Zoster B02.9

Authors: Prof. Dr. med. Peter Altmeyer, Dr. med. Nikolas Bounas-Pyrros , Dr. med. Laine Ludriksone

Co-Autors: Dr. med. Jeton Luzha, Hadrian Tran

All authors of this article

Last updated on: 25.09.2022

Dieser Artikel auf Deutsch

Synonym(s)

ignis sacer; shingles; Shingles; Zona; Zoster infection; Zoster infections

Definition
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Endogenous, mostly unilateral, neurotropic recurrent infection with the varicella zoster virus (HHV-3; see below herpes viruses, human). Zoster (zoser from Greek zostrix = belt) is, in contrast to varicella, a disease of the elderly and is one of the most common acute diseases in dermatology.

Classification
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Depending on the localisation, a further distinction is made:

Occurrence/Epidemiology
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Worldwide the rate of zoster disease is increasing.

In Germany, about 350,000 - 400,000 people fall ill every year, about 2/3 of whom are > 50 years old.

Incidence in persons aged 0-14 years: 0.45/1000 inhabitants/year.

In a larger collective, Germany found an average incidence of 5.79 per 1000 persons/year.

Incidence for persons > 50 years: 9.6/1000, between 60-70 years: 9-11/1000, for >80 years 13/1000 persons/year.

Etiopathogenesis
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Reinfection with the varicella zoster virus in the case of partial immunity as a result of humoral immunization that has taken place or reactivation of the virus present in the body due to a reduction in resistance.

Trigger factors for zoster infection are chemical, physical or actinic stimuli, chronic stress, malignancies, immunosuppressive therapy and HIV infection.

If the specific defense directed against VZV falls below a critical level, viral replication in the afflicted ganglion, inflammatory symptomatology with neuronal necrosis and pain occur. With the development of sensory neuritis, infectious virus particles are transported within the affected nerve into the skin, where they lead to the classic vesicular and blister-forming zoster symptomatology.

Diseases associated with an increased risk of zoster (Wollina U 2018):

  • Immunodeficiencies: incidence rate in all forms of immunodeficiencies (incidence rate increased 2-fold). Nearly 50% of patients with bone marrow transplants develop zoster, as well as about 20% of HIV-infected patients, depending on their immune status. Similarly, an increased incidence rate is found in patients on immunosuppressants and biologics.
  • Severe psoriasis HazardRatio: 1.61
  • Cancer (adults) Odds Ratio: 2.46
  • Rheumatoid arthritis: odds ratio 1.95-2.30
  • Celiac disease: Hazard ratio: 1.62

Manifestation
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Occurs mainly in older age and in immunocompromised patients. Zoster infections in the newborn are rare. Women become ill more often than men.

Localization
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Mostly one-sided (segmental zoster), very rarely double-sided (zoster duplex). Basically all dermatomes can be affected.

Most frequently, however, the zoster affects thoracic segments (zoster thoracicus - about 50%); 20% affect the innervation areas of cranial nerves - here the innervation areas of N.V. (especially its first branch, the ophthalmic nerve) and less frequently of N. VII and N. VIII are affected.

Less frequently, in descending order, the cervical, lumbar and sacral segments are affected, most frequently in supply area T3, L3.

Clinical features
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Incubation period 7-18 days. Uncharacteristic prodromal stage lasting 2-5 days with mildly elevated temperature. Rarely zoster fever. Tingling, burning, and sharp, shooting pain may occur before skin symptoms.

The zoster rash is unilateral and segmental. Initially, discrete red spots appear that confluence to form unilateral, painful, extensive patches.

Within 12-24 hours, grouped standing papules appear on the red patches with rapid transformation into initially clear, later opacified vesicles/blisters and pustules.

Usually, the zoster blisters dry within 7-12 days with formation of crusts. The lesions heal without scarring in immunocompetent individuals. Hypo- or hyperpigmentation is possible.

Zoster pain: Since sensory nerves are predominantly affected, pain is reported by many affected individuals (more so than the actual skin sympathetic symptoms) as a leading clinical symptom.

  • Acute zoster pain, described as burning or stabbing, often begins 4-5 days before vesicle eruption. It sits for 4-5 weeks and often requires treatment (anti-inflammatories).
  • Chronic zoster pain(postzoster neuralgia = persistence of pain > 4 weeks after healing of skin lesions). The formerly affected skin areas remain hypersensitive(allodynia), so that, for example, tight-fitting clothing is not tolerated. In more severe cases, an excruciating constant pain is reported, which can also occur in seizure-like, lancing fashion.

In the elderly and immunocompetent, delayed healing with scarring is observed.

Rarely, hemorrhagic staining of the zoster vesicles and blisters(hemorrhagic-necrotic zoster).

Segmental paresis: in addition to the afferent limb, the motor limb of the nerve may also be affected in VZV infection. The consequences are segmental pareses.

In zoster oticus: risk of facial paresis.

Zoster sine herpete: reactivation of VZV without any skin manifestation. Mostly diffuse pain in the affected dermatome.

Scarring especially in necrotizing zoster.

Special forms:

Diagnostics
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Usually, the typical history and clinical manifestations are sufficient to make a diagnosis.

In some cases, extended diagnostics may be useful. The causative agent of the viruses can be detected from vesicular secretions by PCR. In cases of clinical suspicion of herpes encephalitis, a lumbar puncture is mandatory. CAVE: In case of neurological acuity and clouding of consciousness, emergency imaging (cMRI, cCT) must be performed.

In patients under 50 years of age, an HIV examination should be offered. In addition, a small tumor screening may be performed.

Other diagnostic measures required:

Zoster ophthalmicus: Presentation to anophthalmologist to exclude ocular involvement (e.g., neuritis, acute retinal necrosis).

Zoster oticus: Interdisciplinary treatment with the ENT department and neurologists, especially in case of cranial nerve involvement.

Zoster sine herpete: Serology from serum, plasma or nasopharyngeal smear may be considered.

Laboratory
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The routine laboratory shows no special features in an uncomplicated course.

Virus DNA can be detected in body fluid and tissue by polymerase chain reaction.

Retrospectively, VZV serology is of importance. Antibodies of the IgG, IgA and IgM classes indicate reactivation by increasing.

Histology
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Intraepidermal vesicles, ballooning degeneration, multinuclear giant cell formation, eosinophilic nuclear inclusions.

Differential diagnosis
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Erysipelas: flat, bizarrely limited, painful red plaque, fever, lymphadenopathy

Herpes simplex: the zosteriform herpes simplex infection is an important differential diagnosis. Mostly small blisters and small foci.

Zoster generalisatus: varicella; the zoster generalisatus still shows a segmental infestation pattern.

In zoster sine herpete: neuralgia (DD in facial nerve palsy)

Complication(s)
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Ulcers: On the skin in the acute stage mainly bacterial secondary infections, sometimes with ecthymata-like ulcers. Other important dermatological complications are bleeding (haemorrhagic zoster), circumscribed or extensive necrosis ( zoster gangraenosus), persistence of pain symptoms.

Scars: Chronic, disturbing secondary skin conditions are hypo- and depigmented scars, hypaesthesia or hyperaesthesia.

Isotopic reactions: Less frequent are isotopic reactions (= occurrence of a second skin disease at the same site after healing of the primary skin changes) such as acne-like reactions, lichen planus, circumscribed scleroderma, granuloma anulare, tuberculoid and sarcoidal infiltrates, granulomatous vasculitis and lymphomas.

Ophthalmologic complications: These include eyelid skin lesions with subsequent scarring, conjunctivitis, episcleritis, scleritis, keratitis, endothelitis, uveitis with the risk of secondary glaucoma. Acute retinal necrosis is feared. Chorioretinitis and neuritis of the optic nerve are complications that are more frequently observed in AIDS patients. A Hutchinson sign is the zoster infestation of the nasal slope and bridge due to involvement of the nasociliary branches of the ophthalmic nerve.

Otological complications: These concern the so-called Ramsay-Hunt syndrome. The Ramsay-Hunt syndrome is a triad of

  1. Painful blisters in the external auditory canal and on the auricle
  2. Earache
  3. ipsilateral peripheral facial nerve palsy

Neurological complications:

  • They include zoster meningitis and zoster encephalitis, motor neuropathies and paralysis, Guillain-Barré syndrome, granulomatous arteritis and cerebral nerve deficits.
  • Postzosteric neuralgia: The most frequent and important complication is acute and chronic pain (see below zoster neuralgia). This complication occurs in about 20% of zoster patients.
  • Segmental paralysis in the wake of zoster is possible but rather rare.
  • The risk of developing Parkinson's disease post-zoster is proven by a hazard ratio of 1.17.

Urological complications: Cystitis, which often remains undiagnosed.

Vascular complications: The risk of vascular diseases such as TIA (G45.92), apoplexy (I64) and ischemic myocardial infarction (I21.9) is significantly increased in the first 3 months after onset of zoster. The risk of peripheral arterial occlusive disease (pAVK) is associated with a hazard rate of 1.3; that of giant cell arteritis with a hazard ratio of 1.99-2.16.

Postzosteric cancer risk: Highest incidence 180 days after diagnosis of herpes zoster. Lymphomas are leading. The relative risk for cancer is between 1.42-1.83 (Wollina U 2018).

General therapy
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Therapeutic goals include the reduction of complications (e.g. dissemination), the containment of acute pain and the prevention of chronic, zoster-associated pain. Early use of virustatics (especially in patients > 50 years of age, in immunosuppression, in zoster in the head area) within 72 hours after the appearance of the first skin changes.

Pain medication for acute zoster pain: Gradual medication in collaboration with the pain therapist.

  • Level 1 of the WHO pain scale: Starting with non-steroidal anti-inflammatory drugs such as paracetamol (e.g. Ben-u-ron) 3-4 times/day 500 mg or indometacin (e.g. Amuno) 50-150 mg/day p.o. or ibuprofen (e.g. Ibuprofen-ratiopharm) 2 times/day 800 mg p.o. Alternatively: Naproxen (e.g. Proxen) 2 times/day 500 mg or Acetylsalicylic acid (e.g. ASS) 3-4 times/day 0,5-1,0 g or Metamizol (e.g. Novalgin) 1-4 times/day 500-1000 mg p.o.
  • Grade 2 of the WHO pain scale: Low-potency opioids such as tramadol once/day 200-600 mg or tilidine plus naloxone once/day 300-600 mg. Possibly combinations of low-potency opioids with so-called "coanalgesics" such as amitriptyline once/day 20-50 mg p.o., gabapentin once/day 900-2400 mg, clonazepam once/day 1.0-3.0 mg or nerve blocks.
  • Level 3 of the WHO pain scale: Highly potent opioids, individually in combination with coanalgesics. Morphine initial 1-2 times/day 5.0-20 mg or buprenorphine once/day 0.8-4.0 mg or sympathetic blockade.

Glucocorticoids: Controversial in the initial phase, rapid improvement of the inflammation and reduction of pain after the vesicle stage has subsided. Initially high, then decreasing dosage, e.g. 20-60 mg prednisolone equivalent/day p.o.

Postzosteric neuralgia: S.u. Zosterneuralgia.

External therapy
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In uncomplicated course and/or concomitant to systemic antiviral therapy:

  • Moist compresses, antiseptic, drying, tanning therapy with oak bark extract (Tannosynt; Tannolact) or with 2-3% clioquinol in Lotio alba R050 (not in the face), there clioquinol cream (e.g. Linola-Sept, R049 ).

    Reminder.

    Clioquinol should not be used on the hairy head as it colours grey hair yellow! Alternatively, cooling antiseptic gels can be used, e.g. polyhexanide gel 0.02 or 0.04% NRF 11.128 or gels containing octenidine. Topical antibiotics should no longer be used. After the vesicles have dried, use emollient ointments such as dexpanthenol (e.g., Bepanthen).
  • Externals with virustatic additive: 5% idoxuridine solution/ointment (e.g. Zostrum, Virunguent) applied thinly 4 times/day to the diseased skin areas (this therapy is described by many authors as ineffective and dispensable (see u.Wollina U 2018).

Internal therapy
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For milder courses: Aciclovir per os (e.g. Zovirax) 5 times/day 800 mg p.o. for 7-10 days.

  • Alternatively Valaciclovir (Valtrex®): 3 times/day 1000 mg p.o. for 7 days. Valaciclovir has a significantly higher bioavailability of around 65% than aciclovir.
  • Alternatively, famciclovir (Famvir®): 3 times/day 250 mg p.o. for 5-6 days. Famciclovir has a bioavailability of 77%. Significantly better antiviral activity. Compliance advantage due to daily single dose. In immunocompromised patients 25 yrs and older and in herpes zoster ophthalmicus: 3x500mg/day.
  • Alternatively Brivudine: Immunocompetent adults: 1x/day 125mg p.o.; Brividine must not be co-administered with 5-fluorouracil or other 5-fluoropyrimidines within the last 4 weeks (Absolute contraindication).

In severe course (hemorrhagic/necrotizing), head and neck involvement, and immunocompromised patients: Aciclovir systemically (e.g., Zovirax) 10.0 mg/kg bw every 8 h for 5-7 days i.v. If CNS and internal organs are involved or generalization occurs, dose escalation to 3x15 mg/kg bw/day for up to 21 days may be performed.

Superinfection: Antibiotic coverage only if secondary infection is suspected in severe courses or elderly, infection-prone or immunosuppressed patients. Choice of antibiotic according to antibiogram.

Pregnancy:

  • Zoster disease during pregnancy (mother is seropositive) is due to reactivation of a latent VZV infection. There is no viremia except for generalized zoster. Thus, there is no significant risk for mother and child. Therapy is not necessary. In complicated zoster (zoster in atopic eczema, zoster oticus, zoster ophthalmicus, zoster generalisatus) systemic administration of aciclovir (3 times/day 10-20 mg/kg bw i.v.).
  • In case of varicella-zoster contact during pregnancy: determine AK status (VZV ELISA). IgG < 1:64 or seronegative: administer varicella-zoster immunoglobulin (Varitect or Varicellon) Varitect: 1.0 ml/kg bw i.v. within 24-72 hr after contact. Varicellon should be dosed at 0.2 ml/kg bw i.m.

For the rare neonatal infections, aciclovir is administered p.o. (40-80 mg/kg bw/day) or i.v. (30 mg/kg bw/day).

Glucocorticoids: Except for zoster oticus and zoster ophthalmicus, systemic glucocorticoids are not indicated.

For zoster-associated pain, a visual analog scale (VAS) or numeric rating scale (NRS) should be used to assess the patient's subjective perception of pain and treated accordingly to reduce the likelihood of postzoster neuralgia. Neuropathic pain can be treated with anticonvulsants such as gabapentin or pregabalin. In addition, tricyclic antidepressants such as amitryptiline have been shown to be effective.

to be considered: adaptation to renal function, side effects such as fatigue, dizziness, drowsiness, control glucose and pancreatic enzymes in serum.

Dosage: Pregabalin: Initial 2 x 25 mg p.o., increase every 1-2 days by 25 mg, adjusted to tolerability up to max. 2 x 300 mg/Tg

Gabapentin: Initial: 300 mg at night or 3 x 100 mg /day Increase after 3-4 days by 300 mg ( 3 x 100 mg spread over the day), maximum dose: 3 x 1200 mg

Progression/forecast
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Healing after 2 to 3 weeks, usually leaving a lifelong immunity. However, some people develop several episodes of zoster. Presumably these patients benefit from a vaccination. It is highly recommended to vaccinate older patients 6 months after a zoster infection.

Prophylaxis
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The results of a vaccine "Zostavax" in a large collective of elderly people (>60 years) showed a significant reduction in cases of disease (reduction of 55% compared to a non-vaccinated control collective). The vaccine contains VZV from the Oka/Merck strain, but at a 14-fold higher dosage than in the chickenpox vaccine. The preparation has been available in Germany since 2013 (approved for adults 50 years of age and older) and is approved in more than 60 countries. Booster is recommended after 10-30 years. Zoster incidence is reduced by 97% regardless of age.

As of 2008, the vaccine was recommended for all (immunocompetent) persons > 60 years of age in the United States. Zoster vaccination is especially recommended for multimorbid patients, as pain and psychosocial consequences (including postzoster neuralgia) can be avoided (Meier K et al. 2017).

Inactivated vaccine Shingrix®: Recommended by the STIKO as a standard vaccination offer to all persons aged 60 years and older to prevent herpes zoster and its complications and late sequelae. Also recommended for congenital or acquired immunosuppression and/or severe underlying diseases from the age of 50 years.

In immunosuppressed patients), a therapeutic agent with high efficacy has been available since 2018 in the form of the adjuvanted inactivated vaccine Shingrix, which provides age-independent and long-lasting protection against zoster and zoster neuralgia. The drug has been used in a Phase III study program in 38,000 patients worldwide. It should be used as early as possible in zoster infection. The intramuscular injections are applied 2x in intervals of 2 (ggfl. 6) months. People who develop herpes zoster despite vaccination with the inactivated vaccine have significantly less pain and fewer restrictions in the activities of daily living in the event of disease.

Side effects: >90% of all vaccinated people develop pain at the injection site. Almost all local reactions resolve completely within 3 days. About 2/3 of the vaccinated develop mild systemic reactions such as: fatigue (75.3%), myalgias (74%), headache (64%), less frequently backache, chills and symptoms of flu.

Since August 2020, approval extension of the EU Commission (EMA) for persons mti increased risk of zoster from 18 years and all people from 50 years. The STIKO has not yet adopted this recommendation.

Naturopathy
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The acupuncture treatmenthas proven to be the best way to control the shooting pain.

Tables
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Treatment of varicella zoster infection in HIV patients (after Brodt, Helm, Kamps, Aids 2000, Steinhäuser Verlag)

Indication

Drug

Dosage/Application

CD 4 > 200/μl - only one dermatome affected

Aciclovir (e.g. Zovirax)

5 times/day 12 mg/kg bw p.o. = 5 times/day 1 tbl. at 800 mg p.o.

Famciclovir (Famvir)

3 times/day 250 mg p.o.

valaciclovir (Valtrex)

3 times/day 1000 mg p.o.

Brivudine (helpin)

4 times/day 125 mg p.o. over 7 days.

CD 4 < 200/μl and/or several dermatomes affected or disseminated infestation or trigeminal infestation

Aciclovir

3 times/day 10 mg/kg bw i.v. = 34 times/day 500 mg i.v. in 500 ml NaCl solution over 10 days.

For acyclovir resistance

Foscarnet (Foscavir)

Use only if kidney function is intact, check kidney parameters!

3 times/day 40 mg/kg bw i.v. = 3 times/day 2400 mg i.v., each time infuse 100 ml in glucose solution 5% or NaCl solution diluted to 500 ml over 1 hour. Duration of therapy: Until the symptoms subside.

Note(s)
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Shingles is regarded as an early marker of HIV infection. Therefore, the German guideline recommends HIV serology in otherwise healthy patients under 50 years of age with zoster infection.

Important distinguishing features of zoster infestation compared to other exanthema are:

  • the asymmetry (segmental pattern) of zoster infestation,
  • the synchronous development of the skin changes (in contrast to herpes simplex whose vesicles may be in different stages of development)

starting with erythema, followed by blisters, pustules and crusts. Varicella-like exanthema is found especially in AIDS patients and in other immunologically incompetent patients. Here the synchronous isomorphism of zoster infestation is often missing.

According to § 6(1) No. 1 of the Infection Protection Act (IfSG), suspected cases of varicella, the disease and death must be reported by name to the responsible health authority.

Literature
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  1. Breuer J et al. (2014) Herpes zoster as a risk factor for stroke and TIA: a retrospective cohort study in the UK. Neurology 83:e27-33.
  2. Cunningham AL et al (2016) ZOE-70 Study Group. Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older. N Engl J Med 375:1019-1032.
  3. Enright AM et al (2003) Antiviral therapy in children with varicella zoster virus and herpes simplex virus infections. Herpes 10: 32-37
  4. Furuta Y (2005) Varicella-zoster virus reactivation is an important cause of acute peripheral facial paralysis in children. Pediatr Infect Dis J 24: 97-101
  5. Gesierich A et al (2005) Postzoster granulomatous dermatitis with detection of varicella-zoster virus DNA. J Dtsch Dermatol Ges 2: 770-772.
  6. Hambleton S (2005) The impact of varicella vaccination in the United States. Semin Pediatr Infect Dis 16: 38-43
  7. Kempf W et al (1999) Infections with varicella zoster virus. Dermatologist 52: 359-376
  8. Lal H et al (2015) ZOE-50 Study Group. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 372:2087-2106.
  9. Lilie HM, Wassilew SW (2004) Varicella-zoster virus infections. Dermatologist 55: 831-84
  10. Meier K et al (2017) Benefits of zoster vaccination in elderly patients. Dermatologist 68: 418-419.
  11. Müllegger RR et al (2010) Skin infections in pregnancy. Dermatologist 61: 2066-2069
  12. Tseng HFet al (2011) Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA 305: 160-166
  13. Tricco AC et al.(2018) Efficacy, effectiveness, and safety of herpes zoster vaccines in adults aged 50
  14. and older: systematic review and network meta-analysis. BMJ 363: k4029.
  15. Wollina U (2018) Rapid detection and efficient treatment of herpes zsoter. hautnah 34: 32-35.
  16. Vazquez M, Shapiro ED (2005) Varicella vaccine and infection with varicella-zoster virus. N Engl J Med 352: 439-440.
  17. Werner RN,. Herpes zoster-prevention, diagnosis, and treatment [Herpes zoster-prevention, diagnosis, and treatment]. Dermatologist. 73: 442-451
  18. Müller CSI et al (2021) Herpes zoster update-what's new? Act Dermatol 47: 498-509
  19. Schmidt SAJ et al (2021) Perceived psychological stress and risk of herpes zoster: a nationwide population-based cohort study. Br J Dermatol. 185: 130-138

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