The following observations are intended as points for discussion and general information. We do not claim to know everything about the complex and complicated interactions that take place between pathogens (viruses, bacteria, fungi, protozoa, parasites, etc.) and the corresponding virulence factors between these pathogens and the immune system of the affected person (which is where all these pathogens meet). We must discover whether an affected person is ‘only infected’, or whether they fall ill/develop symptoms and then assess the severity of these symptoms.
We would like to invite everyone who is interested to join us in exploring this complex and complicated field by contributing their own ideas. None of the studies below were conducted or commissioned by BCA-clinic, as we only present them here for general information; all of the full studies can be found online.
Suggestions for subjects of discussion
Virus and bacterial species are known to have developed mechanisms to modulate, escape, “mislead” the immune system of the affected person in order to persist and potentially reactivate the infection later (e.g. with herpes simplex virus, HIV, varicella zoster virus, Epstein-Barr virus, TBC and many more). The general medical opinion no longer excludes the possibility of a subclinical (latent) infection of Lyme disease.
It is also known that bacterial and viral species or strains are capable of forming pleomorphic forms (persister forms) and biofilms. Some pathogens are able to modulate T lymphocytes and induce insensitivity (anergy). It would seem that both viruses and bacteria (Staphylokokkus aureus-DÄB, vol. 106, issue 43 of 28.10.2011, p. 1902) can have this affect. Some pathogens can alter their antigens and receptors on their surface, while others can also block the complement system of the affected person. Moreover, other pathogens can “mislead” the cellular immune system and many of these mechanisms are known to exist among Borrelia, cf. (1), (2), (7), (13).
Because of this, is it not possible that some autoimmune diseases (see also here), allergies or endocrine diseases could develop? Normally, immune processes are triggered, pushed and maintained but at some point they have to be reduced and stopped again. What if the permanent activation and/or malfunction of the immune system is also caused by pathogens (viruses, bacteria, etc.)? Some pathogens also intervene in the brain metabolism and can cause disorders, e.g. in the metabolism of the neurotransmitters (serotonin, dopamine, norepinephrine). This can occur from the very inflammations that they trigger. With this in mind, should we consider some cases of depression in which the metabolism of the neurotransmitters is often disturbed?
There are many other factors that have a negative effect on our immune system, such as environmental influences (certain foods, general diet, toxins, heavy metals, mould, softeners in toys and furniture, etc.). It is worth considering where we source our food in this increasingly globalised world, as well as the conditions in which it is produced and processed. There has been a rise in media attention surrounding this issue (e.g. ethoxyquin in industrial salmon farming on salmon farms, antibiotics in animal farming, etc.). We should also consider the processes that are used to manufacture and dye our clothes (e.g. the tanning of leather with chrome) in each individual country of production. There are also countless other factors that influence environmental medicine that cannot be discussed at length in this study.
We know that psychological influences, such as stress and conflict situations, can lead to immunosuppression (weakening) of the immune system through chronic overproduction of stress hormones adrenaline and cortisol. In addition to the stress that the patient puts on themselves, we can also include disturbances of the biorhythm (e.g. working night shifts), noise and infrasound. Reducing these negative factors will certainly be very helpful, but shouldn’t be considered a ‘complete’ therapeutic approach.
Does our food still contain all the necessary minerals and vitamins? Given our busy modern lifestyle, who actually manages to eat a balanced diet?
As we mentioned earlier, we know that some Borrelia strains have the ability to resist the complement system of the person affected (1), (7), (13). The complement system is an important part of the innate immune system. This ability seems to be an important virulence factor of Borrelia. A new study now shows that this ability will differ depending on the Borrelia strain (25).
From this, we can deduce the following ideas:
If the Borrelia strain can block (or is resistant to) the complement system, this leads to a partial weakness or ineffectiveness in the affected person’s immune system and they become ill. If the Borrelia strain cannot block the complement system or is not resistant to it, the person may only become infected but not fall ill. In both cases, we should be able to detect antibodies if the test method is effective enough. The immunodeficiency caused by this blockage of (or resistance to) the complement system is a partial and functional weakness or ineffectiveness of the immune system. Although there are no current test methods that can measure this weakness of the immune system, it has been proven to exist.
This weakening or ineffectiveness of the immune system is certainly less serious than in HIV, as it affects only one component of the immune system whereas the HI-virus can trigger a massive, general weakening of the immune system. However, it could explain why one person gets sick and another does not. This should be investigated further, as should the question of whether this ineffectiveness of the immune system caused by Borrelia also has an effect on the body’s defence against other infections.
Can a multisystemic disease (especially chronic) be successfully treated in all patients and in all cases with a short monotherapy?
Why don’t humans develop sustained immunity to Borrelia?
There is also interaction between the various pathogens and strains (26).
We urgently require a complex (holistic) and interdisciplinary consideration!
All of these discussion points are regularly documented in scientific studies of certain specialist areas, such as psychology, psychiatry, environmental medicine, occupational medicine, immunology, infectious medicine and nutrition science. However, what is often missing is an interdisciplinary combination of all these factors and influences (a.k.a. the holistic view), as the patient is usually exposed to several or all of these factors simultaneously, albeit with varying intensity. What does the sum of all these influences mean for the immune system in its ability to deal with infections? (We must also remember the patient’s genetic factors.)
The affected person is often exposed to several pathogens at the same time, in addition to all of the other influences on their immune system. After all, humans are confronted with and infected by a wide variety of pathogens every day of our lives; however, we do not always fall ill.
Could it not be that chronic infections, which often trigger multisystem and multi-organ diseases, have several causes? This would then lead to the affected person falling ill with the infection(s)? Therefore, surely we need individual, multimodal and holistic therapeutic approaches?
Since all humans are “unique”, we can’t expect everyone to react to infections in the same way. The immune system is one of the most important factors in creating our “uniqueness”. The field of chronic infections (including Lyme disease) is probably much more complex than previously assumed. Therefore, we must compile literature from different fields and view it either in a ‘bigger picture’ or a different sequence in order to reach a better understanding and causality. Unfortunately, the possibility of chronic (even bacterial) infections is often not considered.
Although one might feel as if these factors should not be mixed, this is exactly what happens in nature, in living beings, and in life, much more often than we think.
The tick as vector (and the distribution)
An up-to-date examination of ticks – to see how many of them are infected and with which pathogens (viruses, bacteria, protozoa, etc.) – would be of great help. These studies should be carried out in several European countries (or other regions) (3), (4), (8), (11), (12), (30) and affected patients could be analysed much more specifically (32). We should also investigate how clinically relevant the pathogen findings are with regards to treating humans.
The distribution of infected ticks is subject to temporal, climatic and geographical changes. We must consider the habitats of different wild animals and the changed migratory directions of the birds, as these are host animals for Borrelia and often carry and spread many ticks (3). Regarding birds that spread infected ticks, we usually focus on those that live mainly in grass, bushes and undergrowth and then transport and distribute the infected ticks (5), (14), (27), (28), (29). Dogs (15) and other domestic animals (18) can also spread infected ticks. Let’s also ask whether ticks and pathogens are more likely to survive in new regions of the world as a result of climate change. Finally, in this increasingly globalised world, our own travel behaviour could also lead to the spread of infected ticks (taking them on transport, in our clothing, luggage, etc.). There are also several different types of ticks, some of which are also infected with other pathogens (31).
Another human pathogenic Borrelia strain has been identified recently: Borrelia miyamotoi (6), (13). As nobody thought that this strain and its antigens to be pathogenic to humans, we don’t know whether it will be detected by the existing antibody test systems. This strain has already been widely distributed by birds. Who knows how many undiscovered human pathogenic Borrelia strains (33) and co-pathogens still exist?
In addition to this, we know that Borrelia can live and survive in several different animal species; these hosts include many mammals, but also birds, different tick species and humans. The pathogen must therefore be able to exhibit complex survival and ‘escape’ mechanisms (1), (2), (7), (13).
Humans and their individuality
Most affected patients will not display one single infection, but a mixture of various infections that are affected by environmental and stress-related influences.
A lack of vitamins, minerals and trace elements may also be a factor. While healthy people usually don’t require supplements, such ‘substitution therapy’ can be very helpful for those who are sick (e.g. vitamin B12, H, D, zinc, etc.). When a patient undergoes substitution therapy, their vitamin levels can be monitored to rule out ‘over-therapy’. The importance of vitamin D – not just in bone metabolism – is becoming more and more apparent (9), (10), (24). During substitution therapy, it is recommended that a patient’s vitamin D stay within the normal range (10).
We know that everyone reacts differently to treatment and some people will have problems with the metabolism (uptake, processing and detoxification) of drugs (keyword: cytochrome P 450 enzymes and cascades etc.). There are also differences in metabolism between the sexes (gender medicine) and between children and adults, which will influence the effects of medicine. For example, there are indications that the cytochrome P 450 system can be directly influenced by an infection (19).
The intestine – an important immunological organ system
Do we really already know everything about the intestine (17) (21), in which numerous immune processes take place? Probiotics were added to the S3 guidelines for the treatment of irritable bowel syndrome, which illustrates the importance of further research in this field. Fortunately, there are already professors who are dealing with this topic (1st Microbiom Conference in September 2014 in Berchtesgaden).
We’d also like to focus on with the intracellular pathogens (e.g. Chlamydia, Ehrlichia) and intracellular forms that can develop some pathogens (e.g. mycoplasma, Rickettsia). Intracellular pathogens are often acid-resistant and fat-soluble, as are the pathogens of tuberculosis and leprosy. These intracellular pathogens and their various forms control numerous mechanisms with which they can evade both their host’s immune system and the effect of antibiotics. These pathogens also change their appearance to adapt to their environment; they’re pleomorphic, which means that they are difficult to identify for diagnosis. The spiral form of Borrelia does not ‘fit’ into an erythrocyte (red blood cell), but perhaps fits into other ‘persister’ forms of Borrelia and in larger body cells.
Persister forms of Borrelia seem to exist “in vivo”, which necessitates new treatment strategies (2).
Dosage of Doxycycline
It’s important to note that Doxycycline is often used to treat Lyme disease. The official recommended dose is 200 mg/d but sometimes up to 400 mg/d is prescribed. Laboratories can determine the level of Doxycycline in a patient’s blood after three or four days after the treatment begins; in order to check whether 200 mg/d places the patient within the ‘therapeutic range’. If this is not the case, the dose can be adjusted based on the individual requirements of the patient. Due to a variety of reasons (see above), some patients will not reach the therapeutic range when prescribed 200 mg/d Doxycycline. If the patient is underdosed then the treatment is less likely to work. Measuring the level of Doxycycline can also help to explain or discover some apparent failures of therapy. Additionally, an incorrect intake of antibiotics, e.g. taking them with milk products, can also explain why the therapy isn’t working.
Health economic aspects
Our aim should be for patients’ symptoms to disappear completely. They should feel well enough to work, no longer require frequent visits to the doctor or undergo any hospital stays that result in complex diagnostics and unsatisfactory symptomatic therapies. If they do not receive a solution for their symptoms, patients will understandably continue to search for a sufficient treatment for Lyme disease. This is particularly notable from a health economic point of view (20). In an article by the Johns Hopkins Bloomberg School of Public Health, the researchers conclude that the problems with Lyme disease appear to be more widespread than previously assumed. Research may be very expensive, yet it seems unreasonable to continue to ignore existing patients and the disease itself. “These patients are lost. No one really knows what to do with them. It’s a challenge, but the first thing we need to do is to recognise this is a problem…” (23).
Suction time of the tick (nymph) and transmission of Borrelia and co-pathogens.
Fortunately, there is now a review paper regarding a literature study by an independent scientist on this (often emotional) topic: “Suction time of the tick (or nymph) and probability of transmission of pathogens (especially Borrelia)”. The paper emphasises that the transmission of Borrelia can take place in less than the (generally assumed) 24 or 48 hours. Borrelia have been detected in the salivary glands of nymphs and adult ticks, so the potential for this decreased transmission time cannot be ignored. We must also consider the possibility of other pathogens being transmitted during this suction time. In addition, the affected person can rarely give an exact time as to when the tick (or nymph) begins sucking on them, if they notice at all. Perhaps this study will enable the discussion surrounding this topic to become more objective (22).
For those who are interested, we have selected a few further points for discussion.
We are not alone in thinking that there is a general problem in the area of tick-borne diseases. The Entomological Society of America (ESA) and Dr. John Aucott from the Johns Hopkins University in the USA also identify these problems and seek out further research and studies as well as a more objective discussion around the topic. These problems are not exclusive to the USA.
We are happy to organise constructive and objective discussions through presentations and workshops, which may lead to many more important points of discussion.
We have provided literature sources for all chapters referenced above.
(1) Norbert Satz: Klinik der Lyme-Borreliose; 3. Auflage 2010, Huber Verlag, S. 173 ff
(2) Jie Feng et. al. „Identification of novel activity against Borrelia burgdorferi persisters using an FDA approaved drug library“, Emerging microbes and Infections (2014) 3,e49;doi:10
(3) Obsomer, V. et. al.:“Spatial disaggregation of tick occurence and ecology at a local scale as a preliminary step for spatial surveillance of tick born diseases: general framework and health implications in Belgium”, in parasites&vectors, 22.6:190 Epub 2013, Jun. 22
(4) Marion Blaschitz et al.: “Babesia Species Occurring in Austrian Ixodes ricinus Ticks”, Applied and environmental Microbiology, Aug. 2008, Vol. 74, No. 15, p. 4841-4846
(5) Studie von der Universität Coimbra, Portugal, und Universität Neuchatel, Schweiz: „First study on birds as hosts of Lyme Disease“, vgl. Pravda.ru vom 09.01.2013
(6) Borrelia miyamotoi: A Lesson in Disease Discovery, Annals of Internal Medicine, 2013 American College of Physicians; vgl. Centers for Disease Control and Prevention 24/7: Saving Lives. <protecting People™; www.cdc.gov/ticks/miyamotoi.html
(7) Axel Teegler et.al. „The relapsing fever spirochaete borrelia miyamotoi resists complement-mediated killing by human serum”, Tick and Tick-borne Diseases (2014), www.elsevier.com/locate/ttbdis
(8) Mark W. Eshoo et.al. „Broad-Range Survey of Tick-Borne Pathogens in Southern Germany Reveals a High prevalence of Babesia microti and a Diversity of Other Tick-Borne Pathogens”, Vector-Borne and Zoonotic Diseases, Volume 14, Number 8, 2014
(9) Gurmukh Singh, Aaron J Bonham:” A Predictive Equation to Guide Vitamin D Replacement Dose in Patients”, J Am Board Fam. Med. 2014;27(4):495-509
(10) Prof. Dr. Jörg Spitz: „Vitamin D“, ISBN 978-3-00-027740-5
(11) Lorraine Michelet et.al. „High-throughput screening of tick-borne pathogens in Europe“ Frontiers in Cellular and infection Microbiology, Volume 4, Article 103, July 2014
(12) Platonov AE et.al. “Humans Infected with Relapsing Fever Spirochete Borrelia miyamotoi, Russia , Emerg. Infect. Dis. Oct 2011
(13) Wagemakers A., Oei Anneke et.al “The relapsing fever spirochete Borrelia miyamotoi is cultivable in a modified Kelly-Pettenkofer medium, and resistant to human complement” Academic Medical Center Amsterdam, The Netherlands
(14) Dingler RJ, Wright SA et.al. “Survaillance for Ixodes pacificus and the tick-borne pathogens Anaplasma phagocytophilum and Borrelia burgdorferi in birds from California`s Inner Coast Range”, Ticks Tick Borne Dis. 2014, Jun;5(4):436-45
(15) McCown ME, Monterroso VH, Cardona W “Surveillance for Ehrlichia canis, Anaplasma phagocytophilum, Borrelia burgdorferi, and Dirofilaria immitis in Dogs From Three Cities in Colombia”, J Spec Oper Med 2014 Spring;14(1):86-90
(16) Dibernardo Antonia et al.: The prevalence of Borrelia miyamotoi infection, and co-infections with other Borrelia spp. in Ixodes scapularis ticks collected in Canada; Parasites & Vectors 2014, 7:183.
(17) Bohorquez DV et.al. „Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells“, J Clin Invest. doi:10.1172/JCI78361, Nov 2014
(18) Hornok et.al. „Synanthropic rodents and thier ectoparasites as carriers of an novel haemoplasma and vector-borne, zoonotic pathogens indoors“, Parasites & Vectors (2015) 8:27 DOI 10.1186/s13071-014-0630-3
(19) Shimamoto Yoshinori et.al. „Downregulation of Hepatic Cytochrome P450 3A in Mice Infected with Babesia microti“, J.Vet.Med.Sci. 74(2):241-245, 2012
(20) Rizzoli A et.al. „Ixodes ricinus and its transmitted pathogens in urban and peri-urban areas in Europe: new hazards and relevance for public health“, frontiers in Public Health, Dezember 2014, volume 2, Article 251, doi:10.3389/fpubh.2014.00251
(21) Bravo JA et.al. „Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via vagus nerve“, www.pnas.org/cgl/doi/10.1073/pnas.1102999108; Sep. 2011, Vol. 108, no.38
(22) Michael J Cook: „Lyme borreliosis: a review of data on trasmission time after tick attachment“, International Journal of General Medicine 2015:8 1-8
(23) „Lyme disease costs up to $ 1.3 billion per year to treat, study finds“ (2015, February 5) retrieved 6 February 2015 from Http://medicalxpress.com/news/2015-02-lyme-disease-billions-year.html
(24) Alleskönner Vitamin-D? Bei niedrigen Spiegeln sind Hirninfarkte verheerender: Medscape. 17. Feb 2015. ; 1. International Stroke Conference (ISC), 11. bis 13. Februar 2015 Nashville/Tennessee – Henninger N, et al: Abstract W MP62, 11. Februar 2015
(25) K. Brangulis, etal., „Crystal structures of the Erp protein family members ErpP and ErpC from Borrelia burgdorferi reveal the reason for different affinities for complement regulator factor H“ Biochim. Biophys. Acta (2015). http://dx.doi.org/10.1016/j.bbapap.2014.12.025
(26) Godefroy Devevey et. al.: „First arrived takes all: inhibitory priority effects dominate competition between co-infecting Borrelia burgdorferi strains“, BMC Microbiology (2015) 15:61, DOI 10.1186/s12866-015-0381-0
(27) Comstedt P et. al.: „Migratory passerine birds as reservoirs of Lyme borreliosis in Europe“, Emerg Infect Dis. 2006 Jul; 12(7): 1087-95
(28) Marie-Angele Poupon et.al.: „Prevalence of Borrelia burgdorferi Sensu lato in Ticks collected from migratory birds in Switzerland“, Appl. Environ. Microbiol. 2006; 72:1, 976-979, doi: 10.1128/AEM.72.1.976-979.2006
(29) Fobito Ishiguro et. al.: „Prevalence of Lyme Disease Borrelia spp in Ticks from Migratory Birds on the Japanese Mainland“, Appl. Environm. Microbiol. March 2000; 66:3, 982-986 doi: 10.1128/AEM.66.3.982-986.2000
(30) Muqing Li et.al.:“ Lyme Disease Borrelia Species in Northeastern China resemble those isolated from far Eastern Russia and Japan“, Appl. Environm. Microbiol. July 1998; 64:7, 2705-2709
(31) Medlin, J.S., et al.:“Vector potential and population dynamics for Amblyomma inornatum“, Ticks Tick borne Dis. (2015), http://dx.doi.org/10.1016/j.ttbdis.2015.03.014
(32) May K et al.: „Borrelia burgdorferi sensu lato and co-infections with Anaplasma phagocytophilum and Rickettsia spp. in Ixodes ricinus in Hamburg, Germany“. Med. Vet. Entomol. 2015(Jun), DOI: 10.1111/mve.12125
(33) N. Rudenko et.al.; „Isolation of live Borrelia burgdorferi senso lato spirochetes (also Borrelia bissettii-like strain) from patients with undefined disorders and symptoms not typical for Lyme borreliosis“, doi:10.1016/j.cmi.2015.11.009