Primary infection with VZV results in varicella or chickenpox, a generalized vesicular exanthem typically preceded by a brief prodromal phase characterized by low-grade fever, malaise, and mild respiratory symptoms.31–33 The eruption classically follows a craniocaudal progression and manifests as successive crops of pruritic vesicles on an erythematous base, often described as a “dew drop on a rose petal” (Fig. 1).31,34 These lesions evolve asynchronously into pustules and crusts, and consequently, lesions at different stages of development commonly coexist within the same anatomical area (Fig. 2).31,35 The exanthem predominates on the trunk and face, with relative sparing of the extremities.31 In addition to cutaneous involvement, vesicles or erosions of the oral mucosa are frequent, and conjunctival involvement may also occur, although less commonly.31,35

Figure 1.

Acute varicella lesion. Courtesy: Lauro Lourival Lopes Filho, MD, Ph.D.

Figure 2.

Polymorphic rash of varicella. Courtesy: Silvio Alencar Marques, MD, PhD.

In healthy children, varicella is usually self-limiting.33,35 However, in adults, pregnant women, and immunocompromised patients, the disease can be severe, with complications such as pneumonia, hepatitis, and encephalitis.31,33,35 Secondary bacterial infections of excoriated lesions are common, particularly in young children.31,33,35 Cutaneous scarring may occur in severe or hemorrhagic forms of the disease, which is rare.31

Herpes zoster, or shingles, represents reactivation of latent VZV from sensory ganglia.9,36,37 The condition typically begins with localized pain, burning, or paresthesia along a dermatomal distribution, followed by the appearance of grouped vesicles on an erythematous base.37 The eruption is unilateral and does not cross the midline, providing a key diagnostic clue.9,37 The thoracic and cranial dermatomes are the most frequently involved (Fig. 3).9,24,38

Figure 3.

Herpes zoster: typical dermatomal involvement with erythema and vesicles.

In selected patients (particularly those who are immunocompromised), VZV reactivation may be accompanied by transient viremia, leading to the appearance of vesicular lesions at sites distant from the primary dermatome.39,40 In such cases, disseminated herpes zoster may partially mimic primary varicella, with scattered varicella-like lesions coexisting with a dominant unilateral dermatomal eruption.39–41 This atypical presentation can complicate clinical recognition and management, underscoring the importance of careful assessment of lesion distribution and host immune status.

Lesions typically evolve through vesicular, pustular, and crusting stages over 7–10 days.9 New vesicles may continue to emerge for several days, and pain frequently precedes the appearance of the rash or persists beyond its resolution.9 In a subset of patients (particularly older adults), postherpetic neuralgia may endure for months or even years.12,42

Atypical presentations are relatively common and may obscure diagnosis. Herpes zoster sine herpete presents as dermatomal pain in the absence of cutaneous lesions, whereas disseminated zoster can mimic primary varicella infection, particularly in immunocompromised individuals.10,11,43 In this context, herpes zoster may manifest as exuberant and destructive morphologies, including extensive vesiculation with necrotic changes. Fig. 4 illustrates a severe necrotic presentation in an HIV-infected patient, in which, despite marked tissue damage, lesions remained strictly confined to a single dermatomal distribution, reinforcing unilateral involvement as a critical diagnostic feature, even in advanced or atypical cases.23,44

Figure 4.

Extensive necrotic herpes zoster in an HIV-infected patient. Severe unilateral dermatomal involvement with extensive vesiculation and necrotic changes. Courtesy: Hiram Larangeira de Almeida Jr., MD, PhD.

The involvement of anatomically complex regions, such as the cervical and facial areas, can complicate diagnosis.10,45 Cervical and facial herpes zoster may resemble other inflammatory, vesiculobullous, or infectious dermatoses, especially early on (Figs. 5 and 6).2,9,10,45 In both cases, recognition of a unilateral dermatomal pattern that respects the midline is essential for accurate diagnosis.36

Figure 5.

Cervical herpes zoster. Grouped vesicles on an erythematous base were distributed unilaterally along a cervical dermatome, respecting the midline. Courtesy: Hiram Larangeira de Almeida Jr., MD, PhD.

Figure 6.

Facial herpes zoster. Unilateral vesicular eruption involving the facial region, consistent with the trigeminal nerve distribution.

Reactivation of the trigeminal ganglion, on the face, may lead to ophthalmic complications, including keratitis, uveitis, and permanent visual impairment.3,23,45,46 Ramsay Hunt syndrome, resulting from facial nerve involvement, is characterized by vesicular lesions affecting the external ear or oral mucosa and is frequently accompanied by facial paralysis and auditory symptoms.3,23,45

In dermatological practice, prompt recognition of early, atypical, and anatomically challenging presentations is essential. Early initiation of antiviral therapy limits viral replication, shortens the duration of acute pain, and reduces the risk of cutaneous and neurological complications.47–49

The most frequent cutaneous complication is a secondary bacterial infection of excoriated or ruptured vesicles, commonly caused by Staphylococcus aureus or Streptococcus pyogenes.3,5 Impetiginization can result in scarring or post-inflammatory dyspigmentation.33,35 In rare instances, necrotizing fasciitis may develop, particularly in immunocompromised patients.3,5 Chronic or ulcerative lesions are also observed in patients receiving long-term corticosteroid or other immunosuppressant therapy.3,5,23

Postherpetic Neuralgia (PHN) is the most debilitating sequelae of herpes zoster.51 It is characterized by persistent neuropathic pain lasting for at least 90-days after rash onset.52 The incidence and severity of PHN increase with age, reflecting cumulative neuronal injury and reduced regenerative capacity of the nervous system.53 Pathophysiologically, PHN results from inflammation, demyelination, and necrosis of the affected sensory neurons, leading to altered pain signaling within the dorsal horn.54–56 Clinically, patients describe burning, shooting, or stabbing pain, often accompanied by allodynia or hyperesthesia.50,52

Other rare neurological complications include meningoencephalitis, transverse myelitis, and cranial nerve paralysis.3,5 VZV vasculopathy, resulting from viral invasion of the cerebral arteries, can manifest as stroke or focal neurological deficits.3,5,9 In immunocompromised individuals, disseminated infections may involve the central nervous system, with high morbidity.23,44,57

Herpes zoster ophthalmicus, arising from the reactivation of the ophthalmic branch of the trigeminal nerve, can cause keratitis, uveitis, and retinitis, potentially leading to permanent vision loss.46,58 The presence of vesicular lesions on the tip of the nose (Hutchinson’s sign) indicates nasociliary nerve involvement and predicts ocular complications.46,58 Ramsay Hunt syndrome, caused by involvement of the geniculate ganglion, presents with auricular vesicles, facial paralysis, and sensorineural hearing loss, often requiring multidisciplinary care.58,59

Systemic dissemination of VZV can lead to serious extracutaneous complications, including pneumonitis, hepatitis, and disseminated intravascular coagulation.33,35,45 These events occur predominantly in immunocompromised individuals and during pregnancy, in whom viral replication is often more extensive and immune control is diminished.23,60 Varicella pneumonia represents the most severe of these manifestations, carrying a mortality rate of 10%‒30% in untreated adults and requiring prompt recognition to avoid rapid respiratory deterioration.33,35

Transplacental transmission during pregnancy may result in congenital varicella syndrome, a rare but devastating condition marked by limb hypoplasia, cicatricial skin lesions, ocular abnormalities, and neurodevelopmental impairment.35,60 Additional risks emerge when aspirin is administered during active varicella infection, given its association with Reye syndrome, characterized by acute encephalopathy and hepatic steatosis.35

For dermatologists, maintaining a high index of suspicion regarding these systemic outcomes is essential. Early identification of cutaneous patterns suggestive of severe or disseminated disease supports timely referral, multidisciplinary coordination, and initiation of appropriate antiviral therapy, thereby reducing the likelihood of long-term morbidity.

Pattern recognition remains central to the clinical diagnosis of varicella-zoster virus infections.2,11 Varicella typically presents with lesions at different stages of evolution (macules, papules, vesicles, and crusts) distributed in a centripetal pattern involving the trunk, face, and scalp.33,35 In contrast, herpes zoster produces a unilateral dermatomal eruption of grouped vesicles on an erythematous base, frequently preceded or accompanied by neuropathic pain. The lack of lesions crossing the midline is a key diagnostic feature.2,11,43

Immunocompromised individuals and patients with disseminated disease may exhibit atypical or ambiguous presentations that resemble other vesiculobullous conditions.23,44,61 Relevant differential diagnoses include herpes simplex virus infections, impetigo, allergic contact dermatitis, bullous drug reactions, and autoimmune blistering disorders.2,11,35 A careful evaluation of the lesion distribution, morphology, temporal evolution, and pain characteristics helps delineate VZV from these mimickers.33,35

Additional differentials for varicella include Mpox and, historically, smallpox. Although smallpox was eradicated in 1980, this comparison is clinically instructive.35 Mpox lesions are typically monomorphic and evolve more slowly, whereas varicella lesions are asynchronous at multiple developmental stages.35 Hand-foot-and-mouth disease may also resemble early varicella; however, its vesicles are confined predominantly to the hands, feet, and oral mucosa, with no tendency toward diffuse involvement.35

Other entities that may enter the differential diagnosis (particularly in atypical, severe, or disseminated presentations) include disseminated herpes simplex infection, pityriasis lichenoides et varioliformis acuta, rickettsial infections, drug eruptions, arthropod reactions, and scabies.2,33,35 A systematic approach that integrates morphology, distribution, symptom patterns, and host immune status enhances diagnostic accuracy and guides early therapeutic intervention.

Laboratory confirmation is recommended when the clinical diagnosis is uncertain or in high-risk settings such as pregnancy or immunosuppression.62,63 Polymerase Chain Reaction (PCR) testing, which detects VZV DNA in vesicular fluid, lesion crusts, or tissue biopsy specimens, is the most sensitive and specific method.62 PCR can differentiate between wild-type and vaccine strains and has largely replaced viral culture in clinical practice because of its rapid turnaround and higher sensitivity.63

Direct Fluorescent Antibody (DFA) testing remains a useful rapid diagnostic option when PCR is unavailable, although with lower sensitivity.62,64,65 The Tzanck smear, once widely used, can reveal multinucleated giant cells but cannot distinguish VZV from herpes simplex infection and is now of mainly historical interest.66,67

Serological testing can demonstrate prior exposure or immune status by detecting VZV-specific IgG; however, it is not useful for diagnosing acute herpes zoster.62,64,65 Rising IgM titers may indicate recent infection; however, false negatives are frequent in reactivation cases.62,64,65

Skin biopsy is rarely required but can be valuable in atypical, severe, and disseminated presentations. Histopathological examination typically demonstrates intraepidermal vesiculation with multinucleated keratinocytes, acantholysis, and eosinophilic nuclear inclusion bodies (Fig. 7).68 A superficial perivascular lymphocytic infiltrate, sometimes with scattered eosinophils, is also characteristic.68

Figure 7.

Skin histological section showing an intraepidermal vesicle with acantholysis, ballooning, and reticular degeneration in the epidermis. Note the multinucleated keratinocytes (arrow) and lymphocytic inflammatory infiltrate in the superficial dermis (Hematoxilyn & eosin, ×85) (A) Higher magnification demonstrating viral cytopathic changes. Multinucleated keratinocytes, nuclear molding, and peripheral chromatin margination ('ground glass' appearance) were observed (arrows) (Hematoxilyn & eosin, ×400) (B). Courtesy: Thiago Jeunon, MD.

The microscopic appearance of varicella closely mirrors that of herpes simplex virus infection, with both displaying multinucleated keratinocytes with molded nuclei and marginated chromatin.68 Because routine histology cannot reliably distinguish between the two, confirmatory studies are often necessary when morphology is ambiguous.68 Immunohistochemistry using VZV-specific antibodies or in situ hybridization can accurately identify viral DNA and resolve cases in which clinical or histological overlap complicates the diagnosis.64,65,68

In immunocompromised individuals (such as patients with hematologic malignancies, organ transplants, or those undergoing immunomodulatory therapy), VZV infection may present without the classic vesicular eruption.19,20,44,57 Lesions can be necrotic or hemorrhagic and can mimic bacterial or autoimmune blistering diseases.35 Disseminated zoster may develop without clear dermatomal limitation, and pain can be absent or minimal, leading to misdiagnosis as a drug reaction or vasculitis.23,44,57

Older adults may exhibit similar diagnostic challenges, particularly when neuralgia precedes the rash or when the eruption remains localized and subtle.12,69 Misattributing this pain to musculoskeletal or neuropathic pain can delay antiviral treatment initiation and increase the risk of postherpetic neuralgia.12,26,69 Dermatologists should maintain a high suspicion in older adults or immunocompromised patients presenting with localized neuropathic pain or atypical vesiculobullous lesions.

Early PCR testing of lesion material or biopsy for VZV detection is recommended in ambiguous presentations, as prompt confirmation allows for immediate antiviral therapy and prevents dissemination.64,65

Supportive care remains essential for both varicella and herpes zoster, complementing antiviral therapy when indicated. Adequate hydration should be encouraged, particularly in patients with high fever, extensive lesions, or oral discomfort that may limit fluid intake.33,70 Rest during the acute phase helps reduce systemic symptoms and may lower the risk of complications.36,49,70

Acetaminophen or ibuprofen is appropriate for fever and pain control across age groups. Acetylsalicylic acid is contraindicated in children and adolescents because of its association with Reye's syndrome.33,35 Pruritus can be managed with topical agents such as calamine lotion, oatmeal baths, cold compresses, and regular emollient use, along with oral antihistamines when needed.70 To minimize excoriation and secondary bacterial infection, patients should be advised to keep their nails short and avoid scratching.33,35

Preventing secondary infections is particularly important.9 Gentle cleansing of the affected area and application of antiseptic solutions, such as povidone-iodine, chlorhexidine, or boric acid, can reduce bacterial colonization.37,49 When signs of impetiginization arise, topical antibiotics may be used as adjunctive therapy while antiviral treatment proceeds.9,49,71

Oral antiviral therapy should be considered for patients with a substantial likelihood of severe disease to shorten the clinical course of varicella, reduce symptom intensity, and limit the risk of complications, oral antiviral therapy should be considered for patients with a substantial likelihood of severe disease.33,35 This group includes unvaccinated individuals aged ≥13-years, secondary household cases (which often manifest more intense presentations due to higher inoculum), patients with chronic dermatologic or pulmonary conditions, children receiving prolonged oral or inhaled corticosteroids, individuals with long-term acetylsalicylic acid exposure, and pregnancy.33,35 In contrast, healthy children typically do not benefit from antiviral therapy, as varicella in this population follows a self-limited course, and treatment provides only modest improvements.33,35

Intravenous antiviral therapy is recommended for immunocompromised individuals, such as those with malignant neoplasms, HIV infection, or ongoing immunosuppressive regimens.35,49,63 In varicella, timing is essential: treatment started within the first twenty-four hours after rash onset consistently yields the greatest reduction in viral replication and lesion progression.33,35

For herpes zoster, systemic antiviral therapy is recommended for all patients.9,72,73 Initiation within seventy-two hours of rash onset provides clearer clinical benefits, notably by limiting the formation of new lesions and reducing acute neuritic pain.63,74 Most patients can be effectively managed with oral agents; intravenous therapy becomes necessary when dissemination, ocular involvement, or significant immunosuppression is present.47,49,63

Acyclovir, valacyclovir, and famciclovir remain the principal therapeutic agents (Table 1). Valacyclovir and famciclovir provide superior bioavailability and simpler dosing schedules compared with acyclovir, which often facilitates adherence and supports a more consistent therapeutic response.58,59,73,75,76

Adjunctive corticosteroids may be considered for herpes zoster in selected immunocompetent adults with severe pain or extensive rashes, provided that antiviral therapy is administered concomitantly.49,72 Their use remains controversial because they do not prevent postherpetic neuralgia and may pose risks to older or frail individuals.47 Topical antivirals have limited efficacy and are not recommended for use.63

Pain control is central to the management of herpes zoster and often requires a multimodal approach. During the acute phase, nonsteroidal anti-inflammatory drugs, analgesics, or short courses of opioids can be used to treat nociceptive pain.77 Neuropathic pain agents, such as gabapentin, pregabalin, or tricyclic antidepressants, should be introduced early if neuralgia develops, and even in the acute phase.24,77,78 Topical lidocaine patches and capsaicin creams may provide additional relief.9

Persistent pain lasting beyond 90-days is defined as PHN.24,77,78 Management may require higher doses of gabapentinoids, combination therapy, or referral to pain specialists.24,79,80 Preventive strategies, particularly early antiviral therapy and vaccination, are more effective than late-stage treatment.47

Vaccination has transformed the epidemiology of VZV infections, markedly reducing the incidence of varicella and herpes zoster.81,82

For the prevention of varicella, routine childhood immunization is based on a two-dose schedule with a live-attenuated varicella vaccine administered at 15-months (as part of the tetravalent formulation) and at 4-years of age, conferring durable protection.83 Although breakthrough infections may occur, they are typically mild. In a small proportion of vaccinated individuals, the attenuated vaccine strain may later reactivate and manifest as herpes zoster.31

Recent updates in immunization policies have refined the recommendations regarding combined formulations. In 2025, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC) recommended the suspension of the combined Measles, Mumps, Rubella, and Varicella (MMRV) vaccine due to safety concerns, favoring the separate administration of MMR and varicella vaccines in young children.84 Divergent positions remain among professional societies, and national schedules may continue to evolve.85

In contrast, the prevention of herpes zoster has undergone a definitive shift. Although a live-attenuated zoster vaccine (Zostavax®) was previously available, it is no longer recommended by the CDC and was discontinued in the United States in 2020.86,87 In Europe, its marketing authorization was formally withdrawn by the European Commission in June 2025 at the request of the manufacturer.86,87 Consequently, live-attenuated zoster vaccines no longer play a role in current prevention strategies against VZV.

The recombinant subunit vaccine (Shingrix®) is now the global standard of care for herpes zoster prevention.82 It is composed of VZV glycoprotein E combined with the AS01B adjuvant and induces robust and sustained immune responses, including in older adults and immunocompromised populations.4,27 The vaccine is administered in two intramuscular doses given 2–6 months apart and is recommended even for individuals with a prior history of herpes zoster.88 Vaccination may be initiated six months after an acute episode, with earlier administration acceptable when clinically appropriate.88 Efficacy consistently exceeds 90% against herpes zoster and postherpetic neuralgia.29,30,88,89 Local reactogenicity is common but transient.89 In comparison, live-attenuated zoster vaccines confer lower and less durable protection and are contraindicated in immunocompromised individuals.90,91