Epstein-Barr virus and cytomegalovirus infection — branching viva

Opening question

Examiner: Take me through this adolescent. What is the diagnosis, and what is the significance of the rash? [2]

Candidate: The diagnosis is Epstein-Barr virus infectious mononucleosis. The triad of fever, exudative pharyngitis and posterior cervical lymphadenopathy, with splenomegaly and a positive Monospot, is classic. The maculopapular rash that appeared after amoxicillin is an EBV-driven immune phenomenon rather than a true penicillin allergy — it develops in nearly all patients with EBV mononucleosis given ampicillin or amoxicillin and resolves when the antibiotic stops. The clinical error was giving the antibiotic at all, because the sore throat is viral. [6] [2]

Examiner: Why does EBV produce this illness at all? [1]

Candidate: EBV enters through the oropharynx, infects the epithelium, and then infects B cells via the CD21 complement receptor. It drives polyclonal B-cell activation and establishes lifelong latency in memory B cells. But the symptoms of mononucleosis are largely the host CD8 cytotoxic T-cell response to those infected B cells — the atypical lymphocytes on the blood film are reactive T cells, not infected B cells. The illness is the immune response. [1] [4]

Branch 1 — pathophysiology and the host

Examiner: You said the illness is the immune response. What happens when that response fails? [4]

Candidate: When T-cell surveillance of EBV fails, the virus escapes immune control and drives uncontrolled B-cell proliferation. In a transplant recipient on immunosuppression that is post-transplant lymphoproliferative disorder; in a boy with X-linked lymphoproliferative disease — a defect in the SH2D1A gene — primary EBV can trigger fatal haemophagocytic lymphohistiocytosis. The same virus that causes a self-limiting glandular fever in the immunocompetent adolescent becomes lethal when the T-cell response is absent. [4] [1]

Examiner: How does that contrast with CMV disease? [4]

Candidate: CMV works by direct cytopathic injury rather than immunopathology. It infects epithelial, endothelial and mononuclear cells and produces the characteristic owl's-eye intranuclear inclusions — swollen, virus-laden cells. Where EBV disease is largely the immune response, CMV disease is largely direct viral damage to the target organ: colitis when the gut mucosa is destroyed, retinitis when the retina is invaded. Both viruses are governed by host cellular immunity — CMV stays latent in the healthy child and reactivates when cellular immunity falls. [9] [4]

Branch 2 — management of the adolescent

Examiner: How will you manage this adolescent? [2]

Candidate: Supportively — rest, hydration, analgesia and antipyretics. I will withhold antibiotics, because none is indicated for a viral illness, and no antiviral is routine for uncomplicated mononucleosis because aciclovir does not change the clinical course. I will restrict contact sport and heavy lifting for at least three to four weeks from symptom onset, and longer if splenomegaly persists, because the enlarged soft spleen is vulnerable to rupture. Corticosteroids I reserve for impending airway obstruction, severe autoimmune haemolytic anaemia or aplastic anaemia. [7] [2]

Examiner: Why the contact-sport restriction, and how long? [7]

Candidate: Because the spleen is enlarged and softened in mononucleosis, it can rupture from even minor trauma, and spontaneous rupture can occur. The American Medical Society for Sports Medicine position statement advises avoiding contact sport for at least three to four weeks from symptom onset, and longer if splenomegaly persists, with a graded return once the adolescent is asymptomatic and the spleen has returned to normal size. A premature return to rugby is the preventable disaster in EBV mononucleosis. [7]

Branch 3 — the congenital CMV contrast

Examiner: Now contrast this with a neonate who presents with petechiae, jaundice and microcephaly. What are you thinking, and what is the single most important test? [10]

Candidate: I am thinking congenital cytomegalovirus, the most common congenital infection and the leading non-genetic cause of sensorineural hearing loss. The single most important test is saliva or urine PCR for CMV, and it must be obtained within the first 21 days of life — after that window, a positive result cannot distinguish congenital infection from CMV acquired perinatally via breast milk or the birth canal. The 21-day window is the critical diagnostic fact. [11] [9]

Examiner: What treatment do you offer, and on what evidence? [8]

Candidate: For symptomatic congenital CMV — with sensorineural hearing loss and/or central nervous system involvement — I offer valganciclovir 16 mg/kg/dose orally twice daily for six months. The Kimberlin trial established a hearing benefit, and the extension showed that a six-month course improves hearing and neurodevelopmental outcomes beyond a six-week course, which shifted the standard of care. I monitor the neutrophil count for myelosuppression and arrange audiology and developmental follow-up into school age, because CMV-related hearing loss is often late-onset or progressive. [8] [10]

Branch 4 — CMV in the immunocompromised host

Examiner: How does CMV management differ in a transplant recipient? [9]

Candidate: In the transplant recipient the approach is pre-emptive therapy guided by quantitative PCR. The protocol monitors CMV PCR at intervals, and a rising titre triggers treatment before end-organ disease develops. Established disease is treated with intravenous ganciclovir induction then oral valganciclovir, with foscarnet for resistance or toxicity. I reduce immunosuppression where the graft allows, use CMV-specific immunoglobulin as an adjunct for severe disease, and match prophylaxis to risk — the highest-risk recipient is the donor-positive, recipient-negative mismatch. The aim is to treat before tissue invasion, because ganciclovir and foscarnet carry significant myelosuppression and nephrotoxicity. [9] [4]

Branch 5 — the EBV-MS association

Examiner: You mentioned that EBV is more than glandular fever. What is the recent high-yield association? [1]

Candidate: The 2022 Bjornevik cohort study in Science established EBV as a near-necessary cause of multiple sclerosis — the infection precedes the disease in nearly every case, and EBV seroconversion dramatically increases the risk of developing MS. This reframed EBV as not merely a cause of glandular fever but as the precursor event in a major neurological disease, and it has made an EBV vaccine a serious target. EBV also drives the lymphoproliferative spectrum — post-transplant lymphoproliferative disorder, Burkitt and Hodgkin lymphoma, nasopharyngeal carcinoma — when immune surveillance fails. [4] [1]

Wrap

Examiner: Summarise the EBV and CMV stance in one sentence. [9]

Candidate: Match the treatment to the host: the immunocompetent adolescent with EBV mononucleosis gets supportive care, an activity restriction, no antibiotics and steroids only if the airway is threatened; the symptomatic newborn with congenital CMV gets valganciclovir for six months with audiology into school age, confirmed by PCR within the 21-day window; and the immunocompromised host with a rising CMV PCR gets pre-emptive ganciclovir — because both are herpesviruses, but it is the host, not the organism, that decides the treatment. [8] [9]