Key Terms
Herpes Zoster
Herpes zoster ophthalmicus
Ramsey-Hunt syndrome
Herpes Simplex
Disseminated infection
Eczema herpeticum
Herpes gladiatorum
Herpetic whitlow
Hutchinson sign
Neonatal herpes simplex virus infections
Blisters and vesicles represent a common category of cutaneous disease. Blisters are an important physical finding because only a limited number of diseases present in this fashion. Usually, in bullous conditions, the clinical presentation, biopsy results, and results of direct immunofluorescent studies will allow for a singular diagnosis. A biopsy from a fresh blister is of greater use in the diagnosis because blisters can occur by different mechanisms (e.g., spongiosis, acantholysis). Blisters may be broadly divided into fragile and and tense blisters.
- •
Allergic contact dermatitis (severe)
- •
Bullous pemphigoid
- •
Bullous drug eruption
- •
Bullous eruption of diabetes
- •
Bullous fixed drug eruption
- •
Cicatricial pemphigoid
- •
Dermatitis herpetiformis
- •
Dyshidrotic hand dermatitis
- •
Epidermolysis bullosa acquisita
- •
Epidermolysis bullosa (genetic)
- •
Erythema multiforme
- •
Hand, foot, and mouth disease
- •
Herpes simplex virus infection
- •
Herpes gestationis
- •
Linear immunoglobulin A (IgA) bullous dermatosis
- •
Porphyria cutanea tarda
- •
Second-degree sunburn
- •
Smallpox
- •
Toxic epidermal necrolysis
- •
Vaccinia infection
- •
Varicella-zoster virus infection
Important History Questions
How long have the blisters been present?
Some conditions, such as allergic contact dermatitis due to poison ivy, may cause acute blistering, whereas other processes, such as bullous pemphigoid, may be chronic in nature.
Have you had blisters before, and do the blisters occur at the same site(s)?
Repetitive blistering could indicate an ongoing exposure, such as poison ivy, ongoing drug use or drug exposure (e.g., fixed drug eruption, repeat Stevens-Johnson syndrome), recurrent bullous erythema multiforme, or recurrent herpes simplex infection.
Are the blisters symptomatic?
Some vesiculobullous disorders are asymptomatic (bullous diabeticorum), whereas others are painful (e.g., toxic epidermal necrolysis) and others are pruritic (e.g., dermatitis herpetiformis).
Are you taking any medications?
Medications may produce blistering disorders, such as bullous drug eruptions, drug-induced linear IgA bullous dermatosis, drug-induced pemphigus, toxic epidermal necrolysis, bullous fixed drug reactions, and Stevens-Johnson syndrome or toxic epidermal necrolysis. Also, some other vesiculobullous diseases may be aggravated by medications.
Important Physical Findings
How old is the patient?
Some blistering disorders occur chiefly in neonates (incontinentia pigmenti), whereas other disorders are more likely to occur in children (e.g., chickenpox), in young adults (e.g., erythema multiforme), in middle-aged adults (e.g., porphyria cutanea tarda), or in geriatric patients (e.g., bullous pemphigoid).
Is the patient a woman of childbearing years, is she pregnant, or has she just delivered a baby?
Gravid or recently gravid status is important in establishing a diagnosis of herpes gestationis.
What is the distribution of the blisters?
Some blisters have characteristic distributions or configurations. For example, sharp lines or irregular shapes often suggest an exogenous origin, such as contact dermatitis or toxic injuries to the skin.
Is the oral mucosa (or other mucosal surfaces) involved?
Mucosal surfaces are often involved in herpes simplex infections and in erythema multiforme (Stevens-Johnson syndrome), toxic epidermal necrolysis, and pemphigus vulgaris or paraneoplastic pemphigus.
Important History Questions
How long have the blisters been present?
Some conditions, such as allergic contact dermatitis due to poison ivy, may cause acute blistering, whereas other processes, such as bullous pemphigoid, may be chronic in nature.
Have you had blisters before, and do the blisters occur at the same site(s)?
Repetitive blistering could indicate an ongoing exposure, such as poison ivy, ongoing drug use or drug exposure (e.g., fixed drug eruption, repeat Stevens-Johnson syndrome), recurrent bullous erythema multiforme, or recurrent herpes simplex infection.
Are the blisters symptomatic?
Some vesiculobullous disorders are asymptomatic (bullous diabeticorum), whereas others are painful (e.g., toxic epidermal necrolysis) and others are pruritic (e.g., dermatitis herpetiformis).
Are you taking any medications?
Medications may produce blistering disorders, such as bullous drug eruptions, drug-induced linear IgA bullous dermatosis, drug-induced pemphigus, toxic epidermal necrolysis, bullous fixed drug reactions, and Stevens-Johnson syndrome or toxic epidermal necrolysis. Also, some other vesiculobullous diseases may be aggravated by medications.
Important Physical Findings
How old is the patient?
Some blistering disorders occur chiefly in neonates (incontinentia pigmenti), whereas other disorders are more likely to occur in children (e.g., chickenpox), in young adults (e.g., erythema multiforme), in middle-aged adults (e.g., porphyria cutanea tarda), or in geriatric patients (e.g., bullous pemphigoid).
Is the patient a woman of childbearing years, is she pregnant, or has she just delivered a baby?
Gravid or recently gravid status is important in establishing a diagnosis of herpes gestationis.
What is the distribution of the blisters?
Some blisters have characteristic distributions or configurations. For example, sharp lines or irregular shapes often suggest an exogenous origin, such as contact dermatitis or toxic injuries to the skin.
Is the oral mucosa (or other mucosal surfaces) involved?
Mucosal surfaces are often involved in herpes simplex infections and in erythema multiforme (Stevens-Johnson syndrome), toxic epidermal necrolysis, and pemphigus vulgaris or paraneoplastic pemphigus.
Bullous Impetigo
ICD10 code L01.03
BACTERIAL INFECTION
Pathogenesis
Impetigo caused by staphylococcal infection is usually associated with group II (phage group 71) Staphylococcus aureus . The blister is caused by a toxin, elaborated by the bacterium that lyses an adhesion molecule (desmoglein 1) necessary for keratinocyte adhesion. The split occurs in the superficial aspects of the skin. Infections are more common in the summer months and in humid climates.
Clinical Features
- •
Bullous staphylococcal impetigo is more common in neonates, small children ( Fig. 11.1 ), and HIV-infected individuals.
Fig. 11.1
Bullous impetigo in an infant.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
- •
The primary lesions are small vesicles that progress rapidly to flaccid, pus-filled, and fragile bullae.
- •
The purulence inside the blister space may layer out, with a turbid yellow color ( Figs. 11.2 and 11.3 ).
Fig. 11.2
Patient whose axilla demonstrated numerous flaccid blisters in various stages of development.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
Fig. 11.3
Patient with a flaccid blister demonstrating layering of pus at the base, a finding sometimes seen in bullous impetigo. Note that the superficial blister on the right has broken.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
- •
The surrounding skin demonstrates minimal or mild erythema.
- •
Blisters collapse easily, yielding a varnished appearance to the skin where the blister was located.
- •
Some variations demonstrate only yellow-colored exudative erosions, without active blisters.
Diagnosis
- •
The clinical presentation of flaccid, pus-filled bullae, with yellow crusting, is often diagnostic.
- •
Gram-positive cocci in flaccid blisters, as demonstrated with a Gram stain, supports the diagnosis but does not allow for accurate differentiation between streptococcal and staphylococcal causes.
- •
The diagnostic test of choice is a surface culture, with antibacterial sensitivity testing.
- •
The diagnosis may be made by biopsy, but this is not usually required.
Treatment
- •
Topical mupirocin or retapamulin ointment (applied bid for 5 days) is a suitable treatment for limited disease.
- •
More generalized cases of bullous impetigo are treated empirically with a β-lactam antibiotic, such as oral dicloxacillin (250 mg PO qid for 7–10 days) or cephalexin (250–500 mg PO tid to qid for 7–10 days), because most community-acquired bullous impetigo is not methicillin resistant; this may vary in different areas. This is in contrast to staphylococcal folliculitis, furunculosis, and dermal abscesses.
- •
Any antibiotic regimen prescribed empirically can be altered once antibiotic susceptibility studies have concluded, based upon the results of culture.
- •
Oral erythromycin or azithromycin may be used for penicillin-allergic patients, although erythromycin-resistant staphylococci are prevalent (19%–50% of strains) in some regions of the country.
- •
Methicillin-resistant strains (MRSA) can be treated with ciprofloxacin, trimethoprim, doxycycline (in older children or adults), or topical mupirocin. The management of recurrent impetigo, often due to colonization of S. aureus , is a complex issue beyond the scope of this text.
Clinical Course
Most cases do not require follow-up but if the patient continues to get new lesions, beyond 3 days after starting the antibiotic, the veracity of the diagnosis should be reassessed. Correlation with culture or bacterial susceptibility studies should be made. Some patients may become chronic carriers of impetigo-producing S. aureus strains.
Pemphigus Foliaceus
ICD10 code L10.2
AUTOIMMUNE DISORDER
- •
Captopril (common)
- •
d -Penicillamine (common)
- •
Enalapril (rare)
- •
Sulfasalazine (rare)
Pathogenesis
Pemphigus foliaceus (PF) is an uncommon autoimmune bullous condition caused by immunoglobulin G (IgG) autoantibodies directed against desmoglein 1, a molecule involved in the normal cohesion of keratinocytes. In this condition, the split occurs below the cornified layer or in the superficial granular layer. This is the same location as the split in bullous impetigo and SSSS. PF can also be induced by some medications.
Clinical Features
- •
Middle-aged and older adults are usually affected, but, on occasion, children may be affected.
- •
There is a predilection for the head and trunk, but in some cases it may involve the entire body surface area, causing erythroderma.
- •
Primary lesions are often ruptured vesicles or, less often, intact bullae that arise on normal or erythematous skin ( Figs. 11.10 and 11.11 ).
Fig. 11.10
Large erythematous plaques of pemphigus foliaceus, with an edge of flaccid blisters.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
Fig. 11.11
Close-up of a more subtle example of pemphigus foliaceus presenting as red papules, with flaccid vesicles.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
- •
In some cases, the blister may become cloudy or even appear pustular.
- •
The Nikolsky sign is present in many cases (see p. 166 ).
- •
Scaling and crusting are common, and, in some cases, the condition may resemble dermatitis ( Fig. 11.12 ). Verrucous lesions may even resemble a seborrheic keratosis.
Fig. 11.12
Severe generalized pemphigus foliaceus that, at first glance, has the appearance of dermatitis rather than a blistering disorder.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
- •
Drug-induced PF appears clinically identical to idiopathic cases ( Fig. 11.13 ).
Fig. 11.13
Subtle case of pemphigus foliaceus induced by d -penicillamine.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
Diagnosis
- •
Recurrent, superficial, often ruptured blisters, with a background of scaling and crusting, are highly suggestive of the diagnosis. There should be no oral involvement.
- •
It is useful to culture the blister contents to exclude bullous impetigo.
- •
A shave or punch biopsy, performed at the edge of the lesion, is necessary to establish an acantholytic blistering disorder; this is a cardinal feature of PF.
- •
DIF of perilesional skin is the diagnostic method of choice. This can be performed using a shave (preferred) or punch biopsy. The tissue must be placed in immunofluorescence transport media, normal saline (for periods of <24–48 hours), or snap frozen.
- •
If a direct immunofluorescent medium is not readily available, blood can be drawn in a red-top tube (serum separator tube) and sent to an immunofluorescence laboratory for indirect immunofluorescence or to a reference laboratory for enzyme-linked immunosorbent assay (ELISA) measurement of desmoglein antibodies.
Treatment
- •
First-line therapy is oral prednisone (0.5–1.0 mg/kg per day) with a slow taper, using steroid-sparing agents as the taper proceeds.
- •
Other medications and/or steroid-sparing agents include methotrexate, azathioprine, dapsone, cyclophosphamide, and rituximab.
- •
Any drug known to induce PF should be discontinued or substituted with an unrelated agent.
Clinical Course
The disease is often chronic and may last for years. Children are more likely to demonstrate a short course of disease. In contrast to pemphigus vulgaris, PF has a more benign course, and fatal outcomes are uncommon. Patients with drug-induced PF typically demonstrate resolution over weeks to months, after withdrawal of the inciting medication.
Pemphigus Vulgaris
ICD10 code L10.0
AUTOIMMUNE DISORDER
Pathogenesis
Pemphigus vulgaris is a serious autoimmune bullous disorder caused by autoantibodies directed against desmoglein 1 and desmoglein 3 ( Fig. 11.14 ). These molecules are involved in the normal cohesion of keratinocytes, and hence, the condition leads to large flaccid bullae that are easily ruptured. The mouth is often involved. Rarely, pemphigus vulgaris is triggered by drugs (see box) or foods such as garlic and leeks.
- •
Captopril (common)
- •
d -Penicillamine (common)
- •
Amoxicillin (rare)
- •
Ampicillin (rare)
- •
Cephalosporins (rare)
- •
Penicillin (rare)
- •
Rifampin (rare)
Clinical Features
- •
The condition typically affects older adults (40–60 years old).
- •
Persons of Jewish or Hispanic heritage are more often affected.
- •
The condition may be localized (often on the head or trunk), or it may eventuate as a generalized eruption ( Fig. 11.15 ).
Fig. 11.15
Generalized pemphigus vulgaris demonstrating a classic admixture of crusts, erosions, and superficial blisters.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
- •
Vesicles and bullae (up to several centimeters) arise on normal or erythematous skin ( Fig. 11.16 ).
Fig. 11.16
Flaccid vesicles and bullae of pemphigus vulgaris on the trunk, with crusting of an older lesion.
- •
The Nikolsky sign may be present.
- •
Blisters rupture in 1 to 3 days, with a painful, raw, erythematous base.
- •
Scaling and crusting of older lesions are common.
- •
Oral involvement is present in more than 90% of patients ( Fig. 11.17 ) during the course of the illness, and often it is the initial site of the presentation.
Fig. 11.17
Typical oral pemphigus vulgaris demonstrating erosions. Blisters are not typically seen in oral lesions.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
Diagnosis
- •
A vesiculobullous disorder with marked mucosal involvement suggests the diagnosis, especially if the Nikolsky sign is present.
- •
A shave or punch biopsy from the edge of the lesion should always be done.
- •
DIF using perilesional skin may be performed on a shave biopsy (preferred) or punch biopsy and submitted in immunofluorescent transport media, in saline (for up to 24–48 hours), or snap frozen.
- •
If a direct immunofluorescent medium is not available, blood can be drawn in a red-top (serum separator) tube and sent for indirect immunofluorescence examination or ELISA testing.
Treatment
- •
First-line therapy is oral prednisone (0.5–1.0 mg/kg per day) with a slow taper, using steroid-sparing agents as the taper proceeds.
- •
Pulse corticosteroids (250–1000 mg/day of methylprednisolone sodium succinate) for 1 to 5 days may be used for severe disease or for patients with a poor response to oral prednisone.
- •
Intravenous immunoglobulin (IVIG), 400 mg/kg per day for 5 days, with the addition of cyclophosphamide (100–150 mg/day) in severe cases, results in clearing in 80% of patients within 2 weeks.
- •
Methotrexate, azathioprine, rituximab, and cyclophosphamide are steroid-sparing agents that may be used in select cases.
Clinical Course
Untreated, pemphigus vulgaris has a fatality rate of more than 90%. Treated pemphigus has a fatality rate of about 10%. Typically, the disease has a chronic course, lasting years, but spontaneous remissions may occur. Maintenance of hydration and proper nutrition are challenges in those with marked mucosal involvement.
Bullous Allergic Contact Dermatitis
ICD10 codes L23.0 to L23.9
EXTERNAL ETIOLOGY
Introduction
Allergic contact dermatitis (ACD) is discussed in depth in Chapter 10 . Although most cases of ACD present as an eczematous process, severe ACD may present with marked blistering, particularly if contact is prolonged or if the host response is intense. One should suspect a bullous ACD when blisters are in a distribution (linear) that suggests an exogenous process and/or when pruritus is extreme. Some allergens, such as poison ivy, are well recognized to produce blisters.
Clinical Features
- •
This presents with erythema and blisters 24 to 72 hours after contact in sensitized patients ( Fig. 11.18 ).
Fig. 11.18
Classic linear distribution of blisters seen in poison ivy contact dermatitis.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
- •
The distribution initially follows points of contact but may involve adjacent areas later in the course.
- •
The configuration is typically asymmetric and does not follow normal anatomic lines. Sharp unnatural lines are often present ( Fig. 11.19 ) due to contact with the exogenous agent.
Fig. 11.19
Unilateral, severe, bullous allergic contact dermatitis caused by benzocaine (Lanacane). The patient was mistakenly diagnosed as having toxic epidermal necrolysis and was transferred from the emergency room to the burn unit.
- •
Bullous ACD is nearly always intensely pruritic.
- •
In bullous ACD, overlying tense blisters may be unilocular or multilocular ( Fig. 11.20 ).
Fig. 11.20
Bullous allergic contact dermatitis due to contact with adhesive tape. Note the multilocular nature of the blisters, a finding seen in many types of intraepidermal blisters.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
- •
New blisters and erythema may develop for up to 3 weeks, even without additional exposure.
Diagnosis
- •
Bullous ACD should be suspected in any blistering condition with an asymmetric and exogenous distribution pattern, particularly when linear arrangements are present.
- •
A careful history of potential recent exposures to allergens, such as poison ivy or topical medications, is important in establishing the diagnosis.
- •
A shave or punch biopsy may be useful to rule out other bullous conditions.
- •
In rare cases, a perilesional skin biopsy may be useful to exclude autoimmune bullous disorders.
- •
In patients for whom an allergen cannot be otherwise identified, patch testing may be used to establish the diagnosis and cause.
Treatment
- •
Remove or discontinue suspected and/or potential allergens.
- •
Apply potent or ultrapotent topical steroids (e.g., fluocinonide, clobetasol) bid until resolution.
- •
Generalized cases may require oral prednisone (20–40 mg qd for 7–21 days).
- •
Antihistamines may provide symptomatic relief for pruritus but do not shorten the disease course.
Clinical Course
Even though the patient may have only had a single exposure to an allergen, new lesions may continue to appear for up to 3 weeks in severe cases. In particular, the allergen in poison ivy (uroshiol) binds irreversibly to the skin and will require treatment for up to 21 days. So-called dose packs of steroids, used for about 5 days, should be avoided because the patient will frequently rebound and flare after the dose pack is completed.
Bullous Insect and Arthropod Reactions
ICD10 code T14.1
ARTHROPOD REACTION
Pathogenesis
Insects and arthropods can produce hypersensitivity reactions in the skin. Saliva from the bite of the organism (e.g., bedbugs, ticks) or feces (e.g., scybala of scabies) may serve as an allergen. When allergen exposure is limited, the host response is usually minor. However, when the antigen exposure is more substantial, or the host response is exaggerated, a vesiculobullous reaction can ensue. Common causes of bullous arthropod reactions include bedbugs (Cimex lectularius), fleas ( Fig. 11.21 ), and chiggers.
Clinical Features
- •
Patients may or may not recall the insect or arthropod bite.
- •
Lesions are often located on exposed areas of the body and range from urticarial papules to bullae.
- •
Lesions may be solitary or multiple, and lesions can be grouped, especially in bedbug bites.
- •
The blister may be unilocular or multilocular on an erythematous base ( Figs. 11.22 and 11.23 ).
Fig. 11.22
Two arthropod reactions received at the same time. One is a crusted papule that never blistered, whereas the second demonstrates a pruritic, tense, unilocular blister.
Fig. 11.23
Arthropod reaction demonstrating a central punctum that represents the bite site. This bite is instructive in that it shows that both unilocular (left side) and multilocular (right side) blisters can occur in an arthropod reaction.
(From the Fitzsimons Army Medical Center Collection, Aurora, CO.)
- •
Bedbug bites occur most often on parts of the body exposed during sleep (face, neck, hands, and arms), and bites are often arranged in linear configurations (so-called breakfast, lunch, and dinner arrangement).
- •
Bullous insect and arthropod bite reactions are nearly always intensely pruritic, except for blistering reactions caused by cutaneous exposure to members of the blister beetle family.
Diagnosis
- •
In some cases, the patient may bring in the offending insect or arthropod (see Fig. 11.21 ).
- •
Bedbugs are a particular problem of travelers, and a travel history should be elicited.
- •
According to a major national extermination company, the top 10 cities for bedbugs includes Detroit, Philadelphia, Cleveland, Los Angeles, Dayton, Chicago, Columbus, Cincinnati, Dallas–Fort Worth, and San Francisco.
- •
A shave or punch biopsy is not usually indicated but, in problematic cases, the findings in a biopsy can be supportive of the diagnosis.
Treatment
- •
Sedating antihistamines (e.g., diphenhydramine) may be used at night for symptomatic relief and to promote sleep.
- •
Potent or ultrapotent forms may be used in a directed manner for a limited duration.
- •
Oral antibiotics may be appropriate if a secondary bacterial infection is suspected.
- •
Depending on the clinical situation, other treatments might include repellants, removal of pets or wildlife (e.g., an abandoned bird’s nest near a bedroom window), and/or professional extermination.
Chickenpox
ICD10 code B01.9
VIRAL INFECTION
Pathogenesis
Chickenpox, or varicella, is a primary infection with the varicella-zoster virus (VZV). Prior to the introduction of a live attenuated vaccine in 1995, there were about 4 million new cases/year, with approximately 100 deaths annually. Since mass vaccinations began, there has been a continued progressive decline in reported cases. VZV is acquired mostly in an aerorespiratory fashion.
Clinical Features
- •
The incubation period is 14 to 17 days.
- •
A prodrome of mild upper respiratory tract infection—malaise, low-grade fever—may be present.
- •
Primary lesions are 1- to 4-mm vesicles arising on an erythematous base (so-called dewdrops on a rose petal; Figs. 11.24 and 11.25 ).
