Lyme Disease

See Also

Epidemiology

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
Demographics
1. Gender: Much more common in males
2. Age: Bimodal peak distribution (ages 5-9 and 55-59 years old)
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]
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]

History

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

Pathophysiology

Borrelia Burgdorferi
1. Causative Spirochete organism
2. Carried by white tail deer
3. Transmitted by Deer Ticks
4. Natural reservoirs
  1. White-footed mouse and other small mammals
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)
Deer Ticks have two year life cycle:
1. Egg to Larva
2. Larva to Nymph
3. Nymph to Adult
In endemic areas:
1. Nymphs infected: 12-30%
2. Adult ticks infected: 28-65%
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

Differential Diagnosis

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
Other Ixodes tick (Deer Tick) borne infection
1. Babesiosis
2. Human Granulocytic Anaplasmosis

Signs and Symptoms
Stage 1 (Early localized disease)

Less than 20% of people recall Tick Bite
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
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

Signs and Symptoms
Stage 2 (Early disseminated disease)

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
Musculoskeletal
1. Arthralgias
2. Myalgias
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
Ophthalmologic
1. Conjunctivitis
2. Iritis
Urologic
1. Microscopic Hematuria
2. Proteinuria
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)
Miscellaneous
1. Regional Lymphadenopathy or General Lymphadenopathy
2. Hepatitis

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

Large Joint Arthritis
1. Occurs in 10-60% of untreated Lyme Disease (most common presentation for disseminated lymes)
2. Arthritis presents at approximately 6 months after infection onset
3. Monoarticular or asymmetric Oligoarticular Arthritis (especially knees; hips may also be involved)
4. Fever is less common than with other Septic Arthritis
5. Persistent Joint Pain in 10-20% of patients despite appropriate Antibiotic treatment
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

Labs
Modified Two Tiered Lyme Test Protocol (modified 2019)

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
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
References
1. Mead (2019) MMWR Morb Mortal Wkly Rep 68(32): 703 +PMID:31415492 [PubMed]

Labs
Other

See Lyme Test
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
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

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

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

Differential Diagnosis

See Erythema Chronicum Migrans
See Tick-Borne Illness
See Deer Tick
See Acute Monoarthritis
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
Other tick borne infections with similar presentations to Lyme Disease
1. Lone Star Tick borne STARI
  1. Similar appearance to Erythema Migrans

Precautions

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
However, avoid testing for Lyme Disease to explain behavioral disorders
1. Avoid routine Lyme Disease Testing to explain psychiatric illness or behavioral disorders
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
Other guidelines (e.g. ILADS) are not reviewed here
1. ILADS: International Lyme and Associated Diseases
2. ILADS guidelines are considered controversial

Management
Deer Tick Bite

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

Management
Stage 1 (Early Lyme Disease and Erythema Migrans)

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
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)
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)
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)
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
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)
Antibiotics to avoid (not indicated)
1. Avoid First Generation Cephalosporins (Cephalexin)
2. Avoid Fluoroquinolones
3. Avoid Septra, Metronidazole, Penicillin G

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

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
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
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
Ceftriaxone (Rocephin)
1. Adult: 2g/day IV for 14 to 28 days
2. Child: 75 mg/kg/day IV for 14 to 28 days
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
Other Antibiotics
1. Penicillin G IV may be used for lymes Meningitis and Lyme Arthritis

Management
Stage 3 (Late Disseminated Lyme Disease)

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
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]

Management
Other Lyme Related Conditions

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

Complications
Post-Lyme Disease Syndrome

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

Prevention

See Prevention of Vector-borne Infection
See Antibiotic Prophylaxis After Known Deer Tick Bite
Lyme Vaccine (No longer available in U.S.)
Insecticide
1. Acaricide applied to residential areas in mid May
2. Provides 97% protection during peak nymph activity

Resources

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

Reference

Della-Giustina, Fox and Siegel (2021) Crit Dec Emerg Med 35(4): 17-23
Hensley and Swaminathan in Herbert (2016) EM:Rap 16(7): 7-9
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