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Monday, November 24, 2008

Towards a unified perspective

As confusing as Lyme disease is for patients; it is more confusing for me. As I became indoctrinated into the world of "Lyme literacy" it became easy to say/think that all the text books(and doctors) are wrong- Lyme is the cause of all the ill's of the world- why can't you blind doctors see that?. If one finds himself in such a manic state he either needs to take a Xanax, or slow down- take a deep breath, and look again. Are all the rheumatologists and neurologists wrong? Have I lost my mind. Can I be so pompous as to believe that only folks who think like me are right and that everyone else is wrong? (Lets leave infectious disease physicians out for the time being.) There are a "zillion" articles and texts which validate the paradigms they work under. Perhaps a more humble approach is needed. Perhaps everyone is a little right (and a little wrong). The more you are a hammer, the more everything around you takes on characteristics of nails.

At the core is the concept of inflammation. Inflammation is primarily an immunological response. The inflammatory process always begins when a foreign protein is introduced to the body. This is called an antigen. The sentries of the immune system, such as macrophages, sniff out the protein that doesn't belong. This leads to a complex process in which the immune system becomes activated. Without this process we could not survive. Not only does the immune system remove germs: its myriad functions include responding to allergens (proteins to which we have allergic responses) and even removing mutated cells, which if left unchecked could develop into cancer. Without this system we would be doomed. The system cannot be too efficient, it has to be quite selective. It has to recognize normal tissues and leave them undisturbed- we know this is not always the case; it even has to recognize "friendly" bacteria and other microbes, such as those that live in our gut. It has to be an awfully "smart" system.

If the immune system operates normally, things are kept in a state of equilibrium. If it is over activated we can become sick. Many checks and balances are in place- there is a delicate balance required for "normal" health. Sometimes, something very small- like an infection, can disturb the natural order and make us ill. I will confine my remarks to the imbalances caused by small micro-organisms known as bacteria.

When undesirable germs (we are speaking of bacteria here) enter the body the macrophages "gobble" them up. They are processed through the lens of histocompatibility complexes and presented to cells called helper T cell lymphocytes. These T cells somehow "read" the proteins on the surface of these antigens and transmit the information to B cell lymphocytes. These B cells quickly get to work, becoming factory which makes antibodies- special proteins called immunoglobulins, which are able to attach to germs and mark them for destruction. A vigorous response may be needed with alarm bells rung. The B cells can morph into monocytes which are even better antibody (immunoglobulin) factories. Quickly the macrophages and other immune cells crank out other immune system proteins called cytokines, which mobilize the natural immune processes. The cytokines are messenger proteins known as hormones. One can visualize the cytokines as traffic cops frantically directing speeding traffic coming from all directions-performed with pinpoint precision. While this process occurs at "light speed," A complex symphony of players melds into one. The complement system is activated. Special proteins are produced through a complex cascade which also directly attack the offending bacteria. Special proteins are released in very specific ways. Some of these are called: chemokines, bradykin, interleukins, tumor necrosis factor and interferons ( the last three are considered cytokines) and many other molecules. At this time more than 100 distinct cytokines have been discovered. So call "acute phase reactants" are released. These include C-reactive protein of which many of us are familiar. Then granulocytes move in. These are the big guns which gobble up and digest those doomed germs or antigens which have been marked for destruction. In the process granuals are released shedding other inflammatory proteins such as histamine, prostaglandins and leukotriones. The inflammatory process affects many tissues. For example, it affects the lining of the blood vessels, the endothelium, leading to the leaking of fluids (serum) into the surrounding areas. Nitrous oxide is released which promotes an inflammatory response. There is an increase in the clotting pathways of blood proteins. Of course the story is much more complex than this.

Since perhaps millions of pages have been written about the above topic, keep in mind that this represents a vast oversimplification, and that the author is a simple country doctor- trying hard to make sense of a disease many of my colleagues insist does not exist.

How are all these proteins made? They are made in cellular structures called ribosomes of which you have heard much. The ribosomes in our cells, (eucariotic) are quite different from those in bacteria, (procariotic). Antibiotics know which ones to attack. Protein synthesis in each case is directed by RNA, which comes directly from DNA, the blueprint for everything that transpires in our bodies.

Like everything in the universe: the immune system if not infallible. Sometimes mistakes are made.

Let us turn our attention to what rheumatologist know. They actually know quite a lot. They know that variations in histocompatibility complexes, genetically mediated, are associated with various illnesses. These genes have names like: DR and DQ. Small mutations in these genes are associated with differing autoimmune diseases.
Numerous auto-antibodies have been discovered. Theses include rheumatoid factor, ANA, Anti-Sm, Anti-RPN, Anti-Ro, Anti-La and numerous others. These antibodies have special relevance with regard to well characterized rheumatological disorders. Autoimmune disorders are defined based on various clinical and laboratory criteria. There is a great deal of overlap. Symptoms from column A and antibodies from column B are combined in various complex ways to make the diagnosis. Lupus, rheumatoid arthritis and scleroderma constitue only a small fraction of these varied autoimmune disorders. Sometimes these disorders are broken down into those which respond to steroids and those which do not. Rheumatologists and rheumatological literature prominently claims that these disorders are of unknown cause.
Now let us take a look at what rheumatologists have forgotten.

Rheumatic fever is a autoimmune rheumatolgical disorder. It occurs after a Streptoccal infection, usually in the throat (pharyx). It occurs some time after the initial infection. It is an autoimmune disorder because it affects organs which are distant from the site of infection. Typically in affects the skin, the joints, the heart, the kidneys and the brain. Although early treatment generally prevents its occurrence, it can occur despite the lack of signs of ongoing Strep infection (the infections may be considered occult) Recurrent or persistent infection is associated with a relapse of the disease. In some cases indefinite use of antibiotics is recommended to prevent recurrence of the disease.

Another disease associated with Strep infection goes by the name PANDAS. This is an autoimmune disorder affecting the brains of children. It is associated with occult Strep infection. The sufferers have psychiatric symptoms including obsessive compulsive disorder and tics(not ticks). Patients can frequently be taken off psychotropic medication and successfully treated with antibiotics.

Many disorders diagnosed by rheumatologists are called reactive. They follow an infection. The paradigm is that the infection has resolved but that an autoimmune disorder, triggered by the infection remains. Rheumatologic sources point to evidence that continued antibiotic therapy does not influence the outcome. What have they forgotten?

Continued antibiotic therapy does influence the course of rheumatic fever and PANDAS.
Let us consider a little microbiology. Strep is an easy germ to kill. It has no known ability to develop resistance to antibiotics; it replicates quickly and it does not form spores.

How about rheumatoid arthritis? Studies have demonstrated M. fermantans in the synovial fluid of patients with RA. This has been confirmed by 16S rDNA. Viable organisms have also been demonstrated in the synovial tissues. Treatment with antibiotics hasn't helped- or has it. Numerous studies show that Doxycyline and Minocyline are in fact effective drugs for RA. I have observed that rheumatologists tend to avoid these drugs preferring agents which are much more toxic in my opinion.
And unlike the case with Strep- Mycoplasmas are very difficult to eradicate.

Inflammation is bad- so we are constantly told. It in the media all the time. C-reactive protein is a stronger indicator of heart attack risk than cholesterol measurements. Chlamydia pneumonia and other bacteria have been shown to be present in atherosclerotic plaques inside the walls of arteries which can rupture and lead to heart attack and stroke. Some studies have been with drugs like Doxycyline. Is this going to work? Stratton has shown that this organism is very resistant to eradication and that complex multi-drug regimens are needed.

Let us go full circle. Why are people sick who have contracted Lyme disease? We know the causative germ is invasive and nearly impossible to eradicate. We know patients have co-infections which aggravate the disease. Still, some folks who are infected remain relatively unaffected. They are mildly ill or altogether well. The immune response must be a key part of this mystery. For example, the most commonly measured autoimmune antibody is the rheumatoid factor. This is an IgM antibody directed against IgG antibodies. IgM antibodies represent the acute response to an infection. They are made quickly but are not all that effective. In general, they should be supplanted by the more effective, second phase IgG antibodies. Some physicians are troubled by the fact that so called chronic Lyme patients primarily have an IgM response, not an IgG response. If the disease were chronic they reason, one should see IgG responses in the blood. (Actually it turns out that patients who have a robust IgG response to Lyme infection are healthier and respond better to treatment). Is this logical? IgG responses indicate a full immunological/antibody response. These responses are seen in patients who are no longer ill but are in fact recovering from an infectious disease. These are smaller antibodies which bind better to the target sites. So this is not the response one would expect to see in patients with chronic Lyme disease- if such an entity does indeed exist? If the infection is active one would expect IgM antibodies- there is active inflammation. Is this not analagous to the phenomenon which observed with rheumatoid arthritis? Remember, the rheumatoid factor is an IgM antibody. The sickest Lyme patients in fact never have a good IgG response. For some reason the sickest patients are unable to mount a protective immune response. Such patients may suffer and endless cycle of infection and inflammation which becomes very difficult to treat.

And what do we see in chronic Lyme patients? They have an increased incidence of autoimmune antibodies. They have elevated CRP and sed rates. They have elevated complement levels including C3a, C3b and C4a. They have increased circulating immune complexes. They have increased levels of cytokines. They experience inflammatory hematologic abnormalities: the white blood cell count is low. An increased, lymphocyte response may be present, platelet levels may be decreased and abnormalities of blood coagulation may be seen. Alterations in vitamin B12, folic acid and vitamin D may correspond to an active inflammatory process.

Is it post Lyme syndrome? Are the germs gone and we are simply seeing an autoimmune disorder as suggested by the IDSA? This begs the question: What are autoimmune disorders? We have seen evidence that they are in fact promoted by ongoing infection. Autoimmune disorders occur because auto-antibodies are produced. Antibodies are produced when macrophages are activated by foreign proteins. For some yet unexplained reason, sometimes auto-antibodies are produced rather than normal antibodies which would target the offending antigen(protein). The distaff argument then becomes, auto-antibodies are produced because memory cells are activated. When B cells and plasma cells "learn" how to make a particular antibody memory cells are created. These cells "remember" how to make the antibodies and quickly kick into gear when the offending antibody is present. This is why vaccines work. However, there is no reason to believe that these memory cells make antibodies spontaneously. It makes sense that the process is triggered by new antigen exposure. This would explain for example, why rheumatic fever flares up with new exposure to Streptococcal bacteria. The immune system is activated by continued exposure to antigen. In Lyme disease, this dovetails with the observation that IgM antibodies predominate. The immune pump is constantly being primed. I would suggest that a theory of autoimmune disease should include the notion of repeated antigenic stimulation and therefore persistent infection. There is good experimental evidence that patients with "autoimmune" disease, such as rheumatoid arthritis, do in fact show persistent infection.

What do rheumatologist do with their patients? They use steroids. These medications are immunosuppressive. They damp down the entire immune cascade. They reduce activity of macrophages, lymphocytes, granulocytes and cytokines. Patients certainly feel better. The underlying infections may be unchecked with an undesirable effect.
Patients with Lyme who are pregnant feel better. Pregnancy is associated with an immunsuppressed state. After delivery the patients generally have severe relapses as the immune system returns to baseline. Rheumatologists typically prescribe a wide array of immune suppressing drugs. These medications have serious side effects such as life threatening infections and cancers. Concerns regarding the overuse of antibiotics seem less significant in this context.

Are antibiotics bad? Readers of my blog seem very preoccupied with this question.
Antibiotics are neither good nor bad. They are very useful tools essential to the treatment of disorders such as chronic Lyme disease.
A second question is: are alternative and complementary therapies bad? I am concerned about this issue. Many patients who use such therapies claim they help; however, the same patients speak about chronic suffering- the implication: Lyme disease cannot be cured. I am concerned that a focus on these therapies can deprive patients of more effective therapies which offer improvement and a high likelihood of long term remission.

Severe Lyme disease is very bad and must be treated with the most effective tools at our disposal.

Are there ways to make the immune system work better? This question is oft raised. At this time there are no great answers. But perhaps there may be some clues. The relaxation response improves immune function. Exercise improves immune function. A positive mental attitude improves immune function. Correction of sleep disturbances, especially sleep apnea improves immune function. Not being obese improves immune function. Certain diets may improve immune function. Gluten sensitivity and food allergies may stress the immune system and compound the effects of Lyme disease. It is possible that a stressed immune system may experience a tipping point. Removing some of those stressors may allow for quicker overall healing.

What about vitamins and supplements? I am not convinced, sorry. Vitamin A deficiency can cause a decrement in immune responses- but do not take this- it is fat soluble and can be toxic. What about vitamin D. Lately I have given this some thought. In the past I have espoused the belief that vitamin D dysregulation is a pathogen induced process which increases the survival of intracellular pathogens. This theory came from my reading of Marshall's theories. Perhaps this is completely wrong. Another possibility is that vitamin D levels are raised not by the bacteria, but by the host. Perhaps this is an adaptive response to damp down an exuberant immune response which the host senses is causing harm to our bodies. I will stop criticizing doctors who give LD patients D. For now I don't know, and I will leave this topic alone.

All of these ramblings- and not once have I mentioned the helper cell Th1 versus Th2 controversy. This issue has received too much press. The same can be said for the natural killer T cell issue. These immune cells are probably down regulated by a cytokine response. But I have not found the CD57 marker to offer clinical benefit.

Let me finally return to the title of this entry: Towards a unified perspective.
Rheumatologists are right in their characterization of autoimmune disorders. They claim that the cause of such disorders remains unknown. I am simply suggesting that one can take the process back a notch, and posit that the precipitating causes are infection(s), of which Borrelia burdorferi- the Lyme bacteria may be one. And to the neurologists who asked me: "Are you trying to tell me the patient has Lyme disease, not MS." My response would be the same. MS is a well characterized autoimmune disorder associated with destruction of the protective myelin sheath of neurons. You say it is of unknown cause. I am simply offering a theory which provides an explanation of the underlying cause. Such an explanation may also offer therapeutic considerations. So you see- we can all agree, can't we?
As I said early on- I am omitting infectious disease specialists for the time being.


AllClearInVirginia said...

Why do ID doctors mistreat people with Lyme Disease?

I think it SO funny that one offered to treat me but that Lyme didn't exist in my state and there's no such thing as chronic lyme and that he would certainly NOT prescribe any antibiotics, as those drugs don't help.

My reply was if he has a better therapy, one that is also based on the stringent research required by the CDC, I'd LOVE to try it. And so would a lot of other people.

He got out of altogther when I suggested it be researched further.

Michele said...

For Lyme patients, what symptoms should we look for to indicate the heart muscle is infected?

Lyme report: Montgomery County, MD said...

Lyme classically affects the specialized tissues in the heart which conduct electrical impulses. These changes can be asymptomatic and only show up on an EKG. In severe cases it can cause heart block with serious disturbances of cardiac rhythm. Sometimes and emergency pacemaker is required. this has happened to several of my patients. It may also cause pericarditis, a painful condition of inflammation of the lining around the heart. A life threatening complication can occur if the fluid constricts the heart. One of my patients required emergency surgery for this condition. Lyme has also been associated with carditis- a direct infection or inflammation of the heart muscle, and can sometimes cause heart failure. Most commonly, Lyme is associated with non specific palpitations or mild irregularities of the heart rhythm. These minor symptoms are usually without significant consequences and improve with treatment.

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