Stephen Buhner: Considerations In The Clinical Treatment Of Lyme Coinfections
Although prominent physicians in the mid to late twentieth century announced with great fan- fare the end of infectious disease for all time such has not turned out to be the case. In fact infectious dis- ease is becoming more of a problem in the industrialized world every year. Resistant bacteria are making massive inroads in hospitals; one of the more common sentences in newspaper obituaries is "died of complications following surgery." They rarely say that in nearly all cases those "complications" are resist- ant bacteria the patient picked up in the hospital.
It has also become clear that many new infections, and others, simply not recognized as being infections (e.g. endocarditis from Bartonella infection or arthritis from Lyme bacteria), are emerging with greater frequency and virulence in the human population.
One major grouping of these types of infections are those that are often coinfectious with Lyme disease. This includes, but is not limited to, infections caused by Babesia, Bartonella, Ehrlichia, Anaplasma, Mycoplasma, Coxiella, and Rickettsia organisms.
Clinicians specializing in Lyme disease treatment have long been aware of the complex problems attendant with treating someone with multiple coinfections. Though slow on the uptake, as usual, this awareness is now becoming more common among researchers. In consequence, some good information is emerging on the synergy between coinfectious agents during active infections. This is a brief look at some of the factors that need to be taken into account when treating coinfections.
Studies on the complex interactions that occur between co-infectious bacteria are uncommon but, when combined with the experience of clinicians, they are revealing. Coinfective bacteria interact both in the vector that spreads them and then in the host they are transferred to and those interactions have a great deal of impact on patient out- comes.One of the first things to understand is the tremendous genetic flexibility of coinfectious organisms.
Genetic Flexibility and Evolution Among Bartonella
Bartonella organisms, like many related members of the proteobacteria (among whom are coinfectious agents such as Ehrlichia and Anaplasma), are undergoing rapid genetic alterations in response to environmental factors such as climate change, habitat damage, and human population increase.
As Bruno Chomel, et al, note in their paper, "Ecological fitness and strategies of adaptation of Bartonella species to their hosts and vectors":
“Massive natural or man made changes to historically stable ecosystems that result in alterations in vector biology and reservoir host density, increased international movement of a wide range of reservoir hosts across continents, recent human behavioral and societal changes that bring animals into increasingly close human contact, as well as medical interventions, HIV infection and an aging immunosenescent human population con- tribute to ongoing and dynamic interactions among Bartonella species and their hosts and vectors." (Chomel, et al, 2009)
Studies have found that Bartonella exists within infected hosts as a mosaic of different genetic variants. This kind of variation is not found during in vitro studies, only in living hosts. In response to the immune system of the host Bartonella, much like Lyme spirochetes, generate a number of genetic variants in order to maximize survival in the host. The various variants are able to live within different niches of the host more easily than others, e.g. the bone marrow or the lymph system, in order to maximize survival over time. It is not uncommon that several variants can be found within those niches, the several strains exchanging genetic material in order to stay ahead of the immune response. The outer membrane proteins on the exterior of the bacterial cell are often altered (as are many of the adhesion molecules such as BadA) which makes the variants harder to recognize by the immune system. Simple rearrangements of certain portions of the genome can create as many as 420,000 variants of a species of bacteria in a short period of time. As Chomel, et al, observe, "When the host produces antibodies targeted against the invading microorganisms, the infecting pathogen is usually killed. However, if the pathogen alters the protein expressed (antigenic varia-tion), or no longer expresses the protein on its surface (phase variation), the microorganism can survive and multiply in the host." (Chomel, 2009) In those with persistent or chronic Bartonella infection, both phase variation and anti-genic variation appear to be the norm, with the immune system unable to keep up. Study has found that the immune system is compromised in chronic cases, at least minimally.
All Bartonella species contain a very similar, fairly small, core genome and multiple accessory genome structures that they can weave into the core genome if needed. Most of the accessory genomes exist as genomic islands and were obtained through horizontal gene transfer from other bacteria. Some of these genomic islands are host specific, much as they are in Lyme spirochetes. Upon entry into a new host, the necessary genomic island can be incorporated into the core genome to facilitate host infection. As Chomel, et al comment, the horizontal gene transfer of so many genomic islands has "facilitated the remark-able evolutionary success of the modern lineage [of Bartonella] by conferring host adaptability" . . . and has stimulated "the adaptation of the generally host-restricted bartonellae to novel hosts." (Chomel, 2009)
The impetus for genetic rearrangement come from both the organ-ism itself and the immune environment in which it finds itself. Examination of the Bartonella genome has found a number of segments that are prone to rearrangement under environmental stress. In addition, Bartonella, like most bacteria, are able to both give and receive plasmids, strands of genetic material that can be woven into the genome to alter phenotype. Essentially, they can alter their physical form to make themselves more resistant to antibiotics, become more virulent, or more resistant to immune responses. Plasmids are exchanged with other bacteria, both inside of and outside the genus. In general, about 25 percent of the population of any mammal species, including humans, that can act as hosts for Bartonella will be infected, only a small portion of which will become symptomatic. Genetic variation in the mammal species is huge, over 22 genetic variants being found in one study.
Many of the arthropod vectors of Bartonella (i.e., ticks, fleas, and so on) contain multiple species of the bacteria, all of whom exchange DNA segments in order to facilitate their adaptation to new hosts. Variants develop in infected hosts such as humans, vectors take a blood meal, ingesting the new variants. The new variants, taken as blood meals from multiple species, interact in the gut of the vector, alter their genome structures, and then are injected into new hosts. There is a continual and very elegant genetic recombination occurring.
Research in 2007 found "that isolates responsible for human disease are not drawn randomly from the feline reservoir." (Arvand, 2007) In other words, there are specific human-infectious Bartonella held in the cats that are generated inside the cat to infect the human hosts that own the cats. (In fact, B. quintana, which is considered to be human specific, is an evolved off-shoot of B. henselae - a generally cat-specific species - that adapted itself to specialize in infecting humans. Research has found that B. henselae is still easily able to shift its outer membrane proteins to allow it to infect human red blood cells.)
Lindroos, et al, note, "the variable gene pool in the B. henselae population plays an important role in the establishment of long-term persistent infection in the natural host by promoting antigenic variation and escape from immune response. . . . the results suggest multiple sources of human infection from feline
B. henselae strains of diverse genotypes." (Lindroos, 2006) In spite of numerous comments to the contrary, Bartonella infec-tion of human beings is not a random or accidental event; we are not inadvertent hosts. All mammals are potential hosts for all Bartonella species and B. henselae (along with others that infect human companion animals) is not "accidentally" infecting humans. And the infection is wide spread, much more so than is commonly recognized among physicians or the CDC. As Mietze, et al note, in their research among Germans: "The prevalence of bartonellosis among humans in Germany appears to be high and severe clinical cases have been described." (Mietze, 2011)
There is tremendous genetic shifting occurring in response to multiple environmental factors. Coinfectious organisms that congregate inside ticks or other arthropod vectors are exchanging information with each other, including how to alter DNA in order to avoid both antibiotics and host immune responses. It should be assumed whenever a chronic case of Lyme or Lyme coinfections is encountered that multiple genetic variants exist and are being regularly generated within the infected per-son. This is becoming the norm rather than the exception. Treatment has to become more sophisticated in order to be successful. Looking at cytokine cascade is one way to get to a more sophisticated, approach.
Coinfections and Cytokine Cascades
One of the better articles on cytokine cascades is Andrea Graham, et al. "Transmission consequences of coinfection: cytokines writ large" that appeared in Trends in Parasitology, volume 23, number 6, in 2007. The authors propose a unique approach to understanding the dynamics of coinfections. Instead of focusing on the organisms them-selves, they suggest focusing on the cytokine cascades that the organisms produce in the body. They comment that "When the taxonomic identities of parasites are replaced with their cytokine signatures, for example, it becomes possible to predict the with-in-host consequences of coinfection for microparasite replication" as well as symptom picture, treatment approaches, and treatment outcomes.
Cytokines are small cell-signaling molecules secreted by the immune system and the glial cells of the nervous system that are important in intercellular communications in the body. They tend to produce unique forms of inflammation and alteration in the cell surface structure, depending on what is occurring during the infection. In practical terms, when a bacterium touches a cell, the cell gives off a signal, a cytokine, that tells the immune system what is happening and what kind of help that cell needs. Each type of infectious bacterium initiates a particular kind of cytokine cascade.
When treating a coinfection, it is important to take the time to under-stand the cytokine cascade that occurs from each organism. This determines many of the most effective approaches to treat the condition. For example, if the infectious bacteria, say Bartonella for example, stimulate high levels of interleukin-8 in the body, then reducing interleukin-8 levels through the use of phytomedicinals that have that particular action will in fact reduce many of the symptoms associated with Bartonella.
It is moderately easy to explore the cytokine cascade that one organism initiates but when you have two or more bacteria involved in an infection, each causing unique cytokine cascades, the dynamic becomes a great deal more complex. Most coinfectious bacteria have learned to work synergistically with each other. This means that the outcomes are not just additive; the bacteria actually work together and, just as with people working together, produce a much more powerful outcome than if merely one bacterial species is involved. As well, most bacterial species have learned how to use the host's own cytokine immune responses for their purposes.
As Graham, et al, note: "The influence of cytokines on effector responses is so powerful that many parasites manipulate host-cytokine path-ways for their own benefit," as is indeed the case with Lyme and its coinfectious agents such as Bartonella. Most crucially, they continue, "the magnitude and type of cytokine response influence host susceptibility and infectiousness. Susceptibility to a given parasite will be affected by cytokine responses that are ongoing at the time of expo-sure, including responses to pre-existing infections." In other words, if you are already suffering some inflammatory condition, however mild, the bacteria will use it to facilitate their spread in the body. If more than one microorganism is involved such spreading is enhanced considerably. As Graham, et al, put it "coinfection increases the reproductive number for the incoming parasite species and facilitates its transmission through the host population." While the immune system is often compromised by the cytokine dynamics initiated by one type of bacteria, multiple, simultaneously initiated cascades are even more potent in their impacts. In addition, you begin to get assaults on multiple body systems.
If Bartonella is a coinfection with Lyme, for example, what you then get is assault on and resultant degradation of the collagen systems of the body by the Lyme spirochetes and a simultaneous assault on red blood cells along with continual subversion and abnormalization of endothelial cells and their functions. Since Lyme spirochetes damage collagen tissues, for instance in the joints of the knee, the body will send CD34+ cells to that site to help repair the damage but some of those cells will be infected with Bartonella (which has a tendency to infect those precursor cells in the bone marrow). The Bartonella will take advantage of the local inflammation to establish a colony in that location that itself will contribute to collagen degradation the Lyme spirochetes are causing. If the person were to be already suffering with a preexisting inflammation in that joint location, the process is even easier for the bacteria.
If you add other coinfectious bacteria to the mix, the picture is even more complicated. For example, if Babesia are present, then the red blood cells are going to have two organisms infecting them (Bartonella and Babesia), thus increasing the deleterious impacts on the red blood cells. This is, as Graham, et al, comment, more common than not. "Hosts that are coinfected by multiple parasite species seem to be the rule rather than the exception in natural systems and some of the most devastating human diseases are associated with coinfections that challenge immune response efficacy."
The foundations of this are ecological more than anything else. As those researchers observe:
"Coinfections could, thus, increase vulnerability to the emergence of new parasites by facilitating species jumps if the coinfected portion of a population provides favorable conditions for an emerging parasite to adapt to a new host species." And research is bearing out that such adaptation is in fact occurring.
Another very fine paper on the dynamics of coinfections is by Telfer, et al, "Parasite interactions in natural populations: insights from longitudinal data," in Parasitology, volume 135, number 7, 2008. They echo Graham, et al, when they note, "in natural populations 'concomitant' or 'mixed' infections by more than one parasite species or genotype are common. Consequently, interactions between different parasite genotypes or species frequently occur. These interactions may be synergistic or antagonistic with potential fitness implications for both the host (morbidity and/or mortali-ty) and parasite (transmis-sion potential)."
They continue:
There is mounting evidence from experimental studies that the outcome of interactions during co-infections (for either the host or the parasite) is context dependent, potentially varying with different host or parasite genotypes or environmental conditions. Perhaps most critically, outcome can depend on the timing and sequence of infections. . . .
Susceptibility is a property of an individual host at a given time. . . . The ability of a parasite to establish an infection successfully will depend on the initial immune response of the exposed host. On entry into the host, a parasite will experience an "immunoenvironment" potentially determined by both previous and current infections, as well as intrinsic factors such as sex, age, nutritional status and genotype. The immediate immunoeffectors in a naive host will be dominated by cells and molecules that comprise the innate immune response, and thus the efficiency of this arm of host immunity at reducing and clearing an infection will be influential in determining susceptibility.
In other words, attention to the health of the immune system is essential when dealing with coinfections. Resto-Ruiz, et al, emphasize this as well, as do so many other researchers, "The reduced ability of the host's immune response to control bacterial infection apparently results in a bacteremia of longer duration. . . people with intact immune function who become infected with B. henselae usually" do not experience severe symptoms. (Resto-Ruiz, et al, 2003)
The immune status of someone with coinfections must be addressed as part of any treatment protocol. Due to the synergistic nature of coinfections there is an inescapable truth: The weaker or more compromised the immune system, the more likely someone is to become infected and the more likely they are to have a debilitating course of ill-ness. Improving the immune status of those with chronic bartonellosis, for instance, allows the immune system, refined over very long evolutionary time, to do what it does best, which is to use very elegant mechanisms to control and clear infection. Eventually, the healthy immune system begins to identify the outer membrane proteins of the bacteria and creates antibodies to them. Due to the sophistication of the bacteria's sub-version of the host immune system this often takes any-where from 4-8 months with Bartonella infections. In those whose immune systems are compromised it may take longer, how long is directly proportional to the health of the immune system. Once the immune system creates the proper antigens, the bacteria are then eliminated fairly rapidly from the body. Reinfection is difficult as the antibodies remain in the body for some time.
The synergy of the coinfections' impacts on immune function has to be addressed as well. As Telfer, et al, comment, "Attempts by the immune system to simultaneously counter the multiple parasite species involved in a coinfection can lead to immunopathological disease and pathology that are more than the simple additive pathogenic effects of the different parasite species."
For example, infection with both Babesia and Bartonella are synergistically impactful on red blood cells and can reduced red blood cell counts up to 25 percent, leading to anemia, fatigue, breathlessness, and general weakness. (One positive note, because both bacteria are competing for red blood cells, longer studies have found that the Babesia, over time, tends to clear the Bartonella infection by outcompeting them. In the initial stages, however, the impact on red blood cells is immense.) Babesia are thought to sequester themselves in the capillary networks of the spleen and liver. Bartonella species sequester themselves in the endothelial cells of the capillary networks of the spleen and liver. Both then seed the blood stream from those locations at regular intervals. The impacts of infection with both para-sites on the spleen and liver are much greater than either alone and this has to be taken into account in any treatment approach.
Telfer, et al's, research also found that infection with Anaplasma for example made subsequent infection by Babesia much more certain, in fact, it made it twice as likely to occur. Reversing the order of infection found the same rate of increase. As well, animals infected with one Bartonella species who were also infected by other Bartonella species were much more likely to have long term infections. Coinfection with
Anaplasma and Bartonella (or Babesia and Ehrlichia), for example, are often more severe in the disease progression in that both white blood cells and red blood cells are infected. Specifically, Anaplasma and Ehrlichia infect neutrophils, the most abundant form of white blood cell in the body and an essential part of the innate immune system. Thus the immune system is fighting not only bacteria in the red blood cells and vascular tissues but bacteria inside itself.
In my experience, the technological medical community tends to down-play both the impact and occurrence of coinfections in the people they see while the alternative community tends to exaggerate it. Oddly, in spite of their training, most physicians don't really understand bacterial organisms very well, nor how to treat them. They usually tend to look for a pharmaceutical that is active for the bacteria in question and apply it, a fairly superficial approach that is increasingly failing in practice. If they have not definitively identified the cause of the condition they will generally prescribe a broad-spectrum antibiotic that will, as often as it helps, do more harm than good. The alternative community often fails at rigor of analysis and the focus, and courage, needed to confront deadly or life debilitating infections. Both make too much money off people's suffering though, in fairness, most (not all) of the alternative community tends to make much less. I just don't see that many herbalists with their own private airplanes.
In treating coinfections, the approach should be depth based with rigor of analysis. The bacterial infections need to be identified (and no, muscle testing is not reliable enough, but then, neither is Elisa -neither should be relied upon as diagnostically definitive) and then a treatment protocol initiated. In some cases antibiotics are very effective and with diseases as debilitating as Lyme and its coinfections they should be considered. However, if that kind of superficial approach fails, then a depth under-standing of the cytokine cascades and the likely interactions between the coinfections should be undertaken and a treatment protocol initiated that addresses it in depth. The most important thing in treating coinfections is to reduce the inflammatory processes the bacteria initiate and reduce the cytokine cascades that occur. That stops the majority of symptoms right there especially if treatment protocols are initiated that are designed to protect the areas of the body that are affected.
As Telfer et al, observe, "An immune response that effectively cleared the infection from endothelial cells would therefore ultimately control an infection [by Bartonella]." This applies as well to any intervention that will protect endothelial tissue from the bacteria. The bacteria can't survive if they are not able to initiate their particular form of inflammation in the body; it is how they make habitat and scavenge food. Enhancing immune function then allows the body to deal with the infection on its own. The addition of protocols to reduce the specific symptoms that are occurring (e.g. arthritis) and help restore quality of life are also important. Antibacterials can help but comprehensive treatment protocols that address these initial three conditions are essential:
1. Reducing cytokine cascade
2. Enhancing the exact immune function that is depressed
3. Addressing symptom picture
Relying on a "kill the invaders" approach is going to become increasingly ineffective as time goes on. In fact, it is already failing. The bacteria are evolving. We should, too.
Arvand, M. et al, Multi-Locus Sequence Typing of Bartonella hense-lae Isolates from Three Continents Reveals Hypervirulent and Feline-Associated Clones, PloS One, December 2007, Issue 12.
Chomel, B. et al, Ecological fitness and strategies of adaptation of Bartonella species to their hosts and vectors, Vet Res 40(29), 2009.
Graham, A. et al. "Transmission conse-quences of coinfection: cytokines writ large" that appeared in Trends in Parasitology, volume 23, number 6, in 2007.
Lindroos, H. Et al Genome rearrangements, deletions, and amplifications in the natural population of Bartonella henselae, Journal of Bacteriology 188(21): 7426-39, 2006.
Mietze, A. Et al. Combined MLST and SFLP typing of Bartonella henselae isolated from cats reveals new sequence types and suggests clonal evolution," Vet Microbiol 148(2-4):238-45, 2011.
Resto-Ruiz, S. Et al, The role of the host immune response in the pathogenesis of Bartonella henselae, DNA Cell Biology 22(6): 431-40, 2003.