Viral Syndromes by Organ System: Questions

A dendritic corneal ulcer is the classic sign of HSV keratitis, and recurrent herpetic keratitis is, after trauma, the leading infectious cause of corneal blindness.

Adenovirus causes a follicular keratoconjunctivitis without a true dendrite, bacterial keratitis a suppurative ulcer, and cytomegalovirus retinitis and VZV acute retinal necrosis affect the retina rather than the corneal surface.

Disseminated HSV infection of eczematous skin, called eczema herpeticum (Kaposi varicelliform eruption), produces clusters of monomorphic punched-out vesicles and can be severe.

Impetigo gives honey-crusted lesions, chickenpox a centripetal rash with lesions at different stages, hand, foot and mouth disease acral and oral vesicles, and molluscum contagiosum painless umbilicated papules without fever.

Low-risk HPV 6 and 11 cause the great majority of anogenital warts (condylomata acuminata). They are not premalignant but recur often.

HPV 16 and 18 are the high-risk oncogenic types, 31 and 33 other high-risk mucosal types, and 5 and 8 cutaneous beta types.

Glycoprotein D binds nectin-1, an adhesion molecule on epithelial cells and neurons, and also the herpesvirus entry mediator and 3-O-sulfated heparan sulfate. This receptor engagement triggers the fusion machinery; ordinary heparan sulfate is only the initial attachment site, via glycoproteins B and C.

The distractors are the receptors of other viruses: CD4 for HIV, sialic acid for influenza, the mannose-6-phosphate receptor for varicella-zoster virus, and ACE2 for SARS-CoV-2.

Genital ulceration breaches the mucosa and draws in activated CD4 T cells bearing the CCR5 co-receptor, the very cells HIV infects, so HSV-2 raises HIV acquisition roughly threefold and contributes a substantial share of new HIV infections where both are common.

It does not reduce or abolish the risk, and the effect is seen in both sexes rather than men alone.

HPV gene expression is coupled to epithelial differentiation. Late genes (L1 and L2) are expressed and virions assembled only in the most superficial, differentiating keratinocytes, which is why the virus could not be grown in conventional monolayer culture.

The basal layer maintains only the silent episome; there is no viraemia, no lymphocyte infection, and no separate latency programme.

Daily suppressive valaciclovir lowers recurrences and asymptomatic shedding and cuts transmission to a susceptible partner by about half.

Because it reduces but does not abolish shedding, the protection is partial, so the higher figures overstate it and it is certainly better than no effect.

As childhood oral acquisition of HSV-1 declines, more young adults reach sexual debut without HSV-1 antibody and acquire it genitally, so HSV-1 now causes more than half of new genital herpes in many such settings.

HSV-2 remains the leading cause of recurrent genital herpes but no longer of first episodes in these populations; the other herpesviruses are not significant causes of genital ulceration.

HSV-2 is shed intermittently from the genital tract without symptoms, and more than 70% of transmission occurs during such asymptomatic shedding rather than from recognised lesions.

Transmission is not confined to visible ulcers, the primary episode or recurrences, and HSV is not spread meaningfully by contaminated surfaces.

HSV-1 establishes latency chiefly in the trigeminal ganglion, the source of recurrent orolabial herpes, while HSV-2 favours the sacral ganglia.

The other options invert or invent the site: HSV-2 latency is sacral rather than trigeminal or in the olfactory bulb, and HSV does not reside in anterior horn cells as its principal reservoir.

Type-specific serology based on glycoprotein G, with gG1 for HSV-1 and gG2 for HSV-2, distinguishes past infection with the two types and is used for counselling.

IgM is unreliable and does not type; viral culture and the Tzanck smear identify HSV but do not reliably type it (the Tzanck smear cannot even separate HSV from VZV); complement fixation is outdated and not type-specific.

a. Pathogenesis. After a respiratory or gastrointestinal infection the virus, typically an enterovirus such as coxsackievirus B, reaches the heart by viraemia. Injury then occurs in two phases: direct viral damage to myocytes, followed by immune-mediated injury in which cytotoxic T cells attack both infected and, through autoreactivity, uninfected myocytes. Interstitial inflammation and myocyte loss cause ventricular dilation and failure, and healing fibrosis and viral persistence may progress to dilated cardiomyopathy.

b. Acute investigation for a viral cause. Combine cardiac and virological tests. Troponin and creatine kinase MB confirm myocardial injury, the ECG shows sinus tachycardia with low-voltage complexes, and echocardiography or cardiac magnetic resonance imaging shows the dilated, inflamed ventricle. The specific viral evidence comes from endomyocardial biopsy with PCR (and in situ hybridisation) on heart tissue, since peripheral samples are unreliable; supporting serology and throat or stool viral studies may identify a circulating enterovirus. Note that a genome detected in the myocardium supports, but does not alone prove, causation.

a. The picture is a viral (aseptic) meningitis: a lymphocytic pleocytosis with normal glucose and mildly raised protein, and a positive herpes simplex virus type 2 (HSV-2) PCR (polymerase chain reaction) confirms HSV-2 as the cause.

b. This is HSV-2 aseptic meningitis, which commonly accompanies a primary genital HSV-2 infection (in up to a quarter of affected women). When such episodes recur over time the condition is called Mollaret meningitis.

c. Supportive care with analgesia; intravenous aciclovir for a severe presentation, stepping down to oral valaciclovir to complete a course of about 10 to 14 days; and counselling about genital HSV and recurrence. The prognosis is good and the illness self-limiting, unlike HSV-1 encephalitis.

Tests. Check the CD4 count and HIV viral load (corticosteroid for IRIS implies recent immune status), arrange fundoscopy, and confirm with PCR of ocular fluid (and blood) for CMV.

Diagnosis. The most likely diagnosis is CMV retinitis, unmasked by profound immunosuppression; steroid for IRIS may have worsened it.

Management. Treat with ganciclovir or oral valganciclovir (systemic, with intravitreal therapy if sight-threatening), and continue and optimise antiretroviral therapy to restore immunity; review the steroid.

Complications. Treatment and immune recovery carry the risk of immune recovery uveitis, and the retinitis itself can lead to retinal detachment and permanent visual loss in the long term.

a. Recurrent genital herpes, most likely HSV-2 given the frequent recurrences (HSV-1 is possible but recurs much less at the genital site).

b. A swab of the ulcer base (deroof a fresh vesicle) sent for HSV PCR (polymerase chain reaction) with typing, which is more sensitive than culture. Type-specific serology is for counselling, not for diagnosing the acute lesion.

c. Either episodic antiviral therapy (aciclovir, valaciclovir or famciclovir) started at the first prodrome, or daily suppressive therapy. With frequent, distressing recurrences the treatment of choice is daily suppressive valaciclovir, which reduces both recurrences and transmission to a partner.

Specimen and test. Take a swab from the base of an ulcer or from a fresh vesicle and test by PCR, which is the diagnostic test of choice and has replaced insensitive culture. Type-specific serology can establish whether the infection is HSV-1 or HSV-2 but does not diagnose the acute lesion.

Treatment options. The aciclic nucleoside analogues aciclovir, valaciclovir or famciclovir, given either episodically at the onset of each recurrence or as daily suppressive therapy.

Treatment of choice. For a patient with recurrent disease, daily suppressive therapy is preferred, as it reduces the frequency of recurrences and asymptomatic shedding, and therefore transmission.

Diagnosis. Herpes zoster ophthalmicus, reactivation of varicella-zoster virus in the ophthalmic division of the trigeminal nerve. The vesicle on the tip of the nose (Hutchinson’s sign) indicates nasociliary involvement and predicts ocular disease.

Indications for antiviral treatment. Systemic aciclovir, valaciclovir or famciclovir, started within 72 hours of rash onset, which hastens healing and reduces ocular complications. Treatment is also indicated in any ocular involvement, older or immunosuppressed patients, with intravenous aciclovir for the immunosuppressed to prevent dissemination.

a. Diagnosis. Smallpox (variola), suggested by a synchronous vesiculopustular rash healing with scarring, the lesions all at the same stage.

b. Classification. Family Poxviridae, genus Orthopoxvirus, species variola virus.

c. Another genus. For example Parapoxvirus (orf, milker’s nodule) or Molluscipoxvirus (molluscum contagiosum).

d. Modern threat. Although eradicated in 1980, variola poses a bioterrorism threat because the population is now largely unvaccinated and susceptible.

• Adenoviral conjunctivitis is highly contagious and spreads by hands, secretions and contaminated surfaces and objects.
• Advise frequent handwashing by the child and classmates, and avoiding touching or rubbing the eyes.
• Keep the affected child at home until the discharge settles, as shedding continues for up to two weeks.
• Do not share towels, face cloths, toys or other items, and clean shared surfaces, since the virus survives on surfaces.

The virus is adenovirus, the commonest cause of viral conjunctivitis. Its ocular syndromes are:

• Pharyngoconjunctival fever (fever, sore throat and conjunctivitis).
• Epidemic keratoconjunctivitis (a highly contagious keratoconjunctivitis).
• Nonspecific follicular conjunctivitis (mild, self-limiting, the commonest form).
• Chronic keratoconjunctivitis (rare, with prolonged irritation).

• Lifelong latency in sensory neurons that are poorly accessible to immune surveillance, so a vaccine cannot easily prevent or clear established infection.
• Sophisticated immune evasion and the absence of a validated correlate of protective immunity to guide vaccine design.
• No suitable animal model that faithfully reproduces human infection, latency and recurrence; the leading glycoprotein D subunit candidate failed against HSV-2 in trials.

• HPV infection is very common in women under 30, with peak prevalence in the early twenties.
• Most of these infections are transient and clear spontaneously without ever progressing to significant disease.
• Testing younger women therefore detects many infections that would resolve on their own, leading to unnecessary follow-up and treatment; a positive test above 30 is more likely to represent a persistent infection at real risk of progression.

• How and when it is produced: after amplification is complete, the product is heated gradually while fluorescence from a double-stranded-DNA-binding dye (or probe) is monitored. As the duplex denatures, fluorescence falls steeply at the melting temperature (Tm); plotting the negative first derivative of fluorescence against temperature gives a peak at the Tm. It is a post-amplification step.
• Why HSV-1 and HSV-2 differ: their amplicons differ in sequence and guanine-and-cytosine content, so they melt at different temperatures and give distinct peaks.
• Why it is useful: it allows single-tube typing of HSV-1 versus HSV-2 without separate probes or gels, detects mixed infection, and confirms that the signal is the specific amplicon rather than primer-dimer or non-specific product.

Taxonomy. Species Simplexvirus humanalpha1, genus Simplexvirus, subfamily Alphaherpesvirinae, family Orthoherpesviridae (formerly Herpesviridae), order Herpesvirales.

Genome. Linear double-stranded DNA of about 152 kilobases, organised as a long unique (UL) and a short unique (US) region, each flanked by inverted repeats, so the segments invert to give four genome isomers; around 84 genes.

Capsid. Icosahedral, triangulation number 16, built from 162 capsomeres, with a single portal vertex through which the genome is packaged.

Tegument. A protein layer between capsid and envelope that delivers regulatory proteins at entry, including the transactivator VP16 and the host-shutoff RNase (vhs).

Envelope. A lipid bilayer carrying up to twelve glycoproteins; the core entry machinery is glycoprotein B with the glycoprotein H and L pair, triggered by glycoprotein D, the receptor-binding protein (glycoprotein G is the type-specific antigen used to tell HSV-1 from HSV-2).

• Encephalitis or meningoencephalitis: haemorrhagic, necrotising infection of the brain.
• Hepatitis: which can progress to fulminant hepatic failure, classically in pregnancy or immunosuppression.
• Pneumonitis: with, in severe dissemination, adrenal involvement, widespread mucocutaneous lesions and coagulopathy.

• Recurrent respiratory (laryngeal) papillomatosis is caused by HPV-6 and HPV-11, the same low-risk types that cause genital warts.
• The infant acquires the virus at vaginal delivery from maternal genital warts.
• The quadrivalent and nine-valent HPV vaccines include HPV-6 and HPV-11, so vaccinating girls before childbearing prevents maternal genital warts and, in turn, transmission to the infant, which is expected to reduce laryngeal papillomatosis.

• Classification: a small non-enveloped double-stranded DNA virus of the family Polyomaviridae, genus Alphapolyomavirus, with a circular genome of about 5 kilobases.
• Skin commensal: a near-universal component of the normal skin flora, acquired in childhood and carried lifelong without symptoms, with adult seroprevalence around 60 to 80%.
• Causal role in cancer: the established cause of about 80% of Merkel cell carcinomas, making it the only human polyomavirus with a proven oncogenic role; the remaining Merkel cell carcinomas are ultraviolet-driven and virus-negative.
• Oncogenic mechanism: in the tumour the viral genome is clonally integrated into host DNA and expresses a truncated large T antigen that retains the retinoblastoma protein (RB)-binding region but has lost the capacity to replicate the virus, so it drives proliferation, while the small t antigen supports transformation.
• Merkel cell carcinoma: an aggressive cutaneous neuroendocrine carcinoma presenting as a rapidly enlarging, painless red or violet nodule on sun-exposed skin of older or immunosuppressed people, identified histologically by a dot-like cytokeratin 20 pattern and treated in advanced disease with programmed death-1 (PD-1) or its ligand (PD-L1) checkpoint inhibitors.

• Agent. Molluscum contagiosum virus, a poxvirus (genus Molluscipoxvirus).
• Distribution. Common worldwide, chiefly in children.
• Transmission. By direct skin-to-skin contact and fomites, and by autoinoculation.
• In adults. Frequently sexually transmitted, giving genital lesions.
• In immunocompromise. Florid, widespread disease with hundreds of lesions in advanced HIV, often with facial involvement.

A complete answer names the common causes, gives discriminating clinical features, uses the laboratory sparingly and correctly, and identifies measles as the eradication target.

Common viral causes. The commonest are measles, rubella and parvovirus B19 (erythema infectiosum), with HHV-6 (roseola) and the enteroviruses also frequent.

Distinguishing features. Measles gives a prodrome of fever, cough, coryza and conjunctivitis with Koplik spots, then a rash spreading from the head downward. Rubella is milder with a finer rash and posterior auricular and suboccipital lymphadenopathy. Parvovirus B19 gives the slapped-cheek face and a lacy limb rash.

Laboratory. Most cases are diagnosed clinically. Where confirmation is needed, serum IgM (or a rising IgG) confirms measles, rubella and parvovirus, with PCR or reference-laboratory testing reserved for unclear or public-health-important cases. Suspected measles is notified and the child isolated, so testing serves infection control as much as the individual.

Eradication target. Measles is targeted for global eradication: humans are the only reservoir, there is no animal host, and a highly effective live vaccine gives durable immunity, so interrupting transmission is feasible.

A complete answer names the likely agent, the specimens to collect, the assay of choice and its interpretation, and the environmental sampling that links the cases to a source.

The likely agent in a waterborne outbreak affecting all ages is norovirus. Collect stool specimens from several cases early in the illness, when shedding is highest, since a single positive is weak evidence in an outbreak. The method of choice is reverse-transcription polymerase chain reaction (RT-PCR), which is far more sensitive than antigen enzyme immunoassay; norovirus antigen assays have low sensitivity and are useful only for confirming the agent across a group, not for excluding it in an individual. Sequencing the RT-PCR product allows genotyping, which is what ties cases to each other and to the source.

Test in parallel for rotavirus and enteric adenovirus by antigen assay to exclude the endemic childhood agents. Sample the suspected water source, and any implicated food or environmental surfaces, for the same virus. Because norovirus is frequently detected in well people, interpret results against the clinical and epidemiological picture. A single matching strain across cases and the water source confirms the outbreak and its vehicle.

A complete answer covers the taxonomy, how types are defined, and the clinical risk grouping.

Family and genera

HPV belongs to the family Papillomaviridae. More than 450 human types fall into five genera: Alphapapillomavirus (mucosal and some cutaneous, containing the oncogenic types), Betapapillomavirus (cutaneous, linked to skin cancer in epidermodysplasia verruciformis), Gammapapillomavirus, Mupapillomavirus and Nupapillomavirus (cutaneous).

How types are defined

A type differs by more than 10% in its L1 gene sequence from the nearest known type; smaller differences define subtypes and variants. Classification is genetic because the virus could not be cultured and raises little cross-reacting antibody.

High-risk versus low-risk

High-risk mucosal types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59) encode E6 and E7 proteins that inactivate p53 and the retinoblastoma protein and cause cancer; HPV16 and 18 cause most cervical cancer. Low-risk types (chiefly 6 and 11) cause anogenital warts and respiratory papillomatosis but not cancer.

A complete answer follows the virus up through the epithelium and links each phase to the differentiation state.

Infection and maintenance

The virus reaches dividing basal keratinocytes only through a microabrasion, binding heparan sulphate then a secondary receptor. The genome enters the nucleus during mitosis and is maintained as a low-copy episome by E1 and E2, held quiet so little viral protein is made: a near-silent reservoir.

Productive phase tied to differentiation

Productive replication begins only as infected cells leave the basal layer and differentiate. Because differentiated cells have left the cell cycle, E6 and E7 re-drive it and recruit the host replication machinery; the genome amplifies, and L1 and L2 are expressed with virion assembly only in the most superficial cells. E4 weakens the cornified layer so virions shed passively in squames, with no lysis and no viraemia.

Why culture is hard

Because the full cycle requires a stratified, differentiating epithelium, the virus cannot complete replication in ordinary monolayer culture; propagation needed organotypic raft cultures or xenografts, which is why HPV was characterised genetically rather than by isolation.

A complete answer traces infection, persistence, integration, and the action of the E6 and E7 oncoproteins.

From infection to persistence

HPV infects the basal keratinocytes of the cervical transformation zone through a microabrasion. Most infections are productive and cleared within about two years; malignant risk arises only when a high-risk type persists.

Integration and loss of E2

Progression is associated with integration of viral DNA into the host genome, which typically disrupts the E2 gene. Because E2 represses the early promoter, its loss derepresses the E6 and E7 oncogenes, which are then overexpressed.

E6 and E7 drive transformation

E6 recruits the E6-AP ubiquitin ligase to degrade p53, disabling apoptosis and the DNA-damage response. E7 binds and inactivates the retinoblastoma protein (Rb), releasing E2F and forcing cell-cycle entry. Together they cause genomic instability and aneuploidy, and persistent expression drives graded cervical intraepithelial neoplasia (CIN) to invasive carcinoma over years to decades.

A complete answer spans the complications of primary varicella and of zoster, and notes that severity concentrates where cell-mediated immunity is immature or failing.

Skin and soft tissue

• Secondary bacterial infection, the commonest, from group A streptococci and Staphylococcus aureus, occasionally reaching necrotising fasciitis.
• Haemorrhagic varicella, around days 2 to 3 of the rash, with epistaxis, melaena or haematuria, mainly in the immunocompromised.

Pulmonary

• Varicella pneumonia, the leading cause of varicella death, affecting ~1 in 200 adults and far fewer children, typically 1 to 6 days after the rash; greatly increased in the immunocompromised and in pregnancy.

Neurological

• Cerebellar ataxia, benign and self-limiting, and the more serious encephalitis (~3 to 4 per 100,000), some 4 to 8 days after the rash.
• Guillain–Barré syndrome, and after zoster, postherpetic neuralgia.

Ocular

• Keratitis, uveitis, iritis and retinitis, mainly with zoster ophthalmicus and threatening sight; progressive outer retinal necrosis occurs in advanced HIV.

Other

• Reye syndrome if aspirin is given, and disseminated disease with visceral involvement in the immunocompromised.

Greatest severity falls on neonates, pregnant women, adults and the immunocompromised.

A complete answer covers what the test detects, its place in screening, and the South African programme.

What it detects. Human papillomavirus cannot be cultured and serology is unhelpful, so molecular methods detecting HPV DNA or messenger RNA are the only specific tests, targeting the high-risk oncogenic types, above all HPV-16 and HPV-18.

Place in screening. High-risk HPV testing is more sensitive than cytology for detecting cervical pre-cancer, and South Africa is moving from cytology towards primary HPV testing, with positive results triaged (by cytology or directly) to colposcopy.

South African programme. Screening is offered from about age 30 in the general population and starts earlier and is repeated more often in women living with HIV, in whom HPV persists and progresses more readily. The shift supports the national goal of cervical cancer elimination.

A complete answer covers the virus, the clinical picture and its distinction from smallpox, and diagnosis and prevention.

Virus. Mpox virus is an orthopoxvirus of the family Poxviridae, a zoonosis endemic in parts of Africa, and it produces disease resembling a milder smallpox.

Clinical features. After an incubation of about 10 to 14 days come a prodrome of fever, malaise and prominent lymphadenopathy, then a rash that begins on the trunk and spreads peripherally, which may involve the palms, soles and mucous membranes; mortality is around 10%.

Distinction and diagnosis. The lymphadenopathy is characteristic of mpox and was not a feature of smallpox, but the poxviruses can be told apart reliably only by PCR.

Prevention. There is no proven specific treatment, but smallpox vaccination is highly protective.

The dendritic ulcer is the classic epithelial lesion of herpes simplex keratitis, best seen with fluorescein.

The other viruses cause different corneal pictures.

Sinus tachycardia with low-voltage QRS complexes and T-wave changes is typical, sometimes with a pseudo-infarct pattern or arrhythmia.

Peaked T waves, a short PR, U waves and delta waves point to other conditions.

The measles rash is largely a cell-mediated immune response to virus in the skin, so a child who cannot mount that response may have measles with no rash, which hinders diagnosis.

It is not driven by bacterial superinfection, direct necrosis, maternal antibody or IgE.

Erythema infectiosum (fifth disease), caused by parvovirus B19, gives the slapped-cheek appearance and a lacy reticular limb rash.

Roseola, rubella, measles and scarlet fever produce different rashes and prodromes.

Prominent lymphadenopathy in the prodrome is characteristic of mpox and was not a feature of smallpox, though PCR is needed to separate the poxviruses reliably.

A febrile prodrome, palmar involvement and scarring occur in both.

Varicella lesions appear in crops and are at different stages at any one time (macule, papule, vesicle, pustule, crust), whereas smallpox lesions were all synchronous.

The other options do not describe chickenpox.

The inflammation is patchy and widely distributed, so sampling frequently misses it, giving biopsy a low and variable sensitivity.

Biopsy can detect genomes by PCR, the Dallas criteria are applied to it, and its risk is greatest, not absent, in small children.

Ramsay Hunt syndrome is reactivation of VZV in the geniculate ganglion of the facial nerve, producing an ipsilateral facial palsy with vesicles in the ear, sometimes with hearing loss and altered taste.

Ophthalmic-division zoster affects the eye and forehead rather than the ear and facial nerve, and a facial palsy without the characteristic vesicular rash and dermatomal distribution would not point to VZV.

VZV cerebral vasculopathy, an inflammation of the cerebral arteries that follows reactivation, raises the risk of ischaemic and haemorrhagic stroke for months after an episode of zoster. The risk is particularly increased after herpes zoster ophthalmicus, rising around 4.5-fold.

Merkel cell carcinoma classically appears as a firm, painless, rapidly enlarging red or violet nodule on sun-exposed skin of an older person, summarised by the AEIOU features (asymptomatic, expanding rapidly, immunosuppressed, older than 50 years, ultraviolet-exposed skin).

A pigmented irregular mole suggests melanoma, a pearly telangiectatic papule basal cell carcinoma, and a scaly patch actinic keratosis or squamous carcinoma.

A variant of coxsackievirus A24 and enterovirus 70 cause acute haemorrhagic conjunctivitis, an explosive, self-limiting conjunctivitis with subconjunctival haemorrhages.

Adenovirus 8 and 19 cause epidemic keratoconjunctivitis, not the haemorrhagic form.

Adenovirus types 11 and 21 cause acute haemorrhagic cystitis in young boys; BK polyomavirus causes it in the immunosuppressed.

The other viruses cause different genitourinary problems.

Adenovirus is non-enveloped, resists disinfection and survives on instruments and surfaces, so it spreads readily in eye clinics through contaminated equipment.

It is not vector-borne or long-range airborne, and it infects the immunocompetent.

Roseola infantum (exanthem subitum, sixth disease) is caused by HHV-6 (and HHV-7): high fever precedes a rash that appears as the fever resolves, and it may provoke a febrile seizure.

The other agents do not show this fever-then-rash sequence.

HSV establishes latency in the sacral dorsal root ganglia, from which it travels down the sensory nerve to cause recurrent genital lesions.

It does not persist latently in epithelium, nodes, lymphocytes or marrow.

CMV retinitis occurs at a CD4 count below about 50 cells per cubic millimetre, in advanced immunosuppression.

Higher counts are not the typical threshold for CMV retinitis.

Neonatal myocarditis is typically fulminant with high mortality, often acquired in utero and frequently due to coxsackievirus B.

It is not mild, not rarely enteroviral, not exclusively postnatal, and not treated with immunosuppression.

Both share the coxsackievirus and adenovirus receptor (CAR), which is important in cardiac development and is expressed more highly in the young and in dilated cardiomyopathy.

The other receptors listed are not the shared entry route for these agents.

Suppressive therapy reduces the frequency of recurrences and of asymptomatic shedding, and hence transmission; it does not cure the infection.

Latent virus is not eradicated, and the other options are not effects of the drug.

Molluscum contagiosum, a poxvirus infection, causes umbilicated papules that become florid and widespread in advanced HIV, often with facial involvement.

The other conditions do not give umbilicated papules.

Endocardial fibroelastosis, linked to intrauterine mumps, has all but disappeared since mumps vaccination, supporting a viral cause.

There is no coxsackievirus B vaccine, and the decline is not explained by neonatal care, prophylaxis or screening.

Epidermodysplasia verruciformis (EV) is an inherited inability to control beta papillomaviruses; HPV 5 and 8 are found in most of the sun-exposed cutaneous squamous cell carcinomas that result.

The high-risk alpha mucosal types drive anogenital and oropharyngeal cancers instead, and the low-risk 6 and 11 cause warts.

Ganciclovir or its oral prodrug valganciclovir is first-line, with foscarnet or cidofovir as alternatives, alongside antiretroviral therapy.

Aciclovir is too weak against CMV, and the other agents are for different viruses.

HSV-2 is the commonest cause of genital herpes, although HSV-1 accounts for an increasing proportion.

The other herpesviruses do not cause genital ulcer disease.

The low-risk types HPV-6 and HPV-11 cause over 90% of genital warts, which are benign.

Types 16 and 18 are the oncogenic types driving cancer, while the other viruses cause different genital lesions.

Coxsackievirus A16 (and enterovirus 71) cause hand-foot-and-mouth disease, with vesicles on the palms, soles and buccal mucosa.

The other viruses cause different vesicular or maculopapular eruptions.

In temperate regions chickenpox is a disease of early childhood, with most people infected before the age of ten. The virus transmits less efficiently in warmer climates, so a larger proportion of adolescents and adults remain susceptible in tropical regions, where they meet the more severe adult form of the disease.

The virus circulates worldwide, so it is neither absent from the tropics nor evenly distributed across all ages.

HPV cannot be cultured and serology is unhelpful, so detection relies on HPV DNA or messenger RNA testing.

The other methods do not reliably detect the virus.

The Myocarditis Treatment Trial showed no benefit from immunosuppression in viral myocarditis, though it does help in giant-cell myocarditis.

It neither improves survival routinely, eradicates the virus, serves as first-line therapy, nor prevents dilated cardiomyopathy.

Parvovirus B19 infects erythroid progenitors and halts red-cell production, precipitating a transient aplastic crisis in people with chronic haemolysis who depend on brisk erythropoiesis.

It does not cause autoimmune haemolysis, iron overload, polycythaemia or a coagulopathy.

BK polyomavirus reactivates under immunosuppression to cause an allograft nephropathy that can mimic graft rejection, as well as haemorrhagic cystitis in bone-marrow recipients.

It does not cause the other listed conditions.

Zinc supplementation reduces the severity, duration and incidence of childhood diarrhoea and is a mainstay of paediatric treatment in low- and middle-income countries.

Antibiotics, vitamin A, antimotility drugs and immunoglobulin are not routine adjuncts for uncomplicated viral gastroenteritis.

Hutchinson’s sign reflects involvement of the nasociliary branch of the trigeminal nerve and predicts ocular disease in about half of cases.

It is not a sign of benign disease, superinfection, dissemination or resolution.

Troponin marks myocardial injury but is not specific for myocarditis or for a viral cause, so it is interpreted in clinical context.

It does not confirm a viral aetiology, exclude pericarditis, stay normal, or identify the agent.

Severe dehydration (about a 10% deficit), shock or near-shock, intractable vomiting or failure of oral therapy call for intravenous fluids.

Mild diarrhoea, occasional vomiting, non-bloody stool and low-grade fever are all managed with oral rehydration.

Merkel cell polyomavirus is a non-enveloped double-stranded DNA polyomavirus (genus Alphapolyomavirus) and the only human polyomavirus with a proven causal role in a human cancer, Merkel cell carcinoma.

It is not an RNA virus, a herpesvirus, a retrovirus or a papillomavirus.

Roughly 90% of new HPV infections become undetectable within two years, about half within nine months. Only a persistent minority, mostly high-risk types, carries the risk of progression to cancer.

Clearance within a week or a month is far too fast, and persistence beyond five to ten years is the exception rather than the rule.

Injury occurs in two phases: direct viral damage to myocytes, then immune-mediated injury by cytotoxic and autoreactive T cells.

The process is not ischaemic, not toxin-mediated, not purely autoantibody-driven, and microabscesses indicate bacterial rather than viral disease.

A causal role is hard to affirm because the parvovirus B19 genome persists in many hearts without disease, so detection does not prove causation.

It is not the established commonest cause, is not neonate-restricted, is not readily cultured, and does persist in the myocardium.

The low-risk types 6 and 11 that cause anogenital warts also cause recurrent respiratory papillomatosis, the juvenile form acquired perinatally from maternal genital infection.

HPV 16 and 18 are high-risk oncogenic types, 5 and 8 are cutaneous beta types, and 31 and 45 are other high-risk mucosal types.

Antibiotics have no role in uncomplicated viral gastroenteritis and may cause harm, including antibiotic-resistant carriage and adverse events.

They neither shorten the illness, prevent dehydration, nor eradicate shedding, and vomiting is not an indication for them.

Virus is readily recovered from the fluid of vesicular lesions, whereas maculopapular rashes shed little or no virus, which is why varicella and zoster require contact and airborne precautions.

Some virus is present in lesions generally, but the vesicle fluid is the infectious source, not maculopapular rashes, pustules alone or old crusts.

Norovirus attaches to histo-blood-group antigens on the gut mucosa, so an inactivating FUT2 mutation (the nonsecretor phenotype) confers relative resistance to the dominant GII.4 genotype.

Blood group O, vaccination, IgA deficiency and cystic fibrosis do not confer this genetic resistance.

Rotavirus is a reovirus with 11 segments of double-stranded RNA, the segmentation allowing reassortment and genotype diversity.

The caliciviruses (norovirus, sapovirus) and astroviruses carry single-stranded RNA; the enteric adenoviruses carry double-stranded DNA.

Rotavirus is shed in huge numbers and is easily detected by a rapid, sensitive stool antigen enzyme immunoassay, which is cheap and field-usable.

PCR works but is not required, culture is not routine, and serology and electron microscopy are not first-line for the individual case.

The rotavirus non-structural protein NSP4 acts as a viral enterotoxin, raising intracellular calcium and driving chloride and water secretion, so diarrhoea occurs without tissue invasion.

There is no mucosal invasion or preformed food toxin, and the mechanism is not autoimmune or a cytokine storm.

Cervical screening uses cervical cytology (the Pap smear) together with, and increasingly replaced by, high-risk HPV DNA testing, with colposcopy for positive results.

Serology, culture, radiography and urine testing have no role in cervical screening.

The enteric adenoviruses, types 40 and 41, cause endemic childhood gastroenteritis.

Types 3 and 7 cause respiratory and conjunctival disease, types 8 and 19 keratoconjunctivitis, type 14 severe respiratory outbreaks, and types 1 and 2 common childhood respiratory infection.

CMV retinitis shows a “pizza-pie” fundus of necrosis and haemorrhage, with owl’s eye intranuclear inclusions histologically.

Cotton-wool spots suggest HIV retinopathy, and salt-and-pepper retinopathy congenital rubella.

Congenital rubella causes cataract, a salt-and-pepper pigmentary retinopathy, glaucoma and microphthalmia.

The other findings belong to CMV, HSV, enterovirus and HHV-8 respectively.

Measles is the commonest viral cause of childhood blindness in developing countries, causing keratomalacia and corneal ulceration where vitamin A deficiency coexists; vitamin A is a treatment priority.

The other viruses are not the leading cause of childhood corneal blindness.

Rotavirus is globally the leading cause of severe childhood gastroenteritis, because it best combines high infectivity with a heavy inoculum and severe fluid loss in the under-fives.

Norovirus dominates outbreaks and, where rotavirus vaccine is used, endemic disease; astrovirus, adenovirus and sapovirus cause milder endemic illness.

Postherpetic neuralgia, pain persisting beyond 8 to 12 weeks, is the commonest important complication of shingles, and its risk rises with age.

The other conditions are not complications of herpes zoster.

Stromal keratitis is the commonest sight-threatening manifestation, an immune-mediated reaction that scars the cornea and may require a graft.

The other manifestations rarely threaten sight.

Adenovirus is the commonest cause of viral conjunctivitis and of eye-clinic epidemics.

The others cause conjunctivitis less often or in specific settings.

The enteroviruses, above all coxsackievirus B, are the classical and commonest cause of viral myocarditis.

The other viruses can involve the heart but do so far less often, and rhinovirus and rotavirus are essentially confined to the respiratory and enteric tracts.

The Dallas criteria are histopathological, grading a biopsy as active, borderline or no myocarditis by the infiltrate and myocyte damage.

They are not based on troponin, ejection fraction, blood viral load or the chest film.

PCR of a swab from the ulcer or vesicle is the test of choice, being far more sensitive than culture.

Serology dates past infection but not the acute lesion, and the Tzanck smear and electron microscopy are insensitive and non-specific.

Protease 2A cleaves dystrophin, the cytoskeletal protein whose inherited mutation causes familial dilated cardiomyopathy and the cardiomyopathy of Duchenne and Becker muscular dystrophy, giving a direct link to chronic disease.

The other mechanisms are not how protease 2A damages the myocardium.

HPV has a small circular double-stranded DNA genome of about 8 kilobases (kb), with all genes on one strand: early genes (E1, E2, E4, E5, E6, E7), late genes (L1, L2) and a non-coding regulatory region.

It is not an RNA virus and does not reverse-transcribe; a partially double-stranded, reverse-transcribing genome describes hepatitis B virus.

The high-risk types HPV-16 and HPV-18 cause about 70% of cervical cancer and a large share of other anogenital and oropharyngeal cancers.

The other types cause benign warts (6/11, 1/2), enteric disease (40/41) or epidermodysplasia verruciformis (5).

Reverse-transcription PCR is the method of choice for norovirus, being highly sensitive; genotyping the product links outbreak cases.

Antigen assays have low sensitivity, the virus is not readily cultured, and electron microscopy and single-sample serology are insensitive or impractical.

Why E

As with the other polyomaviruses, control depends on cellular immunity, so the central measure is to reduce immunosuppression where the underlying condition allows, supported by topical antivirals such as cidofovir. Chemotherapy, excision and radiotherapy are treatments for cancer, not for this benign follicular disease, and corticosteroids would deepen the immunosuppression that drives it.

Low-osmolarity oral rehydration solution is the mainstay, correcting the fluid and electrolyte loss that causes death; breastfeeding and early refeeding continue.

Antibiotics have no role, antimotility drugs are avoided in young children, intravenous fluids are reserved for severe cases, and no specific antiviral exists.

Genital warts appear after a mean incubation of about 2 to 3 months (ranging from 3 weeks to beyond 8 months).

The other intervals are too short or too long.

PCR of the aqueous or vitreous fluid is the most sensitive method, more so than culture or antigen detection; intraocular antibody production can be quantified by the Goldmann-Witmer coefficient.

The other methods are less sensitive for intraocular infection.

PCR on vesicle fluid is the most sensitive test and has largely replaced culture for herpes simplex and varicella-zoster.

A Tzanck smear is quick but non-specific, culture is insensitive, and serology and electron microscopy are second-line.

Cardiac magnetic resonance imaging with gadolinium maps the site and extent of myocardial inflammation and has become a valuable non-invasive test.

The chest film and electrocardiogram are non-specific, angiography is invasive and assesses coronaries, and abdominal ultrasound is irrelevant.

Rubella itself is mild, but infection in early pregnancy causes the congenital rubella syndrome, so control protects the fetus rather than the patient.

Rubella does not typically cause severe patient illness, encephalitis, pneumonia or later reactivation.

The morbilliform measles rash spreads from the forehead and behind the ears downward to the trunk, limbs, palms and soles, following the prodrome and Koplik spots.

Acral onset, cropping, dermatomal confinement and facial sparing describe other eruptions.

Why A

In a few immunosuppressed patients HPyV7 has been linked to a pruritic, brown, plaque-like hyperproliferative eruption. A neuroendocrine nodule is Merkel cell carcinoma, facial keratin spicules are trichodysplasia spinulosa, dermatomal vesicles are zoster, and a genital ulcer points to other causes.

Because the tumour expresses foreign viral antigens and is immunogenic, immune checkpoint inhibitors directed at programmed death-1 (PD-1) or its ligand (PD-L1) are now the standard treatment for metastatic Merkel cell carcinoma, having displaced cytotoxic chemotherapy.

Aciclovir and cidofovir have no role, and reducing immunosuppression assists but is not sufficient alone.

Imiquimod is a Toll-like receptor 7 agonist that induces interferon and other cytokines, giving a low recurrence rate after clearance.

It is not directly cytolytic, a polymerase inhibitor, a caustic agent, or an entry blocker.

Norovirus causes most gastroenteritis outbreaks, spreading rapidly in hospitals, care homes, cruise ships and around contaminated food and water.

The other agents cause mainly endemic childhood diarrhoea; group A rotavirus is the endemic paediatric leader rather than an outbreak agent.

Steroids let the virus replicate freely, enlarging a dendritic ulcer into a geographical ulcer, so they are never used alone for epithelial keratitis; under antiviral cover they help control stromal inflammation.

They neither cure nor prevent scarring when used alone.

Why C

Trichodysplasia spinulosa produces follicular papules each bearing a fine keratin spicule on the central face, with loss of the eyebrows and eyelashes and sometimes a leonine appearance. Dermatomal vesicles suggest zoster, a violet nodule Merkel cell carcinoma, flaccid bullae pemphigus, and annular scaly plaques dermatophyte infection.

Why A

The disease occurs almost only in immunosuppressed patients, in whom loss of T-cell control permits productive replication of the virus in hair follicle cells. It is not a disease of primary infection, does not involve integration and transformation (that is Merkel cell polyomavirus), and has nothing to do with ganglionic latency or ultraviolet mutagenesis.

The koilocyte, a squamous cell with a perinuclear halo and an enlarged, irregular nucleus, is the morphological signature of productive HPV infection.

Owl-eye inclusions are cytomegalovirus, Negri bodies are rabies, Downey cells are the reactive lymphocytes of infectious mononucleosis, and multinucleated syncytia point to herpes simplex or measles.

The virus is a near-universal skin commensal acquired in childhood and carried for life without symptoms; Merkel cell carcinoma is a rare late event in older or immunosuppressed people.

The other options describe hepatitis viruses, herpesviruses, BK virus and respiratory viruses respectively.

Merkel cell carcinoma is a small round blue cell tumour with neuroendocrine differentiation, identified by a characteristic paranuclear dot-like cytokeratin 20 pattern with synaptophysin and chromogranin.

Koilocytes indicate human papillomavirus (HPV), owl-eye cells cytomegalovirus, and Cowdry inclusions herpesviruses.

Norovirus needs fewer than 100 particles to infect and is a non-enveloped virus that survives on surfaces, so it transmits readily by contact, food, water and aerosolised vomitus.

It is not confined to water or droplets, has a short incubation, and needs no vector.

Blood and mucus in the stool indicate an invasive, inflammatory process such as bacterial dysentery, which is not a feature of viral gastroenteritis.

Watery non-bloody stool, early vomiting, low-grade fever and a three-to-five-day course are all typical of the viral illness.

Progressive outer retinal necrosis is an aggressive VZV retinitis seen in advanced HIV infection and a major threat to sight. Acute retinal necrosis is the corresponding VZV retinal disease in immunocompetent people.

Cytomegalovirus retinitis is a separate entity caused by a different virus, included here as a distractor rather than the answer.

Why D

The biopsy shows greatly distended hair follicles with an expanded population of inner root sheath cells rich in eosinophilic trichohyalin, the histological hallmark of trichodysplasia spinulosa. Dot-like cytokeratin 20 indicates Merkel cell carcinoma, koilocytes HPV, caseating granulomas tuberculosis, and an eosinophil-rich subepidermal blister bullous pemphigoid.

HIV is transmitted sexually but produces systemic immunodeficiency, not genital-tract disease.

Genital HSV-2, HPV warts and cancers, and genital molluscum are all organ-tropic infections of the genital tract.

Because the VZV glycoproteins are tagged with mannose-6-phosphate, newly enveloped virions are diverted into lysosomes and degraded in most tissues, so the virus spreads cell-to-cell rather than releasing free virus.

Maturing keratinocytes at the skin surface lose this receptor, allowing infectious cell-free virus into the vesicle fluid, the source of airborne transmission and of the virus that seeds the sensory nerves.

A complete answer spans the benign and malignant ends and notes the rising entities.

Benign disease

Cutaneous warts (common, plantar and flat, mostly HPV 1, 2, 27 and 57); anogenital warts (condylomata acuminata, HPV 6 and 11), the commonest clinical HPV disease; and recurrent respiratory papillomatosis (HPV 6 and 11), bimodal with a perinatally acquired juvenile form.

Inherited susceptibility

Epidermodysplasia verruciformis, an inherited inability to control beta HPV, causes widespread warts and cutaneous squamous cell carcinoma on sun-exposed skin.

Malignant disease

Persistent high-risk infection causes intraepithelial neoplasia and cancer of the cervix, vulva, vagina, penis and anus, each preceded by a gradable precancerous phase. Anal cancer is rising in men who have sex with men and people living with HIV, and HPV-positive oropharyngeal cancer is a distinct, rising and better-prognosis entity driven by HPV16.

Why C

HPyV7 is part of the normal skin flora, so finding its DNA on intact skin carries no clinical meaning; the rare associated disease is diagnosed on biopsy of an actual lesion, not by detection of the virus on healthy skin. It does not confirm disease, predict cancer, or by itself warrant treatment.

Why D

HPyV7 (Deltapolyomavirus septihominis) is a deltapolyomavirus, the genus of human skin and gut commensals that also contains HPyV6, 10 and 11. The alphapolyomaviruses include Merkel cell and trichodysplasia spinulosa viruses, and the betapolyomaviruses include BK and JC.

Why B

HPyV7 is a near-universal, generally harmless component of the skin flora, with no recognised disease in immunocompetent people. PML is JC virus, haemorrhagic cystitis is BK virus, and HPyV7 is not oncogenic and does not cause hepatitis.

Why E

Control of the polyomaviruses depends on cellular immunity, so the principal measure is to reduce immunosuppression where the underlying condition allows, with supportive skin care otherwise. There is no antiviral of proven benefit, no vaccine, and the disease is benign, so excision and chemotherapy have no place.

Why B

It is a non-enveloped double-stranded DNA polyomavirus, species Alphapolyomavirus octihominis, in the same genus as Merkel cell polyomavirus. It is not a herpesvirus, an RNA virus, a papillomavirus or a poxvirus.