tick borne disease may be more than just borreliosis

Discussion in 'Lyme Disease Archives' started by tansy, Jul 20, 2006.

  1. tansy

    tansy New Member

    University of Wales, College of Medicine,
    Accident and Emergency, Heath Park, Cardiff
    United Kingdom, Cardiff, United Kingdom

    Received 22 March 2006; accepted 30 March 2006.
    Available online 30 June 2006.

    Summary

    Lyme disease is considered to be caused
    by Borrelia species of bacteria but slowly
    evidence is accumulating which suggests
    that Lyme disease is a far more complex
    condition than Borreliosis alone. This
    hypothesis suggests that it may be more
    appropriate to regard Lyme disease as a
    tick borne disease complex. Over recent
    years numerous different microbes have
    been found in ticks which are known to
    be zoonotic and can coinfect the human
    host. The hypothesis suggests that
    multiple coinfections are invariably
    present in the clinical syndromes
    associated with Lyme disease and it is
    suggested that these act synergistically
    in complex ways. It may be that patterns
    of coinfection and host factors are the
    main determinants of the variable clinical
    features of Lyme disease rather than
    Borrelia types. An analogy with a jigsaw
    puzzle is presented with pieces representing
    Borreliae, coinfections and host factors.
    It is suggested that many pieces of the
    puzzle are missing and our knowledge of
    how the pieces fit together is rudimentary.
    It is hoped that the hypothesis will help
    our understanding of this complex, enigmatic
    condition.

    Introduction

    Lyme disease is a condition associated with
    spirochete bacteria of the Borrelia genus
    transmitted by ticks of the Ixodes species.
    This association was made in 1982 [1]. An
    expanding clinical entity of Lyme disease
    was already recognised [2]. Since its
    recognition Lyme disease has caused
    controversy within the medical profession
    with frequent lack of agreement about
    diagnosis and treatment. This paper suggests
    that a possible source of the confusion has
    been the preoccupation with Borrelia as the
    cause of Lyme disease. A hypothesis is
    presented that Borrelia alone does not
    result in the clinical syndromes we associate
    with Lyme disease.

    The prevalence of Lyme disease in the USA
    is reported to be increasing [3]. This may
    partly reflect a true increase in incidence
    but is also likely to reflect increasing
    recognition of the disease. The CDC recognises
    that the reported cases of Lyme disease
    underestimate the true prevalence of Lyme
    disease. The true prevalence remains unknown [3].

    The CDC criteria for reporting Lyme disease
    includes two tier serological testing [3]
    but it is accepted that this may not be
    appropriate for diagnosis in a clinical
    setting [3]. Both false positive and false
    negative results can occur using serologically
    based tests and laboratories have been found
    to yield inconsistent results when reporting
    results of serological testing [4] and [5].

    Culturing of spirochetes is difficult and
    Borrelia PCR testing has been suggested to
    hold promise for diagnosis [6] but the
    sensitivity of the test is low especially
    if blood is used as the material for
    testing [6].

    Where the main clinical hallmark of Lyme
    disease, the Erythema migrans rash, is
    present diagnosis of Lyme disease in an
    endemic area is relatively straightforward
    and the diagnosis should be purely clinical
    [7]. Lyme disease may be present in the
    absence of EM however [8] and while some
    fear this may result in over-diagnosis of
    Lyme disease [8] it should be recalled that
    the true prevalence of Lyme disease is not
    known.

    In Lyme disease classical inflammatory
    indices may be normal and objective features
    traditionally associated with infection such
    as temperature are usually absent although
    subjective symptoms such as chills are common
    [9]. As we have noted diverse presentations
    of Lyme disease occur and the encephalopathy
    may be the presenting feature [9] and [10].

    The optimum treatment for Lyme disease has
    not been established [9]. Courses of treatment
    recommended in many medical textbooks may be
    adequate for early infection but will
    frequently fail in chronic Lyme disease.
    Retrieval of Borrelia by culture and PCR
    has been reported from Lyme disease patients
    even after repeated antibiotic courses [11]
    and [12].

    Coinfections are being increasingly recognised
    in Lyme disease but their precise role is
    proving difficult to elucidate. There are many
    different micro-organisms found in ticks which
    are capable of causing a Zoonosis. They
    include species of Anaplasma (Erhlichia)
    [13], Babesia [14], Bartonella [15] Mycoplasma
    [16] and Rickettsiae [17] as well as others.
    All may be transmitted by other vectors as
    well as ticks and all have a very wide
    geographic distribution.

    The hypothesis

    This hypothesis suggests that Lyme disease
    only results when certain synergistic
    combinations of micro-organisms occur in
    the host. Borreliosis alone may be an
    insufficient condition for the development
    of Lyme disease.

    It is postulated that only in the presence
    of other micro-organisms in addition to
    Borrelia can Lyme disease develop. These
    other micro-organisms may be tick borne,
    other vector borne or non vector borne
    microbes and may be bacterial, protozoan,
    viral or even fungal.

    Pathogenic micro-organisms which may be
    chronic and are not associated with
    traditional markers of infection have
    been termed stealth organisms but this
    term has not been widely used in the
    medical literature to date.

    An analogy with a jigsaw puzzle is
    suggested whereby symptomatic disease
    only occurs when certain pieces of the
    jigsaw puzzle are in place, the pieces
    representing coinfections, known and unknown,
    and host factors.

    Evidence for the hypothesis

    (1) Coinfections. Coinfections are recognised
    to be important in Lyme disease [18] and it
    is not possible to consider the topic of Lyme
    disease without also considering coinfections
    although some authors have attempted to do
    this [7].

    In one study of 240 patients diagnosed with
    Lyme disease 11% were found to have evidence
    of concurrent Babesia infection [19]. In
    another study of 27 Lyme disease patients
    100% were found to have evidence of persistent
    Mycoplasma fermentans infection by PCR analysis
    despite previous lengthy antibiotic treatment
    [20].

    The frequent finding of coinfections in Lyme
    disease patients is one piece of evidence
    suggesting that Borrelia alone may be
    insufficient for the development of Lyme
    disease. Just as it can be difficult to
    confirm the presence of Borrelia in Lyme
    disease it can also be difficult to confirm
    the presence of coinfections. This implies
    that we are likely to underestimate the
    frequency with which coinfections occur
    in Lyme disease.

    Attempts to distinguish which symptoms are
    due to Borrelia and which are due to
    coinfections in a patient can be difficult.
    For example it has been reported that the
    symptoms of Babesia and Borrelia may be
    difficult to distinguish [19] and [21].
    Presentation of Anaplasma infection is
    usually non specific with flu like symptoms
    similar to those which may occur in early
    Borrelia infection [22].

    Since it is likely that there are
    coinfections which remain to be discovered
    a picture emerges that in Lyme disease
    multiple coinfections may be present in
    most if not all cases and attempting to
    ascribe different symptoms to different
    organisms will prove difficult.

    Detection of the presence of the organisms
    associated with Lyme disease can be difficult
    for the following reasons:

    (a) The organisms are few in number.

    (b) The organisms are difficult to culture.

    (c) There may be failure to elicit an
    antibody response due to insufficient
    antigen numbers, immunomodulation or immune
    evasion by the organisms.

    (2) Known carrier state for Borrelia. There
    is evidence for a carrier state of Borreliosis
    [23] whereby an individual may harbour
    Borrelia but be asymptomatic. The frequency
    with which this occurs is not known since
    patients who are asymptomatic rarely have
    tests which would indicate the presence of
    viable Borreliae. In the context of this
    hypothesis latent Borreliosis may exist
    because of the absence of other necessary
    micro-organisms although many alternative
    mechanisms could be postulated to account
    for the phenomenon.

    (3) Variable clinical manifestations of
    Lyme disease. We have already noted that
    the presentation of Lyme disease can be
    highly variable and there could be many
    possible reasons for this. One possible
    reason is that the variable manifestations
    correlate with variations in type and load
    of coinfections. As we have noted attempts
    to distinguish which symptoms are due to
    which coinfection in Lyme disease are
    difficult as would be expected if a complex,
    variable, poly-microbial eco-system is present.

    One aspect of the variable clinical features
    of Lyme disease is the apparent difference
    in presentation between different geographic
    areas. For example differences have been
    noted between the American and European forms
    of the disease [7]. While this may in part
    be due to differences between strains of
    Borreliae it may also be that the differences
    reflect a differing coinfecting load in the
    two groups.

    (4) Multi-system nature of Lyme disease. Lyme
    disease is a multi-system illness and this is
    recognised in the CDC criteria for diagnosis.
    Objective criteria for multi-system involvement
    may be absent and patients with confirmed
    Borreliosis on occasion have symptoms of
    multi-system involvement without signs [24].
    Lyme disease patients frequently have
    differing symptoms [3], [9] and [25] and
    this might lead one to question how it is
    that one condition can result in such a
    vast array of symptoms. This hypothesis
    suggests that the answer is that Lyme
    disease is not one condition but a disease
    complex caused by a variable system of
    interdependent micro-organisms.

    (5) Difficulty in treating Lyme disease. It
    is known that Lyme disease can be difficult
    to treat [9] and [12] and there is evidence
    that Lyme disease treatment is more likely
    to be successful when undertaken early on
    [26]. Various reasons have been suggested
    for the difficulties in treating the
    condition and there is evidence for a
    cystic, dormant form of Borrelia which
    is unresponsive to antibiotics [27].
    In the context of the present hypothesis
    another possible reason for the
    difficulties in treatment could be the
    complex, variable microbial load.

    (6) Lyme like illness with Erythema
    migrans in the apparent absence of
    Borrelia burgdorferi – Masters or STARI
    disease. The condition often referred to
    as Masters disease is a condition which
    may follow the bite of a Lonestar tick,
    Amblyomma americanum [28]. Masters
    Disease resembles Lyme disease but
    despite intensive efforts Borreliae
    have so far not been recovered from
    patients with this condition and the
    putative organism Borrelia lonestari
    has not been cultured [29] and [30].
    Within lonestar ticks Borreliae have
    been found but their role in the
    pathogenesis of masters disease remains
    unproven [31]. Erythema migrans does
    occur following lone star tick bites
    [28] and Erythema migrans is normally
    considered to be pathognomonic of
    Borreliosis. However it may be the case
    that other types of micro-organisms
    found in the lonestar tick can produce
    Erythema migrans in the absence of
    Borrelia and this is consistent with
    the present hypothesis. Using a jigsaw
    puzzle analogy there may be sufficient
    pieces in place for Erythema migrans to
    develop in the absence of the jigsaw
    piece which represents Borrelia. The
    suggestion that Borrelia may sometimes
    not be necessary for the development of
    a Lyme disease like illness goes beyond
    the current hypothesis but it is plausible.
    In a recent study [32] it was found that
    the clinical features associated with
    Erythema migrans in Missouri where Lone
    star ticks are common were quite different
    to patients presenting with Erythema migrans
    from New York State where B. burgdorferi
    is prevalent in Ixodes ticks. While
    different Borrelia types may explain
    the differences in clinical features an
    alternative explanation is that the
    differences reflect the presence of
    different complements of coinfection.

    Evidence for synergism between Borrelia and
    coinfections

    Implicit in this hypothesis is the concept
    that in Lyme disease Borrelia acts in concert
    with other micro-organisms for their mutual
    benefit but to the detriment of the host.
    It should be appreciated that if this
    hypothesis is true it will be virtually
    impossible to study synergism within the
    human host since by the time people become
    symptomatic they will invariably be multiply
    coinfected.

    In one study in humans [19] it was found
    that clinical symptoms appeared to be more
    severe in patients who had both Borrelia and
    Babesia infection than in either condition alone.

    Using a mouse model it has been found that
    coinfection with Babesia microti and B. burgdorferi
    results in greater severity of carditis and
    arthritis than by either infection alone [33].

    A similar finding of increased severity of Lyme
    arthritis has been found in mice coinfected
    with Anaplasma phagocytophilum, the agent
    of HGE, and B. burgdorferi [34]. In
    another study in mice coinfected with
    Anaplasma and Borrelia it was shown that
    an increase in spirochaete numbers occurred
    in the presence of Anaplasma [35]. It was
    postulated that the ability of A.
    phagocytophilum to functionally impair
    neutrophils was a possible mechanism for
    the observed synergy [35].

    Beyond modification of the host immune
    response there are many possible mechanisms
    in which synergism between tick borne
    pathogens may occur but such discussion
    is beyond the scope of this article. Borrelia
    is a highly complex microbe [36] and certainly
    has the genetic capacity for complex interactions
    with the host, other tick borne and possibly non
    tick borne microbes.

    Implications of the hypothesis

    If it is true that Lyme disease is invariably
    due to the presence of a complex of different
    micro-organisms then the implications are
    profound. The role played by Borrelia in
    the condition is diminished and it may become
    necessary to redefine Lyme disease in terms
    of a tick borne disease complex rather than
    a condition caused by Borrelia.

    The hypothesis implies that Lyme disease as a
    tick borne disease complex will remain an
    illness which is diagnosed clinically.
    Difficulties will arise when tick borne
    micro-organisms are found in a patient who
    exhibits features of another illness and it
    may be that dual diagnosis will become more
    common.

    An interesting implication of the hypothesis
    is that Lyme disease may develop in stages
    analogous to adding pieces to a jigsaw puzzle.
    Latent Borreliosis from an earlier tick bite
    may not become symptomatic until the necessary
    coinfections have been introduced.

    An important implication of the hypothesis
    relates to treatment. The hypothesis suggests
    that treatment may need to be tailored to
    patients according to the complement of
    coinfecting organisms. This tailoring will
    be difficult to achieve until methods of
    detection of Borrelia and its coinfections
    are improved. In the meantime the hypothesis
    suggests that it is unlikely a definitive
    treatment protocol for Lyme disease will be
    found. If synergism is occurring between
    pathogens the hypothesis lends support to
    either a monotherapy or combination therapy
    approach as being reasonable.

    The hypothesis has implications for clinical
    research into Lyme disease. It will be
    difficult to produce matching controls of
    Lyme disease patients for clinical trials
    as it is unlikely the full complement of
    the infecting load will be the same for
    any two cases. At the scientific level the
    hypothesis suggests that research into Lyme
    disease should focus on mechanisms of microbial
    interaction within the host. Such an ecological
    approach will be difficult technically but
    modern molecular biological techniques have
    enabled this work to begin [37].

    Using the jigsaw puzzle analogy it is likely
    that numerous pieces of the puzzle are yet to
    be found: It is highly likely new coinfections
    and host factors will be discovered in this
    truly complex and highly evolved disease.


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  2. jarjar

    jarjar New Member

    For posting this on the lyme board. You always come up with some good stuff! Hope to see your name pop up more often.


    jay
  3. tansy

    tansy New Member

    Hi Jay

    It's good to be back. There's been a lot going on, and the computer problems continue, so life's been challenging.

    Take care,
    Tansy