CLINICAL CASE DISCUSSION: ASTHMA AND ANAPHYLAXIS LEARNING OBJECTIVE To review the information described in the hypersensitivity lecture by presenting two cases. These cases will be discussed by Drs. Katherine Gundling and Homer Boushey, from the Clinical Division of Allergy/Immunology in the Department of Medicine. CASE #1:
A 20 year old woman is referred to the Allergy/Immunology Clinic after a recent episode of anaphylaxis. On a beautiful summer day she and her boyfriend drove to the Sonoma Valley for a picnic in the vineyards. They chose a lovely, grassy knoll that was surrounded by flowers. Upon arrival they unfolded their picnic blanket and set out their lunch, which consisted of celery and shrimp dip, apples, cheese, peanut butter sandwiches, and a bottle of red wine. Just as they were pouring the first glass of wine, his cell phone rang. He walked to the other side of a nearby tree to take the call. After 10 minutes or so, he came back to the picnic site, only to find his girlfriend in significant distress. She was flushed, had a blotchy, red rash, and was short of breath. She was unable to speak and the boyfriend called 911 for assistance. (Q 1, 2) The emergency team administered epinephrine, oxygen and bronchodilator therapy by nebulization. She was taken to the hospital in Santa Rosa where she was also given corticosteroids and antihistamines. (Q 3, 4) She was released the next day in good condition and advised to consult her physician for followup. QUESTIONS:
1. What are some possible triggers for her symptoms at the picnic lunch? SHRIMP, PEANUTS, AND BEE VENOM ARE THE MOST LIKELY 2. What is the underlying mechanism of her symptoms? PREFORMED IgE ANTIBODIES ON SURFACE OF MAST CELLS AND BASOPHILS ARE CROSS-LINKED BY ALLERGEN. THIS TRIGGERS RELEASE
OF HISTAMINE, WHICH CAUSES NEARLY INSTANTANEOUS SYMPTOMS. OTHER MEDIATORS, SOME PREFORMED AND SOME DELAYED, ALSO CONTRIBUTE TO SYMPTOMS. 3. What is the most important component of the treatment for anaphylaxis? What effects does it have? EPINEPHRINE. NOTE: ANTIHISTAMINES ARE NOT USEFUL EPINEPHRINE HAS 2 MAIN EFFECTS: A. BRONCHODILATION, WHICH REVERSES THE BRONCHOCONSTRICTION B. VASOCONSTRICTION, WHICH REVERSES THE VASODILATION THAT CONTRIBUTES TO HYPOTENSION (SHOCK) 4. What tests are available to help diagnose anaphylaxis in the emergency department? A. URINE OR SERUM HISTAMINE B. SERUM TRYPTASE –TRYPTASE IS A PROTEASE RELEASED BY MAST CELLS IN IgE-MEDIATED REACTIONS 5. How does the allergy/immunology physician determine which “bee” caused the anaphylaxis, and does it make a difference? A. USE "SKIN PRICK" TEST THAT INSTILLS VARIOUS ALLERGENS (VARIOUS BEE VENOMS IN THIS CASE) INTO SKIN. SEE WHEAL AND FLARE AT SITE OF OFFENDING ALLERGEN. B. CAN MEASURE IgE IN SERUM THAT IS SPECIFIC FOR ALLERGEN. YES, IT MAKES A DIFFERENCE IF IMMUNOTHERAPY (SEE BELOW) IS TO BE UNDERTAKEN BECAUSE YOU NEED TO KNOW THE ALLERGEN. 6. What can the allergy/immunology physician offer this patient? A. PRESCRIBE/DEMONSTRATE/DISCUSS USE OF THE EPI PEN AND RECOMMEND MEDIC ALERT BRACELET. B. DISCUSS METHODS OF PREVENTION, USE OF OTHER MEDICINES (E.G. ANTIHISTAMINES) THAT CAN REDUCE SYMPTOMS, C. OFFER IMMUNOTHERAPY. IMMUNOTHERAPY (DESENSITIZATION) CONSISTS OF INJECTING GRADUALLY INCREASING AMOUNTS OF
ALLERGEN OVER A PERIOD OF MONTHS. THIS INDUCES CD4+ CD25+ REGULATORY T CELLS TO PRODUCE IL-10, WHICH HAS SEVERAL POTENT ANTI-ALLERGIC PROPERTIES. IT IS SAFE AND EFFECTIVE IN THE MAJORITY OF PATIENTS AND OFFERS LONG-TERM PROTECTION (YEARS) 7. Is there a way to prevent further episodes? AVOID EXPOSURE TO ALLERGEN 8. Should this patient receive immunotherapy for her allergy to Hymenoptera? YES CASE #2:
A 22 year old medical student presents for emergency care of shortness of breath, chest tightness, wheezing, cough and sputum production for the past four hours, unrelieved by hourly inhalations of 2-4 puffs of albuterol from a metered-dose inhaler. He reports that he was diagnosed with asthma at age eight and was found to have positive skin tests "to nearly everything". (Q 1, 2, 3) Both parents were smokers; his mother had occasional "hay fever;" he has no siblings. (Q 4) He was treated with allergy shots and daily inhalations of cromolyn from age 4-13 y.o., when his asthma improved. Throughout high school and college, he avoided sports because of exertional shortness of breath and required short courses of prednisone "once or twice a year" for asthmatic attacks. Between these episodes, he took 2-6 puffs of albuterol per day on an "as needed" basis for relief of symptoms. QUESTIONS: 1. What is a “positive skin test”, i.e., what is the appearance of the skin in a positive test? WHEAL (LOCALIZED EDEMA) AND FLARE (ERYTHEMA) 2. What is the mechanism of this reaction? HISTAMINE CAUSES VASCULAR PERMEABILTY SO LOCALIZED EDEMA (WHEAL) OCCURS. ALSO CAUSES VASODILATION SO ERYTHEMA OCCURS (FLARE). INJECTION OF PURIFIED HISTAMINE CAUSES A “WHEAL AND FLARE” REACTION. 3. What is its relationship to his symptoms of asthma? EARLY (IMMEDIATE) PHASE IS CAUSED BY HISTAMINE RELEASE BUT NOT THE LATE PHASE (SEE BELOW).
4. Is there any significance to his mother's history of "hay fever"? ATOPY IS THE TERM USED TO DESCRIBE THE FAMILIAL PREDISPOSITION TO ALLERGIES. THE TARGET ORGAN CAN DIFFER IN MEMBERS OF A FAMILY (HAY FEVER: NOSE AND EYES; ASTHMA: BRONCHIOLES; ECZEMA: SKIN) BUT ALL RESPOND TO ANTIGEN (ALLERGEN) WITH INCREASED IgE. To his parents' smoking habits? PARENTAL SMOKING PREDISPOSES TO ASTHMA IN CHILDREN. To his having no siblings? OLDER SIBLINGS BRING MICROBES INTO CONTACT WITH YOUNGER SIB CAUSING INFECTIONS WHICH SHIFT THE TH-2 BIASED (ALLERGIC) RESPONSE TO A TH-1 BIASED RESPONSE, ie, AWAY FROM ALLERGY.
On the evening before this admission, he dined in his girl friend's apartment,
where she kept two cats as pets. Thirty minutes after arriving, he noted the onset of chest tightness and shortness of breath. (Q 5, 6) These symptoms at first improved after 4 inhalations of albuterol, but worsened over the next two hours, despite repeated use of his inhaler, so he excused himself shortly after dinner to go home. QUESTIONS: 5. What mediators likely caused this rapid onset of symptoms? HISTAMINE, PROSTAGLANDINS 6. Is cat dander necessarily responsible for his symptoms? PROBABLY BUT THERE MAY BE OTHER ALLERGENS SUCH AS DUST MITE FECES, MOLD, COCKROACH, ETC
He felt better about an hour after returning to his own apartment, but woke at
3 AM with severe shortness of breath, chest tightness and cough. These symptoms were only partially relieved by albuterol. He was unable to go back to sleep and spent the rest of the night sitting in a chair, taking 2-4 puffs of albuterol every hour until daybreak, when he came to the Emergency Department for treatment. (Q 7) QUESTION:
7. The patient has been away from his girlfriend’s house for several hours by now, and had gone back in his home where he ordinarily sleeps without difficulty. What accounts for the recurrence of symptoms? LATE PHASE REACTION: 4 TO 8 HOURS AFTER EXPOSURE TO ALLERGEN, INFLAMMATION OCCURS IN AIRWAYS CAUSED BY LEUKOTRIENES. ALSO CHEMOKINE FOR EOSINOPHILS (EOSINOPHIL CHEMOTACTIC FACTOR) IS MADE BY MAST CELLS. INFLAMMATORY CELLS SUCH AS EOSINOPHILS AND NEUTROPHILS INFILTRATE THE AIRWAY MUCOSA.
The physical examination reveals a distressed-appearing young man
breathing rapidly (24 breaths/min), with a rapid, regular heart rate (124/min), normal blood pressure (135/80) and oxygen saturation of 88% while breathing room air. He is using accessory muscles of respiration; his chest appears over- inflated, and he has diffuse expiratory wheezing over all lung fields. During the exam, he coughs up thick, yellowish sputum. (Q 8) Measurement of his peak expiratory flow (PEF), and of his forced expired volume in one second (FEV1) show values less than 30% of predicted. QUESTION: 8. What would a Wright's stain and cell count of his sputum sample likely show? INCREASED EOSINOPHILS. INCREASED NEUTROPHILS AS WELL.
The patient is treated with continuous supplemental oxygen, and with
nebulized albuterol and ipratropium bromide (Atrovent) solution and intravenous methylprednisolone (60 mg) every four hours. He is kept in the ED for twenty-four hours and is discharged home with a tapering course of prednisone (60mg/day, tapered to 0 over ten days), a fluticasone inhaler, and albuterol to take "as needed." His symptoms fully resolved over the next 10 days, and he presents in the Chest/Allergy Clinic on the 14th day for further evaluation. His appearance and physical exam are now normal, but his FEV1 is only 64% of predicted.
The patient's prednisone therapy is stopped, but he is advised to continue on
inhaled fluticasone at the same dose. When he returns for follow-up evaluation six weeks later, he reports that he now rarely needs albuterol. His physical exam is normal, but his FEV1 is still low, 68% of predicted. QUESTIONS:
9. Why is his FEV1 still low, 8 weeks after his acute attack of asthma? PATIENT PROBABLY HAS "AIRWAY REMODELING" CHARACTERIZED BY HYPERPLASIA OF MANY CELL TYPES IN BRONCHIAL WALL. ALSO FIBROSIS AND INCREASED EXTRACELLULAR MATRIX. 10. Is he a candidate for anti-IgE monoclonal antibody therapy? YES, BUT ONLY IF HIS ASTHMA IS NOT CONTROLLED BY STANDARD THERAPY, OMALIZUMAB (XOLAIR) IS HUMANIZED MONOCLONAL ANTIBODY AGAINST THE HEAVY CHAIN OF IgE. IT BINDS TO THE HEAVY CHAIN AT THE SAME SITE AS THE IgE RECEPTOR SO BLOCKS BINDING TO RECEPTOR. THE IgE-OMALIZUMAB COMPLEX IS THEN CLEARED BY MACROPHAGES. 11. Are there differences in asthma morbidity and mortality in different racial/ethnic groups in the U.S.? AFRICAN-AMERICANS HAVE HIGHER ASTHMA MORBIDITY AND MORTALITY. WHILE MORBIDITY AND MORTALITY ARE ALSO HIGHER IN HISPANIC AMERICANS IN THE NORTH-EAST, THEY ARE LOWER IN THE WEST. THESE DIFFERENCES ARE BEING EXAMINED IN STUDIES OF THE GENETIC PREDISPOSITION TO ASTHMA, OR TO ASTHMA SEVERITY.
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