Viral Syndromes by Organ System — Questions

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.

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.

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).

• 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.

• 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.

• 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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.