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December 23, 2003

By Ernest N. Charlesworth, M.D.
Department of Allergy and Dermatology
Shannon Clinic, San Angelo, Texas
Clinical Associate Professor of Medicine, 
University of Texas Medical School at Houston


With a background in both dermatology and allergy, I have become well aware of the frustrations that urticaria presents to both the physician and the patient. Fifteen percent of the general population will experience urticaria at one time or another, and some of these patients will develop chronic urticaria. The latter frequently go from one physician to another in hopes of finding the elusive cause for their “hives.”

Today we know a little more about chronic idiopathic urticaria. In fact, we now recognize that 30 percent to 40 percent of patients with CIU have an autoantibody directed against the high affinity IgE receptor on mast cells and basophils. When the serums from these patients are analyzed, the following distinct subtypes can be identified:

  1. Immunoreactive histamine releasing anti-Fc epsilon R1 autoantibodies in 26 percent
  2. Immunoreactive anti-Fc epsilon R1 atuoantibodies without histamine release (15 percent)
  3. Anti-IgE antibodies
  4. Mast cell histamine releasing factor (9 percent)
  5. Serum with no factor (41 percent)

The propensity to form antibodies has been extended to auto-thyroid antibodies in a subgroup of patients. Additiononally, it is recognized that patients with systemic lupus erythematosus may have urticaria. Urticarial vasculitis is another forme fruste of urticaria, which is a true leukocytoclastic vasculitis.

With the above brief introduction, there are a few questions that I would like to briefly address while remembering that there is nothing simple about urticaria. In fact, it might be best to think of urticaria as symptom and not as a disease. Just as there are many causes for a fever, there are many causes for urticaria. In reality, there is no such thing as idiopathic urticaria since there must be an underlying mechanism. A patient once asked me what idiopathic meant, and I answered that it “means that the doctor is an idiot.” In your practice, you will also find treating and evaluating urticaria as a humbling experience and at times you may feel that you are that idiot in idiopathic.

How should we evaluate a patient who has had an individual urticarial lesion for greater than 24 hours?
Now that is a good question, and it illustrates the importance of tying the clinical setting of the urticaria with mechanism of the disease. Briefly, urticaria, which remains in the exact same location, is urticarial vasculitis until proven otherwise. This is a histopathologic diagnosis, and it mandates the performance of a skin biopsy. The biopsy will show neutrophils invading the post capillary venules of the skin, associated with fibrin deposition, swelling of the intimal lining of the vessel and “nuclear dust.” Sometimes, one may see a polymorphic infiltrate with urticaria in which the lesions last 12-24 hours in the absence of an associated vasculitis. Bottom line: biopsy the skin.

In general, what are the essential features of physical urticarias that distinguish them from IgE mediated urticaria?
Simple question, complicated answer. The physical urticarias are a group of diseases in which symptoms develop simply by physical environmental changes. Mechanical sources produce dermatographism, delayed pressure urticaria and vibratory urticaria. Thermal changes are responsible for cholinergic and cold urticaria. Exposure to light, water and exercise are the trigger for solar urticaria, aquagenic urticaria and exercise-induced anaphylaxis, respectively. Physical agents are involved in 10 percent to 20 percent of all chronic urticarial reactions.

What recent advances in chronic urticaria should we review when preparing for our boards, and at what point should we refer a patient for a skin biopsy?
Well, the answer to the first part of the question is addressed in my introduction, above. For the boards, you should know the recent data regarding autoantibodies and the clinical subtypes that I discussed. In regard to knowing when to refer a patient for a skin biopsy, my answer is that you should not have to refer for a skin biopsy because you should be able to do a simple 4-mm punch biopsy in your office. If you don’t know how to do a skin biopsy, there are workshops given at the both the ACAAI and AAAAI meetings. Urticaria in which the lesions persist beyond 24 hours should definitely be biopsied. Remember, the most important part of the skin biopsy is sending the specimen to a dermatopatholgist familiar with the histologic types of urticaria. It is critical that you give the dermatopatholgist an adequate medical history. 
I find that a skin biopsy is quite helpful and there are three distinct histologic patterns as follows:

  1. Group 1: Neutrophilic vasculitis
  2. Group 2: Polymorphous perivascular infiltrate
    i. Neutrophils
    ii. Eosinophils
    iii. Mononuclear cells
  3. Group 3: Sparse perivascular lymphocytic infiltrate

This can be helpful from a therapeutic standpoint since Group 3 responds nicely to H1 antihistamines, whereas, Group I and Group II will pose a challenge that may require the use of systemic steroids, hydroxychloroquine, cyclosporine and Dapsone.

References
1. Sabroe RA, Fiebiger E, et al. Classification of anti-Fc epsilon R1 and anti-IgE autoantibodies in chronic idiopathic urticaria and correlation with disease activity. J Allergy Clini Immunol 2002;110:492-9.
2. Asero R. Intolerance to nonsteroidal anti-inflammatory drugs might precede by years the onset of chronic urticaria. J Allergy Clin Immunol 2003;111:1095-8.
3. Mehregan DR, Hall MJ, Gibson LE: Urticarial vasculitis: a histopatholigc and clinical review of 72 cases. J Am Acad Dernatikg 1992; 26:441-448, 1992. 
4. Immunology and Allergy Clinics of North America. Ernest N. Charlesworth, MD, guest editor. Volume 15. Number 4. November 1995.


December 10, 2003

Diagnostic Modalities II: Allergy Diagnostic Testing
By William K. Dolen, M.D.

1.  A 36-year-old female presents to you as a new patient because of a recent change in insurance. She wishes to continue allergen immunotherapy for allergic rhinitis, and you have chosen to repeat her skin testing. Modified prick tests are negative to a variety of pollens, danders, mites and other inhalant allergens. The histamine control produced a wheal 5 mm diameter with flare 26 mm diameter. She is astonished because skin testing done only 6 months previously was positive to nearly everything tested. Past medical records are unavailable for review. Which of the following is the most likely explanation for this predicament?

a. She is dermographic.
b. In the previous testing, the test sites were too close together (< 2 cm distance).
c. She has had an immunologic response to immunotherapy that has resulted in suppression of her previously positive tests.
d. She forgot to mention that she has been taking an over-the-counter cold preparation that contains an antihistamine.
e. She was previously tested on the upper back, but you had chosen to repeat testing on her forearms.

2. In which of the following situations would measurement of the total serum IgE level be most appropriate?

a. A 12-year-old male with perennial clear rhinorrhea, nasal and ocular pruritus, and bouts of sneezing.
b. A 42-year-old female with daily urticaria, except when taking antihistamines, for the past 6 months.
c. A 40-year-old male with asthma, a history of recurrent upper lobe pulmonary infiltrates, and a positive skin test to Aspergillus fumigatus.
d. A 4-month-old female with vomiting after feedings
e. A 28-year-old male with chronic rhinitis and a nasal smear positive for eosinophils. Allergy skin tests are negative with appropriately positive controls.

3. A 37-year-old female presents to your practice for evaluation of severe steroid-requiring asthma. At a time when she is not having symptoms, she has a flow-volume loop as depicted in Figure A. Several nights later, she presents to a local emergency room in severe respiratory distress and has a flow-volume loop as in Figure B. Which of the following is the most likely explanation for these findings?

a. Severe intermittent asthma causing variable intrathoracic obstruction
b. A laryngeal polyp causing variable intrathoracic obstruction
c. A bronchogenic cyst causing fixed intrathoracic obstruction
d. Vocal cord dysfunction syndrome causing variable extrathoracic obstruction
e. Vocal cord dysfunction syndrome causing variable intrathoracic obstruction

4. A 16-year-old cheerleader reports daily episodes of shortness of breath and wheezing not related to exercise. On forced expiratory spirometry, the FVC is 105 percent of predicted and the FEV1 is 102 percent of predicted. After nebulization of 2 mg of albuterol, the FEV1 increases to 104 percent of predicted. Review of a diary of symptoms and peak expiratory flow measurements shows no drop in peak flow when symptoms are present and no diurnal variation in peak flow. Symptoms, however, seem to be improved within 45 minutes of using albuterol from a metered dose inhaler. A methacholine challenge is performed, and the concentration of methacholine producing a 20-percent decrease in baseline FEV1 is reported as 15 mg/mL. Which of the following statements is most appropriate?

a. He has asthma, and in accordance with published guidelines should be placed on a controller medication with a short-acting beta adrenergic agonist provided for symptom relief.
b. She has a degree of methacholine reactivity that is present in the normal population. Asthma therapy does not appear to be appropriate, but she should be evaluated for other causes of shortness of breath and wheezing while maintaining close followup.
c. There would be no need to check the test solutions used in order to determine when they had been reconstituted and how they had been stored after reconstitution.
d. The methacholine challenge should be repeated using a dosimeter and a cumulative breath unit protocol.
e. This degree of methacholine reactivity is concerning because of studies that have shown that such individuals are at high risk of developing overt asthma in long-term followup.

5. A 47-year-old male reports progressively severe malaise and fatigue, headaches, dizziness, and difficulty thinking. He notes that symptoms began several months after a large quantity of cleaning solvent was spilled at his workplace. Now, various chemicals, tobacco smoke, polyester clothing, food additives, and chlorinated drinking water aggravate his nearly constant symptoms. His suspicions have been confirmed by provocation-neutralization testing, and he wishes to begin treatment which is to consist of isolation from his modern environment, a rotating diet of natural foods, and injections based on the neutralizing dose. He would like for these injections to be given in your office, which is close to his home. Which of the following statements is the best approach to this situation?
a. Administer the injections as directed by the other physician.
b. Explain that this form of testing and these methods of treatment are not used in your practice. Inform him that he may wish to seek a second opinion before beginning this course of treatment.
c. Perform prick skin testing to inhalants and foods. Perform selected intradermal tests.
d. Tell him that the other physician is clearly a charlatan, that the methods used are experimental, and that the other physician should be reported to the state licensing agency. Refer the patient directly to a psychiatrist.
e. Exclude immunodeficiency by checking lymphocyte subsets by cytofluorometry, as well as mitogen and antigen stimulation.

Answers:

1. A
2. C
3. D
4. B
5. B

November 26, 2003

Pediatric Asthma, CF, RSV & Croup by Jay M. Portnoy, M.D.

1. A 12-year-old has difficulty breathing with exercise. Symptoms consist of substernal pain, difficulty breathing in, a seal-like wheezing sound, and very little coughing. Pretreatment with albuterol gives some relief. Rest and drinking water helps.

The most likely diagnosis is:
A. Exercise-induced asthma
B. Vocal cord dysfunction
C. Hyperventilation
D. Chest wall pain
E. GE reflux

2. Which describes the typical findings in “Early Wheezers”?
Lung function at birth  9 month IgE 6 year IgE Maternal Asthma
A. Low Low Elevated Present
B. Low Low Low Present
C. Low Elevated Elevated Not Present
D. Low Low Low Not Present
E. Low Elevated Elevated Present

 
3.
Which is true about RSV infection?
A. Production of IL-11 is decreased in infected cells.
B. The ratio of IFN-gamma/IL-4 is increased in RS- infected cells stimulated by PHA.
C. The PD20 decreases more in atopic than nonatopic individuals who become infected.
D. There are increased numbers of CD19 and CD8 cells.

4. A true statement about cystic fibrosis is:
A. The most common CFTR mutation is abbreviated ΔF508.
B. It is most prevalent in Native Americans.
C. Adults generally have lower sweat chloride concentrations than children.
D. All genotypes are associated with pancreatic insufficiency.

5. Risk factors for asthma death include all but which one?
A. History of respiratory failure requiring ventilation
B. Increase in steroid dosage 50 percent one month before attack
C. Family dysfunction
D. Reaction to separation or loss
E. Hopelessness within one month before attack

Answers:
1. B 
2. D
3. C
4. A
5. B


November 12, 2003
Occupational Asthma, Hypersensitivity Pneumonitis, Sarcoidosis and Interstitial Pneumonitis by
Emil J. Bardana, Jr., M.D.

1. All of the following chemicals have been reported to cause reactive airways dysfunction syndrome (RADS) EXCEPT:

A. Anhydrous ammonia
B. Chlorine gas
C. Carbon dioxide
D. Phosgene
E. Toluene diisocyanate

2. All of the following agents have been shown to cause both occupational asthma and hypersensitivity pneumonitis EXCEPT:

A. Toluene diisocyanate
B. Trimellitic anhydride
C. Micropolyspora faeni
D. Bacillus subtilis
E. Diphenylmethane diisocyanate

3. Three weeks ago, a 28-year-old woman developed large subcutaneous nodules over the pretibial area of both lower extremities which are quite tender. There is prominent bilateral hilar adenopathy on chest x-ray. The most likely diagnosis is:

A. Hypersensitivity pneumonitis
B. Lymphomatoid granulomatosis
C. Organic dust toxic syndrome
D. Sarcoidosis
E. Leukocytoclastic vasculitis

4. A 52-year-old farmer presents with paroxysmal cough, breathlessness, polymyalgia and malaise after extensive cleaning of his hay barn. Examination reveals temperature of 38.6 degrees Celsius and bibasilar crepitant rales. The chest roentgenogram is normal. Hemogram reveals leukocytosis with a predominance of polymorphonuclear leukocytes. Spirometry reveals a restrictive pattern. Precipitating antibody to which of the following antigens would be MOST helpful in establishing a diagnosis?

A. Micropolyspora faeni
B. Alternaria tenuis
C. Aspergillus clavatus
D. Cryptostroma corticale
E. Penicillium frequentans

5. Therapeutic agents that can cause interstitial pneumonitis include all of the following, EXCEPT:

A. Nitrofurantoin
B. Amiodarone
C. Danocrine
D. Bleomycin
E. Methotrexate

ANSWERS:
1. C
2. C
3. D
4. A
5. C

October 29, 2003

The Nuts and Bolts of Allergy & Immunology Laboratory Testing
By Rohit K. Katial, M.D.

1. A 35-year-old man presents with a history of episodic subcutaneous swelling, colicky abdominal pain lasting 1-3 days and at times associated with nausea and vomiting. The abdominal pain occurs independent of the swelling. He has also had episodes of throat swelling. General chemistries normal, along with normal ECG, CxR, and UA.

Which of the following tests is most likely to be abnormal in this patient:

A. CH50
B. C3 level
C. C4 level
D. C5 level
E. IgE level

2. A 15-year-old student develops dyspnea and cough. CxR revealed cotton ball densities. Needle aspiration of the densities revealed Aspergillus fumigatus. Past history was also significant for Pseudomonas infections. The patient seemed to recall similar infections in some of his siblings. A DHR assay was run on the patient and his siblings. The results are shown below.

Match the flow pattern most consistent with the appropriate mode of inheritance.

I. ___________ XL CGD
II. ___________ XL CGD carrier
III. ____________ autosomal recessive CGD
 

  A)  
  B)  
  C)  



3. Match the different molecular causes of autosomal recessive SCID with the corresponding cellular profile seen with lymphocyte enumeration.

I. Very low CD3+/CD56+ and CD19+ cells normal or increased
II. Very low CD3+/CD19+/CD56+
III. Very low CD3+/CD19+, normal CD56+
IV. Very low CD3+, normal CD19+/CD56+

A. Jak 3 gene mutations
B. RAG1 or RAG2 mutations
C. IL7R gene mutations
D. ADA mutations

4. A 56-year-old male is golfing on a spring day and begins to experience shortness of breath followed by loss of consciousness. His friend thinks he may have been stung by a bee but is not certain. He is rushed to the emergency room within one hour and is treated with fluid resuscitation, epinephrine, and an H1 blocker. He improves. The emergency room physician consults you to ask if there is any blood work that would help determine if this was anaphylaxis. Which of the following laboratory tests is most likely to be abnormal?

A. Serum histamine
B. Urine histamine
C. Urine N-methyl histamine
D. Serum tryptase
E. Serum chymase

5. Antibodies to polysaccharides in humans are most likely to be which one of the following isotypes?

A. IgG1
B. IgG2
C. IgG3
D. IgG4
E. IgA2


Answers:
1. C
2. I – B
II – C
III – A
3. I – A
II – D
III – B
IV – C
4. D
5. B


October 15, 2003
Endocrine Disorders and Churg Strauss Vasculitis
by James R. Baker, Jr., MD

1. A Immune mechanism underlying type 1 diabetes include all of the following except:
A. Amylase antigen recognition
B. T cell (CD8) cytotoxicity
C. Beta cell apoptosis
D. Immune complex injury of the pancreatic islets
E. Autoantibody production

2. All these autoimmune diseases are similar in their pathogenesis except:
A. Type I diabetes
B. Addision’s Disease
C. Atrophic gastritis
D. Graves disease
E. Hashimoto’s disease

3. Patients with autoimmune thyroid disease display immune responses to which of the following autoantigens:
A. Na+ H+ ATPase
B. Glutamic acid decarboxylase
C. Myelin Basic protein
D. Peroxidase enzyme
E. Insulin

4. Fas antigen mediated apoptosis is:
A. Mediated by soluble TNF
B. Different in morphology from necrosis
C. Occurs only in diabetes
D. Restricted to immune cells
E. Mediated by CD4 cells

5. Match the antigen and the disease:
A) GBM                     i) Goodpasture’s DX
B) Na+ I- transporter ii) Graves diseases
C) C3                      iii) Addison’s Disease
D) TSH receptor        iv) lupus nephritis
E) 21 hydroxylase      v) thyroiditis

6. Features of Churg Strauss vasculitis can include all of the following EXCEPT:
A. Glomerulonephritis
B. Cerebrovascular accident
C. Arthralgias
D. Abdominal pain
E. Hypogammaglobulinemia

Answers:
1. D
2. D
3. D
4. B

October 1, 2003
Skin Disorders: The Skin Also Rises
Atopic and Contact Dermatitis, Urticaria and Angioedema, by Mark Boguniewicz, M.D.

1. A 62-year-old male is sent to you for consultation of an eczematous rash on his chest. He reports that the rash has been present for approximately eight years. It is quite pruritic leading to incessant scratching that has resulted in secondary infections a number of times. He has been treated with topical corticosteroids as well as oral antibiotics with only partial improvement. His past history is negative for childhood eczema, asthma or allergies. He is otherwise in good health. On physical examination, he has a large indurated plaque on the lateral aspect of his trunk with excoriations, but no pustules or vesicles. No other cutaneous lesions except for a few pigmented nevi. His toenails are dystrophic, but otherwise, his nails show no pitting. He has no lymphadenopathy. The remainder of the exam is unremarkable.

The most appropriate step in the management of this patient would be:

A. Patch test the patient.
B. Start the patient on prednisone 60 mg for 10 days, followed by a gradual taper.
C. Biopsy the skin lesion.
D. Prescribe a sedating antihistamine.
E. Obtain a scraping for fungal culture.

2. A 23-month-old male presents with an eczematous rash that has been present since approximately six months of age. Despite treatment with a topical steroid, he continues to have red, indurated lesions on his face and all four extremities. He is constantly scratching, often waking up with bloody sheets. He was breast fed for almost six months and currently is on a non-restricted age-appropriate diet. His mother suspects strawberries and chocolate as triggers and brings him to you for evaluation of food allergies.

Appropriate advice regarding this child’s atopic dermatitis and food allergies would be:

A. Food allergy has no relationship to this child’s eczema.
B. Serum RAST to foods including strawberry and chocolate would be the most sensitive test to evaluate for allergies.
C. Selected prick tests to several common food allergens could be done.
D. The child should be put on a restricted diet of rice, turkey, sweet potato and applesauce.

3. A 28-year-old female presents for evaluation of severe atopic dermatitis. She has had an eczematous rash since infancy that got better during early adolescence, but recurred during her college years. On exam, she has lichenified lesions on her eyelids, neck, as well as the flexural aspects of her extremities.

Which of the following statements would be true with respect to this patient?

A. The predominant T cell-derived cytokine from an acute lesion would be IFN-~
B. A positive prick skin test to egg protein would be definitive for food allergy-induced atopic dermatitis.
C. A skin culture from an uninvolved area of skin would grow toxin-secreting S. aureus.
D. Serum eosinophil cationic protein and major basic protein levels would be low.

4. A 38-year-old female presents for evaluation of chronic hives. She has had recurrent hives along with occasional periocular angioedema for the past 3 months that are extremely itchy, often cause her to have swelling of hands or feet and tend to last for several hours. Extensive review does not suggest any specific physical, allergen, medication or other trigger. Review of systems is unremarkable. Examination reveals several raised, blanching erythematous lesions on the trunk and legs.

The true statement regarding this patient is:

A. Patient’s serum complement 4 level will be low.
B. Patient’s lesions are likely associated with a hidden allergen in her diet.
C. Patient may have histamine-releasing IgG antibodies directed against the alpha chain of the high affinity IgE receptor on mast cells and basophils.
D. Patient has an autosomal dominant disease.

5. A 43-year-old female presents with an 18-month history of chronic periocular dermatitis. She describes her rash as extremely itchy with red, scaling lesions and occasional oozing that is worse in the winter months, but is present all year. She has been using an over-the-counter topical steroid. She has a history of seasonal allergic rhinitis. On examination, she has eczematous lesions with induration of the upper and lower eyelids and injected conjunctivae.

The most appropriate recommendation would be:

A. Prescribe steroid eye drops.
B. Prescribe a more potent topical steroid for 14 days, then resume the low potency steroid.
C. Have the patient try an antifungal cream in the a.m. and a topical nonsteroidal cream in the p.m.
D. Patch testing.

Answers:
1. C
2. C
3. C
4. C
5. D

September 17, 2003

Anaphylaxis – Drug, Insect, Food & Vaccine Reactions, Prepared by Mark S. Dykewicz, MD

1. Which of the following is true?
A. Recent food ingestion promotes episodes of exercise-induced anaphylaxis in approximately 50 to 60 percent of patients.
B. H-2 receptor antagonists are more effective than H-1 receptor antagonists in blunting diastolic hypotension induced by intravenous histamine.
C. In most patients, plasma histamine levels remain elevated for 60 to 90 minutes after the onset of anaphylaxis.
D. Serum tryptase levels generally peak within 30 minutes after the onset of IgE-mediated anaphylaxis.

Comparison Questions

A. Systemic mastocytosis
B. Idiopathic anaphylaxis
C. Both
D. Neither

2. Associated with elevated serum total IgE levels.

3. Elevated urine histamine levels during acute episodes.

4. Elevated plasma histamine levels between acute episodes.

5. May be associated with increased numbers of mast cells on bone marrow biopsy.

6. May be associated with myelofibrosis on bone marrow biopsy.

7. All of the following are true about aspirin sensitivity EXCEPT:
A. Most aspirin-sensitive patients can tolerate sodium salicylate.
B. Naso-ocular reactions to aspirin are associated with increases in histamine in nasal lavage fluid.
C. Successful "desensitization" to aspirin will not induce tolerance to ibuprofen.
D. Airway reactivity to LTE4 is increased in patients who develop respiratory reactions to aspirin.
E. Acute reactions to aspirin may be associated with elevated serum tryptase levels.

8. Which one of the following is true about stinging insect allergy?
A. There is considerable allergenic cross reactivity between yellow jacket and hornet venom.
B. A skin test concentration of 0.1 ug/ml of honey bee venom may give an irritant reaction.
C. The major allergenic constituent of honey bee venom is mellitin
D. Immunotherapy with whole body extracts of fire ants is ineffective at preventing recurrent anaphylaxis.
E. Wasps typically leave a stinger at a sting site.

9. Which one of the following statements about food reactions is NOT correct?
A. Most patients with cow’s milk allergy will be allergic to goat’s milk.
B. Ragweed allergy is associated with a higher risk of allergy to honeydew.
C. Most patients with allergy to one tree nut will also be allergic to another tree nut.
D. Allergy to cantaloupe is associated with an increased risk for allergy to avocado.
E. Birch pollen allergy is associated with a higher risk of allergy to apple.

Answers:
1. A
2. D
3. C
4. A
5. A
6. A
7. C
8. A
9. C


September 3, 2003

Topic: Statistics in Clinical Medicine
Prepared by Joyce Hershey, Research Associate,
Walter Reed Army Medical Center, Washington, D.C.

1. A recent study* evaluating commercial in-vitro tests for latex-specific IgE antibodies tested 143 subjects with or without latex allergy (as defined by a combination of history and skin testing to latex — the gold standard) by an in-vitro assay. Here are the results:

o 66 subjects with latex allergy tested positive in the in-vitro assay
o 17 subjects with latex allergy tested negative in the in-vitro assay
o 6 subjects without latex allergy tested positive in the in-vitro assay
o 54 subjects without latex allergy tested negative in the in-vitro assay

Prepare a 2 x 2 table and answer the following questions:

a) What is the sensitivity of the in-vitro assay?

b) What is the specificity of the commercial skin prick test?

c) What is the prevalence of actual disease in this population?

d) What is the positive predictive value (PPV)?

e) What is the negative predictive value?

f) What is the diagnostic accuracy (efficiency)?

g) What is the likelihood ratio for a positive test?

h) What is the likelihood ratio for a negative test?


2. Calculate the PPV of a test that has a sensitivity of 94%, a specificity of 78% for a disease with a population prevalence of 20%.

3. What would the PPV be if the prevalence was 80%?

4. Given the 2 x 2 table below, match the following:


Disease +     Disease -             Total
Test  + a (true positive)   b (false positive)    a + b
Test   - c (false negative)   d (true negative)   c + d
Total   a + c            b + d        a + b + c + d
 

a. Sensitivity
b. Specificity
c. Prevalence
d. PPV
e. NPV
f. Diagnostic accuracy
i. (a + c) / (a + b + c + d)
ii. a / (a + b)
iii. (a + d ) / (a + b + c + d)
iv. a / (a + c)
v. d / (b + d)
vi. d / (c + d)

ANSWERS:
1.
a. 79.5%
b. 90%
c. 58%
d. 91.7%
e. 76.1%
f. 83.9%
g. ~8
h. 0.23

2. ~52%
3. ~95%
4.
a. (iv)
b. (v)
c. (i)
d. (ii)
e. (vi)
f. (iii)

*Ownby DR et al. A blinded, multi-center evaluation of two commercial in vitro tests for latex-specific IgE antibodies. Ann Allergy Asthma Immunol. 2000, 84:193-196.


August 20, 2003
Topic: Immunization Update
By: Renata J. M. Engler, M.D.
Walter Reed National Vaccine Healthcare Center
Allergy-Immunology Department, Walter Reed Army Medical Center
Uniformed Services University of the Health Sciences

1. Only which of the following advances exceeds the health and quality of life benefits of immunization programs during the past 200 years?
a. Penicillin and other antibiotics
b. Intensive care, including respirators and cardiovascular surgery
c. Clean water sources and waste disposal
d. Access to health care services
e. Insect control

2. Which vaccines does the Vaccine Injury Compensation Act cover for patients of all ages?
a. Smallpox vaccine
b. Anthrax vaccine
c. Vaccinia vaccine
d. Hepatitis B vaccine
e. Rabies vaccine

3. A mother presents with the chief complaint that her child had a local reaction greater than 6 cm in diameter to the second dose of hepatitis B vaccine with some fever and swollen glands. She wants an exemption from the next dose of vaccine because she thinks her child does not need the third dose and may have more serious reactions. Which of the following is a true statement?
a. The child should receive the third dose of hepatitis B strictly adhering to the schedule recommended by the Advisory Committee on Immunization Practices.
b. The reaction described is normal and not a contraindication for further immunization.
c. There is no way to determine whether or not a third dose of vaccine is needed and the only option is to administer the third dose of hepatitis B for full protection.
d. Hepatitis B surface antibody can be measured and if strongly positive (> 100 IU/ml) suggests the child is a high responder and may not need a third dose of vaccine for many years.
e. A negative hepatitis B core antibody level suggests that the child needs the third dose of hepatitis B vaccine.

4. Anaphylaxis with vaccines occurs at an increased rate with which of the following vaccines?
a. Tetanus-diphtheria
b. Japanese encephalitis
c. Typhoid Vi
d. Anthrax
e. Pneumococcal

5. Which of the following smallpox vaccine reactions is NOT preventable through proper screening and education of patients prior to vaccine administration?
a. Ophthalmologic vaccinia infection
b. Eczema vaccinatum
c. Progressive vaccinia
d. Cellulitis surrounding the primary vaccination site
e. Encephalitis

6. Atopic dermatitis is a risk factor for which of the following smallpox vaccine complications?
a. Pericarditis
b. Toxic erythema
c. Cellulitis
d. Scarring at vaccine site
e. Eczema vaccinatum

7. Which of the following vaccine components is most likely the cause of an anaphylactic reaction to measles, mumps, and rubella vaccination?
a. Gelatin
b. Egg protein
c. Neomycin
d. Thimerosal
e. Phenol

8. Which of the following passive immunizations does not interfere with the efficacy of the measles vaccine 1 month later?
a. Intravenous immune globulin
b. Monoclonal antibody to respiratory syncytial virus
c. Hepatitis B hyper-immune globulin
d. Rabies hyper-immune globulin
e. Hepatitis A immune globulin therapy

9. Anthrax vaccine contains which of the following adjuvants associated with prominent local reactions when administered by the subcutaneous route?
a. Phenol
b. CPG DNA
c. Aluminum hydroxide
d. Freund’s adjuvant
e. Thimerosal

10. Which of the following vaccines is absolutely contraindicated in patients with isolated humoral immunodeficiency disease (intact T-cell functional immunity)?
a. Vaccinia
b. Varicella
c. Influenza
d. Hemophilus influenza type B- protein conjugated
e. All of the above

11. Which of the following vaccines are live vaccines? (More than 1 answer possible)
a. Oral typhoid
b. BCG
c. Tetanus-diphtheria
d. Rabies
e. Hepatitis A
f. Hepatitis B
g. MMR
h. Varicella
i. Influenza
j. Typhoid

ANSWERS:
1. c
2. d
3. d
4. b
5. e
6. e
7. a
8. b
9. c
10. a
11. a/b/g/h

August 6, 2003
Topic: Immunotherapy
1) The purpose of standardized allergen extracts is to:
A. Provide pharmaceutical-grade extracts with minimal lot-to-lot variability that can be interchanged without risk of adverse reactions in immunotherapy
B. Provide extract with clinically irrelevant components removed
C. Lessen the variability in potency from manufacturer-to-manufacturer, and lot-to-lot
D. Assign meaningful potency units to allergen extracts in a manner that reflects the allergen content of extracts
E. Develop a single worldwide system for assigning potency units to allergen extracts

2) To minimize loss in potency, allergen extracts:
A. Should be diluted and stored at room temperature
B. Should be diluted in normal saline with phenol used as a preservative
C. Should be mixed with fungal or dust mite extracts containing significant protease activity
D. Should be stored in the refrigerator in the most concentrated form available
E. Should be standardized

3) The proper maintenance dose of immunotherapy for an individual patient:
A. Must be individualized
B. Requires life-long administration for persistent resolution of symptoms
C. May be determined by titrated intradermal skin testing prior to the start of injections
D. May be determined from published immunotherapy studies using standardized extracts with known major allergen content
E. May be determined by results of quantitative allergen-specific IgE immunoassays performed prior to the start of injections

4) Immunotherapy in asthma:
A. Is contraindicated due to evidence demonstrating minimal efficacy and high prevalence of severe side effects
B. Has been shown to produce symptomatic improvement in double-blind, placebo-controlled trials
C. Primarily benefits the associated rhinitis symptoms
D. Requires lower doses than those needed in rhinitis
E. Produces a clinical effect primarily by augmenting the Th2 cytokine response to lymphocyte stimulation

5) Controversial treatments for allergic diseases include:
A. Autologous urine injection
B. Immunotherapy for allergy mediated by allergen-specific IgG
C. Elimination diets and antifungal therapy for excessive yeast growth
D. Sublingual administration of chemicals to which the patient has been shown to be allergic
E. All of the above

Answers:
1. C
2. D
3. A
4. B
5. E


July 23, 2003
Topic: Aerobiology

Match the allergens with the appropriate characteristic
A. Cyn d 7 from Bermuda grass
B. Pol p 4 from paper wasp
C. Per a 7 from American cockroach
D. Lol p 1 from perennial ryegrass pollen

1. A minor allergen with calcium-binding properties with homology to Bet v 4
2. A tropomyosin with cross-reactivity with shrimp allergen
3. A serine protease
4. A papain-like cysteine protease with beta expansin activity

5. Which of the following statements concerning environmental control of indoor allergens is correct?
A. Tristan de Cunha islanders born at least one year after the removal of all cats from the island show no sensitization to Fel d 1
B. Synthetic fiber pillows will show slower accumulation and lower absolute levels of Der p 1 than down feather pillows
C. A meta-analysis of 23 house dust mite control measures in the management of asthma revealed no impact on PEFR or standardized asthma symptom improvement
D. In European homes with atopic children, mold growth could not be correlated with PEFR variability
E. None of the above

6. Which of the following statements concerning arthropod inhalant allergy is FALSE
A. In the absence of special cleaning efforts, German cockroach extermination does not impact on Bla g 1 or Bla g 2 levels in single-family homes within the first 6 months
B. The majority of airborne particles carrying Bla g 1 in undisturbed rooms are under 10 microns in size
C. Reducing the mean daily relative humidity below 50%, even with levels greater than 50% for 2-8 hours, restricts D. farinae population growth
D. Large local reactions to mosquito bites in small children appear to be mediated by IgE and IgG conjointly

Cross-reactivity between each of the following pairs is due to which substances?
A. Zucchini and melon
B. Birch and celery
C. Both
D. Neither

7. Profillin and carbohydrate determinants
8. Bet v 1, Bet v 2, and 40-60 kilodalton molecules

Match the correct fungal allergens with the following statements
A. Enolase
B. Acid ribosomal protein P2
C. Both
D. Neither

9. Major Cladosporium and Alernaria allergens Cla h 6 and Alt a 11
10. Highly conserved human SLE antigen which is Alt a 6 and Cla h 4

Answers:
1. A
2. C
3. B
4. D
5. C
6. B
7. A
8. B
9. A
10. B


July 9, 2003
Topic: Allergy and Pulmonary Function Testing Methods
1. A 36-year-old female patient presents as a new patient because of a recent change in insurance. She wished to continue allergen immunotherapy for allergic rhinitis, and you have chosen to repeat her skin testing. Modified prick tests are negative to a variety of pollens, danders, mites and other inhalant allergens. The histamine control produced a wheal 5 mm in diameter with a flare of 26 mm. She is astonished because skin testing done only 6 months previously showed positive skin test reactions to nearly everything tested. Past medical records are unavailable for review. Which of the following is the most likely for this predicament?

A. She is dermographic
B. In the previous testing, the test sites were too close together (<2 cm)
C. She has had an immunologic response to immunotherapy that has resulted in suppression of her previously positive tests
D. She forgot to mention that she has taken an OTC cold preparation that contains an antihistamine
E. She was previously tested on the upper back, but you had chosen to repeat testing on her forearm

2. A 16-year-old cheerleader reports daily episodes of shortness of breath and wheezing not related to exercise. On forced expiratory spirometry, the FVC is 105% of predicted and the FEV1 is 102% of predicted. After nebulization of 2 mg of albuterol, the FEV1 increases to 104% of predicted. Review of a diary of symptoms and peak expiratory flow measurements show no drop in peak flow when symptoms are present and no diurnal variation in peak flow. Symptoms, however, seem to be improved within 45 minutes of using albuterol from a metered dose inhaler. A methacholine challenge is performed and the concentration of methacholine producing a 20% decrease in baseline FEV1 is reported as 15mg/ mL. Which of the following statements is most appropriate?

A. She has asthma, and in accordance with published guidelines should be placed on a controller medication with a short-acting beta agonist for symptom relief.
B. She has a degree of methacholine reactivity that is present in the normal population. Asthma therapy does not appear to be appropriate, but she should be evaluated for other causes of shortness of breath and wheezing while maintaining close follow-up.
C. There would be no need to check the test solutions used in order to determine when they had been reconstituted and how they had been stored after reconstitution.
D. The methacholine challenge should be repeated using a dosimeter and a cumulative breath unit protocol.
E. This degree of methacholine reactivity is concerning because of studies that have shown that such individuals are at high risk of developing overt asthma in long-term follow-up.

3. A 47-year-old man reports progressively severe malaise and fatigue, headaches, dizziness, and difficulty thinking. He notes that symptoms began several months after a large quantity of cleaning solvent was spilled at his workplace. Now, various chemical, tobacco smoke, polyester clothing, food additives, and chlorinated drinking water aggravate his nearly constant symptoms. His suspicions have been confirmed by provocation-neutralization testing, and he wishes to begin treatment which consists of isolation from his modern environment, a rotating diet of natural foods, and injections based on the neutralizing dose. He would like for these injections to be given in your office, which is close to his home. Which of the following is the best approach to this situation?

A. Administer the injections as directed by the other physician.
B. Explain that this form of testing and these methods of treatment are not used in your practice. Inform him that he may wish to seek a second opinion before beginning this course of treatment.
C. Perform prick skin testing to inhalants and foods. Perform selected intradermal tests.
D. Tell him that the other physician is clearly a charlatan, that the methods used are experimental, and that the other physician should be reported to the state licensing agency. Refer the patient to a psychiatrist.
E. Exclude immunodeficiency by checking lymphocyte subsets by cytofluorometry, as well as mitogen and antigen stimulation.

4. In which of the following situations would measurement of the total IgE level be appropriate?

A. A 12-year-old boy with perennial clear rhinorrhea, nasal and ocular pruritus and bouts of sneezing.
B. A 42-year-old woman with daily urticaria, except when taking antihistamines, for the past 6 months.
C. A 40-year-old man with asthma, a history of recurrent upper lobe pulmonary infiltrates, and a positive skin test to Aspergillus fumigatus.
D. A 4-month-old girl with vomiting after feedings.
E. A 28-year-old man with chronic rhinitis and a nasal smear positive for eosinophils. Allergy skin tests are negative with appropriately positive controls.

5. A 37-year-old woman presents for evaluation of severe steroid-requiring asthma. At a time when she is not having symptoms, her flow-volume loop is normal. Several nights later, she presents to a local ER in severe respiratory distress. Her flow-volume loop shows markedly reduced inspiratory and expiratory flow with a flat inspiratory loop. Which of the following is the most likely explanation for these findings?

A. Severe intermittent asthma causing variable intra-thoracic obstruction.
B. A laryngeal polyp causing variable intra-thoracic obstruction.
C. A bronchogenic cyst causing fixed intra-thoracic obstruction.
D. Vocal cord dysfunction syndrome causing variable extra-thoracic obstruction.
E. Vocal cord dysfunction syndrome causing variable intra-thoracic obstruction.

Answers:
1. A
2. B
3. B
4. C
5. E

June 25, 2003

Topic: Immunohematologic Disorders

1) A 19-year-old male student presents to your office complaining of weakness and exertional shortness of breath. Approximately 10 days ago, he had the onset of a sore throat, fever, and headache. Physical examination: pale young man. Throat injected. Cervical adenopathy. Spleen palpable just below the left costal margin. Lab: Hct=19, WBC=6000. Atypical lymphocytes on blood smear. Some red cells clumped. UA – red brown color, Hemoglobin +. DAT +. Which of the following is likely NOT to be present in this patient?

A. The DAT test will be positive for only C3.
B. The cold agglutinin may show specificity for the small I antigen.
C. The cold agglutinin is usually a monoclonal IgM.
D. Cold agglutinin titer may be positive only with cord red blood cells.
E. Haptoglobin will be low.

2) Match the following autoantibodies with the clinical disorder:
 

1. Anti-neutrophil antibodies A. Chronic cold hemagglutinin disease
2. Monoclonal IgM antibodies B. Felty’s syndrome
3. Anti-protease antibody C. Warm type autoimmune hemolytic anemia
4. IgG antibodies to antigens in Rh complex D. Thrombotic thrombocytopenic purpura
5. Donath-Landsteiner antibody E. Paroxysmal cold hemoglobinuria

3) Match the following clinical features with the clinical disorders:

1. Carpal tunnel syndrome A. Multiple myeloma
2. Streptococcal pneumonia B. Gamma heavy chain disease
3. Hyperviscosity syndrome C. Amyloidosis
4. Red cell aplasia D. Waldenstrom’s macroglobulinemia
5. Palatal edema E. Thymoma

4) All of the following are true regarding patients with essential mixed cryoglobulinemia EXCEPT:

A. The serum C4 is elevated.
B. Rheumatoid factor is positive.
C. HCV RNA is frequently present in the serum.
D. Presence of glomerulonephritis.
E. IgM-IgG is most often found in the cryoglobulin.

5) Match the following features with the clinical disorders below:

1. Chronic neutropenia A. Burkitt’s leukemia/lymphoma
2. Philadelphia chromosome B. Hairy cell leukemia
3. Epstein Barr virus C. Large granular lymphocytic leukemia
4. Vasculitis D. Chronic lymphocytic leukemia
5. CD19+, CD20+, CD22+, CD23+, CD5+ E. Chronic myelogenous leukemia

6) All of the following are true regarding immune thrombocytopenia EXCEPT:

A. Can be a presenting feature of systemic lupus erythematosus.
B. Heparin induced thrombocytopenia may be associated with life threatening vascular occlusion.
C. Can occur in HIV infection.
D. In ITP, the anti-platelet antibody is directed to platelet factor 4.
E. In young children, ITP is usually acute and self limited.

Answers: 1) C
2) 1=B, 2=A, 3=D, 4=C, 5=E
3) 1=C, 2=A, 3=D, 4=E, 5=B
4) A
5) 1=C, 2=E, 3=A, 4=B, 5=D
6) D


June 15, 2003
Topic: Mucosal Immunity and Food Allergy

1) The dominant response in the gut-associated lymphoid tissue is suppression or tolerance. The means by which the immune system is ‘educated’ to avoid sensitization to ingested food antigens is not completely understood, but recent investigations indicate that which of the following may be the central antigen presenting cell used for generation oral tolerance in the gut?
A. Intestinal M cells
B. Intestinal epithelial cells (IECs)
C. Intestinal Langerhans cells
D. Kupffer cells in the liver

2) A 19-year-old female undergraduate student is transported to a local ER for the management of anaphylactic shock. She has a significant past medical history of peanut allergy. Apparently, she ingested a dessert at a party that contained peanuts. All of the following are risk factors for fatalities resulting from an anaphylactic reaction to a food allergen EXCEPT:
A. Previous or current medical history of severe atopic dermatitis
B. History of previous severe reactions due to food allergy
C. Denial of symptoms or failure to recognize an allergic reaction
D. Lack of use and/or delay in the use of injectable epinephrine
E. Concomitant history of asthma and food allergy

3) You are asked to consult with a family of a child with a significant past medial history of moderate to severe atopic dermatitis and presumed allergic reactions to egg, cow milk, and peanut. There has been a strong clinical suspicion that these foods have contributed to skin symptoms as well as adverse respiratory and GI symptoms. No confirmatory oral food challenges have been undertaken. The child’s diet has been significantly restricted and the family is very interested in confirming which food(s) really need to be continually eliminated from the diet. In counseling this family, which of the following methods would provide the best predictive information regarding the likelihood of a positive clinical reaction during an oral food challenge with one of these food allergens?
A. Standard epicutaneous (puncture/prick) skin testing
B. Standard RAST testing
C. Pharmacia ImmunoCAP RAST system
D. Diet and symptom diary
E. Two-week elimination diet

4) A 35-year-old patient seeks your medical opinion regarding his long-standing history of allergic reactions to peanuts. As a teenager, he experienced two separate episodes of generalized urticaria, laryngeal edema and emesis. The first episode followed the ingestion of dry roasted peanuts and the second episode occurred after the ingestion of a peanut butter candy. Allergy skin testing at that time revealed positive responses to multiple related legumes including soy, green pea, green bean, and chick pea. He was told to completely restrict all legumes from his diet. Over the past year, he has been interested in following a vegetarian diet, but is limited because of his current dietary restrictions. What advice can you provide regarding the relevant percentage of clinical cross-reactivity between peanut and other related legumes?
A. 0%
B. <5-10%
C. 30-50%
D. 50-75%
E. 100%

5) A local pediatrician refers to your practice an 18-month-old patient with a history of a recent, severe and generalized allergic reaction following the administration of a group of vaccines in his office. The patient received the MMR, DtaP, and Varicella vaccines on the same day. The infant patient has a fairly unremarkable past medical history except for very mild, limited atopic dermatitis that has on occasion flared with the ingestion of egg-containing foods. There is no history of severe anaphylactic reactions following the ingestion of egg or egg-containing foods. An allergic sensitivity to which vaccine ingredient is the most likely explanation for this patient’s reaction and is the most likely predisposing factor to other allergic reactions to vaccines containing this ingredient?
A. Gelatin
B. Chicken egg
C. Neomycin
D. Mercury
E. Thimerosol

Answers:
1)B
2) A
3) C
4) B
5) A

May 28, 2003

Topic: Immunopharmacology II

Of the following statements (#1-#9), select the appropriate answer

A. Azathioprine B. Cyclophospamide
C. Both D. Neither

1) Is a purine analog related to 6-mercaptopurine
2) Does not appear to have major effects on T cell proliferation and established delayed hypersensitivity reactions
3) Liver function tests should be performed regularly to detect hepatotoxicity
4) Is an alkylating agent related to nitrogen mustard
5) Granulocytopenia is the most common dose-related hematologic toxicity
6) Is an absolute contraindication in pregnant women
7) Hair loss is common
8) Patients with a history of daily administration require life-long surveillance for bladder cancer
9) The principle pathway of detoxification of the drug(s) is inhibited by allopurinol

10) Match the interferon or interleukin listed below with the appropriate clinical indication

i. INF- ii. INF-
iii. INF- iv. IL-2
v. GM-CSF vi. IL-12
   .
A. Advanced renal cell carcinoma
B. Peripheralize progenitor cells for autologous peripheral blood transplantation
C. Hepatitis C
D. Hairy cell leukemia
E. Multiple sclerosis
F. AIDS-related Kaposi’s sarcoma
G. Advanced melanoma
H. CGD
I. Reduce neutropenia associated with chemotherapy
J. Intracellular microbial pathogens


Answers:
1) A
2) A
3) A
4) B
5)C
6) B
7) B
8) B
9) A
10) A=4, B=5, C=1, D=1, E=2, F=1, G=4, H=3, I=5, J=6


May 12, 2003
Topic: Immunopharmacology I

1) Identify the most inclusive statement about complications of therapeutic apheresis
A. May be complicated by hemorrhage, infection, and hypotension
B. May be complicated by paesthesias, cramps, tetany, seizures, prolonged QT interval, arrhythmiasC. May be complicated by infection, hemorrhage, hypotension, vasovagal reactions, hypokalemia
D. May be complicated by decreased circulating erythrocytes, decreased circulating platelets, hemorrhage, infection, and hypotension
E. All of the above

2) True statements about methotrexate include all of the following EXCEPT
A. Methotrexate is a folic acid antagonist
B. Methotrexate administration may be accompanied by anaphylactic reactions, even on the first known exposure
C. Routine pulmonary function testing may be used to identify patients who subsequently develop drug-induced pulmonary disease
D. Risk factors for liver toxicity include IDDM, morbid obesity, renal insufficiency, alcohol consumption, daily or several doses per week and cumulative dose of methotrexate
E. Liver biopsy recommended for patients who develop persistent liver function abnormalities as detected by blood test

True or False
3) Glucocorticoids inhibit production of pro-inflammatory cytokines IL-1, IL-6, TNF-, and decrease the transcription of other cytokines and chemokines

4) Glucocorticoids have no indirect effects on mast cells

5) Glucocorticoids exclude neutrophils from inflammatory sites by decreasing the vascular endothelial cell expression of ICAM-1 and ELAM-1

6) IVIG inhibits B cell function and antigen presenting cells via Fc receptor

7) IVIG is not able to neutralize toxin superantigens

Answers:
1)E
2) C
3) T
4) F
5) T
6) T
7) F

April 30, 2003
Topic: Allergic Skin Diseases

1) Which one of the following is a pre-formed skin mast cell mediator
A. LTC4
B. Chymotrypsin
C. PGD2
D. AGEPC (platelet activating factor)
E. LTB4

2) Which of the following symptoms is LEAST characteristic of urticarial vasculitis
A. Pruritis
B. Burning
C. Stinging
D. Soreness
E. Arthralgia

3) Which statement concerning urticaria and the role of foods is TRUE
A. Urticaria is frequently caused by a combination of foods that individually will not cause hives
B. The season of the year may contribute to which foods cause hives
C. Pork should be eliminated from the diet in urticarial patients allergic to pigweed
D. Foods that cause urticaria are usually obvious to the patient

4) There are 2 types of allergic reactions to latex: IgE mediated allergy and allergic contact dermatitis. Which of the following agents would not be expected to be positive on patch testing in a patient with an allergic contact dermatitis to latex
A. Mercapto mix
B. Parabens
C. Black rubber mix
D. Mercaptobenzothiazole (MBT)
E. Thiuram mix

5) Which of the following statements regarding atopic dermatitis is FALSE
A. Atopic dermatitis is ‘an itch which rashes, rather than a rash that itches’
B. Like allergic rhinitis and asthma, AD is characterized by an imbalance in Th1 CD4+ lymphocytes that produce certain ‘pro-allergic’ cytokines
C. Staphylococcal exotoxins may act as superantigens in atopic dermatitis patients and result in the activation of as many as 40 percent of the lymphocytes without the presence of a protein antigen
D.Tacrolimus inhibits all of the following cytokines: IL-2, IL-3, IL-4, IL-5, GM-CSF, TNF-(, IFN-(
E. Tacrolimus decreases the expression of intracellular attachment molecule ICAM-1

Answers:
1) B
2) D
3) D
4) B
5) B


April 16, 2003
Topic: Rhinitis, Sinustitis, Conjunctivitis

1) Which of the following statements is INCORRECT
A. Seasonal allergic conjunctivitis is characterized by pruritus, chemosis, white stringy secretions and bilateral keratoconus
B. House dust mite sensitivity is the most common allergen implicated in perennial allergic conjunctivitis
C. Atopic kertoconjunctivitis is characterized by blepharaconjunctivitis, cataract formation, corneal scarring, and ocular herpes
D. Vernal conjunctivitis is recognized clinically by the presence of Horner’s points, Trantas dots, corneal ulcers and Dennie’s lines
E. Giant papillary conjunctivitis is found in both hard and soft contact lens wearers, and preferentially involves the upper tarsal conjunctiva

2) Which of the following statements is INCORRECT
A. M. catarrhalis is a more important pathogen for children with acute sinusitis than it is for adults
B. Over 40% of H. influenzae produced beta lactamase in 1998
C. S. pneumoniae which is highly resistant to penicillin, is usually resistant to macrolides as well
D. Currently acceptable choices for treatment of acute rhinosinusitis in children include: amoxicillin-clavulante, amoxicillin, cefpodoxime, levofloxacin
E. Currently acceptable choices for the treatment of acute rhinosinusitis in adults include: amoxicillin-clavulanate, amoxicillin, cefpodoxime, cefuroxime

3) Among the following diseases, which is the least common cause of chronic rhinosinusitis
A. Aspirin sensitivity
B. Allergic rhinitis
C. Non-allergic (vasomotor) rhinitis
D. IgG deficiency
E. Ciliary dyskinesia

4) Which of the following statements does NOT describe an observation that supports a direct link between the upper and lower airway
A. More than 90% of allergic subjects with asthma have concomitant rhinitis
B. Allergic reaction of both the nasal and airway mucosa lead to epithelial denudation
C. Nasal and airway responses to methacholine are exaggerated in allergic subjects versus normals
D. Treatment of allergic rhinitis with corticosteroids results in reduced asthma symptoms
E. Resolution of sinusitis leads to improved asthma symptoms

Answers:
1) A
2) D
3) E
4) B

April 2, 2003
Topic: HIV/AIDS

1) In the US, the segment of the population experiencing the greatest increase in HIV infections is
A. Infants 0-1 year
B. Children 2-13 years
C. Males 18-35 years
D. Females 18-35 years
E. Males 35-55 years

2) The clinical importance of chemokines and HIV infection is documented by
A. Single allele mutant chemokine receptors are observed in long-term survivors
B. MIP-1a increases HIV entry into target cells
C. CXCR4 bind to GP120 of macrophage trophic virus
D. D32 double allele mutant CCR5 receptors accelerate the progression of HIV disease
E. RANTES competitively inhibits binding of HIV to CD4+ T cells

3) The most likely cause of failure of anti-retroviral therapy of HIV infection is
A. Patient non-compliance
B. Viral resistance
C. Tissue sanctuaries
D. Non-replicating CD4+ T cells
E. High HIV burden

4) The most important immune cell in reconstitution of AIDS patients is
A. CD4+CD8+ thymocyte
B. CD19+ B cells
C. CD45A+ T cells
D. CD14+ macrophage
E. CD56+ NK cells

Answers:
1) D
2) A
3) A
4) C

March 19, 2003

Topic: Autoimmune Diseases

Topic: Immunodeficiencies

1) A 2-year-old boy and his 3-year-old sister both suffer from repeated infections of the skin, lymph nodes, and gingiva. White blood cell counts repeatedly show extremely elevated values, even when their infections subside. The mother and father are both healthy, and there is no family history of similar infections. What diagnosis is most consistent with these findings?

A. Complement component 6 deficiency
B. Selective IgA deficiency
C. Bruton’s tyrosine kinase deficiency
D. Leukocyte adhesion deficiency
E. Chronic granulomatous disease

2) A 10-month-old girl develops empyema of the lung and fistulous tract through the diaphragm, leading to peritonitis. Here serum immunoglobulins are moderately elevated, she has a 10mm Candida skin test reaction at 48 hours, normal NBT test, and a total hemoltyic complement (CH50) of 0. What laboratory test would reveal her diagnosis?

A. Mitogen stimulation of T cells
B. Adhesion glycoproteins of neutrophils
C. C3 complement component
D. Bacteriophage (fX 174) immunization
E. Immunoglobulin subclass measurement

3) Which patient has X-linked agammaglobulinemia

Phenotype

Patient 1

Patient 2

Patient 3

Patient 4

Normal

CD3

12

1525

3

5061

493-1739

CD4

22

1090

12

2671

341-1175

CD8

3

435

0

1748

138-678

CD19

2775

121

1149

7

42-302

CD20

2782

115

1171

7

57-379

Mitogen

 

 

 

 

 

PHA

191

91542

612

156099

51224-189758

ConA

685

67504

183

63739

44013-189222

PWM

111

78397

123

69022

36959-161176

A. Patient 1
B. Patient 2
C. Patient 3
D. Patient 4

4) A kindergarten school teacher is the mother of a 4-year-old boy and a 4-month-old boy, both of whom attend a nursery school during her work days. The mother has had two bouts of pneumonia within the last year, which coincide with the oldest boy’s fever and upper respiratory infection; all documented by a physician. Upon a repeated family illness, serum immunoglobulin levels, functional antibody tests, and lymphocyte subsets are obtained:

 

4-Month Old Boy

4-Year Old Boy

Mother

Serum Igs

 

 

 

IgG

250 mg/dL

610 mg/dL

275 mg/dL

IgA

10 mg/dl

50 mg/dL

15 mg/dL

IgM

45 mg/dL

75 mg/dL

40 mg/dL

Antibody Titers

 

 

 

Anti-A

1:4

1:32

1:4

Anti-B

1:2

1:16

1:2

Lymphocyte Subsets

 

 

 

CD4+

2500 cells/ul

545 cells/ul

650 cells/ul

CD8+

1250 cells/ul

275 cells/ul

305 cells/ul

CD19+

450 cells/ul

115 cells/ul

125 cells/ul

The correct diagnosis of this family’s problem is:
A. The 4-month-old has transient hypogammaglobulinemia of childhood
B. All of the family members have normal immunity
C. The 4-month-old has X-linked agammaglobulinemia (Bruton’s disease)
D.The 4-month-old has a pre-malignant disease of lymphocytes
E. The mother has a B cell deficiency

5) In terms of possible treatment with IVIG, your choice would be:
A. Treat the 4-month-old with 2-4 months of IVIG
B. Give the boys and the mother a therapeutic trial of IVIG
C. Initiate life-long IVIG for the 4-month-old
D. Give no IVIG but refer the 4-month-old to an oncologist
E. Consider giving IVIG to the mother

Answers:
1) D
2) C
3) D
4) E
5) E


March 5, 2003

Topic: Autoimmune Diseases

1) Immune mechanisms underlying type 1 diabetes include all of the following EXCEPT:
A. Antigen recognition and co-stimulation
B. T cell (CD8) cytotoxicity
C. Beta cell apoptosis
D. Immune complex injury of the pancreatic islets
E. Autoantibody production

2) All these autoimmune diseases are similar in their pathogenesis except:
A. Type 1 diabetes
B. Addison’s disease
C. Atrophic gastritis
D. Grave’s disease
E. Hashimoto’s thyroiditis

3) Patients with autoimmune thyroid disease display immune responses to which of the following autoantigens:
A. Na=H+ ATPase
B. Glutamic acid decarboxylase
C. Myelin basic protein
D. Peroxidase enzyme
E. Insulin

4) Fas antigen mediated apoptosis is:
A. Mediated by soluble TNF
B. Different in morphology from necrosis
C. Occurs only in diabetes
D. Restricted to immune cells
E. Mediated by CD4 cells

5) Match the antigen and the disease
A. GBM 1. Goodpasture’s Disease
B. Na+ I transporter 2. Graves Disease
C. C3 3. Addison’s Disease
D. TSH receptor 4. Lupus nephritis
E. 21 hydroxylase 5. Thyroditis

Answers:
1) D
2) D
3) D
4) B 
5) 1=A, 2=D, 3=E, 4=C, 5=B


February 19, 2003

Topic: Complement Deficiency and Phagocytotic Cell Deficiencies

1) Patients with CGD are unduly susceptible to which of the following microorganisms
A. Retroviruses
B. Bacteria that are catalase positive and have no net production of hydrogen peroxide
C. Bacteria that are catalase positive and have a net production of hydrogen peroxide
D. Bacteria that are catalase negative and have no net production of hydrogen peroxide
E. Bacteria that are catalase negative and have a net production of hydrogen peroxide

2) Patients with genetically determined deficiencies of C5, C6, C7, C8, or C9 are unduly susceptible to which of the following microorganisms
A. Pneumococcus
B. Streptococcus
C. Enteroviruses
D. Meningococcus
E. All of the above

3) The most common genetically determined complement deficiency is
A. C1 esterase inhibitor deficiency
B. Factor B deficiency
C. C2 deficiency
D. C3 deficiency
E. C5 deficiency

4) The diagnosis of leukocyte adhesion defect is suspected in the proper clinical setting when:
A. There is leukopenia
B. There is neutropenia
C. There is neutrophilia
D. There is both leukopenia and neutropenia
E. None of the above

5) Which statement about the cutaneous lesions of hereditary angioedema is true:
A. They are warm, pruritic and red
B. They are pale, pruritic and cool
C. They are transient within minutes
D. They are non-pruritic and pale
E. None of the above

Answers:
1) B
2) D
3) C
4) C
5) D

February 5, 2003

Topic: Occupational Asthma, ABPA, Hypersensitivity Pneumonitis

1) Match the occupation with the agent responsible for occupational asthma

1. Lens Maker
2. Detergent Worker
3. Printer 
4. Carpenter
5. Urethane Foam Worker

A. Bacillus Subtilis
B. Tragacanth
C. Grain Dust
D. Toluene Diisocyanate
E. Plicatic Acid
F. Papain
G. Psyllium

2) Match the characteristic with the disease condition

1. Precipitating antibody 
2. Decreased DLCO 
3. Elevated IgE 
4. Good response to steroids 
5. Anergy
A. ABPA
B. Hypersensitivity pneumonitis
C. Both
D. Neither

3) The immunologic basis of hypersensitivity pneumonitis appears to be:

A. Type 3 (immune complex)
B. Type 1 (IgE)
C. Type 4 (Cell mediated)
D. Combination of Type 3 and Type 4
E. Combination of Type 1 and Type 3

4) Which of the following scenarios is most indicative of sarcoidosis?

A. Restrictive pattern on PFT, increased ACE, increased T suppressor cells in BAL
B. Obstructive pattern on PFT, decreased ACE, increase in T helper cells in BAL
C. Restrictive pattern on PFT, increased ACE, increase in T helper cells in BAL
D. Obstructive pattern on PFT, increased ACE, increase in T suppressor cells in BAL

5) Which of the following is NOT characteristic of hypereosinophilia?

A. Commonly affects the heart
B. Peripheral neuropathy
C. Urticaria
D. Vasculitis
E. Predominance in males

Answers:
1) 1=F 2=A 3=B 4=E 5=D
2) 1=C 2=B 3=A 4=C 5=D
3) D
4) C
5) D


January 22, 2003
Topic: Asthma in Adults, COPD

1) Which of the following is characteristic of patients with sudden asphyxic asthma?
A. Elevated total serum IgE
B. Increased IL-4 in BAL fluid
C. Co-existent nasal polyposis
D. Neutrophilic inflammation of airway mucosa
E. Deposition of fibronectin beneath basement membrane

2) Which of the following is effective in the treatment of nicotine dependence?
A. Amitriptyline
B. Buproprion
C. Diazepam
D. Doxepin
E. Fluoxetine

3) Which of the following groups has a high prevalence of sarcoidosis in the U.S.?
A. African Americans
B. Asian Americans
C. Hispanic Americans
D. Native American
E. Irish Americans

4) The median survival after diagnosis of idiopathic pulmonary fibrosis is:
A. 3 months
B. 6 months
C. 1 year
D. 5 years
E. No effect on survival

5) Select the true statement about b-2 adrenergic receptors in asthma
A. Gene located on chromosome 11 q13
B. Gene linked to high affinity IgE receptor gene
C. Glu 27 variant associated with lower airway reactivity
D. Gly 16 variant associated with lower airway reactivity
E. All of the above

Answers:
1) D
2) B
3) A
4) D
5) C

January 8, 2003
Topic: Asthma and other respiratory illness in children

1) Primary ciliary dyskinesia syndrome is characterized by the following:
A. Autosomal recessive inheritance without sex predilection
B. Also known as Kartagener’s syndrome
C. Chronic disease of lower respiratory tract only
D. A and B
E. All of the above

2) Croup is caused by infection which results in edema with upper respiratory obstruction. The following are true of viral croup:
A. Most common form of airway obstruction in children aged 6 months to 6 years
B. Usually caused by Parainfluenza I, II, III and less often RSV, adenovirus, and influenza A and B
C. Treatment often includes oxygen, racemic epinephrine and steroids
D. Radiologic findings include steeple sign
E. All of the above

3) The following statements are true of RSV bronchiolitis in children:
A. One of the major causes of hospital admission in infants under year of age
B. During an epidemic all age groups are affected
C. The initial pathological findings include necrosis of respiratory epithelium and peribronchiolar infiltrates
D. Preventative measures include the use of palivizumabe, a humanized RSV monoclonal antibody in premature children and those with BPD
E. All of the above

4) The following statement(s) are true of cystic fibrosis:
A. Autosomal dominant inheritance pattern
B. The CF gene codes for the CFTR – CF transmembrane conductance regulator
C. Neonatal screening is not possible
D. Inhaled antibiotics are not used for treatment of this disease
E. All of the above are true

5) Special issues in pediatric asthma include:
A. Risk factors: family history of atopy, maternal smoking, small lungs, environmental exposures
B. Early treatment of the inflammatory process
C. Side effects of corticosteroids including growth retardation
D. Side effects of albuterol including hyperactivity and restlessness
E. All of the above

Answers:
1) D
2) E
3) E
4) B
5) E

December 24, 2002
Topic: IgE Receptors and Regulation

1) Which of the following is FALSE regarding the high affinity IgE receptor (FceRI)?

A. The alpha subunit is solely responsible for binding to the ligand IgE
B. There is homology between the gamma chain of FceRI and the zeta chain of the T cell receptor
C. To have a functional human high affinity receptor, one needs all 3 chains.     (a, b, and g)
D. The beta chain serves as an amplifier of receptor signaling
E. Tyrosine kinases involved in FceRI signaling are lyn and syk

2) What are the critical signals necessary for human IgE synthesis in vitro and in vivo?

1. IL-4
2. IL-13
3. CD40-CD40 Ligand interaction
4. IFNy
5. IL-3
A. 1, 2, and 3 are correct
B. 2 and 4 are correct
C. 1 and 3 are correct
D. None of the above
E. All of the above

3) What are the functions of the beta subunit of the FceRI?

1. To amplify signals that are transduced through the alpha chain
2. To enhance surface expression of the FceRI complex
3. To allow surface display of the human FceRI complex
4. To allow IgE binding of the receptor complex
5. To dampen down-stream activation responses
A. 1, 2, and 3 are correct
B. 2 and 4 are correct
C. 1 and 3 are correct
D. None of the above
E. All of the above

4) Which of the following are true regarding the low affinity IgE receptor (CD23/FceRII)

1. It is expressed on B cells, monocytes, eosinophils and T cells
2. It binds to IgE at the third heavy chain domain
3. It can regulate IgE production
4. It has 2 isoforms
A. 1, 2 and 3 are correct
B. 2 and 4 are correct
C. 1 and 3 are correct
D. None of the above
E. All of the above

5) Which of the following statements is/are FALSE?

A. IgE can regulate the expression of its own high affinity receptor FceRI
B. The therapeutic anti-IgE antibody does not bind IgE attached to receptors
C. Anti-IgE therapy permanently turns off IgE synthesis
D. All of the above
E. None of the above

Answers:
1) C
2) A
3) A
4) E
5) C


December 11, 2002
Topic: Cells of the Immune System

1) On which cell type is the B2-integrin adhesion molecule CD11a/CD18 (LFA-1) expressed?
A. Neutrophils
B. Eosinophils
C. Both
D. Neither

2) Which cell type expresses the B1-integrin molecule VLA-4?
A. Neutrophils
B. Eosinophils
C. Both
D. Neither

3) Chediak Higashi syndrome is characterized by a defect in which of the following PMN functions?
A. Degranulation
B. Chemotaxis
C. Stimulated adherence
D. Microbicidal activity
E. All of the above

4) Which of the following inheritance patterns is observed for chronic granulomatous disease?
A. Autosomal recessive
B. X-linked dominant
C. X-linked recessive
D. Complex (polygenic) inheritance
E. A and C only

5) VLA-4 is expressed on all of the following cells types EXCEPT:
A. Eosinophils
B. Neutrophils
C. Lymphocytes
D. Monocytes
E. Basophils

6) Each of the following cytokines stimulate eosinophil survival and proliferation EXCEPT:
A. IL-3
B. IL-4
C. IL-5
D. Eotaxin
E. GM-CSF

7) All of the following are constituents of eosinophil granules EXCEPT:
A. Lysophospholipase
B. Eosinophil peroxidase
C. Eosinophil cationic peptide
D. Major basic protein
E. Eosinophil derived neurotoxin (protein X)


Answers:
1) C
2) B
3) E
4) E
5) B
6) B
7) A

November 27, 2002
Topic: Hybridoma and Monoclonal Antibodies, Flow Cytometry, Cell Surface Markers and Receptors

1) Flow cytometric analysis of T and B lymphocytes has demonstrated clinical utility in:
1. Diagnosis of primary immunodeficiency disorders
2. Diagnosis of lymphomas and leukemias
3. Monitoring of immunosuppressive therapy
4. Prognosis of HIV infected patients
5. Diagnosis of rheumatologic disorders
Diagnosis of pulmonary disorders

A. 1, 2, 5, 6 are true
B. 1, 2, 3, 4 are true
C. All are true
D. 1, 3, 4, 5 are true

2) 
1. T cell associated antigens include CD3, CD4, CD8, CD29
2. B cell associated surface markers include CD19, CD5, surface Ig, MHC class II molecules
3. Natural killer cell can be distinguished from T lymphocytes in that they express CD56 but can share CD8 with T lymphocytes
4. The CD4 molecule binds to MHC class II molecules, CD8 binds to MHC DR antigen
Choose one:
A. Only 1 and 3 are correct
B. Only 1, 2, and 3 are correct
A. Only 1 and 4 are correct
B. All are correct
C. None are correct

3) A young child presents with frequent infections. The history suggests a delay in separation of the umbilical cord. There is no family history of immunodeficiency. Recurrent and indolent infections of the soft tissue have occurred involving staphylococci. Biopsy of the infected tissue interestingly yielded inflammatory infiltrates devoid of neutrophils despite a marked peripheral blood leukocytosis. Healing of surgical wounds appears to be impaired. A normal serum IgE and a normal NBT are present. 
Which finding on flow cytometry on peripheral blood cells leads to the diagnosis?


A. Reduced number of CD19 cell which bear surface immunoglobulin
B. Markedly diminished expression of CD18 (Beta chain common to LFA-1 molecules)
C. Increased ratio of CD4 to CD8 cells
D. Increased expression of MHC class II molecules on CD3+, CD4+ cells


4) T cell activation DOES NOT produce which of the following
A. Increased expression of MHC class II molecules
B. Increased expression of CD25, the receptor of IL-2
C. Decreased expression of CD29
D. An alteration in the form of CD45, the leukocyte common antigen

5) Which of the following is FALSE
A. HIV infected patients have a poorer prognosis when the CD4 absolute count is less than 200 in comparison to patients with CD4 counts of about 500
B. The majority of peripheral blood lymphocytes in normal individuals are T lymphocytes and the majority of T lymphocytes are CD4+
C. The ratio of CD4 to Cd8 lymphocytes may be altered by stress, sample storage, or diurnal variation
D. Acute infection with herpes group viruses (eg. CMV or EBV) is often associated with an increase in the CD4 population
E. CD4, CD45RA cells are often decreased in rheumatoid arthritis and a decrease in CD8 cells has been associated with activity of many autoimmune diseases


Answers:
1) B
2) B
3) B
4) C
5) D

October 31, 2002

Topic: Anaphylaxis, Sting Insect Allergy, Drug Reactions, and CPR

1) Which one of the following is TRUE
A. Recent food ingestion promotes episodes of exercise-induced anaphylaxis in approximately 50-60% of patients
B. H-2 receptor antagonists are more effective than H-1 receptor antagonists in blunting diastolic hypotension induced by intravenous histamine
C. In most patients, plasma histamine levels remain elevated for 60-90 minutes after the onset of anaphylaxis
D. Serum tryptase levels generally peak within 30 minutes after the onset of IgE-mediated anaphylaxis
E. Alpha tryptase is stored in secretory granules of mast cells

2) Which one of the following statements is FALSE about systemic mastocytosis
A. Associated with elevated serum total IgE levels
B. Elevated urine histamine levels during acute episodes
C. Elevated plasma histamine levels between acute episodes
D. May be associated with increased numbers of mast cells on bone marrow biopsy
E. May be associated with myelofibrosis on bone marrow biopsy

3) All of the following are true about aspirin sensitivity EXCEPT
A. Most aspirin-sensitive patients can tolerate sodium salicylate
B. Naso-ocular reactions to aspirin are associated with increases in histamine in nasal lavage fluid
C. Successful ‘desensitization’ to aspirin will not induce tolerance to ibuprofen
D. Airway reactivity to LTE4 is increased in patients with respiratory reactions to aspirin
E. Acute reactions to aspirin may be associated with elevated serum tryptase levels

4) Which of the following is FALSE about the Red Man syndrome from vancomycin
A. A majority of patients receiving vancomycin develop manifestations of the syndrome
B. Ranitidine is beneficial in reducing pruritus
C. Diphenhydramine is beneficial in reducing flushing
D. The severity of the reaction correlates with the degree of elevation of plasma histamine levels
E. Reduction of infusion rate reduces the risk of reaction

5) Which one of the following is TRUE about sting insect allergy
A. There is considerable allergenic cross reactivity between honey bee and hornet venom
B. A skin test concentration of 0.1 ug/ml of honey bee venom may be irritating
C. The major allergenic constituent of honey bee venom is phospholipase A
D. Immunotherapy with whole body extracts of fire ants is not effective at preventing recurrent anaphylaxis
E. Wasps typically leave a stinger at a sting site

Answers:
1) A
2) A
3) C
4) B
5) C


October 17, 2002
Topic: Mast Cells, Basophils and Mastocytosis

1) Each of the following are cytokines which stimulate mast cell proliferation and survival, EXCEPT
A. IL-3
B. IL-4
C. Stem Cell Factor
D. GM-CSF

2) Which surface marker is expressed more on the surface of human mast cells than basophils
A. c-kit (stem cell factor receptor)
B. low affinity IgE receptor
C. LFA-1
D. IL-3 receptor

3) Human basophils release the following mediators upon IgE receptor mediated stimulation, EXCEP:
A. chondroitin sulfate A
B. PGD2
C. TNF-alpha
D. IL-13

4) Which of the following statements is INCORRECT
A. Granule morphology of connective tissue type human mast cells are characterized by grating/lattice structures
B. Mucosal type human mast cells are deficient in intestines of patients with SCID
C. There appears to be an inhibitory effect of disodium cromoglycate on human mucosal type mast cells but not connective tissue type mast cells
D. Human mucosal type mast cells are characterized by production of chymase

5) Consensus diagnostic work-up for systemic mastocytosis include all the following, EXCEPT
A. Examine skin: gross and microscopic
B. Bone marrow biopsy and aspiration
C. 24-hour urine study for mediators
D. Bone scan and skeletal survey
E. pulmonary function tests

Answers:
1) D
2) A
3) B
4) D
5) E

October 3, 2002
Imported Fire Ant Venom

Our expert is Dr. Chester Stafford, professor emeritus of Pediatrics and Medicine at the Medical College of Georgia. Dr. Stafford has published numerous research and review articles on imported fire ant hypersensitivity.

1) Since the introduction of imported fire ants to the United States through Mobile, they have spread throughout the Southeast. How far have they spread and will this spread continue?

The two species of imported fire ants were probably introduced into the United States on produce shipped through the port of Mobile, S. richteriin about 1918 and Solenopsis invicta in about 1939.S. richteri is presently limited to a small area along the northern border between Mississippi and Alabama. S. invicta, the most aggressive species, now infests 13 Southern states where it has become a considerable agricultural pest and a significant health hazard. The 10°F isotherm has long been considered to be the thermal boundary for fire ant infestation, but. invicta-richteri hybrids appear to be adapting to cooler climates as they continue to migrate northward. Imported fire ants have already advanced up the east coast as far north as Maryland. Over the next decade, S. invicta is expected to spread westward to California and up the Pacific coast as far north as the Canadian border.

2) What are the cardinal differences between the two species of imported fire ant, S. richteri and S. invicta?

The black imported fire ant, S. richteri, is originally from Uruguay and eastern Argentina. The red imported fire ant, S. invicta, is native to the Mato Grasso region of Brazil where its range extends northward along the Guapore river and southward along the Paraguay river basin into northern Argentina. Both IFA species have similar physical features. Four major protein allergens have been isolated and characterized from S. invictavenom, while there is no molecule analogous to Sol i 4 in S. richteri venom.

3) How can one tell the difference between an imported fire ant and other, less worrisome ants?

Imported fire ants have almost completely eradicated other ant species in endemic areas of the southern United States where more than 260 million acres are infested. Fire ant mounds measure up to a meter in diameter and half a meter in height. Each colony may be teeming with as many as 100,000 to 500,000 worker ants. Fire ant workers of both species range in size from 1.8 to 6 mm in length, averaging 3-4 mm. The queen is larger, measuring approximately one centimeter in length; she also has wings used during her nuptial flight. Characteristically, fire ants have two humps on the petiole which connects the thorax and abdomen, an antenna scape that extends more than two-thirds the distance to the back of the head, and prominent mandibles with four teeth.

4) What are some of the clinical hallmarks of imported fire ant stings and hypersensitivity, especially those that would distinguish them from other stinging insects?

Named for the fierce burning pain inflicted by its sting, the imported fire ant attacks with little warning. Firmly grasping the skin with its powerful mandibles, the fire ant arches its back, inserts its stinger into the flesh, and injects venom from the attached venom sac. It then pivots at the head and inflicts an average of 7 to 8 stings in a circular pattern. Sting reactions range from immediate localizedwheal and flare responses to large local or systemic reactions, including fatal anaphylaxis.The usual response to fire ant stings is the development of an immediate 25-50 mm dermal flare with formation of a wheal within 1 minute and papules within 2 hours. Vesicles develop within 4 hours, at first filled with clear fluid that becomes cloudy within 8 hours and develops into sterile pustules by 24 hours.

5) What are the relevant antigens found in fire ant venom?

Four major protein allergens have been isolated and characterized from Sol i venom. The largest molecular weight protein, Sol i 1, is present in the smallest amount (2-5%).Sol i 2, the largest fraction (67%), is a disulfide bonded dimeric protein of 26,224 molecular weight, which has been protein sequenced and cloned. Sol i 3 comprises about 20% of the venom protein and contains 212 amino acid residues, giving a molecular weight of 24,040 daltons. It is not related by sequence to other known proteins. Sol i 4 comprises about 9% of the venom protein and has 117 amino acid residues and a molecular weight of 13,340 daltons. The allergens of the black imported fire ant, Solenopsis richteri, have also been isolated and studied. Sol r 2 shows 78% sequence identity with Sol i 2; Sol r 3 is much more closely related to Sol i 3. There is no molecule analogous to Sol i 4 in the venom.

6) Is there clinically relevant cross-reactivity between any of these antigens and those of other stinging insects? If so, how can one tease this apart during an evaluation?

Sol i 1 appears to be a phospholipase of the vespid venom type that cross-reacts with sera from many vespid allergic patients. This may explain reactions reported by some vespid-sensitive individuals to their initial fire ant sting. Sol i 3 is a member of the antigen 5 family of wasp venom proteins. However, despite this high degree of sequence homology, it does not appear to exhibit immunologic cross-reactivity. Sera from allergic patients from both IFA endemic areas show a very high degree of cross-reactivity between S. invicta and S. richteri. Venom of S. invicta-richteri hybrid ants contains allergens from both species. Sera from patients sensitized by the native fire ant species, Solenopsis xyloni and aurea, show a high degree of reactivity with imported fire ant venom allergens.

7) How does fire ant skin testing differ from testing for other venoms?

The diagnosis of fire ant allergy is determined by correlation of the clinical manifestations of fire ant sting reactions with imported fire ant-specific IgE determined by skin testing or RAST. Unlike honey bee and vespid whole body extracts, imported fire ant whole body extract has been shown to contain relevant venom allergens and appears to be appear to be useful for diagnostic testing. After screening prick tests, usually at 10-3 weight/volume, intradermal skin tests are performed with 0.02-0.03 mL of 10-6 weight/volume and 10-fold increments in concentration to 10-3 weight/volume or until a positive reaction is obtained. Skin tests are considered positive if a wheal at least 6x6 mm and erythema at least 11x11 mm develop within 15 minutes and the reaction is at least 3 mm greater than the negative control.

8) Currently, only whole body extract is available for testing and treatment of fire ant allergy. How does the WBE fair in practice and might we some day see pure venom extract?

Imported fire ant whole body extract is the only reagent presently available for diagnostic testing and immunotherapy for fire ant sting allergy. Because of high degree of cross-reactivity between the two imported species, skin testing and immunotherapy with S. invicta alone is probably sufficient in most cases. The initial dose is determined by skin test titration as previously described. The dosage schedule is similar to that for aeroallergen immunotherapy. Patients are usually maintained on the maximum tolerated dose up to 0.5 mL of 1:100 weight/volume. Extrapolating from the Sol i 3 content, a good quality 1:10 weight/volume whole body extract has been estimated to contain approximately 30 to 45 mg/mL of total antigenic venom protein; therefore, a maintenance dose of 0.5 mL should deliver 15 to 22 mg of venom protein. Since most patients suffer an average of 8 fire ant stings per incident and each sting contains less than 100 ng of venom protein, this dose has been estimated to be sufficient to provide adequate protection. Based on clinical experience most authorities consider a maintenance dose of 0.5 mL of 1:100 weight/volume to be protective for most patients. However, the degree of protection compared to that which may be achieved with fire ant venom or specific Sol i allergens has not been determined. Fire ant venom is not expected to be available in the near future. Therefore, it has been suggested that, until fire ant venom is available, the dosage of fire ant whole body extract used for skin testing and immunotherapy should be based on protein or Sol i allergen concentration which should be specified on the label.

9) Briefly describe to whom and how you prescribe IFA immunotherapy.

Allergen immunotherapy has proved to be an extremely effective form of treatment for individuals at risk of insect sting anaphylaxis, including anaphylactic reactions caused by fire ant stings. Treatment criteria are similar to that for sting reactions to other Hymenoptera. The strongest evidence for the efficacy of immunotherapy with fire ant whole body extract is the report by Freeman et al, who treated 65 patients with fire ant whole body extract immunotherapy for anaphylaxis. Of the 47/65 (72%) patients who sustained field stings, only one suffered anaphylaxis. Of the 30 patients who were stung while on maintenance immunotherapy, none had anaphylaxis. The control group consisted of 11 insect allergic patients who were not treated. Six of the eleven control patients were stung and all six suffered anaphylaxis. Thus, imported fire ant whole body extract appears to contain relevant allergens and imported fire ant whole body extract immunotherapy appears to be efficacious.

10) How long should a patient stay on IFA immunotherapy and are there any markers one could follow to determine when termination is appropriate (e.g. RAST testing)?

The natural history of fire ant allergy is unknown and the optimal duration of immunotherapy has not been clearly established. In one study, immunotherapy was discontinued in seventeen patients after 2 to 19 years of treatment. All patients were re-tested and stung three months later. Thirteen of 17 (76%) had positive skin tests and 16/17 (94%) had no reaction to re-sting. The investigators concluded that most patients on immunotherapy for at least two years could probably tolerate a sting without reaction. A reduction in fire ant skin test titer or RAST level may be helpful signs. Patients who have experienced severe hypotension or loss of consciousness may require immunotherapy indefinitely. Additional studies are warranted to clarify the optimal duration of fire ant immunotherapy.

11) Is there any particularly useful text or review on IFA and insect allergy in general you would recommend to someone studying for the Boards?

Most relevant information may be obtained from the Practice Parameters for Insect Sting Hypersensitivity or from the following review article: Stafford CT. Fire ant venom hypersensitivity. Ann Allergy, Asthma & Immunol 1996; 77:87-99



Topic: Tissue Typing, Transplantation, Cellular Reconstitution, and GVH

1) HLA typing of a family in which 2 boys have X-linked Hyper IgM reveals the following antigens:
Father: A11, A2, B15, B44, DR1, DR5
Mother: A24, A3, B7, DR15
Boy #1: A11, A24, B7, B15, DR1, DR15
Boy #2: A3, A11, B7, B15, DR1, DR15
Sister: A11, A24, B7, B15, DR1, DR15

True statements bout the above family reveals which one of the following:
A. The normal sister is HLA identical to both boys
B. The mother is homozygous for B and DR antigens
C. A mixed leukocyte study between blood leukocytes from Boy #2 and the sister would be mutually reactive
D. A mixed leukocyte study would reveal that the mother would not react against the boys’ cells but the boys would react against the mother’s cells
E. The sister could not be a safe donor of unfractionated marrow for Boy #2

2) The mechanism of action of mycophenolate mofetil is that it’s metabolite inhibits which of the following enzymes
A. Adenosine deaminase
B. Protein kinase C
C. Purine nucleoside phosphorylase
D. Inosine monophosphate dehydrogenase
E. CD45 phosphatase

3) HLA typing for heart and liver transplantation is currently most commonly done by which of the following methods
A. Serologic typing by microcytotoxicity
B. Sequence-specific olionuleotide probe (SSOP) typing
C. Sequence-specific primers (SSP) for each HLA gene
D. Herteroduplex typing
E. Reference Strand Mediated Conformation Analysis (RSCA)

4) The most effective approach to mitigation of graft-versus-host disease is which of the following
A. GVHD prophylaxis with cyclosporine
B. GVHD prophylaxis with cyclosporine and treatment with steroids
C. GVHD prophylaxis with methotrexate and cyclosporine
D. Rigorous (4 log) T cell depletion of donor marrow
E. Combination of dacluzimab and mycophenolate mofitil

5) True Statements about stem cell transplantation for SCID include which one of the following
A. It is necessary to wait for 3 months before performing a bone marrow transplant in a neonate diagnosed at birth with SCID
B. If there is no HLA-identical related donor, the treatment of choice is an unfractionated matched unrelated cord blood transplant
C. Transplantation is no longer the treatment of choice because gene therapy has been shown to be more efficacious
D. A mother of father can be used as a donor of stem cells if there is no HLA-identical sibling
E. It is necessary to use pre-transplant chemotherapy and GVHD prophylaxis

Answers:
1) B
2) D
3) A
4) D
5) D

September 19, 2002
Topic: Tissue Typing, Transplantation, Cellular Reconstitution, and GVH

1) HLA typing of a family in which 2 boys have X-linked Hyper IgM reveals the following antigens:

Father: A11, A2, B15, B44, DR1, DR5
Mother: A24, A3, B7, DR15
Boy #1: A11, A24, B7, B15, DR1, DR15
Boy #2: A3, A11, B7, B15, DR1, DR15
Sister: A11, A24, B7, B15, DR1, DR15

True statements bout the above family reveals which one of the following:

A. The normal sister is HLA identical to both boys
B. The mother is homozygous for B and DR antigens
C. A mixed leukocyte study between blood leukocytes from Boy #2 and the sister would be mutually reactive
D. A mixed leukocyte study would reveal that the mother would not react against the boys’ cells but the boys would react against the mother’s cells
E. The sister could not be a safe donor of unfractionated marrow for Boy #2

2) The mechanism of action of mycophenolate mofetil is that it’s metabolite inhibits which of the following enzymes

A. Adenosine deaminase
B. Protein kinase C
C. Purine nucleoside phosphorylase
D. Inosine monophosphate dehydrogenase
E. CD45 phosphatase

3) HLA typing for heart and liver transplantation is currently most commonly done by which of the following methods

A. Serologic typing by microcytotoxicity
B. Sequence-specific olionuleotide probe (SSOP) typing
C. Sequence-specific primers (SSP) for each HLA gene
D. Herteroduplex typing
E. Reference Strand Mediated Conformation Analysis (RSCA)

4) The most effective approach to mitigation of graft-versus-host disease is which of the following

A. GVHD prophylaxis with cyclosporine
B. GVHD prophylaxis with cyclosporine and treatment with steroids
C. GVHD prophylaxis with methotrexate and cyclosporine
D. Rigorous (4 log) T cell depletion of donor marrow
E. Combination of dacluzimab and mycophenolate mofitil

5) True Statements about stem cell transplantation for SCID include which one of the following

A. It is necessary to wait for 3 months before performing a bone marrow transplant in a neonate diagnosed at birth with SCID
B. If there is no HLA-identical related donor, the treatment of choice is an unfractionated matched unrelated cord blood transplant
C. Transplantation is no longer the treatment of choice because gene therapy has been shown to be more efficacious
D. A mother of father can be used as a donor of stem cells if there is no HLA-identical sibling
E. It is necessary to use pre-transplant chemotherapy and GVHD prophylaxis

Answers:
1) B
2) D
3) A
4) D
5) D

September 5, 2002

Topic: Immunoglobulin Structure, Function, Measurement and Replacement

Items 1-4: Select the correct answer A-D:

  1. Fab fragment of IgM
  2. Fc fragment of IgG
  3. Both
  4. Neither

1) Binds specifically to receptors on neutrophils

2) Binds specifically to C1q

3) Idiotypic determinants

4) Binds specifically to endothelial cells

Items 5-9: Select the one best answer

5) IgG is the immunoglobulin most commonly used for replacement because:

A. IgG stays in the intravascular space and is more effective than IgM in fixing complement
B. IgG has a longer half-life than IgM or IgA and therefore more able to attain adequate levels
C. IgM is more likely to cause adverse effects when administered intravenously
D. IgG has a more rapid onset of action than IgM or IgA and therefore is more effective if used in septic patients
E. IgA is effective only when given to patients with selective IgA deficiency

6) Immunoglobulin levels are most appropriately determined by which of the following techniques

A. Complement fixation
B. Serum protein electrophoresis
C. Isoelectric focusing
D. Nephelometry
E. Countercurrent electrophoresis

7) Intravenous gammaglobulin is indicated and has been shown to have clinical efficacy for all of the following EXCEPT

A. Common variable immunodeficiency
B. Immune thrombocytopenic pupura
C. Selective IgA deficiency
D. Myasthenia gravis
E. Kawasaki disease

8) A 4-year old boy with X-linked agammaglobulinemia is started on treatment with IVIG. After 2 monthly infusions of 400 mg/kg his peak IgG level is 800 mg/dL and trough just before the next dose is due is 200 mg/dL. It is desired to maintain the trough level over 400 mg/dL. The most appropriate intervention would include

A. Doubling the dose of IVIG to attain the higher trough level
B. Decreasing the interval to every 2 weeks at the same dose and measuring peak and trough levels after every infusion
C. Increasing the dose of IVIG by 20% and following for another few months until he attains steady state
D. Changing to another IVIG preparation with a longer half-life
E. Determining losses of IVIG in urine and stool

9) Adverse events related to infusions of IVIG have included each of the following EXCEPT

A. Anaphylaxis
B. Transmission of Hepatitis C
C. Aseptic meningitis
D. Transmission of HIV
E. Thrombotic events

Answers:
1) B
2) B
3) A
4) D
5) B
6) D
7) C
8) C
9) D


Ask The Expert

Familial Cold Autoinflammatory Syndrome

Our expert is Hal M. Hoffman, MD of the University of California at San Diego, whose groundbreaking research on familial cold autoinflammatory syndrome (previously called familial cold urticaria) recently led to the discovery of the genetic abnormality involved in this disorder.

1. What is FCAS?
Familial cold autoinflammatory syndrome (FCAS) is a rare inherited inflammatory disease characterized by recurrent episodes of rash, arthralgia and fever after generalized cold exposure. 

2. Why FCAS instead of FCU?

FCAS is most commonly known as familial cold urticaria (FCU) because of its similarities to acquired cold urticaria, a disease characterized by the immediate development of pruritic hives and occasionally anaphylaxis after localized or direct cold exposure. However, the rash in FCAS is macular papular and its pathology does not resemble urticaria. In the past, FCAS was classified as a physical urticaria; however, the symptoms are more consistent with a newly described classification of diseases called autoinflammatory syndromes. These diseases are characterized by recurrent inflammatory episodes in the absence of autoantibodies or antigen specific T cells and include common diseases such as inflammatory bowel disease and less common diseases such as the periodic fever disorders. 

3. What distinguishes FCAS from other urticarias or auto-inflammatory conditions?

FCAS can be distinguished from physical urticarias by its autosomal dominant inheritance pattern, early age of onset, delay of symptoms after exposure, non-urticarial nature of the rash and the presence of fever and arthralgia. FCAS is characterized by rash, fever and arthralgia, which are all features of the periodic fever disorders. FCAS episodes are usually precipitated by cold exposure, last less than 24 hours and begin within the first year of life, whereas episodes in other periodic fever disorders, such as familial Mediterranean fever and hyper IgD syndrome, are usually not precipitated by any identifiable trigger, last several days and usually present later in childhood. 

4. What is the relationship to Muckle-Wells Syndrome?
FCAS is often confused with Muckle-Wells syndrome (MWS), a periodic fever disorder characterized by short episodes of rash, fever, and arthralgia. However, MWS is not usually precipitated by cold exposure. MWS is also often associated with the development of progressive sensorineural deafness and late onset systemic amyloidosis. Both MWS and FCAS were genetically linked to chromosome 1q44, and recently a single gene was identified that causes both diseases.

5. Are there any consistent lab findings, and what labs should you order?
Patients with FCAS regularly have moderately elevated WBC counts (8,000-12,000) and significantly elevated WBC counts (15,000-30,000) during attacks. FCAS patients also have elevated sedimentation rates and C reactive protein. Diagnosis is usually made by history, but now there is a genetic test available in research labs.

6. What causes this condition?

The pathophysiology of FCAS is still unclear. It does not appear to be mast cell or histamine mediated. There is no evidence of cryoglobulins, cold agglutinins or autoantibodies. Recent evidence suggests FCAS may be caused by aberrant innate immune system function.

7. How do you treat the disorder or prevent the reaction?
Unfortunately, there are no clearly effective treatments. High dose corticosteroids will suppress symptoms, but patients choose symptoms over steroid side effects. Arthralgias are often partially relieved by NSAIDs. Most patients prevent symptoms by dressing warmly and avoiding cold environments.

8. Have there been any advancements in the genetics of the disorder?
Mutations in a recently identified gene called CIAS1 (cold induced autoinflammatory syndrome1) are responsible for FCAS and MWS. This gene codes for a protein called cryopyrin that is expressed in inflammatory cells and appears to be involved in innate immune function.

9. Are there any ongoing studies looking at this syndrome?
We are currently studying the immunologic features of this syndrome using an experimental cold challenge model. We and several other groups are studying this gene and other genes in this new family of inflammatory genes. 

10. Are there resources out there to aid affected patients and families?
There are two Web sites created by and for patients and families with FCAS. There is also a newsletter created by our group.

http://pweb.netcom.com/~islnddrm/familial.htm

If you have patients with suspected FCAS, MWS, or other periodic fever disorders, then I can be contacted at hahoffman@ucsd.edu or 858-534-2108.


August 23, 2002

Innate and Adaptive Immune Responses

1) Which ONE of the following statements best describes the innate immune system?

  1. Acitvates the complement cascade only by activating the first component of complement.
  2. Recognizes antigens with receptors capable of somatic mutation.
  3. Recognizes pathogen-associated molecular patterns.
  4. Recognizes antigens presented by CD1 molecules.

2) Which of the following statements best describes the adaptive immune response?

  1. Includes polymorphonuclear leukocytes, natural killer cells and the complement system.
  2. Recognizes antigens with germline-encoded receptors.
  3. Recognizes highly conserved antigenic molecules expressed by pathogens
  4. Antigent is presented in the context of HLA molecules.

3) Which ONE of the following statements best describes a requirement for T cell activation?

  1. Ligation o9f CD152 with CD80/86.
  2. Ligation of CD40 with CD28.
  3. Ligation of CD4 with CD3.
  4. Ligation of CD8 with HLA class I molecules.

4) Which ONE of the following statements best describes a mechanism of peripheral T cell tolerance?

  1. Ligation of CD152 with CD80/86.
  2. Ligation of CD40 with CD40 ligand.
  3. Ligation of CD28 with CD80/86
  4. Ligation of CD4 with HLA class II molecules.

5) Which ONE of the following statements best describes B cells in the immune response?

  1. Expression of CD28.
  2. Only linear peptides are recognized by transmembrane immunoglobulin.
  3. Express HLA class I and class II molecules.
  4. Expression of CD152

Answers:
1. C
2. D
3. D
4. A
5. C


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