Zoster B02.9

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

Co-Autors: Jeton Luzha, Hadrian Tran

Our authors

Last updated on: 29.10.2020

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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 case of partial immunity due to humoral immunisation or reactivation of the virus present in the body by reducing its resistance.

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

If the specific defence against VZV falls below a critical value, the virus multiplies in the infected ganglion, causing inflammatory symptoms with nerve cell necrosis and pain. Under development of sensory neuritis, infectious virus particles are transported within the affected nerve into the skin, where they lead to the classic blister and blister-forming zoster symptoms.

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

  • Immunodeficiencies: Incidence rate for all forms of immunodeficiencies (incidence rate increased 2-fold). Nearly 50% of bone marrow transplant patients develop zoster and, depending on their immune status, about 20% of HIV-infected patients. There is also an increased incidence rate in patients under immunosuppressive drugs 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. 2-5 days uncharacteristic prodromal stage with slightly elevated temperature. Rarely zoster fever. Tingling, burning and stabbing, shooting pains may occur even before skin symptoms.

The zoster rash is unilateral and segmental. Initially, discrete red patches appear, which confluent into unilateral, painful, large-area patches.

Within 12-24 hours, grouped standing papules appear on the red patches, rapidly transforming into initially clear, later cloudy blisters/bubbles and pustules.

The zoster blisters usually dry out within 7-12 days, forming crusts. The lesions heal without scarring in immunocompetent people. Hypo- or hyperpigmentations are possible.

Pain of zoster: Since mainly sensory nerves are affected, pain is given by many affected persons (even stronger than the actual skin sympotaxis) as a clinical leading symptom.

  • The acute zostom pain, which is described as burning or stinging, often begins 4-5 days before the vesicle eruption. It lasts 4-5 weeks and often requires treatment (anti-inflammatory drugs).
  • The chronic zoster pain(post-zosteric neuralgia = persistence of pain > 4 weeks after healing of the skin lesions). The formerly affected skin areas remain hypersensitive(allodynia), so that e.g. tight-fitting clothing is not tolerated. In more pronounced cases, there are reports of torturous permanent pain, which can also occur in the form of attacks and lancing.

Delayed healing with scarring is observed in older people and in immunocompromised patients.

Hemorrhagic staining of the zoster vesicles and blisters(hemorrhagic-necrotic zoster) is rare.

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

With oticus zoster: danger of facial nerve paresis.

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

Scarring, especially in necrotizing zoster.

Special forms:

Laboratory
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The routine boron does not show any special features if the course is uncomplicated.

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

In retrospect, VZV serology is of importance. Antibodies of the IgG, IgA and IgM classes indicate reactivation by an increase.

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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If the course is uncomplicated and/or accompanying 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 ).

    Notice!

    Clioquinol not on the hairy head, dyes grey hair yellow! If necessary, creams with antibiotic additives, especially in case of secondary infection R084. After drying of the blisters softening ointments like dexpanthenol (e.g. Bepanthen).
  • Externa with virustatic addition: 5% idoxuridine solution/omicide (e.g. Zostrum, Virunguent) 4 times/day thinly on the diseased skin areas (this therapy is called by many authors as ineffective and dispensable (see below Wollina U 2018).

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

  • Alternatively Valaciclovir (Valtrex®): 3 times/day 1000 mg p.o. for 7 days. Valaciclovir has a significantly higher bioavailability than Aciclovir with about 65%.
  • 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 of a single daily dose. In immunocompromised patients from the 25th LJ and in herpes zoster ophthalmicus: 3x500mg/day.
  • Alternative Brivudine: Immunocompetent adults: 1x/day 125mg p.o.; Brividin must not be administered together with 5-fluorouracil or other 5-fluoropyrimidines within the last 4 weeks (absolute contraindication).

In severe cases (haemorrhagic/necrotizing), head and neck infections and in immunocompromised patients: Aciclovir systemic (e.g. Zovirax) 10.0 mg/kg bw every 8 hours for 5-7 days i.v. In case of involvement of CNS and internal organs or generalization a dose escalation to 3x15 mg/kg bw/day can be performed for up to 21 days.

Inactivated vaccine Shingrix: In the group of persons > 5o years of age (also in immunocompromised patients), the adjuvanted inactivated vaccine Shingrix has been available since 2018 as a highly effective therapeutic agent that offers age-independent and long-lasting protection against zoster and zoster neuralgia. The preparation was used in a Phase III study program in 38,000 patients worldwide. The approval refers to patients >50 years. It should be used as early as possible in the zoster infection. The intramuscular injections are administered twice at intervals of 2 (ggfl. 6) months. People who develop herpes zoster despite vaccination with the dead vaccine have significantly less pain and fewer restrictions in the activities of daily life in case of illness.

Side effects: >90% of all vaccinated persons develop pain at the injection site. Almost all local reactions subside completely within 3 days. About 2/3 of the vaccinated persons develop slight systemic reactions such as: fatigue (75,3%), myalgia (74%), headache (64%), less often back pain, chills and symptoms of flu.

Superinfection: antibiotic coverage only in case of suspected secondary infections in severe forms of the disease or in older, infection-prone or immunosuppressed patients. Choice of antibiotic according to the antibioticogram.

Pregnancy:

  • In case of zoster disease during pregnancy (mother is seropositive) the reactivation of a latent VZV infection is the basis. With the exception of generalized zoster there is no viremia. Therefore 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 acyclovir (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: administration of varicella zoster immunoglobulin (Varitect or Varicellon) Varitect: 1.0 ml/kg bw i.v. within 24-72 hours after contact. Varicellon is to be dosed with 0.2 ml/kg KG i.v.

In the rare cases of newborn infections, Aciclovir p.o. (40-80 mg/kg bw/day) or i.v. (30 mg/kg bw/day) is administered.

Glucocorticoids: Systemic glucocorticoids are not indicated except for zoster oticus and zoster ophthalmicus.

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

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 in a 14-fold higher dosage than in the chickenpox vaccine. The preparation has been available in Germany since 2013 (approved for adults over 50 years of age) and is approved in more than 60 countries. A booster is recommended after 10-30 years. The zoster incidence is reduced by 97% regardless of age.

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

Note: Since April 2018, a dead vaccine is also available. In the ZOE-50 and ZOE-70 study the vaccination effectiveness was >90%. The basic immunisation comprises two intramuscular doses at intervals of 2-6 months. The vaccine is not indicated for the prevention of a primary infection with VZV, which usually manifests itself as chickenpox. In a meta-analytical comparison of attenuated live vaccine and recombinant subunit vaccine, Pat. > 50 years showed a superiority of the inactivated vaccine (Tricco et al. 2018). It is not yet possible to say whether a booster is necessary (Lal H et al. 2015; Cunningham AL et al. 2016).

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. Pediatric Infect Dis J 24: 97-101
  5. Gesierich A et al (2005) Postzosteric 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. Seminar Pediatric 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. Lily 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 during 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. close up 34: 32-35
  16. Vazquez M, Shapiro ED (2005) Varicella vaccine and infection with varicella-zoster virus. N Engl J Med 352: 439-440

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