Infectious Mononucleosis (Epstein-Barr Virus)

Meet the patient

A 19-year-old undergraduate turns up in the second week of a sore throat that has shrugged off two courses of something for the tonsils. He is washed out, febrile at 38.9 degrees C, his tonsils are carpeted in white exudate, and the nodes that hurt most run down the back of his neck — not the front.[1]

Two questions will decide his next fortnight, and they decide every mononucleosis stem on the exam: is this EBV or a mimic? (Monospot and serology answer that), and will his spleen survive the rugby match on Saturday? (the 3-to-4-week rule answers that). Hold those two questions and the whole topic lines up behind them.[2]

One virus, one triad, four pitfalls

Infectious mononucleosis is the acute, self-limiting syndrome of primary Epstein-Barr virus (EBV, HHV-4) infection, and its signature is a single triad — fever, exudative tonsillar pharyngitis, and posterior cervical lymphadenopathy — propped up by fatigue, splenomegaly, mild hepatitis, and atypical lymphocytes on the film.[1]

The disease is usually kind to the patient and cruel to the unwary doctor. It earns its exam weight through four pitfalls that examiners return to like a drumbeat, not through the mostly benign course itself:[1]

1. The ampicillin rash — diffuse and non-allergic in 80 to 100 percent of IM patients given ampicillin or amoxicillin, and the commonest reason a teenager leaves with a permanent penicillin-allergy label he does not deserve.[6]
2. Splenic rupture — rare, around 0.1 to 0.5 percent, but the killer of the condition; it peaks in week 2, and it is why contact sport is off the table for 3 to 4 weeks.[7]
3. Prolonged fatigue — symptoms linger for weeks to months in a meaningful minority; a few meet chronic-fatigue-syndrome criteria.
4. EBV oncogenicity — over a lifetime EBV drives endemic Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, EBV-positive gastric cancer, post-transplant lymphoproliferative disease, and oral hairy leukoplakia, and it is the strongest known risk factor for multiple sclerosis.[9][11]

Etymology for viva gold: mononucleosis names the blood film — the absolute lymphocytosis full of atypical mononuclear cells, not a single thing about the throat. Glandular fever and the kissing disease both point at the same salivary spread. The Downey cells take their name from Hal Downey, the anatomist who first drew them.[3]

EBV is the archetype of the acute viral syndrome in young adults, so the clinical job is four fixed moves: recognise the syndrome, confirm with Monospot and serology, exclude the mimics, and counsel on the two avoidances — amoxicillin and contact sport — all while watching for the rare, lethal complications. The rest of this page is those four moves, unpacked.[1][4]

The mononucleosis syndromes — one blood-film pattern, four causes

The word mononucleosis describes a blood film, not a virus. That absolute lymphocytosis with atypical lymphocytes turns up in four infections, and separating them at the bedside is a favourite viva fork:[3]

• EBV mononucleosis — the classic adolescent triad with exudative pharyngitis and marked cervical nodes; heterophile positive.
• CMV mononucleosis — older patients, less pharyngitis and adenopathy, more fever and fatigue; heterophile negative.[1]
• Toxoplasma mononucleosis — cervical nodes but no pharyngitis; ask about cats and undercooked meat.
• HIV seroconversion illness — rash, mucosal ulcers, and a sexual or blood-borne exposure history; never miss it.

EBV infection also wears several long-term faces worth naming in the same breath, because they are the complications and the oncology rolled into one list:[9]

• Symptomatic IM — the exam archetype; everything in this page.
• EBV hepatitis — transaminitis that dominates the picture, with or without jaundice.
• EBV neurological disease — meningoencephalitis, Guillain-Barre syndrome, transverse myelitis, Bell palsy, cerebellitis.
• EBV haematological disease — autoimmune haemolytic anaemia, immune thrombocytopenia, aplastic anaemia, disseminated intravascular coagulation, and haemophagocytic lymphohistiocytosis (HLH).
• Chronic active EBV disease (CAEBD) — a persistent IM-like illness with high EBV load and organ damage, most often in East Asia.[8]
• EBV in the immunocompromised — post-transplant lymphoproliferative disease (PTLD), and fulminant EBV-HLH in X-linked lymphoproliferative disease (Duncan syndrome).
• EBV-associated malignancies — endemic Burkitt, Hodgkin (nodular sclerosis and mixed cellularity), nasopharyngeal carcinoma, EBV-positive gastric cancer, and extranodal NK or T-cell lymphoma.[9]

Who gets it — and the age split that decides the picture

EBV is ubiquitous — over 90 percent of adults worldwide are seropositive — yet who actually falls ill with florid mononucleosis is decided almost entirely by the age at which they first meet the virus.[1][10]

• Age and geography shape everything. In low- and middle-income countries, including India, most children meet EBV by age 3 to 5 and barely notice — so florid IM is uncommon on the ward. In high-income settings, primary infection is postponed into adolescence and young adulthood (15 to 24 years), where the symptomatic rate jumps to around 30 to 70 percent of primary infections. The student with classic IM is, in short, a disease-of-affluence presentation.[1]
• Transmission is salivary. Intimate oral contact earned it the name kissing disease; shared utensils, toys, blood, and transplant spread it less efficiently. The virus sheds in saliva for months after primary infection and intermittently for life, and the incubation is a long 4 to 6 weeks.
• The risk factors that matter are intimate oral contact in young adults, crowded living, immunosuppression (solid-organ or stem-cell transplant, HIV), and one genetic landmine — X-linked lymphoproliferative disease (XLP, Duncan syndrome, SAP or SH2D1A mutation), in which a first EBV infection detonates fulminant, often fatal EBV-HLH.[10]

[1]

The CD21 handshake — and why the immune response IS the disease

EBV is a gamma-1 herpesvirus (Lymphocryptovirus): enveloped, double-stranded DNA, honed by evolution to do one thing supremely well — establish lifelong latency in B lymphocytes.[1][3]

Entry is a single handshake. The viral glycoprotein gp350/220 binds the CD21 (CR2) complement receptor on oropharyngeal epithelial cells and mature B cells. EBV replicates first in the nasopharyngeal and tonsillar epithelium, then infects B cells passing through the mucosa; its genome circularises inside the B-cell nucleus as an episome and settles into latency, expressing a restricted cast of latent proteins — EBNA-1, EBNA-2, EBNA-3A/B/C, EBNA-LP, LMP-1, and LMP-2.[3][9]

Polyclonal B-cell activation follows. EBNA-2 and LMP-1 mimic constitutively active CD40 and BCR signalling, so the infected B cells proliferate in a polyclonal wave — the engine behind the lymphocytosis, the lymphadenopathy and splenomegaly, and, over decades, EBV's contribution to B-cell malignancy.[9]

The cellular immune response IS the disease — remember this, it is the single most examinable mechanism in the topic. The fever, the swollen tonsils, the bone-deep fatigue — none of it is EBV killing cells. It is the vigorous CD8+ cytotoxic T-cell response hunting the infected B cells. Those atypical lymphocytes on the film, the Downey cells, are reactive antigen-experienced CD8+ T cells: large, with abundant basophilic cytoplasm that scallops around neighbouring red cells. That is why the lymphocytosis is reactive, not clonal — and why florid atypical lymphocytosis is not leukaemia until proven otherwise.[1][3]

Everyone forgets: the patient feels awful because his own T cells are winning, not because the virus is. The severity of IM tracks the vigour of the T-cell response, which is why adolescents — a brisk immune system meeting EBV for the first time — suffer far more than toddlers, who barely notice.[3]

Organ consequences cascade from reactive T cells and infected B cells infiltrating lymphoid tissue:[1]

• Lymph nodes and tonsils — reactive hyperplasia, cervical and generalised.
• Spleen — congestion, sinusoidal and red-pulp infiltration, and capsular distension and oedema. This is the pathology behind splenic rupture: a spleen that is enlarged, soft, and friable, with rupture risk peaking at weeks 2 to 3. Trivial trauma — sometimes no trauma at all — can rupture it.[7]
• Liver — portal and sinusoidal lymphocytic infiltrate drives the mild transaminitis seen in around 90 percent; jaundice is uncommon, around 5 percent.
• Bone marrow — suppressed megakaryopoiesis plus immune destruction give mild thrombocytopenia in around half; rarer are severe autoimmune haemolysis (Coombs-positive, anti-i specificity), aplastic anaemia, or DIC.
• Nervous system — neural, meningeal, and perivascular lymphocytic infiltrates underlie the EBV neurology (meningoencephalitis, Guillain-Barre, Bell palsy, transverse myelitis).
• Fatigue — poorly defined, probably cytokine-mediated (interferon-gamma, IL-6, TNF-alpha), reflecting sustained immune activation.

Latency programmes — the table that predicts the tumour

EBV persists for life in a small pool of memory B cells as a silent episome, reactivating periodically in the oropharynx. Its latent genes — especially EBNA-2 and LMP-1 — are B-cell growth-transforming; when latency is dysregulated (immunosuppression, malaria, host genetics, a c-myc translocation), EBV drives malignant B-cell and epithelial tumours. The latency programmes map so cleanly onto the tumours that the table below is a recurring viva:[9]

[9]

Read the table once and the management logic follows: latency I and II tumours are relatively invisible to the EBV-specific T-cell response, whereas the latency III programme of PTLD — unleashed by iatrogenic immunosuppression — is exquisitely sensitive to reducing immunosuppression and to rituximab.[9]

Recognise the triad — and the three named signs

Presentation is governed by age and immune competence. A previously well adolescent or young adult arrives with the triad; an older adult arrives with fever and jaundice and almost no nodes; an immunocompromised host arrives with HLH. Same virus, three faces.[1][2]

Prodrome (3 to 5 days): malaise, fatigue, anorexia, headache, myalgia, and chills — indistinguishable from any nonspecific viral illness, and the Monospot is usually still negative here.[1]

Established IM is the triad, fully expressed:[1]

• Fever — typically 38 to 40 degrees C, often peaking late afternoon or evening, settling over 1 to 2 weeks.
• Tonsillar pharyngitis — exudative; a white, grey-white, or yellow-green membrane on enlarged erythematous tonsils, with palatal petechiae that are nearly pathognomonic. Dysphagia and odynophagia can be severe.
• Lymphadenopathy — tender and symmetric; the posterior cervical chain is larger than the anterior, though it generalises to cervical, axillary, epitrochlear, and inguinal nodes. Epitrochlear nodes are a quiet pointer to a viral rather than streptococcal cause.
• Splenomegaly — palpable in around half, peaking in the second to third week, when the capsule is stretched and most vulnerable.
• Hepatomegaly and hepatitis — transaminitis in around 90 percent (usually mild); frank jaundice in around 5 percent.
• Cutaneous — the ampicillin rash (below); a morbilliform or urticarial EBV rash in around 5 percent of untreated patients; and periorbital oedema, the Hoagland sign, in up to a third.
• Fatigue — often the most disabling symptom; the patient is floored by trivial activity, and it can persist for weeks to months.[1]

The temporal arc is itself diagnostic — knowing the expected curve separates a normal protracted recovery from a complication, and it is the backbone of return-to-play advice:[2]

[1]

Three named signs carry disproportionate viva weight — commit them, because they are how a one-liner stem is built:[1]

[6]

The faces that are not the triad — atypical and dangerous

When IM is not the triad, it is at its most dangerous. Three groups break the classic mould and earn their own paragraphs:[10]

• The elderly present with prolonged fever, jaundice, and little lymphadenopathy — easily mistaken for lymphoma, hepatitis, or occult malignancy. The heterophile may be weak; send EBV serology.[10]
• The immunocompromised or XLP host — primary EBV in X-linked lymphoproliferative disease (Duncan syndrome, SAP or SH2D1A mutation), after transplant, or in congenital immunodeficiency detonates fulminant EBV-associated haemophagocytic lymphohistiocytosis (EBV-HLH): fever, hepatosplenomegaly, pancytopenia, ferritin often over 10,000 micrograms per litre, hypertriglyceridaemia, hypofibrinogenaemia, haemophagocytosis on marrow, high EBV viral load. Mortality is high without specific therapy — humour off, this is a haematology emergency.[8]
• Chronic active EBV disease (CAEBD) runs a persistent IM-like course with organ involvement (hydroa vacciniforme-like skin lesions, myocarditis, lymphoid interstitial pneumonitis), persistently high EBV DNA, and progression to EBV-positive T or NK-cell lymphoproliferative disease. The only curative therapy is haematopoietic stem-cell transplantation.[8]

The mimics that bite — the heterophile-negative fork

A young adult with fever, sore throat, and nodes is not always EBV — and the three mimics most often missed are CMV, HIV seroconversion, and group-A strep. Make the distinction at the bedside:[1][5]

[1]

The classic trap: a heterophile-negative mono illness is not a failed Monospot — it is an instruction to look harder. CMV, HIV seroconversion, and toxoplasmosis all hide behind a negative Monospot, and missing HIV seroconversion is the one with lifelong consequences.[5]

The bedside round — examine the abdomen gently

Examination rarely secures the diagnosis in IM; its job is to screen for the complications that change management. Run it in this order:[1][4]

• Vital signs and airway first — fever pattern and hydration, and critically stridor, drooling, a muffled hot-potato voice, dyspnoea, or intercostal recession: the signs of impending airway obstruction from massive tonsillar or adenoidal hypertrophy, a surgical emergency.
• Throat — exudate, palatal petechiae, exclude a peritonsillar abscess.
• Lymph nodes — size, tenderness, distribution (cervical, epitrochlear, axillary, inguinal); hard, fixed, or supraclavicular nodes suggest malignancy, not IM.
• Abdomen — palpate gently. Examine for splenomegaly and hepatomegaly without pummelling the spleen (rupture risk), and actively look for peritoneal signs, LUQ tenderness, or shoulder-tip referred pain — the Kehr sign — that would signal splenic rupture.
• Skin — ampicillin rash, jaundice, periorbital oedema.
• Neurology — any meningism, cranial-nerve deficit, weakness, or altered consciousness prompts assessment for EBV neurology (meningoencephalitis, Guillain-Barre, Bell palsy, transverse myelitis).[1]

Escalate immediately for airway compromise; splenic rupture (LUQ pain, falling haemoglobin, shock); severe thrombocytopenia with bleeding; severe haemolysis (falling haemoglobin, jaundice); neurological signs; or an HLH picture (high fever, hepatosplenomegaly, cytopenias, high ferritin) in the immunocompromised.[1]

Two tests do the work — Monospot then serology

Diagnosis is clinical, confirmed by Monospot and EBV-specific serology; the film and LFTs are the supporting cast.[1][4][5]

The first-line work-up:[1]

• Full blood count and film — lymphocytosis (over 50 percent, or absolute lymphocytosis over 4.5 x 10⁹ per litre) with atypical lymphocytes over 10 percent of lymphocytes — the Downey cells. Three forms are described: type I (small, round, hyperchromatic), type II (the commonest — large cells with abundant basophilic cytoplasm that scallops around neighbouring red cells, the one undergraduates picture), and type III (large, plasmacytoid, deeply basophilic with a perinuclear hof). All three are reactive CD8+ T cells, not blasts. Mild thrombocytopenia in around half; haemoglobin usually normal unless autoimmune haemolysis supervenes.
• Heterophile antibody (Monospot or Paul-Bunnell-Davidsohn) — detects IgM that agglutinates horse, sheep, or bovine red cells. The classical differential absorption separates true heterophile from Forssman antibody: heterophile is absorbed by beef (ox) cells but NOT by guinea-pig kidney, while Forssman is absorbed by guinea-pig kidney. Sensitivity around 85 percent, specificity around 97 percent in adults. It turns positive in the first week, peaks at 2 to 3 weeks, and may persist up to a year.[1]
• EBV-specific serology (definitive) — the antibody pattern that pins down the disease phase (table below).
• Liver function tests — AST and ALT typically 2 to 3 times the upper limit (mild hepatitis in around 90 percent); bilirubin mildly raised; LDH raised (lymphocyte turnover); gamma-GT often mildly elevated. Coagulation is usually normal; a rising INR means severe hepatitis or fulminant failure — urgent hepatology.
• Cold agglutinins — a low-titre anti-i autoantibody in around 50 to 70 percent during the second week; high titre produces cold autoimmune haemolytic anaemia (complement-mediated, Coombs-positive with anti-C3), the mechanism of the haemolytic complication and occasionally a Donath-Landsteiner-type picture.
• EBV DNA PCR (quantitative) — reserved for the immunocompromised, CAEBD, suspected CNS disease (CSF), and PTLD monitoring; not for routine immunocompetent IM, where serology suffices. Whole-blood PCR beats plasma in PTLD surveillance.

Two Monospot traps worth a viva mark each: it is negative in children under 4 years (who do not mount a heterophile response — only around 30 percent are positive under age 12), and it is negative in the first few days of illness — recheck at week 2, or go straight to EBV serology.[5]

EBV antibody kinetics are the highest-yield exam fact in the topic. VCA IgM appears first (peaks at 2 to 3 weeks, fades by 3 to 6 months); VCA IgG appears early and persists for life; EA (early antigen, diffuse) IgG appears in acute infection and fades over months; and EBNA IgG appears late — only after 3 to 4 weeks — and persists for life. That late EBNA is the discriminator: VCA IgM positive plus EBNA IgG negative is acute IM; VCA IgG positive plus EBNA IgG positive is past infection.[1]

[1]

The diagnostic algorithm matches the test to the context and stops you over-testing or mislabelling:[4][5]

[1]

Imaging is selective. Abdominal ultrasound measures the spleen and screens for rupture (free intraperitoneal fluid) when there is LUQ pain; CT abdomen is more sensitive for rupture and characterises a splenic laceration. A chest X-ray is unnecessary unless a complication (effusion, pneumonitis) is suspected.[1]

Test for strep co-infection with Centor or McIsaac plus a rapid strep or throat swab. Streptococcal co-infection occurs in around 5 to 30 percent of IM — but it never justifies ampicillin or amoxicillin; use phenoxymethylpenicillin or cephalexin.[5]

Do NOT send the atypical lymphocytes down a leukaemia pathway unless they are bizarre, persistent, or accompanied by significant cytopenias — then blood film, flow cytometry, and marrow.[1]

The 3-to-4-week rule — and the drugs to refuse

Uncomplicated IM is treated with rest, analgesia, and patient counselling — the trick is knowing what to refuse, not what to prescribe.[1][4][5]

1. Supportive care is the mainstay:[1]

• Rest as tolerated — strict bed rest is not required unless the illness is severe; pace activity to symptoms.
• Hydration and a nutritious diet.
• Antipyretic and analgesic: paracetamol 1 g orally every 6 hours (adult; maximum 4 g per day), or ibuprofen 400 mg every 8 hours, for fever, throat pain, and headache. Avoid codeine or opioids if the airway is under threat.
• Salt-water gargles and throat lozenges for odynophagia.[1]

2. Drugs to refuse:[1]

• AVOID ampicillin, amoxicillin, and where possible cefprozil — they trigger the diffuse maculopapular rash in 80 to 100 percent of IM patients.[6] If a beta-lactam is genuinely needed for proven streptococcal co-infection, use phenoxymethylpenicillin (penicillin V) 500 mg orally four times daily for 10 days, or cephalexin, or azithromycin if penicillin-allergic.
• AVOID alcohol during the hepatitis phase.
• AVOID contact sport, strenuous exercise, heavy lifting, and abdominal trauma for a minimum of 3 to 4 weeks from onset — until the patient is asymptomatic, the spleen is non-palpable or normal on ultrasound, and the bloods are normal.[7]

3. Drugs that are NOT routinely indicated:[1]

• Corticosteroids are not recommended for symptom control in uncomplicated IM — Cochrane 2015 found no consistent benefit and a theoretical risk of secondary infection and rebound. Reserve steroids for impending airway obstruction, severe thrombocytopenia with bleeding, autoimmune haemolytic anaemia, severe neurological complications, and HIV-associated EBV.[4] A typical regimen is prednisolone 0.5 to 1 mg per kg per day (maximum 60 mg) for 5 to 10 days, tapered.
• Antivirals (aciclovir, valaciclovir, ganciclovir) reduce oropharyngeal EBV shedding but do not alter the clinical course of uncomplicated IM — not recommended.[4]

4. Activity restriction and return-to-play:[7]

• 3 weeks minimum off all contact sport and vigorous exertion, in every patient — including those without palpable splenomegaly, because the spleen can be enlarged and friable without being clinically palpable.
• 4 weeks for competitive athletes; some sports-medicine guidance requires an ultrasound at 3 to 4 weeks confirming the spleen has returned to normal before return.
• Graded return once asymptomatic, with a normal spleen and normal bloods.[1]

5. Patient counselling seals the visit: explain the 2-to-3-week acute course, that fatigue may persist for weeks to months, the drug and activity avoidances, and the warning signs that mandate return — LUQ or shoulder-tip pain, dyspnoea, bleeding, severe headache, weakness, confusion.[1]

When IM becomes an emergency — SPLAAT

Most IM is ambulatory and self-limiting; resuscitation is reserved for the rare, life-threatening complications. Humour is off here — these are the pathways that kill the patient if you miss them.[1][7]

Airway obstruction (massive tonsillar or adenoidal hypertrophy, drooling, stridor):[1]

• Urgent ENT and anaesthetic involvement.
• Sit upright, humidified oxygen, nebulised adrenaline if stridor.
• IV dexamethasone 0.6 mg per kg (maximum 10 mg) once, then oral prednisolone for a short course.
• Be ready to secure the airway (nasopharyngeal airway, expert intubation, rarely tracheostomy) — the inflamed, friable tissue makes this difficult.[1]

Splenic rupture (LUQ pain, shoulder-tip or Kehr sign, falling haemoglobin, shock):[1]

• ABC, two large-bore IV cannulae, crossmatch, IV crystalloid resuscitation, treat for haemorrhagic shock.
• Urgent focused ultrasound (FAST) or CT abdomen.
• Urgent surgical referral; many stable ruptures are managed non-operatively (observation, bed rest, serial haematocrit) — unstable or continuing bleed means splenectomy or splenic artery embolisation.[1]

Autoimmune haemolytic anaemia (severe Coombs-positive with anti-i antibody, falling haemoglobin): transfuse if symptomatic; IV corticosteroids (prednisolone 1 mg per kg per day).[1]

Severe thrombocytopenia with bleeding: IVIG (1 g per kg per day for 1 to 2 days) and/or corticosteroids; platelet transfusion only if actively bleeding.[1]

EBV-HLH (XLP, immunocompromised): treat per the HLH-2004 protocol (etoposide, dexamethasone, ciclosporin), with EBV-targeted rituximab for B-cell disease; refer urgently to a haematology or immunology centre.[8]

[1]

The subtypes that bite

The same virus behaves differently in different hosts — name the subtype and the management follows.[1]

• Classic adolescent IM — the archetype; managed supportively with the counselling above.
• Childhood EBV — usually asymptomatic or mild; heterophile often negative, so rely on EBV serology (VCA IgM). Supportive.
• CMV mononucleosis — the commonest mimic; older patients, less pharyngitis and adenopathy, heterophile negative, CMV IgM positive. Supportive.
• EBV hepatitis — predominant transaminitis with or without jaundice; usually self-limiting; supportive.
• EBV neurological disease — meningoencephalitis (CSF lymphocytic pleocytosis, EBV DNA PCR positive), Guillain-Barre syndrome (ascending paralysis — support or IVIG), Bell palsy, transverse myelitis, cerebellitis. Steroids considered for severe disease; supportive plus neurology input.
• EBV haematological disease — autoimmune haemolytic anaemia (anti-i antibody, Coombs positive; transfuse plus or minus steroids), immune thrombocytopenia (steroids or IVIG), rare aplastic anaemia, DIC, and EBV-HLH.
• Chronic active EBV disease (CAEBD) — persistent IM-like illness, high EBV load, organ damage (skin, marrow, heart, lung); haematopoietic stem-cell transplantation is the only curative therapy.[8]
• PTLD in transplant recipients — EBV-driven B-cell proliferation under immunosuppression; managed by reducing immunosuppression, rituximab (anti-CD20) for CD20-positive disease, and R-CHOP for overt lymphoma. Monitor EBV DNA viral load post-transplant.[9]
• EBV-associated malignancies (lifetime risk): endemic (African) Burkitt lymphoma (EBV in over 95 percent; t(8;14) c-myc translocation; jaw mass in children), Hodgkin lymphoma (EBV in around 40 percent overall, higher in mixed-cellularity and HIV), nasopharyngeal carcinoma (almost 100 percent EBV; South Chinese or Cantonese predisposition), EBV-positive gastric cancer (around 10 percent of gastric adenocarcinomas), extranodal NK or T-cell lymphoma (nasal type), and oral hairy leukoplakia (HIV, on the lateral tongue).[9]

Complications by clock — SPLAAT

The complications of IM sort by system, but what examiners want is the named mnemonic and the clock for each.[1]

Haematological: autoimmune haemolytic anaemia (Coombs-positive, anti-i; 1 to 3 percent), immune thrombocytopenia, rare aplastic anaemia, DIC, and EBV-HLH (especially XLP or immunocompromised).[1]

Splenic: splenic rupture (around 0.1 to 0.5 percent; peaks weeks 2 to 3; LUQ pain, Kehr sign, falling haemoglobin; some cases atraumatic).[7]

Airway: impending airway obstruction from massive tonsillar or adenoidal hypertrophy — rare, but a surgical emergency, more common in children and young adults.[1]

Hepatic: mild hepatitis in around 90 percent; jaundice in around 5 percent; rare fulminant hepatic failure; pancreatitis uncommon.[1]

Neurological (1 to 5 percent): meningoencephalitis, Guillain-Barre syndrome, transverse myelitis, Bell palsy, optic neuritis, cerebellitis.[1]

Cardiac (rare): myocarditis, pericarditis, rarely heart block. Renal: interstitial nephritis, microscopic haematuria. Pulmonary: interstitial pneumonitis, pleural effusion.[1]

Prognosis and who goes home

Almost every patient goes home — the skill is naming the few who do not.[1]

• Acute illness (fever, pharyngitis) settles in 1 to 2 weeks; lymphadenopathy and splenomegaly over 3 to 6 weeks.
• Fatigue persists weeks to months in around 10 to 20 percent; a small minority meet chronic-fatigue-syndrome-like criteria — reassurance and graded activity are the treatment.
• EBV infection is lifelong — intermittent reactivation and salivary shedding continue, and the oncogenic potential persists.
• Overall mortality is very low; death is from splenic rupture, airway obstruction, neurological disease, HLH, or underlying immunodeficiency (XLP).[1]

Disposition. Admit for airway compromise (ENT, anaesthetic, HDU); splenic rupture (surgical); severe cytopenias, haemolysis, or bleeding (haematology); neurological complications (neurology, watch for GBS respiratory involvement); severe hepatitis or dehydration; immunocompromise, HLH, or PTLD (specialist team); or social concerns (the student who cannot manage at home).[1]

Special populations

Examiners use these scenarios heavily on NEET-PG and INICET — same virus, different thresholds.[1]

• Athletes and the military. Serial ultrasound of the spleen; NO contact sport for a minimum of 3 to 4 weeks (competitive athletes often 4 weeks), and a graded return-to-play only once asymptomatic with a normal spleen and normal bloods. Document the counselling — splenic rupture is a leading cause of avoidable death in this group.[7]
• Pregnancy. Primary EBV is rare in pregnancy (most women are already seropositive); where it occurs the disease is self-limiting and no proven teratogenicity has been shown — CMV, not EBV, is the herpesvirus that harms the fetus. Manage supportively; avoid ampicillin, amoxicillin, and contact sport.
• Immunocompromised or transplant. Monitor EBV DNA viral load; reduce immunosuppression at the first sign of PTLD; rituximab for CD20-positive PTLD; R-CHOP for overt lymphoma. Primary EBV can be fulminant.[9]
• X-linked lymphoproliferative disease (Duncan syndrome, SAP or SH2D1A mutation). Primary EBV triggers fulminant EBV-HLH with high mortality; refer urgently for HLH-2004 therapy and consider haematopoietic stem-cell transplantation.[8]
• Children. Usually mild or asymptomatic; heterophile negative — send EBV serology; supportive care.
• Elderly. Atypical — prolonged fever, jaundice, less adenopathy; send EBV serology and exclude malignancy and HIV.

The evidence that anchors practice

A handful of papers settle every IM argument — know them by name and conclusion.[4]

• Cochrane 2015 (Reitman et al., Cochrane Database Syst Rev). Antivirals (aciclovir, valaciclovir) and corticosteroids do not improve symptom control in uncomplicated IM; steroids are not recommended routinely.[4]
• Systematic review of splenic rupture (Bartlett et al., Injury 2016). Rupture is rare but peaks at week 2; many cases are managed non-operatively; case fatality is low with prompt recognition.[7]
• Updated CAEBV guidelines (Kawada et al., Int J Hematol 2023). Haematopoietic stem-cell transplantation is the only curative therapy for CAEBD; EBV DNA load thresholds and rituximab or cytotoxic chemo bridge to transplant.[8]
• EBV and multiple sclerosis (Soldan and Lieberman, Nat Rev Microbiol 2023). A large US military cohort (Bjornevik 2022, NEJM) showed that EBV seroconversion precedes essentially all MS, establishing EBV as the single strongest known risk factor for MS.[11]
• EBV and cancer (Farrell, Annu Rev Pathol 2019). EBV contributes to around 1.5 percent of the global cancer burden through Burkitt, Hodgkin, NPC, and EBV-positive gastric carcinoma.[9]
• Regional note (India). Most Indian children are EBV-seropositive before adolescence, so florid IM is uncommon; a young adult with apparent IM should prompt exclusion of CMV, HIV seroconversion, dengue, enteric fever, and leptospirosis — all of which mimic the syndrome here. Use EBV-specific serology (VCA IgM) rather than relying on Monospot in young children, in whom heterophile is often negative.[1]

[4] [1] [1]

How mononucleosis patients come to harm — the preventable list

• Mislabelling the ampicillin rash as true penicillin allergy and branding a teenager for life — most tolerate penicillins later without reaction.[6]
• Missing splenic rupture in a patient sent home with just glandular fever who returns with LUQ or shoulder-tip pain.[7]
• Over-treating uncomplicated IM with steroids or antivirals that the evidence says do not help.[4]
• Missing CMV, HIV seroconversion, or toxoplasmosis behind a heterophile-negative illness — the missed-HIV harm is the one that lasts a lifetime.[5]
• Missing EBV-HLH or PTLD in the immunocompromised patient with fever and cytopenias.[8]
• Prematurely diagnosing leukaemia on a florid reactive atypical lymphocytosis — IM is reactive, not clonal.[3]

The high-yield one-liner

[1]

Six red flags in mononucleosis

The mantra, and the mnemonic

[1]

The mantra: triad plus fatigue, Monospot the older child, no amoxicillin, no contact sport for three weeks.[1][7]

Ward-round test — three stems

Stem 1 — the student who erupted in a rash (answer)

A 19-year-old is given amoxicillin for tonsillitis by his GP. Twenty-four hours later he returns covered head to toe in a diffuse maculopapular rash, febrile, with shovelfuls of exudate on his tonsils and tender posterior cervical nodes. What just happened, and what do you do? Model: This is infectious mononucleosis unmasked by the ampicillin rash — the 80-to-100-percent non-allergic rash of EBV-driven polyclonal B-cell activation. Stop the amoxicillin; it is a diagnostic clue, not a true penicillin allergy, so do not brand him penicillin-allergic for life. Confirm with a Monospot (positive in the right clinical context) and EBV serology (VCA IgM positive, EBNA IgG negative). Treat supportively — paracetamol, rest, hydration — and counsel: no contact sport for 3 to 4 weeks, because the spleen ruptures in week 2. If a beta-lactam is truly needed later for strep, penicillin V or cephalexin is the safe choice.[6]

Stem 2 — the rugby player with LUQ pain in week 2 (answer)

A 20-year-old rugby player, two weeks into proven IM, develops left upper quadrant pain radiating to the tip of his shoulder, with dizziness and a falling haemoglobin. He stayed in training. What happened, and what do you do in the next 15 minutes? Model: This is splenic rupture — rare (around 0.1 to 0.5 percent of IM) but peaking exactly in week 2, and trivial trauma from a tackle is enough. The LUQ pain with shoulder-tip referral is the Kehr sign from diaphragmatic irritation. Resuscitate for haemorrhagic shock — ABC, two large-bore cannulae, crossmatch, IV crystalloid; urgent focused ultrasound (FAST) or CT abdomen; urgent surgical referral. Many stable ruptures are managed non-operatively (bed rest, serial haematocrit); the unstable or continuously bleeding patient needs splenectomy or splenic artery embolisation. The prevention is the counsel you should have given at diagnosis: no contact sport for at least 3 to 4 weeks.[7]

Stem 3 — the heterophile-negative atypical case (answer)

A 28-year-old has three weeks of fever, profound fatigue, and mild cervical lymphadenopathy with little pharyngitis. Monospot is negative at week 3. What is your differential, and which test is non-negotiable? Model: A heterophile-negative mononucleosis illness is an instruction to look harder, not a failed test. The three mimics are CMV mononucleosis (older, less pharyngitis, CMV IgM positive), HIV seroconversion illness (sexual or blood-borne exposure, mucosal ulcers, rash — HIV RNA positive before antibodies; a 4th-generation Ag-Ab test is non-negotiable), and toxoplasmosis (cervical nodes without pharyngitis, cat or undercooked-meat exposure, Toxoplasma IgM). Send EBV-specific serology too, because primary EBV can be heterophile-negative; and review the film for atypical lymphocytes and blasts. The test you must not leave the room without is the HIV 4th-generation Ag-Ab plus RNA — missing HIV seroconversion is the harm with lifelong consequences.[5]

References

1. [1]Dunmire SK, Hogquist KA, Balfour HH. Infectious Mononucleosis Curr Top Microbiol Immunol, 2015.PMID 26424648
2. [2]Leung AKC, Lam JM, Barankin B, et al. Infectious Mononucleosis: An Updated Review Curr Pediatr Rev, 2024.PMID 37526456
3. [3]Luzuriaga K, Sullivan JL. Infectious mononucleosis N Engl J Med, 2010.PMID 20505178
4. [4]Sylvester JE, Buchanan BK, Silva TW. Infectious Mononucleosis: Rapid Evidence Review Am Fam Physician, 2023.PMID 36689975
5. [5]Womack J, Jimenez M. Common questions about infectious mononucleosis Am Fam Physician, 2015.PMID 25822555
6. [6]Thompson DF, Ramos CL. Antibiotic-Induced Rash in Patients With Infectious Mononucleosis Ann Pharmacother, 2017.PMID 27620494
7. [7]Bartlett A, Williams R, Hilton M. Splenic rupture in infectious mononucleosis: A systematic review of published case reports Injury, 2016.PMID 26563483
8. [8]Kawada JI, Ito Y, Ohshima K, et al. Updated guidelines for chronic active Epstein-Barr virus disease Int J Hematol, 2023.PMID 37728704
9. [9]Farrell PJ. Epstein-Barr Virus and Cancer Annu Rev Pathol, 2019.PMID 30125149
10. [10]Fugl A, Andersen CL. Epstein-Barr virus and its association with disease - a review of relevance to general practice BMC Fam Pract, 2019.PMID 31088382
11. [11]Soldan SS, Lieberman PM. Epstein-Barr virus and multiple sclerosis Nat Rev Microbiol, 2023.PMID 35931816