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ILADS
DIAGNOSTIC HINTS AND TREATMENT GUIDELINES
FOR LYME AND OTHER TICK BORNE ILLNESSES
JOSEPH J. BURRASCANO JR., M.D.
Fourteenth Edition
November, 2002
Copyright, November, 2002
TABLE OF CONTENTS
INTRODUCTION
BACKGROUND
INFORMATION
SPIROCHETE
LOAD AND IMMUNE SUPPRESSION IN LYME DISEASE
CO-INFECTION
COLLATERAL CONDITIONS
LYME
BORRELIOSIS
DIAGNOSTIC
HINTS
ERYTHEMA MIGRANS
DIAGNOSING LATER DISEASE
DIAGNOSTIC CHECKLIST
SYMPTOM CHECKLIST
LYME
DISEASE TREATMENT GUIDELINES
LYME BORRELIOSIS
GENERAL
INFORMATION
TREATMENT RESISTANCE
COURSE DURING THERAPY
BORRELIA NEUROTOXIN
LYME
DISEASE TREATMENT INFORMATION
ANTIBIOTICS
COMBINATION THERAPY
PULSE THERAPY
MONITORING THERAPY
INDICATORS FOR PARENTERAL THERAPY
ANTIBIOTIC
CHOICES
ORAL
THERAPY
PARENTERAL THERAPY
TREATMENT
CATEGORIES
PROPHYLAXIS
TICK BITES
EARLY LOCALIZED
DISSEMINATED DISEASE
EARLY DISSEMINATED
PARENTERAL ALTERNATIVES
LATE DISSEMINATED
CHRONIC
LYME DISEASE
SAFETY
CO-INFECTIONS
IN LYME
PIROPLASMOSIS
(Babesiosis)
GENERAL
INFORMATION
SYMPTOMS
DIAGNOSTIC TESTS
TREATMENT
EHRLICHIOSIS
GENERAL
INFORMATION
DIAGNOSTIC TESTING
TREATMENT
BARTONELLA
NUTRITIONAL
SUPPLEMENTS IN DISSEMINATED LYME DISEASE
BASIC
DAILY REGIMEN
OPTIONAL SUPPLEMENTS FOR SPECIAL CIRCUMSTANCES
LYME
DISEASE REHABILITATION
LYME
REHAB — PHYSICAL THERAPY PRESCRIPTION
MANAGING
YEAST OVERGROWTH
YEAST
CONTROL DIET
PATIENT
INSTRUCTIONS ON BITE PREVENTION AND TICK REMOVAL
HOW
TO PROTECT YOURSELF FROM TICK BITES
HOW TO REMOVE AN ATTACHED TICK
APPENDIX
RATIONALE
FOR TREATING TICK BITES
INTRODUCTION
Welcome to the fourteenth
edition of the "Guidelines." With the passage of time, our understanding
of tick-borne illness has grown, so new information is presented to help
us further refine our management techniques.
“Lyme Disease”
is not simply an infection with Borrelia burgdorferi, but a complex
illness potentially complicated by multiple tick-borne co-infections.
In later stages, it also includes a very significant degree of immune
suppression. This not only serves to perpetuate the infections, but it
is probably responsible for the reactivation of latent infections, such
as herpes-type viruses. Many collateral conditions result in those who
have been chronically ill so it is not surprising that damage to virtually
all bodily systems can result. To fully recover, all of these issues must
be addressed in a thorough and systematic manner. No single treatment
or medication will result in full recovery of the more ill patient. Only
by addressing all these smaller issues and engineering treatments and
solutions for all of them will we be able to restore full health to our
patients.
Once again, the full
spectrum of Lyme Borreliosis will be addressed, from the new bite, through
early and late disseminated infections, and certainly to chronic Lyme
Disease.
A very important
issue is the definition of “Chronic Lyme Disease.” Based on
my clinical data and the latest published information, I offer the following
definition. To be said to have chronic Lyme, these three criteria must
be present:
- Illness present
for at least one year
- Have persistent
major neurologic involvement (such as encephalitis/encephalopathy, meningitis,
etc.) or active arthritic manifestations (active synovitis).
- Still have active
infection with B. burgdorferi, regardless of prior antibiotic therapy
(if any).
It is clear that
in the great majority of patients, chronic Lyme is a disease affecting
predominantly the nervous system. Thus, careful evaluation often includes
neuropsychiatric testing, SPECT and MRI brain scans, CSF analysis when
appropriate, regular input from Lyme-aware neurologists and psychiatrists,
pain clinics, and occasionally specialists in psychopharmacology.
As an extension of
the effect of chronic Lyme Disease on the central nervous system, new
information has demonstrated a deleterious effect on the hypothalamic-pituitary
axis. Varying degrees of pituitary insufficiency are being seen in these
patients, the correction of which has resulted in restoration of energy,
stamina and libido, and resolution of persistent hypotension. Unfortunately,
not all specialists recognize pituitary insufficiency, partly because
of the difficulty in making the laboratory diagnosis. However, the potential
benefits of diagnosing and treating this justify the effort needed for
full evaluation.
The concept of a
“therapeutic alliance” between the caregiver and patient must
again be emphasized. This means that the patient has to work with and
become part of the medical team, and must take responsibility for complying
with the recommendations given, maintaining the best possible health status,
reporting promptly any problems or new symptoms, and especially in realizing
that despite all our best efforts, success in diagnosis and treatment
is never assured. The medical team must make great efforts to listen carefully
to the patient and not be too quick to dismiss seemingly bizarre or illogical
complaints.
I once again extend
my best wishes to the many patients and caregivers who deal with Lyme,
and a sincere thank you to my colleagues whose endless contributions have
helped me shape my approach to tick borne illnesses. I hope that my new
edition proves to be useful. Happy reading!
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BACKGROUND
INFORMATION
SPIROCHETE LOAD
AND IMMUNE SUPPRESSION IN LYME DISEASE
The spirochete load
has a direct bearing on the severity of Lyme presentation. Low spirochete
loads result in mild or even inapparent infections that can be missed
and remain present for years. As spirochete load increases, especially
from subsequent tick bites, the morbidity of Lyme increases. Symptoms
become apparent and more debilitating the larger the load, and testing
for Lyme can become more accurate. Studies have shown that higher loads
also begin to clinically impact the immune system, with invasion and killing
of B- and T-lymphocytes, including Natural Killer Cells, and inhibition
of lymphocyte transformation and mitogenesis. A corollary to the issue
of spirochete load is the delicate balance between defense efficacy vs.
pathogen strength. In other words, more severe illness also results from
weakened defenses, such as from severe stress, immunosuppressant medications,
and severe intercurrent illnesses.
The longer one is
ill with Lyme, the more likely the illness will be more severe and treatment
resistant. The same studies that demonstrated lymphocyte inhibition and
lysis from high spirochete loads also demonstrated increased negative
effects on the immune system the longer the spirochetes were present.
We have seen this clinically, with the ultimate result being full blown
Chronic Lyme Disease.
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CO-INFECTION
A huge body of research
and clinical experience has demonstrated the nearly universal phenomenon
in Lyme patients of co-infection with multiple tick-borne pathogens. Significant
numbers of Lyme patients have been shown to also carry Babesia species,
Ehrlichias, Anaplasmas, Mycoplasmas, Bartonellas and viruses. Rarely,
yeast forms have been seen in peripheral blood. Studies have shown that
co-infection results in a more severe clinical presentation, with more
organ damage, and the pathogens become more difficult to eradicate. It
is known that Babesia infection, like Lyme Borreliosis, is immunosuppressive.
There are changes in the clinical presentation compared to when each infection
is present individually, with different symptoms, and atypical signs.
There may be decreased reliability of standard diagnostic tests, and most
importantly, there is recognition that chronic, persistent forms of each
of these infections do indeed exist. As time goes by, I am convinced that
even more pathogens will be found.
Therefore, real,
clinical Lyme as we have come to know it, especially the later and more
severe presentations, probably represents a mixed infection. I will leave
to the reader the implications of how this may explain the discrepancy
between laboratory study of pure Borrelia infections, and what front-line
physicians have been seeing for years in real patients.
The evaluation of
a Lyme patient must begin with testing for all currently known tick borne
pathogens. Serological studies for Borrelia, Babesia Bartonella and Ehrlichia
should be combined where appropriate with direct antigen assays. Antigen
detection tests (antigen capture and PCR) are especially helpful in evaluating
the seronegative patient and those still ill or relapsing after therapy.
Unfortunately, over a dozen protozoans other than Babesia microti can
be found in ticks, yet commercial tests for only B. microti and WA-1 are
available at this time, so as in Borrelia, clinical assessment is the
primary diagnostic tool. In Ehrlichiosis, test for both the monocytic
and granulocytic forms. Many presently uncharacterized Ehrlichia-like
organisms can be found in ticks and may not be picked up by currently
available assays, so in this illness too, serologies are only an adjunct
in making the diagnosis.
Babesia are parasites,
and I suggest that if a coinfection is found involving this organism,
treat this first, so that subsequent therapy for the other pathogens will
be more effective.
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COLLATERAL
CONDITIONS
Experience has shown
that collateral conditions exist in those who have been ill a long time.
The evaluation should include testing both for differential diagnosis
and for uncovering other subtle abnormalities that may coexist.
Test B12 levels,
and be prepared to aggressively treat with parenteral formulations.
Pituitary and other
endocrine abnormalities are far more common than generally realized. Evaluate
fully, including growth hormone levels. When testing the thyroid, measure
free T3 and free T4 levels and TSH. Nuclear scanning and testing for autoantibodies
may be necessary.
Activation of the
inflammatory cascade has been implicated in blockade of cellular hormone
receptors. One example of this is insulin resistance, which may partly
account for the dyslipidemia and weight gain that is noted in 80% of chronic
Lyme patients. Clinical hypothyroidism can result from receptor blockade
and thus hypothyroidism can exist despite normal serum hormone levels.
In addition to measuring free T3 and T4 levels, check basal A.M. body
temperatures. If hypothyroidism is found, you may need to treat with both
T3 and T4 preparations until blood levels of both are normalized.
Tilt table testing
is another powerful tool which, just as in CFIDS, may demonstrate neurally
mediated hypotension (NMH). NMH can result from autonomic neuropathy and
endocrine dyscrasias. If NMH is present, treatment can dramatically lessen
fatigue, palpitations and wooziness, and increase stamina. This test should
be done by a cardiologist and include Isuprel challenge. This will demonstrate
not only if NMH is present, but also the relative contributions of hypovolemia
and sympathetic dysfunction. Therapy is based on blood volume expansion
(increased sodium and fluid intake and possibly Florinef plus potassium).
If not sufficient, beta blockade may be added based on response to the
Isuprel challenge.
Magnesium deficiency
is very often present and quite severe. Hyperreflexia, muscle twitches,
myocardial irritability, poor stamina and recurrent tight muscle spasms
are clues to this deficiency. Magnesium is predominantly an intracellular
ion, so blood level testing is of little value. Oral preparations are
acceptable for maintenance, but most need additional, parenteral dosing:
1 gram IV or IM at least once a week until neuromuscular irritability
has cleared.
SPECT scanning of
the brain, if done by knowledgeable radiologists using high resolution
equipment, will show characteristic abnormalities in Lyme encephalopathy.
What these scans demonstrate is cerebral vasculitis, which is the underlying
mechanism for much of the symptoms of Lyme. This not only helps with the
differential diagnosis, but if done before and after acetazolamide, it
will guide in the use of vasodilators, which may clear some cognitive
symptoms. Therapy can include acetazolamide, serotonin agonists and even
Ginkgo biloba. Therapeutic trials of these may be needed.
Two different researchers
have provided evidence that B. burgdorferi, like many other pathogenic bacteria,
can produce neurotoxins. Early clinical trials aimed at removing these toxins
have proven quite promising. I will discuss this in more detail in a later
section.
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LYME BORRELIOSIS
DIAGNOSTIC HINTS
Lyme is diagnosed
clinically, as no currently available test, no matter the source or type,
is definitive in ruling in or ruling out infection with these pathogens,
or whether these infections are responsible for the patient's symptoms.
The entire clinical picture must be taken into account, including a search
for concurrent conditions and alternate diagnoses, and other reasons for
some of the presenting complaints. Often, much of the diagnostic process
in late, disseminated Lyme involves ruling out other illnesses and defining
the extent of damage that might require separate evaluation and treatment.
Consideration should
be given to tick exposure, rashes (even atypical ones), evolution of typical
symptoms in a previously asymptomatic individual, and results of tests
for tick-borne pathogens. Another very important factor is response to
treatment — presence or absence of Jarisch Herxheimer-like reactions,
the classic four-week cycle of waxing and waning of symptoms, and improvement
with therapy.
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ERYTHEMA MIGRANS
Erythema migrans
(EM) is diagnostic of Bb infection, but is present in fewer than half.
Even if present, it may go unnoticed by the patient. It is an erythematous,
centrifugally expanding lesion that is raised and warm. Sometimes there
is mild stinging or pruritus. The EM rash will begin four days to several
weeks after the bite, and may be associated with constitutional symptoms.
Multiple lesions are present less than 10% of the time, but do represent
disseminated disease. Some lesions have an atypical appearance and skin
biopsy specimens may be helpful. When an ulcerated or vesicular center
is seen, this may represent a mixed infection, involving other organisms
besides B. burgdorferi.
After a tick bite,
serologic tests (ELISA. IFA, western blots, etc.) are not expected to
become positive until several weeks have passed. Therefore, if EM is present,
treatment must begin immediately, and one should not wait for results
of Borrelia tests. You should not miss the chance to treat early disease,
for this is when the success rate is the highest. Indeed, many knowledgeable
clinicians will not even order a Borrelia test in this circumstance.
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DIAGNOSING LATER DISEASE
When reactive, serologies
indicate exposure only and do not directly indicate whether the spirochete
is now currently present. Because Bb serologies often give inconsistent
results, test at more than one laboratory using, if possible, different
methods. The suggestion that two-tiered testing, utilizing an ELISA as
a screening tool, followed, if positive, by a confirmatory western blot,
is illogical in this illness. The ELISA is not sensitive enough to serve
as an adequate screen, and there are many patients with Lyme who test
negative by ELISA yet have fully diagnostic western blots. I therefore
recommend against using the ELISA. Order IgM and IgG western blots —
but be aware that in late disease there may be repeatedly peaking IgM's
and therefore a reactive IgM may not differentiate early from late disease,
but it does suggest an active infection. When late cases of LB are seronegative,
36% will transiently become seropositive at the completion of successful
therapy.
Western blots are
reported by showing which bands are reactive. 41KD bands appear the earliest
but can cross react with other spirochetes. The 18KD, 23–25KD (Osp
C), 31KD (Osp A), 34KD (Osp B), 37KD, 39KD, 83KD and the 93KD bands are
the most specific but appear later or may not appear at all. You need
to see at least the 41KD and one of the specific bands. 55KD, 60KD, 66KD,
and 73KD are nonspecific and nondiagnostic.
PCR tests are now
available, and although they are very specific, sensitivity remains poor,
possibly less than 30%. This is because Bb causes a deep tissue infection
and is only transiently found in body humors. Therefore, just as in routine
blood culturing, multiple specimens must be collected to increase yield;
a negative result does not rule out infection, but a positive one is significant.
You can test whole blood, buffy coat, serum, urine, spinal and other body
fluids, and tissue biopsies. Several blood PCRs can be done, or you can
run PCRs on whole blood, serum and urine simultaneously at a time of active
symptoms. The patient should be antibiotic free for at least six weeks
before testing to obtain the highest yield.
Antigen capture is
becoming more widely available, and can be done on urine, CSF, and synovial
fluid.
Sensitivity is still
low, but specificity is high.
Spinal taps are not
routinely recommended, as a negative tap does not rule out Lyme. Antibodies
to Bb most commonly are found in Lyme meningitis, but are rarely seen
in non-meningitic CNS infection, including even advanced encephalopathy.
Even in meningitis, antibodies are detected in the CSF in less than 20%
of patients with late disease. Therefore, spinal taps are only performed
on patients with pronounced neurological manifestations in whom the diagnosis
is uncertain, if they are seronegative, or are still significantly symptomatic
after completion of treatment. When done, the goal is to rule out other
conditions, and to determine if Bb antigens or nucleic acids are present.
It is especially important to look for elevated protein and mononuclear
cells, which would dictate the need for more aggressive therapy, as well
as the opening pressure, which can be elevated and add to headaches, especially
in children.
I strongly urge you
to biopsy all unexplained skin lesions/rashes and perform PCR and careful
histology. You will need to alert the pathologist to look for spirochetes.
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DIAGNOSTIC CHECKLIST
To aid the clinician,
a workable set of diagnostic criteria was developed with the input of
dozens of front line physicians. The resultant document has proven to
be extremely useful not only to the clinician, but it also can help clarify
the diagnosis for third party payers and utilization review committees.
It is important to note that the CDC's published reporting criteria
are for surveillance only, not for diagnosis.
| LYME
BORRELIOSIS DIAGNOSTIC CRITERIA |
RELATIVE VALUE
|
| |
1
|
| Tick
exposure in an endemic region |
2
|
| Historical
facts and evolution of symptoms consistent with Lyme |
|
| Systemic
signs & symptoms consistent with Bb infection (other potential diagnoses
excluded): |
|
| |
Single
system, e.g., monoarthritis |
1
|
| |
Two
or more systems, e.g., monoarthritis and facial palsy |
2
|
| Erythema
migrans, physician confirmed |
7
|
| Acrodermatitis
Chronica Atrophicans, biopsy confirmed |
7
|
| Seropositivity |
3
|
| Seroconversion
on paired sera |
4
|
| Tissue
microscopy, silver stain |
3
|
| Tissue
microscopy, monoclonal immunofluorescence |
4
|
| Culture
positivity |
4
|
| B.
burgdorferi antigen recovery |
4
|
| B.
burgdorferi DNA/RNA recovery |
4
|
| |
|
| DIAGNOSIS |
|
| |
|
| Lyme
Borreliosis Highly Likely |
7
or above
|
| Lyme
Borreliosis Possible |
5–6
|
| Lyme
Borreliosis Unlikely |
4
or below
|
I suggest that when
using these criteria, you state Lyme Borreliosis is “unlikely,”
“possible,” or “highly likely” based upon the following
criteria—then list the criteria.
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SYMPTOM
CHECKLIST
This is not meant
to be used as a diagnostic scheme, but is provided to streamline the office
interview. Note the format — complaints referable to specific organ
systems are clustered to better display multisystem involvement.
NAME_______________________________________DATE__________________
RISK PROFILE (PLEASE
CHECK)
Tick infested area
___ Frequent outdoor activities ___ Hiking ___ Fishing ___ Camping ___
Gardening ___
Hunting ___ Ticks noted on pets ___ Other household members with Lyme
___
Do you remember being bitten by a tick? No ___ Yes ___ when ________
Do you remember having the “bull's eye rash?” No ___ Yes ___
Any other rash? No ___ Yes ___
Have you had any
of the following? CIRCLE ALL YES ANSWERS
- Unexplained fevers,
sweats, chills, or flushing
- Unexplained weight
change (loss or gain — circle one)
- Fatigue, tiredness,
poor stamina
- Unexplained hair
loss
- Swollen glands:
list areas _______________________________________________
- Sore throat
- Testicular pain/pelvic
pain
- Unexplained menstrual
irregularity
- Unexplained milk
production; breast pain
- Irritable bladder
or bladder dysfunction
- Sexual dysfunction
or loss of libido
- Upset stomach
or abdominal pain
- Change in bowel
function (constipation, diarrhea)
- Chest pain or
rib soreness
- Shortness of breath,
cough
- Heart palpitations,
pulse skips, heart block
- Any history of
a heart murmur or valve prolapse?
- Joint pain or
swelling: list joints _________________________________________________
- Stiffness of the
joints or back
- Muscle pain or
cramps
- Twitching of the
face or other muscles
- Headache
- Neck creaks and
cracks, neck stiffness, neck pain
- Tingling, numbness,
burning or stabbing sensations, shooting pains, skin hypersensitivity
- Facial paralysis
(Bell's Palsy)
- Eyes/Vision: double,
blurry, increased floaters, light sensitivity
- Ears/Hearing:
buzzing, ringing, ear pain, sound sensitivity
- Increased motion
sickness, vertigo, poor balance
- Lightheadedness,
wooziness, unavoidable need to sit or lie down
- Tremor
- Confusion, difficulty
in thinking
- Difficulty with
concentration, reading
- Forgetfulness,
poor short term memory, poor attention, problem absorbing new information
- Disorientation:
getting lost, going to wrong places
- Difficulty with
speech or writing; word or name block
- Mood swings, irritability,
depression
- Disturbed sleep
— too much, too little, fractionated, early awakening
- Exaggerated symptoms
or worse hangover from alcohol
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LYME
DISEASE TREATMENT GUIDELINES
LYME BORRELIOSIS
GENERAL INFORMATION
After a tick bite,
Bb undergoes rapid hematogenous dissemination, and, for example, can be
found within the central nervous system as soon as twelve hours after
entering the bloodstream. This is why even early infections require full
dose antibiotic therapy with an agent able to penetrate all tissues in
concentrations known to be bactericidal to the organism.
It has been shown
that the longer a patient had been ill with Bb prior to first definitive
therapy, the longer the duration of treatment must be, and the need for
more aggressive treatment increases.
More evidence has
accumulated indicating the severe detrimental effects of immunosuppressants
including steroids in the patient with active B. burgdorferi infection.
Never give steroids or any other immunosuppressant to any patient who
may even remotely be suffering from Lyme, or serious, permanent damage
may result, especially if given for anything greater than a short course.
If immunosuppressive therapy is absolutely necessary, then potent antibiotic
treatment should begin at least 48 hours prior to the immunosuppressants.
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TREATMENT RESISTANCE
Bb contains beta
lactamases, which, with some strains, may confer resistance to cephalosporins
and penicillins. This is apparently a slowly acting enzyme system, and
may be overcome by higher or more continuous drug levels especially when
maintained by continuous infusions (cefotaxime) and by depot preparations
(benzathine penicillin). Nevertheless, some penicillin and cephalosporin
treatment failures do occur and have responded to sulbactam/ampicillin,
imipenim, and vancomycin, which act through different cell wall mechanisms
than penicillin and the cephalosporins.
There is evidence
that B. burgdorferi can remain viable within cells, such as macrophages,
lymphocytes, endothelial cells, neurons, and fibroblasts. Bb has been
shown to evade the effects of beta lactam antibiotics in vitro by sequestering
in these intracellular niches. In addition, Bb can coat itself with host
cell membranes, and it secretes a glycoprotein that can encapsulate the
organism (an “S-layer”). Because this glycoprotein binds host
IgM, it is possible that host protein as well as cell membrane hide Borrelial
antigens. In theory at least, these coatings interfere with immune recognition,
thus affecting the clearing of Bb, and also cause seronegativity.
There are multiple
strains of Borrelia burgdorferi and they vary in their antigen profile
and antibiotic susceptibilities. It has also been recognized that B. burgdorferi
can exist in at least three different morphologic forms: spirochetal,
spheroplast (or l-form), and the recently discovered cystic form.
L-forms and cystic
forms do not contain cell walls, and thus beta lactam antibiotics will
not affect them. Spheroplasts seem to be susceptible to tetracyclines
and some erythromycins, yet the cyst has so far only been proven to be
susceptible to metronidazole. Apparently, Bb can shift among the three
forms during the course of the infection and cause the varying serologic
responses seen over time, including seronegativity. Because of this, it
may be necessary to change antibiotic or even prescribe a combination
of agents.
Vegetative endocarditis
has been associated with Borrelia burgdorferi, but the vegetations may
be too small to detect with echocardiography. Keep this in mind when evaluating
patients with murmurs, as this may explain why some patients seem to continually
relapse after even long courses of antibiotics.
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COURSE DURING THERAPY
As the spirochete
has a very long generation time (12 to 24 hours in vitro and possibly
much longer in living systems) and may have periods of dormancy, during
which time antibiotics will not kill the organism, treatment has to be
continued for a long period of time to eradicate all the active symptoms
and prevent a relapse, especially in late infections. If treatment is
discontinued before all symptoms of active infection have cleared, the
patient will remain ill and possibly relapse further. In general, early
disseminated LB is treated for four to six weeks, and late LB usually
requires a minimum of four to six months of continuous treatment. All
patients respond differently and therapy must be individualized. It is
not uncommon for a patient who has been ill for many years to require
open ended treatment regimens; indeed, some patients will require ongoing
maintenance therapy to remain well.
Several days after
the onset of appropriate antibiotic therapy, symptoms often flare due
to lysis of the spirochetes with release of increased amount of antigenic
material and possibly bacterial toxins. This is referred to as a Jarish
Herxheimer-like reaction. Because it takes 48 to 72 hours of therapy to
initiate bacterial killing, the Herxheimer reaction is therefore delayed.
This is unlike syphilis, in which these reactions can occur within hours.
It has been observed
that symptoms will flare in cycles every four weeks. It is thought that
this reflects the organism's cell cycle, with the growth phase occurring
once per month (intermittent growth is common in Borrelia species). As
antibiotics will only kill bacteria during their growth phase, therapy
is designed to bracket at least one whole generation cycle. This is why
the minimum treatment duration should be at least four weeks. If the antibiotics
are working, over time these flares will lessen in severity and duration.
The very occurrence of ongoing monthly cycles indicates that living organisms
are still present and that antibiotics should be continued.
With treatment, these
monthly symptom flares are exaggerated and presumably represent recurrent
Herxheimer-like reactions as Bb enters its vulnerable growth phase then
are lysed. For unknown reasons, the worst occurs at the fourth week of
treatment. Observation suggest that the more severe this reaction, the
higher the germ load, and the more ill the patient. In those with long-standing
highly symptomatic disease who are on IV therapy, the week-four flare
can be very severe, similar to a serum sickness reaction, and be associated
with transient leucopenia and/or elevations in liver enzymes. If this
happens, decrease the dose temporarily, or interrupt treatment for several
days, then resume with a lower dose. If you are able to continue or resume
therapy, then patients continue to improve. Those whose treatment is stopped
and not restarted at this point usually will need retreatment in the future
due to ongoing or recurrent symptoms because the infection was not eradicated.
Patients on IV therapy who have a strong reaction at the fourth week will
need to continue parenteral antibiotics for several months, for when this
monthly reaction finally lessens in severity, then oral or IM medications
can be substituted. Indeed, it is just this observation that guides the
clinician in determining the endpoint of IV treatment. In general, IV
therapy is given until there is a clear positive response, then treatment
is changed to IM or po until free of signs of active infection for 4 to
8 weeks. Some patients, however, will not respond to IM or po treatment
and IV therapy will have to be used throughout. As mentioned earlier,
leucopenia may be a sign of persistent Ehrlichiosis, so be sure to look
into this.
Repeated treatment
failures should alert the clinician to the possibility of an otherwise
inapparent immune deficiency, and a workup for this may be advised. Obviously,
evaluation for co-infection should be performed, and a search for other
or concurrent diagnoses needs to be entertained.
There are three things
that will predict treatment failure regardless of which regimen is chosen:
Non-compliance, alcohol use on a regular basis, and failure of the patient
to obtain proper rest. Advise them to take a break when (or ideally before)
the inevitable mid afternoon fatigue sets in.
All patients must
keep a carefully detailed daily diary of their symptoms to help us judge
the effects of treatment, the presence of the classic four week cycle,
and treatment endpoint. One must follow such diaries, temperature readings
in late afternoon, physical findings, notes from physical therapists,
and cognitive testing to best judge when to change or end antibiotics.
Remember — there
currently is no test for cure, so this clinical follow-up assumes a major
role in Lyme Disease care.
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BORRELIA NEUROTOXIN (With thanks to Dr. Shoemaker)
Two groups have reported
evidence that Borrelia, like several other bacteria, produce neurotoxins.
These compounds reportedly can cause many of the symptoms of encephalopathy,
cause an ongoing inflammatory reaction manifested as some of the virus-like
symptoms common in late Lyme, and also potentially interfere with hormone
action by blocking hormone receptors. At this time, there is no assay
available to detect whether this compound is present, nor can the amount
of toxin be quantified. Indirect measures are currently employed, such
as measures of cytokine activation and hormone resistance. A visual contrast
sensitivity test (VCS test) reportedly is quite useful in documenting
CNS effects of the neurotoxin, and to follow effects of treatment. This
test is available at some centers and on the internet.
It has been said
that the longer one is ill with Lyme, the more neurotoxin is present in
the body. It probably is stored in fatty tissues, and once present, persists
for a very long time. This may be because of enterohepatic circulation,
where the toxin is excreted via the bile into the intestinal tract, but
then is reabsorbed from the intestinal tract back into the blood stream.
This forms the basis for treatment.
Synthetic fiber agents,
available by prescription for the treatment of high cholesterol, have
the ability to bind some bacterial toxins. When take orally in generous
amounts, the neurotoxin, present in the intestinal tract, binds to the
resin, is trapped, and then excreted. Thus, over several weeks, the level
of neurotoxin is depleted and clinical improvement can be seen. Current
experience is that improvement is first seen in three weeks, and treatment
continues for two to four months. Retreatment is always possible.
Two prescription
medications that can bind these toxins include cholestyramine resin (Questran),
and Welchol pills. These medications may bind not only toxins but also
many drugs and vitamin supplements. Therefore no other oral medications
or supplements should be taken from one hour before, to three hours after
a dose of one of these fiber agents.
Cholestyramine must
be taken four times daily, and Welchol is prescribed at three pills twice
daily. While the latter is obviously much simpler to use, it is less effective
than cholestyramine. The main side effects are bloating and constipation,
best handled with increased fluid intake and gentle laxatives.
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LYME DISEASE TREATMENT
INFORMATION
There is no universally
effective antibiotic for treating LB. The choice of medication used and
the dosage prescribed will vary for different people based on multiple
factors. These include duration and severity of illness, presence of co-infections,
immune deficiencies, prior significant immunosuppressant use while infected,
age, weight, gastrointestinal function, blood levels achieved, and patient
tolerance. Doses found to be effective clinically are often higher than
those recommended in older texts. This is due to deep tissue penetration
by Bb, it's presence in the CNS including the eye, within cells, within
tendons, and because very few of the many strains of this organism now
known to exist have been studied for antibiotic susceptibility. In addition,
all animal studies of susceptibility to date have only addressed early
disease in models that behave differently than human hosts. Therefore,
begin with a regimen appropriate to the setting, and if necessary, modify
it over time based upon response.
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ANTIBIOTICS
There are several
types of antibiotics in general use for Bb treatment. The tetracyclines,
including doxycycline and minocycline, are bacteriostatic unless given
in high doses. If high blood levels are not attained, treatment failures
in early and late disease are common. However, these high doses can be
difficult to tolerate. For example, doxycycline can be very effective
but only if adequate blood levels are achieved either by high oral doses
(300 to 600 mg daily) or by parenteral administration.
Penicillins are bactericidal.
As would be expected in managing an infection with a gram negative organism
such as Bb, amoxicillin has been shown to be more effective than oral
penicillin V. Because of its short half-life and need for high levels,
amoxicillin is usually administered along with probenecid. Since blood
levels are extremely variable they should be measured.
Cephalosporins must
be of advanced generation: first generation drugs are rarely effective,
and second generation drugs are comparable to amoxicillin and doxycycline
both in-vitro and in-vivo. Third generation agents are currently the most
effective of the cephalosporins because of their very low MBC's (0.06
for ceftriaxone) and they have been shown to be effective in penicillin
and tetracycline failures. Cefuroxime axetil (Ceftin), a second generation
agent, is also effective against staph and thus is useful in treating
atypical erythema migrans that may represent a mixed infection, containing
some of the more common skin pathogens in addition to Bb.
When choosing a third
generation cephalosporin, there are several points to remember: Ceftriaxone
has 95% biliary excretion and can crystallize in the biliary tree with
resultant colic and possible cholecystitis. GI excretion results in a
large impact on gut flora. Biliary and superinfection problems with ceftriaxone
can be lessened if this drug is given in interrupted courses, such as
three to five days in a row each week. More recently, chenodeoxycholic
acid, used to dissolve gallstones, is being prescribed along with ceftriaxone
as prophylaxis. Cefotaxime is less convenient to administer because of
the need for either multiple daily doses or continuous infusions, but
as it has only 5% biliary excretion, it never causes biliary concretions,
and may have less impact on gut flora. It is the experience of some clinicians
that cefotaxime can be even more efficacious if given as a continuous
infusion, rather than in interrupted doses.
Erythromycin has
been shown to be almost ineffective as monotherapy. The advanced macrolides
and azalides such as azithromycin and clarithromycin can be difficult
to tolerate orally due to their tendency to promote yeast overgrowth and
poor GI tolerance at the high doses needed. As they have impressively
low MBCs and do concentrate in tissues and penetrate cells, they theoretically
should be ideal agents. However, initial clinical results were disappointing,
especially with oral azithromycin. It has been suggested that when Bb
is within a cell, it is held within a vacuole and bathed in fluid of low
pH, and this acidity may inactivate this class of antibiotics. Therefore,
they are administered concurrently with hydroxychloroquine or amantadine,
which raise vacuolar pH, rendering these antibiotics more effective. It
is not known whether this same technique will make erythromycin a more
effective antibiotic in LB. Another alternative is to administer azithromycin
parenterally. Results are excellent, but expect to see abrupt Jarisch-Herxheimer
reactions.
Metronidazole (Flagyl)
is commonly used in select patients with treatment resistant, chronic
Lyme. When present in a hostile environment, such as growth medium lacking
some nutrients, or spinal fluid, or serum with certain antibiotics added,
Bb will change into a cystic form. This cyst seems to be able to remain
dormant, but when placed into an environment more favorable to its growth,
the cyst can open, and an intact spirochete emerges. The conventional
antibiotics used for Lyme, such as the penicillins, cephalosporins, etc.
do not kill the cystic form of Bb. Furthermore, the cyst lacks the usual
surface antigens found on the spirochete (these are the markers detected
by ELISAs and western blots). This may be another reason for the chronically
sick Lyme patient remaining seronegative.
There is evidence
that metronidazole will kill the cystic form. This fits with the now well
known clinical observations that metronidazole can be remarkably effective
for many chronic Lyme patients. However, this medication apparently has
no effect on intact spirochetes. Therefore, the trend now is to treat
the chronically infected patient who has resistant disease by combining
metronidazole with one or two other antibiotics to target all forms of
Bb. Because there is laboratory evidence that tetracyclines may inhibit
the effect of metronidazole, this class of medication may not be as useful
as others in these two- and three-drug regimens. There have been some
recent reports that Bb does not contain genes that would confer susceptibility
to metronidazole. However, this clearly does not fit with in vitro and
a large body of clinical data, which have demonstrated the usefulness
of this agent in the Lyme patient. Perhaps we do not have all the genetic
information needed to dismiss the use of this agent. Once again, real
world experience is one step ahead of bench research.
Important precautions:
- Pregnancy while
on metronidazole is not advised, as there is a risk of birth defects.
- No alcohol consumption!
A severe, “antabuse” reaction will occur, consisting of severe
nausea, flushing, headache, and other unpleasant symptoms.
- Metronidazole
is potentially neurotoxic. Peripheral neuropathy may result. Therefore,
breaks in treatment are commonly prescribed, such as using this agent
every other week.
- Yeast overgrowth
is especially common. A strict anti-yeast regimen must be followed.
- VERY severe Herxheimer-like
reactions are seen in the more ill patient during the first week of
therapy, and again four weeks later.
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COMBINATION THERAPY
This consists of
using two or more dissimilar antibiotics simultaneously. There are several
reasons for this. Combinations should utilize dissimilar antibiotics for
antibiotic synergism, to better compensate for differing killing profiles
and sites of action of the individual medications, and to cover the three
known morphologic forms of Bb. The idea is to work in body fluids and
in deep tissues, outside and within cells, and effect killing by different
mechanisms for synergism. An example is a combination of amoxicillin and
clarithromycin. Note how complimentary these two are for treating infection
with Bb. GI intolerance and yeast superinfections are the biggest drawbacks
to this type of treatment. However, these complications can often be prevented
or easily treated, and the clinically observed benefits of this type of
regimen clearly have outweighed these problems in selected patients.
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PULSE THERAPY
This consists of
administering antibiotics (usually parenteral ones) two to three days
in a row per week. The efficacy of this regimen is based on the fact that
it takes 48 to 72 hours of continuous bactericidal antibiotic levels to
kill the spirochete, yet it will take longer than the four to five days
between pulses for the spirochetes to recover. This allows for several
advantages:
- Dosages are doubled
(ie: cefotaxime, 12 g daily), increasing efficacy
- More toxic medications
can be used with increased safety (ie: vancomycin)
- May be effective
when conventional, daily regimens have failed.
- IV access may
be easier or more tolerable
- More agreeable
lifestyle for the patient
- Often less costly
than daily regimens
Note that this type
of treatment is expected to continue for a minimum of ten weeks, and often
must continue beyond twenty weeks. As with all Lyme treatments, specific
dosing and scheduling must be tailored to the individual patient's clinical
picture based upon the treating physician's best clinical judgment.
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MONITORING THERAPY
Drug levels are measured,
where possible, to confirm adequate dosing. The regimen may have to be
modified to optimize the dose, and again at any time major changes in
the treatment regimen occur. With parenteral therapy, CBC and chem/liver
panels are done at least twice each month, especially during symptom flares,
with urinalysis and protime monitored monthly.
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INDICATORS FOR PARENTERAL
THERAPY
The following are
guidelines only and are not meant to be absolute. It is based on retrospective
study of over 600 patients with late Lyme disease.
- Illness for greater
than one year
- Prior immunosuppressive
therapy
- Major neurological
involvement
- Active synovitis
with high sedimentation rate
- Elevated protein
or cells in the CSF
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ANTIBIOTIC CHOICES
ORAL THERAPY
Always check blood
levels when using agents marked with an *, and adjust dose to achieve a
peak level in the mid- teens and a trough greater than five. Because
of this, the doses listed below may have to be raised. Consider Doxycycline
first due to concern for Ehrlichia.
| *Amoxicillin |
Adults: 1g q8h
plus probenecid 500mg q8h; doses up to 6 grams daily are often needed |
| |
Pregnancy: 1g
q6h and adjust |
| |
Children: 50
mg/kg/day divided into q8h doses |
| *Doxycycline |
Adults: 100
mg qid with food; doses of up to 600 mg daily are often needed, as
doxycycline is only effective at high blood levels. |
| |
Not for children
or in pregnancy. |
| |
If levels are
too low at tolerated doses, give parenterally. |
| *Cefuroxime
axetil |
Oral alternative
that may be effective in amoxicillin and doxycycline failures. Useful
in EM rashes co-infected with common skin pathogens. |
| |
Adults and pregnancy:
1g q12h and adjust. |
| |
Children: 125
to 500 mg q12h based on weight. |
| Tetracycline |
Adults only,
and not in pregnancy. 500 mg tid to qid |
| Erythromycin |
Poor response
and not recommended. |
| Clarithromycin |
Adults: 500
to 1000 mg q12h. Add hydroxychloroquine, 200–400 mg/d or amantadine
100–200 mg/d. |
| |
Cannot be used
in pregnancy or in younger children |
| Azithromycin |
Adults: 500
to 1200 mg/d. |
| |
Adolescents:
250 to 500 mg/d. |
| |
Add hydroxychloroquine,
200–400 mg/d, or amantadine 100–200 mg/d |
| |
Cannot be used
in pregnancy. |
| |
Oral azithromycin
is not as effective as clarithromycin. |
| Augmentin |
Cannot exceed
three tablets daily due to the clavulanate, thus is given with amoxicillin. |
| |
This combination
can be effective when Bb beta lactamase is felt to be present. |
| Chloramphenicol |
Not recommended
as not proven and potentially toxic. |
| Metronidazole
(see text) |
500 to 1500
mg daily in divided doses. Adults only. |
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PARENTERAL
THERAPY
| Ceftriaxone |
Risk of biliary
sludging can be minimized with intermittent breaks in therapy (ie:
infuse five or less days in a row per week). |
| |
Adults and pregnancy:
2g q12h, four days in a row each week. |
| |
Children: 75
mg/kg/day up to 2g/day |
| Cefotaxime |
Comparable efficacy
to ceftriaxone; no biliary complications. |
| |
Adults and pregnancy:
2g q8h; may dose as high as 12g daily. Suggest a continuous infusion. |
| |
Children: 90
to 180 mg/kg/day dosed q6h (preferred) or q8h, not to exceed 12 g
daily. |
| *Doxycycline |
Requires central
line as is caustic. Surprisingly effective, probably because higher
overall, and spiked blood levels when given parenterally. |
| |
Always measure
blood levels. |
| |
Adults: 400
mg q24h and adjust based on levels. |
| |
Cannot be used
in pregnancy or in younger children. |
| Azithromycin |
Requires central
line as is caustic. |
| |
Dose: 500 to
1000 mg daily in adolescents and adults. |
| Penicillin G |
IV penicillin
G is minimally effective and not recommended. |
| Benzathine penicillin |
Surprisingly
effective IM alternative to oral therapy. |
| |
May need to
begin at lower doses as strong, prolonged (6 or more week) Herxheimer-like
reactions have been observed. |
| |
Adults: 1.2
million U three times per week (higher doses with large body habitus) |
| |
Adolescents:
300,000 to 2.4 million U weekly. |
| |
May be used
in pregnancy. |
| Poorly
studied but anecdotally effective |
| Vancomycin |
Observed to
be one of the best drugs in treating Lyme, but potential toxicity
limits its use. It is a perfect candidate for pulse therapy to minimize
these concerns. |
| |
Use standard
doses and confirm levels. |
| Imipenim and
Unisyn |
Similar in efficacy
to cefotaxime, but often works when cephalosporins have failed. |
| |
Must be given
q6 to q8 hours. |
| Cefuroxime |
Useful but not
demonstrably better than ceftriaxone or cefotaxime. |
| Ampicillin IV |
More effective
than penicillin G. Must be given q6 hours. |
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TREATMENT CATEGORIES
PROPHYLAXIS
of high risk groups — education and preventive measures. Antibiotics
are not given.
TICK BITES
— Embedded Deer Tick With No Signs or Symptoms of Lyme (see appendix)
Decide to treat based
on the type of tick, whether it came from an endemic area and percent
infected, how it was removed, and length of attachment (nymphs: at least
one day; adults: anecdotally, as little as four hours). The risk of transmission
is greater if the tick is engorged, or of it was removed improperly allowing
the tick's contents to spill into the bite wound. High risk bites are
treated as follows (remember the possibility of coinfection!):
- Adults: Oral
therapy for 21 days.
- Pregnancy: Amoxicillin
1000 mg q6h for 6 weeks. Test for Babesia, Bartonella and Ehrlichia.
Alternative: Cefuroxime axetil 1000 mg q12h for 6 weeks.
- Young Children:
Oral therapy for 21 days.
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EARLY LOCALIZED
— Single erythema migrans with no constitutional symptoms:
- Adults: oral therapy
for 6 weeks.
- Pregnancy: 1st
and 2nd trimesters: IV X 21 days then oral X 6 weeks
3rd trimester: Oral therapy X 6 weeks.
Any trimester — test for Babesia, Bartonella, and Ehrlichia
- Children: oral
therapy for 6 weeks.
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DISSEMINATED DISEASE
— Multiple lesions, constitutional symptoms, lymphadenopathy, or any
other manifestations of dissemination.
EARLY DISSEMINATED
— Milder symptoms present for less than one year and not complicated
by immune deficiency or prior immunosuppressive treatment:
- Adults: Oral therapy
until no active disease for 4 weeks (4–6 months typical)
- Pregnancy: As
in localized disease, but duration as above. Treat throughout pregnancy,
and do not breast feed.
- Children: Oral
therapy with duration based upon clinical response.
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PARENTERAL ALTERNATIVES
for more ill patients and those unresponsive to or intolerant of oral medications:
- Adults and children:
IV therapy for at least 6 weeks (until clearly improved).
Follow with oral therapy or IM benzathine penicillin until no active
disease for 6–8 weeks.
IV may have to be resumed if oral or IM therapy fails.
- Pregnancy: IV
then oral therapy as above.
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LATE DISSEMINATED
— Present greater than one year, more severely ill patients, and those
with prior significant steroid therapy or any other cause of impaired immunity:
- Adults and pregnancy:
Extended IV therapy (10 or more weeks), then oral or IM, if effective,
to same endpoint.
- Children: IV therapy
for 6 or more weeks, then oral or IM follow up as above.
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CHRONIC LYME DISEASE
By definition, this
category consists of patients with active infection, of a more prolonged
duration, and most likely have higher spirochete loads, weaker defense
mechanisms, possibly more virulent or resistant strains, and probably
are significantly co-infected. Neurotoxins may also be significant in
these patients. Search for and treat concurrent illnesses including viruses,
chlamydias, and mycoplasmas. These patients require a full evaluation
for all of these problems, and each abnormality must be addressed.
This group will most
likely need parenteral therapy, especially high dose, pulsed therapy,
and antibiotic combinations, including metronidazole. Antibiotic therapy
will need to continue for many months, and the antibiotics may have to
be changed periodically to break plateaus in recovery. Be vigilant for
treatment-related problems such as antibiotic-associated colitis, yeast
overgrowth, intravenous catheter complications, and abnormalities in blood
counts and chemistries.
If treatment can
be continued long term, then a remarkable degree of recovery is possible.
However, attention must be paid to all treatment modalities for such a
recovery — not only antibiotics, but rehab programs, nutritional
supplements, enforced rest, low carbohydrate, high fiber diets, attention
to food sensitivities, avoidance of stress, abstinence from caffeine and
alcohol, and absolutely no immunosuppressants, even local doses of steroids
(intra articular injections, for example).
Unfortunately, not
all patients with chronic Lyme disease will fully recover and treatment
may not eradicate the active Borrelia infection. Such individuals may
have to be maintained on open-ended, ongoing antibiotic therapy, for they
repeatedly relapse after antibiotics are stopped. Maintenance antibiotic
therapy is thus mandatory.
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SAFETY
Nearly two decades
of experience in treating thousands of patients with Lyme has proven that
therapy as described above, although intense, is generally well tolerated.
The most common adverse reaction seen is allergy to probenecid. In addition,
yeast superinfections are seen, but these are generally easily recognized
and managed. The induction of Clostridium difficile toxin production is
seen most commonly with ceftriaxone, but can occur with any of the antibiotic
regimens mentioned in this document. However, pulsed dose therapy and
regular use of the lactobacillus preparations seems to be helpful in controlling
yeast and antibiotic related colitis, as the number of cases of C. difficile
in Lyme patients is low when these guidelines are followed.
When using central
intravenous lines including PICC lines (peripherally inserted central
catheters), if ANY line problems arise, it is recommended that the line
be pulled for patient safety. Salvage attempts (urokinase, repairing holes)
are often ineffective and may not be safe.
Please advise all
patients who take the tetracyclines of skin and eye sensitivity to sunlight
and the proper precautions, and advise birth control if appropriate. When
doxycycline is given parenterally, do not refreeze the solution prior
to use!
Remember, years of
experience with chronic antibiotic therapy in other conditions, including
rheumatic fever, acne, gingivitis, recurrent otitis, recurrent cystitis,
COPD, bronchiectasis, and others have not revealed any consistent dire consequences
as a result of such medication use. Indeed, the very real consequences of
untreated, chronic persistent infection by B. burgdorferi can be far worse
than the potential consequences of this treatment.
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CO-INFECTIONS IN LYME
PIROPLASMOSIS (Babesiosis)
GENERAL INFORMATION
Piroplasms are not
bacteria, they are protozoans. Therefore, they will not be eradicated
by any of the currently used Lyme treatment regimens. Therein lies the
significance of co-infections — if a Lyme patient has been extensively
treated yet is still ill, suspect a co-infection.
Babesia infection
is becoming more commonly recognized, especially in patients who already
have Lyme Disease. It has been published that as many as 66% of Lyme patients
show evidence of co-infection with Babesia. It has also been reported
that Babesial infections can range in severity from mild, subclinical
infection, to fulminant, potentially life-threatening illness. The more
severe presentations are more likely to be seen in immunocompromised and
elderly patients. Milder infections are often missed because the symptoms
are incorrectly ascribed to Lyme. Babesial infections, even mild ones,
may recrudesce and cause severe illness. This phenomenon has been reported
to occur at any time, even up to several years after the initial infection.
Furthermore, asymptomatic carriers pose risks: to the blood supply as
this infection has been reported to be passed on by blood transfusion,
and to the unborn child from an infected mother as it can be transmitted
in utero. Some quotes from the literature:
Krause, PJ. Spielman,
A, Telford, SR et.al. Persistent parasitemia after acute Babesiosis
N Engl J Med 1998. 339:160
“The clinical
spectrum of human Babesiosis ranges from an apparently silent infection
to a fulminant malaria-like disease.”
“When
left untreated, silent Babesial infection may persist for months to
years."
“Silent
infections, which occur in about a third of infected people, may recrudesce."
“Babesial
infection may recrudesce after many months of asymptomatic parasitemia.”
“Although
parasites were initially detected microscopically in the blood of two
of the untreated subjects, and all of the treated subjects, none could
be found a week after the onset of illness.”
“Persistent
symptoms of Babesiosis accompanied persistent blood-borne Babesial DNA.”
“The
persistence of seroreactivity increasingly correlated with the persistence
of Babesial DNA.”
“In
those with only subtle symptoms, Babesiosis often remains undiagnosed.”
“Furthermore,
physicians tend not to recognize Babesial infection in those who are
co-infected with the agent of Lyme Disease, because Babesial symptoms
tend to be ascribed to Lyme Disease.”
“Physicians
caring for patients with moderate to severe Lyme disease should consider
obtaining diagnostic tests for Babesiosis and possibly other tick-borne
pathogens... especially in patients experiencing "atypical Lyme disease”
or patients in whom the response to antibiotic treatment is delayed
or absent.”
Krause, PJ, Telford,
SR, Spielman, A, et.al. Concurrent Lyme disease and Babesiosis.
JAMA 1996. 275 (21):1657
“Subjects
with evidence of both infections reported a greater array of symptoms
than those infected by the spirochete or piroplasm alone.”
“Co-infection generally results in more intense acute illness and
a more prolonged convalescence than accompany either infection alone.”
“Spirochete DNA was evident more often and remained in the circulation
longer in co-infected subjects than in those experiencing either infection
alone.”
“Co-infection might also synergize spirochete-induced lesions in
human joints, heart and nerves.”
“Babesial infections may impair human host defense mechanisms”
“The possibility of concomitant Babesial infection should be considered
when moderate to severe Lyme Disease has been diagnosed.”
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SYMPTOMS
In milder forms,
symptoms may include a vague sense of imbalance without true vertigo,
headache, mild encephalopathy, fatigue, sweats, air hunger and occasionally
cough. When present as a co-infection with Lyme, initial symptoms of the
illness are often more acute and severe. Suggestions of co-infection include
the above symptoms, but the headaches are more severe, and encephalopathy
is out of proportion to the other Borrelia symptoms. The fulminant presentations
include high fevers, shaking chills and hemolysis, and can be fatal.
DIAGNOSTIC TESTS
Diagnostic tests
are insensitive and problematic. There are at least thirteen Babesial
forms found in ticks, yet we can currently only test for B. microti and
WA-1 with our serologic and nuclear tests. Standard blood smears reportedly
are reliable for only the first two weeks of infection, thus are not useful
for diagnosing later infections and milder ones including carrier states
where the germ load is too low to be detected.
Krause, PJ, Telford,
SR, Spielman, A, et.al. Concurrent Lyme disease and Babesiosis.
JAMA 1996. 275 (21):1660
“As is common
in the case of Babesial infections, parasites frequently cannot be seen
in blood films.”
Therefore, multiple
diagnostic test methods are available and each have their own benefits
and limitations and often several tests must be done. Be prepared to treat
based on clinical presentation, even with negative tests.
SEROLOGY
Unlike Lyme, Babesia
titers can reflect infection status. Thus, persistently positive titers
or western blots suggest persistent infection.
PCR
This is more sensitive
than smears for B. microti, but will not detect other species.
ENHANCED SMEAR
This utilizes buffy
coat, prolonged scanning (up to three hours per sample!) and digital photography
through custom-made microscopes. Although more sensitive than standard
smears, infections can still be missed. The big advantage is that it will
display multiple species, not just B. microti.
FLUORESCENT IN-SITU
HYBRIDIZATION ASSAY (FISH)
This technique is
also a form of blood smear. It is said to be 100-fold more sensitive than
standard smears for B. microti, because instead of utilizing standard,
ink-based stains, it uses a fluorescent-linked RNA probe and ultraviolet
light. The Babesial organisms are then much easier to spot when the slides
are scanned. The disadvantage is that currently only B. microti is detected.
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TREATMENT
Treating Babesia
infections had always been difficult, because the therapy that had been
recommended until 1998 consisted of a combination of clindamycin plus
quinine. Published reports and clinical experience have shown this regimen
to be unacceptable, as nearly half of patients so treated have had to
abandon treatment due to serious side effects, many of which were disabling.
Furthermore, even in patients who could tolerate these drugs, there was
a failure rate approaching 50%.
Krause, PJ. Spielman,
A, Telford, SR et.al.. Persistent parasitemia after acute Babesiosis
N Engl J Med 1998. 339:162
“Of the treated
subjects, almost half had symptoms that were consistent with reactions
to quinine, including hearing loss, tinnitus, hypotension, and such
gastrointestinal symptoms as anorexia, vomiting, and diarrhea.”
“Although treatment with clindamycin and quinine reduces the duration
of parasitemia, infection may persist and recrudesce and side effects
are common.”
Because of these
dismal statistics, the current regimen of choice for Babesiosis is the
combination of atovaquone plus azithromycin. This combination was initially
studied in animals, and then applied to Humans with good success, because
when atovaquone was used alone, resistance developed in 20% of cases,
but reportedly did not occur when azithromycin was added. Fewer than 5%
of patients have to halt treatment due to side effects, and the success
rate is clearly better than that of clindamycin plus quinine.
The duration of
treatment with atovaquone plus azithromycin for Babesiosis varies depending
on the degree of infection, duration of illness before diagnosis, the
health and immune status of the patient, and whether the patient is co-infected
with Borrelia burgdorferi. Typically, a three-week course is prescribed
for acute cases, while chronic, longstanding infections with significant
morbidity and co-infection will require several months of therapy. Relapses
have occurred, and retreatment is occasionally needed.
Problems during
therapy include diarrhea, mild nausea, the expense of atovaquone (over
$600.00 per bottle — enough for three weeks of treatment), and rarely,
a temporary yellowish discoloration of the vision. Regular blood counts,
liver panels and amylase levels are recommended during any prolonged course
of therapy. Patients who are not cured with this regimen can be retreated
but with higher doses, as this has proven effective in many of my patients.
Artemesia (a non-prescription herb) may be added, but is not effective
when used alone. Metronidazole can also be added to increase efficacy,
but there is minimal clinical data on how much more effective this regimen
is.
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EHRLICHIOSIS
GENERAL INFORMATION
While it is true
that this illness can have a fulminant presentation, and may even become
fatal if not treated, milder forms do exist, as does chronic low-grade
infection, especially when other tick-borne organisms are present. The
potential transmission of Ehrlichia during tick bites is the main reason
why doxycycline is now the first choice in treating tick bites and early
Lyme, before serologies can become positive. When present alone or co-infecting
with B. burgdorferi, persistent leukopenia is an important clue. Thrombocytopenia
and elevated liver enzymes are less common, but likewise should not be
ignored. Headaches, myalgias, and ongoing fatigue seem to relate to this
illness, but are extremely difficult to separate from symptoms caused
by Bb.
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DIAGNOSTIC TESTING
Testing is problematic
with Ehrlichia, similar to the situation with Babesiosis. More species
are known to be present in ticks than can be tested for with clinically
available serologies and PCRs. In addition, serologies and PCRs are of
unknown sensitivity and specificity. Standard blood smears for direct
visualization of organisms in leukocytes are of low yield. Enhanced smears
using buffy coats significantly raises sensitivity and will indicate a
wider variety of species. Despite this, infection can be missed, so clinical
diagnosis remains the primary diagnostic tool. Again, consider this diagnosis
in a Lyme Borreliosis (LB) patient not responding well to therapy.
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TREATMENT
Standard treatment
consists of Doxycycline, 200 mg daily for two to four weeks. Higher doses,
parenteral therapy, and longer treatment durations may be needed based
on the duration and severity of illness, and whether immune defects or
extreme age is present. However, there are reports of treatment failure
even when higher doses and long duration treatment with doxycycline is
given. In such cases, consideration may be given for adding rifampin,
600 mg daily, to the regimen.
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BARTONELLA
Bartonella henselae,
the agent of cat scratch disease, has been found in Ixodid ticks and as
a co-infection in patients with Lyme Disease. With co-infection, symptoms
of Bartonella are almost impossible to distinguish from Lyme, but may
include lymphadenopathy, splenomegaly, hepatomegaly, headache, encephalopathy,
somnolence, flu-like malaise, weight loss, sore throat, and a papular
or angiomatous rash. In acute cases, there can be hemolysis with anemia,
high fever, weakened immune response, jaundice, abnormal liver enzymes,
and myalgias. Endocarditis and myocarditis have been reported. More severe
infections are associated with immune deficiency and possibly occurrence
of opportunistic infections. As in Lyme Disease and Babesiosis, Bartonella
may be transmitted to the fetus in the infected pregnant patient.
Diagnostic tests
include serology, blood and CSF PCR, and biopsy of skin lesions and lymph
nodes.
In the co-infected
Lyme patient, eradication may be difficult. Many antibiotic agents have
been reported to be effective, including cephalosporins, fluoroquinolones,
erythromycins, gentamicin, rifampin and streptomycin. In practice, these
patients seem to do best with a combination regimen that utilizes agents
that can penetrate cells. Typical combinations include an erythromycin,
plus a fluoroquinolone or rifampin. Treatment progress is most commonly
assessed by PCR post treatment and serial titers.
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NUTRITIONAL SUPPLEMENTS
IN DISSEMINATED LYME DISEASE
Studies on patients
with chronic illnesses such as Lyme and Chronic Fatigue have demonstrated
that some of the late symptoms are related to cellular damage and deficiencies
in certain essential nutrients. Double blinded, placebo controlled studies,
and in one case direct assay of biopsy specimens have proven the value
of some of the supplements listed. Some are required, while others are
optional — see below. They are listed in order of importance.
The quality of supplements
used is often more important than the dose. In fact, “mega doses”
are not recommended. Instead, seek out, if possible, pharmaceutical grade
products, especially if USP certified. Pharmanex brand products are recommended
because they fit these criteria. In the list below, it is indicated whether
the product should be gotten from Pharmanex, or whether a different source
or generic substitute is OK. To order Pharmanex brand products, call 1-800-487-1000
and give the following US reference # 9256681.
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BASIC DAILY REGIMEN
ACIDOPHILUS (required
when on antibiotics)
Essential daily
supplement to maintain the normal balance of bowel flora, especially if
on antibiotics, or if gastrointestinal disturbances are present. Always
try to get enteric coated, milk-free acidophilus. The best kinds are frozen
or refrigerated to ensure potency. Take two with each meal.
MULTI-VITAMIN (required)
I recommend the
Life Pack family of multivitamins. These are unique supplements —
Pharmaceutical grade and USP certified, they are the only products clinically
proven in double-blinded, placebo controlled crossover studies to quench
free radicals and raise antioxidant levels in the blood and lipids. Choose
LifePak for males under 40, LifePak Women for hormonally active women,
and LifePak Prime for postmenopausal women and for men over 40. They are
available through Pharmanex. Continue long term.
CO-Q10 (ubiquinone)
— required if not taking the prescription drug atovaquone (Mepron)
Deficiencies have
been related to poor function of the heart, limitations of stamina, gum
disease, and poor resistance to infections. Heart biopsy studies in Lyme
patients indicated that they should take between 200 and 300mg daily of
standard CoQ 10, or 90 mg of the well absorbed, highly purified, crystalline
CoQ 10 product sold by Pharmanex, (surprisingly, the Pharmanex brand is
far less expensive than the generic). The body will manufacture its own
C0Q 10 when the original illness is controlled, but only if stimulated
by aggressive exercise. Therefore, use this supplement until the patient
is feeling well and exercising regularly.
VITAMIN B (required)
Clinical studies
demonstrated the need for supplement vitamin B in infections with Borrelia,
to help clear neurological symptoms. Take one 50 mg B-complex capsule
daily. If neuropathy is severe, an additional 50 to 100 mg of B6 daily
may be helpful. Generics are OK.
MAGNESIUM (required)
Magnesium supplementation
is very helpful for the tremors, twitches, cramps, muscle soreness, heart
skips and weakness. It may also help in energy level and cognition. The
best source is magnesium L-lactate dehydrate (“Mag-tab SR,”
sold by Niche Pharmaceuticals [1-800-677-0355], and available at Wal-Mart).
DO NOT rely on “cal-mag,” calcium plus magnesium combination
tablets, as they are not well absorbed. Take at least one to two tablet
twice daily. Higher doses may cause diarrhea, and you should check with
your physician before using more than this. In some cases, injections
or intravenous doses may be necessary. Continue long term.
ESSENTIAL FATTY
ACIDS (required)
Studies show that
when EFAs are taken regularly, statistically significant improvements
in fatigue, aches weakness, vertigo, dizziness, memory, concentration
and depression are likely. There are two broad classes: GLA (omega-6 oils)
and EPA (omega-3 oils), derived respectively from plant and fish oils.
This is what to take:
Plant Oils: borage
oil, evening primrose oil, or black currant seed oil (choose one). Do
NOT use Flax seed oil!
Fish Oil: Omega-3
(Fish Oil) capsules, 1000 mg per capsule. Use “Optimum Omega”
by Pharmanex, if a higher quality product is desired, or to minimize the
“fishy” aftertaste.
RECOMMENDATION: four
plant oil capsules and four fish oil capsules daily, taken with meals.
Continue for three to four months then try to taper down the dose.
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OPTIONAL SUPPLEMENTS
FOR SPECIAL CIRCUMSTANCES
CORDYMAX (optional)
Cordyceps is a well-known
herb from Tibet and has been shown in clinical studies to improve stamina,
fatigue, and enhance lung and antioxidant function. It increases mitochondrial
ATP levels and also raises superoxide dismutase levels. The positive effects
can be so dramatic, I strongly urge all people with fatigue to try this.
Available only from Pharmanex as “CordyMax.”
METHYLCOBALAMIN
(Methyl B12) (optional)
This is a prescription
drug available only from compounding pharmacies. It is related to vitamin
B12 and has several documented benefits: it helps to heal damage to the
nervous system, enhances diminished T-cell function, can restore the normal
diurnal cycle, and can help with memory and cognition. Methyl B12 must
injected into the muscle as it will not be absorbed if swallowed or used
sublingually. Dose ranges from 25 to 50 mg daily, based on weight.
REISHI MAX (optional)
This enhanced extract
from cracked spores of the reishi mushroom has been shown in clinical
studies to augment function of the Natural Killer Cells and macrophages.
Take two a day for maintenance, and four a day in disease states. Available
only from Pharmanex.
ECHINACEA (optional)
May be helpful in
fighting acute and chronic viral illnesses. Choose a pharmaceutical grade
brand (“Immune Formula” by Pharmanex), and do not use the liquid
form as this contains alcohol. Do not take daily on a long-term basis,
as the benefit may wear off. For a chronic illness, double the usual daily
dose but take in cycles — use daily three weeks on, one week off
each month.
BIO-GINKGO (optional)
The most effective
ginkgo brand in my experience — pharmaceutical grade, and very high
potency to assure full bioavailability. Available only from Pharmanex.
Ginkgo has been shown to increa
