A Review on - Herpes Zoster

 

Miss. Shreya Parkar*, Miss. Prajakta Kegade, Mr. Akshay Gade, Miss. Rutuja Sawant

Department of Pharmaceutics, M Pharmacy, University of Mumbai, Vidya Nagari, Kalina, Santacruz East, Mumbai, Maharashtra 400098.

 

ABSTRACT:

Varicella zoster virus is one of the eight herpes viruses that are pathogenic only for humans. It is a alphaherpes zoster of the genus varicellovirus, which causes varicella (chickenpox) and zoster (shingles). Herpes zoster is described as a multivesicular eruptive rash that follows a single or multiple adjacent dermatomal distribution. VZV infection begins with replication in epithelial cells of upper respiratory mucosa, which is followed by widely distributed vesicular rash. Cell-mediated immunity plays a role in this reactivation. Patients with conditions that decrease cell-mediated immunity are 20 to 100 times more prone to develop herpes zoster.It is often accompanied by acute pain and itchiness. Complications may be dermatological (e.g. secondary bacterial infection), neurological (e.g. long-term pain, segmental paresis, stroke), ophthalmological (e.g. keratitis, iridocyclitis, secondary glaucoma) or visceral (e.g. pneumonia, hepatitis). Most common Complications of the infection are post herpetic neuralgia and ophthalmic zoster. Treatment includes antiviral medications such as acyclovir, famciclovir, and valacyclovir given within 72 hours of symptom has been shown to reduce severity and complications associated with herpes zoster and post-herpetic neuralgia, both these diseases are vaccine preventable. Before the invention of the recombinant VZV vaccine, live VZV vaccine was the recommended immunization, approved for adults 50 years and older.

 

 

 

INTRODUCTION:

Herpes zosteror shingles, occurs due to the reactivation of varicella zoster virus. Adults above 50 years are at an increased risk for developing herpes zoster, probably due to the reduced immunity associated with advancing age, but it can affect individuals of any age, especially those with a suppressed cell-mediated immunity.⁽¹⁾ The infection usually occurs as two entities: 1. chickenpox - the primary infection and 2. herpes zoster - a secondary condition.

 

Chickenpox is characterized by a generalized rash that begins as maculopapular lesions and progresses to vesicles that spread to the extremities, accompanied by fever.⁽²⁾ The virus then migrates from the skin lesions via nerve axons and, probably also by viremic spread, to spinal and cranial sensory ganglia where it becomes dormant. Later in life, in some individuals the virus is reactivated (usually within a single ganglion) to cause a secondary infection known as herpes zoster.⁽³⁾

 

The rash is mainly accompanied by severe pain, which, in some people, does not subside after healing but persists for months or years. This prolonged zoster associated pain, usually defined as pain persisting for more than four months after the rash has healed, is known as postherpetic neuralgia and is the most common complication of herpes zoster.⁽⁴⁾ Risk factors and complications associated with herpes zoster depend on the age, immune status and the time of initializing treatment. The risk of getting shingles increases as patients age or become immunosuppressed.⁽⁵⁾ Transmission occurs via the fluid from the shingles blisters. Accordingly, people with shingles blisters are advised to avoid bringing blistered areas in contact with others.

 

There are a number of effective antiviral therapies for managing zoster reactivation, including acyclovir, valacyclovir and famciclovir. The most important factor in successfully treating a zoster infection is early detection and initiation of therapy, with the best results being achieved when treatment is started within 72 hours of symptom.⁽⁶⁾ Wider use of varicella vaccination leads to reduced prevalence of varicella, thereby resulting in reduced chances of periodic re-exposure to varicella. This in turn can reduce natural boosting of immunity and lead to an increased incidence of herpes zoster.⁽⁷⁾ The estimated average overall incidence of HZ is about 3.4–4.82 per 1000 person years which increases to more than 11 per 1000 person years in those aged at least 80 years.⁽⁸⁾ The main purpose of study is to determine the risk, and complications of herpes zoster among healthy and immunocompromised patients and to improve the care of patients by accurate diagnosis, early management, and by methods to prevent herpes zoster and its recurrence.

 

ETIOLOGY AND PATHOLOGY:

Varicella zoster virus (VZV), which is a human alphaherpesvirus of the genus Varicellovirus, It causes a primary infection known as varicella (chicken pox). The virus then migrates from the skin lesions via nerve axons and, probably also by viremic spread, to spinal and cranial sensory ganglia where it becomes dormant. Later in life, in some individuals the virus is reactivated (usually within a single ganglion) to cause a secondary infection known as herpes zoster (HZ; shingles). Individuals with HZ can transmit VZV to their seronegative contacts, who may develop varicella, but not HZ.⁽⁹⁾ It is most commonly transmitted by the airborne route from person to person or by direct contact with the lesion. During the primary infection, the virus disseminates through the blood stream to the skin, oral mucosa, and lymph nodes, causing the generalized rash of varicella.⁽¹⁰⁾ After a primary infection or vaccination, the varicella zoster virus remains dormant in the sensory dorsal root ganglion cells. Resolution of the primary infection causes an induction of the varicella zoster virus-specific memory T cells. The memory T cell immunity declines over time. The decline below a theoretical “zoster threshold” correlates with an increased risk of herpes zoster infection.^(11,12) virions presumably gain access to the sensory nerve cell bodies in ganglia by retrograde axonal transport from skin sites of replication or by T cell viraemia, and latent infection is established.⁽¹³⁾ When viral replication is reactivated, VZV reaches the skin via anterograde axonal transport to cause the symptoms of zoster, which is characterized by a vesicular rash in the dermatome that is innervated by the affected ganglion.⁽¹⁴⁾ The average period of immunity against varicella following an infection is 20 years. Age, stress, immunocompromised status, and immunosuppressive drugs are known factors for virus reactivation.⁽¹⁵⁾ Herpes zoster infection is usually characterized by a unilateral, painful vesicular rash which is limited to a single dermatome.⁽¹⁶⁾ After an infection with herpes zoster, the chance of injury to the peripheral and central nervous system is high leading to post-herpetic neuralgia. The two main factors that play a role in the development of post-herpetic neuralgia are sensitization and deafferentiation.^(17,18,19)

 

Fig. 1: VZV Pathogenesis⁽²⁰⁾

 

Fig. 2: herpes lesions⁽²¹⁾

 

VIRUS STRUCTURE:

The VZV virion consists of following:

1.     Nucleocapsid: It surrounding a core that contains the linear, double-stranded DNA genome

2.     A protein tegument: separates the capsid from the lipid envelope, which incorporates the major viral glycoproteins

3.     Vzv DNA: consists of approximately 125,000 bp with at least 69 open reading frames (ORFs)^(22,23)

 

Fig. 3: herpes zoster virus⁽²⁴⁾

 

REPLICATION AND LIFE CYCLE OF HZV:

VZV particles enter cells by fusion of the virion by endocytosis followed by the transport of capsids and associated virion tegument proteins to the cell nucleus ⁽²⁵⁾ virion glycoprotein mature in the trans golgi region and tegument proteins assemble in vesicles; capsids undergoes secondary envelopment and are transported to the cell surface, where newly assembled virus particles are release.⁽²⁶⁾ Virus is spread to the tonsils and other local lymphoid tissues, from where infected T cells can transport the virus via the bloodstream to the skin.⁽²⁷⁾ During primary infection, virions presumably gain access to the sensory nerve cell bodies in ganglia by retrograde axonal transport from skin sites of replication or by T cell viraemia, and latent infection is established.⁽²⁸⁾ When viral replication is reactivated, VZVreaches the skin via anterograde axonal transport to cause the symptoms of zoster, which ischaracterized by a vesicular rash in the dermatome that is innervated by the affectedganglion.⁽²⁹⁾

 

Fig. 4: virus life cycle⁽³⁰⁾

 

POST THERAPEUTIC NEURALGIA:

Post herpetic neuralgia (PHN) is one of the most resistant chronic pain problems, occurs after the resolution of the rash caused by herpes zoster (HZ). It occurs in three stages An acute herpetic neuralgia, sub-acute herpetic neuralgia and post-herpetic neuralgia, the pain that accompanies the rash lasts up to 30 days after the onset of rash.⁽³¹⁾ PHN is characterized by constant, severe, stabbing or burning, dysesthetic pain that persists for at least 3 months and sometimes years after resolution of rash. Primary varicella causes chickenpox in a non- immune person. During the primary infection, the virus enter into the sensory dorsal root ganglia. Reactivation of the virus occurs usually within single ganglion, following depression of cell-mediated immunity.⁽³²⁾ The reactivated virus replicates and migrates down the sensory nerve leading to the distribution of pain in the cutaneous area which is supplied by a single spinal nerve root. The associated inflammation in the peripheral nerves leads to demyelination, wallerian degeneration, and fibrosis. Thus, as a result, uninhibited and amplified activity in unmyelinated primary afferents leads to pain associated with post-herpetic neuralgia.⁽³³⁾ For the management of PHN tricyclic antidepressants like amitriptyline, nortriptyline, desipramine are used. They act by increasing serotonin and norepinephrine levels and blocking voltage-dependent sodium channels important in modulating descending pain pathways.^(34,35)

 

HERPES ZOSTER OPTHALMICUS:

Herpes zoster ophthalmicusis a secondary condition, occurs when the varicella-zoster virus is reactivated in the ophthalmic division of the trigeminal nerve. ophthalmic division of the trigeminal nerve, namely the supraorbital, lacrimal, and nasociliary branches. The virus damages the eye and sur- rounding structures by secondary perineural and intraneural inflammation of sensory nerves.⁽³⁶⁾ About 60 percent of patients have varying degrees of dermatomal pain in the distribution of the ophthalmic nerve. Subse- quently, erythematous macules appear along the involved dermatome, rapidly progressing over several days to papules and vesicles containing clear serous fluid and, later, pustules. These lesions rupture and typically crust over, requiring several weeks to heal completely.⁽³⁷⁾

 

Fig. 5: herpes zoster opthalmicus ⁽³⁸⁾

 

TREATMENT:

·       Antiviral agents:

Antiviral agents have been shown to decrease the duration of herpes zoster rash and the severity of pain associated with the rash.⁽³⁹⁾ Other antiviral agents, specifically valacyclovir (Valtrex) and famciclovir (Famvir), appear to be as effective as acyclovir. Acyclovir is a DNA polymerase inhibitor. Valacyclovir, a prodrug of acyclovir Compared with acyclovir, valacyclovir may be slightly better at decreasing the severity of pain associated with herpes zoster, as well as the duration of postherpetic neuralgia.⁽⁴⁰⁾

 

·       Analgesics:

Analgesics are used to reduce pain associated with rash. Lotions containing calamine may be used on open lesions to reduce pain also drugs like tramadol and gabapentine can be encorporated. Once the lesions have crusted over, capsaicin cream (Zostrix) may be applied. Topically administered lidocaine (Xylocaine) and nerve blocks have also been reported to be effective in reducing pain.⁽⁴¹⁾

 

·       Corticosteroids:

Orally administered corticosteroids are commonly used in the treatment of herpes zoster, Prednisone used in conjunction with acyclovir has been shown to reduce the pain associated with herpes zoster.The likely mechanism involves decreasing the degree of neuritis caused by active infection and possibly, decreasing residual damage to affected nerves.⁽⁴²⁾

 

·       Antiviral eye ointment:

Although the additional effectiveness of acyclovir eye ointment has never been established, topical acyclovir can be considered in cases of severe eye infection, as much higher concentrations of the drug in the anterior eye segment will be achieved by this route. Mono-therapy with antiviral ointment is, however, insufficient and should be adjuvant to oral treatment.⁽⁴³⁾

 

CONCLUSION:

Herpes zoster is a virological disease which can affect any age group and mainly occurs in immunosuppressed individuals. Treatment with anti viralswithin 72 hrs of onset of rash has shown a reduction in herpes zoster and its complications. Herpes zoster vaccination also reduces the zoster incidences. The most frequent complication of HZ, especially in the elderly, is post therapeutic neuralgia. Herpes zoster opthalmicus is a potentially serious reactivation of VZV in the distribution of the ophthalmic division of the trigeminal nerve. Current treatment of the acute and chronic symptoms of herpes zoster includes the use of antiviral agents and analgesic drugs, but no single medication or combination of medications can prevent or completely relieve zoster symptoms. Despite several therapeutic modalities for herpes zoster and its complications, the treatment remains a challenge.

 

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