Download Alice Prescott AAO 2014 Lyme O3

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Transcript
The Lyme Enigma
Complexity 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
2
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
3
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
Borrelia spp
• Borrelia burgdorferi
• Borrelia andersonii
• Borrelia miyamotoi
• Borrelia bissettii (DN 127)
• Borrelia garinii
• Borrelia afzelii
• Borrelia japonica
5
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_st
rains_alphabetic.html
• Fleas? Ctenocephalides felis also harbors Bb
6
Reservoirs
• Mammals and birds
• Migratory
• Climate change
7
8
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
9
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 LLC 320 Needham St., Suite 200 Newton, MA
02464 http://identify.us.com [email protected]$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.
11
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
14
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
15
Diagnosis
• antibodies,
• antigen,
• PCR,
• T-cell response,
• culture
Direct testing
PCR: low yield
Lyme 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 Brunner
AbstractBorrelia 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.
Antibodies
Initial lag time to seroconversion
Conversion of IgM to IgG
sensitivity of ELISA
sensitivity of WB
WB comparison: Igenex vs other
C6LPE
afzelii and garinii
Coyle’s research
T-cell response
aka iSpot
Lyme culture
fussy bug:
long incubation, preferred media, preferred
surfaces
Associated Lab
Findings
low CD57, low WBC
possibly low IgG3 or slightly elevated ANA
normal ESR, CRP
first-degree heart block
Co-infections
Babesia, Bartonella, Ehrlichia,
Anaplasmosis...
Treatments
antibiotics,
herbs,
oxidative therapies,
silver
Herbs
Artemisinin
Cat’s Claw/Samento/Banderol
Stephen Buhner
Oxidative therapies
Ozone
Hydrogen Peroxide
SILVER ENHANCES ANTIBIOTIC EFFECTS
Sci 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
silver sensitizes Gram-negative bacteria to the
Gram-positive specific antibiotic, vancomycin, thereby expanding the antibacterial
models of peritonitis that
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 weeks
Children: 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”
IDSA
Post 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?
38
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
39
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 antibioticsquinolones, 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.
40
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.
41
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
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
43
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
44
Vaccine?
45