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Volume: 1
Issue: 14
Date: 28-Jun-93


Table of Contents:

                CHRONIC PERSISTENT INFECTION AND
      CHRONIC PERSISTENT DENIAL OF CHRONIC PERSISTENT INFECTION
                         IN LYME DISEASE
                     Kenneth B. Liegner, M.D.
                Internal & Critical Care Medicine
               Lyme Borreliosis & Related Disorders


Newsletter:

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                     Volume 1 - Number 14 - 6/28/93


                          *** SPECIAL ISSUE ***
                     CHRONIC PERSISTENT INFECTION AND
          CHRONIC PERSISTENT DENIAL OF CHRONIC PERSISTENT INFECTION
                             IN LYME DISEASE



I.   Introduction
II.  Special Section
III. Jargon Index
IV.  How to Subscribe, Contribute and Get Back Issues



I. ***** INTRODUCTION *****

Lyme disease has become a highly controversial and politically charged
illness.  The issue that has probably generated the most controversy is
the existence and prevalence of persistent infection despite antibiotic
therapy.


Most of the handful of physicians and researchers accorded LD "expert status"
by the national media dismiss chronic infection as an extremely rare and
insignificant phenomenon.  In fact, in Dr. Allen Steere's recent paper in
JAMA entitled "The Overdiagnosis of Lyme Disease," he refused to categorize
any of his 788 patients as chronically infected.  Chronic infection was
casually alluded to in the second-to-last paragraph of the 7 page paper.


The media accept these views as incontroverted fact, and physicians
are given the same message via the medical literature.  When patients
do not recover with the so called "accepted" protocols, they are referred
to psychologists as they are presumed to be imagining their symptoms.


However, a growing number of clinicians are rejecting the Steere et al
philosophy in favor of a model that recognizes chronic infection as a real
problem.  Emerging research is validating what they see in their practices:
many patients do not recover with the "accepted" protocols (typically no
more than 4 weeks of treatment).


In this essay presented at the 6th Annual International Conference on Lyme
Borreliosis, Atlantic City, May 1993, Dr. Kenneth Liegner gives us his
perspective on this controversy.


Thanks to Contributing Editor Carl Brenner for obtaining reprint permission.

-Marc.


II. ***** SPECIAL SECTION *****

                          Kenneth B. Liegner, M.D.
                     Internal & Critical Care Medicine
                    Lyme Borreliosis & Related Disorders
                              8 Barnard Road
                             Armonk, N.Y. 10504


CHRONIC PERSISTENT INFECTION IN LYME DISEASE:

Relapsing disease is obvious to any good clinician and to Lyme patients.
Relapses usually respond to re-institution of antibiotic therapy. In some
patients, Lyme disease is a chronic infection that antibiotic treatment
suppresses, but does not eradicate.  Mechanisms of evasion of destruction
of the organism by antibiotics and the immune system: intracellular
sequestration; antigenic variation of surface proteins?; development of
antibiotic resistance?; dormant states?; Bb DNA/RNA into host cells?; HLA-DR
2,3,4 related molecular mimicry or evasion of humoral or cell-mediated
immune response.


Ample documentation of survival of _Borrelia burgdorferi_ in human
beings despite intensive antibiotic treatment already exists in published
peer-reviewed literature.  Isolation of organism in culture is rare
(pre- _or_ post-treatment); this does _not_ mean the phenomenon is rare.
Rather, these apparently anomalous observations give insight into what is
happening with many other patients in whom we are NOT able to produce the
incontrovertible level of proof provided by isolating the organism.  Direct
antigen detection methods (RML-antigen capture in urine; OspA antigen
detection in CSF) support the concept that _many_ patients have chronic
persistent infection post-treatment (see Refs.).


PROBLEM: CHRONIC PERSISTENT DENIAL OF CHRONIC PERSISTENT INFECTION

Reasons for denial of chronic persistent infection:

1) Over-reliance on (presently very) imperfect tests.
This leads to _circular reasoning in Lyme disease_.  Fallacy that a negative
Western blot vitiates the diagnosis of Lyme disease.


2) Paradigm change resisted. (see Kuhn, TS)

3) A "belief system" is involved, powerfully entrenched and resistant to
modification despite objective factual evidence.  This "belief system"
filters _what_ is observed and _colours_ the  _interpretation_ of the
_significance_ of what is observed such that the concept of chronic
persisting infection is _rejected_ despite _overwhelming clinical evidence_
and _compelling_ emerging research findings.  This is testimony to the power
of mental constructs.  Analogy to Galileo and the Catholic church: Catholic
church only recently admitted it was mistaken in making Galileo recant,
_300_ years later.


4) Adverse economic implications of chronic persistent infection:
Long-term/open-ended treatment for a chronic infection becomes a "bottomless
pit" and thus a true dilemma from the point of view of an employer/insurer/
government.  A readily curable infection, on the other hand, is a much more
tractable entity, with predictable and controllable economic consequences.
Thus, it is in the economic interests of insurers/employers/government to
deny the reality of chronic persisting infection.  Liability issues for
government/insurers/ and employers pertain and are aggravated by the
implications of chronic persisting infection.


5) Chronic infection implies the _primary driving force_ in the pathogenesis
of the illness is _ongoing infection_.  Thus, infectious disease treatment
and prevention becomes the primary focus of research.  _Immunologic aspects
become epiphenomena_; important epiphenomena, but epiphenomena nonetheless.
The crucial issue is that we are dealing with an infectious disease, and
_persistence of the infection is driving the immunopathogenetic processes_.
Means to stay the infection and desirably "cure" the infection become the
focus of attention.  Immunologic intervenentions to modify or arrest the
expression of the disease, though also important, become _adjunctive_
measures.  Alternatively, if _post_-infectious _immunologic_ mechanisms are
_primary_ in the pathogenesis of the disease, then _immunologic/
rheumatologic_ interventions become the _primary_ focus of research and
treatment.


6) Acknowledgment of Lyme disease in a geographic region, and particularly
that it may be an incurable infection, has painful economic consequences to
affected regions: tourism adversely affected, home values may decline, local
government may suffer a serious economic burden due to the high cost of
treatment for employees covered under self-insured Workers' Compensation
plans.


7) Seronegativity.  _Seronegativity is a real phenomenon_, occurring both in
early _and_ late cases.  This has been apparent to astute clinicians for some
time, and cutting-edge direct antigen detection assays are making this clear
in black and white.  Seronegativity is difficult for many to accept or
comprehend and has raised the spectre of mis-diagnosis and over-treatment
of patients suspected of having Lyme disease.  This reinforces the denial of
Lyme disease in individuals who may actually have it, by those who discount
the importance or reality of patients' subjective experience of their
illness.  Exclusion from study of seronegative subjects with symptoms
compatible with Lyme disease in the past may represent a serious conceptual
and methodological error.


8) Resources of government are already stretched thin by AIDS, multiply
resistant tuberculosis, and health sequelae of drug addiction and other
societal problems.  _Funding for Lyme disease research, prevention, and
treatment is grossly inadequate as a result_.  Restrictive surveillance
definition and misuse of the surveillance case definition as a clinical
diagnostic case definition leads to egregious underestimation of the true
number of cases and implications for the health population at risk, with
consequent gross under-allocation of resources needed to effectively deal
with the problem.


CONSEQUENCES OF CHRONIC PERSISTENT DENIAL OF CHRONIC PERSISTENT INFECTION
IN LYME DISEASE:


1) Preventive measures become less salient; if the disease is so easily
cured, why make a fuss about preventing it in the first place?  Fosters a
casual attitude towards deer-tick attachments.


2) Imposition of arbitrary restrictions on allowable length of insurers and
other "managers of care" results in under-treatment or non-treatment of
infected individuals with long-term deleterious consequences.


3) Ill individuals are likely to be denied disability.

4) Inadequate allocation of funding by government to deal with the scope and
potential seriousness of the problem, as indicated above.


5) The truly huge populations at risk are likely to demonstrate increasing
incidence of preventable late sequelae of Lyme disease over time, due to non-
treatment of deer-tick bites.  Latent infection of un-prophylaxed individuals
will result in avoidable chronic persisting infection in some, with all of
its unfavorable sequelae.  Also, denial of chronic persistent infection will
lead to non-treatment of those who actually have chronic persisting
infection.  This will prove costlier in the long run in terms of then having
to deal with more complicated and perhaps irreversible illness, loss of
individual economic productivity as well the incalculable toll of human
suffering.


6) In view of early dissemination of Bb to the central nervous system, the
inadequacy of commonly prescribed regimens for Erythema Migrans to treat the
CNS, and the reality of chronic persisting infection, it is to be expected
that of patients treated for early disease, increasing numbers developing
late CNS sequelae will accumulate over time.


COROLLARIES TO CHRONIC PERSISTENT INFECTION:

1) Greater emphasis must be placed on prevention:

  A) Vector control: CDC and other governmental health agencies must be
     encouraged to take a formal stand on the advisability and safety of
     tick-vector control by means of acaricide proving the efficacy of
     safety of this approach.  Insecticide use is a highly controversial
     and emotionally-charged issue and will result in predictable
     politician opposition by some environmental activists yet such an
     extreme position is not based on rational evaluation of facts.  
     CDC and state and local health departments ought not shy away from
     the issues and should exhibit the courage to take a position regarding
     reasonable preventive measures to protect large "at risk" populations
     from Lyme disease in view of the serious long-term health consequences
     of human infection with _B. burgdorferi._  This is _underscored_ by
     the _inability_ to cure the infection in certain subsets of patients
     with currently available methods of treatment.


  B) Avoidance of tick-infested areas if possible.

  C) Prophylactic treatment of bites by ticks known to be capable of
     transmitting Lyme disease becomes more defensible.  Extrapolation
     from limited animal transmission studies to advocacy of non-treatment
     of humans with documented deer-tick bites less than 48 hours duration
     is not justified and fosters a casual attitude toward deer-tick
     attachments which will result in avoidable human infection.


  D) Vaccine development (laudable, but a practical vaccine seems years
     away).


  E) Daily tick-checks.  Great dedication is necessary to adhere to a tick-
     check protocol.  Many individuals/families cannot maintain the
     necessary vigilance.


  F) Barrier methods.  Use of repellant & acaricides on clothing (e.g.
     permethrin) when entering tick-infested terrain.


2) Open-minded investigation of possible pathogenetic role of Bb in a variety
  of disorders, as the spectrum of the disease is continually expanding:


  M.S.-like and Lupus-like disorders
  Motor neurone disease
  Dementias/Organic brain syndromes
  (neuro-) psychiatric presentations
  ACLA-syndrome
  "idiopathic" cardiomyopathies
  "primary" pulmonary hypertension
  Lyme disease-associated fibromyalgia
  Lyme disease-associated chronic fatigue syndrome
  etc. etc. etc.


3) Necessity for long-term surveillance of all patients who have Lyme
  disease.


4) Need for development and _wide-spread commercial availability_ of
  _validated sensitive_ direct antigen detection methods.


5) Need to develop more effective and less costly means of treating/
  controlling the infection in persons already affected.


6) Recognition of the _need_ to find a _CURE_ for Lyme disease.  Denial of
  chronic persisting infection obviates the need to try to find a cure.


SOLUTION TO THE PROBLEM OF CHRONIC PERSISTENT DENIAL OF CHRONIC PERSISTENT
INFECTION:


1) Additional research assessing the scope of the problem of chronic
persisting infection and devising cost-effective and practical stratagems
to deal with it, is needed.  Funding for such research and for the
researchers who are interested in studying the problem and finding
solutions to it must be encouraged.  This research is already emerging,
but there will be a lag time of at least several years and possibly a
decade or more before enough published data will be amassed to convince all
skeptics of the reality and extent of the problem.  Lyme disease will
continue to be trivialized and ridiculed for some time.  Many patients with
active Lyme disease will remain undiagnosed or be dismissed as
"misdiagnosed" until widespread availability of a "gold standard" test.


2) Ill patients and their families, and the physicians responsible for the
health of patients with Lyme disease can not afford to wait until the
preponderance of scientific data overwhelming proves that chronic persistent
infection is real and prevalent.  The epidemic is occurring _now_ along with
its severely damaging health consequences.  A distinction must be made
between what is truly experimental versus exploration of options for dosage,
duration, and combinations of FDA-approved drugs, which is the prerogative
of and within the discretion of the treating physician to prescribe.
Withholding of treatment from ill individuals may be viewed as experimental
(see Jones) as opposed to attempting to treat disease as best we can with
available tools; _at present times antibiotics remain the main-stay of
treatment_ for Lyme disease.  Efforts to secure/restore patients' health
must not be sacrificed on the "altar" of science.


REFERENCES:

Coyle PK et. al. _B. burgdorferi_-specific Immune Complexes in Cerebrospinal
Fluid. [Abstract 167]. V International Conference on Lyme Borreliosis, May
31- June 2, 1992, Arlington, Virginia.


Garcia Monco JC, et. al. _Borrelia burgdorferi_ in the central nervous
system: experimental and clinical evidence for early invasion. J Infect Dis
1990;161:1187-93


Haupl T, et. al. Persistence of _Borrelia burgdorferi_ in chronic Lyme
disease:; altered immune regulation or evasion into immunologically
privileged sites?  [Abstract 149]. V International Conference on Lyme
Borreliosis, May 31-June 2, 1992, Arlington, Virginia.


Jones JH. BAD BLOOD The Tuskegee Syphilis experiment. The Free Press. New
York. 1981.


Kuhn TS. The Structure of Scientific Revolutions. University of Chicago
Press. 1963.


Liegner KB, Rosenkilde CE, Campell GL, et. al. Culture-confirmed treatment
failure of cefotaxime and minocycline in a case of Lyme
meningoencephalomyelitis in the United States [Abstract 63]. V International
Conference on Lyme Borreliosis, May 31- June 2, 1992, Arlington, Virginia.


Liegner Kb, Garon C, Dorward D. Lyme borreliosis studied with the Rocky
Mountain Laboratory (RML) antigen capture assay in urine [Abstract 104]. V
International Conference on Lyme Borreliosis, May 31- June 2, 1992,
Arlington, Virginia.


Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L. Recurrent
erythema migrans despite extended antibiotic treatment with minocycline in a
patient with persisting _Borrelia burgdorferi_ infection. J Amer Acad Derm
1993;28:312-314.


Liegner KB. Lyme Disease (Letter). N Engl J Med 1990; 322:474-475.

Liegner KB. Prevention of Lyme Disease After Tick Bites (Letter). N Engl J
Med 1993;328:136-7.


Liegner KB. A Controlled Trial of Antimicrobial Prophylaxis for Lyme Disease
after Deer-Tick Bites (Letter). N Engl J Med. IN PRESS.


Preac-Mursic V, Weber K, Pfister W, et. al. Survival of _Borrelia
burgdorferi_ in antibiotically treated patients with Lyme borreliosis.
Infection 1989;17:355-9.


Schutzer SE et. al. Specific Serum Immune Complexes in Lyme disease (LD).
[Abstract 135]. V International Conference on Lyme Borreliosis, May 31-
June 2, 1992, Arlington, Virginia.



III. ***** JARGON INDEX *****

Bb - Borrelia burgdorferi - The scientific name for the LD bacterium.
CDC - Centers for Disease Control - Federal agency in charge of tracking
     diseases and programs to prevent them.
CNS - Central Nervous System.
ELISA - Enzyme-linked Immunosorbent Assays - Common antibody test
EM - Erythema Migrans - The name of the "bull's eye" rash that appears in
    ~60% of the patients early in the infection.
IFA - Indirect Fluorescent Antibody - Common antibody test.
LD - Common abbreviation for Lyme Disease.
NIH - National Institutes of Health - Federal agency that conducts medical
     research and issues grants to research interests.
PCR - Polymerase Chain Reaction - A new test that detects the DNA sequence
     of the microbe in question.  Currently being tested for use in
     detecting LD, TB, and AIDS.
Spirochete - The LD bacterium.  It's given this name due to it's spiral
     shape.
Western Blot - A more precise antibody test.



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