The Lyme EnigmaComplexity and Controversy

Introduction to Lyme Disease

• infectious illness affecting all organ systems• Ubiquity: reported in every state, and all

northern continents• Pattern recognition: inflammation• Diagnosis! Not always straightforward• Key to successful early treatment is timing• Keys to long-term treatment for chronic case is

fortitude, compassion, and flexibility

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Why study Lyme?

• Avoid missing the early case~• How chronic Lyme affects the patient: loss of physical functioning, loss of mental functioning loss of employment, loss of joy and emotional stability, loss of relationships, psychospiritual crisis

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Lyme Life Cycle

• Lyme disease is caused by a tick-borne spirochete, Borrelia burgdorferi.• Humans are an incidental host• The lifecycle of the spirochete is predominantly

between mice, deer and the deer tick. In CA ixodes pacificus is the vector and in the east coast it is ixodes scapularis• The nymph deer tick is the most likely to transmit

Lyme, and they are generally feeding in the spring and summer, adults feed in the fall

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Borrelia spp• Borrelia burgdorferi• Borrelia andersonii • Borrelia miyamotoi• Borrelia bissettii (DN 127)• Borrelia garinii • Borrelia afzelii• Borrelia japonica

Transmission: Vectors

• Conventional thought: Ticks only• Ixodes scapularis, pacificus, dentatus• Amblyomma americanum, the Lone Star tick• Ixodes ricinus: Scandinavia-Russia-N Africa • Ixodes persulcatus, Haemaphysalis flava: Japan• http://www.pasteur.fr/recherche/borrelia/Bb_str

ains_alphabetic.html• Fleas? Ctenocephalides felis also harbors Bb

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Reservoirs

• Mammals and birds• Migratory• Climate change

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Direct transmission

• Placental transmission• Transfusion: current testing is for hep B and C,

HIV, HTLV, syphilis, Chagas, West Nile Virus (see John Hopkins and American Red Cross). AABB says you shouldn’t donate if you’ve ever had babesiosis. CDC says you can donate if you’ve finished treatment.• Sexual transmission

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Early signs and symptoms of Lyme• Erythema Migrans onset 7-14 days after bite• Sore throat, myalgias, arthralgias, fever, chills,

and headache within days to 2 weeks after infection• If symptoms are severe and high fever is present

consider co-infection with human granulocytic anaplasmosis(HGA) and Babesia.• Babesia microti/duncani in the East and babesia

duncani in CA

TICK ID• IdentifyUS LLC320 Needham St., Suite 200Newton, MA 02464

http://identify.us.comhelp@identify.us.com$20 per specimen or image evaluation (species identification, stage of development & estimated feeding duration). Turn-around time is usually the same day the specimens are received. Digital images, if of sufficient quality, can be uploaded to the web site for even faster service. Imaging instructions are provided on the website.

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Early disseminated Lyme

• Arthralgias, • Neurologic symptoms, headaches, cranial

neuropathy, diffuse or focal mononeuropathy multiplex, lymphocytic meningitis, plexopathy,• Radiculoneuropathy (Bannwarth syndrome)• Cardiac symptoms syncope, dyspnea, chest pain,

palpitations, A-V block• Skin involvement-secondary erythema migrans,

acrodermatitis chronicum atrophicans (afzelii)

Late Lyme disease

•Occurs months to years after infection and often a period of latency• Joint and neurologic symptoms most common• Sub acute encephalopathies, axonal neuropathies

and peripheral neuropathy• Bannwarth syndrome • Neuropsychiatric symptoms

When should I think of Lyme?

• Nonsensical fatigue• Headaches• Any palsy, neuropathy or tremor• Joint pain, especially knees, neck, upper back• Muscle pain and/or fasciculations• Rashes: especially EM, but any asymmetrical

rash;recovered, persistent, or intermittent• Cyclic symptoms, esp every month• New palpitations

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CDC Recommendations

• http://www.cdc.gov/lyme/healthcare/clinician• Enzyme Immunoassay (EIA)OR

Immunofluorescence Assay: If negative consider alternative diagnosis• If positive, and symptoms >30 days, do IgG WB• If positive, and symptoms <30 days, do IgG and

IgM WB

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Diagnosis

• antibodies,• antigen, • PCR, • T-cell response, • culture

Direct testing

PCR: low yieldLyme antigen

Coyle’s research

J Clin Invest. Jul 1994; 94(1): 454–457.doi:  10.1172/JCI117346PMCID: PMC296331Early and specific antibody response to OspA in Lyme Disease.S E Schutzer, P K Coyle, J J Dunn, B J Luft, and M

BrunnerAbstractBorrelia burgdorferi (Bb), the cause of Lyme disease, has appeared not to evoke a

detectable specific antibody response in humans until long after infection. This delayed response has been a biologic puzzle and has hampered early diagnosis. Antibody to the

abundant organism-specific outer surface proteins, such as the 31-kD OspA, has rarely been detected less than 6 mo after infection. Antibody to a less organism-specific 41-kD flagellin protein, sharing common determinants with other bacteria and thus limiting its diagnostic

potential, may appear after 4 to 6 wks. To investigate our hypothesis that specific antibody to OspA may actually be formed early but remain at low levels or bound in immune complexes, we

analyzed serum samples from patients with concurrent erythema migrans (EM). This is the earliest sign of Lyme disease and occurs in 60-70% of patients, generally 4-14 d after infection.

We used less conventional but more sensitive methods: biotin-avidin Western blots and immune complex dissociation techniques. Antibody specificity was confirmed with recombinant

OspA. Specific complexed antibody to whole Bb and recombinant OspA was detected in 10 of 11 of the EM patients compared to

0 of 20 endemic area controls. IgM was the predominant isotype to OspA in these EM patients. Free IgM to OspA was found in half the EM cases. IgM to OspA was also detected in 10 of 10 European patients with EM who also had reactive T cells to recombinant OspA. In conclusion a specific antibody

response to OspA occurs early in Lyme disease. This is likely to have diagnostic implications.

AntibodiesInitial lag time to seroconversion

Conversion of IgM to IgGsensitivity of ELISAsensitivity of WB

WB comparison: Igenex vs otherC6LPE

afzelii and gariniiCoyle’s research

T-cell responseaka iSpot

Lyme culture

fussy bug:long incubation, preferred media, preferred surfaces

Associated Lab Findings

low CD57, low WBCpossibly low IgG3 or slightly elevated ANA

normal ESR, CRPfirst-degree heart block

Co-infections

Babesia, Bartonella, Ehrlichia, Anaplasmosis...

Treatments antibiotics,

herbs, oxidative therapies,

silver

HerbsArtemisinin

Cat’s Claw/Samento/BanderolStephen Buhner

Oxidative therapies

OzoneHydrogen Peroxide

SILVER ENHANCES ANTIBIOTIC EFFECTSSci Transl Med. Author manuscript; available in PMC Sep 12, 2013.Published in final edited form as:Sci

Transl Med. Jun 19, 2013; 5(190): 190ra81.doi:  10.1126/scitranslmed.3006276PMCID: PMC3771099NIHMSID: NIHMS511274Silver Enhances Antibiotic Activity Against Gram-negative

BacteriaJ. Ruben Morones-Ramirez,#1,4 Jonathan A. Winkler,#1,2 Catherine S. Spina,3,4 and James J. Collins1,2,3,4,*

Abstract: declining pipeline of clinically useful antibiotics has made it imperative to develop more effective antimicrobial therapies, particularly against difficult-to-treat Gram-negative pathogens.

Silver has been used as an antimicrobial since antiquity, yet its mechanism of action remains unclear. Here, we show that silver disrupts multiple bacterial cellular processes, including disulfide bond

formation, metabolism and iron homeostasis. These changes lead to increased production of reactive oxygen species (ROS) and increased membrane permeability of Gram-negative bacteria, that can potentiate the activity of a broad range of antibiotics against Gram-negative bacteria in different

metabolic states, as well as restore antibiotic susceptibility to a resistant bacterial strain. We show both in vitro and in a mouse model of urinary tract infection that the ability of silver to induce

oxidative stress can be harnessed to potentiate antibiotic activity. Additionally, we demonstrate in

vitro and in two different mouse models of peritonitis that silver sensitizes Gram-negative bacteria to the Gram-positive specific antibiotic, vancomycin, thereby expanding the antibacterial spectrum of this drug. Finally, we used

silver and antibiotic combinations in vitro to eradicate bacterial persister cells, and show both in vitro

and in a mouse biofilm infection model, that silver can enhance antibacterial action against biofilms. This work shows that silver can be used to enhance the

action of existing antibiotics against Gram-negative bacteria thus strengthening the antibiotic arsenal for fighting bacterial infections

IDSA Treatment of early Lyme disease without significant neurological or

cardiac symptoms

• Doxycycline 200mg bid• Amoxicillin 500mg tid • Cefuroxime 500mg bid• All the above are given for 14-21 days

ILADS treatment of Erythema Migrans without other symptoms

• Doxycycline 100mg qid or 200mg bid with food• Cefuroxime 1g bid• Amoxicillin 1g tid with probenicid 500mg tid if

pregnant dose Amoxicillin q6h• Treat for 21 days • If pregnant treat for 6 weeks and test for Babesia,

HGA, and Bartonella

IDSA treatment of Lyme carditis

• Ceftriaxone 2gm qd for 10-28 days• Doxycycline 100-200mg po bid for 10-28 days• For AV block or myopericarditis use either of

above regimes with appropriate inpatient monitoring. With resolution of heart block patient may be discharged home on po meds

ILADS

Early disseminated Lyme• Milder symptoms present for less than one year with

multiple Erythems Migrans lesions, constitutional symptoms, and lymphadenopathy, • Treat with oral therapy until no active disease for 4

weeks (4–6 months typical) using same antibiotic doses as outlined for Erythema Migrans • Pregnancy: As in Erythema Migrans, but duration as

above. Treat throughout pregnancy, and do not breast feed.

IDSA treatment of late Lyme disease arthritis

• Doxycycline 100mg bid• Amoxicillin 500mg tid • Cefuroxime 500mg bid• Treat for 28 days• If persistent or recurrent joint swelling retreat

with another 28 days of above antibiotics or 2-4 weeks of IV ceftriaxone

IDSA late neurologic Lyme disease

• This includes encephalopathy's and radiculopathies, Bannwarth syndrome• Treat with ceftriaxone 2 gm qd for 2-4 weeks• “Response to treatment is usually slow and may

be incomplete”• “Re-treatment is not recommended unless

relapse is shown by reliable objective measures”

ILADS Late Disseminated/ Chronic Lyme

• Symptoms present greater than one year, more severely ill patients, and those with prior significant steroid therapy or any other cause of impaired immunity: • Treat adults and pregnant woman with 10 or more

weeks of IV therapy , then oral or IM till asymptomatic for 6-8 weeksChildren: IV therapy for 6 or more weeks, then oral or IM follow up as above.

IDSA treatment of late Lyme disease arthritis

• Doxycycline 100mg bid• Amoxicillin 500mg tid • Cefuroxime 500mg bid• Treat for 28 days• If persistent or recurrent joint swelling retreat

with another 28 days of above antibiotics or 2-4 weeks of IV ceftriaxone

IDSA late neurologic Lyme disease

• This includes encephalopathy's and radiculopathies, Bannwarth syndrome• Treat with ceftriaxone 2 gm qd for 2-4 weeks• “Response to treatment is usually slow and may

be incomplete”• “Re-treatment is not recommended unless

relapse is shown by reliable objective measures”

IDSAPost Lyme disease syndrome proposed

definition•Onset of the following symptoms within 6

months of a documented case of Lyme that has been treated by IDSA guidelines• Fatigue•Widespread musculoskeletal pain• Complaints of cognitive difficulties• Exclusion of any diagnosable disease

Protocols vs Real Life

• Keep trying until you find a regimen that works, and use it while the patient continues to improve on it.• Listen to the patient.• Don’t give up on the patient.• What does the patient need besides direct

treatment for Lyme?

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Why antibiotic treatments don’t work

• three forms of lyme (spirochete, L-form, cyst) • biofilm• tissue sequestration• patient’s intolerance to treatment: toxicity,

gastritis, mycosis, mitochondrial fatigue• co-infections• evolution of bacteria, i.e. resistance• targeted vs comprehensive treatment strategy

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Antibiotics and mitochondria• Sci Transl Med. Jul 3, 2013; 5(192): 192ra85. Bactericidal antibiotics induce mitochondrial

dysfunction and oxidative damage in Mammalian cells.Kalghatgi S1, Spina CS, Costello JC, Liesa M, Morones-Ramirez JR, Slomovic S, Molina A, Shirihai OS, Collins JJ.

• Prolonged antibiotic treatment can lead to detrimental side effects in patients, including ototoxicity, nephrotoxicity, and tendinopathy, yet the mechanisms underlying the effects of antibiotics in mammalian systems remain unclear. It has been suggested that bactericidal antibiotics induce the formation of toxic reactive oxygen species (ROS) in bacteria. We show that clinically relevant doses of bactericidal antibiotics-quinolones, aminoglycosides, and β-lactams-cause mitochondrial dysfunction and ROS overproduction in mammalian cells. We demonstrate that these bactericidal antibiotic-induced effects lead to oxidative damage to DNA, proteins, and membrane lipids. Mice treated with bactericidal antibiotics exhibited elevated oxidative stress markers in the blood, oxidative tissue damage, and up-regulated expression of key genes involved in antioxidant defense mechanisms, which points to the potential physiological relevance of these

antibiotic effects. The deleterious effects of bactericidal antibiotics were alleviated in cell culture and in mice by the administration of the antioxidant N-acetyl-l-cysteine or prevented by preferential use of bacteriostatic antibiotics. This work highlights the role of antibiotics in the production of oxidative tissue damage in mammalian cells and presents strategies to mitigate or prevent the resulting damage, with the goal of improving the safety of antibiotic treatment in people.

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Why treatments don’t work

• Immune evasion• Mutate surface proteins. Encysting. Biofilm.• Using proteins that look like ours (ID badges), to

avoid recognition and therefore destruction by complement pathway.• Using proteins that look like ours (feeding

misinformation), to activate the immune system non-productively.

Immune Evasion

•Modulation of it’s surface antigens, OspA and OspC• Evades complement pathway: OspC, CD59-like

complement inhibiting protein• OspA potent neutrophil stimulator and inducer of

IL-1b, TNF-a, and IL-6• Induces IL-10 initially to downregulate immune

response. Functional immune deficiency. New or worsening allergic reactivity.• Delayed conversion of IgM to IgG

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Comprehensive Support

• anti-inflammatory: diet, herbs, proteolytic enzymes• lymphatics: walking, skin brushing, massage• gastro-intestinal: probiotics, regularity• liver support: phase I and II• brain/nerves: B12, good fats, omega-3s,

neurotransmitters• methylation, glutathione• Immune support: medicinal mushrooms, IgG

Don’t give up on your patient!

• Emotional/spiritual support• Consider less aggressive or more aggressive

treatment• Consider complaint: system-based support• Consider backdrop of patient’s biochemical

individuality, such as methylation deficiency• Consider backdrop of patient’s environment, such

as mold in the house….• Refer

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Vaccine?

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