Author Archives: lassesen

Unknown's avatar lassesen 1:03 am on March 29, 2015  

Honesty in informing Patients

As a statistician I like to know the actual odds so I can make a rational decision. I have encounter situations where the operation was successful and there was a 40% risk of patient death within 6 months — and that was never disclosed to the patient or the family. Personally, I would love to see printed risk statement required to be given with each drug (and compulsory reporting of any or odd reaction — typically MDs will dismiss them and not report them). – the patient reports  (giving the MD’s name) and the MD reports giving patient name.

“There is a low risk of ….”  is misinformation.. numbers are needed!

” Idiosyncratic DILI is like other adverse effects of drugs underestimated and under reported in most epidemiological studies.” [2015]

Another post from a different blogger that found studies suggesting that the risk of cancer was 12x higher with some anti-TNF drugs. (i.e. from a 0.4% risk to a 5% risk of cancer [source])

Case Study: Infliximab

Infliximab aka  Remicade, Remsima, Inflectra has been cited in the immediate prior posts and is likely a good example because it has been heavily used — including for:

So what are the risks if you use it? A PubMed search returned over 3000 articles dealing with adverse effects.

  • “Infliximab caused liver injury in 8.3% of treated patients” [2015]
  • “10~20 % of patients was Remicade-resistant.” [2014]
    • “primary-non response” 22% [2014]
    • “65.5%/69.4% for clinical response”[2014]
      • high pre-treatment hemoglobin was also a predictor of good response [2014]
      • The sensitivity and specificity in predicting response to IFX based on this gene profiling was 95% and 85%, respectively.[2014]
      • all of these studies more severe disease was associated to adverse outcomes and less favorable response to anti-TNF [2014]
  • “Chronic sinusitis.. approximately 2%”[2014]
  • infusion reactions and delayed hypersensitivity 10% [2014] 27% [2014]
    • Mild and moderate IR occurred in 17% [2014]
  • Adverse drug reaction: 41.4% [2014] 35%[2014]
  • Serious adverse events: 67.9% [2014]
  • 48.48 % of patients who received infliximab presented (ANA, ENA, anti-dsDNA) autoantibodies [2014]
  • Infections and elevation of transaminases occurred in 28.40% [2014]
    • severe infections 6%  [2014]
  • [2014]
    • Anaphylaxis:  6%
    • mild acute infusion reaction in 6%
    • hypotension in 6%
    • respiratory distress 6%
    • skin rash and eruptions 6%
    • hypertension 3%
    • tightness in the chest 3%

No statistics on, but..

  • ” an increase in weight” [2015]
  • “an association between focal mucinosis and thyroid dysfunction, as well as possible adverse effects of biological therapy with TNF-α antagonists.”[2014]
  • ” probably exert a direct, toxic effect on the bone marrow”[2014]
  • Mycobacterium chelonae bacteremia [2014]
  • Hepatitis [2013]
  • Herpes zoster[2014]
  • Aseptic meningitis [2014] – 5 cases at least reported
  • a significant association with lupus [2014]

Bottom Line

While the analysis is not complete, we may sum it up as: This drug as a 70-80% response (and for many diseases it is used for, less than 25% chance of remission) with probablity a 10% of having liver damage (regardless of outcome), 30% change of getting an infection (with the immune system depressed), 70% chance of adverse reaction. The odds of taking it and everything going “fine” is about 1 in 15. 14 in 15 people will have problems.

As a side note, I found two of the studies found success (or issues, such as developing APS) was predictable from DNA. I really doubt that more than 1% of patients prescribe this are testing for DNA, exposing patients to needless risks with little chance of success.

Addendum

After the above article, someone who was about to take  aka  Remicade, contacted me and allow access to their DNA (from 23andMe.com ).  I found a beautiful table at: http://www.nature.com/tpj/journal/v13/n4/fig_tab/tpj201253t2.html (Gene polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases (Aug 2013) R Prieto-Pérez, T Cabaleiro, E Daudén and F Abad-Santos) and both created a LiveWello.com panel from it and walked their DNA SNPS. The result was a strong prediction that they would be a non-responder (i.e. 6x more ↓ than ↑). I wonder how the MD is going to respond to “According to the latest studies (2013), my DNA says that I am going to be a non-responder to Infliximab and other anti-TNF-Alpha drugs. What do you suggest next?”

The sweet thing would be for Insurance Companies to demand DNA testing before approving the use of Remicade — it will save them money (and cut premiums too!) and save patients side-effects!

Unknown's avatar lassesen 8:26 pm on March 28, 2015  

TNF-Alpha Suppressors and Histamines

After the last post, a reader sent me some articles showing the relationship between TNF-Alpha and Histamines. Earlier on this blog, I have discussed the possibility of some CFS patients having histamine sensitivity. It turns out that reducing histamines may increase the inflammatory response :-(. Things are never simple – unfortunately.

“These results suggest that histamine may act as an autocrine regulator of cytokine release by MC and thus modulate inflammatory responses[TNF-Alpha] in allergic asthma.” [1996]

“Histamine injection into human skin engrafted on immunodeficient mice similarly caused shedding of TNFR1 and diminished TNF-mediated induction of endothelial adhesion molecules. These results both clarify relationships among TNFR1 populations and reveal a novel anti-inflammatory activity of histamine.” [2003]

Digging a bit deeper we find:

“Histamine is recognized as a neurotransmitter or neuromodulator in the brain, and it plays a major role in the pathogenic progression after cerebral ischemia. Extracellular histamine increases gradually after ischemia, and this may come from histaminergic neurons or mast cells. Histamine alleviates neuronal damage and infarct volume, and it promotes recovery of neurological function after ischemia; the H1, H2, and H3 receptors are all involved. Further studies suggest that histamine alleviates excitotoxicity, suppresses the release of glutamate and dopamine, and inhibits inflammation and glial scar formation. Histamine may also affect cerebral blood flow by targeting to vascular smooth muscle cells, and promote neurogenesis. Moreover, endogenous histamine is an essential mediator in the cerebral ischemic tolerance. Due to its multiple actions, affecting neurons, glia, vascular cells, and inflammatory cells, histamine is likely to be an important target in cerebral ischemia. But due to its low penetration of the blood-brain barrier and its wide actions in the periphery, histamine-related agents, like H3 antagonists and carnosine, show potential for cerebral ischemia therapy.” [2012] and similar in Cerebral ischemia and brain histamine[2005]

This raises an interesting prospect that histamine levels in CFS may increase in response to the brain trauma which is a typical part of CFS (as seen by SPECT scans). Checking PubMed, we find nothing about histamine levels with Chronic Fatigue Syndrome. On the general internet, there appear to be conjecture and speculation:

  • ” Dr. Cheney has speculated..”  “Tufts University researcher Theorharis Theorharides. For years Theorharides has believed that mast cell activities play a role in a number of chronic illnesses including autism, fibromyalgia, ME/CFS, interstitial cystitus, IBS, migraines, cardiovascular disorders, asthma and multiple sclerosis.” [Phoenix Rising, 2012]

What we find is hypersensitive and not over-production…

“What is more, most ME patients are also hypersensitive to biogenic amines (histamine and tyramine) and alcohol.” Prof. K. De Meirleir /  Christine Tobback

 

Hypersensitive does not mean over-production. “These results demonstrate, that increased reactivity to histamine and airway contraction to allergen induced by passive sensitization, occur through independent mechanisms and that, unlike allergen-sensitivity, histamine hypersensitivity is caused by a serum factor other than IgE.” [1998]  this is echo by another study ” In patients with low serum IgE current smoking is associated with increased bronchial responsiveness to histamine in vitro” [2001].

The bottom line is that we do not know the mechanism for hypersensitivity to histamine. 😦 We should be careful not to go down the over production of histamines route because it may result in increase (and permanent) cognitive issues.

 

Unknown's avatar lassesen 4:54 am on March 28, 2015  

Immunosuppressions, Herbs/Supplements and Probiotics.

A reader recently asked if CFS patients are  immunocompromised. If they are taking no herbs, prescriptions or supplements — then the answer is clear: No, their immune system is generally regarded to be up-regulated, the opposite of immunocompromised. The problem comes when the patient starts to take things to reduce the up-regulation. Then the problem becomes where does the patient ends up. The other side is extremely long term CFS patients that can become  immunocompromised because their immune system has become exhausted.

Looking at a TNF-Alpha Suppressor (Infliximab)

Trying to find literature of immunosuppressing herbs and probiotics is a challenge. In an earlier post, I had given some known TNF-Alpha reducing herbs (Turmeric, Alpha Lipoic Acid, Ashwagandha, Boswellia, Tulsi (Ocimum sanctum) [2014],Neem [many studies]), I am going to drill down on Infliximab, a prescription drug (and “one of the most widely used anti-tumor necrosis factor-α molecules”)

 

“According to a review of cases of infections caused by bacteria of the genus Lactobacillus from 2005 (collected by J.P. Cannot’a), 1.7% of infections have been linked directly with intensive dairy probiotic consumption by patients.” [2014]

“We describe a case ofLactobacillus bacteremia in a 17-year-old boy with ulcerative colitis managed with systemic corticosteroids and infliximab, who presented with fever to 102°F, flushing, and chills 1 week after starting Lactobacillus rhamnosus GG probiotics. Initial blood culture on day 2 of his fever was positive forLactobacillus, however, subsequent blood cultures on day 3 and 5 were negative. He was treated empirically with antibiotics for 5 days and defervesced by day 8 of his illness. 16 S rRNA sequence analysis identified the organism from the patient’s blood culture and probiotic capsule as L. rhamnosus with a 99.78% match for both the strains. This case report highlights the potential risk of Lactobacillus bacteremia in immunosuppressed patients with severe active ulcerative colitis.” Lactobacillus bacteremia associated with probiotic use in a pediatric patient with ulcerative colitis.[2013]

“Six cases of bacteraemia in hospitalized patients, 5 with a depressed immune status, were caused by lactobacilli. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of whole-cell proteins and API 50 CH carbohydrate patterns assigned the causative agents to the speciesLactobacillus rhamnosus, Lactobacillus curvatus, Lactobacillus delbrueckii subsp. lactis and Lactobacillus paracasei subsp. paracasei.” –Six cases of Lactobacillus bacteraemia: identification of organisms and antibiotic susceptibility and therapy.[2003]

” a case of meningitis due to Lactobacillus rhamnosus in a child undergoing allogeneic hematopoietic stem cell transplantation” [2010]

” we documented 2 cases of Bifidobacterium longum subspecies infantis bacteremia in newborns receiving probiotics. By comparative genomics, we confirmed that the strains isolated from each patient originated from the probiotics.” Bifidobacterium longum Bacteremia in Preterm Infants Receiving Probiotics.[2015]

“The occurrence of bacteremia with bifidobacteria after its prophylactic administration in VLBW infants” – Case series of Bifidobacterium longum bacteremia in three preterm infants on probiotic therapy. [2015]

There were over 100 articles listed on Pub Med.

 Bottom Line

The risk of bacteremia (unhealthy bacteria growth that could be potentially fatal) appears significant if the immune system is suppressed too much either by supplements, drugs or immune-system exhaustion. This is not a total surprise because many of the studies on the health benefits of probiotics were done on “near-normal” populations. There are documented cases for all of the families of bacteria that have been recommended on this site (with the exception of Mutaflor – E.Coli Nissle 1917, and the lack of studies does not imply that it is safe).

This complicated things for long term CFS patients — if you are prone to infections, gum disease, etc then your risk of problems from probiotics are likely higher. Consult with a knowledgeable medical professional (and make sure you quiz them to verify they are knowledgeable and not pompous!).

 

Unknown's avatar lassesen 1:32 am on March 12, 2015  

Chronic Fatigue Syndrome 101

A reader asked:

Out of curiosity, what tests can be taken for chronic fatigue? Because of it running in my family, and because of how exhausted I’ve become from recent events, I’m wondering if I’m in early stages of development of it as well. I’ve been lucky so far, but the right combo of triggers could certainly cause it to occur as well. I really need to find a way to get some extended time off, because I’m not gonna last long otherwise.

I will address the following key questions:

  • Are there any accepted-by-most MDs tests for Chronic Fatigue Syndrome?
  • What are the best tests available in your opinion?
  • What is the probable cause of Chronic Fatigue Syndrome?
  • How does onset happen?
  • What can be done to defend against full out CFS

Accepted Tests for CFS?

None — CFS is officially a diagnosis of having a set of symptoms with no known cause (and by inference, no test abnormality that would explain it).  While it is similar around the world, each country has a slightly different medical take on it. The unfortunate part is “A CFS diagnosis requires that the patient has been fatigued for 6 months or more and has 4 of the 8 symptoms for CFS for 6 months or more.“ – you have to be down with it for at least  6 months — by which time it may be well established and harder to prevent from becoming a permanent state.

Best Tests to Confirm CFS or indicating Increased Risk

There are three tests that I have found works as indicator of CFS status. In theory, they may be early predictors. Two require a MD to order, one does not require a MD. The best one (IMHO) does not require a MD.

  • SPECT Scan — not a MRI, but a SPECT. It will show major abnormalities in 80% of CFS patients. For myself, the radiologist read it as Alzheimer’s Disease (“Early” because I was too young). It was very similar to the results of SPECT scan done by Dr. Daniel Amen (seen on PBS) on a teenager with CFS that I am familiar with.
  • Abnormally high Vitamin 1,25 D levels (this is not the usual vitamin D lab). My readings were so high, that the lab repeated the test because they thought there must be a mistake. As I recovered, the level dropped back to normal levels. IMHO, an elevated level is a indicator of high risk. Article
  • Shifts of Microbiome — there is a very major shift with CFS. As the condition develop, the microbiome is expected to alter more and more towards the very distinct pattern seen with CFS. – This does NOT require a MD, you can buy the kit for $100 (in fact, I have a few kits on the shelf as a reserve if there is a concern).

If you are concerned — first step get the Microbiome testing done ASAP … it takes a few weeks to get the results. It is likely the most sensitive because the shift of microbiome is slow and progressive.

Probable Cause

Having been thru CFS three times and reading almost every summary on PubMed, my model of CFS meets the classic scientific criteria of the simplest model that explains all of the observations.

  • CFS (and likely many autoimmune conditions) is a shift of gut bacteria (microbiome) caused by bacteria, virus or chemicals that do not return to healthy-normal in a reasonable time.

The bacteria, virus or chemical does not directly cause CFS, it is a catalyst or trigger to the self-maintaining shift. The shifted bacteria population pumps inflammation signals and other chemicals into the body causing a host of symptoms. Gut bacteria is actually inherited and is very connected with your DNA.  Your DNA favors certain bacteria mixtures. My own experience is that some symptoms seems specific to certain species. Neem took away one group of symptoms. Ashwanganda removed other symptoms.

How does onset happens

The mechanism is some events that alters the chemical signals passed to the gut bacteria. Some species are encouraged and others are discouraged. Stress alters the chemicals flowing in the body and is often a contributing factor. A bacteria or virus can also trigger it. Recent studies suggests that the immune response to an infection alters the chemical signals so that certain chemicals are produced in greater quantities to fight the infection. The problem is that the chemical signals ends up establishing a feed back loop that results in those chemical signals not being turned off. In some cases, light can trigger an increase of these chemical signals, for example UV can trigger lupus [WebMd] and been reported to trigger other autoimmune conditions.

How to slow or reverse onset

Working from the model above and literature (plus personal experience) – the key is reduce the bad bacteria and increase the good ones.  Conceptually this is easy. In reality, it’s complex because we know so little on which ones are bad or good — or how to change them either way. My best suggestions(short list) is:

  • Probiotics:
  • Herbs and Spices (available in bulk at most East-Indian stores)
    • Neem
    • Tulsi — start drinking lots of Tulsi tea!
    • Ashwanganda
    • More items
  • Supplements:
    • Vitamin D3 — 20,000 IU/day
    • Magnesium supplements
    • B-12
  • Antibiotics
    • Only Tetracyclines are advised – they have been successfully used with CFS in the past.

I do not know how the microbiome shifts during onset, so if you suspect you may be developing CFS and get microbiome testing with abnormal results — please forward them to me.

Unknown's avatar lassesen 6:48 am on March 2, 2015  

Short and Long Term CFS and other autoimmune conditions

This last week there has been much news about CFS and markers, “Columbia University’s Mailman School of Public Health, looked at 51 proteins, also known as cytokines, released by cells involved in the immune system. Among 646 patients studied, including CFS patients and healthy controls, people who were ill for three years or less had higher protein levels than the others, the researchers found.” Wall Street Journal To me this is just confirmation of a pattern that I have seen reported in related diseases where fatigue persisted after a technical recovery. The typical onset scenario consists of two items: a probable viral infection with stress. This is not only true for CFS but for many co-morbid conditions such as:

Going through a series of studies that looked at fatigue after a severe stomach infection, I derived the table below.

Recover Period Percentage Remaining that Recover Patients remaining
6 – 12 Months ~ 50% ~ 14%
12 – 24 Months (2 yrs) ~ 50% >~7%
24 – 48 Months (4 yrs) ? 50%> ~4%
48 96 Months (8 yrs)

? 50%

 >~2%
96-192 Months (16 yrs) ? 50% ~1%

My take of the mechanism is that infection setups a gut alteration that keeps triggering production of cytokines. The alteration was an appropriate response when the infection occurred. The normal gut flora did not suppress it after the infection was take care of. Recently I had a bug, and after I recovered from it, I found that my psoriasis flared and I had post-infection signs of inflammation. My wife reminded me of a reader reporting that her psoriasis disappeared like magic from taking the probiotic Align (which she tried after I posted about it). I took it, and hit the probiotics hard for 2 weeks (almost all of them were bifidobacterium) and these post-infection symptoms faded. This is echoed in some recent studies:

Doing a PubMed search for the main cytokine reference and microbiome found over 120 articles.