T. pallidum & B. burgdorferi

This section details the intricacies of Treponema pallidum (syphilis) and Borrelia burgdorferi (Lyme disease) serodiagnosis, focusing on the stages of infection and how antibody responses change over time. Understanding these nuances is critical for accurate diagnosis and treatment

Treponema pallidum (Syphilis)

Causative Agent: Treponema pallidum, a spirochete bacterium
Transmission: Primarily through sexual contact, but also congenitally (mother to fetus)
Stages of Infection: Syphilis progresses through distinct stages, each with its own clinical manifestations and serological profile

Stages of Syphilis

Primary Syphilis
- Clinical Presentation: Characterized by a painless chancre (ulcer) at the site of infection (usually on the genitals, anus, or mouth)
- Timing: Chancre typically appears 10-90 days after infection (average 3 weeks)
- Serodiagnosis
  - Nontreponemal tests (RPR, VDRL) may be negative early in the primary stage, but become positive within 1-4 weeks after the chancre appears
  - Treponemal tests (FTA-ABS, TP-PA, EIA) are usually positive at the time the chancre appears or shortly thereafter
Secondary Syphilis
- Clinical Presentation: Characterized by a widespread rash (often on the palms and soles), fever, fatigue, lymphadenopathy, and mucous membrane lesions (condyloma latum)
- Timing: Occurs weeks to months after the chancre heals
- Serodiagnosis
  - Nontreponemal tests (RPR, VDRL) are usually highly positive (high titers)
  - Treponemal tests (FTA-ABS, TP-PA, EIA) remain positive
Latent Syphilis
- Clinical Presentation: No clinical symptoms are present. The infection is only detectable through serological testing
- Timing: Follows secondary syphilis
- Early Latent: Infection acquired within the past year
- Late Latent: Infection acquired more than a year ago or of unknown duration
- Serodiagnosis
  - Nontreponemal tests (RPR, VDRL) may be positive (low titers) or negative
  - Treponemal tests (FTA-ABS, TP-PA, EIA) remain positive
Tertiary Syphilis
- Clinical Presentation: Characterized by severe complications affecting the heart, brain, nerves, bones, and skin (gummas)
- Timing: Occurs years to decades after the initial infection
- Serodiagnosis
  - Nontreponemal tests (RPR, VDRL) may be positive or negative
  - Treponemal tests (FTA-ABS, TP-PA, EIA) remain positive
Neurosyphilis
- Clinical Presentation: Syphilis that affects the central nervous system, causing a range of neurological symptoms (meningitis, stroke, dementia, tabes dorsalis)
- Diagnosis: Requires CSF analysis (VDRL-CSF) in addition to serum serology
- Serodiagnosis
  - Serum treponemal and nontreponemal tests are usually positive
  - CSF-VDRL is specific for neurosyphilis, but has low sensitivity
  - CSF-FTA-ABS is more sensitive, but less specific
Congenital Syphilis
- Clinical Presentation: Occurs when Treponema pallidum is transmitted from a pregnant woman to her fetus. Can result in stillbirth, neonatal death, or congenital abnormalities (Hutchinson’s teeth, saddle nose, saber shins)
- Diagnosis: Difficult to diagnose in newborns because maternal IgG antibodies can cross the placenta. Requires careful clinical evaluation and serological testing
- Serodiagnosis
  - Newborns may have positive treponemal and nontreponemal tests due to maternal antibodies
  - Rising titers of nontreponemal tests in the infant suggest active infection
  - IgM treponemal tests can be helpful, but are not always reliable

Serological Tests for Syphilis

Nontreponemal Tests
- Examples: Rapid Plasma Reagin (RPR), Venereal Disease Research Laboratory (VDRL)
- Antigen: Cardiolipin, lecithin, and cholesterol
- Detects: Reagin antibodies (IgG and IgM) that are produced in response to tissue damage caused by syphilis
- Advantages: Inexpensive, easy to perform, quantitative (titers can be measured), useful for screening and monitoring treatment response
- Disadvantages: Lower specificity, false positives can occur due to other conditions (autoimmune diseases, pregnancy, infections)
- Interpretation
  - Reactive (positive): Indicates possible syphilis infection
  - Nonreactive (negative): May indicate no infection, early infection, or late-stage infection
  - Titer: Reflects the amount of reagin antibodies present. Higher titers suggest active infection. A fourfold decrease in titer after treatment indicates successful therapy
Treponemal Tests
- Examples: Fluorescent Treponemal Antibody Absorption (FTA-ABS), Treponema pallidum Particle Agglutination (TP-PA), Enzyme Immunoassay (EIA) for treponemal antibodies, Chemiluminescence Immunoassay (CLIA) for treponemal antibodies
- Antigen: Treponema pallidum antigens
- Detects: Antibodies specifically directed against Treponema pallidum
- Advantages: High specificity, used to confirm diagnosis of syphilis
- Disadvantages: More complex and expensive than nontreponemal tests, remain positive for life (not useful for monitoring treatment response)
- Interpretation
  - Reactive (positive): Indicates past or present syphilis infection
  - Nonreactive (negative): Usually indicates no syphilis infection, but can be negative in early primary syphilis

Syphilis Testing Algorithms

Traditional Algorithm
- Screen with a nontreponemal test (e.g., RPR)
- If positive, confirm with a treponemal test (e.g., TP-PA)
Reverse Algorithm
- Screen with a treponemal test (e.g., EIA)
- If positive, perform a nontreponemal test (e.g., RPR)
- If the nontreponemal test is negative, perform a second treponemal test (different from the first) to resolve the discrepancy

Borrelia burgdorferi (Lyme Disease)

Causative Agent: Borrelia burgdorferi, a spirochete bacterium
Transmission: Through the bite of infected Ixodes ticks (deer ticks or black-legged ticks)
Stages of Infection: Lyme disease progresses through distinct stages, each with its own clinical manifestations and serological profile

Stages of Lyme Disease

Early Localized Lyme Disease
- Clinical Presentation: Characterized by erythema migrans (EM) rash, a bull’s-eye-shaped rash that expands from the site of the tick bite. May also have flu-like symptoms (fever, fatigue, headache, muscle aches)
- Timing: EM rash typically appears 3-30 days after the tick bite (average 7 days)
- Serodiagnosis
  - Antibodies may be negative early in the localized stage (especially within the first few weeks of infection)
  - EIA or ELISA is used for initial screening. If positive or equivocal, a Western blot is performed for confirmation
Early Disseminated Lyme Disease
- Clinical Presentation: Occurs weeks to months after the initial infection. Characterized by multiple EM rashes, neurological symptoms (meningitis, facial palsy), cardiac symptoms (AV block), and musculoskeletal symptoms (migratory pain in joints, muscles, and tendons)
- Serodiagnosis
  - Antibodies are usually positive (both IgM and IgG)
  - EIA or ELISA is used for initial screening. If positive or equivocal, a Western blot is performed for confirmation
Late Disseminated Lyme Disease
- Clinical Presentation: Occurs months to years after the initial infection. Characterized by arthritis (especially in the large joints, such as the knee), neurological symptoms (encephalomyelitis, peripheral neuropathy), and skin manifestations (acrodermatitis chronica atrophicans)
- Serodiagnosis
  - Antibodies are usually positive (primarily IgG)
  - EIA or ELISA is used for initial screening. If positive or equivocal, a Western blot is performed for confirmation

Two-Tiered Testing for Lyme Disease

First Tier: Screening Test (EIA or ELISA)
- Detects antibodies (IgM and IgG) against Borrelia burgdorferi
- High sensitivity, but lower specificity (false positives can occur)
- If the EIA/ELISA is negative, no further testing is needed (unless the patient has had symptoms for less than 30 days)
Second Tier: Confirmatory Test (Western Blot)
- Used to confirm positive or equivocal EIA/ELISA results
- More specific than EIA/ELISA
- Identifies antibodies to specific Borrelia burgdorferi proteins
- Separate criteria for IgM and IgG Western blots

Western Blot Interpretation

IgM Western Blot
- Used to confirm early Lyme disease (symptoms present for less than 30 days)
- Requires at least two of the following bands to be positive: 24 kDa (OspC), 39 kDa (BmpA), and 41 kDa (FlaB)
IgG Western Blot
- Used to confirm later Lyme disease (symptoms present for more than 30 days)
- Requires at least five of the following bands to be positive: 18 kDa, 21 kDa (OspC), 28 kDa, 30 kDa, 39 kDa (BmpA), 41 kDa (FlaB), 45 kDa, 58 kDa, 66 kDa, 93 kDa

Important Considerations

Early Lyme Disease: Serological tests may be negative in the early stages of Lyme disease. If the patient has a typical EM rash, treatment should be initiated without waiting for serological confirmation
Post-Treatment Lyme Disease Syndrome (PTLDS): Some patients continue to experience symptoms after treatment for Lyme disease. Serological tests are not useful for diagnosing PTLDS, as antibodies may persist for years after successful treatment
Other Borrelia Species: In some geographic areas, other Borrelia species (e.g., Borrelia mayonii, Borrelia miyamotoi) can cause Lyme-like illness. Standard serological tests may not detect antibodies to these species

Key Terms

Chancre: A painless ulcer that is characteristic of primary syphilis
Erythema Migrans (EM): A bull’s-eye-shaped rash that is characteristic of early Lyme disease
Reagin Antibodies: Antibodies that are produced in response to tissue damage caused by syphilis. Detected by nontreponemal tests (RPR, VDRL)
Western Blot: A laboratory technique used to detect specific proteins in a sample. Used as a confirmatory test for Lyme disease
Post-Treatment Lyme Disease Syndrome (PTLDS): A condition in which patients continue to experience symptoms after treatment for Lyme disease

Agents of Encephalitis

Tuberculosis