Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME):

pathogenesis, diagnostic biomarkers & clinical trials

Dr Jonathan R Kerr MD, PhD, FRCPath

Sir Joseph Hotung Senior Lecturer in Inflammation

St George’s University of London

Chronic Fatigue Syndrome (CFS)

Epidemiology

Prevalence of 0.5%More common in females (6:1)Sudden onsetPreceding virus infection (‘flu-like illness, outbreaks, specific

viruses)Exposure to toxins, chemicals, pesticides, vaccinationPre-existing emotional stress

Chronic Fatigue Syndrome (CFS)

Studies of PathogenesisImmune system - IC’s, IgG, B cells, NK

Th2 phenotypecytokine dysregulation / chronic immune

activation

Infection - virus, bacteriumNervous system - paresis, visual loss, ataxia, confusion

abnormal metabolism of 5-HIAA, A-V, 5-HT, PRL

brain scan abnormalities

Endocrine system - slight HPA axisCardiovascular system - vasodilatationPsychological function - depression & anxietyGenetic predisposition - deduced from twin studies

Active infections / insults in 200 CFS patients

Enterovirus 109Chlamydia pneumoniae 18Epstein-Barr virus 6Recurrent VZV infection6Parvovirus B19 infection3Hepatitis C virus3Cytomegalovirus3Postvaccination (pn, MMR or flu)3Toxic mould exposure 2Recurrent HHV-6 infection 1

Unknown 44

Chia et al. Clin Infect Dis 2003;36:671-2.

Chronic Fatigue Syndrome (CFS)

Treatment

Graded exercise therapy (GET)Cognitive behavioural therapy (CBT)Immunological – IVIG, interferon, terfenadine, Pharmacological – hydrocortisone, NADH, DA agonist, MAOI, Vit B

analog, galanthamine, fludrocortisone, antidep, SSRI, acyclovir, IFN inducer

Supplements – magnesiumComplementary / alternative – massage, osteopathyOther – buddy/mentor program

specific treatment of virus infection

ABCDEFGHIJK

Hypothesis for prolonged fatigue / CFS

Final common pathway(s)

InsultsInitial processes

CFS

Overview of basic cell processes

Microarray

Microarray

Taqman real-time PCRGENES

Test gen

e

Control gene

Hypothesis: that abnormalities of gene regulation occur in CFS

25 CFS patients & 25 normal controlsGene levels determined by Microarray analysis (9,522 genes) & real-

time PCR

Study of Gene Expression in Chronic fatigue syndrome

Pilot study - 2005

Pilot stud

y

16 CFS-associated Genes

Immune IL-10RA IL-10 receptor alphaCD2BP2 CD2 antigen binding protein 2

Neurological PRKCL1 Protein kinase C-like 1GABARAPL1 GABA(A) receptor associated protein like-1KHSRP KH-type splicing regulatory proteinNTE Neuropathy target esteraseGSN Gelsolin

Mitochondrion MRPL23 Mitochondrial ribosomal protein L23EIF2B4 Euk. translation initiation factor 2B, subunit 4δ, tv-1EIF4G1 Euk. Translation initiation factor 4G, subunit 1, tv-5

Apoptosis / cell cycle PDCD2 Programmed cell death 2, tv-1ANAPC11 Anaphase promoting complex subunit 11

homologBRMS1 Breast cancer metastasis suppressor 1

Peroxisome ABCD4 ATP-binding cassette subfamily D, member 4PEX16 Peroxisomal biogenesis factor 16

Transcription POLR2G RNA polymerase II (DNA-directed) polypeptide G

Pilot stud

y

GENES

A complex pathogenesis

Support for a biological process in CFS

Conclusion

Pilot stud

y

A working model of CFSHypothesi

s

MacrophageT lymphocyte

A working model of CFSHypothesi

s

Macrophage

T lymphocyte

cytokines, etc

What are the human and virus gene signatures of CFS?

Repeat microarray study

CFS patients and normal controls

Determine levels of ALL human and virus genes

GENES

Phase 1-continued

Phase-1 continued Study Phase-1

cont.

Clinical aspects

1. Diagnosis according to CDC criteria(Fukuda et al, 1994)

2. Assessment of health & associated symptoms: CIDI Cantab McGill Chalder MOS-SF36 SPHERE Pittsburgh

Virus & Human genes in CFS

Microarraystudy

MPSSStudy

GENES

Microarray47,000 human genes

27 CFS pts / 54 normals

East Dorset CFS Service

MPSSALL genes sequenced

20 CFS pts / 20 normals

University of Cardiff

Microarray MPSS

GENES

15 52182

Immune ResponseNeurological genesMitochondrial genesSelective Regulation

Phase-1 cont.

GENES

GENES

Human microRNAs in CFSGENES

Confirmation of specificity of CFS gene signature

GENES

Idiopathic CFS (n=500)Infection-associated CFS (n=50)Prolonged fatigue (n=50)Normal fatigue (n=25)Normals (n=100)Rheumatoid arthritis (n=50)Osteoarthritis (n=50)Endogenous depression (n=50)

Phase 2

Associations of CFS-associated genes with symptomsPhase 3

Time (12 months)

CFS-associated

genes

CFS-associatedsymptoms

GENES

Virus genes in CFS

MPSSStudy

GENES

Known virus

triggers

28 microbes

28 microbes

HerpesvirusesEnterovirusesParvoviruses

Coxiella burnetiiMycoplasma pneumoniae

Chlamydia pneumoniaeetc.etc.

Clinical trials of treatment candidatesPhase 4

TREATMENTDEVELOPMEN

T

Human Virus

NFKBIL-6

Interferon-bHIF1a

T cell activation

AcyclovirPleconoril

Clarithromycin

Interferon-b

Clinical trials of treatment candidatesPhase 4

TREATMENTDEVELOPMEN

T

Human Virus

Interferon-b

NFKBIL-6

HIF1aT cell

activation

AcyclovirPleconoril

Clarithromycin

SELDI-PC

Development of a diagnostic test for CFS

Biomarkers

SELDI-PC

Biomarkers

Diagnostic test for CFS

Biomarkers

**Collaboration with Dept of Paediatrics, Imperial College London

Clinical Centres

CLINICAL COLLABORATORSDr Selwyn Richards, Dorset CFS ServiceDr Janice Main, Imperial College LondonProfessor Terry Daymond, SunderlandProfessor Andrew Smith, University of CardiffDr David Honeybourne, Birmingham Dr Amolak Bansal, St Helier Hospital, SurreyProfessor Jon Ayres, Aberdeen UniversityProfessor Robert Peveler, University of Southampton Professor David Nutt, University of BristolDr John Axford, St George’s University of LondonDr Russell Lane, Charing Cross Hospital, LondonDr John K Chia, UCLA Medical Centre, CA, USADr Derek Enlander, NY, USADr Paul Langford, Imperial College LondonProfessor Mike Levin, Imperial College London

FUNDINGCFS Research Foundation, Hertfordshire, UK

Acknowledgements

STUDY DESIGN & LABORATORY WORKDeepika Devanur, St George’s University of LondonRobert Petty, St George’s University of LondonBeverley Burke, St George’s University of LondonNarendra Kaushik, Imperial College LondonRob Wilkinson, Imperial College LondonClare McDermott, Dorset CFS ServiceJane Montgomery, Dorset CFS ServiceDavid Fear, Kings College LondonTim Harrison, UCLPaul Kellam, UCLDavid AJ Tyrrell, CFS Research Foundation Stephen T Holgate, University of SouthamptonEmile Nuwaysir, Nimblegen Inc, USA.Don Baldwin, University of Pennsylvania, USAPeter Rogers, NBSDiana Carr, NBSJulie Williams, NBSFrank Boulton, NBSAndrew Bell, Poole Hospital