Varicella-Zoster Virus Infections

• Introduction.
• Primary infection.
  • Chickenpox.
• Latency.
• Reactivation.
  • Shingles.
    • Postherpetic neuralgia.
  • Ramsay Hunt Syndrome.

   

Introduction

• VZV (HHV3) is a neurotrophic alpha-herpesvirus that only naturally occurs in humans. There are no animal reservoirs.
• VZV is named after:
  • Varicella, an alternative name for chickenpox (the primary VZV infection)
  • Zoster, another name for shingles (reactivation of latent VZV infection).
• Prevalence rates of VZV infection are higher (90% or more) in young adults living in temperate countries, compared to tropical countries (50% of young adults). Reasons for this are unclear.
• VZV is of direct relevance to the practice of dentistry as:
  • VZV is highly infectious and good Cross Infection practices are essential.
  • Chickenpox has oral manifestations.
  • Shingles may involve the oro-facial tissues.
  • Ramsay Hunt Syndrome is a cause of facial palsy.
  • Postherpetic Neuralgia can mimic other causes of oral pain.
• A live attenuated Oka strain VZV vaccine has been available for over 20 years.
• This results in lifelong infection with an altered strain of VZV. The longterm sequelae of this remain unknown.
• The vaccine is not used in the UK:
  • But, in the U.S.A. it has been available since 1992 and there has been a mass immunization programme of more than 10 million children since 1995.
• VZV, in common with other HHVs, causes primary infection, latency for life (in sensory neurones), and reactivation that may be symptomatic.

1. Primary Infection

• VZV is the most infectious of the HHVs. Infection is via inhalation of an aerosol of nasopharyngeal secretions from an infected patient with chickenpox. Shingles lesions are also infectious, but to a lesser extent. The highly infectious natures of VZV contrasts with other HHVs.
  • Patients with chickenpox are infective for:
    • Two days before the mucocutaneous manifestations develop.
    • Until after the last skin lesion has crusted over and dried.
• Primary infection with VZV can be:
  • Asymptomatic - many, particularly in developing countries where infection occurs early in life.
  • Symptomatic - when it causes Chickenpox.
• For reasons that are not clear, the older the patient's age at the time of primary VZV infection, the more likely it is that
  • Chickenpox will develop.
  • The chickenpox will be severe.

Chickenpox

• After infection of the upper aerodigestive tract there is an initial viraemia when VZV spreads to the reticuloendothelial system. A second viraemia occurs shortly before clinical symptoms develop, approximately 15 days (10-21 days) after infection.
  • The viraemias increase the risk of systemic complications, particularly in those who are not immunocompetent (e.g. neonates or the immunocompromised).
• Some patients (especially adults and less commonly children) experience prodromal ('running before') symptoms shortly before the mucocutaneous lesions develop. These include:
  • Headaches (can be severe).
  • General aches and pains (especially backache).
  • General malaise.
  • Fever.
• The typical exanthem (rash) of chickenpox then develops and is a consequence of both:
  • Direct viral damage to epithelial cells as the virus replicates.
  • The host response that is mounted to this cytotoxicity.
• Skin lesions pass through several stages of evolution as follows:
  • A transient pink rash occurs in some.
  • Macules (flat lesions) that are typically itchy.
  • Papules (raised lesions).
  • Vesicles that include highly infectious fluid.
  • Pustules (reflects high white blood cell numbers within the vesicles).
  • Crusting and healing around 10 days after developing. It is only once the lesion has crusted and dried that it becomes non-infectious. Healing occurs without scarring, unless scratching (due to the pruritis) has occurred.
    • Secondary bacterial infection (usually with Staphylococci or Streptococci) may occur, especially if the lesions have been scratched.
      • This can potentially lead to septicaemia.
• . The exanthem of chickenpox is described as a centripetal rash that develops in crops.
  • 'Centripetal' reflects that the rash starts on the head and then spreads to the trunk, and finally the limbs.
  • 'Crops' reflects that new lesions develop over 3 to 4 days. This means that adjacent skin lesions can be at different stages.
• The severity of the rash is highly variable between individuals.
  • Some patients get only a few lesions and the rash may pass undetected.
  • Other patients experience a severe rash.
• Oral lesions occur in chickenpox.
  • Vesicles develop on an erythematous base and then burst to leave painful ulcers.

A. Identification of skin lesions at different stages of their evolution (macules, papules, pustules and so on) at any one time is an important clinical feature of chickenpox. B. Oral ulceration may be a feature of chickenpox.

Investigation and Subsequent Management

• The diagnosis of chickenpox is usually made clinically in the absence of special investigations.
• Where doubt exists, the diagnosis should be confirmed by either VZV serology or culture.
• Management is supportive as the condition is self-limiting in uncomplicated immunocompetent patients:
  • Keep hydrated.
  • Paracetamol.
  • Calamine lotion applied to the skin to sooth the lesions.
  • Avoid scratching skin lesions (increased risk of secondary bacterial infection or subsequent scar formation).
• Infectious individuals should be kept away from those who have not already been infected, especially if they are immunocompromised in any way.
  • Pregnant women who have never been infected with VZV are at particularly high risk.
  • As part of cross infection control measures, it is wise to postpone non-urgent treatment in patients.
    • Known, or suspected to be in the acute phases of primary VZV infection.
    • With exposed shingles lesions that have not yet crusted over.
• Less than 5% of all cases of chickenpox occur in adults, but:
  • Complication rates are 10-20 times higher than in children.
  • Half of all chickenpox-related deaths occur in adults.
    • The mortality rate in adults is around 1 in 3000 cases (compared to 1 in 70,000 in children aged between 1 to 14 years old).
• Neonates and pregnant women are susceptible to severe primary VZV infection, but:
  • Most chickenpox-related deaths occur in individuals who are otherwise well and do not have conditions that would predispose them to severe infection.

2. Latency

• VZV is latent in sensory nerve ganglia including the dorsal root spinal ganglia and the geniculate ganglion of each VII cranial nerve.
• During this time the host defences are unable to detect and eliminate HSV from the body.
  • Accordingly, VZV infections are lifelong.
  • Latent VZV is in an inactive state that is not directly toxic to the cell.
    • In contrast to primary infection, there is no cell lysis or indirect cell damage due to inflammation.
• In some individuals, HSV can be reactivated from a latent state.

3. Reactivation

• VZV can be reactivated from the latent state. Symptomatic reactivation causes either Shingles or Ramsay Hunt Syndrome.
• Factors determining the switch from latency to reactivation remain poorly understood. T-cell immunity is known to be important in maintaining VZV in a latent state.

Shingles

• Shingles is also known as 'zoster' (from the Greek for a 'belt'). This reflects that shingles commonly involves a single truncal dermatome and produces a skin lesion with a unilateral 'belt-like' distribution.
• Shingles is due to reactivation of latent VZV from sensory ganglia.
  • During reactivation VZV travels from one (or rarely more than one) sensory ganglion to the stratified squamous epithelium supplied by that ganglion.
  • Viral proliferation occurs in epithelial cells.
• Shingles is common:
  • 20% of adults have an attack of shingles at some point in their life.
  • 1% of adults have more than one attack.
• Control of VZV reactivation to cause shingles remains poorly understood, although immune status is important. The prevalence of shingles increases with age (as T-lymphocyte immunity efficiency diminishes).
  • Symptomatic reactivation mostly occurs in the elderly:
    • <50 years old: <2 cases of shingles per 1000 adults per year (<2/1000/year).
    • 50-79 years old: 5-7/1000/year.
    • >80 years old: 11/1000/year.
• Sometimes, a factor triggering an attack of shingles can be identified:
  • Physical trauma (local or general).
  • Stressful events including emotional stress or surgery.
  • Serious illness such as malignancy.

Clinical Features of Shingles

• A key feature of zoster lesions is that have distinctive anatomical distributions with well-defined borders that reflect the area supplied by the involved nerve. As such, shingles lesions are unilateral and do not cross the midline (except in the very rare cases where there is concurrent bilateral involvement).
  • For spinal nerves this will be a dermatome (the area of skin supplied by a single sensory ganglion). The clinical lesions have well-defined anatomical boundaries. Shingles most commonly involves skin of the trunk of the body.
  • Involvement of a cranial nerve is less common, and mostly involves a single division, rather than all three divisions of either the left or right trigeminal nerve.
    • Involvement of the ophthalmic division is 20x more common than involvement of either the maxillary or mandibular divisions of the trigeminal nerve.
    • Oral lesions are less common than cutaneous shingles, but do occur and are painful. They are characterised by a localised unilateral (i.e. does not cross the midline) vesicular eruption that rapidly ulcerates.
• The severity of shingles is extremely variable and can be so mild that the illness is barely noticed by the patient. Others experience very florid and unpleasant symptoms.
• Some patients experience mild fever and constitutional upset.
• Over half of patients have abnormal sensations in the skin that will subsequently be involved by the rash. These may include:
  • Paraesthesia of the affected skin in some patients.
  • Pre-herpetic neuralgia characterised by recurrent episodes of shooting, electric-shock-like pain that can be excrutiating. This can occur upto 3 weeks prior to rash formation.
• A vesicular rash restricted to the distribution of a single sensory nerve is the classic skin lesion of shingles.
  • The severity and discomfort of the rash is extremely variable.
  • The rash develops over 3-5 days.
  • Vesicular fluid is infectious and may cause chickenpox in uninfected individuals.
  • Once the vesicles have burst, the lesions scab over and heal over 7-10 days. Lesions that have scabbed over are no longer infectious.
• Skin lesions are prone to secondary bacterial infection, particularly if scratched.

There can be great variation in the severity of shingles lesions. A. Erythema of the forehead in a patient with mild shingles. B. The shingles lesions are more extensive in this patient with definite areas of crusting. C. In some patients there are severe lesions. This case illustrates the precise anatomical distribution of the lesion (left ophthalmic division of the trigeminal nerve). An urgent ophthalmology opinion would have been essential in this patient.

Investigation and Subsequent Management

• The diagnosis of shingles is usually made clinically in the absence of special investigations.
• Where doubt exists, the diagnosis should be confirmed by either VZV serology (rise in antibody titres over a 4 week period) or culture (from vesicle fluid).
• Management in the majority of patients is supportive as the condition is self-limiting in the uncomplicated cases:
  • Keep hydrated.
  • Paracetamol.
  • Calamine lotion applied to the skin to sooth the lesions.
  • Avoid scratching skin lesions (increased risk of secondary bacterial infection or subsequent scar formation).
• Infectious individuals should be kept away from those who have never been infected with VZV, especially if they are immunocompromised in any way:
  • Shingles is much less infective than chickenpox.
• Involvement of the ophthalmic division of the trigeminal nerve is a medical emergency and an urgent ophthalmology opinion is essential due to conjunctival and corneal lesions. Subsequent scar formation can result in blindness.
• Shingles may be followed by Postherpetic Neuralgia.

Postherpetic Neuralgia

• Postherpetic neuralgia (PHN) is pain that persists after resolution of the skin rash of shingles.
• PHN only occurs in some patients.
• The likelhood of developing PHN that persists for longer than 3 months increases with age:
  • <50 years old: few develop PHN
  • >70 years old: 18% develop PHN
  • >80 years old: 34% develop PHN
• PHN is a neuropathic pain that arises due to direct damage to nervous tissue. VZV-induced inflammation results in:
  • Scarring of dorsal root ganglia.
  • Atrophy of the dorsal horn.
• The nature of the pain is variable:
  • Constant burning/aching pain, or
  • Paroxysmal lanciating pain.
• Most cases of PHN are mild with relatively few moderate or severe cases.
  • Most of the severe symptoms occur in the oldest patients.
• Once PHN has resolved, there is practically no risk that the pain will recur in the future (unless the patient has a subsequent attack of shingles involving the same area).
  • This is a significant difference from trigeminal neuralgia where episodes of pain can relapse and remit over time.
• There is some weak evidence from random controlled trials that early prescription of anti-viral medication early in the evolution of shingles reduces the severity of PHN.
• Several different drugs can be effective in control of PHN symptoms including
  • Tricyclic antidepressants (e.g. nortriptyline) which are used for their ability to control neuropathic pain (rather than their role as antidepressants, although this may be a useful secondary effect in some patients).
  • Anticonvulsants (e.g. gabapentin).
• PHN can mimic other causes of oro-facial pain.
  • Ask about previous attacks of shingles.
• Dental care may not only be difficult due to the pain experienced by the patient, but also
  • Depression related to chronic pain.
  • Diminished saliva production secondary to drugs such as tricyclic antidepressants.

Ramsay Hunt Syndrome

• Ramsay Hunt Syndrome (RHS) is due to reactivation of latent VZV from the geniculate ganglion of the facial nerve.
• Only a small proportion of those with latent VZV develop RHS.
  • RHS can occur at any age, but is more common in adults than children,
    • Particularly in adults over 60 years old.
  • The trigger(s) for development of RHS are unknown.
• The classic triad of RHS is:
  • Herpetic eruption involving the external auditory meatus (vesciles, then crusting) and/or the posterior soft palate and pharynx (vesicles, then erythema and ulceration).
  • Lower motor neurone facial nerve weakness or paralysis of acute onset.
    • RHS is a significant cause of LMN facial nerve weakness.
      • In one series of 1507 patients with LMN facial nerve weakness, RHS was the diagnosis in 12%.
    • Some cases of RHS are misdiagnosed as 'Bell's Palsy', possibly because a diagnosis of RHS is not considered, or the external auditory meatus and soft palate were not examined for lesions.
      • A greater severity of facial nerve weakness, hearing loss, ear pain, hyperacuisis and decreased tears are more likely in RHS compared to Bell's palsy.
      • Facial numbness is less common in RHS than Bell's palsy.
  • Ear pain.
• Other clinical signs and symptoms can occur and reflect not only involvement of the facial nerve, but also the vestibulocochlear (VIIIth) cranial nerve. These include:
  • Hyperacuisis (sounds are harsh due to diminished stapedial muscle function - VII).
  • Decreased tears (diminished secretomotor function - VII).
  • Hearing loss (VIII).
  • Vertigo (VIII).
• Onset of the different clinical symptoms may not occur at the same time. For example, facial weakness may occur either before or after vesicle formation.
• Resolution is spontanous, although there may not be complete resolution of all or some of the symptoms.
• The diagnosis is primarily made clinically. Confirmation of an acute VZV infection can be made by detection of a four-fold rise in serum VZV antibody titres over a four week period from the onset of clinical symptoms and signs.
• Management is largely supportive. There is some evidence that systemic Prednisolone and Aciclovir given early in RHS is associated with an improved prognosis.

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