chronic fatigue syndrome / myalgic encephalomyelitis (cfs/me): pathogenesis, diagnostic biomarkers...
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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