VESICULOBULLOUS LESIONS OF ORAL CAVITY

According to Fitzpatrick classification:

According to separation at intraepithelial level:

Granular layer

Spinous layer

Suprabasal layer

Basal layer

Pemphigus foliaceous

Familial benign pemphigus

Pemphigus vulgaris

Erythema multiforme

Pemphigus erythematosus

Herpes simplex virus infection

Pemphigus vegetans

Toxic epidermal necrolysis (TEN)

Frictional blisters

Herpes zoster andvaricella

Darier’s disease

Lichen planus

Bullous impetigo

Eczematous dermatitis

 

Lupus erythematous

   

Epidermolysis bullosa simplex

According to separation at dermo-epidermal junction

Lamina lucida

Below basal lamina (sublamina densa)

Bullous pemphigoid

Epidermolysis bullosa acquisita

Cicatricial pemphigoid

Epidermolysis bullosa dystrophica

Epidermolysis bullosa junctional

Linear IgA dermatosis

Dermatitis herpetiformis

Bullous systemic lupus erythematous (SLE)

Antigens targeted by antibodies in vesiculobullous (VB) lesion:

Autoimmune VB lesions

Antigen

Pemphigus vulgaris

Desmoglein 1 and 3

Paraneoplastic pemphigus

Desmoglein 1 and 3, plakin proteins

Pemphigus foliaceous

Desmoglein 1

IgA pemphigus

Dsg3, desmocolin 1and 2

Pemphigus herpetiformis

Desmoglein 1

Cicatricial pemphigoid

BP 180, laminin V

Bullous pemphigoid

BP 180 and 230

Epidermolysis bullosa acquisita

Type VII collagen

Epidermolysis bullosa simplex

Keratin 5 and 14

Epidermolysis bullosa junctional

Laminin 5 andtype XVII collagen

Epidermolysis bullosa dystrophic

Type VII collagen

Erythema multiforme

Desmoplakins

Dermatitis herpetiformis

Tissue transglutaminase

  1. Clinical test
    • Nikolsky’s test.
  2. Histological test
    • Biopsy.
    • Tzanck test.
    • LE cell test.
  3. Molecular techniques
    • Immunofluorescence.
    • Salt split technique.
    • ELISA and western blotting.
  • First described by Piotr Vasiliyevich Nikolsky.
  • The sign is present when slight rubbing of the skin results in exfoliation of the outermost layer, forming a blister within minutes. 
  • Marginal Nikolsky’s sign: When the sign is elicited in the normal looking skin in the vicinity of the blister it is called marginal Nikolsky sign.
  • Direct Nikolsky’s sign: When the sign is elicited away from the blister it is called direct Nikolsky sign.
  • Pseudo Nikolsky’s sign or epidermal peeling sign:  Is positive in Stevens-Johnson syndrome, toxic epidermal necrolysis, burns and bullous ichthyosiform erythroderma.

Pemphigus vulgaris, pemphigus foliaceous, paraneoplastic pemphigus, mucous membrane pemphigoid, bullous pemphigoid, epidermolysis bullosa, Stevens-Johnson Syndrome, Staphylococcal scalded skin syndrome (SSSS), toxic epidermal necrolysis (TEN).

Instructions:

  • The ulcerated tissues should be avoided for biopsy site, as it may not show the roof of the vesicle and also the tissues may also be masked by secondary inflammation and necrosis
  • Ask patient to stop topical steroids at least a month before the biopsy procedure (prevent false negative results).
  • A 3–4 mm punch biopsy of uninvolved skin and an unblistered perilesional skin taken from an elliptical biopsy are adequate specimens.
  • Obtain two biopsy specimens:
  1. One specimen is kept in 10% neutral buffered formalin for hematoxylin and eosin staining
  2. Second is submitted in Michel’s medium for direct immunofluorescence (DIF) studies.
  • Michel’s medium prevents tissue degradation without damaging the immunoreactants such as immunoglobulins, complement, and fibrin for upto 6 months.
  • Perilesional skin is best for DIF testing of bullous diseases.
  • Sample of the patient’s serum or blood is required for indirect immunofluorescence (IDIF)
  • The ideal lesions for biopsy should be fresh (less than 24–48 h old), intact, and nonexcoriated vesiculobullae, with normal or erythematous perilesional skin included in the biopsy field.
  • Tzanck smear is a very simple and rapid technique.
  • For viral infections, samples should be taken from a fresh vesicle, rather than a crusted one.
  • Identification of the giant cells in vesicular viral infections (herpes simplex, varicella and herpes zoster)
  • Identification of acantholysis (pemphigus).

Following are the steps:

  • First clean the area and allow it to dry.
  • Then insert a sterile needle at the base of blister
  • Then take the smear from the base of the blister that contains acantholytic cells.
  • Smear is then prepared on a clean glass slide and stained using Leishman stain.
  • Smear reveals the presence of Tzanck cell which are formed following detachment, disintegeration and dissolution of normal squamous cell.
  • First explained by Hargraves for systemic LE (SLE).
  • In tissues, nuclei of damaged cells react with antinuclear antibodies (ANAs), lose their chromatin pattern and become homogenous to produce LE or hematoxylin bodies (amorphous round body in the cytoplasm of the cell).
  • If the serum from a patient suffering from SLE is added to the buffy coat of normal blood, a typical LE cell will develop.
  • LE cell is any phagocytic leukocyte (neutrophils or macrophage) that has engulfed the denatured nucleus of an injured cell and tagged (labeled) with a fluorescent dye and the antigen–antibody complex is visualized using ultraviolet (fluorescent) microscope.
  • Used for detection of wide variety of antigens in tissues or on cells in suspension.
  • Coons developed indirect immunofluorescence (IF) in 1940 with blue fluorescing compound, beta anthracene.
  • When a quantum of light is absorbed by an atom or molecule, an electron jumps to a higher energy level, thus displaces an electron from its shelf.
  • When this displaced electron returns backs to its original ground state, it emits a quantum of light.
  • This phenomenon is called photoluminescence and is of two types:
  1. Fluorescence
  2. Phosphorescence
  • It is the property of certain substances which when illuminated by a light of certain wavelength, re-emit the light to a longer wavelength.
  • These substances show fluorescence and are called fluorochromes.
  • Fluorescein iso thiocyanate (FITC) : Produces apple-green color;
  • Tetramethylrhodamine isothiocyanate (TRITC): Produce a red color of fluorescence
  • Phycoerythrin: Shows red fluorescence

These markers are detected using fluorescence microscope housed with a mercury vapor or xenon light source along with exciter and barrier filters.

In phosphorescence, emission continues to persist even after the exciting light is cut off.

  • Direct Immunofluorescence
  • Indirect Immunofluorescence
  • Sandwich technique
  • Multiple layer technique
  • Salt split technique:(Variant of IIF)
  • Via complement
  1. Michel’s medium that contains:
  • Buffer: 0.81 g
  • Potassium citrate 0.0625 g
  • N-ethylmaleimide (should be handled carefully)
  • 123 g magnesium sulphate
  • 100 ml distilled water
  • Before use add 55 g ammonium sulphate and allow to dissolve
  • Adjust pH to 7.0-7.2 with 1M KOH
  1. Saline solution

Normal saline solution (0.9% Nacl) without addition of calcium or magnesium

The principal application of DIF is in the identification of antibodies and other inflammatory proteins in tissue sections.

Procedure:

  • The procedures are performed on thin (<6 μm) cryostat sections of fresh unfixed material.
  • Sections are washed with 0.1 M phosphate buffered saline (PBS)with three changes over a period of 30 min.
  • Drain off excess PBS and wipe around section with cellulose tissue. Cover section with diluted conjugated and allow to react for at least 30 min at room temperature.
  • Drain off conjugate and wash with 3 changes of PBS over a period of 30 min.
  • Ideally the PBS should be gently agitated, too much agitation can easily remove sections from the slides.
  • Excess PBS is drained off and the area around the section carefully dried with cellulose tissue.
  • The sections are mounted using a PBS/Glycerol/1,4 – Diazabicyclooctane DABCO solution. It is important not to maneuver the cover slip since this will distort unfixed tissue.
  • The edges of the cover slip are then sealed using nail varnish(polyvinyl alcohol).
  • Read the preparations on a fluorescent microscope as soon as possible or store at 4°C.
  • Avoid direct sunlight on the slides at all times.
  • Provided bacterial/fungal contamination is avoided and drying out is prevented, it is possible to re-evaluate slides after more than 1 year’s storage at 4°C, even where weakly fluorescent reactions are involved.
  • Indirect immunofluorescence (IIF) is a test in which a patient’s serum is examined for the presence of antibodies to a defined antigen.
  • This is the two-stage procedure for in vitro demonstration of circulating antibodies in the patient’s serum.
  • The serum is added to substrate (the frozen section of tissue that is similar to human oral mucosa as monkey oesophagus) and incubated resulting in fixation of circulating antibodies to the antigen in the substrate.
  • The next step consists of the application of fluorescein labeled antihuman gammaglobulin to the substrate.

Procedure:

  • Prepare patient serum dilution in Phosphate-buffered saline (PBS). In most routine tests a 1:10 dilution is used, conveniently 50 μl + 450 μl PBS.
  • Expose sections to serum dilution for atleast 30 min, at room temperature. This is adequate for most reactions, the use of a longer time will not adversely affect results, although drying – out must be prevented.
  • Wash over 30 min, in PBS with 3 changes.
  • Remove excess PBS with cellulose tissue.
  • Cover sections with appropriately diluted antihuman Ig/FITC conjugate.
  • Routinely a broad spectrum polyvalent conjugate is used.
  • After 30 min drain off excess conjugated and wash over 30 min with three changes of PBS.
  • Mount cover slip as outlined under direct technique.
  • The smear or section is first treated with unlabeled antigen that will attach itself to antibody.
  • After an appropriate time this is washed off and replaced by a fluorescent tagged antibody.
  • The tagged antibody will react (or bind) with the antigen that has attached itself in the first stage to the antibody in the original specimen, thus making a sandwich.
  • The presence and location of positive fluorescence now indicates antibody sites in the original specimen. 
  • This is an extension of the sandwich technique.
  • This technique for antigen (or antibody) can be made more sensitive by successive layering of antibodies.

For example:

  • If mouse antibody (globulin) is to be detected, the specimen is treated with unlabeled rabbit – anti-mouse gamma globulin.
  • This will combine with any mouse globulin that may be present. Uncombined antisera are washed off.
  • Then tissue is treated with unlabeled goat – anti – rabbit sera that will combine with the rabbit globulin used in step 1. 
  • In this procedure, normal human skin is incubated in 1M NaCl (sodium chloride) for 48-72 h to split it at the level of the lamina lucida.
  • Bullous pemphigoid antibodies bind to the roof and floor of the blister while epidermolysis bullosa aquisita antibodies bind solely to the dermal (floor) side of the split skin. 

Autoimmune vesiculobullous lesions

Appearance

Pemphigus vulgaris

Intercellular deposition of IgG (IgG 1 and 4) throughout the epidermis-“chicken wire/fishnet appearance”

Paraneoplastic pemphigus

IgG with or without C3 binds in an intercellular pattern within the epidermis. Granular or linear deposition of C3, IgG, and/or IgM along dermal-epidermal junction in minor cases

Pemphigus herpetiformis

Deposition of IgG with or without C3 around cell surfaces of keratinocytes

Cicatricial pemphigoid

Linear deposits of complement (C3) and IgG, IgA at dermal-epidermal junction-“shore line appearance”

Bullous pemphigoid dermatosis (LAD)

IgG (70-90%) and C3 (90-100%) deposition in a linear band at dermal-epidermal junction

Epidermolysis bullosa acquisita

Thick band of IgG and to a lesser extent C3, deposited linearly at the basement membrane zone

Linear IgA

Linear deposition of IgA at basement membrane zone

Dermatitis herpetiformis

Deposition of IgA at dermal-epidermal junction

Erythema multiforme

Granular deposits of IgG, C3, IgM, and fibrinogen present around dermal vessels or at dermoepidermal junction

Systemic lupus erythematous

Deposition of IgG, IgM, or C3 in a shaggy or granular band at the basement membrane zone-“positive lupus band test”

Lichen planus

Shaggy deposits at dermoepidermal junction of IgM (within scattered cytoid bodies), C3, and IgG along with fibrinogen deposition at the basement membrane zone

Autoimmune vesiculobullous lesions

Appearance

Pemphigus vulgaris

Intercellular circulating IgG autoantibodies that bind to epidermis in 80-90% cases

Paraneoplastic pemphigus

Both intercellular intraepidermal antibody deposition+deposition along dermoepidermal junction

Pemphigus herpetiformis

Circulating IgG autoantibodies to epidermal cell surfaces

Cicatricial pemphigoid

Circulating IgG autoantibodies directed against basement membrane zone in 20% cases+circulating autoantibodies-epiligrin (laminin 5)

Bullous pemphigoid

Circulating IgG autoantibodies against the basement membrane zone

Epidermolysis bullosa acquisita

IgG circulating autoantibodies against skin basement membrane component-type VII collagen

Linear IgA dermatosis (LAD)

50% of patients have circulating antibody that bind to the basement membrane zone

Autoimmune vesiculobullous lesions

Appearance

Cicatricial pemphigoid (CP)

Patient with CP associated with BPAg2 binds to the epidermal roof Patient with autoantibodies associated with epiligrin bind to the blister floor

Bullous pemphigoid (BP)

IgG autoantibodies binds on the blister roof (epidermal side of salt split skin)

Epidermolysis bullosa acquisita (EBA)

IgG autoantibodies bind to the dermal floor of salt split skin

Linear IgA dermatosis (LAD)

IgA deposition on either the dermal side (blister      floor) or the epidermal side (blister roof)

  • Also called ELISA or EIA, is a test that detects and measures antibodies in blood.
  • This test can be used to determine the antibodies related to certain conditions.
  • Antibodies are proteins that body produces in response to harmful substances called antigens.
  • EIA/ELISA uses the basic immunology concept of an antigen binding to its specific antibody, which allows detection of very small quantities of antigens such as proteins, peptides, hormones, or antibody in a fluid sample.
  • EIA and ELISA utilize enzyme-labeled antigens and antibodies to detect the biological molecules, the most commonly used enzymes being alkaline phosphatase and glucose oxidase.
  • The antigen in fluid phase is immobilized, usually in 96-well microtiter plates.
  • The antigen is allowed to bind to a specific antibody, which is itself subsequently detected by a secondary, enzyme-coupled antibody.
  • A chromogenic substrate for the enzyme yields a visible color change or fluorescence, indicating the presence of antigen.
  • Quantitative or qualitative measures can be assessed based on such colorimetric reading.
  • Fluorogenic substrates have higher sensitivity and can accurately measure levels of antigen concentrations in the sample.
  • Direct ELISA: Attachment of an antigen to a polystyrene plate followed by an enzyme-labeled antibody that can react with the antigen and a substrate that can be measured.
  • Indirect ELISA: Attachment of an antigen to a polystyrene plate followed by an unlabeled or primary antibody followed by an enzyme-labeled antibody that can react with both the primary antibody and substrate.
  • Sandwich ELISA: A capture antibody is attached to the polystyrene plate, the antigen is added that specifically attaches or captures the antigen. A second antibody, also specific for the antigen but not the same as the capture antibody is added and “sandwiches” the antigen. The second antibody is followed by enzyme-labeled antibody. It is specific for the second antibody that can react with a substrate and can be measured.
  • Competitive ELISA: This test is like the sandwich ELISA but involves the addition of competing antibodies or proteins when the second antibody is added. This results in a decrease in the substrate signal that is generated. This test is considered to give good, highly specific results.
  • Macules: Well-circumscribed, flat lesions that is noticeable because of their change from normal skin color.
  • They may be red due to the presence of vascular lesions or inflammation, or pigmented due to the presence of melanin, hemosiderin, and drugs.
  • Papules: Solid lesions raised above the skin surface that are smaller than 1 cm in diameter. E.g erythema multiforme, simplex, rubella, lupus erythematosus, and sarcoidosis.
  • Plaques: Solid raised lesions that are over 1 cm in diameter; they are large papules.
  • Nodules: These lesions are present deep in the dermis, and the epidermis can be easily moved over them.
  • Vesicles: Elevated blisters containing clear fluid that are under 1 cm in diameter.
  • Bullae: Elevated blister-like lesions containing clear fluid that are over 1 cm in diameter.
  • Erosions: Moist red lesions often caused by the rupture of vesicles or bullae as well as trauma.
  • Pustules: Raised lesions containing purulent material.
  • Ulcers: A defect in the epithelium; it is a well-circumscribed depressed lesion over which the epidermal layer has been lost.
  • Purpura: Reddish to purple flat lesions caused by blood from vessels leaking into the subcutaneous tissue.

Purpuric lesions 1 to 2 mm in diameter known asPetechiae.

Larger purpuric lesions are called ecchymoses.

Acute multiple lesions

  • Herpesvirus Infections
  • Primary Herpes Simplex Virus Infections
  • Coxsackievirus Infections
  • Varicella-Zoster Virus Infection
  • Erythema Multiforme
  • Contact Allergic Stomatitis
  • Oral Ulcers Secondary to Cancer Chemotherapy
  • Acute Necrotizing Ulcerative Gingivitis

Recurring Oral Ulcers

  • Recurrent Aphthous Stomatitis
  • Behçet’s Syndrome
  • Recurrent Herpes Simplex Virus Infection

Chronic multiple lesions

  • Pemphigus
  • Subepithelial Bullous Dermatoses
  • Herpes Simplex Virus Infection in Immunosuppressed Patients

Single ulcers

  • Histoplasmosis
  • Blastomycosis
  • Mucormycosis

Note: Herpesvirus Infections, Primary Herpes Simplex Virus Infections, Coxsackievirus Infections and Varicella-Zoster Virus Infection discussed under viral infection of oral cavity.

It is a rare acute mucocutaneous condition caused by a hypersensitivity reaction with the appearance of cytotoxic T lymphocytes in the epithelium that induce apoptosis in keratinocytes, which leads to satellite cell necrosis.

Immune-mediated disease (deposition of immune complexes in the superficial microvasculature of skin and mucosa).

  1. Micro-organisms
  • Viruses: herpes viruses (HSV, VZV, EBV), adenoviruses, enteroviruses, hepatitis viruses (A, B and C), HIV, influenza
  • Bacteria: Mycoplasma pneumoniae, Chlamydia, Corynebacterium diphtheria, Hemolytic streptococci, Legionellosis
  • Fungi and parasites: coccidioidomycosis, dermatophytes, histoplasmosis, sporotrichosis
  1. Drugs: Allopurinol, barbiturates, cancer chemotherapeutic agents, carbamazepine, cephalosporins, non-steroidal anti-inflammatory drugs, penicillins, phenytoin, protease inhibitors.
  2. Food additives or chemicals: benzoates, nitrobenzene, terpenes, ethanol
  3. Immune and other conditions: graft versus host disease, immunisation (BCG, hepatitis B), inflammatory bowel disease,pregnancy, sarcoidosis, systemic lupus erythematous.
  • EMm, erythema multiforme minor.
  • EMM, erythema multiforme major.
  • SJS, Stevens-Johnson syndrome.
  • TEN, toxicepidermal necrolysis.
  • Acute, self-limiting disease that may be episodic or recurrent.
  • Arise in the third and fourth decades of life, it can also affect children and adolescents.
  • Rarely affects individuals under the age of 3 or older than 50.
  • Characterized by cutaneous disease, including the typical and/or atypical raised targets affecting less than 10% of skin surface.
  • Mucosal involvement is uncommon and not severe.
  • Cutaneous target lesions follow a symmetric distribution with a predilection for the extensor surfaces of the extremities.
  • Involvement of the skin of the face or trunk is less.
  • The Nikolsky’s sign is negative.
  • Lesions last for 1 to 3 weeks and heal without scarring to leave areas of hyperpigmentation and/or hypopigmentation.
  • Mucosal disease is limited to only 1 site, most commonly the mouth.
  • Oral lesions manifest with edema, erythema, and erythematous macules of the lips and buccal mucosa, followed by the development of multiple vesicles and bullae that quickly rupture and result in pseudomembrane formation.
  • Lips tend to become swollen and show distinctive bloody encrustations
  • Intact vesicles are rarely observed because they rapidly break down to form ill-definedulcers.
  • Mild extension oferythematous patches or superficial erosions of the oralmucosa and the lip.
  • EMM differs from EMm by the involvement of at least 2 different mucosal sites, which typically includes the oral mucosa.
  • Oral lesions commonly appear along with skin lesions
  • Cutaneous involvement of EMM is usually less than 10% of the body surface but is generally more severe than that of EMm.
  • Erythema multiforme major can be preceded by erythematous macules.
  • Oral lesions usually widespread and severe.
  • The vesicles tend to rupture to leave multiple areas of superficial irregular erosions that are usually covered by a yellow fibrinous pseudomembrane.
  • Eventually, multiple, large, shallow, irregular, painful ulcers surrounded by an erythematous margin and covered by whitish plaques of desquamated epithelium occur.
  • Affect the lingual, buccal, and/or labial mucosa, and less frequently the floor of the mouth, palate, and the gingivae.
  • Trismus, dysphonia, dysarthria, and/or dysphagia.
  • Oral lesions of EMM usually heal without scarring.

Individual lesions less than three cm diameter with a regular round shape, well-defined border, and at least 3 different zones, that is, 2 concentric rings around a central disk. One ring consists of palpable edema, paler than the center disk.

Round, edematous, palpable lesions similar to EM but with only 2 zones and/or a poorly defined border.

Round lesions characteristic of EM but with only 2 zones and/or a poorly defined border and non palpable with the exception of a potential central blister.

Non palpable, erythematous, or purpuric macules with an irregular shape and size and often confluent. Blisters often occur on all or part of the macule.

  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis (TEN) 
  • Stevens-Johnson syndrome (SJS) was first described in 1922 by M. Stevens and F. C. Johnson.
  • Severe bullous form of erythema multiforme with widespread involvement of skin, oral cavity, eyes and genitalia.
  • Abrupt fever.
  • Malaise.

Skin lesions

Similar to erythema multiforme, although they are commonly hemorrhagic and are often vesicular or bullous.

Oral mucous membrane lesions

  • Lesions are severe and extremely painful.
  • Mucosal vesicles or bullae occur that rupture and leave surfaces covered with a thick white or yellow exudate.
  • Erosions of the pharynx
  • Ulceration of lips with bloody crusting.

Eye lesions:

  • Photophobia.
  • Corneal ulceration.
  • Panophthalmitis.
  • Blindness due tointercurrent bacterial infection.

Genital lesions

  • Urethritis.
  • Balanitis and/or vaginal ulcers.
  • The first described by the Scottish dermatologist Alan Lyell in 1956.
  • It is a rare, acute, and life-threatening mucocutaneous disease that is usually drug related.
  • It is considered as a confluent form of Stevens-Johnson syndrome.
  • This condition is due to extensive keratinocyte cell death that results in the separation of significant areas of skin at the dermal-epidermal junction with the production of bullae followed by skin sloughing.
  • Cutaneous lesions appear in the face, palms, and soles of the feet.
  • Mucosal involvement occurs in more than 90% (mouth, genitalia, and/or ocular region)
  • Erythema and erosions characterize the lesions.
  • Early cutaneous lesions present as livid, erythematous maculae.
  • During the course of the disease, the lesions rapidly coalesce and become tense bullae.
  • With disease progressions, they form large confluent areas of epidermal detachment. 

A classification system for SJS and TEN according to the extent of skin detachment:

  • 1–10%: SJS
  • 11–30%: SJS-TEN overlap disease
  • >30%: TEN
  • Erythema multiforme is diagnosed clinically.
  • Laboratory tests (e.g., HSV-1 and -2, immunoglobulin M and G) may confirm a suspected history of HSV infection.
  • Histological examination and immunostaining often shows:
  1. Moderate to dense perivascular inflammatory infiltrate (CD4+ lymphocytes and histocytes) within the papillary dermis and along the dermoepidermal junction, dermal edema.
  2. Intraepithelial/subepithelial vesicles and/or bullae.
  3. Hydropic degeneration of basal keratinocytes
  4. Non-specific immune deposits of IgM, C3 and fibrin along basement membrane.
  5. Direct and indirect immunofluorescence is unhelpful.
  • Oral antihistamines and topical steroids.
  • Prednisone at dosages of 40 to 80 mg per day for one to two weeks then tapered rapidly.

Patients with co-existing or recent HSV infection:

  • Oral acyclovir (400 mg two times per day).
  • Valacyclovir (Valtrex; 500 to 1,000 mg per day) and famciclovir (Famvir; 125 to 250 mg per day).

Lupus erythematosus, herpetic gingivostomatitis, Behçet’s disease, erosive lichen planus. 

It is an oral mucosal immune inflammatory disorder variably characterized clinically by erythematous plaques, vesiculation, ulceration, and/or hyperkeratosis and by pain, burning sensation, or itchiness.

  • Contact with dental materials (amalgam, gold in crowns, free monomer in acrylic, and nickel in orthodontic wire).
  • Oral hygiene products (Pyrophosphates and zinc citrate).
  • Certain foods.
  • Toothpaste, mouthwash and dental floss.

Contact stomatitis is less common than contact dermatitis due to:

  • Saliva quickly dilutes potential antigens and physically washes them away and digests them before they can penetrate the oral mucosa.
  • Due to high vascularity potential antigens that do penetrate the mucosa are rapidly removed before an allergic reaction can be established.
  • The oral mucosa has less keratin than the skin, decreasing the possibility that haptens will be formed.

Acute lesions:

  • Develop soon after antigenic exposure.
  • Diagnosis is straightforward since a cause-and-effect relationship can be easily established.

Chronic lesions:

  • Present as areas of erythema, edema, desquamation and occasionally ulceration.
  • Also present as erosions with rough surface and irregular borders, often surrounded by a red halo.
  • Objective examination.
  • The personal medical history is helpful to perform a correct diagnosis.
  • Histology.
  • Histology in the more uncertain lesions is mandatory.

Patch test

  • In patch test protocol, certain amounts of suspected haptens are applied onto the skin for 48 h (24 h in some countries), and the subsequent assessment of skin reaction is done at defined time points, typically after 2, 3 and 4 days.
  • It is performed by placing the suspected allergens in small aluminium disks, called Finn chambers,which are taped onto hairless portions of the skin.The disks remain in place for 48 hours. A positive response to a contact allergen is identified by inflammation at the site of the test,which is graded on a scale of 0 to 3.

Pathologies of secure allergic origin        

  • Allergic contact stomatitis
  • Allergic contact cheilitis

Pathologies of suspected allergic origin

  • Geographic tongue.
  • Oral lichenoid reactions.
  • Burning mouth syndrome.
  • It is a superficial inflammation of the lip that can occur either alone or be associated with stomatitis or perioral eczema.
  • Caused by cosmetic and hygiene products. 

OLRs are often associated with a known identifiable inciting factor.

The presentation of OLR can be reticular white patches, papules, plaques, erosions, or ulceration.

Anti malarial drugs, oral anti diabetic medication, antihypertensive agents and non steroidal anti inflammatory drugs, acrylic resins and metals, dental amalgam(due to the release of mercury).

  • Eliminating the allergenic agent.
  • Complete disappearance of the lesions can take up to 2 weeks.
  • Antihistamines.
  • Cetirizine:
  1. Adults—5 to 10 milligrams (mg) once a day.
  2. Children 6 years of age and older—5 to 10 mg once a day.
  3. Children 4 to 6 years of age—2.5 mg once a day, up to a maximum of 5 mg once a day or 2.5 mg twice a day.

Chlorpheniramine

  1. For regular (short-acting) oral dosage forms (tablets or liquid):
  2. Adults and teenagers—4 milligrams (mg) every four to six hours as needed.
  3. Children 6 to 12 years of age—2 mg three or four times a day as needed.
  • Topical anesthetics and topical corticosteroids.
  • Use of antihistamine suspensions in a swish and swallow method is useful.
  • Also known as trench mouth, fusospirochetal gingivitis, Vincent’s stomatitis and Vincent infection.
  • First described by Plaut in 1894 and Vincent in 1896.
  • ANUG is characterized by marginal gingival necrosis, gingival bleeding and painful ulceration of the gingival surface.

This term is used when the attachments of the teeth (periodontal and alveolar ligaments) are disrupted.

Is the term for when the necrosis has progressed beyond the mucogingival junction.

  1. Bacterial causes:
  • Prevotella intermediaand Peptostreptococcus species
  • SpirochetesFusobacteriaand Porphyromonas species
  1. Fungal causes:
  • Candida albicansand Aspergillus species
  1. Viral aetiologies: CMV, human herpesvirus type 6 and Epstein-Barr virus.
  2. Predisposing factors:
  • Poor oral hygiene with pre-existing marginal gingivitis or faulty dental restorations.
  • Smoking.
  • Emotional stress.

Disease of sudden onset with:

  • Pain.
  • Tenderness.
  • Profuse salivation.
  • Peculiar metallic taste.
  • Spontaneous bleeding.
  • Loss of taste sensation.
  • Extrusion of teeth.
  • Teeth are sensitive to pressure, or to have a “woody sensation.”
  • Blunting of the interdental papillae.
  • The typical lesions consist of necrotic punchedout ulcerations on the interdental papillae and the marginal gingivae.
  • Ulcers may develop on the cheeks, the lips, and the tongue, where these tissues come in contact with the gingival lesions or following trauma.
  • Lymphadenopathy.
  • Bad breath.
  • Ulcerative lesions may progress to involve the alveolarprocess, with sequestration of the teeth and bone.

Bacteriologic Examination, Smears show vast numbers of:

  • Fusiform bacilli (genus Fusobacterium or Fusiformis).
  • Oral spirochete (Borrelia vincentii).
  • Various other spirochetes, filamentous organisms, vibrios, cocci, desquamated epithelial cells and varying numbers of polymorphonuclear leukocytes.
  • Lower CD4+ T-lymphocyte counts area risk factor for HIV.
  • HIV specific test
  • Avoid tobacco, alcohol.
  • Mouth rinse (3% hydrogen peroxide + warm water or 0.12% chlorhexidine solution)

Antibiotics:

  • Penicillin 250 mg or 500mg orally every 6 hours.
  • Metrogyl 400 mg three times daily.

For Penicillin sensitive:

  • Erythromycin 250 or 500 mg every 6 hourly.
  • Scaling and root planning.
  • Recurrent aphthous stomatitis is a disorder characterized by recurring ulcers in the oral mucosa in the patient with no other signs of disease.
  • The term “aphthous” is derived from a Greek word “aphtha” which means ulceration.

Based on nature of recurrence as follows:

  • Simple aphthosis – Here the recurrence occurs two to four times in a year.
  • Complex aphthosis – Associated with systemic disease and activity of disease continues throughout the year and as older lesions heal newer lesion develops.

Classification for determining the management strategies:

  • Type A: RAS episodes lasting a few days with tolerable pain and a few occurrences in a year.
  • Type B: Painful RAS lasting 3 to 10 days recurrence every month.
  • Type C: Chronic painful course with disease activity almost continuous throughout the year.

 Recurrent aphthous ulcers can also be divided in to:

  • Major recurrent aphthous stomatitis.
  • Minor recurrent aphthous stomatitis.
  • Herpetiform ulcers. 

Local:

  • Trauma
  • Smoking
  • Dysregulated saliva composition

Microbial:  

  • Bacterial: Streptococci
  • Viral: Varicella zoster, Cytomegalovirus

Systemic:  

  • Behçet’s disease
  • Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome
  • Crohn’s disease
  • Ulcerative colitis
  • HIV infection
  • Periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) or Marshall’s syndrome
  • Cyclic neutropenia

Stress:Psychological imbalance, menstrual cycle

Nutritional:         

  • Gluten sensitive enteropathy
  • Iron, folic acid, zinc deficiencies
  • Vitamin B1, B2, B6 and B12 deficiencies

Genetic:    

  • Ethnicity.
  • HLA haplotypes.

Allergic/Immunologic:

  • Local T-lymphocyte cytotoxicity.
  • Abnormal CD4:CD8 ratio.
  • Dysregulated cytokine levels.
  • Microbe-induced hypersensitivity.
  • Sodium lauryl sulfate (SLS) sensitivity.
  • Food sensitivity.

Others:      

  • Antioxidants.
  • Non-steroidal anti-inflammatory drugs (NSAIDS).
  • Beta blockers.
  • Immunosuppressive drugs.
  • It is cell mediated immune response in which TNF- alpha plays a major role.
  • A mononuclear (lymphocyte cell) infiltrate in the epithelium in pre ulcerative stage followed by a localized papular swelling due to keratinocyte vacuolation surrounded by a reactive erythmatous halo representing vasculitis.
  • The painful papule then turns in to a vesicle which ulcerates and fibrinous membrane covers the ulcer that is infiltrated by neutrophils, lymphocytes and plasma cells.

Finally there is healing with epithelial regeneration.

  • Also known as Periadenitis mucosa necrotica recurrens, Sutton’s disease
  • Rare and severe form.
  • Sex ratio :M= F
  • Age of onset (yrs): 10-19
  • Number of ulcers: 1-10
  • Size of ulcers: (mm) > 10
  • Duration (days):> 30
  • Rate of recurrence (months): < Monthly.
  • Sites: lips, cheeks, tongue, palate, pharynx.
  • Permanent scarring: Common
  • Lesions are oval in shape and painful.

Rarely major aphthae may present as numerous ulcers affecting a large area or several giant lesions that persists for months. These lesions are referred as giant aphthae, relapsing aphthae or refractory aphthae.

  • Also known as mild aphthae or Mikulicz’s aphthae
  • Sex ratio: M= F
  • Age of onset (yrs): 5-19
  • Number of ulcers: 1-5
  • Size of ulcers: (mm) < 10
  • Duration (days): 4-14
  • Rate of recurrence(months): 1-4
  • Permanent scarring: uncommon
  • These ulcers are usually oval or round in shapeenveloped by thin eryhematous halo with grey-white pseudomembrane.
  • The labial and buccal mucosa and the floor of the mouth.
  • Gingiva, palate, or dorsum of the tongue is rarely affected.
  • Prodromal symptoms like localized burning sensation and pain may occur before the appearance of ulcers.
  • Ulceration and pain lasts for about 3 to 4 days, and then re-epithelialization begins after which pain starts subsiding.
  • Sex ratio : F > M
  • Age of onset (yrs): 20-29
  • Number of ulcers: 10-100
  • Size of ulcers: (mm) > 1-2
  • Duration (days): < 30
  • Rate of recurrence (months): < Monthly
  • Sites: Lips, cheeks, tongue, palate, pharynx, palate, gingiva, floor of mouth.
  • Permanent scarring: uncommon
  • Rare presentation.
  • Accounts for 5 to 10 % of all RAS cases.
  • Characterized by multiple recurrent crops of small, painful ulcers (5-100) that are widespread and may be distributed throughout the oral cavity.
  • They tend to fuse, producing large irregular ulcers.
  • These ulcers have later age of onset with more predisposition for women.

Blood investigations-  Serum iron, folate, vitamin B12, and ferritin levels.

Immuno Histochemistry – The epithelial basalcells in pre-ulcerative RAS lesions and epithelium at the ulcer stage contain Class I and Class II MHC antigens, both being consistent with active cell mediated inflammation.

RAS biopsy tissue on immunological study reveals numerous cells with variable ratios of CD4+:CD8+T lymphocytes depending on ulcer duration.

Topical preparation

  • Topical corticosteroid such as:
  1. Clobetasol proprionate 0.05% in Orabase, Clobetasol proprinate 0.05% or fluocinonide 0.05% in Orabase (1:1).
  2. Hyaluronic acid gel 0.2%

Systemic Steroid Therapy

Systemic prednisone must be started at dose of 1mg/kg single dose and should be tapered after 1 to 2 weeks.

Levamisole:

  • Have immunostimulatory effects.
  • Levamisole has the ability to normalize the CD4+ cell/ CD8+ cell ratio and improve symptoms in recurrent aphthous ulcers.
  • 150 mg of levamisole is given for 3 consecutive days every fortnightly.

Thalidomide

  • It is a potent anti-inflammatory and immunomodulatory drug.
  • Effective dosages of 100 and 300 mg/day.

Pentoxifylline

  • Immunosuppressive action by interfering with neutrophil adherence and inhibition of lymphocyte activation.
  • Pentoxifylline (Trental) 400 mg three times a day for one day.

Colchicine – Systemically 0.6 mg three times daily.

Zinc sulphate – It is given systemically, a total of 660 mg of zinc sulphate per day in divided doses.

Bioadhesive Patches – Bio-adhesive hydrogel patches.

  • Also known as an oculo-orogenital syndrome.
  • It is a chronic remitting and relapsing inflammatory disorder characterized by recurrent oral aphthous ulcers, genital ulcerations, ocular manifestations.
  • Etiology is unknown.
  • Autoimmune disease triggered by infections:
  1. Herpes simplex virus (HSV).
  2. Streptococcus
  3. Staphylococcus in genetically predisposed individuals.
  • Genetic predisposition in HLA-B51 carriers.
  • Characterized by vasculitis of all sized vessels that involves both arterial and venous sides of the circulation.
  • Cell-mediated immunity plays a major role.
  • Helper T- cells type-1 activation leads to increased circulating levels of CD-4 positive and cytotoxic (CD8 positive) lymphocytes in the peripheral blood which target the oral mucosa, skin and other systems of the body.
  • Recurrent painful oral lesions (aphthous ulcers) with odynophagia, foul-smelling breath, photophobia, vision loss, joint pains, and painful genital lesions.
  • Multiple aphthous ulcers involving the soft palate, hard palate, buccal mucosa, and tonsils, having a sharp regular border with a greyish base and surrounding bright red halo.
  • Genital lesions may occur on the scrotum in males and vulva and vagina in females.
  • Ocular manifestations: conjunctivitis, uveitis and hypopyon.
  • Non-deforming arthritis of medium and large joints may be seen.
  • Neurological manifestations: Meningoencephalitis, cerebral venous thrombosis, benign intracranial hypertension, cranial nerve palsies and various pyramidal and extrapyramidal lesions.

Diagnosis is mainly clinical, and the diagnostic criteria consist of recurrent oral aphthous stomatitis with two or more of the following clinical findings in the absence of other systemic diseases:

  1. Recurrent painful genital lesions.
  2. Ocular lesions; retinal vasculitis or uveitis.
  3. Skin lesions (e.g., erythema nodosum, papulopustular lesions)or a positive Pathergy test (a sterile pustule that appears after local trauma to the skin)
  4. Central nervous system (CNS) lesions (e.g., cerebral infarction, meningoencephalitis).
  • Mucocutaneous involvement: Topical antibiotics, topical corticosteroids, sucralfate
  • Ocular disease: topical corticosteroids+mydriatics or cycloplegics
  • Articular involvement (arthritis): Colchicine, NSAIDs, Benzathine penicillins
  • Vascular involvement: Systemic corticosteroids
  • CNS involvement: Systemic corticosteroids
  • GIT involvement: Sulfasalazine, corticosteroids
  • In pregnancy, prednisolone is the systemic drug of choice without potential side effects related to pregnancy.
  • For refractory cases, the following drugs are being used:
  1. Immunomodulators (e.g., azathioprine, cyclosporine)
  2. Immunosuppressive drugs (methotrexate, cyclophosphamide)
  3. Anti-Tumor Necrosis Factor-alpha (e.g., infliximab)

Sweet syndrome, erythema multiforme, pemphigus.

  • The term pemphigus stems from the Greek ‘pemphix’, which means blister or bubble.
  • In this there is production of IgG auto-antibodies against extracellular domains of cell membrane proteins of keratinocytes results in acantholysis (the loss of cell–cell adhesion between keratinocytes).
  • In pemphigus, IgG auto-antibodies are characteristically directed against desmogleins (1 and 3), part of the cadherin family of cell–cell adhesion molecules that are found in desmosomes, which are responsible for maintaining intercellular adhesion in stratified squamous epithelia, such as the skin and oral mucosa. 

It can be classified into three major forms:

  • Pemphigus vulgaris.
  • Pemphigus foliaceus.
  • Paraneoplastic pemphigus. 

Pemphigus vulgaris (PV) is a chronic, autoimmune, mucocutaneous, vesiculobullous disease.

  • Etiology is unknown.
  • Association with certain HLA Class II alleles.
  • Initiating factors: certain foods (garlic), infections, neoplasms, and drugs.
  • Drugs: Thiol group(captopril), penicillamine, rifamipicin.

 Autoantibodies are produced against desmosomes (adhesion proteins), specially desmoglein 3 (Dsg 3).

  • Mucosal-dominant type (limited cutaneous involvement): blisters in the deep layers of the oral mucosa owing to anti-desmoglein 3 IgG autoantibodies
  • Mucocutaneous type (both mucosal and cutaneous involvement): blisters in the deep layers of the oral mucosa and epidermis, owing to anti-desmoglein 3 and anti-desmoglein 1 IgG autoantibodies, respectively.
  • Cutaneous type (cutaneous involvement alone): blisters in the deep layers of the epidermis owing to anti-desmoglein 1 and pathogenically weak anti-desmoglein 3 autoantibodies.
  • Characterized by cutaneous or mucosal blistering.
  • Oral lesions appear earlier than skin.
  • Affects patients in the 4th and 5th  decades of life.
  • Females more frequently affected than males.
  • Thin-walled bulla appears on normal skin or mucosa.
  • Bulla ruptures and continues to extend peripherally, leaving large areas denuded of skin.
  • Lesions of skin affect the head, upper trunk and groin.
  • Skin lesions are characterized by flaccid blisters and partly crusted erosions on healthy-appearing or erythematous skin.
  • Positive Nikolsky’s sign
  • Oral lesions are first sign.
  • Appear as bullae on anon-inflamed base.
  • Bullae breaks and leave shallow irregular ulcers.
  • Edges of the lesion continue to extend peripherally.

Site involved:

  • Buccal mucosa (areas of trauma along the occlusal plane).
  • Palate
  • Gingiva (desquamative gingivitis).

Pregnant women passively transfer pathogenic autoantibodies to their child, leading to transient blisters and erosions of the skin of the neonates.

  • Biopsy should be done on intact vesicles and bullae less than 24 hours old.
  • Histologic findings include acantholysis in the suprabasal region showing the hallmark of ‘suprabasillar split’. Intraepithelial vesicle also showed Tzanck cells.
  • Direct immunofluorescence: Shows IgG deposits and less commonly IgM and C3 deposits in intercellular spaces in the epithelium.
  • Blood tests: ELISA testing for Dsg3 and Dsg1 autoantibodies
  1. What is Tzanck cell?

A typical Tzanck cell is a large round keratinocyte with a hyperchromatic nucleus with peripheral condensation of chromatin, hazy or prominent nucleoli, and abundant basophilic cytoplasm.

The aim of pharmacologic therapy for PV is to reduce inflammatory response and autoantibody production.

Steroids

  • Initial prednisolone dose at 0.5 mg–1.5 mg/kg/d, if control of the disease is not reached within 2 weeks, a higher prednisolone dose (up to 2 mg/kg) could be administered.
  • CSs can be combined with an immunosuppressive agent, when complications due to expected prolonged use (>4 months).
  • If doses of prednisolone above 100 mg/d are required, pulse treatment with either oral or intravenous (IV) steroids may be considered.

Azathioprine

  • Dose varies between 1 and 3 mg/kg/d, based on the activity of the thiopurine methyltransferase (TPMT) enzyme.
  • In High TPMT levels, give normal doses of azathioprine (up to 2.5 mg/kg/d).
  • PV and intermediate or low TPMT levels should receive a maintenance dose (up to 0.5–1.5 mg/kg/d).
  • Azathioprine should not be used with no TPMT activity.  

Mycophenolate mofetil

  • MMF is a safe steroid-sparing agent.
  • First-line adjuvant immunosuppressant.
  • The optimal dose is weight dependent with a dose of 2 g/d recommended for the average patient of 75 kg.
  • Progressive dose increase by 500 mg/wk until the final dose of 2 g/d.

Cyclophosphamide

  • Second-line immunosuppressant.
  • Administered either as a 500 mg IV infusion or as 2 mg/kg/d orally.

Dapsone

  • Recommended in a dose of 100 mg/d or up to ≤1.5 mg/kg/d as a steroid-sparing agent.
  • Before initiating therapy with dapsone, serum G6PD activity should be tested.

Methotrexate

  • Can be used as a steroid-sparing agent in a dose of 10–20 mg/wk.
  • Steroids can be tapered after 6 months when using adjuvant therapy with 15 mg of methotrexate per week.

Rituximab

  • Rituximab is an anti-CD20 monoclonal humanized antibody with the potential to reduce desmoglein autoantibodies and selectively deplete B cells.
  • Indicated in patients who remain dependent on more than 10 mg prednisolone combined with an immunosuppressive adjuvant.
  • Administration schedule is either 1,000 mg IV every 2 weeks or 375 mg/m2 every week.

Intravenous immunoglobulins

  • IVIG can be used in refractory disease or in case of contraindications to immunosuppressive adjuvants.
  • Usual dose is 2 g/kg/cycle IV administered over 2–5 consecutive days, monthly.

Infliximab

  • Infliximab is a chimeric monoclonal antibody against tumor necrosis factor alpha (TNF-alpha).
  • TNF-alpha has been found to strongly express the acantholytic cells in PV.

Immunoadsorption

  • Rapid removal of circulating autoantibodies against Dsg1 and Dsg3 can be achieved by immunoadsorption.
  • Indicated in refractory PV when CSs combined with azathioprine or mycophenolate fail to control the disease.
  • Four treatments of immunoadsorption on 4 consecutive days (2.5-fold plasma volume/d), repeated after 4 weeks, if needed, are the recommended schedule.

Therapeutic plasma exchange – plasmapheresis

  • It is an extracorporeal blood purification technique, in which the blood is continuously removed from the patient and separated into cellular components and plasma; the cellular compartments are returned to the patients along with replacement fluidlike albumin.
  • Four or five plasma exchanges, each exchange consisting of 1–1.5 plasma volumes, over a period of 7–10 days constitute an adequate short-term therapy to remove 90% of the total initial body immunoglobulin burden.

Dermatitis herpetiformis, erythema multiforme bullosum, bullous lichen planus, epidermolysis bullosa.

  • First described by Neumann in 1876.
  • Caused by autoantibodies directed against antigens on the surface of keratinocytes.
  • Characterized by vegetative plaques in the inguinal folds, flexural areas, and oral mucosa accompanied by the presence of autoantibodies against desmoglein 3.

Neumann type:

  • Is more common.
  • Early lesions are similar to pemphigus vulgaris, with large bullae and denuded areas.
  • These areas attempt healing by developing vegetations of hyperplastic granulation tissue.

Hallopeau type:

  • Less aggressive, pustules are the initial lesions.
  • These pustules are followed by verrucous hyperkeratotic vegetations.
  • Affects chiefly middle-aged adults. 
  • Heaped up, cauliflower-like vegetating plaques in the flexures
  • Vegetations may occur at any site
  • Oral lesions are common in both forms.
  • Gingival lesions may be lace-like ulcers with a purulentsurface on a red base or have a granular or cobblestoneappearance.
  • Cerebriform tongue, characterized by a pattern of sulci and gyri on the dorsum of the tongue.
  • Histopathological examination:
  1. Hallopeau type: demonstrate eosinophilic spongiosis with transmigration of eosinophils into the epidermis and eosinophilic microabscesses.
  2. Neumann type: shows suprabasal vesicles with acantholytic cells but no eosinophilic microabscesses.
  3. Chronic vegetative lesions in both subtypes reveal hyperkeratosis, acanthosis, papillomatosis and a suprabasal cleft with eosinophils.
  • Direct immunofluorescence:

Shows IgG deposits usually associated with C3 on the keratinocyte cell surface; however, coexistence of IgA anti-Dsg3 antibodies also occur.

Treatment of pemphigus vegetans is similar to that of pemphigus vulgaris

  • Also known as superficial pemphigus, fogo selvage.
  • It is a benign variety of pemphigus.
  • It is an autoimmune skin disorder.
  1. Drugs:

ACE Inhibitors

  • Captopril
  • Lisinopril
  • Enalapril
  • Fosinopril

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

  • Penicillamine
  • Bucillamine

Angiotensin-II Receptor Blockers (ARBs)

  • Candesartan

Antibiotics

  • Rifampicin

Orphan Drugs

  • Tiopronin
  1. Associated with certain neoplasm:
  • B-cell lymphoma.
  • T-cell lymphoma.
  • Prostate cancer.
  • Cutaneous squamous cell carcinoma. 
  • In this body’s immune system produces immunoglobulin G (IgG) autoantibodies that target the intercellular adhesion glycoprotein desmoglein-1 (dsg-1).
  • The binding of these autoantibodies to dsg-1, which is principally expressed in the granular layer of the epidermis, results in the loss of intercellular connections between keratinocytes (acantholysis) and the formation of subcorneal blisters within the epidermis. 
  • The pathogenic autoantibodies of PF are of the IgG4 subclass.
  1. Two predominant types:
  • Idiopathic PF: Found universally and occurs sporadically,
  • Fogo selvagem (FS): An endemic variety linked exclusively to multiple distinct geographical areas.
  1. Rare:
  • Pemphigus erythematosus (PE, Senear-Usher syndrome):affects the face and overlaps with lupus erythematosus, and may be exacerbated by UV exposure
  1. Pemphigus herpetiformis (PH): Resembles dermatitis herpetiformis in the early phase. 
  2. Drug-induced PF.
  3. IgA pemphigus
  • PF symptom onset ranges from 40 to 60 years of age.
  • FS affects children and young adults.
  • Both sporadic and endemic PF are seen equally in men and women.
  • Both forms affect all races and ethnicities.
  • No mucosal involvement
  • Blister formation on the skin.
  • Onset is usually insidious with scattered, scaly lesions in a ‘seborrhoeic’ distribution, i.e. the scalp, face and upper trunk
  • The Nikolsky sign is positive.
  • Fogo selvagemoccurs often in children and young adults.
  • Mild endemic form of pemphigus foliaceus.
  • Found in tropical regions.
  • Clinically, histologically and immunopathologically the same as sporadic PF.

Histopathology

  • The earliest pre-acantholytic findings in PF are the formation of vacuoles within the intercellular spaces of the granular and/or upper spinous layers of the epidermis.
  • Eosinophilic spongiosis of the epidermis.
  • Older PF lesions show evidence of chronic inflammation, including papillomatosis, acanthosis, hyperkeratosis, parakeratosis, and follicular plugging.
  • Keratinocytes of the granular layer display dyskeratotic changes.

Direct Immunofluorescence

  • Characterized by fluorescent staining around keratinocytes, which is known as the intercellular space (ICS) staining pattern.
  • Fluorescent stain in PF may be greater in the upper epidermis due to the increased density of dsg-1 and subsequent antibody deposition in the superficial epidermis.
  • Complement component 3 (C3) may also stain at the ICS in PF.

Indirect Immunofluorescence

  • IIF will show ICS staining in PF with a potential greater fluorescent intensity in the upper epidermis.
  • IgG subclass staining for PF shows both IgG1 and IgG4 subclasses are produced against dsg-1, with IgG4 being the predominant autoantibody subclass.

Enzyme-linked immunosorbent assay (ELISA)

  • Detect dsg-1 autoantibodies 
  • Less aggressive than pemphigus vulgaris.
  • Patients need referring to dermatologist for diagnosis and management

Topical steroids 

Potent / superpotent topical steroids can be used for less severe cases

Systemic treatment (the majority)

Prednisolone 20-40 mg/day initially.

Where high doses of oral steroids are required other drugs can be used to reduce the dose of steroids to safer levels like: hydroxychloroquine, dapsone, azathioprine and mycophenolate mofetil (dosages discussed under PV).

  • Described by Anhalt et al in 1990.
  • It is a rare and often fatal autoimmune blistering disease accompanied by both benign and malignant neoplasms.

Associated  malignancies are lymphomatoid and hematologic like:

  • B-cell lymphoma.
  • Chronic lymphocytic leukemia.
  • Castleman’s disease.
  • Waldenstrom’s macroglobulinemia.
  • Thymoma
  • Interactions between the immune system and concomitant neoplasm is basis of pathogenesis, with autoantibodies directed against both desmosomal and hemidesmosomal antigens.
  • In PNP, the vast majority of patients have autoantibodies to periplakins and envoplakins.
  • Skin lesions are caused by an autoimmune response generated by antibodies to tumor antigens that cross-react with epithelial antigens.
  • The mean age at onset is 60 years (range7 to 76 years).
  • Males and females are affected equally
  • Severe painful oral erosions, frequently hemorrhagic, which spread to involve the entire vermilion and tongue.
  • Lesions are polymorphic, and symptoms such as blisters, erosions, spots, papules, and plaques can occur.
  • Positive Nikolsky sign.
  • Cutaneous lesions usually appear subsequent to the onset of mucosal.
  • Cutaneous lesions involve any site, but frequently the upper body.
  • Mucous membranes of the esophagus, stomach, duodenum, intestines and pulmonary epithelium is also involved.

Original diagnostic criteria of PNP given by Anhalt et al.

  • Painful mucosal erosions and a polymorphous skin eruption in the context of an occult or known neoplasm generating a spectrum of histological features
  • Intraepidermal acantholysis, dyskeratosis/keratinocyte necrosis, and vacuolar interface changes in histopathology  
  • Deposition of IgG and complement in intercellular epidermal and basement membrane zone seen on direct immunofluorescence  
  • Detection of serum autoantibodies to stratified squamous epithelia, columnar, and transitional epithelia by indirect immunofluorescence  
  • Serum immunoprecipitation of a characteristic complex of four proteins (250, 230, 210, and 190 kDa) from keratinocytes transitional epithelia by indirect immunofluorescence.

Pemphigus vulgaris, mucous membrane pemphigoid, erythema multiforme, Stevens–Johnson syndrome, lichen planus.

Treat the associated cancer in PNP.

  • Glucocorticosteroid therapy: Prednisone (0.5–1.0 mg/kg)
  • Immunosuppressants: Cyclosporin, cyclophosphamide, azathioprine, and mycophenolate mofetil are often used in combination with prednisone(Doses discussed under PV)

Rituximab

  • A chimeric anti-CD20 monoclonal antibody
  • Patients can be treated with the lymphoma protocol at a dose of 375 mg/m weekly for 4 weeks, or the rheumatologic protocol of 1 g once and repeated in 2 weeks.
  • Additional cycles may be administered every 6–12 months depending on clinical response and recovery of the B-cell (CD-20) population.

Rituximab with intravenous immunoglobulin (IVIG)

IVIG is dosed at 2 g/kg per cycle, and cycles are repeated on a monthly basis.

Linear IgA disease (LAD) is a blistering disorder characterized by linear deposits of IgA at the basement membrane zone (BMZ).

Etiology is still unknown.

Precipitated factors:

  • Drugs:
  1. Vancomycin
  2. Insulin
  • Infection
  • Associated with malignancy.
  • Association with autoimmune haplotypes HLA-B8, CW7, and DR3.
  1. What is pathogenesis of LAD?
  • Antibody deposition leads to complement activation and neutrophil chemotaxis, which results in loss of adhesion at the dermal–epidermal junction and blister formation.
  • IgA autoantibodies from LAD sera react with antigens of 97 and 120 kDa, both of which are fragments of the extracellular domain of bullous pemphigoid antigen 180 (type XVII collagen).
  • LAD has a bimodal age of onset:
  1. Linear IgA bullous dermatosis of childhood
  2. Linear IgA bullous dermatosis of adult.
  • Childhood type also known as chronic bullous disease of childhood (CBDC).
  • Appears before the age of 5.
  • Adult linear IgA appears after the age of 40 years with female predilection.
  • In children, the onset is acute and presents as papules, urticarial plaques and polycyclic lesions with blisterson the face, abdomen, and perineum.
  • Adult variant is characterized by pruritic papules and blisters at sites of trauma (knees and elbows).
  • Ocular and oral lesions also present.
  • Tendency for new blisters to arise in a ring around an old one is called the “string of beads” sign, usually present in children.
  • Histologically LAD shows subepidermal blisters with an infiltrate primarily consisting of neutrophils.
  • Direct immunofluorescence shows deposition of IgA along the BMZ in a homogenous linear pattern.

Dermatitis herpetiformis, epidermolysis bullosa acquisita, bullous pemphigoid, and bullous systemic lupus erythematosus. 

  • Dapsone is the drug of choice.
  • Tetracycline, erythromycin, niacinamide, colchicines, systemic corticosteroids, mycophenolate mofetil, methotrexate, cyclosporine, azathioprine, interferon-alpha, thalidomide, and intravenous immunoglobulins are also useful (doses discussed under PV).
  1. What is bullous pemphigoid?
  • Also known as Parapemphigus
  • Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering disease.
  • It is characterized by autoantibodies directed against the 180 kD antigen (BP180) and the 230 kD antigen (BP230).
  • The auto-Ab are IgE and IgG, especially IgG4.
  • Affects elderly(over 60 years)
  • No gender predilection.

Cutaneous lesions:

  • Begin as nonspecific rash.
  • Site of involvement: Limbs, abdomen.
  • Appear as urticarial or eczematous that lasts for several weeks to several months.
  • Thick walled vesicles and bullae arise in these skin lesions along with normal skin.
  • On rupturing they leave a raw, eroded area which heals rapidly.
  • Gingiva is most frequently involved.
  • Gingiva becomes extremely painful, erythmatous and desquamates on minor trauma.
  • Vesicles and erosions may also develop on buccal mucosa, palate, floor of the mouth and the tongue.
  • DIF revealed linear IgG (in most cases) and C3 deposition (basically in all patients) in the BMZ.
  • Indirect Salt Split Skin (indirect SSS) showed autoantibody deposition on the epidermal side of the cleavage (as the major target Ag are located in the upper portion of the LL).
  • Immunoelectron microscopy of a skin biopsy showing immune deposits (IgG, C3) in the upper part of the lamina lucida.
  • Serological techniques to detect antibodies to BP230 and, especially, BP180 by enzyme-linked immunosorbent assay (ELISA)
  • Topical corticosteroids: Clobetasol.
  • Prednisone is usually used in low doses (0.5 mg / kg), as well as dapsone, tetracycline, erythromycin, minocycline, nicotinamide, azathioprine, methotrexate and mycophenolate mofetil.
  • Intravenous pulse therapy with corticosteroids and intravenous gammaglobulin are reserved for the most severe and refractory cases.
  • Also known as Hailey–Hailey disease (HHD).
  • It is a genodermatosis that affects the action of desmosomes between keratinocytes in the epidermis.
  • Autosomal dominant mutation takes place in the ATP2C1gene, which affects the function of calcium-dependent ATPases whose usual function is sequestration of calcium within the Golgi apparatus.
  • Calcium dysregulation affects epidermal desmosomes and leads to suprabasilar acantholysis (epidermal blistering).
  • Erosions and vesicles, often coalescing into weeping and crusting plaques.
  • Lesions localized in symmetrical intertriginous areas, such as the axillae, groin, and infra-mammary folds.
  • Rare variants of HHD distributed in linear or unilateral conformations and/or involving mucosal surfaces or nail plates.
  • Vesicles and plaques are accompanied by pain and itching.
  • Increased risk of squamous cell carcinoma.
  • Symptoms exacerbated by factors including sun exposure, heat, sweat, and friction.
  • Oral lesions occasionally occur incrops of vesicles which rapidly rupture leaving raw erodedareas.

Based on histopathological examination:

  • Suprabasilar acantholysis is often described as “a row of tombstones” or a “dilapidated brick wall” – the “tombstones” or “bricks” referring to the basilar keratinocytes.
  • Dyskeratosis may be present.
  • Dermis is rarely affected.
  • Lymphocytic infiltrate may be found surrounding the vascular structures.
  • Anti desmosomal autoantibodies might not be detected.
  • Topical treatments.
  • Topical steroids: used for acute exacerbations
  • Moderate- to high-intensity steroids creams or ointments twice a day, up to 2–16 weeks.
  • Topical steroid sparing agents: typically used for maintenance
  • Tacrolimus 0.1% ointment twice a day, up to 2 weeks.
  • Topical antimicrobials: Used for mild superficial infections e.g.
  1. Clindamycin 1% lotion or cream
  2. Gentamicin 0.1% cream
  3. Mupirocin 2% cream

Systemic agents used in HHD

  1. Antimicrobials
  • Erythromycin, penicillins
  • Doxycycline 100 mg PO daily, consider low-dose maintenance.
  1. Retinoids
  • Etretinate
  • Alitretinoin 30 mg/d and NB-UVB twice a week
  • Acitretin 25 mg PO daily.
  1. DMARDs(disease-modifying anti-rheumatic drugs)
  • MTX(methotrexate) 15 mg per week
  • MTX (methotrexate) maintenance 7.5 mg IM
  • Thalidomide 100 mg TID with topical steroids and antimicrobials
  • Glycopyrrolate 1 mg daily, topical mometasone ointment 0.1% once daily, and oral minocycline 50 mg daily.

Bullous pemphigoid, pemphigoid gestationis, mucous membrane pemphigoid (MMP), dermatitis herpetiformis, and linear IgA disease.

  • Also known as Benign mucous membrane pemphigoid, ocular pemphigus.
  • Wickmann in 1794 reported the first case.
  • Immune-mediated subepithelial blistering diseases 
  • MMP is an autoimmune, chronic inflammatory subepithelial blistering disorder that primarily affects the mucous membranes.
  • Exact etiology is unclear.
  • Predisposing factors are:
  1. Severe mucosal inflammatory injury
  2. Drugs (clonidine, indomethacin, D-penicillamine),
  3. Viruses
  4. Ultraviolet light.
  5. Genetic predisposition such as HLA DQB1*0301.
  • Various basement membrane zone components have been identified as targets of auto antibodies these include:
  1. Bullous pemphigoid antigen 1 (BPAg1, 230 kd)
  2. Bullous pemphigoid antigen 2 (BPAg2, 180 kd)
  3. Laminin 5
  4. Laminin 6
  5. α6-integrin subunit.
  6. β4-integrin subunit.
  7. Collagen VII
  8. Other proteins of unknown identity and/or function
  • Elderly females are more affected
  • Mean age of onset is 50–80 years.
  • Mucosal sites involved are the oral mucosa, ocular mucosa, oropharynx, larynx, and genital region.
  • Skin involvement is restricted to the regions of head, neck, and upper torso.
  • The distinguishing feature is the scarring of the mucosa after the erosions, and the blisters heal.

Ocular findings:

  • Conjunctival erosions with subsequent scarring.
  • Progressive cicatrization with foreshortening of the fornices.
  • Palpebral conjunctiva lining the lids may fuse with the bulbar conjunctiva (symblepharon).
  • Scar bands between the lid and globe.
  • Loss of goblet cells with subsequent dry eye and disruption of corneal epithelium.

Anogenital findings:

Blisters and erosions result in scarring.

Severe vulvar scarring and phimosis.

Oral findings:

  • Desquamative gingivitis(main clinical sign).
  • Erythematous gingiva.
  • Loss of stippling.
  • Extending apically from gingival margins to alveolar mucosa.
  • Mild, small patches to widespread erythema with a glazed appearance.
  • Vesicles or bullae present at any other site in oral mucosa, positive for Nikolsky sign.
  • Vesicles or bullae are thick-walled, and may persist for 24– 48 hours before rupturing and desquamating.
  • The vesicles break, leading to pseudo membrane-covered irregular erosions which has yellowish slough surrounded by an inflammatory halo.
  • Erosions spread slowly and are self-limiting.
  • Hard palate, soft palate, buccal mucosae, alveolar ridge, tongue may be involved.
  • Life-threatening complications may result from involvement of the larynx, esophagus, and rarely the lower airway

Direct immunofluorescence (DIF):

  • Shows a continuous, linear deposition of IgG, C3, less commonly IgA, along the basement membrane zone.
  • Standard indirect immunofluorescence (IIF) is usually negative, (due to low titer of antiepithelial–connective tissue junction autoantibodies )
  • Salt-split skin by IIF is sensitive and detects circulating autoantibodies. Immuno blotting, immune precipitation
  • Target antigen is achieved with ELISA for BP180 and laminin 332.
  • Biopsy
  • Biopsy in gingiva is contra indicated as the already existing chronic gingival inflammation may confuse with the diagnosis.

Mild disease

Dapsone:

  • 25 to 50 mg per day, increasing monthly by 25 to 50 mg until remission occurs or until the maximum tolerated dose is reached (usually 200 mg per day).

Severe disease

Corticosteroids:

Treatment, combined with steroid-sparing agents for long-term maintenance.

Prednisone at a dose of 1–1.5 mg/kg/day.

Steroid-sparing agents: like Cyclophosphamide, Azathioprine, Mycophenolate mofetil discussed under PV.

Intravenous immunoglobulin

IVIG dosage ranges from 2 to 3 g/kg/cycle, usually infused in divided doses over 3 to 5 days. The frequency of infusion varies from every 3 to 4 weeks initially, until disease activity subsides. 

Eye care

  • Eye care should be provided by an ophthalmologist.

Oral care

  • Includes appropriate dental hygiene, referral for dental care, monitoring for candidiasis, and topical anesthetics for pain.
  • Soft, bland foods.
  • It is a heterogeneous group of hereditary disorders characterized by extreme fragility of the skin and mucous membranes, which gives rise to the formation of blisters following minor trauma.
  • This dermatological condition is a severe autoimmune disease.

There are four major types:

  1. Simplex (EBS).
  2. Junctional (JEB).
  3. Dystrophic (DEB.)
  4. Kindler’s syndrome.

Etiology:

EB Simplex subtypes are caused by mutations in the PKP1, DSP, KRT5, KRT14, PLEC1, ITGA6 and genes.

Generalized form:

  • Inherited as an autosomal dominant.
  • Manifests itself at birth or shortly thereafter.
  • Characterized by the formation of vesicles and bullae, on the hands and feet at sites of friction or trauma.
  • Healing of blisters heal within 2–10 days.
  • No scarring or permanent pigmentation.

Localized form (Weber-Cockayne syndrome)

  • Familial may occur early in childhood or later in life and is commonly recurrent.
  • Bullae only develop on the hands and feet, are related to frictional trauma and tend to exacerbate in hot weather.
  • No scarring upon healing.

Oral signs

  • The genes cause intra-epidermal cleavage in the skin and in the oral mucosa.
  • There is an increased fragility of the oral mucosa and occur most often secondary to trauma or tissue manipulation.
  • Typically oral soft tissue lesions heal without scarring

Dental caries:

  • There is a normal tooth formation.

Salivary function:

  • Normal

Caused by mutations in LAMA3, LAMB3, LAMC3, COL17A1, ITG6A, and ITGB4

Proteins transcribed from these genes are important in epithelia cell adhesion in both the oral mucosa and the developing tooth bud.

Oral signs

  • Increased fragility of the oral mucosa.
  • No significant oral scarring.

Dental caries

  • Increased risk for developing dental caries.
  • Marked enamel defects.
  • Presence of extensive pitting over the tooth surface.

Salivary function

  • Normal

Mutations in COL7A1 gene that codes for anchoring fibril protein that are located below the basal lamina at the dermal-epidermal basement membrane zone EB.

Oral signs

  • Increased tissue fragility of oral and perioral mucosa
  • Oral ulcerations, healing with scarring.
  • Positive Nikolsky’s sign.
  • Blister formation and healing with scarring.
  • Tongue looses the lingual papillae 
  • Ankyloglossia
  • Restricted oral aperture and microstomia.
  • Oral ulcerations affect all areas of the oral mucosa including the tongue.
  • Palatal rugae are ablated.
  • Oral vestibules become obliterated

Dental caries:

The loss of normal tongue mobility and obliteration of the oral vestibule decrease the normal food clearance causing additional prolongation of the dental surfaces to potentially cariogenic substrates

Salivary function: Normal salivary secretion

Oral cavity tends to be inoculated with high numbers of bacteria, excessive tooth plaque formation that further promote the formation of dental caries.

 Kindler syndrome is a rare genodermatosis characterized by acral bullae formation, fusion of fingers and toes, and generalized as progressive poikiloderma.

  • Caused by genetic defects in the focal contact-associated protein, fermitin family homologue 1 (FFH1), encoded by the gene FERMT1 (known as KIND1).
  • Kindlin-1 is known to express by the oral epithelium including the surface of the tongue.
  • kindlin-1 is expressed mainly in basal keratinocytes and important for attachment of the actin cytoskeleton via focal contacts to the extracellular matrix.

Oral signs:

  • Increased tissue fragility of oral and perioral mucosa.
  • Oral blistering.
  • Chronic erosive gingivitis in young children.
  • Rapidly progressive form of periodontal disease (aggressive periodontitis).
  • Alveolar bone loss.

Other clinical features:

  • Dysphagia
  • Esophageal and urethral strictures.
  • Ectropion
  • An increased risk of mucocutaneous squamous cell carcinoma.

Laboratory tests:

  • Histopathological examination.
  • Immunofluorescence antigen mapping (IFM).
  • Transmission electron microscopy (TEM).
  • Mutation analysis.
  • Treatment includes proper skin care to prevent blisters, treating blisters and infections, and a good diet.
  • Management includes corticosteroids, dapsone, azathioprine, mycophenolate mofetil, rituximab, and intravenous immunoglobulin (doses are discussed under PV)
  • Milder cases: No treatment other than local wound care may be needed.

Sterile drainage of larger blisters and the use of topical antibiotics.

  • Severe cases: Intensive management with oral antibiotics may be necessary.
  • The “mitten”deformity of the hands, in recessive dystrophic epidermolysis bullosa, can be corrected with plastic surgery.
  • With esophageal involvement: Placement of a gastrostomy tube is necessary.
  • Recessive dystrophic forms may lead to development of cutaneous squamous cell carcinoma.
  • Malignancy often develops in areas of chronic ulceration during the second through third decades of life.

Treatment of Kindler syndrome is symptomatic:

  • Avoid sun exposure
  • Use external photoprotection.
  • Trauma should be avoided to reduce blister formation, which can progress into disabling scars.
  • Blisters tend to fade after childhood, usually without scars but poikiloderma and skin atrophy progresses over a period of time.

Cause of single ulcers:

Trauma (due to teeth, food, dental appliances, dental treatment, heat, chemicals, or electricity).

Infections

  • Deep mycoses
  • Histoplasmosis
  • Blastomycosis
  • Mucormycosis
  • Aspergillosis
  • Cryptococcosis
  • Coccidioidomycosis
  • Chronic herpes simplex infection.
  • Syphilis
  • Histoplasmosis is a dimorphic fungus, which grows in the yeast form in infected tissues.
  • First identified by Samuel Darling in 1905, hence known as “Darling’s disease”.
  • Caused by the dimorphic fungus Histoplasma Capsulatum.
  • African form caused by a larger yeast (variant of capsulatum) and is called H. duboisii.
  1. Primary acute pulmonary.
  2. Chronic pulmonary.
  3. Disseminated form, and (DH) occurring in infants, elderly, or immunocompromised patients.
  • Common in men(male to female ratio of 9:1)
  • Age of occurrence 39 years(range from 26 to 65 years).

Primary infection:

  • Mild and manifest as a self-limiting pulmonarydisease that heals to leave fibrosis and calcification.
  • Progressive disease results in cavitation of the lung.
  • Liver, spleen, adrenal glands, and meninges are also involved.
  • Anemia
  • Leukopenia secondary to bone marrow involvement.

Disseminated form:

  • Fever
  • Weakness
  • Weight loss.
  • Hepatosplenomegaly

Mucocutaneous lesions: Range from papules and plaques with or without crusts, pustules and nodules to mucosal ulcers and erosions, molluscum contagiosum-like lesions, acneiform eruptions, erythematous papules, and keratotic plaque 

  • Oral lesions occur in the disseminated form of the disease.
  • May affect any area of the oral cavity.
  • Occur as granular ulcerations, multiple painful ulcers and verrucous growths.
  • Deep ulcers surrounded by infiltrative edges with erythematous or white areas with irregular surfaces, as hardened and irregular nodular lesions accompanied by local lymphadenopathy.
  • Sites commonly involve tongue, the palate, the oral mucosa, the gingivae, and the pharynx.
  • Biopsy: Shows spores of capsulatum are visualized in sections stained with hematoxylin and eosin and special stains like Periodic Acid Schiff.
  • Western blot and enzyme immune assays

A. Moderately Severe to Severe Acute Pulmonary Histoplasmosis

  1. Lipid formulation of amphotericin B (3.0–5.0 mg/kg daily intravenously for 1–2 weeks) followed by itraconazole (200 mg 3 times daily for 3 days and then 200 mg twice daily, for a total of 12 weeks)
  2. The deoxycholate formulation of amphotericin B (0.7– 1.0 mg/kg daily intravenously) is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity.
  3. Methylprednisolone (0.5–1.0 mg/kg daily intravenously) during the first 1–2 weeks of antifungal therapy is recommended who develop respiratory complications, including hypoxemia or significant respiratory distress.

B. Mild-to-Moderate Acute Pulmonary Histoplasmosis

Itraconazole (200 mg 3 times daily for 3 days and then 200 mg once or twice daily for 6–12 weeks) is recommended for patients who continue to have symptoms for 11 month.

C. Chronic Cavitary Pulmonary Histoplasmosis

Itraconazole (200 mg 3 times daily for 3 days and then once or twice daily for at least 1 year).

Squamous cell carcinoma, hematologic malignancies, tuberculosis, other deep fungal infections, oral lesions observed with Crohn’s disease, necrotizing sialometaplasia of the palate.

  • Fungal infection caused by Blastomyces dermatitidis.
  • Also known as Gilchrist’s disease.
  • Infection by the same organism, in Mexico and Central and South Americas known as “North American blastomycosis.”

Pulmonary Blastomycosis: Presents clinically as

  • Acute pneumonia.
  • Chronic pneumonia or asymptomatic radiographic abnormality.

Acute pneumonia

  • Fever
  • Chills
  • Productive cough(with or without hemoptysis)

Chronic pneumonia

  • 2- to 6-month illness
  • Weight loss.
  • Fever
  • Night sweats.
  • Cough with sputum.
  • Chest pain.
  • Mass-like pulmonary infiltrates.

Extrapulmonary Blastomycosis

A. Cutaneous: occurs in two forms:

  • Verrucous: Verrucous skin lesions, which lie above subcutaneous abscesses, are raised and crusted with an irregular shape and sharp borders.
  • Ulcerative:Cutaneous ulcer occurs when a subcutaneous abscess drains out through the skin. Ulcers have heaped-up borders with or without an exudative base.

B. Osseous:

  • Osteomyelitis is present.
  • Any bone can be involved, the vertebrae, ribs, skull, and long bones are affected.
  • Radiographically it appears as a clearly demarcated osteolytic lesion without periosteal involvement or as a diffuse, destructive process with periosteal new bone formation.
  • Infection can spread into an adjacent joint, causing purulent arthritis.
  • Extension into the soft tissues causes a painful subcutaneous abscess with draining sinuses.

C. Genitourinary

  • Genitourinary sites of disease are the prostate, the testicle, and the epididymis.
  • Epididymo-orchitis causes swelling, pain, and prostatitis with dysuria and symptoms of obstruction.
  • Tubo-ovarian abscess.

D. Central nervous system

  • CNS infection(meningitis or mass lesions)
  • Central diabetes insipidus.
  • Pituitary involvement in conjunction with chronic meningitis, chronic pneumonia, and genitourinary infection.

E. Oral lesions

  • Nonspecific painless verrucous ulcer with indurated borders.
  • Hard nodules and radiolucent jaw lesions.
  • Chest radiographs showed concomitant pulmonary involvement.
  • Culture
  • Histopathology/Cytopathology
  • Antibody Tests: Tests for detection of antibodies to B. dermatitidis.
  • Nucleic Acid Amplification
  1. Mild to moderate pulmonary or disseminated disease

Itraconazole 200 mg orally once or twice per day for 6-12 months.

  1. Moderately severe to severe pulmonary or disseminated disease, but not in the central nervous system

0.7-1.0 mg amphotericin B deoxycholate/kg per day, or 3-5 mg lipid amphotericin B/kg per day for 1-2 wk, followed by 200 mg itraconazole twice per day for 6-12 months (pulmonary) or 12 months (disseminated)

  1. Central nervous system disease

Lipid amphotericin B, 5 mg /kg per day for 4-6 wk, followed by an oral azole for at least 1 yr.

  1. Immunosuppressed patients

Amphotericin B deoxycholate 0.7-1.0 mg/kg per day, or lipid amphotericin B, 3-5 mg/kg per day for 1-2 wk, followed by itraconazole 200 mg twice per day for 12 months

  1. Pregnant patient

3-5 mg lipid amphotericin B/kg per day

  • Acute opportunistic infection.
  • Paltauf in 1885 was the first to describe mucormycosis.
  • Caused by a saprophytic fungus, mainly Mucoror Rhizopus.
  • Seen in immunocompromised patients, uncontrolled diabetes and leukemia.

Risk factors:

  1. Systemic
  • Burns
  • Protein energy malnutrition,
  • Pneumonia

Local

  • Teeth extraction.
  • Periodontal surgeries.

A. Clinical presentation:

  • Rhinocerebral
  • Pulmonary
  • Cutaneous forms (superficial).

B. Rare

  • Gastrointestinal
  • Disseminated
  • Miscellaneous forms.

Rhinocerebral mucormycosis:

  • The rhinocerebral (rhinomaxillary) form is the most common form.
  • Seen in uncontrolled diabetes mellitus.
  • Present with malaise, headache, facial pain, swelling and with low-grade fever.
  • Initiates in the nasal mucosa or palate and extends to the paranasal sinuses spreading through the surrounding vessels such as angular, lacrimal, and ethmoidal vessels.
  • Retro-orbital region also involve by direct extension.
  • Fungal hyphae can spread to other organs via blood stream such as cerebrum or lungs which can be fatal for the patient.
  • Mucormycosis of the oral cavity can be of two different origins:
  1. From disseminated infection where the gateway of entry is inhalation (through the nose).
  2. Through direct wound contamination with dissemination to other viscera as a common complication.
  • When it arises from nose and PNS, the infection may cause palatal ulceration leading to necrosis and the affected area appears black.
  • When the infection spreads from direct wound contamination, it can affect anywhere in the oral cavity, including the mandible.
  • Cavernous sinus thrombosis, a serious complication of maxillary infections.
  • Histologic examination.
  • Molecular pathologic examination. 
  1. First-line antifungal options for mucormycosis
  • Primary antifungal therapy AmB 1.0–1.5 mg/kg/day.
  • LAmB 5–10 mg/kg/day.
  • ABLC 5–7.5 mg/kg/d
  1. Primary combination therapy

Caspofungin plus lipid polyene

  • 70 mg iv load, then 50 mg/day for ≥2 weeks
  • 50 mg/m2 IV for children.

Micafungin OR anidulafungin plus lipid polyene

  • 100 mg/day for ≥2 weeks
  • Micafungin 4 mg/kg/day for children
  • Micafungin 10 mg/kg/day for low-birth weight infants
  • Anidulafungin 1.5 mg/kg/day for children
  • Deferasirox plus lipid polyene 20 mg/kg po qd for 2–4 weeks

ABLC, amphotericin B lipid complex; AmB, amphotericin B deoxycholate; CNS, central nervous system; iv, intravenous; LAmB, liposomal amphotericin B; po, oral; qd, once per day.

  1. Salvage therapy for mucormycosis

A. Posaconazole with or without lipid polyenes: 200 mg po qid or 400 mg po bid

B. Deferasirox plus lipid polyenes 20 mg/kg po qd for 2–4 weeks.

C. Granulocyte transfusions (for persistently neutropenic patients) ∼109 cells/k

D. Recombinant cytokines G-CSF, GM-CSF, or IFN-γ:

  • Dose G-CSF at 5 µmg/kg/day; GM-CSF at 100–250 µmg/m2
  • IFN-γ at 50 µmg/ m2 for those with body surface area≥5 m2 and 1.5 µmg/kg for those with body surface area <0.5 m2

ABLC, amphotericin B lipid complex; bid, twice per day; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony stimulating factor; IFN, interferon; PMN, polymorphonuclear leukocyte; po, oral; qd, once per day, IFN-γ; Interferon gamma

Squamous cell carcinoma, chronic granulomatous infection such as tuberculosis, tertiary syphilis, midline lethal granuloma. 

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