B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

Sundheds- og Ældreudvalget 2015-16
B 25 Bilag 1
Offentligt

1/5

Idéoplæg til borrelia-tiltag

Oplæg til forbedring af borreliose-diagnostik og behandling i det offentlige sundhedsvæsen

v/ Alex Holmstedt

dato 2015.12.04

”For nuværende er retningslinjer for diagnosticering og behandling baseret på en

smal personkreds, hvor særlige interesser og færdigdefinerede forestillinger spiller en

væsentlig rolle. Det har resulteret i slet videnskabelige retningslinjer, hvor relevant

viden og erfaringer er udeladt.”

Alex Holmstedt, seronegativ borrelia-patient

(Om flåtbårne sygdomme) ”Vi ved ikke ret meget. Det er sådan lidt et stort, sort hul

hvis man sammenligner os med vores nabolande. I Norge Sverige og Tyskland gør

man rigtig meget …”

Nanna Skaarup Andersen, Ph.d. Center for Vektorbårne Infektioner, Odense

Universitetshospital

ref:

Flåt-sygdomme: Danmark er et sort hul - TV Syd

Oversigt



Borrelia-diagnosticering –

primært en klinisk diagnose

Udfasning af ELISA borrelia-test

Testalternativer

Forlænget antibiotikabehandling -

patientens eget valg

Obligatorisk efteruddannelse i flåtsygdomme

Patientindrapportering

Videnscenter for vektorbårne sygdomme –

Fokusområde Borrelia- og co-infektioner

Borrelia-diagnosticering

- primært en klinisk diagnose

Der er bred lægelig konsensus om at borrelia primært er en klinisk diagnose og at

ingen blodprøve er 100 % sikker.

Et stort problem for borrelia-patienter er, at moderne diagnostik i vid udstrækning

baserer sig på automatiseret prøvetagning, og at ”gammeldags” diagnostik, hvor

lægen ved sin kliniske færdighed – i dialog og føling med patienten – finder frem til en

diagnose, er gledet i baggrunden. Den automatiserede prøvetagning er blevet en

bekvem genvej.

Staten Virginia i USA udfærdigede i 2011 rapport med anbefalinger vedrørende

diagnostik og behandling af borrelia. I rapporten erkendte CDC, at borrelia i mange

tilfælde ikke kan diagnosticeres i tilstrækkelig grad alene ved serologi.

ref:

Staten Virginias borrelia-rapport: The Governor’s Task Force on Lyme Disease

B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

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CDC er den amerikanske pendant til Sundhedsstyrelsen, og serologi er den

testmetode, ”den danske borrelia-test” er baseret på.

Påkrævet er en overordnet klinisk diagnosticerings-systematik. Baseret på

erfaringsmæssig evidens, som f.eks. den Richard Horowitz, MD i New York, har

opbygget efter kontakt med mange tusinde borrelia-patienter.

ref:

Richard Horowitz, MD

ref:

Horowitz Borrelia - MSIDS (Borrelia) spørgeskema

Udfasning af ELISA borrelia-test

ELISA er en indirekte testmetode, der måler om immunsystemet producerer

antistoffer i blodet mod en borrelia-infektion. Hvis testen ikke finder tilstrækkelig

borrelia-antistoffer er testresultatet negativ for borrelia.

For at der dannes antistof, skal antistofproduktion startes af immunsystemet ved at

hvide blodlegemer af B-lymfocyt typen kommer i direkte kontakt med en given

infektion. Som redegjort for i borrelia-klaringsrapport 2. udgave har borrelia flere

måder til at undvige immunsystemet og derved undgå dannelse af borrelia-antistoffer.

Udover ovennævnte problemstilling peger Mikrobiologen Tom Grier i sin

sammenfatning ”An Accurate Test for Lyme Disease?” også på følgende:

Hvis det sæt af antistoffer der testes for, ikke afspejler dem som patienten

producerer, vil testen ikke formå at detektere borrelia-infektionen. Dette er et problem

hvis der er tale om borrelia-typer, som endnu ikke er registreret i Danmark eller som

er ”hjembragt” fra udlandet.

ELISA-tests er ikke standardiserede, og forskellige fabrikater og laboratorier har i

undersøgelser vist sig at producere forskellige testresultater på de samme blodprøver

med store mængder borrelia-antistof.

Konklusionen må nødvendigvis være ELISA borrelia-testen er til fare for

patientsikkerheden og bør udfases.

ref:

Borrelia klaringsrapport - 2. Udgave 2014 – Ram Dessau et al.

bilag i pdf:

An Accurate Test for Lyme Disease? – T. Grier, BA kemi, biologi, MS mikrobiologi

For nuværende regnes det karakteristiske røde hududslæt som det eneste sikre

kliniske tegn på borrelia, hvor det ikke er nødvendigt at foretage en ELISA-test.

En patient med klassiske borrelia symptomer, der ikke opdagede det karakteristisk

røde hududslæt – eller slet ikke får udslættet, som det er tilfældet med Borrelia

miyamotoi – kan blive fejldiagnosticeret og dermed ikke få den nødvendige

behandling.

For nuværende meddeles resultatet af en ELISA borrelia-test udelukkende som

”negativ” eller ”positiv”. Talværdier er udeladt, hvilket betyder at testresultater med

grænseværdier ikke vurderes. En patient med klassiske borrelia-symptomer og med

en ELISA-test med grænseværdier vil for nuværende altså ikke få behandling

B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

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Testalternativer

Western Blot

– tobånds-tolkning

Western Blot er en indirekte test, der måler borrelia-antistoffer i blodet ligesom

ELISA-testen. I Mikrobiolog Tom Griers sammenfatning ”An Accurate Test for Lyme

Disease?” forklares at Western Blot lider af de samme svagheder som ELISA-

metoden men har to fordele. Testen er mere følsom og mere specifik i forhold til

hvilke antistoffer der er tale om.

I USA blev test-følsomheden dog meget formindsket, da man i 1994 ved et ønske om

standardisering gik fra to til fem ”bånd” som kriteriet for et positivt test-resultat.

I 2013 konkluderede et studie udført af Kinas Center for Sygdomskontrol og -

forebyggelse at en Western Blot-test kan betragtes som positiv efter et kriterie med

kun to ”bånd”.

bilag i pdf:

An Accurate Test for Lyme Disease? - Grier BA kemi, biologi, MS mikrobiologi

ref:

IgM immunoblot - National Conference on Serologic Diagnosis, Lyme Disease 1994

ref:

Interpretation criteria for standardized Western blot for the predominant species of

borrelia burgdorferi sensu lato in China - Jiang et al.

MELISA-LTT,

MELISA Medica Foundation

T-celle diagnostik for borrelia, LTT

LTT metoden anbefales af Deutsche Borreliose-Gesellschaft (DBG). Ifølge MELISA

Medical Foundation selv anerkender flere forsikringsselskaber i Storbritannien testen.

MELISA-LTT er blevet evalueret i en større tysk videnskabelig artikel.

ref:

Diagnosis and treatment of Lyme borreliosis guidelines - Deutsche Borreliose-

Gesellschaft

ref:

MELISA Medica Foundation

ref:The

Lymphocyte Transformation Test for Borrelia Detects Active Lyme Borreliosis and

Verifies Effective Antibiotic Treatment, 2012 - Volker von Baehr et al.

EliSpot,

InfectoLab/BCA

T-celle diagnostik for borrelia, LTT

LTT metoden anbefales af Deutsche Borreliose-Gesellschaft (DBG)

ref:

Diagnosis and treatment of Lyme borreliosis guidelines - Deutsche Borreliose-

Gesellschaft

ref:

Borreliose Centrum Augsburg (BCA) information om ELISPOT

Nanotrap Lyme Antigen Test,

Ceres Nanosciences Inc.

Ny test der er undervejs, detekterer borrelia direkte.

Testen udvikles i samarbejde med USA's National Center for Biodefense and

Infectious Diseases (NCBID). Forventes at være på markedet primo 2016.

ref:

Ceres Nanosciences Inc. information om Lyme Antigen Test

ref:

National Center for Biodefense and Infectious Diseases (NCBID)

B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

4/5

Forlænget antibiotikabehandling

patientens eget valg

Borrelia-klaringsrapporten der definer retningslinjerne for brug af antibiotika til

behandling af borrelia, begrænser for nuværende varigheden til maks. 21 dage.

Ifølge Deutsche Borreliose-Gesellschaft (DBG) er succesraten for behandling af

borrelia med antibiotika 90 %, når der behandles inden for de første 4 uger af

sygdomsudbruddet. Hvorimod behandling af sent diagnosticerede tilfælde, hvor

infektionen er blevet kronisk, kan have en succesrate på kun 50 %. DBG anbefaler

derfor antibiotikabehandling op til 3 måneder eller mere.

Gavnligheden af længerevarende antibiotikabehandling af kronisk borrelia diskuteres

i artiklen ”Lyme disease: a turning point” af Raphael Stricker og Lorraine Johnson.

Her fremhæves forskningsresultater med kognitive og fysiske forbedringer efter

længerevarende behandling hos patenter med kronisk borrelia.

Det må være patientens eget valg der er afgørende i en behandlingssituation, især

når alternativet er svær invaliditet og meget ringe livskvalitet…

bilag i pdf:

Lyme disease: a turning point 2007 - Raphael Stricker, MD, CPMC not-for-profit,

academic medical centers

ref:

Lang antibiotikakur hjælper mod borrelia 2007 - Dagens Medicin

ref:

Diagnosis and treatment of Lyme borreliosis guidelines - Deutsche Borreliose-

Gesellschaft

ref:

Borrelia klaringsrapport - 2. Udgave 2014 – Ram Dessau et al.

For at sætte det lidt i perspektiv bliver cancerpatienter rask væk tilbudt langvarig

kemoterapi uden at der nødvendigvis kan regnes med en gavnlig effekt, som

redegjort i artiklen ”How Effective Is Chemo Therapy?” af Ralph Moss. At resultatet

blot kan være svækket modstandskraft og en ringere livskvalitet, vægtes ikke særligt

ved denne form for behandlingstilbud.

ref:

How Effective Is Chemo Therapy? 2008 - Ralph W. Moss

Senest har Danske Regioner meldt ud, at man vil satse på udviklingen af personlig medicin.

Blandt andet i erkendelse af at 75% af alle kræftpatienter, ikke har gavn af den medicin de får.

ref:

Tusindvis af danskere skal gentestes 2015 - DR

Obligatorisk efteruddannelse i flåtsygdomme

Alle diagnosticerende læger bør undergå en obligatorisk efteruddannelse i

flåtsygdomme.

Mange danske læger har ringe viden om borrelia og tolker ofte det komplekse

symptom-billede som værende psykisk, hvorved patienter overlades til sig selv med

deres alvorlige sygdom.

B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

5/5

Patientindrapportering

Webbaseret indrapportering for patient-erfaring med diagnosticering og behandling.

I USA har U.S. Food and Drug Administration oprette MAUDE hvor patienter kan lave

indrapportering om utilsigtede hændelser med medicinsk udstyr.

ref:

U.S. Food and Drug Administration oprette MAUDE

Videnscenter for vektorbårne sygdomme

- Fokusområde Borrelia- og co-infektioner

Et stærkt nationalt vidensbaseret center for vektorbårne sygdomme, med fokus på

Borrelia- og co-infektioner som særområde, vil kunne udstikke retningslinjer for

diagnosticering og behandling såvel som efteruddannelse.

Videncentret bør baseres på en åben og sund videnskabelig tilgang med:



Indsamling af ”erfaringsmæssig evidens” fra klinikker

Indsamling af patienterfaring

Indsamling og granskning af videnskabelige artikler

Indsamling og granskning af obduktionsresultater

Føling med igangværende forskning

Afholdelse af symposier

(Om behandling i Tyskland) ”Tiden læger i hvert fald nogle sår, om ikke alle, så dog nogle sår, og

øhh.. så derfor vil der være nogle, der bliver raske i disse forløb …”

Ram Dessau hoveforfatter af borrelia-klaringsrapport 1. og 2.udgave

ref:

Dansk borrelia-test er kritisabel - TV2 Nyhederne

B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

Will There Ever Be

An Accurate Test for Lyme Disease?

A Reference Booklet For Lyme Patients

Tom Grier

Lyme Disease is a complex systemic disease that is caused by highly motile bacterium in the

spirochete family. The bacteria

Borrelia burgdorferi

was first isolated from the skin of a Lyme patient

with the distinctive bull’s-eye rash in the early 1980s. Since that time, culturing the elusive bacterium has

been difficult, frustratingly unpredictable, and miserably inconsistent.

Borrelia burgdorferi

can very quickly move from the site of a tick bite into the circulatory

system, where it can circulate throughout the body. This unique bacterium has a distinct and insidious

method for passing through the capillary walls of blood vessels and nestling its way deep inside many

organs and tissues of the human body. In animal models, the Lyme spirochete within mere hours of a tick

bite, can cause a breakdown of the

blood-brain-barrier.

It is the bacteria’s ability to exit the blood stream, hide, and survive that makes Lyme disease so

difficult to detect with any one test. It is the unique microbiology of the bacteria that gives it the ability to

hide and survive undetected within the human body. That is why using other bacterial diseases as a model

for Lyme disease is difficult and leads to misunderstandings in the medical community on how to

diagnose and treat Lyme disease. Infections causd by the family of bacteria known as

Borrelia

are unique

in their microbiology and cannot be dismissed with a rubber stamped one-treatment-fits-all approach.

There are five main methods of testing for Lyme disease:

Antibody tests (either the Elisa or Western Blot serology tests)

Bacterial DNA detection by polymerase-chain-reaction test (PCR)

Live culture

Antigen detection: Finding particles and proteins of the bacteria in blood, CSF, urine, or

tissue samples.

5. Direct observation by microscope: This can employ the use of biopsy and stain, or

centrifuged blood, spinal fluid, and urine.

By far, the most commonly used tests for Lyme disease are antibody serologies. These tests are

indirect measurements of your body’s response to the bacterial pathogen. Antibody serology tests are

most often employed not for their accuracy, but more for their convenience, low risks, and low costs.

Essentially, these tests look for your antibody response to an infection in the blood stream.

The most common of the antibody tests is the

Enzyme Linked Immune Sera Assay

test

(ELISA). This test is often the first test given to Lyme patients and can only give you a very general idea

of the presence or absence of anti-Lyme antibodies.

The Main Drawbacks of Using Elisa Tests for Lyme Disease:

First, each lab can have their own version of an ELISA test, using different enzyme-linked

antigens that are used to trap specific anti-Lyme antibodies in the patient’s blood. When an enzyme is in

the presence of the correct anti-Lyme antibody, there is an enzymatic color change that occurs which is

read by a machine. If the lab chooses antigens that do not reflect the same set of antibodies that the patient

is producing then the test will fail to detect Lyme disease. The individual that tests negative with one lab’s

test may have a have detectable Lyme antibodies if another lab’s ELISA test is given employing a slightly

different set of antigens.

B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

Think of it like this: If you take a gold fish bowl and drop a paperclip and a penny into the bowl

and then use a magnet to find the paper clip, you cannot conclude that there is no other metal in the bowl.

The magnet is simply incapable of detecting the penny. The same is true if you look for the wrong

antibodies in a Lyme patient.

Another problem is consistent accuracy within labs in interpreting results. his lack of consistency in

laboratory accuracy was borne out in Lori Bakken’s ELISA test study. This study showed that more than

50% of the time, labs could not correctly or consistently replicate identical results in identical triple-

paired serum samples highly positive for Lyme antibodies. This is despite claims by labs of being 99%

specific and accurate. However, what is accurate by laboratory definition has

nothing

to do with accuracy

as a diagnostic test to determine the presence or absence of active infection in a patient.

•

Bakken LL, Callister SM, Wand PJ, Schell RF. Interlaboratory Comparison of Test

Results for the Detection of Lyme Disease by 516 Participants in the Wisconsin State

Lab of Hygiene/College of American Pathologists Proficiency Testing Program. J

Clin Microbiol 1997; Vol 35, No. 3:537-543

Bakken LL, Case KL, Callister SM et al. Performance of 45 Laboratories

Participating in a Proficiency Testing Program for Lyme Disease Serology. JAMA

1992;268:891-895

•

You see, when companies marketing their products use buzzword terms like

specific, sensitive,

accurate,

these marketing terms do

not

mean

diagnostically

accurate!

The next problem for both the Western Blot and the ELISA tests is timing. In Lyme disease,

timing is everything! Timing is everything for both successful diagnosis and successful treatment.

In most infections of the human body, the body’s immune system releases early and late antibody

responses. However, there are some caveats to this general assumption. First, the immune system is most

effective when infection is in the blood stream, or places where blood can travel to easily. This is because

several white blood cells in the blood stream must interact with the pathogen and then with each other to

create the proper immune response.

About four to six weeks after first detecting a harmful pathogen within the blood-stream, a white

blood cell called the B-cell lymphocyte expands and becomes a plasma cell and produces

immunoglobulin type M (IgM) antibody. Then, in another four weeks, if the infection is still in the blood

stream, a new set of plasma cells creates IgG antibodies. Therefore, in general, the presence of IgM

antibody and the absence of IgG antibody mean an early infection. (Early means the initial exposure to

the bacteria was probably within eight to twelve weeks.) Unfortunately, in Lyme disease this general rule

of the lone presence IgM antibody as an indicator of early infection does not apply: IgM antibody can and

will appear throughout the infection.

Within mere days after an infected tick bite, the Lyme bacteria can already find its way into the

brain and joints of patients. Since

Borrelia burgdorferi

is prefers other locations within the human body

other than the blood, it is equipped to seek out those environs more suitable to long-term survival of the

bacteria

The migration of the Lyme spirochete from the human blood stream into the tissues has the same

effect as muting the patient’s antibody response. This happens because the fewer bacteria that remain in

the bloodstream, the less stimulation there is to evoke and provoke a B-Cell to become a plasma cell. If

the initial infection never makes a strong presence in the blood stream, the host’s antibody response may

be muted or never initiated. In primate studies a strong antibody response was dependent on the infection-

load that the animal was given. The more bacteria injected the greater the antibody titer.

The next problem with timing is this: If you give an antibody serology test too early, it will

always be negative. This is simply by virtue of not allowing the immune system enough time to clone

enough of the correct plasma cells to create a measurable antibody response. The immune system must

manufacture exact copies of the cells that can fight the disease. In some patients it is thought that they

may not have the correct B-cells to even make an effective assault against this highly variable pathogen. It

B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

is akin to trying to fix a broken motor with the wrong tools. You do the best you can but will it be good

enough?

Finally, since the infection can already be beyond the reach of the blood stream, the antibody

serology tests are worthless for early-sequestered infections of the brain, joints, bladder, skin, and

tendons. These are sites where the immune system has little effect. The assumption that the absence of

antibodies means the absence of infection could prove disastrous if the infection has already established

itself in the brain. There is evidence from looking at spinal taps on dozens of

“Early”

Lyme patients with

a bull’s-eye rash that the infection can penetrate into the CNS early and without symptoms! If not treated

effectively a trapped infection within the CNS is hard to detect and very hard to treat.

Unlike other

infections of the brain, Lyme does not routinely produce immune cells and antibodies in the spinal

fluid.

Further Considerations:

IgM antibodies in Lyme disease can occur at

any

point in the infection, early or late. This is most

probably because of the infection seeding from one site to another via the breach of capillaries in that

area. In other words, if the Lyme spirochete can escape out of the capillaries during early infection by

stimulating the blood vessel cells to produce digestive enzymes, then it also reasons that the sequestered

spirochetes can occasionally seed back into the circulatory system by a similar mechanism.

The ELISA test is sometimes used to test

cerebrospinal fluid (

CSF) in order to detect antibodies in

the central nervous system (CNS). While the presence of Lyme antibodies in the CNS is highly

significant, no accurate conclusion whatsoever can be made by the absence of Lyme antibodies in CSF.

Short of an autopsy, an infection of the brain with

Borrelia burgdorferi

is almost impossible to rule out.

The brain is a very poor producer of immune responses. This is why Lyme infections of the brain appear

to be aseptic (the absence of white blood cells in the spinal fluid or brain.).

ELISA Recap:

•

The ELISA test is useless within the first four weeks of a tick bite.

The ELISA may not detect late infection because the bacteria can find immune privileged sites in

which to hide.

The ELISA test is not a standardized test. The design of the test can vary greatly from lab to lab.

The choice of antigens used in the test is derived from a laboratory strain B-31 instead of the

naturally occurring wild strains. The B-31 strain is proving to be highly variable and changing.

Using a high passage lab strain may be cheap and convenient, but not an accurate representation

of the various strains of Borrelia found in nature.

The accuracy of the test varies even on identical samples, meaning that even the labs themselves

introduce a variable of inaccuracy by poor procedure, interpretation, or quality control.

•

Western Blot:

The Western Blot antibody test has only two

slight

advantages over the ELISA test. First, it is slightly

more sensitive, probably due to the inclusion of more bacterial antigens. Second, it tells us which

bacterial proteins are eliciting an antibody response in that patient. However, in the end, the Western Blot

still suffers from all the same downfalls as the ELISA, with one additional disadvantage. In Dearborn,

Michigan, a group of state epidemiologists decided to standardize the interpretation of the Western Blot

test:

The IgM Western Blot must have two significant bands to be positive and the IgG Western Blot

must have 5 out of 10 possible bands present.

These numbers are somewhat arbitrary, because the

presence of the single band 39 kda is specific for

only Borrelia burgdorferi,

and

other bacteria yet

discovered.

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Lyme antibodies in the patient’s serum at the bottom of the filter paper infuse upward and are trapped

as lines where the corresponding bacterial protein is found.

Diagram of Western Blot

Band 41 kda Flagellin

OSP-B Antigen 34

OSP-C Antigen 23

39 kda band the most specific band

OSP-A Antigen 31 kda

In essence, the conference in Dearborn, Michigan, chose to eliminate the reporting of a half dozen

significant bacterial proteins from the test. Even if antibodies are found present against these significant

excluded bacterial proteins the Western Blot using these new reporting criteria cannot be interpreted as a

positive test.

The IgG Western Blot must show the strong presence of five out of ten pre-selected bacterial

proteins, and the presence of any other highly significant bands is to be ignored. In fact, most state labs

are prohibited from even reporting these other significant bands. They are allowed only to report the test

as positive or negative, thus taking the ability to interpret the test away from the physicians.

How badly did the new reporting criteria bootstrap the Western Blot accuracy? Compare these

results in a 66-patient study on children with physician-diagnosed bull’s-eye Lyme skin rashes:

•

1995 Rheumatology Symposia Abstract # 1254 Dr. Paul Fawcett et al.

This abstract shows that,

under the old criteria, all 66 pediatric patients with a history of a tick bite and bull’s-eye rash who

were symptomatic were accepted as positive under the old Western Blot interpretation. Under the

newly proposed criteria, only 20 were now considered positive. This means 46 children, all

symptomatic, would probably be denied treatment. That’s a success rate of only 31%!

Sixty-Six Children with Bull’s-Eye Rash Tested by Both Criteria

Old Western Blot criteria: 100 % positive

New NIH criteria: 31% positive

False positives on controls: 0%

False Positives on controls: 0%

* Note:

A misconception about Western Blots and ELISA tests is that they have as many false positives as

false negatives. This is not true. False positives are rare. Negative serologies despite a rash or a positive

culture is routine. Remember words like sensitivity, specificity, and accuracy DO NOT MEAN

DIAGNOSTICALLY ACCURATE to determine if a patient has an infection. A NEGATIVE TEST

CANNOT RULE OUT AN INFECTION THAT HAS ESCAPED THE BLOODSTREAM.

The conclusion of the researchers in this pediatric study was:

“The proposed Western Blot

Reporting Criteria are grossly inadequate, because it excluded 69% of the infected children”

B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

Finally, the failings of all antibody tests are that they can only capture

uncomplexed

antibody.

Once an antibody finds something to latch on to in the bloodstream, it is no longer available to be

detected with our current tests.

Ab + Ag = Ab/Ag-complex

(Antibody + Antigen = Antibody/Antigen complex)

(free)

(complexed)

Free antibodies are detectable with the current Lyme tests, but antigen/antibody complexes are

undetectable using either the ELISA or Western Blot tests. It has been suggested that complexes are the

biggest weakness of both the ELISA and Western Blot tests and yet they are completely ignored when

Lyme tests are given.

•

Schutzer SE, Coyle PK, Belman AL, Golightly MG, Drulle J. Sequestration of antibody to Borrelia

burgdorferi in immune complexes in seronegative Lyme disease. Lancet 1990;335:312-315

When the ELISA or Western Blot tests are positive, they are significant. However,

when they are

negative, they are incapable of determining the complete absence of active infection somewhere in the

body.

All it takes to validate this is a single case history of a patient who is sero-negative for Lyme

disease (the absence of Lyme antibodies), but is culture positive for the bacteria. Here are a few such

examples of patients found to be actively infected despite having no measurable antibodies.

•

Masters EJ, Lynxwiler P, Rawlings J. Spirochetemia after Continuous High Dose Oral Amoxicillin

Therapy.

Infect Dis Clin Practice

1994;3:207-208

Schmidli J, Hunzicker T, Moesli P, et al. Cultivation of Bb from Joint Fluid Three Months After Treatment

of Facial Palsy Due to Lyme Borreliosis. J Infect Dis 1988;158:905-906

Liegner KB, Shapiro JR, Ramsey D, Halperin AJ, Hogrefe W, and Kong L. Recurrent erythema migrans

despite extended antibiotic treatment with minocycline in a patient with persisting Borrelia burgdorferi

infection. J. American Acad Dermatol. 1993;28:312-314

The biggest misunderstanding physicians have about Lyme antibody tests is thinking that a high

titer of antibody in a patient means that the patient is more ill than a patient with a low titer of

antibodies. What these tests are really measuring is the body’s natural immunity against the

bacteria. A patient who is able to mount a strong antibody defense against this pathogen is far

better off than a patient who makes little or no antibody. It only stands to reason that a patient with

a high infection load and no antibodies is going to be more symptomatic than a patient with a high

natural immunity. Unfortunately, most physicians look at higher titers and assume those patients

are the most ill, but their reasoning is backwards. Low titers in a highly symptomatic Lyme patient

is a very bad thing.

DNA Amplification or PCR (Polymerase Chain Reaction) Tests:

Every living cell has DNA that is unique to that species of organism. This is true from the

simplest bacteria to the most complex mammal. The polymerase chain reaction test is a test that can

search for a specific sequence of DNA and multiply that sequence a billion times in less than a day. It is

often said that the PCR test is the most sensitive and specific diagnostic test available. However, PCR

tests are not without their drawbacks.

Specificity is a big problem with today’s Lyme tests. It sounds good to hear things like, “This is

the most specific test on the market!” Those buzz words meant to promote and sell a test, however, should

throw up a red flag to anyone who understands this family of bacteria. The family of bacteria that Lyme

disease spirochetes belong to is

the borrelia

family.

Borrelia

is the same group of bacteria that cause tick-

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borne-relapsing-fever. There are more than 40 different disease-causing subspecies of borrelia that are

closely related to the Lyme spirochete.

Variability in the borrelia family of bacteria is not only routine; it is actually built into the

genetics of the bacteria to add variations its proteins when stressed during division. This is what causes

relapses of symptoms in relapsing fever. The bacteria presents one set of proteins to your immune system

and then six weeks later, the bacteria adapt and present new variations of surface proteins to your immune

system. In turn, your own immune system is what makes you feel sick, sweaty, feverish, and ill with each

new set of antigens presented.* The Lyme bacteria uses a slightly more subtle form of this morphogenic

antigen variability, but it, too, like its cousins, is capable of changing its outward appearance like a

criminal changing his disguise.

Escaping the immune system is very important if you want to survive as a bacterium.

Borrelia

has several mechanisms to do this, but this mechanism of gene variability and variable proteins make both

serology antibody tests and PCR tests less effective.

One could easily make a case that Lyme disease and all of its Lyme-like cousins are nothing more

than variations of Relapsing-Fever. In America, we now have at least two geno-species that cause Lyme

disease, which are not

Borrelia burgdorferi.

The truth is, we may have a situation with Lyme disease that

is similar to relapsing fever, in that there are dozens of yet to be discovered species of borrelia that cause

disease but are not

Borrelia burgdorferi.

Would you want to be denied medical treatment, medical coverage, and your good health, all

because the test you are given is so specific that it excludes all other borrelia? What we need in America

and other Lyme-endemic countries is not a hundred different species-specific tests, but rather one general

screening test for Borrelia. This is true for the antibody tests as well as the PCR DNA tests. Suddenly the

buzz-word SPECIFICITY has become a dirty word. Specific also can mean exclusionary!

*NOTE:

There is no substantial evidence that a Herxheimer reaction during antibiotic treatment

is due to the release of bacterial toxins. There is good evidence that a true Herxheimer reaction is the

rapid synthesis of cytokines from your immune cells. This increases when internal bacterial antigens are

exposed when the bacteria ruptures with treatment. This was established in Relapsing Fever patients in

the late 1960s. To date the evidence of

Borrelia burgdorferi

producing significant toxins in symptomatic

patients is virtually non-existent.

How a PCR test works:

The first step is to create a template or primer for the PCR test that is specific to the organism you

are looking for. Second, you have to be sure that the test sample has a high probability of containing the

DNA sequence for which you are searching. Another concern is inhibitory factors in the samples. Finally,

you have to be sure there are no false positives from lab contamination due to DNA floating around like

dust in the air.

In Lyme disease, the PCR test really has limited value. The main problem is that doctors and labs

like to use blood, urine, and spinal fluid to test simply because of the ease of collection. In the case of

Lyme disease, however, the borrelia spirochete does not like the blood stream, and PCR tests of fluids are

frequently negative while the same PCR tests of skin biopsies in the same patient are positive. This

indicates that finding a sample with the bacterium’s DNA is a bit like finding a needle in a haystack.

The example I like to use to demonstrate this is the parable about the bucket and the hailstorm. If

it is hailing outside, you could run around all day with a teacup, trying to catch just one hailstone. Just one

hailstone in the teacup would be proof that it is hailing outside: But your chance of success is low. If,

however, you used a bucket to catch the hailstones, you would have a slightly better chance to make your

case. If you had an entire parking lot to catch hail you would have even a better chance!

However, remember, just because it is hailing in New Jersey doesn’t mean it’s hailing in New

York. If the hail represents borrelia DNA, it is clear the bigger and better the sample you collect the better

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the result. However, if New Jersey represents your blood and New York represents your brain, you cannot

use a hailstone from New Jersey to prove whether it’s hailing in New York. To make matters worse, the

tests we have now are not as good as they could be, so it compares to using teacups with holes in the

bottom to collect hailstones! Absence of proof is not proof of absence of infection.

It has been reported that there are inhibitory enzymes in the urine that can affect the PCR tests.

Most labs using PCR tests don’t address this but the truth is the whole organism rarely shows up in the

urine so a PCR test like serology tests can be inconclusive if negative.

Cerebrospinal fluid has been reported PCR positive in only 7% of the cases of documented

neurological Lyme disease. This indicates that the organism is highly tissue bound in the CNS and that

bacterial DNA in the spinal fluid is the exception, not the rule, during infection.

The biggest problem with the PCR test in Lyme disease isn’t its accuracy or sensitivity, but the

squabbling over patents. Every lab wants its own patent on its own test and will often present data on

their tests in a favorable way to sell the test, but is misrepresentative of the test’s abilities to diagnose

Lyme disease at any stage.

Most labs use the OSP-A gene as a primer for its PCR test, but, in truth, a PCR test that can use

multiple primers is probably better, there are some species of

Borrelia burgdorferi

don’t even have a gene

for OSP-A. However, using multiple primers can mean paying royalties to many different labs for the use

of proprietary patents. This raises costs and means cooperation between competitors.

PCR Recap:

No single sample from a patient can be diagnostic for Lyme disease using PCR as the test. Even

the University of Minnesota reported a mere 18% success rate in early Lyme when skin biopsies were

obtained from culture positive bull’s-eye rashes.

Patent disputes often result in poor PCR tests being marketed with little or no sharing of

technology between competitors. This competition often leads to over-hyped performance and over hyped

accuracy claims by manufacturers.

Often the best tissues for PCR tests are tissue biopsies, which are rarely done because of costs,

risk, and inconvenience. In truth, PCR tests are best used in the post-mortem exam on tissues such as the

brain, bladder, and heart. As a diagnostic tool, it can be useful when positive, but tells us nothing when

negative. I see few patients lining up for a brain biopsy.

•

Appel MJ, Allan S, Jacobson RH, Lauderdale TL, Chang YF et al. Experimental Lyme disease in dogs

produces arthritis and persistent infection. J Infect Dis, March 1993;167(3):651-4

Culturing

Borrelia burgdorferi:

Culturing spirochetes can be difficult (see my article on the Lyme Alliance web site). Some

spirochetes, such as T. pallidum, which causes syphilis, have never been successfully cultured in culture

media, and are maintained only in live animal models.

Borrelia burgdorferi

is difficult to culture. The

University of Minnesota, when comparing culturing of erythema migrans rashes to their early PCR test,

reported culture success rates as low as 4%.

As discussed earlier, culturing blood is frustrating because the bacteria do not like the blood

stream. The same is true for the spinal fluid and urine. Therefore, once again we are left with the option to

biopsy at great expense and risk, or to use other, less costly, tests. Culturing is the gold standard for

confirmation of an infection, and a positive culture is highly important. However, as a diagnostic tool in

Lyme diagnosis, culturing has a poor success rate, and the cost and time often make it prohibitive except

as a research tool.

The technique of culturing the non-classical form of the spirochete known as spheroid-forms or

L-forms is controversial and has yet to be corroborated and commercially reproducible. L-forms seem to

be shed by the spirochetes when they are stressed and moribund. They appear to be able to transform back

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into viable spirochete indicating that the vesicles retain a full compliment of bacterial genetic material.

Until the link can be established between these L-forms and disease, and the cultures can be corroborated

by PCR and consistently reproducible by other labs the presence of L-forms will be debated by opponents

as artifacts and aberrations.

Just as in the case of PCR and antibody tests, culturing can also be affected by the species of

bacteria that is present. Some laboratory strains of Lyme disease have been known to take months to

culture. Most hospital labs don’t even stock culture media that is suitable for culturing Borrelia, and the

choices for culture media are extremely limited. Until better techniques and culture medias are made

available, culturing spirochetes is a techniques best used as a research tool. But the inexperience of

hospital labs with spirochete culturing techniques is by far the biggest hurdle in seeing this test flourish.

Microscopic observation of the organism:

Using a microscope to find the Lyme bacteria is quite literally like looking for a needle in a

haystack. The

Borrelia burgdorferi

organism is found in such low numbers in fluids and tissue that it

requires hours and hours of lab time to do an adequate search of just a few millimeters of tissue. As a

research tool biopsy and stain is useful, but to use microscopy to diagnose Lyme is too slow, too costly,

and quite unreliable.

The methods used today have remained, for the most part, unchanged for a hundred years. It has

been known since the turn of the century that spirochetes stain heavily with silver acid-loving stains. This

means spirochetes normally invisible under a light microscope will stain jet black and can be seen in

silver-stained tissue biopsies. (Nucleic acids in the bacteria’s membrane absorb the silver-stain.)

The modern variation of spirochete microscopy is to use a fluorescent stain attached to an

antibody that will latch on to the bacteria. Under a fluorescent microscope, the bacteria stand out as

brightly colored spirals.

The final method is simply to take a bodily fluid, such as CSF or urine, and ultra centrifuge it,

then look for spirochetes under a light microscope with a drop of acrodine orange dye.

All of these techniques are direct observation of the organism, but it is impossible to determine

the species just by looking at the bacterium’s gross morphology. The most useful place for this tool is in

the post-mortem exam, where deep tissues can be collected, preserved in paraffin, stained, and studied

months later. Any autopsy performed on a Lyme patient should include silver stain sections of paraffin-

fixed brain biopsies. However, using microscopic exam to diagnose Lyme would be expensive and time

consuming, and would yield poor results. (In a post-mortem exam the presence of spirochetes is

significant. Spirochetes should never be found in the brain. One wonders what percentage of dementia

patients would have spirochetes in the brain if we looked for them?

Conclusion:

One of the biggest misconceptions about Lyme disease antibody tests, which has led to years of

unnecessary morbidity and mortality for Lyme disease patients, is

the insistence that the absence of

Lyme antibodies means the absence of active infection.

You cannot equate the absence of antibodies

with the absence of infection, nor can you use antibody serologies as an endpoint in treatment studies to

determine the effectiveness of any treatment regimen. It isn’t just a bad idea - it is just plain bad science.

Will there ever be a Lyme test that can be used dependably to diagnose Lyme disease? I don’t

believe such a test is within our current technology, and until such a test exists denying patients treatment

using our current tests is bad medicine.

Key words and concepts used in this article:

Systemic:

Borrelia burgdorferi

and other spirochetes in the tick-borne relapsing fever family of bacteria

circulate through the blood stream to the entire body. They can find passage through blood vessel walls

and invade other tissues and organs, including known target tissues such as skin, tendons, joints, heart,

nerves, and brain.

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Sequestered:

The Lyme spirochete can find haven in areas of the body that are poorly protected by the

immune system (the brain), have poor areas of blood circulation (tendons), or where the bacteria can lay

metabolically inactive for lengths of time and resist antibiotic penetration (the skin and the brain).

Multi-systemic:

The bacteria has affected more than one system of the body, such as: Peripheral nervous

system, skin, joints and connective tissues, cardiovascular system and circulatory system, eyes, muscles,

liver and spleen, and central nervous system.

Blood Brain Barrier (BBB):

The network of capillaries surrounding the brain that selectively let things

in and out of the brain. A healthy BBB prevents infections, white blood cells, and many medicines from

entering the brain. A breakdown of the BBB is not a good thing, and occurs very early in most animal

models of Lyme disease.

Antigen:

A protein usually on the surface of the bacteria that stimulates the immune system to make

antibodies against that protein. Antigens can also stimulate other immune responses, such as T-cell and

macrophage responses.

Serologies:

Using the centrifuged serum extracted from blood to look for antibodies against the Lyme

bacterium.

Titer:

A measurement of antibody content in the serum. Titers are usually reported as dilution series. The

higher the dilution of serum where antibodies are still detectable means there are more antibodies present

in that patient’s serum. The cut off for reporting a positive is a bit arbitrary and varies from lab to lab.

Institutions conservative on the diagnosis of Lyme have raised their cutoffs from 1:256 to 1:1024 Which

is rare to see in most Lyme patients.

Infection Load:

The actual number of bacteria in a host. If the bacteria remain in the bloodstream, the

number of bacteria per unit of blood can be calculated, but this number is meaningless if the infection has

moved beyond the bloodstream. In Lyme disease, there is no accurate way of determining true infection

load. If the bacteria out pace antibody production then there is no FREE ANTIBODY only ANTIBODY

COMPLEXES.

References:

•

Cimmino MA, Azzolini A, Tobia F, Pesce CM. Spirochetes in the Spleen of a Patient with Chronic Lyme

Disease. American J Clin Pathol 1989;91(1):95-97

DeKoning J, Hoogkamp-Korstanje JAA, van der linde MR, Crjins HJGM. Demonstration of Spirochetes in

Cardiac Biopsies of Patients with Lyme Disease.

J Infect Dis

1989;160:150-153

Waniek C, Prohovnik I, Kaufman MA. Rapid Progressive Frontal-Type Dementia and Death with Subcortical

Degeneration Associated with Lyme Disease. A case report/abstract/poster presentation. The Lyme bacterium is

isolated from the brain of a deceased Lyme patient treated with antibiotics. LDF State of the Art Conference,

with emphasis on neurological Lyme. April 1994, Stanford, CT*

Lawrence C, Lipton RB, Lowy FD, and Coyle PK. Seronegative Chronic Relapsing Neuroborreliosis.

European

Neurology.

1995;35(2):113-117

Cleveland CP, Dennler PS, Durray PH. Recurrence of Lyme Disease Presenting as a Chest Wall Mass:

Borrelia

burgdorferi

was present despite five months of IV ceftriaxone 2g, and three months of oral Cefixime 400 mg

BID. The husband was seronegative for Lyme and highly symptomatic. The wife had a high tier of antibodies,

but had mild symptoms. The excised fibrous mass was culture positive for Borrelia burgdorferi despite eight

months of continuous high dose antibiotics. Poster presentation, LDF International Conference on Lyme

Disease Research, Stamford, CT, April 1992 *

Preac-Mursic V, Wilske B, Schierz G, et al. Repeated Isolation of Spirochetes From the Cerebrospinal Fluid of

an Antibiotic-treated Patient with Meningoradiculitis Bannwarth’ Syndrome.

Eur J Clin Microbiol

1984;3:564-

565

Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross B, Baumann A, and Prokop J. Survival of

Borrelia

Burgdorferi

in Antibiotically-treated Patients with Lyme Borreliosis.

Infection

1989;17:335-339

Schmidli J, Hunzicker T, Moesli P, et al. Cultivation of

from Joint Fluid Three Months After Treatment of

Facial Palsy Due to Lyme Borreliosis.

J Infect Dis

1988;158:905-906

Stanek G, Klein J, Bittner R, Glogar D. Isolation of

Borrelia Burgdorferi

from the Myocardium of a Patient

with Long-Standing Cardiomyopathy.

•

B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

•

Abstract # D654: J. Nowakowski, et al. Culture-Confirmed Treatment Failures of Cephalexin Therapy for

Erythema Migrans. Two of six patients biopsied had culture-confirmed

Borrelia burgdorferi

infections despite

up to 21 days of Cephalexin (500 mg TID) antibiotic treatment.

Abstract # D655: Nowakowski, et al. Culture-confirmed Infection and Reinfection with Borrelia Burgdorferi. A

patient, despite antibiotic therapy, had a recurring Erythema Migrans rash on three separate occasions. On each

occasion, it was biopsied and revealed the active presence of

Borrelia burgdorferi

on two separate occasions,

indicating reinfection had occurred.

Abstract # D657: J. Cimperman, F. Strle, et al. Repeated Isolation of Borrelia Burgdorferi from the CSF of Two

Patients Treated for Lyme Neuroborreliosis. Patient 1 was a twenty-year-old woman who presented with

meningitis, but was seronegative for Borrelia burgdorferi. Subsequently, six weeks later, Bb was cultured from

her CSF and she was treated with IV Rocephin, 2 grams a day for 14 days. Three months later, the symptoms

returned, and Bb was once again isolated from the CSF. Patient 2 was a 51-year-old female who developed an

EM rash after tick bite. Within two months, she had severe neurological symptoms, but her serology was

negative. She was denied treatment until her CSF was culture positive, nine months post-tick bite. She was

treated with 2 grams of Rocephin for 14 days. Two months post-antibiotic treatment, Bb was once again

cultured from her CSF. In both of these cases, the patients had negative antibodies but were culture positive,

suggesting that the antibody tests are not reliable predictors of neurological Lyme disease. In addition, standard

treatment regimens are insufficient when infection of the CNS is established, and Bb can survive in the brain

despite intravenous antibiotic treatment.

Abstract # D658: F. Strle et al. Reinfection with Borrelia Burgdorferi in Endemic Areas. Conclusion: Even

despite high antibody titers, as seen in ACA patients, 7% of 2273 patients with previous Lyme disease became

reinfected and presented with an EM rash and late symptoms after a recent tick bite.

_____________________________________________________________________________________

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Editorial

For reprint orders, please contact [email protected]

Lyme disease: a turning point

‘…the medical community should keep an open mind

regarding treatment options for Lyme disease and not

jump to conclusions based on a solitary study with

poor generalizability.’

Expert Rev. Anti Infect. Ther.

5(5), 759–762 (2007)

Raphael B Stricker

†

and

Lorraine Johnson

†

Author for correspondence

International Lyme and Associated

Diseases Society, 450 Sutter Street,

Suite 1504, San Francisco,

CA 94108, USA

Tel.: +1 415 399 1035

Fax: +1 415 399 1057

[email protected]

Lyme disease is one of the most controversial between basic science studies and clinical

illnesses in the history of medicine

[1,2]

. Over research articles is striking: while basic science

the past decade, two opposing camps have studies continue to highlight the invasiveness

emerged in the controversy over this tick-borne and elusiveness of

B. burgdorferi

in culture sys-

illness. One camp is represented by the Infect- tems and animal models, clinical research articles

ious Diseases Society of America (IDSA), adhere to the dogma that

B. burgdorferi

produces

which maintains that Lyme disease is a rare ill- a limited infection that is eradicated easily

[5,6]

ness localized to well-defined areas of the Patients with persistent symptoms are labeled as

world. According to the IDSA, the disease is having ‘post-Lyme syndrome’, hypothesized to

‘hard to catch and easy to cure’ because the be an autoimmune response to the previously

infection is rarely encountered, easily diagnosed eradicated infection. To date, attempts to eluci-

in its early stage by means of accurate commer- date the autoimmune mechanism of post-Lyme

cial laboratory tests and effectively treated with syndrome have been unsuccessful

[7,8]

a short course of antibiotics over 2–4 weeks.

While IDSA followers have embraced the

Chronic infection with the Lyme spirochete, post-Lyme syndrome concept and foresworn

Borrelia burgdorferi,

is rare or nonexistent

[3]

long-term antibiotic treatment, followers of

the ILADS have continued

The opposing camp is rep-

resented by the International

‘Over the past decade,

to use antibiotics to treat

persistently

symptomatic

Lyme and Associated Dis-

two opposing camps

Lyme patients for chronic

eases Society (ILADS), which

argues that Lyme disease is

have emerged in the

infection with

B. burgdorferi

controversy over this

and coinfecting tick-borne

not rare and, because its

agents. They cite animal

spread is facilitated by

tick-borne illness.’

studies that demonstrate

rodents, deer and birds, it can

be found in an unpredictable distribution persistent infection by a complex organism,

around the world accompanied by other tick- as well as numerous clinical reports that doc-

borne coinfections that may complicate the ument failure of the standard 2–4 weeks of

clinical picture. According to the ILADS, tick antibiotic therapy recommended by the

bites often go unnoticed and commercial labo- IDSA

[1,9–12]

. The controversy came to a head

ratory testing for Lyme disease is inaccurate

[1,4]

. in November 2006 when the IDSA released

Consequently, the disease is often not recog- new guidelines severely limiting treatment

nized and may persist in a large number of options for patients with persistent Lyme

patients, requiring prolonged antibiotic therapy symptoms

[3]

. The guidelines were so restric-

to eradicate persistent infection with the evasive tive that the Attorney General of Connecticut

Lyme spirochete

[1,4]

(USA) initiated an unprecedented investiga-

The battle over chronic Lyme disease has taken tion into possible antitrust violations by the

some unprecedented turns. As of 2007, more IDSA, the dominant infectious disease soci-

than 19,000 scientific articles about tick-borne ety in the USA, in its formulation of the

diseases have been published, and the dichotomy guidelines

[13,101]

10.1586/14787210.5.5.759

ISSN

1478-7210

759

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Stricker & Johnson

To support its restrictive stance on Lyme disease, the IDSA

cites a study by Klempner and colleagues published in the

New

England Journal of Medicine

in 2001

[14]

. Sponsored by the

US NIH, the trial examined a well-defined cohort of patients

with persistent symptoms of Lyme disease despite treatment

with standard antibiotic therapy. The patients were randomized

to receive either placebo or 1 month of intravenous ceftriaxone

followed by 2 months of oral doxycycline. Treatment was

administered in a blinded fashion and response to treatment was

evaluated with a validated quality-of-life outcome tool in an

intent-to-treat analysis. The conclusion of this randomized, con-

trolled trial was that patients who received 90 days of antibiotic

therapy were no more likely to improve than patients who

received placebo. In fact, 60% of patients in the study either

stayed the same or became worse, regardless of treatment.

The results of this investigation were interpreted as showing

that long-term antibiotic therapy is ineffective for patients with

persistent symptoms of Lyme disease

[15,16]

. Owing to the pres-

tigious nature of the study sponsor and publisher, this interpret-

ation was circulated widely in the medical literature and the lay

press, and was immediately adopted by insurance companies,

who used the study results to deny antibiotic therapy beyond

the 2–4-week IDSA limit to patients with chronic Lyme disease.

As a result of the IDSA’s promotion of the study conclusions,

chronic Lyme disease ceased to be a treatable infection in the

eyes of the medical community. Physicians who continued to

treat beyond the IDSA limit risked medical board sanctions or

medical license revocation based on this solitary study

[11]

More than 5 years after publication of the Klempner article, the

‘over-reaching impact’ of the study has finally been challenged.

Cameron examined the generalizability of the Klempner study

findings in terms of the patient cohort, the treatment regimen

and subsequent studies of prolonged antibiotic therapy in chronic

Lyme disease

[17]

. Patients in the study cohort had been sick for an

average of 4.7 years and had been treated with an average of three

courses of antibiotics, making this a ‘retreatment’ study of

patients who had already failed similar therapy. Furthermore,

based on the health-related quality-of-life scale that was used, the

treatment regimen was inadequate for the degree of functional

compromise in these patients in terms of intravenous antibiotic

duration and oral antibiotic dose. Cameron concluded that the

study represents a ‘too-little too-late’ approach to a highly

selected, extensively treated patient group that differs significantly

from more typical chronic Lyme patients who are either untreated

or undertreated. Based on the lack of generalizability of the study

results, the blanket interpretation that long-term antibiotics are

ineffective for chronic Lyme disease is invalid

[17]

Subsequent randomized, placebo-controlled trials of antibiotic

treatment in chronic Lyme disease have failed to support the con-

clusions of the Klempner trial

(TABLE 1)

. Krupp

et al.

showed that

1 month of intravenous ceftriaxone improved the primary out-

come measure of fatigue in a cohort of chronic Lyme patients

[18]

For the other two primary outcome measures, cognitive function

remained unchanged and borrelial antigen persisted in cerebrospi-

nal fluid in a subset of patients after this relatively short treatment

course (1 vs 3 months in the other placebo-controlled trials

described here). Of interest, patients who had not received previ-

ous intravenous antibiotic therapy did significantly better than

controls in terms of improvement in fatigue (69 vs 0% improve-

ment; p < 0.01). This observation underscores the significance of

prior treatment failure and the poor generalizability of the Klemp-

ner trial. Three cases of life-threatening sepsis occurred in the

placebo group (11%) versus none in the ceftriaxone group

(0%). This finding demonstrates the relative safety of indwelling

Table 1. Placebo-controlled trials of antibiotic treatment in chronic Lyme disease.

Study

Klempner

et al.

(2001)

Treatment

Ceftriaxone iv. for 4 weeks,

then oral doxycycline for

2 months vs placebo

Results

No improvement in fatigue or

quality of life

Comment

Study criticized because subjects had been

sick for an average of 4.7 years and had

already failed similar treatment. Treatment

regimen inadequate for degree of

functional impairment

Exact duration of illness not stated

(

≤

6 months). Relatively short treatment.

Previously untreated patients did significantly

better than controls in terms of fatigue

improvement (69 vs 0%; p < 0.01)

Improvement in physical functioning but not

cognitive functioning sustained in treatment

group at 24 weeks

Treatment successful in two-thirds of patients

with best initial quality of life but failed in a

third of patients with worst initial quality of life

Ref.

[14]

Krupp

et al.

(2003)

Ceftriaxone iv. for 4 weeks

vs placebo

Significant improvement in

fatigue noted in 64% of

treatment group vs 19% of

controls. No improvement

in cognition

Significant improvement in

cognitive and physical

functioning at 12 weeks in

treatment group vs controls

Significant improvement in

cognitive and physical

functioning in treatment group

vs controls

[

18]

Fallon

et al.

(2005)

Ceftriaxone iv. for 10 weeks

vs placebo

[20]

Cameron

(2005)

Oral amoxicillin for

3 months vs placebo

[22]

iv.: Intravenous.

760

Expert Rev. Anti Infect. Ther.

5(5), (2007)

B 25 - 2015-16 - Bilag 1: Henvendelse af 4/12-15 fra Alex Holmstedt

Lyme disease: a turning point

catheters when antibiotic therapy is administered through these

catheters

[19] [STRICKER RB, UNPUBLISHED DATA]

. Conversely, the

risks of placebo treatment with these catheters may limit future

controlled trials of long-term therapy in chronic Lyme disease.

In two additional studies, Fallon

et al.

showed that retreat-

ment with 10 weeks of intravenous ceftriaxone improved cog-

nitive and physical function in chronic Lyme patients

[20]

Although improvement in physical functioning was sustained

for 14 weeks after treatment cessation, cognitive improvement

was not. The investigators employed a highly sensitive testing

system to define the cognitive deficits in their patients

[21]

Cameron showed that 90 days of oral amoxicillin improved

quality of life in a similar group of patients

[22]

. In this study,

patients with the best initial quality of life did significantly bet-

ter with retreatment than patients with the worst initial quality

of life. Cameron noted that patients with the best quality of life

were significantly different from patients in the Klempner trial

in terms of baseline level of dysfunction and treatment failure

rate

[22]

. In a subsequent analysis, Cameron found that poor

quality of life was associated with delay of initial antibiotic

treatment, a variable that was not examined in the Klempner

trial

[23]

. Taken as a whole, these studies support the conclusion

that longer antibiotic therapy is effective in subsets of patients

with chronic Lyme disease, and that adoption of the opposite

interpretation based on the Klempner study is premature.

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In the absence of consensus regarding the diagnosis and

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[24]

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B. burgdorferi

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[24]

. The les-

son here is that the medical community should keep an open

mind regarding treatment options for Lyme disease and not

jump to conclusions based on a solitary study with poor

generalizability.

Financial & competing interests disclosure

RB Stricker serves on the advisory panel for QMedRx Inc.. The

authors have no other relevant affiliations or financial involvement

with any organization or entity with a financial interest in or

financial conflict with the subject matter or materials discussed in

the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this

manuscript.

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Affiliations

•

Raphael B Stricker

, MD

International Lyme and Associated Diseases

Society, 450 Sutter Street, Suite 1504

San Francisco, CA 94108, USA

Tel.: +1 415 399 1035

Fax: +1 415 399 1057

[email protected]

Lorraine Johnson

, JD, MBA

International Lyme and Associated Diseases

Society, PO Box 341461, Bethesda,

MD 20827–1461, USA

Tel.: +1 323 461 6184

Fax: +1 323 461 6143

[email protected]

•

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5(5), (2007)