Multisystem Processes & Disorders

Mononucleosis: diagnosis and management

Clinical Overview and When to Suspect Mononucleosis

— Peak incidence ages 15–24 (high school and college students); seroprevalence reaches ~90% in adults globally

— In children <10, primary EBV is often subclinical or mild and nonspecific

— Reactivation occurs but is rarely the cause of the classic mono syndrome in immunocompetent hosts

— EBV (~90% of cases)

— CMV (~5–7%) — often older patients, less pharyngitis, more hepatitis

— Others: acute HIV, HHV-6, Toxoplasma gondii, adenovirus

— Adolescent or young adult with ≥1 week of sore throat, fatigue, fever, and posterior cervical lymphadenopathy

— Sore throat that fails to improve on a beta-lactam, especially with a generalized maculopapular rash after amoxicillin/ampicillin

— College athlete with persistent fatigue and LUQ discomfort (splenomegaly)

— Persistent fatigue lasting weeks to months after an apparent viral URI

— Prodrome of 3–5 days of malaise, headache, myalgias → classic triad of fever, pharyngitis, lymphadenopathy → fatigue that may persist 4–8 weeks or longer

— No isolation required beyond standard precautions; transmission via shared drinks, utensils, kissing

— Virus is shed intermittently in saliva for months after symptom resolution — total prevention is impractical, so counseling emphasizes avoiding contact sports and managing fatigue rather than quarantine.

Infectious mononucleosis (IM) is a clinical syndrome most often caused by primary Epstein-Barr virus (EBV, HHV-4) infection, transmitted via saliva ("kissing disease") with an incubation period of 30–50 days.

Epidemiology

Causative organisms (clinical mono syndrome)

When to suspect on the Step 3 stem

Clinical pearl on tempo

Board pearl: A young adult with exudative pharyngitis, a negative rapid strep, posterior (not just anterior) cervical adenopathy, and atypical lymphocytosis should trigger heterophile antibody testing before empirically retreating for "resistant strep."

Public health context

Presentation Patterns and Key History

— Fever (often 38.5–40°C, lasting 1–2 weeks)

— Pharyngitis/tonsillitis with exudates that can mimic GAS

— Lymphadenopathy — symmetric, tender, posterior cervical is the hallmark; may extend to axillary, inguinal

— Profound fatigue out of proportion to other symptoms — often the chief lingering complaint

— Headache, myalgias, anorexia

— LUQ or left shoulder pain suggests splenomegaly or, rarely, splenic rupture

— RUQ discomfort, nausea → hepatitis (subclinical transaminitis in ~80%)

— Periorbital or eyelid edema (Hoagland sign) early in course

— Faint maculopapular or petechial palatal rash in ~5% spontaneously

— Amoxicillin/ampicillin-induced morbilliform rash in 80–90% of EBV patients given these antibiotics — not a true penicillin allergy, mediated by transient immune dysregulation

— New intimate partner, dormitory living, recent kissing

— Sick contacts with similar prolonged sore throat

— Sexual history and HIV risk — acute retroviral syndrome can mimic mono exactly

— Travel, cat exposure (toxoplasmosis), blood transfusion (CMV)

— Severe sore throat with drooling, trismus, muffled "hot potato" voice, stridor → airway compromise from tonsillar hypertrophy or peritonsillar abscess

— Sudden severe abdominal/left shoulder pain → splenic rupture

— Jaundice, confusion, dark urine → hepatitis or hemolysis

Classic symptom triad (present in most adolescent/young adult cases)

Other high-yield history elements

Rash patterns

Exposure and risk history to elicit

Red flag symptoms requiring urgent eval

Key distinction: Streptococcal pharyngitis typically causes anterior cervical adenopathy and lacks profound fatigue or splenomegaly; mono causes posterior cervical chains and systemic symptoms. About 30% of mono patients have concurrent GAS colonization, so a positive rapid strep does not exclude mono if the clinical picture is atypical.

Duration counseling: acute phase 2–4 weeks; fatigue may persist 1–6 months — set expectations early to prevent repeat unnecessary visits.

Physical Exam Findings and Systemic Assessment

— Fever 38.5–40°C is typical; persistent high fevers >2 weeks warrant reassessment for complications or alternative diagnosis

— Tachycardia proportional to fever; hypotension is not part of uncomplicated mono — consider splenic rupture or sepsis if present

— Exudative tonsillitis: large, symmetric tonsils with white-gray or necrotic-appearing exudates ("dirty" exudates more than strep)

— Palatal petechiae at junction of hard and soft palate (~25–50%)

— Periorbital edema (Hoagland sign) — relatively specific

— Uvular edema; assess airway patency

— Posterior pharyngeal erythema and edema

— Posterior cervical lymphadenopathy — tender, mobile, symmetric, often striking

— Generalized adenopathy including epitrochlear, axillary, inguinal in ~50%

— Splenomegaly in ~50–60% (often clinically subtle; imaging detects more)

— Hepatomegaly in 10–20%; mild RUQ tenderness

— Spleen tip best palpated with patient in right lateral decubitus; avoid deep, repeated palpation (rupture risk)

— Generalized maculopapular rash, especially after recent aminopenicillin use

— Rare: jaundice, periorbital edema, urticaria

— Cranial nerve palsies, encephalitis, Guillain-Barré, transverse myelitis, "Alice in Wonderland" syndrome in children

— If a patient cannot manage secretions, has stridor, or tonsils nearly meet midline ("kissing tonsils"), evaluate for impending airway obstruction — admit, ENT consult, IV steroids, and consider lateral neck imaging.

Vital signs

HEENT

Lymphatic

Abdominal

Skin

Neurologic (uncommon but examinable)

Step 3 management: In an athlete or active adolescent with confirmed mono, document spleen size by exam at each visit and counsel that absence of palpable splenomegaly does NOT exclude splenic enlargement — ultrasound is more sensitive but routine US is not required for return-to-play decisions in non-contact athletes.

Pearl on airway assessment

Diagnostic Workup — Initial Labs and Heterophile Testing

— CBC with differential — hallmark is lymphocytosis (>50% lymphocytes) with >10% atypical lymphocytes (Downey cells)

— Heterophile antibody test (Monospot) — rapid latex agglutination detecting IgM antibodies that cross-react with horse/sheep RBCs

— LFTs — mild transaminitis in 80%; alk phos and bilirubin may rise

— Rapid strep ± throat culture if pharyngitis prominent (treat coinfection)

— Consider HIV RNA or 4th-gen Ag/Ab if any risk factors — acute HIV is the can't-miss mimic

— Sensitivity ~85% overall but only ~25–50% in the first week, climbing to 90%+ by week 2–3

— Specificity ~95–100%

— False negatives: early disease, children <4 years (poor heterophile response), non-EBV mono (CMV, toxo, HIV)

— False positives: rare — lymphoma, lupus, HIV, viral hepatitis

— Repeat in 5–7 days, or order EBV-specific serology (next chunk)

— Always reconsider acute HIV, CMV, toxoplasmosis, acute leukemia

— Blasts, pancytopenia, or extreme leukocytosis → urgent peripheral smear and heme/onc evaluation for acute leukemia

— Isolated severe neutropenia with no lymphocytosis → think drug or other viral etiology

— Hemolytic anemia with positive Coombs → EBV-associated cold agglutinin (anti-i) hemolysis

— Routine imaging is not indicated in uncomplicated mono

— CT neck only if peritonsillar/retropharyngeal abscess is suspected

— Abdominal US only if equivocal splenic findings change management (e.g., athlete return-to-play decisions in select cases).

Initial labs to order in a suspected mono presentation

Monospot performance characteristics

When monospot is negative but suspicion persists

CBC patterns suggesting alternative diagnosis

Board pearl: In a child <4 years old with a mono-like syndrome, skip the monospot and go directly to EBV-specific serology — heterophile antibodies are unreliable in this age group.

Avoid unnecessary testing

Diagnostic Workup — EBV-Specific Serology and Confirmatory Studies

— Heterophile-negative but clinical suspicion remains

— Children <4 years

— Atypical or prolonged course

— Pregnant patient (need to distinguish from CMV/toxoplasmosis)

— Immunocompromised host

— VCA-IgM positive → acute primary infection (rises early, falls by 3 months)

— VCA-IgG positive → appears early, persists for life (past or current)

— EA (early antigen) IgG → acute or reactivation; declines over 3–6 months

— EBNA-1 IgG → appears 6–8 weeks AFTER infection and persists for life

— Acute primary: VCA-IgM (+), VCA-IgG (+), EA (+/−), EBNA (−)

— Past infection: VCA-IgM (−), VCA-IgG (+), EBNA (+)

— Reactivation: VCA-IgG high, EA (+), EBNA (+), VCA-IgM usually (−)

— Susceptible (never infected): all negative

— Quantitative plasma/whole-blood EBV DNA — reserved for immunocompromised (post-transplant lymphoproliferative disease surveillance), CNS disease, or oncologic contexts

— Not used to diagnose routine mono

— CMV: CMV IgM, CMV PCR

— Acute HIV: HIV RNA viral load (Ab may be negative); 4th-gen Ag/Ab

— Toxoplasmosis: Toxoplasma IgM/IgG

— Acute hepatitis A/B/C if jaundice or marked transaminitis

When to use EBV-specific serology

EBV antibody panel interpretation (high-yield)

Classic serologic patterns

Key distinction: The presence of EBNA-1 IgG essentially rules out acute infection because it takes 6–8 weeks to develop — a useful "exclude acute" marker in confusing cases.

EBV PCR

Workup for mono-mimics if EBV negative

Step 3 management: A college student with classic mono, negative monospot at day 5, and persistent symptoms — repeat heterophile at day 10–14 OR order VCA-IgM/IgG and EBNA panel; do not start empiric antivirals or steroids while awaiting results.

Peripheral smear pearl: "atypical lymphocytes" are reactive CD8+ T cells responding to EBV-infected B cells — not malignant — and are seen in many viral illnesses, not just EBV.

Risk Stratification and Management Framework

— Mild/uncomplicated (most adolescents/young adults): outpatient supportive care

— Moderate: significant pharyngitis, dehydration, marked fatigue impairing function → still outpatient with close follow-up

— Severe/complicated: airway compromise, splenic rupture, severe hemolysis, hepatitis with coagulopathy, neurologic involvement → inpatient

— Rest as needed; gradual return to normal activity as tolerated

— Hydration — oral, IV only if cannot maintain

— Analgesia/antipyretics: acetaminophen or NSAIDs (use NSAIDs cautiously if thrombocytopenia or hepatitis)

— Saltwater gargles, throat lozenges for symptomatic pharyngitis

— Avoid alcohol for ~4 weeks if hepatitis

— Not indicated for EBV

— Avoid amoxicillin/ampicillin even if strep is suspected — use penicillin V or cephalexin if GAS coinfection confirmed

— Avoid contact/collision sports and strenuous activity for at least 3–4 weeks from symptom onset (some guidelines: 4 weeks for any sport, longer for contact)

— Light activity (walking, daily ADLs) is fine when symptoms allow

— Most splenic ruptures occur in the first 3 weeks, very rare after 4 weeks

— Symptom resolution + ≥3–4 weeks since onset for non-contact athletes

— Contact athletes: 4 weeks minimum; many providers add documented exam ± US showing normal spleen

— No evidence routine imaging changes outcomes for non-elite athletes

Approach the patient by severity tier

Core outpatient management principles

Antibiotics

Activity restriction — splenic rupture prevention

Return-to-play decision

CCS pearl: For a hospitalized patient with severe mono, your CCS order set should include: IV fluids, acetaminophen, monitor airway, continuous pulse ox, NPO if tonsillar swelling severe, ENT consult for airway concerns, and type & screen if splenic concerns — not routine antibiotics, not routine steroids unless airway compromise.

Counseling at first visit: expected illness duration (2–4 weeks acute, fatigue up to months), avoidance of contact sports, return precautions for abdominal pain/syncope.

Pharmacotherapy — Supportive and Targeted Agents

— Acetaminophen 650–1000 mg q6h PRN — preferred if transaminitis is mild and stable

— NSAIDs (ibuprofen 400–600 mg q6h, naproxen 500 mg BID) — effective for sore throat and fever; avoid if thrombocytopenia, severe hepatitis, or dehydration

— Indicated: impending airway obstruction from tonsillar hypertrophy, severe autoimmune hemolytic anemia or thrombocytopenia, severe CNS involvement, myocarditis

— Not routinely indicated for uncomplicated mono — no clear benefit on fatigue duration and theoretical concern about immunomodulation

— Typical regimen: prednisone 40–60 mg/day tapered over 1–2 weeks, or IV dexamethasone for acute airway

— Acyclovir, valacyclovir, ganciclovir reduce oropharyngeal EBV shedding but do NOT improve clinical course, duration of symptoms, or fatigue

— Not recommended for routine immunocompetent mono

— Considered in immunocompromised hosts with EBV-driven complications (e.g., PTLD, oral hairy leukoplakia) under specialist guidance

— Penicillin V 500 mg PO BID–QID × 10 days or amoxicillin — wait, avoid amoxicillin during active EBV

— Preferred: penicillin V or cephalexin 500 mg BID × 10 days

— Macrolides (azithromycin) acceptable but watch for rash

— Topical anesthetic lozenges/sprays (benzocaine, lidocaine viscous) for sore throat

— IV fluids for those unable to tolerate PO

— Antiemetics (ondansetron) for nausea

— Amoxicillin/ampicillin — characteristic rash

— Aspirin in children/adolescents — Reye syndrome risk

— Hepatotoxic agents during active hepatitis phase.

First-line pharmacotherapy is symptomatic

Corticosteroids — indications are narrow

Antivirals

Treatment of GAS coinfection

Other adjuncts

Board pearl: A board question showing a mono patient with worsening stridor and dyspnea expects you to order IV dexamethasone + ENT consult + airway monitoring in a monitored setting — NOT antivirals, NOT routine steroids "to shorten course."

Medications to avoid or use cautiously

Procedures and Inpatient Management Considerations

— IV dexamethasone 10 mg, repeat as needed; methylprednisolone alternative

— Head-of-bed elevation, supplemental O2 as needed

— ENT consult — may require nasopharyngeal airway, rarely intubation (difficult airway — prepare for fiberoptic technique)

— Awake fiberoptic intubation or surgical airway in extremis

— Tonsillectomy is not acute treatment; abscess drainage (peritonsillar) if coexisting

— Sudden LUQ/left shoulder pain, hypotension, tachycardia

— Resuscitate: 2 large-bore IVs, crystalloid bolus, type & cross

— FAST exam or CT abdomen to confirm

— Hemodynamically stable → observation in monitored setting, serial Hb, bed rest

— Unstable → emergent surgical consult; splenic artery embolization by IR is increasingly first-line for stable-but-bleeding patients to preserve spleen; splenectomy if uncontrolled

— Post-splenectomy: vaccinate against encapsulated organisms (pneumococcus, meningococcus, Hib), daily penicillin prophylaxis in children

— Cold agglutinin (anti-i) hemolysis or warm AIHA — corticosteroids; transfusion if symptomatic

— Severe ITP — steroids ± IVIG

— Lymph node biopsy if adenopathy persists >6 weeks despite resolution of other symptoms or has worrisome features (firm, fixed, supraclavicular, B symptoms) — rule out lymphoma

— Liver biopsy almost never required

— Activity restriction for ≥8 weeks, follow-up imaging, vaccination if splenectomy performed, MedicAlert bracelet.

Most mono is non-procedural — but anticipate these scenarios

Airway management for severe tonsillar obstruction

Splenic rupture management

Hemolytic anemia / ITP

Diagnostic procedures rarely needed

CCS pearl: For acute splenic rupture in mono, the high-yield CCS sequence is: ABCs → 2 large-bore IVs → IVF bolus → type & cross → FAST/CT → surgery consult → ICU admission → serial vitals and hemoglobin. Do not delay imaging for labs in unstable patients.

Discharge after splenic rupture

Special Populations — Elderly, Renal, and Hepatic Considerations

— IM is uncommon but increasingly recognized; presentation often atypical

— Less pharyngitis and lymphadenopathy; more prolonged fever, hepatitis, and jaundice

— Higher rate of hospitalization and complications

— Heterophile antibody sensitivity is lower in older adults — go to EBV-specific serology earlier

— Strongly consider CMV mononucleosis in this demographic — CMV is the most common cause of heterophile-negative mono in older adults

— Drug reaction (DRESS), lymphoma, acute HIV, autoimmune hepatitis, leptospirosis

— Always perform age-appropriate cancer screening before attributing prolonged constitutional symptoms to mono

— EBV-associated acute interstitial nephritis and rarely glomerulonephritis can occur

— Dose-adjust acyclovir/valacyclovir if used; ensure adequate hydration to avoid crystal nephropathy

— NSAIDs — avoid in significant CKD or AKI

— Transaminitis (mild, 2–3× ULN) in 80% is expected and self-resolving in 4–6 weeks

— Severe hepatitis with jaundice or coagulopathy is rare — exclude alternative causes (viral hepatitis A/B/C, autoimmune, drug-induced)

— Avoid hepatotoxic drugs (alcohol, high-dose acetaminophen, methotrexate hold) during active hepatitis

— Transplant recipients: monitor for post-transplant lymphoproliferative disorder (PTLD) — quantitative EBV PCR surveillance

— HIV: EBV drives oral hairy leukoplakia, primary CNS lymphoma, smooth muscle tumors in children

— Treatment may involve reducing immunosuppression, rituximab, antivirals — specialist-directed

Older adults (>40 years)

Differential broadens with age

Renal impairment

Hepatic involvement

Step 3 management: A 55-year-old with 3 weeks of fever, fatigue, transaminitis, and mild splenomegaly with a negative monospot — order CMV IgM/PCR, EBV VCA-IgM, HIV Ag/Ab + RNA, hepatitis panel, and consider lymphoma workup if adenopathy persists.

Immunocompromised patients

Board pearl: Heterophile-negative mono in a patient >40 → think CMV first, then HIV and toxoplasmosis; EBV is still possible but less likely.

Special Populations — Pregnancy, Pediatrics, and Athletes

— Primary EBV in pregnancy is uncommon (most women already seropositive) and generally not associated with fetal anomalies

— However, the mono-mimickers matter: primary CMV and Toxoplasma gondii in pregnancy carry significant fetal risk (congenital CMV: SNHL, microcephaly; toxo: chorioretinitis, hydrocephalus)

— Always test for CMV and toxoplasmosis in a pregnant patient with mono-like syndrome

— HIV testing per universal prenatal protocol; acute HIV in pregnancy mandates urgent ID/OB coordination

— Acetaminophen preferred for symptom control; avoid NSAIDs after 20 weeks (renal/PDA effects, oligohydramnios)

— Often subclinical or mild URI-like in children <10

— Heterophile antibody unreliable <4 years — use EBV-specific serology

— Classic Hoagland-style presentation more common in adolescents

— Avoid aspirin in children/adolescents — Reye syndrome

— School attendance: may return when afebrile and feeling well; no isolation required

— Activity restriction same as adults — no contact sports for ≥3–4 weeks

— Splenic rupture occurs in ~0.1–0.5%, typically within first 3 weeks

— Return-to-play guidance

— — Non-contact, low-intensity: after 3 weeks if asymptomatic

— — Contact/collision sports: minimum 4 weeks from symptom onset, asymptomatic, normal exam

— — Routine US not required, but some sports medicine programs use it in elite athletes

— Document discussion of risks; provide written return-to-play plan

Pregnancy

Pediatric considerations

Athletes

Step 3 management: A 19-year-old college football player diagnosed with mono on day 5 asks when he can return — counsel minimum 4 weeks from symptom onset, gradual return, avoid contact until cleared, and obtain US only if exam is equivocal or symptoms persist.

Board pearl: A pregnant patient with mono symptoms and a negative EBV serology should be evaluated for CMV and Toxoplasma, both of which cause congenital infections — this is a frequent USMLE distractor pattern.

Breastfeeding compatible with EBV/CMV in healthy term infants of seropositive mothers (CMV in preterm requires NICU-specific guidance).

Complications and Adverse Outcomes

— Mild thrombocytopenia and neutropenia are common and self-limited

— Autoimmune hemolytic anemia — cold agglutinin (anti-i) type, peaks 2–3 weeks into illness

— Severe thrombocytopenia/ITP, aplastic anemia (rare)

— Hemophagocytic lymphohistiocytosis (HLH) — rare, severe; fever, cytopenias, hyperferritinemia, hepatosplenomegaly

— Splenic rupture — 0.1–0.5%, mostly within first 3 weeks; may occur spontaneously without trauma

— Subcapsular hematoma

— Tonsillar hypertrophy with airway obstruction — most common indication for hospitalization

— Peritonsillar abscess (often bacterial coinfection)

— Transaminitis (very common, mild); rare severe hepatitis or fulminant liver failure

— Cholestatic hepatitis with jaundice

— Encephalitis, meningitis, transverse myelitis

— Guillain-Barré syndrome

— Cerebellar ataxia, especially in children

— Bell palsy, optic neuritis

— "Alice in Wonderland" syndrome — metamorphopsia (children)

— Myocarditis, pericarditis (uncommon)

— Acute interstitial nephritis, IgA nephropathy flare

— Chronic active EBV — rare; persistent symptoms with elevated EBV DNA >6 months

— EBV-associated malignancies: Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, primary CNS lymphoma in HIV, PTLD post-transplant, gastric carcinoma

— Association with multiple sclerosis — recent large epidemiologic data (Bjornevik 2022) support EBV as a near-necessary causal factor

— Chronic fatigue — fatigue may persist months; rarely meets ME/CFS criteria

Hematologic

Splenic

Airway

Hepatic

Neurologic (rare but examinable)

Cardiac

Renal

Long-term and chronic

Key distinction: Acute splenic rupture in mono is dramatic (sudden LUQ pain, hypotension), while subcapsular hematoma may be more insidious — both warrant urgent imaging and surgical consultation.

Board pearl: EBV is associated with endemic Burkitt lymphoma (African children, with malaria cofactor — t(8;14) c-myc), Hodgkin lymphoma (mixed cellularity), nasopharyngeal carcinoma (Southeast Asian adults), and PTLD in transplant recipients.

When to Escalate Care — Admission and Consultation Triggers

— Airway compromise: stridor, drooling, inability to manage secretions, "kissing tonsils"

— Severe dehydration with inability to tolerate PO despite outpatient measures

— Splenic rupture or subcapsular hematoma (suspected or confirmed)

— Severe hepatitis with coagulopathy, encephalopathy, or jaundice with bilirubin >5

— Severe cytopenias: Hb <7, plt <20K, severe neutropenia with fever

— Neurologic complications: encephalitis, GBS, transverse myelitis

— Myocarditis with troponin elevation or arrhythmia

— HLH — emergent hematology referral and possible ICU admission

— Impending or actual airway loss

— Hemodynamic instability from splenic rupture

— Fulminant hepatic failure

— Severe HLH, status epilepticus, respiratory failure

— ENT/Otolaryngology: airway compromise, peritonsillar abscess, persistent tonsillar hypertrophy

— General surgery: splenic rupture, severe abdominal pain

— Hematology: severe cytopenias, hemolysis, suspected HLH, persistent adenopathy concerning for lymphoma

— Infectious disease: immunocompromised host, chronic active EBV, atypical course

— Hepatology: severe or prolonged hepatitis

— Neurology: any CNS or peripheral nervous system involvement

— Return for: severe abdominal/left shoulder pain, syncope, worsening sore throat with drooling, jaundice, confusion, severe headache, persistent high fever >2 weeks

Indications for hospital admission

ICU triggers

Consultations to consider

CCS pearl: When ordering admission for severe mono with airway concerns, your CCS sequence should include: continuous pulse oximetry, IV access, IV fluids, IV dexamethasone, NPO, ENT consult, monitored bed (step-down or ICU), serial airway exams. Do not order routine antivirals.

Outpatient red-flag counseling at discharge

Step 3 management: A patient on day 10 with persistent fever, jaundice, and INR 1.8 needs admission, hepatology consult, repeat hepatitis serologies, and reassessment of medications — not outpatient reassurance.

Coordination of care — communicate diagnosis and activity restrictions clearly to school, athletic trainers, and primary care.

Key Differentials — Other Infectious Mono-like Syndromes

— Anterior cervical adenopathy, sudden sore throat, fever, palatal petechiae, NO posterior adenopathy or splenomegaly

— Centor criteria; rapid antigen + culture

— Concurrent GAS in ~30% of mono patients — positive strep does not rule out mono

— Treat: penicillin V or cephalexin; avoid amoxicillin

— Less pharyngitis and lymphadenopathy; more fever, fatigue, hepatitis

— Older adults more often affected; heterophile negative

— Diagnosis: CMV IgM, CMV PCR

— Important in pregnancy (congenital CMV)

— 2–4 weeks after exposure: fever, sore throat, rash, lymphadenopathy, mucocutaneous ulcers, GI symptoms

— Diagnosis: HIV RNA viral load (Ab may be negative) + 4th-gen Ag/Ab

— Always test in mono-like illness with risk factors — can't-miss diagnosis

— Generalized lymphadenopathy, mild systemic symptoms, less pharyngitis

— Cat exposure, undercooked meat

— Toxo IgM/IgG; important in pregnancy and immunocompromised

— More common in young children (roseola); rare in adolescents

— Pharyngoconjunctival fever; conjunctivitis prominent

— Marked jaundice, transaminitis often >10× ULN, RUQ pain

— Risk factors: travel, IVDU, sexual exposure

— Vesicles/ulcers, gingivostomatitis in children

— Pseudomembranous pharyngitis, bull neck

— Persistent pharyngitis → septic IJ thrombophlebitis with pulmonary septic emboli

— Young adults; persistent worsening sore throat with neck swelling/tenderness and respiratory symptoms

Group A streptococcal pharyngitis (GAS)

CMV mononucleosis

Acute HIV (retroviral syndrome)

Toxoplasmosis

HHV-6 mononucleosis-like syndrome

Adenovirus

Acute viral hepatitis (A/B/C)

Primary herpes simplex pharyngitis

Diphtheria (rare in US, consider in unvaccinated/travelers)

Lemierre syndrome (Fusobacterium necrophorum)

Board pearl: A young adult with mono-like syndrome AND a maculopapular rash, mouth ulcers, and high-risk sexual history → think acute HIV and order HIV RNA (not just Ab) — earliest detectable marker.

Key distinction: GAS lacks posterior adenopathy, splenomegaly, and atypical lymphocytes. CMV lacks pharyngitis. HIV adds mucocutaneous ulcers and rash. Toxo emphasizes nodes over throat.

Key Differentials — Non-Infectious Mimics

— Fatigue, fever, bleeding/bruising, bone pain

— CBC: blasts, pancytopenia, or marked leukocytosis

— Always review peripheral smear in atypical mono; blasts mandate urgent heme consult and bone marrow biopsy

— Painless, firm, persistent lymphadenopathy (especially supraclavicular)

— B symptoms: fever, drenching night sweats, weight loss >10% in 6 months

— Persistent adenopathy >4–6 weeks → excisional biopsy (not FNA)

— Fever, rash, lymphadenopathy, eosinophilia, hepatitis 2–6 weeks after starting drug (anticonvulsants, allopurinol, sulfonamides, vancomycin)

— Discontinue offending agent; supportive care; steroids for severe

— Young women, cervical lymphadenopathy, fever; self-limited; biopsy diagnosis

— Fatigue, lymphadenopathy, cytopenias, rash, arthralgias

— ANA, anti-dsDNA, anti-Smith

— Quotidian fevers, salmon-colored rash, arthritis, very high ferritin

— Bilateral hilar adenopathy, uveitis, erythema nodosum

— Regional lymphadenopathy after cat scratch/bite

— Chronic cervical adenopathy, especially in endemic areas/immunocompromised

— Fatigue, anterior neck tenderness, fever — uncommon mimic but consider in atypical cases

— Postinfectious in some cases (including post-EBV); diagnosis of exclusion after 6 months

Acute leukemia (ALL, AML)

Lymphoma (Hodgkin and non-Hodgkin)

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Kikuchi-Fujimoto disease

Systemic lupus erythematosus (SLE)

Adult-onset Still disease

Sarcoidosis

Cat scratch disease (Bartonella henselae)

Tuberculosis lymphadenitis ("scrofula")

Hyperthyroidism / subacute thyroiditis

Chronic fatigue syndrome / ME-CFS

Step 3 management: Persistent adenopathy >6 weeks, firm/fixed nodes, supraclavicular location, or B symptoms despite resolved acute syndrome → excisional lymph node biopsy and imaging (CT chest/abdomen/pelvis) to evaluate for lymphoma — do not continue to attribute to "post-mono."

Board pearl: A young adult with a "mono-like" picture but blasts on peripheral smear or pancytopenia needs immediate hematology evaluation — missed acute leukemia is a board-favorite catastrophic miss.

Secondary Prevention, Discharge Plan, and Long-Term Care

— Written instructions on diagnosis, expected course, activity restrictions

— Activity restriction: no contact/collision sports or strenuous activity for minimum 3–4 weeks from symptom onset; longer for contact athletes

— Hydration, rest, return-to-work/school when febrile-free and energy permits

— Avoid alcohol for ~4 weeks if hepatitis

— Avoid sharing food, drinks, utensils, kissing during acute illness (though shedding continues months)

— Acetaminophen or NSAIDs PRN

— Avoid hepatotoxins until LFTs normalize

— Avoid amoxicillin/ampicillin — document in chart and counsel patient

— Update problem list — but the amoxicillin rash is NOT a true allergy and should not preclude future use of penicillins if needed

— No EBV vaccine currently licensed (in development)

— Catch up on routine vaccines once acute illness resolves

— Counsel about EBV transmission via saliva — long-term shedding is intermittent

— Fatigue may persist 1–6 months; reassure most fully recover

— Discuss the association between EBV and multiple sclerosis if patient asks — strong epidemiologic link but absolute risk remains low

— In immunocompromised patients (transplant), arrange EBV PCR surveillance

— In endemic regions, EBV is linked to nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin lymphoma, gastric carcinoma — no general population screening recommended

— Severe abdominal/left shoulder pain, syncope, worsening sore throat, jaundice, confusion, persistent high fever >2 weeks, persistent adenopathy >6 weeks

Discharge planning from outpatient or inpatient encounter

Medications to continue/avoid

Vaccines and prevention

Long-term considerations

Cancer screening implications

Return precautions to document

Step 3 management: On discharge after uncomplicated mono, schedule follow-up in 1–2 weeks to reassess fatigue, spleen size, and LFTs (if previously abnormal); avoid blanket sports clearance — re-evaluate at the 3–4 week mark.

Workplace/school accommodation letters may be appropriate for prolonged fatigue — encourage gradual return rather than complete inactivity.

Follow-Up, Monitoring, and Counseling

— First follow-up: 1–2 weeks after diagnosis

— Reassess: symptom trajectory, spleen size, hydration, ability to work/study

— Repeat LFTs if previously elevated, until trending toward normal

— Second follow-up: 3–4 weeks — return-to-sport clearance discussion, screen for residual fatigue

— If symptoms or adenopathy persist >6 weeks → broaden differential (lymphoma, chronic active EBV)

— Symptoms: fever curve, energy level, throat pain, abdominal pain

— Exam: spleen size, lymph nodes, hydration, mental status

— Labs (only if indicated, not routine): CBC for cytopenias, LFTs if hepatitis, repeat as clinically warranted

— Document conversation in chart

— Non-contact sports: gradual return after 3 weeks if asymptomatic

— Contact/collision: minimum 4 weeks, asymptomatic, normal exam

— Consider US for elite or scholarship athletes

— Prolonged illness in students/young adults can trigger anxiety, depression, academic disruption

— Screen with PHQ-2/PHQ-9 at follow-up

— Coordinate with school health services for academic accommodations

— Connect to counseling resources if fatigue exceeds 3 months

— EBV is shed in genital secretions and saliva; transmission via saliva predominates

— Routine precautions; not classified as an STI

— Hematology for persistent cytopenias or adenopathy

— Sports medicine for elite athlete clearance disputes

— Infectious disease for chronic active EBV or immunocompromised hosts

Follow-up cadence

Monitoring parameters

Return-to-play counseling for athletes

Mental health and quality of life

Sexual activity counseling

When to refer

Board pearl: Persistent fatigue alone at 6 weeks in an otherwise improving mono patient is expected and not a reason for extensive workup; persistent fever, weight loss, adenopathy, or hepatosplenomegaly at 6 weeks IS a reason for broader evaluation.

Step 3 management: Use shared decision-making for return-to-sport timing — provide patient and family with written guidance, and document risks/benefits discussion, especially for collegiate or scholarship-bound athletes.

Ethical, Legal, and Patient Safety Considerations

— Splenic rupture risk in athletes is small but real and potentially catastrophic

— Document shared decision-making, including risks of return prior to 4 weeks

— In minors, consent involves both adolescent assent and parental permission; college athletes typically consent themselves but team physicians should coordinate with athletic trainers

— Avoid pressure from coaches/programs to clear early — physician's duty is to patient

— When acute HIV is on the differential, obtain consent per state law — many states allow minors to consent to STI/HIV testing independently

— Disclose results sensitively; arrange linkage to care and partner notification (provider- or patient-assisted) per public health protocols

— Mandatory HIV reporting to public health in all US states; ensure compliance

— Provide accurate work/school notes — avoid overly restrictive duration that lacks clinical justification

— Privacy: minimum necessary disclosure; share diagnosis only with patient consent

— Avoid empiric antibiotics in pharyngitis without supportive testing

— Document amoxicillin/ampicillin rash clearly but do not label as penicillin allergy — this avoids future inappropriate avoidance of beta-lactams

— At ED-to-outpatient handoff, ensure clear instructions on activity restriction (especially splenic precautions), red-flag symptoms, and follow-up

— College health: coordinate with primary team if student returns home during recovery

— EBV/mono itself: not reportable

— Coinfections that may be detected (HIV, hepatitis B/C, syphilis, GAS-related acute rheumatic fever): reportable per state requirements

— Wrong-medication risk: avoid amoxicillin in suspected mono — review medication list and double-check

— Missed leukemia: peripheral smear review prevents catastrophic miss

— Missed splenic rupture: clear return precautions, athletic restriction, and documented exam

Return-to-play decisions and informed consent

Adolescent confidentiality and HIV testing

School and work documentation

Antibiotic stewardship

Transition of care safety

Mandatory reporting

Patient safety scenarios

Step 3 management: A 19-year-old college athlete with confirmed mono asks for clearance to play in a championship game at week 3 — physician should decline, explain rationale, document the conversation, and provide written restrictions; pressure from coach or athletic director is not a clinical indication.

High-Yield Associations and Rapid-Fire Clinical Facts

— VCA-IgM → acute

— VCA-IgG → ever infected

— EBNA → past infection (6–8 weeks post)

— Burkitt lymphoma (endemic, t(8;14), c-myc)

— Hodgkin lymphoma (mixed cellularity)

— Nasopharyngeal carcinoma (Southeast Asia)

— Primary CNS lymphoma in HIV

— Post-transplant lymphoproliferative disorder (PTLD)

— Gastric carcinoma (subset)

— Smooth muscle tumors in immunocompromised

EBV is in the herpesvirus family (HHV-4) — establishes latency in B lymphocytes via CD21 receptor

Atypical lymphocytes (Downey cells) = reactive CD8+ T cells, not infected B cells

Heterophile antibodies are IgM that agglutinate horse/sheep RBCs — cross-reactive, not EBV-specific

Classic triad: fever, exudative pharyngitis, posterior cervical lymphadenopathy

Splenomegaly in ~50–60%; splenic rupture risk highest in first 3 weeks

Amoxicillin/ampicillin → morbilliform rash in 80–90% — not true allergy

Hoagland sign = transient periorbital/eyelid edema

EBV serology mantra

EBV-associated malignancies

EBV strongly associated with multiple sclerosis (Bjornevik 2022)

Oral hairy leukoplakia in HIV — corrugated white lateral tongue lesions, does NOT scrape off

X-linked lymphoproliferative disease (Duncan disease, SH2D1A mutation) — fatal EBV in males

Chronic active EBV — rare, persistent symptoms + high EBV DNA >6 months

Most common heterophile-negative mono cause: CMV, then HIV, then toxo

Mono without sore throat → suspect CMV

Mono with mucocutaneous ulcers + rash → suspect acute HIV

Mono in pregnancy → screen for CMV and toxoplasmosis

Avoid contact sports for 3–4 weeks minimum; 4+ weeks for contact athletes

Steroids only for airway obstruction, severe cytopenia, neurologic involvement, myocarditis

Antivirals (acyclovir) → NOT routinely useful

Lemierre syndrome — Fusobacterium → septic IJ thrombophlebitis with pulmonary emboli; severe sore throat that worsens

Board pearl: "Posterior cervical adenopathy + atypical lymphocytes + post-amoxicillin rash" is the pathognomonic Step 3 stem for EBV mono.

Board Question Stem Patterns

— 19-year-old college student with 1 week of sore throat, fatigue, fever; exudative tonsillitis, posterior cervical adenopathy, palpable spleen tip; CBC shows 60% lymphocytes with 15% atypical

— Best initial test: heterophile antibody (Monospot)

— Patient with sore throat treated empirically with amoxicillin develops generalized maculopapular rash on day 3

— Diagnosis: infectious mononucleosis with amoxicillin-induced rash; document but do NOT label as penicillin allergy

— Adolescent with classic mono picture but negative heterophile at day 4

— Next step: repeat heterophile in 5–7 days OR EBV-specific serology (VCA-IgM, EBNA)

— 50-year-old with 3 weeks fever, transaminitis, mild splenomegaly, negative monospot

— Next test: CMV IgM/PCR, also rule out HIV, toxoplasmosis

— Young adult with mono-like syndrome, mucocutaneous ulcers, rash, recent unprotected sex, negative monospot

— Next test: HIV RNA viral load (Ab may still be negative)

— Mono patient day 14 with sudden LUQ pain, left shoulder pain, hypotension after sneezing

— Management: IV fluids, type & cross, FAST/CT, surgery consult

— Mono patient with stridor, drooling, "kissing tonsils"

— Management: IV dexamethasone, ENT consult, airway monitoring, admit

— Football player with mono at week 3 asks to return

— Answer: defer, minimum 4 weeks from symptom onset, asymptomatic, normal exam

— "Mono" patient with pancytopenia or blasts on smear

— Answer: peripheral smear review, bone marrow biopsy, heme consult

— Pregnant patient with mono-like illness, negative EBV

— Next: CMV and Toxoplasma serology for congenital infection risk

Stem 1 — Classic presentation

Stem 2 — Amoxicillin rash

Stem 3 — Negative monospot, persistent symptoms

Stem 4 — Heterophile-negative mono in older adult

Stem 5 — Acute HIV mimic

Stem 6 — Splenic rupture

Stem 7 — Airway compromise

Stem 8 — Return to play

Stem 9 — Missed leukemia

Stem 10 — Pregnant patient

Board pearl: The most common "trick" on Step 3 mono questions is choosing antivirals or routine steroids — both are wrong for uncomplicated mono. Supportive care and activity restriction win nearly every time.

Stem-recognition shortcut: any young adult + posterior cervical nodes + atypical lymphs = EBV until proven otherwise.

One-Line Recap

Infectious mononucleosis is a primary EBV infection of adolescents and young adults presenting with fever, exudative pharyngitis, posterior cervical lymphadenopathy, splenomegaly, and atypical lymphocytosis — diagnosed by heterophile antibody (or EBV-specific serology in children <4 or heterophile-negative cases), managed with supportive care and 3–4 weeks of contact-sport restriction, with steroids reserved for airway/hematologic/neurologic complications and antibiotics avoided unless GAS is confirmed.

— Classic triad + atypical lymphocytes + positive monospot = EBV mono

— Heterophile-negative? → repeat in a week, or EBV VCA-IgM/EBNA; consider CMV, HIV, toxoplasmosis

— Supportive care: rest, hydration, acetaminophen/NSAIDs

— NO routine antivirals, NO routine steroids, NO amoxicillin

— Steroids only for: airway obstruction, severe hemolysis/thrombocytopenia, CNS involvement, myocarditis

— Avoid contact/collision sports minimum 3–4 weeks from symptom onset

— Splenic rupture risk highest in first 3 weeks

— Document return-to-play counseling

— Splenic rupture, airway obstruction, hepatitis, hemolysis, GBS, encephalitis, HLH

— Long-term: EBV-associated lymphomas, nasopharyngeal carcinoma, PTLD in transplant, strong MS association

Diagnosis pearl

Treatment pearl

Activity pearl

Complications pearl

Step 3 management: The exam rewards the candidate who recognizes that mono is a clinical diagnosis confirmed serologically, managed supportively, and counseled longitudinally — with appropriate restraint on antibiotics, antivirals, and steroids, and careful attention to splenic precautions, return-to-play, transition of care, and the small set of can't-miss mimics (acute HIV, acute leukemia, lymphoma, CMV in pregnancy).

Board pearl: When in doubt on a Step 3 mono stem, the right answer is almost always "supportive care, avoid contact sports, follow up in 1–2 weeks" — not antibiotics, not antivirals, not steroids.