Lyme Disease

Aka: Lyme Disease, Borrelia Burgdorferi, Lyme borreliosis

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II. Epidemiology

  1. Incidence
    1. Most common tick borne disease in North America
    2. Cases in U.S. in 1994: 13,000
    3. Cases in U.S. in 1999: 16,000
    4. Cases in U.S. in 2006: 20,000
    5. Cases in U.S. in 2014: 19,985
    6. Annual Incidence in endemic areas: 0.5%
    7. Peak occurrence in North America: May to August
  2. Demographics
    1. Gender: Much more common in males
    2. Age: Bimodal peak distribution (ages 5-9 and 55-59 years old)
  3. Geographic areas involved
    1. Worldwide cases have occurred in Canada, Europe, Asia
    2. U.S. cases clustered in Northeast and Upper Midwest (90% of U.S. cases)
      1. High-Risk States
        1. Connecticut (Nantucket County: 1198 case/100,000)
        2. Delaware
        3. Maryland
        4. New Jersey
        5. New York
        6. Pennsylvania
        7. Rhode Island
        8. Wisconsin
      2. Moderate-Risk States
        1. Maine
        2. Massachusetts
        3. Minnesota
        4. New Hampshire
        5. Vermont
    3. Reference
      1. (1995) MMWR Morb Mortal Wkly Rep 44:459-62 [PubMed]
  4. Concurrent Lyme and Babesiosis is common (n=1156)
    1. Coinfection occurs 10% in southern New England
    2. Reference
      1. Krause (1996) JAMA 275:1657-60 [PubMed]

III. History

  1. 1975: Lyme Disease first reported in Lyme, Connecticut
    1. Cluster of new cases of Arthritis in children
  2. 1981: Borrelia Burgdorferi identified as cause

IV. Pathophysiology

  1. Borrelia Burgdorferi
    1. Causative Spirochete organism
      1. Lyme Disease is similar to Syphilis, another Spirochete
      2. Like Syphilis, Lyme Disease has multiple stages (initial rash, later multisystem involvement)
    2. Transmitted by Deer Ticks
    3. Natural reservoirs
      1. Carried by white tail deer
      2. White-footed mouse and other small mammals
  2. Deer Ticks or Black Legged Tick
    1. Vectors for several infections
      1. Borrelia Burgdorferi (Lyme Disease)
      2. Babesia Microti (Babesiosis)
      3. Anaplasma phagocytophila (causes HGA)
        1. Prior: Ehrilichia phagocytophila (Ehrlichiosis)
    2. Tick species
      1. Ixodes Scapularis
      2. Ixodes pacificus (West coast)
  3. Deer Ticks have two year life cycle:
    1. Egg to Larva
    2. Larva to Nymph
    3. Nymph to Adult
  4. In endemic areas:
    1. Nymphs infected: 12-30%
    2. Adult ticks infected: 28-65%
  5. Nymphs outnumber adult ticks 10:1
    1. Nymphs are responsible for 90% of Lyme Disease cases
    2. Transmission relies on the time it takes for Borrelia to migrate from tick midgut to its Salivary Glands
      1. Nymphs must attach for >36-48 hours for transmission
      2. Adult ticks must attach for >48-72 hours for transmission

V. Differential Diagnosis

  1. Erythema Migrans
    1. See Annular Lesion
    2. Cellulitis
    3. Tinea Corporis
    4. Granuloma Annulare
    5. Arthropod Bite reaction
      1. Usually <5 cm, painful, develops in minutes to hours
      2. Rash is often pruritic
      3. Resolves within 48 hours without viral symptoms
  2. Other Ixodes tick (Deer Tick) borne infection
    1. Babesiosis
    2. Human Granulocytic Anaplasmosis

VI. Signs and Symptoms: Stage 1 (Early localized disease)

  1. Less than 20% of people recall Tick Bite
  2. Localized Erythema Chronicum Migrans at Tick Bite site (present in 80% of cases)
    1. See Erythema Migrans
    2. Expanding red Macule or Papule
    3. Size >=5 cm at outer ring diameter
      1. Rapid and prolonged expansion is unique (typically increases in diameter to >10-16 cm)
    4. Central clearing is variably present
    5. Onset within 3-30 days (typically 7-14 days) of Tick Bite and fades after 3-4 weeks
  3. Mild constitutional Symptoms (onset shortly after rash appears)
    1. Fever (also consider HGA or Babesiosis)
    2. Malaise
    3. Arthralgias (esp. Monoarthritis of the knee or hip)
    4. Headache
    5. Neck stiff
    6. Other skin lesions

VII. Signs and Symptoms: Stage 2 (Early disseminated disease)

  1. Cardiac (<10% of patients; onset typically within 1-2 months of infection)
    1. Atrioventricular Block (49% with third degree AV Block)
    2. Pericarditis
    3. Myocarditis
    4. Chest Pain
    5. Palpitations
    6. Dyspnea
    7. Syncope
  2. Musculoskeletal
    1. Arthralgias
    2. Myalgias
  3. Neurologic
    1. Bell's Palsy (or other Cranial NerveNeuropathy)
      1. Strongly consider empiric treatment for Lymes Disease with Bell's Palsy (esp. bilateral) in Lyme endemic regions
    2. Lymphocytic Meningitis or Encephalitis
      1. Often affebrile, with prolonged illness (7 days instead of typical 2 days for Viral Meningitis)
    3. Pseudotumor Cerebri
    4. Headache
    5. Vision changes
    6. Weakness
    7. Paresthesias
    8. Radiculopathy
    9. Nuchal Rigidity
  4. Ophthalmologic
    1. Conjunctivitis
    2. Iritis
  5. Urologic
    1. Microscopic Hematuria
    2. Proteinuria
  6. Skin: Disseminated Erythema Migrans (most common Stage 2 finding)
    1. Multiple Erythema Migrans lesions (hematogenous spread of infection)
    2. Smaller lesions than with initial Erythema Migrans
    3. Lesions often lack central clearing
    4. Diffuse involvement (but spares palms and soles)
  7. Miscellaneous
    1. Regional Lymphadenopathy or General Lymphadenopathy
    2. Hepatitis

VIII. Signs and Symptoms: Stage 3 (Late Disseminated, chronic disease)

  1. Large Joint Arthritis
    1. Occurs in 10-60% of untreated Lyme Disease (most common presentation for disseminated lymes)
    2. Increased risk with HLA-DR*0401 haplotype
    3. Arthritis presents at approximately 6 months after infection onset
    4. Monoarticular or asymmetric Oligoarticular Arthritis (especially knees; hips may also be involved)
    5. Fever is less common than with other Septic Arthritis
    6. Persistent Joint Pain in 10-20% of patients despite appropriate Antibiotic treatment
  2. Neurologic (10-15% of untreated patients)
    1. See Stage 2 neurologic conditions
    2. Symptoms
      1. Altered Mental Status
      2. Headaches
      3. Neck Pain or stiffness
      4. Sudden Hearing Loss
    3. Classic triad
      1. Lymphocytic Meningitis
      2. Cranial Neuropathy (especially Bell's Palsy)
      3. Radiculoneuropathy
    4. Other manifestations
      1. Subacute encephalopathy
      2. Axonal Polyneuropathy
      3. Leukoencephalopathy
      4. Cerebellar Ataxia
      5. Mononeuritis multiplex

IX. Labs: Modified Two Tiered Lyme Test Protocol (modified 2019)

  1. Tier 1: Initial Lyme Titer
    1. Obtain polyvalent enzyme immunoassay (EIA such as ELISA), or immunofluorescence assay (IF)
    2. Not needed if Erythema Migrans in endemic areas
    3. False Positive Rate is high
    4. Positive results are reflexed to confirmation testing
  2. Tier 2: Lyme confirmatory testing (if tier 1 test equivocal or positive)
    1. Option 1: Lyme Serology Second Generation Tests (approved by FDA, 2019, preferred)
      1. New pathway established for tests with better Test Sensitivity, Test Specificity and precision than the first test
      2. Since 2019, modified 2 tier confirmation is with another enzyme immunoassay (EIA), and recommended by CDC
    2. Option 2: Lyme Western Blot (conventional, older protocol, replaced by option 1)
      1. Western Blot for Lyme IgM and IgG has been historically used for confirmation before 2019
      2. Higher False Negatives than EIA testing in acute and early disseminated Lyme Disease
        1. False Negative in 60-75% of patients without disseminated disease (decreases to 10% in later stages)
      3. With Lyme Serology, Test Specificity: 99-100%
      4. IgG must be positive for symptoms >4 weeks
  3. References
    1. Mead (2019) MMWR Morb Mortal Wkly Rep 68(32): 703 +PMID:31415492 [PubMed]

X. Labs: Other

  1. See Lyme Test
  2. Tests indicated in specific cases (in addition to two tiered protocol above)
    1. Synovial FluidLyme PCR
      1. Joint Aspiration in cases of suspected Lyme Arthritis
      2. Test Sensitivity approaches 100%
      3. Test Specificity 42 to 100%
    2. Cerebrospinal fluid (CSF) for Intrathecal Lyme Antibody production
      1. Indicated for neurologic symptoms
    3. C6 Peptide assay (IgG Enzyme Linked Immunosorbent Assay)
      1. Under study as of 2012 for replacement of the two tiered protocol
  3. Precautions
    1. Borrelia Burgdorferi IgG and IgM
      1. Persists for years following effective Antibiotic treatment
      2. Positive test after treatment does not indicate failed Antibiotics or chronic infection
    2. Lyme urine Antigen
      1. High False Positive Rate and not recommended

XI. Labs: General Tests to Consider (e.g. Identify Other Causes in Differential)

  1. Complete Blood Count (CBC)
    1. Contrast with findings in Anaplasma and Babesia (Thrombocytopenia, Leukopenia or Neutropenia)
    2. Leukocytosis
    3. Anemia
  2. Comprehensive Metabolic panel
    1. Typically normal in Lyme Disease (but abnornal in Anaplasma and Babesia)
  3. Rheumatologic Testing
    1. Rheumatoid Factor (RF) negative
    2. C-Reactive Protenin positive
    3. Erythrocyte Sedimentation Rate (ESR) elevated
  4. Deer Tick borne infection testing (Peripheral Smear, PCR)
    1. Babesiosis
    2. Human Granulocytic Anaplasmosis

XII. Differential Diagnosis

  1. See Erythema Chronicum Migrans
  2. See Tick-Borne Illness
  3. See Deer Tick
  4. See Acute Monoarthritis
  5. Other Infections from Deer Ticks
    1. In addition to Lyme Disease, Deer Ticks transmit Babesiosis and Human Granulocytic Anaplasmosis
    2. Consider Parasite stain and Serology for Babesia and Anaplasma in febrile patients
    3. Babesia and Anaplasma are more commonly associated with Anemia, Leukopenia or Neutropenia
      1. Thrombocytopenia is seen with anaplasma
  6. Other tick borne infections with similar presentations to Lyme Disease
    1. Lone Star Tick borne STARI
      1. Similar appearance to Erythema Migrans

XIII. Precautions

  1. Consider Lyme Disease in unexplained symptoms (Arthralgias, focal weakness) despite lack of bite history
    1. Fluctuating meningoencephalitis symptoms
    2. Cranial Nerve palsy (e.g. Bell's Palsy, especially if bilateral)
    3. Peripheral Neuropathy or radiculopathy
    4. New first-degree AV Block or Dysrhythmia
    5. New left-ventricular dysfunction
  2. However, avoid testing for Lyme Disease to explain behavioral disorders
    1. Avoid routine Lyme Disease Testing to explain psychiatric illness or behavioral disorders
  3. Information based on IDSA and CDC guidelines
    1. IDSA: Infectious Disease Society of America
    2. IDSA is considered standard of care recommendations
    3. Tertiary centers (e.g. Mayo) follow these guidelines
  4. Other guidelines (e.g. ILADS) are not reviewed here
    1. ILADS: International Lyme and Associated Diseases
    2. ILADS guidelines are considered controversial

XIV. Management: Deer Tick Bite

  1. See Deer Tick Bite (includes Antibiotic Prophylaxis After Known Deer Tick Bite)
  2. See Tick Removal

XV. Management: Stage 1 (Early Lyme Disease and Erythema Migrans)

  1. Antibiotic treatment risks Jarisch-Herxheimer Reaction (affects 15% of patients)
    1. Borrelia is a Spirochete with potential for similar reaction to Antibiotics as for Syphilis
    2. Manifests as increased Temperature, myalgias and Arthralgias in first 24 hours of treatment
  2. Doxycycline (Avoid in pregnancy and under age 9 years)
    1. Preferred oral agent due to cross-coverage of other tick-borne infections
    2. Adult: 100 mg orally twice daily for 10 to 21 days (typically 10 days)
    3. Child (age >8): 4 mg/kg orally divided twice daily (max 100 mg/dose) for 10-21 days (typically 10 days)
  3. Amoxicillin
    1. Adult: 500 mg orally three times daily for 14 to 21 days (typically 14 days)
    2. Child: 50 mg/kg/day divided three times daily (max 500 mg/dose) for 14 to 21 days (typically 14 days)
  4. Cefuroxime (Ceftin)
    1. Adult: 500 mg orally twice daily for 14 to 21 days (typically 14 days)
    2. Child: 30 mg/kg/day divided twice daily (max: 500 mg/dose) for 14 to 21 days (typically 14 days)
  5. Macrolides have lower efficacy (consider other agents above if possible)
    1. Use only if allergic to above agents
    2. Azithromycin
      1. Adult: 500 mg daily for 7 to 10 days (typically 7 days)
      2. Child: 10 mg/kg daily for 7 to 10 days (typically 7 days)
    3. Clarithromycin
      1. Adult: 500 mg orally twice daily for 21 days
      2. Child: 7.5 mg/kg (max: 500 mg/dose) orally twice daily for 21 days
    4. Erythromycin
      1. Adult: 500 mg orally four times daily for 21 days
      2. Child: 12.5 mg/kg (max 500 mg/dose) orally four times daily for 21 days
  6. If suspect Cellulitis versus Erythema Migrans
    1. Augmentin 50 mg/kg/day divided bid or tid (up to 875 mg twice daily)
    2. Cefuroxime 30 mg/kg/day divided twice daily (up to 500 mg twice daily)
    3. Doxycycline 4 mg/kg divided twice daily (up to 100 mg twice daily)
  7. Antibiotics to avoid (not indicated)
    1. Avoid First Generation Cephalosporins (Cephalexin)
    2. Avoid Fluoroquinolones
    3. Avoid Septra, Metronidazole, Penicillin G

XVI. Management: Stage 2 (Early disseminated with cardiac or neurologic findings)

  1. Indications for hospitalization and ParenteralAntibiotics
    1. New first degree AV Block with PR >300 ms
    2. Chest Pain, Syncope or Dyspnea
    3. Lyme Meningitis or Encephalitis
    4. New second or third degree AV Block
      1. AV Block typically resolves with Lyme Disease treatment
      2. However, temporary Pacemaker placement may be needed
  2. Protocol: Indications to treat with agents as Stage 1 disease for 14-21 days
    1. Isolated Bell's Palsy or radiculopathy
    2. Asymptomatic, isolated first degree AV Block
  3. Protocol
    1. Obtain Lumbar Puncture for neurologic findings attributed to Lymes Disease
    2. Treat lyme Arthritis for 28 days
    3. Treat neurologic and carditis complications for 14 to 21 days
  4. Ceftriaxone (Rocephin)
    1. Adult: 2g/day IV for 14 to 28 days
    2. Child: 75 mg/kg/day IV for 14 to 28 days
  5. Cefotaxime (Claforan)
    1. Adult: 2g every 8 hours for 14 to 28 days
    2. Child: 150-200 mg/kg/day divided every 6 to 8 hours IV for 14-28 days
  6. Other Antibiotics
    1. Penicillin G IV may be used for lymes Meningitis and Lyme Arthritis

XVII. Management: Stage 3 (Late Disseminated Lyme Disease)

  1. Arthritis
    1. Use same oral Antibiotic protocols as under Stage 1 - Erythema Migrans management for 28 days
    2. Persistent or recurrent Joint Swelling despite initial Antibiotics course
      1. Consider repeating a 4 week course of oral Antibiotics or 2-4 week course of Ceftriaxone
  2. Neurologic findings
    1. Use same intravenous Antibiotic protocols as under Stage 2 - early disseminated management
    2. Post-Lyme Disease syndrome of persistent Fatigue or cognitive difficulties
      1. No benefit to prolonged Antibiotic courses or other medication management
      2. Klempner (2013) Am J Med 126(8):665-9 +PMID:23764268 [PubMed]

XVIII. Management: Other Lyme Related Conditions

  1. Borrelial Lymphocytoma
    1. Oral Doxycycline, Amoxicillin or Cefuroxime for 14 days
  2. Acrodermatitis Chronica Atrophicans
    1. Oral Doxycycline, Amoxicillin or Cefuroxime for 21 to 28 days

XIX. Complications: Post-Lyme Disease Syndrome

  1. Post-Lyme Disease Syndrome Criteria (reported in 10-20% of cases)
    1. Persistent vague symptoms >6 months after completing treatment
  2. Causes
    1. Idiopathic in most cases
    2. Untreated comorbid tickborne illness (e.g. Babesiosis)
    3. Comorbid unrelated medical condition
  3. Management
    1. Prolonged Antibiotic use is not recommended (beyond specific indications as above)

XX. Prevention

  1. See Prevention of Vector-borne Infection
  2. See Antibiotic Prophylaxis After Known Deer Tick Bite
  3. Lyme Vaccine (No longer available in U.S.)
    1. OspA had only a 3 tenure when it was withdrawn from U.S. market in 2002 due to poor sales
  4. Insecticide
    1. Acaricide applied to residential areas in mid May
    2. Provides 97% protection during peak nymph activity

XXI. Resources

  1. IDSA Guidelines
    1. http://www.journals.uchicago.edu/IDSA/guidelines/

XXII. Reference

  1. Della-Giustina, Fox and Siegel (2021) Crit Dec Emerg Med 35(4): 17-23
  2. Hensley and Swaminathan in Herbert (2016) EM:Rap 16(7): 7-9
  3. Steere in Mandell (2000) Infectious Disease, p. 2504-14
  4. (2000) Med Lett Drugs Ther 42(1077): 37 [PubMed]
  5. (1997) Med Lett Drugs Ther 39(1000) [PubMed]
  6. Fix (1998) JAMA 279(3): 206-10 [PubMed]
  7. Lantos (2021) Clin Infect Dis 72(1):e1-e48 +PMID: 33417672 [PubMed]
  8. Pace (2020) Am Fam Physician 101(9): 530-40 [PubMed]
  9. Rahn (1998) Postgrad Med 103(5):51-70 [PubMed]
  10. Still (1997) Postgrad Med 102(1):65-72 [PubMed]
  11. Verdon (1997) Am Fam Physician, 56(1): 427-436 [PubMed]
  12. Nadelman (1995) Am J Med 98:15S-24S [PubMed]
  13. Stanek (2003) Lancet 362:1639-47 [PubMed]
  14. Wormser (2006) Clin Infect Dis 43(9):1089-134 [PubMed]
  15. Wright (2012) Am Fam Physician 85(11): 1086-93 [PubMed]

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