ABIM ALLERGY IMMUNOLOGY REVIEW2014

Richard D. deShazo, MD with thanks to the many colleagues from whom I

have borrowed material

Questions:• What are the major diagnostic

criteria for asthma?• How can you separate asthma

from COPD?• What does a positive methacholine

inhalation test mean?

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Spirometry before and after an inhaled bronchodilator showing reversible airway obstruction

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Asthma Diagnosis FEV1 improvement of 12% and 200mL

after beta-agonist is evidence for asthma according to ATS

Decreased FEV1/FVC ratio 20-39yr 85% 40-59yr 80% 60-80yr 70%

Methacholine challenge – not diagnostic of asthma + with 20% decrease FEV1 with <8-16mg/mL True benefit is in negative predictive value

Question:• What test should be considered in

a young asthmatic female with recurrent episodes of wheezing poorly responsive to bronchodilators?

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Vocal Cord Dysfunction Is Not Asthma, But May Occur In AsthmaticsFlow volume loops showing maximum inspiratory and expiratory flow-volume relationships in a patient with vocal cord dysfunction during asymptomatic (left) and symptomatic (right) periods. Note also the marked adduction of the vocal cords with severe reduction of the glottic aperture during a symptomatic period (right) of airway obstruction.

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Vocal Cord Dysfunction Female 2:1 Athletes Bronchodilator non

responsive

Many (up to 1/3) can have coexist asthma

Difficulty getting breath in

2 Questions:• What is the likely diagnosis in a man with

persistent cough, shortness of breath, dyspnea, and episodic wheeze that developed after working as a police officer in the 9/11 exposure area in NYC?

• A 22 year old with recent onset cough and wheeze works in a custom sailboat shop in Biloxi sealing the inside of boats with epoxy resins. What is the most likely low molecular weight chemical causing his symptoms?

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Reactive Airways Dysfunction Syndrome (RADS): Not Asthma

Treatment – Time + corticosteroids Occurs after a single inhalation of a

caustic irritant in a non-asthmatic Obstruction on PFT (+) methalcholine inhalation challenge Limited PFT-response to beta-agonists Not “reactive airways disease”

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Occupational Asthma Basically, asthma occurring because of

exposure at work. Testing difficult, so sometimes need to do

pulmonary evaluation at the workplace. (Start with peak flows at work versus home).

Earlier you diagnose the better, because may lead to permanent asthma even when removed from environment.

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Risk Factors for Asthma Death

Previous life-threatening asthma such as respiratory arrest

Hospitalization or ED visit for asthma within the last year

Use of 2 or more canisters of rescue inhaler/month

Poor perception of hypoxia or airway obstruction

Psychosocial disturbance

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Components of Severity

Mild Moderate Severe

Impairment Intermittent ------------------------

----Persistent---- ------------------------

Symptoms <2 days/weeks >2 days/week but not daily

>1 x/week but not nightly

Throughout the day

Nighttime awakenings

<2 x/month 3-4 x/month >1 x/week but not nightly

Often 7 x/week

SABA use for symptom control (not prevention of EIB)

< 2 days/week >2 days/week but not more than 1 x/d

Daily Several times a day

Interference with normal activity

None Minor limitation Some limitation Extremely limited

Lung function Normal FEV1 between exacerbations FEV1 >80% of predicted FEV1/FVC normal

FEV1 >80% of predicted FEV1/FVC normal

FEV1 >60% but <80% of predicted FEV1/FVC reduced 5%

FEV1 <60% of predicted FEV1/FVC reduced >5%

RiskExacerbations (consider frequency and severity)

0-2/year >2/year

Classification of Asthma Severity

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Asthma Pharmacotherapy Rescue medicines

Short acting agonists (SABA) Anticholinergic

Controller medicines Inhaled corticosteroids (ICS) Long acting agonists (LABA) Leukotriene receptor antagonists (LTRA) Combinations of ICS & LABA Anti-IgE (omalizamab) Others

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Stacking Asthma Drugs

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What Meds Should You Think About Adding On In Severe

Asthma?

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Things to consider in the out of control asthmatic

Vocal cord dysfunction GERD Sinusitis Churg-Strauss syndrome ABPA Compliance/technique

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How Do You Assess Asthma Control?

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How Do You Use A

Metered Dose Inhaler (MDI)?

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What Does Every Asthmatic Have to Have?

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3 Eosinophilic Lung Diseases

Churg-Strauss Vasculitis Sinusitis, asthma, eosinophilia, vasculitis Transient pulmonary infiltrates Small vessel vasculitis Neuropathies (mononeuritis multiplex) MPO- ab/P-ANCA test (+) in about 50% RX: steroids (cyclophosphamide/azathioprine

in severe) ? relationship to LTRA

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Allergic Bronchopulmonary Mycosis (ABPM)

Includes allergic bronchopulmonary aspergillosis (ABPA) and other allergic mycoses

Criteria Asthma Fleeting pulmonary infiltrates High total IgE (>1000 ng/mL or 417 kU/L) Positive immediate skin test (IgE) to fungus (A.

fumigatus, etc.) or Positive RAST test Elevated serum specific IgE to fungus (A.

fumigatus, etc.) CT with central bronchiectasis reflects chronic

disease

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Treatment of ABPM

Oral corticosteroids Follow total serum IgE and CXR No long term studies on Itraconazole as

steroid sparing agent

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Hypereosinophilic Syndrome

No increase asthma but may have allergic – like dermatitis

Paramalignant syndrome Peripheral blood eos count >1500 µL for at least 6

months Absence of any other known cause of eosinophilia Presumptive signs/symptoms of organ invasion by

eosinophils 9:1 male:female Systemic disease Cardiac disease (thrombosis, fibrosis, necrosis) is the

most common cause of death FIP1L1/PDGFA fusion-gene present in some patients

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Organs Involved in Hypereosinophlic

Syndrome Heart Skin, Lungs, GI tract, Nervous System Vascular thrombosis is a feared

complication Treatment

Steroids Hydroxyurea Interferon α Gleevac (imatinib) - for FIP1L1-PDGFRα gene

rearrangement

Question:• A 50 year old woman with asthma

and atopic dermatitis has her 3rd episode of food impaction. What findings should be sought from endoscopy to confirm the diagnosis?

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Eosinophilic Gastroenteritis

Atopic individuals Usually in upper tract Food impaction in esophagus Mucous furrowing and white specks on

endoscopy More than 12 eosinophils/HPF on biopsy Food allergy in some Treated with non-absorbable steroids

Question:• A 50 year old bird breeder has

persistent shortness of breath, cough, and dyspnea. What should be done?

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Hypersensitivity Pneumonitis Fever, chills, malaise, cough, dyspnea Acute, subacute, chronic A systemic illness Also known as “extrinsic allergic alveolitis” Non allergic, not IgE mediated, no eosinophilia,

no asthma except pigeon breeder’s (bird fancier’s) lung

T-cell mediated CXR/CT scan abnormal: ground glass/diffuse

alveolar pattern PFT – restriction not obstruction except for pigeon

breeders Chronic pulmonary fibrosis

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Approach to Allergic Rhinitis

Characterize chronicity looking for seasonal variation.

Ask for family history, indoor triggers and nasal itching.

Swollen nasal mucosa usually more blue that red. Treat If there is treatment failure, do allergy skin tests or

RASTs to determine specific allergen and consider allergy shots.

Allergy shots are very effective for allergic rhinitis and insect anaphylaxis.

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Allergic Rhinitis Nasal steroids – first line treatment Antihistamines and leukotriene receptor

antagonists – second line (about equal efficacy as second line agents)

To prevent symptoms on planned exposures, chromolyn or antihistamines work best

Allergen immunotherapy by subcutaneous or sublingual techniques

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Mimics of Allergic Rhinitis Vasomotor rhinitis Rhinitis medicamentosa Nasal manifestations of systemic disease:

Diabetes mellitus – mucor mycosis (nasal eschar; black crust)

Wegener’s granulomatosis (saddle nose) Midline granuloma (saddle nose) Relapsing polychondritis (saddle nose) Sarcoidosis (bloody crusts) Cystic fibrosis (nasal polyps) CSF leak – check beta 2 transferrin (very specific)

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Rhinosinusitis Syndromes withNasal Polyposis

Immunodeficiency Cystic fibrosis Aspirin – sensitive respiratory disease Allergic fungal sinusitis Anosmia is a big tip off for polyps

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Acute & Chronic Sinusitis

Ethmoid cell

Question:• A 30 year old nurse has a severe

chronic dry and cracking dermatitis of both hands. What should you do first?

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Patch testing can detect both irritant and allergic contact dermatitis, if the tests are read at appropriate times. Consider a patch test a TB skin test. Positive results are

erythema and induration maximum at 24-48 hours.

Irritant vs. Allergic Contact Dermatitis

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Allergen Common Route of Patient ExposureNickel sulfate JewelryNeomycin Topical antibioticsBalsam of Peru (marker for fragrance allergy)

Cologne or perfume

Fragrance mix Most personal care products; products labeled “unscented” may contain masking fragrances

Thimerosal (frequently positive, but rarely relevant)

Eye-care products (eye drops, contact lens solutions); preservative in some vaccines

Sodium gold thiosulfate Jewelry; dental workQuaternium-15 (formaldehyde-releasing preservative)

Personal care products

Formaldehyde Personal care productsBacitracin Topical antibiotic; may cross-react with

neomycinCobalt chloride Blue paint; vitamin B12 (cyanocobalamin); may

cross-react with other metals, including nickel

MKSAPMost Frequently Positive Patch -Test Results

in Allergic Contact Dermatitis

Question:• A 16 year old male with asthma

has a chronic pruritic dermatitis in the flexural areas of his elbows and knees. What treatment would be best for this problem?

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Atopic dermatitis with involvement of a flexural surface. The frequently involved anticubital and popliteal fossae.

Atopic Dermatitis (Eczema) (1)

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Atopic Dermatitis (2) Increased susceptibility to

Staph aureus, HSV (eczema herpeticum), vaccinia Differential diagnosis

Allergic contact dermatitis Irritant contact dermatitis (gloves) Cutaneous T – cell lymphoma

An adult presenting with eczematous dermatitis with an erythrodermatous appearance by skin biopsy with genetic studies

Atopic dermatitis is associated with abnormalities in the filaggrin gene which encodes for filaggrin protein important in statium corneam moisturization

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Treatment of Atopic Dermatitis

Skin hydration/moisturization (Aquaphor) Medium strength topical corticosteroids

and combinations (equal parts 0.1% triamcinolone and Aquaphor)

Oral antibiotics (Staph) Antihistamines (control itch) Topical calcineurin inhibitors (protopic/

elidel)

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Cause History Physical Examination Findings

Laboratory Findings

Atopic dermatitis

Personal or family history of atopic dermatitis, allergic rhinitis, or asthma; preexisting skin lesions; severe pruritus

Lichenification Eosinophilia; elevated serum IgE level

Psoriasis Personal or family history of psoriasis; preexisting psoriatic skin lesions; history of corticosteroid withdrawal

Nail pitting, oil droplet sign, onycholysis; psoriatic arthritis

Skin biopsy may be diagnostic

Cutaneous T-cell lymphoma/Sézary syndrome

Slowly progressive; extreme, intractable pruritus

Lymphadenopathy; painful, fissured keratoderma; alopecia; leonine facies

Peripheral blood smear with >20% Sézary cells; clonal T-cell population in skin, blood, and/or lymph node

Hypersensitivity drug eruption

Onset 3-6 weeks after start of a new medication; most common causative medications are allopurinol, aromatic anticonvulsants, dapsone, NSAIDs, sulfonamides, lamotrigine

Facial edema; cervical lymphadenopathy; fine scale around nose; hepatosplenomegaly

Leukocytosis with eosinophilia or atypical lymphocytosis; elevated serum aminotransferases; elevated blood urea nitrogen or serum creatinine levels

MKSAP Clinical Clues to the Diagnosis of Selected Causes of Erythroderma

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Urticaria

Classification of Urticaria• Acute urticaria (<6 weeks)• Chronic urticaria (>6 weeks)• Physical urticaria (pressure, cold,

vibratory, etc.)• Urticarial vasculitis• Contact urticaria (touching a cat)• Urticaria and angioedema as

components of anaphylaxis

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Classification CharacteristicsPapular urticaria Associated with insect bitesCholinergic urticaria Occurs in response to an increase

in core body temperature; lesions present as small papules with a prominent surrounding erythematous flare

Delayed pressure-induced urticaria

Patients often experience systemic symptoms

Exercise-induced urticaria On a continuum with exercise-induced anaphylaxis; many patients only develop symptoms if primed by an ingested allergen prior to exercise

Solar urticaria Some patients who appear to have solar urticaria prove to have lupus erythematosus or porphyria

Cold urticaria Acquired cold urticaria is often related to an underlying infection, whereas familial cold urticaria represents an autoinflammatory syndrome

Vibrational urticaria —

Classification of Physical Urticarias

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Palpable purpura is a clinical sign of a small vessel (leukocytoclastic) vasculitis which may present as chronic urticaria.

Question:

• A 68 year old female with chronic mylogenous leukemia presents with non itchy swelling of the lips and throat. What diagnostic tests would be most useful to diagnose acquired angioedema?

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Differential Diagnosis: Cutaneous and/or Laryngeal Swelling

Allergic reactions and anaphylaxis Idiopathic angioedema Drug induced angioedema Allergic contact dermatitis Autoimmune conditions Thyroid disorders Superior vena cava syndrome and tumors Cheilitis granulomatosa (Miescher’s cheilitis) and

Melkersson-Rosenthal syndrome Trichinosis Low C-4 levels

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Hereditary Angioedema Autosomal Dominant Hiveless, itchless edema Hereditary angioedema form more

likely to have symptoms precipitated by trauma - dental visit, surgery, auto accident, menses, puberty Visceral attacks may present as an

acute abdomen with normal findings at surgery

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Symptoms: Painless, itchless angioedma with/without family history

Diagnosis of HAE5

HAE 1 - low C41, 2 low C1 INH, low C1INH-F HAE2 - low C41, 2 normal C1 INH, low C1INH-F Acquired – low C41, 3 low C1 INH, low C1INH-F, low Clq HAE3 – normal C4 4 normal C1 INH, normal C1INH-F,

normal C1f level

1. Always low during attacks2. SERPING1 gene abnormalities3. Antibodies to C1INH4. Abnormalities in Factor XII genes5. Family members should be screened in all types

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Acquired Angioedema

Associated with lymphoproliferative disorders

Have low C1q levels Mechanism unclear Low C1 of levels appear to reflect

autoactivationAnti – C1 esterase inhibitor antibodies have been described as well

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Tests for Hereditary/Acquired

Angioedema C4 – is a great screening test, but is

normal in HAE Type 3 Test for C1 esterase inhibitor level and

function to discriminate between two hereditary types

Test C1q level for the acquired form Genetic testing for HAE Type 3

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Therapy of HAE On-demand treatment

Treatment of attacks with upper airways symptoms is mandatory

Acute attacks should be treated with C1INH (plasma derived) Berinert Escallantide (inhibits HMW Kininogen to bradykinen) Kalbitor Icatibant (bradykinen recepptor antagonist) Firazyr

Intubation or trachestomy should be early in progressive airway obstruction

Antifibronolytics are not to be used Procedural prophylaxis with procedures involving the

upper airway is recommended without evidence Pregnancy – C1INH advised Long-term Prophylaxis

C1INH - immunizations, screens Androgens – frequent screens for liver toxicity Antifibrolytics not recommended

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First-line therapies for acute attacks of HAE include

Purified (C1INHRP) or recombinant (rhC1INH) human C1 inhibitor (various products available worldwide)

Ecallantide, a kallikrein inhibitor (available only in the United States)

Icatibant, a bradykinin B2 receptor antagonist (available in the United States and the European Union)

Question 23:• What should be prescribed for a

patient after treatment for acute anaphylaxis and how should it be used?

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Anaphylaxis Usually starts with urticaria and itching but can

present with syncope, hypotension, or erythoderma.

Most common causes are foods (peanut/ tree nut ingestion, etc.), insect stings, drug allergy (beta lactam)

Don’t forget latex, especially in medical spaces No obvious trigger- think mastocytosis (check

serum mast cell tryptase) or idiopathic anaphylaxis

All who have insect anaphylaxis patients require evaluation for venom immunotherapy

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AnaphylaxisEarly Management

Hypotension - supine, IV (NS) Respiratory distress - oxygen and albuterol,

intubation Epinephrine

1:1000 .3-.5cc IM for adults (note this is NOT the 1:10,000 dilution - (1mg/10ml) on crash carts

Can repeat in 5 minutes If on beta blocker and not responsive to epi, consider

glucagon 1mg IM, IV, SC Can start epi infusion if not responsive to IM epi

(1:10,000) 1-3 mg over 3 min, then 3-5mg over 3 minutes, then 4-10ug/min infusion

All who recover must leave with an Epipen®.

Consider 1 mg of glucagon IV if on beta blocker

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Cutaneous Mastocytosis Cutaneous Mastocytosis

Have urticaria pigmentosa – reddish brown or tan macules. Darier’s sign

Indolent, benign course Itching, burning skin, flushing, CNS

symptoms

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Criteria for Systemic Mastocytosis

Major Multifocal dense infiltrates of mast cells in bone

marrow or extracutaneous organ Minor

>25% mast cells are spindle-shaped or atypical Presence of c-kit point mutation Mast cells co-express Kit and CD2 Persistent serum tryptase >20ng/mL

Need one major and one minor, or 3 minor Other:

Skin involvement improves prognosis Insect stings may induce anaphylactoid reactions

in patients with mastocytosis.

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Drug Reactions MKSAP

Common Drug Reaction Patterns

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Vancomycin Reactions “Red man syndrome” – pruritis and

erythema of face, neck, upper torso, occasionally with hypotension

Non-immunologic release of histamine Not IgE mediated Rx: slow the infusion and pre-treat

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Anticonvulsant Hypersensitivity Cause the “hypersensitivity

syndrome” Deficiency of epoxide hydrolase Fever, maculopapular rash, generalized

lymphadenopathy Node bx resembles Hodgkin’s Phenytoin, carbamazepine, phenobarb Can also cause DRESS: Drug reaction

with eosinophilia and systemic symptoms. Rash, fever, multi-organ failure

½ actually have eosinophilia

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Serum Sickness

Question 24:• A 21 year old college student has

recurrent sinupulmonary infections. What test in addition to HIV should be performed to exclude immunodeficiency?

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Immunodeficiency T- cell (cellular immunity) – virus, fungi,

protozoa, mycobacteria and other intracellular organisms

Humoral (antibody mediated immunity) – infection with extracellular pyogenic organisms Haemophilus Pneumococcus Streptococcus Increased infections Recurrent respiratory infections Multiple systems involved Unusual organisms Malabsorption Big LNs or absent LNs

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Common Variable Immunodeficiency

Decreased IgG, M, A, normal to increased IgE

Recurrent sinopulmonary infections Lymph tissue present or enlarged High incidence of autoimmune disease

(22%) Increased risk of adenocarcinoma and

lymphomas In addition to encapsulated organisms

Giardia, yersinia, H. pylori, and H. jejuni are common

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IgA deficiency Most common form of primary

immunodeficiency (1:333) IgA <5mg/dL (VERY LOW) Most patients with IgA def. are NORMAL Have increased risk of infections:

collagen vascular , allergic, and GI disease, and malignancy

Can make anti-IgA antibodies Leads to anaphylaxis with IgA containing

blood products

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IVIG Indicated for common variable

immunodeficiency and specific antibody deficiency

Not indicated for IgA deficiency Side effects

Never transmitted of HIV Fever, chills, HA, muscle pain. Aseptic meningitis Renal failure (was due to osmotic load, not as

common now), stroke, MI

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Complement Deficiency C2 deficiency (most common) – sepsis,

pneumonia, meningitis, pyogenic arthritis with Strep pneumo

C2 deficiency – increased risk of rheumatoid arthritis, SLE

Terminal Complement Components – Neisseria sp infections Think about if recurrent meningitis or if

unusual strain

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Live Vaccines to Avoid in Cellular Immune Deficiency

Measles Mumps Oral Polio Rubella Varicella MMR Smallpox (vaccinia) Flumist

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Egg Allergy and Vaccines Influenza and Yellow fever

Question 28:What dietary pattern do bedbugs follow?

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Bedbug Bites Often Occur in a Series

“Breakfast, lunch, and dinner”Lesions are usually painless and appear as pruritic, urticarial-like

papules. Dinner

Lunch

Breakfast

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Bedbugs are nocturnal, hiding in cracks and crevices within 10

feet of a bed and especially on the cords of the mattress during

the day and biting at night.

Hungry Fed