1034–41. Epub 2011/06/16. [PubMed: 21672500]
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Table 1
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Demographic and clinical characteristics of the cohort (n=114). PTSD Screen Characteristic
Negative (n=80)
Positive (n=34)
50 (25–60)
50 (31–61)
51 (64%)
21 (62%)
African American
53 (66.25)
24 (70.59)
Caucasian
22 (27.75)
10 (29.41)
5 (6.25)
0
Age, years (mean, range) Male, n (%) Race, self-reported, n (%)
Other# Completed high school Time since HIV Diagnosis, years (mean, range)
72 (90.00)
28 (82.35)
18 (4.7–30.3) (1.3–30.3)
20 (3.9–34.3)
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CD4 nadir, reported, cells/uL (mean, range)
204 (1–1000)
189 (1–540)
Reported Adherence (%)
97.5 (80–100)
97.9 (84.61–100)
587 (112–1492)
579 (146–1536)
29 (18–63)
30 (19–43)
Systolic Blood Pressure
122 (95–169)
126 (94–161)
Diastolic Blood Pressure
75 (54–105)
77 (60–94)
Diabetes, reported
3/47 (6.38)
2/20 (10)
Smoking, current*
48 (60)
27 (79.4)
Chronic HCV
9 (11.2)
4 (11.7)
73 (91.25)
33 (97.06)
7 (8.75)
1 (2.94)
350 n (%)
61 (76.25)
27 (79.41)
CD4 %
31 (6–56)
28 (9–45)
Glucose, mg/dL
98 (70–247)
112.85 (48–372)
D-dimer, ug/mL
0.32 (0.21–0.79)
0.32 (0.21–2.41)
HCV Ab Positive
15/78 (19.2)
9/32 (28.1)
Cocaine
5/75 (6.6)
4/33 (12.1)
Amphetamines
1/75 (1.3)
1/33 (3)
Cannabinoids
3/75 (4)
1/33 (3)
Total CD4 count, cells/uL (mean, range) Body Mass Index
HIV viral load, copies/mL 3mg/L, n (%)*
1.35 (0–6)
1.35 (0–4)
0.93
3.7 (0.1–22)
6.1 (0.2–42)
0.12
29 (36%)
20 (59%)
0.03
Mean with range presented unless otherwise noted.
*
denotes significance at alpha of 0.05
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Table 3
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Group differences between PTSD and no PTSD using ANCOVA with current smoking as a covariate (n=114). Parameter
p-value between groups
WBC*
0.03
ANC*
0.02
CD8%
0.08
CD8_naive%*
0.02
CD8_memory%*
0.02
hsCRP
0.06
hsCRP, binary*
0.04
*
denotes significance at alpha of 0.05
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Table 4
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Post-hoc analysis using smokers only by PTSD status (n=75). PTSD Screen (n=75) Outcome
Negative (n=48)
Positive (n=27)
p-value
5587.41 (2860–13580)
6564.07 (3690–13030)
0.05
2891 (1110–8570)
3710.1 (1330–7490)
0.02
CD8%*
43.33 (21–69)
48.96 (35–71)
0.05
CD8_naive%*
31.21 (7–72)
21.85 (5–51)
0.04
CD8_memory%*
69.04 (29–92)
78.37 (49–95)
0.04
3.95 (0.14–21.90)
5.01 (0.2–33)
0.63
19/48 (39.58)
15/27 (55.56)
0.18
Total WBC* ANC*
hsCRP, mg/L hsCRP > 3mg/L, n (%)
*
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denotes significance at alpha of 0.05
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Psychosomatics. Author manuscript; available in PMC 2017 July 01. Published in final edited form as: Psychosomatics. 2016 ; 57(4): 423–430. doi:10.1016/j.psym.2016.02.015.
The Association between Post-Traumatic Stress Disorder and Markers of Inflammation and Immune Activation in HIV-Infected individuals with Controlled Viremia
Author Manuscript
Peter Siyahhan Julnesa, Sungyoung Auhb, Rebecca Krakorac, Keenan Withersd, Diana Norad, Lindsay Matthewsc, Sally Steinbacha,e, Joseph Snowd, Bryan Smitha, Avindra Natha, Caryn Morsec, and Suad Kapetanovicd,f aSection
of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
bNational
Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
cCritical
Care Medicine Department, National Institutes of Health, Bethesda, MD, USA
dNational
Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
eClinical
Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702
fDepartment
Author Manuscript
of Psychiatry and The Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Abstract Introduction—Post-traumatic stress disorder (PTSD) may be associated with chronic immune dysregulation and a pro-inflammatory state. Among HIV-infected individuals, PTSD is associated with greater morbidity and mortality, but the association with immune dysfunction has not been evaluated. This study explores the association between PTSD and selected markers of inflammation and immune activation in a cohort of HIV-infected, virally-suppressed individuals. Methods—HIV-infected adults who were virologically controlled on anti-retroviral medications were recruited through a screening protocol for studies of HIV-related neurocognitive disorders.
Author Manuscript
Corresponding author: Peter Siyahhan Julnes, [email protected], National Institutes of Health, Bldg. 10 Rm. 7C103 MSC 1430, Bethesda, Maryland 20892. Disclaimers: All authors contributed to this article as part of their official duties. This research was supported by the Intramural Research Training Award program at the National Institutes of Health; by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke; the authors have no relevant financial or non-financial relationships to disclose. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institute of Health, under Contract No HHSN261200800001E. (SS) The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This data was presented in part in a poster session at the Annual Meeting of the Academy of Psychosomatic Medicine, in New Orleans, in November 2015. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Siyahhan Julnes et al.
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Each participant underwent blood draws, urine toxicology screen, and completed the Client Diagnostic Questionnaire (CDQ), a semi-structured psychiatric interview. Results—Of 114 eligible volunteers; 72 (63%) were male, 77 (68%) African American, and 34 (30%) participants met criteria for PTSD. Participants with PTSD were more likely to be current smokers (79%) than those without (60%) (p=0.05). The PTSD cohort had significantly higher total white blood cell counts (5318 and 6404 cells/uL, p=0.03), absolute neutrophil count (2767 and 3577 cells/uL, p=0.02), CD8% (43 and 48, p=0.05) and memory CD8% (70 and 78%, p=0.04); lower naïve CD8% (30 and 22%, p=0.04), and higher rate of high-sensitivity C-reactive protein >3 mg/L (29 and 20, p=0.03). Discussion—A high prevalence of PTSD was identified in this cohort of HIV-infected adults who were virally-suppressed. These results suggest that PTSD may be associated with immune dysregulation even among ART-adherent HIV-infected individuals.
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Keywords immunophenotyping; antiretroviral therapy; Client Diagnostic Questionnaire; neuropsychoimmunology; PLWH
BACKGROUND
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Post-traumatic stress disorder (PTSD) is a highly prevalent comorbidity among adults with human immunodeficiency virus (HIV) infection, with the prevalence rates ranging from 23% to 42% (1–3). Such high prevalence stands in sharp contrast to the 9.7% prevalence of PTSD in the general US population reported in large epidemiologic surveys (4, 5), but is less surprising considering that more than half of HIV-infected individuals report experiencing at least one severe traumatic event in their lifetime. (1, 2).
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Evidence suggests that PTSD and, to a smaller extent, a history of psychological trauma without PTSD, may be associated with alterations in immune responsiveness and a proinflammatory state. Psychological trauma survivors tend to have significantly lower percentages of naïve CD8+ T cells, increased proportions of CD3+ central and effector memory T cells, and a major reduction in the proportion of regulatory T cells compared to non-traumatized individuals (6, 7). This effect is relatively more pronounced among trauma survivors with current PTSD than among trauma survivors without current PTSD (6, 7), and the severity of PTSD symptoms correlates with the degree of T cell activation (6). In vitro experiments with peripheral blood mononuclear cells harvested from trauma survivors either with or without current PTSD, and controls without trauma or PTSD, demonstrated decreased leukocyte glucocorticoid receptor density in both groups of trauma survivors and decreased dexamethasone-induced inhibition of T-cell proliferation only from individuals with current PTSD, suggesting that PTSD may be associated with a qualitatively different effect on immune regulation compared to trauma exposure alone (8). In a prospective lifecourse study, a history of childhood maltreatment was predictive of serum high-sensitivity C-reactive protein (hsCRP) levels >3mg/mL (a marker of a pro-inflammatory state and increased cardiovascular disease risk) 20 years later, even after controlling for key health behaviors, including smoking (9). These reported associations of PTSD and trauma history
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with compromised immune responsiveness and pro-inflammatory state may explain why individuals suffering from PTSD are more likely to have infections, autoimmune disorders, and other inflammatory diseases than those without PTSD (6, 7).
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To date, the effect of PTSD on circulating markers of immune activation or inflammation has not been evaluated in HIV-infected individuals. Growing evidence suggests that even a history of psychological trauma alone is independently associated with a number of unfavorable clinical and behavioral outcomes among HIV-infected individuals. This includes increased AIDS-related mortality, opportunistic infections (10), increased HIV viral load, as well as ART non-adherence and unprotected sex, even after controlling for psychosocial factors and comorbidities (i.e., coping style, self-efficacy, social support, trust in the medical system, recent stressors, mental health and substance abuse) (11). Given the high prevalence of PTSD among HIV-infected individuals, and the importance of immune regulation to HIV disease outcomes, it is important to know if the reported associations between PTSD and alterations in T-cell compartments and inflammation also exist among HIV-infected individuals with co-morbid PTSD.
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The hypothetical effect of PTSD on immune and inflammatory markers might be caused by the neuroendocrine or neuroimmune mechanisms suggested by the studies described above (6,7,8). Alternatively, given the reported associations between psychological trauma and ART non-adherence among HIV-infected individuals (11), this effect may be caused by or mediated through ART non-adherence. This project is a cross-sectional exploratory analysis of selected immune and inflammatory biomarkers in a cohort of HIV-infected adults screened for both trauma and PTSD. To minimize the potential confounding effect of ART non-adherence on the association between PTSD and the biomarkers, this analysis was restricted to virally-suppressed HIV-infected individuals.
METHODS Study Sample and Procedures Participants were recruited through a natural history screening study of HIV-associated neurocognitive disorders (HAND). The objective of the natural history study is to determine the eligibility of HIV-infected individuals for participation in other Neuro-HIV studies at the NIH Clinical Center. The Institutional Review Board of the National Institute of Allergy and Infectious Diseases approved the study. Written informed consent was obtained from all participants.
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Eligible HIV-infected participants were 18–61 years old, had at a least seventh grade educational level by self-report and were able to speak, read, and understand English. Volunteers were excluded if they had a history of central nervous system (CNS) infection, other CNS condition associated with cognitive impairment (e.g. untreated sleep apnea), a history of head injury with loss of consciousness >30 minutes, current substance abuse that in the opinion of the investigator would impede participation in study procedures or interpretation of results, or severe or untreated psychiatric illness. Participants taking psychotropic medications were eligible for participation if on a stable treatment regimen for at least 6 months.
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All participants underwent a screening assessment that included a detailed history and physical examination, a blood draw for safety and research studies, and a semi-structured psychiatric interview. This analysis was restricted to HIV-infected participants receiving ART with controlled viremia (HIV viral load 3 mg/L (p=0.03). The mean hsCRP as a continuous variable was not significantly different by PTSD status (p=0.12). Adjusted Analyses
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Immune markers that differed by PTSD status with a p-value 3 vs. =3 by PTSD status was examined using a logistic regression with current smoking as an independent variable. After adjusting for current smoking status, the PTSD group had a significantly larger mean WBC count (p=0.03), ANC (p=0.02) and memory CD8+ T cell % (p=0.02); and lower mean naïve CD8+ T cell % (p=0.02) compared to the group without PTSD. The likelihood of having hsCRP >3 mg/L was 2.5 times higher in the PTSD group compared to the group without PTSD (95% confidence interval (1.65, 5.66), p=0.04). There was no significant difference in continuous hsCRP (p=0.06), CD8% (p=0.08), or CD8+CD27+ (p=0.13) between the two groups.
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In the post-hoc analysis using smokers only (Table 4), the differences by PTSD status remained significant in total WBC (p=0.05), ANC (p=0.02), CD8% (p=0.05), memory CD8+ T cell % (p=0.04), and naïve CD8+ T cell % (p=0.04). However, among smokers only, there was no significant difference between the two cohorts in proportions of participants with CRP >3 mg/L (p=0.18).
DISCUSSION
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6This project was an exploratory analysis of the association between current active PTSD symptoms and selected markers of inflammation and immune activation in a cohort of virally-suppressed HIV-infected adults receiving ART. Consistent with previous studies with HIV-infected populations (1–3), there was a high prevalence of PTSD in this cohort, with 30% screening positive. Additionally, PTSD was associated with significantly higher mean total WBC counts, ANC, CD8% and memory CD8%; lower naïve CD8%, and higher rates of hsCRP >3 mg/L. These data suggests that previously observed associations between PTSD and immune dysregulation and inflammation also apply to HIV-infected individuals, even in the setting of suppressed HIV viremia on ART. Mechanisms underlying the association between PTSD and immune outcomes are not well understood. Proposed mechanisms include chronically elevated stress and stress hormone (e.g. cortisol) level or chronically increased sympathetic arousal and elevated circulating norepinephrine levels. Additionally, as in other populations, PTSD may affect health behaviors and lead to poor decision making and subsequent adverse health outcomes (1, 8, 10). The present analysis included only HIV-infected individuals with ART-suppressed viremia, thus minimizing the potential confounding effect of poor health behaviors, and possibly highlighting the role of neuro-endocrine or neuro-autonomic pathways.
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The observed associations between PTSD and immune and inflammatory markers remained significant after controlling for smoking status. However, in the sensitivity analysis restricted to smokers only, the association between hsCRP >3 and PTSD was no longer significant. This suggests a robust effect of smoking on hsCRP relative to that associated with PTSD, contradicting the reports of long-term effect of childhood trauma on hsCRP (9), possibly because the prevalence of smoking was lower in that study (i.e., ~1/3 vs. ~2/3 in the present analysis) and the sensitivity analysis for smoking status was not indicated. Alternatively, the long-term effects of childhood trauma on hsCRP may be mediated through pathways that do not necessarily involve active symptoms of PTSD.
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The PTSD group had significantly higher proportions of CD8+ and memory CD8+, and lower proportions of naïve CD8+ T-cells, a pattern that is associated with compromised immune responsiveness and increased susceptibility to novel pathogens. The elevated WBC and ANC in the PTSD cohort are consistent with such immune dysregulation. These differences may or may not be biologically important. Yet, statistically significant associations between PTSD and markers of immune dysregulation have been previously reported in HIV-uninfected populations (6, 7, 15, 16), and they may have additional clinical implications in the context of HIV infection. Indeed, a history of psychological trauma has been associated with detrimental HIV clinical outcomes such as increased AIDS-related
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mortality and opportunistic infections (10), and the findings from the present study suggest that such associations could be mediated though alterations in immune regulation and inflammation, even under circumstance of controlled viremia. This clinical concern is further augmented in light of the markedly high prevalence of PTSD in HIV-infected populations.
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Taken together, these findings may be of high clinical relevance as they suggest that a substantial proportion of HIV-infected individuals are actively struggling with a psychiatric condition that not only causes significant distress and functional impairment, but also may be associated with factors that interfere with optimal immune reconstitution in the context of viremia suppression. Clinically, this means that HIV-infected patients should be carefully screened for the history of psychological trauma and symptoms of PTSD, and referred for appropriate mental health care as indicated. Recent literature review of the HIV and trauma syndemic recommends implementing a “trauma-informed model of care” in clinical facilities caring for HIV-infected patients, outlines key characteristics of the model, and provides general guidelines for its implementation (1). Future randomized controlled trials, evaluating specific mental-health interventions for virally-suppressed HIV-infected persons with co-morbid PTSD, could provide important information about potential impact of such interventions on the biological and clinical outcomes.
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Future research should investigate additional markers of altered immunity or inflammatory processes associated with PTSD in ART-adherent HIV-infected individuals. Levels of immune cell products (i.e., cytokines, chemokines) from plasma and cerebrospinal fluid should be evaluated in relation to PTSD status. In addition, future studies should evaluate the role of clinical interventions in optimizing immune outcomes in HIV-infected patients with PTSD, and mechanistic studies may help identify novel therapeutic targets to achieve that objective.
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This study has several limitations. First, the cross-sectional design precludes inferences about direction or causality of the observed associations. Second, statistical adjustments were not made for multiple comparisons in this exploratory study, and thus p-values < 0.05 were reported as significant. This approach was used to allow maximum sensitivity in identifying signals of potential effects of PTSD on immune and inflammatory outcomes in this relatively small cohort. Although exploratory, these findings are bolstered by the congruent findings reported by other groups examining biomarkers of PTSD in non-HIV populations (7, 15, 16). To minimize impact of multiple comparisons, future confirmatory studies should focus only on the few identified candidate biomarkers, and be sufficiently statistically powered to allow controlling for multiple comparisons, ideally in a prospective, longitudinal design. Third, although the CDQ is validated for adult HIV-infected populations (12), it is still a screening tool and is not diagnostic. Ideally, PTSD would be diagnosed or ruled out in a comprehensive psychiatric interview; however the structured interview of the CDQ provides strong reproducibility which is essential in a research setting. Forth, the relatively homogenous nature of the study population limits the generalizability of the findings to other socio-demographic groups. On the other hand, this study sample was sociodemographically representative of the HIV epidemic in the US, making the findings relevant in the context of HIV/AIDS epidemic in the US. Lastly, cross-study comparisons in PTSD
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are limited by the evolving understanding of PTSD and the subsequent changes in diagnostic criteria (e.g. International Classification of Diseases [ICD], and in the DSM-IV-TR and DSM-5) (17, 18). In conclusion, current active symptoms of PTSD were detected in almost one-third of this sample of HIV-infected adults with ART-controlled viremia. Previously reported associations between PTSD and immune dysregulation or inflammation may also apply to viremia-controlled HIV-infected individuals. The consequences of this association may be especially costly in the context of HIV-infection and may need to be addressed as more is understood about PTSD and HIV disease.
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The authors would like to extend a special thanks to Cheryl Chairez, Angela Summers, Talia Shirazi, the OP8 Clinic staff, and all research participants.
References
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12. Aidala AHJ, Mellins CA, Dodds S, Whetten K, Martin D, Gillis L, Ko P. Development and validation of the Client Diagnostic Questionnaire (CDQ): A mental health screening tool for use in HIV/AIDS service settings. Psychol Health Med. 2004; 9:362–80. 13. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA. 1999; 282(18):1737–44. Epub 1999/11/24. [PubMed: 10568646] 14. American Psychiatric Association. Electronic DSM-IV-TR plus. Washington, D.C: American Psychiatric Association; 2000. 15. Boscarino JA, Chang J. Higher abnormal leukocyte and lymphocyte counts 20 years after exposure to severe stress: research and clinical implications. Psychosom Med. 1999; 61(3):378–86. Epub 1999/06/15. [PubMed: 10367620] 16. Vidovic A, Gotovac K, Vilibic M, Sabioncello A, Jovanovic T, Rabatic S, et al. Repeated assessments of endocrine- and immune-related changes in posttraumatic stress disorder. Neuroimmunomodulation. 2011; 18(4):199–211. Epub 2011/02/22. [PubMed: 21335985] 17. Stein DJ, McLaughlin KA, Koenen KC, Atwoli L, Friedman MJ, Hill ED, et al. DSM-5 and ICD-11 definitions of posttraumatic stress disorder: investigating “narrow” and “broad” approaches. Depression and anxiety. 2014; 31(6):494–505. Epub 2014/06/05. [PubMed: 24894802] 18. Van Ameringen M, Mancini C, Patterson B. The impact of changing diagnostic criteria in posttraumatic stress disorder in a Canadian epidemiologic sample. The Journal of clinical psychiatry. 2011; 72(8):1034–41. Epub 2011/06/16. [PubMed: 21672500]
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Table 1
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Demographic and clinical characteristics of the cohort (n=114). PTSD Screen Characteristic
Negative (n=80)
Positive (n=34)
50 (25–60)
50 (31–61)
51 (64%)
21 (62%)
African American
53 (66.25)
24 (70.59)
Caucasian
22 (27.75)
10 (29.41)
5 (6.25)
0
Age, years (mean, range) Male, n (%) Race, self-reported, n (%)
Other# Completed high school Time since HIV Diagnosis, years (mean, range)
72 (90.00)
28 (82.35)
18 (4.7–30.3) (1.3–30.3)
20 (3.9–34.3)
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CD4 nadir, reported, cells/uL (mean, range)
204 (1–1000)
189 (1–540)
Reported Adherence (%)
97.5 (80–100)
97.9 (84.61–100)
587 (112–1492)
579 (146–1536)
29 (18–63)
30 (19–43)
Systolic Blood Pressure
122 (95–169)
126 (94–161)
Diastolic Blood Pressure
75 (54–105)
77 (60–94)
Diabetes, reported
3/47 (6.38)
2/20 (10)
Smoking, current*
48 (60)
27 (79.4)
Chronic HCV
9 (11.2)
4 (11.7)
73 (91.25)
33 (97.06)
7 (8.75)
1 (2.94)
350 n (%)
61 (76.25)
27 (79.41)
CD4 %
31 (6–56)
28 (9–45)
Glucose, mg/dL
98 (70–247)
112.85 (48–372)
D-dimer, ug/mL
0.32 (0.21–0.79)
0.32 (0.21–2.41)
HCV Ab Positive
15/78 (19.2)
9/32 (28.1)
Cocaine
5/75 (6.6)
4/33 (12.1)
Amphetamines
1/75 (1.3)
1/33 (3)
Cannabinoids
3/75 (4)
1/33 (3)
Total CD4 count, cells/uL (mean, range) Body Mass Index
HIV viral load, copies/mL 3mg/L, n (%)*
1.35 (0–6)
1.35 (0–4)
0.93
3.7 (0.1–22)
6.1 (0.2–42)
0.12
29 (36%)
20 (59%)
0.03
Mean with range presented unless otherwise noted.
*
denotes significance at alpha of 0.05
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Table 3
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Group differences between PTSD and no PTSD using ANCOVA with current smoking as a covariate (n=114). Parameter
p-value between groups
WBC*
0.03
ANC*
0.02
CD8%
0.08
CD8_naive%*
0.02
CD8_memory%*
0.02
hsCRP
0.06
hsCRP, binary*
0.04
*
denotes significance at alpha of 0.05
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Table 4
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Post-hoc analysis using smokers only by PTSD status (n=75). PTSD Screen (n=75) Outcome
Negative (n=48)
Positive (n=27)
p-value
5587.41 (2860–13580)
6564.07 (3690–13030)
0.05
2891 (1110–8570)
3710.1 (1330–7490)
0.02
CD8%*
43.33 (21–69)
48.96 (35–71)
0.05
CD8_naive%*
31.21 (7–72)
21.85 (5–51)
0.04
CD8_memory%*
69.04 (29–92)
78.37 (49–95)
0.04
3.95 (0.14–21.90)
5.01 (0.2–33)
0.63
19/48 (39.58)
15/27 (55.56)
0.18
Total WBC* ANC*
hsCRP, mg/L hsCRP > 3mg/L, n (%)
*
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denotes significance at alpha of 0.05
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