Human Herpesviruses PDF

SECTION 12 INFECTIONS, INFESTATIONS, AND BITES 80 Human Herpesviruses Joseph Jebain, Alfredo Siller Jr. and Stephen K. Tyring...

SECTION 12 INFECTIONS, INFESTATIONS, AND BITES 80 Human Herpesviruses Joseph Jebain, Alfredo Siller Jr. and Stephen K. Tyring HSV types, but it was not until 1968 that Nahmias and Dowdle demon- Chapter Contents strated that HSV-1 was more frequently associated with orolabial and Herpes Simplex Viruses (HSV-1 and HSV-2).............. 1412 HSV-2 with genital infections1. In the past several decades, there have Varicella–Zoster Virus (VZV; HHV-3)................... 1418 been critical insights into the pathogenesis of HSV infections as well as Epstein–Barr Virus (HHV-4)........................ 1427 advances in their diagnosis, treatment, and prevention. Cytomegalovirus (HHV-5)......................... 1429 Human Herpesvirus Type 6 (HHV-6).................. 1431 Epidemiology Human Herpesvirus Type 7 (HHV-7).................. 1433 Herpes simplex viruses have a worldwide distribution. Their inter- action with human hosts has the following components: (1) primary Human Herpesvirus Type 8 (HHV-8).................. 1433 infection – initial HSV infection, without pre-existing antibodies to HSV-1 or HSV-2; (2) non-primary initial infection – infection with one HSV type in an individual with pre-existing antibodies to the other The human herpesviruses (HHVs) are categorized into three groups: HSV type; (3) latency – virus in sensory ganglia; and (4) reactivation – alpha, beta, and gamma herpesvirinae (Table 80.1). Each virus contains a recurrent infection with asymptomatic viral shedding or clinical core of linear double-stranded DNA, an icosahedral capsid 100–110 nm manifestations (recrudescence). Primary, non-primary initial, and in diameter, and an envelope with glycoprotein spikes on its surface. recurrent infections can each be symptomatic or asymptomatic. It is The pathogenesis of herpesvirus infections follows the sequence of estimated that approximately one-third of the world’s population has primary infection, latency, and reactivation. The eight human herpes- experienced a symptomatic HSV infection. viruses are discussed in this chapter and include the following: herpes In children adults with atopic dermatitis Rapid, widespread cutaneous dissemination of HSV infection in (Kaposi varicel- (Fig. 80.5); risk is associated with mutations in the gene areas of dermatitis/skin barrier disruption liform eruption) encoding filaggrin Monomorphic, discrete, 2–3 mm punched-out erosions with A similar presentation can occur in patients with an impaired hemorrhagic crusts (see Fig. 80.5) are evident more often than skin barrier due to other conditions such as burns, irritant intact vesicles contact dermatitis, pemphigus (foliaceus, vulgaris), Darier May have fevers, malaise, and lymphadenopathy disease, Hailey–Hailey disease, mycosis fungoides, Sézary Occasionally complicated by bacterial superinfections (e.g. syndrome, ichthyoses, and rarely Grover disease and pityriasis Staphylococcus aureus, group A streptococci) or systemic rubra pilaris with acantholysis, as well as following ablative laser dissemination of HSV infection procedures or application of topical 5-fluorouracil Differential diagnosis includes “eczema coxsackium” due to Usually due to HSV-1 coxsackievirus A6 infection and streptococcal infection and eczema vaccinatum Herpetic whitlow Often in young children, usually due to HSV-1 (Fig. 80.6A) Pain, swelling, and clustered vesicles on a digit (Fig. 80.6); Increasing frequency in adolescents/adults (Fig. 80.6B,C) appearance of vesicles may be delayed secondary to digital–genital contact, usually due to HSV-2 Recurrences in the same location can be a clue to the diagnosis Historically in dental and medical personnel who did not use Often misdiagnosed as blistering dactylitis or paronychia gloves Herpes gladiatorum Participation in contact sports such as wrestling (Fig. 80.7) Distribution reflects sites of contact with another athlete’s skin Usually due to HSV-1 lesions and is sometimes widespread Herpes simplex Shaving with a blade razor (e.g. herpetic sycosis in a man’s Rapid development of follicular vesicles and pustules folliculitis beard area) See Table 38.1 Usually due to HSV-1 HIV-positive or otherwise immunocompromised individuals Severe/chronic HSV Immunocompromised patients, e.g. hematopoietic stem cell or Most common presentation is chronic, enlarging ulcerations infections solid organ transplant recipients, individuals with HIV infection (Fig. 80.8A,B) or leukemia/lymphoma Cutaneous lesions may affect multiple sites or be disseminated Skin findings are often atypical, i.e. verrucous, exophytic, or pustular lesions Recurrences can involve oral mucosa, including the tongue (Fig. 80.8C) and movable areas that do not overlie bone Involvement of the respiratory tract, esophagus, and remainder of the gastrointestinal tract may also occur Predominantly extracutaneous Ocular HSV infection Often due to HSV-2 in newborns (see below) Primary infection: unilateral or bilateral keratoconjunctivitis with Usually due to HSV-1 in children and adults eyelid edema, tearing, photophobia, chemosis, and preauricular lymphadenopathy Branching dendritic lesions of the cornea represent a patho­ gnomonic finding Recurrent episodes are common and typically unilateral Complications include corneal ulceration and scarring, globe rupture, and blindness Herpes encephalitis Most common cause of fatal sporadic viral encephalitis in Manifestations can include fever, altered mental status, bizarre the US behavior, and localized neurologic findings Associated with mutations in the genes encoding Toll-like The temporal lobe is often involved receptor 3 or UNC-93B, which impair interferon-based cellular Mortality ≥70% without treatment; residual neurologic defects in antiviral responses (see Table 80.2) most survivors Usually due to HSV-1 Herpes labialis may be a coincidental finding Natalizumab, an anti-α4 integrin monoclonal antibody used for the treatment of multiple sclerosis and Crohn disease, increases the risk of encephalitis and meningitis due to HSV and VZV Proctitis Most common in men who have sex with men Manifestations include diarrhea, anal pain, and a feeling of rectal fullness Cutaneous and extracutaneous Neonatal HSV Occurs in ~1 : 10 000 newborns in the US8,9, usually resulting Onset from birth to 2 weeks of age, but usually ≥5 days of age infection from exposure to HSV during a vaginal delivery Localized (favoring the scalp and trunk; Fig. 80.9) or disseminated Risk of transmission is highest (30%–50%) for women who cutaneous lesions; involvement of the oral mucosa, eye, CNS, and acquire a genital HSV infection (which is often asymptomatic) multiple internal organs can occur near the time of delivery Vesicles may progress to bullae and erosions (see Ch. 34) Risk of transmission is low (50% without cases treatment and ~15% with treatment; many survivors have neuro- logic deficits Table 80.3 Other clinical presentations of herpes simplex virus (HSV) infections. 1417 Downloaded for moria amnony ([email protected]) at Shamir Medical Center Assaf Harofeh from ClinicalKey.com by Elsevier on January 26, 2025. For personal use only. No other uses without permission. Copyright ©2025. Elsevier Inc. All rights reserved. SECTION 12 INFECTIONS, INFESTATIONS, AND BITES A B A C Fig. 80.6 Herpetic whitlow. A Coalescing vesicles and erosions on the distal finger of a child. B An edematous erythematous plaque with relatively subtle central vesicle formation on the thumb of a child. C Grouped vesicles on the toe of an adult. Herpetic whitlow is sometimes misdiagnosed as cellulitis or blistering distal dactylitis, or, depending on the distribution, paronychia. B C, Courtesy Louis A. Fragola, Jr, MD. Fig. 80.5 Eczema herpeticum. A Monomorphic, punched-out erosions with a scalloped border in this infant with a history of facial atopic dermatitis. B Monomorphic, small hemorrhagic crusts and erosions coalescing in the popliteal fossae, an area of pre-existing atopic dermatitis. A, Courtesy Julie V. Schaffer, asymptomatic viral shedding. Sexual abstinence is the only method MD; B, Courtesy Kalman Watsky, MD. for absolute prevention of genital herpes, which can be transmitted even with the use of condoms27. In addition to antiviral therapy, patient education regarding prevention of genital herpes trans- The emergence of acyclovir-resistant HSV is an increasing concern mission is essential. for immunocompromised individuals. Foscarnet is the only antiviral There is currently no licensed vaccine available for HSV, although drug approved by the FDA for treatment of acyclovir-resistant HSV several vaccines are under development and evaluation for prevention (see Fig. 127.11). Cidofovir is another antiviral agent that has of HSV infection and recurrences. GEN-003, a therapeutic vaccine shown efficacy in the treatment of acyclovir-resistant HSV. The use under investigation for genital HSV-2 infection, was found in phase I/ of foscarnet or systemic cidofovir is limited by potentially severe II clinical trials to reduce the rates of outbreaks and asymptomatic viral renal toxicity and the requirement for intravenous administration. shedding28. In randomized controlled studies, adults with a history Although not FDA-approved, compounded topical cidofovir has been of genital herpes due to HSV-2 who received the helicase-primase advocated by the CDC as a “user-friendly”, albeit expensive, alter- inhibitor pritelivir had significantly decreased HSV shedding and fewer native treatment25. days with genital lesions than those who received placebo or valacy- Individuals co-infected with HIV and HSV have more severe clovir29. There is currently an ongoing trial of the use of oral pritelivir outbreaks and more frequent viral shedding than those without HIV for acyclovir-resistant mucocutaneous HSV infections in immunocom- infection. When added to the medical regimen of HIV-infected patients, promised hosts. antiherpetic suppressive therapy appears to allow the co-infected person to respond better to antiretroviral therapy and to reduce genital and plasma HIV-1 RNA levels, but it does not seem to decrease the risk of VARICELLA–ZOSTER VIRUS (VZV; HHV-3) HIV-1 transmission26. Oral acyclovir, famciclovir, and valacyclovir can be used for genital and orolabial HSV in the setting of HIV infection if there is no evidence of acyclovir resistance. Synonyms/clinical forms:  Varicella – chickenpox  Herpes 1418 There is significant interest in prevention of HSV disease. zoster – shingles Between 70% and 80% of HSV is transmitted during periods of Downloaded for moria amnony ([email protected]) at Shamir Medical Center Assaf Harofeh from ClinicalKey.com by Elsevier on January 26, 2025. For personal use only. No other uses without permission. Copyright ©2025. Elsevier Inc. All rights reserved.  CHAPTER 80 Human Herpesviruses A A B Fig. 80.8 Herpes simplex virus infec- B tions in immunocom- promised hosts. A, B Fig. 80.7 Herpes simplex infections in less common locations. A Herpes Enlarging ulcerations gladiatorum presenting as grouped vesicles and erosions on the neck of a high- in a child with acute school wrestler. B Small vesicles and punched-out erosions clustered on the lymphocytic leukemia nipple and areola. A, Courtesy Louis A. Fragola, Jr, MD; B, Courtesy Kalman Watsky, MD. who was presumed to have a Rhizopus infection (A) and in a young man with AIDS (B). C Coalescence of Key features eroded, yellow–white papules and plaques on „ VZV is the etiologic agent of varicella (chickenpox) and herpes the tongue. zoster (shingles) „ VZV has a high morbidity and mortality rate in immunocompro- mised hosts „ Antiviral treatment as well as vaccination can reduce or eliminate C serious disease-associated sequelae and decrease the incidence of VZV infection History Heberden first distinguished chickenpox from smallpox in 1767. The term “chickenpox” is thought to come from either the French word Introduction “chiche-pois” for chickpea (referring to the size of the vesicles) or the VZV is the etiology of varicella (chickenpox) and herpes zoster Old English word “gigan” meaning “to itch”. The relationship between (shingles). Varicella is usually symptomatic, and before the advent varicella and herpes zoster was first recognized in 1888, when von Bokay of the varicella vaccine, it occurred in 90% of children in the US described the development of varicella in children following exposure to by the time they reached 10 years of age. Herpes zoster represents those with herpes zoster infection. Kundratitz (1922) and Bruusgaard reactivation of latent VZV infection and develops in ~20% of healthy (1932) more convincingly demonstrated the association between the adults and 50% of immunocompromised persons, with substantial two diseases by the development of varicella in susceptible children morbidity and mortality in the latter group. Early initiation of who had been inoculated with vesicle fluid from patients with herpes antiviral treatment can reduce or eliminate serious sequelae of VZV zoster. This was followed by the identification of the same virus in both 1419 infections. diseases, confirming that their etiologies were identical. Downloaded for moria amnony ([email protected]) at Shamir Medical Center Assaf Harofeh from ClinicalKey.com by Elsevier on January 26, 2025. For personal use only. No other uses without permission. Copyright ©2025. Elsevier Inc. All rights reserved. SECTION Fig. 80.9 Neonatal 12 herpes. Grouped papulovesicles with Since the introduction of the varicella vaccine in 1995, the overall incidence of varicella has decreased by ~85%, with evidence of herd immunity. The age of peak incidence also shifted from 5–9 years an erythematous base INFECTIONS, INFESTATIONS, AND BITES on the chest. Note the to 10–14 years, and a higher rate of breakthrough varicella among scalloped borders in immunized children in the latter age group led to the addition of a areas of coalescence. second varicella vaccine dose to the routine childhood immunization Courtesy Frank Samarin, MD. schedule in 200630. Although the incidence and severity of herpes zoster increase substan- tially in middle to late adulthood, it can occur at any age and is more common in younger persons who had a varicella infection within the first year of life. Overall, individuals with a history of varicella have a 20% lifetime chance of developing zoster. The annual incidence of herpes zoster in the US and Europe is classically 2.5/1000 persons between ages 20 and 50 years, 5/1000 between ages 51 and 79 years, and 10/1000 in those >80 years of age. However, there is evidence that exposure to varicella can protect seropositive adults from the development of zoster, and it has been postulated that widespread vaccination against varicella could reduce this immune boosting effect and increase the incidence of zoster. Whether this hypothetical increase will be counterbalanced by zoster vaccination remains to be determined. Other risk factors for herpes zoster include mental and physical stress, a family history of zoster, use of JAK inhibitors or proteasome inhibitors (e.g. bortezomib, carfilzomib), and an immunocompromised state, especially when due to HIV infection and allogeneic hematopoietic stem cell transplantation (HSCT)31,32. Pathogenesis Airborne droplets are the usual route of transmission of varicella, although direct contact with vesicular fluid is another mode of spread, and the incubation period is 11–20 days. Varicella is extremely conta- gious, and 80%–90% of susceptible household contacts develop a clini- cally evident infection. 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 postex- posure. During this period, the virus enters the epidermis by invading Fig. 80.10 Tzanck smear. Note the multinucleated epithelial giant cells from a capillary endothelial cells. VZV subsequently travels from mucocuta- patient with herpes simplex viral infection. Courtesy Louis A. Fragola, Jr, MD. neous 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. The transmission rate to susceptible household contacts is ~15% for zoster, compared to 80%–90% for varicella. Clinical Features Varicella A prodrome of mild fever, malaise, and myalgia may occur, especially in adults. This is followed by an eruption of pruritic, erythematous macules and papules, which starts on the scalp and face, and then spreads to the trunk and extremities (Fig. 80.12). Lesions rapidly evolve over ~12 hours into 1–3 mm clear vesicles surrounded by narrow red halos (“dew drops on a rose petal”). The number of vesicles varies from only a few to several hundred, and there is often involvement of the oral Fig. 80.11 Histology of herpes simplex viral infection. Intraepidermal vesicle mucosa (see Fig. 80.12D). Sparing of the distal and lower extremities with ballooning degeneration of keratinocytes and multinucleated giant cells; the is common. Older vesicles evolve to form pustules and crusts, with latter arise from the fusion of infected keratinocytes. Note the steel-gray nuclei individual lesions healing within 7–10 days. The presence of lesions in with margination of chromatin and inclusions (insets). Courtesy Lorenzo Cerroni, MD. all stages of development is a hallmark of varicella. The disease course is usually self-limited and benign in healthy children. However, prior to introduction of the varicella vaccine, Epidemiology complications resulted in 11 000 hospitalizations annually in the US. VZV has a worldwide distribution and 98% of the adult population Secondary bacterial infection of the skin with subsequent scarring is is seropositive. In the pre-vaccine era, 90% of children