Varicella or chickenpox is caused by the herpes zoster virus (HZV). It is transmitted through droplet infection or direct contact with vesicle fluid and is very contagious. HZV is a neurotrophic virus, ie. it has the ability to invade and reside within neural tissue. Primary infection with HZV results in the typical vesicular eruption of varicella (chickenpox). During the systemic, viraemic phase of varicella the virus invades the sensory nerve endings and travels up the sensory fibres, eventually settling in the cranial or dorsal root ganglia. Here it remains latent for the duration of the host’s life, ie. it is a lifelong infection.
Reactivation of the latent infection, with replication of HZV in one or more of the dorsal root ganglia may occur at any point in the future. All who have had chickenpox in childhood are at risk of reactivation. With reactivation, the HZV spreads along the sensory nerve from the dorsal root ganglion, giving rise to either asymptomatic shedding or a vesicular eruption of the skin dermatome supplied by the affected nerve (varicella zoster or shingles).
It is rare that the HZV is transmitted to a close contact from a patient with herpes zoster (shingles). Such transmission may result in varicella. It is a popular misconception that patients with varicella or varicella zoster can cause herpes zoster in contacts. Such transmission can only give rise to varicella. Herpes zoster is a reactivation phenomenon, not an infection acquired from an individual with varicella or herpes zoster.
Who is at increased risk of herpes zoster?
Increasing age. T-cell-mediated immunity protects against reactivation of latent HZV. This declines with age. It is not related to antibody titres which may remain unchanged or increase with age
Immunocompromised patients with impaired T-cell immunity
Patients on immunosuppressive treatments
Patients with lymphoma, leukaemia, or HIV
Rheumatoid arthritis, inflammatory bowel disease, COPD, asthma, chronic kidney disease, type 1 but not type 2 diabetes.
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In contrast with healthy individuals, the increased risk in these patient groups is proportionally greater in younger age. Periodic exposure to individuals with varicella, throughout life, boosts immunity to HZV. Healthcare workers who are regularly in contact with children with chickenpox infection probably benefit from such regular boosts to their immunity.
Reactivation
The reactivated HZV spreads down the nerve, eventually reaching the skin, leading to the vesicular eruption of herpes zoster. While progressing down the nerve HZV causes a severe inflammatory neuritis. This neuritis gives rise to the prodromal and acute phase pain of herpes zoster; 90% of patients experience prodromal pain in the affected dermatome. Usually this phase lasts for five to seven days before the rash becomes evident. The eruption is usually limited to one to three adjacent dermatomes.
Involvement of the anterior root may give rise to motor weakness. Reactivation, if accompanied by significant host immune response, may present with pain but no rash, so called ‘zoster sine eruptione’. Indeed, most attempts by the virus to reactivate are suppressed by the host’s immune response, resulting in neither pain nor rash. At the other extreme, in patients who are unable to mount an adequate immune response, the virus may disseminate, giving rise to a widespread, varicella-like eruption and multisystem organ involvement with a 10% fatality rate.
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Clinical presentation
Classical HZ presents as a unilateral, dermatomal rash. It generally starts proximally, before spreading distally along the affected dermatome, with new lesions developing over three to six days. The duration of the rash has been correlated with patient age (advancing age associated with longer duration) and site of infection (face healing more rapidly than other loci). The entire dermatome may not be involved.
Initial lesions are erythematous macules or papules which develop vesicles within 12 to 24 hours. Vesicles may become haemorrhagic or pustular. After five to seven days crusts develop and the lesions resolve, sometimes with either hypopigmentation or hyperpigmentation. Complications include encephalitis, myelitis, and motor paralysis. The thoracic dermatomes are most frequently involved (55%), followed by the trigeminal nerve (20%), cervical (11%), lumbar (13%) and sacral (2%).
Zoster-associated pain (ZAP)
There are three phases of zoster-associated pain:
Prodromal pain in the period before the eruption develops
Acute phase pain occurs in the first 30 days
Post-herpetic neuralgia.
Prodromal and acute phase herpes zoster pain
Up to 90% of patients experience acute, neuritic pain and hypersensitivity due to the acute inflammatory neuritis in the affected sensory nerve. Pain often precedes the rash (prodromal) and may be continuous or episodic. It fades as the rash resolves. The degree of pain can be variable. Severe acute pain is correlated with an increased risk of post herpetic neuralgia (PHN). Because of the latency between reactivation and the development of the eruption, the pain is often misdiagnosed as myocardial infarction, pleurisy, cholecystitis, appendicitis, duodenal ulcer, ovarian cyst, or prolapsed disc.
Paraesthesia (burning, stabbing, shooting, tingling), dysaesthesia (painful sensitivity to touch), allodynia (pain induced by non-painful stimuli) or hyperesthesia (exaggerated or prolonged response to a painful stimulus) may occur. In contrast with PHN, which requires medication targeted at neuropathic pain, oral analgesics may be used to treat prodromal and acute phase pain – paracetamol, non-steroidal anti-inflammatory, codeine.
Apart from improving functional status and health-related quality of life, controlling acute ZAP is presumed to reduce the risk of PHN, although evidence from controlled studies to support this presumption is not available.
Oral antivirals
HZ is generally a self-limiting disease and, in the absence of risk factors for complicated courses, treatment aims are to reduce the extent and duration of the cutaneous manifestations and the severity and duration of acute ZAP and the incidence, severity and duration of PHN
Oral antivirals hasten rash resolution and reduce both the duration and severity of ZAP but do not reduce the incidence of PHN. Three antiviral drugs are licensed for treating zoster – aciclovir, 800mg orally five times per day, famciclovir, 500mg eight-hourly, and valaciclovir, 1g eight-hourly. There is limited evidence that famciclovir and valaciclovir are more effective than aciclovir at reducing zoster-associated pain.
There is no evidence to support continuing antivirals beyond seven days. All three antivirals are excreted by the kidney and it is advised to check creatinine in patients with known or suspected renal insufficiency.1 There is no evidence to support giving antivirals more than 72 hours after the onset of the rash.
Beyond this time antivirals might be given if new vesicles are still appearing in a patient at risk of a complicated course or with manifest complications (cutaneous, visceral or neurological dissemination, HZ ophthalmicus or HZ oticus, immunocompromised).
Post-herpetic neuralgia (PHN)
In the prodromal and acute phases of herpes zoster, neuritis results in nerve fibre damage. In the process of repair, nerve fibres may be wrongly ‘rewired’. A nerve fibre transmitting touch may connect with a fibre transmitting pain. This explains why patients develop neuropathic problems post-zoster.
Allodynia is the perception of pain from a non-painful stimulus, such as touch. Hyperalgesia is an exaggerated pain sensation from a mildly painful stimulus. Other manifestations of neuropathy include reduced or loss of sensation in the affected dermatome and pruritus.
PHN is defined as dermatomal pain persisting at least 90 days after appearance of rash. Twenty per cent of patients have some pain at three months. The incidence of PHN following HZ rises with age (8% at 50 to 54 years, 21% at 80 to 84 years). Those with more severe pain during the prodrome and rash phase, the immunocompromised, number of lesions > 50, cranial/sacral localisation, haemorrhagic lesions and those with trigeminal nerve involvement are also at increased risk of developing PHN.
Prevention of PHN
Trials of antiviral drugs were not designed to assess subsequent incidence of PHN. We cannot say that antivirals reduce either the incidence or course of PHN as what evidence we have is inconsistent. The addition of oral glucocorticoids to an antiviral medication decreases the pain of the acute phase HZ and speeds lesion resolution but does not reduce the incidence PHN. They may be considered in the elderly provided there are no contraindications.
The European Dermatology Forum in co-operation with the European Academy of Dermatology and Venereology recommend treating the following patient subgroups with an antiviral medication1:
• HZ of any localisation in patients ≥ 50 years of age
• HZ of the head and/or neck area
• HZ of any localisation with
– moderate to severe zoster-associated pain
– haemorrhagic or necrotising lesions
– > 1 segment involved
– aberrant vesicles/satellite lesions
– involvement of mucous membranes
• HZ in immunocompromised patients
• HZ in patients with severe predisposing skin diseases (eg. atopic dermatitis)
• HZ in children and adolescents under long-term treatment with salicylic acid or corticosteroids
They suggest IV aciclovir in patients with complicated HZ or who are at risk of a complicated course:
• HZ of the head and/or neck area, particularly in elderly patients
• HZ with haemorrhagic/necrotizing lesions, >1 segment involved, aberrant vesicles/ satellite lesions, involvement of mucous membranes or generalised zoster
• HZ in immunocompromised patients
• HZ with signs of visceral or central nervous system involvement (dosage escalation up to 15mg/kg bodyweight 3x/d possible, treatment for up to 21 days).
An episode of herpes zoster boosts the host’s immunity to the virus. Recurrence in immunocompetent patients does however, occur in 6% of cases.
Vaccination
A live attenuated vaccine for HZ is approved for use in Ireland for persons over the age of 50 years. It is indicated for prevention of herpes zoster and herpes zoster-related PHN. It is the same vaccine strain as is used to prevent chickenpox in childhood, but given at a higher dose.
A large study of adults, the Shingles Prevention Study3 over 60 showed that it reduced the incidence of HZ by 51% and PHN by 66.5%.
The vaccine is administered as a single dose. It is contraindicated in patients with haematological malignancy, HIV infection and those who are on long-term oral corticosteroids or who are pregnant.
Drug treatment of PHN
Tricyclic antidepressants are recommended, eg. amitriptyline, starting at a dose of 10mg at night and titrated depending on response and side-effects. The main side-effect at this low dose is sedation that may persist into the following morning. As the dose is increased, anticholinergic effects such as dry mouth and constipation may develop.
Anticonvulsant drugs, eg. gabapentin, can be started at a dose of 300mg TID titrated over three days, pregabalin starting at a dose of 25-50mg BD titrated to 300mg BD, if needed. Following an increase in the number of deaths linked to gabapentin and pregabalin between 2012 and 2016, the UK government reclassified pregabalin as a controlled substance and proposes reclassifying gabapentin.
Topical capsaicin cream 0.075% applied sparingly up to QID is an option if the patient is unable to or prefer not to use oral drugs.
Topical lidocaine is licensed for the treatment of PHN. However, a systematic review concluded that there is no evidence from high-quality studies to support its use in neuropathic pain.2
Case study
A 72-year-old man presented with pain associated with rash on the right side of his abdomen and back. The pain was severe and interfered with his sleep. He described the pain as sudden bursts of burning. The pain had been present for four days before he noticed the rash. The rash was present for three days at this stage. When told that this was shingles he remembered that he had shingles in the same area about 20 years ago.
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Issues raised in this particular case:
• Is oral antiviral medication indicated when the rash has been present for three days?
Yes it is. Indications for antiviral medication in this case include the patient being older than 50 years, the zoster-associated pain is severe, greater than one dermatome are involved and satellite lesions are present above the main area of involvement. The European guidelines recommend treatment in all these instances.
• What analgesia might be offered at this consultation?
Both prodromal and acute phase pains may be very severe and interfere with sleep and daily functioning. Paracetamol and a non-steroidal anti-inflammatory drug may help in the first instance. If these are ineffective you might consider codeine. On occasions a short course of a strong opioid may be needed for the acute phase pain.
• When should anti-neuropathic medication be considered for this patient?
There is some limited evidence that starting anti-neuropathic medication at this early stage of HZ may reduce the long-term severity of PHN. After one week, gabapentin was added to this man’s medication when paracetamol plus naproxen had only limited effect on his pain. The dose was titrated upwards. The pain improved and the patient was able to sleep.
• Having had one episode of HZ, should this man have been protected from recurrence?
Having an episode of HZ boosts a patient’s immunity against the virus. However, this is not sufficient to prevent future episodes of HZ in all patients. Patients who have had an episode of HZ may be advised that while they are at very low risk of recurrence it is not a zero risk.
References
Werner RN et al. European consensus-based (S2k) Guideline on the Management of Herpes Zoster – guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV), Part 2: Treatment. J Eur Acad Dermatol Venereol 2017; 31: 20-29
Derry S, Wiffen PJ, Moore RA, Quinlan J. Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev 2014; 7: CD010958
Oxman M, Levin M and Shingles Prevention Study Group. Vaccination against herpes zoster and postherpetic neuralgia. J Infect Dis 2008 Mar 1; 197(Suppl 2): S228–S236. doi: 10.1086/522159
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