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Microbiology - Lecture 24 - Spirochetes

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What are spirochetes?
Motile, spiral-shaped bacteria.
What are the 3 genera of spirochetes that cause human infections?
1. Treponema causes syphilis.

2. Borrelia causes Lyme disease and relapsing fever.

3. Leptospira causes leptospirosis.
What is the main pathogen of Treponema?
Treponema pallidum is the main pathogen and the cause of syphilis.
How does T. pallidum grown in lab and in humans?
Treponema pallidum cannot be grown on media or in cell culture.

Grows very slowly in humans
-Antibiotics have to be present for several weeks to kill the bacterium.
What is the pathogenesis of T. pallidum?
Infects endothelium of small blood vessels: causes endarteritis.

In response to a Treponema pallidum infection, the body makes specific antibodies against treponemal antigens as well as non-specific antibodies (called reagin antibodies).
What is the epidemiology of T. pallidum?
Increasing incidence
-Especially in MSM (men who have sex with men).

Transmitted by sexual contact.

Lesions on skin and mucous membranes (genitalia, mouth, rectum) contain heavy load of organisms.

Can also be transmitted from pregnant woman to fetus.
What are the main stages of Syphilis?
Syphilis is a chronic infection marked by different stages.

Early syphilis: stages of syphilis that occur within the first year of infection.
-Primary, secondary and early latent syphilis.

Late syphilis: stages after early syphilis
-Late latent syphilis, tertiary syphilis and neurosyphilis.
Describe primary syphilis.
Primary syphilis: Painless ulcer (chancre) at site of inoculation.
-Usually located on genitalia
-Occurs several weeks after exposure
-Chancre is very infectious
-Heals spontaneously (patients often don't seek medical attention)!!!
-But organism has spread hematogenously already
Describe secondary syphilis. What happens if untreated?
Secondary syphilis:
-Weeks to months after primary syphilis
-Marked systemic symptoms: malaise, fever, headache.
-Maculopapular rash on body (characteristic feature is rash on palms and soles).
-Condylomata lata (moist genital lesions - highly infectious because of high load of organisms)
-Also resolves spontaneously!!!

If untreated:
1/3 will be spontaneously cured
1/3 will progress to latent syphilis
1/3 will progress to tertiary syphilis
Describe latent syphilis.
Latent syphilis: asymptomatic infection with normal physical exam but positive serology.

Early latent syphilis:
-Within 1 year of infection
-Can have recurrences of secondary syphilis symptoms (infectious at the time)

Late latent syphilis:
> 1 year of infection
-Lasts for many years
-Asymptomatic and not infectious
-If duration is unknown, treat as late latent syphilis.
Why is it important to distinguish between early syphilis and late latent syphilis?
Contact tracing is focused on patients with early syphilis.
-Transmission is unlikely with late latent syphilis.

Longer duration of treatment for late latent syphilis.
Describe tertiary syphilis.
Gummas: granulomas of skin and bones

Cardiovascular: aortitis, aneurysm of ascending aorta.
Describe neurosyphilis.
Neurosyphilis: CNS involvement
-Most common manifestation of late syphilis
-Grand paresis is a progressive dementia
-Tabes dorsalis (a slow degeneration, demyelination, of the sensory neurons that carry afferent information) manifests as ataxia, stabbing pain and pupillary abnormalities.
Pro Tip
Spirochetes are rarely seen in tertiary syphilis or neurosyphilis
Describe congenital syphilis.
Transmitted across placenta

Skin and bones involved

Often results in stillbirth or multiple fetal abnormalities
What is the differential?

Patent was seen by you in the student health center
21 year old undergraduate with fever, malaise and maculopapular rash
3 weeks ago had a painless ulcer on his penis that resolved without any treatment
Secondary syphilis
What are microscopic diagnostic tests for T. pallidum?
1. Darkfield microscopy
-Easily visualize motile spirochetes in chancres and condylomata lata.


2. Direct fluorescent antibody (DFA)
What are serological diagnostic tests for T. pallidum?
Serology is used as the main diagnostic test.

Nontreponemal serologic tests detect antibodies against nontreponemal antigens (e.g. cardiolipin)
-Nonspecific but used for initial screening because they are inexpensive

Treponemal serologic tests detect antibodies against T. pallidum antigens
-Generally used to confirm infection, i.e. that the nontreponemal serologic test was not a false positive

These tests are complementary.
Describe nontreponemal serologic tests.
Different tests are used in different hospitals.
-VDRL (Venereal Disease Research Lab)
-RPR (rapid plasma reagin)

Positive for primary and secondary syphilis

Titer reflects activity of the infection

Become negative after treatment: used to determine response to treatment

Disadvantages:
Can have false positive result (other acute infection or chronic disease such as autoimmune disorder) and so need to confirm with specific treponemal tests
Can have false negative result due to prozone effect: antibody titer is too high and won't get positive result until the serum is diluted

Advantages:
Inexpensive and easy to perform
Describe treponemal serologic tests.
Different tests are used in different hospitals.
-FTA-ABS (fluorescent treponemal antibody absorption)
-TPHA
-MHA-TP

Positive within 2-3 weeks of infection

Test remains positive for life even after treatment.
-Cannot use to determine response to treatment.

Disadvantages:
-More expensive and more difficult to perform than nontreponemal serologic tests.

Advantages:
-More specific because they detect antibodies against treponemal antigens.
What is the treatment for T. pallidum?
Penicillin is effective against all stages of syphilis.
-Single dose of 2.4 million units of benzathine penicillin IM cures early syphilis (long-acting form of penicillin)
-3 doses a week apart for late latent syphilis (and syphilis of unknown duration) and tertiary syphilis.

Treat neurosyphilis with iv aqueous penicillin G.
-Benzathine penicillin penetrates poorly into CNS.
What reaction do you get with T. pallidum treatment?
Jarisch-Herxheimer reaction: fever, chills and myalgia in patient with early syphilis a few hours after being treated with penicillin.
-Lysis of treponemes and release of endotoxin.
How can you prevent T. pallidum?
Condoms

Treat infected individuals to reduce transmission
-Contact tracing

Test for syphilis if patient has an STD

No vaccine
What are nonvenereal treponemes?
Rarely seen in U.S.

Endemic in many parts of the world

Cause diseases such bejel (Africa), yaws (humid tropical countries), pinta (Central and South America)

Transmitted by direct contact

Produce positive treponemal and nontreponemal serologic tests

Treat with penicillin.

Note: Venereal means that has to do with sexual intercourse.
What are the two species of Borrelia that affect humans?
Genus of spirochetes that causes 2 main vector-borne diseases.

-Borrelia burgdorferi causes Lyme disease.

-Borrelia recurrentis and Borrelia hermsii cause relapsing fever.
How do you microscopically visualize Borrelia?
Darkfield microscopy
-Visualize motile spirochetes

Stain with Giemsa or silver stain
What is the pathogenesis of Borrelia burgdorferi ?
Tick bite -> organism spreads through skin -> hematogenous spread to other organs (heart, joints, CNS).
What is the epidemiology of Borrelia burgdorferi ?
Lyme disease is named after Lyme, CT where the original cluster was described

Also called Lyme borelliosis

Most common vector-borne disease in U.S.
20,000 cases of Lyme disease are reported to the CDC each year
-The actual number is thought to be much less because of misdiagnosis.
Describe transmission for Borrelia burgdorferi ?
Transmitted by tick bite: hard ticks
-Ixodes scapularis (can also transmit human granulocytic ehrlichiosis and babesiosis)
-Ixodes pacificus is the vector on the West Coast

Lower incidence in West Coast is because a much lower percentage of Ixodes pacificus ticks are infected.

Animal reservoir: small mammals
-White-footed mouse
-Deer are part of the tick's life-cycle but not an important reservoir for B. burgdorferi

Transmission mainly occurs in the summer
-Greater exposure because people are outdoors
-Nymphs mainly feed in the summer

Organism transmitted by tick bite
-Requires 24-48 hours to transmit an infectious dose

Ixodes scapularis can also transmit human granulocytic ehrlichiosis and babesiosis
-Patient can have more than one infection
What stage of the tick is involved in transmission?
Transmission is by the nymphal stage of the tick.

Larvae and adult stages not important for transmission.

Stages: Nymph -> Larva -> Adult
What is the clinical theme for Lyme disease?
Like syphilis, 3 stages of Lyme disease have been described but the stages are not discrete.
Describe stage 1 of Lyme disease.
Stage 1: Erythema chronicum migrans.

-Appears 3-30 days after tick bite.
-Painless, erythematous macular rash with central clearing: looks like "bull's eye."
-Expands and gets very large.
-May have nonspecific symptoms: fever, chills, fatigue, headache.
Describe stage 2 of Lyme disease.
Stage 2

Cardiac involvement
-Myocarditis and heart block.

Neurologic involvement
-Bilateral Bell's palsy (facial nerve palsy) is highly suggestive of Lyme disease.
Describe stage 3 of Lyme disease.
Stage 3

Chronic arthritis of large joints.
What is the differential?

Patient has had painless erythematous maculopapular rash for a week that has been spreading
Remembers finding ticks on his body when he went camping 2 weeks ago
Lyme Disease

Erythema chronicum migrans
What are the diagnostic tests for B. burgdorferi?
Serologic tests: IgG and IgM
-ELISA
-Confirm positive ELISA with western blot.

Routine cultures from patients are usually negative and so are not done.
What is the treatment for B. burgdorferi?
Treat Stage 1 infection with doxycycline or amoxicillin.

Treat severe or later stage with ceftriaxone.
What to do if you have a tick bite?
Depends on percentage of ticks that are infected with Borrelia burgdorferi and length of time that the tick has fed.

Can wait to see if rash develops and then treat.

Only consider prophylactic antibiotics before skin rash appears if the area has a high percentage of infected ticks and the tick has been on the body for a long time (> 48 hours).

Lyme disease vaccine was developed but is no longer commercially available.
What do Borrelia recurrentis and Borrelia hermsii cause? What is the mechanism of the disease?
Cause relapsing fever: recurrent episodes of fever, chills headache separated by 1-2 weeks.
-Patient is afebrile and feels fine between episodes.

Relapses are due to antigenic variation
-Bacteremia with a different subtype that is antigenically distinct and not neutralized by antibodies produced during prior episodes.
-Induces antibody response that then controls the bacteremia leading to transient recovery until the next relapse.

Can have several relapses.
How are Borrelia recurrentis and Borrelia hermsii transmitted?
Borrelia recurrentis is transmitted by the human body louse, and humans are the reservoir.

Borrelia hermsii is transmitted by soft ticks, and rodents are the main reservoir.
How do you diagnose and treat Borrelia recurrentis and Borrelia hermsii?
Diagnosis: Large spirochetes in stained peripheral blood smears.

Treat with tetracycline.
What is the differential?

Patient in the Emergency Department
2-day history of fever, chills and headache
Had similar episode a week ago that resolved without treatment
Patient recently went camping in the Sierras and stayed in a log cabin that had a nest of rats beneath it
Relapsing fever
What does Leptospira interrogans cause? How is it transmitted?
Causes leptospirosis.

Transmission is by exposure to animal urine, which contaminates water and soil.
-Swimming in or drinking contaminated water.

Dogs are main reservoir in U.S.

Rats and other rodents

Outbreaks in triathlons and adventure racing.
What is the pathogenesis of Leptospira interrogans?
Organism enter body by ingestion or passing through mucous membranes and skin -> hematogenous spread to other organs.

Biphasic illnes:

-Initially fever, chills, severe headache and conjunctival suffusion (conjunctival reddening), which resolves

-Aseptic meningitis, jaundice and renal failure
How do you diagnose and treat Leptospira interrogans?
Diagnose by serology

Treat with penicillin G
Spirochetes Summary
Spiral-shaped bacteria

3 genera cause human infections

Treponema causes syphilis, a classic disease with multiple stages

Borrelia causes Lyme disease and relapsing fever, which are vector-borne infections

Leptospira causes leptospirosis, which is associated with contaminated water in the outdoors
Concepts: 1. Transmission
Human-to-human
-Treponema pallidum

Via an arthopod vector
-Borrelia burgdorferi (hard ticks), B. hermsii (soft ticks), B. recurrentis (body louse)

Ingestion or contact with animal urine
-Leptospira
Concepts: 2. Site and course of infection
Generally have hematogenous dissemination from initial site of entry

Often have multiple stages of infection
Concepts: 3. Diagnosis
Difficult to grow organism in the Micro lab

Usually diagnose by serologic test
Concepts: 4. Treatment
Spirochetes can generally be treated with penicillin.

Antibiotic resistance has not been an issue.
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