INTRODUCTION — Cutaneous blisters occur in a wide variety of clinical settings, including autoimmune disorders, drug reactions, infections, genetic disorders, and physical injury. The ability to narrow the differential diagnosis for patients with blistering skin lesions is essential for the prompt recognition of life-threatening disorders and the appropriate management of other blistering diseases (algorithm 1).
The clinical approach to the diagnosis of disorders that present with cutaneous blisters and a summary of common investigative tests used to assist with diagnosis is discussed here. Blistering disorders in the newborn infant and specific blistering disorders are discussed in greater detail separately. (See "Vesicular, pustular, and bullous lesions in the newborn and infant".)
DEFINITION — Blistering skin disorders are characterized by the presence of fluid-filled lesions on the skin that occur as a result of a loss of adhesion between cells within the epidermis (acantholysis), edema between epidermal cells (spongiosis), or disassociation of the epidermis and dermis. Pathologic events that may lead to the formation of blisters include the following:
●Disruption of cellular or extracellular adhesion molecules (eg, autoimmune blistering disorders, congenital epidermolysis bullosa)
●Epidermal cell injury or death (eg, toxic epidermal necrolysis, erythema multiforme)
●Accumulation of excessive edema (spongiosis) within the epidermis (eg, contact dermatitis, acute and chronic vesicular palmoplantar dermatitis)
●Traumatic injury (eg, friction or coma blisters)
Specific terms are used to describe cutaneous blisters based upon lesion size. Vesicles are usually designated as lesions that are less than 1 cm in diameter (picture 1A). In contrast, bullae are classified as lesions that are greater than 1 cm in size (picture 2).
The watery clear fluid content of vesicles and bullae distinguishes these lesions from pustules, which contain thicker, yellow-white purulent material (see "Approach to the patient with pustular skin lesions"). Although the clear fluid contents of vesicles and bullae may develop a more turbid quality over time, the watery quality is retained and such lesions are still easily distinguished from pustules. In cases in which blister formation is associated with damage to the blood vessels in the dermis, red blood cells may enter the blister cavity, resulting in red-colored blister fluid. The term "hemorrhagic blister" is used to refer to such lesions.
Blisters may occur at a variety of histologic locations within the skin. The location in which blisters form is often useful for diagnosis and can be determined via histopathologic examination (table 1). The general categories used to describe the location of blister formation include :
●Intracorneal or subcorneal – Cleavage plane within the stratum corneum or immediately beneath the stratum corneum (eg, pemphigus foliaceus, staphylococcal scalded skin syndrome) (picture 3)
●Intraepidermal – Cleavage plane within the malpighian layer of the epidermis, excluding subcorneal and suprabasilar disorders (eg, contact dermatitis, viral infections) (picture 4A-B)
●Suprabasilar – Cleavage plane within the epidermis with only an intact basal layer (picture 5A) (eg, pemphigus vulgaris, paraneoplastic pemphigus)
●Subepidermal – Cleavage plane within or below the basement membrane zone (picture 5B) (eg, bullous pemphigoid, porphyria cutanea tarda)
The clinical features of a blistering disorder often correlate with the histopathologic subtype. Whereas subcorneal blistering disorders tend to present with extremely fragile blisters that quickly evolve to scale, erosions, and desquamation, slightly less fragile flaccid vesicles or bullae are characteristic of intraepidermal or suprabasilar blisters. Lastly, tense bullae are typically seen in subepidermal blistering disorders due to the relatively greater proportion of epidermis overlying the blister cavity.
LIFE-THREATENING EMERGENCIES — Several blistering disorders represent potentially life-threatening emergencies, warranting the need for early diagnosis and therapy. These include:
●Toxic epidermal necrolysis – Widespread sloughing of skin and severe mucositis in this disorder are associated with risk for sepsis (picture 6A-C). (See 'Generalized blisters with systemic illness' below.)
●Disseminated herpes simplex or herpes zoster infection in immunocompromised patients – May result in life-threatening internal complications (picture 8). (See 'Generalized blisters with systemic illness' below.)
●Purpura fulminans – Although retiform purpura are the primary feature of purpura fulminans, associated necrotic bullae may also be present (picture 9). (See "Approach to the patient with retiform (angulated) purpura", section on 'Recognition of life-threatening emergencies'.)
PATIENT ASSESSMENT — Blistering skin lesions can present a diagnostic challenge since the differential diagnosis is vast. The recognition of the distribution of the lesions is a useful clinical tool to begin to narrow the differential diagnosis (algorithm 1). A thorough patient history, the identification of additional clinical features, and pathologic and laboratory studies are often of additional value.
Examples of questions that may be useful during the assessment of the patient with cutaneous blisters include:
●Where are the lesions located (generalized, localized, specific sites)?
●Are mucous membranes involved?
●What is the size and configuration of blisters?
●If bullae are present, are they flaccid or tense?
●What is the patient's age?
●Does the patient have a history of exposure to a new medication?
Lesion distribution — The identification of cutaneous blisters as generalized, localized, or associated with mucous membrane involvement can offer valuable clues for diagnosis (table 2A-C).
Generalized blisters with systemic illness — Acute or chronic signs or symptoms of systemic illness are frequent features of several disorders that present with generalized blisters:
●Stevens-Johnson syndrome and toxic epidermal necrolysis – Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) are acute, severe disorders characterized by epidermal sloughing of the skin and mucous membranes. These conditions most commonly occur as a result of exposure to an inciting medication . Following a brief prodromal period of fever and flu-like symptoms, patients develop painful erythematous and purpuric macules or areas of diffuse macular erythema that progress to vesicles, bullae, and skin sloughing (picture 6A-D). The extent of body surface area involvement differentiates Stevens-Johnson syndrome (<10 percent) from TEN (>30 percent). Skin biopsies of fully developed lesions demonstrate epidermal-dermal separation and full-thickness epidermal necrosis. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
●Staphylococcal scalded skin syndrome – Staphylococcal scalded syndrome occurs as a reaction to toxin released by Staphylococcus aureus, and most commonly occurs in infants, young children, and adults with renal failure . Fever, malaise, and skin tenderness typically precede the eruption. The fragile subcorneal bullae often demonstrate the appearance of wrinkled skin with subsequent desquamation (picture 7A-C). Examination of a frozen tissue specimen of sloughed epidermis can be used to rapidly distinguish staphylococcal scalded skin from the epidermal sloughing of toxic epidermal necrolysis. Frozen sections taken from staphylococcal scalded skin syndrome demonstrate cleavage at the granular layer, whereas full-thickness epidermal necrosis and cleavage at the dermal-epidermal junction characterize toxic epidermal necrolysis. The site of the primary staphylococcal infection also should be identified. (See "Staphylococcal scalded skin syndrome".)
●Varicella zoster virus infection – Varicella (chicken pox) is a disorder that most frequently occurs in children who are not vaccinated against the disease. Patients experience a prodrome of fever and malaise followed by the development of a generalized eruption of 1 to 3 mm intraepidermal or subepidermal vesicles surrounded by erythema. These lesions are often described as "dew drops on a rose petal," and subsequently evolve to form pustules and crusts (picture 1A-B). (See "Clinical features of varicella-zoster virus infection: Chickenpox".)
●Disseminated herpes zoster – Disseminated herpes zoster can occur in immunocompromised patients. Unlike classic herpes zoster, the vesicular lesions are not restricted to a dermatome (picture 8). Disseminated herpes zoster may also result in life-threatening infection including pneumonia, hepatitis, encephalitis, or other organ involvement. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Special considerations in immunocompromised hosts'.)
●Disseminated herpes simplex virus – Immunocompromised patients and patients with a compromised skin barrier (eg, atopic dermatitis, Darier disease) may develop widespread vesicles, pustules, and crusts due to herpes simplex virus infection. The term eczema herpeticum is used to describe this occurrence in patients with atopic dermatitis (picture 10A-B). (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)
●Sweet syndrome (acute febrile neutrophilic dermatosis) – Although edematous, erythematous plaques with a pseudovesicular quality are most characteristic of Sweet syndrome, the plaques occasionally exhibit frank vesicle or bulla formation (picture 11A-B). The plaques are most frequently found on the upper body; fever and leukocytosis are also typically present. Sweet syndrome may occur in the setting of malignancy, infection, drug exposure, autoimmune disease, or inflammatory bowel disease. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)
●Bullous systemic lupus erythematosus – Bullous systemic lupus erythematosus presents as widespread, tense, subepidermal bullae in patients with systemic lupus erythematosus. The skin lesions may resemble bullous pemphigoid or dermatitis herpetiformis (picture 12) . Antibodies against type VII collagen have been associated with this disease. (See "Bullous systemic lupus erythematosus".)
●Paraneoplastic pemphigus – Paraneoplastic pemphigus is an uncommon mucocutaneous suprabasilar or subepidermal blistering disorder that occurs in the setting of malignancy. Stomatitis is characteristically severe (picture 13), but the morphology of skin lesions is variable . In some cases, the skin lesions may resemble blisters of pemphigus vulgaris or erythema multiforme (picture 14A-B). Non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Castleman's disease are the conditions most commonly associated with this disorder . Serologic testing reveals reactivity with multiple antigens, including desmoplakins, desmogleins, and bullous pemphigoid antigen 1 (BPAg1, BP230) [6,7]. (See "Paraneoplastic pemphigus".)
Other generalized blistering disorders — Examples of generalized blistering disorders that are not necessarily associated with systemic illness are listed below:
●Miliaria crystallina – Miliaria crystallina results from the obstruction of the ducts of eccrine sweat glands and usually occurs in the setting of excessive warmth. The fragile intracorneal or subcorneal 1 mm vesicles typically occur on the face and trunk (picture 15). (See "Miliaria".)
●Bullous impetigo – Subcorneal vesicles and bullae containing clear or yellow fluid on the face, trunk, perineum, or extremities characterize bullous impetigo, a disorder that most frequently occurs in neonates and children (picture 16). The bullae rupture easily, leaving erosions with a collarette of scale. (See "Impetigo", section on 'Bullous impetigo'.)
●Pemphigus – The formation of flaccid bullae that quickly evolve to erosions are typical of pemphigus vulgaris (picture 17) . Mucous membrane vesicles and erosions are a frequent associated finding (picture 18A-B). The level of blister formation in pemphigus vulgaris is suprabasilar. By contrast, the most prominent feature of pemphigus foliaceus, a subcorneal blistering disorder, is erythematous plaques with overlying scale or crust (picture 19A-B). These patients do not develop mucosal blisters. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)
●Bullous pemphigoid – Bullous pemphigoid is a subepidermal blistering disorder that most commonly occurs in older adults (picture 20A-B) . The classic skin lesions are urticarial plaques and tense bullae on the trunk and extremities. Intense pruritus is common, and lesions typically do not scar. Localized forms of bullous pemphigoid may also occur . Bullous pemphigoid patients may also develop mucosal involvement. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)
●Pemphigoid gestationis – Pemphigoid gestationis is a subepidermal blistering disorder that occurs during pregnancy or in the immediate postpartum period. Urticarial plaques and vesicles typically begin around the umbilicus prior to spreading elsewhere with large bulla formation (picture 21A-C). (See "Dermatoses of pregnancy", section on 'Pemphigoid gestationis'.)
●Linear IgA bullous dermatosis – Linear IgA bullous dermatosis is a subepidermal blistering disorder associated with the deposition of IgA at the basement membrane zone of skin and mucosal tissues . This disorder may occur as a primary autoimmune disease or as a drug reaction. The cutaneous bullae often have a distinctive grouped appearance that resembles a cluster of jewels (picture 22). The term chronic bullous disease of childhood is used to refer to this disorder in children. (See "Linear IgA bullous dermatosis".)
●Dermatitis herpetiformis – Dermatitis herpetiformis is a cutaneous manifestation of gluten sensitivity that presents with grouped vesicles and excoriated papules with a predilection for the extensor extremities, scalp, and buttocks (picture 23) [12,13]. The lesions of this subepidermal blistering disorder are intensely pruritic. (See "Dermatitis herpetiformis".)
●Epidermolysis bullosa – Congenital epidermolysis bullosa is a rare genetic disorder that consists of multiple variants. Depending on the type of epidermolysis bullosa, lesions may be intraepidermal or subepidermal, localized or generalized, and detected as early as birth or not until adulthood (picture 24). (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features".)
●Epidermolysis bullosa acquisita – Epidermolysis bullosa acquisita is a rare, acquired subepidermal blistering disorder that may affect both skin and mucous membranes (picture 25). Tense bullae, scarring, and milia formation are common associated features. Antibodies against type VII collagen are pathogenic in this disease and can be measured in serum . (See "Epidermolysis bullosa acquisita".)
Localized distribution — The recognition that blisters are primarily located in certain body locations, such as dependent areas, acral areas, or sun-exposed skin may assist with diagnosis (table 2B and algorithm 1). In addition, a linear distribution of skin lesions suggests the possibility of an external insult as the cause of blistering.
●Coma blisters – Coma blisters are tense, subepidermal bullae that have been reported to occur in sites of pressure in comatose patients. These lesions have been associated with exposure to drugs (eg, opiates, tricyclic antidepressants, antipsychotics) and a variety of medical conditions, such as chronic renal failure, diabetic ketoacidosis, hyperparathyroidism, and neurologic disease . Erythematous or ecchymotic patches or plaques may precede the development of bullous lesions. The blisters spontaneously resolve within two to four weeks .
●Bullous disease of diabetes (bullosis diabeticorum) – Bullous disease of diabetes is a term used to describe the abrupt development of noninflammatory, tense, subepidermal bullae in patients with diabetes in sites of otherwise normal-appearing skin (picture 2) . Lesions most commonly occur on the feet or lower legs and may be up to several centimeters in diameter. The bullae spontaneously resolve over the course of a few weeks. The term bullous diabeticorum has also been used to refer to this disorder.
●Bullous leukocytoclastic vasculitis – Hemorrhagic vesicles or bullae may occur among the purpuric macules, papules, or plaques of cutaneous leukocytoclastic vasculitis (picture 26). Necrosis of the skin overlying areas of small vessel vasculitis leads to the development of these subepidermal bullous lesions. (See "Evaluation of adults with cutaneous lesions of vasculitis".)
●Edema (stasis) blisters – Bullae may form in areas of edema. These asymptomatic lesions often occur on the lower legs and resolve upon resolution of the cause of edema (picture 27) . There is little published information on edema blisters, and it is not definitively known whether the majority of these blisters are subepidermal or intraepidermal. (See "Stasis dermatitis", section on 'Clinical presentation'.)
Hands or feet
●Acute palmoplantar (dyshidrotic) eczema – Intensely pruritic vesicles or bullae on the hands or feet are consistent with this disorder (picture 28A-B). The palms, soles, and sides of the digits are typical sites for involvement. Spongiotic intraepidermal vesicles are present on histopathologic examination. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)
●Dermatophytosis – Blistering tinea pedis is most often associated with Trichophyton mentagrophytes or Epidermophyton floccosum infection . The associated intraepidermal spongiotic vesicles and bullae are often present on the soles or between the toes (picture 29). In addition, dermatophytid reactions (autoeczematization or id reactions that occur in the setting of dermatophyte infection) may result in vesicular eruptions on the hands (picture 30). (See "Dermatophyte (tinea) infections", section on 'Tinea pedis' and "Dermatophyte (tinea) infections", section on 'Id reactions'.)
●Friction blister – Friction blisters are intraepidermal blisters that result from trauma-induced separation within the epidermis. They most frequently occur on the heels and soles of the feet due to friction from shoes during walking or running. The possibility of epidermolysis bullosa simplex should be considered in patients with frequent and excessive blistering. (See "Friction blisters".)
●Sucking blisters – Blisters on the hands or feet due to intrauterine sucking may be detected in neonates (picture 31A-B).
●Erythema multiforme – The acral extremities are a site of predilection for lesions of erythema multiforme, a disorder that most commonly occurs in association with herpes simplex virus infection. The classic dusky erythematous target lesions of erythema multiforme may exhibit a central subepidermal blister (picture 32). Mucosal involvement is also frequently present (picture 33A-B). (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)
●Localized epidermolysis bullosa simplex – Localized epidermolysis bullosa simplex (formerly known as the Weber-Cockayne variant of epidermolysis bullosa simplex) is a rare autosomal dominant genetic disorder in which intraepidermal blisters form in sites of friction or trauma. The hands and feet are frequently affected (picture 34A-B). (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Localized epidermolysis bullosa simplex'.)
●Polymorphous light eruption – Polymorphous light eruption is a fairly common disorder that usually develops within hours of sun exposure. Although the most common manifestations are pruritic erythematous papules or plaques, vesicles or bullae may also occur as a manifestation of extensive dermal edema (picture 35). (See "Polymorphous light eruption".)
●Porphyria cutanea tarda – Photosensitivity is a key feature of porphyria cutanea tarda, an inherited or acquired metabolic disorder that may present with the formation of predominantly noninflammatory vesicles and bullae (picture 36A-B). Sun-exposed areas are typically affected. The dorsal hands and forearms are common sites of involvement, and crusts, scars, and milia are often present. Other cutaneous features of porphyria cutanea tarda include hyperpigmentation, hypertrichosis, and localized sclerodermoid plaques . (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical features'.)
●Pseudoporphyria – Although pseudoporphyria presents with clinical and histopathologic features that resemble porphyria cutanea tarda, abnormalities of porphyrin metabolism are absent. Like porphyria cutanea tarda, subepidermal bullae, crusts, and scarring on the dorsal hands are common clinical findings (picture 37). A number of medications have been associated with this condition . (See "Pseudoporphyria".)
●Sunburn and phototoxic reactions – Severe sunburns can result in blister formation on the skin (picture 38). Phototoxic eruptions, which usually occur due to sun exposure after ingestion of a photosensitizing drug, resemble sunburns and can also present with blistering. (See "Sunburn" and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)
●Herpes zoster – Herpes zoster (shingles) presents with a grouped eruption of painful intraepidermal vesicles in a dermatomal distribution (picture 39A-B). In immunocompromised patients, disseminated lesions may occur. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)
●Contact dermatitis – Intensely pruritic dermatitis and intraepidermal spongiotic bullae often develop in patients with severe contact dermatitis, such as can occur after exposure to poison ivy (picture 40). Lesions develop in sites of contact of the inciting substance with the skin. A linear distribution is common. (See "Clinical features and diagnosis of allergic contact dermatitis".)
●Phytophotodermatitis – Erythema, edema, and vesiculation occurring in a linear or odd configuration may develop after topical exposure to certain of plant-derived substances (eg, lemons, limes, celery, wild parsnip, or parsley) followed by sun exposure (picture 41A-B) . The term "berloque dermatitis" has been used to refer to lesions secondary to natural oil of bergamot in products used on the skin. Significant postinflammatory hyperpigmentation after resolution of the acute process is common. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phytophotodermatitis'.)
Other localized blistering disorders
●Herpes simplex virus – A localized eruption composed of grouped, small, often umbilicated vesicles or vesicopustules is characteristic of herpes simplex virus infection (picture 42A-B). The lips, genitals, and buttocks are common sites of involvement. Primary infections tend to be most severe and can be accompanied by lymphadenopathy and flu-like symptoms. Extensive lesions may occur in patients with atopic dermatitis, a condition referred to as eczema herpeticum (also referred to as Kaposi's varicelliform eruption). (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection" and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection".)
●Fixed drug eruption – Central bullae may appear in lesions of fixed drug eruptions, which present as single or multiple dusky erythematous to violaceous round plaques (picture 44). The lips, genitalia, face, and acral areas are common sites of involvement. The lesions tend to heal with significant postinflammatory hyperpigmentation and typically recur in the same sites with subsequent drug exposure. (See "Fixed drug eruption".)
●Transient acantholytic dermatosis (Grover's disease) – Transient acantholytic dermatosis is a disorder that is most commonly detected in middle-aged White men. Pruritic, erythematous papules and papulovesicles are typically localized to the trunk (picture 45). Acantholysis and dyskeratosis are evident on histopathologic examination of papulovesicular lesions. (See "Grover's disease (transient and persistent acantholytic dermatosis)".)
●Hailey-Hailey disease – Hailey-Hailey disease is an uncommon genetic disorder that presents with fragile acantholytic blisters that quickly evolve to erosions that are primarily localized to the neck and intertriginous areas (picture 46A-C). Erythematous vegetative plaques develop in involved areas as the disease progresses. (See "Hailey-Hailey disease (benign familial pemphigus)".)
●Bullous pyoderma gangrenosum – Atypical variants of pyoderma gangrenosum may present with subepidermal bullae in conjunction with superficial ulcers (picture 47). (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)
Mucous membrane involvement — Many blistering eruptions may also have mucosal involvement. When blistering disorders involve the mucous membranes, frank vesicles and bullae often are not seen. Rather, mucosal inflammation or erosions tend to be the predominant clinical finding.
The following disorders are examples of blistering diseases that may present with both cutaneous and mucosal findings (table 2C):
●Mucous membrane pemphigoid – Mucous membrane pemphigoid (MMP) is defined as a diverse group of blistering disorders characterized by mucous membranes as the primary site of involvement. Inflamed, eroded, or scarred mucosa may be present (picture 48A-E). Cutaneous blisters accompany the mucosal lesions in some patients. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)
●Pemphigus vulgaris (see 'Other generalized blistering disorders' above).
●Paraneoplastic pemphigus (see 'Generalized blisters with systemic illness' above).
●Bullous pemphigoid (see 'Other generalized blistering disorders' above).
●Linear IgA bullous dermatosis (see 'Other generalized blistering disorders' above).
●Epidermolysis bullosa acquisita (see 'Other generalized blistering disorders' above).
●Erythema multiforme (see 'Hands or feet' above).
●Stevens-Johnson syndrome and toxic epidermolytic necrolysis (see 'Generalized blisters with systemic illness' above).
●Herpes simplex virus infection (see 'Other localized blistering disorders' above).
Additional clinical features — In addition to the recognition of the distribution of cutaneous blisters, knowledge of the patient's age, blister characteristics, and the patient's drug history may help to narrow the differential diagnosis.
Patient age — Although patient age cannot be used to definitively exclude most blistering disorders, this information may provide additional clues for diagnosis:
●Neonates – In neonates, blistering lesions can occur due to intrauterine or postpartum exposure to infections or trauma, congenital disorders, miliaria crystallina, or other disorders. The differential diagnosis for neonates with cutaneous blisters is reviewed separately. (See "Vesicular, pustular, and bullous lesions in the newborn and infant".)
●Young children – Disorders such as bullous impetigo and staphylococcal scalded skin occur with greater frequency in infants and young children than in other age populations.
●Older adults – Pemphigus and pemphigoid occur with greater frequency in older adults than in younger individuals.
Blister configuration — Grouped blisters are characteristic of herpes simplex virus infection (picture 39A), herpes zoster (picture 39B), dermatitis herpetiformis (picture 23), and linear IgA bullous dermatosis. An annular configuration is often present in linear IgA bullous dermatosis (picture 22) and a linear arrangement of bullous lesions suggests the possibility of contact dermatitis or phytophotodermatitis.
Blister size — Small vesicles are the primary lesions in miliaria crystallina, acute palmoplantar eczema, herpes simplex virus or varicella zoster virus infection, and dermatitis herpetiformis.
Blister quality — Tense blisters are a characteristic feature of subepidermal blistering disorders, such as bullous pemphigoid, pemphigoid gestationis, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, and porphyria cutanea tarda. More flaccid blisters are typically seen in conditions in which the level of bulla formation is more superficial.
History of drug exposure — Drug exposure is frequently associated with fixed drug eruptions, pseudoporphyria, Stevens-Johnson syndrome, toxic epidermal necrolysis, and linear IgA dermatosis (table 3). Occasionally, erythema multiforme, pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, and mucous membrane pemphigoid are linked to an inciting pharmacologic agent.
Nikolsky sign — The Nikolsky (or Nikolskiy) sign is a clinical finding that describes the elicitation of skin blistering as a result of gentle mechanical pressure on the skin. Depending on the clinical scenario, a positive Nikolsky sign may be observed at the edge of an existing lesion, in an area of normal-appearing skin, or in both locations .
The Nikolsky sign is often cited as a feature of the acantholytic, suprabasilar blistering disorder pemphigus vulgaris; however, the absence of this finding does not rule out this diagnosis. In addition, the Nikolsky sign has been detected in multiple blistering diseases with divergent modes of blister formation and levels of blister cleavage, including among them toxic epidermal necrolysis, staphylococcal scalded skin syndrome, and a subset of patients with bullous pemphigoid . (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Clinical features'.)
DIAGNOSTIC TESTS — Many blistering disorders share clinical features, and diagnostic tests are essential in differentiating these conditions and making an accurate diagnosis. The principle tests utilized in the evaluation of blistering diseases include light microscopy, direct immunofluorescence, indirect immunofluorescence, antigen-specific serologic testing, and microbiologic studies. The selection of the most appropriate studies to order is patient-specific and based upon the suspected diagnoses.
Skin biopsy — A skin biopsy with or without direct immunofluorescence studies is often the first step in the evaluation of patients with an unknown skin blistering disorder.
Light microscopy — Examination of a skin biopsy with light microscopy is useful for identifying the histopathologic features that characterize specific disorders. Light microscopy can detect the level of blister formation, the type of inflammatory cell infiltrate, the presence of dyskeratotic cells, and histopathologic features suggestive of infection (picture 5A-B).
Specimens for light microscopic examination are usually obtained from lesional tissue. If small vesicles are present, removal of an entire lesion is preferred. For larger lesions, the specimen should be obtained from the edge of a blister; the specimen should contain both portions of the blister and intact skin.
Punch biopsies are most frequently utilized for the evaluation of blistering lesions, as they allow for evaluation of the full thickness of the epidermis and dermis, which can be useful in cases in which dermal findings may offer additional clues for diagnosis. A deep shave biopsy that extends into the reticular dermis can also be utilized, but may result in a larger, scoop-like scar. Specimens for light microscopy can be placed in formalin for preservation. (See "Skin biopsy techniques", section on 'Punch biopsy' and "Skin biopsy techniques", section on 'Shave biopsy'.)
Direct immunofluorescence — Direct immunofluorescence is a technique that allows for the detection of antibody or complement deposition within the skin. Direct immunofluorescence studies are typically utilized when an autoimmune blistering disorder is suspected. The recognition of the pattern and location of antibody binding can offer valuable insight for diagnosis. For example, intercellular antibody deposition in the epidermis characterizes pemphigus vulgaris and pemphigus foliaceus, whereas linear antibody deposition along the basement membrane zone is detected in bullous pemphigoid (picture 49A-C).
The specimen should be taken from normal-appearing skin adjacent to the blister, which is referred to as a perilesional biopsy. A biopsy of lesional skin is more likely to result in false negative results because of destruction of the immunoreactants by the inflammatory process. Tissue obtained for direct immunofluorescence should not be placed in formalin; rather, Michel's medium or Zeus medium can be used for preservation. Fresh specimens also may be sent to the laboratory, provided they are kept moist with saline, and processing within 24 hours is feasible.
The basic procedure for direct immunofluorescence is as follows :
●Cut sections from the specimen are placed on microscope slides.
●A solution containing antisera against IgG, IgA, IgM, complement factor C3, and fibrinogen conjugated to fluorescent dye is incubated with the sections.
●The sections are subsequently washed and mounted for examination utilizing an epifluorescence microscope.
Serologic tests — Indirect immunofluorescence studies and antigen-specific serologic testing may be useful for the evaluation of autoimmune blistering disorders.
Indirect immunofluorescence — Indirect immunofluorescence can be used to detect antibodies within the circulation. In this technique, the presence of antibodies in the patient's serum that are capable of binding to components of an epithelial specimen that is not from the patient is assessed (picture 50). Similar to direct immunofluorescence, this test is typically utilized to aid in the diagnosis of autoimmune blistering disease.
The basic procedure for indirect immunofluorescence is as follows :
●Blood is drawn from the patients and centrifuged to separate serum.
●The selected substrate (eg, monkey esophagus, guinea pig esophagus, rat bladder, or human skin depending upon the suspected diagnosis) is incubated with progressive dilutions of patient serum.
●The tissue is incubated with antibodies conjugated to a fluorescent dye that are directed against the antibodies bound to the substrate.
●The slides are washed, mounted, and examined utilizing an epifluorescent microscope.
●Results are reported as the limiting dilution in which specific fluorescence is detected.
Antigen-specific serologic testing — If the target of circulating antibodies associated with specific autoimmune blistering diseases is known, antigen-specific testing can be used to detect the presence of antibodies in serum. Enzyme-linked immunosorbent assay (ELISA) is the most common test utilized and is frequently employed in disorders such as bullous pemphigoid, pemphigoid gestationis, and pemphigus vulgaris. Other antigen-specific serologic tests, such as immunoblotting and immunohistochemistry, have also been utilized for the diagnosis of autoimmune blistering diseases. These tests are more labor-intensive than ELISA, but may be the only way to definitively identify epidermolysis bullosa acquisita and laminin-332 pemphigoid. These disorders may be associated with inflammatory bowel disease or malignancy, respectively.
Basement membrane zone-split skin technique — Tissue specimens with an artificially induced cleavage zone between the epidermis and dermis (known as basement membrane zone-split skin or salt-split skin) are utilized to obtain more precise information on the localization of antibody binding within the basement membrane zone in direct and indirect immunofluorescence studies . Incubation of the skin substrate in a 1 M sodium chloride (NaCl) or ethylenediaminetetraacetic acid (EDTA) solution induces separation at the level of the lamina lucida. The location of antibody binding to the epidermal (roof) or dermal (floor) side of the split can be used to further narrow the differential diagnosis (picture 51). (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Confirmatory testing'.)
Microbiologic studies — If infection is suspected, microbiologic tests can be useful for diagnosis. A potassium hydroxide (KOH) preparation is a quick diagnostic test for bullous tinea pedis (picture 52). In addition, bacterial cultures of the blister site may aid in the diagnosis of bullous impetigo, and in staphylococcal scalded skin syndrome, culture of the potential sites of the primary staphylococcal infection can be of value. In patients with suspected herpes simplex virus or varicella zoster virus infection, studies such as Tzanck smear (picture 53), viral culture, polymerase chain reaction, and direct fluorescent antibody testing may be used to confirm a diagnosis. (See "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation' and "Office-based dermatologic diagnostic procedures", section on 'Tzanck smear'.)
INDICATIONS FOR REFERRAL — Referral to a dermatologist is indicated if an autoimmune blistering disease is suspected, if the cause of blistering is unknown, or if the disease continues to progress despite appropriate treatment. Patients with suspected toxic epidermal necrolysis require immediate transfer to an experienced burn unit. Patients with staphylococcal scalded skin syndrome require hospital admission for intravenous antibiotic therapy. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae" and "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Staphylococcal scalded skin syndrome'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Blisters (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview – A wide variety of disorders can result in the formation of blisters on the skin. Autoimmune disorders, drug reactions, infections, genetic disorders, and traumatic injury are among the potential causes of cutaneous blistering. (See 'Introduction' above and 'Definition' above.)
●Histopathologic features – Cutaneous blisters may occur at various sites within the skin (table 1). Blisters that form within the epidermis tend to be more fragile and flaccid than the tense blisters that are typically associated with subepidermal blistering diseases. (See 'Definition' above.)
●Life-threatening emergencies – Life-threatening cutaneous blistering disorders include toxic epidermal necrolysis, staphylococcal scalded skin syndrome, disseminated herpes simplex virus infection, disseminated herpes zoster, and purpura fulminans. Identification of these disorders should be prompt to reduce the risk of fatal complications. (See 'Life-threatening emergencies' above.)
●Patient assessment – The distribution of cutaneous blisters is often useful for narrowing the differential diagnosis (table 2A-C and algorithm 1). Blistering conditions may be divided in to generalized or localized disorders, and additional features such as the patient's age, blister characteristics, and the patient's drug history may also offer clues for diagnosis (table 3). (See 'Patient assessment' above.)
●Diagnostic tests – Diagnostic tests commonly utilized in the evaluation of blistering skin disorders include light microscopy, direct and indirect immunofluorescence studies, antigen-specific serologic studies, and microbiologic tests. The specific disorders considered in the differential diagnosis determine the selection of the most appropriate test(s). (See 'Diagnostic tests' above.)
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