Approach

Initial indications to the correct diagnosis can be derived from the history and physical examination. Additional diagnostic testing (e.g., skin biopsy, tissue cultures, and immunofluorescence) is often, but not always, necessary to make a definitive diagnosis.

History

Clinical information obtained by history and physical examination is the first step in classifying patients into groups, specifically genetic, acquired, or autoimmune aetiologies. Rarely, however, some forms of acquired blistering disease present in the neonatal period through the transfer of maternal antibodies. A maternal history of an immunobullous disease is helpful in these cases.

Relevant factors in the history include:

  • Age of onset (e.g., varicella zoster virus infection [VZV] predominantly affects children; mild forms of epidermolysis bullosa [EB] simplex may not manifest until early adulthood)

  • Duration of eruption (e.g., atypical enterovirus infection can cause a widespread vesicular eruption that clears in a few days to a week, whereas epidermolysis bullosa acquisita is a progressive process)

  • Evolution of lesions over time (e.g., most cases of herpes zoster virus [HZV] infection resolve without sequelae, but with increasing age and levels of immunocompromise, complications - including post-herpetic neuralgia, scarring, secondary bacterial infection, and pneumonitis - occur more frequently and with greater severity)

  • Past history of conditions (e.g., autoimmune bullous diseases and herpes simplex)

  • Ingestion of new medications in the days or weeks before onset of eruption indicating bullous drug eruption (e.g., fixed drug eruption resulting in bullae formation, bullous pemphigoid, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis)

  • Contact with people who are or have recently been unwell (especially in consideration of viral illness)

  • Family or maternal history of similar eruption (e.g., pemphigoid gestationis)

  • Previous history of the condition (e.g., herpes simplex can be re-activated either spontaneously or by stimuli such as fever, stress, ultraviolet light, or immunosuppression).[7]

Associated important symptoms include:

  • Pruritus (a common symptom of dermatitis herpetiformis, allergic contact dermatitis)

  • Pain (a symptom of HZV infection).

Recurrent diseases may present with a history of specific triggers:

  • A history of repetitive trauma is associated with EB

  • A history of exposure to allergens or certain products is associated with contact dermatitis.

A thorough review of systems - including oral, ocular, genitourinary, gastrointestinal (GI), and respiratory - helps to determine whether the process has internal organ involvement or is strictly cutaneous. Systemic involvement is associated with the following diseases.[1]

  • EB: oral, ocular, genitourinary, GI, and respiratory systems.

  • Epidermolysis bullosa acquisita (EBA): blindness and oesophageal strictures.

  • Dermatitis herpetiformis: thyroid disorders and increased incidence of malignancy, specifically small bowel lymphoma.

  • Mucous membrane pemphigoid: blindness and stenosis of laryngeal and pharyngeal mucosa.

  • Incontinentia pigmenti: ophthalmological findings occur in 20% to 35% of patients; neurological complications occur in 30% of patients and often manifest within the neonatal period. Neurological complications are a major cause of morbidity and mortality in affected patients.[42]

  • Niacin deficiency: photosensitivity, photophobia, hoarseness, stomatitis, and corneal opacities.[20][43]

  • Mpox: fever, lymphadenopathy, headache, backache, and myalgia may appear before or after the rash, or not at all.[44][45][46]​​​​​

Physical examination

Physical examination of all skin, including hair and nails, as well as oral, conjunctival, and genital mucosae, and an overall assessment of the patient's condition, will guide diagnosis.[20] It is important to note whether blisters appear on skin that appears normal or are associated with erythema, urticaria, or erosions.

The size, location, distribution, and character of blisters should be characterised by type:

  • Single (e.g., friction blister, bullosis diabeticorum)

  • Multiple (e.g., pressure sites such as the hands, wrists, scapulae, sacrum, knees, ankles, and heel of coma bullae)

  • Generalised (e.g., epidermolysis bullosa, toxic epidermal necrolysis)

  • Grouped (e.g., scabies with involvement of interdigital web spaces of hands, axillae, waist, ankles, flexural aspects of wrists, scrotum and penis in men, and areolae in women)

  • Linear (e.g., Rhus dermatitis).

Patients with junctional EB may present with extensive denudation, which typically spares the hands. Prominent periorificial granulation tissue is another characteristic finding.

Clues to viral aetiology

  • In herpes simplex virus and VZV infection there is development of small grouped vesicles, often on an erythematous base. On skin, grouped vesicles evolve to grouped pustules that rupture, resulting in crusted ulcers. On mucosal surfaces, the vesicles rupture easily and are superseded by yellow-grey plaques or ulcers. The lesions are typically painful and may itch or sting.

  • In hand-foot-and-mouth disease, the location of blisters may be the most useful clue to diagnosis. Lesions begin as small blisters on the palms or soles accompanied by small erythematous papules that soon evolve into small oval or linear grey-white vesicles.[8]

  • In mpox, lesions simultaneously progress through four stages - macular, papular, vesicular, and pustular - before scabbing over and resolving.[14]​[15]​ Lesions are typically 5-10 mm in diameter, may be discrete or confluent, and may be few in number or several thousand.[12][44]​ The clinical presentation has, however, been atypical in recent outbreaks.

Clues to fungal aetiology

  • Dermatophytosis is a superficial variant of fungal infection involving skin, hair, nails, and mucous membranes. When infection involves the skin, it is commonly caused by the 'ringworm' fungi (Microsporum, Trichophyton, and Epidermophyton).

  • Cutaneous ringworm on non-hairy skin presents as slowly enlarging, scaly, erythematous annular lesions with central clearing. Of most relevance is dermatophyte infection with Trichophyton mentagrophytes, which can cause bullous tinea pedis. This form of dermatophyte (tinea) infection presents with multi-locular bullae involving the thin skin of the plantar arch and along the sides of feet and heel.

Clues to bacterial aetiology

  • Superficial blisters that appear rapidly, become cloudy, then rupture, and manifest with a seropurulent crust that is thin, are often observed in bullous impetigo. The flaccid bullae are seen most commonly on the face, buttocks, trunk, perineum, and extremities.[47] This contrasts with the non-bullous variant, which is characterised by a thick adherent crust.

  • In staphylococcal scalded skin syndrome, the age of the patient is helpful as it occurs almost exclusively in neonates and young children. The development of blisters is preceded by a macular scarlatiniform eruption, skin tenderness, and oedema. The blisters are flaccid and rupture easily, leaving a red glistening surface. Although rare, vesicles and bullae (particularly on the palms and soles of the feet) are skin findings that are closely associated with congenital syphilis.[32]

An attempt should be made to assess the level of lesional split:

  • Friction blisters form with a split in the upper epidermis and the cavity is filled with transudate

  • Superficial blisters typically manifest as crusted erosions

  • Intraepidermal blisters are flaccid and may expand under pressure (Asboe-Hansen sign)

  • Central basement membrane zone or intralamina lucida blisters are tense, but heal without scarring

  • Sublamina densa blisters are tense and heal with scarring and milia.

Laboratory tests

If the diagnosis is not clear from the clinical features, then laboratory or other tests are necessary. Swabs for bacterial and viral culture may help in the investigation of acute vesicular-bullous rashes, and a skin biopsy may be required for the diagnosis of both acute and chronic disease.

Skin biopsy will often be the most important step in making a diagnosis in patients with a blistering disorder. A biopsy provides information about the blister location, in terms of the subcorneal, suprabasilar, or subepidermal areas of the skin.

For routine histopathological examination, a fresh vesicle or blister (<24 hours old) is often biopsied in its entirety by punch technique and placed in formalin for haematoxylin and eosin (H&E) staining.

If the blistering process occurs on an inflammatory base or urticarial plaque, a biopsy can be performed in this area when active blisters are not present. Some blistering diseases have an early inflammatory stage, such as bullous pemphigoid (urticarial stage), and a biopsy from these areas can provide useful diagnostic information.

Gram stain is suitable for bacteria, while fungal elements are best examined with periodic acid-Schiff stain or Grocott-Gomori-methenamine silver nitrate stain. Staining can also be performed on routine H&E sections when an infectious aetiology is suspected.

A Tzanck smear can be helpful in cases of suspected herpes virus infection. The base of a blister is scraped with a scalpel and the cellular material spread onto microscope slides. After air-drying, the slides are stained and examined for the typical cytopathological changes associated with herpes virus infection, multinucleated giant cells, and acantholytic cells.[48]

Immunofluorescent studies

The diagnosis of autoimmune blistering diseases requires detection of tissue-bound and circulating auto-antibodies in the skin and mucous membranes.[29][49][50] Deposition of immunoreactants in tissue is detected by direct immunofluorescence (DIF), and circulating serum auto-antibodies are detected by indirect immunofluorescence (IIF).

In some cases, DIF and IIF studies are done at the same time as a skin biopsy for H&E if autoimmune disease is suspected clinically. They may also be performed subsequently once histological findings suggest an autoimmune blistering disorder. DIF is considered the gold standard for the detection of auto-antibodies.

  • Immunofluorescence studies provide information regarding localisation of the auto-antibodies within the skin and the site of cleavage produced by a blistering disorder. For example, auto-antibodies bound to the epidermal intercellular spaces are characteristic of pemphigus vulgaris and pemphigus foliaceus, while anti-basement membrane zone (dermal-epidermal junction) auto-antibodies are typical of bullous pemphigoid, pemphigoid gestationis, mucous membrane pemphigoid, linear IgA disease, EBA, and bullous lupus erythematosus.

  • Additional information to reach a more precise diagnosis may be obtained by using electron microscopy and immunoelectron microscopy.[51] However, this is rarely done in clinical practice.

  • Biopsy for DIF should be taken from peri-lesional skin (i.e., involved skin that has not yet begun to blister, which is less than 1 cm from the blistered skin). The biopsy must be either placed in normal saline and taken straight to the laboratory if it is on site, or snap-frozen immediately and stored at temperatures below -70°C (-94°F), or placed in a special transport medium such as Michel's solution.[29]

  • IIF is used as a screening tool for circulating auto-antibodies in autoimmune blistering diseases. IIF microscopy detects circulating serum auto-antibodies by use of frozen sections of normal tissues including human skin, monkey oesophagus, and rat and monkey bladder. It is not as sensitive as DIF.

  • In pemphigus, guinea-pig or monkey oesophagus is the most sensitive non-human substrate. In pemphigoid, human skin that has been incubated in sodium chloride 1 M solution to induce splitting of the dermal-epidermal junction, is optimal. The latter preparation allows differentiation between serum auto-antibodies that bind to the roof and those that bind to the floor of the blister, reflecting the different auto-antibody specificities.

Serological assay

Molecular specificity of circulating auto-antibodies can be characterised by serological assays including immunoblot, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA).[29] Immunoprecipitation and immunoblotting techniques are particularly useful adjunctive studies for detecting characteristic auto-antibodies in paraneoplastic pemphigus and bullous pemphigoid. ELISA testing is useful both to diagnose pemphigus and to monitor serum antibody levels during the course of the disease.

Molecular biology techniques should be used to make a precise diagnosis of any congenital blistering. For example, non-treponemal serological tests (Venereal Disease Research Laboratory or rapid plasma reagin) are used in infants with suspected syphilis.

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