Research Advances in Research Advances in Chronic Fatigue Chronic Fatigue

SyndromeSyndrome

Nancy Klimas, MDNancy Klimas, MD

University of Miami University of Miami

CFS and GWI Research CenterCFS and GWI Research Center

Miami VA Medical CenterMiami VA Medical Center

Definition - CFSDefinition - CFS

>6 mo. debilitating fatigue, unexplained by preexisting >6 mo. debilitating fatigue, unexplained by preexisting illness or psychiatric co morbidity, and at least 4 of illness or psychiatric co morbidity, and at least 4 of eight symptom criteria:eight symptom criteria:post exertional relapsepost exertional relapseconcentration and cognitive complaintsconcentration and cognitive complaintsmyalgiamyalgiaarthralgiaarthralgiasore throatsore throatpainful lymph nodespainful lymph nodesnew headachesnew headachesunrefreshing sleepunrefreshing sleep

CFS/ME Clinical Case DefinitionCFS/ME Clinical Case Definition

1. Substantial reduction in activity level due to new 1. Substantial reduction in activity level due to new onset, persistent fatigueonset, persistent fatigue2. Post exertional malaise2. Post exertional malaise3. Sleep dysfunction3. Sleep dysfunction4. Pain – myalgia, headaches 4. Pain – myalgia, headaches 5. Neurologic/Cognitive Manifestations5. Neurologic/Cognitive Manifestations6. At least one symptom from 2 of the following:6. At least one symptom from 2 of the following:

- Autonomic manifestations eg. OI, IBS- Autonomic manifestations eg. OI, IBS- Neuroendocrine manifestations eg. temperature - Neuroendocrine manifestations eg. temperature

intolerance, weight changeintolerance, weight change- Immune manifestations eg. tender lymph nodes, sore - Immune manifestations eg. tender lymph nodes, sore

throat, flu-like symptomsthroat, flu-like symptomsLink to full report Link to full report www.iacfs.netwww.iacfs.net

CFS “Caseness”CFS “Caseness”

SubpopulationsSubpopulations

HPA

CFS

AutonomicImmune

CFS “Caseness”CFS “Caseness”

SubpopulationsSubpopulations

HPA

AutonomicImmune

Other overlapping conditionsOther overlapping conditionsFibromyalgiaFibromyalgia

Gulf War Illness (VA CSP 16 fold increased Gulf War Illness (VA CSP 16 fold increased risk of CFS in Gulf War veterans)risk of CFS in Gulf War veterans)

Eisen et al Ann Int Med 2005 7;142(11):881Eisen et al Ann Int Med 2005 7;142(11):881

Multiple Chemical SensitivityMultiple Chemical Sensitivity

Epidemiology: DePaul Epidemiology: DePaul UniversityUniversity

• LatinosLatinos: 726 per 100,000 : 726 per 100,000 • African AmericansAfrican Americans: 337 per 100,000: 337 per 100,000• CaucasiansCaucasians: 224 per 100,000: 224 per 100,000

• Women:Women: 522 per 100,000 522 per 100,000 • Men:Men: 291 per 100,000 291 per 100,000

CDC Wichita study: 85% undiagnosed, CDC Wichita study: 85% undiagnosed, 50% reduction in household income – 9 billion/yr US loss 50% reduction in household income – 9 billion/yr US loss

productivityproductivity

Jason et al Psychosom Med. 2000 Sep-Oct;62(5):655-63Jason et al Psychosom Med. 2000 Sep-Oct;62(5):655-63Reeves et al Biomed Central 2005Reeves et al Biomed Central 2005

Attitudes of PhysiciansAttitudes of Physicians

Of 811 GP’s 44% did not feel confident making Of 811 GP’s 44% did not feel confident making the diagnosis, 41% did not feel confident treatingthe diagnosis, 41% did not feel confident treating

More likely to have confidence if they had a More likely to have confidence if they had a friend or family member with CFS, having more friend or family member with CFS, having more patients with CFS.patients with CFS.

Concludes that education emphasizing Concludes that education emphasizing acceptance of CFS as a real entity results in acceptance of CFS as a real entity results in improved confidence in treatmentimproved confidence in treatment

Bowen J et al Family Pract 2005 April 1

Model of CFS PathogenesisModel of CFS Pathogenesis

Genetic PredispositionGenetic Predisposition

Triggering event / infectionTriggering event / infection

Mediators (Immune, endocrine, Mediators (Immune, endocrine, neuroendocrine, psychosocial)neuroendocrine, psychosocial)

Health Outcome/PersistenceHealth Outcome/Persistence

Genetic Predisposition - CFSGenetic Predisposition - CFS

HLA DR haplotypes in 112 South Florida CFS HLA DR haplotypes in 112 South Florida CFS patients, compared to 5,000 regional and patients, compared to 5,000 regional and national controlsnational controls

4 to 6 fold increased relative risk for DR4, DR3 4 to 6 fold increased relative risk for DR4, DR3 and DQ3. (Keller et al, 1992)and DQ3. (Keller et al, 1992)

Seattle CFS Cooperative Research Center Twin Seattle CFS Cooperative Research Center Twin study - genetic predisposition, hereditability study - genetic predisposition, hereditability estimate of 51% (2nd World Conf)estimate of 51% (2nd World Conf)

Evidence for Triggering Evidence for Triggering event/ infection - CFS event/ infection - CFS

60 to 80% of CFS subjects date the onset of 60 to 80% of CFS subjects date the onset of their illness to an acute viral-like illness their illness to an acute viral-like illness (Komaroff, Buchwald) Less so in population (Komaroff, Buchwald) Less so in population based studies. (Reeves, Jason)based studies. (Reeves, Jason)Andrew Lloyd and colleagues in Australia Andrew Lloyd and colleagues in Australia performed a prospective study during and after performed a prospective study during and after acute EBV, Q fever or Ross River Virus -Anergy acute EBV, Q fever or Ross River Virus -Anergy during acute infection predicted persistent CFS during acute infection predicted persistent CFS like symptomslike symptomsPeter White described post EBV illness in a Peter White described post EBV illness in a prospective trialprospective trial

Model of CFS PathogenesisModel of CFS Pathogenesis

Genetic PredispositionGenetic Predisposition

Triggering event / infectionTriggering event / infection

Mediators (Immune, endocrine, Mediators (Immune, endocrine, neuroendocrine, psychosocial)neuroendocrine, psychosocial)

Health Outcome/PersistenceHealth Outcome/Persistence

CRFCRF

Hypothalamic-Pituitary-Adrenal Axis• Relative Hypocortisolemia

Heart and Blood Vessels• Altered blood pressure responses• Dizziness

Immune System • Lymph node tenderness• Sore throat• Enhanced Cytokines

Gastrointestinal Tract• Altered bowel habits• Abdominal pain

CNS Symptoms• Altered perceptions

- fatigue- pain

• Cognitive changes- concentration- memory

• Mood alterations- depression- anxiety

• Sleep disturbances- unrefreshing sleep- altered sleep-wake cycle

Musculoskeletal System• Myalgia & Arthralgia

Physical stress activates immune system and HPA axisEmotional stress activates immune system and HPA axis

Immune cascade

N atura l K iller

C ells (T h1)

C D 8 cellskill virus

H elper C D 4 cellT h1 cytokines

IL-2, IN F ac tivates C D 8

B ce llsm ake antibody

prevent and helpc lear in fec tion

H elper C D 4 cellT h2 cytokines

IL-6, IL-10ac tivates B ce lls

Macrophage presents antigen

..

Immune abnormalities in CFSImmune abnormalities in CFS

Immune ActivationImmune Activation

DR, CD26 expressionDR, CD26 expression

TH2 cytokine shiftTH2 cytokine shift

Proinflammatory Proinflammatory cytokines expression cytokines expression TNF-a, IL-1, IL6TNF-a, IL-1, IL6

Functional defectsFunctional defects

NK Cell dysfunctionNK Cell dysfunction

CD8 abnormalitiesCD8 abnormalities

perforins, granzymesperforins, granzymes

Macrophage abnormalitiesMacrophage abnormalities

Antibody productionAntibody production

Immunology What’s New?Immunology What’s New?Exercise induced complement activationExercise induced complement activation11

NK phenotypes predict riskNK phenotypes predict risk 2 2

Lower mRNA and TGF-beta1 production 3 3

Increased neutrophil apoptosis 4 4

Autoantibodies - anti-microtubule-associated Autoantibodies - anti-microtubule-associated protein 2, sDNAprotein 2, sDNA55

CTL defect equals that of NK cellsCTL defect equals that of NK cells

1 Sorensen, Jones et al J Allergy Clin Immun 2003 112(2):397-4031 Sorensen, Jones et al J Allergy Clin Immun 2003 112(2):397-4032 Stewart et al Cytometry 2003 53(1)26332 Stewart et al Cytometry 2003 53(1)26333 Tomoda A et al Psychiatry Res 2005 134(1):1013 Tomoda A et al Psychiatry Res 2005 134(1):1014 Kennedy et al J Clin Parhol 2004 57(8) 8914 Kennedy et al J Clin Parhol 2004 57(8) 8915 5 Vernon and Reeves, J Autoimmune Dis 2005 25:2:5Vernon and Reeves, J Autoimmune Dis 2005 25:2:56 Maher Fletcher and Klimas 20066 Maher Fletcher and Klimas 2006

Viral Persistence/Reactivation Viral Persistence/Reactivation

HHV6 virus is present in 22 to 54% of patients in cross HHV6 virus is present in 22 to 54% of patients in cross sectional studies (Ablashi, Krueger, Knox), HHV6 sectional studies (Ablashi, Krueger, Knox), HHV6 virus is present in 79% of CFS patients in longitudinal virus is present in 79% of CFS patients in longitudinal studies (HHV6 PCR assay, Knox)studies (HHV6 PCR assay, Knox)

HHV6 virus is present in the spinal fluid of 28 of 120 CFS HHV6 virus is present in the spinal fluid of 28 of 120 CFS patients (Peterson), and 7 of 35 CFS samples (Knox). patients (Peterson), and 7 of 35 CFS samples (Knox).

Enterovirus is present in 13% of CFS muscle samples Enterovirus is present in 13% of CFS muscle samples (Douche-Aourik, 2003)(Douche-Aourik, 2003)

EBV – dUTPase as a immune modulator, up regulating EBV – dUTPase as a immune modulator, up regulating inflammatory cytokines (Glaser, 2005)inflammatory cytokines (Glaser, 2005)

(Glaser et al Brain Behavior and Immunity 2005 19(2):91-103)(Glaser et al Brain Behavior and Immunity 2005 19(2):91-103)

HPA Axis dysregulationHPA Axis dysregulation

Demitrack low basal cortisols in CFS subjects, Demitrack low basal cortisols in CFS subjects, hypothalamic dysfunction-hypothalamic dysfunction- Dinan and colleagues - evidence of deficiency Dinan and colleagues - evidence of deficiency of hypothalamus, pituitary, of hypothalamus, pituitary, andand adrenal adrenal hypofunction.hypofunction.Small adrenal gland in depressed and non Small adrenal gland in depressed and non depressed CFS subjects, enlarged adrenal in depressed CFS subjects, enlarged adrenal in depressed control group.depressed control group.Bennett et al studied 500 FM patients with Bennett et al studied 500 FM patients with basal IGF-I levels which were significantly basal IGF-I levels which were significantly lower than controls.lower than controls.

EndocrinologyEndocrinologyReduced Cortisol output via several mechanismsReduced Cortisol output via several mechanismsA) heightened negative feedbackA) heightened negative feedbackB) heightened receptor functionB) heightened receptor functionC) impaired ACTH and cortisol responses to challengeC) impaired ACTH and cortisol responses to challenge DHEA functional abnormality (early data) DHEA functional abnormality (early data) Abnormal seritonin functionAbnormal seritonin functionIL-6 increase associates with low cortisol CRH mediatedIL-6 increase associates with low cortisol CRH mediatedMany confounding factors (deconditioning, sleep, comorbid depression, Many confounding factors (deconditioning, sleep, comorbid depression,

stress, medication)stress, medication)

Cleare AJ Endocr Rev 2003 24(2):236-52Cleare AJ Endocr Rev 2003 24(2):236-52Papanicolau Neuroimmunomodulation 2004 11(2)65-74Papanicolau Neuroimmunomodulation 2004 11(2)65-74Maes M Neuro Endocrinol Lett 2005 Oct 30;26(5)Maes M Neuro Endocrinol Lett 2005 Oct 30;26(5)

Renin Aldosterone AxisRenin Aldosterone Axis

High Prevalence of Renin-Aldosterone Axis Abnormalities in Patients with High Prevalence of Renin-Aldosterone Axis Abnormalities in Patients with Chronic Fatigue Syndrome (CFS)Chronic Fatigue Syndrome (CFS)30 of the 33 patients had at least one value of supine or upright PRA or 30 of the 33 patients had at least one value of supine or upright PRA or supine or upright serum AL outside of the 95% Tolerance Interval (TI) for supine or upright serum AL outside of the 95% Tolerance Interval (TI) for normal volunteers normal volunteers 16 patients had low serum AL and low or normal PRA, consistent with 16 patients had low serum AL and low or normal PRA, consistent with Hyporeninemic Hypoaldosteronism (HH) Hyporeninemic Hypoaldosteronism (HH)

The underlying defect may be autonomic nervous system dysfunction The underlying defect may be autonomic nervous system dysfunction and/or a primary adrenal defect.and/or a primary adrenal defect.

Zuckerbraun, E, Kim, HS, Daigle, K, Lee, ML, Friedman, TC, Charles R. Drew UniversityZuckerbraun, E, Kim, HS, Daigle, K, Lee, ML, Friedman, TC, Charles R. Drew University

Autonomic DysfunctionAutonomic Dysfunction

Neurally mediated hypotension (Rowe)Neurally mediated hypotension (Rowe)

Orthostatic hypotension (Streeten)Orthostatic hypotension (Streeten)

Parasympathetic dysfunction(Sisto)Parasympathetic dysfunction(Sisto)

Sympathetic over activation (Pagini, De Sympathetic over activation (Pagini, De Becker)Becker)

Study in adolescents mirrored that of Study in adolescents mirrored that of adultsadults

Balancing ActBalancing Act

sympathetic parasympatheticsympathetic parasympathetic

Autonomic Nervous SystemAutonomic Nervous System

Haemodynamic Instability Score taken during tilt Haemodynamic Instability Score taken during tilt table testing predicts CFS with 90% sensitivity. table testing predicts CFS with 90% sensitivity. 11

Heart Rate variability as a predictor of CFSHeart Rate variability as a predictor of CFS 2 2

Gastric emptying delayed in 23/32 CFS subjects Gastric emptying delayed in 23/32 CFS subjects 3

1 Naschitz QJ Med 2003 96(133-142)1 Naschitz QJ Med 2003 96(133-142)

2 Yamamoto2 Yamamoto Exp Biol Med 2003 228(2):167-74Exp Biol Med 2003 228(2):167-74

3 Burnet BMC Gastrenterol 2004 (1):32

Autonomic DysfunctionAutonomic Dysfunction

Drops in BP followed by CFS relapseDrops in BP followed by CFS relapse

Exhaustive treadmill testing results in Exhaustive treadmill testing results in cognitive function decline (LaManca et al)cognitive function decline (LaManca et al)

Perfusion abnormalities of brain stem, Perfusion abnormalities of brain stem, cerebellum (Costa et al)cerebellum (Costa et al)

Mid cerebral reduced perfusion (Schwartz Mid cerebral reduced perfusion (Schwartz et al)et al)

NeuropeptidesNeuropeptides

Seritonin and its precursers: abnormalities Seritonin and its precursers: abnormalities of CSF tryptophan levelsof CSF tryptophan levels

Badawy et al J Psychopharm 2005 19(4):385Badawy et al J Psychopharm 2005 19(4):385

PET scan – 5HT1A receptor binding reduced in PET scan – 5HT1A receptor binding reduced in CFS, particularly in the hippocampusCFS, particularly in the hippocampusCleare AJ et al Biol Psychiatry 2005 1;57(3):239-46Cleare AJ et al Biol Psychiatry 2005 1;57(3):239-46

Reduction of seritonin transporters (5HTTs) Reduction of seritonin transporters (5HTTs) most pronounced in the anterior cingulate by most pronounced in the anterior cingulate by PET scanPET scan. Yamamoto S et al Neuroreport 2004 15(17):2571. Yamamoto S et al Neuroreport 2004 15(17):2571

NeuroimagingNeuroimaging

Reductions in global grey matter Reductions in global grey matter associated with reductions in physical associated with reductions in physical activity (28 subjects, 28 matched controls).activity (28 subjects, 28 matched controls). deLange et al Neuroimage 200526(3):777deLange et al Neuroimage 200526(3):777

Utilization of more extensive regions of the Utilization of more extensive regions of the brain to process tasks using fMRI and brain to process tasks using fMRI and mPASAT. mPASAT. Lange G et al Neuroimage 2005 26(2):513Lange G et al Neuroimage 2005 26(2):513

Sleep PhysiologySleep Physiology

Circadian Sleep - Wake neuroendocrine and Circadian Sleep - Wake neuroendocrine and immune functions in CFS (Modolfsky)immune functions in CFS (Modolfsky)

altered diurnal patterns in cortisol, prolactinaltered diurnal patterns in cortisol, prolactin

altered diurnal patterns of NK cell functionaltered diurnal patterns of NK cell function

alpha wave intrusion on sleep EEG , reduced alpha wave intrusion on sleep EEG , reduced stage III and IVstage III and IV

Higher %REM (Twin study, 22 discordant twins)Higher %REM (Twin study, 22 discordant twins)11

1 Watson1 Watson et al Sleep 2003 26(3):32-8et al Sleep 2003 26(3):32-8

MuscleMuscle

Oxidative stress study, measuring protein carbonyls suggested Oxidative stress study, measuring protein carbonyls suggested higher levels of protein oxidation than controls higher levels of protein oxidation than controls 11

Exercise testing in 189 CFS subjects resulted in clinically Exercise testing in 189 CFS subjects resulted in clinically significant subgroups 50% showing moderate to severe functional significant subgroups 50% showing moderate to severe functional impairment. Unexpected blunted HR and BP responses noted. impairment. Unexpected blunted HR and BP responses noted. 22 Sarcoplasmic reticulum defect – conduction and calcium transport Sarcoplasmic reticulum defect – conduction and calcium transport abnormalitiesabnormalities33

1 Smirnova et al Mol Chem Biochem 2003 248(1-2):93-51 Smirnova et al Mol Chem Biochem 2003 248(1-2):93-5

22 Vaness Med Sci Sports Exerc 2003 35(6):908-13Vaness Med Sci Sports Exerc 2003 35(6):908-13

33 Fulle et al NeuromusculFulle et al Neuromuscul Disord 2003 13(6):479-84Disord 2003 13(6):479-84

MuscleMuscle

Cardiac muscle – cardiac output related to Cardiac muscle – cardiac output related to severity,and predicted exercise induced relapseseverity,and predicted exercise induced relapse11

Subset of CFS patients with IgM EBV or CMV Ab at Subset of CFS patients with IgM EBV or CMV Ab at risk for cardiac motility abnormalities and risk for cardiac motility abnormalities and occassionally true cardiomyopathyoccassionally true cardiomyopathy 2 2

Raises the issue of incomplete viral replication, activating immune responses as suggested by Glaser et al 3

1 Peckerman et al AJ Med Sci 2003 326(2)551 Peckerman et al AJ Med Sci 2003 326(2)55

2 Lerner M et al In Vivo 2004(18) 4:4172 Lerner M et al In Vivo 2004(18) 4:417

3 Glaser R Brain Behavior Immun 2005 19(2):913 Glaser R Brain Behavior Immun 2005 19(2):91

Exercise – new studiesExercise – new studies

No association between pain related fear of No association between pain related fear of movement and exercise capacity and disability movement and exercise capacity and disability Nijs J et al Phys Ther 2004 84(8):696Nijs J et al Phys Ther 2004 84(8):696

Exercise induced pain thresholds increase in Exercise induced pain thresholds increase in controls and decrease in CFS subjects controls and decrease in CFS subjects Whiteside A et

al Pain 109(3):497

Exercise – new studiesExercise – new studies

A subset of fit healthy controls deprived of exercise A subset of fit healthy controls deprived of exercise develop symptoms similar to CFS/FM. The subset is develop symptoms similar to CFS/FM. The subset is predicted by baseline abnormalities of autonomic, predicted by baseline abnormalities of autonomic, immune and HPA axis abnormalities.immune and HPA axis abnormalities.11

Patients with Rnase L abnormalities have abnormal Patients with Rnase L abnormalities have abnormal exercise physiology which is mediated in part by exercise physiology which is mediated in part by immune dysfunction immune dysfunction 22

Response to exercise shows accentuated oxidative Response to exercise shows accentuated oxidative stress, and marked alterations of muscle membrane stress, and marked alterations of muscle membrane excitablility, sufficient to explain muscle pain and post excitablility, sufficient to explain muscle pain and post exertional malaiseexertional malaise. 3. 3

1Glass JM et al J Psychosom res 2004 57(4):391

2 Snell CR In Vivo 2005 19(2)387, Nijs J et al Med Sci Sports Exerc 2005 Oct 37(10):1647

3 Jammes Y et al J Intern Med 2005 257(3):229

Model of CFS PathogenesisModel of CFS Pathogenesis

Genetic PredispositionGenetic Predisposition

Triggering event / infectionTriggering event / infection

Mediators (Immune, endocrine, Mediators (Immune, endocrine, neuroendocrine, psychosocial)neuroendocrine, psychosocial)

Health Outcome/PersistenceHealth Outcome/Persistence

DNADNA

mRNAmRNA ProteinAbundanceProteinAbundance

ProteinFunctionProteinFunction

GenomicsGenomics ProteomicsProteomics Activity-based Protein ProfilingActivity-based Protein Profiling

Molecular Epidemiology Laboratory StrategyMolecular Epidemiology Laboratory Strategy

Microarray Technology

Robotic printing

PCR amplification Purification

DNA clonesoligonucleotides

Microarray Production

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Total RNA

Sample Preparation

PBMCsLymphoprep

Erythrocytes + Granulocytes

Plasma

PBMCsBlood

Labelled cDNA

Hybridization

Sudden onsetGradual onset

23 women with CFS from Wichita23 women with CFS from WichitaMeasure expression of 3,800 genesMeasure expression of 3,800 genesQuestion:Question:

Could gene expression profiles Could gene expression profiles and differentially expressed and differentially expressed genes distinguish subtypes of genes distinguish subtypes of CFS? CFS? Of the 3,800 genes, 117 were significantly

Different between gradual vs sudden onset

Differentially Expressed Genes

in Numerous Pathways

Genetic studiesGenetic studiesDifferential expression of 35 genes of 9522 tested. Differential expression of 35 genes of 9522 tested. T Cell activation, neuronal and mitochondrial T Cell activation, neuronal and mitochondrial regulatory abnormalitiesregulatory abnormalities Kaushik J Clin pathol 2005 58(8):826 Kaushik J Clin pathol 2005 58(8):826

Abnormalities of Immune response genes in post-Abnormalities of Immune response genes in post-infection fatigue suggest genetic variations in infection fatigue suggest genetic variations in susceptibility to persistent fatigue.susceptibility to persistent fatigue. Helbig QJM 2005 98(8):565 Helbig QJM 2005 98(8):565

Pre-post exercise challenge gene studies saw Pre-post exercise challenge gene studies saw differences in genes that regulate ion transport, differences in genes that regulate ion transport, intracellular cell functions. Challenge studies such intracellular cell functions. Challenge studies such as these may be more useful than single cross as these may be more useful than single cross sectional studies.sectional studies. Whistler et al BMC Physiol 2005 24;5(1):5 Whistler et al BMC Physiol 2005 24;5(1):5

Illness represents alterations in Illness represents alterations in complex systems of homeostasiscomplex systems of homeostasis

Not a result of a single mutation Not a result of a single mutation or single environmental factoror single environmental factor

Arise from a combined action of Arise from a combined action of many genes, environmental many genes, environmental factors and risk-conferring factors and risk-conferring behaviorbehavior

CFS is a Complex IllnessCFS is a Complex Illness

TreatmentTreatment

Pathogenesis based approachesPathogenesis based approaches

Pathogenesis Directed Pathogenesis Directed InterventionsInterventions

Immune - Ampligen, future Immune - Ampligen, future immunomodulators immunomodulators

HPA axis interventions - Growth hormone, HPA axis interventions - Growth hormone, cortisol cortisol

NMH treatments (plasma expansion, NMH treatments (plasma expansion, sympathetic and parasympathetic sympathetic and parasympathetic stimulants/inhibitors); stimulants/inhibitors);

Sleep - pharmacologic and Sleep - pharmacologic and nonpharmacologicnonpharmacologic

Immune cascade

N atura l K iller

C ells (T h1)

C D 8 cellskill virus

H elper C D 4 cellT h1 cytokines

IL-2, IN F ac tivates C D 8

B ce llsm ake antibody

prevent and helpc lear in fec tion

H elper C D 4 cellT h2 cytokines

IL-6, IL-10ac tivates B ce lls

Macrophage presents antigen

..

Immune modulatory approachesImmune modulatory approachesAmpligen, a immune modulator and Ampligen, a immune modulator and

antiviral (Phase 3 recently completed)antiviral (Phase 3 recently completed)Allergy immunotherapy to down regulate Allergy immunotherapy to down regulate

allergic driveallergic drive Future immunomodulators (trials Future immunomodulators (trials

underway): Isoprinosine, thalidomide, anti-underway): Isoprinosine, thalidomide, anti-TNFa monoclonal AbTNFa monoclonal Ab

Proof of concept: Autologous lymphocyte Proof of concept: Autologous lymphocyte studystudy

Treating HHV6a?Treating HHV6a?Association vs. causationAssociation vs. causation

Blood PCR HHV6 a did not predict HHV6 virus is present in Blood PCR HHV6 a did not predict HHV6 virus is present in the spinal fluid the spinal fluid CSF did not predict bloodCSF did not predict bloodOf 120 CSF samples, 44 had abnormalities of protein, Of 120 CSF samples, 44 had abnormalities of protein, glucose or cells. Of the 44 , 28 were positive for glucose or cells. Of the 44 , 28 were positive for HHV6(26), EBV (1), or CMV(1).HHV6(26), EBV (1), or CMV(1).

5 of 8 CSF PCR positive treated until CSF cleared returned 5 of 8 CSF PCR positive treated until CSF cleared returned to full time employment (Peterson); in his experience TK to full time employment (Peterson); in his experience TK inhibitors did not clear CSF, patients required foscarnet or inhibitors did not clear CSF, patients required foscarnet or cidofovircidofovirOpen label valgancyclovir 9 of 12 responders in high titer Open label valgancyclovir 9 of 12 responders in high titer EBV plus HHV6 selected cohort , (Jose Montoya of EBV plus HHV6 selected cohort , (Jose Montoya of Stanford) Stanford)

Placebo control trials have not been completedPlacebo control trials have not been completed

Balancing ActBalancing Act

sympathetic parasympatheticsympathetic parasympathetic

Autonomic DysfunctionAutonomic DysfunctionNeurally mediated hypotension (Rowe)Neurally mediated hypotension (Rowe)Orthostatic hypotension (Streeten)Orthostatic hypotension (Streeten)Parasympathetic dysfunction (Sisto)Parasympathetic dysfunction (Sisto)Sympathetic over activation (Pagini, De Becker)Sympathetic over activation (Pagini, De Becker)

Implications for treatment - Implications for treatment - NMHNMH

““Pipes and a pump”, wired by the Pipes and a pump”, wired by the autonomic nervous systemautonomic nervous system

Fill the space - fluid vs. cellsFill the space - fluid vs. cells

compress the space - alpha 1 compress the space - alpha 1 agonists (e.g. midodrine), agonists (e.g. midodrine),

anti-phlebitic stockingsanti-phlebitic stockings

regulate the pump - beta blockersregulate the pump - beta blockers

HPA axis interventions -HPA axis interventions -

Growth hormone – phase 1 Growth hormone – phase 1 (Antwerp study)(Antwerp study)

Cortisol – conflicting phase 2 Cortisol – conflicting phase 2 study results (London, NIH) study results (London, NIH)

Restoration of sleep cycle Restoration of sleep cycle (circadian rhythm)(circadian rhythm)

SleepSleepRe-establish circadian rhythmRe-establish circadian rhythm

Conditioned response to bed - avoid bed for resting, Conditioned response to bed - avoid bed for resting, reading, use bed for sleeping. Establish “bedtime”.reading, use bed for sleeping. Establish “bedtime”. Avoid short acting hypnotics (alpha trappers)Avoid short acting hypnotics (alpha trappers) tricyclics, doxepan are longer acting, and don’t trap tricyclics, doxepan are longer acting, and don’t trap in alpha wavein alpha wave mirtazapine (Remeron), sodium oxybate or gamma mirtazapine (Remeron), sodium oxybate or gamma hydroxybutyrate, (Xyrem) act as stage 4 inducershydroxybutyrate, (Xyrem) act as stage 4 inducers

Pain and SleepPain and Sleep

pregabulin (Lyrica) 529 subjects, placebo pregabulin (Lyrica) 529 subjects, placebo control trial in fibromyalgiacontrol trial in fibromyalgia

Significant improvement in pain, sleep and Significant improvement in pain, sleep and fatigue (48% improved vs 27% placebo), fatigue (48% improved vs 27% placebo), 450 mg dose had greater reduction in pain 450 mg dose had greater reduction in pain scores.scores.

Nutritional interventionsNutritional interventions

Oxidative stress studies suggest Oxidative stress studies suggest interventions such as glutathione, N-interventions such as glutathione, N-acytylcysteine, alpha lipoic acid, acytylcysteine, alpha lipoic acid, NADHNADH

Vitamin studies suggest B vitamins, Vitamin studies suggest B vitamins, Vitamin C, Vitamin C, magnesiummagnesium, sodium, zinc, l-, sodium, zinc, l-tryptophan, tryptophan, L carnitineL carnitine, co-Q10, and , co-Q10, and essential fatty acids essential fatty acids highlighted interventions have phase 2 studies publishedhighlighted interventions have phase 2 studies published

Nutritional interventionsNutritional interventions

Dangers:Dangers:Licorice root – potassium deficienciesLicorice root – potassium deficiencies““supplements” that are actually hormonessupplements” that are actually hormones““supplements” that have iffy contents – eg. supplements” that have iffy contents – eg. St John’s wort, melatoninSt John’s wort, melatonin Products that make unsubstantiated Products that make unsubstantiated claimsclaimsUnder and over hydrationUnder and over hydration

ReconditioningReconditioning

Poor orthostatic resilience leads to Poor orthostatic resilience leads to substantial changes in usual substantial changes in usual reconditioning programsreconditioning programsLimit upright head up time to 5 minutes Limit upright head up time to 5 minutes alternating with 5 minutes flat, use flat alternating with 5 minutes flat, use flat or near flat aerobic conditions or near flat aerobic conditions (swimming, recumbent bike)(swimming, recumbent bike)Concentrate on muscle bulking Concentrate on muscle bulking exercises, increasing metabolic ate exercises, increasing metabolic ate (weight training, light weights)(weight training, light weights)Flexibility , stretching and balance as Flexibility , stretching and balance as core component.core component.

Recent reports - interventionsRecent reports - interventions

Brewers Yeast Extract - in a mouse model , using a chronic Brewers Yeast Extract - in a mouse model , using a chronic immune activation model, the BYE prep quieted the immune immune activation model, the BYE prep quieted the immune response and prevented further over activation in subsequent response and prevented further over activation in subsequent immune challenges. Activity level increased in the treated immune challenges. Activity level increased in the treated animals as compared to placeboanimals as compared to placeboUse of antibiotics for Coxiella burnetii infection(Q fever). TCN Use of antibiotics for Coxiella burnetii infection(Q fever). TCN was given to 4 CFS patients and 58 ICFS PCR positive was given to 4 CFS patients and 58 ICFS PCR positive patients: all cleared the infection, CFS patients failed to patients: all cleared the infection, CFS patients failed to improve, ICFS patients improved in performance and in improve, ICFS patients improved in performance and in temperature and headaches scores. temperature and headaches scores. Neurotropin - 6 mo treatment resolved all symptoms. Neurotropin - 6 mo treatment resolved all symptoms. Neurotropin is a immune modulator that is currently used in Neurotropin is a immune modulator that is currently used in Japan to treat RSD and other painful conditions.Japan to treat RSD and other painful conditions.

Toda Hiroshima J Med Sci 2006 mar 55(1) 35-77.Toda Hiroshima J Med Sci 2006 mar 55(1) 35-77.Takasha Evid based Compl Alt Med 2006 mar 3(1)109Takasha Evid based Compl Alt Med 2006 mar 3(1)109Twakami et al Intern Med 2005 Dec 44(12):1258-63Twakami et al Intern Med 2005 Dec 44(12):1258-63

Recent reports - interventionsRecent reports - interventionsMelatonin 29 patients, 5mg open label study, 8 of 27 Melatonin 29 patients, 5mg open label study, 8 of 27 normalized fatigue scores. Measured patients dim normalized fatigue scores. Measured patients dim light melatonin onset, patients whose result was later light melatonin onset, patients whose result was later than 22 hours were more likely to respond to than 22 hours were more likely to respond to treatment. treatment. Methylphenidate (ritalin) in CFS 10 mg BID study in Methylphenidate (ritalin) in CFS 10 mg BID study in 60 patients, placebo control: 17% reported decreased 60 patients, placebo control: 17% reported decreased fatigue, 22% improvement in concentration. ..further fatigue, 22% improvement in concentration. ..further studies needed. studies needed.

Modafinil not helpful (N=14 cross over study) – mixed Modafinil not helpful (N=14 cross over study) – mixed effect on cognitive testing, some dose effect.effect on cognitive testing, some dose effect. Van Van Heukelom et al Eur J neurol 2006 Jan 13(1):55-60Heukelom et al Eur J neurol 2006 Jan 13(1):55-60Blockman D et al Am J Med 2006 feb 119(2):167Blockman D et al Am J Med 2006 feb 119(2):167Randall DC et al J Psychopharm 2005 nov 19(6): 647-60 Randall DC et al J Psychopharm 2005 nov 19(6): 647-60

Recent reports - interventionsRecent reports - interventions

Walking program notes an initial ability to meet Walking program notes an initial ability to meet goals (4 to 10 days), then develop exercise goals (4 to 10 days), then develop exercise intolerance and worsening symptomatology intolerance and worsening symptomatology

Patients report: of 155 patients taking Patients report: of 155 patients taking everything under the sun, most helpful everything under the sun, most helpful supplements coQ10 (69%) DHEA (65%), supplements coQ10 (69%) DHEA (65%), ginsing (56%) by self report. Vitamins, ginsing (56%) by self report. Vitamins, exercise, yoga, predicted improvement. Yoga exercise, yoga, predicted improvement. Yoga seemed the most helpful. seemed the most helpful.

Black CD and McCully KK. Dyn Med 2005 Oct 28;3:10Black CD and McCully KK. Dyn Med 2005 Oct 28;3:10

Bentler SE J Clin Psychiatry 2005 may 66(5):625Bentler SE J Clin Psychiatry 2005 may 66(5):625

University of Miami CFS Research University of Miami CFS Research and Clinical Center– and Clinical Center– Research ProtocolsResearch Protocols

SMART Energy Study (CBT)SMART Energy Study (CBT) Erythropoetin (Procrit) phase 2 protocolErythropoetin (Procrit) phase 2 protocol Pathogenesis of NK cell defect in CFSPathogenesis of NK cell defect in CFS Thalidomide Phase 1 protocolThalidomide Phase 1 protocol Isoprinosine Phase 2 protocol Isoprinosine Phase 2 protocol Natural history studyNatural history study Gene expression with exercise challenge in Gene expression with exercise challenge in

CFS and GWICFS and GWI

ConclusionConclusion

There has been significant progress in our There has been significant progress in our understanding of CFS .understanding of CFS . The neuroendocrine, immune, and central The neuroendocrine, immune, and central nervous system are linked, and can’t be nervous system are linked, and can’t be considered separately. considered separately. More effective therapies, based on this More effective therapies, based on this new understanding are available, with new understanding are available, with others under study.others under study.

All CFS patients can All CFS patients can experience a better quality of experience a better quality of life with compassionate care life with compassionate care

and a multidisciplinary and a multidisciplinary approach.approach.

Thank You!Thank You!

Professional links:Professional links:

AACFS on line: AACFS on line: www.aacfs.orgCDC on line: CDC on line: www.cdc.govNIH on line: NIH on line: www.nih.gov

Advocacy organizations:Advocacy organizations:CFIDS Association of AmericaCFIDS Association of AmericaOn-line: On-line: www.cfids.org Information: info@cfids.orgAmerican Fibromyalgia Syndrome Assn. American Fibromyalgia Syndrome Assn. Online: Online: www.afsafund.orgwww.afsafund.orgNational Gulf War Resource Center online: National Gulf War Resource Center online: www.ngwrc.orgNew Zealand: Associated Myalgic Encephalopathy New Zealand: Associated Myalgic Encephalopathy Society Inc Society Inc www.anzmes.org.nz

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