Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for Chronic Fatigue Syndrome

Lead Research Organisation: King's College London
Department Name: Psychological Medicine

Abstract

Chronic fatigue syndrome (CFS) is a medical condition in which patients feel persistently and overwhelmingly tired and run down, both physically and mentally. In addition, they have difficulty with concentration, flu-like symptoms and aches and pains. This condition interferes with daily life activity, and, in some patients, is profoundly disabling. Although many years of research have been conduced on CFS, we still do not know what is causing it.

One biological system that is involved in CFS is the "immune system", that is, the system dedicated to fight infections in our body. Indeed, in many cases CFS is triggered by an infection, but then the symptoms continue even after the infection has been eliminated. Specifically, infections are always accompanied by acute fatigue and flu-like symptoms, as a consequence of the infection-driven immune activation; however, in patients with CFS the immune activation and the associated fatigue and flu-like symptoms persist for months or years. Moreover, there is evidence that the immune system is in a state of "hyper-activity" in patients with CFS, as if they were fighting an infective agent, even though they do not have an ongoing infection.

This project aims to understand exactly this process: how the infection and the acute immune activation evolve into CFS, and what are the risk factors that make this process occur in some individuals but not others. Clearly, trying to study this process in subjects experiencing naturally-acquired infections is very difficult, for the unpredictability of these events. In contrast, we want to model the development of CFS by studying a group of patients that have a pre-existing infection (chronic viral hepatitis C, HCV) and that receive a course of treatment (lasting months) with the immune activator, interferon-alpha (IFN-alpha). IFN-alpha is the treatment of choice for HCV infection. Because it activates the immune system, IFN-alpha also induces fatigue and flu-like symptoms in all patients. Moreover, and of particular relevance for this study, a considerable proportion of patients continue to experience debilitating persistent fatigue, and other symptoms that are similar to CFS, for 6 months or even one year after the cessation of IFN-alpha. This phenomenon strikingly resembles CFS, which, as mentioned above, also persists after the infective/immune trigger has been eliminated. Therefore, we are proposing to use IFN-alpha as a model to understand how an immune trigger induces persistent fatigue even when the initial immune trigger is no longer present.

To do this, we will assess these patients throughout the many months of IFN-alpha treatment and at 6 months after cessation of treatment, in order to identify those with persistent "post-IFN-alpha-treatment" fatigue, and understand what biological and clinical changes lead to this outcome. Moreover, we will compare these patients with a group of patients with CFS and with a group of healthy individuals, conducting the same biological and clinical assessment. We will measure changes occurring in blood hormones that are relevant to the immune function, such as "cytokines" and "cortisol". In addition, we will asses changes in measures of well-being, including physical fitness, concentration, sleep and mood.

We are confident that creating and validating this model of CFS will generate a host of future studies aimed at improving the health of people with CFS. For example, we will be able to build a check-list of blood measures that could predict who will, and who will not, develop CFS; we will test novel treatments for "post-IFN-alpha-treatment" fatigue, facilitated by the fact that these patients are homogeneous in their clinical background, and then extend these treatments to patients with CFS; and, finally, we will truly understand what happens in the body during the development of CFS, and thus identify novel therapeutic approaches to interrupt this development.

Technical Summary

We propose to model chronic fatigue syndrome (CFS) by studying patients taking interferon-alpha (IFN-alpha) for chronic viral hepatitis C (HCV) infection. IFN-alpha treatment leads to acute fatigue in the majority of patients. Most importantly, a proportion of patients continue to experience persistent fatigue, together with other CFS-like-symptoms, for many months after the cessation of treatment, that is, in the absence of the pro-inflammatory stimulus. This phenomenon strikingly resembles CFS, which also persists after the viral/immune trigger has been eliminated.

In order to develop this as a model of CFS, in our three-year project we want to:
1) assess a cohort (n=100) of patients throughout the IFN-alpha treatment and at 6 months after cessation of treatment, and identify the group who develop the persistent post-treatment fatigue (expected n=50);
2) validate this model, by comparing the clinical and biomarkers profiles in patients who experience persistent post-treatment fatigue, patients with CFS (n=50), and healthy controls (n=50);
3) identify the risk factors and the biomarkers trajectories (before and during IFN-alpha treatment) that identify those patients who will later experience persistent post-treatment fatigue.

We will measure: fatigue, mood, and other CFS-like symptoms; medical and psychiatric history; childhood and recent stressors; social support; illness and treatment perceptions; physical fitness; quality of life; and occupational function. Moreover, we will measure blood biomarkers: serum cytokines; cortisol at awakening and during the day; and leukocytes gene expression.

The project will build onto an existing pilot study in HCV patients, an established collaboration with Liver Units across London, and the research-led clinical service for CFS patients at King's College Hospital. Thus, the project has great chances of success.

Planned Impact

Our research on chronic fatigue syndrome (CFS) will benefit health and biological scientists; policy makers; stakeholders in health care; the interested lay public (especially those with a personal investment in understanding CFS), and, finally, patients with CFS.

Social and health scientists will benefit from our data: we will explain the mechanisms underlying the development of chronic fatigue, offer novel aetiological hypotheses to be confirmed in CFS patients, identify a group who are particularly indicated to test novel therapeutic interventions, and suggest new potential biological targets for the pharmacological treatment of CFS.

Policy makers will benefit from the evidence offered by our study: it will guide them in prioritising resources, in the difficult times ahead, by identifying important stages in the development of chronic fatigues and hence where and when to deliver screening and intervention programmes.

Stakeholders will benefit from understanding what happens to people while they are developing chronic fatigue: charities, non-governmental organisations, and regulatory bodies, all aimed at improving the clinical and social outcomes of CFS patients, will want to know how health, well-being, quality of life and occupational functioning is impacted by changes in biology and behaviour, and how these people can thus be helped.

Finally, the lay public, and especially patients and carers who have been personally touched by CFS, will benefit from all of our work: a non-stigmatising approach based on a sound biological basis, and an explanatory model that is not deterministic and that emphasises not only risk factors but also the protective factors that could be sought out.

Publications

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Barnes J (2017) Genetic Contributions of Inflammation to Depression. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Borsini A (2015) The role of inflammatory cytokines as key modulators of neurogenesis. in Trends in neurosciences

 
Title For all sad words 
Description Developed in collaboration with Prof Carmine Pariante, this work is a metaphorical blood exchange. It draws from Prof Pariante's research at King's College on blood inflammation in patients with depression, Stanford University's studies that show transfusion of young blood in old mice reversed aging, and Lund University's proposition that a protein found in beetroot (incidentally an anti-inflammatory food) could substitute human blood. The artist, Lynn Lu, invited participants to tell her about a significant personal regret. Then she pricked their finger and place a drop of blood in a petri dish. In exchange, she offers them a shot of anti-inflammatory beet juice. Over the weekend, the petri dishes fill with blood "inflamed" with lament, while vials of detoxifying beetroot empty one by one. 
Type Of Art Performance (Music, Dance, Drama, etc) 
Year Produced 2017 
Impact Engagement with the Science Gallery and other artistic organisation interested in using art to disseminate science 
URL https://lynnlu.info/for-of-all-sad-words-of-tongue-and-pen-the-saddest-are-these-it-might-have-been/...
 
Title Recording for live performance of artist Lynn Lu 
Description Drawing deeply from her personal experience, the artist Lynn Lu has spent some time during the development process of a performance for the CCLAP Festival with Professor Carmine Pariante, and his team at King's College London. Their research has found a clear link between mothers with postnatal depression not adequately nurturing their children and these children in time becoming themselves mothers who suffer from postnatal depression. At Deptford Lounge, the artist will create a safe space, one that she would have liked to have had, as a mother with postnatal depression. This safe space is offered to all mothers, as well as for anyone who might need an experience of nurturing. Together the artist and participants will put in words their darkest thoughts and feelings that have not been voiced. The anonymous texts will then be sealed in palm-sized clay envelops, and fired for strength / privacy / resilience. These accumulating tablets will be exhibited throughout the week. Participants will be invited to be cocooned and rocked in a wide fabric hammock for as long as they wish - as if in the womb, or a rockabye baby. In doing so, they will listen to a RECORDING OF THE INTERVIEW BETWEEN PROFESSOR PARIANTE AND THE ARTIST, which has been digitally modified so to make the words unintelligeble and similar to relaxing music. This performance will take place at Deptford Lounge. Full schedule for CCLAP 2015. 
Type Of Art Performance (Music, Dance, Drama, etc) 
Year Produced 2015 
Impact The recording was used in the performance, as above, so was publicly used. 
URL http://cclap.me/2015/10/26/cclap-2015-lynn-lu-the-hand-that-rocks-the-cradle/
 
Description 2013 CMO Report on Mental Health - Chapter on Neuroscience
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact Improved understanding of neuroscience issues relevant to mental health
 
Description Biomedical Research Centre - Affective Disorder and Interface with Medicine Theme
Amount £3,250,000 (GBP)
Funding ID NIHR Biomedical Research Centre at the South London and Maudsley NHS Trust and King's College London 
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description Distinguished Investigator Award
Amount $100,000 (USD)
Organisation Brain & Behaviour Research Foundation 
Sector Charity/Non Profit
Country United States
Start 07/2018 
End 06/2019
 
Description MRC Immunopsychiatry consortium
Amount £200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2014 
End 09/2016
 
Description Wellcome Trust Neuroimmunology Consortium
Amount £1,100,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Institutional Strategic Support Fund
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2019
 
Title Genes list for depression 
Description The genes list obtained by transcriptomics of blood MRNA of patients with depression before and after antidepressant (GENDEP sample) and before and after interferon-alpha treatment (MRC-funded project), both as raw data and as combined gene lists with statistical enrichment for overlapping genes. 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact collaboration and cross validation across independent research groups 
 
Description MRC Immunopsychiatry Consortium 
Organisation GlaxoSmithKline (GSK)
Department Psychiatry (GSK)
Country United Kingdom 
Sector Private 
PI Contribution Design of studies, execution of studies and experiments
Collaborator Contribution Funding of studies, contribution to research strategy and design
Impact Data exchange, publications (in preparation)
Start Year 2014
 
Description MRC Immunopsychiatry Consortium 
Organisation Medical Research Council (MRC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Design of studies, execution of studies and experiments
Collaborator Contribution Funding of studies, contribution to research strategy and design
Impact Data exchange, publications (in preparation)
Start Year 2014
 
Description Wellcome Trust Neuroimmunology Consortium 
Organisation H. Lundbeck A/S
Department Neuroscience; Lundbeck
Country Denmark 
Sector Private 
PI Contribution A research consortium; we recruit and select patients and deliver research
Collaborator Contribution They participate to the research strategy
Impact Data collection, publications (all still in preparation), novel potential targets for antidepressants discovery
Start Year 2014
 
Description Wellcome Trust Neuroimmunology Consortium 
Organisation Johnson & Johnson
Country United States 
Sector Private 
PI Contribution A research consortium; we recruit and select patients and deliver research
Collaborator Contribution They participate to the research strategy
Impact Data collection, publications (all still in preparation), novel potential targets for antidepressants discovery
Start Year 2014
 
Description Wellcome Trust Neuroimmunology Consortium 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution A research consortium; we recruit and select patients and deliver research
Collaborator Contribution They participate to the research strategy
Impact Data collection, publications (all still in preparation), novel potential targets for antidepressants discovery
Start Year 2014
 
Description Wellcome Trust Neuroimmunology Consortium 
Organisation Wellcome Trust
Department Wellcome Trust Strategic Award
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution A research consortium; we recruit and select patients and deliver research
Collaborator Contribution They participate to the research strategy
Impact Data collection, publications (all still in preparation), novel potential targets for antidepressants discovery
Start Year 2014
 
Title Clinical Trial with Minocycline in depressed patients with high-inflammation 
Description A proof-of-concept placebo-controlled RCT using minocycline as adjuvant to antidepressant treatment in depressed patients who are treatment-resistant and have high levels of inflammation as measured by C-reactive protein. funded by NIHR through the SLAM and KCL Biomedical Research Centre. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This is the first trial selecting depressed patients based on a blood-test, hence the first attempt to bring personalised medicine into psychiatry 
URL https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003413-26/GB#A
 
Description Antidepressants may not be perfect, but they DO save lives: Expert reveals how life-changing the drug can be when used in the right way 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Professor Carmine Pariante has treated thousands of patients with depression Despite expert claims the pills have devastating side-effects, he stands by them
They work when used correctly, especially alongside psychological therapy

Read more: http://www.dailymail.co.uk/health/article-4243156/Antidepressants-not-perfect-save-lives.html#ixzz4awYvDP2Q
Year(s) Of Engagement Activity 2017
URL http://www.dailymail.co.uk/health/article-4243156/Antidepressants-not-perfect-save-lives.html
 
Description Article for The Independent 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact An opinion piece defending the safe use of antidepressants. As a psychiatrist, I know that Johann Hari is wrong to cast doubt on antidepressants
Suggesting that prescribing antidepressants to a patient who suffers from clinical depression is the equivalent of treating them as a 'machine with malfunctioning parts' is wrong, unhelpful and even dangerous

Carmine Pariante Wednesday 10 January 2018 14:00 GMT
Year(s) Of Engagement Activity 2018
URL http://www.independent.co.uk/voices/johann-hari-depression-anti-depressants-psychiatrists-pills-ther...
 
Description Blog on the Huffington Post 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A regular blog entry that I have on the Huffington Post on topics of mental health
Year(s) Of Engagement Activity 2012,2015,2016,2017
URL http://www.huffingtonpost.co.uk/author/carmine-pariante
 
Description Cheltenham Science festival 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Many questions and subsequent emails

I was reached by journalists for further interviews
Year(s) Of Engagement Activity 2012
 
Description Daily Mail 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interview of perinatal depression

Attracted public interest
Year(s) Of Engagement Activity 2010
 
Description Interview for BBC Radio 4 Programme 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact BBC health reporter James Gallagher explores the increasing body of evidence that a dysfunctional immune system is responsible for the depression or psychotic illness experienced by hundreds of thousands, perhaps millions, of people in the UK. James talks to the psychiatrists investigating this new understanding of mental illness and to people who may benefit from treatments aimed at the immune systems rather than their brain cells.

"I believe this is one of the strongest discoveries in psychiatry in the last twenty years", says Professor Carmine Pariante of his and other research on the immune system and depression. "It allows us to understand depression no longer as just a disorder of the mind and not even a disorder of the brain, but a disorder of the whole body. It shifts conceptually what we understand about depression."

James also talks to New York journalist Susannah Cahalan. She began to experience paranoid delusions and florid hallucinations when her immune system made damaging antibodies against part of the molecular circuitry in her brain. Treatment to eliminate the antibodies prevented her committal to psychiatric hospital. Psychiatrist Professor Belinda Lennox at the University of Oxford says she has evidence that a significant proportion of people presenting for the first time with psychotic symptoms are victims of a similar autoimmune problem.

Producer: Rachael Buchanan and Andrew Luck-Baker.
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/programmes/b07pj2pw
 
Description Personal blog on the Huffington Post 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact regular entry blogs on topics related to mental health
Year(s) Of Engagement Activity 2015,2016
URL http://www.huffingtonpost.co.uk/carmine-pariante/
 
Description Plenary Lecture at the Conference of Forensic Psychiatry of the Royal College of Psychiatrists 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A plenary lecture on my research on depression and inflammation
Year(s) Of Engagement Activity 2017
 
Description Plenary Lecture at the Italian Society for Psychopathology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A plenary lecture on my research on depression and the immune system
Year(s) Of Engagement Activity 2017
 
Description Press conference 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Press conference associated with a symposium on depression

Private interviews with a radio, description on news websites
Year(s) Of Engagement Activity 2009
 
Description Symposium at the Royal College of Psychiatrists 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact S33 Predicting response to antidepressants: Is it possible? Wednesday 1st of July 2015
Chair: Dr Hamish McAllister-Williams, Newcastle University

HPA axis and inflammatory cytokines *Professor Carmine Pariante, Institute of Psychiatry, London

Cognition and emotional processing Professor Catherine Harmer, University of Oxford EEG variables
Dr Hamish McAllister-Williams, Newcastle University


S54 Inflammation & Mental Health: An overview of perinatal and later life infection/inflammation on risk for common mental illnesses - - Thursday 2nd of July
Chair: Prof Hugo Critchley, Brighton & Sussex Medical School

Early-life infection alters glial function and increases susceptibility to cognitive and neuropsychiatric disorders including schizophrenia and
autism
Dr Staci Bilbo, Duke University

Can blood and brain MRI biomarkers be used to identify patients most likely to benefit from 'anti-inflammatory' treatments?
Dr Neil Harrison, University of Sussex

Update on the current evidence supporting a role for 'anti-inflammatory' agents in the management of treatment resistant depression *Professor Carmine Pariante, Kings College London
Year(s) Of Engagement Activity 2015
 
Description Visit of HRH The Duchess of Cambridge to Professor Pariante's laboratory 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The Duchess of Cambridge visits King's College London's IoPPN and the Mother and Baby Unit at Bethlem Royal Hospital

The Duchess of Cambridge visited Professor Pariante's laboratory at the Maurice Wohl Clinical Neuroscience Institute at King's College London to find out more about the Institute of Psychiatry, Psychology & Neuroscience's (IoPPN) pioneering 'bench to bedside' mental health research and to meet leading scientists in the area. The Duchess continued to the Mother and Baby Unit, Royal Bethlem Hospital, South London and Maudsley NHS Foundation Trust, to meet clinicians and patients.
Year(s) Of Engagement Activity 2018
URL https://www.kcl.ac.uk/ioppn/news/records/2018/january/duchess-of-cambridge-visits-kings-college-lond...