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Billy
100
Bacteria that causes Lyme Disease
However, subsequent studies have determined that a complex of at least 10 Borrelia species is responsible for Lyme disease in animals and humans. Three species, B. burgdorferi, B. garinii, and Borrelia afzelii, cause human disease, with B. burgdorferi found in the United States and Europe and B. garinii and B. afzelii found in Europe and central to eastern Asia.
100
Diseases caused by Borrellia
Members of the genus Borrelia cause two important human diseases: Lyme disease and relapsing fever.
100
Prevention of tick-borne Borrelia diseases
Prevention of tick-borne Borrelia diseases includes: avoiding ticks and their natural habitats, wearing protective clothing (e.g., long pants tucked into socks), and applying insect repellents.
A recombinant vaccine directed against the OspA antigen of B. burgdorferi was removed from the market in 2002.
100
Relate Billy's HPI (1st paragraph) to the pathogenesis of Lyme Disease
Billy Gray, 25yo M
A one-week history of fatigue, headache, arthralgia, neck stiffness, and fever. His maximum temperature was 38.3°C (101°F) three days ago when a painless rash developed on his right arm.
Mr. Gray went camping and hiking three weeks ago in an East Texas state park. He denies recent contact with any wild or domestic animals, and he denies a history of known tick bites. Mr. Gray’s medical history is unremarkable. He is allergic to penicillin.
200
Clinical features of Lyme Disease
Early signs and symptoms: malaise, severe fatigue, headache, fever, chills, musculoskeletal pains, myalgias, and lymphadenopathy. These symptoms last for an average of 4 weeks.
1. Stage I - Early localized disease, spirochetes multiply and spread in the dermis at the site of a tick bite, causing an expanding area of redness, often with a pale center. This lesion, called erythema migrans, may be accompanied by fever and lymphadenopathy. The rash spontaneously disappears in 4 to 12 weeks.
2. Stage II - Early disseminated disease, spirochetes spread hematogenously throughout the body and cause secondary skin lesions, lymphadenopathy, migratory joint and muscle pain (60% of patients with untreated Lyme disease will develop arthritis, typically involving the knee), cardiac arrhythmias (5% will have cardiac complications, usually varying degrees of atrioventricular block), and meningitis often associated with cranial nerve involvement (10% to 20% will develop neurologic manifestations, most commonly facial nerve palsy).
3. Stage III - late disseminated disease, manifests many months after the tick bite. B. burgdorferi usually causes chronic arthritis sometimes with severe damage to large joints. Less often, patients will have polyneuropathy and encephalitis that vary from mild to debilitating.
After an incubation period of 3 to 30 days, one or more skin lesions typically develop at the site of the tick bite. The lesion (erythema migrans) begins as a small macule or papule and then enlarges over the next few weeks, ultimately covering an area ranging from 5 cm to more than 50 cm in diameter. The lesion typically has a flat, red border and central clearing as it develops; however, erythema, vesicle formation, and central necrosis can also be seen. The lesion fades and disappears within weeks, although new transient lesions may subsequently appear. Although the skin lesion is characteristic of Lyme disease, it is not pathognomonic.
200
What is the physiology and structure of Borrelia?
Members of the genus Borrelia:
- stain poorly with the Gram stain reagents and are considered neither gram-positive nor gram-negative, even though they have an outer membrane similar to gram-negative bacteria.
- They are larger than other spirochetes (0.2 to 0.5 × 8 to 30 μm)
- Stain well with aniline dyes (e.g., Giemsa or Wright stain)
- Not easily seen by light microscopy when present in smears of peripheral blood from patients with Lyme disease (too few organisms to be observed)
- Borreliae are microaerophilic and have complex nutritional needs requiring:
--- N -acetylglucosamine
--- long-chain saturated and unsaturated fatty acids
--- glucose
--- amino acids
This makes them difficult to grow in the lab so culture is generally unsuccessful, diagnosis of diseases caused by borreliae is by serology (Lyme disease) or microscopy (relapsing fever).
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Treatment for the early manifestation of Lyme Disease
The early manifestations of Lyme disease are managed effectively with orally administered amoxicillin, doxycycline, or cefuroxime.
Antibiotic treatment lessens the likelihood and severity of late complications.
Despite this intervention, Lyme arthritis still occurs in a small number of patients. Oral cefuroxime, doxycycline, or amoxicillin have been used for the treatment.
200
Relate Billy's PE (Stage 1) to the pathophysiology of Lyme Disease
Vital Signs: T 37.3°C (99.1°F), HR 90/min, BP 125/82 mmHg, RR 14/min
Eyes: No conjunctival injection or scleral erythema
Mouth: Pharyngeal erythema; no tonsillar or pharyngeal exudates
Hematologic/Lymphatics: Right axillary lymphadenopathy
Gastrointestinal (Abdomen): Nontender; mild hepatosplenomegaly
Musculoskeletal: No synovitis, effusions or loss of range of motion
Skin/Integumentary: Uniformly erythematous, annular macule with central clearing measuring 5cm on the medial aspect of the right arm (Figure 1); no ticks seen.
Osteopathic Structural Exam: Right sternocleidomastoid hypertonicity; right clavicle is superior; right first rib is superior
300
Lyme Disease Diagnostic Approach
Because culture is generally unsuccessful, diagnosis of diseases caused by borreliae is by serology (Lyme disease) or microscopy (relapsing fever).
Microscopy - Microscopic examination of blood or tissues from patients with Lyme disease is not recommended because B. burgdorferi is rarely seen in clinical specimens.
Culture - There has been limited success with the culture of B. burgdorferi, although isolation of the organism has been improved through the use of specialized media. However, the sensitivity of culture is low for all specimens except the initial skin lesion.
Nucleic Acid–Based Tests - sensitivity of approximately 65% to 75% with skin biopsies, 50% to 85% with synovial fluid, and 25% with CSF specimens from patients with documented Lyme disease. These tests are generally restricted to research and reference laboratories, and the negative test results should be confirmed by serology.
Antibody Detection - serologic testing is the diagnostic test of choice for patients with suspected Lyme disease. The tests most commonly used are the immunofluorescence assay (IFA) and EIA.
- All serologic tests are relatively insensitive during the early acute stage of the disease.
- IgM antibodies appear 2 to 4 weeks after the onset of erythema migrans in untreated patients; the levels peak after 6 to 8 weeks of illness and then decline to a normal range after 4 to 6 months. The IgM level may remain elevated in some patients with a persistent infection.
- The IgG antibodies appear later. Their levels peak after 4 to 6 months of illness and persist during the late manifestations of the disease. Thus most patients with late complications of Lyme disease have detectable antibodies to B. burgdorferi, although the antibody level may be ablated in patients treated with antibiotics.
- Detection of antibodies in CSF is strong evidence for neuroborreliosis.
- At present, serologic tests should be considered confirmatory and should not be performed in the absence of an appropriate history and clinical symptoms of Lyme disease.
300
What is the pathogenesis & immunity of Borrelia?
The growth of borreliae in both arthropod vectors and mammalian hosts is regulated by differential gene expression with upregulation or downregulation of outer surface proteins. For example,
- Outer surface protein A (OspA) is expressed on the surface of B. burgdorferi residing in the midgut of unfed ticks. This protein binds specifically to gut proteins. On feeding, expression of this protein is repressed, allowing the spirochete to migrate to the salivary glands, and outer surface protein C (OspC) expression, which appears critical for transmission from ticks to mammals, is upregulated.
- B. burgdorferi organisms are present in low numbers in the skin when erythema migrans develops. This has been shown by culture of the organism from skin lesions and detection of bacterial nucleic acids by PCR amplification; however, culture and PCR tests are relatively insensitive in the early phase of disease.
In addition, spirochetes are infrequently isolated from clinical material late in the disease. It is not known whether the viable organisms cause these late manifestations of disease or whether they represent immunologic cross-reactivity to Borrelia antigens.
Although the immune response to the organism is depressed at the time that skin lesions initially develop, antibodies develop over months to years and are responsible for producing the complement-mediated clearance of the borreliae.
300
Treatment for late-stage Lyme Disease
Patients with recurrent arthritis or central or peripheral nervous system disease typically require parenteral treatment with intravenous ceftriaxone, cefotaxime, or penicillin G. Previously treated patients with chronic symptoms (“post–Lyme disease syndrome”) should be treated symptomatically because there is no evidence that multiple courses of oral or parenteral antibiotics relieve the symptoms.
300
Relate Billy's knee symptoms to the pathophysiology of Lyme disease
Six weeks later, Mr. Gray returns to see Dr. Jimenez with severe fatigue, intermittent headaches, right ear pain, right-sided facial droop, and right knee pain with swelling. Review of systems is positive for hyperacusis, right facial paresthesia, and the loss of taste sensation on the right side of his tongue. Physical examination reveals unilateral paralysis of the right upper and lower facial muscles, consistent with Bell’s palsy. The right knee is swollen, warm, and ballotable.
400
Differential diagnoses associated with the clinical presentation of Lyme disease
- Different stages of Lyme Disease
- Tick paralysis
- Rocky Mountain spotted fever (RMSF)[HDC.LGS.01b]
- Babesiosis
- Ehrlichiosis
- Anaplasmosis
- Tularemia
- Colorado tick fever (CTF)
- Tick-borne relapsing fever [MedMicro Borrelia chapter]
- Southern tick‑associated rash illness (STARI) [MedMicro Borrelia chapter]
- Although the skin lesion is characteristic of Lyme disease, it is not pathognomonic. A similar skin lesion associated with a disease of unknown etiology SARI) occurs after the bite of the Amblyomma americanum tick (lone star tick). These ticks, found in the southeast and south-central regions of the United States, are not infected with B. burgdorferi. Other early signs and symptoms of Lyme disease include malaise, severe fatigue, headache, fever, chills, musculoskeletal pains, myalgias, and lymphadenopathy. These symptoms last for an average of 4 weeks.
400
What is the epidemiology of Borrelia?
Lyme disease is the leading vector-borne disease in the United States.
Geographic Location: Northeast and Mid-Atlantic states (Maine to Virginia) and the Upper Midwest (Minnesota and Wisconsin). 
Vector (US): Hard ticks (Ixodes scapularis)
Reservoir Hosts (US): white-footed mouse & the white-tailed deer.
- The white-footed mouse is the primary host of larval and nymph forms of Ixodes species.
--- Nymph stage > 90% of the cases
--- Ixodes larvae become infected when they feed on the mouse reservoir. The larva molts to a nymph in late spring and takes a second blood meal; in this case, humans can be accidental hosts.
--- Although the borreliae are transmitted in the tick’s saliva during a prolonged period of feeding (≥48 hours), most patients do not remember having had a specific tick bite because the nymph is the size of a poppy seed. The nymphs mature into adults in the late summer and take a third feeding.
--- Adult Ixodes species infest the white-tailed deer. Although the white-tailed deer is the natural host, humans can also be infected at this stage. Most infected patients are identified in June and July, although the disease can be encountered throughout the year.
400
Post-treatment Lyme disease syndrome (PTLDS) definition, pathophysiology, diagnostics, differential diagnosis, and treatment
Definition: nonspecific symptoms (e.g., pain, fatigue, cognitive impairment) lasting > 6 months after successful treatment for Lyme disease
Pathophysiology: unknown
Diagnostics
- Clinical diagnosis based on new or residual symptoms following antibiotic treatment for serologically confirmed Lyme disease
- Rule out treatment failure and reinfection.
- Inflammatory markers are typically normal.
Differential diagnosis: somatoform disorders, fibromyalgia, chronic fatigue syndrome
Treatment: There are no established effective therapies.
- Provide reassurance, education, and patient-centered counseling.
- Long-term antibiotic therapy has no proven benefit.
400
Relate Billy's Bell's Palsy to the pathophysiology of Lyme Disease
Six weeks later, Mr. Gray returns to see Dr. Jimenez with severe fatigue, intermittent headaches, right ear pain, right-sided facial droop, and right knee pain with swelling. Review of systems is positive for hyperacusis, right facial paresthesia, and the loss of taste sensation on the right side of his tongue. Physical examination reveals unilateral paralysis of the right upper and lower facial muscles, consistent with Bell’s palsy. The right knee is swollen, warm, and ballotable.
Dr. Jimenez learns that Mr. Gray did not fill the initial antibiotic prescription and suspects he has early disseminated (stage 2) Lyme disease. Dr. Jimenez advises Mr. Gray that long-term sequelae may ensue in cases of inadequately treated Lyme disease. He recommends blood work to confirm the diagnosis. He then prescribes an extended 28-day course of doxycycline. To manage Bell’s palsy optimally, he recommends Mr. Gray avoid corneal drying by using artificial tears during the day and patching the right eye at night.
500
Complications of Lyme Disease & Post-treatment Lyme disease syndrome (PTLDS)
1. Erythema Migrans
2. Neuroborreliosis
3. Lyme Carditis
4. Lyme Arthritis
5. Post-treatment Lyme disease syndrome (PTLDS)
500
Doxycycline drug classification, mechanism of action, route of elimination, spectrum, adverse effects, contraindications, and mechanism of resistance.
Classification: Antibiotic ->Tetracycline -> Doxycycline
Mechanism of Action
- Bind 30S subunit → aminoacyl-tRNA is blocked from binding to ribosome acceptor site → inhibition of bacterial protein synthesis (bacteriostatic effect)
Route of Elimination
- Only gastrointestinal elimination (doxycycline is the only tetracycline that is not contraindicated in patients with renal failure)
Spectrum
- Bacteria that lack a cell wall (e.g, Mycoplasma pneumoniae, Ureaplasma)
- Intracellular bacteria, such as Rickettsia, Chlamydia, or Anaplasma (tetracyclines accumulate intracellularly and are, therefore, effective against intracellular pathogens)
- Borrelia burgdorferi
- Other: Ehrlichia, Vibrio cholerae, Francisella tularensis
- Cutibacterium acnes (topical tetracycline is used to treat acne)
- Community-acquired MRSA
Special considerations
- Oral tetracyclines should not be taken with substances that contain large amounts of Ca2+, Mg2+, or Fe2+ (e.g., milk, antacids, iron supplements, respectively) because divalent cations inhibit the intestinal absorption of tetracyclines.
- CNS penetration is limited
Adverse effects
- Hepatotoxicity
- Deposition in bones and teeth → inhibition of bone growth (in children) and discoloration of teeth
- Damage to mucous membranes (e.g., esophagitis, GI upset)
- Photosensitivity: drug or metabolite in the skin absorbs UV radiation → photochemical reaction → formation of free radicals → damage to cellular components → inflammation (sunburn-like)
- Degraded tetracyclines are associated with Fanconi syndrome.
- Rarely: pseudotumor cerebri
Contraindications
- Pregnant women
- Breastfeeding women
- Cautious use in patients with hepatic dysfunction
Mechanisms of resistance
Plasmid-encoded transport pumps increase efflux out of the bacterial cell and decrease uptake of tetracyclines
500
Mr. Gray follows up in the office several weeks later and confirms that he completed the full course of antibiotics and has resolution of the initial signs and symptoms; however, he continues to experience persistent, mild fatigue.
Next Steps?