Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome.

The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p = 0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.

Exposure to and Content of Marijuana Product Reviews.

Many individuals now seek out product reviews in order to make an informed decision prior to making a purchase. In this study, we investigate consumers' exposure to and content within product reviews about marijuana because of their potential to shape marijuana purchasing decisions. The terms "weed review," "marijuana review," and "cannabis review" were searched on YouTube on June 10-11, 2015; the team viewed and coded the content of 83 product review videos about marijuana. In addition, we surveyed young adult (18-34 years old) current (past month) marijuana users (n = 742) from across the USA online to assess exposure to product reviews about marijuana and associations with socio-demographic characteristics and marijuana use behaviors. In our content analysis of videos, we observed that the reviewers tended to consume marijuana during the video and often shared personal, favorable experiences towards the marijuana they ingested (e.g., became as high as possible or experienced positive effects on physical and mental health). Most videos normalized marijuana use and could be easily accessed by underage youth. About one third (34%) of the survey participants viewed/sought a product review about marijuana in the past 30 days. In a multivariable logistic regression model, living in a state where recreational use is legal or using multiple forms of marijuana was associated with increased odds of viewing/seeking marijuana reviews. Prevention messages should counter product reviews about marijuana that tend to normalize and promote marijuana use given that they are more readily viewed by individuals who are increasingly susceptible to marijuana's potential harms.

The International Collaborative on Fatigue Following Infection (COFFI).

BACKGROUND: The purpose of the Collaborative on Fatigue Following Infection (COFFI) is for investigators of post-infection fatigue (PIF) and other syndromes to collaborate on these enigmatic and poorly understood conditions by studying relatively homogeneous populations with known infectious triggers. Utilizing COFFI, pooled data and stored biosamples will support both epidemiological and laboratory research to better understand the etiology and risk factors for development and progression of PIF. METHODS: COFFI consists of prospective cohorts from the UK, Netherlands, Norway, USA, New Zealand and Australia, with some cohorts closed and some open to recruitment. The 9 cohorts closed to recruitment total over 3,000 participants, including nearly 1000 with infectious mononucleosis (IM), > 500 with Q fever, > 800 with giardiasis, > 600 with campylobacter gastroenteritis (CG), 190 with Legionnaires disease and 60 with Ross River virus. Follow-ups have been at least 6 months and up to 10 years. All studies use the Fukuda criteria for defining chronic fatigue syndrome (CFS). RESULTS: Preliminary analyses indicated that risk factors for non-recovery from PIF included lower physical fitness, female gender, severity of the acute sickness response, and autonomic dysfunction. CONCLUSIONS: COFFI (https://internationalcoffi.wordpress.com/) is an international collaboration which should be able to answer questions based on pooled data that are not answerable in the individual cohorts. Possible questions may include the following: Do different infectious triggers different PIF syndromes (e.g., CFS vs. irritable bowel syndrome)?; What are longitudinal predictors of PIF and its severity?

Response to the editorial by Dr Geraghty.

This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty's views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.

Treatment Outcome and Metacognitive Change in CBT and GET for Chronic Fatigue Syndrome.

BACKGROUND: Studies have reported that Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET) are effective treatments for Chronic Fatigue Syndrome (CFS). METHOD: One hundred and seventy-one patients undertook a course of either CBT (n = 116) or GET (n = 55) and were assessed on a variety of self-report measures at pre- and posttreatment and follow-up. AIMS: In this paper we present analyses on treatment outcomes for CBT and GET in routine clinical practice and evaluate whether changes on subscales of the Metacognitions Questionnaire-30 (MCQ-30) predict fatigue severity independently of changes in other covariates, and across the two treatment modalities. RESULTS: Both CBT and GET were equally effective at decreasing fatigue, anxiety, and depression, and at increasing physical functioning. Changes on the subscales of the MCQ-30 were also found to have a significant effect on fatigue severity independently of changes in other covariates and across treatment modalities. CONCLUSION: The findings from the current study suggest that CFS treatment protocols for CBT and GET, based on those from the PACE trial, achieve similar to poorer outcomes in routine clinical practice as in a RCT.

The Metacognitions about Symptoms Control Scale: Development and Concurrent Validity.

OBJECTIVE: This paper presents the development and preliminary validation of a self-report instrument designed to measure metacognitions pertaining to symptoms control in the form of the following: (1) symptoms focusing and (2) symptoms conceptual thinking. METHODS: A total of 124 patients (95 female and 29 male) presenting with chronic fatigue syndrome (CFS) contributed data to the study to test the structure and psychometric properties of the Metacognitions about Symptoms Control Scale (MaSCS). RESULTS: A principal components factor analysis indicated that a two-factor solution best fitted the data. The factors were labelled positive and negative metacognitions about symptoms control. Further analyses revealed that both factors had good internal consistency. Correlation analyses established preliminary concurrent validity, indicating that both positive and negative metacognitions about symptoms control were significantly associated with levels of fatigue in CFS. Regression analysis revealed that positive and negative metacognitions about symptoms control significantly predicted fatigue severity when controlling for anxiety and depression. CONCLUSIONS: The newly developed instrument may help future research that examines the role of metacognitions in CFS, as well as aiding clinical assessment and case formulation. KEY PRACTITIONER MESSAGE: The MaSCS is a useful first instrument to assess metacognitions in CFS. The MaSCS may help to deepen our understanding of symptoms control (symptoms focusing and conceptual thinking about symptoms) in the experience of CFS symptoms. Assessing and conceptualizing symptoms control through the MaSCS may aid treatment of CFS.

Metacognitive factors in chronic fatigue syndrome.

UNLABELLED: Chronic fatigue syndrome (CFS), which is characterized by fatigue and flu-like symptoms that are not alleviated by rest, is a poorly understood condition and an often controversial diagnosis. Earlier research has indicated that general metacognitions are associated with the severity of symptoms in patients with CFS. In the current study, we aimed to determine whether specific metacognitive factors are implicated in CFS. Using the metacognitive profiling interview template we investigated the following: (1) whether patients held positive or negative metacognitions about conceptual processes; (2) what their goals with respect to engaging in these processes were; and (3) what indicated that it was appropriate to stop. We also examined attention focus when experiencing CFS symptoms, and its advantages and disadvantages. Results showed that patients endorsed positive and negative metacognitions pertaining to conceptual processes. The goals of engaging in these processes were to identify the cause of, and devise strategies to cope with, symptoms. Patients were either unable to identify a stop signal for conceptual processing or identified an improvement in fatigue-related symptoms as representing the stop signal. Finally, patients reported that their attention focus when experiencing symptoms included distraction and monitoring of symptoms. Advantages to these strategies included symptom management, whereas disadvantages included an escalation of negative affect. The present findings provide preliminary evidence that specific metacognitive factors may be involved in CFS. KEY PRACTITIONER MESSAGE: Metacognitive profiling that may aid assessment and conceptualisation of psychological distress in CFS.

Metacognitions and negative emotions as predictors of symptom severity in chronic fatigue syndrome.

OBJECTIVE: Chronic fatigue syndrome (CFS) describes a condition that is primarily characterized by fatigue and flu-like symptoms that are not alleviated by rest. This study investigated the relationship among metacognitions, negative emotions, and symptom severity in CFS. METHODS: A total of 96 patients who had received a diagnosis of CFS according to the Oxford Criteria completed a battery of self-report measures that consisted of the Depression Anxiety Stress Scales, the 30-Item Metacognitions Questionnaire, the Chalder Fatigue Questionnaire (CFQ), and the RAND 36-Item Short-Form Health Survey-Physical Functioning. RESULTS: Correlation analyses showed that negative emotions and metacognitions were positively correlated with measures of symptom severity and that metacognitions were a better predictor of symptom severity than anxiety and depression. Hierarchical regression analyses indicated that (1) lack of cognitive confidence predicted both mental and physical factors of the CFQ and physical functioning independently of negative emotions and (2) beliefs about the need to control thoughts predicted the mental factor of the CFQ independently of negative emotions and lack of cognitive confidence. CONCLUSION: The data support the potential application of the metacognitive model of psychological disorder to understanding CFS.

Late presenters in the era of highly active antiretroviral therapy: uptake of and responses to antiretroviral therapy.

OBJECTIVES: To investigate the characteristics and clinical, immunological and virological outcomes for individuals presenting for care with low CD4 cell counts. METHODS: Individuals aged > 16 years presenting for care for the first time were identified between 1 January 1996 and 31 December 2002. Late presenters were those with CD4 cell count < 50 x 10(6) cells/l. Follow-up was until last contact, death or 31 December 2002. RESULTS: Late presenters formed 15.3% (110) of the group; they were more likely to be female (35% versus 24%), heterosexual (53% versus 38%), and of Black-African ethnicity (39% versus 27%) than other individuals. Over a median follow-up of 2.5 years, 13% of late presenters died. Ninety-nine patients started antiretroviral treatment; Of the 11 patients who did not start antiretroviral treatment, eight died within 3 months of presentation. Among those starting treatment, 87 (87.9%) achieved a viral load < 400 copies/ml and median CD4 cell counts increased from 43 x 10(6) cells/l at 0-2 months after presentation to 204 x 10(6) cells/l at 1 year. Over the first year, 71 patients attended at least one outpatient visit (median, 4.5; range, 0-39), 21 attended at least one day case visit (median, 0; range, 0-15) and 49 were admitted as an inpatient (median, 0; range, 0-4). CONCLUSIONS: Those presenting for care with very low CD4 cell counts may make large demands on clinical resources, particularly over the first few months. While some patients do have a poor outcome on highly active antiretroviral therapy, many will benefit from this therapy and will experience good immunological and virological responses.