Varicella-zoster virus — Questions

Cerebrospinal fluid PCR is positive in only about 30% of cases of VZV vasculopathy, so a negative result does not exclude it. Demonstrating intrathecal synthesis of anti-VZV immunoglobulin G is the more sensitive approach, and the same principle applies to other rash-free neurological presentations of the virus.

Because VZV spreads largely from cell to cell, cell-mediated immunity rather than antibody is the decisive control. Children who cannot make antibody are not unusually susceptible to severe chickenpox, whereas any failure of T-cell immunity predisposes to severe primary disease and to reactivation.

The decline of this arm with age or immunosuppression is what permits zoster.

The recombinant glycoprotein E subunit vaccine with the AS01B adjuvant, given as two doses, has superseded the older live-attenuated zoster vaccine. It gives high, durable protection of around 90% that does not wane with age, and because it is non-live it is safe in the immunocompromised, the group at greatest need.

The childhood varicella vaccine prevents primary chickenpox, and immunoglobulin is for post-exposure prophylaxis, neither being active immunisation against zoster.

Antiviral treatment is indicated for complicated varicella and for any immunocompromised patient, in whom the disease can progress and disseminate. Aciclovir should be started as early as possible, given intravenously when the disease is severe.

Uncomplicated chickenpox in a healthy child is self-limiting and does not require antivirals.

Antivirals shorten the acute illness and reduce acute pain when started early, within the first two to three days of the rash, but they do not prevent postherpetic neuralgia.

That established neuropathic pain is managed separately, with agents such as gabapentin or pregabalin, tricyclic antidepressants, and topical lidocaine.

Aciclovir must first be activated by the viral thymidine kinase, and resistance, which arises mainly during prolonged exposure in advanced HIV infection, is usually due to mutation of that kinase.

Foscarnet and cidofovir inhibit the viral DNA polymerase directly, without needing viral activation, so they retain activity against thymidine-kinase-deficient resistant strains.

• (a) False. Inactivated influenza vaccine is recommended, not contraindicated, in pregnancy and in HIV at any CD4 count; it is non-live and safe, and both pregnancy and HIV raise the risk of severe influenza.
• (b) True. HPV vaccination is recommended for HIV-infected people regardless of CD4 count, ART use or viral load, including men who have sex with men up to about 40 years, because of their high HPV-associated cancer risk.
• (c) True. Hepatitis A vaccine is inactivated and safe in HIV; the standard two-dose schedule is appropriate, and chronic liver disease is itself an indication. Checking post-vaccination antibody is reasonable, as the response may be reduced.
• (d) False. The varicella vaccine is live and contraindicated at a CD4 count of 150 cells/uL. Give varicella-zoster immunoglobulin (VZIG) for post-exposure prophylaxis instead.

• Pfizer-BioNTech COVID-19 vaccine (Comirnaty): mRNA vaccine in a lipid nanoparticle, encoding the pre-fusion spike protein.
• Cervarix: virus-like particle (HPV L1) vaccine, bivalent (types 16 and 18), with the AS04 adjuvant.
• Annual inactivated influenza vaccine: inactivated (killed) vaccine, usually split or subunit, grown in eggs or cell culture.
• Mumps vaccine: live attenuated vaccine (the Jeryl Lynn strain), given within MMR.
• Shingrix: recombinant protein subunit vaccine (varicella-zoster glycoprotein E) with the AS01B adjuvant.

A complete answer first checks existing immunity, then separates live from inactivated vaccines and sequences the doses within the time available.

Assessment first. Take a vaccination history and, where useful, check serology (measles, rubella, varicella, hepatitis B). Do a pregnancy test: the live vaccines (MMR and varicella) are contraindicated in pregnancy, and pregnancy should be avoided for one month after them.

Live vaccines (give on the same day, or at least 4 weeks apart).

• MMR: one or two doses depending on documented immunity.
• Varicella: two doses 4 to 8 weeks apart if there is no history or evidence of immunity.

Inactivated vaccines (flexible timing, may be co-administered at separate sites).

• Hepatitis A: two doses at 0 and 6 to 12 months.
• Hepatitis B: three doses at 0, 1 and 6 months (an accelerated 0, 7, 21 days plus a 12-month dose if time is short). Combined hepatitis A and B is an option.
• Typhoid: single-dose Vi polysaccharide (inactivated).
• Polio: an inactivated polio (IPV) booster.
• dTaP: a single adult Tdap dose, reviewing tetanus and diphtheria status.

A workable sequence. Day 0: MMR, varicella (1), hepatitis A (1), hepatitis B (1), IPV, Tdap and typhoid together at separate sites. Then varicella (2) at 4 to 8 weeks; hepatitis B (2) at 1 month and (3) at 6 months; hepatitis A (2) at 6 to 12 months. Document everything for the destination country’s entry requirements.

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.

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.

Varicella-zoster immunoglobulin, given as soon as possible and ideally within 96 hours of exposure, is the mainstay for high-risk susceptible contacts: susceptible pregnant women, the immunocompromised, and neonates whose mothers develop varicella around delivery.

The live vaccine is contraindicated in pregnancy, and immunoglobulin attenuates rather than always prevents disease.

Reactivation of varicella-zoster as shingles occurs at a relatively high CD4 count and is often the first clue to undiagnosed HIV in a young adult, so it should prompt HIV testing. As immunity falls further, zoster becomes multidermatomal or disseminated and can cause encephalitis, a retinal necrosis and a stroke-causing vasculopathy.

Reassurance alone misses an opportunity to diagnose HIV, lifelong suppression is not indicated for a single episode, a live vaccine is inappropriate when immunodeficiency is suspected, and a clotting screen is irrelevant.

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.

A person with chickenpox is infectious from about two days before the rash appears until the last lesion has crusted over. Transmissibility before the rash is what makes the disease so difficult to contain, and a patient is no longer infectious once every lesion has dried.

AS01B, a liposomal combination of monophosphoryl lipid A and the saponin QS-21, drives the strong CD4 T cell response behind the recombinant zoster vaccine’s durable protection.

Alum alone is a weaker adjuvant; MF59 is used in influenza vaccines; CpG 1018 is in a hepatitis B vaccine; and AS04 is used in an HPV vaccine.

The varicella vaccine is a live-attenuated Oka-strain preparation, so it is contraindicated in pregnancy and in significant immunosuppression, and pregnancy should be avoided for a month after vaccination.

None of the other options is a contraindication:

• a past history of mild chickenpox
• contact with an elderly relative
• recent receipt of an inactivated vaccine
• a family history of postherpetic neuralgia

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.

Herpes simplex

HSV reactivates earliest, within the first month. Aciclovir or valaciclovir prophylaxis during this period cuts HSV reactivation from around 70 per cent to under 5 per cent. (CMV prophylaxis with ganciclovir or valganciclovir also covers HSV, so separate aciclovir is not needed while that is running.)

Varicella-zoster

VZV reactivation (zoster) is late, often after day 100, and can disseminate. A seronegative recipient exposed to chickenpox or shingles is given varicella-zoster immunoglobulin within the recommended window, with aciclovir post-exposure prophylaxis as an adjunct. Live varicella and zoster vaccines are contraindicated after transplant and should be given to seronegative candidates before transplant; the non-live recombinant zoster vaccine is an option after transplant where available.

Why the distractors are wrong

B wrongly calls these infections harmless; C gives a live vaccine when it is contraindicated; D withholds prophylaxis until after disease and misstates the resistance picture (long-term prophylaxis actually keeps resistance low); and E misapplies immunoglobulin to everyone and assumes CMV prophylaxis always covers HSV.

VZV establishes lifelong latency in neurons, and not only in the dorsal-root sensory ganglia but also in cranial-nerve, autonomic and enteric ganglia.

In the latent state the virus shuts down almost all gene expression, restricting itself largely to a non-coding latency-associated transcript that suppresses ORF61 and so blocks the cascade that would otherwise drive replication.

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.

Varicella has an incubation period of 10 to 21 days, averaging about two weeks. The long interval reflects the time the virus takes to overcome the innate barrier in the skin before the generalised rash erupts in successive crops.

VZV carries a linear double-stranded DNA genome of about 125 kilobases, the smallest of the human herpesviruses. Unusually for an alphaherpesvirus it has no glycoprotein D ortholog, relying instead on glycoprotein E for cell-to-cell spread, and it is the only human herpesvirus against which licensed vaccines exist.