Transcript The Parvoviridae
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 onset Preceding virus infection (‘flu-like illness, outbreaks, specific viruses) Exposure to toxins, chemicals, pesticides, vaccination Pre-existing emotional stress
Chronic Fatigue Syndrome (CFS)
Studies of Pathogenesis
Immune system Infection Nervous system Endocrine system Cardiovascular system Psychological function Genetic predisposition IC’s, IgG, B cells, NK Th2 phenotype cytokine dysregulation / chronic immune activation virus, bacterium paresis, visual loss, ataxia, confusion abnormal metabolism of 5-HIAA, A-V, 5-HT, PRL brain scan abnormalities slight HPA axis vasodilatation depression & anxiety deduced from twin studies
Active infections / insults in 200 CFS patients
Enterovirus
Chlamydia pneumoniae
Epstein-Barr virus Recurrent VZV infection Parvovirus B19 infection Hepatitis C virus Cytomegalovirus Postvaccination (pn, MMR or flu) Toxic mould exposure Recurrent HHV-6 infection Unknown 3 2 1 3 3 3 109 18 6 6 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 – magnesium Complementary / alternative – massage, osteopathy Other – buddy/mentor program specific treatment of virus infection
Hypothesis for prolonged fatigue / CFS
Insults I J K A B C D E F G H Initial processes Final common pathway(s) CFS
Overview of basic cell processes
Microarray
Microarray
GENES
Taqman real-time PCR Test gene Control gene
Pilot study Study of Gene Expression in Chronic fatigue syndrome Pilot study - 2005 Hypothesis: that abnormalities of gene regulation occur in CFS 25 CFS patients & 25 normal controls Gene levels determined by Microarray analysis (9,522 genes) & real-time PCR
Pilot study
16
CFS-associated Genes Immune Neurological Mitochondrion IL-10RA CD2BP2 PRKCL1 GABARAPL1 KHSRP NTE GSN MRPL23 EIF2B4 EIF4G1 IL-10 receptor alpha CD2 antigen binding protein 2 Protein kinase C-like 1 GABA(A) receptor associated protein like-1 KH-type splicing regulatory protein Neuropathy target esterase Gelsolin Mitochondrial ribosomal protein L23 Euk. translation initiation factor 2B, subunit 4δ, tv-1 Euk. Translation initiation factor 4G, subunit 1, tv-5 Apoptosis / cell cycle PDCD2 ANAPC11 BRMS1 PeroxisomeABCD4 Transcription PEX16 POLR2G Programmed cell death 2, tv-1 Anaphase promoting complex subunit 11 homolog Breast cancer metastasis suppressor 1 ATP-binding cassette subfamily D, member 4 Peroxisomal biogenesis factor 16 RNA polymerase II (DNA-directed) polypeptide G
GENES
Pilot study
Conclusion
A complex pathogenesis Support for a biological process in CFS
Hypothesis
Macrophage A working model of CFS T lymphocyte
Hypothesis
Macrophage A working model of CFS T lymphocyte cytokines, etc
GENES
What are the human and virus gene signatures of CFS?
Phase 1-continued Repeat microarray study CFS patients and normal controls Determine levels of ALL human and virus genes
Phase-1 cont.
Phase-1 continued Study
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
GENES
Virus & Human genes in CFS
Microarray study MPSS Study Microarray 47,000 human genes 27 CFS pts / 54 normals
East Dorset CFS Service
MPSS ALL genes sequenced 20 CFS pts / 20 normals
University of Cardiff
GENES
Microarray
MPSS
182 15 52 Immune Response Neurological genes Mitochondrial genes Selective Regulation
Phase-1 cont.
GENES
GENES
GENES
Human microRNAs in CFS
GENES
Confirmation of specificity of CFS gene signature Phase 2 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)
GENES
Associations of CFS-associated genes with symptoms Phase 3 CFS-associated symptoms CFS-associated genes Time (12 months)
GENES
Virus genes in CFS
MPSS Study Known virus triggers
28 microbes
Herpesviruses Enteroviruses Parvoviruses Coxiella burnetii Mycoplasma pneumoniae Chlamydia pneumoniae etc.
etc.
28 microbes
TREATMENT DEVELOPMENT
Clinical trials of treatment candidates
Phase 4 Human NFKB IL-6 Interferon-b HIF1a T cell activation Acyclovir Pleconoril Clarithromycin Interferon-b Virus
TREATMENT DEVELOPMENT
Clinical trials of treatment candidates
Phase 4 Human NFKB IL-6 HIF1a T cell activation Interferon-b Virus Acyclovir Pleconoril Clarithromycin
Biomarkers
Development of a diagnostic test for CFS SELDI-PC
Biomarkers
SELDI-PC
Biomarkers
Diagnostic test for CFS
**Collaboration with Dept of Paediatrics, Imperial College London
Clinical Centres
Acknowledgements
CLINICAL COLLABORATORS Dr Selwyn Richards, Dorset CFS Service Dr Janice Main, Imperial College London Professor Terry Daymond, Sunderland Professor Andrew Smith, University of Cardiff Dr David Honeybourne, Birmingham Dr Amolak Bansal, St Helier Hospital, Surrey Professor Jon Ayres, Aberdeen University Professor Robert Peveler, University of Southampton Professor David Nutt, University of Bristol Dr John Axford, St George’s University of London Dr Russell Lane, Charing Cross Hospital, London Dr John K Chia, UCLA Medical Centre, CA, USA Dr Derek Enlander, NY, USA Dr Paul Langford, Imperial College London Professor Mike Levin, Imperial College London FUNDING CFS Research Foundation, Hertfordshire, UK STUDY DESIGN & LABORATORY WORK Deepika Devanur, St George’s University of London Robert Petty, St George’s University of London Beverley Burke, St George’s University of London Narendra Kaushik, Imperial College London Rob Wilkinson, Imperial College London Clare McDermott, Dorset CFS Service Jane Montgomery, Dorset CFS Service David Fear, Kings College London Tim Harrison, UCL Paul Kellam, UCL David AJ Tyrrell, CFS Research Foundation Stephen T Holgate, University of Southampton Emile Nuwaysir, Nimblegen Inc, USA.
Don Baldwin, University of Pennsylvania, USA Peter Rogers, NBS Diana Carr, NBS Julie Williams, NBS Frank Boulton, NBS Andrew Bell, Poole Hospital