- 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: 836338

An 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:
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

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: 7043737

A 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:
  1. 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!
  2. 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 antibodyotherwise 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.

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:  and    

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!      


A PubMed search for "(borreli*+OR+Lyme)+immune+complex" gave about 100 hits:*+OR+Lyme)+immune+complex

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