Aspirin-sensitive asthma: Tolerance to aspirin after positive oral aspirin challenges

Aspirin-sensitive asthma: Tolerance to aspirin after positive oral aspirin challenges Donald D. Stevenson, M.D., Ronald A. Simon, David A. Mathison, M.D. La Jollu, Calif.

M.D., and

7‘a.o aspirin-sensitive usthmatic patients underwent oral aspirin challenges for investigative purposes. Following the expected respiratory reuction to aspirin, the putients becume refructor! to the further adverse effects of aspirin. Additionally they began tuking 325 mg aspirin per dq. und ufter 6 and 8 mo aspirin dosage was increased to 650 rng per duy. We have noted an improvement in their rhinitis and usthmu during this open drug trial. Furthermore, maintenance swemic corticosteroids huve been reduced in one patient and discontinued in the other without u decline in lung,function values. If these initiul observations are found in a larger number of trspirin-sensitive asthmatic patients, changes in our understanding of the puthogenesis qf rhinosinusitis-asthma-aspirin syndrome would fdlow, and treatment for such asthmatic patients might be improved.

The rapid onset of asthma after ingestion of aspirin tablets segregates the subset of asthmatic patients who have the rhinosinusitis-asthma-aspirin-sensitive syndrome.‘-” In these patients asthma attacks occur within minutes to 4 hr after ingesting aspirin and other nonsteroidal anti-inflammatory drugs. Currently there are no in vitro tests to identify individuals with this syndrome. Therefore in asthmatic patients who are not taking aspirin or nonsteroidal anti-inflammatory drugs or who give an equivocal history of asthma after ingesting these compounds, oral aspirin challenges have been used to provoke asthma attacks and thereby detect the presence of the aspirin-sensitive syndrome.2-” Although the clinical usefulness of oral aspirin challenges is to detect aspirin sensitivity in individuals with unsuspected disease, some patients with known aspirin sensitivity have volunteered to undergo oral aspirin challenges for investigative purposes. For example, we have measured plasma histamine levels during aspirin challenges and compared them with histamine levels during control challenges From the Department of Clinical Research, Research Institute of Scripps Clinic. Supported by National Institutes of Health Grants Al 10386 and RR 0083. Received for publication Sept. 26, 1979. Accepted for publication Jan. 2, 1980. Reprint requests to: Donald D. Stevenson, M.D., 10666 N. Torrey Pines Rd.. La Jolla, CA 92037. Vol.

66, No. 1, pp. 82-88

with placebos.6 As a part of these continuing studies we have observed in two patients that after a positive aspirin challenge a refractory period to the further adverse effects of aspirin occurs. Furthermore these patients have continued to ingest aspirin each day and have not experienced an exacerbation of their asthma or rhinitis. In fact, their rhinitis and asthma have improved, and they have been able to reduce their maintenance corticosteroid drugs. CASE REPORTS Patient 1 (N. F.). A 43.yr-old

white

woman

with

a I-yr

history

of asthma

associatedwith perennial nasal congestion was first seenat Scripps CXnic in 1970. She could not recall having taken aspirin tablets during the year preceding her admission. Physical examination revealed blue-pale congested nasal membranes,poor transillumination of available paranasal sinuses,and inspiratory as well as expiratory wheezesin her chest. Nasal smearcontained sheetsof eosinophiles, polymorphonuclear leukocytes, and bacteria. There was a 15% peripheral blood eosinophilia. She was found to have bilateral maxillary sinusitis, and a maxillary sinus aspirategrew Pseudomonas

j?uorescens.

Cutaneous

tests

to house

dust

and desert ragweed extracts produced wheal-and-flare responses,but bronchial challenges to these antigen extracts at a later date produced no decline in the forced expiratory volume In 1 set (FEV,). After treatment with corticosteroids and improvement in her lung function, she underwent aspirin challenge for diagnostic purposes.’ Shereceived640 OOSI-6749/80/070082+07$00.70/0

0

1980

The

C. V. Mosby

Co.

VOLUME NUMBER

66 1

mg aspirin orally, and 50 min later her FEV, values decreased from 2,650 to 600 ml, associated with severe rhinorrhea, facial flushing, conjunctival injection, and an asthma attack (Fig. I).’ A placebo challenge with antacid (Maalox; William H. Rorer, Inc., Ft. Washington, Pa.) on another day was associated with FEV, values between 2,500 and 2,650 ml. Oral challenges with tartrazine 25 mg and acetominophen 640 mg were also negative. From 1970 through 1974 the patient was treated with maintenance dosages of prednisone, varying between 10 and 20 mg every other day with additional bursts of prednisone for asthmatic relapses associated with respiratory infections. In addition she took theophylline and ephedrine. In November 1974 the patient volunteered to participate in aspirin-challenge investigative studies (patient 2, reference 6). On November 24, 1974, she underwent sodium salicylate challenge (320 mg), and her FEV, values remained between 1,975 and 2.000 ml following this challenge. On November 25, 1974, she received aspirin (325 mg) plus Maalox (Ascriptin), and her FEV, fell from 1.950 to700 ml within 30 min.” From 1974 until February 1975 she took methylprednisolone 16 mg on alternate days, but began using beclomethasone dipropionate (100 pg by inhalation four times a day) and reduced methylprednisolone to 8 mg on alternate days, with the limiting factors for further reduction in corticosteroids being either intractable nasal congestion or intercurrent upper- respiratory tract infections. In 1978 beclomethasone dipropionate (one 50-pg nasal insufflation twice daily) was initiated, which provided additional relief for nasal congestion. She required bursts of methylprednisolone (32 mgiday for 5 days) approximately once every other month for respiratory infections or intractable nasal congestion. On March 12, 1979, the patient was admitted to the General Clinical Research Center to undergo oral aspirin challenge for investigative purposes. She was taking methylprednisolone 8 mg on alternate days; beclomethasone dipropionate by nasal inhalation twice daily; beclomethasane diproprionate two inhalations four times a day; a bronchodilator (Marax) ltwice a day; aminophylline tablets (Aminodur Dura-Tab) twice daily; and was avoiding aspirin. Nasal membranes were congested with moderate obstruction, and nasal smear showed sheets of eosinophils. The patient participated in an oral aspirin challenge, during which measurements ‘of ventilation-perfusion ratios and arterial, peripheral venous, and central venous sampling of blood for histamine and other mediators were carried out simultaneously. The details of her aspirin challenge and subsequent daily treatment with aspirin during the postchallenge refractory period are presented in Fig. 2. On March 20, 1979, she underwent methacholine inhalation challenge (I .2S mgiml, five inhalations), and the FEV, values fell from a baseline of 2,000 to 1,600 ml (20% decline). This fall of FEV, was quickly and easily reversed with inhalation of isoetharine. She was discharged on March 21, 1979. Table I contains the details of her clinical course. During the first 2 wk of June 1979 she noted increasing nasal congestion coincident with reduction of methylpred-

Tolerance to aspirin after challenges

3lJoO- RSA 640mg (Ascriptinl (Orally) +

(

t Treatment I 0 1

2 Time (HoursJ

83

N.F. l/8/70 ASA Challenge

3

4

FIG. 1. Fifty minutes after ingesting 640 mg aspirin, patient 1 (N. F.) had a severe respiratory reaction with chest tightness, wheezing, and a 70% decrease in FEV, values. Upper respiratory tract symptoms occurred simultaneously. Antacid (Maalox) challenge on another day was negative. nisolone to 2 mg every other day and was readmitted on June 18, 1979, having not ingested aspirin for 72 hr. Her FEV, value was reduced to 1,400 ml, and she was treated with isoetharine in an intermittent positive pressure breathing (IPPB) device, methylprednisolone 16 mg, a bronchodilator (Marax), and aspirin 325 mg. Over the next 2 hr she became asymptomatic, her FEV, improved to 2,100 ml, and she was discharged on June 19, 1979. In August 1979 she again experienced a flare of rhinitis and asthma, which may have been triggered by air pollution. She again received a short burst of methylprednisolone. Her aspirin dosage was increased to 650 mgiday, and she has subsequently been improved.

Patient

2 (I?. B.).

A 60.yr-old white man developed naso-ocular symptoms in August 1976, followed within 3 mo by the appearance of asthma. In June 1977 he was first seen at Scripps Clinic. He denied any knowledge of aspirin-induced asthma attacks in the past. For approximately 5 yr he had been taking acetaminophen for occasional headaches and therefore to his knowledge had not been exposed to aspirin. He had hypertension, for which he received treatment. Physical examination revealed blood pressure of 150/f 10. Nasal examination revealed congested, purple membranes, which completely obstructed the nasal passages. His maxillary antra could not be transilluminated with light. Chest was clear to auscultation while taking antiasthmatic medications. Nasal smear revealed no eosinophils and many bacteria. Sputum and nasal cultures did not grow pathogens. Serun IgE level was 99 p/ml. IgA was 82, IgG 760, and IgM 222 mg/lOO ml. White blood cell count was I 1,000 without any peripheral eosinophils. Sinus roentgenograms showed thickening of the mucosa of all paranasal sinuses. Cutaneous tests for immediate hypersensitivity to common aeroallergens were negative. Methacholine inhalation challenge on June 22, 1977, induced bronchospasm (Fig. 3). On June 24. 1977, the patient underwent an aspirin challenge,

J. ALLERGY

84 Stevenson et al.

CLIN. IMMUNOL. JULY 1980

Methacholine Inhalation Challenge

ASA Oral

Oate119791 FIG. 2. Patient 1 (N. F.). Simultaneous presentation of FEV, values in liters and aspirin dosage and methylprednisolone dosage in milligrams per 24 hr during nine days hospitalization. Aspirin challenge occurred on day 3 with 300 mg aspirin, and daily treatment with aspirin occurred during days 4 through 9 (arrowsj. On day 8 she received 1,200 mg aspirin. Methacholine inhalation challenge occurred on day 9 (arrow) and produced significant bronchospasm.

TABLE I. Clinical

course

of patient

1 (N. F.) Beclomethasone diproprionate bddayl

Date 3/12/79 3/20/79 3/30/79 4/18/79 6/18/79 6/19/79 g/22/79 9/17/79 10/17/79 12/10/79

Aspirin (mgfday) 0 325 325 325 325 325 325 650 650 650

Methylprednisolone orally bgf 8 4 4 4 2 16 8 6 4 2

q.o.d. q.o.d. q.o.d. q.o.d. q.o.d. q.d. q.o.d. q.o.d. q.o.d. q.o.d.

Orally

Nasally

400 400 400 400 400 -

200 200 200 200 200 -

400 400 400 400

200 200 200 200

FEV,

Nasal symptoms*

ml

3+

1,900

1+ I+

2,300 2,320 2,320 1,400 2,100

2-k 2+ 2+ 3+

1+ 0 0

1,900 1,850 1,910

1,950

Predicted (%I

t

70 84 85 85 52 78 70 68 70 71

q.o.d. = every other day; q.d. = every day. *O, None; I+. mild; 2+, moderate and intermittent; 3+, moderateand constant; 4+, severe. tPredicted FEV,, 2,730 ml. ingesting 3 mg aspirin at 8:15 A.M., 30 mg at 8:45, and 300 mg at 9: 15. Two hours later ( 11: 15) the patient developed nasal congestion and wheezing. The FEV, values decreased from a baseline of 2,700 to 1,140 ml (59% reduction in FEV,) with a concomitant reduction in the descending limb of the flow volume curve from a baseline MEF at 50% of FVC of 4.9 to 0.9 L/set (Fig. 4). He was treated with inhalations of isoproterenol aerosol and intravenous amino-

phylline

and methylprednisolone.

The FEV, values im-

proved to 1,690 ml in 15 min, 1,730 ml in 3 hr, and 2,160 ml in 4 hr. On another day the patient ingested an antacid,

and FEV, values declined by less than 10% from baseline values over the ensuing 3 hr. The patient was treated with a program of anhydrous theophylline (250 mg three times a day) and metaproterenol (one inhalation four times a day), followed by beclo-

VOLUME NUMBER

Tolerance to aspirin after challenges 85

66 1

llmin

Baseline

Baseline

4 Llmtn

z

After 2.5mglml Methacholine

(41%5 FEV,)

2 Hours After Ingesting 2

300mg of Aspirin

Llmin

(59% 4 FEV,l

b

1

2 L

FIG. 3. Patient 2 (R. B.). Flow-volume curves before and after methacholine inhalation challenge 6/22/77,which induced a 41% decline in FEV, values.

FIG. 4. Patient 2 (Ft. B.). Oral aspirin challenge 6/24/77 with a similar but more pronounced contraction of the expiratory flow-volume curve as compared with Fig. 3. FEV, values decreased 59% 2 hr after ingesting 300 mg aspirin.

methasone(three oral inhalations four times a day and one nasalinsufflation twice daily), one nasaldecongestanttablet (Drixoral) at night, and prednisone 10 mg each morning. Prednisonewas reduced to 5 mg each morning, and by the fall of 1977to 7.5 mg on alternatedays. However, attempts to reduce prednisone below this level were not successful because of breakthrough of asthma or nasal congestion. Theophyfiine was discontinued becauseof intractable nauseaeven with low theophylline plasma levels. In preparation for investigative studies a second aspirin challenge was carried out on March 26, 1979, using 325 mg aspirin and produced identical results as shown in Fig. 4. On April 1, 1979, the patient was admitted to the General Clinical ResearchCenter to participate in aspirin-challenge studies with simultaneous measurementsof ventilationperfusion ratios and sampling of arterial, venous, and central venous blood (Fig. 5). On April 4, 1979, the patient underwent aspirin challenge. Following ingestion of 300 mg aspirin the FEV, values dropped 25% in 1 hr, and another 150 mg aspirin was added for a total challenge dosageof 450 mg. This produced rhinorrhea, flushing, ocular lacrimation, and dyspnea accompaniedby a 50% reduction in FEV,. The patient was treated with inhalations of isoproterenol aerosol, subcutaneousepinephrine, and intravenous

corticosteroids, and on the following morning he was asymptomatic.Aspirin ingestion was repeatedusing 450 mg aspirin, but he remainedasymptomaticand the FEV, values remained unchanged. On April 7, 1979, he was discharged with the following program: aspirin (Bayer) 325 mg each morning; beclomethasone(two inhalations orally four times a day and one nasally twice daily), 1 nasal decongestant tablet (Drixoral) twice daily, antihypertensive (Dyazide) once daily, Methyldopa (Aldomet) 500 mg four times a day, allopurinol 100mg four times a day, prazosin hydrochloride (Minipress) 1 mg three times daily, and prednisone5 mg on alternate days. His subsequent clinical course is outlined in Table II. Prednisone was discontinued in August 1979, and aspirin dosagewas increasedto 625 mg/day in November 1979. He has not required additional bursts of corticosteroids and remains asymptomatic. DISCUSSION Two aspirin-sensitive patients were shown to have aspirin sensitivity by oral aspirin challenges, using or exceeding the criteria for a positive aspirin reaction used by most investigators.2, 3, 5 Each patient under-

86

Stevenson

J. ALLERGY

et al.

CLIN.

IMMUNOL. JULY 1980

Oral

Challange

! I

1 8 I NasalCongestion Wheezing Coughing 600

1

Aspirin lmgl

3oo 1

Prednisone hgl 412 Date 11979)

FIG. 5. Patient 2 (R. B.). Simultaneous presentation of FEV, values in liters and aspirin dosages and prednisone dosages in milligrams per 24 hr during a 7-day hospitalization. Aspirin challenge occurred on day 4 with 450 mg aspirin, and daily treatment with aspirin occurred on days 5 through 7 (arrows). TABLE

II. Clinical

course

of patient

2 (R. B.) Beclomethasone diproprionate @!/day)

Aspirin (mglday)

Date

0 325 325 325 325 325 32.5 650 650

4/01/79 4/18/79 6/13/79 7/20/79 8/20/79 9/21/79 IO/21 /79 ll/l4/79 12/10/79

Prednisone orally (mg)

Orally

Nasally

5 q.o.d. 5 q.o.d. 5 q.o.d. 2.5 q.o.d. 0 0 0 0 0

400 400 200 200 400 400 400 400 400

200 200 200 200 200 200 200 200 200

q.o.d. = every other day. *O, None; I + , mild; 2+, moderate and intermittent: tPredicted

FEV,,

3+,

moderate

Nasal symptoms* 3+ If I+ 0 I+

1+ If It 1+ 4+,

ml 2,100 2,700 2,650 2,380 2,140 1.980 2,150

1,950 2,100

Predicted t 1%) 60 77 76 68 61 57 61 56 60

severe.

3,SYJ ml.

a total of three oral aspirin challenges, in which the FEV, values declined by greater than 30% (sometimes up to 70%), with associated nasal congestion, rhinorrhea, dyspnea, wheezing, and flushing but without urticaria or angioedema. Zeiss and Lackey’ described a patient with rhinosinusitis, nasal polyps, and asthma in whom repeated double-blind challenges with aspirin or placebo on

went

and constam;

FEV,

-

consecutive days led to the serendipitous discovery of a 72-hr refractory period to the adverse effects of aspirin after initial ingestion of 300 mg aspirin resulted in respiratory and systemic symptoms. Bianco et al.,X using a system to inhale acetyl salicylate, found that a refractory period to the further adverse effects of aspirin persisted after original inhalation challenge.

VOLUME NUMBER

66 1

Because of these observations, we felt it would be safe to readminister aspirin to our patients who had undergone a positive oral aspirin challenge if we administered the aspirin during the 72-hr refractory period. However, as illustrated in the case reports, our aspirin-sensitive patients were able to continue daily ingestion of 325 mg or more of aspirin, which appeared to maintain their resistance to the deleterious effects of aspirin. Furthermore, we were able to increase the dosage of aspirin, up to 1,200 mg/day in patient 1 and up to 625 mg/day in patient 2, with no alteration in their normal lung function values. Patient 1 remained refractory to aspirin when she did not take aspirin for 72 hr and was able to resume taking aspirin without adverse effects. An interesting and potentially important observation is that the clinical courses of both patients appeared to improve while they continued to take daily aspirin. Patient 1 (N. F.) described less nasal congestion, and by October 1979 her nasal examination was normal. Prior to her aspirin treatment program in March 1979, she required bursts of corticosteroids every second month, and in June and August she experienced flares of asthma, the latter probably triggered by air-pollution, and corticosteroid dosages had to be temporarily increased. However, by December I979 her maintenance methylprednisolone dosage had been reduced by 75% and her FEV, values had not declined. In a complicated disorder such as asthma. where multiple provoking factors are operative, it can be difficult to determine whether improvement has occurred and, if so, what variable is responsible for such improvement. On the surface, it appears that this patient’s clinical course is improved. Patient 2 (R. B.) has also improved while taking daily aspirin tablets. He feels better, denies significant nasal congestion, and has not had an asthmatic relapse since April 4, 1979. Objective evidence for his improvement includes a change in appearance of his nasal membranes to normal and stable FEV, values, and discontinuation of alternate-day prednisone without the previously encountered flare in rhinitis or asthma. There are some differences between these two patients. Patient 1 has sheets of eosinophiles on her nasal smear and a more hypertrophic rhinitis with excessive rhinorrhea. Patient 2 has a more traditional vasomotor rhinitis with normal epithelial cells on his nasal smear. Second, patient 2 has hypertension and is also taking antihypertensive drugs. Hypothetically, aspirin could be interacting with one of these drugs before or after its action on his lung tissues. Third, patient 2 cannot tolerate even small dosages of theophylline, because ofgastrointestinal tract symptoms.

Tolerance

to aspirin

after challenges

87

However, despite these differences both patients appeared to benefit from taking daily aspirin, particularly when the daily dosage was increased from 325 to 650 mg. To extend these promising initial observations to a larger number of aspirin-sensitive asthmatic patients, we have started a double-blind, placebo crossover study of the effects of daily aspirin versus placebo on the clinical course of aspirin-sensitive asthmatic patients. If aspirin desensitization and a refractory state prove to be attainable in some or all patients with aspirin sensitivity, several interesting points about the hypothetical mechanisms of aspirin sensitivity can also be raised. Several hypotheses that might explain aspirin sensitivity have been proposed. One is that aspirin stimulates mast cells to release mediators. This could occur if aspirin reacts directly with membranes of lung mast cells, through receptors in selected individuals, activating massive discharge of mediators. Alternatively, activation of complement with formation of C,, could stimulate mast cell discharge.g Neither sequence requires an immunologic or IgE-dependent system to deplete mast cells of their mediator burden, and both hypothetical pathways are consistent with clinical observations of cross-sensitivity with a number of antigenically distinct nonsteroidal anti-inflammatory drugs and dyes.Z, ‘. ” Evidence for this hypothesis is largely circumstantial. In a previous publication” we have reported elevated levels of venous plasma histamine in 717 aspirinsensitive patients during aspirin-provoked bronchospasm but no elevation of histamine during control challenges with placebo or sodium salicylate. More recent studies measuring histamine changes in arterial plasma samples also show elevation of this mediator during oral aspirin challenges. ” In our second patient (R. B.) histamine was released into the arterial plasma during the first aspirin challenge, where bronchospasm occurred, but no histamine could be measured in either prechallenge specimens nor after readdition of aspirin 450 mg 48 hr after the original positive challenge. Such studies suggest that mast cell discharge occurred at the time of initial aspirin reaction with histamine spilling into the peripheral circulation. However, histamine release was not occurring in the refractory state after the original aspirin challenge in patient 2. Perhaps daily additions of aspirin, either acting directly or through Csar stimulate mast cells to leak mediators into the surrounding milieu but do not provide mast cells the opportunity to reaccumulate stored mediator in high enough concentration to participate in further massive anaphylactoid reactions. In this way a postanaphylactoid state might be maintained indefinitely by readdition of aspirin. Further

88

Stevenson

J ALLERGY

et al.

evidence that lung mast cells discharge their mediators during aspirin reactions is provided by recent reports that aspirin reactions can be inhibited by prior treatment with cromolyn sodium.12. Ix Another major hypothesis grew out of the observations of Vane’” and later of Szczeklik et al.‘” that aspirin and structurally unrelated nonsteroidal antiinflammatory drugs interfere with biosynthesis of those prostaglandirrs that are dependent on the cyclooxygenase complex to convert arachidonic acid to cyclic endoperoxides. I6 Using this information, several explanations are available that might explain aspirin reactions. A blockade by aspirin at the cyclooxygenase step might encourage conversion of arachidonic acid, via lipoxygenase, into the hydroperoxide or hydroxyacid prostaglandins with formation of potent bronchoconstrictors, one of which may actually be a slowreacting substance.” Furthermore, interference of biosynthesis of cyclic endoperoxides would deprive the aspirin-sensitive asthmatic of an important homeostatic regulatory prostaglandin, whose modulation in the aspirinsensitive asthma attack might be either inhibition of mast cell discharge or bronchodilation. PGE, qualifies for such a role.” If mast cells that had been stimulated by aspirin and related compounds to release stored mediator were also deprived of PGE, by aspirin’s inhibition of cyclooxygenase, further exacerbation of the seriousness and length of the reaction might occur. Interference of cyclooxygenase by daily ingestion of aspirin would theoretically promote daily biosynthesis of lipooxygenase-dependent prostaglandins, resulting in increasing and continued asthma. Therefore any explanation for the clinical improvement in our two patients cannot be readily accounted for by continued formation of prostaglandin bronchoconstriction or depletion of prostaglandin bronchodilators by daily inactivation of cyclooxygenase by aspirin. Bronchial smooth muscle tachyphylaxis could occur, such that prostaglandin bronchoconstrictors are formed but end organ responsiveness becomes exhausted. Further fundamental studies are necessary to test these clinical observations and hypotheses. Clarification of the length of the refractory period after an aspirin-induced respiratory reaction and its applicability to a larger sample of aspirin-sensitive patients will also be important. Initial information suggests that a refractory period persisted for 72 hr after an aspirin-induced asthmatic attack in our patient 1 and in one other patient .’

CLIN

IMMUNOL. JULY 1980

Finally, we present these new findings about the behavior of aspirin-sensitive asthmatic patients to stimulate additional investigations into the mechanisms responsible for the refractory state after aspirininduced asthma and rhinitis, the length of the refractory state, and the therapeutic implications this state might have for some or all of these asthmatic patients. REFERENCES I. Cooke 2.

3.

4. 5.

6.

I.

8.

9.

10. 11.

12

13

14 I5

16 17

RA: Allergy in drug idiosyncrasy. JAMA 73:759, 1919. Samter M, Beers RF Jr: Intolerance to aspirin: Clinical studies and consideration of its pathogenesis. Ann Intern Med 68:975. 1968. Harnett JC, Spector SL, Fat-r RS: Aspirin idiosyncrasy: Asthma and urticaria, in Middleton E Jr. Reed CE, Ellis EF. editors: Allergy: Principles and practice, St. Louis, 1978, The C. V. Mosby Co., p, 1002. McDonald JR, Mathison DA, Stevenson DD: Aspinn intolerance In asthma. J ALLERGY CLIN IMMUNOI 50~198, 1972. Mathison DA, Stevenson DD: Hypersensitivity to nonsteroidal anti-inflammatory drugs: Indications and methods for oral challenge. J ALLERGY CLIN IMMUNOL 64:669, 1979. Stevenson DD, Arroyave CM, Bhat KN. Tan EM: Oral aspirin challenges in asthmatic patients: A study of plasma histamine. Clin Allergy 6:493, 1976. Zeiss CR, Lackey RF: Refractory period to aspirin in a patient with aspirin-induced asthma. J ALLERGY CLIN IMMUNOL 57~440, 1976. Bianco S. Robuschi M, Petrigni G: Aspirin induced tolerance in aspirin-asthma detected by a new challenge test. IRCS. J Med Sci 5(3):129, 1977. Arroyave CM, Stevenson DD, Vaughan JH, anb Tan EM: Plasma complement changes during bronchospasm provoked in asthmatic patients. Clin Allergy 7:173. 1977. Smith AP: Response of aspirin-allergic patients to challenge by some analgesics in common use. Br Med J 2 :494. 197 I. Simon RA, Mathiaon DA, Stevenson DD: Arterial plasma histamine and complement levels during aspirin provoked bronchospasm. International Congress of Allergology, Jerusalem, Nov. 4-11, 1979. (Abst.) Basomba A, Romar A, Pelaez A, Villamanzo IG, Campos A: The effect of sodium cromoglycate in preventing aspirininduced bronchospasm. Clin Allergy 7:269, 1976. Martelli NA, Usandivaras G: Inhibition of aspirin-induced bronchoconstriction by sodium cromoglycate inhalation. Thorax32:684, 1977. Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action of aspirin-like drugs. Nature 231:232, 1971. Sczekiik, Gryglewski RJ, Czemiawska-Mysik G: Relationship of inhibition of prostaglandin biosynthesis by analgesics to analgesics to asthma attacks in aspirin-sensitive patients. Br Med J 1:67, 1975. Vane JR: The mode of action of aspirin and similar compounds. J ALLERGY CLIN IMMUNOL 58:691, 1976. Jakschik B, Parker CW: Probable precursor role for arachidonic acid (AA) in slow reacting substance (SRS) biosynthesis. Clin Res24:575A, 1976.