Herpes zoster is an acute viral infection that mainly affects middle-aged and elderly people. The causative agent is varicella-zoster virus (VZV), which mostly infects humans during childhood and manifests clinically as chickenpox. When the systemic specific immune mechanism is established in varicella patients, most of the VZV is cleared out of the body, and only a very small amount of VZV is hosted in the dorsal root ganglion of the spinal cord or brain ganglion, in a non-replicating latent state, coexisting with the specific immune formation in the host. When the cellular immune status of the body decreases, such as in the elderly, patients receiving immunosuppressive therapy, and HIV patients, the VZV hosted in the ganglia is activated again and replicates in large numbers and enters the dermatomes along the nerve roots, forming clusters of blisters and pustules with a typical unilateral distribution, and can cause a series of complications. The highest incidence is postherpetic neuralgia, which can last for months to years after the rash subsides and is mostly seen in middle-aged and elderly people. Due to the unclear cause and limited treatment, it seriously affects the quality of life of middle-aged and elderly people, causing them great pain and imposing a great burden on society.
Morbidity
The lifetime incidence of herpes zoster in the general population is about 10% to 20%, and about 50% of herpes zoster occurs in people over 50 years of age, while about 50% of people over 85 years of age may develop herpes zoster [1]. The annual incidence of herpes zoster increases with age, with 1.1 to 2.9 per 1000 persons per year in people under 50 years of age, 4.6 and 6.9 per 1000 persons per year in people aged 50 to 59 and 60 to 69 years of age, respectively, and even more in people aged 70 to 79 and 80 to 89 years of age, with 9.5 and 10.9 per 1000 persons per year, respectively. and 10.9 person/year/1000 persons, respectively [2]. The increase in the incidence of herpes zoster with increasing age may be related to the progressive deterioration of cellular immune function in the elderly. The incidence of herpes zoster is significantly higher in patients with AIDS and in patients on long-term immunosuppressive drugs. People with normal immune mechanisms are also susceptible to herpes zoster in the presence of exertion, viral infection, and chronic emotional depression.
Natural course of disease
When the infection is absorbed, most of the virus is cleared and a small amount of the remaining VZV provirus fragments travel from the peripheral sensory nerve endings along the nerve roots and are eventually deposited in the dorsal root ganglia or brain ganglia of the spinal cord. Because the virus is integrated in the nucleus of neuronal cells or peripheral satellite cells, it can escape the action of extracellular high-titer specific antibodies and remain in a long-term non-replicating latent state, but can replicate again in large numbers at any time. Although the exact mechanism of VZV reactivation for replication is unclear, a decrease in cellular immunity in vivo to a certain level is an important trigger for herpes zoster attacks. In middle-aged and elderly patients and immunocompromised patients, the number of memory CD4 T cells and killer CD8 T cells in the body is significantly decreased and the incidence of herpes zoster is correspondingly significantly higher [3].
Risk factors for the development of herpes zoster
The vast majority of patients with herpes zoster had chickenpox as children, and although chickenpox is not a requirement for developing herpes zoster, people with a history of chickenpox are significantly more likely to develop herpes zoster [4]. According to statistics, about 90% of the general population has had chickenpox and are at risk for possible herpes zoster attacks. Age is the most important risk factor for the development of herpes zoster, with the majority of herpes zoster occurring in people over 45 years of age, and about half of the patients with herpes zoster are over 60 years of age, and the incidence of herpes zoster increases with age as the body’s cellular immune function gradually decreases. [5]
In addition to age, immune compromise or immunosuppressive therapy is an important risk factor for the development of herpes zoster, and the incidence of herpes zoster in HIV-positive patients is 29.4 per 1000 population per year [6]. Patients undergoing bone marrow transplantation and organ transplantation, cancer patients, and patients with autoimmune diseases have a corresponding increase in the incidence of herpes zoster due to long-term immunosuppressive or heavy glucocorticoid therapy [4]. In addition, trauma and prolonged stress are also risk factors for the development of herpes zoster [7, 8]. (See Table 1)
Symptoms in the acute phase
The typical symptoms of herpes zoster are clusters of blisters involving 1-3 skin areas occurring unilaterally and traveling along the nerve distribution. A typical rash attack is usually preceded by 4 days to 2 weeks of prodromal symptoms, and the patient may present with fever, pain, or sensory abnormalities in the corresponding dermal area where the rash occurs. The pain may be intermittent or persistent dull, stabbing, throbbing, or burning pain, or numbness, itching, or other sensory abnormalities [9].
In most patients, the rash appears on the anterior or posterior chest, mostly starting with erythema proximal to the spinal nerve course and gradually progressing to the distal nerve course. 12-24 hours later, typical clusters of blisters appear in the erythematous area, and the rash appears completely within 3-7 days. The duration of the rash is related to age (the older the age, the longer the duration of the rash) and the location of the rash (the duration of the rash on the face is shorter than that on the trunk). The blisters can transform into pustules after about 3 days and eventually crust off after 7-10 days [10]. The duration of the virus in the skin is short, and the VZV virus is undetectable in the blister area several days after the onset of the rash. Only in immunocompromised patients, the rash may spread along the skin area, forming an atypical rash distribution (i.e., not following the neurological route [9]).
In approximately 10-15% of patients with herpes zoster, the rash involves the first branch of the trigeminal nerve, and the rash involves the unilateral forehead, periorbital area, and nasal root, also known as ocular herpes zoster. Ocular herpes zoster is the most dangerous type of herpes zoster and can cause serious complications of unilateral ocular vision loss or even blindness due to damage to the ocular branch of the trigeminal nerve and a severe inflammatory response in the eye [11].
Neuralgia can occur in 60-90% of patients during the acute phase of a herpes zoster attack, [9] the pain may be caused by direct stimulation of the peripheral sensory nerves in the rash area by a large number of inflammatory mediators produced by the marked inflammatory response in the rash area, or by nerve damage due to direct destruction of nerve axons and nerve cells by intense inflammation, or by hemorrhage of neuronal cells following inflammation [12, 13]. Neuralgia in the acute phase usually worsens with the progression of the rash and decreases after the gradual absorption of the rash. In addition to acute neuralgia, it can be accompanied by nociceptive abnormalities as well as nociceptive hypersensitivity. Although the presentation of acute pain varies widely from patient to patient, most of it decreases or disappears significantly within a few days after the rash resolves. The severity and duration of pain in the acute phase correlates significantly with postherpetic neuralgia, a complication of herpes zoster D [14].
Diagnosis
The diagnosis of herpes zoster is not difficult based on the prodromal symptoms of herpes zoster, the typical distribution of the rash and the pronounced neuralgia. However, the prodromal painful symptoms must be differentiated from coronary heart disease, biliary colic, renal colic, appendicitis, and dental pain before the typical rash is present. Atypical rashes require further laboratory testing to confirm the diagnosis, including viral culture and direct immunofluorescence testing. In addition, nested PCR and real-time quantitative fluorescence PCR for herpes zoster are more sensitive and accurate, and are extremely fast and suitable for detecting herpes zoster at atypical sites to differentiate from other types of herpes viruses (e.g., herpes simplex).
Complications
Herpes zoster can cause several complications; serious complications include meningitis, myelitis, and motor nerve palsy, which have serious consequences but have a low incidence, usually less than 5% [13]. In addition, herpes zoster occurring in the geniculate ganglion (Ramsay Hunt syndrome) can cause hearing impairment, facial nerve palsy, vertigo, and cerebral arteritis, even causing stroke [10].
The most common complications of herpes zoster include postherpetic neuralgia and ocular complications due to ocular herpes zoster. Postherpetic neuralgia occurs after the absorption of herpes zoster and is a chronic pain that can last for months to years and occurs in middle-aged and elderly patients, patients with prodromal pain, patients with severe pain in the acute phase, and patients with a widely distributed rash. 34% of patients with herpes zoster can develop postherpetic neuralgia, with 70% of patients over 60 years of age developing this complication [15]. 71 percent of patients with ocular herpes zoster can have ocular complications, including persistent eye damage and impaired vision or even blindness [16]. Other: secondary glaucoma, neurogenic bladder, etc.
Treatment
The goals of herpes zoster treatment are to accelerate herpes resorption, reduce the intensity and duration of pain, and reduce the incidence of complications. Current treatment consists of antiviral therapy and glucocorticoid therapy. Antiviral therapy has been shown to be effective in reducing the severity and duration of herpes zoster, especially when given before 72 hours after the rash appears. The recommended dose of acyclovir, the most commonly used antiviral for herpes zoster, is 200-800 mg orally five times a day (once every four hours) for 7-10 days. Large-scale double-blind, randomized, placebo-controlled trials have demonstrated that this treatment significantly reduces pain in the acute phase of herpes zoster, shortens the duration of the rash and has a beneficial effect on the prevention of postherpetic neuralgia. Due to its short half-life (0.8 hours), acyclovir is gradually being replaced by famciclovir, which has a longer half-life (9.1 hours). The therapeutic dose of famciclovir is 250-500 mg orally three times a day (once every 8 hours) for 7 days, and its effect is comparable to that of acyclovir, but with fewer adverse drug reactions than acyclovir. In addition, intravenous acyclovir can be more effective in patients who are less compliant.
Although herpes zoster has a tendency to heal spontaneously, antiviral therapy is extremely important in patients who are immunocompromised or taking immunosuppressive drugs, as well as in patients with herpes zoster that occurs in the eye. Early and adequate antiviral therapy plays a critical role in reducing the severity and complications of herpes zoster in these patients.
Short-term oral low-dose hormones can reduce the acute pain of herpes zoster, but have no significant effect on preventing complications, especially postherpetic neuralgia. Oral hormones must be combined with antiviral therapy and an assessment of the patient’s general condition, and oral hormone therapy must be weighed against the advantages and disadvantages because of the possible complications of glaucoma, diabetes mellitus and hypertension in middle-aged and elderly people [17].
Postherpetic neuralgia
Morbidity and risk factors
Postherpetic neuralgia (PHN) is the most common complication of herpes zoster. It occurs in middle-aged and elderly people and has no effective treatment except for symptomatic analgesia, which seriously affects patients’ work and quality of life. There is still no uniform definition of PHN, but the more widely accepted definition is pain lasting more than one month after clinical cure of acute herpes zoster. The average age of onset of PHN is 67 years, and the incidence of herpes zoster over 50 years of age is about 14 times higher than that of those under 50 years of age [18]. the trunk. In addition, severe pain during the acute phase of herpes zoster, the presence of painful prodromal symptoms before the onset of herpes, and fever over 38°C during the acute phase are risk factors for the development of PHN [19].
Symptoms
PHN is generally considered to be the result of residual nerve damage after the acute phase. Pain can last from months to years, with approximately 3-5% of patients with herpes zoster complicated by PHN for 6-12 months, and the pain tends to decrease spontaneously to subside within 1 year [20]. Most patients experience intractable pain with multiple sensory abnormalities or loss of sensation. Pain sensations are persistent, and sleep temporarily reduces pain levels, but mood swings, increased ambient temperature, and fatigue can exacerbate pain sensations.
The pain sensations experienced by patients can be divided into the following three main categories
1.Persistent spontaneous pain Almost all patients experience this sensation, i.e., persistent deep pain or deep throbbing pain in the rash area.
2.Intermittent sharp pain or shooting-like pain Most often occurs in the first year of PHN, and patients complain of sharp, electric shock-like, intensive pins and needles pain.
3, abnormal pain Most patients with PHN have abnormal pain, that is, pain caused by normal non-painful stimuli, the duration of each PHN patient varies, but most patients find this pain most unbearable.
Pain is accompanied by a loss of sensation, including warmth, pain, touch, and two-point resolution, and patients often report abnormal sensations, such as inversion of cold and heat sensations and abnormal sensitivity to pain. In addition, some patients with PHN have intolerable pruritus [21].
Pathogenesis
The pathogenesis of PHN is still unclear, and studies in terms of neuropathophysiology have revealed that the destruction of the nervous system by acute inflammation of herpes zoster leads to lesions in peripheral and central nerves, degeneration of injury receptors in the rash area leading to abnormal synaptic regeneration in the center, and hyperfunction of injury receptors leading to central hypersensitivity to nociception are related. There are few studies on the microscopic molecular biology related to PHN [22].
During nerve conduction, the depolarization of ion channels, especially the generation of action potentials in sodium channels, is the initiating step in the transmission of various sensations, especially nociception. The relationship between sodium channels and nociception has been confirmed in recent years by several disease models, and in particular the role of tetrodotoxin-sensitive sodium channel 1.7 (encoded by the SCN9A gene for its alpha subunit) is crucial in pain production. Functionally enhancing missense mutations in sodium channel 1.7 can cause primary erythema limbicum and familial rectal pain [23, 24], both of which are characterized by abnormal sensitivity to pain and can cause paroxysms of severe pain in response to thermal or other emotional stimuli that are unbearable for the patient and last for life, with no effective treatment options. In contrast, a loss-of-function pure nonsense mutation in sodium channel 1.7 can cause congenital anosmia, in which the patient does not experience any pain throughout life but has normal other sensations [25]. Since sodium channels are so closely related to nociception, and since sodium channel blockers, such as slow heart rhythm (Mesiloride), are significantly effective in the treatment of PHN, the relationship between VZV and sodium channels in the pathogenesis of PHN is gradually becoming a direction of research.
In 2002, Nina Storey et al. found that in vitro experiments, herpes simplex virus type 1 (HSV-1) infection of rat dorsal root ganglion cells caused internalization (cytosolic endocytosis) of sodium channels in neuronal cells in the rat dorsal root ganglion, and the internalization was associated with the late expression of a neurotoxic factor by HSV-1 virus, namely infected cell protein 34.5 ( HSV-1 and VZV are structurally similar and both have neurophilic properties, and infection can result in recurrent herpes simplex with neurosensory abnormalities such as numbness and abnormal nociception.In 2005, Garry et al. found in an animal model of VZV in rats that VZV infection induced a significant increase in the expression of sodium channels 1.3 and 1.8 in rat spinal ganglion cells and a significant decrease in pain response after blockade using sodium channel blockers [27]. These two studies suggest that sodium channel changes may be an extremely important part of the pathogenesis of PHN, in addition to neuroinflammatory destruction.
Treatment
There is still no satisfactory treatment for PHN, and now the proven effective treatment includes antidepressants, the more effective being amitriptyline, a tricyclic antidepressant that blocks the depression-pain cycle through antidepressant action to achieve analgesia; antispasmodics, such as carbamazepine, are effective for paroxysmal sharp pain and tingling because of their inhibitory effect on ion channels of high-frequency discharge However, both types of drugs have obvious side effects and are not widely used clinically for the treatment of PHN. More commonly used at present are topical lidocaine gel and capsaicin ointment for topical application, which can have the dual effect of small side effects and satisfactory analgesic effect [22]. In addition, acupuncture in Chinese traditional medicine has been shown to be a safe and effective treatment for postherpetic neuralgia.
Prevention
Since the risk factors for PHN are relatively clear, early prevention for high-risk groups can be effective. Live attenuated VZV vaccination has been shown to be effective in reducing the incidence and severity of herpes zoster episodes and in reducing the incidence and severity of PHN after an episode. In addition, in people at high risk for PHN, such as the elderly, a full course of acyclovir antiviral therapy given before 72 hours after the onset of the herpes zoster rash is effective in reducing the severity of PHN. [22]
Conclusion
As our population ages, the incidence of herpes zoster will increase year by year, and the proportion of older adults who develop herpes zoster complicated by PHN increases significantly. According to statistics, in the UK, the government pays an average of more than £700 for the treatment of each patient with PHN. In a country with such a large population and efforts to achieve universal health care, efforts to reduce the incidence of complications of PHN through increased publicity, prevention, and early treatment of herpes zoster disease, as well as increased investment in research on the pathogenesis of PHN and early development of effective drugs to treat PHN would be some effective solutions to this impending problem.
Table 1: Risk factors for the development of herpes zoster
Development of varicella
Age >50 years
Immunosuppressive status (oral immunosuppression, AIDS, etc.)
Bone marrow transplantation
Malignancy
Long-term glucocorticoid therapy
Excessive mental stress
Traumatic injury
[References]
[1] Katz J, Cooper EM, Walther RR, Sweeney EW, Dworkin RH. Acute pain in herpes zoster and its impact on health-related quality of life. Clin Infect Dis 2004 ; 39:342-8.
[2]Insinga RP, Itzler RF, Pellissier JM, Saddier P, Nikas AA. The incidence of herpes zoster in aUnited Statesadministrative database. J Gen Intern Med 2005; 20:748-53.
[3] Arvin A. Aging, immunity, and the varicella-zoster virus. N Engl J Med 2005; 352:2266-7.
[4] Arvin AM. Varicella-zoster virus. Clin Microbiol Rev 1996;9: 361-81.
[5] Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al, for the Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352:2271-84.
[6] Buchbinder SP, Katz MH, Hessol NA, Liu JY, O’Malley PM, Underwood R, et al. Herpes zoster and human immunodeficiency virus infection. Infect Dis 1992; 166:1153-6.
[7]Thomas SL, Wheeler JG, Hall AJ. Case-control study of the effect of mechanical trauma on the risk of herpes zoster. BMJ 2004; 328:439.
[8] Schmader K, Studenski S, MacMillan J, Grufferman S, Cohen HJ. Are stressful life events risk factors for herpes zoster? J Am Geriatr Soc 1990; 38:1188- 94.
[9] Wood MJ, Easterbrook P. Shingles, scourge of the elderly: the acute illness. in: Sacks SL, Straus SE, Whitley RJ, Griffiths PD, editors. clinical management of herpes zoster. management of herpes zoster. Washington (DC): IOS Press; 1995. pp. 193-209.
[10]Johnson RW, Whitton TL. Management of herpes zoster (shingles) and postherpetic neuralgia. Expert Opin Pharmacother 2004;5:551-9.
[11]Gnann JW Jr, Whitley RJ. Clinical practice: herpes zoster. N Engl J Med 2002;347:340-6.
[12]Bennett GJ. Hypotheses on the pathogenesis of herpes zoster associated pain. Ann Neurol 1994;35(Suppl):S38-41.
[13] Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis 1996; 22:341-7.
[14] Dworkin RH, Hartstein G, Rosner HL, Walther RR, Sweeney EW, Brand L. A high-risk method for studying psychosocial antecedents of chronic pain: the prospective investigation of herpes zoster. J Abnorm Psychol 1992; 101:200-5.
[15] Schmader K. Herpes zoster in older adults. Clin Infect Dis 2001; 32:1481-6.
[16]Womack LW, Liesegang TJ. Complications of herpes zoster ophthalmicus. Arch Ophthalmol 1983; 101:42-5.
[17]Stephen K. Tyring, MD, PhD Houston, Texas. management of herpes zoster and postherpetic neuralgia. j am acad dermatol 2007; 57: s136-s141
[18] Kost RG, Straus SE. postherpetic neuralgia-pathogenesis, treatment, and prevention. n Engl J Med 1996; 335: 32C42.
[19] Higa H, Dan K, Manabe H et al. Factors influencing the duration of treatment of acute herpes zoster with sympathetic nerve block: importance of severity of herpes zoster assessed by the maximum antibody titers to varicella-zoster virus in otherwise healthy patients. Pain 1988; 32: 147C57.
[20] Wood MJ, Kay R, Dworkin RH et al. Oral acyclovir accelerates pain resolution in herpes zoster: a metaanalysis of placebo-controlled trials. Clin Infect Dis 1996; 22: 341C47.
[21] Bowsher D. Sensory change in postherpetic neuralgia. Pain Res Clin Manage 1993: 8: 97C107.
[22] Kenjiro Dan, Toshikatsu Yokota, Natsu Koyama, Kazuhiko Hirata1 and Koichiro Hori1. Mechanism-based treatment of zoster-associated pain. Pain Reviews 2000; 7: 157C180
[23] Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L, Fan J, Bu D, Liu B, Fan Z, Wu G, Jin J, Ding B, Zhu X, Shen Y. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet 2004; 41(3):171-4.
[24] Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, Ostman J, Klugbauer N, Wood JN, Gardiner RM, Rees M. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 2006; 52(5):767-74
[25] Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006; 444(7121):894 -8.
[26] Storey N, Latchman D, Bevan S. Selective internalization of sodium channels in rat dorsal root ganglion neurons infected with herpes simplex virus-1. J Cell Bio 2002;158(7):1251-62.
[27] Garry EM, Delaney A, Anderson HA, Sirinathsinghji EC, Clapp RH, Martin WJ, Kinchington PR, Krah DL, Abbadie C, Fleetwood-Walker SM. Varicella zoster virus induces neuropathic changes in rat dorsal root ganglia and behavioral reflex sensitisation that is attenuated by gabapentin or sodium channel blocking drugs. Pain 2005; 118(1-2):97-111.