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Q1: A 20-year-old presents with fever, exudative sore throat, posterior cervical lymphadenopathy and fatigue. Discuss the diagnosis and its pathogen. (2 min)
This is the classic triad of infectious mononucleosis — fever, exudative tonsillar pharyngitis, and (especially posterior cervical) lymphadenopathy, with fatigue. The pathogen is Epstein-Barr virus (EBV, human herpesvirus 4) — a gamma-1 herpesvirus (Lymphocryptovirus), enveloped double-stranded DNA. Transmission is via saliva ("kissing disease"), with an incubation of 4 to 6 weeks; symptomatic disease peaks in adolescents and young adults (15-24 years) in high-income settings, because in developing countries most children are infected asymptomatically before age 5. EBV enters B lymphocytes and oropharyngeal epithelial cells via gp350 binding the CD21 (CR2) complement receptor, establishes latency expressing EBNAs and LMPs, and drives polyclonal B-cell proliferation. The clinical illness is the vigorous CD8+ cytotoxic T-cell response against infected B cells — these are the atypical lymphocytes (Downey cells) seen on the blood film.
Q2: How would you confirm the diagnosis? (3 min)
Diagnosis is clinical, supported by laboratory tests. First-line: full blood count and film showing lymphocytosis with atypical lymphocytes over 10 percent of lymphocytes, mild thrombocytopenia (around 50 percent), and a mild transaminitis (around 90 percent). The heterophile antibody (Monospot / Paul-Bunnell) test detects IgM that agglutinates horse/sheep RBC (absorbed by guinea-pig kidney, not beef cells); sensitivity around 85 percent, specificity around 97 percent in adults; positive in the first week, peaks at 2-3 weeks, persists up to a year; NEGATIVE in children under 4 years and in the first few days of illness. When Monospot is negative or equivocal, send EBV-specific serology — the definitive test: VCA IgM POSITIVE = acute primary infection; VCA IgG positive + EBNA IgG NEGATIVE = acute; VCA IgG positive + EBNA IgG POSITIVE = past infection (EBNA appears at 3-4 weeks and persists for life). EBV DNA PCR is reserved for immunocompromised patients, suspected CNS disease (CSF), and PTLD monitoring. I would also exclude mimics — rapid strep/ASO (group-A strep), CMV IgM (CMV mono), Toxoplasma IgM, and HIV RNA / 4th-generation Ag-Ab (seroconversion illness) — particularly in a heterophile-negative or atypical case.
Q3: What is your management, and what must you specifically avoid? (2 min)
Management is supportive: rest as tolerated (strict bed rest is not required), hydration, paracetamol 1 g every 6 hours (max 4 g/day) or ibuprofen for fever and throat pain, salt-water gargles and throat lozenges. I would specifically AVOID four things: (1) ampicillin/amoxicillin (and cefprozil) — they cause a diffuse maculopapular rash in 80-100 percent of IM patients, not a true penicillin allergy (mechanism is EBV-driven polyclonal B-cell activation); if streptococcal co-infection is proven I use phenoxymethylpenicillin or cephalexin; (2) alcohol during the hepatitis phase; (3) contact sport, strenuous exercise, heavy lifting for a minimum of 3-4 weeks until asymptomatic with a normal spleen on ultrasound — splenic rupture peaks at weeks 2-3; (4) routine corticosteroids and antivirals — Cochrane 2015 showed no benefit in uncomplicated IM. Steroids are reserved for impending airway obstruction, severe thrombocytopenia/haemolysis, or neurology. I would counsel the patient on the disease course (acute illness 1-2 weeks; fatigue may persist weeks-months) and on warning signs (LUQ/shoulder pain, dyspnoea, bleeding, severe headache, weakness).
Q4: Discuss the complications and the long-term significance of EBV infection. (2 min)
Complications (mnemonic SPLAAT): Splenomegaly and splenic rupture (around 0.1-0.5 percent; LUQ pain, Kehr sign; managed with fluid resuscitation, imaging and surgical referral); Pancytopenia and EBV-HLH (especially X-linked lymphoproliferative disease / Duncan syndrome, SAP/SH2D1A mutation — fulminant and often fatal); Liver (mild hepatitis in around 90 percent, rare fulminant failure); Airway obstruction from massive tonsillar hypertrophy; Autoimmune haemolytic anaemia (Coombs-positive, anti-i antibody) and immune thrombocytopenia; Tiredness (fatigue) persisting weeks-months. Neurological complications (1-5 percent): meningoencephalitis, Guillain-Barre syndrome, Bell palsy, transverse myelitis. Rare cardiac (myocarditis, pericarditis), pulmonary (interstitial pneumonitis), and renal (interstitial nephritis) complications.
Long-term significance: EBV establishes lifelong latency in memory B cells with intermittent salivary shedding, and is oncogenic — associated with endemic Burkitt lymphoma (t(8;14), c-myc), Hodgkin lymphoma (mixed-cellularity), nasopharyngeal carcinoma, EBV-positive gastric carcinoma, extranodal NK/T-cell lymphoma, post-transplant lymphoproliferative disease (PTLD) and oral hairy leukoplakia in HIV. Recent evidence (Bjornevik 2022, NEJM; Soldan & Lieberman 2023, Nat Rev Microbiol) shows EBV is the strongest known risk factor for multiple sclerosis. In transplant recipients I monitor EBV DNA viral load and reduce immunosuppression at the first sign of PTLD, using rituximab for CD20-positive disease.
Q5 (examiner's probe): The Monospot is negative but you still suspect IM. What do you do?
Send EBV-specific serology (VCA IgM) — the Monospot is negative in around 15 percent of adults, in children under 4 years, and in the first days of illness; VCA IgM positivity confirms acute primary EBV even with a negative heterophile test. I would also actively exclude mimics of a heterophile-negative mononucleosis syndrome: CMV IgM and CMV DNA PCR (CMV mononucleosis — older patients, less pharyngitis/adenopathy), Toxoplasma IgM (cervical nodes, no pharyngitis), and — critically — HIV RNA / 4th-generation Ag-Ab test for HIV seroconversion illness (rash, mucosal ulcers, sexual/blood-borne exposure). Acute viral hepatitis serology and, if cytopenias or bizarre cells persist, a blood film and flow cytometry to exclude leukaemia/lymphoma.