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The protean characteristics of Bb disease are undoubtedly accounted for by several factors. First, several hundred Bb strains exist (7,57,58,59) and there is a limited, but growing, understanding about their significance in the clinical spectrum of LD, in either acute or chronic infection (2,3). At present, strain differentiation is strictly in the province of a research laboratory. Likewise, in vitro sensitivity data for various Bb strains is scarce and testing for antimicrobial sensitivity, as is done routinely on other bacterial pathogens, is unavailable except at a research level. In fact, most of the published information comes from Vera Preac-Mursic, who began reporting both in vitro and in vivo (gerbil model) data in the mid-80s (60). Her excellent research program includes a recent description of an animal model evaluating 20 strains of Bb, which compared responses to a range of antimicrobial therapies (61). Despite apparent similarities amongst the strains, her findings are disconcerting to LD treating practitioners because she noted wide discrepancies in antimicrobial sensitivities between strains in the response to the antibiotics selected. Naturally, the antibiotics studied were selected on the basis of conventional therapy at this time and included, among others, ceftriaxone, cefotaxime, amoxacillin, doxycycline, and azithromycin. While some Bb strains are non-pathogenic and the description of an experiment with gerbils may not parallel the human experience, Preac-Mursic’s work raises the serious question of potential antimicrobial failure in our patients due to drug resistance. A recent report suggests that markers for antibiotic resistance have been identified by researchers at New York Medical College (62). These findings will accelerate the understanding of genetic vectors that govern resistance patterns in Bb strains. This knowledge may ultimately translate into improved clinical management of Bb infections through a better understanding of drug resistance mechanisms and patterns.
Documentation of infection with multiple Bb strains in the same human host has now been reported (2). This begs the question about the clinical implications for persistent Bb infections in a particular host over time. Furthermore, the Bb organism has the ability to alter its molecular structure even as it passes through the gut of the tick vector (63), and in the host where it can “morph” into an L form (lacking a cell wall) or, more significantly, into a cystic form which is antigentically dissimilar from the spirochetal form (64) (see photos below). This process occurs in reverse when it is advantageous to Bb. Undoubtedly these are survival mechanisms developed by Bb. Whether all Bb strains have a like capacity to do this is not known, but strain variability in terms of propensity to develop the cyst form may theoretically explain some of the clinical differences observed in the treatment of individuals with persistent LD.
Likewise, strain variation in terms of the degree of oxygen tolerance, or the extent to which a strain is microaerophilic or tolerates oxygen, may explain observed differences among our patients’ response to various therapies. In addition, in recognition of Bb’s intolerance to higher oxygen partial pressures (65,66), interest in use of hyperbaric oxygen treatment (HBO) has emerged as an adjunctive program for difficult or poorly responsive cases of neuroborreliosis.
It is interesting to speculate that metronidazole (flagyl), which is arguably the most potent anaerobic antimicrobial available, and which is used by LD treating physicians to eradicate the cystic form of Bb (see below), may actually be effectively treating some highly anaerobic Bb strains which ceftriaxone and other commonly used antimicrobials would not be expected to eradicate (see below) The venerable antibiotic clindamycin, which has excellent activity against both strict anaerobes and facultative anaerobes, may provide a therapeutic option not generally employed by others and certainly not recognized to date in the Lyme literature. At the Jemsek Specialty Clinic, we have treated over 30 patients to date with either oral or IV clindamycin as adjunctive therapy to their main program (see treatment section below). In our more difficult cases where response to intensive combination antimicrobials was not forthcoming, we serendipitously discovered positive clinical responses whenever clindamycin was employed in therapy. Since then, we have been consistently and profoundly impressed by the clinical response to clindamycin therapy, particularly when administered intravenously. Thus, in our view, clindamycin may ascend to a role of first line intravenous therapy, alone or in combination with more conventional approaches such as ceftriaxone or imipenem.
The host response is critical in any infection model. In the case of Bb, as with other infections, the host response may be influenced by the Bb inoculum, the diversity of infecting strains, and the presence of co infecting organisms. At the Jemsek Specialty Clinic, we have elicited several case histories in which the patient describes a single or multiple EM rash in the appropriate setting (e.g. deer hunting and skinning) without any recognizable immediate sequelae. However, months or years later, after experiencing a second or third EM outbreak, usually at different body site, the patient becomes acutely ill and may go on to develop persistent symptoms. We argue that these events represent recurrent, rather than reactivation episodes, perhaps caused by a different Bb strain(s). Alternatively, it is conceivable that multiple Bb infections simply overwhelm the immune system over time. Multiple strain infection with Bb has been described (67) but there are no prevalence data whatsoever which might provide insight into these issues. Intuitively speaking, it might be of considerable clinical import with regard to the recommended length and types of therapy one should offer, were we able to correlate or predict that, for example, simultaneous infection with multiple Bb strains led to a more serious illness. Likewise, in chronic neuroborreliosis, the identification of infection with multiple coexisting Bb strains could conceivably influence a clinician’s approach to therapy. In fact, there are pertinent biologic correlates to support the notion that multiple strain infection has clinical implications. In recent news at the 10th Clinical Retrovirus and Opportunistic Infection conference, there were reports of well documented infection with two separate strains of HIV that led to accelerated and more severe symptoms (68). We now believe that some Bb infections which manifest EM may in fact simply represent the first known manifestation of Bb infection in previously infected patients, some of whom go on to develop persistent symptoms. We also speculate that infection with multiple Bb strains, whether it occurs through initial simultaneous infections or through repeated serial exposure, may have profound implications on immune response and disease expression. In other words, when EM is identified with LD, one cannot assume that this is the first encounter for the human host for Bb infection. Only extensive epidemiologic prevalence studies using more sensitive serologic tests than are currently available, which logically ought to be done in known “hot pocket areas”, can answer that question. Of course, in these cases, the presence of co infections would also need to be considered, as this likely occurs more than commonly appreciated and clearly correlates with more severe illness (29,30,31,32,33). Studies to clarify these issues are desperately needed.
In addition to an extracellular phase, Bb has been identified as an intracellular pathogen (69). The organism has been identified to reside in macrophages (69), fibroblasts (70,71), glial and neuron cells (19) and presumably many other sites. The capacity for an organism to exist in an intracellular habitat carries certain implications. For example, most persistent intracellular infections evoke a predominately Th-1, or cell-mediated, response from the immune system. Activation of Th-1 and the attendant cytokine release (see below) in chronic infection state accounts for and generally lead to a number of debilitating symptoms. A model for this in humans is Mycobacterium tuberculosis, which manifests several of the properties we are attempting to ascribe to Bb, namely latency, slow replicative properties, reactivation, and escape from immune surveillance. Perhaps the conventional tuberculosis model for treatment, which in the past has consisted of therapy for up to 18 months, is a good way to begin to think about the approach to neuroborreliosis therapy. We know that, with the proper antimicrobial molecule, we have the capability to eradicate intracellular pathogens (72), so it would be important to use antibiotics known to work by penetrating the cell and interfering with critical intracellular bacterial processes, which generally imply bacterial ribosomal or DNA sequencing interference (73). Examples of these agents include tetracyclines, quinolones, and macrolides which, incidentally, also work well on susceptible organisms outside the cell. In contrast, cell wall active agents, such as penicillins and cephalosporins, may work well against Bb in the extracellular state, but would have no effect in the intracellular compartment. To further complicate the treatment issue, while we do have some limited in vitro susceptibility data on Bb (60), we have no information about the organism’s ability, if any, to develop drug resistance, a routine occurrence with almost all other bacterial pathogens. Acknowledging the capacity for Bb to alter its molecular structure inside the tick gut and elsewhere, we feel it is likely that Bb has the capacity to mutate against antibiotic pressure in vivo. In addition, we now assume that the neuroborreliosis patient may have multiple Bb strains, some of which may be resistant to conventional antimicrobial therapy. This then presents a presently unsolvable clinical conundrum in therapy when our patient on long term therapy fails to respond. We are then left with clinical empiricism as the only rational approach.
Patient-to-patient variability in the spectrum of host response is well accepted and may depend not only on the immune experience, but also on various unique individual immune markers such as HLA type, natural killer cell activity, lymphocyte subset profiles, and so forth. In other words, we all respond in our individual way to an invading microbe. It is clear to us that a significant portion of our LD cases occur as a result of a reactivation phenomenon, which in turn implies that Bb is a dormant infection in these individuals. It is conceivable that many Bb infections, both recognized and unapparent, have their genesis in a latent infected state which has the potential for reactivation whenever the proper circumstances occur, such as immune activation for any number of reasons. One could then theorize that there are individual predetermined immune sets whose variations account for one patient being able to suppress Bb infection indefinitely and another patient suffering the manifestations of Bb infection to varying degrees.
It would seem that the entire field of Bb infection and human immunologic response lies before us and that we need to begin to do systematic reviews on HLA haplotype status, analysis of T cell subsets, and other immunologic markers so that we can better understand the factors involved in primary response and chronic infection.
In summary, regarding host-organism interaction, we espouse the view that Bb may be a true persistent infection in a significant number of cases, associated with persistent clinical symptoms in a small percentage of these cases, and lie dormant via “immune suppression” in the vast majority of these persistently infected individuals. We believe that persistence is more common in unrecognized or untreated cases versus those treated within the first 2-3 weeks of the EM rash or other symptoms, but that early treatment for Bb by no means guarantees that persistent LD, i.e. neuroborreliosis, will not develop.
We support this idea of latency or dormancy by describing a group of patients at Jemsek Specialty Clinic who developed clinically consistent and laboratory confirmed cases of LD in a low incidence area (North Carolina) at the wrong time of year (winter). In addition, a significant number of our cases have provided a history of documented LD sometime in the past, as long as 15 years earlier, which had been treated according to the convention of the time and in which the patient had appeared to recover. Later, these patients present with clinical and laboratory evidence for neuroborreliosis, often in dramatic fashion. None of these cases suggested reexposure to Bb in the interim or “asymptomatic” periods, and several had actually moved from a high endemic area (northeast sector) to the Carolinas. In most of these cases, the patient had an easily identifiable “trigger”, such as a severe illness, e.g. documented parvovirus infection, or a severe and sustained emotional trauma that preceded the recurrence of Bb syndrome. This situation would then seem akin to what is described for chronic fatigue, or immune dysfunction syndrome (IDS), or for that matter, herpes simplex or herpes zoster reactivation infections. The immune system is “turned on”, or “activated” and a chronic endogenous or latent infection is reactivated. Since the immune system was not able to eradicate Bb in the first place, it cannot be expected to perform well in this reactivation event. Instead, what usually occurs is that one develops a persistent state of immune activation with its attendant cytokine barrage and cascade of immunologically active proteins or cytokines (76,78,79). These cytokines, which include tumor necrosis factor, IL-6, IL-1, and others (see above), are well known to be associated with symptoms of fatigue, cognitive dysfunction, and abnormal muscle pain, just to name a few unpleasant symptoms (80). What is poorly understood and seems counterintuitive is the realization that, in the patient with reactivation Bb, the immune system was in fact able to suppress the infection for extended periods of time. Paradoxically, once this immune surveillance and suppression is lost, these patients can become quite ill for lengthy periods and present very difficult treatment challenges. It would appear that a fundamental shift in immune competence as it relates to Bb has occurred in these cases.