HUMAN

HERPESVIRUSES
Christopher Downing, Natalia Mendoza, Karan Sra and Stephen K. Tyring
HERPES SIMPLEX VIRUSES (HSV-1 AND
HSV-2)
• Virus replicates at the mucocutaneous site of infection and then
travels by retrograde axonal flow to the dorsal root ganglia, where it
establishes latency until reactivation.
• HSV can be reactivated either spontaneously or by a trigger such as
emotional stress, ultraviolet light, fever, menstruation,
immunosuppression, surgical or dental procedures, and other local
tissue damage.
• Typically, reactivation produces vesicular lesions localized to the skin.
• However, viremia followed by widespread internal organ involvement
can occur in immunocompromised hosts
 Clinical features

• Asymptomatic infection is very common.

• In primary infections, symptoms typically occur within 3 to 7
days after exposure. Painful, grouped vesicles appear on an
erythematous base and may become umbilicated, followed by
progression to pustules, erosions, and/or ulcerations with a
characteristic scalloped border. Crusting of lesions and
resolution of symptoms typically occurs within 2 to 6 weeks.

• Recurrent lesions appear most often on the vermilion border

of the lip (Fig. 80.1C). Less common sites are perioral skin,
nasal mucosa, cheek, and attached oral mucosa overlying
bone (e.g. gingiva, hard palate). In immunocompromised
hosts, recurrent herpes infections can involve intraoral
movable mucosa not overlying bone (see Fig. 72.1).
• Primary and non-primary initial genital herpes
infections are frequently asymptomatic but
(especially with the former) can also present as
an excruciatingly painful, erosive balanitis,
vulvitis, or vaginitis. In women, lesions often also
involve the cervix, buttocks, and perineum and
may be associated with inguinal adenopathy and
dysuria (Fig. 80.3). Genital lesions in men
typically occur on the glans or shaft of the penis,
and the buttocks are occasionally affected.
• Systemic complaint and complications are more
common in women. Extragenital lesions, urinary
retention, and aseptic meningitis occur in 20%,
10–15%, and 10% of affected women,
respectively7. In contrast, aseptic meningitis is a
rare complication of primary genital herpes
infection in men.
• viral culture
• direct fluorescent antibody assays (DFA; Fig 80.10),
• molecular techniques
• serology.
• A Tzanck smear of scrapings from early lesions, in
particular the base/edges of a freshly unroofed
vesicle, reveals multinucleated epithelial giant cells.
HSV-1 cannot be differentiated from HSV-2.
• Enlarged, slate-gray keratinocyte nuclei with
margination of chromatin represent an early
histologic finding. This is followed by intraepidermal
vesiculation associated with ballooning degeneration
of keratinocytes, which is most prominent at the
vesicle base.
• Orolabial herpes can sometimes be
confused with aphthous stomatitis,
erythema multiforme major or Stevens–
Johnson syndrome, herpangina (posterior
pharnynx)
• and other coxsackievirus infections,
pharyngitis (e.g. due to EBV), oral
candidiasis, Behçet disease, and
chemotherapy-induced mucositis.
• Trauma, syphilitic chancres, chancroid, and
lymphogranuloma venereum are
considerations in the differential diagnosis
of genital herpes (see Ch. 82).
Treatment
• Treatment of recurrent episodes of orolabial herpes in immunocompetent persons include
valacyclovir 2 g twice daily for 1 day, a single 1.5-g dose of famciclovir, and the topical treatments
listed in Table
• For treatment of primary and recurrent genital herpes, oral antivirals are the agents of choice (see
Table 80.4).
• Intravenous acyclovir is indicated for neonatal HSV infection, severe infections in
immunocompromised hosts, severe eczema herpeticum, and patients with systemic complications.
• Foscarnet is the only antiviral drug approved by the FDA for treatment of acyclovir-resistant HSV
(see Fig. 127.10) or Cidofovir.
• ual abstinence is the only method for absoluteprevention of genital herpes, which can be
transmitted even with the use of condom
• GEN-003, a therapeutic vaccine under investigation for genital HSV-2 infection, was found in a
phase I/IIa clinical trial to reduce the rates of outbreaks and asymptomaticviral shedding.
• Rout of transmission: airborne droplets, direct contact with vesicular fluid
• Incubation period is 11–20 days.
• The affected individual is infectious from 1–2 days before skin lesions appear until all the vesicles have crusted.
• During varicella infection, primary viremia occurs after an initial 2–4 days of viral replication within regional lymph
nodes. A cycle of viral replication in the liver, spleen, and other organs is then followed by a secondary viremia,
which seeds the entire body 14–16 days postexposure.
• During this period, the virus enters the epidermis by invading capillary endothelial cells. VZV subsequently travels
from mucocutaneous lesions to dorsal root ganglion cells, where it remains latent until reactivation at a later time.
• Herpes zoster appears upon reactivation of latent VZV, which may occur spontaneously or be induced by stress,
fever, radiation therapy, local trauma, or immunosuppression. During a herpes zoster outbreak, the virus continues
to replicate in the affected dorsal root ganglion and produces a painful ganglionitis. Neuronal inflammation and
necrosis can result in a severe neuralgia that intensifies as the virus spreads down the sensory nerve.
• Fluid from herpes zoster vesicles can transmit VZV to seronegative individuals, leading to varicella but not herpes
zoster.
Clinical features
Varicella
• Eruption of pruritic, erythematous macules and papules, which starts
on the scalp and face, and then spreads to the trunk and extremities
-> Lesions rapidly evolve over 12 hours into 1–3 mm clear vesicles
surrounded by narrow red halos (“dew drops on a rose petal”) there
is often involvement of the oral mucosa. Sparing of the distal and
lower extremities is common. Older vesicles evolve to form pustules
and crusts, with individual lesions healing within 7–10 days. The
presence of lesions in all stages of development is a hallmark of
varicella.

• Maternal varicella during the first 20 weeks of pregnancy is

associated with a ~2% risk of congenital varicella syndrome (varicella
embryopathy).
• Possible congenital defects include a low birth weight, cutaneous
scarring, ocular abnormalities, cortical atrophy, psychomotor
retardation, and hypoplastic limbs. Children whose mothers had
varicella during pregnancy may also develop zoster early in life
without ever having extrauterine varicella. Severe neonatal varicella,
in which amelioration by maternal antibodies is lacking, can occur
when maternal varicella develops between 5 days before and 2 days
after delivery.
Zoster
• In >90% of patients, herpes zoster begins with a prodrome of pruritus,
tingling, tenderness, hyperesthesia, and/or intense pain, which can mimic a
myocardial infarction, surgical abdomen, or toothache. lesions,., most
patients develop a painful eruption of grouped vesicles on an erythematous
base in a dermatomal distribution (Figs 80.14–80.16); the lesions can involve
more than one contiguous dermatome and occasionally cross the midline.
Edematous papules and plaques may precede the appearance of vesicles, and
progression to pustules or bullae can occur (see Fig. 80.15). Any cutaneous
site may be affected, with the trunk representing the most common location,
followed by the face. VZV DNA can often be detected in the peripheral blood
and saliva of patients with herpes zoster, even after initiation of antiviral
treatment33,34.
• Herpes zoster usually resolves without sequelae in immunocompetent
children and young adults. However, the pain, cutaneous lesions, and
complications of herpes zoster become more severe with increasing age and
immune compromise. The most common complication is postherpetic
neuralgia.
• Other complications can include secondary bacterial infection, scarring,
meningoencephalitis, pneumonitis, and hepatitis.
• Cutaneous disorders that can develop within sites of previous herpes zoster,
including granulomatous (Fig. 80.17) and pseudolymphomatous Lesions..
Disseminated cutaneous disease, defined as more than 20 vesicles outside
the area of primary or adjacent dermatomes, and/or visceral involvement
occurs in ~10% of immunocompromised persons with zoster.
• Clinical diagnosis: history (previous varicella or vaccine
administration) and physical examination.
• A Tzanck smear, PCR or DFA.The latter two (but not the Tzanck smear)
can differentiate between HSV and VZV.
• Viral culture and serology (diagnostic of VZV if the convalescent
serum has at least a 4x increase relative to the acute serum.
DDx
• Varicella: vesicular viral exanthems (e.g. due to
coxsackieviruses),disseminated HSV infection, Pityriasis lichenoides et
varioliformis acuta (PLEVA), rickettsialpox, drug eruptions, bullous
insect bite reactions and scabies.
• Herpes zoster: zosteriform HSV infections, bacterial skin infections
(e.g. cellulitis, bullous impetigo), contact dermatitis, and
phytophotodermatitis.
Treatment and Prevention
Varicella
• antipyretics (e.g. acetaminophen), antihistamines, calamine lotion, and tepid baths.
• Oral acyclovir and valacyclovir are FDA-approved for the treatment of varicella in children (2–17 years of age) while acyclovir is
approved for adults (see Table 80.4).
• However, routine antiviral therapy is not recommended for otherwise healthy children with varicella due to the self-limited
disease course and modest benefits of treatment.
• Intravenous acyclovir is indicated for varicella in immunocompromised patients,
• Administration of varicella zoster immune globulin (125 U/10 kg, 625 U maximum) i.m. within 96 hours of varicella exposure is
recommended to provide passive prophylaxis to nonimmune immunocompromised individuals and pregnant women as well as
highrisk neonates (see above)
• Prophylactic oral acyclovir administration with usual varicella dosing for 1 week, starting 7–10 days after exposure.

• Postexposure varicella vaccination (within 72–120 hours) may prevent or modifydisease in nonimmune individuals who are ≥12
months of age, immunocompetent, and eligible to receive this live attenuated vaccine (see below). Because this is a live viral
vaccine, administration is contraindicated during pregnancy and in individuals with immunosuppression
• Live attenuated VZV vaccine (Oka strain; Varivax®): two doses of the vaccine, routinely given at ages 12–15 months and 4–6
years.
Herpes Zoster
• For herpes zoster, beginning antiviral treatment within 72 hours of the development of skin lesions is optimal, but
initiation up to 7 days after onset also appears to be beneficial. Acyclovir, famciclovir, and valacyclovir are all FDA-
approved for the treatment of herpes zoster in immunocompetent individuals and result in decreased severity and
duration of both skin lesions and pain (see Table 80.4).
• Intravenous acyclovir is indicated for the treatment of zoster in immunocompromised patients as well as those with
serious complications.
• Postherpetic neuralgia
• Low-dose tricyclic antidepressants
• gabapentin (up to 3600 mg/day) / gabapentin together with valacyclovir.
• prednisone in addition to acyclovir
• 8% capsaicin patch
• analgesics, EMLA cream,
• lidocaine patches, narcotic analgesics, pregabalin, nerve blocks, and
• Biofeedback commends a single dose for immunocompetent individuals ≥60 years of age, whether or not they have a
history of varicella or herpes zoster. It is not indicated as a treatment for active herpes zoster or postherpetic
neuralgia.
EPSTEIN–BARR VIRUS (HHV-4)
• EBV is a ubiquitous human herpesvirus (HHV-4) that is responsible for
a broad spectrum of clinical diseases, including infectious
mononucleosis, oral hairy leukoplakia (see Ch. 78), hydroa
vacciniforme (see Ch. 87), and a variety of lymphoproliferative
disorders, lymphomas (B- and T-cell), and other malignancies (Table
80.8). It replicates well in B lymphocytes and can lead to their
immortalization.
• EBV is transmitted primarily through infectious saliva and occasionally via blood transfusion.
• The virus preferentially infects human mucosal epithelial cells and B lymphocytes, with primary
infection originating within the oropharyngeal epithelium. Infectious mononucleosis results from
active viral replication, which is subsequently terminated by the host immune response.
• After infectious mononucleosis resolves, circulating B lymphocytes can become latently infected with
EBV as the virus enters cells by specifically binding to cell surface complement receptors CR2 or CD21.
• As the B lymphocyte divides, expression of the EBV nuclear antigen-1 gene (EBNA-1) is essential for
replication of EBV DNA. Furthermore, the EBNA-1 protein and the virally encoded latent membrane
protein-2
• (LMP-2) are important in establishment of EBV latency within B lymphocytes and evasion from the
cellular immune system57. In the presence of a normally functioning immune system, cell-mediated
immune responses toward EBV antigens generally prevent the transformation and immortalization of
B lymphocytes. However, in patients with deficient cell-mediated immunity, B lymphocytes can
become immortalized and give rise to EBV-induced lymphoproliferative disorders.
• BV-induced infectious mononucleosis most commonly occurs in adolescents
• and young adults 15–25 years of age. After an incubation
• period of 30–50 days, the clinical triad of pharyngitis, fever lasting up
• to 10 days, and lymphadenopathy (especially cervical) occurs in >80%
• of patients.

• BV infection can have a variety of dermatologic manifestations. A

• faint, nonspecific erythematous exanthem has been reported in up to
• 70% of hospitalized patients and ~10% of all patients with infectious
• mononucleosis58. The exanthem typically develops on day 4–6 of the
• illness and may last up to 1 week. It can be morbilliform, urticarial,
• scarlatiniform, vesicular, erythema multiforme-like, purpuric, or petechial
• in nature, usually beginning on the trunk and proximal upper
• extremities with later extension to the face and forearms. Eyelid petechiae,
• periorbital edema, and petechiae at the junction of the hard and
• soft palate may also be observed. Resolution of the illness usually
• occurs after 2 to 3 weeks, although symptoms of fatigue and malaise
• may last longer.
• Painful genital ulcers, often measuring >1 cm, occasionally develop
• in patients (especially adolescent girls) with primary EBV infection (Fig.
• 80.21); PCR or in situ hybridization has confirmed the presence of
• lesional EBV in some cases59. Cutaneous conditions that are occasionally
• associated with primary EBV infection include Gianotti–Crosti
• syndrome (see Ch. 81), erythema nodosum, urticaria, acrocyanosis,
• erythema multiforme, erythema annulare centrifugum, and pityriasis
• lichenoides.
• Administration of ampicillin or amoxicillin, and less commonly penicillin
• or cephalosporins, to patients with infectious mononucleosis,
• frequently (up to 90% with the former agents) leads to the development
• of a “hypersensitivity” skin reaction. This usually develops 7–10 days
• following institution of the antibiotic. Typically, a pruritic, pink to
• copper-colored, scarlatiniform or morbilliform eruption develops onextensor surfaces and pressure points and then becomes confluent as
• it spreads onto the trunk and extremities (Fig. 80.22).
Diagnosis and Patology
• moderately elevated hepatic transaminase levels, mild thrombocytopenia,
• and an absolute and relative lymphocytosis (up to
• 50 000 cells/dl) with 20–40% atypical lymphocytes.
• . Diagnosis is usually
• made by a positive monospot test, a simple slide test that detects IgM
• heterophile antibodies, or by increased titers of heterophile antibodies;
• the latter reach a titer of >1 : 40 in ~90% of young adults infected with
• EBV. Heterophile antibodies are capable of agglutinating sheep, horse,
• or bovine erythrocytes, and they typically become detectable 1 week to
• 1 month after the onset of symptoms and persist for 3 to 18 months.
• Because heterophile antibody titers are positive in only a minority of
• young children with a primary EBV infection, EBV-specific serologies
• are often necessary to establish the diagnosis in this age group. Titers
• of at least three different antibodies should be assessed to determine
• the stage of EBV infection, allowing differentiation between an acute
• primary, past/latent, and reactivated infection (Table 80.9)58.
• PCR-based assays to detect EBV DNA in peripheral blood or tissue
• samples are also available. Markedly elevated peripheral blood levels
• are found in patients with infectious mononucleosis and in immunodeficient
• individuals with EBV-associated lymphoproliferative disorders.
• Of note, lower levels of EBV DNA can also be detected in the
• peripheral blood of healthy individuals with a latent EBV infection. In
• situ hybridization for EBV-encoded small RNA (EBER) represents a
• widely available, sensitive, and specific method to detect EBV-infected
• cells in the skin and other tissues. This assay can be performed on
• paraffin-embedded specimens, and EBER-positive cells are prominent
• in EBV-related dermatoses (e.g. T cells in hydroa vacciniforme; see Fig.
• 87.10) and malignancies, but absent in inflammatory dermatoses and
• lymphomas that are not related to EBV infection.
• The differential diagnosis of EBV-induced infectious mononucleosis
• includes drug reaction with eosinophilia and systemic symptoms
• (DRESS, see Ch. 21 and HHV-6 section below), which can be distinguished
• by exposure to an implicated drug and features such as eosinophilia
• and marked facial edema, as well as group A streptococcal
• infection, acute viral hepatitis, toxoplasmosis, lymphoma, and primary
• CMV, HHV-6, and HIV infections. A combination of history, physical
• examination, and laboratory studies can differentiate among these
• diseases.
• In most cases of infectious mononucleosis, the disease is self-limited
• and treatment is supportive.
• Acyclovir
• valacyclovir
• . Due to their
• multiple side effects, corticosteroids are reserved for only complicated
• cases of infectious mononucleosis associated with hemolytic anemia,
• severe thrombocytopenia, liver failure, or lymphadenopathy resulting
• in airway compromise62.
CMV
• More than 90% of primary CMV infections are subclinical, although
• a “mononucleosis-like syndrome” similar to that seen with EBV occasionally
develops in immunocompetent persons (Table 80.10).Infected patients develop
non-exudative pharyngitis in addition to fever, malaise, myalgias,
lymphadenopathy, and hepatosplenomegaly. Atypical lymphocytosis and elevated
liver enzymes may also occur. An exanthem, which can be morbilliform, urticarial,
petechial or purpuric, develops in a small percentage of patients. As with
infectious mononucleosis, the administration of ampicillin or related drugs during
this symptomatic period leads to a cutaneous eruption in 80–100% of individuals.
• Congenital CMV infection is the leading infectious cause of deafness and
intellectual disability, presenting with jaundice, hepatosplenomegaly, intrauterine
growth retardation, thrombocytopenia, chorioretinitis, seizures, and/or
intracranial calcifications. Cutaneous manifestations include purpuric papules
and nodules of dermalhematopoiesis which are sometimes referred to as
“blueberry muffin” lesions (Fig. 80.23; see Ch. 121), in addition to petechiae,
purpura, and vesicles.
• Perinatal CMV infection is often asymptomatic; however, a limited number of
infected infants develop pneumonitis, lymphadenopathy, or hepatosplenomegaly.
• Transmission of CMV is via body fluids, including saliva, blood, urine, semen, breast milk,
and cervical and vaginal secretions, as well as in transplanted organs and hematopoietic
stem cells. CMV can also be spread indirectly by contaminated fomites, such as toys.
• Transplacental transmission of CMV to the fetus is more likely in the setting of a primary
infection in the mother, with 40% of fetuses becoming infected, compared to <1% in
recurrent cases.
• CMV has an estimated incubation period of 4–8 weeks, followed by viremia via infected
blood leukocytes and spread to various organs.
• Following primary infection, CMV persists in a latent state for the life of the host and
rarely causes disease. In immunocompromised individuals, however, reactivation of
latent virus can lead to recurrent infection characterized by persistent viral replication,
viremia, and dissemination to distant organs.
• Culture of CMV in human fibroblasts is the traditional diagnostic
“gold standard”, but this takes several days to weeks.
• Detection of CMV in tissue cultures within 24–48 hours is
possible with the shell vial assay, in which monoclonal antibodies
specific for early CMV antigens are employed.
• In addition to CMV-specific serologies, assays that detect CMV
antigens (e.g. pp65) within leukocytes or CMV DNA via PCR
(necessary in neutropenic patients) are commonly employed to
identify and monitor viremia and systemic infection.
• Like other viral exanthems, the histologic features of the acute
exanthem of CMV infection include mild spongiosis and a sparse
perivascular lymphocytic infiltrate in the upper dermis. Epidermal
changes are minimal since CMV does not infect keratinocytes.
However, it does infect endothelial cells, which can have an “owl’s
eye” appearance that is pathognomonic for CMV infection.
DDX
• The clinical differential diagnosis of the mononucleosis-like syndrome
• of CMV infection includes EBV-induced infectious mononucleosis,
• which is generally more severe and often associated with exudative
• pharyngitis, as well as toxoplasmosis, viral hepatitis, DRESS, and
• lymphoma.
Treatment
• Management is targeted at prevention plus prophylactic antiviral treatment
• in susceptible immunocompromised individuals as well as antiviral
• treatment in those who are symptomatic. Treatment of
• CMV-induced mononucleosis in immunocompetent individuals,
• however, is only supportive.
• The first-line agents for treatment as well as prophylaxis of CMV
• infections in immunocompromised patients are intravenous ganciclovir
• or oral valganciclovir; intravitreal injections/implants of ganciclovir
• are used for localized retinitis. When patients fail to respond to these
• medications or develop significant side effects, foscarnet and cidofovir
• are additional options69 (Table 80.11).
HHV-6
• HHV-6 is the etiologic agent of exanthem subitum (roseola infantum),
• Although HHV-6 infection usually is a benign disease without long-
term sequelae, the virus remains latent and can be life-threatening if
reactivated in the setting of immunosuppression.
• HHV-6 has a tropism for CD4+ T lymphocytes although has been
isolated from the cervix and may cause perinatal infection.
• Transmission is typically through infected saliva. After primary HHV-6
infection, the virus establishes lifelong latency in CD4+ T lymphocytes,
with the potential for reactivation.
• The incubation period ranges from 5–15 days.
Typically, an otherwise well-appearing infant presents
with a high fever (38.9–40.6°C) that lasts for 3–5 days,
followed by a cutaneous eruption as the fever begins
to subside.
• The cutaneous eruption usually lasts for 24–48 hours.
• The lesions are discrete, circular or elliptical, “rose-
red” macules and papules that are 2–5 mm in
diameter and occasionally surrounded by a white
halo. An enanthem of red papules on the soft palate
(Nagayama’s spots) may also be seen, and ulcers on
the uvula and at the palatoglossal junction represent
a characteristic finding.
• The most common complication of exanthem subitum
is febrile seizures, which occur in 10–15% of affected
infants and children.
• is typically diagnosed clinically.
• Serology may be helpful in ambiguous situations.
• PCR detection of cell-free HHV-6 DNA in serum or plasma has
diagnostic utility. However, qualitative PCR using cellular specimens
(e.g. peripheral blood mononuclear cells) cannot reliably distinguish
between latent and active infection.
• Viral colture
DDx
• primarily other viral exanthems such as rubeola, rubella, and
enterovirus, adenovirus, EBV, and parvovirus infections. Other
considerations may include scarlet fever, Rocky Mountain spotted
fever, and Kawasaki disease.
• Although HHV-6 infection is usually self-limited, serious complications
• can occur in immunocompromised patients. Evidence-based
recommendations regarding specific antiviral agents and dosages are
not currently available to guide treatment in immunocompromised
hosts.
HUMAN HERPESVIRUS TYPE 7 (HHV-7)
• Infections mainly occur during the first 5 years of life and then
typically remain latent.
• Transmission via saliva is most likely, HHV-7 has also been found in
cervical secretions.
• Significant homology exists between HHV-7 and HHV-6A
• The cutaneous eruption associated with HHV-7-induced exanthem subitum is lighter
in color and presents later in the disease course than that of primary HHV-6 infection

• HHV-7 and pityriasis rosea (PR)

• Methods to detect HHV-7 infection include serologic tests, PCR, viral

• culture, and immunohistochemical staining.

• DDx: exanthem subitum

• Treatment
HUMAN HERPESVIRUS TYPE 8 (HHV-8)

• is a latent virus found in all types of Kaposi sarcoma (KS) worldwide

Patogenesis: not fully understood.

• High risk: Receptive anal intercourse, number of same-sex male
partners and the presence of HIV infection , saliva.
Clinical features
Clinical Features
• The 4 KS types all typically feature red,
brown, or violaceous papules, plaques,
and nodules.
• Edema is often present in all types.
Classic KS favors the lower legs and can
become hyperkeratotic or eczematous;
it tends to be slowly progressive.
• AIDS-related KS typically presents as
more widely distributed lesions.
Diagnosis and Pathology
• Skin biopsy
• Serology
• Immunohistochemical staining for latency-associated nuclear antigen
(LANA-1)