Allergy and Immunology Board Review Corner: Table of Contents

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1 Allergy and Immunology Board Review Corner: 2011 Table of Contents Middleton s Allergy Principles and Practice, 7th Edition, edited by N. Franklin Adkinson, et al. January Chapter 69: Hypersensitivity to Aspirin and Non-Steroidal Anti-inflammatory Drugs Chapter 70: Laboratory Tests February Chapter 71: In Vivo Study of Allergy Chapter 74: Oral Food Challenge Testing March Chapter 75: Approach to Infants and Children with Asthma Chapter 76: Approach to Adults with Asthma April Chapter 81: Asthma and Allergic Diseases during Pregnancy Chapter 82: Allergen Control May Chapter 85: Beta-Adrenergic Agonists Chapter 86: Theophylline and Phosphodiesterase Inhibitors June Chapter 87: Histamine and H-1 Anti-Histamines Chapter 88: Pharmacology of Glucocorticoids July Chapter 89: Glucocorticoids: Clinical Pharmacology Chapter 90: The Chromones: Cromoly Sodium and Nedocromil Sodium August Chapter 91: Cholinergic Mechanisms and Anticholinergic Therapy Chapter 92: Antileukotriene Therapy Page 1 of 82

2 September Chapter 94: Immunomodulators Chapter 95: Immunotherapy for Inhalant Allergens October Chapter 96: Anti-IgE Therapy Chapter 97: Unconventional Theories and Unproven Methods in Allergy Cellular and Molecular Immunology, 7th Edition, by Abul K. Abbas, Andrew H. Lichtman and Shiv Pillai November Chapter 1: Properties and Overview of Immune Responses Chapter 2: Cells and Tissues of the Immune System December Chapter 3 Part A: Leukocyte Migration into Tissues Chapter 3 Part B: Leukocyte Migration into Tissues Page 2 of 82

3 Allergy and Immunology Review Corner: Chapter 69 of Middleton s Allergy Principles and Practice, 7 th Edition, edited by N. Franklin Adkinson, et al. Chapter 69: Hypersensitivity to Aspirin and Non-Steroidal Anti-inflammatory Drugs Prepared by Rebecca Saff, MD, Massachusetts General Hospital, and John Seyerle, MD, Ohio State University 1. In a substantial minority of adult patients with asthma or chronic idiopathic urticaria, NSAIDs can elicit or aggravate symptoms of the disease. What causes the reaction? A. Direct degranulation of mast cells by the medication B. Inhibition of cyclooxygenase-1 by the medication C. IgE- mediated reaction to the medication D. IgG-medicated reaction to the medication 2. The main product of COX-1 and COX-2 is: A. Prostaglandin E 2 B. Leukotriene C 4 C. Prostaglandin D 2 D. Thromboxane 3. The progression of aspirin-induced asthma occurs as A. Severe asthma followed by aspirin hypersensitivity and then persistent rhinosinusitis B. Persistent rhinosinusitis, commonly with polyposis, followed by asthma, and then aspirin hypersensitivity C. Aspirin hypersensitivity followed by nasal polyposis and asthma D. There is no progression of symptoms in aspirin-induced asthma 4. Aspirin-sensitive urticaria and angioedema typcially occurs: A. 2 weeks after taking aspirin B. Only after repeated exposure C. Within 2 to 4 hours D. Immediately 5. NSAIDS which typically do not cause a reaction in aspirin-induced asthma include: A. Ketorolac B. Naproxen C. Ibuprofen D. Celecoxib 6. Histological criteria of urticaria include all of the following: A. Leukocytoclasis B. Fibrin deposition C. Red blood cell extravasatioin D. Mast cells around blood vessels Page 3 of 82

4 7. Which of the following is true of aspirin-induced asthma (AIA)? A. Asthma usually runs a protracted course, despite avoidance of NSAIDs, and often requires frequent or daily corticosteroids. B. AIA is associated with high levels of aspirin-specific IgE C. AIA is accompanied by low blood and sputum eosinophilia. D. Most patients are asymptomatic. 8. NSAIDs are most likely to induce which of the following adverse reactions: A. Elevated LFTs B. Hematuria C. Fever D. Thyroiditis 9. Which of the following chemicals is overproduced in aspirin hypersensitivity? A. Cox-1 B. Cox-2 C. Leukotriene D. Prostaglandin 10. For the diagnosis of aspirin hypersensitivity, which of the following types of aspirin challenges are available in the United States? A. Oral B. Nasal C. Inhalation D. All of the above Answers 1. B, page 1228 These acute non-allergic hypersensitivity reactions are elicited via inhibition of cyclooxygenase- 1 by NSAIDs. 2. A, page 1230 The main product of COX-1 and COX-2 is Prostaglandin E 2 3. B, page 1233 Aspirin-induced asthma develops according to a distinctive pattern characterized by a natural sequence of symptoms: first persistent rhinosinusitis, commonly with polyposis, followed by asthma, and then aspirin hypersensitivity. 4. C, page 1237 Aspirin-sensitive urticaria and angioedema typcially occurs within 1 to 4 hours. 5. D, page 1234 Celecoxib is a selective COX-2 inhibitor and does not cause a reaction in aspirin-induced asthma. Page 4 of 82

5 6. D, page 1238 Histological criteria of urticaria includes interstitial eosinophils and neutrophils, dermal edema, and mast cells around blood vessels. It does not include red blood cell extravasation, leukocytoclasis, or fibrin deposition which would suggest vasculitis. 7. A, page 1230 Asthma usually runs a protracted course, despite avoidance of NSAIDs, and often requires frequent or daily corticosteroids. Patients experience significant symptoms and generally have blood and sputum eosinophilia. AIA is not associated with high levels of aspirin-specific IgE. 8. B, page 1239 NSAIDs can cause hematuria via increased bleeding or interstitial nephritis. NSAIDs can also cause erythema multiforme or Stevens Johnson Syndrome but generally do not cause elevated LFTs, fever, or thyroiditis. 9. C, page 1230 Aspirin hypersensitivity is associated with increased production of cysteinyl leukotrienes. 10. A, page 1235 In the U.S., only oral aspirin challenges are available. Oral, Nasal, And inhalation challenge guidelines are available in Europe. Allergy and Immunology Review Corner: Chapter 70 of Middleton s Allergy Principles and Practice, 7 th Edition, edited by N. Franklin Adkinson, et al. Chapter 70: Laboratory Tests Prepared by John Seyerle, MD, Ohio State University 1. For IgE, an international unit (IU) equals how many nanograms of protein? A. 1 B C D In healthy adult serum, which of the following immunoglobulins is usually found in the highest amounts? A. IgA B. IgE C. IgG1 D. IgG4 3. Which of the following antibodies is most efficient at activating complement? A. IgG2 B. IgG3 Page 5 of 82

6 C. IgG4 D. IgE 4. The diagnosis of primary or secondary immunodeficiency can be made in an individual 2 years or older with recurrent infections if the IgG concentration is less than what percentage of the individual s age-adjusted normal range? A. 20% B. 30% C. 40% D. 50% 5. Approximately what percentage of serum IgA circulates in a polymeric form? A. 10% B. 20% C. 80% D. 90% 6. Which of the following laboratory methods uses visually detectable precipitating immune complexes in gel or solution? A. Immunoasssay B. Nephelometry C. Radial Immunodiffusion D. Quantitative Precipitin Reaction 7. Which of the following laboratory methods uses antigen placed in a well in a media such as agar? A. Immunoasssay B. Nephelometry C. Radial Immunodiffusion D. Quantitative Precipitin Reaction 8. Which of the following laboratory methods measures light scatter utilizing a spectrophotomeric reaction cell? A. Immunoasssay B. Nephelometry C. Radial Immunodiffusion D. Quantitative Precipitin Reaction 9. What substance can be found in the urine indicating exposure to tobacco smoke?\ A. Nicotine B. Cotinine C. 5-hydroxynicotine D. Aldehyde oxidase 10. Which of the following is correlated with the amount of side scatter in flow cytometry? A. Cell size Page 6 of 82

7 B. Cell granularity C. Cell surface antigens D. Intracellular antigens Answers 1. B, page 1248 One IU equals 2.42 nanograms of protein. This can be important in diseases such as Allergic Bronchopulmonary Aspergillosis (ABPA) where the diagnostic criteria include total IgE level. 2. C, page 1249 IgG makes up about 75% of total serum immunoglobulins. Of this, 60-70% is IgG1 while only 2-6% is IgG4. 3. B, page 1249 IgG1 and IgG3 activate complement efficiently, while IgG2 is less efficient and IgG4 does not bind C1 or activate complement. IgE effector functions occur via mast cell and basophil Fcε receptor binding. 4. B, page 1249 The diagnosis of primary or secondary immunodeficiency can be made in an individual 2 years or older with recurrent infections if the IgG concentration is less than 30% of the individual s age-adjusted normal range. 5. A, page 1249 Approximately 10% of serum IgA circulates in polymeric form, while most circulates in monomeric form. 6. D, page 1252 Quantitative Precipitin Reaction uses visually detectable precipitating immune complexes in gel or solution. 7. C, page 1252 In Radial Immunodiffusion, antigen placed in a well diffuses through the gel, moves through an antibody excess zone, and forms a precipitin ring around the well at the point of equivalence. 8. B, page 1253 Nephelometry uses light scatter to measure size of immune complexes. Rate nephelometry measures the initial rate at which complexes are formed. Either can be used to calculate antigen with a fixed antibody solution. 9. B, page 1260 Nicotine is converted 5-hydroxynicotine by p450, which is then converted to cotinine by aldehyde oxidase. Cotinine is then excreted in the urine and can be measured to assess for tobacco exposure. 10. B, page 1262 Page 7 of 82

8 Cell granularity correlates with side scatter. Cell size correlates with forward scatter while cell surface antigens and intracellular antigens are determined by fluorescence after mixing with labeled antibodies. Page 8 of 82

9 Allergy and Immunology Review Corner: Chapter 71 of Middleton s Allergy Principles and Practice, 7 th Edition, edited by N. Franklin Adkinson, et al. Chapter 71: In Vivo Study of Allergy Prepared by Jacob Turnquist, MD, Walter Reed Army Medical Center, and Rebecca Saff, MD, Massachusetts General Hospital 1. What are characteristics of the immediate reaction? A. The size of the wheal is correlated with the degree of allergy. B. Histamine and tryptase release begins about 5 minutes after allergen injection and peaks at 30 minutes. C. It is always followed by a late-phase reaction that starts between 1 and 2 hours later, peaks at 6 12 hours, and resolves in approximately hours. D. The immediate reaction is mediated primarily by Substance P. 2. Precautions for skin testing include: A. Have emergency equipment readily available, including epinephrine. B. Include a positive and a negative control solution. C. Evaluate the patient for dermographism. D. Make sure a physician is available to treat systemic reactions. E. All of the above 3. Common errors in intradermal skin testing include: A. Volume injected too small B. Subcutaneous injection leading to false-positive test C. High concentration leading to false-negative results D. Test sites are too close together and false-positive results can be observed 4. Factors affecting skin tests include: A. Quality of the allergen extract B. Gender C. Circadian rhythm D. Short term administration of corticosteroids 5. When interpreting skin tests, which of the following considerations should be included? A. Skin prick testing is an expensive screening method for detecting allergic reactions in most patients. B. A positive skin test response confirms the presence of allergic disease. C. The presence of allergic sensitization with no correlative allergic disease is a common finding, occurring in 8 30% of the population when using a local standard panel of aeroallergens. D. Allergen-specific IgE testing is more sensitive than skin testing. 6. Infants have been shown to have positive wheal and flare reactions to prick-puncture tests with histamine or allergen extracts after what age? Page 9 of 82

10 A. 3 months B. 6 months C. 9 months D. 12 months 7. Which of the following disorders can reduce the wheal and flare reaction following prickpuncture testing? A. Renal failure requiring dialysis B. Some patients with cancer C. Spinal cord injuries D. Diabetic neuropathy E. All of the above 8. Which of the following medications would have the longest suppression of IgE-mediated skin tests? A. Azelastine B. Chlorpheniramine D. Diphenhydramine E. Promethazine 9. Which of the following medications is most likely to suppress skin testing response? A. Cimetidine B. Imipramine C. Albuterol D. Montelukast 10. Which of the following medications is most likely to suppress skin testing response? A. Theophylline B. Cromolyn C. Ketotifen D. Dopamine Answers 1. B, page 1267 Histamine and tryptase release begins about 5 minutes after allergen injection and peaks at 30 minutes is the correct answer. The size of the wheal does not correlate with degree of allergy and the immediate reaction is primarily mediated by histamine. The presence of a late-phase reaction is variable. 2. E, page 1268 All of the above are correct. 3. D, page 1269 Test sites are too close together and false-positive results can be observed is correct. Subcutaneous injection can lead to false-negative and high concentration or a large volume can lead to false-positive results. Page 10 of 82

11 4. A, page 1272 Quality of the allergen extract is an important factor in skin testing. Gender, circadian rhythm, and corticosteroids do not affect the skin test results. 5. C, page 1277 The correct answer is the presence of allergic sensitization with no correlative allergic disease is a common finding, occurring in 8 30% of the population when using a local standard panel of aeroallergens. A positive test does not confirm allergic disease only allergic sensitization. Skin prick testing is an inexpensive screening test and is more sensitive than allergen-specific IgE testing. 6. A, page 1272 Using prick-puncture tests it has been observed that a significant wheal was detectable after 3 months of age in most infants tested with either histamine, codeine phosphate, or allergen extracts. 7. E, page 1273 All of the above disorders can reduce the wheal and flare reaction with skin testing. 8. A, page 1274 Azelastine can suppress skin tests for 3-10 days. All of the others suppress skin tests for only 1-3 days. 9. B, page 1274 Imipramine, used commonly to treat bedwetting, can suppress skin test wheal and flare responses for more than 10 days. None of the other medications cause clinically significant suppression. 10. C, page 1274 Ketotifen can suppress skin test results for more than 5 days. None of the other medications cause clinically significant suppression. Allergy and Immunology Review Corner: Chapter 74 of Middleton s Allergy Principles and Practice, 7 th Edition, edited by N. Franklin Adkinson, et al. Chapter 74: Oral Food Challenge Testing Prepared by Sarah Bozeman, DO, University of Mississippi, and John Seyerle, MD, Ohio State University 1. An open oral food challenge will result in what percent false positive results? A. 5% B. 10% C. 15% D. 30% Page 11 of 82

12 2. Several adverse reactions can occur during an oral food challenge. Which of the following, according to a study performed by Perry et al, was the most common reaction seen? A. Gastrointestinal B. Cutaneous C. Oral D. Lower respiratory 3. There are several dosing strategies that can be adopted for an oral food challenge, but for most IgE-mediated reactions typical total doses administered are for dry foods and for wet foods? A. 5g, 200ml B. 10g, 50ml C. 8g, 100ml D. 10g, 300ml 4. Double-blind placebo-controlled food challenge is the gold standard for the diagnosis of food allergy. However, this is not perfect. What are the estimated false positive and false negative rates? A. 1% and 3% B. 3% and 5% C. 5% and 10% D. 10% and 15% 5. Which of the following clinical scenarios is an oral food challenge not necessary? A. A patient has urticaria several hours after eating peanut butter for the first time and PST is negative to peanut B. A patient with chronic eczema has a suspected egg allergy, but the history provided is unclear. RAST level was screened for egg and was below the predictive level C. A patient experiences anaphylaxis 15 minutes after ingesting raw unseasoned shrimp, however patient had eaten raw unseasoned shrimp several times prior without a reaction. D. A patient has a known history of egg allergy. PST upon reevaluation was negative. 6. Which of the following can be used to predict the severity of the reaction in a positive food challenge? A. Type of food B. Specific IgE level C. Dose ingested D. None of the above 7. An IV should be placed for food challenges in which of the following conditions? A. Previous mild reaction B. Food dependent, exercise-induced anaphylaxis C. Food-protein induced enterocolitis D. History of asthma 8. Which of the following is required prior to starting an oral food challenge? Page 12 of 82

13 A. Informed consent B. Properly trained personnel C. Accessible medications and equipment for resuscitation D. Normal baseline physical exam E. All of the above 9. Some suggest the false-positive rate for open challenges could be as high as what? A. 10% B. 20% C. 30% D. 40% 10. What can be done to minimize challenge risks? A. Use standard starting dose and challenge protocol in patients with a history of severe reactions B. Give Benadryl as soon as a reaction is occurring C. Continue the challenge for mild symptoms D. Re-examine the patient at regular intervals Answers 1. D, page 1310 Limitations of open challenges relate to the chance of bias on the part of both the patient and the observer. The bias will most often result on false positive challenge results. 2. B, pages Of the 584 challenges, 43% resulted in an allergic reaction. 78% cutaneous, 43% GI, 26% oral, 26% lower respiratory, 25% upper respiratory. 3. C, page 1313 Typical total doses administered for most IgE-mediated reactions are 8-10grams of the dry food or 100mL of wet food, doubling the amounts for meat or fish. 4. A, page 1311 Although DBPCFC is the best available test, the false-positive and false-negative rates have been estimated to be between 1% and 3% 5. C, pages When a patient has an acute reaction of urticaria or anaphylaxis, a convincing history, and/or confirmation by PST and or sige. 6. D, page 1314 There are no differences in the type of food and the severity of the reaction. No relationship was detected between specific IgE levels or the dose ingested and the severity of the reaction. 7. C, page 1312 Page 13 of 82

14 Reactions in Food-protein-induced enterocolitis generally involve hypotension and require fluid resuscitation. 8. E, page 1312 Oral food challenges should be performed in a setting that maximizes comfort and safety. 9. C, page 1312 Some suggest that the false positive rate for open challenges could be as high as 30%, particularly when there is significant anxiety. 10. D, page 1316 Challenges should be performed by experienced personnel who continually interact with and reexamine the patient at regular intervals. Food challenges should be stopped as soon as a reaction begins. Benadryl is not appropriate for stopping a severe reaction. Starting dose and challenge protocol may need to be adjusted for patients with a history of a severe reaction. Page 14 of 82

15 Allergy and Immunology Review Corner: Chapter 75 of Middleton s Allergy Principles and Practice, 7 th Edition, edited by N. Franklin Adkinson, et al. Chapter 75: Approach to Infants and Children with Asthma Prepared by Martha K. Elias, Mayo Clinic, and John Seyerle, Ohio State University 1. A child with a wheeziing episode in the first three years of life is most likely to be classified in which of the following categories? A. Transient early wheezing B. Non-atopic persistent wheezing C. IgE-associated persistent wheezing D. Late-onset wheezers 2. Which of the following are risk factors for the transient early wheezing phenotype? A. Absence of school-age older children B. Female sex C. Allergen exposure D. Breast feeding 3. Non-atopic persistent wheezing is found in what percentage of children who wheezed before age 3? A. 10% B. 20% C. 30% D. 40% 4. Which of the following phenotypes generally presents after age 1 year? A. Transient early wheezing B. Non-atopic persistent wheezing C. IgE-associated persistent wheezing D. Non-wheezers 5. In the Tuscon study, sensitivity to what allergen was associated with increased likelihood of persistent asthma by age 11? A. Dust mite B. Bermuda grass C. Cockroach D. Alternaria 6. What percentage of children who wheeze in the first 3 years of life have resolution of their symptoms by 6 years of age according to the Tucson Children s Respiratory Study (TCRS)? A. 40% B. 50% Page 15 of 82

16 C. 60% D. 70% 7. IgE- associated/atopic persistent wheezing phenotype is associated with which risk factors? A. Female sex B. Seborrheic dermatitis C. Eosinophilia at 9 months D. Parental contact dermatitis 8. Which is a risk factor for fatal asthma? A. Two or more asthma hospitalizations for asthma in the past year B. Five or more emergency department visits for asthma in the past year C. Hospitalization or ED visit for asthma in the past week D. Use of >3 canisters per month of short acting bronchodilator (SABA) 9. Which asthma susceptibility gene codes for a metalloproteinase? A. T-bet B. GPRA C. DENND1B D. ADAM Which is the only childhood asthma treatment that can potentially modify existing allergic sensitization and secondarily reduce allergic asthma in regard to specific exposures? A. Anti- histamines B. Specific subcutaneous allergen immunotherapy C. Inhaled corticosteroids D. Environmental controls Answers 1. A, page 1320 Some 60% of children who wheeze in the first 3 years of life have resolution of their symptoms by 6 years of age. 2. C, page 1321 Risk factors for the transient early wheezing phenotype include maternal smoking, school-aged older siblings, day-care attendance, house-dust endotoxin, allergen exposure, male sex, and bottle-feeding. 3. B, page 1321 Non-atopic persistent wheezing is found in 20 percent of children who wheezed before age C, page 1321 Atopic persistent wheezing is present in 20% of children who wheeze before age 3, with Page 16 of 82

17 symptoms typically presenting after 1 year of age. 5. D, page 1321 In the Tuscon study, sensitivity to Alternaria was associated with increased likelihood of persistent asthma by age C, page 1321 Some 60% of children who wheeze in the first 3 years of life have resolution of their symptoms by 6 years of age according to the TCRS. 7. C, page 1321 Risk factors associated with atopic wheeze include male sex, parental asthma, atopic dermatitis, eosinophilia at 9 months, early sensitization to food or aeroallergen and a history of wheezing with lower respiratory tract infections. 8. A, page 1322 Risk factors for fatal asthma are: Two or more asthma hospitalizations for asthma in the past year, three or more emergency department visits for asthma in the past year, Hospitalization or ED visit for asthma in the past month, Use of >2 canisters per month of SABA. 9. D, page 1324 Polymorphisms in the asthma susceptibility gene ADAM33, which codes for a metalloproteinase, have a role in the inflammatory response or smooth muscle hypertrophy or hyperreactivity in asthma. C_7947 polymorphism in T-bet regulates Th1 lineage development and is associated with airway hyperresponsiveness. GPRA is a G- protein coupled receptor that binds to neuropeptide S and has been linked to asthma susceptibility and allergy in children and adults. DENND1B encodes a protein that interacts with the tumor necrosis factor (TNF) α receptor and represses inflammatory-cell TNF-receptor signaling. 10. B, page 1333 Specific subcutaneous allergen immunotherapy is the only childhood asthma treatment that can potentially modify existing allergic sensitization and secondarily reduce allergic asthma in regard to specific exposures. Allergy and Immunology Review Corner: Chapter 76 of Middleton s Allergy Principles and Practice, 7 th Edition, edited by N. Franklin Adkinson, et al. Chapter 76: Approach to Adults with Asthma Prepared by John Seyerle, MD, Ohio State University 1. What is the approximate worldwide prevalence of asthma? A. 3 million Page 17 of 82

18 B. 15 million C. 150 million D. 300 million 2. Asthma is responsible for approximately how many deaths worldwide each year? A. 50,000 B. 150,000 C. 250,000 D. 350, Criteria for the diagnosis of asthma in adults generally include demonstration what minimum improvement in FEV1? A. 120mL B. 180mL C. 240mL D. 300mL 4. Diagnosis of asthma can also be made with what improvement in FEV1 over time following treatment with corticosteroids? A. 12% B. 15% C. 20% D. 24% 5. If using PEF instead of FEV1, what percentage increase following bronchodilator is considered suggestive of asthma? A. 12% B. 15% C. 20% D. 24% 6. Which of the following is the best method for diagnosing asthma and assessing control? A. Spirometry B. Physical exam C. Peak Expiratory Flow D. Chest Radiograph 7. For testing of airway responsiveness using methacholine or mannitol, the degree of responsiveness is measured as the dose required to induce what fall in FEV1? A. 12% B. 16% C. 20% D. 24% 8. Exhaled nitric oxide is a surrogate marker for what type of inflammation? Page 18 of 82

19 A. Eosinophilic B. Neutrophilic C. Bacterial D. Mast cell 9. What frequency of limitation of activity is allowed to occur to still call a person with asthma well-controlled? A. None B. Less than 2x per week C. Less than 2x per month D. Less than 2x per year 10. A person with asthma symptoms 3x per week, FEV1 of 85% predicted with a 15% increase following bronchodilator, and no exacerbations, nocturnal symptoms or limitations of activity would initially be classified as what type of asthma? A. Intermittent B. Mild persistent C. Moderate persistent D. Severe persistent Answers 1. D, page 1346 The approximate worldwide prevalence of asthma is 300 million. 2. C, page 1346 Asthma is responsible for approximately 250,000 deaths worldwide each year according to the World Health Organization. 3. B, page 1348 Criteria for the diagnosis of asthma generally include the demonstration of improvement in FEV1 of at least 12% post bronchodilator with a minimum of 180mL in adults. 4. C, page 1328 Diagnosis of asthma can also be made with 20% improvement in FEV1 over time following treatment with corticosteroids. 5. C, page 1348 If using PEF instead of FEV1, a 20% increase following bronchodilator is considered suggestive of asthma. 6. A, page 1350 Spirometry is the preferred method of measurement of airway obstruction. Physical exam is unreliable as it is only helpful during episodes of bronchoconstriction. Peak expiratory flow is effort dependent and may underestimate the degree of airflow limitation. Page 19 of 82

20 7. C, page 1350 For testing of airway responsiveness using methacholine or mannitol, the degree of responsiveness is measured as the dose required to induce a 20% fall in FEV1. 8. A, page 1350 Exhaled nitric oxide is a surrogate marker for eosinophilic inflammation. 9. A, page 1351 Any limitation of activity excludes calling asthma well-controlled. 10. B, page 1351 Mild persistent asthma is characterized by symptoms more than once a week but less than daily, nocturnal symptoms more than twice a month but less than once a week, FEV1 80%, or FEV1 variability <20%. Page 20 of 82

21 Allergy and Immunology Review Corner: Chapter 81 of Middleton s Allergy Principles and Practice, 7th Edition, edited by N. Franklin Adkinson, et al. (top) Chapter 81: Asthma and Allergic Diseases during Pregnancy Prepared by Paul Keiser, MD, Walter Reed Army Medical Center, and Irene Fung, MD, Children s Hospital of Philadelphia 1. Which of the following drugs would be considered pregnancy category B by the FDA? A. Animal and human studies both show teratogenicity. B. Neither animal nor human studies have shown teratogenicity. C. Animal studies show teratogenicity, human studies do not. D. Animal studies show no teratogenicity, human studies do. E. Neither animal nor human studies of teratogenicity have been done. 2. Which of the following statements about antibody levels in pregnant women is correct? A. IgG levels decrease in proportion to the hemodilution of pregnancy. B. IgG2 levels decrease disproportionately as a result of active placental transport. C. IgM levels increase in the third trimester as a result of exposure to fetal antigens. D. IgE levels increase in proportion to the hemodilution of pregnancy. E. IgE levels decrease in proportion to the hemodilution of pregnancy. 3. The clinical course of which of the following infectious diseases is not altered by pregnancy? A. Influenza B. Measles C. Varicella pneumonia D. HIV E. Leprosy 4. Which of the following oral medications are considered to be pregnancy category A (adequate and well-controlled studies in pregnant women show no potential for causing congenital malformations) by the FDA? A. Chlorpheniramine B. Prednisone C. Loratadine D. None of the above. 5. Which of the following pruritic disorders of pregnancy is diagnosed by immunofluorescence staining for C3 on skin biopsy? A. Pruritic urticarial papules and plaques of pregnancy. B. Pemphigoid gestationis. C. Prurigo of pregnancy. D. Cholestasis of pregnancy. Page 21 of 82

22 6. The use of which allergy and asthma medication has been associated with an increased risk of oral clefts in infants of mothers on this particular medication? A. 1st generation antihistamines B. 2nd generation antihistamines C. Inhaled corticosteroids D. Oral corticosteroids 7. Asthma in the pregnant woman is associated with the following in the fetus A. Intrauterine growth failure B. Respiratory distress syndrome C. Chronic lung disease D. Necrotizing enterocolitis 8. The following is true in regards to vasomotor rhinitis in pregnancy A. It is most prominent in the first half of pregnancy B. It usually persists for months after the pregnancy C. There is decreased levels of serum placental growth hormone in patients with rhinitis compared to those without D. There is a higher nasal mucociliary transport speed 9. Which medication has the best safety profile and is thus considered to be the first choice medication for allergic rhinitis during pregnancy? A. Intranasal corticosteroids B. Intranasal antihistamine C. Intranasal mast cell stabilizer D. Oral antihistamine 10. In general, pregnant women with a good history of venom sensitivity should: A. Be instructed insect avoidance measures and receive an EpiPen prescription B. The above, and have skin prick testing done C. The above in a and b and start immunotherapy Answers 1. C, page 1432, table 81.2 Category B is used for both drugs for which animal studies are negative for teratogenicity in which human studies have not been done as well as studies in which animal studies show teratogenicity but human studies do not. 2. A, page 1424, section on Serum Immunoglobulin Levels. Numerous studies have found that a decrease in immunoglobulin G (IgG) levels is about proportionate to the hemodilution of pregnancy. All IgG subclasses are transported across the placenta, and although some preferential transport of IgG1 may occur, this does not lead to any change in subclass distribution in maternal blood. Levels of IgM, IgA, and IgE do not change significantly. Page 22 of 82

23 3. D, page 1425, section on Clinical Observations > Infectious Diseases. Influenza is the most common infection that seems to cause greater morbidity in pregnancy, but only particularly virulent strains have been associated with increased risk. Pregnant women are three times as likely to be diagnosed as having measles pneumonia and six times as likely to die from measles complications than age-comparable non-pregnant women. Even when treated with acyclovir, mortality from Varicella pneumonia in pregnancy is substantial. Worsening of leprosy status with increased concentrations of bacilli in cutaneous smears occurred in 35% of prospectively followed women during pregnancy, with the majority of these women worsening during the third trimester (as opposed to 2% worsening during an unspecified period before conception). Patients whose immune system is being undermined by human immunodeficiency virus (HIV) infection might be expected to be a sensitive indicator of a pregnancy effect on the immune system. However, Prins et al conclude that the studies we reviewed failed to find any harmful effect of pregnancy on HIV disease progression. 4. D, page 1428, section on Specific Medications. No asthma or allergy medication meets the requirements for pregnancy category A. 5. B, page 1442, section on Other Dermatoses of Pregnancy. Pemphigoid gestationis (PG) is characterized by true bullae and is an autoimmune disorder. It can abruptly start in abdominal striae and mimic pruritic urticarial papules and plaques of pregnancy (PUPPP). It typically starts in the second or third trimester, but the clinical presentation and course can be extremely variable. PG is much rarer than PUPPP, occurring in only 1 in 50,000 pregnancies. A skin biopsy with positive immunofluorescence staining for C3 component confirms the diagnosis. PG is treated with systemic steroids, typically prednisone 0.5 mg/kg/day. 6. D, page 1433, section on Pharmacological Management > Pregnancy and Teratogens. This was shown in meta-analysis of 4 retrospective case control studies in which woman took oral corticosteroids for various reasons in the first trimester; however, no study controlled for potential effect of the various underlying maternal diseases. 7. A, page 1438, section on Obstetric Management of Asthmatic Women. Because asthma may be associated with intrauterine growth retardation and preterm birth, it is important to establish pregnancy dating accurately by first trimester ultrasound when possible. 8. D, page 1438, section on Course and Management of Specific Diseases > Rhinitis. Symptoms in vasomotor rhinitis of pregnancy tend to be most prominent in the second half of pregnancy and usually disappear within 5 days postpartum. Ellegard found elevated levels of serum placental growth hormone in patients with versus those without pregnancy rhinitis. In addition, he reported a higher nasal mucociliary transport speed in patients with pregnancy rhinitis. 9. C, page 1439, section on Course and Management of Specific Diseases > Rhinitis. For patients with allergic rhinitis, intranasal cromolyn may be considered first because it is generally regarded as safe. For patients inadequately controlled by intranasal cromolyn, antihistamine therapy may be useful. Page 23 of 82

24 10. A, page 1440, section on Anaphylaxis > Prevention. All venom-sensitive pregnant women with a history of Hymenoptera sting anaphylaxis should be reinstructed in insect avoidance measures and receive a prescription for an epinephrine autoinjector. Benefit-to-risk considerations indicate that pregnant women receiving maintenance venom immunotherapy before pregnancy should continue such treatment during pregnancy. Pregnant women with histories suggestive of Hymenoptera sting anaphylaxis who have not been previously skin tested should receive avoidance instructions and an emergency kit, but the authors recommend deferring skin testing until postpartum. Allergy and Immunology Review Corner: Chapter 82 of Middleton s Allergy Principles and Practice, 7 th Edition, edited by N. Franklin Adkinson, et al. Chapter 82: Allergen Control Prepared by John Seyerle, MD, Ohio State University, Nina Poliak, MD, MPH, Children s Hospital of Philadelphia 1. Which of the following antigens would have the highest airborne levels in an undisturbed house? A. Cat B. Dust mite C. Cockroach 2. Which of the following is the most effective measure at reducing dust mite allergen exposure? A. HEPA filter B. Dust mite covers C. Dehumidifier D. Washing bedding 3. Which of the following methods is effective at reducing the amount of inhaled cat allergen in a home that has a cat? A. HEPA filters on air cleaning units B. Twice weekly washing C. Twice weekly vacuuming with HEPA filters and double-thickness bags D. None of the above 4. Pesticides and appropriate cleaning can control cockroach populations for up to how long? A. 1 month B. 2 months C. 6 months D. 12 months 5. Dust mite avoidance measures are most likely to be of benefit to patients with which of the following conditions? Page 24 of 82

25 A. Childhood asthma B. Adult asthma C. Allergic Rhinitis D. Eczema 6. How often should the washing of the cat be conducted to reduce airborne cat allergen level? A. Every other day B. Weekly C. Once a month D. Once in 6 month 7. By approximately what amount do the active covers for pillows, mattress, and duvets reduce mite allergen level? A. 30% B. 50% C. 75% D. 100% 8. If the carpets remain in place, what methods can be used to decrease the dust mite allergen level? A. Exposing carpets to direct strong sunlight B. Steam cleaning C. Use of acaricides or tannic acid D. Freezing with liquid nitrogen E. All of the above 9. What are the results of The Primary Prevention of Asthma in Children ( PREVASC) study? A. At 2 years of age, the intervention group appeared to have fewer asthma-like symptoms. B. There was a significant difference in total and specific IgE. C. Incidence of asthma like symptoms during the first 2 years of life was different in both groups. 10. What are the main conclusions of the Manchester Asthma and Allergy Study (MAAS)? A. Slightly more atopy in the intervention group than in the control group at age 1year B. Asthma-like symptoms were consistently lower in the intervention than in control group. C. No difference between the group for eczema. D. Increased risk of mite sensitization in the intervention group at age of 3 years. E. Better lung function at age 3 years in the intervention group. F. All of the above. Answers 1. A, page 1448 Some cat allergen has a molecular weight of less than 5μm and will remain airborne for long periods. Levels are detectable in all homes. Dust mite and Cockroach allergens are greater than 10μm and settle quickly after being disturbed. Page 25 of 82

26 2. B, page 1448 The most effective measure to reduce allergen exposure is to cover the mattress, duvet, and pillows with casings that are impermeable to mite allergens. HEPA filters are more effective at reducing cat and dog allergen than the heavier mite allergen. Dehumidifiers and frequent washing of bedding in hot water are effective but not as important as mite covers. 3. D, page 1449 Removing the pet from the home is the only effective advice to patients with pet allergy who experience symptoms on exposure. 4. C, page 1450 Pesticides and appropriate cleaning can reduce exposure within two weeks, has maximal effect within 1 month, and will keep populations under control for up to 6 months. 5. A, page 1452 Several studies have indicated that simple environmental control interventions may improve airway reactivity, lung function, and reduce acute emergency room visits due to asthma among mite-sensitized asthmatic children. Cochrane reviews failed to find benefit in allergic rhinitis, eczema, or adult asthma. 6. B, page 1449 Several studies have investigated the effect of pet washing on allergen levels. A reduction in airborne cat allergens was reported following washing of one cat weekly over 4-week period, and a similar short-lived reduction was confirmed in a later study. However, it is unlikely that a modest reduction in allergen exposure achieved by pet washing would be sufficient to translate into a clinical benefit. 7. A, page 1452 A total of 279 mite-sensitized subjects aged 8-50 years with perennial rhinitis and a positive nasal challenge test to mite extract were randomized to receive either active or placebo covers, with the primary outcome measure being symptom scores. The active covers reduced mite allergen levels collected from the mattress to approximately 30% of the baseline, whereas the placebo covers had no effect. 8. E, page 1448 Ideally, carpets should be removed and replaced by hard flooring ( e.g.wood or linoleum). If carpets remain in place, several methods have been suggested for reducing mite allergen levels ( e.g. exposing carpets to direct strong sunlight, steam cleaning, use of acaricides or tannic acid, freezing with liquid nitrogen, etc). However, these methods are only partially effective. 9. A, page 1454 PREVASC study included 476 children who were recruited in the prenatal period and randomized to either a control group ( receiving usual care) or an intervention group in which families received instruction from nurses on how to reduce exposure of newborns to mite, pet and food allergens, and passive smoking. At age of 2 years, the intervention group appeared to have fewer asthma-like symptoms, including wheezing, shortness of breath, and night-time Page 26 of 82

27 cough, than control group. No significant differences in total or specific IgE were found between the groups. Furthermore, the incidence of asthma-like symptoms during the first 2 years of life was similar in both groups. 10. F, page 1455 MAAS is a whole-population birth cohort study of more than 1000 children, with a nested intervention study in the high-risk group. Only children with 2 atopic parents who had no pets in their home were randomly allocated before birth to a stringent environmental control and normal regime. At age 1 year there was slightly more atopy in the intervention group than in the control group, but did not reach statistical significant. Asthma-like symptoms were consistently lower in the intervention than in control group. No difference between the groups was seen for eczema. Stringent environmental control was associated with an increased risk of mite sensitization but better lung function at age 3 years. Page 27 of 82

28 Allergy and Immunology Review Corner: Chapter 85 of Middleton s Allergy Principles and Practice, 7 th Edition, edited by N. Franklin Adkinson, et al. Chapter 85: Beta-Adrenergic Agonists Prepared by Autumn Guyer, MD, Massachusetts General Hospital, and Paul Keiser, MD, Walter Reed Army Medical Center 1. Compared to the closed mouth technique of using an MDI, the open-mouth technique (where the MDI is held two inches away from the mouth) has the following advantage: A. Consistent enhancement of efficacy in clinical trials. B. Increased time for the propellant to evaporate before being inhaled, resulting in a more uniform particle size. C. Increased turbulence of air flow, which decreases deposition in the upper airway. D. Additional time for the medication to settle in the lungs. E. Improved hand-lung coordination 2. An important advantage of a jet nebulizer versus an MDI with spacer and holding chambers is: A. Less tachycardia with the nebulizer B. Better clinical response C. Better improvement in pulmonary function D. Less time required by staff for administration and maintenance of therapy E. Longer duration of response 3. Non-bronchodilator actions of beta-2 agonists include which of the following: A. Increased eosinophils in sputum and BAL fluid B. Decreased ion and water secretion C. Increased microvascular permeability D. Enhancement of cholinergic transmission E. Priming of the glucocorticoid receptor 4. Adverse effects of inhaled beta-2 agonists include which of the following: A. Hypoglycemia B. Hyperkalemia C. Tremor D. Increased gastric acid secretion E. Shortened QTc 5. Which of the following statements about salmeterol is true? A. It possesses a long, hydrophilic side chain that increases its uptake into cell membranes, prolonging its duration of action. B. Compared with formoterol, it has a more rapid onset of action. C. Because of its anti-inflammatory action, it is recommended as monotherapy for longterm control of asthma Page 28 of 82

29 D. The SMART study concluded that there were no statistically significant increases in respiratory-related and asthma-related deaths in the total population receiving salmeterol. E. It is resistant to degradation by catechol-o-methyltransferase (COMT) because one of the hydroxyl groups on the benzene ring has been replaced by a hydroxymethyl group 6. Which of the following is an advantage of using a pressurized metered-dose inhaler (MDI)? A. Little hand-lung coordination is needed B. The MDI is effective with tidal breathing C. There is high dose-dose reproducibility D. There is low oropharyngeal deposition with use 7. What structural characteristic of catecholamines leads to more selectivity for the β 2 - receptor? A. Modification of the 3, 4-hydroxyl groups on the benzene ring B. Increasing the bulk of the side chain C. Substitution of a hydroxymethyl group for a 3-hydroxyl group D. Substitution of a formylamino group 8. Which of the following is an example of a short acting beta-agonist? A. Formoterol B. Salmeterol C. Terbutaline D. Aformoterol 9. Which of the following is true regarding the use of β 2 adrenergic agonists? A. Adverse reactions including paradoxical bronchoconstriction are commonly seen in diabetic patients with multiple co-morbidities B. Continued therapy leads to hypoglycemia to which tolerance rapidly develops C. Chronic use leads to high levels of magnesium in the blood from β 2 -adrenergic stimulation D. Administration of β 2 -adrenergic agonists may cause a transient fall in arterial oxygen tension (PaO 2) 10. What is the limitation in using β 2 -agonists by the oral route? A. The oral route is limited by dose dependent side effects of tremor B. Bronchodilation was only effectively demonstrated in adult patients C. The oral formulations last for more than 24 hours because only extended release formulas are available D. When used as a sole bronchodilator there was no improvement in pulmonary function Answers 1. B, page 1490 Particles leaving an MDI consist largely of propellant, which must evaporate for the particles to achieve a size suitable for entering the lungs. It would be anticipated that a longer distance from actuator to oropharynx would allow more complete evaporation of Page 29 of 82

30 propellant as well as slowing of the particles. Some investigators have advocated use of an open-mouth technique, where the MDI is held 2 inches away from the open mouth. However, this technique has not been shown to enhance clinical benefit consistently compared with the closed-mouth technique. 2. D, page 1492 The delivery of β2-agonists in the acute care setting by nebulizers or MDIs with holding chambers is equally effective for improving pulmonary function and reducing symptoms of acute asthma in both adult and pediatric patients. Nebulizer use in the emergency department is associated with greater increases in heart rate than the use of an MDI with spacer/holding chamber, suggesting that a larger systemically absorbed dose is administered by nebulizer. In the inpatient setting, the available evidence suggests that there is no difference in the pulmonary function response between using a nebulizer and using an MDI with a spacer/holding chamber for administering short-acting β2-agonists. 3. E, page 1493 and Table 85.2 LABAs, when added to suboptimal concentrations of ICS, resulted in enhanced translocation of the glucocorticoid receptor into the nucleus of cells. The mechanism appears to be through priming of the glucocorticoid receptor by mitogen-activated protein kinases (MAPKs) generated as a result of prolonged stimulation of the β2-adrenergic receptor. 4. C, page 1494 The principal side effect of adrenergic therapy is tremor, which is caused by direct stimulation of β2-adrenergic receptors in skeletal muscles (Box 85.3). Tremor is inseparable from the bronchodilator action but does decrease significantly over 2 weeks of continuous therapy; it is not clear whether tolerance reflects desensitization of the β2- receptors of skeletal muscle or adaptation within the central nervous system (CNS). Other side effects include hyperglycemia, hypokalemia, and prolonged QTc. 5. E, page 1486 The basic structure of the catecholamines can be modified by two strategies (Fig. 85.1). The first strategy is modification of the 3,4-hydroxyl groups on the benzene ring, which are required for the action of the enzyme catechol O-methyltransferase (COMT). This can be accomplished by substituting a hydroxymethyl group for the 3-hydroxyl, as in the case of albuterol (salbutamol), pirbuterol, and salmeterol. See also page The SMARTdata represented a serious safety concern for the use of LABAs but the significant benefit provided to a large number of patients, particularly in conjunction with ICS therapy, warranted continued use of LABA as adjunctive therapy for patients who have asthma that is not well controlled with ICS alone. 6. C, page 1491, Table 85.2 Advantages of pressurized metered-dose inhalers (MDI) include high dose-dose reproducibility. MDIs require hand-lung coordination and have a high oropharyngeal deposition. With optimal MDI technique, a maximum of 12 14% of the dose released by an MDI can be deposited in the lungs. Page 30 of 82

31 7. B, page 1486 Increasing the bulk of the side chain results in more selectivity for the β 2 -receptor. For albuterol, terbutaline, and pirbuterol, a tertiary butyl group replaces the isopropyl group of isoproterenol and metaproterenol; in the case of fenoterol, the substituted 4- hydroxybenzyl moiety is larger. 8. C, page 1486 Terbutaline is a non-catecholamine short acting β 2 -agonist. Bronchodilation occurs rapidly after inhalation and effects persist for 4 6 hours. 9. D, page 1495 When a patient is initially placed on β 2 -adrenergic stimulants, hyperglycemia occurs from glycogenolysis, but the response declines rapidly with chronic stimulation and β 2 - Adrenergic stimulation increases urinary excretion of magnesium, partly explaining the decreased serum levels of magnesium. Administration of β 2 -adrenergic agonists may cause a transient fall in arterial oxygen tension (PaO 2 ) of >5 mmhg in up to 50% of patients with asthma and the frequency with which this fall in PaO 2 is observed suggests the need for precautionary administration of oxygen-enriched air before beginning intensive therapy with β 2 -adrenergic agonists in acutely ill patients. 10. A, page 1490 Administration of a β 2 -adrenergic agonist by the oral route is limited by dose-dependent side effects of tremor, tachycardia, and palpitations. Tremor is often the dose-limiting effect however the intensity of this symptom usually declines over 2 weeks with continued administration. Allergy and Immunology Review Corner: Chapter 86 of Middleton s Allergy Principles and Practice, 7 th Edition, edited by N. Franklin Adkinson, et al. Chapter 86: Theophylline and Phosphodiesterase Inhibitors Prepared by John Seyerle, MD, Ohio State University, and Arnaldo Perez, MD, University of Pureto Rico School of Medicine 1. Therapeutic concentrations of Theophylline inhibit phosphodiesterase (PDE) activity in human lung extracts by what percentage? A. 5-10% B % C % D % 2. Nausea and vomiting as side effects of Theophylline are likely due to inhibition of which of the following? A. PDE3 B. PDE4 Page 31 of 82