01OverviewDefinition, clinical context and the essential points that orientate the chapter.
Epstein–Barr virus spreads mainly through saliva and infects oropharyngeal epithelium and B lymphocytes. Adolescents and young adults commonly develop the recognisable mononucleosis syndrome, whereas children may have mild disease. Fatigue can persist for weeks even after fever and throat symptoms resolve.
Diagnosis is clinical plus selective testing. Full blood count may show lymphocytosis and atypical lymphocytes; liver enzymes are often raised. Heterophile antibody testing is convenient but imperfect early in illness. EBV viral-capsid and nuclear-antigen patterns can establish acute versus previous infection when uncertainty changes counselling or investigation.
Management protects airway, hydration and spleen while avoiding iatrogenic harm. Antibiotics are used only for proven bacterial coinfection. Severe tonsillar obstruction, haemolysis, thrombocytopenia or neurological disease may require hospital and specialist management. Persistent nodes, cytopenia or systemic decline deserve reassessment rather than indefinite attribution to EBV.
Key points
- The typical syndrome combines fever, pharyngitis, posterior cervical lymphadenopathy and fatigue, but age and immune status alter presentation.
- Examine the airway, hydration, liver and spleen and ask about abdominal pain; tonsillar appearance alone cannot determine severity.
- A heterophile antibody test may be negative early or in younger people. EBV-specific serology clarifies timing when the diagnosis matters and the initial test is non-diagnostic.
- Avoid amoxicillin or ampicillin for uncomplicated suspected EBV because they do not treat the virus and commonly provoke a widespread rash.
- Treatment is usually rest, fluids and appropriate analgesia. Corticosteroids are not routine and are reserved for selected severe complications with specialist input.
- Advise no contact or collision sport, heavy lifting or other trauma-risk activity for at least the first month after symptom onset and until clinically recovered; use individual specialist review for ongoing splenomegaly or high-risk return.
- Consider acute HIV, cytomegalovirus, streptococcal tonsillitis, toxoplasmosis, haematological malignancy and diphtheria where epidemiology or features do not fit.
02AetiologyUnderlying causes, associations and risk factors, with why each one matters.
Epstein-Barr virus exposure
Salivary transmission introduces EBV to the oropharynx, with close contact increasing exposure during adolescence and young adulthood.
Age-related expression
Primary infection is often mild in childhood but more commonly produces mononucleosis when first acquired during adolescence or adulthood.
Immune status
Altered cellular immunity changes clinical expression and increases the risk of persistent replication or EBV-associated lymphoproliferative disease.
03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.
- 1Oropharyngeal infection
EBV replicates in oropharyngeal tissue and infects B lymphocytes through specific surface receptors before spreading through lymphoid tissue.
- 2B-cell expansion
Infected B cells circulate and activate, while viral latency allows lifelong persistence after the acute illness resolves.
- 3Cytotoxic immune response
Reactive T lymphocytes expand to control infected B cells, producing atypical lymphocytosis, lymph-node enlargement and systemic symptoms.
- 4Reticuloendothelial enlargement
Immune-cell proliferation in liver and spleen causes hepatitis and splenomegaly, creating a temporary risk of splenic injury.
04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.
Fever, marked fatigue, exudative pharyngitis and posterior cervical or generalised lymphadenopathy with lymphocytosis support infectious mononucleosis.
Progressive tonsillar swelling, muffled voice, drooling, stridor, inability to swallow or respiratory effort requires urgent airway-capable assessment.
Left upper-quadrant or shoulder-tip pain, dizziness, hypotension or collapse during acute illness suggests splenic injury or rupture.
Prominent genital ulceration, cytopenias, progressive focal nodes, substantial jaundice or symptoms beyond the expected trajectory prompts a broader differential.
05InvestigationsWhat to request, why it matters and how to interpret it.
Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.
- 01
Full blood count and blood filmFirst step - Why
- Identify lymphocytosis, atypical lymphocytes, cytopenia and an alternative haematological pattern.
- Interpretation and limitations
- Atypical lymphocytes support but do not prove EBV. Severe anaemia, thrombocytopenia, blasts or persistent abnormalities require urgent review.
- 02
Heterophile antibody test - Why
- Provide rapid support for infectious mononucleosis in an appropriate age and illness window.
- Interpretation and limitations
- Early false negatives occur and sensitivity is lower in children. A positive result is interpreted with the syndrome rather than used as a population screen.
- 03
EBV-specific serology - Why
- Resolve acute, past or absent infection when heterophile testing is negative or diagnostic certainty matters.
- Interpretation and limitations
- Viral capsid IgM supports recent infection, while EBV nuclear antigen usually indicates later or past infection; laboratory pattern and immune status require interpretation.
- 04
Liver tests and coagulation when indicated - Why
- Assess common hepatitis and identify rare severe hepatic dysfunction.
- Interpretation and limitations
- Mild transaminase elevation is frequent. Marked jaundice, rising INR or encephalopathy is not routine and requires urgent specialist investigation.
- 05
Targeted alternative-infection testing - Why
- Investigate streptococcus, acute HIV, CMV, toxoplasma or diphtheria according to exposure and phenotype.
- Interpretation and limitations
- Avoid indiscriminate panels. Acute HIV requires the correct antigen-antibody or nucleic-acid pathway and appropriate consent and follow-up.
06Differential diagnosisRealistic alternatives and the features that help distinguish them.
Streptococcal tonsillitis
Prominent sore throat and exudate overlap; validated clinical assessment and bacterial testing identify patients who may benefit from antibiotics.
Acute HIV infection
Fever, rash, pharyngitis and lymphadenopathy with relevant exposure require the correct antigen-antibody and nucleic-acid pathway, consent and reliable result follow-up.
Cytomegalovirus or toxoplasmosis
Mononucleosis-like fever and atypical lymphocytes with negative EBV testing suggest alternative infections according to immune and exposure context.
Haematological malignancy
Persistent focal nodes, cytopenia, weight loss or blasts require haematology assessment and sometimes tissue rather than repeated viral attribution.
07ManagementImmediate care, first-line treatment, alternatives and escalation.
01Uncomplicated syndromeSupport recovery and protect the spleenFirst stepThe patient is stable, drinking and has no airway, hepatic, haematological or abdominal emergency.+
- 1Confirm the clinical pattern, use selective FBC and EBV testing when helpful and avoid antibiotics unless bacterial infection is established.
- 2Provide fluids, appropriate analgesia, rest and written advice about fatigue, alcohol while liver tests are abnormal and transmission through saliva.
- 3Advise no collision sport, heavy lifting or other trauma-risk activity for at least the first month after symptom onset and until clinically recovered, with individual review before high-risk return.
02Airway or severe complicationEscalate beyond routine supportive careEscalationThere is stridor, inability to swallow, severe cytopenia, neurological disease, hepatic failure or suspected splenic rupture.+
- 1Perform ABCDE, involve ENT, anaesthetic, surgical, haematology or liver teams according to the complication and obtain urgent blood tests and imaging without destabilising the airway.
- 2Use corticosteroids only for a selected severe indication through specialist care; treat bacterial coinfection or haemodynamic compromise on its own evidence.
- 3Monitor closely until airway, hydration, blood counts, liver function or abdominal findings have demonstrably stabilised.
03Diagnosis remains uncertainTest the competing syndromeHeterophile testing is negative early, exposure is atypical or symptoms and results do not fit EBV.+
- 1Review timing, sexual and travel exposure, medicines, vaccination and exact lymph-node distribution and inspect for rash, hepatosplenomegaly and mucosal disease.
- 2Use EBV-specific serology and targeted HIV, CMV, streptococcal, toxoplasma or haematological investigations rather than repeating one screening test indefinitely.
- 3Reassess persistent focal lymphadenopathy, cytopenia or systemic decline for malignancy or another chronic infection and arrange tissue when indicated.
Key medicines and prescribing safety2 treatments · regimens, roles and cautions+
Paracetamol
For most adults give 500 mg to 1 g by mouth at intervals of at least four hours, no more than 4 g daily.Reduce maximum exposure in low weight, liver dysfunction, malnutrition or heavy alcohol use, and check combination remedies to avoid overdose.
Corticosteroid for selected severe complication
Use a short specialist-directed systemic regimen only for threatened airway or another accepted severe immune complication.Not routine for fatigue or uncomplicated pharyngitis; exclude bacterial deep-neck infection, monitor glucose and secondary infection, and document the precise indication and stop plan.
08ComplicationsImportant consequences, why they occur and why they matter clinically.
Upper-airway obstruction
Marked tonsillar and pharyngeal inflammation can impair swallowing and ventilation and may require airway-capable specialist management.
Splenic rupture
Enlarged friable spleen can bleed spontaneously or after trauma, causing abdominal or shoulder pain, shock and emergency surgery.
Haematological or neurological disease
Haemolytic anaemia, thrombocytopenia, encephalitis, meningitis and neuropathy are uncommon immune-mediated complications that may require admission and specialist treatment.
Prolonged functional impairment
Fatigue and reduced exercise capacity can continue for weeks, disrupting study and work even after acute inflammation settles.
09Monitoring and follow-upTreatment response, safety checks and longer-term review.
- Reassess airway, swallowing and hydration promptly if throat swelling progresses or oral intake falls.
- Provide emergency advice for left upper-quadrant or shoulder-tip pain, dizziness and collapse; document the first-month restriction on contact sport, heavy lifting and trauma-risk work and the criteria for individual return.
- Repeat FBC or liver tests only when initial abnormalities are clinically important, worsening or needed to guide return to activity and treatment.
- Review persistent fever, focal lymphadenopathy, weight loss, cytopenia or deteriorating function for alternative infection or malignancy.
- Explain that fatigue may outlast infectivity and throat symptoms, while graded return to activity should avoid both premature trauma risk and unnecessary prolonged bed rest.
10Special situationsVariants, exceptions and circumstances that change the usual approach.
The rash is not simple penicillin proof
An aminopenicillin-associated rash during EBV does not automatically establish persistent IgE-mediated allergy; record the phenotype and arrange later assessment when relevant.
Early screening can be negative
A negative heterophile test in the first illness days should prompt timing-aware serology or reassessment rather than immediate exclusion.
The spleen may be silent
Palpation is insensitive for enlargement, so absence of a palpable spleen cannot alone authorise early collision sport.
Fatigue needs a second look when atypical
Persistent tiredness is common, but progressive nodes, anaemia, weight loss or organ dysfunction should not be labelled post-viral without reassessment.
11Common pitfallsFrequent interpretation and management errors.
- 01
Prescribing amoxicillin for exudative pharyngitis without assessing EBV.
- 02
Excluding infectious mononucleosis after one early negative heterophile test.
- 03
Using routine corticosteroids for uncomplicated sore throat or fatigue.
- 04
Clearing collision sport solely because the spleen is not palpable.
- 05
Attributing persistent focal lymphadenopathy and cytopenia indefinitely to previous EBV.