February 2015 Dermatology Look-Alikes
February 2015 Dermatology Look-Alikes
A 19-year-old male presented with a 1-day history of painful lip blisters. Two days ago, he felt as if the affected area was tingling and reported a subjective fever. He had 3 similar outbreaks in the last year, for which he only used topical anesthetics with limited relief after 2 weeks. He had no history of other medical issues. Physical examination revealed grouped pustules on an erythematous base along the vermilion border of his upper lip. The lesions were tender with associated submandibular lymphadenopathy. His nose, oral mucosae, and eyes were normal.
A 17-year-old male with B-cell lymphoma and on chemotherapy presented with a 5-day history of a painful rash. One week ago, he felt pain and pruritus before the rash appeared on his arm. It spread to his back and leg 2 days later. Papulovesicular lesions were seen on his left medial arm. His lower back exhibited ulcerated vesicles on an erythematous base in a linear pattern. Grouped vesicles on an erythematous base were seen on his left medial thigh and lateral calf. They exhibited exquisite tenderness. There was no associated lymphadenopathy.
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Herpes simplex viruses type 1 (HSV1) and type 2 (HSV2) produce primary and recurrent vesicular eruptions. They are ubiquitous infections that affect over half of the world’s population.1
While HSV1 is classically associated with orolabial lesions, it has become a significant cause of genital herpes among young adults. However, HSV2 remains the most common cause of genital ulcers and is mainly transmitted sexually,2 whereas HSV1 is often transmitted through nonsexual contacts and contaminated oral secretions.
Asymptomatic individuals can transmit HSV to others via chronic viral shedding. The virus replicates at the site of inoculation and travels by retrograde motion to the dorsal root ganglia. It remains latent until reactivation, which occurs spontaneously or is triggered by stress, ultraviolet light, fever, local tissue damage, or immunosuppression.3 When the virus is reactivated, it moves along sensory neurons to innervated sites, replicates, and forms vesicles. Seroconversion occurs in 3 to 4 weeks.1
The clinical presentation of HSV varies. Symptoms present 3 to 7 days after primary exposure with a prodrome of tender lymphadenopathy, malaise, anorexia, and fever before mucocutaneous lesions appear. Localized pain, burning, or tingling can also precede the lesions. The vesicles, which are painful, grouped, and on an erythematous base, may be umbilicated initially and then become pustules or ulcerations with a scalloped border. The lesions develop a crust and resolve within 2 to 6 weeks. Prodromes can precede recurrent lesions, but are often fewer in number, are not as severe, and last for a shorter duration than prodromes that precede primary infections.1,3 HSV is also a common trigger of erythema multiforme major.4
While most primary orolabial infections are asymptomatic, symptomatic primary orolabial infections present as gingivostomatitis5 or as pharyngitis and a syndrome that resembles mononucleosis, with lesions on the gingivae and buccal mucosa.2 Recurrent lesions appear most often on the vermilion border of the lip (i.e., cold sores).1,2,5 The majority of individuals with HSV1 do not have recurring lesions, but 5% to 10% of patients with HSV1 have more than 5 recurrences per year. With genital herpes, the frequency and severity of recurrences correlate with the severity of the primary infection and tend to decrease over time.1,3
In addition to the classic presentations of HSV1 and HSV2, HSV can present in other anatomic locations. Herpetic whitlow occurs after inoculation of the skin of the distal phalanx. It is self-limited, but must be differentiated from bacterial felon or paronychia.3 Herpes gladiatorum is the passage of HSV1 through the skin of athletes in contact sports. Athletes may require prophylactic antiviral therapy.6 Eczema herpeticum, the widespread cutaneous dissemination of HSV, occurs in children with atopic dermatitis or patients with impaired skin barriers and can be complicated by bacterial superinfections. Ocular herpes, a cause of corneal blindness, causes keratoconjunctivitis and requires antiviral therapy. Serious and fatal forms of herpes include neonatal herpes, meningoencephalitis, and disseminated disease in immunocompromised hosts.1,3
Several methods exist for the diagnosis of HSV infection. The Tzanck smear is rapid and inexpensive; it identifies multinucleated epithelial giant cells, intranuclear inclusion bodies (Cowdry type-A inclusions), and ballooning degeneration from scrapings of a vesicle’s base. However, it cannot differentiate HSV from herpes zoster. Direct fluorescent antibody (DFA) testing is often preferred due to its greater sensitivity and ability to differentiate between HSV and zoster. Viral culture requires 2 to 7 days and is reserved for active lesions in undiagnosed primary cases. Polymerase chain reaction (PCR) is useful for detecting HSV in the cerebrospinal fluid for the diagnosis of herpes encephalitis. For prevalence studies and establishing serostatus, Western blot is the serologic assay that can distinguish between different types of HSV.2,3
The differential diagnosis of oral HSV infection includes herpes zoster, aphthous stomatitis, erythema multiforme, herpangina, hand, foot, and mouth disease, pemphigus vulgaris, oral candidiasis, Behcet disease, and chemotherapy-induced mucositis. Herpes zoster may be hard to distinguish from HSV infection if herpes zoster is not accompanied by a dermatomal distribution. However, herpes zoster is intensely symptomatic and can be distinguished by DFA or PCR. Unlike HSV infection, aphthous ulcers have no vesicular stage, prodrome, or systemic symptoms. Erythema multiforme exhibits an explosive and widespread onset of irregular ulcers with or without target lesions. Herpangina has a predilection for the posterior oral cavity and exhibits seasonal prevalence, unlike HSV. Hand, foot, and mouth disease is common in children, has a predilection for the anterior oral cavity, and is accompanied by characteristic lesions on the hands and feet.1,3 Pemphigus vulgaris involves vesicular eruptions like HSV infection, but the ulcers are generalized, irregular and produce a positive Nikolsky sign.7 Oral candidiasis can present with erythema, but typically exhibits a white, cheese-like coating of the oral mucosae.1 Behcet disease is a small-vessel vasculitis affecting the mouth, genitals, eyes, and/or skin; it does not typically present on the external lip.8 A history of chemotherapy or human immunodeficiency virus infection should raise suspicion for coexisting infections or drug-induced reactions.3
Various antiviral agents are available to decrease the duration and frequency of lesions, viral shedding, and pain. Oral valacyclovir, oral famciclovir, and topical penciclovir are preferred for serious and recurrent orolabial herpes in immunocompetent hosts. Oral agents can also be used prophylactically before exposure to known triggers and are generally preferred for genital herpes. Intravenous acyclovir is necessary for neonatal HSV, severe eczema herpeticum, systemic complications, and serious infections in immunocompromised patients.2,5,6 Furthermore, strains of HSV that are resistant to acyclovir are a growing problem in immunocompromised patients, and foscarnet is the only drug approved by the FDA for these cases.1,3
Oral agents can be used for chronic suppressive therapy, especially in patients with more than 6 outbreaks per year; they can also reduce asymptomatic viral shedding. Recommending daily suppressive therapy, along with education about condom use and abstinence during active outbreaks, is important when treating patients with seronegative partners.3,6
The patient was prescribed 2g of oral valacyclovir twice daily for 1 day. He returned 3 days later with complete resolution of his symptoms.
Illneses to consider in differential diagnosis for oral herpes simplex infection
|Hand, foot, and mouth disease|
The varicella-zoster virus (VZV) causes both varicella (chickenpox) and herpes zoster (shingles). Prior to the introduction of the varicella vaccine in the United States in 1995, most children were infected with wild-type VZV causing varicella, a self-limited disease with a highly pruritic, contagious rash. VZV remains latent and reactivates later in life causing herpes zoster in 20% of healthy adults and 50% of immunocompromised individuals.
Herpes zoster can occur at any age, but incidence and severity increase in late adulthood and with weakened immune systems. Risk factors include stress, fever, radiation therapy, local trauma, compromised immune systems, and a positive family history of herpes zoster.1,9
An outbreak of herpes zoster occurs when the virus, which remains latent in the dorsal root ganglia, begins replicating. This replication causes painful ganglionitis and neuronal inflammation with intensifying neuralgia as the virus moves down the sensory nerve axon to the associated mucocutaneous regions. The vesicles that develop in herpes zoster contain fluid that can transmit the VZV, causing varicella in seronegative individuals. Asymptomatic viral shedding and transmission is not common.9,10
Outbreaks of herpes zoster are preceded by a prodrome of localized pruritus, tingling, tenderness, pain, and/or hyperesthesia. The pain can be severe. Some persons have these symptoms without subsequent cutaneous lesions (zoster sine herpete), but most exhibit a dermatomal distribution of painful, grouped vesicles on an erythematous base. The lesions can present in multiple dermatomes, and while most are unilateral, some can cross the midline. The trunk and face are most often affected.1,9
Immunocompromising factors that increase risk for herpes zoster
|Cancer, especially leukemia and lymphoma|
|Human immunodeficiency virus infection|
|Bone-marrow or solid-organ (renal, cardiac, liver, and lung) transplantation|
|Use of immunosuppressive medications, including steroids, chemotherapy, or transplant-related immunosuppressive medications|
|Source: Centers for Disease Control and Prevention. Shingles (herpes zoster): Clinical overview. Available at cdc.gov/shingles/hcp/clinical-overview.html|
Although these outbreaks typically resolve without sequelae in children and young adults, complications arise in older and immunocompromised patients. Postherpetic neuralgia, a burning and stabbing sensation in the affected dermatome, causes exquisite pain approximately 1 month after the cutaneous lesions have resolved. Postherpetic neuralgia increases with age and does not respond to antiviral therapy.11 Lesions on the nasal tip in the distribution of the nasociliary branch (Hutchinson sign) involve the ophthalmic division of the trigeminal nerve and require ophthalmological evaluation. If the geniculate ganglion of the facial nerve is involved (Ramsay Hunt syndrome), the external auditory canal, tympanic membrane, and anterior tongue can be affected. Lesions in cervical, thoracic, and lumbar dermatomes may lead to peripheral motor neuropathies and temporary weakness.1,9,12
Disseminated herpes zoster is a serious complication in elderly or immunocompromised patients with lymphoreticular malignancy or acquired immune deficiency syndrome (AIDS). Low levels of anti-VZV antibodies are a significant risk factor. It is defined as more than 20 cutaneous lesions outside the initially affected dermatome. The lesions may exhibit atypical features, such as umbilication, hemorrhage, or gangrene, and the vesicles are not always grouped. Intravenous antiviral therapy is necessary for 2-3 days, or until visceral dissemination has been ruled out.13,14
The diagnosis of herpes zoster is usually made by history and physical examination, especially if the patient has a history of varicella or administration of the live vaccine.1 A Tzanck smear can confirm the diagnosis, although direct fluorescent antibody (DFA) or polymerase chain reaction (PCR) may be necessary if the patient’s history indicates that a herpes simplex virus (HSV) is equally probable. Immunohistochemical staining can differentiate between HSV and VZV in samples of vesicular fluid. PCR, however, has the highest sensitivity, can be detected in a variety of secretions, and is preferred in severely immunocompromised individuals.9,10
The differential diagnosis for herpes zoster includes HSV, bacterial skin infections, pemphigus vulgaris, Behcet disease, local contact dermatitis, and phytophotodermatitis. History of present illness and past medical history is usually sufficient to differentiate herpes zoster from the other entities. Diagnostic laboratory techniques and histology can confirm the diagnosis in equivocal cases.1,9
Herpes zoster, like HSV infection, has no cure, so therapy is directed at decreasing morbidity. Oral antiviral agents acyclovir, valacyclovir, and famciclovir are most effective when given within 3 days of disease onset, but they are still helpful 1 week later. Famciclovir and valacyclovir reduces the duration of postherpetic neuralgia in the elderly, but those agents have not been shown to decrease the incidence of postherpetic neuralgia.
In immunocompromised patients or patients with serious complications, intravenous acyclovir is necessary.1,9 Postherpetic neuralgia is at least partially relieved by gabapentin, nortriptyline, pregabalin, and topical lidocaine or capsaicin.11 The live attenuated herpes zoster vaccine decreases the development of herpes zoster and the incidence of postherpetic neuralgia. The vaccine is now recommended to all immunocompetent individuals older than age 60 years.15
In our patient, vesicle fluid was positive for VZV and negative for HSV by PCR. He was admitted to the hospital and treated with intravenous acyclovir (10mg/kg) for 3 days. Once discharged, he took 1g of valacyclovir by mouth thrice daily for 1 week. The patient returned 2 weeks later with complete resolution of his lesions.
Ms. Bahrani is a third-year medical student and Dr. Holcomb is a second-year dermatology resident at Baylor College of Medicine in Houston.
- Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, Pa.: Elsevier Saunders; 2012:1321-1334.
- Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296(8):964-973. Available at jama.jamanetwork.com/article.aspx?articleid=203222
- Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 2007;57(5):737-763.
- Kamala KA, Ashok L, Annigeri RG. Herpes-associated erythema multiforme. Contemp Clin Dent. 2011;2(4):372-375. Available at ncbi.nlm.nih.gov/pmc/articles/PMC3276871
- Arduino PG, Porter SR. Oral and perioral herpes simplex virus type 1 (HSV-1) infection: review of its management. Oral Dis. 2006;12(3):254-270.
- Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections: an evidence-based review. Arch Intern Med. 2008;168(11):1137-1144. Available at archinte.jamanetwork.com/article.aspx?articleid=414294
- Kershenovich R, Hodak E, Mimouni D. Diagnosis and classification of pemphigus and bullous pemphigoid. Autoimmun Rev. 2014;13(4-5):477-481.
- Ambrose NL, Haskard DO. Differential diagnosis and management of Behcet syndrome. Nat Rev Rheumatol. 2013;9(2):79-89.
- Gershon AA, Gershon MD. Pathogenesis and current approaches to control of varicella-zoster virus infections. Clin Microbiol Rev. 2013;26(4):728-743. Available at cmr.asm.org/content/26/4/728.long
- Nagel MA, Choe A, Cohrs RJ, et al. Persistence of varicella zoster virus DNA in saliva after herpes zoster. J Infect Dis. 2011:204(6):820-824. Available at jid.oxfordjournals.org/content/204/6/820.long
- Johnson RW, Rice AS. Clinical practice. Postherpetic neuralgia. N Engl J Med. 2014;371(16):1526-1533.
- Yawn BP, Saddier P, Wollan PC, et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82(11):1341-1349.
- Gomez E, Chernev I. Disseminated cutaneous herpes zoster in an immunocompetent elderly patient. Infect Dis Rep. 2014;6(3):5513.
- James WD, Berger TG, Elston DM, eds. Andrews’ Diseases of the Skin. 11th ed. Philadelphia, Pa.: Elsevier Saunders; 2011:373.
- Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352(22):2271-2284. Available at nejm.org/doi/full/10.1056/NEJMoa051016
All electronic documents accessed on January 29, 2015.