LymeNet Newsletter Volume 1 Issue 14

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:

***************************************************************************** * Lyme Disease Electronic Mail Network * * LymeNet Newsletter * ***************************************************************************** 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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