Eklavya College of Pharmacy, Tasgaon Sangli Maharashtra, India 416312
The varicella-zoster virus, which causes chickenpox, reactivates to cause herpes zoster, which some people refer to as shingles. Those with weakened immune systems or the elderly are primarily affected. A severe, blistering skin rash that is often limited to a single dermatome is the disease's defining feature. This review focuses on the mechanism, clinical manifestation, diagnosis, treatment, and epidemiology of herpes zoster. The article also discusses immunization's function in preventing the sickness and adverse effects including post-herpetic neuralgia. The most recent advancements in immune response regulation and antiviral therapies are included in the comprehensive assessment of current methods for managing and preventing shingles. This review focuses on the following elements of HZ: a etiology, epidemiology, pathophysiology, clinical stages, complications, diagnosis, treatment, prevention, and conclusion. The review offers broad information on shingles. The viral infection that causes the illness is caused by the varicella zoster virus.
Herpes zoster (HZ), a well-known viral disease, usually presents as a painful unilateral vesicular rash that is restricted to the distribution of a sensory nerve. HZ, often known as shingles, is an acute viral infection caused by the reactivation of the DNA virus varicella zoster, which causes chickenpox. It typically manifests as an uncomfortable vesicular rash that takes four to five weeks to appear. The agony may last for months or even years after the skin lesions have healed. This condition is known as postherpetic neuralgia (PHN). Ten to eighteen percent of zoster patients are susceptible to PHN. Nearly 3% of zoster patients are admitted to hospitals. Zoster-related morbidity is common in patients with compromised immune systems. HZ can affect any one of the three branches of the trigeminal nerve. It is a somewhat rare incidence as just 1.7% of all HZ cases involve the mandibular and maxillary branches without ocular branch involvement. [1] PubMed and Google Scholar were used to search the literature for relevant published publications on HZ. Clinical trials, clinical investigations, review articles, systematic reviews, meta-analyses, case series, and case reports were all taken into account. "Varicella-zoster virus," "Herpes zoster," "treatment AND Herpes zoster," and "prevention AND Herpes zoster" were the keywords used to search the papers. [2]
Epidemiology of Herpes Zoster
The occurrence of HZ is worldwide and does not vary seasonally. The incidence of HZ is age-dependent, ranging from 1.2 to 3.4 per 1000 people per year in younger individuals to 3.9 to 11.8 per 1000 people per year in older patients (i.e., those over 65). The cumulative incidence, with a female predominance, has been estimated to be between 2.9 and 19.5 cases per 1000 people, according to a comprehensive review of research done between 2002 and 2018. Common risk factors for HZ include immunosuppression, infections, mental stress, and age over 50. A meta-analysis of 16 research published up until January 2021 found that patients with diabetes mellitus are also more vulnerable (pooled relative risk: 1.38; 95% CI: 1.21–1.57). A recent Indian study published in 2021 found a substantial correlation between pediatric HZ and megaloblastic anemia. Folic acid or vitamin B12 deficiency is the main cause of megaloblastic anaemia. The Global Burden of Disease database shows that the death rate from HZ for people over 65 ranges from 0.0022 to 82.21 per 100,000 population. The annual fatality rate of HZ has been determined to be 0.29 for women and 0.10 for males per 100,000 patient years based on German outpatient incidence data from 2007 and 2008. [3] It is important to take note of any potential heterogeneity in epidemiological data brought on by differences in reporting. The population of nations lacking efficient reporting systems may be smaller than that of nations with such systems. [4
Fig. Representative image of herpes zoster
Pathophysiology
Herpes zoster remission is caused by interferon Alfa production, whereas varicella-zoster virus-specific T-cell proliferation takes place in cutaneous lesions. Because some antibodies (IgG, IgM, and IgA) form more quickly and reach higher titters during reactivation (herpes zoster) than during the first infection, immunocompetent people have long-lasting, enhanced cell-mediated protection against the varicella-zoster virus. [5] The dermatological involvement is centripetal and follows a dermatome. The lumbar and cervical roots are usually impacted, while motor involvement is rare. The virus can infect people who have never had varicella-zoster, despite the low rates of transmission. The virus can be transferred by inhaling contaminated droplets or by direct skin contact. It's important to keep in mind that herpes infections may occur concurrently. Human herpes viruses, including CMV, EBV, and herpes simplex, have been found in shingles patients. [6]
Randomized Clinical Stages of Herpes Zoster
Pre-eruptive, acute exudative, and chronic are the three stages of clinical symptoms. [7] The pre-eruptive stage, which occurs at least two days prior to cutaneous eruptions, is marked by burning or pain inside the affected dermatome. Non-cutaneous symptoms like headaches, a general sense of illness, and photophobia are also possible. During the acute eruptive phase, a lot of painful, umbilicated vesicles emerge. The vesicles often burst, become ulcerated, and eventually dry out. This stage is the most contagious. For extreme pain, nonsteroidal medicines frequently don't work. The acute eruptive phase may last two to four weeks. Pain may last for longer lengths of time. [8] A persistent HZ infection is characterized by severe pain that persists for longer than four weeks. Patients report paraesthesia, dysesthesia, and even shock-like feelings. For months, the debilitating pain may persist. [8] Most patients have a clinical diagnosis. Due to uncommon instances and a variety of clinical presentations, diagnosing HZ in some patients may be challenging. [9]
1. Pre-eruptive phase - Usually lasting 48 hours, the pre-eruptive phase—also known as the pre-herpetic neuralgia stage—occasionally lasts up to 10 days. Sensory abnormalities along one or more dermatomes—a section of skin mostly supplied by a single spinal nerve—are what set it apart. This stage is characterized by fever, light sensitivity, headaches, and general exhaustion.
2. Acute phase - In addition to the formation of lesions and intense pain, the physical symptoms that began during the pre-eruptive phase persist during the acute eruptive phase. The lesions begin as macules, which are tiny, flat, limited alterations in skin pigment, and soon grow into clusters of fluid-filled vesicles. New vesicles continue to form and burst over a period of three to five days. During this phase, the virus is most easily transferred to other individuals. When the vesicles eventually dry out and crust over, it could take up to four weeks for them to heal. Changes in skin pigmentation and long-lasting scarring are possible outcomes of the lesions.
3. Chronic phase - Postherpetic neuralgia, another term for the chronic phase, affects up to 20% of shingles sufferers. This phase is characterized by recurrent pain that lasts longer than four weeks after the vesicles have recovered. Other symptoms include unusual skin sensations such as tingling, burning, and numbness caused by pressure on a nerve (paraesthesia) or nerve injury (dysesthesia). The excruciating and debilitating pain may not go away for months or even years. Although the rash usually resolves on its own without medical intervention, most people require relief from the pain and discomfort associated with having shingles. Physical symptoms can be treated with nonsteroidal anti-inflammatory drugs, calamine lotion, and moist dressings. [10] Only patients with severe symptoms, immunosuppression, ocular involvement, disseminated herpes zoster, and other serious effects are admitted to the hospital. Pain management is notoriously difficult for those with postherpetic neuralgia. There are two options for topical analgesics: lidocaine and capsaicin transdermal patches. Due to childhood chickenpox, 99% of Americans 50 years of age and older carry the varicella zoster virus in their bodies. Nearly a million of these individuals will contract shingles each year. [11] Once the varicella zoster virus has entered the body, vaccination is the only defense against shingles and related issues. In addition to dramatically lowering the risk of shingles, Shingrix also reduces the likelihood that an individual will spread the varicella zoster virus to others, including young children and those without immunity.
PREVENTION
Zostavax, a live attenuated varicella zoster virus-based zoster vaccine, has been shown to reduce the incidence of post-herpetic neuralgia and herpes zoster in immunocompetent individuals 60 years of age and older worldwide. By boosting varicella zoster virus-specific cell-mediated immunity, which in turn regulates the latent varicella zoster virus's reactivation or replication, the vaccine prevents or decreases the severity of herpes zoster infection. [12] The varicella and herpes vaccines are derived from the Oka varicella zoster virus strain. However, the herpes vaccine has a 14-fold higher vaccine virus content than the varicella vaccine. It is not recommended for pregnant women, children, or sick patients to receive this live attenuated immunization. [13] To prevent subsequent outbreaks, those who have previously contracted herpes zoster can receive the herpes immunization. Giving the herpes vaccine to those using biologic drugs such as etanercept, infliximab, or adalimumab is not advised. However, the CDC ACIP allows these individuals to get the herpes vaccine either fourteen days prior to the initiation of immunosuppressive therapy or one month after the end of immunosuppressive therapy. [14] The vaccination should not be administered to a patient undergoing antiviral therapy because the antiviral drug may prevent the vaccine virus from reproducing, which could lead to vaccine failure. Because of this, people undergoing long-term antiviral therapy are required to stop taking their medications at least 24 hours prior to receiving the vaccination and to avoid doing so for 14 days afterward.
DIAGNOSIS
A clinical diagnosis of herpes zoster can be made as soon as the rash appears. The presence of a herpes virus in the vesicle can be determined using a Tzanck smear and an electron microscope (EM). However, it cannot distinguish between the herpes simplex virus and the varicella zoster virus. [15] Viral culture, skin biopsy, polymerase chain reaction (PCR), and direct immunofluorescence assay (DFA) are laboratory diagnostic techniques for atypical herpes zoster. [16] PCR, which can detect varicella zoster virus DNA in vesicular fluid, is the most precise and sensitive diagnostic technique for herpes zoster. PCR can be applied to lesion fluid, blood, plasma, broncho alveolar lavage, and cerebrospinal fluid (CSF). [17] DFA can be used in place of PCR. Because of its high sensitivity, quick turnaround, and inexpensive cost, it is preferred over viral culture. [18] In patients with herpes zoster myelitis, viruses cannot be isolated from blood or CSF fluid. Therefore, magnetic resonance imaging (MRI) of the spine and the clinical appearance of a rash on the particular dermatome with clinical signs of transverse myelitis are the only ways to diagnose herpes zoster myelitis. [19] The diagnosis can be confirmed when segmental zoster paresis presents as a painful dermatomal rash with muscular weakness. An electromyography can show acute denervation of the affected area. [20]
TREATMENT
Reducing pain, promoting rapid healing, and preventing complications are the primary goals of herpes zoster treatment. As soon as a diagnosis of herpes zoster is made, antiviral medication is used to treat the condition and reduce the risk of post-herpetic neuralgia. Corticosteroids can aid in the management of eruptions and discomfort. Other therapeutic elements include treating skin lesions locally and isolating the patient. Isolation of the patient is necessary to prevent nosocomial infections. [21]
1. Antiviral agent – Acute herpes zoster is treated with antiviral drugs such as acyclovir, famciclovir, and valacyclovir. These drugs prevent post-herpetic neuralgia, promote quick healing, and help manage pain. Antiviral therapy should begin within 72 hours of the rash appearing. [22] According to a Japanese study by Ono et al., famciclovir is more effective than Val acyclovir for reducing acute herpes zoster pain. During a seven-day course of famcyclovir medication, they saw an earlier decrease in discomfort within three to four days. [23] Compared to famciclovir, oral acyclovir and Val acyclovir do not increase the risk of acute renal damage, according to a retrospective study by Lam et al. Acute kidney damage is linked to intravenous (IV) acyclovir usage. The drug induces obstruction and cellular. Necrosis in the tubules by precipitating and crystallising. [24] Therefore, patients with renal sickness should not have IV acyclovir. People whose rash lasted longer than 72 hours and those whose rash lasted less than 72 hours responded similarly to a short course of acyclovir treatment (800 mg five times a day for four days).
2. Systemic corticosteroids- Corticosteroid therapy is recommended in specific situations, such as acute zoster pain, Ramsay Hunt syndrome, and ocular sequel. Corticosteroid therapy is more effective when combined with an antiviral drug. Early acyclovir + steroid administration has shown promising results in treating herpes zoster oticus/Ramsay Hunt syndrome in both adults and children. [25] Hearing recovery is also enhanced by early therapy. [26] The prognosis is favorable for patients who develop Ramsay Hunt syndrome at a young age and who receive combined antiviral and steroid treatment within 72 hours of the rash appearing. [27] Numerous studies have used varying dosages, administration methods, and treatment durations. [28] Patients over 50 who receive acyclovir and prednisolone together for herpes zoster have demonstrated an improvement in quality of life. [29] It is unknown if acyclovir + prednisolone will have a long-term impact on preventing post-herpetic neuralgia, but it can clear up rash and lessen acute herpes zoster sickness. [30] Prednisone and ACTH were found to be ineffective in preventing post-herpetic neuralgia in a research comparing the two medications. [31]
3. Treatment of Herpes Zoster in Pregnancy -Acyclovir or Val acyclovir can be used to treat herpes zoster caused by pregnancy. [32] Acyclovir is considered the drug of choice (DOC) in the early stages of pregnancy because there is no increased risk of birth abnormalities or premature delivery. [33] After getting therapy for herpes zoster neuralgia with acyclovir and paracetamol for 28 weeks, the mother responded well to the medicine and gave birth to a healthy baby two months later. [34] A 17-week pregnant woman's herpes zoster was successfully treated with val acyclovir. [35] Varicella zoster immune globulin is strongly advised for immunocompromised children for passive immunization after significant exposure to the varicella zoster virus or herpes zoster virus, as well as for susceptible pregnant women exposed to varicella to prevent varicella-related complications during pregnancy, according to the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (CDC ACIP) recommendations for preventing varicella. Regardless of the mother's history of providing varicella zoster immune globulin, it is suggested that new-borns whose mothers have varicella infection or herpes zoster within five days before to and two days following birth receive the vaccine. Healthy new-borns whose mothers had varicella more than five days before to birth do not need varicella zoster immune globulin since the child is already protected from varicella by transplacental acquired maternal antibodies. [36] Given their compromised immune systems and decreased likelihood of developing trans placental maternal antibody, premature children exposed postnatally to varicella or herpes zoster are advised to receive varicella zoster immune globulin.
4. Treatment of Herpes Zoster in Children – Herpes zoster is rare and usually benign in children. Even after three weeks of illness, if the youngster still gets new lesions, there may be an underlying immunodeficiency [37] Acyclovir can be administered orally to children. It is not commonly used for the treatment of preadolescent children because it is not authorized for their use. For preadolescent children with cancer, immunological compromise, or ocular involvement, acyclovir treatment is recommended. [38] Other than that, no particular attention is given to this age range. [39] Acyclovir was administered orally (in three cases) and intravenously (in one case) to four infants with infantile herpes zoster, ages 4 to 11 months, who recovered fully and without any aftereffects. Each of the four babies had previously been exposed to the varicella zoster virus. [40]
COMPLIATIONS
1. Post herpetic Neuralgia – PHN is the most common HZ complication. According to published estimates, between 5% and 30% of patients may also experience this illness. Severe, scorching, stabbing pain throughout the nerve pathway is the hallmark of PHN, and it can persist for months following the initial rash episode. Stroke, meningitis, myelitis, subsequent bacterial infections, and scarring are further potential consequences. More than 30% of people with PHN experience chronic pain for longer than a year. [41]
2. Secondary Infection - Both those with normal immune function and those with immunodeficiency may experience secondary infections caused by streptococcal or staphylococcal bacteria, which can cause scarring and poor healing. Superficial gangrene can also occur in persons with weakened immune systems. [42]
3. Vaculities and Stroke – A VZV infection in the cranial nerve can progress to the blood vessels in the brain within a few weeks to several months (on average, 7-8 weeks) after the original injury, resulting in contralateral hemiplegia, vasculitis, and stroke. This typically occurs following HZO, however it can also occur when other cranial nerves are infected with herpes zoster. Apart from myocardial infarction, aortic aneurysm, and temporal arteritis, subarachnoid and intraparenchymal haemorrhage can also be indirectly caused by vasculitis or angiitis. [43]
4. Encephalitis – As was previously mentioned in the herpes zoster pathophysiology section, an infection of the proximal part of the ganglion can lead to an infection in the central nervous system. Encephalitis is an uncommon but possible herpes virus side effect that can especially impact the cranial nerves. Symptoms can vary depending on the damaged part of the brain, but in general, affected individuals will experience headaches, nausea, fever, sensory abnormalities, and seizures. Another common sign is cerebellar ataxia. [44]
5. Ramsay Hunt Syndrome - Peripheral facial palsy and the appearance of herpes rashes on the scalp, outer ear canal, and oropharyngeal mucosa are the hallmarks of Ramsay Hunt Syndrome (RHS), a result of VZV infection in the ENT region. Along with the geniculate ganglion, one of the cranial nerves that is commonly impacted by RHS is the vestibulocochlear nerve, which causes tinnitus, vertigo, and unilateral hearing loss. Furthermore, 50% of patients experience a loss of taste in the front two thirds of their tongue. [45]
6. Myelitis - Myelitis may occur if a herpes zoster infection spreads to the proximal area of the spinal ganglia, especially in the thoracic section. Brown-Sequard syndrome, par paresis, reduced sensory function, and sphincter issues are among the symptoms that often appear two to three weeks after the start of herpes lesions. [46]
CONCLUSION
HZ indicates that VZV has reactivated in the host. Numerous signs and consequences are possible for patients with HZ infections. Ramsay Hunt syndrome, deep HZ, purpuric HZ, disseminated HZ, HZ opthalmicus, and central nervous system HZ are a few examples of unique clinical presentations. Postherpetic neuralgia is one of the consequences it may cause. Patients with weakened immune systems and the elderly may experience recurrent HZ. HZ is more common in patients with solid and hematological cancers. Chemotherapy-treated solid cancer patients are more susceptible to HZ than non-treated patients. Acyclovir (ACV) and its prodrug valacyclovir or brivudine are the primary therapies for HZ. The goal of HZ vaccinations is to stop HZ activation and PHN generation. For healthy older persons, there are now two HZ vaccines available.
REFERENCE
Chaitali Gadade*, Shraddha Jamdade, P. A. Mane Patil, Shingles: A Comprehensive Review of Epidemiology, Pathophysiology & Management, Int. J. Sci. R. Tech., 2025, 2 (11), 294-301. https://doi.org/10.5281/zenodo.17573446
10.5281/zenodo.17573446
