Herpes zoster

Herpes zoster (shingles) is an infection of the nerves supplying certain skin areas that is characterized by a painful rash of small crusting blisters. Also called shingles, herpes zoster is especially common among older people.

Types

Herpes zoster usually affects only one side of the body, and follows the path of a nerve. It commonly develops on a strip of skin over the ribs, although the rash may also appear on the neck, arm, or lower part of the body. Sometimes the infection involves the face and eye; this form of the disorder is called herpes zoster ophthalmicus.

Causes

Herpes zoster is caused by the varicella–zoster virus, which also causes chickenpox. After an attack of chicken-pox, some of the viruses survive and lie dormant for many years in the nerve cells near the spinal cord. In some people, a decline in the efficiency of the immune system –especially in old age – because of disease or severe stress, allows the viruses to re-emerge and cause herpes zoster. The disorder is also common in people whose immune system is weakened by stress or by certain drugs, such as corticosteroid drugs or anticancer drugs.

Symptoms

The first indication of herpes zoster is excessive sensitivity in the skin, followed by pain, which is often severe. The infection can be difficult to diagnose at this stage and may be mistaken for a different condition; for example, pain in the chest wall may be mistaken for angina pectoris. After about five days, the rash appears as small, raised, red spots that soon turn into blisters. Within a few days, the blisters dry, flatten, and develop crusts. Over the next two weeks, the crusts drop off, sometimes leaving small pitted scars. The most serious feature of herpes zoster is pain after the attack, known as postherpetic neuralgia, which affects about a third of all infected people. This pain is caused by nerve damage, and may last for months or years. Herpes zoster ophthalmicus may cause a corneal ulcer or uveitis (inflammation of the part of the eye known as the uvea).

Treatment

If treatment is begun soon after the rash appears, antiviral drugs, such as aciclovir, will reduce the severity of the symptoms and minimize nerve damage. Analgesic drugs (painkillers) may also be helpful in relieving pain. If postherpetic neuralgia is a problem, anticonvulsant drugs, such as gabapentin, may be helpful.

The following article is about the herpes varicella zoster virus that causes varicella (chicken pox) and zoster (shingles).

Varicella zoster virus (VZV) - medical summary

This alpha-herpesvirus is presumed to spread by the respiratory route and after an incubation period of 10 to 20 days causes varicella (chickenpox), predominantly an exanthematous disease of childhood, but which may be complicated in adults by pneumonitis and encephalitis. The virus becomes latent in dorsal root ganglia after primary infection, whence it can reactivate to cause herpes zoster (shingles), with pain, erythema, and vesicular lesions occurring in a dermatomal distribution, particularly in elderly and immunosuppressed individuals. Treatment of severe varicella or herpes zoster is with aciclovir, with higher doses being required than for HSV. A live attenuated VZV vaccine is available: this induces 90% protection from natural varicella in children, and also diminishes the incidence of zoster and postherpetic neuralgia when given to older age groups.

Herpes zoster (Varicella-zoster virus infection) in detail - technical

Historical background

There are clinical descriptions of varicella (chickenpox) and herpes zoster (shingles) in very early medical literature, although the skin lesions of herpes simplex and herpes zoster were grouped together under the term herpes. The similarities between the exanthematous rashes associated with smallpox and varicella meant they were not distinguished until the late 19th century. The characteristic clinical appearance of shingles, in a dermatomal distribution, was recognized as a discrete entity in the early Greek literature. The term zoster is derived from the Greek word for a girdle, and shingles from the Latin cingere meaning to encircle.

In 1892 von Bocquet observed that children developed varicella after contact with adults with herpes zoster, and in 1925 it was shown that vesicular fluid from patients with zoster, inoculated into susceptible people, produced chickenpox. The idea that zoster resulted from the reactivation of latent virus remaining in the tissues following childhood varicella was put forward by Garland in 1943, and strengthened by the work of Hope-Simpson, a British general practitioner. Varicella–zoster virus (VZV) was isolated in 1958, and Weller and colleagues showed the similarity between viral isolates from varicella and zoster patients. Restriction endonuclease analysis showed that the isolates from chickenpox and from later zoster in the same immunocompromised patient were identical. The long interval between the two illnesses has prevented such studies in immunocompetent people.

Aetiology

VZV is structurally similar to other members of the herpesvirus family. The genome is a linear double-stranded DNA of 125 kbp. VZV is an alphaherpesvirus, and encodes sets of genes that are largely colinear to those of HSV, and are also expressed in immediate-early, early, and late phases. The virus is closely cell associated, and spreads from cell to cell in tissue culture.

Epidemiology

VZV infects only humans, which are thus the only reservoir. The virus is presumed to spread by the respiratory route. Varicella is predominantly a disease of childhood, affecting both sexes. 90% of cases occur in children under the age of 13 years. The incubation period is about 2 weeks (with a range of 10–20 days); patients are infectious for about 48 h before the vesicles appear, and remain so for 4 to 5 days afterwards, until all the vesicles have crusted over. The secondary attack rate in susceptible contacts with an index case in the household is 70 to 90%. The prevalence of VZV varies in different ethnic groups. In Europe, about 10% of the population over 15 years old is seronegative, and consequently susceptible to infection, although in tropical countries only 50% of young adults may be seropositive. Varicella in adults is uncommon in Europe, and less than 2% of all cases occur in patients older than 20 years. Subclinical infection is unusual, and accounts for less than 5% of all infections, but the disease may be mild, and in some surveys only 10% of people with a negative history were in fact seronegative for VZV. One attack of chickenpox usually confers lifelong immunity.

After primary infection, VZV becomes latent in dorsal root ganglia. Reactivation appears clinically as herpes zoster, which is a common disease affecting all age groups, but particularly older and immunosuppressed people; about 20% of the population will experience an attack. There is no evidence that exposure to people with active VZV infection predisposes to herpes zoster in their contacts, but a seronegative person may catch varicella from contact with the vesicles of a patient with shingles. Nosocomial varicella infection is well recognized, and the isolation of patients with varicella, and immunocompromised patients with herpes zoster, should be ensured in hospitals. Local unidermatomal zoster is less likely to cause infection, and consequently to need isolation.

Pathogenesis

During primary infection, initial virus replication probably occurs in the epithelial cells of the upper respiratory tract mucosa, followed by a phase of viraemia during which VZV can be isolated from leucocytes, and the disseminated rash appears. In the skin, the virus infects capillary endothelial cells, and adjacent fibroblasts and epithelial cells. During the viraemic phase, virus may spread to visceral organs, including alveolar epithelial cells, and transient subclinical hepatitis is probably a normal feature of varicella. VZV encephalitis may be a feature of primary infection, particularly affecting the cerebellum. Patients usually recover completely from encephalitis (unlike that associated with HSV), and it has been suggested its pathogenesis may be immune mediated. Following recovery from primary infection, the virus persists for life in a latent state in dorsal root ganglia. VZV reaches the ganglia by retrograde axonal transport from the skin lesions during primary infection, and all dorsal root ganglia and the trigeminal ganglion can potentially carry latent VZV in neurones and possibly in satellite cells.

As with other herpesviruses, the host response is critical in containing the initial infection. Cellular immunity is important, since varicella may be progressive in patients with severely impaired T-cell immunity. Both CD4 and CD8 cytotoxic T lymphocytes specific for VZV are present in normal people carrying latent VZV. The cellular immune response presumably plays a part in controlling reactivation, since impaired T-cell immunity increases the risk of developing zoster, and of having vesicles in multiple dermatomes, and cutaneous dissemination of reactivated virus. The increasing incidence of herpes zoster with age may reflect waning cellular immunity to VZV.

Clinical features

Primary infection and varicella

The most striking feature of varicella is the rash, which is centripetal (mainly on the trunk). The lesions are initially present on the face and scalp, before progressing to the trunk and later to the limbs. A macular erythematous rash, papules, and vesicles may all be present together. Individual lesions progress from being papules to vesicles to pustules, and then crust over. The scabs normally separate after 10 days, without scarring. The systemic symptoms associated with varicella vary considerably. In most children there is a mild illness with fever. Adults characteristically have a more severe illness, with myalgia, headache, arthralgia, malaise, and higher fever, with the complications listed below. Symptoms may precede the rash by 1 to 2 days.

Complications of varicella

The principal complications of varicella in immunocompetent patients are pneumonitis and encephalitis.

Pneumonitis

In a prospective study, 6% of young adults with chickenpox had respiratory symptoms, although 16% had changes on chest radiography, but the rate of admission to hospital for pneumonia in adults with varicella is only about 0.3%. Patients present with dyspnoea, cough, hypoxia, and bilateral infiltrates on the chest radiograph, occurring 1 to 6 days after the appearance of the rash. Hypoxia may be more severe than expected from the physical signs or the chest radiograph. The interstitial pneumonitis can progress to respiratory failure requiring artificial ventilation and intensive care, but it is more commonly transient, resolving completely within 2 to 3 days. Varicella pneumonia is said to be more common in smokers. Fatalities are rare, and VZV pneumonia is not associated with long-term respiratory problems. Benign nodular calcification throughout the lung occasionally follows.

Encephalitis

Central nervous system involvement during varicella most commonly presents as acute cerebellar ataxia within 1 week of onset of the rash, although it may appear up to 21 days after the rash. It resolves completely over 2 to 4 weeks. A frequency of 1 in 4000 children aged less than 15 years has been quoted. The cerebrospinal fluid of these patients shows lymphocytosis and elevated protein concentration.

More serious encephalitis can occur in 0.1 to 0.2% of cases of varicella. This begins earlier in the course of infection than cerebellar ataxia, with headache, vomiting, confusion, and impaired consciousness. There is evidence of diffuse cerebral oedema, but no defined pattern of CT or MRI abnormality. The encephalitis may be progressive, and the mortality is between 5 and 20%, with neurological sequelae in up to 1% of survivors.

Varicella meningitis can occur. Other rarely reported neurological complications include optic neuritis, transverse myelitis, and Reye’s syndrome.

Other complications

Primary VZV infection may be complicated by acute thrombocytopenia, with petechiae, purpura, haemorrhage into vesicles, and other haemorrhagic manifestations. The platelet count can remain low for weeks after the illness has resolved. Secondary infection of the skin lesions with Staphylococcus aureus or Streptococcus pyogenes may occur. Purpura fulminans is a rare complication associated with arterial thrombosis and haemorrhagic gangrene). Nephritis and arthritis have been reported as occasional complications, and myocarditis, pericarditis, pancreatitis, and orchitis are even more rare.

Special problems in pregnant women

Varicella in pregnant women can be severe, with a maternal mortality of 1%. Varicella in the first trimester can cause varicella embryopathy. Affected infants may have a scarred, atrophic limb, microcephaly, cortical atrophy, and eye defects including chorioretinitis, microophthalmia, and cataracts. The autonomic nervous system may be damaged. Varicella embryopathy is rare; in recent reported series the risk was about 1 to 2% in mothers with varicella in the first 20 weeks of pregnancy. Varicella–zoster immunoglobulin should be considered for pregnant women in contact with varicella, and varicella in pregnancy should be treated with aciclovir on a named-patient basis. Neonatal varicella occurs in babies whose mothers contract varicella just before or after delivery, and is most severe when maternal disease appears from 2 to 7 days after delivery.

Herpes zoster

The clinical syndrome caused by the reactivation of VZV from sensory ganglia is herpes zoster. Typical prodromal localized pain or paraesthesia is followed by erythema and vesicular lesions occurring in a dermatomal distribution. The thoracic dermatomes, especially T4 to T12, are involved in about 50% of cases; the lumbosacral dermatomes in about 16%; and the cranial nerves (mainly the Vth) in 14 to 20% of patients. The first symptoms are usually paraesthesia and shooting pains in the affected dermatome, which precede the eruption of vesicles by several days, occasionally 1 week or more. Erythematous maculopapular lesions then appear and quickly evolve into a vesicular rash, nearly always in a unilateral dermatome, with no vesicles beyond the midline. The vesicles usually form scabs after 3 to 7 days, and these separate after 2 weeks or so, but there is sometimes a more severe locally necrotic reaction. There is a risk of secondary infection, particularly with Staphylococcus aureus. There may be malaise and low-grade fever, but laboratory investigations usually show no abnormalities, although up to 40% of patients with uncomplicated zoster may have lymphocytes and elevated protein in the cerebrospinal fluid. Involvement of the mandibular branch of the Vth cranial nerve can give intraoral lesions on the palate, floor of the mouth, and tongue. Involvement of the geniculate ganglion results in Ramsay Hunt syndrome, with pain and vesicles in the external auditory meatus, a loss of taste in the anterior two-thirds of the tongue, and a lower motor neurone VIIth cranial nerve palsy.

Complications of zoster

Ophthalmic zoster

VZV reactivation from the trigeminal ganglion can affect the ophthalmic division of the trigeminal nerve, resulting in ophthalmic zoster. The features include conjunctivitis, anterior uveitis, keratitis, and sometimes iridocyclitis, with secondary glaucoma and panophthalmitis. However, these latter sight-threatening complications of ophthalmic zoster are unusual. A rare association with ophthalmic zoster is granulomatous cerebral angiitis, which can be associated with arterial thrombosis; cerebral angiography shows segmental narrowing in the cerebral arteries on the side of the ophthalmic zoster occurring weeks after the rash. CT may show cerebral infarcts, particularly in the middle cerebral artery territory, and contralateral hemiparesis can occur.

Motor zoster

Weakness or paralysis can sometimes be associated with zoster, and results from the involvement of the anterior horn cells in the same segment of the spinal cord as the involved dorsal root ganglion. Depending on the segment involved, this can lead to a monoparesis affecting the upper or lower limb, or to diaphragmatic palsy (with the involvement of C5/6). Paralysis usually recovers completely, although the outlook for the recovery of facial nerve palsy is more variable. It is suggested VZV may be responsible for some cases of idiopathic VIIth nerve (Bell’s) palsy.

Autonomic zoster

Lumbosacral herpes zoster can be associated with neurogenic bladder, and acute retention of urine. This may be accompanied by haemorrhagic cystitis resulting from vesicles on the bladder wall. Intestinal ileus and obstruction may occur.

Zoster meningoencephalitis

Meningoencephalitis may accompany zoster at any site, and is heralded by impaired consciousness, headache, photophobia, and meningism. The interval from the onset of skin lesions to symptoms is around 9 days, but may be as long as 6 weeks. Symptomatic encephalitis usually lasts around 2 weeks, and is nearly always followed by full recovery without neurological sequelae.

Transverse myelitis, although rare, can occur at any level of the spinal cord.

Postherpetic neuralgia

The incidence of postherpetic neuralgia rises with the increasing age of the patient. It is uncommon in young people, but can occur in 50% of patients older than 50 years. It is characterized by pain in the affected dermatome persisting for 1 month or more after the acute attack of zoster has resolved. The pain may be steady and burning, or paroxysmal and stabbing in nature; it may occur spontaneously, or be triggered by stimuli such as temperature or touch.

Zoster sine herpete

This term refers to radicular pain similar to that experienced in zoster, but without the antecedent skin lesions of zoster. It was originally applied to patients who did have obvious zoster, but had dermatomal pain in areas distinct from those where there was rash. However, it is more commonly applied to patients with radicular pain and no rash at all. There have been reports describing the use of PCR testing for the detection of VZV DNA in the cerebrospinal fluid of patients with presumed zoster sine herpete. The literature is anecdotal, and it is difficult to regard zoster sine herpete as a diagnostic entity unless there is good evidence for VZV involvement, e.g. by the detection of VZV DNA in cerebrospinal fluid and/or blood mononuclear cells. It should be included in the differential diagnosis of radicular pain of unknown cause. Any possible mechanism is speculative.

VZV infection in immunosuppressed patients

In patients with immunosuppression, particularly of cellular immunity, varicella can be much more severe. The skin lesions are more diffuse, and can take up to 3 times as long to heal. There may be visceral dissemination to the lungs, liver and central nervous system. Patients with lymphoma undergoing chemotherapy are particularly susceptHerpes zoster in immunosuppressed patients is also more severe than in healthy subjects. Before effective antiviral therapy was available, skin lesions were more extensive and could take several weeks longer to heal. Dissemination, presumably because of viraemic spread, with widespread skin lesions as in varicella, occurs in 10 to 40% of patients. Cutaneous dissemination is more likely to be associated with visceral dissemination to the same sites as those associated with varicella.

Patients with HIV infection or AIDS are prone to multidermatomal zoster, which can be one of the defining features of AIDS.

VZV retinitis

This is a combination of pain and blurred vision in one eye, with progressive necrotizing retinitis seen on ophthalmoscopy. Adjacent cutaneous zoster indicates the diagnosis, but occasionally VZV retinitis occurs in immunocompetent patients as the sole manifestation of VZV reactivation. VZV retinitis may be difficult to distinguish from CMV retinitis. A severe form of the disease, seen particularly in patients with HIV infection, and named progressive outer retinal necrosis, is associated with a high incidence of retinal detachment, and may require treatment with ganciclovir, as aciclovir is often ineffective.

Differential diagnosis

Varicella is usually recognized relatively easily. Other causes of a vesicular rash are generalized herpes simplex in the immunosuppressed patient, and enteroviral disease, particularly hand, foot, and mouth disease caused by Coxsackie virus infection, but the rash on the hands and feet is unlike that of varicella, which has a centripetal distribution. Human cases of infection with animal pox viruses (monkey pox and camel pox) have rarely been described. Localized pain before the appearance of shingles or in zoster sine herpete may be severe enough to suggest myocardial ischaemia, or lung or intra-abdominal pathology if it involves the thoracic dermatomes.

Pathology

The histological appearance of VZV infection is similar or indistinguishable from that of HSV infection.

Laboratory diagnosis

The diagnosis of varicella and herpes zoster is usually made on clinical criteria alone. Virus can be seen in vesicular fluid by electron microscopy, or isolated in culture. A serological diagnosis of varicella can be made by demonstrating seroconversion or VZV IgM antibody. Urgent serology is needed to confirm the seronegative status of contacts at risk of severe VZV infection, to determine the need for VZV immunoglobulin (see ‘Prevention and control’ below). PCR-based tests for the detection of VZV DNA are available, and are of most use in testing cerebrospinal fluid in cases of suspected central nervous system disease.

Treatment

Pruritus may be alleviated by calamine lotion and antihistamines in patients with chickenpox. Fingernails should be closely cut to minimize scratching. Skin care is important to prevent secondary bacterial infection in patients with varicella and zoster. Aspirin should be avoided in children with chickenpox because of the risk of Reye’s syndrome. Strong analgesia may be needed in patients with zoster.

Box  The use of aciclovir in varicella–zoster infections

Indications for intravenous aciclovir (10 mg/kg 8 hourly)
 
Chickenpox:
  • Immunocompromised patients
  • Neonatal chickenpox
  • Chickenpox with systemic complications
  • Severe chickenpox in adults and in pregnancy (5 mg/kg 8 hourly)
Shingles:
  • Severe shingles in immunocompromised patients
  • Multidermatomal shingles
  • Shingles complicated by ocular, motor, autonomic, or systemic involvement
  • VZV retinitis (severe forms in AIDS may require foscarnet or ganciclovir)
Indications for oral aciclovir (800 mg 5 times daily)
  • Uncomplicated chickenpox (except for mild chickenpox in children)
  • Uncomplicated shingles in patients over 45 years
  • Uncomplicated shingles in immunosuppressed patients
  • Shingles presenting with severe pain
Infections not requiring active antiviral treatment
  • Uncomplicated mild chickenpox in children
  • Patients presenting more than 48 h after the appearance of the last lesion, or when all lesions have crusted
  • Uncomplicated shingles in patients under 45 years
  • Postherpetic neuralgia

VZV is sensitive to the nucleoside analogues aciclovir, famciclovir, and valaciclovir; as for HSV, VZV encodes a thymidine kinase that preferentially phosphorylates these drugs in infected cells. The median 50% inhibitory concentration of aciclovir against HSV is 0.1µM, but is 2.6µM against VZV, so 800 mg orally is necessary to achieve inhibitory concentrations.

The treatment recommendations for varicella and herpes zoster are summarized in the box above.

Varicella

Whether to treat normal children with varicella (who are the great majority of patients) has been much debated; the argument can be made that the disease is not always mild and it is not possible to predict which child may have a severe case. Therapy with aciclovir is safe, and although it has been suggested that widespread treatment with antivirals might result in viral resistance, or failure to develop normal immune responses, there is no evidence of this in controlled trials. Treatment with aciclovir begun within 24 h of the onset of the rash leads to a 25% decrease in the duration and severity of chickenpox. The argument for treating all adolescents and adults is easier, as chickenpox is more severe for them than it is for young children. Chickenpox in neonates, children with leukaemia, and transplant recipients should always be treated with aciclovir. Intravenous aciclovir limits the visceral spread of the virus if given immediately on diagnosis. Treatment in these immunosuppressed patients can be changed from intravenous to oral aciclovir once the fever has settled, if there is no evidence of visceral varicella.

Herpes zoster

The major justification for the antiviral treatment of herpes zoster in immunocompetent patients has been to limit postherpetic neuralgia. Although there are difficulties in accurately and objectively quantifying the pain of postherpetic neuralgia, trial data indicate that aciclovir, valaciclovir, and famciclovir can limit the duration of zoster-associated pain, and that valaciclovir is slightly more effective. All three drugs accelerate the healing of cutaneous lesions by 2 days over placebo; valaciclovir and famciclovir have the advantage of more convenient dosage, as well as probably being slightly more effective.

Patients over the age of 50 years with zoster have the highest risk of postherpetic neuralgia, and so should be offered antiviral treatment. Younger patients may warrant treatment if they have marked pain. All patients with ophthalmic zoster should be treated urgently with antivirals, even if they present relatively late, as aciclovir reduces the incidence of keratitis. Immunosuppressed patients with herpes zoster should receive intravenous aciclovir to prevent cutaneous and visceral dissemination. Valaciclovir and famciclovir may be used if zoster presents in a localized form in less severely immunosuppressed patients.

Corticosteroids have been advocated in patients with herpes zoster, in order to reduce the severity of postherpetic neuralgia. However, the addition of oral prednisone to aciclovir slightly increases the rate of healing of skin lesions, but does not affect the incidence of postherpetic neuralgia; a role for corticosteroids thus remains unproven. Established postherpetic neuralgia can be managed with analgesics, tricyclic antidepressants, and other agents used for neuropathic pain, such as gabapentin and pregabalin, which were effective for the treatment of postherpetic neuralgia in large placebo-controlled trials. Although the use of opioids for the treatment of neuropathic pain is controversial, several studies support their efficacy and safety; oxycodone and tramadol have been shown to be superior to placebo for the treatment of postherpetic neuralgia. Topical agents such as lidocaine 5% patches and topical capsaicin have been useful in ameliorating postherpetic neuralgia, but are unsatisfactory for use as sole agents.

Prevention and control

Varicella–zoster immune globulin, prepared from high-titre immune human serum, has been shown to prevent or ameliorate varicella in seronegative people at high risk, such as immunocompromised people and pregnant women. It should be given to seronegative immunodeficient patients (including those on high-dose corticosteroid treatment), and pregnant women with definite contact with varicella. It should be administered within 10 days (preferably 2–4 days) of exposure. Neonates whose mothers have had varicella less than 1 week before delivery, or within 28 days after delivery are also recommended to receive varicella–zoster immune globulin.

A VZV vaccine is available; a live attenuated Japanese vaccine containing the Oka strain of VZV. It confers 90% protection from natural varicella when administered to susceptible immunosuppressed people (such as patients with leukaemia and lymphoma receiving chemotherapy), but it produces rash in up to 40% of these recipients. In immunized healthy children the risk of subsequent varicella after community exposure is reduced to less than 5%, and the vaccine-induced rash is much less common (about 5% of recipients). This vaccine is licensed in Japan, some European countries, and the United States of America, where it is recommended for the routine immunization of children aged 12 to 18 months. However, in the United Kingdom it is recommended only for use in seronegative health care workers and children over 1 year in contact with individuals at high risk of severe varicella. Trials have shown that the postinfective immunization of subjects aged 60 years or over diminishes the incidence of zoster and postherpetic neuralgia, and the vaccine is now licensed in the United States of America for the prevention of herpes zoster in this age group.

The nosocomial transmission of VZV by patients with varicella requiring admission to hospital is a significant risk, as 10% of adults are seronegative. Nursing and managing patients with varicella in hospital should be restricted to those staff known to be seropositive for VZV. Patients with varicella in hospital should ideally be isolated in negative-pressure rooms to prevent airborne transmission.