ZosterB02.9

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

Depending on the localisation, a further distinction is made:

• Zoster ophthalmicus
• shingles
• shingles

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.

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

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

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.

Incubation period 7-18 days. Uncharacteristic prodromal stage lasting 2-5 days with slightly elevated temperature. Rarely zoster fever. Tingling, burning and stabbing, shooting pains can occur even before the skin symptoms.

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

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

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

Zoster pain: As sensory nerves are predominantly affected, pain is reported by many patients (even more so than the actual skin symptoms) as the main clinical symptom.

• The acute zoster pain, which is described as burning or stinging, often begins 4-5 days before the vesicle eruption. It persists for 4-5 weeks and often requires treatment (anti-inflammatory drugs).
• Chronic zoster pain(post-zosteric neuralgia = persistence of pain > 4 weeks after the skin lesions have healed). The formerly affected areas of skin remain hypersensitive(allodynia), so that, for example, tight-fitting clothing is not tolerated. In more severe cases, there are reports of excruciating permanent pain, which can also occur in attacks and lancinating.

Delayed healing with scarring is observed in older people and those with immune incompetence.

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

Segmental paresis: in addition to the afferent branch, the motor branch of the nerve can also be affected by VZV infection. The consequences are segmental paresis.

Zosteroticus: risk of facial nerve paresis.

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

Scarring especially with necrotizing zoster.

Special forms:

• Zoster multiplex unilateralis
• Zoster ophthalmicus
• Zoster in the trigeminal area (2nd and 3rd trigeminal branch)
• Cranial zoster (cranial zoster: patients with affections of head or neck nerves (headache, neck stiffness, lymphadenopathy)6
• Zoster oticus
• Zoster generalisatus
• Ramsay-Hunt syndrome (in addition to the facial nerve, the vestibulocochlear nerve is also affected. Tinnitus, dizziness and hearing loss are possible).

As a rule, the typical medical history and clinical manifestations are sufficient to make a diagnosis.

In some cases, extended diagnostics may be useful. Viruses can be detected from vesicle secretions using PCR. If herpes encephalitis is clinically suspected, a lumbar puncture is mandatory. CAVE: Emergency imaging (cMRI, cCT) must be performed in case of neurological acuteity and clouding of consciousness.

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

Further necessary diagnostic measures:

Zosterophthalmicus: Consultation with an ophthalmologist to rule out eye involvement (e.g. neuritis, acute retinal necrosis)

Zosteroticus: Interdisciplinary treatment with the ENT department and neurologist, especially if cranial nerves are affected

Zostersine herpete: Serology from serum, plasma or nasopharyngeal swab may be considered.

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.

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)

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

Scars: Chronic, disturbing sequelae on the skin are hypo- and depigmented scars, hypesthesia or hyperesthesia.

Isotopic reactions: Less common are isotopic reactions (= appearance of a second skin disease at the same site after healing of the primary skin lesions) such as acneiform reactions, lichen planus, circumscritic scleroderma, granuloma anulare, tuberculoid and sarcoid infiltrates, granulomatous vasculitides, and lymphomas.

Zoster react ivations: In very rare cases, zoster reactivations have been observed, such as after COVID vaccinations (Gambichler T et al. 2022).

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

Otologic complications: These involve the so-called Ramsay-Hunt syndrome. Ramsay-Hunt syndrome is a triad of.

1. Painful vesicles in the external auditory canal and on the pinna of the ear.
2. Ear pain
3. Ipsilateral peripheral facial nerve palsy

Neurologic complications:

• They include zoster meningitis and zoster encephalitiss, motor neuropathies and paralysis, Guillain-Barré syndrome, granulomatous arteritis, and cranial nerve deficits.
• Postzosteric neuralgia: The most common and important complication is acute and chronic pain (see zoster neuralgia below). 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 postzoster is documented with a hazard ratio of 1.17.

Urologic complications: Cystitis, which often goes undiagnosed.

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

Postzoster cancer risk: Highest incidence 180 days after herpes zoster diagnosis. Lymphoma Leading. Relative risk for cancer ranges from 1.42-1.83 (Wollina U 2018).

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.

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).

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 in 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

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.

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 in 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 standard vaccination in all persons aged 60 years and older to prevent herpes zoster and its complications and late sequelae. Also recommended in congenital or acquired immunosuppression and/or severe underlying diseases from the age of 50 years.

In immunosuppressed patients, the adjuvanted inactivated vaccine Shingrix has been available since 2018 as a therapeutic agent with high efficacy, providing 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, EU Commission (EMA) approval extension for people with increased risk of zoster from 18 years and all people from 50 years. The STIKO has not yet adopted this recommendation.

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

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.

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