Allergy& Immunology Board Review May 19, 2007

Anna Nowak-Wegrzyn, MD Mount Sinai School of Medicine Pediatric Allergy & Immunology New York, NY

Pediatric Certification Exam

• Allergy and related disorders: 4.5% [ID-5.5%, development 4.5%, neonatology 4.5%] • www.abp.org

: General Pediatrics Exam Information: content outline • Allergic Rhinitis • Asthma • Atopic Dermatitis • Food Allergy • Anaphylaxis • Urticaria, angioedema • Drug Allergy • Hymenoptera Allergy • Diagnosis and treatment of allergic dz • Immunodeficiency disease

Prevalence of Allergic Diseases

• Atopic dermatitis – Up to 15-20% of children • Allergic rhinitis – 20% cumulative prevalence rate in the US [40% in young children] • Asthma – 5.4% in the US • Food allergy – Up to 8% of children less than 3 years of age – Up to 3-4% of adults Prevalence doubled in the past 20 years!

Bonus!

Genetics of Allergic Diseases

– Complex genetic disease, in contrast to simple mendelian trait such as CF – Clear hereditary pattern (one parent atopic-risk in child 40%, both parents atopic-70% risk) – Asthma twin studies: 70-80% of susceptibility due to a genetic component; asthma in twins 4x higher if parents asthmatic – Susceptibility genes: ADAM33 in asthma, SPINK5 in AD

Bonus!

Factors Influencing the Development of Atopic Allergic Disease Factors favoring TH1 phenotype Factors favoring TH2 (allergic) phenotype  Developing countries  Presence of older siblings  Rural homes, livestock, pet (dog) ownership in childhood  Poor sanitation, high orofaecal burden  High helminth burden  Early exposure to day care  Tuberculosis, measles, or HAV infection  Widespread use of antibiotics  Western lifestyle  Urban environment  Diet  Sensitization to house dust mites and cockroaches  Good sanitation

The Atopic March

Food Allergy / Atopic Dermatitis Asthma / Allergic Rhinitis -----Infancy---Toddler------Child--Teen-------Adulthood

AD Prevalence

• Prevalence: – Children: 10-20% – Adults: 1-3% • 85% present in the first year of life (but rarely under 2 months, 95% develop by age 4 years • Less severe by adolescence in 65%, but only 20% outgrow AD by age 11-13 years • Prevalence increased 2-3 fold during the past 3 decades in industrialized countries • Particularly common in Caucasians and Asians • Wide variations in prevalence between groups with similar genetic background imply critical role of environmental factors in determination of AD expression

AD Diagnosis

• No objective diagnostic test • Major criteria [ Hanifin & Rajka

Acta Derm Vener

1980; 92:44] – Pruritus – Chronic relapsing course – Typical distribution of eczema • Facial and extensor eczema in infants and children • Flexural eczema in adults

AD diagnosis-minor criteria

• Xerosis • Atypical vascular response (facial pallor, white dermatographism) • Perioral or periauricular lesions • Allergic shiners • Morgan-Dennie lines • Keratosis pilaris • Pityriasis alba • Palmar / plantar hyperlinearity • Anterior Capsular Cataracts • Keratoconus

Acute

• Pruritic erythematous papules • Serous exudation

AD rash

Chronic (skin remodelling)

• Lichenification • Dry fibrotic papules • Hyperpigmentation • Excoriation

Bonus!

Differential diagnosis of AD

• • • • • • • • • • • SCID/Omen Syndrome Wiskott-Aldrich Syndrome Hyper IgE Syndrome Agammaglobulinemia Ataxia-telangectasia • Seborrheic Dermatitis • Nummular eczema • Contact dermatitis (allergic, irritant) • Psoriasis • Ichtyoses Netherton’s Syndrome Familial keratosis pilaris HIV Scabies • Dermatitis herpetiformis • Pemphigus foliaceus • GVHD • Dermatomyositis Cutaneous T cell lymphoma Letterer-Siwe disease • Phenylketonuria • Zinc deficiency • Vitamin B 6 and niacin deficiency

Bonus!

Skin Barrier Dysfunction

• Dry skin; increased trans-epidermal water loss • Increased allergen absorption, increased cutaneous hyper-reactivity • Reduced content of ceramides in non affected AD skin=primary epidermal defect • AD lesions: inflammation-induced skin damage

Bonus!

Non-allergic AD triggers

• Irritants • Stress, anxiety • Low/high air humidity • Sweating

Scratching Induce and sustain the inflammatory cascade initiated by the release of pro-inflammatory cytokines from atopic keratinocytes

Atopic Dermatitis and Food Allergy

• 35% of children with AD have skin symptoms provoked by food hypersensitivity (Eigenman et al, 1998) • 90% of food allergy caused by egg, cow’s milk, soy, wheat, peanut, and fish • Egg allergy is the single most common food allergy • 7 out of 10 children with AD and egg allergy develop respiratory allergy by age 5 years • Suspect food allergy in uncontrollable eczema that waxes and wanes without particular association with diet

Atopic Dermatitis and Respiratory Allergy

• Up to 80% have positive skin test to environmental allergens • Inhalation of dust mites causes AD flare within 24 hours • Exposure to pollen (tree, grass, ragweed) associated with seasonal AD flares • Skin contact with animal allergens, dust mites, pollens or molds causes eczema worsening or hives • Ingestion of foods cross-reactive with birch tree pollen in the birch season associated with AD • Degree of IgE sensitization to aeroallergens is directly associated with severity of AD

Atopic Dermatitis and Allergic Airway Disease at Age 5 Years

% children

60

50.2

50 40

28.1

30 20 10 0

12.2

FH-/AD AD+ FH++/AD+

AD+ / AD- in the first 3 months of life FH++ / FH- at least two atopic family members Bergmann et al, Clin Exp Allergy, 1998

Bonus!

Microbes

• Most patients are colonized with

Staphylococcus aureus

• Th2 inflammation-IL-4-increased expression of fibronectin on collagen-increased

S.aureus

binding • AD skin is deficient in antimicrobial peptides (innate immunity) against bacteria, fungi, and viruses (HSV, molluscum, vaccinia, smallpox) •

S.aureus

toxins act as super-antigens that activate T cell and macrophages • • Most AD patients make IgE antibodies against staphylococcal super-antigens that correlate with disease severity

S.aureus

super-antigens induce corticosteroid resistance • Treatment with a combination of anti-staphylococcal antibiotics and topical corticosteroids result in greater clinical improvement that treatment with topical Cs alone

AD -

S. aureus

Superinfection

Eczema herpeticum

Pruritus

• Most important symptom • Major cause of morbidity • Interferes with normal sleep pattern

Bonus!

Atopic Dermatitis Management • Identify and avoid relevant food and environmental allergens EDUCATION • Avoid irritants: wool and synthetic clothing, sweating, stress, harsh soap, laundry detergent • Lubrication • Antihistamines: hydroxyzine, cetirizine • Topical anti-inflammatory: steroids, tacrolimus • Systemic anti-inflammatory: steroids, cyclosporine • Phototherapy • Treatment of infections:

S. aureus

, HSV • National Eczema Association for Science and Education

Bonus!

Atopic Dermatitis Lubrication

• Impaired skin barrier as a result of allergic inflammation - increased water loss • Daily soaking baths • Application of moisturizer within 3 minutes

Food Allergy

• Non-toxic, immune-mediated adverse reaction to food • Up to 6-8% of children • 2.5% of infants <1 year allergic to cow’s milk, 85% outgrow by age 3 (Host and Halken, 1994) • 1.3% allergic to egg (Nickel et al, 1997) • 0.5% allergic to peanut in UK and US (Tariq et al, 1996; Sicherer et al, 1999)-recent studies:1% • 35% of children with AD have skin symptoms provoked by food hypersensitivity (Eigenman et al, 1998) • 6% of asthmatic children have food-induced wheezing ( Novembre et al, 1988)

Adverse Food Reactions

Toxic

Food poisoning

Non-Toxic Non-Immune Mediated

Lactase deficiency

Immune-Mediated IgE-Mediated

Eczema Urticaria Anaphylaxis

Non-IgE-Mediated

Enterocolitis Proctocolitis Eosinophilic gastroenteritis

Children



Milk



Egg



Peanut



Soybean



Wheat



Tree nuts



Fish



Shellfish

Food Allergens

Adults



Peanut



Tree nuts



Fish



Shellfish

Food Allergy Syndromes

IgE mediation Mixed Mechanisms Non-IgE Mediation Gastrointestinal Immediate GI Hypersensitivity Oropharyngeal Cutaneous Oral Allergy Syndrome Acute Urticaria & Angioedema Respiratory Acute Bronchospasm* Allergic Eosinophilic Gastroenteritis Food Protein Induced Enterocolitis, Proctocolitis Atopic Dermatitis Asthma* Dermatitis Herpetiformis Food-Induced Pulmonary Hemosiderosis Common Uncommon * Risk factor for severe anaphylaxis

Symptoms of Acute Food Allergy

Cutaneous Manifestations of Food Allergy

Risk Factors for Fatal Food Anaphylaxis

• Peanut and tree nut allergy • Asthma • Delayed administration of epinephrine – Bock, Munoz-Furlong, Sampson, et al, 2001

Bonus!

Treatment of Food Anaphylaxis

• Clear emergency treatment plan for the patient • Prompt recognition of symptoms • Oral antihistamines – Benadryl syrup, 1-1.5 mg/kg/dose • Parenteral epinephrine – Self-injectable device – EpiPen Jr / Twinject Jr. 0.15 mg, under 55-66 lbs – Epi Pen / Twinject 0.3 mg, over 55-66 lbs • Follow up in the ED or call 911

Clinical Pearl: FA & Immunizations

• Children with egg allergy may receive MMR as per routine protocol, no increased risk for allergic reactions • Influenza vaccine contains egg protein and may cause allergic reactions in egg allergic children • Children allergic to gelatin may react to gelatin stabilizer in vaccines, i.e. MMR

!

Asthma-Definition

• Asthma is a chronic inflammatory disorder: – Airway inflammation underlies the airway hyper-responsiveness to asthma triggers. – The airway hyper-responsiveness leads to airway obstruction that is usually fully reversible. – Obstruction leads to the classic symptoms of asthma: cough, wheeze, and dyspnea.

National Asthma Education and Prevention Program.

Highlights of theExpert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma.

Bethesda, MD., May 1997. NIH Publication No. 97-4051A .

Bonus!

Onset of Symptoms in Children With Asthma

20% 1-2 years 30% <1 year 20% 2-3 years 30% >3 years

McNicol and Williams.

BMJ

1973;4:7-11. Wainwright et al.

Med J Aust

1997;167:218-222.

Asthma-Natural History

• The natural history and prognosis of pediatric asthma is incompletely understood. • Most children “don’t grow out of asthma” 1 . Instead, the “loss” of symptoms may actually be related simply to growth of the lungs and not due to a change of airway hyper responsiveness. The “loss” of symptoms may thus represent a period of time when the disease goes through a silent, asymptomatic period only to recur later in life 2 .

– – 1 Martinez, FD. In: Barnes PJ, Leff AR, Grunstein MM, Woolcock AJ., eds. Asthma. Philadelphia PA: Lippincott - Raven; 1997:121-128.

2 Weiss ST, Environmental risk factors in childhood asthma.

Clin Exp Allergy.

1998;28(suppl 5):29-34.

Bonus!

Predictors of Persistent Asthma

• Family history (more important on the maternal than on the paternal side) • Atopy: elevated IgE in the 1 atopic diseases: AD, AR, FA bronchiolitis • Male gender exposures st year of life, peripheral blood eosinophilia >4% (2-3 years of age) and other • Viral infections: RSV, parainfluenza, severe • Smoking: passive or active; pre – or postnatal • Severity of asthma in childhood •   Ehrlich et al. Risk Factors for childhood asthma and wheezing.

Am J Resp Crit Care Med.

1996;154:681-688.

Martinez FD et al. Asthma and wheezing in the first 6 years of life.

N Engl J Med

332:133-8, 1995.

von Mutius E and Martinez FD. In: Murphy S and Kelly HW., eds. Pediatric Asthma: Marcel Dekkar; 1999:17-25.

Clinical Pearl

• The most common

CAUSE

of wheezing in young children is viral respiratory infection BUT • The strongest predictor for wheezing that develops into asthma is ATOPY

!

Role of Allergens in Asthma

Atopy is one of the strongest asthma risk factors Indoor allergens House dust mites Domestic pets Cockroaches Molds Outdoor allergens Alternaria - a risk factor for childhood asthma (Peat et al. 1993, 1994) Ragweed (Creticos et al. 1996) and grass (Reid et al. 1986) associated with seasonal asthma exacerbations

Potential Triggers of Asthma

• The two components of asthma: – Inducers • Allergens • Viral infections • Occupational – Provokers • Exercise • Irritants • Emotions • Aspirin

NHLBI Guidelines for Diagnosis and Management of Asthma 1997& 2002

• Exposure to allergens to which patients are sensitive has been shown to increase asthma symptoms and precipitate asthma exacerbations • For at least those patients with persistent asthma – Identify allergen exposure – Use the patient’s history to assess sensitivity to seasonal allergens – Use skin testing or in vitro testing to assess sensitivity to perennial allergens – Assess the significance of positive tests in context of the patient’s medical history

When Is It Asthma?

• Repeated cough, wheeze, chest tightness • Repeated dx of RAD, allergic bronchitis, or wheezy bronchitis • Symptoms worsened by viral infection, smoke, allergens, exercise, weather • Symptoms occur / worsen at night • Reversible flow limitation ( increase in FEV1 by 12% post-bronchodilator) • Wheezing may or may not be present • Persistent cough may be the only symptom

!

Bonus!

Asthma Severity*

• Intermittent – Daytime sxs < 2x / week – Asymptomatic and normal PEF between exacerbations – Exacerbations brief (few days), varying intensity – Nighttime sxs < 2x / month • Mild persistent – Daytime sxs >2x / week but <1x / day – Exacerbations may affect activity – Nighttime sxs 3-4 x / month • Moderate persistent – Daytime sxs daily – Daily use of inhaled beta2-agonist – Exacerbations affect activity; > 2x / week, may last days – Nighttime sxs 5-9 x / month • Severe persistent – Continual daily sxs, nighttime sxs >10 x / month – Limited physical activity – Frequent exacerbations

*Assessment before starting therapy; on therapy need to adjust for meds by stepping up severity

Bonus!

Goals of Asthma Treatment

• Prevent chronic and troublesome symptoms • Normal lung function ( FEV1 / PEF >80% of predicted/personal best) • Normal activity / exercise • Prevent recurrent exacerbations • Eliminate/minimize ED visits and hospitalizations • Optimal pharmacotherapy with minimal or no adverse effects; minimal use <1x / day of short-acting beta2-agonist

Principles of Asthma Therapy

I.

Avoidance of allergens and environmental triggers: tobacco smoke, fumes, irritants Pharmacologic therapy II.

III. Immunotherapy A. Specific allergen IT (allergy shots) B. Anti-IgE antibody

Bonus!

Severity Intermittent Severity-based Therapy for Asthma Preferred No daily meds Alternative N/A Mild persistent Low-dose ICS Cromolyn, leukotriene modifier, nedocromil, OR sustained release theophylline PRN Oral CS for severe exacerbati ons Moderate persistent Severe persistent Low-medium dose ICS AND long-acting beta2-agonist Increased ICS in medium dose range , OR add leukotriene modifier or theophylline High dose ICS AND long acting beta2 agonist

Bonus!

Acute Asthma Episode

• Acute inset of symptoms, PEF<80% • Short-acting beta2 agonist inhaler/nebulized tx up to 3x in one hour • If PEF>80% or symptoms resolved completely: add or double the dose of ICS for 7-10 days and continue beta2 agonist every 2-4 hours for 1-2 days PRN, contact PCP within 48 hours • If PEF 50-80% or persistent symptoms: beta2 agonist q 2-4 hours and add oral steroid 2mg/kg/day x 5 days; contact PCP within 24 hours • If PEF<50 or severe symptoms: Ed or call 911, repeat treatment while waiting, start oral steroid (if available)

Allergic Rhinitis

• Prevalence 3-19% • Seasonal allergic rhinitis 10% • Perennial allergic rhinitis 10-20% • In the US 20-40 million people affected • Physician-diagnosed AR in 42% of 6-year-old children (Wright et al, 1994) • The most common allergic disease in children • Symptoms develop by 20 years in 80%; 20% by age 2-3 years, 40% by age 6 years, and 30% during adolescence

Allergic Rhinitis: Symptoms

• • • • • • • • •

Sneezing Itching Rhinorrhea Nasal congestion Postnasal drip Cough Halithosis Nasal speech Itchy, runny eyes

Allergic Rhinitis: Physical Findings

Bonus!

United Airway Disease

• • •

58% of patients with SAR have asthma (Mullarkey et al, 1980) 32% of children with AR have asthma as opposed to 8% of children with rhinitis and negative skin tests (Wright et al, 1994) Long term follow up of college students with AR: 3-fold greater risk of developing de novo asthma as compared to subjects without AR (Settipane et al, 1994)

Wright AL, et al. P

ediatrics

. 1994 Dec ;94(6)895-901.

Year-Round Symptoms

• Indoor pets • Moisture or dampness in any room • Visible mold in any part of the house • Cockroaches and or mice in the house in the past month • Assume exposure to dust mites unless patient lives in a semi-arid region

Seasonal Symptoms

• Early spring - trees (oak, maple) • Late spring - grasses (timothy) • Late summer to autumn - weeds (ragweed) • Summer and fall - molds (

Alternaria, Cladosporium

)

Dust Mite Allergy

•

Dermatophagoides farinae, Dermatophagoides pteronyssimus -

major allergens • Exposure to dust mite allergens can induce perennial asthma and AR • Mite bodies and feces are the principal source of the allergens

House Dust Mite Control Improves Asthma

30 25 20 15 10 5 0 Treatment Control Wheezing Medication use Peak flow drops below 80% of predicted Murray and Fergusson, 1983

Bonus!

First Line Dust MiteControls

• Pillow cover (<10 mcm pore, fine weave, or vapor permeable) • Mattress vapor permeable or plastic cover • Box spring vinyl or plastic cover • Weekly bedding washing in hot (130 F) water • Removal of stuffed animals and toys from bed • Weekly vaccum cleaning • Double thickness bags or high-efficiency particulate air filter on an air outlet

Animal Allergy

• Important allergens from: cats, dogs, rats, mice, horses, cows • Sensitivity to cat and dog in 22% to 67% of asthmatics • Cat sensitization even in the absence of obvious exposure • Effects of early life cat exposure???

• Cat and rat challenge studies - acute allergen exposure induces asthma symptoms and pulmonary changes • Less well characterized role of animal allergens in chronic asthma

Cat Allergen

•

Cat hair

Environmental Control of Animal Allergens

• Remove cat from home • Clinical benefit may be delayed for 4-6 months • Extensive cleaning • New bedding or impermeable encasements (cat allergen persists in mattresses for year)

Bonus!

What Works if Pets Stay?

• Keep animals out of patient’s bedroom • Use HEPA or electrostatic air cleaners in bedroom and living room • Remove carpets and other allergen reservoirs • Use mattress and pillow covers

Cockroach Allergy

• Up to 60% of inner city children with asthma sensitized to cockroach • Highest allergen levels in the kitchen and bathroom • Major allergens in the digestive secretions and on body parts of cockroaches • Limited data on health effects of cockroach controls • * Mouse urinary protein is also an important allergen for asthmatic children living in the inner city

Cockroach Allergy and Asthma Hospitalizations in the Inner City Children

0.4

0.3

p=0.001

0.2

0.1

0 Group 1 Group 2 Group 3 Group 4

Group 1 No cockroach allergy, low exposure Group 2 No cockroach allergy, high exposure Group 3 Cockroach allergy, low exposure Group 4 Cockroach allergy, high exposure Rosenstreich et al, NEJM, 1997

Common Cockroaches Found in Homes

• American • Oriental • German • Brown-banded

Bonus!

Cockroach Controls

•

Integrated pest management

• Professional pesticide extermination • Vacuuming and wet-washing of the home • Behavioral changes to prevent re-infestation – place trash outside the home nightly or daily – store food in sealed plastic containers – wash dishes daily – seal cracks and other portals of entry – remove sources of standing water (refrigerator drip pans and leaking plumbing)

Fungal Allergy

• Sensitization to

Alternaria -

risk factor for development of asthma, increased severity of asthma, and fatal asthma • Indoor molds:

Penicillium and Aspergillus

• Outdoor molds:

Alternaria and Cladosporium

• Fungi grow in mycelium and reproduce through spores, which become airborne

Bonus!

Indoor Mold Controls

• Prevent spore infiltration form the outside – door and window closing – air conditioning • Prevent indoor mold growth – control moisture by dehumidification and seal water leaks – clean and remove contaminated materials with fungicides (chlorine bleach with detergent or quarternary amine preparations) – use high-efficiency air filters – maintain heating ventilation – use personal protective equipment (particle mask) when cleaning contaminated materials

Urticaria and Angioedema

• Transient pruritic rash (welts or hives) • Acute – 10-20% of general population – Drugs, food, viral infection, insect bites • Chronic – Over 6 weeks – Difficult to identify the trigger, – Mostly post-viral • Evaluation – History and physical examination – Allergy testing if indicated – Skin biopsy if lesions persist in the same location >24 hrs – Other: CBC, ESR, Stool O&P, TFTs, etc.

Urticaria

“Classic” Cholinergic Cold - induced Solar Dermatographism

Urticaria -Treatment

• Remove the offending agent • Antihistamines • Avoid ASA or NSAIDs • Steroids • Referral

Anaphylaxis

• Systemic IgE-mediated immediate hypersensitivity reaction • Non-IgE-mediated = Anaphylactoid reaction • Release of histamine and other mediators from mast cells and / or basophils • Biphasic course: early and late symptoms • * Skin symptoms may be absent in up to 10-15% of most severe anaphylaxis

Etiology of Anaphylaxis

• In hospital: medications (ASA and NSAIDs, antibiotics, radiocontrast media, induction anesthetic agents, insulin, protamine, progesterone), latex, foods • Outside hospital: – Yocum et al, 1999:

36% foods

, 17% medications, 15% insect stings – Pumphrey et al, 1996:

foods

cause in north-west England (peanut and tree nuts) major – Novembre et al, 1998:

foods

responsible for 50% of anaphylaxis in children treated in the ER

Treatment of Anaphylaxis

• Recognize the symptom pattern • Measure serum tryptase (marker of mast cell degranulation): elevated 30 min up to 18 hours • I. M. epinephrine 1:1000, 0.01 mL/kg (0.3-0.5 ml) • I. V. antihistamine (H1, H2 blockers), steroids, fluids, oxygen • Observation > 4 hours • Refer for allergy evaluation to identify the trigger • Clear emergency treatment plan • Rx self-injectable epinephrine device

Drug Allergy

• IgE-mediated – Hives, anaphylaxis • Non-IgE-mediated – Maculopapular rash – Serum sickness – Stevens-Johnson • Anaphylactoid = direct release of histamine – Radiocontrast media – Vancomycin – Opiates

Drug Allergy - Treatment

• Stop the drug • Use alternatives from a different class • Skin testing to penicillin • Desensitization (gradual administration) – not indicated in SJS, TEN, serum sickness, reactions to anti convulsants • Treat through mild reaction

Radiocontrast Media

• Urticaria, angioedema, laryngo/bronchospasm, shock, death • • Incidence 1.7% of IVP • Recurrence 16% on subsequent administration  risk: atopy, older age, CHD, use of  - blockers, asthma • • Allergy to seafood and sensitivity to iodine are not risk factors  recurrence with newer, non-ionic, lower osmolar RCM • Pre - medication with prednisone 50 mg po 13, 7, and 1 hours prior to procedure, diphenhydramine 50 mg po 1 hour prior   risk by 5-10x • Consider pre - medication for high risk patients without h/o prior reactions: strongly atopic, extensive cardiovascular disease

Insect Sting Allergy

• Most common offenders: Yellow Jacket, Hornets, Wasp, Honeybee, Bumblebee, and Fire Ant • Degrees of severity – Local or large local – Toxic – Delayed – Systemic • Systemic reaction: Rx self-injectable epinephrine device and refer for allergy evaluation – Skin testing and serum venom - IgE – Venom IT reduces risk from >50% to <2% *Under 16 years of age: generalized urticaria is not associated with increased risk for ANA upon subsequent stings, not an indication for VIT

Allergy Evaluation

• History and physical exam • Prick skin testing • Serum allergen specific IgE • Challenge

Bonus!

Allergy Diagnosis

• • • • •

Skin test Less expensive Greater sensitivity Wide allergen selection Immediate results (10 15 minutes)

• • • • • •

Serum Immunoassay No patient risk Convenience Not affected by antihistamines Quantitative results Preferable to skin testing in:

– – –

Dermatographism Extensive eczema Uncooperative patient

Bonus!

Food Allergen-Specific IgE levels (kU/L) in the Diagnosis of Food Allergy Reactive if > (no challenge necessary) Possibly reactive (physician challenge) Unlikely reactive if < (home challenge) Egg Milk Peanut Fish Soy Wheat 7 0.35

15 0.35

14 0.35

20 0.35

65 30 0.35

80 26 0.35

Probability of reaction

Sampson HA, JACI, 2001

Atopy Markers and Risk Factors

• Family history, mother>father • Increased IgE in cord blood and in infancy • Male gender • Brief or no breast-feeding, early introduction of solid foods • Early allergen exposure (foods, mites, pets, pollens season of birth) • Passive smoking in utero and post-natal • RSV infection • Tightly ventilated houses, household dampness

Bonus!

Allergy Prevention

• • • • •

Avoidance of highly allergenic foods in pregnancy and during breast-feeding Prolonged breast-feeding Wean/supplement with extensively hydrolyzed hypoallergenic protein hydrolysate Delayed introduction of solid foods

– – –

Cow’s milk / dairy: 6-12 months Egg: 12-24 months Peanut, tree nuts, fish, shellfish: >36 months Aeroallergen avoidance

– –

Dust mites Animals

Allergen Immunotherapy

• Subcutaneous injections of specific allergen in gradually increasing doses: environmental allergens, insect venoms • Generally indicated for subjects who don’t respond well to pharmacotherapy • Allergen avoidance always recommended • Useful for AR, asthma, venom allergy; generally not indicated for AD and contraindicated in food allergy

Clinical Features of Immunodeficiency

• Increased susceptibility to infection – Chronic / recurrent infections without other explanations – Infections with organisms of low virulence (P.carinii, invasive fungal infections, vaccine Polio, BCG infection after vaccination) – Severe infections: pneumonia with empyema, bacterial meningitis, arthritis, sepsis, mastoiditis • Autoimmune or inflammatory disease – Target cells: hemolytic anemia, ITP, thyroiditis – Target tissues: RA, vasculitis, SLE • Syndrome complexes

ID Syndromes with Increased Sinopulmonary Infections

• Ataxia teleangiectasia: – Ataxia, telangiectasia, variable B and T lymphocyte dysfunction, dysfunctional swallow with pulmonary aspiration • DiGeorge – CHD, hypoparathyroidism, abnormal facies; thymic hypoplasia or aplasia; cleft palate, dysfunction of soft palate • Dysmotile cilia: – Situs inversus [Kartagener’s syndrome], male infertility, ectopic pregnancy, upper and lower resp. tract infections; immotile cilia • Hyper-IgE: – Coarse facies, exczematoid rash, retained primary teeth, bone fractures, pneumonia; elevated serum IgE, eosinophilia • Wiskott-Aldrich – Thrombocytopenia, eczema, variable B and T lymphocyte dysfucntion

Patterns of Illnesses Associated with Primary ID

• • • •

Antibody

: sinopulmonary inf., GI (enterovirus, Giardia); autoimmune dz

T-cell immunity

: pneumonia (bacteria, P. carinii, virus), GI viral inf., skin/mucous membranes (fungi)

Complement

: sepsis, meningitis( Strep, Pneumococcus, Neisseria); autoimmune dz (SLE, gromeluronephritis)

Phagocytosis

mycobacteria) : skin, RES, abscesses (Staphylococcus, enteric bacteria, fungi,

Antibody Deficiency

• • • • • X-linked agammaglobulinemia* – Only boys, infections start by 9-18 months – Absence of tonsils and lymph nodes on PE – Pneumonia, chronic enteroviral meningitis, vaccine-Polio, mycoplasma/ureaplasma arthritis Common variable immunodeficiency* – Onset 1 st and 3 rd decades of life, both sexes – Sinopulmonary infections, asthma, chronic rhinitis, IBD, autoimmnue disorders (pernicious anemia, thrombocytopenia); 1.4-7% develop B cell lymphoma IgA deficiency – Prevalence 1:700 whites; mostly asymptomatic – May be associated with chronic bacterial sinusitis, atopy, autoimmne dz (Crohn’s, IBD, SLE) IgG subclass deficiency – IgG2 and IgG4 – Controversy re: if clinically relevant; may be associated with recurrent sinopulmonary infections

Transient hypogammaglobulinemia of infancy

– IgG transported via placenta, nadir 3-9 months postnatal life – Begins in infancy, resolves spont. By 36-48 months of age – Most asymptomatic but may present with recurrent infections – Some children have food allergy – Typically normal responses to vaccines ( IgG to tetanus, diphtheria) *Treatment: IVIG replacement, antibiotic prophylaxis

Severe Combined Immunodeficiency (SCID) • Positive family hx ( X-linked, parental consanguinity) • Presentation early in life: first 4-6 months of age • Severe respiratory infections (interstitial pneumonia) • Protracted diarrhea • Failure to thrive • Persistent oral thrush • Skin rash, erythrodermia • Laboratory findings: – Lymphopenia (ALC<2000/µl) – Reduced CD3+T lymphocytes (<1500/µl) – Very low or undetectable levels of serum immunoglobulins (although may be initially normal due to transplacental passage of maternal IgG) – Very low to absent

in vitro

proliferative responses to mitogens Treatment: medical emergency! aggressive tx of infections, PCP prophylaxis, IVIG, isolation, irradiate blood products, BMT!!!

White Blood Cell Defects

•

Defective oxidative burst: Chronic granulomatous disease*

– May be X-linked or AR – Recurrent life threatening infections by catalase positive bacteria (Staph aureus, Nocardia, Salmonella, Serratia, Burkholderia cepacia) and fungi (Aspergillus, Candida) and exuberant granuloma formation (liver, gut, GU), abscesses, suppurative adenitis, osteomyelitis; – Peripheral blood neutrophilia during the infection – Aspergillus pneumonia-major cause for mortality – Tx: prophylaxis with Bactrim, itraconazole and IFN  • • •

Neutropenias Defective granule formation and content: Chediak-Higashi syndrome

– AR, oculocutaneous albinism, pyogenic infections, neurologic abnormalities, late onset lymphoma

Leukocyte adhesion deficiency (types 1-4)

– LAD 1: AR, deficiency of CD18 and as result of CD11 a-c – Defective neutrophil chemotaxis and tight adherence – Delayed umbilical cord separation, omphalitis, severe destructive gingivitis and periodontitis, recurrent infections of skin, upper/lower airways, bowel and perirectal area (necrosis, ulceration);

S. aureus

, gram-negative bacilli – Peripheral blood leukocytosis >15,000 /µl (baseline), eosinophilia,

Differential Diagnosis

• Allergy • Cystic fibrosis • Ciliary dysmotility due to recurrent infections • Localized abnormalities of anatomy or physiology (i.e., cleft palate, neurological impairment) • Secondary immunodeficiency; HIV, leukemia/lymphomas, chemotherapy • Environmental factors: – Day care attendance, sick older siblings – Exposure to irritants: tobacco smoke, fumes, etc

Screening Tests

• Antibody: – Serum IgG, IgA, IgM – IgG to immunizations: tetanus, diphtheria, Strep. pneumoniae • T-cell immunity: – Lymphocyte count ( <2000/ul) – T cell enumeration (CD3, CD4, CD8) – HIV serology • Complement: – CH50 • Phagocytosis: – Neutrophil count – Nitroblue tetrazolium test or other tests for oxidative burst