IMMUNE COMPLEX
FORMATION
- as possible explanation of false negative Borrelia
burgdorferi antibody test - and about cyclicity / relapsing nature of infection with
Borrelia species
Around
1975 Steere et
al. was
alerted by
Polly Murray - author of the book "
The Widening Circle: A Lyme Disease Pioneer
Tells Her Story" - to an epidemy of
LYME ARTHRITIS-
and shortly thereafter in
1977 Steere
et al. described Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities.
Steere
AC, Malawista SE, Snydman DR, Shope RE, Andiman WA, Ross MR, Steele FM.
Arthritis Rheum. 1977 Jan-Feb;20(1):7-17. PMID:
836338An epidemic form of arthritis has been occurring in eastern Connecticut at least since 1972, with the peak incidence of new cases in the summer and early fall. Its identification has been possible because of tight geographic clustering in some areas, and because of a characteristic preceding skin lesion in some patients.
The
authors studied 51 residents of three contiguous Connecticut
communities - 39 children and 12 adults - who developed an illness
characterized by recurrent attacks of asymmetric swelling and pain in a few large joints, especially the knee. Attacks
were usually short (median: 1 week) with much longer intervening
periods of complete remission (median: 2.5 months), but some attacks
lasted for months. To date the typical patient has had three recurrences, but 16 patients have had none. A
median of 4 weeks (range: 1-24) before the onset of arthritis, 13
patients (25%) noted an erythematous papule that developed into an
expanding, red, annular lesion, as much as 50 cm in diameter.
Only 2 of 159 family members of patients had such a lesion and did not develop arthritis (P less than 0.000001).
The
overalll prevalence of the arthritis was 4.3 cases per 1,000 residents,
but the prevalence among children living on four roads was 1 in 10.
Six families had more than 1 affected member.
Nine
of 20 symptomatic patients had low serum C3 levels, compared to none of
31 asymptomatic patients (P less than 0.005); no patient had
iridocyclitis or a positive test for antinuclear antibodies. Neither
cultures of synovium and synovial fluid nor serologic tests were
positive for agents known to cause arthritis. "Lyme arthritis" is
thought to be a previously unrecognized clinical entity, the
epidemiology of which suggests transmission by an arthropod vector.
However,
the disease presentations of what now is now known to be caused by
Borrelia
burgdorferi sensu lato species had actually been described since 1880-ies in the European medical literature; this was the subject of
my presentation at the first UK conf. on Lyme disease in
Hull 2001 - listing some of the most important old references.
Just two years later the same authors elaborated on Lyme disease and described the
KEYPOINTS -
the fluctating and relapsing pattern, and not the least the important observation that the amount of complexed IgG
antibodies followed
the changing clinical pattern of Borreliosis:
Quote
from abstract:
"We
have found immunoglobulin (Ig) G-containing material consistent with
immune complexes in the sera of patients with Lyme arthritis.
It was detected in 29 of 55 sera (55%) from 31 patients by at least one
of three assays: (125)I-C1q binding, C1q solid phase, or Raji cell.
The
presence of reactive material correlated
with clinical aspects of
disease activity; it was found early in the illness,
was most prominent in
sera from the sickest patients, was infrequent during remissions,
and often fluctuated
in parallel with changes in clinical status.
In
Science 1982 Burgdorfer
et
al. described the "new"
Borrelia
spirochete -
which got its name after Burgdorfer - that was found in ticks
from Lyme, Connecticut, USA
Lyme disease-a tick-borne spirochetosis?Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP. Science. 1982 Jun 18;216(4552):1317-9. PMID:
7043737A treponema-like spirochete was detected in and isolated from adult
Ixodes dammini, the
incriminated tick vector of Lyme disease.
Causally related to the spirochetes may be
long-lasting cutaneous
lesions that appeared on New Zealand White rabbits 10 to 12 weeks after
infected ticks fed on them.
Samples of serum from patients with Lyme disease were shown by indirect immunofluorescence to contain antibodies to this agent. It is suggested that the newly discovered spirochete is involved in the etiology of Lyme disease.
Further 8 years went by until
Borrelia burgdorferi
immune complexes were found in patients with SERONEGATIVE Lyme disease,
i.e. antibodies were not detected by conventional serology methods
because the antibodies were bound to antigen in immune complexes:
Sequestration
of antibody to Borrelia
burgdorferi in immune complexes in seronegative
Lyme disease.
Schutzer
SE, Coyle PK, Belman AL, Golightly MG, Drulle J. Lancet. 1990
Feb
10;335(8685):312-5. PMID:
1967770
"In
a blinded
analysis the antibody
was detected in all 10
seronegative Lyme disease patients with erythema chronicum
migrans (ECM),
in none of 19 patients with other diseases, and in 4 of
12 seronegative patients who probably had Lyme disease but had no ECM.
These findings were confirmed by western blot,
which also showed that
immune complex dissociation
liberated mainly antibody reactive to the 41 kD antigen and sometimes
antibody to an approximate 30 kD antigen. Complexed B
burgdorferi antibody was also
found in 21 of 22 (95%) of seropositive patients with active
disease, 3
additional seronegative but cell mediated immune reactive
patients, and 3 other seronegative patients who eventually
became seropositive.
* 41 kDa
protein is flagella
The importance of fluctuations in the amount of circulating Borrelia in blood, hence the amount of formed immune complexes eliciting the symptoms, came in:
Lyme borreliosis: a relapsing fever-like
disease?
Burgdorfer W, Schwan TG. Scand J Infect Dis Suppl. 1991;77:17-22.
PMID: 1947807
To determine by
xenodiagnosis length and concentrations of spirochetemias produced by
Borrelia burgdorferi in white-footed mice (Peromyscus leucopus),
laboratory reared mice were inoculated with either
spirochete-containing tick suspensions or BSK II spirochete culture and
were exposed for as long as three months to larval Ixodes dammini. Upon
development to the nymphal stage, ticks were evaluated for spirochetal
infections by direct
immunofluorescence.
All mice were
found to circulate spirochetes for at least three months in
concentrations sufficient to infect ticks. The percentage of infected
ticks alternated from low to high, suggesting occurrence of episodes of
mild and heavy spirochetemias. The results suggest that B.
burgdorferi in its animal hosts and possibly also in humans causes
prolonged spirochetemias characterized by episodes of alternating high
and low concentrations of spirochetes as reflected by similar
percentages of infected ticks. The long persistence of spirochetes in
the peripheral blood stream and the cyclical form of Lyme borreliosis
appear to be related, as in relapsing fevers, to the capacity of B.
burgdorferi to undergo antigenic variations.
IMPORTANT KEY
OBSERVATIONs was
made that IgG immune-complexes in SERUM correlated / fluctuated in parallel with:
*
DISEASE ACTIVITY (pattern like relapsing fever?)
*
was especially found early in infection
*
was highest in the most sick
*
was rarely found during remission
*
fluctuated in parallel with changes in clinical status
=> this early description
should of course have prompted all doctors to:
- KEEP AN EYE ON THE FLUCTUATING CLINICAL
- relapsing fever like - PICTURE OF BORRELIOSIS, with waxing and
waning symptoms, relapses of a week to some months duration,
with relatively symptom free periods in between the relapses!
- always evalutate
the result of serology test in conjunction
with the patients current clinical status!
During
currently active borrelia infection a serology test may show low positive or false
seronegative, in case most / all of the antibodies quickly become bound to
antigen i circulating immune complexes, hence antibody
test are NOT reliable during ACTIVE BORRELIA INFECTION and negative
serology test must therefore never be used to outrule a currently
active Borrelia infection, in which case the patient is symptomatic and
often displaying one of the typical relapse patterns ..
- there
might only be a measurable surplus of free circulating antibodies
that is not bound in immune complexes during remissions (in good
periods) when the amount of circulating antigen in blood is very low or
not present and in this situation antibiotics may not be helpful
at all?
- thus to base ANTIBIOTIC TREATMENT on positive serology
test will tend to treat people with no current disease activity,
while those with no detectable antibodies and active disease will not
be offered treatment at the time it might benefit the patient!
ALL
SEROLOGY TESTS should therefore - already from 1979 and onwards - have taken actions to dissolve eventual immune
complexes and remove Borrelia antigen from the
serum solution before measuring the amount of antibody , otherwise
the antibody test results will not reflect the true amount of
circulating antibodies during the ACTIVE periods of BORRELIA INFECTION!
-
however serology test developers forgot the KEY clues and made
tests that usually do NOT recognize the fact that serology
test
may fail to detect any antibodies during active disease periods due to
anibodies being bound in immune complexes, are not free to bind to the
tests antigen! .... and this is especially the case regarding p41
(flagella) antibodies according to Schutzer ...
Dr. Burrascano
did
observe and took into consideration the typical waxing and waning clinical
pattern of Borreliosis, and was the first ever to describe the MONTHLY recurrent relapses already back in the early 1990-ies
in his diagnostic and
treatment guidelines, from the 2008 version is on ILADS website,
quotes:
page 7:
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.
page17:
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 and 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 I.V. 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 I.V. 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 I.V. treatment. In
general, I.V. therapy is given until there is a clear positive
response, and 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 I.V. 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: Noncompliance, alcohol use, and sleep
deprivation. Advise them to take a break when (or ideally before) the
inevitable mid afternoon fatigue sets in (napping is encouraged).
All patients must keep a
carefully detailed daily diary of their symptoms to help us document
the presence of the
classic four week cycle, judge the effects of treatment, and determine
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.
In
1998 came Brorson's description of Borrelia burgdorferi
two growth patterns in the laboratory, which gave us the
probable explanation for the clinical cyclical relapse
patterns; there are
actually TWO patterns - a weekly and a monthly pattern - depending on the age of
the
"cysts" formed by Borrelia burgdorferi at time of reversal back to the
spirochete form:
A rapid method for
generating cystic forms of Borrelia burgdorferi, and their reversal to
mobile spirochetes.
Brorson O, Brorson SH. APMIS. 1998 Dec;106(12):1131-41. PMID:
10052721
Mobile Borrelia burgdorferi were transferred to distilled water (10(6)
per ml). The cultures were observed by dark field microscopy (DFM),
interference contrast microscopy (ICM) and transmission electron
microscopy (TEM).
95% of
the spirochetes were converted to cysts after 1 min, and after 4 h no
normal mobile borreliae were observed.
When transferred to growth
medium (BSK-H), the cysts became smaller and more irregular, and were
filled with organic substances. After 1 day, 1-5 thin structures
sprouted from the cysts. They continued to grow in both length and
thickness until they attained a normal spirochetal structure.
Finally, these new-born spirochetes detached from the cysts, by which
time their mobility had become normal. The present method for producing
large amounts of cystic forms of
B.
burgdorferi is well suited for further studies of this
unique microbe.
Excerpt from discussion
section:
"The cysts observed in our
study seem to resemble the spheroplast-L-forms
observed by other researchers (11, 35), which seem to have defects in their cell wall
manifested by resistance towards beta-lactam antibiotics
(16). Since the conversion from normal mobile spirochetes to cystic
forms occurred very rapidly, complete absence of cell wall as in
L-forms is dubious, but the similarity with L-forms is shown by the
inability to retain their original shape.
The biological activity of the cystic forms was confirmed by the step
by step development to normal mobile spirochetes in BSK-H medium, and
also indicated by the presence
of RNA in 5-week-old cysts due to red-orange staining with acridine
orange (pH 6.4) (Fig. 4b). This seems to be a new
observation in the development of B.
burgdorferi (20). Bruck et al. (35) also illustrated
biological activity by incorporation or S-methionine in the cysts
(spheroplast). The
creation of as many as five spirochetes from each cyst may explain why
the generation time was shorter for production of mobile spirochetes
from cysts compared to that for normal mobile spirochetes cultivated
conventionally. The generation of the normal mobile
spirochetes which were converted from cysts was somewhat variable in
the sense that they sometimes
seemed to need a long stationary period before exponential growth
occurred. Whether cysts are converted to normal mobile
spirochetes or not depends strongly on the growth medium used, and
possibly also the generation time.
It seems as though normal mobile spirochetes are developed from the
dense core structures or the cyst by being "fed" with core
substances as the "infant-spirochete" protrudes from the cyst.
The development of vegetative bacteria from dense L-forms has been
suggested as a method for Enterococcus faecalis to convert from L-forms
to vegetative forms (40). The
observation by TEM that blebs transformed into thin filaments leads us
to speculate that these filaments develop to normal mobile spirochetes.
If so, the blebs have to contain enough genetic material to synthesize
a new bacterium (22).
Old cystic forms of B.
burgdorferi
require prolonged cultivation to convert to normal mobile spirochetes
(4 weeks as opposed to 9 days for young cysts). Similar
cystic forms may occur in the human organism (11, 14, 15), and they may explain the long periods or
latency, resistance to antibiotics, negative serological results (3-7,
10, 12, 13, 25), and low PCR sensitivity (5, 8, 10). For
these reasons it is important to examine the antigens of the envelope
of the cysts. DNA sequences for PCR analysis, and the cysts sensitivity
to antibiotics and other chemicals. It may be hypothesized that
antigenic variation in B.
burgdorferi (19, 41) occurs inside the cyst while the
microbe is protected against external stress, and therefore antigens
detected on the cyst envelope in vitro differ from the ones present in
vivo. In conclusion, we believe that the present method for rapid and
easy generation of stable cysts will be a useful tool in further
research on B.
burgdorferi."
3. Bunikis J, Olsen B, Westman G,
Bergstrřm S. Variable serum immunoglobulin responses against different Borrelia burgdorferi sensu lato species in a
population at risk for and patients with Lyme disease. J Clin Microbiol 1995;
33: 1473-8.
4. Stiernstedt G. Tick-borne borrelia infection in Sweden. Scand J Infect Dis
1985: (Suppl 45): 1-70.
5. Oksi J. Uksila J, Marjamäki M, Nioskelainen J, Viljanen MK. Antibodies
against whole sonicated Borrelia
burgdorferi spirochetes, 41-kilo-dalton flagellin, and p39 protein in
patients with PCR- or culture-proven late Lyme borreliosis. J Clin Microbiol
1995; 33: 2260-4.
7. Hammers-Berggren S, Lebech AM, Karlsson M, Svenungsson B, Hansen K,
Stiernstedt G. Serological follow-up after treatment of patients with erythema
migrans and neuroborreliosis. J Clin Microbiol 1994; 32: 1519-25.
8. Hansen K. Laboratory diagnostic
methods in Lyme borreliosis. Clin Dermatol 1993; 11: 407-14.
10. Stiernstedt G, Dattwyler R, Duray PH,
Hansen K, Jirous J, Johnson RC, et al. Diagnostic tests in Lyme borreliosis.
Scand J Infect Dis 1991: 77: 136-42.
11. Preac Mursic V, Wanner G, Reinhardt
S, Wilske B, Busch U. Marget W. Formation and cultivation of Borrelia burgdorferi spheroplast-L-form
variants. Infection 1996: 24: 218-26.
12. Preac Mursic V, Weber K, Pfister HW,
Wilske B, Gross B, Baumann A, et al. Survival of Borrelia burgdorferi in antibiotically treated
patients with Lyme borreliosis. Infection 1989; 17: 355-9.
13. Schmidli J, Hunziker T, Moesli P, Schaad
UB. Cultivation of Borrelia burgdorferi
from joint fluid three months after treatment of facial palsy due to Lyme
borreliosis. J Infect Dis 1988; 158: 905-6.
14. MacDonald AB. Concurrent
neocortical borreliosis and Alzheimer’s disease. Ann NY Acad Sci 1988; 539:
468-70.
15. Hulinska D, Barták P, Hercogová J, Hancil J, Basta J, Schramlová
J. Electron microscopy of Langerhans cells and Borrelia burgdorferi in Lyme disease patients.
Zbl Bakt 1994; 280: 348-59.
16. Schaller M, Neubert U. Ultrastructure of
Borrelia burgdorferi after exposure to
benzylpenicillin. Infection 1994: 22: 401-6.
19. Sadziene A. Rosa PA, Thompson PA, Hogan DM, Barbour AG. Antibody-resistant
mutants of Borrelia burgdorferi: In
vitro selection and characterization. J Exp Med 1992: 176: 799-809.
20. Brorson Ř, Brorson SH. Transformation of cystic forms of Borrelia burgdorferi to
normal mobile spirochetes. Infection 1997; 25: 240-6.
22. Garon CF, Dorward DW, Corwin MD. Structural features of Borrelia burgdorferi - the Lyme disease
spirochete: silver staining for nucleic acids. Scanning Microsc 1989: (Suppl 3):
109-15.
25. Dattwyler RJ, Volkman DJ, Halperin JJ, Luft BJ. Treatment of late Lyme
borreliosis - randomised comparison of ceftriaxone and penicillin. Lancet 1988:
8596: 1191-4.
35. Bruck DK, Talbot ML, Cluss RG, Boothby JT. Ultrastructural characterization of
the stages of spheroplast preparation of Borrelia burgdorferi. J Microbiol Methods
1995; 23: 219-28.
40. Domingue GJ, Woody HB. Bacterial persistence and expression of disease. Clin
Microbiol Rev 1997; 10: 320-44.
41. Burgdorfer W, Schwan TG. Lyme borreliosis: a relapsing fever-like disease? Scand
J Infect Dis 1991; (Suppl) 77: 17-22.
I therefore - like Burrascano - ask all chronically
ill suspecting chronic Borreliosis patients to keep a very detailed symptom diary
and I have created a diary in
Microsoft Excel, with automatic curve drawing of any suspected symptom
triggers, all individual symptoms,
calculation of sum scores per organ system and total score when
the patient gives his/her daily
point scores to all their non-normal symptoms on a visual anlog
scale in
4 steps (I have explained the symptom severity in words to ensure the
patient understand when to give which scores, but must use point
scores 2.75); the scores also reflect
the degree of invalidity like in the NYHA heart disease severity
scale; this
was the subject of
my lecture in Leicester, UK in 2007.
The
Excel symptom diary is an ideal tool to help the patient and doctor get good overview over a
long and complex disease course in patients experiencing multiple waxing and waning symptoms from multiple
organ systems, and is an ideal tool to follow response and judge effect of any
tried
intervention - does it improve the patient or?
Since
the diary curves allows us to spot exactly which of
often many symptoms fluctuate in which pattern together with other
symptoms over time and which does not fluctuate
much we can easily spot the disease activity pattern; patients on a
monthly
cycle usually have noticed the cyclicity self and report it
spontaneuusly
to the doctor even without the diary, because they have some
very bad flare-days (2-5 days, perhaps need to be
bedridden), then a
gradual improvement over 1-3 weeks, perhaps they have a
relatively good and nearly normal week before Hell breaks loose again
and
a new montly flare relapse initiates the next cycle, in the chronically
ill continuing month after month, year
after year. Patients often experience extra long worsening
periods during the spring and autumn seasons,
corresponding to high tick activity seasons in nature, when it
gets very bad all
the time, no good days, they tell the doctor! - but actually
during these periods they do shift back to a weekly cycle, but
because of the
frequent relapses their system are probably not able to clear all
formed toxins and immune
complexes and other waste product, that continue to circulate and
stimulate cytokines and symptoms also during time in between
the weekly flares, ocurring at mean 9 days interval ... every time when
going into
large relapse during spring and autumn, their basic
symptom level gradually increases week after week, it takes about 1-3
months until they
stabilize on a relatively high
lag-phase with an overlaid weekly cycle and it is the "neurotoxin
symptoms" and "influenza like symptoms" that add more points to
the curve during weekly flares, plus a large part of the lagphase
consist of neurotoxin symptom plus "reactive symptoms" probably related
to precipitation of immunecomplexes and activation of membrane
attack in joints and vascular endothelium, causing inflammation,
exudation and sometimes bleeding; only active microbes form
neurotoxins, and toxins elicits the cytokine
storm ...
Some curves explained more in detail in the danish version herein. There are always one week between the dates on the X-axis:
Patient
#24 was found coinfected with Borrelia and Babesia; before treatment curve showed a high lagphase
around 60 points and with weekly worsenings; he had
a small
- Jarisch-Herxheimer - worsening during the first few days after start on treatment with
metronidazole and azithromycin, then he experienced a gradual
improvement i.e. gradual DECLINE in
the basic symptom level, but still with an overlaid weekly cycle
for the next 6-8 weeks on; the curve could just be about to shift
to a monthly cycle pattern after 2 months treatment, but unfortunately the patient think the gained improvement means cure, so he stops treatment and the diary
without
telling the doctor; 6 weeks into antibiotic pause he comes back
for more treatment; the lagphase has returned to the
pre-treatment level again a full blown
relapse
occurred! ... this is a very common pattern during start of treatment;
if a patient with Borrelia infection is NOT following a similar pattern
of gradual improvement
with initially weekly flare cycle
eventually - usually within 3 months - shifting to a monthly relapse
pattern, it is time to reconsider the diagnosis, look for other
symptom
causes than Borrelia, co-infection, other complicating factors! - this
is the course the patient with only Borrelia can expect to follow
during antibiotic treatment,
if all co-infections are hit by chosen antibiotics!
Patient
#11 ME/CFS patient was diagnosed with triple-tickborne infections of
Borrelia, HME and babesia in 2002; started with doxycyclin due to HME,
but she did
not have good effect of doxycycline for 4-5
months, then she was shifted to metronidazole and azithromycin. Within
the first week of this combo treatment the
patient felt a
significant gradual improvement similar to what is illustrated in
case#24's curve - but at the time she was using a
simpler manual diary with fewer
symptoms scored per
day, thus the level of curves before is not comparable to the
Excel diary level where more symptoms are being scored daily
if present in
the patient; after about 4 month on
the combo treatment the patient shiftet to use the new Excel diary and
at this time showed a clear monthly relapse cycle,
of which
the next 7 relapses are illustrated on the curve, i.e. her monthly
cycle continued for at least 12 months after effective antibiotic
treatment was started!
- then shifted to rarer relapses.
From the time when the cyclicity had shiftet to a monthly relapse
cycle, the patient only took antibiotics during the activity
periods
(for about 5 days every month as pulse therapy) to reduce side effect,
cost and because the bacteria can only be hit when they are actively
forming
DNA/RNA and proteins anyway - treatment outside activity
periods is wasted; during the following two years the
flares came at about 3-6 monthly intervals;
more
trial pause treatments resulted in gradually increasing symptoms
over the following month, thus necessitated re-treatment in order to
stop furtherdisease
progression! - however,
since 2005 the patient has only felt slight worsenings, not
increasing the symptom level gradually when she did not
take treatment, thus
she felt no need to take more
antibiotic treatment since and has kept a stabile lagphase at about
20-30 points with only very rare smaller flares.
Simultaneusly
with taking the antibiotic treatment, after the first big improvement
and shift to monthly relapse pattern, she also managed to change her
diet to
more vegetables and live a much healthier lifestyle, lost
weight and became more physically active (after her pains due to
inflammation were reduced) - this
diet and life style change probably help her immune system to function better, and better keep infections at bay.
Before
the diagnosis and treatment she was often bedridden and had to use a
wheelchair to get around; after start of treatment she has put the
wheelchair away
and have had no use of it ever since; she was
already on a public sick-pension before entering the project; from 2005
onwards she got a part time job and now
she is under education to
become a dietician focusing on weight managament. She got her good life
back again, she says - but it was a long road ;)
In people co-infected with borrelia and ringformed parasites inside red blood cells I've seen several no effect or relapses on doxycycline! - especially lack of
positive
effect of the normally recommended doxycycline dose 100 mg x
2; I use doxycycline when symptoms or test results point to
rickettsiales infections, but
shift to metronidazole plus
azithromycin when/if the patients does not follow the typical response
pattern, illustrated in curves above!
Continous
treatment until stabile lag-phase and shift to monthly cycle, then
pause but KEEP DIARY for AT LEAST # MONTH to catch early relapse;
possible courses:
1.
no further relapses, no need for re-treatment ... if relapse free for
3+ years, good chance of no more relapses according to dr. B (personal
message) :)
2. quick relapse with return to pre-treatment lap-phase
level within 1-3 months after stopping antibiotic - need for
confirmation of still Borrelia infection (must be
of treatment 6
weeks before attempt to culture Borrelia), if confirmed presence of
Borrelia good indication for re-treatment and next time MUST
continue with
pulse therapy during small flares to prevent
develpment of big relapse, like in case#11 - until activity finally
ceases (stock of dormant microbes is emptied) ...
3. patient
continue on a monthly relapse pattern, but symptom level decline back
to best level before next flare; this signals that the immune system
cleared
the microbes that wen into growht and cleared toxins,
immunecomplexes etc. so inflammation is downregulated normally in
between flares ... observe without
antibiotics as long as
monthly activity contnue, but re-diagnose and re-treat every time basic
symptom level show increasing tendency
4. the flare acitivty
subsides, but the patient still has a pretty high invalidating level of
"neurotoxin" symptoms and abnormal FACT result, symptoms that are
not
cleared spontaneusly as usual gradually within 2-3 months
after flares stopped - but stopping treatment bring no worsening;
this pattern signals that
infectious activity has ceased but the patient probably has defect in his/her detoxification system (much can be measured but is pretty costly); in this situation
the patient may benefit from toxin binder treatment like cholestyramin (CSM), for more information see Ritchie Shoemakers webpages at:
http://chronicneurotoxins.com and http://biotoxin.info
NOTE
some patients who self supect suffering from chronic Lyme
borreliosis due to they express similar symptoms, but then their
diary does NOT show the
for active
borrelia infection typical relapse pattens, i.e. there is no
recurrent activity cycle (they won't get better on antibiotic
treatment!)
- but they express lots of lingering
"NEUROTOXIN" symptoms, like in 4 above, a "post-Lyme treament like
syndrome" ...
=> LOOK FOR OTHER CAUSES OF BIOTOXIN MEDIATED ILLNESS; has the patient been exposed to mold toxins at home, at work? - has the patient perhaps
been exposed to marine toxine producing algae? ... see the webcasts at dr. Shoemakers website!
- no
matter which sort of neurotoxin, cholestryamine
detoxification treatment may help these patient excrete the
accumulated toxins, that else keep stimulating
proinflammatory cytokine response, so they may recover withing usually 2-3 months (unless re-exposed to toxins again!)
...
beware also of eventual nutritious defects that may hamper liver
enzyme function (lack of important co-enzymes perhaps?)!
All
chonicially ill persosn require a holistic overview of the ill
persons life situation; this need is usually not met by
the highly specialized medical doctors that the
patient meets in the hospital specialist departments, who focus on certain particular diseases within their field of expertise!
Chronically ill patients need very clever generalist with much clinical experience, broad knowledge and focus - rather than high-degree specialists!
REFERENCES:
A PubMed search for "(borreli*+OR+Lyme)+immune+complex"
gave about 100 hits:
Selected publications on the subject of the presence of immune complexes in active Borreliosis:
1.
Circulating immune
complexes in Lyme arthritis.
Detection by the 125I-C1q binding, C1q solid phase, and Raji cell
assays.
Hardin JA, Walker LC, Steere AC, Trumble TC, Tung KS,
Williams RC Jr, Ruddy S, Malawista SE. J
Clin Invest. 1979
Mar;63(3):468-77.PMID:
429566
PDF
2. The
pathogenesis of arthritis in Lyme disease: humoral immune responses and
the
role of
intra-articular immune complexes.
Hardin JA, Steere AC, Malawista SE.
Yale J Biol Med. 1984
Jul-Aug;57(4):589-93.PMID:
6334939 PDF
3. Sequestration
of antibody to Borrelia burgdorferi in immune complexes in seronegative
Lyme disease.
Schutzer SE, Coyle PK, Belman AL, Golightly MG, Drulle J. Lancet.
1990 Feb
10;335(8685):312-5.PMID:
1967770
4.
Cerebrospinal
fluid immune complexes in patients exposed to Borrelia
burgdorferi:
detection of Borrelia-specific and -nonspecific complexes.
Coyle PK, Schutzer SE, Belman AL, Krupp LB, Golightly
MG. Ann Neurol. 1990
Dec;28(6):739-44.PMID:
2285261
5. Detection
of Borrelia burgdorferi DNA and complement membrane attack complex
deposits in the sural nerve of a patient with chronic polyneuropathy
and tertiary Lyme disease.
Maimone D, Villanova M, Stanta G, Bonin S, Malandrini A,
Guazzi GC, Annunziata P. Muscle
Nerve. 1997
Aug;20(8):969-75.PMID:
9236787
6.
Detection and
preliminary characterization of
circulating immune complexes in patients with Lyme disease.
Zhong W, Oschmann P, Wellensiek HJ. Med
Microbiol Immunol. 1997
Oct;186(2-3):153-8.PMID:
9403844
7.
Borrelia burgdorferi
detected by culture and PCR
in clinical relapse of disseminated Lyme borreliosis.
Oksi J, Marjamäki M, Nikoskelainen J, Viljanen MK. Ann Med.
1999
Jun;31(3):225-32.PMID:
10442678
8.
Borrelia
burgdorferi-specific immune complexes in
acute Lyme disease.
Schutzer SE, Coyle PK, Reid P, Holland B. JAMA.
1999 Nov 24;282(20):1942-6. Erratum in: JAMA 2000 Oct
25;284(16):2059. PMID:
10580460
PDF
9.
Immune complexes from
serum of patients with lyme
disease contain Borrelia burgdorferi antigen and antigen-specific
antibodies: potential use for improved testing.
Brunner M, Sigal LH. J
Infect Dis. 2000 Aug;182(2):534-9. Epub 2000 Jul 28.PMID:
10915085
10. Use
of serum immune complexes in a new test that accurately confirms early
Lyme disease and active infection with Borrelia burgdorferi.
Brunner M, Sigal LH. J
Clin Microbiol. 2001
Sep;39(9):3213-21.PMID:
11526153
PDF
11.
Early OspA immune
complex formation in animal
models of Lyme disease.
Schutzer SE, Luan J. J
Mol Microbiol Biotechnol. 2003;5(3):167-71.PMID:
12766346
12.
Immune complexes in
early Lyme disease.
Lencáková D, Stefancíková A, Ivanová R, Petko B. Can J
Microbiol.
2007
Dec;53(12):1375-7.PMID:
18059570
PDF