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A. Epidemiology and Cause navigator

  1. Occurs in North America, Eastern Ontario, much of Europe, and northern Asia
  2. Caused by Spirochetes of Borrelia genus
    1. In North America, almost exclusively B. burgdorferi
    2. In Europe and Asia, B. burgdorferi , B afzelii, B. garinii, possibly B. bissettii
    3. Small (1.5 megabases) but unusual genome
    4. Genome: one 950kb linear chromosome, plus 9 linear and 12 circular plasmids
    5. Large numbers of sequences for lipoproteins
    6. Heavy reliance on cell machinery for replication
  3. Spirochetes are carried by the deer (Ixodes) tick
    1. USA: Ixodes scapularis, I. pacificus, I. dammini
    2. Europe and Asia: I. ricinus, I. persulcatus
    3. In hyperendemic area, ~3% of tick bites lead to Lyme Disease (without prophylaxis) [4]
  4. Deer and rodents are natural targets (reservoirs) of the ticks
  5. Three Major Endemic Areas in USA
    1. Endemic in Northeastern USA: Maryland to Massachusetts
    2. Midwest in Wisconsin and Minnesota
    3. Northern California
    4. Prevalence of Lyme Disease on Nantucket, Massachusetts ~14% [5]
  6. Birds have spread dear ticks over increasing distances
  7. Disease has some distinct presentations in North America compared with Europe, Asia
  8. Long term prognosis of culture-confirmed Lyme Disease is good [3]

B. Presentationnavigator

  1. Stage I - Localized infection [7,9]
    1. Erythema migrans (EM), expanding lesion, center at bite site, occurs in ~65% of patients
    2. In USA, EM is has a homogeneous central redness rather than central palor
    3. Patients typically present within 3 days of onset of EM (see below)
    4. In USA, EM lasts ~4 days (versus ~14 days in Slovenia)
    5. Most common symptoms associated with EM: low grade fever, headache, neck stiffness, arthralgia, myalgia, fatigue ("flu-like" syndrome)
    6. Flu-like systemic symptoms can occur in the absence of EM or clinical suspicion and signal frank Lyme infection [22]
    7. EM may be accompanied by regional lymphadenopathy
    8. Liver function abnormalities may be present in about 1/3 of patients
    9. Uncommon to find evidence of advanced Lyme disease when EM is present
    10. However, blood spirochetes (spirochetemia) present in >20% of untreated EM patients [11]
  2. Stage II - Disseminated infection
    1. May follow initial symptoms within days or weeks
    2. Skin Lesions
    3. Annular lesions most common
      1. Malar rash (EM) is uncommon later in disease
      2. Diffuse erythema
      3. Urticaria
    4. Carditis [8]
    5. Palpitations (tachycardias)
      1. AV-Nodal Blockade (usually resolves with treatment)
      2. Myocarditis
      3. Occurs in ~5% of untreated patients, within several weeks of tick bite
    6. Neurologic Disorders
    7. Lymphocytic meningitis
      1. Bell's (Cranial Nerve VIII) and other Cranial Nerve palsies [13]
      2. Radiculoneuritis (pain)
      3. Weaness [13]
    8. Memory loss
      1. Vasculitis can occur
    9. Migratory pain in joints
    10. Swelling of one or a few joints (oligoarthritis)
      1. No tender points
      2. Arthritis may be due to molecular mimicry of OspA and LFA-1
    11. Malaise
  3. Stage III - Chronic Infection (Late Disseminated Lyme Disease) [1]
    1. Usually occurs >1 year post infection
    2. Similar organ involvement as Stage II but persistent
    3. Neurologic disease may progress to chronic paresthesia, dysesthesia, encephalopathy
    4. In untreated patients, up to 5% may develop delayed or late onset neurologic disease
    5. Stage III is usually prevented with antibiotic treatment
    6. Associated with or misdiagnosed as chronic fatigue syndrome or fibromyalgia
    7. Clearly positive Lyme serology is required to make this diagnosis
  4. Chronic Arthritis
    1. Appears to be associated with HLA-DR4 and DR2 alleles
    2. Suggests that genetic/immunological factors play a role in establishing chronic disease
    3. B. burgdorferi OspA (outer surface protein A) DNA can be detected in chronic joint fluid
    4. Polymerase chain reaction (PCR) of joint fluid can be used to detect Spirochete DNA [2]
    5. In about 30% of patients, PCR will be positive even with negative culture results
    6. Antibiotic treatment lowers OspA specific DNA titers in joint fluid
    7. Some patients develop chronic arthritis without organisms or proteins in their joints
    8. Arthritis is very uncommon in European and Asian disease
  5. Lyme Myositis
    1. Diffuse, nonspecific muscle stiffness and myalgia are not uncommon
    2. True myositis is typically localized and is more common in Europe
    3. Histology is focal nodular or interstitial myositis
    4. Interstitial infiltrates consist of lymphocytes and histiocytes with plasma cells
    5. Spirochetes are usually found
    6. Gallium scans (detect white blood cells) may help localize disease
    7. Antibiotics appear effective in limiting disease
  6. Long Term Sequellae [5,6]
    1. Often referred to as "Chronic Lyme Disease" or "Chronic Lyme Syndrome"
    2. Chronic joint pain and/or frank arthritis
    3. Verbal memory impairment
    4. Distal paresthesias
    5. Chronic fatigue
    6. Persons with a previous Lyme Disease diagnosis exhibited no objective sequellae overall (on physical examination) 6.0 years after diagnosis [5]
    7. Long term impairments are not due to ongoing infection [6]
    8. Many of these long term sequellae occur in chronic fatigue syndrome and other functional somatic disorders
    9. Long term antibiotic therapy is not beneficial and harmful in many cases [6]

C. Skin Manifestationsnavigator

  1. Erythema migrans (EM) [9,17]
    1. Most common skin presentation of Lyme Disease
    2. Many patients do not recall a tick bite
    3. Rash commonly seen with coexistant headache and fever
    4. Solitary, annular, erythematous lesions nearly always >5cm in diameter
    5. EM originally described with central clearing, but this is uncommon in endemic regions in USA, where it only occurs in ~20% (~80% in non-endemic regions of USA) [7,17]
    6. EM shows central clearing in ~80% of cases in Europe
    7. EM occurs typically days (up to weeks) after tick bite
    8. Lesions occurring earlier at sites of tick bite are hypersensitivity reactions
  2. Atypical EM
    1. Erythema with central induration, necrosis or purpura
    2. Alternating bands of erythema, confluent red or re-blue lesions
    3. Occasional triangular or rectangular lesions
    4. Central vesiculation
  3. Other Skin Manifestations
    1. Acrodermatitis chronica atrophicans (Europe and Asia only)
    2. Lymphadenosis benigna cutis
    3. Lichen sclerosus et atrophicus
  4. Acrodermatitis chronica atrophicans [2]
    1. Doughy infiltration of skin with induration and hyperpigmentation
    2. Far more common in Europe and Asia than USA following Lyme infection
    3. Dermal edema, telangiectasia, perivascular infiltrate of lymphocytes/plasma cells
  5. Lymphadenosis benigna cutis (Lymphocytoma) [2]
    1. Cutaneous lesions resemble sarcoma histologically
    2. Painless erythematous or violaceous nodules or plaques
    3. Dense B lymphocytic or less commonly histiocytic infiltrate
    4. May occur at presentation, last longer than EM, but resolves spontaneously
  6. Lichen sclerosus et atrophicus
    1. Sclerosis and atrophy of collagen and elastic fibers
    2. May resemble morphea, but spirochetes are present in lichen sclerosis
  7. Differential Diagnosis
    1. Streptococcal Cellulitis
    2. Urticaria
    3. Dermal Hypersensitivity
    4. Rhus Contact Dermatitis
    5. Tick / Arthropod Hypersensitivity Reactions
    6. Tinea Corporus
    7. Serum Sickness

D. Diagnosis [1] navigator

  1. Case Definition
    1. Erythema migrans observed by physician, at least 5cm
    2. At least 1 subsequent manifestation and laboratory evidence for infection
    3. Nervous system
    4. Cardiac system
    5. Musculoskeletal system
    6. Laboratory evidence (isolation of B. burgdorferi OR two step antibody test)
    7. Isolation of B. burgdorferi from tissue or body fluid is ample evidence for infection
  2. Moderate to high degree of suspicion are required if results are to be useful
    1. This is due to test characterstics of the initial Lyme Screening test
    2. ELISA tests for Lyme have sensitivity of ~90%, specificity of 72%
    3. Therefore, if pretest probability is <20%, then positive test result is more likely a false positive than a true positive
    4. For pretest probabilities of Lyme Disease 20-80%, ELISA should be performed
    5. All positive ELISA tests should be followed up with a confirmatory Western Blot
    6. For pretest probability of Lyme Disease >80%, empirical antibiotics should be given
  3. Serologic Testing [14]
    1. Two stage testing is required: ELISA initially; if positive, then Western Blot
    2. Serologic testing early in course of disease is insensitive and may be falsely negative
    3. Serologic testing should be used to support the diagnosis
    4. IgM and IgG ELISA tests are available
    5. IgM antibodies become positive in 2-4 weeks and IgG in 6-8 weeks after infection
    6. ELISA tests may be negative in some (~30%) patients with Lyme disease who have previously been treated with antibiotics
    7. Immunofluoresence antibody (IFA) and immunodot tests are also available for initial evaluation
  4. Western Blot Assay [1]
    1. Any positive or equivocal ELISA, IFA, or immunodot tests should be followed by Western Blot assay
    2. Analysis of Western results depends on acute (<1 month) or chronic infection
    3. Acute disease relies on IgM Western with 2 of 3 (23, 39, 41K) proteins must be positive
    4. IgG blot is positive if at least 5 of 10 (18,23,28,30,39,41,45,58,66,93K) proteins positive
    5. Only IgG response is used to support diagnosis after first month of infection
    6. Patients who are seronegative on Western Blotting and have been evaluated over >3-6 months do not have Lyme Disease
  5. Lyme Disease Specific Immune Complexes [15]
    1. Form very early in the disease
    2. May be present in patients with seronegative, culture-confirmed Lyme disease
    3. Are not found in patients with fatigue in Tick endemic areas who are Lyme negative
    4. Subject or research investigations at present
  6. Rule out central nervous system involvement with lumbar puncture in selected patients
  7. Polymerase Chain Reaction (PCR) tests are being developed for diagnosis
  8. Joint fluids should be tapped, cultured, and OspA and/or PCR analysis can be performed [1]
  9. Lyme testing for myalgias and other nonspecific complaints is strongly discouraged

E. Treatment [2,12,16]navigator

  1. Who to Treat (See Below)
    1. Low threshold to treat patients with a tick bite with symptoms and/or signs [10]
    2. Consider single 200mg doxycycline prophylaxis for asymptomatic tick bites [4,9]
    3. Treat patients with signs and symptoms, even without a (known) tick bite
    4. Parenteral antibiotics are reserved for patients with severe disease
    5. Severe disease: severe cutaneous lesions, or with neurologic, joint or cardiac symptoms
    6. Patients with fibromyalgia and positive Lyme titer are not treated
    7. Prophylaxis for Lyme disease is not indicated even in high prevalence areas
    8. In persons with tick bites in endemic areas, post-bite treatment with single 200mg dose doxycycline reduced risk of EM by ~85% and is very well tolerated [9,10]
    9. Doxycycline should not be used in children <8 years old or in pregnant or lactating women
    10. Amoxicillin or cefotaxine
  2. Treat Early Lyme Disease for 10 Days [23]
    1. Mainly erythema migrans (EM)
    2. Antibiotics clearly shorten the duration of the rash and prevent late sequellae
    3. Doxycycline 100mg po bid x 10 days (or 20 days) is first line
    4. Alternative first line: amoxicillin 500mg po tid or cefuroxime axetil (Ceftin®) 500mg po bid
    5. Extending doxycycline treatment from 10 to 20 days does not improve outcomes
    6. Clarithromycin or azithromycin are second line (higher failure rates)
    7. Azithromycin 500mg po qd (1-3 wks) - generally second line (increased failure rates)
    8. Amoxicillin x 20 days more effective than azithromycin x 7 days for EM
    9. Ceftriaxone 2gm qd IV/IM x 14 days no more effective than 21 days oral doxycycline
    10. Single dose ceftriaxone IV added to 10 days doxycycline does not improve outcomes versus doxycycline alone [23]
  3. Lyme Arthritis
    1. Ceftriaxone 2gm IV qd x 2-4 weeks is the preferred therapy
    2. Doxycycline 100mg po bid x 4 weeks
    3. Amoxicillin 500mg + Probenecid 500mg each qid x 4 weeks
    4. Non-steroidal anti-inflammatory agents may be helpful
  4. Lyme Carditis
    1. First degree heart block (PR interval <0.30 seconds) can be treated with oral agents
    2. Second or third degree heart block should be treated with intravenous (IV) agents
    3. Ceftriaxone 2gm IV qd x 2-4 weeks is first line
    4. Penicillin G 5MU IV q6 hours x 2 weeks
    5. Doxycycline 100mg po bid x 2-3 weeks
    6. Amoxicillin 500mg tid po x 2-3 weeks
    7. Temporary or permanent pacemaker may be required
  5. Neurological Lyme Disease
    1. Facial Nerve Disease - doxycycline or amoxicillin as for early Lyme disease
    2. Meningitis, encephalitis, radiculoneuropathy, peripheral neuropathy:
    3. Ceftriaxone 2gm IV qd x 2-4 weeks is strongly recommended
    4. Cefoxtaxime for 2-4 weeks is also effective
    5. Penicillin G 5MU iv q6 hours x 2-4 weeks can be used
  6. Recurrent Disease [1]
    1. Oral agents may not cure the disease
    2. Some patients will have resistant disease; these need iv antibiotics
    3. Continued infection or immune response may be involved in maintaining chronic disease
    4. Autoimmune mechanisms, including immune complex formation, vasculitis, others
    5. Dead organisms and/or expression of certain proteins from residual DNA may play a role
    6. No evidence that iv antibiotics for >4 weeks are superior to 3 or 4 weeks
  7. Lyme Disease in Pregnancy
    1. Penicillin G is safest regimen - 5MU q6 hours IV
    2. Ceftriaxone 2gm IV qd can also be used (more convenient)
    3. Amoxicillin 500mg po tid
    4. Use at standard doses and avoid doxycycline
  8. Increased risk of babesiosis transmission in patients infected with Lyme disease
  9. Patients who continue to have chronic fatigue should be evaluated for other causes [1,19]

F. Treatment Efficacy [1]navigator

  1. Oral Antibiotics reduce duration of rash and may prevent late sequelae and recurrence
    1. Amoxicillin 500mg tid x 20 days was superior to azithromycin 500mg qd x 7 days
    2. Endpoint was clearance of erythema migrans at day 20
    3. In addition, amoxicillin was superior at reducing replapses within 180 days
  2. Bell's Palsy only - oral antibiotics are nearly always sufficient; glucocorticoids may benefit [18]
  3. CNS Signs / Symptoms: Penicillin (24 mU qd), Ceftriaxone 2gm qd
  4. Lyme Arthritis
    1. Oral antibiotics may be okay initially but course should be at least 1 month
    2. Chronic arthritis treat with iv course, probably 3-4 weeks (qd ceftriaxone)
  5. Chronic Lyme Disease [1,19]
    1. Persistent pain and fatigue may occur in ~10% of patients with acute Lyme Disease
    2. This is despite previous antibiotics, and regardless of seropositivity or negativity
    3. Ceftriaxone 2gm IV qd x 30 days followed by doxycycline 200mg qd x 60 days or placebo
    4. No difference in health outcomes including quality of life for antibiotics versus placebo
    5. No benefits of antibiotics were seen in either seropositive or seronegative patients
    6. Antiobiotic therapy for 90 days does not improve symptoms of chronic Lyme Disease
  6. Overall prognosis is very good, particularly with antibiotic treatment of confirmed disease [3]

G. Prevention of Lyme Disease [1,9]navigator

  1. Prompt removal of ticks reduces risk of transmission
  2. In most areas, asympatomatic tick bites should NOT be treated with antibiotics
  3. In hyperendemic areas, however, strongly consider antiobiotic prophylaxis [10]
    1. Single 200mg doxycycline versus placebo for people with tick bites in endemic area
    2. Rate of Lyme disease 3.2% with placebo versus 0.4% (~85% reduction) with doxycycline
  4. No commercial Lyme Disease vaccine is currently available

H. Lyme Disease Vaccine [20,21]navigator

  1. Vaccines based on B. burgdorferi outer-surface lipoporein A (OspA)
  2. LYMErix® recombinant OspA vaccine was approved [21]
  3. Manufacturer has withdrawn vaccine from the market [1]

References navigator

  1. Steere AC. 2002. JAMA. 288(8):1002 abstract
  2. Stanek G and Strie F. 2003. Lancet. 362(9396):1639 abstract
  3. Nowakowski J, Nadelman RB, Sell R, et al. 2003. Am J Med. 115(2):91 abstract
  4. Nadelman RB, Nowakowski J, Fish D, et al. 2001. NEJM. 345(2):79 abstract
  5. Shadick NA, Phillips CB, Sangha O, et al. 1999. Ann Intern Med. 131(12):919 abstract
  6. Feder HM Jr, Johnston BJ, O'Connell S, et al. 2007. NEJM. 357(14):1422 abstract
  7. Smith RP, Schoen RT, Rahn DW, et al. 2002. Ann Intern Med. 136(6):421 abstract
  8. Hajjar RJ and Kradin RL. 2002. NEJM. 346(22):1732 (Case Record) abstract
  9. Wormser GP. 2006. NEJM. 354(26):2794 abstract
  10. Hayes EB and Piesman J. 2003. NEJM. 348(24):2424 abstract
  11. Wormser GP, McKenna D, Carlin J, et al. 2005. Ann Intern Med. 142(9):751 abstract
  12. Treatment of Lyme Disease. 2007. Med Let. 49(1263):49
  13. Greer DM, Schaefer PW, Plotkin SR, et al. 2007. NEJM. 356(15):1561 (Case Record) abstract
  14. Brown SL, Hansen SL, Langone JJ. 1999. JAMA. 282(1):62 abstract
  15. Schutzer SE, Coyle PK, Reid P, Holland B. 1999. JAMA. 282(20):1942 abstract
  16. Treatment of Lyme Disease. 2005. Med Let. 47(1209):41
  17. Tibbles GD and Edlow JA. 2007. JAMA. 297(23):2617 abstract
  18. Gilden DH. 2004. NEJM. 351(13):1323 abstract
  19. Klempner MS, Hu LT, Evans J, et al. 2001. NEJM. 345(2):85 abstract
  20. Lyme Disease Vaccine. 1999. Med Let. 41(1052):46
  21. Thanassi WT and Schoen RT. 2000. Ann Intern Med. 132(8):661 abstract
  22. Steere AC, Dhar A, Hernandez J, et al. 2003. Am J Med. 114(1):58 abstract
  23. Wormser GP, Ramanathan R, Nowakowski J, et al. 2003. Ann Intern Med. 138(9):697 abstract