The latest edition of the Dutch Journal of Medical Microbiology primarily focuses on autoimmunity, including an article by the Lyme Borreliosis Centre of the Academic Medical Centre in Amsterdam on the role of our immune system in Lyme disease (1). Fortunately, this article is somewhat more constructive than previous Lyme disease articles coming from this quarter. Let’s hope this means that the AMC and NVMM are willing to follow a new route to the planned Lyme Centre of Expertise. The article offers starting points for a discussion on treatment of Lyme disease, a discussion that is now often limited to the question whether or not more antibiotics are needed (yes or yes, according to some patients and their representatives).
Made ill by defence
The article’s central stand is that Lyme disease symptoms are primarily caused by the immune response to the Borrelia bacterium and not by toxic effects of the bacterium itself. I concur with this premise, although there are some disputable aspects. It is not a popular message among patients: they often see Borrelia as a devilish little monster that causes death and destruction and must be destroyed at any price, if necessary with an overdose of antibiotics or other heavy poisons. Some would even prefer a continuous intake of preventive antibiotics (‘pre-exposure prophylaxis’) just in case they might again encounter a tick ;-( I believe that this attitude is an emotional reaction that might make sense psychologically but is not based on sound facts or arguments.
The question how dangerous these Borrelias really are, is important when dealing with the disease and in particular when treating chronic Lyme. Our immune system is important because it protects us against infections and other diseases. But on the other hand, it has become apparent that many Lyme symptoms are caused by the violent reaction of that same immune system to the presence of Borrelia (or remnants of dead Borrelias) and not by the bacterium itself. To what extent these reactions occur depends, among other things, on the Borrelia species and the patient’s genetic factors and is therefore not a constant. Apart from this ‘overreaction’ of our immune system, Borrelia also employs targeted manipulation of the immune system, which might lead to more favourable circumstances for tick bite co-infections or might cause other pre-existing infections to flare up again.
The authors state that Borrelia – unlike many other pathogenic bacteria – has no genes that encode toxins that can cause complaints. Recent research (3), however, provides strong evidence that many Borrelia species can produce so-called SLS toxins, which may be harmful to the patient. You might be familiar with SLS toxins from various pathogenic bacteria from the Streptococcus, Clostridium and Listeria families. It is not yet completely clear why SLS toxins are toxic to their host, but perhaps Borrelia is less dangerous than might appear at first sight. Thus far, these Borrelia toxins have only been demonstrated indirectly, based on DNA sequences on the lp28 plasmid, so it is not certain whether, and if so when, they are produced in the host (perhaps only if you drastically attack the Borrelias with antibiotics?). Research in this area is problematic, because there is no 1:1 correlation between DNA sequencing and produced SLS proteins. Nearly 20 years ago, Donta already hypothesized a Bbtox1 neurotoxin (related to the dangerous Botulinus toxin) based on DNA sequences of one Borrelia species (4). Nothing has been heard since which could indicate a false alarm, although you cannot rule out the possibility that such research remains undisclosed because of military importance. Hopefully, more light will be thrown on this issue in the near future. For the conspiracy thinkers out there: DNA sequencing analysis indicates that the SLS toxins have been present in Borrelia for a long time and therefore have not been added on Plum Island.
The authors acknowledge (progressive insight!) that even after ‘recommended antibiotic treatment’ a substantial proportion of patients continues to experience chronic and sometimes disabling symptoms, known as the so-called “Post-treatment Lyme Disease Syndrome”. They discuss a number of possible explanations for such ongoing complaints. Among patients and ILADS physicians, all the attention goes out to the persistence explanation, i.e. the Borrelias survive the AB treatment. The authors argue that the PLEASE study (just as previous studies) has shown that additional antibiotics are not helpful against ongoing complaints, which makes a persistent infection implausible. While I partially agree with the first part of that statement, I certainly do not concur with the second part. The past few years have clearly shown that a small portion of the Borrelias – the so-called persister cells – exhibit antibiotic tolerance and can survive antibiotic treatment (and thus also an additional AB treatment like in the PLEASE study). This means that the disease can recur after ‘adequate’ antibiotics therapy. A persistent infection does not necessarily imply persisting symptoms, but still …
The importance of improved testing
A number of recent studies with (highly reliable) PCR-sequencing tests have shown us that for perhaps 10% of the patients, Borrelia DNA is still detectable in their blood long after the antibiotic treatment, which is evidence for a persistent infection. Once the sensitivity of these tests has further improved, they might show that persistence of Borrelia is a rather common phenomenon. Patients often deduce from this that even stronger antibiotic treatments, or special “persister-killers”, are required. But if antibiotics are not proven effective, more of the same does not seem the most logical approach to me (compare it to the QE policy of central banks) and the few resources that appear to be effective against Borrelia persister cells (in in-vitro studies) are dangerous or have been inadequately investigated for safety. Since it remains uncertain whether the bacterium itself is the problem, it does not seem wise to use such heavy artillery.
It is unlikely that there is one single explanation for the persistent symptoms in chronic Lyme and that could be why research into better treatment is not making any headway. Research patients most likely exhibit a mix of all sorts of problems, which means that the potential effects of an effective treatment for some may be drowned out in the noise. Nearly all Lyme diagnostics are based on indirect tests, so you do not know whether there is an active Borrelia infection. If you do not know what you are treating, it is difficult to identify why a treatment is effective or not. Unfortunately, decent direct Lyme tests are still blocked by the medical sector, which means that new research, such as the new Lyme Prospect study, makes little sense; hopefully there will be ‘progressive insights’ in that area as well.
Among the explanations for on-going symptoms after antibiotic treatment that the authors briefly touch on, such as ‘residual damage’, ‘post-infectious process’ and untreated coinfections, the NTMM article discusses ‘autoimmunity’: the body creating antibodies against the Borrelia bacterium that would also accidentally attack the body’s own cells and tissues, so that complaints persist after the bacterium has disappeared. While this may play a role in some individual cases, despite many studies it has never been plausibly demonstrated that this mechanism plays an important role in Lyme. Nonetheless, this theory is still alive and kicking, probably because it was introduced by Alan Steere, one of the most influential Lyme researchers in the US who regrettably expresses lots of incorrect facts and theories about Lyme. Based on this theory, corticosteroid treatment is sometimes recommended when a patient experiences persistent Lyme disease symptoms: a dangerous approach if you are not 100% sure that the Borrelia infection has actually disappeared.
The pathogenesis of Lyme disease
Let’s return to our central theme: to what extent are the symptoms of Lyme disease caused by our immune system? If you look around in nature, it is striking that hardly any animals seem to suffer from a Borrelia infection: this is restricted to people, some (farm) animals such as dogs and horses and laboratory and zoo animals. ‘Unnatural circumstances’ seem to be a common factor. In keeping with this, I feel the article fails to address the role of our immune system in the pathogenesis of Lyme disease in the historical sense. Ticks and Borrelias have existed for at least 60 million years and people have always been in contact with them – especially if you go back a few generations. Yet there are no indications that Lyme disease occurred on any significant scale more than 50-100 years ago. This is not unique to Lyme disease but applies to many so-called autoimmune diseases and allergies, although they differ in the moment in time that these diseases started advancing. It is clear, however, that in one way or another, they are often related to the Western lifestyle, they are ‘diseases of civilization’. So is it ‘normal’ to become seriously ill from a Borrelia infection?
It is all because of the deer!
Professors in the IDSA/CBO circle – and unfortunately also many patients – have attributed the sharp increase in Lyme disease in recent decades to the growth in the number of deer (or roe deer, and the number of ticks and Borrelias), increasing contact of unobservant recreationists with ‘real nature’ (really quite dangerous!!) and sometimes even the supposedly decreased use of pesticides (yes, really …). But anyone with a logical mind can understand that this statement is precarious: a sharp increase of deer in human environments is a phenomenon that might happen in many American suburbs, through a unique combination of circumstances in the US, but correlation does not equal causation. Lyme has also seen a sharp increase – particularly in Europe – in areas with few or no deer or similar animals or where the number of deer is dramatically lower than it was roughly 50 or 100 years ago. Several international studies have shown that more and more, people contract Lyme in their immediate surroundings and not in ‘real’ nature. Especially in the Netherlands, only a very limited number of people regularly have deer strolling through the yard. Thus, it would have made more sense, for example, to blame mice or dogs for the Lyme epidemic. Sometimes, it turns out that the presence of deer or somewhat similar grazers even reduces the risk of Lyme for humans. And if we go back a few thousand years, Europe’s forests were overflowing with deer (and ticks, the Romans already had proverbs complaining about the number of ticks in these parts), people rambled through nature and pesticides were never used. Did every Germanic person suffer from chronic Lyme? I do not think so …
Infections and autoimmunity
If you do not fully understand where the current Lyme epidemic originates, how can you really hope to do something about it? The introduction to the special NTMM issue (2) hints at a number of matters concerning infections and (auto) immunity that might also be important in Lyme. The fact that these matters are not addressed in the AMC article is a missed opportunity. Over the course of evolution, our immune system has developed in conjunction with our environment and it is obvious that the dramatic changes in the environment in recent history can have major consequences for the performance of our immune system. This seems to me an important mechanism with which a number of mysteries surrounding Lyme disease could be better understood. This does not only concern negative environmental factors such as pathogens, toxins in the environment or a changed diet, but there may also be some positive influences (or loss thereof), for instance through our microbiome. Many parasites have developed alongside us and offer advantages as well as disadvantages; a parasite that only has serious disadvantages is usually eliminated through evolution.
Much has been written about the strong increase in autoimmune diseases in recent history, most of it of the same quality as ‘Lyme disease is caused by deer’. Along with improved hygiene and the disappearance of infectious diseases, especially in the last century all kinds of autoimmune diseases and allergies began developing and there seems to be a link between these trends. Autoimmunity in the strict sense of the word (defence against one’s own body) often does not provide a credible explanation for the origin of these diseases, particularly in historical terms. Although infections or toxins in the environment can sometimes be a trigger, there often (also) seems to be a connection to the disappearance of infections that were common until recently (such as worm infections and childhood diseases that we vaccinate against), resulting in a disrupted immune system. These types of complex clinical pictures are not restricted to people, take for example the bee mortality (CCD), which simple minds attribute to the Varroa destructor or certain viral infections, while it has long been clear that very different issues play a role in this process – one can see a number of similarities with Lyme disease.
At the same time, we must also conclude that in recent decades, apart from Lyme, many other vector-borne infectious diseases have been advancing that had rarely been a problem before; a common factor seems disruption of the natural environment. Is Lyme an infectious disease, or is the tick bite only a trigger that starts an entire process, like with many autoimmune diseases? An infectious disease is treated with antibiotics, but if the (ongoing) complaints are caused by something else, antibiotics are not a good idea, if only because they often disrupt the immune system even more.
A different approach
In this area, conventional physicians could learn a lot from their colleagues in alternative and non-Western medicine, because a silent revolution is taking place here: in recent years various ‘incurable’ autoimmune diseases seem to have been cured or treated effectively with ‘experimental’ treatments that mainstream medicine, until recently, paid no attention to whatsoever, such as extreme fasting, faecal transplants or ‘worm therapy’. These treatments are starting to receive scientific credibility, thanks to growing knowledge of our immune system, the microbiome and quorum sensing. Nonetheless, it is difficult to patent such treatments and as yet, they do not come in simple pills that enable Big Pharma to make money effortlessly. To achieve useful results, it might be necessary to adapt the treatments to individual patients and this ensures that for the present, very little serious research will be conducted L
For those who want to immerse themselves in this subject, I highly recommend the book An Epidemic of Absence (5). The book does not mention Lyme disease at all, but an observant Lyme patient will notice numerous interesting parallels with their own experiences. If both physicians and patients could take their blinders off, there are interesting perspectives for a better approach to the Lyme dilemma. (N.H.)
For the record: use of antibiotics with Lyme disease is desirable in certain circumstances and this article does not form a recommendation for attempting ‘experimental’ treatments.
- De rol van het immuunsysteem in het ontstaan en het beloop van de ziekte van Lyme. NTMM 2015;23:nr.4 p131-136
http://www.nvmm.nl/system/files/2015-4-23e%20jaargang%20december%202015-nummer%204.pdf (large file, text in Dutch language)
- Auto-immuniteit en infectie: devil in disguise of toch een blessing in disguise? NTMM 2015;23:nr.4 p118 (large file, text in Dutch language)
- Identification of the minimal cytolytic unit for streptolysin S and an expansion of the toxin family.
- Donta ST, Martin SE, Meeting IDSA, Denver CO, Cartwright MJ. A Novel toxin (Bbtox1) of Borrelia burgdorferi. Abstracts of Annual. 1998
- An Epidemic of Absence (Moises Velasquez-Manoff, 2013)
Published december 2015
Aangepast: 18 januari 2016