California 2014: IACFS/ME Day Two: Translating Science into Clinical Care: 21 March 2014

Searcher kicks us off on Day Two, with an autoimmunity overview, then we are into immunology and cytokines, we hear from Susan Levine and the allergy-related signatures study done with Lipkin et. al, a talk about paravirus B-19, Mady Hornig from CFI with more research, John Chia who presents on enteroviruses and we close with Nancy Kimas and Dan Peterson discussing diagnosis and treatments…

We really are getting stuck into some serious science from our top researchers. Day Two (March 21, 2014), of the IACFS/ME four-day conference featured the presentation of new scientific papers.

And yet it began with a great overview of autoimmunity, obviously a popular and perhaps increasingly relevant topic for discussion at the moment, by Dr. Noel Rose, and the day closed with a review of diagnosis and treatment possibilities, delivered by Dr. Nancy Klimas, and Dr. Dan Peterson and with much audience participation.

We will be publishing more in-depth features on the papers that were presented – the ones featured below and the ones that were missed – once we have had time to properly digest all the incoming information including our recordings.

As before, the following is a collation of the live notes submitted by our intrepid patient reporter, searcher, who remains at the conference until the final day – which is actually today!

Friday, March 21st, 2014

Plenary Session: How Do We Recognize an Autoimmune Disease?

Noel R. Rose, M.D., Ph.D. Director, Center for Autoimmune Disease Research, Johns Hopkins University School of Medicine

Searcher 08.52:

“Autoimmunity – an immune response to normal antigens of the host

“Autoimmune disease – disease caused or significantly promoted by autoimmunity – self-reactive T cells/B Cells

“The Professor said when he went to medical school (60-something years ago), they were taught auto-immune disease didn’t exist. But now we know everyone has some auto-immunity. But those of us who are healthy can regulate our self-reactive antibodies

“It is a common disease. At least 80 diseases affecting every organ system

“14.7 million to 23.5 million people in the USA have an autoimmune disease:

• Among the 10 leading causes of mortality among woman under 65

• No cures for any auto-immune diseases even though many can be managed

• Heart disease (22 million), Cancer (9 million)

• Cancer and Heart Disease are decreasing, autoimmune diseases increasing

Searcher 08.56:

“Evidence for autoimmune diseases:

• Direct

• Indirect

• Circumstantial

“Direct Evidence- transfer of disease:

• Ability to transfer serum to humans or other animals

• Maternal-fetal transfer

• Reproduction in vitro (e.g. hemolytic anemia)

• Cell transfer (SCID mouse)

“T-cells are harder to tell, B-cells are easier to show a disease is caused by a specific antibody

Searcher 08.59:

“Indirect Evidence- Experimental models:

• Reproduction w/ equivalent antigen

• and more

“Circumstantial Evidence:

• Autoantibodies

• All autoimmune patients have autoantibodies, but not all with antibodies have an autoimmune disease

• Clustering

• HLA association

• Sex Bias (75% occur in women)

• Response to immunosuppression

Searcher 09.09:

“There are diseases that present like autoimmune diseases, can be treated similarly, but don’t involve uncontrolled T and B cells so are not autoimmune per se.

“Why do we think there is a genetic disposition?

Commonly:

• Family Clustering

• Multiple autoimmune diseases

• 30% twin concordance

• MHC (HLA)

• Immunoregulatory genes

“Evidence on the epigenetic involvement in Lous:

• CD4+T Cell changes

• B cell changes

“A long list that have been reputed to act with a genetic predisposition

In no particular order:

• Drugs (Lupus and MG definitely, drug causes them, so take away drug → illness goes away)

• Viruses

• Bacteria (e.g. beta hemolytic streptoccocus)

• Foods (e.g. excess iodine)

• Pollutants (e.g. mercury)

• very hard to study

• Hormones

• Stress (hard to quantitate)

“Many diseases of unknown etiology show evidence of an autoimmune response, but autoimmunity can be the result, not the cause of the disease process.

Searcher 09.12:

“Narcolepsy is a good example of an autoimmune disease:

• Well defined criteria: yes

• HLA association: yes

• Sex Bias: no

• Environmental trigger: yes (vaccines!)

• Relevant antibodies: yes

• Relevant antigens: yes

• Reproduction in animal model: no

• Response to immunosuppression: unknown

Searcher 09.24:

Q: Can reversing environmental factors remove auto-immune responses instead of using drugs to treat the disease?

A: Yes, it can. It works in rheumatic heart disease. He calls finding the environmental trigger the “low-tech approach”. Working on genes is expensive and risky.

Q: Can microorganisms create antigens that interact with auto-antibodies?

A: Yes, although not antigens but the organism itself. Called molecular mimicry. Has been easy to prove in animal models, harder in humans. One form of Guillain Barre disease works this way.   

Session: The Latest Research in Immunology

Session Chair: Nancy Klimas, M.D. Immediate Past President, IACFS/ME Professor of Medicine & Director, Nova Southeastern University Director, Miami VAMC Gulf War Illness & ME/CFS Research Program

Allergy-Related Immune Signatures and Duration of Illness in CFS

Susan Levine,1 Xiaoyu Che,2 ,2 W. Ian Lipkin,2 Nancy Klimas,3 Lucinda Bateman,4 Dan Peterson,5 Donna Felsenstein,6 Elizabeth Balbin,7,8 Aundrea Carter,9 Korinne Chu,7 Mary Ann Fletcher,3 Anthony Komaroff,6 Gail Ironson7 and Mady Hornig2

1Private practice, NY, NY; 2Columbia U Mailman School of Public Health, NY, NY; 3Nova Southeastern U, Fort-Lauderdale-Davie, FL; 4Fatigue Clinic, Salt Lake City, UT; 5Simmaron Research Inst, Incline Village, NV; 6Harvard Med School, Boston, MA; 7U of Miami, Miami, FL; 8Miami VA, Miami, FL; 9U of North Carolina, Greensboro, NC; 10Physicians for Peace, Norfolk, VA

Searcher 09.47:

“Allergy-related cytokines:

• IL4 (produced by TH2 cells)

• IL13 (Produced by NK and TH2 cells)

• IL10 and gamma interferon are protective

“Eotaxin:

• produced in asthmatics and in patients with food allergies, and in worm infections

• produced by endothelial cells, fibroblasts, and more

“Did a study that merged NIH and CFI controls.

“Split up <=3 years from >3 years:

• Compared with patients with longer duration of ME/CFS (>3 years) IL4, IL10, IL13, and IL17A are increased and eotaxin is decreased in early ME/CFS

• Allergic phenotype does not fully explain differences in cytokine levels in early vs late ME/CFS

Plasma Cytokines in ME/CFS Patients and Controls Before and After a Cardiopulmonary Exercise Test

Ludovic Giloteaux1, Betsy A. Keller2, and Maureen R. Hanson1 

1Cornell University, Dept. of Molecular Biology and Genetics, Ithaca NY, 2Ithaca College, Dept. of Exercise and Sport Sciences, Ithaca NY

Searcher 09.59:

“They have seen a difference in the gut biome from ME/CFS and controls (although that’s not the focus of this presentation.) I will ask him later if I can reveal some of those results.

“Exercise does not appear to exacerbate symptoms in most illnesses associated with fatigue or autoimmune disease.”

“Immune dysregulation = major hypothesis for our symptoms

“Did a CPET on study participants.

“Controls could repeat their VO2 max on day 2, patients went down:

• Il1-RA, IL-8, MCP-1 (CCL2) were significantly lower in CFS after one CPET

• IL1-RA went down more on day 2 for CFS, and up in controls

“Suggests immune dysregulation and potential immune suppression

“Requires more studies to see if this can explain PEM

Note: This conflicts with Stanford’s findings on the CPET test. I hope to have more info this weekend on possible explanations for these differences…

Natural Killer Cell Degranulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis 

Teilah K. Huth1,2, Ekua W. Brenu1,2, Kirsty Fuller1,2, Sharni L. Hardcastle1,2, Sam Johnston1,2, Donald R. Staines1,3, Sonya M. Marshall-Gradisnik1,2.

1National Centre for Neuroimmunology and Emerging Diseases, Griffith Health Institute, Griffith University, Queensland, Australia.

2School of Medical Science, Griffith University, Southport, Queensland, Australia.

3Gold Coast Public Health Unit, Queensland Health, Queensland, Australia.

Searcher 10.08:

“Teilah Huth is speaking…

“She is doing a similar walk-through as yesterday on how apoptosis is induced by Granzyme A, B, and perforin.

“Granzyme B reduction in ME/CFS →reduced NK cytotoxic function.

“I need to take a break but will be back soon. For now, suffice to say NK cell cytotoxic activity is reduced in ME/CFS patients compared to healthy controls. A reduction of Granzyme B appears to be key…

Session: Virology Research

Chair:  Jose Montoya, M.D. Professor of Medicine, Stanford University Medical Center

Chronic Pelvic Pain (CPP) in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is Associated with Chronic Enterovirus Infection of Ovarian Tubes

John Chia, M.D., David Wang, Rabiha El-habbal and Andrew Chia, EV Med Research, Lomita California

Searcher 11.30:

“John Chia is presenting…

Searcher 11.45:

Santa Rasa is presenting…

Pathogenesis of chronic enterovirus infection in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) –in vitro and in vivo studies of infected stomach tissues

John Chia, M.D., Andrew Chia, David Wang, Rabiha El-Habbal. EV Med Research. Lomita, CA

Searcher 11.56:

“Dr Chia is speaking again, this time on EV in ME/CFS. I will write more about his presentation later…

“It is primarily about EV in stomach biopsies of patients and controls, and mice tests. He is going through evidence of the link between EV and ME/CFS and is showing various slides that show evidence of infection.

“Dr Chia’s conclusion: “EV dsRNA plays a central role in the pathogenesis of chronic EV infection and ME/CFS, and should be targeted for antiviral therapy.”

The Chronic Fatigue Initiative (CFI)- Findings from the CFI Cohort Study and Pathogen Discovery & Pathogenesis Project

Non-CME symposium sponsored by the Chronic Fatigue Initiative

Searcher 11.57:

“Next up: CFI is going to announce some results. One of their members, Stella Lee, told me they are very excited about sharing their findings with the Phoenix Rising community, so I think I should have a lot to share…

Searcher 12.30:

“CFI was established in June 2010. They are looking at Epidemiology and mechanism of illness:

• Virology- search for viruses and bacteria

• Mitochondrial Dysfunction- defective energy production

• Immune Dysregulation- abnormalities in immune response

“The last two were based on their initial findings.

Searcher 12.36:

“Began virology study in Oct 2011

“Initial tests showed no evidence of microbrial agents in plasma, and haven’t yet studied white blood cells:

• Elevated level of immune molecules in CFS patients ill for <3 years vs >3 years

“Klimas:

“They recruited 200 patients and controls in a year, usually that takes years.

“What’s key is that they are recruiting patients via true experts: Bateman, Peterson, Levine, Klimas, and Felsenstein…

Searcher 12.37:

“Biorepository includes:

• serum,

• plasma,

• RNA extraction

• urine,

• tears,

• saliva,

• and rectal swabs

“It’s a well characterized cohort.

Searcher 12.41:

“Data overview: Estimated 4000+ variables

“They purposely oversampled for acute samples because they were looking for pathogens.

“Made sure at least 25% of the cohort was <3 years ill and also at least 25% were male.

“These are a severely ill group of patients. The empiric data really reinforced the Canadian consensus definition the way the symptoms clustered:

• 99%+ had PEM, because experts won’t generally diagnose ME/CFS on someone without PEM

“The cognitive dysfunction was as big a complaint as the fatigue complaints.

Searcher 12.43:

“The more acute the onset, the more inflammatory markers.

“Shorter duration had more autonomic dysfunction.

“Women were more severe on average.

Searcher 12.55:

“Talk about subgroups from the statistical analysis (I will write this up as it requires more clarification on the statistic analysis and what the factors mean):

“Factors:

Factors 1-3

1. Fatigue

2. Neuroinflammatory

3. Gastrointestinal- 75% of the patients have thse symptoms

Factors 4-6:

4. Fibromyalgia

5. POTS (more common in younger patients)

6. Hyperlidemia

Factors 7-9:

7. Hypertensive

8. Fever

9. NMH

Additional Factors:

10. Weight Change

11. Age/total cholesterol

12. Stressed: anxiety .745 and depressed .661 (she notes that this is very low in the factor list and likely to be a result, not cause of the illness)

13. Unsteady/dizzy

14. Past Infection

15. Asthma

16. abnormal potassium

17. No evidence of past infection

18. Hypothyroid

“Next Steps:

• Conduct latent class analysis on factors

• “In addition to key indicators we will bringing other variables for a fuller picture of each profile (correlations with factor)”:

• For example, cognitive dysfunction doesn’t show up but is correlated with two different factors.

Searcher 12.57:

“Two study aims are to identify factors that contribute to recovery and relapse and identify successful treatments with long-term benefits.

Searcher 13.00:

“Majority of the deceased samples from Nevada site (59.3%) – an artifact since these samples go back the furthest.

“Causes of death in sample:

• Cancer (37.8%) (4x the background rate)

• Health Disease (18.9%)

• Suicide (18.9%)

Searcher 13.03:

“On average the patients were middle-aged, white, women, born in the US, and hihgly educated.

“Mean duration since CFS diagnosis: 15.4+6.2 years

“Demographics varied a lot per site. One variable was that the Nevada patients were older on average (again because of the history) and “Subjects in Utah sample had more children than average”

“PEM severity and sudden onset were highly correlated

Searcher 13.06:

“Many comorbid and new diagnoses. Most common is fibromyalgia (61%).

“30.4% reported at least one remission! Median duration of remission was 52 weeks.

“Those with most severe initial symptoms were more likely to report improvement in health status over time.

Searcher 13.18:

“Mady Hornig is looking for risk factors and potential biological triggers.

“They found 2 cases with HHV6-B and 1 with parvovirus B19 (control) in 200+ samples which conflicts with earlier presentation on parvovirus

Searcher 13.23:

“Mady Hornig’s slides:

“Proinflammatory cytokines are increased in the plasma in early phase ME/CFS”

“Plasma TH2/counter-regulatory cytokines are also increased in early phase ME/CFS”

• IFNy and IL12p40 are markedly upregulated in early phase ME/CFS

• Interferon gamma is quite significant with a p value of .001.

“Increased IL17 [pro-inflammatory cytokine] and decreased GRO-alpha [a chemokine] are linked to cognitive impairment in ME/CFS”

Searcher 13.28:

“This is all really fantastic but I need to take a bit of a break. As Simon’s recent article stated “Cognitive testing causes mental exhaustion lasting days.” But, more to come soon and CFI is eager to share with Phoenix Rising.”

Searcher 13.34:

“Conveniently that was the end. CFI plan a lot of future studies (including the microbiome: [note: see crowdfunding campaign launched March, 23, 2014 – more news to follow next week!) and want to extensively use the samples…

[box_left_wide]Phoenix Rising and the California Conferences 2014:

You can review all our previous coverage of these conferences, from Stanford through to IACFS/ME in San Francisco, in date order below:

Stanford Symposium, Wednesday, March, 19, 2014: summary article (with added content): here or the original live blog: here.

IACFS/ME Conference, Thursday, March, 20, 2014: summary article (with added content): here or the original live blog: here.

IACFS/ME Conference, Friday, March, 21, 2014: summary article (with added content): original live blog: here.

And don’t forget to watch our feed on TWITTER for all of today’s (and the previous day’s) action.[/box_left_wide]

Session: Treatment Studies

Chair: Daniel Peterson, M.D.

Treatment of Orthostatic Intolerance (OI) Using Midodrine in Patients with Chronic Fatigue Syndrome (CFS); and Assessment Using Hours of Vertical Activity (HVA)

Nicole Baldwin

St. Olaf College, Northfield, MN, and *Lucinda Bateman MD, Fatigue Consultation Clinic, Salt Lake City, UT. 

Intervention Effect of Baduanjin Exercise on the Fatigue State in People with Fatigue-predominant Sub-health – A Cohort Study

Wang Tian-fang1  Liao Yan1, Zhang Cong1, Zhang Yu1, Xue Xiao-lin1, Dai Jin-gang2, Lin Yin1

1 School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing 100029; 2 China Academy of Chinese Medical Sciences)

Effect of Isometric Yoga on Chronic Fatigue Syndrome: A Randomized Controlled Trial

Takakazu Oka, Tokunari Tanahashi, Takeharu Chijiwa, Nobuyuki Sudo

Graduate School of Medical Sciences, Kyushu University

Home-Based Self-Management for Severe CFS/ME:  A Randomized Trial

Fred Friedberg, Ph.D.

Session: Diagnosing CFS/ME; Difficult Clinical Cases

Session Chair: Nancy Klimas, M.D. Immediate Past President, IACFS/ME

Charles Lapp, M.D.

Lucinda Bateman, M.D.

Rosamund Vallings, MNZM, MB BS

Daniel Peterson, M.D.

Searcher 15.59:

“There are a lot of poster presentations here for once or twice a day there is some time for attendees to look at the presentations and talk to the authors. We just ended one of those periods and started:

Diagnosing and treating patients

“Some of the top experts are discussing diagnosing ME/CFS and treating difficult cases. Drs. Klimas, Lapp, Bateman, Vallings, and Peterson are on the panel; each of the doctors are presenting complex cases in detail.

“They are interacting a lot with the doctors in the audience to determine how they would diagnose patients – I would estimate 90% of the audience raised their hands when they were asked if they had prescription privileges.

“Dr Lerner, Dr Chia, Dr Cheney(!), and many others are participating in the audience.

“Dr Batemans and Dr Klimas mentioned they sometimes see EBV IgM positively persist over time, so it’s not only for acute cases. If Dr Peterson saw a patient with persistent positive EBV IgM he would do a PCR test.

“One doctor has had luck with immunoglobulin replacement-level treatment. She has had luck with insurance companies and Medicare once you prove there is a deficiency. Other doctors have had trouble getting coverage once they get on an insurance black-list.

Searcher 16.08:

“Dr Lapp is treating a patient who has POTS that appears to be caused by MCAD. He used H1 and H2 receptor antagonists (“Zyrtec” and “Zantac”) and topical beta blockers after the standard POTS treatments failed.

“He wanted to note that not all POTS is neuropathic/high flow or hyperadregenic/low flow, you should look at Mast Cell Activation Disorder (MCAD). He has seen some patients get better just with OI treatments even though they have many CFS symptoms. This patient feels she is 90% better.

“Dr Klimas said MCAS/MCAD is more common than people realize. You need to catch the blood in the faint/acute change. She mentioned that ketotifen is only available in Canada and can be helpful. H1 and H2 blockers are synergistic.

Searcher 16.18:

“One doctor said the majority of her male patients have low testosterone. Too much can cause weight gain, anger, and other symptoms so patients and doctors have to be careful to find a balance.

Searcher 16.57:

• Dr Peterson: “One thing I do is to try to keep [patients] out of urgent care or an emergency room. They always come out worse; I try to get them in to see me as soon as possible instead.”

• Another doctor concurred and said going into the ER is often a trauma for patients.

• Another well-known practioner said she tells patients not to mention fibromyalgia or chronic fatigue syndrome when they go into the ER because they could be treated so poorly.

• Another says she tries to go in to meet the ER doctors to support her patients.

[box_right_wide]Searcher 17.15:

“Quick opinion piece:

“It has been great to watch many of the top ME/CFS clinicians interacting in this session. Many have different perspectives on etiology and treatment, but they generally seem really open to others’ perspective. Whatever perspective the specialists look at CFS from–infectious disease, immunology, hormones, mitochondria/methylation, or another focus – they want to understand the various treatment options. I wish more patients had access to the specialists since they are light-years ahead of general doctors. Obviously that will require more doctors without a psychiatric bias to take a risk and enter this field, and for insurance and countries with national health care to cover more so everyone can afford to see them.”[/box_right_wide]

Searcher 17.26:

Conclusion:

Klimas asked the audience and panel what top supplements they use:

“Some answers include:

• Coenzyme-Q (worked in a study in gulf war, only taken in the morning since it can impact sleep)

• Methyl-B12 shots (several said it helps patients a lot)

• Some use hydroxy-B12 for patients with amalgams or for those who can’t tolerate methyl-b12. Dr Cheney prefers hydroxy-B12 because he says it works as a detoxifying agent.

• Magnesium — many prefer sublingual, dermal, or injectables since patients have trouble keeping it

• Carnitine

• “make sure people eat” since many patients have to wait for others to make meals

• Inosine or immunovir (Klimas goes for 5 days a week so uric acid doesn’t go too high; it sounded like Cheney didn’t take breaks but I am not certain)

• Most support Vitamin D

• Omega 3

• NAC

• Glutathione (both oral and injectable)

Searcher 17.27:

“End of the day. Thanks for the support all! I will try to get some more answers out of researchers that our milling around.”

Searcher 18.14:

“I want to apologize in advance, but I think there is a decent chance I will miss tomorrow morning since I need to recover a bit in bed. There are some interesting discussions going on first thing in the morning and hopefully one of the other patients will get there early to take notes, and I will get those compiled whenever possible.”

The End of Day 2 of the IACFS/ME Conference from San Francisco.