Heterogeneity in Measures of Illness among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Not Explained by Clinical Practice: A Study in Seven U.S. Specialty Clinics.

Background: One of the goals of the Multi-site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM) study was to evaluate whether clinicians experienced in diagnosing and caring for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) recognized the same clinical entity. Methods: We enrolled participants from seven specialty clinics in the United States. We used baseline data (n = 465) on standardized questions measuring general clinical characteristics, functional impairment, post-exertional malaise, fatigue, sleep, neurocognitive/autonomic symptoms, pain, and other symptoms to evaluate whether patient characteristics differed by clinic. Results: We found few statistically significant and no clinically significant differences between clinics in their patients' standardized measures of ME/CFS symptoms and function. Strikingly, patients in each clinic sample and overall showed a wide distribution in all scores and measures. Conclusions: Illness heterogeneity may be an inherent feature of ME/CFS. Presenting research data in scatter plots or histograms will help clarify the challenge. Relying on case-control study designs without subgrouping or stratification of ME/CFS illness characteristics may limit the reproducibility of research findings and could obscure underlying mechanisms.

A common language for Gulf War Illness (GWI) research studies: GWI common data elements.

AIMS: The Gulf War Illness programs (GWI) of the United States Department of Veteran Affairs and the Department of Defense Congressionally Directed Medical Research Program collaborated with experts to develop Common Data Elements (CDEs) to standardize and systematically collect, analyze, and share data across the (GWI) research community. MAIN METHODS: A collective working group of GWI advocates, Veterans, clinicians, and researchers convened to provide consensus on instruments, case report forms, and guidelines for GWI research. A similar initiative, supported by the National Institute of Neurologic Disorders and Stroke (NINDS) was completed for a comparative illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and provided the foundation for this undertaking. The GWI working group divided into two sub-groups (symptoms and systems assessment). Both groups reviewed the applicability of instruments and forms recommended by the NINDS ME/CFS CDE to GWI research within specific domains and selected assessments of deployment exposures. The GWI CDE recommendations were finalized in March 2018 after soliciting public comments. KEY FINDINGS: GWI CDE recommendations are organized in 12 domains that include instruments, case report forms, and guidelines. Recommendations were categorized as core (essential), supplemental-highly recommended (essential for specified conditions, study types, or designs), supplemental (commonly collected, but not required), and exploratory (reasonable to use, but require further validation). Recommendations will continually be updated as GWI research progresses. SIGNIFICANCE: The GWI CDEs reflect the consensus recommendations of GWI research community stakeholders and will allow studies to standardize data collection, enhance data quality, and facilitate data sharing.

Evaluation of natural killer cell assay performance on shipped blood specimens.

Documenting the importance of NK cell function as a biomarker for diseases and physiologic conditions including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), will require assays amenable to clinical implementation and standardization. Research studies typically perform NK functional assays on the day of sample collection. This pilot study was conducted to compare assay formats and specimen processing to identify those that are most tolerant of conditions required for shipping and amenable to standardization as shown by inter-assay and inter-laboratory correlation of results. We compared performance within and between assays that measure NK cell function using direct cytotoxicity [chromium-51 release (CRCA) or fluorescence (Flow Cytometry Cytotoxicity Assay, FCCA)] or an indirect surrogate marker (CD107a surface expression)]. Additional variables for within/between assay comparisons included time of testing (same day as specimen collection or next day within 24 h), specimen types [whole blood or isolated peripheral blood mononuclear cells (PBMCs)], and processing method (fresh or cryopreserved). Statistical measures included number of samples tested in assay conditions (n), medians (x͂), interquartile range (IQR), Pearson correlation coefficient (R2), and correlation p-value (p). Samples came from 3 clinics and included 31 participants. Same day testing was only available for the subset of participants enrolled from the site of the laboratory performing CRCA. Results from same day CRCA testing of whole blood were considered the gold standard [n = 10, x͂=10.0%, IQR = 7.2%], and correlated well with PBMCs isolated next day [n = 26, x͂= 15.6%, IQR = 13.1%] [R2 = 0.59, p = 0.03]. Next day CRCA results were compromised using whole blood or frozen PBMCs. Next day FCCA cytotoxicity in PBMC [n = 30, x͂=34.1%, IQR = 15.5%] correlated with same day CRCA PMBC [R2 = 0.8, p = 0.001] and next day CRCA PMBC [R2 = 0.5, p < 0.0001]. CD107a expression after induction by PMA and ionomycin did not correlate with other cytotoxicity measures. NK function can be measured in PBMCs isolated after overnight shipping/storage at ambient temperature and CRCA and FCCA results on this sample type are well correlated.

Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness.

Potentially linked to the basic physiology of stress response, Gulf War Illness (GWI) is a debilitating condition presenting with complex immune, endocrine and neurological symptoms. Here we interrogate the immune response to physiological stress by measuring 16 blood-borne immune markers at 8 time points before, during and after maximum exercise challenge in n = 12 GWI veterans and n = 11 healthy veteran controls deployed to the same theater. Immune markers were combined into functional sets and the dynamics of their joint expression described as classical rate equations. These empirical networks were further informed structurally by projection onto prior knowledge networks mined from the literature. Of the 49 literature-informed immune signaling interactions, 21 were found active in the combined exercise response data. However, only 4 signals were common to both subject groups while 7 were uniquely active in GWI and 10 uniquely active in healthy veterans. Feedforward mediation of IL-23 and IL-17 by IL-6 and IL-10 emerged as distinguishing control elements that were characteristically active in GWI versus healthy subjects. Simulated restructuring of the regulatory circuitry in GWI as a result of applying an IL-6 receptor antagonist in combination with either a Th1 (IL-2, IFNγ, and TNFα) or IL-23 receptor antagonist predicted a partial rescue of immune response elements previously associated with illness severity. Overall, results suggest that pharmacologically altering the topology of the immune response circuitry identified as active in GWI can inform on strategies that while not curative, may nonetheless deliver a reduction in symptom burden. A lasting and more complete remission in GWI may therefore require manipulation of a broader physiology, namely one that includes endocrine oversight of immune function.

Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome.

PURPOSE: The complex and varied presentation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has made it difficult to diagnose, study, and treat. Its symptoms and likely etiology involve multiple components of endocrine and immune regulation, including the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, and their interactive oversight of immune function. We propose that the persistence of ME/CFS may involve changes in the regulatory interactions across these physiological axes. We also propose that the robustness of this new pathogenic equilibrium may at least in part explain the limited success of conventional single-target therapies. METHODS: A comprehensive model was constructed of female endocrine-immune signaling consisting of 28 markers linked by 214 documented regulatory interactions. This detailed model was then constrained to adhere to experimental measurements in a subset of 17 candidate immune markers measured in peripheral blood of patients with ME/CFS and healthy control subjects before, during, and after a maximal exercise challenge. A set of 26 competing numerical models satisfied these data to within 5% error. FINDINGS: Mechanistically informed predictions of endocrine and immune markers that were either unmeasured or exhibited high subject-to-subject variability pointed to possible context-specific overexpression in ME/CFS at rest of corticotropin-releasing hormone, chemokine (C-X-C motif) ligand 8, estrogen, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone 1, interleukin (IL)-23, and luteinizing hormone, and underexpression of adrenocorticotropic hormone, cortisol, interferon-γ, IL-10, IL-17, and IL-1α. Simulations of rintatolimod and rituximab treatment predicted a shift in the repertoire of available endocrine-immune regulatory regimens. Rintatolimod was predicted to make available substantial remission in a significant subset of subjects, in particular those with low levels of IL-1α, IL-17, and cortisol; intermediate levels of progesterone and FSH; and high estrogen levels. Rituximab treatment was predicted to support partial remission in a smaller subset of patients with ME/CFS, specifically those with low norepinephrine, IL-1α, chemokine (C-X-C motif) ligand 8, and cortisol levels; intermediate FSH and gonadotropin-releasing hormone 1 levels; and elevated expression of tumor necrosis factor-α, luteinizing hormone, IL-12, and B-cell activation. IMPLICATIONS: Applying a rigorous filter of known signaling mechanisms to experimentally measured immune marker expression in ME/CFS has highlighted potential new context-specific markers of illness. These novel endocrine and immune markers may offer useful candidates in delineating new subtypes of ME/CFS and may inform on refinements to the inclusion criteria and instrumentation of new and ongoing trials involving rintatolimod and rituximab treatment protocols.

Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM): Design and Implementation of a Prospective/Retrospective Rolling Cohort Study.

In the Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM), we relied on expert clinician diagnoses to enroll patients from 7 specialty clinics in the United States in order to perform a systematic collection of data on measures of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). Healthy persons and those with other illnesses that share some features with ME/CFS were enrolled in comparison groups. The major objectives were to: 1) use standardized questionnaires to measure illness domains of ME/CFS and to evaluate patient heterogeneity overall and between clinics; 2) describe the course of illness, identify the measures that best correlate with meaningful clinical differences, and assess the performances of questionnaires as patient/person-reported outcome measures; 3) describe prescribed medications, orders for laboratory and other tests, and management tools used by expert clinicians to care for persons with ME/CFS; 4) collect biospecimens for future hypothesis testing and for evaluation of morning cortisol profiles; and 5) identify measures that best distinguish persons with ME/CFS from those in the comparison groups and detect subgroups of persons with ME/CFS who may have different underlying causes. Enrollment began in 2012 and is planned to continue in multiple stages through 2017. We present the MCAM methods in detail, along with an initial description of the 471 patients with ME/CFS who were enrolled in stage 1.

Illness progression in chronic fatigue syndrome: a shifting immune baseline.

BACKGROUND: Validation of biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) across data sets has proven disappointing. As immune signature may be affected by many factors, our objective was to explore the shift in discriminatory cytokines across ME/CFS subjects separated by duration of illness. METHODS: Cytokine expression collected at rest across multiple studies for female ME/CFS subjects (i) 18 years or younger, ill for 2 years or less (n = 18), (ii) 18-50 years of age, ill for 7 years (n = 22), and (iii) age 50 years or older (n = 28), ill for 11 years on average. Control subjects were matched for age and body mass index (BMI). Data describing the levels of 16 cytokines using a chemiluminescent assay was used to support the identification of separate linear classification models for each subgroup. In order to isolate the effects of duration of illness alone, cytokines that changed significantly with age in the healthy control subjects were excluded a priori. RESULTS: Optimal selection of cytokines in each group resulted in subsets of IL-1α, 6, 8, 15 and TNFα. Common to any 2 of 3 groups were IL-1α, 6 and 8. Setting these 3 markers as a triple screen and adjusting their contribution according to illness duration sub-groups produced ME/CFS classification accuracies of 75-88 %. The contribution of IL-1α, higher in recently ill adolescent ME/CFS subjects was progressively less important with duration. While high levels of IL-8 screened positive for ME/CFS in the recently afflicted, the opposite was true for subjects ill for more than 2 years. Similarly, while low levels of IL-6 suggested early ME/CFS, the reverse was true in subjects over 18 years of age ill for more than 2 years. CONCLUSIONS: These preliminary results suggest that IL-1α, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS.

Health locus of control beliefs and healthy survival with AIDS.

BACKGROUND: Health Locus of Control (HLOC) has been related to a number of psychosocial and medical variables in previous research in HIV. However, there is little information about its relationship to disease status, or about the Doctors subscale (DHLOC), in this population. PURPOSE: The main purpose of the present study was to determine whether HLOC beliefs were related to "healthy survival with AIDS" status, and to do so with the DHLOC subscale in addition to the other HLOC subscales. METHOD: Two HIV-positive groups, healthy survivors (HS; n = 70) who had experienced an asymptomatic period of ≥9 months despite low CD4 cells (<50) without the aid of protease inhibitors and a matched control group (MC; n = 70) of individuals in the mid-range of disease progression were compared on the HLOC scales. Several factors were examined as potential mediators. RESULTS: The HS group had significantly higher DHLOC and lower Internal HLOC (IHLOC) than the MC group. Both DHLOC and IHLOC contributed unique variance in relationship to HS status. These findings were not due to group differences in age, gender, ethnicity, income, education, sexual orientation, or HIV viral load. CONCLUSIONS: HLOC may contribute to the particular psychosocial profile of this relatively "rare" group of HIV-positive individuals who remained asymptomatic despite very low CD4 cells. Higher DHLOC and lower IHLOC beliefs may be adaptive for HIV-positive individuals at an advanced stage of disease progression, and therefore modifying HLOC beliefs may be a worthwhile focus of future interventions.

View of God as benevolent and forgiving or punishing and judgmental predicts HIV disease progression.

This study assessed the predictive relationship between View of God beliefs and change in CD4-cell and Viral Load (VL) in HIV positive people over an extended period. A diverse sample of HIVseropositive participants (N = 101) undergoing comprehensive psychological assessment and blood draws over the course of 4 years completed the View of God Inventory with subscales measuring Positive View (benevolent/forgiving) and Negative View of God (harsh/judgmental/punishing). Adjusting for initial disease status, age, gender, ethnicity, education, and antiretroviral medication (at every 6-month visit), a Positive View of God predicted significantly slower disease-progression (better preservation of CD4-cells, better control of VL), whereas a Negative View of God predicted faster disease-progression over 4 years. Effect sizes were greater than those previously demonstrated for psychosocial variables known to predict HIV-disease-progression, such as depression and coping. Results remained significant even after adjusting for church attendance and psychosocial variables (health behaviors, mood, and coping). These results provide good initial evidence that spiritual beliefs may predict health outcomes.

Perceived stress and norepinephrine predict the effectiveness of response to protease inhibitors in HIV.

BACKGROUND: In vitro evidence has suggested that increasing levels of norepinephrine (NE) can accelerate HIV replication; however, the importance in a clinical setting has not been tested. PURPOSE: The purpose of this study was to determine if perceived stress as well as the stress hormones NE and cortisol would predict the response to starting a new protease inhibitor (PI) prospectively. METHOD: Perceived stress, urinary cortisol and norepinephrine, CD4 and viral load (VL) were measured in people with HIV before starting a new PI and six months later (an average of three months after starting the new PI) in order to determine CD4 and VL response to the PI. RESULTS: Higher perceived stress significantly predicted lower effectiveness of the new PI in increasing CD4 and decreasing VL controlling for age, duration of new PI, baseline CD4/VL, sexually transmitted diseases (STDs), and gender/ethnic risk groups. Higher norepinephrine, but not cortisol, predicted worse VL response to PIs and, in fact, mediated the relationship between perceived stress and change in VL. CONCLUSION: Perceived stress and high norepinephrine levels are prospectively associated with a poorer response to starting a new PI. Assessing stress and norepinephrine levels in patients starting on antiretroviral medications might be clinically useful.

Stressful life events and adherence in HIV.

Because medication adherence is critical to improving the virologic and immunologic response to therapy and reducing the risk of drug resistance, it is important that we understand the predictors of nonadherence. The goal of the current study is to examine demographic, health behavior and psychosocial correlates (e.g., stressful life events, depressive symptoms) of nonadherence among a sample of HIV infected men and women from one south Florida metropolitan area. We collected questionnaire data from on 105 HIV infected men and women who were taking antiretroviral medication during the years 2004 to 2007. In this sample, 44.8% had missed a medication dose in the past 2 weeks, and 22.1% had missed their medication during the previous weekend. Those with three or more stressful life events in the previous 6 months were 2.5 to more than 3 times as likely to be nonadherent (in the past 2 weeks and previous weekend, respectively) compared to those without such events. Fully 86.7% of those with six or more stresses were nonadherent during the prior 2 weeks compared to 22.2% of those with no stressors. Although alcohol consumption, drug use, and symptoms of depression were related to nonadherence in the bivariate analyses, the effects of these predictors were reduced to nonsignificance by the stressful event measure. These findings underscore the importance of addressing the often chaotic and stressful lives of HIV infected persons within medical settings.

Psychosocial factors predict CD4 and viral load change in men and women with human immunodeficiency virus in the era of highly active antiretroviral treatment.

OBJECTIVE: Most previous longitudinal studies demonstrating relationships between psychosocial variables and human immunodeficiency virus (HIV) disease progression utilized samples of gay men accrued before the era of highly active antiretroviral treatment (HAART), without including viral load (VL) as an indicator of disease progression or assessing the impact of medication adherence. This study sought to determine whether psychosocial variables would predict both CD4 and VL changes in a diverse sample assessed entirely during the era of HAART and accounting for adherence effects. METHODS: This longitudinal study assessed a multiethnic HIV+ sample (n = 177) of men and women in the midrange of illness (CD4 number between 150 and 500; no previous acquired immunodeficiency syndrome [AIDS]-defining symptom) every 6 months for 2 years. Hierarchical linear modeling was used to model change in CD4 and VL controlling for sociodemographics (age, gender, ethnicity, education) and medical variables (baseline CD4/VL, antiretroviral medications at each time point, adherence). RESULTS: Baseline depression, hopelessness, and education predicted the slope of CD4 and VL. Avoidant coping and life event stress predicted VL change. Cumulative variables produced stronger relationships (depression, avoidant coping, and hopelessness with CD4/VL slope and life events stress with VL slope). High cumulative depression and avoidant coping were associated with approximately twice the rate of decline in CD4 as low scorers and greater relative increases in VL. Social support was not significantly related to CD4 or VL slope. CONCLUSIONS: Psychosocial factors contribute significantly to the variance in HIV disease progression (assessed through CD4 number and VL) in a diverse sample, accounting for adherence and do so in the era of HAART.

Dispositional optimism and the mechanisms by which it predicts slower disease progression in HIV: proactive behavior, avoidant coping, and depression.

The issue of whether optimism may prospectively protect against disease progression is one that has generated much interest, with mixed results in the literature. The purpose of this study was to determine whether dispositional optimism predicts slower disease progression in HIV. Two indicators of disease progression, CD4 counts and viral load, were assessed over 2 years in a diverse group (men, women, White, African American, Hispanic) of 177 people with HIV in the midrange of disease at entry to the study. Optimism predicted slower disease progression (less decrease in CD4 and less increase in viral load) controlling for baseline CD4 and viral load, antiretroviral treatment, gender, race, education, and drug use. Those low on optimism (25th percentile) lost CD4 cells at a rate 1.55 times faster than those high on optimism (75th percentile). Optimists had higher proactive behavior, less avoidant coping, and less depression: These variables mediated the linear optimism-disease progression relationship. Thus, optimists may reap health benefits partly through behavioral (proactive behavior), cognitive (avoidant coping), and affective (depression) pathways. Implications, limitations, and interpretations are discussed.

Emotional expression and depth processing of trauma and their relation to long-term survival in patients with HIV/AIDS.

OBJECTIVE: This study examined the relationship between emotional expression and depth processing of trauma and long-term survival of patients living with AIDS. A further purpose was to examine the immune, health behavior and psychosocial correlates of emotional disclosure and depth processing. METHOD: Subjects wrote essays describing their reactions to past traumas; these were scored for emotional expression and depth processing (positive cognitive appraisal change, experiential involvement, self-esteem enhancement and adaptive coping strategies). Two HIV-seropositive groups were recruited for this study; long-term survivors (LTS; n=46) patients who had survived at least 4 years past a Category C (AIDS defining) symptom prior to starting protease inhibitors and an equivalent HIV-seropositive comparison group (ECOMP(LTS); n=89) who had CD4+ cells between 150 and 500, and had no history of Category C symptoms. The groups were equivalent on age, gender, ethnicity, education, employment, income, sexual orientation and route of infection. RESULTS: The group LTS were significantly higher than the ECOMP(LTS) group on emotional expression and depth processing. Depth processing mediated the relationship between emotional expression and long-term survival status. Depth processing was positively related to CD4+ cell number for women. Emotional expression was also significantly related to viral load (negatively) and to CD4+ cell number (positively) for women only. Interestingly, only depth processing (and not emotional expression) was related to medication adherence and to psychosocial variables (perceived stress and social support). CONCLUSIONS: Emotional expression and depth processing were related to long-term survival, however, depth processing was the mediator for this relationship and only depth processing was associated with medication adherence, perceived stress and social support. Our results underscore the importance of depth processing (and not just emotional expression) of traumatic experiences for people living with HIV/AIDS.

The Ironson-woods Spirituality/Religiousness Index is associated with long survival, health behaviors, less distress, and low cortisol in people with HIV/AIDS.

The purpose of this study was to determine the reliability and validity of an instrument that measures both spirituality and religiousness, to examine the relation between spirituality and religiousness and important health outcomes for people living with HIV and to examine the potential mediators of these relations. One aim was to determine whether subscales of spirituality, religiousness, or both would be independently related to long survival in people living with AIDS. The Ironson-Woods Spirituality/Religiousness (SR) Index is presented with evidence for its reliability and validity. Four factors were identified on the Ironson-Woods SR Index (Sense of Peace, Faith in God, Religious Behavior, and Compassionate View of Others). Each subscale was significantly related to long survival with AIDS. That is, the long-term survivor (LTS) group (n = 79) scored significantly higher on these factors than did the HIV-positive comparison (COMP) group (n = 200). Long survival was also significantly related to both frequency of prayer (positively) and judgmental attitude (negatively). In addition, the Ironson-Woods SR Index yielded strong and significant correlations with less distress, more hope, social support, health behaviors, helping others, and lower cortisol levels. The relation between religious behavior and health outcomes was not due to social support. Further analyses were conducted, which identified urinary cortisol concentrations and altruistic behavior as mediators of the relation between SR and long survival.