Borellia burgdorferi�THE BODY SYSTEM

Shruti Swami

Case Study

Suzanne is a 24-year-old avid hiker and excited to visit her friends in Halifax for some hiking in some new scenery. When she arrived on the plane from Vancouver, it was a sunny spring day in Halifax and her friends wanted to show her a great view of the city. Her friends picked her up at the airport and they headed to the nearby Admiral’s Cove for a scenic hike to the top of a ridge overlooking the Halifax Harbour. That evening they had a wonderful night out visiting multiple local craft breweries and tasting east coast lobster. The next morning Suzanne noticed a non-painful bump on the back of her calf, but she was on the way out with friends for another hike, so she did not pay much attention to it. On the hike, as Suzanne was climbing up a steep area, one of Suzanne’s friends behind her noticed the back of Suzanne’s leg and asked to look at it. It was a tick, and it had embedded its head into the back of Suzanne’s leg. Her friend removed the tick and they carried on. Over the next few days, Suzanne developed a ring-like red rash at the site of the tick bite. The rash was hot to the touch and felt like it was burning. Suzanne felt chills and fatigued. Knowing that Lyme disease was in the area, her friend took Suzanne to an Urgent Care Centre (UCC) for assessment. At the UCC, Suzanne head a temperature of 38.0 degrees Celsius, a white blood cell count of 14, and the physician examining her said her rash was a classic “bull’s eye” rash caused by Borrelia burgdorferi and prescribed her antibiotics for erythema migrans.

Background

• Lyme disease is caused by Borrelia burgdorferi, a spirochete bacteria.
• Vector for Lyme disease → hard-bodied tics such as:
• western black-legged tick (Ixodes pacificus)
• deer tick/black legged tick (Ixodes scapularis)

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• Tics transmit the bacteria by biting and attachment to the host’s skin → the bacteria enters the host by transmission of tick’s saliva through the attachment site.
• Black-legged ticks are found in Nova Scotia → area that Suzanna went for a hike.

Figure 1 derived from: Levy, S. (2017). Northern Trek: The Spread of Ixodes scapularis into Canada. Environmental Health Perspectives, 125(7), 074002. https://doi.org/10.1289/ehp2095

Figure 1. Ixodes scapularis do not fly or jump on hosts, they perch on vegetation and attach to hosts as they brush by for a blood meal.

Question (I): ��Describe the signs and symptoms presented in the case. ��Are there any other signs or symptoms that could have been commented on but are not presented in the case? ��What are the key history of presenting illness elements presented? ��What laboratory samples are taken and why? ��What are the meanings of the laboratory results reported?

Signs Present

• The non-painful bump on the back of Suzanna’s calf.
• The “bull’s eye” rash which developed over 1-2 days at the site of tick bite.
• Bull’s eye rash → a skin lesion → called erythema migrans (EM) → most common sign indicating Lyme disease.
• The area with the rash was hot to the touch.
• Suzanna developed a fever → head temperature of 38℃

Symptoms Present

• Chills
• Fatigue
• Burning sensation at the rash site

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Signs and Symptoms Not Present

• Influenza-like symptoms
• Headache
• body aches
• neck stiffness
• sore throat
• swollen lymph nodes
• Malaise
• Regional lymphadenopathy

History of Present Illness [HPI]

• HPI → information necessary to generate a differential diagnosis.
• Suzanne’s key history findings:
• Recently bitten by a tick
• Suzanne was recently on a hike around Admiral’s Cove, Halifax 🡪 increasing probability of encountering ticks
• Ticks → the second most common vector of human disease → tick at the site of the rash can explain Suzanne's illness → likely caused by a tick-borne pathogen.

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Laboratory Samples

• Suzanne’s Blood Sample indicated:
• Higher (14,000) than normal white blood cell [WBC] count (11,000) → indicating infection presence that has mounted an immune response.
• To confirm that Suzanne has Lyme disease:
• blood can be tested for antibodies by enzyme-linked immunosorbent assay (ELISA)
• If ELISA test is indeterminate or positive 🡪 Western blot can be used to confirm diagnosis.
• Skin biopsy from the EM skin lesion and culture it in a BSK medium can confirm that Borrelia burgdorferi is the causative agent

Question (II): ��Fever and rash are two features in this case. How did the fever and the rash come about after exposure to the bacteria? ��In what way has the normal physiological functioning of this body system been disturbed by the infection (specifically looking at the physiological changes without detailing the bacterial mechanism of this disturbance as that is the basis of another question). Representing this diagrammatically is helpful to demonstrate understanding.

RASH

• Erythema migrans (EM)
• A skin rash that develops at the site of the tick bite
• Incubation period of approximately 7-14 days
• The rash resembles a bull's eye or a target, ranging 5-70cm diameter.
• Typically starts off as a red macule which continues to expand, forming a large, annular, erythematous lesion🡪 contains a central clearing.
• Can be asymptomatic but can be painful or pruritic.
• Inflammation caused by host’s innate immune response:
• Immune cells of the host release inflammatory mediators, such as bradykinin and histamine 🡪 vasodilators that cause redness, swelling, heat and influx of immune cells in the target area.
• B. burgdorferi replicates at the site of infection → grow at 1-4 um/second → increases redness of the rash

https://www.biotek.com/images/applications/ELISA20.jpg

FEVER

• Possibly a side effect → severe inflammation
• B. burgdorferi activates TLR1/2 homodimers → initiates a signaling pathway of recruiting other immune cells to the site of infection, releasing pro-inflammatory cytokines: IL-6, IL-12, TNF-α and pro-IL-1β → induce higher body temperature
• Triggered by the production of endogenous pyrogens →  IL-1 and IL-6
•  It is the host’s method of increasing rate of metabolism as there is an increase in energy requirements.

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Disruption of Normal Physiology

• Tick bite breaks the skin barrier and transmits the bacteria through the epidermis
• When bacterium is ready to spread → it will initiate the EM rash disrupting extracellular matrix → enter the lymphatic system and blood → to spread to organs or other skin sites.
• Blood tests may not detect Borrelia burgdorferi → as it spreads through the lymphatic system, does not circulate in blood.
• Spread to tissues, organs, joints, heart, brain and bladder.
• This could result in reactive arthritis or atypical rheumatoid arthritis in adults.
• Lyme disease can invade the central nervous system(CNS).
• penetrate Blood Brain Barrier (BBB) using plasminogen
• gain access into the CSF and inflame the meninges
• affect the nerves in the face → bell’s palsy, bacteria can burrow in the spinal cord / brain → more sever Lyme disease.
• The bacteria can lead to abnormal electrical signals in the heart → “heart block” →leading to Lyme carditis.

Question (III): ��What antibiotics might have been given:

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• What are antibacterial treatments,

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• how do these antibiotics work to help the body clear the organism)? Representing this diagrammatically is helpful to demonstrate understanding.

Doxycycline

Mechanism of Action:

• Is an antimicrobial agent → targeting elongation:
• Reversibly binds to 30s ribosomal unit of bacterium→ inhibiting the pathogen’s protein synthesis.
• Binds to the pathogen’s 70S ribosome → inhibiting protein synthesis in the mitochondria.
• Anti-inflammatory and anti-neoplastic:
• Inhibits certain matric metalloproteases (MMPs) → proteolytic enzymes produced by inflammatory immune cells
• Tetracyclines
• inhibit the p38 MAPK and NFκB pathways→ control expression of pro-inflammatory mediators
• inhibition of caspase-1 and caspase-3 activity → reduced cell death and inflammation.
• Doxycycline significantly reduces the release of TNF-alpha, IL-6, and IL-8, IL-1, and IFN-alpha and beta → reduced cell death and inflammation.

• First-choice oral antibiotic → treatment of early disseminated Lyme disease, as well as late Lyme arthritis.
• For patients over the age of eight, not for pregnant women.
• Second generation tetracycline.

Amoxicillin

• Amoxicillin is administered orally → three times a day → for 14-21 days.
• Used to treat infections caused by gram-positive bacteria & a few gram-negative bacteria such as B. burgdorferi.
• Second choice oral antibiotic.

Mechanism of Action:

• Beta-lactam ring → mechanism of bactericidal killing:
1. Binding to penicillin-binding proteins (PBPs) and preventing their catalytic activity by inhibiting transpeptidation
2. Interrupts peptidoglycan (PG) synthesis → activation of autolytic enzymes in the bacterial cell wall
3. Causes lysis of the cell wall and bacterial cell death.

Cefuroxime axetil

Azithromycin

• Third choice oral antibiotic → if patient is allergic to the first two.
• Prescribed orally → twice a day → for 14-21 days.
• Second-generation cephalosporin → targets:
• gram-positive
• and gram-negative bacteria
• Mechanism of Action:
• A beta-lactam
• disrupts PG synthesis by binding to PBPs
• Leads to bacterial cell lysis.
• Similar to amoxicillin.

• Fourth choice oral antibiotic → if patient is allergic to first three.
• Mechanism of Action:
• binds to bacteria’s 50S large ribosomal subunit
• interferes with its assembly + growth of peptide chain.
• Has basic pH → faster penetration of bacterial outer membranes → anti-bacterial to gram-negative bacteria.

Question (IV): ��If Suzanne had not taken antibiotics immediately, what signs and symptoms could develop?

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What additional testing or monitoring could help with diagnosis in more advanced disease?

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Would this stage of the disease be treated differently?

Early Disseminated Disease

• Early disseminated disease → a few days to less than three months after initial infection.
• Multiple secondary erythema migrans lesions, fever, arthralgias, lymphadenopathy and headache
• Musculoskeletal, neurologic and/or cardiovascular manifestations can occur at this stage.

Lyme Carditis

Musculoskeletal & Neurological Manifestations: Early Disseminated Disease

• Neurologic signs → meningitis, radicular neuropathies, and paralysis of the facial cranial nerve.
• Present in 15% of cases
• Neuroborreliosis: disorder of CNS
• With or without aseptic meningitis, cranial nerve involvement.
• Manifests 2 - 8 weeks after erythema migrans.
• Facial Palsy:
• facial weakness and paralysis
• occurs in 10-50% of children and adults → especially in Lyme-disease endemic areas

• Musculoskeletal symptoms → present in 60% of cases
• muscle or migratory joint pain
• with or without joint swelling

Analysis of cerebrospinal fluid (CSF):

• abnormal CSF → elevated white blood cell count (similar to viral meningitis).
• Lyme meningitis→ CSF sample has higher mononuclear cell count
• the patient would experience
• Longer headaches
• Possible cranial nerve involvement
• Reduced incidences of fever

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Treatment:

• Same therapy as early localized disease for adults
• If CNS is involved → choice of three treatments:
• 100-200 mg of doxycycline for 28 days
• IV administration of ceftriaxone (2 g)
• Pen G (4 x106 units) for 14-28 days

Cardiovascular Manifestations: Early Disseminated Disease

• Cardiovascular abnormality:
• Signs found in 8% of infection cases.
• May have temporary atrioventricular blocking at varying degrees.
• 30% of the 8% patients may need temporary pacing → complete heart blocks are rare.
• Lyme carditis:
• Manifests in 10% of patients
• Rarely fatal with effective treatment

Analysis:

• Prolonged PR interval on electrocardiogram
• Lyme carditis without signs of erythema migrans:
• 2-tier serological blood testing is required → starting with ELISA or IFA → followed by reflex Western immunoblot (antibody levels & confirming disease)
• Used to find disease-causing bacteria

Treatment:

• Same treatment as the CNS involvement → IV in case of hospitalization
• Children infected → 30 mg/kg of orally administered antibiotics is provided for 14-21 days:
• amoxicillin,
• penicillin
• or cefuroxime

Late Disseminated Disease

Lyme Arthritis

Lyme Neuroborreliosis

• Lyme disease may progress → late disseminated disease → if patient is untreated or inadequately treated.
• Weeks to months after the initial B. burgdorferi infection
• Seen in 60% of untreated cases

Late Lyme Arthritis

• Present in 60% of untreated Lyme disease cases.
• Manifestation occurs 2 yrs after initial infection
• Swelling and intermittent pain in joints → especially knees and hips
• Synovitis → Synovial inflammation:
• happens to 10% of patients 6 months after Lyme arthritis treatment

Analysis:

Synovial fluid samples for Lyme polymerase chain reaction (PCR) tests :

• used to identify possible re-infection of B. burgdorferi
• research indicate more chances of persistent infection as B. burgdorferi DNA is usually not variable.

Treatment:

Arthrocentesis:

• removal of synovial fluid from the joint capsule
• can provide short-term symptomatic relief in some cases of synovitis

Treating Late Arthritis:

• Doxycycline (100 mg), amoxicillin (500 mg) or cefuroxime (500 mg) prescribed for 28 days → for cases without CNS involvement

Neuroborreliosis : Late Disseminated Disease

• Common in Europe → presents as chronic encephalitis or radiculopathy → Bannwarth’s syndrome
• Europe:
• commonly caused by Ixodes ricinus and Ixodes persulcatus
• chromic encephalomyelitis with spastic paraparesis and cognitive impairment.
• North America
• Subacute encephalopathy with subtle cognitive changes.

Treatment:

• Similar → both North America and Europe
• Infected adults prescribed → ceftriaxone (2 g) or Pen G (4 x106 units) for 14-28 days,
• Children administered → varying pediatric dosing

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Thank You!