Are You Confident of the Diagnosis?
What you should be alert for in the history
A history of prodrome with acute stinging, itching, burning, paresthesias, and hyperesthesia in a single dermatome is characteristic of herpes zoster. Patients may also complain of constitutional symptoms (headache, malaise, fever).
Typically, pain begins and a unilateral rash of erythematous macules, papules, and edematous plaques follow in 4 to 14 days. The macules, papules, and plaques evolve into grouped vesicles or bullae on an erythematous base along the distribution of the sensory nerve (Figure 1). New vesicles continue to form over 3 to 5 days, evolve into pustules, which can occasionally become hemorrhagic, and ultimately crust over. Crusts fall off spontaneously within 4 weeks.
Acute zoster is generally limited to one dermatome and classically does not cross the midline. However, approximately 20% of people have rash that overlaps adjacent dermatomes and less frequently may cross the midline. The face and trunk are the most commonly involved sites and usually correspond to the areas most affected by primary varicella. Patients may have lymphadenopathy in a dependent region. Rarely, patients may have prodromal symptoms without the subsequent development of skin lesions, a phenomenon known as “zoster sine herpete”.
Expected results of diagnostic studies
Diagnosis is usually apparent with characteristic clinical examination alone; however, further testing is available and may be warranted in atypical or disseminated presentations, such as those seen in immunocompromised patients. Polymerase chain reaction (PCR) on a swab from the vesicle base is the most sensitive and specific test. Direct immunofluorescent antibody (DFA) testing can also be used if PCR is unavailable. Serological testing as well as viral culture are also available. Viral culture is very specific but takes 1-2 weeks for results and sensitivity is only 60-75%, and serologic assays are often only useful in retrospect and present significant challenges to interpreting the results.
The differential diagnosis of zoster includes herpes simplex, hand-foot-and-mouth disease, insect bites, drug eruption, scabies, primary varicella infection, and contact dermatitis. Zoster pain preceding findings on the skin may mimic cardiovascular pain if occurring in the appropriate distribution (chest, left arm). Pre-eruptive pain on the trunk may be mistaken for biliary or renal colic, pleurisy, duodenal ulcer, or appendicitis. If occurring in the ear, zoster pain may also mimic otitis media, headache, or stroke.
Herpes simplex virus (HSV) is a great imitator of zoster (Figure 2). Differentiation may be difficult without further testing. However, zoster recurs rarely, so if a patient complains of recurrent symptoms, think herpes simplex. HSV vesicles usually do not occur in a dermatomal distribution and may cross the midline. HSV patients usually will not have the characteristic pain and allodynia in a dermatomal distribution characteristic of zoster infection.
Primary varicella infection may be mistaken for zoster, however, this is less likely. Primary varicella infection is typically not limited to a single dermatome and is characterized by widespread skin involvement. In the history, be alert for lack of prior varicella infection; however, many older patients do not remember having had chickenpox.
Contact dermatitis may be distinguished from zoster based on several factors. Patients will not give a history of painful prodrome. The pruritus and rash usually is not in a dermatomal distribution and may cross the midline. There is typically a history of exposure to or contact with a substance in the area of the outbreak.
Hand-foot-and-mouth disease involves lesions on mucus membranes and distal extremities. Insect bites typically occur on the extremities and are on top of a wheal. A drug eruption may be distinguished from zoster by the time-course of lesions. The lesions of a drug eruption appear simultaneously versus zoster vesicles that appear gradually. Scabies tend to appear in body folds in a linear distribution. The lesions are typically pruritic and not painful as in zoster.
Who is at Risk for Developing this Disease?
According to CDC estimates, herpes zoster will affect 32% of the US population at some point in their lifetime, with that estimate climbing to 50% in persons living up to 85 years of age. There are an estimated 1,000,000 cases per year in the United States; however, the utilization of the varicella zoster virus (VZV) vaccine will likely significantly alter the epidemiology of the disease in years to come. The incidence in all people is 1.2-3.4 cases per 1,000 persons per year. The incidence is moderately higher in elderly patients being 3.9-11.8 per 1,000 persons per year. Immunosuppressed patients (HIV/AIDS, cancers, organ transplants, immune-mediated diseases, and immunosuppressive treatments) are also at higher risk for zoster. Recurrent zoster is uncommon but may occur in 1-6% of patients, with long-term follow-up studies showing higher risk of 5-6%.
A history of VZV exposure whether by vaccine or active chickenpox infection is a requirement for zoster. More than 90% of adults in the United States have been exposed at some point in life. Risk factors for zoster include older age, immunosuppressed states (i.e., HIV infection, leukemia/lymphoma patients, and those on immunosuppressive medications) and family history of zoster. There is a dramatic increase in zoster incidence with every 5 years of life. The sharpest spike is between 50 and 60 years of age. Other risk factors include psychological stress and possibly trauma.
What is the Cause of the Disease?
Zoster is caused by the VZV. Primary infection with VZV by airborne water droplets acquired typically in childhood results in chickenpox within 14 days of exposure.
The virus spreads from the skin along sensory fibers to the cranial or dorsal root ganglia by retrograde transport, infects ganglia tissue, and enters a latent state. VZV remains dormant for many years. Following an unknown trigger, possibly when cell-mediated immunity decreases below a crucial level, VZV is reactivated, replicates, and is transported along nerve axons in an anterograde fashion to the skin where virus particles infect neighboring skin cells. As VZV spreads down the axon it multiplies, causing neuron necrosis and inflammation.
Systemic Implications and Complications
The most common complication of zoster is postherpetic neuralgia (PHN), which is defined as persistent pain for more than 90 days after initial rash appearance. The reported risk of developing PHN varies depending on study and the definitions used, but one systematic review of 49 studies demonstrated risks between 5% to 30%. Studies that reported risk of PHN by age group consistently found that incidence rates increased significantly in patients older than 50 years of age, with rates of PHN being the highest in those 70 years of age or older. Other risk factors for PHN include severe prodromal pain with the acute rash, severe rash, allodynia, and a distribution in the trigeminal or brachial plexus dermatomes.
The best prevention of PHN is the prevention of herpes zoster. Additionally, clinical trials have also shown that early treatment with an antiviral (i.e., valacyclovir) plus gabapentin may reduce the severity and duration of PHN. The first-line treatment for mild PHN are topical treatments such as 5% lidocaine patch or 8% capsaicin patch. For patients with moderate to severe pain systemic therapy with gabapentin or pregabalin can be used. Alternative agents include opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressants (amitriptyline), selective serotonin and norepinephrine reuptake inhibitors (duloxetine and venlafaxine), and nerve blocks.
Of these medications, only gabapentin, pregabalin, 5% lidocaine patch, and 8% capsaicin patch have been approved by the FDA specifically for the treatment of PHN. In January of 2011, the FDA approved Gralise® as a once-daily medication for the treatment of post-herpetic neuralgia. Gralise® is an extended-release form of gabapentin that not only has been shown to significantly decrease PHN pain scores, but may also be associated with fewer side effects than its immediate-release counterpart. In 2012 the FDA approved Horizant®, gabapentin enacarbil, for the once daily therapy of PHN.
A particularly devastating complication of zoster is herpes zoster ophthalmicus (HZO), which results when VZV reactivates in the first branch of the trigeminal nerve (V1). V1 has three branches, including the nasociliary branch, the frontal branch, and the lacrimal branch. The lacrimal branch of V1 is the branch most commonly affected by zoster. When the nasociliary branch is involved, patients present with vesicles on the side and top of the nose, a finding known as Hutchinson’s sign. HZO occurs in 10-20% of zoster patients and is associated with ocular complications, blindness, lid ulceration, conjunctivitis, keratitis, uveitis, optic neuritis, retinal necrosis, and glaucoma. Patients with V1 involvement should be referred to an ophthalmologist (Figure 3).
Cutaneous and visceral dissemination of herpes zoster is of particular concern to immunosuppressed patients. Cutaneous dissemination, defined as greater than 20 vesicles outside the primary and adjacent zoster dermatome, occurs in 40% of immunosuppressed patients. Cutaneous dissemination may be a marker of visceral involvement, which occurs in 10% of immunosuppressed patients, and can herald significant morbidity and mortality. Patients with HIV are observed to have a higher rate of neurological and ophthalmic complications.
Other complications include VZV retinitis, bacterial superinfection (cellulitis, zoster gangrenosum, septicemia), visceral VZV dissemination (pneumonia, hepatitis, myocarditis, pericarditis, arthritis, esophagitis), encephalitis, transverse myelitis, ascending myelitis, peripheral and cranial nerve palsies or paralysis, sensory loss, or the Ramsay Hunt syndrome (hearing loss, vertigo, facial paresis, cerebral arteritis).
In the immunocompetent patient, first-line treatment is valacyclovir 1,000 mg every 8 hours or famciclovir 500 mg every 8 hours for 7 days. If the pain at presentation is equal to or greater than 4 (on a 10-point scale), the addition of gabapentin (and analgesics) to the antiviral therapy may reduce the incidence and/or severity of PHN, and is now the standard of care. The old standard of care was acyclovir 800 mg 5 times daily (every 4 hours) for 7-10 days but often results in decreased patient compliance due to the frequent dosing schedule (but should still be considered in some patients as it is significantly cheaper than valacyclovir and famciclovir).
Treatment with antiviral medication has been shown to reduce the duration of herpes zoster and zoster-related pain specifically by nearly half. At any point if zoster becomes disseminated (>20 vesicles outside the primary and adjacent dermatome), if lesions are nonhealing, or if the patient develops nodules or deep ulcerations, immunosuppression may be suspected and intravenous acyclovir is indicated.
Oral antiviral therapy is acceptable treatment in immunosuppressed patients if the infection is uncomplicated. In patients with suspected visceral involvement or in immunocompromised patients at high risk for dissemination, consider hospitalization and treatment with acyclovir 10 mg/kg IV every 8 hours. Treatment may be switched to oral antivirals when infection is controlled. Acyclovir-resistant VZV is rare, if the patient is not responding to standard treatment, consider intravenous foscarnet or cidofovir.
Pain control is a problem in zoster patients, however, there is poor evidence to recommend a specific regimen. Options include opioids, NSAIDs, gabapentin or pregabalin, amitriptyline, and acetaminophen. Oral corticosteroids may improve pain intensity in the short term but do not prevent PHN and may be associated with other comorbidities.
Zostavax®, a live, attenuated, varicella-zoster vaccine that is greater than 10 times the strength of Varivax® (a live, attenuated vaccine used to prevent against primary varicella infection), was approved in 2006 for use in individuals aged 60 years of age and older for the prevention of herpes zoster. In clinical trials involving more than 38,000 adults 60 years of age or older with no prior history of shingles, the vaccine group had 51% fewer episodes of herpes zoster compared to the placebo group. Efficacy was highest for persons 60-69 years of age (64%) and declined with increasing age, reaching a nadir of only 18% in participants 80 years of age or older. In 2011, the FDA approved Zostavax® for persons 50 to 59 years of age; in this age group the vaccine was shown to reduce the risk of zoster by 69.8%. In patients who develop herpes zoster despite receiving the vaccine, the acute illness is usually milder and the incidence of PHN is decreased by 39%.
Considering that the greatest risk factor for herpes zoster (other than age and immune status) in VZV seropositive persons is familial predisposition, persons with a family history of shingles should be urged to receive the vaccine. The vaccine is contraindicated in pregnancy and in those who are highly immunosuppressed, although a recent phase 3 herpes zoster vaccine (HZ/su vaccine), which utilizes a single VZV glycoprotein in an adjuvant system, may hold promising possibilities for future application. Since this vaccine contains only a single virus protein and therefore cannot replicate, it could prove promising in those with impaired cellular immunity who are at the highest risk for herpes zoster. Additionally, unlike Zostavax®, the HZ/su vaccine did not show decreased efficacy in older adults (>70 years of age).
In patients who have already had acute zoster, a herpes zoster vaccine is probably not necessary depending on the age at which the patient was affected. There is no contraindication to vaccine at this juncture. If the patient had acute zoster at a younger age, vaccination 50 years of age would certainly not be wrong.
Optimal Therapeutic Approach for this Disease
Optimally, patients present within 72 hours of first vesicle formation. Patients should be treated with valacyclovir 1,000 mg every 8 hours or famciclovir 500 mg every 8 hours for 7 days. If patients present after the 72-hour window, they may still benefit from antiviral therapy, especially if new vesicles are still forming. There is not enough evidence to suggest for or against antivirals at this juncture. In immunocompromised patients or patients with suspected visceral involvement, consider hospitalization with acyclovir 10 mg/kg IV every 8 hours until the rash is under control and then switch to oral antivirals.
Expect new vesicles to appear for 3 to 4 additional days, form pustules within 1 week, ulcerate and crust 3 to 5 days later. Crusts will fall off within 3 to 4 weeks. Scarring and hypopigmentation persist for an undetermined amount of time. If there is persistent vesicle formation beyond 7 days or atypical rash healing, be alert for acyclovir-resistant VZV and consult an infectious disease physician for further assistance.
Isolation of patients with active zoster is unnecessary unless the patient is expected to be around immunosuppressed individuals or individuals who have not had chickenpox or the varicella vaccine. Patients should be advised to stay out of sunlight, because heat and ultraviolet light exacerbate zoster. Treatment with antiviral medications has been shown to reduce the duration of herpes zoster and zoster-related pain specifically by nearly half.
Patients should be monitored for progression of rash stages and ultimate resolution of vesicles at 3- to 7-day intervals depending on the area involved and severity of symptoms. If there is persistent vesicle formation beyond 7 days or atypical rash healing, be alert for acyclovir-resistant VZV or immunosuppression. Patients may require infectious disease consult and medication change to intravenous acyclovir, foscarnet, or cidofovir. After resolution of the rash, no antiviral maintenance therapy is necessary.
What is the Evidence?
Tyring, SK, Moore, AY, Lupi, O. “Mucocutaneous manifestations of viral disease”. 2010. (A comprehensive overview of herpes zoster with a large collection of clinical images.)
Arvin, AM, Gershon, AA. “Varicella-zoster virus:virology and clinical management”. 2000. (Textbook dedicated to the varicella zoster virus containing detailed pathophysiology of disease.)
Weinberg, JM, Herpes, zoster. “epidemiology, natural history, and common complications”. J Am Acad Dermatol. vol. 57. 2007. pp. 130-5. (Updated review of herpes zoster epidemiology, risk factors, diagnosis, and common complications.)
Gnann, JW, Whitley, RJ. “Clinical practice: herpes zoster”. N Engl J Med. vol. 347. 2002. pp. 340-6. (Overview of herpes zoster from epidemiology to treatment and prevention of complications.)
Wood, MJ, Kay, R, Dworkin, RH, Soong, SJ, Whitley, RJ. “Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials”. Clin Infect Dis. vol. 22. 1996. pp. 341-7. (Meta-analysis demonstrating better clinical outcomes for acute herpes zoster patients treated with antiviral therapy.)
Hernandez, PO, Javed, S, Mendoza, N, Lapolla, W, Hicks, LD, Tyring, SK. “Family history and herpes zoster risk in the era of shingles vaccination”. J Clin Virol. vol. 52. 2011. pp. 344-8. (Epidemiologic study which demonstrated that a positive family history of shingles significantly increases a person’s risk of developing herpes zoster.)
Lapolla, W, Digiorgio, C, Haitz, K, Magel, G, Mendoza, N, Grady, J, Lu, W, Tyring, S. “Incidence of postherpetic neuralgia after combination treatment with gabapentin and valacyclovir in patients with acute herpes zoster: open-label study”. Arch Dermatol. vol. 147. 2011. pp. 901-7. (Clinical study which demonstrated that addition of gabapentin to antiviral therapy (and analgesics) for acute shingles patients with moderate to severe pain markedly reduced the incidence and severity of PHN.)
Cohen, JI. “A New Vaccine to Prevent Herpes Zoster”. N Engl J Med. vol. 372. 2015. pp. 2149-2150. (Phase 3 clinical study detailing results of HZ/su vaccine and its potential application in those with decreased cellular immunity and in those 70 years of age and older.)
Kawai, K, Gebremeskel, BG, Acosta, CJ. “Systematic review of incidence and complications of herpes zoster: towards a global perspective”. BMJ Open [Internet]. 2016 Apr 11. (Systematic review of incidence of herpes zoster as well as complications including post-herpetic neuralgia.)
Solomon, CG, Johnson, RW, Rice, AS. “Postherpetic Neuralgia”. N Engl J Med. vol. 371. 2014. pp. 1526-1533. (Case presentation and review article about postherpetic neuralgia including overview, epidemiology, and treatment and prevention options.)
Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 2015. (Chapter from CDC textbook with most recent epidemiological data on varicella zoster virus including vaccine information and treatment recommendations.)
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This article originally appeared on Dermatology Advisor