Spirochetes — Syphilis, Lyme Disease and Leptospirosis

• ***Treponema pallidum* — syphilis**, sexually transmitted and vertically transmissible.
• Primary: a painless, indurated chancre with clean base.
• Secondary: diffuse maculopapular rash characteristically involving palms and soles, condylomata lata, lymphadenopathy.
• Latent, then tertiary: gummas, aortitis of the ascending aorta from vasa vasorum endarteritis, and neurosyphilis (tabes dorsalis, general paresis, Argyll Robertson pupil).
• Congenital: snuffles, saddle nose, Hutchinson teeth, saber shins, interstitial keratitis.
• Testing: non-treponemal (RPR/VDRL) for screening and treatment monitoring — falsely positive in pregnancy, SLE and antiphospholipid syndrome — confirmed by treponemal tests, which stay positive for life. Penicillin is the treatment at every stage, with desensitisation in pregnancy rather than substitution.
• Jarisch–Herxheimer reaction: fever and rigors hours after treatment, from cytokine release as organisms are killed.
• ***Borrelia burgdorferi* — Lyme disease**, transmitted by Ixodes ticks. Erythema migrans, then carditis with AV block and facial nerve palsy, then late arthritis.
• Leptospira — water contaminated with animal urine; conjunctival suffusion, myalgia, and Weil disease with jaundice and renal failure.

Shared features

• Structure: thin, helical, Gram-negative-type double membrane with endoflagella (axial filaments) in the periplasmic space, producing the characteristic corkscrew/flexing motility. Diameter is below the resolution of light microscopy with routine stains, which is why Gram stain is useless and darkfield or immunofluorescence is used instead.

Treponema pallidum

• Culture: cannot be grown on standard artificial media — an obligate human pathogen propagated historically only in rabbit testes. This is why diagnosis is serologic.
• Visualization: darkfield microscopy of chancre or condyloma lata exudate; silver stains (Warthin–Starry, Steiner) or direct immunofluorescence/PCR on tissue.
• Virulence: a "stealth pathogen" — an outer membrane nearly devoid of surface-exposed proteins, so little antigen is available for antibody; antigenic variation of the TprK protein allows persistence; host fibronectin coating and hyaluronidase aid tissue invasion. Notably lacks classic LPS endotoxin.

Borrelia burgdorferi

• Size: the largest spirochete — wide enough to be seen with Giemsa/Wright stain (a point tested more often for relapsing-fever Borrelia, whose spirochetemia is visible on peripheral smear).
• Culture: microaerophilic, fastidious, grows slowly in Barbour–Stoenner–Kelly medium; not done clinically.
• Virulence: OspA (expressed in the tick midgut) and OspC (upregulated during the blood meal, required for mammalian infection); VlsE antigenic variation drives immune evasion and is the antigen behind the C6 peptide assay. No LPS; inflammation is driven by lipoproteins acting on TLR2.

Leptospira interrogans

• Morphology: obligate aerobe with tightly coiled spirals and hooked ends — the classic question-mark shape on darkfield.
• Culture: the one spirochete routinely cultivable in the lab, on Ellinghausen–McCullough–Johnson–Harris (EMJH) medium, but growth takes weeks.
• Virulence: possesses LPS (unlike the other two), plus hemolysins and sphingomyelinases; motility permits penetration of intact mucosa and abraded skin.

Syphilis — obliterative endarteritis is the unifying lesion

• Spirochetes penetrate intact mucosa or microabrasions, multiply locally, and provoke a plasma-cell–rich perivascular infiltrate with endothelial proliferation of small arterioles. Ischemia at the center of that infiltrate produces the ulcerated, painless indurated chancre; the lesion heals because local immunity contains it, but the organism has already disseminated hematogenously.
• Secondary syphilis is the systemic immune-complex and bacteremic phase — hence a rash that follows blood supply everywhere, including palms and soles, and generalized lymphadenopathy.
• Tertiary disease reflects two mechanisms: delayed-type hypersensitivity granulomas (gummas) and endarteritis of the vasa vasorum of the ascending aorta, which infarcts the media, destroys elastic tissue, and yields aneurysm, aortic regurgitation, and tree-bark intimal wrinkling. The same endarteritis in the posterior columns and dorsal roots explains tabes dorsalis.

Lyme disease — stage follows organism location

• Ixodes nymphs must feed roughly a day and a half before OspC-expressing spirochetes migrate from midgut to salivary gland; this attachment-duration requirement is the basis of prophylaxis rules.
• Outward radial migration through dermis produces erythema migrans with central clearing; hematogenous spread seeds the heart (spirochetal infiltration around the AV node → AV block), cranial nerves (facial palsy, often bilateral), and joints.
• Late arthritis is largely immune-mediated rather than bacterial burden–driven; antibiotic-refractory arthritis associates with certain HLA-DR alleles.

Leptospirosis — biphasic vasculitis

• Entry through skin/mucosa after contact with animal urine–contaminated water, then a septicemic phase with widespread endothelial injury and capillary leak.
• The immune phase brings conjunctival suffusion, aseptic meningitis, and leptospiruria. In Weil disease, jaundice arises largely from impaired hepatocyte bilirubin transport rather than necrosis (transaminases only mildly up), while renal failure reflects tubulointerstitial injury with characteristic potassium wasting and pulmonary hemorrhage reflects alveolar capillary damage.

Syphilis (risk: unprotected sex, MSM, HIV coinfection, untreated pregnancy)

• Primary: solitary painless chancre with a clean base and indurated edge, appearing weeks after exposure and resolving spontaneously. Contrast with the painful, purulent, ragged ulcer of chancroid.
• Secondary: weeks to months later — copper-colored maculopapular rash on palms and soles, moist wart-like condylomata lata, mucous patches, patchy "moth-eaten" alopecia, fever, and generalized lymphadenopathy.
• Neurosyphilis may occur at any stage; early forms are meningitis, stroke from meningovascular arteritis, and ocular or otic syphilis (uveitis, sudden hearing loss). Late forms are tabes dorsalis with sensory ataxia and lancinating pains, general paresis, and the Argyll Robertson pupil (accommodates but does not react).
• Congenital: hemorrhagic snuffles, hepatosplenomegaly, and desquamating rash early; Hutchinson triad (notched incisors, interstitial keratitis, sensorineural deafness), saddle nose, and saber shins late.

Lyme disease (risk: Northeast/upper Midwest US, spring–summer outdoor exposure)

• Early localized: expanding erythema migrans, typically nonpruritic with central clearing, plus flu-like symptoms — importantly without prominent upper respiratory signs.
• Early disseminated: multiple secondary EM lesions, cranial neuropathy (facial palsy, sometimes bilateral), lymphocytic meningitis, painful radiculoneuritis, and Lyme carditis with fluctuating high-degree AV block in a young patient.
• Late: monoarticular or oligoarticular arthritis of the knee with large effusion and surprisingly modest pain.
• Consider Babesia and Anaplasma coinfection (same tick vector) when hemolysis, severe cytopenias, or morulae are present.

Leptospirosis (risk: tropical exposure, flooding, triathletes, sewer/abattoir/rice-field workers, homeless populations, rodent contact)

• Anicteric: abrupt fever, severe calf and lumbar myalgia, headache, and conjunctival suffusion without exudate — the single most suggestive sign.
• Weil disease: jaundice, acute kidney injury, hemorrhage, and pulmonary hemorrhage syndrome; mortality is substantial.

Syphilis

• Direct detection: darkfield microscopy or PCR of chancre exudate is diagnostic when a lesion is present; a negative study never excludes syphilis.
• Traditional algorithm: nontreponemal screen (RPR/VDRL, antibody to cardiolipin) → confirm with a treponemal test (FTA-ABS, TP-PA, EIA/CIA). CDC also endorses the reverse-sequence algorithm: treponemal immunoassay first, then RPR; if discordant, adjudicate with TP-PA.
• Pitfalls: biologic false-positive RPR in pregnancy, SLE/antiphospholipid syndrome, viral infection, and IV drug use. The prozone phenomenon — antibody excess in secondary syphilis or HIV causing a falsely negative undiluted RPR — is corrected by diluting the serum.
• Response to therapy is defined by a fourfold (two-dilution) fall in RPR titer; treponemal tests stay positive for life and cannot be used for follow-up. Persistently low stable titers define the serofast state.
• Neurosyphilis: lumbar puncture shows lymphocytic pleocytosis and elevated protein. CSF-VDRL is highly specific but insensitive; a negative CSF-VDRL does not exclude it, whereas a negative CSF FTA-ABS argues strongly against it.
• Screening in pregnancy at the first prenatal visit is recommended by USPSTF and CDC.

Lyme disease

• Erythema migrans in an endemic area is a clinical diagnosis — treat, do not serologize (antibodies are often not yet formed).
• Otherwise use CDC/IDSA two-tier serology: an EIA followed by IgM/IgG immunoblot, or the accepted modified two-tier approach using two sequential EIAs. IgM blots are unreliable beyond about a month of illness and are a classic overcall.
• Synovial fluid PCR supports Lyme arthritis; ECG is mandatory when carditis is suspected.

Leptospirosis

• Blood/CSF culture and PCR are highest yield in the first week; urine culture later.
• Microscopic agglutination test (MAT) is the reference standard, requiring paired acute and convalescent sera.
• Labs classically show jaundice with only mildly elevated transaminases, elevated CK, and AKI with hypokalemia.

Syphilis — penicillin at every stage (CDC STI Treatment Guidelines, 2021)

• Primary, secondary, early latent: benzathine penicillin G 2.4 million units IM as a single dose.
• Late latent or latent of unknown duration: benzathine penicillin G 2.4 million units IM weekly for three weeks.
• Neurosyphilis, ocular or otic syphilis: aqueous crystalline penicillin G IV for 10–14 days — benzathine penicillin does not achieve CSF levels and is the classic wrong answer here.
• Penicillin allergy: doxycycline (a tetracycline) is the alternative in nonpregnant adults with early syphilis. In pregnancy there is no acceptable substitute — perform penicillin desensitization, since only penicillin reliably treats the fetus. Doxycycline is contraindicated in pregnancy.
• Congenital syphilis: aqueous crystalline or procaine penicillin G.
• No clinically meaningful penicillin resistance exists in T. pallidum; macrolide resistance is widespread, so azithromycin is not recommended.
• Warn patients about the Jarisch–Herxheimer reaction — fever, rigors, and myalgia within hours of the first dose from lipoprotein-driven cytokine release. It is not an allergy; manage supportively with antipyretics and continue therapy.

Lyme disease (IDSA/AAN/ACR 2020)

• Early localized/early disseminated without severe features: oral doxycycline preferred (also covers Anaplasma); amoxicillin or cefuroxime axetil are alternatives, and are preferred in pregnancy.
• Lyme carditis with high-grade AV block or symptomatic patients: admit, monitor, and give IV ceftriaxone, transitioning to oral therapy; block is usually reversible, so permanent pacing is rarely needed — temporary pacing suffices.
• Lyme arthritis: a month of oral doxycycline; Lyme meningitis/radiculopathy: oral doxycycline or IV ceftriaxone.
• Prophylaxis: a single 200 mg dose of doxycycline within 72 hours of removing an identified engorged Ixodes tick in a highly endemic area. Prolonged antibiotics for "chronic Lyme"/post-treatment Lyme disease syndrome are explicitly not recommended. No human vaccine is currently marketed in the US.

Leptospirosis

• Mild: oral doxycycline (or azithromycin/amoxicillin).
• Severe/Weil disease: IV penicillin G or ceftriaxone, plus dialysis as needed. Weekly doxycycline chemoprophylaxis is used for short high-risk exposures; the human vaccine is not available in the US.

• Painless versus painful genital ulcer: syphilitic chancre is painless and indurated with a clean base; H. ducreyi chancroid is painful with a purulent, ragged base ("you do cry with du-creyi"). This is the most frequently tested discriminator.
• Rash on palms and soles narrows to secondary syphilis, Rocky Mountain spotted fever, and coxsackievirus hand-foot-and-mouth. Add condylomata lata and the answer is syphilis — do not confuse it with the cauliflower condyloma acuminatum of HPV.
• Negative RPR in a patient who clearly has secondary syphilis = prozone phenomenon; the next step is to dilute the serum, not to abandon the diagnosis.
• Neurosyphilis needs IV aqueous penicillin G, never IM benzathine. Any new uveitis or sudden sensorineural hearing loss in a syphilis patient is treated as neurosyphilis with a lumbar puncture.
• Pregnant and penicillin-allergic = desensitize. Doxycycline is the trap answer; it fails the fetus and is contraindicated in pregnancy.
• Fever and rigors a few hours after the first penicillin dose is Jarisch–Herxheimer, not anaphylaxis and not treatment failure — do not stop the drug.
• Treponemal tests stay positive for life; only the RPR/VDRL titer tracks cure (a fourfold drop). A positive FTA-ABS in a treated patient does not mean relapse.
• Erythema migrans in an endemic area → treat empirically with doxycycline. Serology is the distractor because it is often negative this early. Young adult with syncope and third-degree AV block after summer camping → Lyme carditis, IV ceftriaxone and temporary pacing, not a permanent pacemaker.
• Conjunctival suffusion without discharge plus severe calf myalgia after floodwater or triathlon exposure = leptospirosis; jaundice with disproportionately mild transaminase elevation, AKI, and hypokalemia points to Weil disease.