Lyme Borreliosis Complex Evaluation and Preparation, Treatment, and Recovery

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Excerpts from Lyme Borreliosis Complex
Evaluation and Preparation, Treatment, and
RecoveryJoseph G Jemsek MD, FACPPresented at
University of South Florida, January 19, 2008
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Cousins Lyme Disease Syphilis
Borrelia burgdorferi
Syphilis

• Only 22 lipoproteins genes

Chromosome 21 plasmids 132 lipoproteins genes
More genetic material 90 genes unrelated to
any other known bacteria
Syphilis is dumb cousin
Perhaps the most complex bacteria known
J Clin Invest. 2001 Mar107(6)651-6. Review
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Example of Tropism

• Lyme bacteria love brain tissue!
• Neuroborreliosis
• Memory loss
• Severe mood disorders
• Lack of concentration
• Sleep disturbance
• Anxiety
• Word retrieval difficulty
• Headaches

Microbes Infect. 2006 Nov-Dec8(14-15)2832-40.
Emerg Infect Dis. 2006 Jul12(7)1051-7.
Infect. Immun. 2008 Jan76(11)298-307. Epub
2007 Nov 5.
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Proposed Mechanisms of Borrelia burgdorferi
Persistence
Active Immune Suppression
Immune Evasion

• Innate
• Complement
• inhibition
• Induction of anti-
• inflammatory cytokines
• Tolerization of
• monocytes

• Adaptive
• Induction of anti-
• inflammatory cytokines
• Tolerization of
• lymphocytes
• Complement inhibition
• Immune complex
• sequesterization

• Phase and antigenic
• variation
• Gene conversion
• Variable expression
• of antigens

• Physical seclusions
• Intracellular
• Extracellular
• Cysts
• Immunologically
• privileged sites

.Borrelia friends bypass the immune system
Microbes Infect. 2004 Mar6(3)312-8
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Borrelia Blebs

• Sheds antigenic decoys from the spirochete
  membrane
• Self aggregate to form a pearl or tube chain
• Causes increased B cell proliferation and
  response - Spending Immune Capital
• Can contain Bb plasmids
• Possible survival mechanism
• - Not necessarily a degenerative response as
  seen with E. coli

Bleb pearl strand
Antimicrob Agents Chemother. 1995
May39(5)1127-33
Borrelia L-Forms

• Can form under antibiotic pressure
• Lack a cell wall
• Are osmotically fragile
• Can survive during beta-lactam treatments
• Reforms the cell wall upon reversion back to the
  spirochete
• Could be transitional form to cyst

Przegl Epidemiol. 200256 Suppl 157-67.
Infection. 1996 May-Jun24(3)218-26 Infection.
1998 May-Jun26(3)144-50.
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Borrelia Survival Mechanism
Borrelia entering human B cell where it destroys
the cell instead of the cell destroying the
Borrelia as it is supposed to do.
(mag.13,700)?
Dr. David W. Dorward, NIH Rocky Mountain Labs, MT
Slide courtesy of LDA
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Basic Tenets Successful treatment
Regain Maintain Immunologic Control
Reduce the impact of co-pathogens by means of
sophisticated use of antimicrobials Multiple
immunosuppressive infections in play acting as a
barrier to Immunologic Control and
Stabilityantimicrobials may even the field
Find and treat the ringleaders
(co-pathogens) leading to the LBC syndrome
Pathogenic Hierarchy not fully established and
nothing is certainWe do not yet know which one
is most damaging Dormancy is likely
dominant paradigm What reactivates dormant
infections? - Life Stressors - Other
physical illness, including new/recurrent TBIs
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Basic Tenets LBC and immune dysfunction

• Synergy by pathogens in immunosuppression
  Co-Pathogenicity
• Markers ill-defined, largely wanting
• Primarily a TH1 suppressive event with
  significant B cell dysfunction
• Immunologic triggers allow other opportunistic
  events, chronic illness syndromes regards host
  immunologically predisposed
• LBC is an immunologically labile and frail
  condition
• Appreciate wide spectrum of stressors or
  trauma, e.g. biologic, environmental, emotional,
  hormonal
• LBC is a different paradigm from HIV/AIDS, but
  similar conceptually as a form of immunologic
  surrender

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Basic Tenets Lyme Borreliosis Complex (LBC)
Summary
Most evidence suggests LBC reflects Chronic
Acquired Immunodeficiency Clinical Statewith a
High Degree of Dysfunction primarily a TH1
event - e.g. lab markers (depressed
null cell measurements, IgG levels, and CD8
levels), clinical hypersensitivities, etc. LBC is
often associated with Co-morbid Conditions -
One hypothesis would be that the
immunosuppressive nature of LBC is permissive
in the expression of other chronic illness
syndromes, e.g. Crohns, RA, MS..?? Direct
involvement as etiology There are multiple
clinical patterns - We hypothesize a fluid
spectrum of clinical states with most in
waiting or waxing / waning unless a tipping
point Advanced disease is profoundly life
altering without fluidity - Without hope of
spontaneous remission immunologic surrender
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Trigger Mechanisms for LBC The Tipping Point
Any immunostimulating event with the impact to
Tip the immunologic balance. May be -
Biologic - Environmental - Hormonal - Physical or
psychological
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Definition of LBC Clinical Triad
Chronic/Relapsing LBC
I. ENCEPHALOPATHY One or more of the
following Sx - Inflammatory, as in headache /
sensory aversion -
Sleep disturbances - Mood alterations -
Cognitive changes II. ARTHRITIC Symptoms
inflammatory and non-inflammatory - Generally
migratory - Overlap with several rheumatologic
syndromes III. POLYNEUROPATHY / MONONEURITIS
MULTIPLEX - Primarily symmetrical sensory (C
fiber)? - Cord (myelitis) -
Ganglionitis - Motor neurologic Sx
Assumption is that the above qualifiers are
chronic or relapsing and otherwise unexplained
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Selected Head and Neck Clinical Findings in LBC
Scalp hair loss, recurrent ulcerations
Cranial neuropathies common, 7th N or Bells
Palsy, particularly when bilateral, pathognomonic
Eye dry eyes, iritis, scleritis,
papillitis, saccades, anisocoria
Ear pain (carotidynia), tinnitus, hearing loss
or distortion
Mouth gingival and dental decay, dryness,
altered taste
Triggerpointtenderness
Throat recurrent ulcerations
Carotidynia
Thyroid nodules (most TPO)?
Pre-auricular Tap 5th Nerve Irritability
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Support for Polymicrobial Concept of Illness
Co-Pathogenicity Model

• Specific clinical signs pathologic correlation
  associated with co-infections
• Key players are Babesia sp. and Bartonella sp.
• Animal data to support this concept
• Clinical experience revealing
• Supporting laboratory serology and other markers

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Clinical Approach to LBC Three Critical Phases
I. Evaluation and Preparation - Requires
0-12 weeks (or more)? II. Treatment -
Multidisciplinaryimmunologic support -
Sophisticated and individualized use of
antibiotic combination - Pulse and
sequencing combination therapies -
Induction phase 12-24 weeks or more (tolerance
dependant)? III. Recovery - Goal of maximum
immunologic control and tissue repair -
Maintenance antimicrobial therapiesminimalist
schedule
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I. Evaluation and Preparation Know the ELF
E ? Essential L ? Life F ? Functions
Must gain control of the unruly elf!
http//www.sevenoaksart.co.uk/gnomes.htm
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Ia. Evaluation and Preparation Learn Your P O E
M S
P ? Pain O ? Other - family support, access
to care issues E ? Endocrine/Metabolic M ?
Mood/Psychiatric S ? Sleep Critical
Instability in any POEMS Category precludes
clinical success POEMS Categories equate to
Life Stressors capable of immunosuppressive
consequences
http//office.microsoft.com/clipart
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II. Treatment Goals
Assist the dysfunctional immune system
Manage stressors
nutritional/psychiatric/hormonal/
life adjustments/sleep/pain Decide on best
means of administration Based on
multiple factors - Tolerance -
Drug-to-drug interactions - Optimal route
for bioavailability to diseased tissue (CSF
penetration, limited GI absorption issues, etc.)

• Immunologic blockade by pathogens
• - (i.e.) Babesia co-infection up-regulates
  Borrelia infection
• - Address Babesia early as patients reach
  sticking point if not addressed
• Extremely variable clinical responses
• Adequate duration is key!
• - Serious Babesia co-infections may
  require 8-12 weeks of treatment

Pitfalls
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IIa. Treatment Antimicrobials

• Combination Rx Most effective programs and
  combos are based on the treating physicians
  experience
• Antibiotic therapy design based on these
  principles
• - Bb has multiple strains, life forms locations
• - Synergizing co-infections ALWAYS present in LBC
• -- Highly genomically replete microbial pathogens
  capable of immune evasion, immunosuppression and
  antimicrobial resistance
• - No practical retrieval and strain/species
  definition of pathogens, and no practical or
  reliable antimicrobial sensitivity testing
• - Slow replication characteristics of all
  targeted pathogens (allows for pulse approach in
  therapy)?
• - Rest periods or treatment holidays allows for
  cellular repair and detoxification

• Persistence of Bb other pathogens despite Rx
  
• is assumed - The Goal of Rx becomes
  immunologic control
• Therapy designed to address essential issues
• - Bb multiple life forms locations
• - Major co-infections
• The immunosuppressed patients with co-
• morbidities

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III. Recovery/Maintenance Keys

• Minimalist Approach
• Stun and Kill Approach
• - Prominent Herxheimer is a bad sign on
  maintenance
• Once past induction, anticipate 18-24 months on
  maintenance program
• - Without markers, best measure is response to
  intense life stressors

After induction, continued therapy with a
step-down oral treatment program using a pulsed
schedule in various combinations. Rationale for
Maintenance - There is still immune building
and tissue repair to be done! Goal is to restore
optimal levels of immune capital and immunologic
control. Maintenance program should contain - -
Core combination Rx - Periodic imidazole -
Progressive extension of holiday periods until
goal of 1 week per month is attained - QOD
dosing for core is acceptable
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Modern Medicine in the USChange is Needed in
Health Insurance Industry

• Epidemic chronic illness in the world- Estimated
  at 90 million in the US alone consuming 75 of
  the health care dollar
• 24 of 25 top world illnesses with no known
  cause
• Average routine visit time with Internist is 7
  minutes
• Doctors must fight for their patients- The
  patients must feel we are in their corner
• US health care change for the better- Patients
  will lead changes- Doctors limited in ability to
  affect change for many reasons

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A New Paradigm What LBC May Teach Us
LBC, when fully expressed, is a debilitating,
progressive immunosuppressive, multisystemic
disorder in which multiple pathogens with a
variety and range of tropisms work in synergy to
frustrate and exhaust the host immune system.
The manifestations of illness are a reflection
of the inflammatory quotient and subsequent
tissue damage/disturbance at a given site in the
host. Once the host is in a state of
immunologic surrender due to LBC, there is no
hope for clinical improvement without epic
intervention Are we on the threshold of a new
paradigm for chronic illness based on improved
understanding of immunologic profiles and risk
for disease, immunologic capital and control, and
the role of the interplay of a whole host of
dormant, pathogenic and potentially reactivated
microbial organisms?