Multisystem Processes & Disorders

Lyme disease: stages and treatment

Clinical Overview and When to Suspect Lyme Disease

— Erythema migrans (EM) rash in an endemic region, even without recalled tick exposure (only ~25% recall a bite)

— Summer "viral syndrome" (fever, myalgia, headache, fatigue) in an endemic area

— New unilateral or bilateral facial palsy in summer in an endemic state

— Subacute monoarticular knee arthritis weeks to months after outdoor exposure

— Unexplained AV block (especially high-grade) in a young patient from an endemic area

— Early localized (days–1 month): EM, viral-like symptoms

— Early disseminated (weeks–months): multiple EM, neuroborreliosis (cranial neuritis, meningitis, radiculoneuritis), carditis

— Late (months–years): Lyme arthritis (large joints, especially knee), rare late neuroborreliosis (encephalomyelitis, peripheral neuropathy)

Lyme disease is a tick-borne spirochetal infection caused by Borrelia burgdorferi sensu stricto in the US (and B. mayonii in the upper Midwest), transmitted by Ixodes scapularis (Northeast/Midwest) and I. pacificus (Pacific coast).

Most US cases cluster in the Northeast (Maine to Virginia), upper Midwest (Wisconsin, Minnesota), and northern California — geography is a major pretest probability driver on Step 3.

Peak transmission: late spring through early fall, when nymphal ticks (poppy-seed sized, easily missed) feed. Adult ticks transmit less efficiently because they are noticed and removed.

Transmission typically requires tick attachment ≥36–48 hours; ticks removed earlier rarely transmit infection.

When to suspect Lyme on Step 3:

Three clinical stages structure the entire topic:

Board pearl: EM is a clinical diagnosis in an endemic-area patient — do not order serology before treating; antibodies have not yet seroconverted and a negative test falsely reassures. Treat empirically based on the rash alone.

Co-infections to remember in the same Ixodes vector: anaplasmosis (cytopenias, transaminitis), babesiosis (hemolytic anemia, asplenia risk). Suspect if persistent high fevers despite doxycycline.

Presentation Patterns and Key History

— Erythema migrans: expanding erythematous patch ≥5 cm, often homogeneous (classic "bull's-eye" central clearing occurs in a minority); warm, usually nonpruritic and nonpainful

— Constitutional symptoms: low-grade fever, fatigue, headache, myalgia, regional lymphadenopathy

— Key distinction: A tick-bite hypersensitivity reaction appears within hours, is <5 cm, pruritic, and resolves in 24–48 h — not EM.

— Multiple secondary EM lesions from spirochetemia

— Neuroborreliosis: cranial neuritis (CN VII palsy, often bilateral — a near-pathognomonic clue), lymphocytic meningitis (headache, mild neck stiffness, photophobia), painful radiculoneuritis ("Bannwarth syndrome," more common in Europe)

— Lyme carditis: AV conduction block (often fluctuating between 1°, 2°, and 3°), myopericarditis; presents as syncope, lightheadedness, dyspnea

— Migratory arthralgias without frank arthritis

— Lyme arthritis: intermittent or persistent monoarthritis or oligoarthritis of large joints, especially the knee, with surprisingly large effusions and disproportionately mild pain

— Rare late neuro: subtle encephalopathy, axonal polyneuropathy

— Outdoor activity (hiking, gardening, landscaping, hunting) in endemic area

— Tick removal timing and method

— Travel history including endemic states

— Pets that roam outdoors (carry ticks indoors)

— Prior antibiotic use that may have aborted earlier stages

Stage 1 — Early localized (3–30 days post-bite):

Stage 2 — Early disseminated (weeks to months):

Stage 3 — Late (months to years):

History elements that earn points:

Board pearl: Bilateral facial palsy in an adult is Lyme disease until proven otherwise (other ddx: sarcoidosis, GBS, HIV seroconversion). Order Lyme serology and treat empirically while awaiting results if endemic exposure.

Step 3 management: A patient with EM does not need confirmatory testing — initiate doxycycline at the visit and arrange follow-up in 2–3 weeks to confirm clinical resolution.

Physical Exam Findings and Cardiac Assessment

— Single or multiple EM lesions; measure and mark the border — expansion over days confirms EM versus a static hypersensitivity reaction

— Lesions favor the axilla, groin, popliteal fossa, waistline — warm, moist areas where nymphs attach

— In darker skin tones EM may appear as a dusky or bruise-like patch; do not anchor on "red ring"

— CN VII palsy: complete (forehead involved) lower motor neuron pattern, may be bilateral or sequential; check for hyperacusis (stapedius) and taste (chorda tympani)

— Meningismus: usually mild; Kernig/Brudzinski often absent

— Radiculoneuritis: dermatomal burning pain, often nocturnal, with focal weakness or sensory loss

— Bradycardia, irregular rhythm, cannon A waves (AV dissociation)

— Soft S1 with variable intensity (changing PR interval)

— Pericardial rub (rare)

— Always obtain an ECG in any Lyme patient with palpitations, syncope, dyspnea, or chest pain — Lyme carditis can progress from PR prolongation to complete heart block within hours.

— Orthostatic vitals, continuous telemetry if PR >300 ms or any higher-degree block

— Assess for signs of low cardiac output: cool extremities, narrow pulse pressure, altered mentation

— Echocardiogram if myocarditis suspected (LV dysfunction is usually mild and reversible)

— Large, tense knee effusion with relatively preserved range of motion and modest tenderness — "out of proportion swelling, modest pain"

— Baker cyst formation common; check popliteal fossa

— Synovial fluid: inflammatory (WBC 10,000–25,000, neutrophil predominant)

Skin (early localized/disseminated):

Neurologic exam:

Cardiac exam — Lyme carditis red flags:

Hemodynamic assessment in suspected carditis:

Musculoskeletal exam (late):

CCS pearl: In a CCS case of suspected Lyme carditis, order continuous cardiac monitoring, IV access, ECG, troponin, BNP, and admit before starting IV ceftriaxone — do not discharge a patient with PR >300 ms even if asymptomatic.

Board pearl: Lyme arthritis effusion volume often exceeds what septic arthritis produces, but the patient walks in — septic arthritis patients refuse to bear weight.

Diagnostic Workup — Initial Labs and Serology

— Tier 1: Enzyme immunoassay (EIA) or immunofluorescence assay (IFA) for total Lyme antibodies

— Tier 2 (if Tier 1 positive or equivocal): Western blot — IgM (valid only if symptoms <30 days) and IgG

— Modified two-tier testing (MTTT): Two sequential EIAs (CDC-approved 2019) — faster, similar performance, increasingly used

— IgM positive: ≥2 of 3 specific bands (23, 39, 41 kDa)

— IgG positive: ≥5 of 10 bands

— Key distinction: A positive IgM beyond 1 month of symptoms is likely a false positive — do not treat based on isolated late IgM positivity.

— Carditis suspicion: ECG (PR interval is the single most important parameter), troponin, BNP, basic metabolic panel

— Neuroborreliosis: CBC, CMP; lumbar puncture if meningitis or encephalopathy

— Arthritis: CBC, ESR/CRP (mildly elevated), arthrocentesis to exclude septic/crystal arthritis

— Suspected co-infection: CBC with smear (intra-erythrocytic parasites = babesiosis; morulae in granulocytes = anaplasmosis), LDH, haptoglobin, LFTs

Erythema migrans: No testing required. Diagnosis is clinical; serology is typically negative in the first 1–2 weeks because IgM has not developed. Treat empirically.

Standard two-tier serologic testing (for disseminated or late disease, or atypical rash):

Western blot interpretation:

Adjunctive labs based on syndrome:

Board pearl: Lyme serology remains positive for months to years after successful treatment — do not use repeat serology to assess treatment response or "cure." Use clinical resolution instead. This is a favorite Step 3 trap.

Step 3 management: A patient with arthralgias and a positive Lyme IgG but no objective findings and no endemic exposure most likely has a false positive — do not treat; pursue alternative rheumatologic workup (RF, anti-CCP, ANA).

Avoid: PCR of blood (low yield), urine antigen tests (not validated, not recommended).

Diagnostic Workup — Advanced and Confirmatory Studies

— Lymphocytic pleocytosis (typically 100–200 cells/µL), elevated protein, normal-to-mildly-low glucose

— CSF-to-serum Lyme antibody index >1.0 confirms intrathecal antibody production — gold standard for CNS involvement

— PCR of CSF has low sensitivity (~20%) and is not relied upon

— Inflammatory cell count (10,000–25,000 WBC/µL, neutrophil-predominant)

— Synovial fluid PCR for B. burgdorferi DNA: high specificity, moderate sensitivity — useful when diagnosis is uncertain

— Always exclude crystals and Gram stain to rule out gout/septic arthritis

— ECG with attention to PR interval: PR >300 ms triggers hospitalization regardless of symptoms

— Continuous telemetry; transcutaneous pacer pads at bedside for high-grade block

— Echocardiography: assess for myocarditis, effusion, LV dysfunction

— Cardiac MRI rarely needed but can confirm myocarditis if diagnosis ambiguous

— Lymphocyte transformation test

— Urinary antigen

— "Chronic Lyme" panels from non-CLIA labs

— Repeat serology to document cure

— CD57 subset testing

CSF analysis (neuroborreliosis):

Synovial fluid (Lyme arthritis):

Cardiac imaging and monitoring:

Skin biopsy: Rarely needed for EM; reserved for atypical lesions where diagnosis is unclear. Histology shows perivascular lymphocytic infiltrate; PCR or culture of biopsy can confirm.

Tests to avoid (low-value, common Step 3 distractors):

Board pearl: "Post-treatment Lyme disease syndrome" (PTLDS) is defined by persistent subjective symptoms ≥6 months after documented appropriate treatment, without objective findings or evidence of ongoing infection. Do not prescribe prolonged antibiotics — multiple RCTs show no benefit and significant harm (line infections, C. difficile).

Key distinction: Active Lyme = objective findings + serologic or clinical confirmation → treat. PTLDS = subjective symptoms alone after treatment → supportive care, symptom-directed therapy, address sleep and exercise reconditioning, screen for depression. Do not retreat.

CCS pearl: When ordering LP for suspected Lyme meningitis, simultaneously send serum Lyme antibodies — the index calculation requires both.

Risk Stratification and Management Logic

— Single dose doxycycline 200 mg PO within 72 hours of tick removal if ALL of the following:

— Tick identified as Ixodes scapularis (deer tick)

— Attached ≥36 hours (engorgement or known timing)

— Bite occurred in an area where local Lyme infection rate in ticks is ≥20%

— No contraindication to doxycycline

— Otherwise: observe and educate on EM watch for 30 days

— Oral antibiotics (doxycycline, amoxicillin, cefuroxime axetil) for:

— Early localized disease (EM)

— Early disseminated with isolated cranial neuritis (including Lyme facial palsy without meningitis)

— Lyme arthritis (initial course)

— First-degree AV block with PR <300 ms and no symptoms

— IV antibiotics (ceftriaxone preferred) for:

— Meningitis, encephalitis, radiculoneuritis

— Lyme carditis with PR ≥300 ms, any 2°/3° AV block, or symptoms (syncope, chest pain, dyspnea)

— Persistent or recurrent arthritis after two oral courses

— Late neuroborreliosis

— Outpatient: EM, isolated facial palsy without meningitis, mild arthritis

— Hospital admission with telemetry: any Lyme carditis with PR ≥300 ms, higher-degree block, or symptoms

— Hospital admission: meningitis (until improving on IV therapy, then transition)

Tick bite without rash or symptoms — prophylaxis decision tree:

Treatment route decision — oral vs. IV:

Triage decisions:

Step 3 management: A patient with EM in Connecticut + pregnancy → use amoxicillin 500 mg TID × 10–14 days (doxycycline relatively avoided in pregnancy historically; recent data suggest short courses are likely safe, but boards still favor amoxicillin).

Board pearl: Even patients with high-grade AV block from Lyme carditis usually recover conduction completely with antibiotics — temporary pacing may be needed acutely, but avoid permanent pacemaker placement during active infection; conduction typically normalizes within 1–6 weeks.

Public health: Lyme is a nationally notifiable disease — report confirmed cases to the state health department.

Pharmacotherapy — First-Line Regimens

— Doxycycline 100 mg PO BID × 10 days (preferred — also covers anaplasmosis)

— Amoxicillin 500 mg PO TID × 14 days (pregnancy, children <8, doxycycline allergy)

— Cefuroxime axetil 500 mg PO BID × 14 days (alternative for doxycycline intolerance)

— Azithromycin 500 mg PO daily × 7 days — second-line only (lower efficacy)

— Ceftriaxone 2 g IV daily × 14–21 days

— Alternatives: cefotaxime, IV penicillin G

— Oral doxycycline 100 mg BID × 14–21 days is equally effective for isolated cranial neuritis (e.g., Lyme facial palsy) without meningitis — this is a high-yield update.

— Hospitalized/symptomatic/PR ≥300 ms: Ceftriaxone 2 g IV daily, transition to oral doxycycline 100 mg BID when PR <300 ms and symptoms resolve

— Total course: 14–21 days

— Mild (PR <300 ms, asymptomatic): outpatient oral doxycycline 100 mg BID × 14–21 days with close follow-up

— Doxycycline 100 mg PO BID × 28 days (first course)

— Persistent: second 28-day oral course OR ceftriaxone 2 g IV daily × 2–4 weeks

— "Post-antibiotic Lyme arthritis" (refractory after 2 courses): refer to rheumatology for DMARD therapy (hydroxychloroquine, methotrexate) — immune-mediated, not active infection

Early localized and uncomplicated early disseminated disease (oral):

Updated 2020 IDSA/AAN/ACR guidelines: shorter doxycycline courses (10 days) for EM are equivalent to 14–21 days and are now preferred.

Lyme neuroborreliosis (meningitis, encephalitis, radiculoneuritis):

Lyme carditis:

Lyme arthritis:

Jarisch-Herxheimer reaction: Fever, chills, myalgias within hours of first dose due to spirochete lysis. Self-limited; treat supportively with NSAIDs/acetaminophen. Do not stop antibiotics.

Board pearl: Doxycycline is now considered safe for short courses (≤21 days) in children of any age per AAP — tooth staining risk is minimal with modern formulations. This updates older teaching.

Step 3 management: Counsel doxycycline users on photosensitivity, esophagitis (take with water, upright), and to avoid concurrent antacids/iron/calcium within 2 hours.

Expanded Pharmacology and Co-Infection Management

— Bacteriostatic; inhibits 30S ribosome

— Excellent CNS penetration — basis for oral treatment of isolated Lyme facial palsy

— Not significantly renally adjusted; safe in CKD

— Avoid in pregnancy when alternatives exist; avoid prolonged courses in young children

— Drug interactions: warfarin (potentiates), oral contraceptives (minimal clinically significant interaction per current evidence), retinoids (intracranial hypertension risk)

— Safe in pregnancy and young children

— TID dosing — adherence concern

— Allergy cross-reactivity with cephalosporins is low (<2%)

— 1 g IM single dose is insufficient — Lyme requires 2 g IV daily

— Biliary sludging with prolonged use; risk of C. difficile

— Outpatient parenteral antibiotic therapy (OPAT) via PICC for 14–21 days requires home health and weekly CBC/CMP monitoring

— Anaplasmosis: doxycycline (same regimen overlaps with Lyme — convenient)

— Babesiosis (mild–moderate): atovaquone + azithromycin × 7–10 days

— Babesiosis (severe, asplenic, immunocompromised): clindamycin + quinine, consider exchange transfusion if parasitemia >10% or end-organ damage

— Powassan virus: no specific therapy — supportive care; consider in severe encephalitis from Northeast

— Persistent high fevers >48 hours despite doxycycline → babesiosis (doxycycline doesn't cover)

— Leukopenia, thrombocytopenia, transaminitis → anaplasmosis

— Hemolytic anemia, elevated LDH, low haptoglobin → babesiosis

Doxycycline pharmacology pearls:

Amoxicillin considerations:

Ceftriaxone:

Co-infection treatment (same tick, same encounter):

When to suspect co-infection on Step 3:

Board pearl: Doxycycline treats Lyme AND anaplasmosis but does NOT treat babesiosis. If a patient on doxycycline for "Lyme" remains febrile and develops hemolytic anemia, send a peripheral smear for parasites and add atovaquone + azithromycin.

Key distinction: Persistent symptoms despite adequate antibiotics → think (1) missed babesiosis, (2) wrong diagnosis, (3) PTLDS — not "chronic Lyme requiring prolonged antibiotics."

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher risk of severe Lyme carditis and complete heart block; lower threshold to hospitalize and obtain ECG

— Atypical presentations common: fatigue, cognitive complaints, falls (from undiagnosed AV block syncope) — broaden differential

— EM may be missed on darker, sun-damaged, or wrinkled skin; examine intertriginous areas thoroughly

— Polypharmacy: review for warfarin (doxycycline potentiates INR — monitor and consider empiric dose reduction), digoxin, and QT-prolonging agents

— Doxycycline: no renal adjustment — preferred in CKD and ESRD

— Amoxicillin: reduce dose if CrCl <30 mL/min (e.g., 500 mg q12h or q24h)

— Cefuroxime axetil: adjust if CrCl <30 mL/min

— Ceftriaxone: no renal adjustment; monitor for biliary sludging and pseudocholelithiasis with prolonged use

— Doxycycline: use cautiously in severe hepatic disease; hepatotoxicity is rare

— Ceftriaxone: minimal hepatic metabolism; safe

— Avoid azithromycin in severe hepatic dysfunction

— Doxycycline + warfarin → INR rises within days; check INR at 3–5 days

— Doxycycline + iron/calcium/magnesium/antacids → chelation, separate by 2 hours

— Ceftriaxone + IV calcium-containing solutions in neonates → fatal precipitation (not adults, but classic exam fact)

— Patients with preexisting bundle branch block or first-degree AV block at baseline: small additional Lyme-induced PR prolongation may push them to high-grade block — admit at lower thresholds.

— Avoid AV-nodal blockers (β-blockers, non-DHP CCBs, digoxin) during active Lyme carditis — they worsen block.

Elderly patients:

Renal impairment:

Hepatic impairment:

Drug-drug interaction red flags in older adults:

Cardiac comorbidity considerations:

Step 3 management: An 80-year-old with EM, CrCl 25, and atrial fibrillation on warfarin → doxycycline 100 mg BID × 10 days, check INR at day 3, hold or reduce warfarin as needed. No renal adjustment.

Board pearl: The combination of new-onset AV block + summer + Northeast + age >60 should prompt Lyme serology even without EM — elderly patients often don't recall tick exposure or rash.

Special Populations — Pregnancy and Pediatrics

— Untreated Lyme during pregnancy is associated with adverse outcomes (rare congenital infection reports, fetal loss); treated Lyme has outcomes equivalent to uninfected pregnancies.

— First-line: amoxicillin 500 mg PO TID × 14 days for EM

— Alternative: cefuroxime axetil 500 mg PO BID × 14 days

— Doxycycline traditionally avoided, though recent data suggest short courses are likely safe; boards still favor amoxicillin

— Neuroborreliosis or carditis: ceftriaxone 2 g IV daily × 14–21 days — safe in pregnancy

— No evidence supports prolonged or "intensified" courses for pregnant patients

— No transmission via breast milk; breastfeeding is safe during treatment

— Doxycycline is now first-line for children of any age for short courses per AAP/IDSA — tooth staining risk minimal with modern preparations and ≤21-day courses

— Alternatives: amoxicillin 50 mg/kg/day divided TID (max 500 mg/dose), cefuroxime axetil 30 mg/kg/day divided BID

— Treatment durations same as adults (10 days for EM)

— Lyme arthritis in children: doxycycline or amoxicillin × 28 days

— Pediatric facial palsy: oral doxycycline × 14–21 days — no LP needed unless meningismus present

— Single-dose doxycycline 4.4 mg/kg (max 200 mg) within 72 hours of tick removal, if same criteria met as adults

— Previously avoided in <8 years — now acceptable per updated guidelines

Pregnancy:

Pediatrics:

Post-exposure prophylaxis in children:

Congenital Lyme: No defined congenital syndrome despite historical concern; routine cord blood testing not recommended.

Tick removal in any age: Fine-tipped tweezers, grasp close to skin, steady upward pull; do not twist, burn, or apply petroleum jelly. Save tick in plastic bag for identification if needed (though species testing of removed ticks is not routinely recommended).

Step 3 management: A pregnant patient in Massachusetts with classic EM → amoxicillin 500 mg TID × 14 days, no serology needed, follow-up in 2 weeks. Reassure about pregnancy outcomes with treatment.

Board pearl: No documented person-to-person transmission — partners and family members do not need testing or prophylaxis.

Complications and Adverse Outcomes

— Lyme carditis with high-grade AV block — most common serious acute complication; rarely fatal (sudden cardiac death reported, especially in young athletes returning to sport)

— Myopericarditis with transient LV dysfunction — usually fully reversible

— Pericardial effusion (rare)

— Endocarditis is not a typical feature — consider alternative diagnosis

— Residual facial weakness in ~10% after Lyme facial palsy (similar to Bell palsy)

— Persistent radicular pain in untreated radiculoneuritis

— Rare late encephalomyelitis with spastic paraparesis, bladder dysfunction (more in European B. garinii)

— Cognitive complaints in PTLDS — subjective, no structural pathology

— Antibiotic-refractory Lyme arthritis (5–10%): persistent synovitis after 2–3 antibiotic courses, driven by autoimmune mechanisms (HLA-DR4 association, anti-OspA antibodies); treat with DMARDs and intra-articular steroids, not more antibiotics

— Chronic joint damage rare with treatment

— Persistent fatigue, musculoskeletal pain, cognitive complaints ≥6 months after documented treatment

— Occurs in ~10–20% of treated patients

— No evidence of ongoing infection and no benefit from prolonged antibiotics (Klempner, Krupp, Fallon trials)

— Manage with graded exercise, sleep optimization, CBT, treatment of comorbid depression/fibromyalgia

— Central line infections and bacteremia from prolonged IV therapy

— C. difficile colitis

— Cholelithiasis and biliary sludging from ceftriaxone

— Antibiotic resistance pressure

Cardiac complications:

Neurologic complications:

Articular complications:

Post-treatment Lyme disease syndrome (PTLDS):

Iatrogenic complications from inappropriate "chronic Lyme" treatment:

Key distinction: Antibiotic-refractory Lyme arthritis (objective persistent synovitis, anti-OspA antibodies) vs. PTLDS (subjective symptoms, no objective findings) — different mechanisms, different management. Both are post-infectious immune phenomena, not active infection.

Board pearl: A patient on month 3 of IV ceftriaxone for "chronic Lyme" presents with fever and shaking chills → suspect catheter-related bloodstream infection, not Lyme — pull the line, blood cultures, broad-spectrum antibiotics. This iatrogenic harm is a Step 3 patient safety theme.

When to Escalate Care

— Lyme carditis with PR ≥300 ms, any 2°/3° AV block, or symptoms (syncope, chest pain, dyspnea) — admit to telemetry

— Lyme meningitis or encephalitis with concerning neurologic exam, altered mental status

— Severe neuroborreliosis with cranial nerve involvement beyond CN VII plus systemic illness

— Severe co-infection: babesiosis with parasitemia >4%, hemodynamic instability, asplenia, severe anemia

— Inability to tolerate or absorb oral antibiotics

— Complete heart block with hemodynamic compromise requiring temporary transvenous or transcutaneous pacing

— Acute heart failure or cardiogenic shock from severe myocarditis (rare)

— Severe babesiosis with multiorgan failure requiring exchange transfusion

— Severe encephalitis with airway compromise or seizures

— Cardiology: any Lyme carditis with conduction disease — guide telemetry duration, temporary pacing decisions, return-to-sport

— Infectious disease: complicated cases, treatment failure, IV therapy planning, co-infection management

— Neurology: neuroborreliosis with atypical features, persistent deficits, late neuroborreliosis

— Rheumatology: antibiotic-refractory Lyme arthritis for DMARD consideration

— Ophthalmology: rare uveitis, keratitis

Hospital admission indicated:

ICU criteria:

Specialist consults:

CCS pearl: For a CCS Lyme carditis case: admit, continuous cardiac monitoring, IV access × 2, ECG every shift initially, ceftriaxone 2 g IV daily, troponin, BNP, echo, hold AV-nodal blockers, transcutaneous pacer pads at bedside. Transition to oral doxycycline only after PR <300 ms and symptoms resolve. Discharge with cardiology follow-up in 1–2 weeks.

Step 3 management: A patient admitted with complete heart block from Lyme who needed temporary pacing during hospitalization — at discharge, arrange Holter or event monitor at 2 weeks and cardiology follow-up; do not place a permanent pacemaker during the acute illness because conduction nearly always recovers.

Board pearl: Asymptomatic PR prolongation <300 ms in a confirmed Lyme patient can be managed outpatient with oral doxycycline and close follow-up — but document a careful history for syncope, palpitations, and a baseline ECG.

Key Differentials — Same Category (Other Tick-Borne and Spirochetal Diseases)

— Lone star tick (Amblyomma americanum) in southeastern/south-central US

— EM-like rash but smaller, more uniform, often more pruritic

— Etiology uncertain; not B. burgdorferi

— Self-limited; many clinicians treat empirically with doxycycline given diagnostic uncertainty

— Key distinction: Geography — Lyme is Northeast/Midwest/Pacific; STARI is Southeast.

— Rickettsia rickettsii, Dermacentor ticks

— Fever, headache, myalgia, then maculopapular rash starting on wrists/ankles spreading centrally, often involving palms/soles and becoming petechial

— Severe — treat empirically with doxycycline pending serology; mortality if delayed

— Key distinction: RMSF rash is centripetal and petechial; Lyme EM is single expanding annular lesion.

— Same Ixodes tick as Lyme; co-infection common

— Fever, headache, myalgia without rash; leukopenia, thrombocytopenia, elevated transaminases

— Morulae in granulocytes on smear

— Treat with doxycycline (overlaps Lyme therapy)

— Lone star tick, Southeast/South-central

— Similar to anaplasmosis; morulae in monocytes

— Doxycycline

— Same Ixodes tick; hemolytic anemia, fever; intra-erythrocytic parasites

— Severe in asplenic/immunocompromised

— Atovaquone + azithromycin

— Recurrent fevers, headache, myalgia; B. miyamotoi shares Ixodes vector with Lyme

— Treated with doxycycline

— Other spirochetosis; diffuse maculopapular rash including palms/soles, condyloma lata, mucous patches

— RPR/VDRL with confirmatory treponemal test

— Treat with penicillin G

Southern Tick-Associated Rash Illness (STARI):

Rocky Mountain Spotted Fever (RMSF):

Anaplasmosis (Anaplasma phagocytophilum):

Ehrlichiosis (Ehrlichia chaffeensis):

Babesiosis (Babesia microti):

Relapsing fever (Borrelia hermsii, B. miyamotoi):

Syphilis (secondary):

Board pearl: Doxycycline empirically covers Lyme, anaplasmosis, ehrlichiosis, RMSF, and STARI — when the diagnosis is tick-borne but unclear in an endemic area with febrile illness, start doxycycline while workup proceeds. It does not cover babesiosis.

Key Differentials — Other Categories

— Cellulitis: more painful, warmer, less well-demarcated, may have lymphangitic streaking; treat with anti-staph/strep coverage

— Tinea corporis: smaller, scaly border with central clearing; KOH prep diagnostic

— Granuloma annulare: chronic, smaller, non-expanding, no constitutional symptoms

— Erythema multiforme: target lesions on palms/soles, drug or HSV trigger

— Fixed drug eruption: recurs at same site with drug exposure

— Insect bite hypersensitivity: smaller, pruritic, appears within hours

— Bell palsy is idiopathic, often associated with HSV reactivation

— Lyme facial palsy: endemic area, summer, possible EM or other systemic features, may be bilateral

— Bilateral facial palsy ddx: Lyme, sarcoidosis (Heerfordt syndrome), GBS, HIV seroconversion, multiple sclerosis

— Viral meningitis: shorter duration, no cranial nerve findings, no intrathecal Lyme antibody production

— Lyme: cranial neuropathy, radiculoneuritis, endemic exposure, positive CSF antibody index

— Drug-induced (β-blocker, CCB, digoxin toxicity)

— Ischemic (inferior MI causes AV block)

— Sarcoidosis (younger patient with AV block, lymphadenopathy)

— Infiltrative (amyloidosis)

— Congenital

— Key distinction: Reversibility with antibiotics is what makes Lyme carditis unique — avoid permanent pacemaker.

— Septic arthritis: refuses to bear weight, very tender, synovial WBC often >50,000

— Gout/pseudogout: crystals on polarized microscopy

— Reactive arthritis: post-GU/GI infection, often oligoarticular, enthesitis

— JIA: in children, multiple joints, ANA positivity

— Considerable overlap; manage similarly with multimodal supportive care; avoid prolonged antibiotics in all three.

EM mimics:

Lyme facial palsy vs. Bell palsy:

Lyme meningitis vs. viral aseptic meningitis:

Lyme carditis vs. other AV block causes:

Lyme arthritis vs. other monoarthritides:

PTLDS vs. fibromyalgia/chronic fatigue:

Board pearl: A young patient with knee swelling out of proportion to pain, walks into clinic, large effusion → think Lyme; a young patient who refuses to bear weight with a hot painful knee → septic arthritis until proven otherwise. Arthrocentesis distinguishes.

Secondary Prevention and Long-Term Plan

— DEET 20–30% on exposed skin, picaridin as alternative

— Permethrin-treated clothing (lasts through multiple washes)

— Long sleeves, pants tucked into socks when in wooded/grassy areas

— Light-colored clothing makes ticks easier to spot

— Post-exposure tick checks within 2 hours of coming indoors — including scalp, axillae, groin, behind knees

— Shower within 2 hours to wash off unattached ticks

— Tumble-dry clothes on high heat × 10 minutes to kill ticks

— Maintain landscaped barriers between lawns and woods

— Discourage deer by fencing or removing attractants

— Treat pets with veterinarian-recommended tick prevention

— Re-infection is possible — prior Lyme does not confer durable immunity; maintain prevention behaviors

— Serology may remain positive for years — do not use to monitor cure or diagnose reinfection (use clinical findings + new EM)

— Reassure that completed standard antibiotic courses are sufficient; counsel against unproven "chronic Lyme" therapies

— For PTLDS: explain pathophysiology, set expectations for gradual recovery over 6–12 months

— Complete oral doxycycline to total 14–21 days

— Avoid AV-nodal blockers until conduction normalizes

— Resume exercise gradually after cardiology clearance

— No currently approved Lyme vaccine in the US (LYMErix withdrawn in 2002); investigational vaccines in trials

— Maintain routine adult immunizations including Tdap (tick-borne diseases don't change Td schedule)

Personal protective measures (counsel every patient post-treatment and at routine visits in endemic areas):

Environmental measures:

Post-treatment counseling:

Discharge medication considerations after carditis:

Vaccine status:

Step 3 management: At a wellness visit in Connecticut in May, counsel a hiker on permethrin-treated clothing, DEET, daily tick checks, and what EM looks like — and that they should call within 72 hours of a recognized Ixodes bite to discuss prophylactic doxycycline.

Board pearl: Reinfection causes a new EM — treat as a fresh episode with a new course of doxycycline. Don't be misled by persistently positive serology from the prior infection.

Follow-Up, Monitoring, and Counseling

— Phone or in-person check at 2–3 weeks post-treatment to confirm resolution of rash and constitutional symptoms

— No serology required for treatment monitoring

— Reassure patient that mild fatigue may persist for weeks but should be improving

— Re-examine at 2 and 6 weeks

— Eye care: artificial tears, nighttime lubricant, tape eye closed at night to prevent exposure keratitis

— Ophthalmology referral if corneal symptoms

— Most recover fully by 3–6 months; refer to neurology if no improvement by 6 months

— Repeat ECG at hospital discharge, 1 week, and 1 month

— Cardiology follow-up at 1–2 weeks

— Holter or event monitor at 2–4 weeks to confirm conduction recovery

— Echocardiogram at 1 month if myocarditis was present

— Return to vigorous exercise/sport only after normalization and cardiology clearance

— Reassess at 4 weeks (end of first oral course)

— Persistent effusion → second 28-day oral course OR 2–4 weeks IV ceftriaxone

— Continued synovitis after 2 courses → rheumatology for DMARD consideration

— Synovial fluid PCR can guide whether residual disease is infectious vs. immune-mediated

— Neurology follow-up 2–4 weeks after IV therapy completion

— Repeat LP not routinely needed; based on clinical course

— Cognitive symptoms warrant formal neuropsychological testing if persistent

— Realistic recovery timeline: fatigue and arthralgias may linger weeks even after successful treatment

— Recognize symptoms of co-infection (persistent fevers, hemolysis) — return precautions

— Mental health: chronic illness perception drives anxiety/depression in PTLDS — screen with PHQ-9

Early localized (EM) follow-up:

Lyme facial palsy follow-up:

Lyme carditis follow-up:

Lyme arthritis follow-up:

Neuroborreliosis follow-up:

Counseling themes:

Board pearl: Do not order repeat Lyme serology to "prove cure" — it remains positive for years and creates unnecessary patient anxiety and inappropriate retreatment. Document clinical resolution instead.

Step 3 management: At a 3-week follow-up after EM treatment, the rash has resolved but the patient reports mild fatigue. Reassure, continue observation, no further antibiotics, return in 4 weeks if not improving — and screen for sleep and mood.

Ethical, Legal, and Patient Safety

— Non-evidence-based "chronic Lyme" practices (prolonged IV antibiotics, herbal regimens, hyperbaric oxygen) cause documented harm: central line infections, C. difficile, biliary disease, drug toxicity, financial harm

— Physicians have ethical and professional obligations to provide evidence-based counsel while respecting patient autonomy — engage patients with empathy, validate suffering, but do not provide non-indicated therapy

— When patients request prolonged antibiotics: explain risks, document discussion, decline to prescribe, offer symptom-directed care and referral

— IV antibiotic therapy via PICC for legitimate indications (neuroborreliosis, refractory arthritis) requires documented consent including infection, thrombosis, C. difficile risk

— Pregnant patients with EM: discuss amoxicillin first-line; if doxycycline is being considered, document shared decision-making

— Lyme disease is a nationally notifiable condition — report confirmed and probable cases per state requirements

— Reporting drives surveillance, public health resource allocation, and tick-mapping; failure to report is a public health gap

— Patient discharged after Lyme carditis on oral doxycycline: ensure ECG follow-up scheduled, cardiology appointment booked, AV-nodal blockers held, return precautions documented

— Hand-off from inpatient to PCP must include the antibiotic stop date and that serology should not be repeated

— Medication reconciliation for doxycycline-warfarin interaction

— Outdoor workers (landscapers, utility workers, foresters): document occupational exposure for workers' compensation claims if disease occurs

— Counseling on workplace prevention practices

— EM may be underdiagnosed in patients with darker skin tones; ensure clinicians are trained to recognize atypical rash appearance

— Access to specialist follow-up for carditis and neuroborreliosis varies geographically — coordinate care actively

"Chronic Lyme" and patient safety:

Informed consent edge cases:

Mandatory reporting:

Transition-of-care risks (high Step 3 yield):

Occupational considerations:

Health equity:

Board pearl: A patient on month 6 of IV antibiotics from an outside "Lyme specialist" presents febrile — your job is not to continue the regimen. Pull the line, culture, treat the iatrogenic infection, and have a frank, documented conversation about evidence-based care.

Step 3 management: Decline to prescribe prolonged antibiotics for PTLDS; offer multidisciplinary supportive care, document the conversation, and avoid abandonment by maintaining the therapeutic relationship.

High-Yield Associations and Rapid-Fire Facts

Vector by region: Ixodes scapularis (Northeast/Midwest), I. pacificus (Pacific coast); Amblyomma = lone star → STARI/ehrlichiosis/alpha-gal; Dermacentor → RMSF.

Transmission window: ≥36–48 hours of attachment required.

Nymphal ticks (poppy-seed sized, late spring–summer) cause most human cases.

EM = clinical diagnosis, no testing, treat empirically.

First-line therapy (EM, most early disease): doxycycline 100 mg BID × 10 days.

Pregnancy first-line: amoxicillin 500 mg TID × 14 days.

Bilateral CN VII palsy in summer in Connecticut = Lyme until proven otherwise.

Lyme carditis PR cutoff for admission: ≥300 ms or any symptoms or higher-degree block.

No permanent pacemaker during acute Lyme carditis — conduction recovers.

Doxycycline for facial palsy without meningitis — oral works, no IV needed.

Neuroborreliosis with meningitis/encephalitis: IV ceftriaxone 2 g daily × 14–21 days.

Lyme arthritis: 28 days of oral doxycycline first; refractory → DMARDs, not more antibiotics.

HLA-DR4 association with antibiotic-refractory Lyme arthritis.

CSF Lyme antibody index >1 = intrathecal antibody production = neuroborreliosis.

Serology stays positive for years — don't use to monitor cure or re-treat.

PTLDS: ≥6 months post-treatment subjective symptoms; no benefit from prolonged antibiotics (Klempner, Krupp, Fallon RCTs).

Co-infections: anaplasmosis (covered by doxy), babesiosis (NOT covered — needs atovaquone + azithromycin), Powassan virus (no therapy).

Post-exposure prophylaxis: single-dose doxycycline 200 mg within 72 h if Ixodes, ≥36 h attached, ≥20% local infection rate.

Jarisch-Herxheimer: first-dose febrile reaction; continue antibiotics, treat supportively.

No congenital Lyme syndrome when adequately treated in pregnancy.

Reinfection is possible — new EM = new course.

Lyme is nationally notifiable — report it.

Board pearl: If the question stem includes "Connecticut," "Lyme, CT," "Cape Cod," "Wisconsin lakes," or "summer hike," the diagnosis is Lyme — focus on which stage and which antibiotic.

Key distinction: Doxycycline = Lyme + anaplasmosis + RMSF + ehrlichiosis. Babesiosis needs azithromycin + atovaquone added. Memorize this overlap.

Board Question Stem Patterns

— "30-year-old hiker in Vermont with a 10-cm expanding erythematous rash on the thigh, low-grade fever, fatigue."

— Trap: serology now (negative, falsely reassures). Answer: treat with doxycycline 100 mg BID × 10 days; no testing needed.

— "25-year-old camp counselor in Maine with bilateral lower-motor-neuron facial weakness in July."

— Answer: oral doxycycline; obtain serology to confirm but treat empirically; LP only if meningismus.

— "22-year-old with dizziness; ECG shows third-degree AV block; recent hiking in Massachusetts."

— Answer: admit, telemetry, IV ceftriaxone 2 g daily, hold AV-nodal blockers, temporary pacing if needed, no permanent pacemaker.

— "Teenager with recurrent painless knee effusion months after summer camp; large effusion, can bear weight."

— Answer: arthrocentesis (rule out septic, crystals), Lyme serology with confirmatory Western blot, doxycycline × 28 days.

— "Patient pulls an engorged deer tick attached for 2 days from leg in Rhode Island; presents within 24 hours."

— Answer: single-dose doxycycline 200 mg PO.

— "Patient treated 1 year ago for documented Lyme; now with fatigue, arthralgia, brain fog; serology still positive."

— Answer: supportive care, CBT, graded exercise; do NOT prescribe more antibiotics.

— "Patient on doxycycline for Lyme develops worsening fever, hemolytic anemia, parasitemia on smear."

— Answer: babesiosis — add atovaquone + azithromycin.

— "Pregnant patient in upstate New York with EM."

— Answer: amoxicillin 500 mg TID × 14 days.

— "Patient on month 4 of IV ceftriaxone via PICC for 'chronic Lyme' presents febrile with rigors."

— Answer: blood cultures, remove the line, broad-spectrum antibiotics for CLABSI; discontinue inappropriate Lyme therapy.

— "Patient with vague fatigue and a positive Lyme IgG screen from a state with no Lyme."

— Answer: do not treat; alternative workup.

Pattern 1 — Classic EM:

Pattern 2 — Bilateral facial palsy:

Pattern 3 — Lyme carditis:

Pattern 4 — Lyme arthritis:

Pattern 5 — Post-exposure prophylaxis:

Pattern 6 — PTLDS:

Pattern 7 — Co-infection trap:

Pattern 8 — Pregnancy:

Pattern 9 — Inappropriate care:

Pattern 10 — False positive:

Board pearl: Step 3 stems test management nuance — admit vs. discharge, IV vs. oral, treat vs. don't test. The correct answer is rarely "more antibiotics for longer."

One-Line Recap

Lyme disease — staged tick-borne spirochetosis (Borrelia burgdorferi, Ixodes vector) where clinical recognition by stage (early localized EM, early disseminated with neuroborreliosis or carditis, late arthritis) drives oral doxycycline as default therapy and IV ceftriaxone for meningitis/encephalitis or high-grade carditis, with serology used only when EM is absent and never to monitor cure.

Recognize: EM in endemic area = clinical diagnosis, treat empirically with doxycycline 100 mg BID × 10 days, no serology needed.

Escalate: Lyme carditis with PR ≥300 ms, any higher-degree block, or symptoms → admit, telemetry, IV ceftriaxone, hold AV-nodal blockers, NO permanent pacemaker (conduction recovers).

Adapt for population: Pregnancy and young children → amoxicillin first; doxycycline now acceptable for short courses in kids of any age per AAP/IDSA; no renal adjustment for doxycycline.

Don't overtreat: PTLDS (≥6 months subjective symptoms post-treatment) gets supportive care, not prolonged antibiotics — RCT-proven harm without benefit; refractory arthritis after 2 courses gets rheumatology and DMARDs, not more antibiotics.

Don't miss co-infections: Persistent fever or hemolysis on doxycycline → babesiosis (atovaquone + azithromycin); cytopenias + transaminitis → anaplasmosis (already covered by doxycycline).

Prevent: DEET/picaridin, permethrin-treated clothing, tick checks, prophylactic single-dose doxycycline 200 mg within 72 h if Ixodes tick attached ≥36 h in high-prevalence area.

Board pearl: When in doubt on Step 3, the safest Lyme answer is usually "doxycycline orally and clinical follow-up" unless the stem screams carditis with high-grade block or meningoencephalitis — then it's IV ceftriaxone and admission. Repeat serology is almost never the right answer.

Step 3 management: Lyme exemplifies primary care decision-making — geography + season + exam → empiric treatment → structured follow-up → public health reporting → patient counseling on prevention and realistic recovery expectations.