Multisystem Processes & Disorders

Tick-borne diseases: RMSF, ehrlichiosis, babesiosis, anaplasmosis

Clinical Overview and When to Suspect Tick-Borne Disease

— Rocky Mountain spotted fever (RMSF, Rickettsia rickettsii): South Atlantic, South Central (NC, OK, AR, TN, MO); also AZ tribal lands via brown dog tick

— Ehrlichiosis (E. chaffeensis): Southeast/South Central via Lone Star tick (Amblyomma americanum)

— Anaplasmosis (A. phagocytophilum): Upper Midwest, Northeast via Ixodes scapularis (same vector as Lyme/babesia)

— Babesiosis (Babesia microti): Northeast (especially islands of MA, NY, RI), Upper Midwest; Ixodes scapularis

— Fever ≥38.5°C + headache + thrombocytopenia, leukopenia, or hyponatremia

— Rash optional (absent early in RMSF, usually absent in ehrlichiosis/anaplasmosis)

— Exposure history or endemic residence

Core teaching: In a patient with fever + headache + thrombocytopenia ± transaminitis during spring/summer in an endemic US region, empirically treat for a tick-borne illness while awaiting confirmation — do not wait for serology.

Geography drives suspicion (US):

Season: ~90% of cases occur April–September; ask about hiking, camping, gardening, hunting, pets.

Tick attachment time matters for prevention counseling, but absence of recall is common — only ~60% of RMSF patients remember a tick bite.

Red-flag triad prompting empiric doxycycline:

Coinfection alert: Ixodes ticks transmit Lyme, anaplasmosis, and babesia simultaneously — if a "Lyme" patient is sicker than expected with hemolysis or severe cytopenias, hunt for babesia coinfection.

Step 3 management: In the ambulatory clinic, a febrile patient with tick exposure and any cytopenia should get empiric doxycycline 100 mg BID started at the visit while CBC, CMP, LDH, peripheral smear, and tick-borne PCR panel are sent — delay in doxycycline beyond day 5 of RMSF illness is the single strongest predictor of mortality.

Board pearl: Doxycycline covers RMSF, ehrlichiosis, and anaplasmosis — but not babesiosis, which needs atovaquone + azithromycin.

Presentation Patterns and Key History

— Day 1–3: fever, severe headache, myalgia, nausea, abdominal pain (mimics gastroenteritis/appendicitis in kids)

— Day 3–5: blanching macular rash on wrists/ankles → palms/soles → centripetal spread to trunk; evolves to petechial/purpuric by day 5–6 (late, ominous sign)

— ~10% are "spotless RMSF" — more common in Black patients and elderly; higher mortality from delayed diagnosis

— Recent outdoor activity, occupation (forestry, military, landscapers)

— Travel to endemic region in last 30 days

— Splenectomy (babesia severity ↑↑)

— Blood transfusion in last 6 months (babesia is the #1 transfusion-transmitted parasite in US)

— Pet dogs with ticks

— Immunosuppression (rituximab patients get prolonged/relapsing babesiosis)

Incubation: RMSF 2–14 days (median 5–7); ehrlichiosis/anaplasmosis 5–14 days; babesiosis 1–6 weeks (longer; can be months if transfusion-transmitted).

RMSF — "the great imitator":

Ehrlichiosis: fever, headache, myalgia, GI symptoms prominent; rash in ~30% adults, ~60% children (can mimic RMSF rash); confusion/meningoencephalitis in severe cases.

Anaplasmosis: fever, headache, myalgia, rash uncommon (<10%); think anaplasmosis when a Northeast/Upper Midwest patient looks like ehrlichiosis but has no rash.

Babesiosis: gradual onset fever, drenching sweats, fatigue, hemolytic anemia (dark urine, jaundice); often asymptomatic in young immunocompetent, severe in asplenic, elderly, HIV, immunosuppressed.

High-yield history questions:

Key distinction: Rash on palms/soles narrows differential to RMSF, secondary syphilis, coxsackie (hand-foot-mouth), meningococcemia, toxic shock — in a febrile outdoor exposure patient, treat as RMSF until proven otherwise.

Board pearl: Hyponatremia + thrombocytopenia + transaminitis in a summer febrile illness = rickettsial until proven otherwise.

Physical Exam Findings (and Hemodynamic Assessment)

— Fever often 39–40°C; relative bradycardia is not characteristic (unlike typhoid)

— Tachycardia + hypotension + narrow pulse pressure → vasculitic shock in RMSF (capillary leak from endothelial infection) — resuscitate but avoid over-aggressive fluids which worsen pulmonary/cerebral edema

— Hypoxia → consider ARDS (RMSF, severe babesiosis)

— RMSF rash: starts day 3–5 as blanching pink macules 1–5 mm on wrists, forearms, ankles; spreads centripetally; palms and soles involved in ~50–80% by day 5; becomes petechial → purpuric → necrotic (digital gangrene in severe cases)

— Eschar: absent in RMSF (distinguishes from R. parkeri, African tick-bite fever, scrub typhus, which have eschars)

— Ehrlichiosis: maculopapular or petechial, trunk-predominant, spares palms/soles

— Anaplasmosis: usually no rash — rash should make you reconsider

— Babesiosis: pallor, scleral icterus, no primary rash; petechiae if DIC

— Conjunctival injection, photophobia, meningismus

— Altered mental status, focal deficits, seizures → rickettsial encephalitis (poor prognostic marker) or severe babesiosis

Vital signs to anchor severity:

Skin (highest yield):

HEENT/Neuro:

Abdomen: hepatosplenomegaly (especially babesiosis, ehrlichiosis); RUQ tenderness with transaminitis.

Pulmonary: crackles → non-cardiogenic pulmonary edema/ARDS (RMSF, babesiosis).

Extremities: peripheral edema, digital ischemia/gangrene in late RMSF.

Step 3 management: Bedside checklist on admission — mental status, skin (palms/soles/genitalia/scalp), spleen, oxygenation, urine output. Reassess skin every 12 hours in suspected RMSF; new petechiae upgrade severity and lower threshold for ICU.

Board pearl: A child with fever, headache, and a rash that starts at the wrists/ankles in summer in NC/OK is RMSF until proven otherwise — start doxycycline regardless of age.

Diagnostic Workup — Initial Labs

— Thrombocytopenia: hallmark of all four (most profound in ehrlichiosis/anaplasmosis, often <100k)

— Leukopenia with left shift: ehrlichiosis/anaplasmosis (lymphopenia early)

— RMSF: WBC often normal but with left shift and bandemia

— Hemolytic anemia: babesiosis (↓Hgb, ↑retic, ↑LDH, ↑indirect bili, ↓haptoglobin)

— Hyponatremia (SIADH-like from vasculitis) — classic in RMSF (~50%)

— Transaminitis (AST/ALT 2–10× ULN) — all four

— ↑BUN/Cr → AKI from hypovolemia, hemolysis (babesia), or vasculitis

— Hyperbilirubinemia (babesia hemolysis)

— Babesia: intraerythrocytic ring forms, occasional "Maltese cross" tetrads (pathognomonic), no pigment (vs Plasmodium falciparum)

— Anaplasmosis: morulae in neutrophils (~20–80% of cases)

— Ehrlichiosis: morulae in monocytes (less commonly seen, ~10%)

— RMSF: no organism on smear

CBC with differential:

Comprehensive metabolic panel:

Coagulation: PT/PTT usually normal in early RMSF (distinguishes from DIC); fibrinogen and D-dimer if petechiae/purpura.

LDH, haptoglobin, reticulocyte count, direct Coombs: if suspecting babesiosis (Coombs negative — intraerythrocytic parasite).

Urinalysis: hemoglobinuria (babesia), proteinuria (RMSF vasculitis).

Peripheral blood smear — single highest-yield test:

CRP and procalcitonin: elevated but nonspecific.

HIV test, pregnancy test: influence management/dosing.

Lactate: elevated → consider shock.

CCS pearl: Order set for febrile tick-exposed patient: CBC w/ diff, CMP, LDH, haptoglobin, retic, peripheral smear with manual review, UA, blood cultures ×2, tick-borne PCR panel (Babesia/Anaplasma/Ehrlichia), RMSF serology (acute), HIV, pregnancy — then start doxycycline before results return.

Board pearl: Negative smear does not rule out babesiosis at low parasitemia — confirm with PCR.

Diagnostic Workup — Confirmatory Studies

— Anaplasma, Ehrlichia, Babesia: PCR is sensitive and specific in first week before antibody response; turnaround 1–3 days

— RMSF PCR on blood is insensitive (organism is intracellular in endothelium, not bloodstream) — better on skin biopsy of rash (sensitivity ~70%)

— RMSF: 4-fold rise between acute (week 1) and convalescent (weeks 2–4) titers is gold standard — but retrospective; never delay treatment

— Single titer ≥1:64 supportive; cross-reactivity with other spotted fever group rickettsiae

— Ehrlichia/Anaplasma: IFA titer ≥1:64, fourfold rise confirms

— Babesia: IFA ≥1:256 indicative; PCR preferred acutely

— <4%: mild; outpatient oral therapy reasonable in immunocompetent

— ≥4% or severe hemolysis/organ dysfunction: severe babesiosis → IV clindamycin + quinine ± RBC exchange transfusion

— CXR if hypoxic — ARDS pattern

— CT head if AMS/focal deficits — rule out other causes; rickettsial encephalitis may show meningeal enhancement

— Abdominal US if splenomegaly/RUQ pain

PCR (whole blood, EDTA tube) — best acute-phase test:

Serology (IFA, indirect immunofluorescence):

Skin biopsy with immunohistochemistry: RMSF in rash biopsy — useful when serology pending and diagnosis uncertain.

Babesia parasitemia quantification: percent parasitized RBCs guides severity:

Imaging (selective):

Lumbar puncture: if meningismus/encephalopathy — CSF in rickettsial disease often shows mild lymphocytic pleocytosis, normal glucose, mildly elevated protein (mimics aseptic meningitis).

Key distinction: PCR is the test of choice in the acute setting for ehrlichia, anaplasma, and babesia; serology is the test of choice for RMSF (but treatment is always empiric).

Board pearl: Convalescent serology drawn at 2–4 weeks documenting seroconversion is the most commonly tested confirmatory step for RMSF on Step 3 — but the diagnostic step on the exam is "start doxycycline now."

Risk Stratification and Management Logic

— Mild/outpatient: stable vitals, no organ dysfunction, plt >50k, normal mentation, able to tolerate PO → oral doxycycline, follow-up in 48–72 hours

— Moderate/inpatient ward: AKI, plt <50k, transaminitis >5× ULN, vomiting, elderly, comorbidities → admit, IV doxycycline

— Severe/ICU: AMS, shock, ARDS, DIC, organ failure, babesia parasitemia ≥4%, severe hemolysis → ICU

— Parasitemia ≥4%

— Hemoglobin <10 g/dL

— Pulmonary, renal, hepatic, or cardiac compromise

— Asplenia, immunocompromise, age >50

— Delay in doxycycline beyond day 5 of illness → mortality rises from <1% to >20%

— Age extremes, G6PD deficiency, Black race (often due to delayed/missed diagnosis), absence of rash

Universal first move: if tick-borne disease is even moderately suspected → empiric doxycycline 100 mg PO/IV BID regardless of age or pregnancy status (RMSF caveats below).

Severity stratification at presentation:

Clinical response is itself diagnostic: defervescence within 48 hours of doxycycline strongly supports rickettsial/ehrlichial disease. Lack of response by 48 hours → reconsider babesia, alternate diagnosis, or coinfection.

Babesiosis severity criteria (any one = severe):

RMSF mortality drivers:

Coinfection logic: Ixodes-borne patient who is sicker than Lyme alone explains → add atovaquone + azithromycin for babesia while doxycycline covers Lyme/anaplasma.

Step 3 management: A summer febrile patient from NC with headache, plt 90k, Na 130, AST 110 — even before serology — gets doxycycline 100 mg BID immediately, blood cultures, supportive care, and admission if any organ dysfunction. The wrong answer is "wait for serology."

Board pearl: Empiric treatment based on epidemiology and syndrome is the standard of care — delay is the most common board "wrong answer."

Pharmacotherapy — First-Line Regimens

— Adults: 100 mg PO/IV BID

— Children of any age and any weight: 2.2 mg/kg/dose BID (max 100 mg/dose) — CDC and AAP explicitly endorse doxycycline in children <8 for suspected RMSF; short courses do not cause dental staining

— Duration: continue for at least 3 days after defervescence, typically 5–7 days total (longer if severe or coinfection with Lyme — then 10–14 days)

— IV if vomiting, severe disease, AMS; transition to PO when tolerating

— Chloramphenicol: historical RMSF alternative in pregnancy, but higher mortality than doxycycline in RMSF; rarely used; aplastic anemia risk

— Rifampin: considered for anaplasmosis in pregnancy (case-based); not adequate for RMSF

— Mild–moderate (outpatient): atovaquone 750 mg PO BID + azithromycin 500 mg day 1 then 250 mg daily × 7–10 days

— Severe: IV clindamycin 600 mg q6h + oral quinine 650 mg q6–8h × 7–10 days (clinda + quinine) — quinine is hard to tolerate (cinchonism, hypoglycemia, QT prolongation); azithromycin IV + atovaquone is an alternative

— Immunocompromised (e.g., rituximab): extend treatment ≥6 weeks and continue ≥2 weeks after parasitemia clears

— RBC exchange transfusion if parasitemia ≥10%, severe hemolysis, or end-organ damage

— Transfusion support for symptomatic anemia

— Doxycycline + warfarin → INR ↑

— Doxycycline + oral contraceptives → minimal effect (myth, but counsel)

— Doxycycline absorption ↓ by calcium, iron, antacids — separate by 2 hours

— Azithromycin/quinine → QT prolongation, get baseline ECG

Doxycycline — drug of choice for RMSF, ehrlichiosis, anaplasmosis:

Alternatives (limited):

Babesiosis regimens:

Adjuncts in severe babesiosis:

Drug interactions to flag:

Board pearl: Step 3 favorite — "a 5-year-old with suspected RMSF should receive doxycycline," not chloramphenicol, not waiting for confirmation.

Procedural and Advanced Management

— Indications (any of): parasitemia ≥10%, hemoglobin <10 g/dL with hemolysis, pulmonary/renal/hepatic compromise

— Removes parasitized RBCs and cytokines; rapidly lowers parasite burden

— Performed via apheresis; requires central access; coordinate with hematology and blood bank

— Target post-exchange parasitemia <5%

— Corticosteroids (not standard; may consider in fulminant rickettsial encephalitis case-by-case)

— Routine IVIG

— Empiric antimalarials (babesia is not malaria — do not give chloroquine/artemisinin)

— Fine-tipped tweezers, grasp close to skin, steady upward traction; do not twist, burn, or use petroleum jelly

— Clean site, save tick in alcohol if patient wishes (tick testing not routinely recommended)

RBC exchange transfusion (babesiosis):

Simple transfusion: for symptomatic anemia or Hgb <7 g/dL without meeting exchange criteria.

Mechanical ventilation: for ARDS (more common in severe RMSF and babesiosis); use lung-protective strategy (Vt 6 mL/kg IBW, plateau <30).

Vasopressor support: norepinephrine first-line for distributive/vasculitic shock; cautious fluid resuscitation in RMSF (capillary leak).

Renal replacement therapy: for AKI with refractory acidosis, hyperkalemia, volume overload — especially in severe babesia hemolysis.

No role for:

Tick removal (if attached on exam):

Lyme post-exposure prophylaxis (if Ixodes attached): single dose doxycycline 200 mg PO within 72 hours if attached ≥36 hours in endemic area — does not prevent babesiosis or anaplasmosis reliably, but is standard.

CCS pearl: In a CCS-style case of severe babesiosis, the sequence is: admit ICU → CBC, smear, parasitemia % → IV clindamycin + quinine → consult hematology for exchange transfusion if ≥10% → recheck parasitemia q12–24h → transition to oral atovaquone-azithromycin once <4% and improving.

Board pearl: Exchange transfusion + clindamycin/quinine is the answer for asplenic patient with babesiosis and parasitemia 15%.

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher mortality across all four tick-borne diseases (RMSF mortality ~5× higher >60)

— Atypical presentation: blunted fever, AMS may dominate, rash less recognized

— Lower threshold to admit and treat empirically

— Polypharmacy: doxycycline + warfarin (INR ↑), doxycycline + digoxin (levels ↑)

— Doxycycline: no dose adjustment in CKD/ESRD — preferred tetracycline in renal failure (vs tetracycline itself which is renally cleared)

— Atovaquone: no adjustment, but absorption requires fatty meal — counsel

— Azithromycin: no renal adjustment

— Clindamycin: no renal adjustment

— Quinine: reduce dose in severe renal failure; monitor for cinchonism, hypoglycemia (insulin release), QT

— Monitor AKI in babesiosis (hemolysis-induced); urine output, BUN/Cr daily

— Doxycycline: use with caution; rare hepatotoxicity

— Azithromycin: rare cholestatic hepatitis

— Quinine: hepatic metabolism — reduce dose

— Atovaquone: caution in severe hepatic disease

— Babesiosis is particularly severe and relapsing — treat for ≥6 weeks total and at least 2 weeks past first negative blood smear/PCR

— Consider triple/quadruple therapy (atovaquone + azithromycin + clindamycin ± quinine) for refractory cases

Elderly (>60):

Renal impairment:

Hepatic impairment:

Immunosuppression (functional asplenia, HIV with low CD4, post-transplant, B-cell depletion with rituximab/obinutuzumab):

G6PD deficiency: avoid primaquine, dapsone (not standard for these anyway); quinine generally safe but monitor for hemolysis.

Step 3 management: A 72-year-old farmer in Arkansas with fever, confusion, plt 60k, Cr 2.1 — admit, start IV doxycycline, supportive care for AKI, monitor closely for ARDS. Do not delay doxycycline awaiting serology; do not dose-reduce doxycycline for renal function.

Board pearl: Doxycycline does not need renal adjustment — this is high-yield versus aminoglycosides/vancomycin in renal failure scenarios.

Special Populations — Pregnancy and Pediatrics

— RMSF: mortality risk to mother is high; doxycycline is still recommended by CDC for confirmed/strongly suspected RMSF when alternatives inadequate — risk of maternal death outweighs theoretical fetal dental risk from short courses

— Historical alternative: chloramphenicol — but higher mortality, gray baby syndrome near term; avoid in third trimester

— Ehrlichiosis/anaplasmosis in pregnancy: doxycycline preferred; rifampin is an alternative for anaplasmosis specifically (not RMSF/ehrlichia)

— Babesiosis in pregnancy: atovaquone + azithromycin; transplacental transmission has been reported — screen neonate

— Doxycycline is first-line for RMSF, ehrlichiosis, anaplasmosis in children of ANY age (CDC, AAP, Red Book)

— Short courses (≤21 days) do not stain teeth or affect enamel — this paradigm shift is heavily tested

— Dose: 2.2 mg/kg/dose PO/IV BID (max 100 mg)

— RMSF kills children faster than adults; rash often atypical or absent early

— Babesiosis in children: atovaquone + azithromycin, weight-based

— DEET 20–30% or picaridin on skin, permethrin on clothing

— Tuck pants into socks, light-colored clothing

— Daily tick checks including scalp, behind ears, axillae, groin, popliteal fossae

— Shower within 2 hours of outdoor activity

— Prompt tick removal — risk of B. burgdorferi transmission rises sharply after 36–48 hours attachment

Pregnancy:

Pediatrics:

Lactation: doxycycline compatible with breastfeeding for short courses; minimal infant exposure.

Neonates with congenital babesiosis: consult ID/pediatric heme; treat with clindamycin + quinine.

Vaccination: none available for any of these (Lyme vaccine pipeline only).

Counseling — pediatric prevention:

Step 3 management: Pregnant patient in Oklahoma with fever, headache, palmar rash, plt 80k, Na 131 → doxycycline, not chloramphenicol, and disclose the rationale (maternal mortality > theoretical fetal risk).

Board pearl: "Don't give tetracyclines to kids" is wrong for suspected RMSF — doxycycline is the answer.

Complications and Adverse Outcomes

— Encephalitis, seizures, coma — long-term neurocognitive deficits in survivors of severe disease (especially children: hearing loss, paraparesis, cognitive impairment)

— Non-cardiogenic pulmonary edema/ARDS

— Myocarditis, arrhythmias

— DIC, purpura fulminans, digital/limb gangrene — may require amputation

— AKI from vasculitis and shock

— Death — 5–10% even with treatment; >20% if delayed >5 days

— Toxic shock-like syndrome, ARDS, meningoencephalitis

— Hemophagocytic lymphohistiocytosis (HLH) — consider in patients with fever, cytopenias, hyperferritinemia, splenomegaly

— Opportunistic superinfections (depresses cellular immunity)

— Mortality ~3% overall, higher in immunocompromised

— Generally milder; septic/toxic shock, ARDS, opportunistic infections (HSV, candida, aspergillus reported)

— Rhabdomyolysis, demyelinating polyneuropathy (rare)

— Mortality <1% treated

— Severe hemolytic anemia, jaundice, hemoglobinuria

— DIC, ARDS, CHF, AKI, splenic rupture/infarction

— Persistent/relapsing infection in immunocompromised → months of low-grade illness

— Mortality 5–10% in hospitalized; >20% in asplenic/immunocompromised

— Doxycycline: photosensitivity, pill esophagitis (take upright with water), GI upset

— Quinine: cinchonism (tinnitus, headache, vertigo), hypoglycemia, thrombocytopenia, QT prolongation

— Azithromycin: QT prolongation, hepatotoxicity

RMSF:

Ehrlichiosis (E. chaffeensis):

Anaplasmosis:

Babesiosis:

Drug-related:

Post-infectious sequelae: prolonged fatigue, myalgia (months) — not equivalent to "chronic Lyme"; supportive care.

Key distinction: A "sepsis-like syndrome without an obvious source" in a tick-exposure region should always be screened for tick-borne disease — bacterial cultures will be negative, and time-to-doxycycline determines survival.

Board pearl: Splenic rupture/infarction in babesiosis is a tested but rare complication — sudden LUQ pain + hypotension in a babesia patient.

When to Escalate — ICU, Consults, Inpatient Triage

— Hemodynamic instability requiring vasopressors

— Respiratory failure / ARDS / SpO₂ <90% on supplemental O₂

— Altered mental status, seizures, GCS decline

— DIC, active bleeding, purpura fulminans

— Babesia parasitemia ≥10% or rapid rise

— Severe AKI requiring RRT

— Severe hemolysis (Hgb <7, ongoing drop)

— Unable to tolerate PO

— Plt <50k, AST/ALT >5× ULN, Cr >1.5× baseline

— Age >60 or significant comorbidity

— Babesia parasitemia 4–10%

— Pregnancy with suspected/confirmed disease

— Uncertain diagnosis with toxic appearance

— Stable vitals, plt ≥50k, no organ dysfunction

— Reliable patient with follow-up in 48–72 hours

— Mild babesia parasitemia <4% in immunocompetent non-asplenic adult

— Infectious disease: all severe cases, immunocompromised, pregnant, treatment failure, suspected coinfection

— Hematology / transfusion medicine: babesia parasitemia ≥10% for exchange transfusion

— Critical care: ARDS, shock

— Neurology: seizures, encephalopathy

— Public health: RMSF, ehrlichiosis, anaplasmosis, and babesiosis are all nationally notifiable — report to local/state health department

— At discharge: confirm 48 hours of clinical improvement, complete antibiotic course outpatient, primary care follow-up in 1 week

— Document tick exposure counseling for prevention of re-infection

— Communicate pending serologies/PCR to outpatient provider

ICU criteria:

Ward admission criteria (any):

Outpatient management appropriate when:

Consults to consider:

Transitions of care:

CCS pearl: On the CCS case of severe RMSF with shock: transfer to ICU → IV doxycycline → norepinephrine for MAP ≥65 → cautious crystalloid (capillary leak) → daily CBC/CMP/coags → report to public health → ID consult.

Board pearl: Failure to defervesce within 48 hours of doxycycline → reconsider diagnosis (babesia coinfection? alternate dx?) and escalate care.

Differentials — Other Tick-Borne and Vector-Borne Causes

— Same vector as babesia/anaplasma (Ixodes scapularis)

— Erythema migrans, arthritis, carditis, neuro Lyme — generally less acutely ill, fewer cytopenias

— Treat with doxycycline (same drug — covers both Lyme and anaplasma)

— Amblyomma americanum (Lone Star tick)

— EM-like rash without systemic illness; doxycycline empirically

— R. parkeri rickettsiosis: Gulf Coast tick; eschar at bite site (vs RMSF — no eschar)

— Rickettsialpox: mites, urban; eschar + papulovesicular rash

— Murine typhus (R. typhi): fleas; Texas, southern CA

— Epidemic typhus (R. prowazekii): lice; outbreak settings

Lyme disease (Borrelia burgdorferi):

Southern tick-associated rash illness (STARI):

Other rickettsial diseases:

Tularemia (Francisella tularensis): Lone Star/Dermacentor; ulceroglandular form (eschar + LAD); treat with streptomycin/gentamicin (not doxycycline first-line for severe disease).

Powassan virus: Ixodes-borne flavivirus; encephalitis; no specific treatment.

Heartland virus, Bourbon virus: Lone Star tick; viral; supportive care.

Colorado tick fever: Rocky Mountain wood tick; biphasic fever, leukopenia.

Alpha-gal syndrome: Lone Star tick bite induces IgE to galactose-α-1,3-galactose → delayed anaphylaxis to mammalian meat (not infection but ddx for tick-exposed patient with unusual symptoms).

Malaria: in returned traveler with hemolysis and fever — smear shows pigment and schizonts (babesia: no pigment, Maltese cross). Travel history is key.

Key distinction: Eschar present? Think R. parkeri, rickettsialpox, scrub typhus, African tick-bite fever, tularemia — NOT classic RMSF. Eschar absent + palms/soles rash + endemic US? = RMSF.

Board pearl: A returned traveler from sub-Saharan Africa with fever, eschar, regional LAD, and rash = African tick-bite fever (R. africae) — also doxycycline-responsive.

Differentials — Non-Tick Causes

— Fever + petechial/purpuric rash + shock

— Younger patients, dorm/military, rapid progression hours not days

— Empiric ceftriaxone — and if suspected, add doxycycline anyway until RMSF excluded

— TTP: MAHA + thrombocytopenia + fever + neuro + renal — schistocytes on smear, ADAMTS13 <10%; treat with plasma exchange + steroids

— HUS: post-diarrheal, schistocytes, AKI dominant

— Acute leukemia: blasts on smear, cytopenias

— HLH: fever, splenomegaly, cytopenias, ferritin >500 (often >10,000), hypertriglyceridemia, hypofibrinogenemia

— Adult-onset Still's disease: quotidian fever, salmon rash, arthritis, ferritin ↑↑↑

— SLE flare: rash, cytopenias, multisystem

Meningococcemia:

Sepsis from other gram-negatives, staphylococcal/streptococcal toxic shock: consider blood cultures; cover broadly until tick-borne ruled out.

Viral hemorrhagic fevers / dengue / leptospirosis: travel history, conjunctival suffusion (lepto), thrombocytopenia, hemorrhage.

Acute HIV: fever, rash, lymphadenopathy, transaminitis — order HIV RNA and 4th-gen Ag/Ab; risk factors.

Secondary syphilis: rash on palms/soles, mucous patches, condyloma lata — RPR + treponemal test.

Measles: prodrome with cough, coryza, conjunctivitis, Koplik spots; cephalocaudal rash.

Drug reactions (DRESS, SJS/TEN): recent new medication, eosinophilia, mucosal involvement.

Hematologic emergencies mimicking labs:

Autoimmune:

Endocarditis: Janeway lesions, Osler nodes, splinter hemorrhages, murmur, embolic phenomena — blood cultures, TEE.

Key distinction: Schistocytes + thrombocytopenia + fever + neuro + renal → think TTP (not RMSF); peripheral smear differentiates. RMSF smear shows no schistocytes, no organisms — diagnosis remains clinical/serologic.

Board pearl: When fever + thrombocytopenia + MAHA appear in a tick-exposure patient, do both workups in parallel — empiric doxycycline + ADAMTS13 send-out — because misdiagnosis either way kills.

Secondary Prevention / Discharge Plan

— RMSF/ehrlichia/anaplasma: complete 5–7 days total, continue ≥3 days past defervescence

— Lyme coinfection: extend to 10–14 days

— Babesiosis: 7–10 days standard; ≥6 weeks if immunocompromised, until 2 weeks past clearance

— Doxycycline PO with discharge prescription; counsel on photosensitivity (sunscreen, hat, long sleeves), pill esophagitis (take with full glass of water, remain upright 30 min), GI upset

— Atovaquone with fatty meal (absorption); azithromycin — check for QT-prolonging meds

— Acetaminophen for residual myalgias; avoid NSAIDs in AKI/thrombocytopenia

— Permethrin-treated clothing, DEET 20–30% or picaridin on skin

— Avoid tall grass, leaf litter; stay on trails

— Daily full-body tick checks; check pets and gear

— Shower within 2 hours

— Tumble-dry clothing on high heat for 10 minutes to kill ticks

— Adult: doxycycline 200 mg × 1 dose

— Pediatric: 4.4 mg/kg × 1 (max 200 mg)

— Criteria: Ixodes scapularis attached ≥36 hours, prophylaxis within 72 hours of removal, endemic area

— History of babesiosis → lifetime deferral from blood donation (FDA)

— Donors in endemic areas are now screened for B. microti (NY, NJ, MA, CT, RI, MN, WI, NH, ME, MD, DE, DC, VA)

Antibiotic course completion:

Discharge medications:

Tick-bite prevention counseling (every visit, every season):

Single-dose doxycycline post-exposure prophylaxis (Lyme):

Blood donation:

Vaccination: none for these pathogens; ensure tetanus up to date, routine immunizations.

Step 3 management: Discharge bundle = (1) complete antibiotic course; (2) prevention counseling; (3) follow-up in 1 week; (4) report to public health; (5) babesia survivors counseled on lifetime blood donor deferral.

Board pearl: Post-babesiosis blood donation deferral is lifetime — a tested Step 3 detail.

Follow-Up, Monitoring, Rehab, Counseling

— 48–72 hours after starting therapy: assess defervescence, symptom improvement, repeat CBC/CMP if abnormal at baseline

— 1 week: clinical exam, ensure resolution of rash, normalization of labs

— 2–4 weeks: convalescent serology if needed for RMSF confirmation

— Babesiosis: weekly parasitemia (smear or PCR) until clearance; immunocompromised need extended monitoring

— Temperature, mental status, vital signs

— CBC with platelets, CMP (Na, Cr, LFTs), LDH/haptoglobin in babesia

— Coagulation if petechiae

— Babesia parasitemia % daily in hospitalized patients

— Fatigue, arthralgia, headache for weeks–months is common; supportive care, reassurance

— Persistent fever or worsening → reconsider diagnosis, coinfection (babesia in Ixodes patient), relapse, or alternative

— Severe RMSF survivors (especially children) may need audiology, neuropsych, PT/OT

— Schedule formal neurodevelopmental assessment in pediatric ICU survivors

— Risk of reinfection — endemic exposure continues; no lasting immunity

— Family/household prevention strategies

— Pet tick prevention (vet-prescribed acaricides)

— Recognize early symptoms — "if fever returns within 2 weeks of tick exposure, call us"

— Mental health: post-illness anxiety, fatigue, and (in severe cases) PTSD — screen and refer

— Pending labs (serologies) communicated to PCP

— Discharge summary lists treatment duration, follow-up plan, prevention counseling delivered

Outpatient follow-up cadence:

Monitoring parameters during active treatment:

Persistent symptoms post-treatment:

Cognitive/neurologic rehab:

Counseling content:

Public health reporting: confirmed cases reported to state health department; physicians complete case report forms.

Documentation for transitions of care:

Step 3 management: Schedule the 48-hour recheck before discharge from the ED for outpatient-managed cases — a missed early follow-up is the most common safety failure in tick-borne disease.

Board pearl: Convalescent serology at 2–4 weeks confirms RMSF retrospectively; it does not change acute management.

Ethical, Legal, and Patient Safety

— RMSF, ehrlichiosis, anaplasmosis, and babesiosis are nationally notifiable (CDC NNDSS)

— Physician obligation to report regardless of patient consent — overrides routine confidentiality for public health surveillance

— Failure to report can carry state-level penalties

— Historically, doxycycline avoided <8 yo for dental staining

— Current CDC/AAP guidance: doxycycline is the drug of choice for suspected RMSF in children of any age — short courses do not stain teeth

— Discuss the risk of withholding doxycycline (death) vs theoretical/refuted cosmetic risk; document shared decision-making

— If parent refuses, escalate via ethics consultation; in life-threatening RMSF, physician duty to treat may override parental refusal (analogous to other life-saving pediatric interventions — involve hospital legal/CPS as needed)

— Doxycycline in pregnancy for confirmed RMSF: maternal mortality without doxycycline far exceeds theoretical fetal risk; document discussion, obtain informed consent

— Pending serologies and parasitemia trends must be communicated to PCP — closed-loop follow-up is a Joint Commission patient safety priority

— Patients discharged on doxycycline must be counseled on photosensitivity, esophagitis (taking upright with water) — these are preventable harms

— Lifetime donor deferral for babesiosis history; donors in endemic areas screened

— Transfusion-transmitted babesia has caused fatal cases — clinicians must report suspected transfusion-transmitted infection to blood bank and FDA (Biological Product Deviation Report)

— RMSF mortality disproportionately affects Black patients and rural/uninsured — likely from delayed recognition of rash on darker skin and access barriers

— Tribal communities (Arizona) face high RMSF burden; engage public health partnerships

Mandatory public health reporting:

Pediatric doxycycline — informed consent nuance:

Pregnancy — risk communication:

Transitions of care risks:

Blood supply safety:

Health equity:

Step 3 management: When a parent refuses doxycycline for their child with suspected RMSF, the correct first step is education and shared decision-making with documentation, then escalate to ethics/legal if refusal persists — do not silently use a less effective alternative.

Board pearl: Withholding doxycycline from a child with RMSF for dental concerns is a medical error — heavily tested.

High-Yield Associations and Rapid-Fire Facts

— Dermacentor variabilis (American dog tick) — RMSF in eastern US

— Dermacentor andersoni (Rocky Mountain wood tick) — RMSF in western US

— Rhipicephalus sanguineus (brown dog tick) — RMSF in AZ tribal lands

— Amblyomma americanum (Lone Star tick) — ehrlichiosis, STARI, tularemia, alpha-gal

— Ixodes scapularis (blacklegged/deer tick) — Lyme, anaplasmosis, babesiosis, Powassan

— Maltese cross tetrads in RBCs → babesiosis

— Morulae in neutrophils → anaplasmosis

— Morulae in monocytes → ehrlichiosis (E. chaffeensis)

— Centripetal rash from wrists/ankles to trunk/palms/soles → RMSF

— Thrombocytopenia, leukopenia, transaminitis, hyponatremia

— RMSF, ehrlichia, anaplasma → doxycycline

— Babesia (mild) → atovaquone + azithromycin

— Babesia (severe) → clindamycin + quinine ± exchange transfusion

— Treated RMSF 5–10%; untreated/delayed >20–25%

— Treated babesia <5% immunocompetent; >20% asplenic/immunocompromised

— Asplenia + tick exposure = babesia until proven otherwise

— Transfusion-transmitted = babesia (most common parasitic transfusion infection in US)

— Coinfection of Lyme + anaplasma + babesia from single Ixodes bite is real

Vectors at a glance:

Pathognomonic/near-pathognomonic:

Lab quadrad of rickettsial/ehrlichial disease:

Treatment one-liners:

Mortality:

Don't forget:

Single-dose Lyme prophylaxis: doxycycline 200 mg once within 72 hours of Ixodes removal if attached ≥36 hours in endemic area.

Lifetime blood donor deferral after babesiosis.

Board pearl: When a question stem mentions Cape Cod, Nantucket, Block Island, Martha's Vineyard, eastern Long Island, expect babesia/Lyme/anaplasma. When it mentions North Carolina, Oklahoma, Arkansas, Tennessee, expect RMSF/ehrlichiosis.

Board Question Stem Patterns

Pattern 1 — "Spotless RMSF": Adult from Oklahoma, 6 days of fever/headache/myalgia, plt 70k, Na 131, AST 140, no rash yet. Best next step? → Start doxycycline empirically, send serology and PCR. Wrong answers: wait for serology, ceftriaxone alone, chloramphenicol.

Pattern 2 — Pediatric RMSF dilemma: 5-year-old, Tennessee, fever, headache, rash starting on wrists/ankles. Parents concerned about tooth staining. Best therapy? → Doxycycline regardless of age. Wrong answers: chloramphenicol, azithromycin, ceftriaxone.

Pattern 3 — Asplenic with babesia: Asplenic adult, Massachusetts, fever, fatigue, Hgb 8, LDH 800, indirect bili 3.5, smear shows intraerythrocytic ring forms and rare tetrads, parasitemia 12%. Management? → IV clindamycin + quinine + RBC exchange transfusion; admit ICU.

Pattern 4 — Coinfection: Northeast patient with EM rash treated for Lyme, returns with persistent fever, hemolysis, smear shows Maltese cross. Diagnosis? → Babesia coinfection. Treat: atovaquone + azithromycin (mild) added to doxycycline.

Pattern 5 — Morulae: Upper Midwest patient, summer, fever, plt 60k, AST 200, smear shows morulae in neutrophils. Diagnosis? → Anaplasmosis. Treat: doxycycline.

Pattern 6 — Pregnancy & RMSF: Pregnant patient with confirmed RMSF. Best treatment? → Doxycycline (CDC endorses; maternal mortality outweighs fetal risk).

Pattern 7 — Transfusion babesia: Recent transfusion recipient develops weeks later: fever, hemolysis, smear with ring forms. Diagnosis? → Transfusion-transmitted babesiosis. Report to blood bank.

Pattern 8 — Tick removal & prophylaxis: Hiker removes engorged Ixodes attached ~2 days in Connecticut. Best next step? → Single-dose doxycycline 200 mg within 72 hours.

Pattern 9 — Failure to defervesce: Patient on doxycycline 72 hours for presumed anaplasmosis, still febrile, hemolyzing. Next step? → Add atovaquone + azithromycin for babesia coinfection; verify with smear/PCR.

Pattern 10 — Mandatory reporting: Confirmed RMSF case — next administrative step? → Report to state public health department.

Board pearl: When in doubt on a tick question, the answer is almost always "start doxycycline now."

One-Line Recap

In a febrile patient with tick exposure and any combination of headache, thrombocytopenia, transaminitis, hyponatremia, or hemolysis, start empiric doxycycline immediately — and add atovaquone/azithromycin if babesiosis is suspected — because the diagnostic confirmation is retrospective but the mortality benefit is time-dependent.

Recognize: Geography + season + cytopenias + transaminitis = tick-borne until proven otherwise; rash on palms/soles in summer = RMSF until proven otherwise; intraerythrocytic Maltese cross = babesia; morulae in neutrophils = anaplasma, in monocytes = ehrlichia.

Treat: Doxycycline 100 mg BID (any age, including children and pregnancy when RMSF suspected) for rickettsial/ehrlichial/anaplasma disease; atovaquone + azithromycin for mild babesia; clindamycin + quinine ± RBC exchange transfusion for severe babesia (parasitemia ≥10%, asplenic, organ dysfunction).

Never delay doxycycline for serology — RMSF mortality climbs past day 5 of illness; defervescence within 48 hours both treats and supports the diagnosis.

Close the loop: Report to public health (nationally notifiable), counsel on prevention (DEET/permethrin, daily tick checks, 36-hour attachment threshold for Lyme prophylaxis), and remember lifetime blood-donor deferral after babesiosis plus screening for coinfection when Ixodes exposure produces atypical severity.

Step 3 management: The single most tested decision is "empiric doxycycline now" — and the second is recognizing the asplenic/immunocompromised babesia patient who needs exchange transfusion and prolonged combination therapy.

Board pearl: Time-to-doxycycline is the strongest modifiable predictor of survival in RMSF — when the question asks "next best step," the answer is the prescription, not the test.