Herpes simplex virus infectionsB00.1

Mostly contact infection, rarely droplet infection, caused by the herpes simplex virus -1 or HSV-2. See also Herpes viruses, human (herpes from Greek herpein = to crawl). The viruses prefer the transition area from skin to mucous membranes. Small defects in the epithelium of the skin or mucous membranes serve as ports of entry. Both HSV types can cause orofacial (mainly HSV-1) and anogential (mainly HSV-2) infections, but with different frequencies (see figure). The frequent recurrences of the disease result from edogenous reactivation of the viruses. They often affect the same site(herpes simplex recidivans). Herpes simplex encephalitis is highly complicating, as hemorrhagic-necrotizing herd encephalitis, which leads to death in about 70% of patients if left untreated.

The clinical classification of herpes simplex diseases is handled differently. They are generally classified according to the site of manifestation (e.g. genital herpes simplex, labial herpes simplex) but also according to aetiology (e.g. herpes simplex solaris) or clinical course (herpes simplex recidivans, recurrent herpes); the suffix "simplex", which characterizes the difference to other human herpes viruses (HHV), is also often not used (e.g. genital herpes, labial herpes). A distinction is made between:

• Herpes simplex labialis (herpes labialis)
• Herpes simplex genitalis (genital herpes):
  • Balanitis herpetica
  • Vulvovaginitis herpetica
• Herpes simplex solaris (herpes simplex recurrence after UV exposure, often after alpine skiing)
• Herpes simplex corneae
• Herpes (simplex) gladiatorum
• Panaritium due to herpes viruses+ (L99.8)
• Herpes simplex recidivans (classic course pattern in different localization)
• Herpes simplex vegetans (atypical course with immunosuppression)
• Eccema herpeticatum (generalized exanthematic form in atopic eczema)
• Gingivostomatitis herpetica (initial manifestation of herpes simplex infection)
• Other herpes simplex infections
  • Hepatitis due to herpes viruses+ (K77.0)
  • Encephalitis due to herpes viruses(herpes simplex encephalitis(B00.4+)
  • Herpes simplex infections of the eye
    • Iridocyclitis+ (H22.0)
    • Iritis+ (H22.0)
    • Keratitis+ (H19.1)
    • Keratoconjunctivitis (H19.1)
    • Conjunctivitis+ (H13.1)
    • Uveitis anterior+ (H22.0)
  • Herpes simplex of the newborn (herpes neonatorum):
    • Herpes sepsis of the newborn.

Infectious disease occurring worldwide; the infestation of the adult population with HSV-1 viruses is > 85% and already occurs in early childhood or infancy via the family environment. In Germany, every 5th child is HSV-1 positive at the age of 2-3 years. Clinical particularities are the other organ diseases caused by the herpes simplex infections (e.g. hepatitis caused by herpes simplex viruses, infections of the eye, infections of the urogenital tract, meningitis and encephalitis caused by herpes simplex viruses) as well as the herpes neonatorum with the highly complicative herpes sepsis.

HSV-1: Primary infection with herpes simplex virus type 1 usually via oral contact with virally infected secretions or close physical contact with HSV-infected individuals in childhood.

HSV-2: The route of infection in HSV-2 infection is less clear. Primary infection with herpes simplex virus type 2 is often asymptomatic. Transmission is very often through asymptomatic viral excretors. It occurs predominantly from puberty onwards (transmission by droplet or smear infection, e.g. kissing, sexual intercourse). In the vast majority of cases (>90%), the course is inapparent; only in <10% is there a clinical manifestation in various clinical pictures (see Table 1). The primary infection is also possible as a connatal infection (herpes sepsis of the newborn) or as an infection of the newborn during birth.

Incubation period: The incubation period for both HSV types is about 1 week.
Route of spread: Both HSV-1 and HSV-2 are epidermotropic and also neurotropic. From the site of primary infection, the viruses migrate into the free nerve terminals and travel retrogradely along the nerve axon to the sensory ganglia of the dorsal spinal cord roots or cranial nerves.

Usually lifelong persistence of the virus in ganglion cells despite antibody formation. The virus inhibits the presentation of immunologically important protein fragments via the MHC class I proteins, thus preventing apoptosis of HSV-infected neurons.

Endogenous reactivation by various trigger factors leads to recidivism. Trigger factors lead to recurrent secondary infections. Trigger factors described include fever, trauma, UV radiation, stress, immunosuppression, menstruation and pregnancy. After reactivation, the viruses migrate centrifugally along the nerve axon into the skin or mucosa. There they multiply explosively in the epithelial cells and lead to the typical clinical finding of herpes recurrence or also to an asymptomatic, nevertheless infectious virus excretion (virus shedding).

Common localizations:

• Lips (see Herpes simplex labialis)
• Genito-anal in male/female (see herpes simplex genitalis)

Rare localizations:

• face, palm, fingers, abdomen, back/chest, buttocks

Generalized: Eccema herpeticatum

Extensive herpes simplex infections during sporting events, e.g. wrestling (Herpes gladiatorum)

Primary infections:

• HSV-2 primary infections (incubation period 4-7 days) can be asymptomatic or unrecognized as such. They manifest themselves, usually postpubertal, as painful and often feverish balanitis, anitis or vulvovaginitis herpetica. In addition, general complaints such as headaches or muscle aches can occur. Duration of the disease up to 28 days. A complicative primary HSV-2 infection can develop in newborns in the form of connatal or neonatal herpes simplex infection ( > 70% HSV-2 infection in acute maternal infection. Clinical: vesiculo-pustular exanthema). Its maximum variant is the herpes pessis of the newborn.
• HSV-1 primary infections:
  • Asymptomatic primary infections (>90%): they are usually not noticed.
  • Symptomatic primary infections: Uncharacteristic prodromal stage with feeling of tension, itching or pain, rarely fever and swelling of the draining lymph nodes (depending on the location of the infection: head and neck lymph nodes). Shooting of solitary or grouped standing vesicles of 0.1-0.3 cm in size, initially clear, taut and taut on erythematous skin. In the further course of the disease the content of the vesicles becomes cloudy, erosions or ulcerations as well as yellowish crusts appear. In uncomplicated cases, healing usually takes 5-10 days.
  • Complicative primary infections: In a few cases (<1%) the initial manifestation leads to a clinically severe infection of the oral mucosa and the perioral region under the picture of gingivostomatitis herpetica or its maximum variant, the so-called aphthoid Pospischill-Feyrter.

Latent infections:

• In this phase of infection the patient is asymptomatic, but can excrete viruses and is therefore infectious.

Recurrent infections (type 1 and 2):

• S.u. Herpes simplex recidivans: Most frequent manifestation of a herpes simplex virus infection (usually recurrent) on the skin or mucous membrane in the form of eruptions, usually chronic recurrent eruptions of grouped standing vesicles the size of a pinhead.
• The reactivation of the viruses often occurs without any particular clinical cause, but also after various other diseases. Irritations (UV-irradiation = herpes simplex solaris; traumas (herpes simplex traumaticus) (physical or psychological stress; infections of other genesis).
• A massive, large-scale spread of a herpes simplex virus infection in atopic eczema is called Eccema herpeticatum.
• A dreaded infection of the mucous membranes is herpes simplex corneae.

Clinical: clinical picture is sufficient for clinical classification in most cases.

Serology: Detection of type-specific IgG against glycoprotein G of HSV-1 (gG-1) or HSV-2 (gG-2). Detection of antibodies has limited value due to high population infestation.

Culture: Cultural detection of viruses from fresh lesions is possible.

Antigen detection: By using specific antibodies, the antigen can be detected in sample material.

PCR: Detection of HSV DNA from fresh sample material (biospie material, cerebrospinal fluid).

• DD on HSV skin lesions: Zoster; impetigo; paronychia; mycoses.
• DD to orofacial herpes: Stevens-Johnson syndrome; herpangina; hand-foot-mouth disease; recurrent aphthae.
• DD for HSV infection of the eye: Zoster ophthalmicus.
• DD on HSV infection of the genital area: Syphilis acquisita; Ulcus molle; Candidosis.

• Severe local or even disseminated HSV infections in immunocompromised persons, especially in HIV infection, in permanently immunocompromised persons
• Herpetic keratoconjunctivitis possibly with complicated corneal damage
• Vegetative herpes simplex (Herpes simplex vegetans) also develops during severe immunosuppression. Large-scale, progressive, pyodemic erosions that turn into persistent muddy ulcers with no tendency to heal as a sign of persistent herpes simplex infection are the clinical leading symptoms of this severe clinical constellation.
• Eccema herpeticatum: a disseminated herpes simplex infection that often has a difficult course and is associated with severe disturbance of the epidermal skin barrier over a large area, especially in pre-existing atopic eczema (see also Eccema herpeticatum).
• Generalized severe course (often in immunosuppression): Infection of the lungs (HSV-pneumonia), liver, esophagus.
• Urological complications with anogenital herpes simplex (urinary retention)
• Herpes encephalitis (mortality: untreated > 70%). Most common viral encephalitis (mainly HSV-1): mainly affects the limbic system and temporal lobe. Rapid diagnosis is important (MRI, PCR test in CSF). Early therapy (Aciclovir) is crucial for prognosis!
• Aseptic meningitis: usually mild recurrent aseptic meningitis(mollaret meningitis)
• Facial nerve palsy: idiopathic facial nerve palsy may be caused by HSV-1.
• Neonatal herpes infection by vertical transmission (complicative maximum variant: neonatal herpes sepsis).
• Post-herpetic erythema exsudativum multiforme: this complication has a special genetic disposition with association to certain HLA types (HLA-DR1/HLA-DR4).

For uncomplicated herpes simplex, virustatic, disinfecting, astringent and possibly antibiotic local therapeutic agents are indicated.

Prodromal stage and uncomplicated eruption stage:

• In uncomplicated cases of herpes simplex, local therapy with zinc sulphate (virudermine) is recommended because it is inexpensive and effective. Otherwise external idoxuridine in dimethyl sulfoxide (as penetration accelerator) leads to a fast healing of the herpes (Zostrum®: 5% idoxuridine in pure dimethyl sulfoxide, Virunguent®: 0,2% idoxuridine).
• For the acute episode of recurrent herpes simplex labialis a cream of acyclovir (5%) plus hydrocortisone (0.1%) (e.g. Zovirax Duo®, over-the-counter) is recommended as first choice, but only in the initial phase, since topical acyclovir and corticosteroids are more effective in combination than alone. Furthermore, the combination is sometimes also helpful in the vesicle stage [Nguyen H. P. et al., Recent approval of Xerese in Canada: 5% acyclovir and 1% hydrocorisone topical cream in the treatment of herpes labialis, Skin Therapy Lett, 2014, 19(3), 5-8]. The entire section, with the exception of the product name, is a literal quotation from: consilium Dermatologie live, issue 06/2018 Cord Sunderkötter, p. 21: 4 "Irritational topics" of practical dermatology].
• Good results can be achieved with a 2% foscarnet cream(e.g. Triapten Antiviral Cream®) or a 5% aiclovir ointment(e.g. Zovirax Ointment, Zovirax Lip Herpes Cream®). These agents are also suitable for the mucous membrane area. However, they are expensive. In the meantime, resistance to acyclovir has become known so that this preparation cannot be recommended without reservation for uncomplicated herpes simplex.
• Penciclovir (e.g. Fenistil Pencivir®), like Aciclovir a nucleoside analogue, should be used in cases of cold sores as soon as possible after the first symptoms (e.g. burning, itching) appear.
• Alternative: ointments containing balm (e.g. Lomaherpan®)

For painful accompanying inflammations:

• In this case a combination of a glucocorticoid and a disinfectant (e.g. Fucicort cream, 1% hydrocortisone, 2% clioquinol cream R052 ) is recommended for a short period of time. Cave! Spread and ulceration of the herpes! If light-provoked herpes simplex labialis is possible, intensive light protection of the lips should be applied prophylactically (e.g. Ilrido lipstick!).

Bubble stage:

• No ointments or creams, but drying and astringent external dry brushes (e.g. 2% Clioquinol lotion or cream R050, R049 ), menthol-iron oxide zinc paste (e.g. Labiosan) or zinc sulfate hydrogel R298.
• Alternative: In genital herpes, local hyperthermia is recommended.

Crust stage:

• Blande greasing topicals such as 5% panthenol cream R064.

Infection of mucous membranes:

• Several times daily mouthwashes with Kamillosan.

• In cases of extensive complicated herpes simplex, internal treatment with acyclovir i.v. (5 mg/kg bw/day) is recommended until the blisters have healed (approx. 5-10 days).
• In HIV-infected persons increase the acyclovir dosage (10 mg/max. 20 mg/kg bw/day).
• Alternatively Famciclovir p.o. (e.g. Famvir Filmtbl.) 3 times/day 250 mg or Valaciclovir (Valtrex Filmtbl.) 3 times/day 1000 mg p.o.
• In case of therapy failure Foscarnet (Foscavir) 3 times/day 40-60 mg/kg bw/day i.v. in 500 NaCl over 2 hours
• Alternatively: The amino acid lysine leads in a dose of 3 x 500-1000 mg / day to a faster relief and healing of acute herpes simplex. Commercial preparation for dietary treatment: Lyranda® chewable tablets. Besides L-lysine, these contain zinc, selenium, vitamins and bioflavonoids. Recommended dosage until healing 3 tablets per day.
• In case of recurrent course with irregular and rare episodes, oral short-term therapy with Aciclovir (3 times/day 400 mg p.o. over 5-10 days) is recommended. Alternatively Valaciclovir (2 times/day 1000 mg p.o.) or Famciclovir (2 times/day 500 mg p.o.) for 5-10 days.
• In case of recurrent course with frequent relapses a long-term therapy (several months) with Aciclovir 2 x/day 400 mg p.o. is recommended. Alternatively Valaciclovir (1 x/day 500-1000 mg p.o.) or Famciclovir (2 x/day 125 mg p.o.).

• Experimental: There are convincing study results available in large groups (>8000 persons) with herpes vaccines against HSV type I (GlaxoSmithKline) and HSV type II. In these studies a significant protective protection against herpes simplex infections could be proven.

• In clinical studies: Helicase-primase inhibitors. Prevent the formation of viral DNA by binding to the helicase-primase complex independently of thymine kinase. Could be used in eciclovir-resistant herpes infections.

• Pregnancy: Data from a population-based cohort study (data from 837,795 live births) show that treatment of herpes simplex or herpes zoster virus infections with the antiviral agents acyclovir, famciclovir and valciclovir at the usual doses during the first trimester of pregnancy is unlikely to cause increased rates of foetal malformation.

Local therapy with lemon balm leaves (Lomaherpan cream) applied several times a day has proven effective.

In recurrent herpes simplex, systemic therapy with extracts ofechinacea (Echinaceae purpureae herba) is recommended (Echinacin Liquidum - 1.5-1.5-2.5ml/day).

Overview of diseases caused by herpes simplex viruses

Remember! Since all virustatics are only effective during the viral replication, a very early start of therapy after the first symptoms appear is recommended!

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