This document provides an overview of HSV (herpes simplex virus) infections, including classification, virology, transmission, epidemiology, clinical manifestations, treatment, and more. It begins with an introduction to HSV and outlines the contents to be covered. The main sections discuss virus structure and lifecycle, transmission routes, epidemiology of HSV-1 and HSV-2 globally and in Ethiopia, disease domains, immunology, and clinical manifestations both cutaneous and extracutaneous. Treatment options including antivirals and vaccine development are also mentioned.

1. HSV
infections(cutaneous
and Genital)
• Presented by:-Biniyam Simeneh (MD)
• Dermatovenerology year 1 resident
• Moderators
• Dr.Amel (Assistant professor of dermatovenerology)
• Dr.Mikiyas (year 3 resident of Dermatovenerology)
• AAU
• June 7, 2021, G.C

2. Contents
• Introduction
• Classification
• Virology of HSV
• Transmission
• Epidemiology of HSV
• Cutaneous HSV
• HSV diseases domains
• Immunology of HSV
• Clinical manifestations
• Genital herpes
• HSV in pregnancy
• Neonatal herpes
• Disseminated HSV
• HSV in HIV infected people
• Non dermatologic HSV
manifestations
• Investigations done for HSV
• Antivirals used for HSV
treatment
• HSV vaccine development
• References
6/7/2021 2
Biniyam Simeneh(MD)

3. Introduction
• Hippocrates used the Greek word herpes to describe lesions that seem to creep or crawl along the
skin.
• The herpesvirus group consists of relatively large, enveloped double stranded DNA viruses and are
sub grouped, according to genome similarities, into the α, β and γ herpesviruses
• Human herpes simplex virus (HSV) causes contagious infection with a large reservoir in the
general population
• There are in fact two serotypes of HSV—HSV-1 and HSV-2.
• Herpes simplex viruses produce primary and recurrent vesicular eruptions that favor the orolabial
and genital regions
• Disease caused by HSV tends to be relatively mild and self-limited in immunocompetent persons,
although severe and quite unusual disease can be seen with immunosuppression.
6/7/2021 3
Biniyam Simeneh(MD)

4. Introduction
• Herpesviruses can establish lifelong persistent infections in their hosts and undergo
periodic reactivation ; incurable.
• HSV-1 is normally associated with orofacial infections and encephalitis
• HSV-2 usually causes genital infections and can be transmitted from infected mothers to
neonates
• Lesion location, however, is not necessarily indicative of viral type, as HSV-1 is
associated with genital infections more often than HSV-2 in some unique subpopulations.
• Both viruses establish latent infections in sensory neurons and, upon reactivation, cause
lesions at or near point of entry into the body
6/7/2021 4
Biniyam Simeneh(MD)

5. Classification of
Herpesviridae
• Eight members of the group
can infect humans.
• Herpes simplex virus (HSV)
and varicella‐zoster virus
(VZV) predominantly cause
cutaneous disease and viral
exanthems can occur with β
herpesvirus infections.
6/7/2021 5
Biniyam Simeneh(MD)

6. VIRION STRUCTURE
• The HSV virion consists of four
elements:
• (a) An electron Opaque core
containing the viral DNA
• (b) An icosahedral capsid
surrounding the core
• (c) A largely unstructured
proteinaceous layer called
the Tegument that surrounds
the capsid
• (d) An outer lipid bilayer
envelope exhibiting spikes
on its surface
• A spherical particle with an
average diameter of 186 nm,
which extended to 225 nm with
spikes included
6/7/2021 6
Biniyam Simeneh(MD)

7. Virus lifecycle
Virus adsorption and penetration
Viral DNA replication and nucleocapsid
assembly
Acquisition of the viral envelope
Latency
6/7/2021 7
Biniyam Simeneh(MD)

8. ENTRY AND UNCOATING
• Five envelope glycoproteins mediate binding and entry, gB, gH, and gL, are believed to constitute
the core fusion complex.
• Binding of the virus to the host cell is mediated by interaction of Glycoprotein B(gB) and
Glycoprotein C(gC) with cell surface Glycosaminoglycans more specifically heparan sulphate.
• Glycoprotein D(gD) interacts with at least with one of the three entry receptors
• HVEM(herpes virus entry mediator
• Nectin-1
• 3-O sulphated heparan sulphate
• Interaction of gD with the entry receptors brings about conformational change and interacts with
gH and gL forming a fusion complex.
• Final interaction of gB with the fusion complex results in pore formation in the hosts cell
membrane.
6/7/2021 8
Biniyam Simeneh(MD)

9. Viral entry
6/7/2021 9
Biniyam Simeneh(MD)

10. HSV nucleocapsid budding
6/7/2021 10
Biniyam Simeneh(MD)

11. • Following entry of the host cell a myriad of viral proteins are transcribed called
• Immediate early
• Early
• Late
• After infection, 5 ”immediate-early” genes are transcribed
• This immidiate early gene products stimulate synthesis of early proteins which are crucial
for viral replication
• Two importants early proteins are thymidylate synthase and viral DNA polymerase
• Expression of the more than 60 late proteins follows DNA replication
• Latency is estabilished in dorsal root ganglion after the virus infects the dermal nerves
with subsequent retrograde axonal transport and stays dormant till reactivation.
6/7/2021 11
Biniyam Simeneh(MD)

12. HSV infection phases
Replication phase
HSV actively replicates
and spreads from cell to
cell.
Latency phase
With few exceptions viral
genes are silent, or at best,
randomly transcribed at a very
low frequency. Relatively
noninfectious
Reactivation phase
The virus recurs from
dormancy.
Recurrence:-viral shedding
only
Recrudesnce:-viral shedding
with symptoms
6/7/2021 12
Biniyam Simeneh(MD)

13. Transmission
• Transmission of HSV can occur during asymptomatic periods of viral shedding.
• HSV-1 is spread primarily through direct contact with contaminated saliva or other
infected secretions.
• HSV-2 is spread primarily by sexual contact.
• Mode of transmission:
• Skin-to-skin
• Skin-mucosa
• Mucosa-skin contacts
• Vertical
6/7/2021 13
Biniyam Simeneh(MD)

14. Epidemiology
• HSV-1
• Have a worldwide distribution affecting nearly 60-95% of human adults. While one-third of
the world’s population has experienced a symptomatic HSV infection.
• In children <10 years of age, ~80–90% of herpetic infections are caused by HSV-1.
• In crowded areas of the developing world, over 90% of children have antibody by the age of 5
years.
• No animal reservoirs or vectors for both HSV-1&2
• Traditionally used to be regarded as affecting the skin above the waist
• Recently HSV-1 has replaced HSV-2 as the major cause of genital herpes in young adults in
areas like US, Canada and the UK.
6/7/2021 14
Biniyam Simeneh(MD)

15. Epidemiology
• HSV-2
• Acquisition of HSV-2 correlates with sexual behavior and the prevalence of infection in one’s
potential sexual partners.
• The presence of HSV-2 can be used as an indirect measure of sexual activity.
• HSV-2 genital infections in children can be an indication of sexual abuse.
• Accounts 70-90% of genital herpes overall and 60-95% in sub-Saharan countries.
• The Pooled mean HSV-2 seroprevalence Mean (%) (95% CI) in Ethiopia is 27.3 (16.8-39.3)
• Seropositivity to HSV-2 is more common in women (25%) than in men (17%).
• Average risk of transmission for discordant couples of genital herpes is approximately 5 per
10,000 sexual contacts.
• Genital HSV infection increase risk of transmission and acquisition of HIV.
6/7/2021 15
Biniyam Simeneh(MD)

16. HSV disease domains
Primary initial infection
• Occurs in a previously seronegative
individual and is often subclinical.
• If clinically overt, the symptomatology
is greater than recurrence.
• Genital primary disease is more
commonly symptomatic than oral.
• Without pre-existing antibodies to
HSV-1 or HSV-2
Non-primary initial infection
• Infection with one HSV type in an
individual with pre-existing antibodies
to the other HSV type or HSV
infection at a new site in a patient with
a history of infection at a different site.
• Tends to be milder than primary
infection
• Marked by a shorter duration, fewer
lesions, less pain, and a decreased
likelihood of complications.
6/7/2021 16
Biniyam Simeneh(MD)

17. HSV disease domains
Recurrent infection
• Occurs when virus replicate in sensory ganglia
• HSV-1 reactivates from trigeminal ganglia
• HSV-2 reactivates from lumbosacral ganglia
• Can be triggered by several factors
• Infections
• Trauma
• Emotional stress
• Surgeries
• Laser ablation
• Premenstrual periods
• Smaller sizes of the lesions, close grouping of
lesions and absence of systemic symptoms
differentiates recurrence from primary infections
Sub clinical viral shedding
• More common in HSV-2 infections
• More common in the first year of
infection
6/7/2021 17
Biniyam Simeneh(MD)

18. Immunology of HSV
• TLR-2 binds with viral glycoproteins and results in proinflammatory cytokine release
• TLR-3 binds with viral dS RNA and initiates IFN-β and IFN-λ production
• TLR-9 binds with viral genomic DNA and subsequent IFN-α production
• NK cells release IFN-γ and destroy virus-infected cells
• Intracellular nucleic acid sensors detect HSV DNA and stimulate type I IFN (IFN-α and -β)
Innate immunity
• Recruitment and activation of CD4+ T cells by dendritic cells
• CD4+ T cells recruit CD8+ T cells by releasing IFN-γ.
• CD8+ T cells kill infected cells by perforins and Fas-mediated pathways.
• Memory cell formation
• B cell recruitment by CD4+ T cells and antibody production.
• Regulatory T cells present but exact role in HSV is not clear
Adaptive immunity
6/7/2021 18
Biniyam Simeneh(MD)

19. Mechanisms of
immunoevasion
• TLR-2 signal reduction by viral proteins(eg:-ICP0 protein of HSV-1)
• Degradation of mRNA by the VHS(virion host shutdown)
• Reduced expression of CD1d by APC
• Reduced langerin expression with subsequent apoptosis LCs
• Induction of Fas-ligand on monocyte/macrophage resulting in apoptosis of T cells
and NK cells
• Induction of expression of SOCS-1(suppressor of cytokine signaling-1) by
keratinocytes nullifying the effects of IFN-γ
6/7/2021 19
Biniyam Simeneh(MD)

20. Clinical
manifestations
of HSV
infections
• Orolabial herpes (Herpetic gingivostomatitis)
• Primary and Recurrent
• Eczema herpeticum
• Herpetic whitlow
• Herpes gladiatorum /Herpes rugbiorum
• HSV folliculitis
• HSV-associated erythema multiforme
• Genital herpes
Predominantly mucocutaneous
• HSV encephalitis(Mollaret's meningitis)
• Ocular HSV
• Disseminated HSV in the immunocompromised
• Neonatal Herpes
Predominantly extracutaneous
6/7/2021 20
Biniyam Simeneh(MD)

21. 1° Orolabial herpes(herpetic gingivostomatitis)
• The most common clinical manifestation of primary infection by HSV- 1.
• The incubation period ranges from 3-7 days
• Occur mainly in infants and young children and is usually subclinical and may rarely produce a painful
vesicular stomatitis.
• Characterized by ulcerative lesions of the gingiva and mucous membranes of the mouth , often with perioral
vesicular lesions
• The symptoms may resemble aphthous stomatitis and may have ulceration of the hard and soft palate, tongue
and buccal mucosa
• Systemic symptoms like fever, malaise, myalgias and irritability with cervical LAP and odynophagia are
common symptoms
Epidemiology
• Lower incidence and prevalence in children living in temperate regions and higher income countries but up to
90% of elderlies are seropositive
• Most cases occur in children between 1 and 5 years of age. And no seasonal predilection.
6/7/2021 21
Biniyam Simeneh(MD)

22. Clinical presentation
• The stomatitis begins with fever, which may be high, malaise, restlessness and excessive dribbling.
Drinking and eating are very painful, and the breath is foul smelling.
• Swollen and inflamed gums which bleed easily
• Vesicles presenting as white plaques are present on the tongue, pharynx, palate and buccal mucosa.
• Ulceration of the plaques with formation of a yellowish pseudo membrane., mild lesions heal with
in a week, but severe lesions may take longer to heal. And becomes dormant in the trigeminal
ganglia. And may recur as recurrent stomatitis or herpes labialis.
• Painful regional LAP
Developmental
stage
• Erythema
• Papule
Disease stage
• Vesicle
formation
• Ulcerations
and crusting
Resolution stage
• Flaking
• Residual
swelling
Prodromal stage
• Regional LAP
• Flu like Sxs
6/7/2021 22
Biniyam Simeneh(MD)

23. Gingivostomatitis • Widespread labial lesions
6/7/2021 23
Biniyam Simeneh(MD)

24. Differential diagnosis
Streptococcal infections
Diphtheria
Candidiasis
Aphthosis
Coxsackie infections including herpangina
• Hand, foot, and mouth disease (HFMD)
Behcet syndrome
Stevens–Johnson syndrome
6/7/2021 24
Biniyam Simeneh(MD)

25. Complications
Dehydration
Herpetic whitlow
Eczema herpeticum
Lip adhesions
Secondary bacterial infections
Hsv encephalitis, esophagitis, epiglottitis and pneumonitis,transverse myelitis
6/7/2021 25
Biniyam Simeneh(MD)

26. Investigations
• Isolation of virus is most successful when lesions are cultured during the
vesicular stage and when specimens are taken from immunocompromised
patients or from patients suffering from a primary infection.
Culture and/or PCR of the
virus from vesicle fluid
• Differentiate a primary episode from a recurrent infection
Serology
Immunofluorescence
• Helpful in rapid diagnosis of herpesvirus infections, less sensitive.
• performed by scraping the base of a freshly-ruptured vesicle and staining
the slides with Giemsa or Wright stain
Tzanck smear
6/7/2021 26
Biniyam Simeneh(MD)

27. Management
• Mild uncomplicated cases need no intervention
• Anesthetic mouth washes to relive pain
• Topical antiseptics to reduce secondary bacterial infections
• Antivirals are indicated in all immunocompromised patients,
immunocompetent patients who present within 96 hours, those unable to
drink and those with severe pain
• First line treatment choices
• Acyclovir 200mg 5xdaily po for 5 days or more
• Acyclovir 800mg Bid po
• 15mg/kg of acyclovir five times daily in oral suspension formulation
• Valaciclovir 1000mg Bid po for 10 days
6/7/2021 27
Biniyam Simeneh(MD)

28. Biniyam
Simeneh(MD)
6/7/2021 28
Supportive
cares
Hydration
Pain control
Prevention of lip
adhesions

29. Indications for inpatient treatment
• Inability to maintain adequate hydration
• Immunocompromisation
• Eczema herpeticum
• Herpetic encephalitis, epiglottitis, pneumonitis and keratitis
• For patients with any of the above acyclovir 5mg/kg Tid in iv
formulations is recommended
• Dose adjustment should be considered in patients with renal
impairment
• In such circumstances slow infusion over 1 hour with adequate hydration is
recommended
6/7/2021 29
Biniyam Simeneh(MD)

30. Recurrent orolabial herpes
• Reactivation of the latent virus can cause asymptomatic shedding or clinically evident recurrent disease.
• Herpes labialis (cold sore) is a recurrence of oral HSV. The most frequent site is at the vermilion border
of the lips
• Recurrent intra-oral ulcers are rarely caused by HSV.
• May be prevented or reduced in intensity by using a topical sunscreen
Clinical features
• Itching or burning precedes by an hour or two the development of small closely grouped vesicles on an
inflamed base.
• Constitutional symptoms are rare
• Redness appears followed by papules and then vesicles, These vesicles then burst, weep, dry, scab and
then heal
• They occur most frequently on the face, particularly around the mouth
• Recurrences tend to be in the same region, but not always on the identical site.
6/7/2021 30
Biniyam Simeneh(MD)

31. Complications
Erythema multiforme (herpes‐associated erythema multiforme)
• In 65% of patients with recurrent erythema multiforme, there is a history of herpes labialis.
• The herpes labialis usually precedes the EM by several days to 2 weeks
• Virus is not seen in EM lesions but viral antigens(gB) and HSV DNA has been demonstrated in EM skin lesions
• Treatment of recurrent HSV during prodromal stage has been shown to halt progression to EM
• A 6-month course of prophylactic acyclovir can be used for recurrent EM
Bells palsy
• Believed to be due to viral reactivation including VZV
• Antiviral use has benn shown to fasten recovery
Recurrent lymphocytic meningitis
Encephalitis
6/7/2021 31
Biniyam Simeneh(MD)

32. Management
• Mild attacks may not need any treatment.
• First line
• 5% topical acyclovir and a thin hydrocolloid dressing
• Topical penciclovir
• Oral acyclovir
• Second line
• Acyclovir, long-term, prophylactic 200–400 mg twice daily for 4–6 months.
• Third line
• Acyclovir Iv
• Penciclovir Iv
• Foscarnet
• Cidofovir Iv
• Imiquimod topical
6/7/2021 32
Biniyam Simeneh(MD)

33. Eczema herpeticum
• Results from widespread infection following inoculation of virus to skin damaged by eczema.
• Usually a manifestation of primary HSV-1 infection in a child with atopic dermatitis.
• Severity of eczema herpeticum ranges from mild to fatal, with mortality rates of up to 10% being
reported in the era before the advent of antivirals.
• Predisposing factors
• Atopic dermatitis
• Darriers disease
• Bulous disorders
• Icthyotic disorders
• Myosis fungoides
• Skin burn
• Psoriasis
6/7/2021 33
Biniyam Simeneh(MD)

34. Clinical presentation
• Vesicles, which rapidly become pustular, erupt in massive crops. May be confined to the abnormal
skin but often they tend to involve a wider area and may resemble lesions of chicken and small pox
• The vesicles rupture quickly leaving small round superficial erosions which weep and crust
• Impetiginization may be there as a result of bacterial infections of the lesions
• Grossly edematous face
• The skin is painful and generally erythematous.
• High fever with debilitating constitutional symptoms and Regional LAP
• If possible, blister fluid or a surface swab should be analyzed for HSV.
6/7/2021 34
Biniyam Simeneh(MD)

35. A man with atopic dermatitis. Note the
monomorphic vesicles and punched
out erosions
• Confluent and discrete crusted erosions
associated with erythema and edema of the
face of a child
6/7/2021 35
Biniyam Simeneh(MD)

36. Management
• Patients with atopic eczema, especially those with a history of eczema herpeticum,
should avoid close contact with relatives and friends with active herpes simplex.
• Treatment of bacterial superinfection and cautious use of topical steroids in
treating the underlying conditions
• First line
• Oral acyclovir
• Oral valaciclovir
• Oral famciclovir
• Second line
• Iv acyclovir
• Frequently recurrent disease may benefit from low‐dose prophylactic acyclovir or
valaciclovir
6/7/2021 36
Biniyam Simeneh(MD)

37. Herpetic whitlow
• HSV infection of the finger, occur by inoculation of the virus through a break in
the skin barrier.
• Often misdiagnosed as a bacterial infection
• Has a bimodal age distribution affecting children less than 10 years of age and
young adults between 20 and 30 years of age
• Historically in dental and medical personnel who did not use gloves
• Is caused by HSV-1 in children, and in adults, it can be caused by either HSV-1 or
HSV-2.
• The natural history of untreated uncomplicated herpetic whitlow is complete
resolution within three weeks.
• The diagnosis of herpetic whitlow is clinical.
6/7/2021 37
Biniyam Simeneh(MD)

38. Clinical manifestation
• The lesions are initially clear but become turbid, yellow, and appear
purulent with an erythematous base and can coalesce to form larger blisters.
• The lesions may spread around the paronychial folds, and satellite lesions
may appear
• When the blisters are unroofed a non purulent fluid is exuded, and the
underlying tissue has a honeycomb appearance which is characteristic of
herpetic whitlow.
• Associated tingling and burning sensation of the hand disproportionate to
the clinical findings
• Occasional flu like symptoms with epitrochlear and axillary LAP
• Unlike acute paronychia or pulp abscess the pulp space is not tense
• Single digit involvement is the rule
6/7/2021 38
Biniyam Simeneh(MD)

39. 6/7/2021 39
Biniyam Simeneh(MD)

40. Management
Conservative measures
• Rest
• Elevation
• Anti-inflammatory drugs
• Dry dressings
Treatment of secondary bacterial infection
Oral acyclovir has been suggested in a total daily dose of 1600-2000mg during prodromal stage in
immunocompetent individuals
Iv acyclovir is only indicated in immunocompromised individuals or in those with disseminated
HSV with herpetic whitlow
6/7/2021 40
Biniyam Simeneh(MD)

41. Herpes gladiatorum /Herpes rugbiorum
• Is a skin infection that classically occurs on the face, neck, and arms of wrestlers and
other contact sport athletes(rugby players)
• Presents initially with a vesiculopustular rash on an erythematous base that progresses to
ulceration
• May be misdiagnosed as folliculitis or impetigo
• Any wrestler wth episode of orolabial herpes should be on suppressive antiviral therapy
• Distribution reflects sites of contact with another athlete’s skin lesions and is sometimes
widespread
6/7/2021 41
Biniyam Simeneh(MD)

42. Herpetic sycosis
• A rare manifestation of herpesvirus infections.
• HSV is less likely than VZV to target the hair follicle.
• Erythematous papules, pustules, vesicles, papulo-vesicles, and plaques are the most
common presentations of herpetic folliculitis
• Reported most in immunocompromised patients.
• The possibility of a herpetic sycosis of the beard must be considered in the case of non-
response to antibiotic or antifungal treatment.
6/7/2021 42
Biniyam Simeneh(MD)

43. Herpetic sycosis
• Multiple vesicular and pustular
follicular lesions of the beard, yellow
crusting lesions and an underlying
erythema.
6/7/2021 43
Biniyam Simeneh(MD)

44. HSV-associated erythema multiforme
• The development of EM secondary to HSV infection is thought to involve a cell-mediated
immune process directed against viral antigens deposited in lesional skin.
• 15% to nearly all patients with EM, especially individuals with recurrent EM (60%)
• The lesions are usually disseminated & symmetrically occur on acral extremities & face
• There is grouping of the lesions over the elbow and knees, as well as nail fold
involvement
• Photodistribution & isomorphic phenomenon can occur
• Mucosal involvement is usually mild & restricted to the mouth
• Constitutional symptoms are rare, & the skin lesions heal without scarring
6/7/2021 44
Biniyam Simeneh(MD)

45. Genital herpes
• Infection of the genital skin or mucosa with herpes simplex virus which can be primary or
recurrent
• Is a major global health problem and is the most common cause of genital ulceration.
• Infection with HSV-2 are more symptomatic than HSV-1 infections.
• Most cases of recurrent genital herpes are caused by HSV-2
• Majority of the cases are acquired from other asymptomatic sexual partners
6/7/2021 45
Biniyam Simeneh(MD)

46. Epidemiology
• Two of the most important demographic factors determining HSV-2
seropositivity are age and gender.
• A consistent finding throughout the world is that HSV-2 infection is more
common in women.
• women usually acquire HSV-2 at a younger age than men.
• Antibodies are rarely detected before puberty, HSV-2 prevalence increases
with increasing age.
• HSV-2 is more common in individuals from lower socio-economic
backgrounds
• HSV accounts for between 13–84% of genital ulcers
6/7/2021 46
Biniyam Simeneh(MD)

47. Transmission
• The overall transmission rate for HSV-2 infection to a seronegative partner is
estimated to be 3–12% per year with higher rates noted in men.
• Newly acquired HSV genital infection, the median duration of the sexual
relationship was 3.5 months and the median number of sex acts before
transmission was 40.
• Increased risk of transmission during the first year of the infection.
• Asymptomatic viral shedding is extremely common, occurring in up to 30% of
days.
6/7/2021 47
Biniyam Simeneh(MD)

48. Clinical features
• Primary genital herpes
• Most patients are asymptomatic or have subclinical lesions
• When symptoms occur, they can be severe and prolonged
• The severity of initial genital herpes depends upon whether there is prior cross-reactive
immunity following infection with HSV-1 and systemic symptoms are common.
• In women, the genital symptoms include genital pain, dysuria, and a vaginal discharge, and on
examination, lesions may be noticed on the vulva, suprapubic area, perineum, perianal area,
buttocks, thighs, vagina, cervix, and anal canal.
• In males, lesions can occur anywhere on the penis, including the urinary meatus, scrotum,
suprapubic area, perineum, perianal area, buttocks, thighs, and anal canal
6/7/2021 48
Biniyam Simeneh(MD)

49. Clinical features
• Lesions usually commence as erythema, and then painful vesicles or blisters occur. These then
rupture to leave painful weeping crust which heal eventually
• Lesions on the cervix, although not often visualized, may be atypical and the entire cervix may be
erythematous or even appear to be necrotic.
• Inguinal lymph nodes are usually enlarged and painful.
• Urethritis may be the only manifestation of the infection in some males, but the dysuria tends to be
very severe.
• Patients with proctitis usually present with rectal pain, tenesmus, and rectal discharge.
• Symptoms are generally more severe in women than in men.
• Pharyngeal infection may occasionally be seen in conjunction with genital lesions in people who
practice oro-genital sex.
6/7/2021 49
Biniyam Simeneh(MD)

50. Clinical images
6/7/2021 50
Biniyam Simeneh(MD)

51. Clinical features
• Recurrent genital herpes
• Systemic symptoms are uncommon, and the duration of episodes is
shorter.
• Preceded by prodromal symptoms consisting of pain, burning, itching,
paresthesia or sacral neuralgia in the genital area, thigh, buttocks, or
legs. occur in up to 50% of recurrence.
• A single lesion or a small crop of lesions that occur particularly on the
keratinized skin of the vulva, perianal area, thigh, buttock, or penis.
• Internal lesions are not common.
• Tender inguinal LAP
6/7/2021 51
Biniyam Simeneh(MD)

52. Diagnosis
• Often clinical particularly in primary infections.
• Matted lymph nodes and rubbery, non-tender lymph nodes should always raise the
suspicion of a non-herpetic STIs
• All genital ulcers, irrespective of their appearance, should be swabbed for HSV.
• Culture
• PCR
• Tzanck smear
• Immunofluorescence or ELISA
• Serology
6/7/2021 52
Biniyam Simeneh(MD)

53. Management
• Reduce duration
• Reduce severity of symptoms
• Hasten healing
• Prevent new lesion formation
• Reduce/prevent complications
The objective in management of primary genital herpes is
to
• Reduce duration and severity of prodrome
• Reduce further recurrence
Objectives of managing recurrent genital herpes is to
6/7/2021 53
Biniyam Simeneh(MD)

54. Antiviral treatment for primary genital herpes
• Antivirals are recommended for those presenting:-
• First episode of genital herpes
• Within 5 days of onset
• Vesicles or ulcerations still present
• Those with complications(meningitis, urinary problems, sacral radiculomyelitis)
• Acyclovir 400mg po Tid or 200mg po 5x/d
• Valaciclovir 1g po bid
• Famciclovir 250mg po Tid
• Therapy should be administered for 7 to 10 days.
• Parenteral therapy should be initiated in patients with genital herpes infection accompanied by more severe clinical
manifestations
• Adjuvant therapies like analgesics and sitz bath may be beneficial to alleviate pain, urinary retention can be
treated with catheterization
6/7/2021 54
Biniyam Simeneh(MD)

55. Treatment of recurrent genital herpes
• Oral antiviral therapy is often administered to patients with recurrent genital infection to
• Reduce the severity of symptoms,
• Decrease the risk of recurrences,
• Reduce the risk of transmission to an uninfected sexual partner.
• Episodic therapy
• Treating outbreaks with antivirals starting at the prodrome
• Acyclovir 800mg tid for 2 days, 400mg Tid for 5 days or 800 mg Bid for 5 days
• Chronic suppressive therapy
• Administration of daily antivirals in those with very frequent and severe recurrence and in those having
discordant partner to reduce transmission
• Acyclovir 400mg bid, famciclovir 250 mg Bid or Valaciclovir 500mg or 1g/day
6/7/2021 55
Biniyam Simeneh(MD)

56. HSV in pregnancy
• During pregnancy, the major concern of maternal HSV infection is transmission to the fetus, as
neonatal infection can result in serious morbidity and mortality.
• Viral shedding can occur in the absence of maternal symptoms and lesions.
• Management strategies for women who have genital herpes during pregnancy include suppressive
antiviral therapy starting at 36 weeks to reduce the risk of recurrence at labor.
• Cesarean delivery for select women to reduce the risk of neonatal transmission.
• Acyclovir 400mg po Tid for 7-10 days for primary infections and restarted at 36 weeks. And
continued treatment in those infected at third trimester.
• Suppressive therapy for those with prior history of genital HSV starting from the 36th week.
6/7/2021 56
Biniyam Simeneh(MD)

57. Neonatal Herpes
• Usually transmitted during delivery. A typical sign is vesicular eruption, which
may be accompanied by or progress to disseminated disease.
• Occurs in 1 out of every 3200 to 10,000 live births
• Has high mortality and significant morbidity, HSV type 2 causes more cases than
HSV type 1.
• Classified into three main categories.
1.Localized skin, eye, and mouth (SEM)-39%
2.CNS with/without SEM-35%
3.Disseminated disease-29%
• Transmission can be intrauterine, perinatal or postnatal.
6/7/2021 57
Biniyam Simeneh(MD)

58. Clinical manifestation
• May appear benign at onset of illness.
• SEM disease usually presents in the first two weeks of life but may occur at any
time during the first six weeks of life.
• Localized skin disease is associated with coalescing or clustering vesicular lesions
with an erythematous base
• Vesicles may begin or cluster at the presenting part of the body, or at sites of
localized trauma, such as scalp monitor sites.
• Skin vesicles also may appear late in the course of disseminated disease.
6/7/2021 58
Biniyam Simeneh(MD)

59. Neonatal herpes(SEM)
6/7/2021 59
Biniyam Simeneh(MD)

60. Diagnosis of SEM
• The diagnosis of SEM disease is based upon the following clinical and
laboratory parameters:
• Localized skin disease with the characteristic vesicular lesions with eye
involvement; and/or localized ulcerative lesions of the mouth, palate, and
tongue, AND
• Absence of CNS disease (including negative CSF HSV PCR) or other organ
system involvement, AND One or more of the following:
• Isolation of HSV in surface cultures or skin lesion swabs/scraping collected >12 to 24
hours after birth (present in >90 percent)
• Positive HSV DNA PCR in the blood or plasma (present in 75 to 80 percent and does not
necessarily signify disseminated disease)
• Detection of HSV in skin lesion scraping by DFA (less sensitive than viral culture)
6/7/2021 60
Biniyam Simeneh(MD)

61. Management
• Supportive measures
• All forms of neonatal herpes should be treated with acyclovir
• Acyclovir is given to those neonates with virologically proven HSV, those
with clinically suspected HSV and those who are at risk of acquiring HSV
from the mother.
• Acyclovir 60 mg/kg per day intravenously divided every eight hours. for a
minimum of 14 days for SEM
6/7/2021 61
Biniyam Simeneh(MD)

62. Disseminated HSV
• Typical oral or genital lesions are often not present
• Risk factors for severe disease include
• HIV infection,
• Malignancy,
• Organ and hematopoietic stem cell transplantation,
• Malnutrition,
• Burn and skin disorders,
• Pregnancy,
• Advanced age
• Affects organs like the brain and meninges, the eyes, respiratory tracts
and liver.
6/7/2021 62
Biniyam Simeneh(MD)

63. HSV in HIV infected individuals
• Genital HSV increases the risk of HIV transmission
• Patients with advanced HIV infection (CD4 count <200 cells/microL) are at
increased risk for recurrent and extensive HSV infections.
• HSV infections can occur anywhere on the skin or mucosal surfaces, often
presenting as extensive oral or perianal ulcers.
6/7/2021 63
Biniyam Simeneh(MD)

64. Acyclovir
resistant HSV
infections
• Acyclovir-resistant HSV infections are often seen
in immunocompromised patients
• Resistant isolates result in severe, debilitating
mucosal disease, and visceral dissemination.
• Should be considered whenever
• Lesions persist for more than 1 week without
appreciable decrease in size
• When they develop an atypical appearance
• When new satellite lesions develop after 3 to
4 days of therapy
• The options for treatment include cidofovir and
foscarnet, but both are very nephrotoxic
Biniyam Simeneh(MD) 6/7/2021 64

65. Non
dermatologic
HSV
manifestations
6/7/2021 Biniyam Simeneh(MD) 65
• Keratitis
• Acute retinal necrosis
• Conjuctivitis and blepharitis
• Chorioretinitis
Occular manifestations
• Encephalitis
• Aseptic meningitis(mollarets meningitis)
• Bell's palsy
Neurologic manifestations
Fulminant hepatitis

66. Investigations for HSV infections
CBC
• May have lymphocytosis with atypical lymphocytes resembling infectious
mononucleosis(downey cells)
PCR
• Detection of HSV with PCR is more sensitive than culture
• Sensitivity of the PCR assay is dependent on the amount of virus present
• Standard for the diagnosis of HSV meningitis and encephalitis.
• Can be utilized to test vitreous fluid for HSV in the setting of acute retinal
necrosis.
6/7/2021 66
Biniyam Simeneh(MD)

67. Investigations for HSV infections
Viral culture
• To obtain an adequate specimen for PCR or culture, the vesicle should be
"unroofed" with a sterile swab. The base of the ulcer should be swabbed to isolate
epidermal cells, which contain HSV
• Immediate transportation of the samples but can be stored for up to 9 hours at 4°C
• Cytopathic effects appear in the selected cell line within 24 to 48 hours
Direct fluorescent antibody assay
• Is an antigen detection test that can be performed in patients with active
mucocutaneous lesions.
• Provides rapid results.
6/7/2021 67
Biniyam Simeneh(MD)

68. Investigations for HSV infections
Tzanck smear
• Performed by smearing material scraped from the base of a vesicle onto a slide and
staining it with Wright's stain.
• Demonstrates the characteristic cytopathic effect (multinucleate cells with or
without intranuclear inclusions)
• Limited utility because of its poor sensitivity and specificity
Serology
• Can distinguish between HSV-1 and HSV-2 but do not differentiate between sites
of infection
• Has a limited role in the diagnosis of HSV-1 infection
6/7/2021 68
Biniyam Simeneh(MD)

69. Tzanck smear
6/7/2021 69
Biniyam Simeneh(MD)

70. Antivirals used in HSV infection
• Acyclovir
• Mechanism of action
• Interferes with DNA polymerase to inhibit DNA replication via chain
termination
• Is converted to acyclovir monophosphate by virus-specific thymidine
kinase then further converted to acyclovir triphosphate by other cellular
enzymes.
• Inhibits DNA synthesis and viral replication by competing with
deoxyguanosine triphosphate for viral DNA polymerase and being
incorporated into viral DNA.
6/7/2021 70
Biniyam Simeneh(MD)

71. Acyclovir
• Pharmacodynamics and Pharmacokinetics
• Absorption, Oral: Poorly absorbed; absorption improves with multiple
small doses
• Distribution: Widely (eg, brain, kidney, lungs, liver, spleen, muscle,
uterus, vagina, CSF)
• Protein binding: 9% to 33%
• Excretion: Urine (62% to 91% as unchanged drug and metabolite)
• Can cross the placenta and is secreted in breast milk
6/7/2021 71
Biniyam Simeneh(MD)

72. Acyclovir
• Acute kidney injury
• Neurotoxicity
• Thrombotic microangiopathy
• Dermatologic: Pruritus (≤2%), skin
rash (≤2%), urticaria (≤2%)
Adverse Reactions
• Reduced or absent thymidine kinase
• Altered thymidine kinase activity
Mechanism of resistance
6/7/2021 72
Biniyam Simeneh(MD)

73. Antivirals
used in HSV
infection
Valacyclovir
• Valyl ester of acyclovir and is converted in vivo
to acyclovir.
• Has three to fivefold greater oral bioavailability
• The main route of elimination is renal, and
dose modification is recommended for patients
with a creatinine clearance below 30
mL/min/1.73 m2.
• Safe during pregnancy
Penciclovir
Famciclovir
6/7/2021 73
Biniyam Simeneh(MD)

74. HSV vaccine development
• Currently no licensed preventative or therapeutic anti-HSV vaccine.
• Viral Glycoprotein D has been of important interest to develop a vaccine.
• Replication-defective HSV-2 strain deleted in two genes essential for virus
replication (UL5 and UL29) (dl5-29) that generates neutralizing antibodies
and low T cell responses.
• A live-attenuated HSV-2 virus deleted in gD (∆gD-2)
• HSV-1 replication-competent-controlled viruses
6/7/2021 74
Biniyam Simeneh(MD)

75. References
• Bolognia, J., Schaffer, J., Cerroni, L. and Callen, J., 2019. Dermatología. 4th ed. Barcelona: Elsevier, pp.1400-1407.
• Griffiths, C., Barker, J., Bleiker, T., Chalmers, R. and Creamer, D., 2016. Rook's Textbook of Dermatology, 4 Volume Set. 9th ed. West Sussex: Wiley, pp.25.15-
25.23.
• Kang, S., Amagai, M., Bruckner, A., Enk, A., Margolis, D., McMichael, A. and Orringer, J., 2019. Fitzpatrick's dermatology in general medicine, 9e. 9th ed. New
York, N.Y.: McGraw-Hill Education LLC, pp.3021-3034.
• Fields, B., Knipe, D. and Howley, P., 2013. Fields virology. 6th ed. Philadelphia [u.a.]: Wolters Kluwer | Lippincott Williams & Wilkins, pp.1802-1897.
• Hewlett, M., Camerini, D., Bloom, D. and Wagner, E., 2008. Basic virology. 3rd ed. 350 Main Street, Malden, MA 02148-5020, USA 9600 Garsington Road, Oxford
OX4 2DQ, UK 550 Swanston Street, Carlton, Victoria 3053, Australia: Blackwell Publishing Ltd, pp.334-351.
• Hodinka, R., Loeffelholz, M., Pinsky, B. and Young, S., 2016. Clinical virology manual. 5th ed. Washington DC: ASM press, pp.363-372.
• Norkin, L., 2010. Virology. 1st ed. Washington, DC: ASM Press, pp.471-520.
• Campanelli, A., Marazza, G., Stucki, L., Abraham, S., Prins, C., Kaya, G., Piguet, V. and Saurat, J., 2004. Fulminant Herpetic Sycosis: Atypical Presentation of
Primary Herpetic Infection. Dermatology, 208(3), pp.284-286.
• Epidemiology of herpes simplex virus type 2 in sub-Saharan Africa: Systematic review, meta-analyses, and meta-regressions Harfouche, Manale et al.
EClinicalMedicine, Volume 35, 100876
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920455/Vaccine Development for Herpes Simplex Viruses: A Commentary of Special Issue
6/7/2021 75
Biniyam Simeneh(MD)

76. References
• Johnston, MD, MPH, C. and Wald, MD, MPH, A., 2021. UpToDate. [online] Uptodate.com. Available at: <https://www.uptodate.com/contents/epidemiology-
clinical-manifestations-and-diagnosis-of-herpes-simplex-virus-type-1-
infection?search=herpes%20simplex&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1> [Accessed 3 June 2021].
• Virology-online.com. 2021. Herpes Simplex Viruses. [online] Available at: <http://virology-online.com/viruses/HSV.htm> [Accessed 3 June 2021].
• O Ayoade, MD, F. and Stuart Bronze, MD, M., 2021. Herpes Simplex: Background, Microbiology, Pathophysiology. [online] Emedicine.medscape.com. Available
at: <https://emedicine.medscape.com/article/218580-overview> [Accessed 3 June 2021].
6/7/2021 76
Biniyam Simeneh(MD)

77. •Thank you
6/7/2021 77
Biniyam Simeneh(MD)