Chapter 25 Bullous viral eruptions
1. What do herpes simplex (HSV) virus and varicella-zoster virus (VZV) have in common?
HSV-1, HSV-2, and VZV are all members of the human herpesvirus family. Other members of this family include cytomegalovirus, Epstein-Barr virus, human herpesvirus–6, human herpesvirus–7, and human herpesvirus–8. The human herpesviruses all contain double-stranded DNA, share certain structural features and mechanisms for infection and replication, and have the capacity to establish latent infection in the human host.
2. What happens during primary HSV infection?
Primary infection refers to an individual’s first infection with HSV, either type 1 or 2, at any site. These patients are seronegative initially but subsequently develop HSV-specific antibodies. During primary infection, HSV gains access to the host through the epithelial surface. Following active replication within the skin or mucosa, HSV infects the associated cutaneous neurons and migrates to the sensory root ganglia, where a latent infection is established. Primary HSV infection may be associated with extensive cutaneous lesions, severe pain, and systemic symptoms. However, in many cases, the primary infection is asymptomatic (or unrecognized).
3. What about recurrent infection?
Recurrent HSV infection represents reactivation of the latent virus in the sensory ganglia. “Reactivated” virus particles migrate along the nerves to the site in the skin where the primary infection occurred, with subsequent viral replication and the development of clinical lesions (Fig. 25-1A). The most common sites for recurrent herpes simplex infection are the lips (herpes labialis, “cold sores”), genitalia (herpes genitalis), and sacral area (Fig. 25-1B). Often, individuals experience a prodrome of tingling or burning in the skin prior to the development of visible lesions. Certain factors, such as fever, stress, menses, and sun exposure, may precipitate recurrent infection. The frequency of recurrent infection varies greatly between individuals. In most individuals, clinically evident recurrence becomes less frequent over time.
4. What is the difference between a primary and an initial HSV infection?
When an individual without preexisting antibodies to either HSV-1 or HSV-2 develops an infection with herpes (either type 1 or 2), it is referred to as the primary infection. When an individual with preexisting antibodies to one type of HSV then experiences an infection with the other HSV type, it is referred to as the initial (or initial, nonprimary) infection.
5. How is HSV transmitted?
HSV is transmitted by direct contact of the infected mucocutaneous surface(s) of one individual with the mucosa or skin of another individual. HSV does not survive long outside its normal habitat, and so transmission by contact with fomites is extremely uncommon. It is assumed that HSV-1 is generally transmitted inadvertently during childhood from infected family members, whereas infection with HSV-2 may develop later when individuals become sexually active.
6. How long is incubation period for HSV (i.e., the time from initial infection to appearance of vesicles)?
The time interval between exposure and development of primary disease is estimated to be 3 to 14 days. However, not all cases of primary disease are symptomatic, and so the first evidence of infection may be a recurrent episode, well after the actual exposure. This is important to note, especially in the case of genital infection where the sudden development of “herpes” in one partner in a monogamous couple could create concerns regarding infidelity.
7. Define asymptomatic shedding.
In individuals previously infected with HSV, virus may periodically be present at the site of infection in the absence of clinically evident lesions. This is referred to as asymptomatic shedding. During asymptomatic shedding, the presence of virus may be documented by viral culture or polymerase chain reaction (PCR). Although the viral titer is lower than during clinically active disease, transmission of the virus can nevertheless occur. In fact, contact during periods of asymptomatic shedding is thought to be responsible for many cases of disease transmission.
8. Can you be infected with HSV and not know it?
Yes. Many individuals who give no history of HSV infection are seropositive for HSV-specific antibodies. Using viral culture or PCR, HSV can periodically be recovered from the mouth and/or anogenital region of such individuals (see “asymptomatic shedding” above). Based on the seroprevalence of herpes-specific antibody, 70% to 80% of the population is infected with HSV-1 and 25% to 30% with HSV-2. It is estimated that out of every four individuals with genital herpes, three do not know they are infected.
9. How do HSV-1 and -2 differ?
HSV types 1 and 2 are very closely related, sharing approximately 50% homology in their genetic composition. As expected, many of their viral proteins are also similar (known as type-common), although each type also produces unique proteins (type-specific). Immunohistologic techniques can be used to distinguish these type-specific proteins and differentiate HSV-1 from HSV-2 in clinical situations. Serologic testing that can accurately identify and differentiate antibodies to HSV-1 versus antibodies to HSV-2 is now also available (glycoprotein G type-specific assays). HSV-1 is usually associated with oral herpes and HSV-2 with genital herpes, although each virus can affect both sites. HSV-1 cannot be differentiated from HSV-2 based on the appearance of the skin lesions alone.
10. How do you diagnose HSV infection?
The clinical history of recurrent blisters or erosions in the same site (especially in an oral or genital distribution) is highly suspicious for HSV infection. A prodrome of tingling or burning is also consistent with this diagnosis. On physical exam, the classic lesion is grouped vesicles on an erythematous base (see Fig. 25-1A), but, more often, only nonspecific crusted erosions are seen. To confirm the diagnosis, laboratory assessment may be needed. The gold standard remains viral culture. However, use of many other rapid and sensitive techniques for detection of viral-specific proteins or nucleic acids is often available. For any method of detection, the age of the lesion sampled is critical. Vesicles are optimal but ulcers and erosions, if they are not dry and crusted, may also yield positive results.
11. How is a Tzanck smear performed?
In a Tzanck smear, the base of the suspected herpetic lesion is gently scraped, and the skin or mucosal cells removed are placed on a glass slide. The cells are stained and then examined by light microscopy for evidence of viral-induced cytologic change, including the characteristic multinucleated giant cells. Tzanck smears provide an efficient and inexpensive method of diagnosis, although the results are not always definitive. This technique cannot distinguish HSV-1 from HSV-2 or HSV from VZV.
12. What are the drugs of choice for treatment of HSV?
There are three systemic antiviral agents routinely used for the treatment of HSV: acyclovir, valacyclovir, and famciclovir (Table 25-1). Valacyclovir is the L-valyl ester of acyclovir with a bioavailability 3 to 5 times greater than acyclovir. Famciclovir is the diacetyl-6-deoxy analog of penciclovir. It is well absorbed and has a long intracellular half-life. Both valacyclovir and famciclovir offer the advantage of less frequent dosing compared to acyclovir. All three drugs are generally safe and highly effective because of their very specific antiviral activity. The antiviral drug is preferentially taken up by infected cells, where it must be converted to its active form by the viral enzyme thymidine kinase. The active form preferentially inhibits viral DNA synthesis, with little impact on host cell metabolism.
Table 25-1. Recommendations for Systemic Antiviral Treatment of Mucocutaneous Herpes Simplex Virus (HSV) Infection*
| DRUG | RECOMMENDED DOSAGE | |
|---|---|---|
| Genital HSV | ||
| Primary/first episode | Acyclovir Valacyclovir Famciclovir |
400 mg PO tid or 200 mg PO 5 times per day for 7–10 days (mild to moderate) 5 mg/kg IV q8h for 5 days (severe) 1 g PO bid for 7–10 days 250 mg PO tid for 10 days |
| Recurrent episode (start at prodrome) | Acyclovir Valacyclovir Famciclovir |
400 mg PO tid or 200 mg PO 5 times per day for 5 days 500 mg PO bid for 3 days 1 g daily for 5 days 1 g PO bid for 1 day 125 mg PO bid for 5 days |
| Chronic suppression | Acyclovir Valacyclovir Famciclovir |
400 mg PO bid or 200 mg PO tid; adjust up or down according to response (>6 outbreaks per year) 500 mg PO qd (<10 outbreaks per year) 1 g PO qd (10 or more outbreaks per year) 250 mg PO bid (6 or more outbreaks per year) |
| Orofacial HSV | ||
| Primary/first episode | Acyclovir Valacyclovir Famciclovir |
15 mg/kg 5 times per day for 7 days 1 g bid for 7 days 500 mg bid for 7 days |
| Recurrent (start at prodrome) | Acyclovir Valacyclovir Famciclovir |
400 mg PO 5 times per day for 5 days 2 g PO bid for 1 day 1500 mg as single dose |
| Chronic suppression | Acyclovir Valacyclovir |
400 mg PO bid–tid 500 mg to 1 g PO qd |
| Orolabial or Genital HSV in Immunosuppressed Patients | ||
| Recurrent/suppressive | Acyclovir Valacyclovir Famciclovir |
400 mg PO 3 times per day or 5–10 mg/kg IV q8h 500 mg to 1 g PO bid 500 mg PO bid |
Bid, Twice daily; IV, intravenous; PO, by mouth; qd, daily; tid, three times a day.
* Dose should be adjusted in the presence of renal insufficiency.
13. When is chronic suppressive therapy indicated?
Once an episode of recurrent HSV infection (whether oral or genital) has begun, initiation of antiviral therapy often provides only mild symptomatic improvement. If antiviral therapy is initiated during the prodromal phase, the response may be somewhat better. In patients with frequently recurrent or severe disease, especially with genital herpes, chronic suppressive therapy may be considered. After 1 year on therapy, a “drug holiday” may be given to assess the continued need for treatment, since the natural history of recurrent infection is to decrease in frequency with time.
14. Are patients with genital herpes at greater risk for becoming infected with the human immunodeficiency virus (HIV)?
15. What recommendations can you make to a patient with genital herpes to reduce the risk of transmission to his or her partner?
At the very least, avoidance of sexual contact during clinically apparent disease (i.e., until lesions are completely dry) is advised. In light of the problem with asymptomatic shedding, the safest practice is the routine use of a condom, even between active episodes. The systemic antiviral agents decrease, but do not eliminate asymptomatic shedding. However, in the case of monogamous but discordant (one partner has genital herpes and the other does not) couples, chronic suppressive therapy taken by the infected partner may reduce the likelihood of transmitting the disease to the uninfected partner.
Gupta R, Warren T, Wald A: Genital herpes, Lancet 370:2127–2137, 2007.
16. Can HSV infect the skin in areas other than around the mouth or anogenital areas?
HSV infection may involve and recur at any location on the mucocutaneous surface. HSV infection of the hand or fingers, known as herpetic whitlow, is usually the result of autoinoculation from another site of infection (Fig. 25-2A). Herpes gladiatorum is a problem most commonly seen in athletes who participate in close contact sports such as wrestling. Typically transmitted from active herpes labialis or asymptomatic shedding in oral secretions of an infected opponent, herpes gladiatorum often affects the head, neck, or shoulders. Eczema herpeticum, also known as Kaposi’s varicelliform eruption, represents a cutaneous dissemination of HSV (Fig. 25-2B). It may develop as a complication of a localized HSV infection in patients with atopic dermatitis or other underlying skin disease.
17. How does a baby get herpes? Is it a serious problem?
In most cases, transmission of HSV to the neonate occurs by delivery through an infected birth canal. Postpartum acquisition occurs less commonly. Development of primary or initial non-primary genital herpes by the mother at or near the time of delivery poses a significant risk for the infant. However, most cases of neonatal herpes are the result of asymptomatic shedding in women with no known history of genital herpes. The usual onset of neonatal herpes is 5 to 21 days following exposure. Approximately 80% of infected neonates have at least some characteristic skin lesions. Herpes infection in the neonatal period can be devastating because of the inadequate immune response seen in neonates.
18. Describe the natural history of varicella.
Varicella, or chickenpox, is the primary infection with varicella-zoster virus (VZV). It is characterized by the appearance of two to three successive crops of diffuse, pruritic vesicles and papules over several days. These lesions then evolve into pustules and crusted erosions, so that lesions in all stages of development are present together (Fig. 25-3). Lesions generally persist for up to 1 week.
Figure 25-3. Varicella with skin lesions at all stages of development.
(Courtesy of Joseph G. Morelli, MD.)
19. What is shingles?
Herpes zoster, or “shingles,” is the recurrent form of infection with VZV and represents reactivation of the latent virus in the sensory ganglia. The cutaneous eruption consists of painful and/or pruritic vesicles, which tend to follow a unilateral, dermatomal distribution (Fig. 25-4). Prodromal pain may often precede the development of visible lesions. The entire course is usually 2 to 3 weeks in duration. The most common area of involvement for herpes zoster is the trunk (dermatomes innervated by the thoracic nerves), followed by the head (first branch of the trigeminal nerve). Herpes zoster is most typically seen in older and/or immunocompromised individuals.
Figure 25-4. Grouped vesicles on an erythematous base in a dermatomal distribution.
(Courtesy of the Fitzsimons Army Medical Center teaching files.)
Whitley RJ: A 70-year-old woman with shingles: review of herpes zoster, JAMA 302:73–80, 2009.
20. Can herpes zoster be recurrent?
Approximately 5% of patients with herpes zoster will experience a recurrence, usually in the same dermatome. However, recurrent HSV may also have a “zosteriform” distribution, indistinguishable from herpes zoster both clinically and on Tzanck smear. Although this presentation is not common, the possibility should be entertained, especially when the dermatomes involved are in the orofacial or genital distribution or the patient presents with “recurrent zoster.”
22. Is herpes zoster contagious?
Herpes zoster is the result of reactivation of latent VZV in the sensory ganglia. There is no evidence that a person can develop herpes zoster as a result of contact with patients with either varicella or herpes zoster. However, direct contact with the cutaneous lesions may result in transmission of primary varicella to a susceptible host.
23. What is postherpetic neuralgia?
Postherpetic neuralgia is the most common complication of herpes zoster. It is defined as the presence of pain after skin lesions have healed, or pain lasting more than 3 months after the onset of cutaneous lesions. The pain is often severe and debilitating. Overall, it occurs in 10% to 15% of patients, but the incidence increases dramatically with age so that over half of patients with herpes zoster who are older than 60 years develop postherpetic neuralgia. Other risk factors include prominent prodromal symptoms and moderate or severe pain at presentation. In most cases, postherpetic neuralgia resolves spontaneously within the first 12 months, but it may persist for years.
24. How do you diagnose VZV infection?
For varicella, the physical findings of lesions in various stages of development (papules, vesicles, pustules, and erosions), especially with a history of exposure to an individual with varicella (or zoster), is generally enough to make the diagnosis. The diagnosis of herpes zoster is also often made on the basis of physical findings. A Tzanck smear may be useful. If additional laboratory evaluation is indicated, immunohistochemical testing to detect viral-specific antigens in infected cells is recommended. A viral culture may be performed, although culturing VZV is more difficult and takes longer than culturing HSV. Use of PCR has become more commonly available. VZV serology is rarely useful for diagnosis.
25. What is the treatment for varicella?
Generally, symptomatic therapy, such as calamine lotion and oral antihistamines, is all that is required. Acyclovir is not routinely recommended for otherwise healthy children from a cost-effective standpoint. However, for varicella in an adult or immunocompromised individual, prompt initiation of systemic antiviral therapy is advised (Table 25-2). Routine childhood vaccination to prevent varicella is now recommended for children and adolescents who have not been infected. Vaccination is also recommended for susceptible adults, especially those at high risk for exposure.
26. How about herpes zoster?
Herpes zoster is a self-limited disease and in most young, otherwise healthy persons, symptomatic measures (cool compresses, antihistamines, analgesics) are sufficient. However, for persons who are over 50 years of age, have ophthalmic zoster, or are immunocompromised, systemic antiviral therapy is recommended (see Table 25-2). If started within 72 hours of the onset of skin lesions, systemic antiviral therapy reduces the discomfort and duration of the acute infection and may reduce the severity of postherpetic neuralgia.
Table 25-2. Recommendations for Systemic Antiviral Treatment of Varicella-Zoster Virus*
IV, Intravenous; PO, by mouth; tid, three times a day.
* Dose should be adjusted in the presence of renal insufficiency.
27. Should I be concerned about the patient with herpes zoster involving the tip of the nose?
Lesions of herpes zoster involving the tip, side, or root of the nose indicate involvement of the nasociliary branch of the first division of the trigeminal nerve. This is known as Hutchinson’s sign and should alert you to the possibility of herpes zoster ophthalmicus (see Fig. 25-4). Ocular disease occurs in 20% to 70% of patients with ophthalmic zoster, and antiviral therapy as well as ophthalmologic evaluation is routinely recommended. The triad of herpes zoster with cutaneous involvement of the auditory canal and auricle, ipsilateral facial palsy, and excruciating ear pain is known as the Ramsay Hunt syndrome and is the result of viral reactivation within the geniculate ganglion.
28. Who should get the herpes zoster vaccine?
29. What is hand, foot, and mouth disease?
Hand, foot, and mouth disease (HFMD), or vesicular stomatitis with exanthem, is usually seen in infants or young children. Following a brief prodrome of fever, malaise, and sore throat, the characteristic enanthem develops. Red macules, vesicles, and ulcers may be seen on the buccal mucosa, tongue, palate, and pharynx (Fig. 25-5A). Lesions may also occur on the hands and feet (dorsal aspects, as well as the palms and soles) (Fig. 25-5B). HFMD is caused by one of several enteroviruses, most commonly coxsackievirus A16. It is highly contagious and spreads by direct contact via the oral–oral or oral–fecal route. Over the past 10 years, outbreaks of HFMD caused by enterovirus 71 have been reported in Asia and Australia. Although HFMD associated with coxsackievirus A16 infection is typically a mild illness, HFMD caused by enterovirus 71 has shown a higher incidence of neurologic involvement including fatal cases of encephalitis.
30. What is orf?
Human orf, or ecthyma contagiosum, is caused by a parapoxvirus that is usually contracted by direct exposure to infected, or recently vaccinated, sheep or goats. Milkers’ nodules are caused by a closely related virus found in cows. The lesions of both orf and milkers’ nodules are identical, consisting of dome-shaped, firm bullae that develop an umbilicated crust (Fig. 25-6). One to several lesions develop, usually on the hands and forearms. They generally resolve without therapy in 4 to 6 weeks.
Figure 25-6. Classic lesions of orf demonstrating a central ulceration and necrotic vesiculobullous edge.
Centers for Disease Control and Prevention (CDC): Orf virus infection in humans—New York, Illinois, California, and Tennessee, 2004–2005, MMWR 55(3):65–68, 2006.
