Atopic Dermatitis, Eczema,

Non-infectious Immunodeficiency Disorders

Chapter 5
Andrews Diseases of the Skin 12th Ed
Atopic Dermatitis
Atopic Dermatitis
• chronic, inflammatory skin disease characterized by pruritus and a chronic course of exacerbations and remissions
• associated with other allergic conditions
• First step in an “atopic march”
• Epidemiology
• Increased std of living = increased prevalence
• RF
• African and Asian race/ethnicity
• male gender
• greater gestational age at birth
• family history of atopy (esp maternal hx of eczema)
• Alteration of intestinal microbiome
• Western diet
• First born
• CS delivery
• Gut colonization with Clostridium Cluster I
• Dow ownership before age 1 decreases risk
• 50% of cases appear in 1st year of life
• Vast majority: first 5 years
• Remaining case of adult AD, before 30 y/o
Atopic Dermatitis
• Genetics, pathogenesis
• If one parent is atopic, more than half the children will develop allergic symptoms by age 2.
• 79% if both parents are atopic
• Different FLG (Filaggrin) gene mutations are associated with AD in Asians
• T-helper 2 (Th2) phenotype
• Thymic stromal lymphopoietin (TSLP)
• promotes the secretion and production of Th2 cytokines and the development of inflammatory Th2
CD4+ T cells
• produced by keratinocytes and is found in high levels in AD skin lesions
• AD appears to represent a disorder character- ized by a barrier defect that engages the production
of a spe- cific Th2 immunophenotype through specific cell types and effected by specific
cytokines. The cytokines produced worsen the already defective barrier.
• Leads to a vicious cycle of barrier failure and progressive inflammation, producing a chronic, relapsing,
pruritic disorder.
Prevention in HR children
• Extensively hydrolyzed casein formulas may be used as a supplement or substitute for breast milk
during the first 4 months of life.
• Maternal allergen avoidance during pregnancy does not reduce the risk of AD in the offspring.
• high levels of HDM in the environ- ment in early life reduces AD risk.
• Aggressive emollient therapy early in life is recommended to repair any genetic or acquired
epidermal barrier defect.
Food allergy in AD
• Approximately 35% of children with moderate to severe AD have food allergy.
• Before food allergy testing is undertaken, treatment of the AD should be optimized.
• Food restriction can cause malnourishment, only pursued in children under age 5 years with more severe AD
in whom standard treatments have failed
• Food allergy testing – should only include food which the child is likely to be exposed
• Gold std: Double-blind placebo- controlled food challenges
• Other test: Skin prick tests
• (+) result: Higher serum IgE levels and larger wheal sizes (>8–10 mm) are associated with greater like- lihood of reacting to
these foods when challenged
• Usually caused by the ff:
• Infants: cow’s milk, egg, soybean, wheat
• Children (2–10 years): cow’s milk, egg, peanut, tree nuts,
• fish, crustacean shellfish, sesame, kiwi fruit
• Older children: peanut, tree nuts, fish, shellfish, sesame,
• pollen-associated foods
• Breastfeeding mothers must avoid the incriminated foods if their infant has been diagnosed with
a food allergy.
Clinical Manifestations
• 3 stages
• Infantile AD: 2mos – 2 yrs
• Childhood AD: 2-10yrs
• Adolescent/Adult AD
• Hallmark: pruritus (often precedes appearance of lesions)
• “itch that rashes”
• Useful diagnostic criteria: high specificity (>90%), low sensitivity
• Hannifin
• Rajka
Infantile atopic dermatitis
• Fifty percent or more of AD cases present in the first year of life, but usually not
until after 2 months
• usually begins as erythema and scaling of the cheeks
• may extend to the scalp, neck, forehead, wrists, extensor extremities, and buttocks
• There may be significant exudate; secondary effects from scratching, rubbing,
and infection include crusts, infiltration, and pustule
• infiltrated plaques eventually take on a characteristic lichenified appearance
• usually disappears by the end of the second year of life.
• Aggravated by
• immunizations and viral infections
• Winter, cold weather
• Wool
• Dry winter air
Childhood atopic dermatitis
• lesions tend to be less exudative
• Usually involve: antecubital and popliteal fossae, flexor wrists, eyelids, face, and around
the neck
• Manifestation
• often lichenified, indurated plaques
• intermingled with isolated, excoriated, 2–4 mm papules that are scattered more widely over the
uncovered parts.
• Nummular morphology and involvement of the feet are more common
• Pruritus – paroxysmal (scratching induces lichenification, may lead to secondary infection)
• Severe bouts of scratching occur during sleep, leading to poor rest and chronic tiredness
• Severe AD involving a large percentage of the body surface area can be associated with
growth retardation
• Restriction diets and steroid use may exacerbate growth impairment.
• Tx should be aggressive: phototherapy, systemic immunosuppresants (for rebound growth)
AD in adolescents and adults
• Most adolescents and adults with AD will give a history of childhood disease
• will begin after age 18 years in only 6–14% of patients diagnosed with AD.
• Manifestation
• Adults: localized erythematous, scaly, papular, exudative, or lichenified plaques (hand, nipple, eyelid)
• Adolescents: often involves the classic antecubital and popliteal fossae, front and sides of the neck, forehead, and area
around the eyes
• skin generally is dry and somewhat erythematous
• Lichenification and prurigolike papules are common
• Papular lesions tend to be dry, slightly elevated, and flat topped (excoriated and often coalesce to form plaques
• In darker- skinned patients, the lesions are often dramatically hyperpigmented, frequently with focal hypopigmented areas
related to healed excoriations.
• Paroxysmal pruritus – often in evening
• Staphylococcal colonization
• Aggravated by emotional upsets (reduce threshold at which itch is perceived)
• Stress
• Anxiety
• Depression
• Sweat, heat (tx: physical conditioning, emollients)
AD in adolescents and adults
• improvement usually occurs over time, and dermatitis is uncommon after middle life.
• patients retain mild stigmata of the disease, such as dry skin, easy skin irritation, and
itching in response to heat and perspiration
• remain susceptible to a flare of their disease when exposed to the specific allergen or
environmental situation.
• Adults: hand dermatitis is common (palmar and/or dorsal surfaces)
• Major factor: wet work
• Other causes: lotions, creams
• Diagnosis: Patch test with clinical correlation (to exclude contact allergy in an atopic px with
chronic hand dermatitis)
• Eyelids often involved
• Bilateral
• Condition flares with cold weather
• Patch testing to exclude irritants and allergic contact allergens)
Associated features and complications
• Cutaneous stigmata
• Dennie-Morgan fold
• A linear transverse fold just below the edge of the lower eyelids
• increased folds and darkening under the eyes
• A prominent nasal crease
• Less involved skin: dry, slightly erythematous, scaly
• Subclinical inflammataion / dermatitis
• Increased transepidermal water loss
• Pityriasis alba
• Keratosis pilaris
• Horny follicular lesions of the outer aspects of the upper arms, legs, cheeks, and buttocks
• kera- tosis pilaris rubra faceii.
• Tx: topical lactic acid, urea, or retinoids (Retinoids can easily irritate the skin of atopic patients use only 1x or 2x a week)
• Hertoghe’s sign
• Thinning of the lateral eyebrows
• occurs from chronic rubbing caused by pruritus and subclinical dermatitis
• Hyperkeratosis, hyperpigmentation
Associated features and complications
• Vascular stigmata
• perioral, perinasal, and peri- orbital pallor (“headlight sign”)
• White dermatographism
• blanching of the skin at the site of stroking with a blunt instrument
• Different from triple response of Lewis
• it typically lacks a wheal, and the third response (flaring) is replaced by blanching to produce
a white line.
• Atopic patients are at increased risk of developing various forms of urticaria
Associated features and complications
• Ophthalmologic abnormalities
• Up to 10% of patients with AD develop cataracts
• more common in patients with severe dermatitis.
• Keratoconus
• Tx
• Contact lenses
• Keratoplasty
• intraocular lenses
Associated features and complications
• Susceptibility to infection
• More than 90% of chronic eczematous lesions contain Staphylococcus aureus
• frequently associated with weeping and crusting of skin lesions
• Tx:
• topical steroids - reduced numbers of pathogenic bacteria on the surface, even if antibiotics are not
used.
• treatment of the “infected” AD patient with oral antibiotics is a community standard of
dermatolo- gists worldwide.
• Bleach baths and reduction of nasal carriage – basis for controlling infection
• Chronic suppressive oral Abx therapy (cephalosporins, TMP-SMX, clindamucon, doxycycline) –
frequent infections
• Very toxic – Streptococcal infection
• Hospital admission + IV abx
• Increased susceptibility to herpes simplex infection (eczema herpeticum) and
widespread vaccinia infection (eczema vaccinatum)
Differential Diagnosis
• Clinical diagnosis
• Dermatoses that may resemble AD include:
• eborrheic dermatitis (especially in infants)
• irritant or allergic contact dermatitis
• nummular dermatitis
• Photodermatitis
• Scabies
• cases of psoriasis with an eczematous morphology.
Histopathology
• Hyperkera- tosis, acanthosis, and excoriatio
• Staphylococcal colonization
• staining for eosinophil major basic protein (MBP) reveals deposition
in many cases.
General Management
• Education and support
• educate patients adequately regarding the multiple factors that are important
in managing AD.
• “written action plans” outlining a “stepwise approach”
• psychological support
• Sleep is lost by both the patient and the parents. Supportive educational techniques can
help the family cope with this burden.
• consider the complexity and time com- mitment of any prescribed regimen
and ensure that the parents/patient understand and are committed to
undertak- ing the treatments proposed.
General Management
• Barrier repair
• moisturize daily, especially after bathing
• petrolatum or a petrolatum-based product, an oil-based product, vegetable shortening, or a “barrier repair” moistur- izer that
contains the essential lipids of the epidermal barrier.
• Soak and smear technique - (soak in tub, then seal in water with a heavy moisturizer or medicated ointments) or wet dressings
(wet wraps) with topical steroids can be very effective.
• Antimicrobial therapy
• Rather than treating once an infection occurs, it appears that the key in AD is to reduce nasal staphylococcal
carriage preemptively and to keep the skin decolonized from Staphylococcus
• Bleach bathes – mainstay
• Twice-weekly bathing in a tepid bath with 14 cup of standard household bleach (6%) diluted in 20 gallons of water
• combines decolonization of the skin with hydration, addressing two of the major factors in worsening of AD.
• Adequate moisturizing after bathing is critical.
• Intra- nasal application of mupirocin is beneficial in reducing nasal carriage.
• If with recurrent infections – treat family and pets
• If recurrent furunculosis = might have immunologic abnormalities (hyper-IgE syndrome)
General Management
• Environmental factors
• Wool garments should be avoided
• Stress, heat, sweating, and external irritants may precipitate an attack of itching and
flare
• Irritants and allergens should be avoided
• Antipruritics
• Antihistamines - only beneficial for their seda- tive properties
• optimally used nightly (not “as needed”).
• Diphenhydramine, hydroxyzine, and doxepin
• gabapentin, SSRIs, mirtazapine, and even opiate antagonists
• Moisturizing lotions containing menthol, phenol, or pramox- ine
Specific Tx
• Topical corticosteroid therapy
• most common class of medica- tions, along with moisturizers, used for the
treatment of AD.
• Infants, low-potency steroid ointments, such as hydrocortisone 1% or 2.5% (+
Regular application of emollients )
• under wet wraps or vinyl suit occlusion (soak and smear) can increase efficiency
• Refractory areas: stronger corticosteroid (desonide, alclometasone, triamcinolone)
• A more potent molecule is more appropriate than escalating concentrations
• Do not undertreat! This leads to loss of faith on the part of the patient/parents and
prolongs the suffering of the patient.
• Older children + adults: medium-potency steroids such as triamcinolone
• Except on face: milder steroids or calcineurin inhibitors
• Thick plaques / lichen simplex chronicus: extremely potent steroids (ointment = more
moisturizing)
• WOF local / systemic toxicity
• Monitor growth parameters in infants and young children
Specific Tx
• Topical calcineurin inhibitors
• Tacrolimus (more effective), pimecrolimus
• Alternative to steroids
• Particularly useful in areas prone to steroid atrophy (eyelids, face), when steroid
allergy is considered
• Tar
• Crude coal tar 1–5% in white petrolatum
• liquor carbonis detergens (LCD) 5–20% in hydrophilic ointment USP
• Phototherapy
• If topical modalities fail to control AD, phototherapy is the next option
• Narrow-band (NB) UVB is highly effective
• Poor tolerance when inflamed
Specific Tx
• Systemic therapy
• Systemic corticosteroids
• Only used to control acute exacerbations
• Short courses <3wks
• WOF: Osteoporosis (tx with bisphosphonate, prevent with calcium supplements, vit D,
exercise, smoking cessation)
• Cyclosporine A
• very useful to gain rapid control of severe AD.
• WOF: renal disease
• Other immunosuppressive agents (long term immunosuppression)
• azathioprine (Imuran), mycophenolate mofetil (CellCept), and methotrexate
(Rheumatrex)
• IVIg – limited success
Management of acute flare
• precipitating cause of the flare should be sought.
• Stressful events
• Secondary infection with S. aureus should be assumed in most cases
• Less frequently, HSV or coxsackievirus may be involved.
Eczema
Eczema
• Acute stage
• red edematous plaque that may have grossly visible, small, grouped vesicles
• Histo: serous exudate between cells of the epidermis (spongiosis), with an underlying dermal perivascular
lymphoid infiltrate and exocytosis (lymphocytes present in overlying epidermis singly or in groups)

• Subacute lesions
• erythematous plaques with scale or crusting
• later, lesions may be covered by a drier scale or may become lichenified
• Manifestations
• Pruritus, prominent at bedtime, results in insomnia (provoked by heat and sweating)
• Chronic stage
• minimal accompanying spongiosis
• crust is composed of serous exudate, acute inflammatory cells, and keratin
• Scale corresponds to foci of parakeratosis produced by the inflamed epidermis.
• Histo: compact hyperkeratosis, irregular acanthosis, and thickening of the collagen bundles in the papillary
portion of the dermis.
Ear eczema
• Eczema of the ears or otitis externa
• may involve the helix, postauricular fold, and external auditory canal
(most frequently affected site)
• Secondary bacterial colonization or infection is common.
• usually caused by staphylococci, streptococci, or Pseudomonas
• Contact dermatitis from neomycin, benzocaine, and preservatives
• Tx
• Removal of causative agents (topically applied allergens)
• Intact TM - scales and cerumen should be removed by gentle lavage with an ear
syringe
• combination of ciprofloxacin plus a topical steroid
• Corticosteroids alone can be effective for noninfected dermatitis.
• For very weepy lesions, aluminum acetate optic solution
Eyelid Dermatitis
• Related to atopic dermatitis or allergic contact dermatitis
• Causes
• Allergic conjunctivitis - may lead to rubbing and scratching of the eyelid and result in secondary eyelid
dermatitis.
• Seborrheic dermatitis
• Psoriasis
• airborne dermatitis
• Ocular medication with allergen = nasolacrimal duct passage = dermatitis below nares
• phenylephrine hydrochloride, sodium cromo- glycate, papain, and idoxuridine
• cocamidopropyl betaine
• Tx
• identify and eliminate any possible triggering allergens
• Preservative-free eye medications
• topical corticosteroids and petrolatum-based emollients
• Cromolyn sodium ophthalmic drops
• WOF: conjunctival complications, measure the intraocular pressure, and monitor for the development of
cataracts
Breast eczema
• usually affects the areolae and may extend on to the surrounding skin
• area around the base of the nipple is usually spared
• the nipple itself is less frequently affected
• Manifestation
• moist type with oozing and crusting
• Painful fissuring is frequently seen
• Cause
• Atopic dermatitis - frequently presents during breastfeeding
• secondary infection with bacteria and Candida
• Irritant dermatitis - occurs from friction (jogger’s nipples), or from poorly fitting brassieres
• >3mos: biopsy to r/o Paget’s disease
• Tx
• Allergic contact derm –
• Oral abx / antifungal for secondary infection
• Analgesia
• Also treat child’s thrush
Hand eczema
• A complete history, careful examination of the rest of the body
surface, and frequently, patch testing are essential in establishing a
diagnosis
• Causes
• ingested nickel
• Environmental allergens
• Wet work (skin in liquids >2 hours per day, handwashing >20x per day)
Hand Eczema
• Vesiculobullous hand eczema (pompholyx, dyshidrosis)
• Idiopathic acute vesicular hand dermatitis
• severe, sudden outbreaks of intensely pruritic vesicles
• Primary lesions: macroscopic, deep-seated multilocular vesicles resembling tapioca on the
sides of the fingers, palms, soles
• eruption is symmetric and pruritic, with pruritus often preceding the eruption
• Resolve spontaneously over several weeks
• Rule out: bullous tinea, allergic contact dermatitis
• Chronic vesiculobullous hand eczema
• lesions may be hyperkeratotic, scaling, and fissured
• pruritic 1–2 mm vesicles tend to be most pronounced at the sides of the fingers.
• In long- standing cases, the nails may become dystrophic.
• dyshidrosiform” pattern may be recog- nized only during exacerbations.
• bilateral and roughly symmetric.
Hand Eczema
• Hyperkeratotic hand dermatitis
• M:F 2:1
• Patients are usually older adults
• hyperkeratotic, fissure- prone, erythematous areas of the middle or proximal palm.
No vesicles
• Histo: chronic spongiotic dermatitis
• Ddx: psoriasis (sharply demarcated plaques, nail pitting, or occasional crops of
pustules)
• Pulpitis (fingertip hand dermatitis)
• affects primarily the fingertips and may extend to merge with eczema of the palm.
Vesicles can occur
• Involvement of the three fingers of the dominant hand suggests a contact
dermatitis (irritant or aller- gic)
• involvement of the nondominant hand suggests vegetables and other items related
to food prepara- tion
Hand Eczema
• Treatment
• hands are essential for work both in and out of the home.
• must be practical and must allow patients to function as normally as possible
• Protection: Vinyl gloves during wet work, rubber gloves if without allergy
• Barrier repair: Moisturizer (cream or ointment)
• Topical agents: Superpotent and potent topical corticosteroids – first line
• Efficacy enhanced by presoaking and occlusion
• Single application with occlusion at night – more effective than multiple daytime applications
• Tx continued until hands are clear
• Phototherapy: high dose UVA I, soak or cream PUVA, oral PUVA
• Botulinum toxin A: palmoplantar hyperhidrosis with hand eczema
• Systemic agents: systemic corticosteroids (WOF relapse)
• Methotrexate, AZN, MMF, cyclosporine, oral retinoids, acitretin
• Workplace modifications: identify major irritants and allergens
Diaper (napkin) dermatitis
• highest prevalence occurs between 6 and 12 months of age.
• erythematous dermatitis limited to exposed surfaces
• folds remain unaffected
• Severe cases: superficial erosion, ulceration (Jacquet erosive diaper dermatitis), violaceous plaques and
nodules (granuloma gluteal infantum), pseudoverrucous papules and nodules
• The tip of the penis may become irritated and crusted, with the baby urinating frequently and spots of
blood appearing on the diaper.
• Cause: Excessive hydration with maceration of the skin
• Moist skin is more easily abraded by friction
• Wet skin is more permeable to irritants.
• Skin wetness also allows the growth of bacteria and yeast
• Prevention is the best treatment
• Diapers that contain super- absorbent gel
• frequent changing of diapers is also critical: every 2 hours for newborns and every 3–4 hours for older infants.
• Zinc oxide paste and petrola- tum are both effective barriers
• Zinc oxide paste with 0.25% miconazole may be considered if Candida may be present.
Circumostomy Eczema
• Eczematization of surrounding skin is common after an ileostomy or
colostomy
• Result of leakage of intestinal fluid onto unprotected skin
• Tx
• Propriety medication with karaya powder
• 20% cholestyramine in Aquaphor
• Topical sucralfate (powder or emollient) 4%g
• Psoriasis may also appear at ostomy sites
• Topical corticosteroid
• Contact dermatitis to ostomy bag adhesive
• Hypoallergenic bag
Autosensitization and conditioned irritability
• he presence of a localized, chronic, and usually severe focus of
dermatitis may affect distant skin
• rom scratching or irritating the skin – “conditioned irritability”
• Autoeczematization - spontaneous development of widespread dermatitis or
dermatitis distant from a local inflammatory focus.
• The agent causing the local inflammatory focus is not the direct cause of the dermatitis
at the distant sites
• most frequently pres- ents as a generalized acute vesicular eruption with a promi- nent
dyshidrosiform component on the hands
Id reactions
• Patients with a variety of infectious disorders may present with
eczematous dermatitis
• vesicu- lar id reactions of the hands in response to an inflammatory tinea
of the feet.
• nflammatory tinea capitis is often associated with a focal or diffuse
dermatitis, primarily of the upper half of the body
• Nummular eczematous lesions or pity- riasis rosea like lesions may occur
in patients with head or pubic louse infestation.
• Id reactions clear when the focus of infection or infestation is treated
• Tx
• topical or systemic anti-inflammatory agents may be required until the triggering
infection is eradicated.
Juvenile plantar dermatosis
• Eczematous disorder of children from age 3 years to puberty
• begins as a patchy, symmetric, smooth, red glazed macule on the base or medial surface
of the great toes, sometimes with fissuring and desquamation.
• evolve into red scaling patches involving the weight-bearing and frictional areas of the feet
• Caused by repeated maceration of the feet by occlusive shoes,
• abrasive effects of pool surfaces or diving boards
• Thin, nonabsorbent, synthetic socks contribute to the problem.
• Diagnosis
• apparent on inspec- tion
• family or personal history of atopy
• toe webs are spared.
• Tx
• Avoidance of maceration
• Foot powders, thick absorbent socks, absorbent insoles, and having alternate pairs of shoes to
wear to allow the shoes to dry out
Xerotic eczema
• dehydrated skin showing redness, dry scaling, and fine crackling
• resemble crackled porcelain or the fissures in the bed of a dried lake.
• primary lesion is an erythematous patch covered with an adherent scale.
• lesion enlarges, fine cracks in the epidermis occur
• anterior shins, extensor arms, and flank.
• Tx
• short tepid showers
• limiting use of soap to soiled and apocrine-bearing areas
• avoiding harsh soaps and using acid pH synthetic detergents
• promptly applying an emollient after bathing
• White petrolatum
• Emollients containing 10% urea or 5% lactic acid
Nummular eczema (Discoid eczema)
• usually begins on the lower legs, dorsa of the hands, or extensor surfaces of the arms.
• primary lesions are discrete, coin-shaped, erythematous, edematous, vesicular, and crusted patches
• Lesions may form after trauma (conditioned hyperirritability).
• As new lesions appear, the old lesions expand as tiny papulovesicular satellite lesions appear at
the periphery and fuse with the main plaque.
• Pruritus is usually severe and of the same paroxys- mal, compulsive quality and nocturnal timing
seen in AD and prurigo nodularis.
• Tx
• simple soaking and greasing with an occlusive ointment
• potent or superpotent topical corticosteroid cream or ointment OD or BID
• Ointments are more effective, and occlu- sion may be necessary.
• If secondary staphylococcal infection is present, an antibiotic with appropriate coverage
• Pruritus: antihistamine, doxepin, or gabapentin at bedtime
• Refractory to topical steroids: phototherapy (NB UVB, PUVA)
Pruritic dermatitis in elderly
• eczema- tous or papular
• may be related to barrier failure due to loss of acidification of the
epidermis
• patients often have urticarial papules on the trunk and proximal
extremities that resemble insect bites.
• Calcium channel blockers may be associated with pruritic dermatitis
• Hydrochlorothia- zide is also more frequently used by itchy elderly patients.
• Tx
• oral antipruritics, emollients, and topical corticosteroids
• Refractory: phototherapy, immunosuppressive agengts
Hormone-Induced Dermatoses
Autoimmune progesterone dermatitis
• Urticarial and ery- thema multiforme like lesions are most characteristic
• appear 5–7 days before menses, and improve or resolve a few days following menses
• Pruritus is common
• When urticaria is the predomi- nant skin lesion, there is a generalized distribution, and it
may be accompanied by laryngospasm. Anaphylactoid reactions may occur.
• Diagnosis: intradermal testing with progesterone
• (+) test: immediate (30min) or delayed (24-96h)
• Flares may be induced by intramuscular, intravaginal, or oral progesterone
• Tx
• Oral contraceptive to suppress ovulation (reducing progesterone levels)
• Topical corticosteroids
• Suppression of preogesterone: conju- gated estrogen and gonadotropin-releasing antagonists
such as leuprolide acetate, danazol, and tamoxifen
Hormone-Induced Dermatoses
Autoimmune estrogen dermatitis
• cyclic skin disorder that may appear eczematous, papular, bullous, or
urticarial.
• Pruritus
• kin eruptions may be chronic but are exacerbated premenstrually or occur
only immediately before the menses.
• clears during pregnancy and at menopause.
• Diagnosis: intracutane- ous skin testing with estrone
• (+) – papule lasting longer than 24h or an immediate urticarial wheal
• Tx
• Tamoxifen
Immunodeficiency Syndromes
Primary immunodeficiency diseases (PIDs)
• PIDs may present with skin manifestations, and the dermatologist
may be instrumental in referring appro- priate patients for
immunodeficiency evaluation
X-linked agammaglobulinemia (Bruton
syndrome)
• mutations in the BTK gene (Bruton tyrosine kinase)
• essential for the development of B lymphocytes
• presents between 4 and 12 months of life,
• infections of the upper and lower respiratory tracts, gastrointestinal (GI) tract, skin,
joints, and central nervous system (CNS).
• Recurrent skin staphylococcal infection may be a prominent component
• Atopic-like derma- titis and pyoderma gangrenosum
• Immunoglobulin A, IgM, IgD, and IgE are virtually absent from the serum
• spleen and lymph nodes lack germinal centers, and plasma cells are absent from the
lymph nodes, spleen, bone marrow, and connective tissues
• Tx
• Gamma globulin
• High dose IVIg
Isolated IgA deficiency
• absence or marked reduction of serum IgA (<7 mg/dL)
• most common immunodeficiency state.
• Drugs that induce IgA deficiency
• Phenytoin, sulfasalazine, cyclosporine, NSAIDs, hydrochloroquine
• the genetic cause in most cases is unknown.
• half have repeated infections of the GI and respiratory tracts, and one-quarter have
autoimmune disease.
• Allergies such as ana- phylactic reactions to transfusion or IVIG, asthma, and atopic
dermatitis are common
• itiligo, alopecia areata, and other autoim- mune diseases (e.g., systemic lupus
erythematosus [SLE], dermatomyositis, scleroderma, thyroiditis, rheumatoid arthri- tis,
polyarteritis-like vasculitis, Sjög ren syndrome) have all been reported to occur
• Malignancy is increased in adults with IgA deficiency.
Common variable immunodeficiency (CVID)
• heteroge- neous disorder
• most common immunodeficiency syndrome after IgA deficiency
• low levels of IgG and IgA, and 50% also have low levels of IgM.
• Multiple genetic defects
• do not form antibodies to bacterial antigens,
• have a predisposition to autoimmune disorders, such as vitiligo and alopecia areata, GI
abnormalities, lymphoreticular malignancy (10-fold increase of lymphoma), and gastric
carcinoma
• Non infectious granulomas
• Tx
• Replacement of the reduced immunoglobulins with IVIG
• Topical, systemic, and intrale- sional corticosteroids may be used for the granulomas
• Infliximab and etanercept have been effective in steroid-refractory cases.
Class-switch recombination defects
• defects that are combined T-cell and B-cell abnormalities
• experience recurrent sino- pulmonary infections, diarrhea, and oral and
anogenital ulcers
• Hypomorphic mutations in NEMO or IKBKG are associated with
hypogammaglobulinemia and elevated IgM
• associated with anhidrotic ectodermal dysplasia with immu- nodeficiency.
• male infants present within the first few months of life with hypohidrosis,
delayed tooth eruption, and immunodeficiency. Hair may be absent.
• eruption has been characterized as an “atopic dermatitis–like eruption,
• some patients may have prominent intertriginous lesions resembling seborrheic
der- matitis
• Tx
• Bone marrow transplantation
Thymoma with immunodeficiency (Good
syndrome)
• occurs in adults in whom profound hypogammaglob- ulinemia and benign
thymoma appear almost simultaneously
• striking deficiency of B and pre-B cells.
• vulvovaginal gingival lichen planus.
• Myelodysplasia and pure red blood cell aplasia may occur.
• Thymectomy does not prevent the development of the infectious or
lymphoreticular complications.
• Tx
• Supportive therapy with IVIG
• granulocyte- macrophage colony-stimulating factor (GM-CSF) transfu- sions
T-cell deficiency: DiGeorge Syndrome
• autosomal dominant
• hemizygous deletion of 22q11, many cases are sporadic
• Syndrome: congenital absence of the parathyroids, abnormal aorta,
absence of thymus
• Facie: notched, low-set ears, micrognathia, shortened phil- trum, and
hypertelorism
• Cell- mediated immunity is absent or depressed
• Opportunistic infections are common
• The condition may present as an atopic-like dermatitis, severe and
extensive seborrheic dermatitis, or an erythroderma
• biopsies: spongiotic dermatitis with eosinophils, necrotic keratinocytes with satellite
necrosis, and characteristically perieccrine and intraeccrine inflammation
T-cell deficiency + Combined immunodeficiency:
IPEX syndrome
• immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome
• classic triad of autoimmune enteropathy, endocrinopathy (diabetes, thyroiditis), and eczematous dermatitis
• Presents neonatally
• mutations in FOXP3 (fork- head box P3 protein (master control gene for regulatory T-cell (Treg) development)

• Elevated IgE levels, eosinophilia, and food allergies, plus the eczematous dermatitis, all are manifestations
of Th2 skewing of the immune system
• present with diffuse and severe erythematous exudative plaques resembling AD
• skin eruption may be follicularly based or may lead to prurigo nodularis.
• The scalp develops hyperkeratotic psoriasiform plaques
• Cheilitis and onychodystrophy can occur
• Alopecia areata, chronic urticaria, and bullous pemphigoid are cutaneous autoimmune manifestations of IPEX syndrome.
• Secondary infection is common
• staphylococcal septicemia can occur.
• Tx: immunomodulator therapy or bone marrow transplantation.
T-cell deficiency + Combined immunodeficiency:
Severe combined immunodeficiency
• heteroge- neous group of genetic disorders
• either autosomal recessive or X-linked.
• severely impaired cellular and humoral immunity.
• Deficiency or total absence of circulating T lymphocytes characterizes SCID
• Immunoglobulin levels are consistently very low, but B-cell numbers may be reduced, normal, or
increased.
• thymus is very small
• Triad: Candidiasis (moniliasis) of the oropharynx and skin, intractable diarrhea, and
pneumonia
• severe recurrent infections may occur, caused by Pseudomonas, Staphylococcus,
Enterobacteriaceae, or Candida.
• overwhelming viral infections are the usual cause of death
• Tx
• Definitive: hematopoietic stem cell transplantation (HSCT, bone marrow transplanta- tion)
Wiskott-Aldrich Syndrome
• X-linked recessive syndrome
• mutation in the WASP gene
• Triad:
• chronic eczematous dermatitis resembling AD
• increased susceptibility to bacterial infections, such as pyoderma or otitis media
• thrombocytopenic purpura with small platelets
• Tx
• platelet transfusions
• Antibiotics
• IVIG
• Splenectomy – to help control bleeding (due to thrombocytopenia)
• leads to increased risk of sepsis and is not routinely recommended
• Immunosuppressive therapy or rituximab may be used to control autoimmune complications.
• Bone marrow transplantation from a human leukocyte antigen (HLA)–identical sibling
Ataxia telangiectasia
• Autosomal recessive
• mutations in a single gene on chromosome 11 (ATM gene & protein, critical in cell cycle control)
• results in immunodeficiency and an increased risk for malignancy.
• initial prominent skin feature is progressive ocular and cutaneous telangiectasias starting at age 3–6.
• begin on the bulbar conjunc- tiva but later develop on the eyelids, ears, and flexors of the arms and legs.
• Premature aging (with loss of subcutaneous fat and graying of hair) and progressive neuro- degeneration
also occur.
• Other cutaneous features include large, irregular segmental café au lait spots, vitiligo, seborrheic der-
matitis, AD, recurrent impetigo, and acanthosis nigricans.
• Lymphopenia is common, with reduction of both B and T cells
• Tx
• high vigilance for infection and malignancy (lymphoma, leukemia)
• In patients with low CD4 counts, prophylaxis to prevent Pneumocystis pneumonia
• When IgG deficiency is present and infections are frequent, IVIG may be beneficial.
• IVIG and intralesional corticosteroids may be used for the cutaneous granulomas.
• minimize radiation exposure.
Primary Immunodeficiency assoc with warts:
WHIM syndrome
• warts, hypogammaglobulinemia, infections, and myelo- kathexis (WHIM)
syndrome
• autosomal dominant disorder with hypogammaglobulinemia, reduced B-cell
numbers, and neutropenia
• most common genetic cause is a truncation mutation of CXCR4 (gain of function mutation)
• 80% of WHIM patients have warts at the time of their diagnosis
• HPV infections: cervical and vulval dysplasia, which can progress to carcinoma
• may develop Epstein-Barr virus (EBV)–induced lymphomas
• Recurrent infections
• Tx
• G-CSF, IVIG, prophylactic antibiotics, aggressive treatment of infections
Primary Immunodeficiency assoc with warts:
• DOCK8 deficiency
• dedicator of cytokinesis 8
• hyper-IgE syndrome.
• susceptibility to cutaneous viral infections, including HSV, molluscum contagiosum, and HPV
• Warts can be flat or verrucous and affect about two thirds of patients.
• GATA2 deficiency
• GATA2 is an important transcription factor involved in hema- topoiesis maintenance of the stem cell
compartment.
• leads to a constellation of syndromes characterized by myelodysplasia, opportunistic infections, and leukemia.
• Patients have profound monocytopenia, often neutropenia, and NK, B, and dendritic cell lymphocytopenia
• More than 75% of patients have severe or dis- seminated HPV infection, usually verruca plana or verruca
vulgaris
• Thirty percent of patients develop a corticosteroid-responsive panniculitis.
• Venous thrombosis occurs in 25% and lymph- edema in 11% of patients.
• Allogeneic hematopoietic stem cell transplantation seems to be curative.
Primary Immunodeficiency assoc with warts:
• WILD Syndrome
• warts, immunodeficiency, lymphedema, and dysplasia (WILD) syndrome
• rare and presents at age 6 months with lower extremity lymphedema
• may involve the upper extremities and groin.
• Warts begin in adolescence and result in anogenital dysplasia and cancer.
• T-cell and B-cell lymphopenia
Defects in phagocytes:
Chronic granulomatous disease
• mutations in one of the genes that encode the subunits of the superoxide-generating
phagocyte NADPH oxidase system responsible for the respiratory burst involved in
organism killing
• Most common: X-linked (CYBB gene)
• repeated and recurrent bacterial and fungal infections of the lungs, skin, lymph nodes,
and bones
• Gingivostomatitis (aphthouslike ulcerations) and a seborrheic dermatitis of the
periauricular, perinasal, and perianal area
• dermatitis is frequently infected with Staphylococcus aureus, and regional adenopathy and
abscesses may complicate the infections
• Tx
• Aggressive tx of infections (TMPSMX, anti-aspergillus, IFNgamma)
• Low threshold to biopsy skin lesions
• Bone marrow or stem cell transplantation
• reduces infection but survival is not increased, not routinely undertaken
Defects in phagocytes:
Leukocyte adhesion deficiency
• 3 types
• LAD I – mutation in CD 18 of beta-2 integrin family
• Recurrent bacterial infections of skin and ucosa (gingivitis, periodontitis)
• Infections begin at birth, characteristic omphalitis with delayed separation of cord
• Marked neutrophilia, absence of neutrophils at site of infection (defective migration)
• Moderate (survive into adulthood) or severe (die in infancy)
• LAD II – mutation in SLC35V1
• general defect in fucose metabolism which results in decreased fucosylation of selectin ligands on leukocytes.
• leads to impaired tethering and rolling on activated endothelial cells
• Severe mental retardation, short stature, a distinctive facies, and the rare hh blood phenotype
• recurrent cellulitis with marked neutrophilia, but the infections are not life threaten- ing.
• After age 3 years, infections become less of a problem and patients develop chronic periodontitis.
• LAD III – mutation in gene FERMT3
• evere recurrent infections, bleeding tendency (from impaired platelet function), and marked neutrophilia.
• Tx
• Bone marrow transplantation
• Required for patients with severe LAD I and LAD III
Defects in phagocytes:
Hyperimmunoglobulinemia E syndrome
• Autosomal dominant: STAT3 mutation
• Jacob’s syndrome or Buckley’s syndrome
• Classic triad: AD like eczematous dermatitis, recurrent skin and lung infections, and high serum IgE
• begins at birth in 19% of cases, within the first week of life in more than 50%, and in the first month in 80%
• The newborn rash begins as pink papules that may initially be diagnosed as “neonatal acne.
• Muskukoskeletal, cardiac abnormalities
• Facie: facial asymmetry, broad nose, deep-set eyes, and a prominent forehead.
• Risk of malignancy: B cell nonHodglin lymphoma
• Autsomal recessive: DOCK8, TYK2
• Less common
• Severe eczema and recurrent skin and lung infections
• Food allergies
• predisposed to cutaneous viral infections, especially warts, molluscum contagiosum, herpes simplex, and varicella-zoster.
• Neurologic disease is much more common
• Normal facies
• Increased malignant risk: leukemia
• Tx
• Infections: bleach baths, Abx prophylaxis TMP SMX, antifungal
• Eczema: topical anti-inflammatories, cyclosporine (if severe)
• Osteopenia: bisphosphonates
• Hematopoietic cell transplantation
Defects in phagocytes:
Complement deficiency
• Inherited deficiencies of complement are usually autosomal recessive traits
• Genetic deficiency of the C1 inhibitor is the only autosomal dominant
form
• In general, deficiencies of the early components of the classical pathway
result in connective tissue disease states
• whereas deficiencies of the late components of complement lead to recurrent
neisserial sepsis or meningitis.
• Deficiency of C3 results in recurrent infections with encapsulated bacteria
such as Pneumococcus, Haemophilus influenzae, and Streptococcus
pyogenes.
• Screening: CH50 determination (positive result: reduced CH50)
•
Defects in phagocytes:
Graft-versus-host disease
• Development of GVHD requires three elements
• transplanted cells must be immunologically competent.
• recipient must express tissue antigens that are not present in the donor and therefore are recognized as foreign.
• recipient must be unable to reject the transplanted cells.
• Acute GVHD
• erythematous morbilliform eruption of the face and trunk, which may become confluent and result in exfoliative erythroderma

• Engraftment syndrome
• Combination of symptoms that occur about the time of engraftment and neutrophil recovery.
• Patients develop fever (without infectious source), diarrhea, pulmonary infiltrates with hypoxia, and capillary leak syndrome with edema and weight gain
• Occurs as soon as 7 days after autologous HSCT and 11–16 days after allogeneic trans- plants.
• mediated by cytokine pro- duction and neutrophil infiltration of the organs damaged by the conditioning chemotherapy, especially the lungs
• Administration of G-CSF and autologous transplantation are risk factors for its development
• Chronic GVHD
• Sclerotic lesions
• depigmentation resembling vitiligo; scarring or nonscarring alopecia; nail dystrophy (e.g., longitudinal ridging, brittle thin nails, pte- rygium, nail loss); and xerostomia and other,
Sjögren like mucosal symptoms.
• Prevention
• irradiating the blood before transfusion
• Acute: topical corticosteroids, TCIs, and UV phototherapy.
• Systemic symptoms: glucocorticoid, cyclosporine, or tacroli- mus
• Extracorporeal photopheresis (for acute or chronic GVHD unresponsive to these first-line therapies)
• Sclerotic cGVHD: Bath PUVA, with or without isotreti- noin
• Steroid refractory: rituximab, imatinib
• Mesenchymal stem cells
Defects in phagocytes:
Graft-versus-host disease
• GVHD in solid-organ transplantation
• risk profile is small intestine > liver/pancreas > kidney > heart.
• onset is usually 1–8 weeks following transplantation but can be delayed for years.
• Fever, rash, and pancytopenia are the cardinal features
• skin is the first site of involvement, and only cutaneous disease occurs in 15% of
cases.
• Both acute and chronic GVHD skin findings can occur.
• kin biopsies tend to show more inflammation than in HSCT-associated GVHD
• Diagnosis
• macrochimerism in the peripheral blood and skin after the first month of transplantation.