VOLUME 78 NUMBER 1, PART 2 Adverse reactions to tartrazine ticaria by the identilication and exclusion of dietary factors. Clin Allergy 10:6’39, 1980 I I Juhlin L: Recurrent urticaria: clinical investigation of 330 pa- tients. Br J Dermatol 104:369. 1981 12 Chafee FH. Settipanc GA: Asthma caused by F.D. and C. approved dyes. J Allergy 4065, 1967 13. Samter M, Beers RF: Concerning the nature of the intolerance to aspirin. J Allergy 40:28 I, 1967 14. Samter hl. Beei-s RF: Intolerance to aspirin. Ann Intern Med 6X:975. 1968 IS. Stenius BSM, Lcmola M: Hypersensitivity to acetylsalicylic acid (AS;\)’ and tartrazine in patients with asthma. Clin Allergy 6: I 19. I”76 16. Kory RC. Hamilton LH: Evaluation of spirometers used in pulmonary function studies. Am Rev Respir Dis 87:228. 1963 17. Fitzgerald MX, Smith AA, Gaensler EA: Evaluation of elec- tronic spirometers. N Engl J Med 289:1283, 1973 IX. Freedman BJ: Asthma induced by sulfur dioxide. benzoate and tartrazinr contamed in orange drinks. Clin Allergy 7:407. 1977 19. Spector SL. Wangaard CH, Farr RS: Aspirin and concomitant idiosyncrasies in adult asthmatic patients. J ALERCY CLIN It+ MUNOI. 61500. 1979 20. Vedanth:m P. Menon MM, Bell TD. Bergin D: Aspirin and tartrazinc oral challenge: incidence of adverse response in chrome childhood asthma. J ALLERGY CLIN IMMUNOL 60:8. I977 21. Weber RW, Hoffman M, Raine DA. Nelson HS: lncidcnce of bronchoconstriction due to aspirin, azo dyes. non-azo dyes and preservatives in a population of perennial asthmatic{. J AL- LERG~ CLIN IMMUNOL 64:32. 1979. 22. Hariparsad D. Wilson N, Dixon C. Silverman M: Oral tartra- zinc schallenge in childhood ashtma: effect on bronchial reac- tivity. Clin Allergy 14:81. 1984 23. Tarlo SM, Broder I: Tartrazine and benzoate challenge and dietary avoidance in chomic asthma. Clin Allergy 12:303, 1982 24. McDonald JR. Mathison DA, Stevenson DD: Aspirm intol- erance in asthma: detection by oral challenge. J ALLERGY CLIN IMMIINOL 50: 198, 1972 25. Pleskow WW. Stevenson DD. Simon RA. Math&n DA, Schatz M, Zieger RS: Aspirin desensitization in aspirin sen- sitive asthmatic patients: clinical manifestations and charac- teriz,ttion of the refractory period. J ALLERGY CLIN IMMUNOI. 69:ll. 1982 26. Gerber JC. Payne NA, Oelz 0. Nies AS, Oates JA: Tartra- zine and the prostaglandin system. J ALLERGY CLIN I~IMUNOL 63:289, 1979 27. Mathison DA, Stevenson DD: Hypersensitivity to nonsteroidal anti-inflammatory drugs: indications and methods for oral chal- lenge. J AI LERGY CLIP IMM~~NOL 64:669. 1979 A critical evaluation of clinical trials in reactions to sulfites Robert K. Bush, M.D., Steve L. Taylor, Ph.D.,. and William Busse, M.D. Madison, Wis Sulfiting agents are defined as sulfur dioxide and several forms of inorganic sulfites that liberate SO, under appropriate conditions. Sulfites are usually added to foods, although they can occur naturally as a consequence of fermentation. For example, Sac- charomyes crrevisiae generates between 1 and 30 From the Department of Medicine and the Food Research Institute, University of Wisconsin, and the William S. Middleton Me- morial Veterans Hospital, Madison, Wis. Supported m part by contributions from the Corn Refiners Asso- ciation, National Fisheries Institute, National Cherry Growers and Industries Foundation, Frito-Lay, Inc., R. T. French Co.. Basic American Foods, Thomas J. Lipton, Inc., Del Monte Corp., Hershey Foods Corp., Stauffer Chemical Co., the Vet- erans Administration, and the College of Agriculture and Life Sciences, University of Wisconsin-Madison. Reprint requests: Robert K. Bush, M.D., William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705. ppm o’f SO? during the fermentation of wine; some strains may produce in excess of 100 ppm.’ Thus naturally occurring sulfites constitute a substantial portion of the total sulfite found in wine and beer. Historically the ancient Greeks used SO, to fumi- gate their homes. Later the Romans and Egyptians used SOI to cleanse their wine vessels. The first re- cordecl use of sulfites as food preservatives occurred in 1664, when cider was added to flasks of SO? to retard spoilage.’ SO, has enjoyed widespread use in the United States since the late 18OOs, and the sulfite salts have been used since the 1920s. They were first used in the manufacture of wine and beer and sub- sequently have been used in many other products. Heretofore, SO,, potassium metabisulfite, sodium metabisulfite, potassium bisulfite, sodium bisulfite, and sodium sulfite have been classified GRAS (gen- erally recognized as safe), by the U.S. Food and Drug Administration, for use in foods. Current federal reg- 191
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`J. ALLERGY CLIN. IMMUNOL. JULY 1986 192 Bush et al. TABLE I. Some common uses of sulfiting agents Use Example Control of enzymatic browning Control of nonenzymatic browning Antimicrobial action Reducing agent Bleaching Processing aid Lettuce, guacamole, cut fruits, fresh mushrooms, shrimp Dehydrated potatoes, white grape juice, dried fruit, wine Occurs naturally in fer- mentation of wine and beer; agents added to control microbial growth in production of corn syrup, beer, and wine Corn wet-milling. dough conditioner Maraschino cherries Beet sugar ulations permit their use in a variety of foods except for meats and other foods recognized as sources of thiamine. However, these regulations are under review and are subject to change. The report by the ad hoc panel of the Life Sciences Research Office, Federation of American Societies for Experimental Biology, in- dicates that for the majority of the population sulfites do not constitute a health hazard at current levels of use; however, for sulfite-sensitive persons use of these agents in fresh food should be discontinued.’ Sulfiting agents serve many important technical purposes in the food industry (Table I). In many prod- ucts, sulfites serve more than one purpose. Alterna- tives to sulfiting agents are currently being investi- gated. However, possible alternatives may be less ef- fective or more expensive and may impose their own health risks. CHEMISTRY Forms of sulfite exist in dynamic equilibrium in foods. In solution a variety of sulfite species can exist (Fig. 1). SO? readily dissolves in water to produce sulfurous acid. Bisulfites or metabisulfite salts react with water producing bisulfite ion, HSO, ~. At low pH, equilibrium favors H,SO,; at intermediate pH (4.0), HSO,- prevails; at high pH, sulfite ion, Sol’-, predominates (as lin the small bowel). SO? can be generated from H,SO, at acidic pH (as in the stomach). At pH 2.5, approximately 16% of the SO, can be liberated from H,SO,; at pH 2.0, 37%; and at pH 1 .O, 86%.’ Thus the effect of pH on these sulfite reactions must be considered in designing challenge studies in sulfite-sensitive individuals. Sulfites can react with food constituents including reducing sugars, proteins, lipids, and other compo- nents to form combined sulfites. Some of these re- actions are reversible, while others are virtually ir- reversible. The dissociable combined forms can serve as reservoirs for “free” sulfites, but irreversible re- actions remove sulfite permanently from the pool of available free SO,. Since free SO, is the most likely cause of adverse responses to sulfiting agents. these chemical reactions have significant implications re- garding which foods may cause difficulty in sensitive patients. When ingested, free sulfite is oxidized to sulfate (which is excreted in the urine) by the enzyme sulfite oxidase. This enzyme is widely distributed in the body, with the highest activity found in the liver and kidney.’ Defects in sulfite oxidase activity may po- tentially Ibe of importance in the pathogenesis of ad- verse reactions to sulfites.4 MEASUREMENT OF SULFITES Several methods for measuring sulfite residue levels in foods are available. Measurement of sulfite levels is important in determining consumption and assess- ing risk for patients suffering adverse reactions to sulfiting iagents. Sulfites exist in foods as H2SOI, inorganic sulfites, and a variety of combined forms. Since sulfite salts can release SO, under some assay conditions, levels of sulfiting agents in foods are usually expressed as SO, equivalents. Variations of the Ripper method’ are used to detect “free” SO2 (undissociated H$O?, HSO,-, and SO,‘-). The Monier-Williams method6 measures “total” S02, which includes the same sub- stances detected by the Ripper method plus some com- bined forms of sulfites. Neither method is entirely satisfactory since nonsulfite substances may interfere in the analyses, some hazardous combined forms of sulfites may not be measured under the assay condi- tions, or some combinecl forms that are not hazardous may be cletected. Ideally, methods can be developed that will enable us to specifically identify and measure those forms of sulfite that pose health risks. LEVELS OF CONSUMPTION/EXPOSURE Adequate assessment of consumer exposure to sul- fites in foods is wanting. This is partially because of difficulties with methods of measuring sulfites in foods. Furthermore, the amounts of sulfites used ini- tially to treat food do not reflect residue levels after processing. Storage and preparation of food will also affect the final amount of sulfite available for con- sumption. Caution should be exercised when evalu- ating reports from other countries incriminating foods in the production of asthma symptoms, since many of these foods (such as orange drinks’) are not typi- c~lly sulfited in this country.
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`VOLUME 78 NUMBER 1. PART 2 Air Evaluation of trials in reactions to sulfites 193 SO2 sulfur dioxide Fluid ( 40) H2S03 sulfurous acid i4 pKa=l.81 bisulfite or HSO; --metabisulfite salts bisulfite ion JT pKa= 6.91 SOJ --sulfite salts sulfite ion i sulfite oxidase so; sulfate ion FIG. 1. Chemical reactions of sulfites in solution. Estimated consumption levels for U.S. citizens have recently been reviewed.’ The total daily per cap- ita intake of sulfites for foods, expressed as SO, equiv- alents, is approximately 6 mg. Beer and wine con- tribute additional amounts, with another 30 mg for each 200 ml of wine and 10 mg for each liter of beer consumed. During the course of a restaurant meal, however, higher amounts may be encountered, the most widely cited example being that of lettuce from salad bars. which may be treated with sulfites. Taylor et al.* treated lettuce with a commercial salad fresh- ener and detected 450 to 950 ppm of SO:. The levels were virtually unchanged after 24 hours of refriger- ation. Thus if an individual consumes a serving of 100 gm of treated lettuce, he would consume 95 mg of sulfite as SO,. Consumption of 200 ml of wine containing 150 ppm of SO, would provide an addi- tional 30 mg; lesser amounts may be contributed by dehydrated potatoes and shrimp, for a total of 175 to 180 mg for a restaurant meal. In addition to exposure through ingestion, individ- uals are also exposed to SO, by inhalation. Using estimates of air quality standards, the Federation of American Sociel.ies for Experimental Biology panel’ predicted that an individual may be exposed to 0.85 mg of SO, per 24 hours, assuming a 0.3 ppm level in the air during the course of 1 year. In industrial environments, higher intermittent levels of up to 5 ppm per 8 hours, are permitted. Such exposure could contribute 59 mg during the g-hour period.’ Last, a variety of pharmaceutical agents, including those used in the treatment of asthma and allergic diseases, contain sulliting agents.‘, ‘(I Ordinarily, ex- posure levels through these agents are quite small. However, infusion of 500 ml of a solution containing 0.1% NaHSO, would result in an intake of 300 mg of SO, equivalents.3 ADVERSE RESPONSES TO SULFITES IN NONASTHMATIC SUBJECTS Exposure to sulfites can occur through a variety of routes (Table II). Toxicity studies in normal individ- uals have been conducted, primarily through oral chal- lenges and inhalation studies. Small numbers of nor- mal individuals have ingested doses of as much as 400 mg of SO, equivalents per day without adverse effect.’ However, doses of 4 to 6 gm per day pre- dictably caused nausea, vomiting, gastric irritation, and occasional gastrointestinal hemorrhaging. ” In- halation studies indicate that SO, at 6 to 12 ppm causes immediate irritation of the nose and throat and bron- choconstriction, and excessive concentrations of SO, cause laryngotracheal and pulmonary edema and death. ” Harkonen et al. ” observed long-term obstruc- tive airway changes and airway hyperreactivity to in- haled histamine in four individuals acutely exposed to high concentrations of SOz. In spite of a great deal of attention in the popular media and anecdotal reports. adverse reactions to sul- fites in nonasthmatics are extremely rare. FisherI de- scribed dermatitis of the hand in a food handler ex- posed to sulfiting agents. Wang et al.‘” implicated NaHSO, contained in an epidural anesthetic, 2-chlo- roprocaine, as the cause of neurologic deficits in a
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`194 Bush et al J ALLERGY CLIN IMMUNOL. JULY 1986 TABLE II. Rob&s of sulfite exposure _________ Route Example Ingestion as solid Oral medication Ingestion as solution Beer, wine, sprays on vcgeta- bles and fruits at salad bar Inhalation Smog, opening package of dried fruit, air above salad bar, bronchodilator solution aerosols Subcutaneous in- Epinephrine, lidocaine jection Intravenous in- Corticosteroid preparations, jcction metoclopramide -__ small number of patients. No direct evidence for this association was presented. However, injection of 1.2 to 2.4 mg of NaHSQ, into the subarachnoid space of rabbits produced a chronic hindlimb paralysis similar to the clinical picture in humans. Administration of the anesthetic without NaHSO, had no effect. Prenner and Stevens” were the first to report al- lergic-like symptorns. These occurred in a SO-year- old man who had generalized urticaria and angio- edema of the tongue with swallowing difficulty and chest tightness after ingesting restaurant salads. When the patient underwent oral challenge with NaHSO, solutions to a total dose of 10 mg, he experienced itching, nausea, warmness, cough, tightness in the throat. and erythema of the shoulder but not urticaria or angioedema. Both scratch and intradermal testing with NaHSO, solution (10 mgiml) produced a wheal- and-flare response. Control individuals were negative to scratch and intradermal testing with the same so- lution. When the patient’s serum was passively trans- ferred to a nonatopic individual and the site challenged with NaHSO, solution, a wheal-and-flare reaction ap- peared. While the passive transfer test suggests an IgE mechanism, a specific antibody to sulfite was not iden- tified. Habenicht et al .I6 described two women who re- ported urticaria and angioedema after ingestion of sul- fited foods. One patient underwent an oral challenge with capsules of K&O, in increasing doses, without a placebo control. Fifteen minutes after the 25 mg dose she developed burning of the scalp and urticaria. No changes in pulmonary function were noted. Schwa&” performed challenge studies in two in- dividuals. The first, a 24-year-old man, had symptoms of angioedema involving the face and periorbital area, abdominal cramps, and diarrhea 10 minutes after in- gesting a lettuce salad in a restaurant. A placebo- controlled. single-blind oral metabisulfite capsule challenge was conducted. After 10 mg, the patient developed tightness in the stomach and light-head- edness; with 25 mg he developed abdominal distress, light-headedness. dizziness, and hypotension. Pul- monary functions were unchanged. The second in- dividual, a 34-year-old woman with asthma, experi- enced dizziness, nausea, dysphasia, and chest tight- ness after a restaurant meal. A similar challenge produced weakness, dizziness, and nausea, with mild hypotension but no change in pulmonary function after a 30 mg dlose of K,S20,. Huang and FraserlX suggested that subcutaneous ad- ministration of sulfites could also provoke urticaria, angioedema, and laryngeal edema. Subcutaneous in- jection of 1.8 ml of lidocaine, which contains 0.5 mg of NaHSCl,, produced palmar pruritus in the patient. No control challenge was administered. Flaherty et al.” identified a patient with sclerosing cholangitis whose liver condition worsened after sul- fited foods were ingested. Liver functions improved on a sulfite-free diet. Double-blind oral challenge with 500 mg of metabisulfite and lactose resulted in an increase in liver enzymes after sulfite challenge but not with placebo. The response could be inhibited by prior oral administration of 3 mg of vitamin B,?. Challenge studies in la.rger numbers of patients with a risk for adverse reactions to sulfites have failed to identify a significant number of reactors. Sonin and Patterson’” challenged 10 control subjects, one patient with chrolnic urticaria, and 12 patients with idiopathic anaphylaxis, nine of whom had a history of reactions associate’d with restaurant meals, with increasing oral doses of Na,S,O, dissolved in lemonade. None of the patients reacted to doses totaling 391 mg. Challenge studies from the National Institutes of Health” con- ducted on 25 patients with unexplained anaphylaxis and eight patients with systemic mastocytosis pro- duced anaphylactic episodes in only two patients, both of whom had unexplained anaphylaxis. However. the same two individuals also reacted to placebo chal- lenge. Therefore it appears that anaphylactoid reac- tions ma.y occur in otherwise normal individuals. but such reactions are rare ASTHMATIC RESPONSES TO SULFITING AGENTS Sufficient data have accumulated to implicate inges- tion of sulfites in the production of attacks of asthma. In the earliest report, Kochen” described a young child with repeated episodes of asthma after ingestion of dried. fruits contained in hermetically sealed bags. However, confirmatory provocative challenges were not conducted. Subsequent studies by Stevenson and Simon” have more convincingly established that some asthmatics can experience episodes of bronchospasm
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`VOLUME 78 NUMBER 1, PAQT 2 Evaluation of trials in reactions to sulfites 195 after ingestion of sulfiting agents. They reported four steroid-dependent women, aged 27 to 65 years, who experienced episodes of asthma associated with ana- phylactoid symptoms such as flushing, weakness, diz- ziness, and cyanosis with loss of consciousness. In a single-blind, placebo-controlled K,&O, oral capsule challenge, all four subjects experienced significant de- creases in FEV, (23% to 49%). The challenge was repeated in one individual, with similar results. Re- sults of skin tests with sulfiting agents were uniformly negative, as were basophil histamine release assays performed on the patients’ peripheral blood. These results suggested that an IgE-mediated reaction was not involved. Simultaneously, Australian investiga- tors” described two steroid-dependent asthmatic women who related attacks of asthma associated with ingestion of sulfited foods and beverages. One also had experienced a respiratory arrest after intravenous infusion (of a sulfited dexamethasone preparation. Both individuals had severe bronchospasm on double- blind challenge with a 500 mg dose of Na2S20s. These studies provide convincing evidence that capsules con- taining sulfiting agents can provoke episodes of wheezing in certain asthmatics. Ingestion of sulfited solutions is more likely to pre- cipitate asthma attacks than is ingestion of encapsu- lated sultites. Towns and Mellis? found that 19 of 29 (66%) steroid-dependent asthmatic children re- sponded to an acidic metabisulfite solution challenge, whereas none of the children reacted to metabisulfite in capsule form. Freedman’ challenged 14 asthmatics with a history of exacerbation of asthma after drinking a sulfited orange drink preparation. The challenge so- lution contained Na,S,O, in citric acid and was cal- culated to contain 100 ppm of SO,. The study was not placebo controlled or double blinded. Eight of the 14 individuals reacted with a 12% or greater drop in FEV, (range, 12% to 57%). One individual who ex- perienced only a 12% drop was rechallenged with an additional 75 mg of Na&O, and responded with a 37% decrease in FEV,. We have prepared a solution similar to that described by Freedman and found the pH to be 2.9. A.t this pH, most of the free SO, would exist as HSO, - and about 10% as HSO,. About 6% of the sulfite would be evolved as gaseous SO, at this pH. Therefore it is highly likely that volatilized SO2 was being inhaled by the individuals reported by Freedman and Towns and Mellis. Asthmatic subjects have significant bronchocon- striction on inhalation of 1 ppm of S02.2h The bron- choconstricting effects of SO, inhalation are further potentiated by mild exercise. SO, is highly soluble in aqueous media such as the mucous or aqueous linings of the respiratory airways. At concentrations of 1 to 50 ppm, approximately 99% of SO, is absorbed by the upper airways. ” Animal studies indicate that in- sufflation of SO, into the isolated upper airway caused constriction of both upper and lower airways. These responses were further shown to be dependent on in- nervation of the larynx and tracheobronchial tree.‘6 The effects can be partly blocked by administration of aerosolized atropine, suggesting that the broncho- spasm caused by SO, is mediated through the para- sympathetic pathway and is probably initiated by stim- ulation of afferent nerve endings lying superficially in the larynx or tracheobronchial tree.‘h To date. no direct proof for this exists in human beings. Not unexpectedly, acute bronchoconstriction can also be provoked when asthmatic subjects are exposed to sulfiting agents by inhalation. Twarog and Leung” described a steroid-dependent asthmatic who on two occasions developed severe airway obstruction re- quiring intubation and mechanical ventilation shortly after receiving nebulized isoetharine (a sulfited bron- chodilator). Intradermal skin testing of the patient to an aqueous NaHSO, solution (0.1 mgiml) produced a wheal-and-flare reaction. Three control subjects in- jected intradermally with 1 mgiml did not react. Leu- kocytes isolated from the patient’s peripheral blood released 20% of their total histamine content when they were exposed to Na,S,O, at lo- ’ to 10 ’ mol/L. Leukocytes from nonsensitive individuals showed no significant histamine ,release when treated in a similar fashion. Attempts to passively sensitize a monkey with the patient’s serum were unsuccessful. The pa- tient’s sensitivity to sulfites was confirmed by a pla- cebo-controlled, double-blind oral challenge. with graded doses of Na&O, in water as the challenge material. Ten minutes after ingesting 5 mg of Na&O, the patient developed acute wheezing and generalized flushing without urticaria, and the FEV, dropped 52% from baseline. There was no evidence of an increased level of histamine in the patient’s plasma, and there was no change in total hemolytic complement values. Koepke et al.” detected varying concentrations of SO? produced during nebulization of several broncho- dilator solutions. These ranged from 6 ppm for iso- proterenol (Isuprel). to 1.4 ppm for isoetharine (Bron- kosol), to 0.4 ppm for metaproterenol (Alupent). The authors performed aerosolized sulfite challenges on two individuals previously shown to be sensitive to sulfiting agents by oral challenge. The subjects re- ceived control inhalations of normal saline solu- tion. After inhalation of varying amounts of the 0.6 mgiml Na&O, solution, the patients had a marked fall in pulmonary function. Interestingly, they exhib- ited a bronchodilator response to inhalation of an isoetharine solution. A third individual. who gave a
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`196 Bush et ill J ALLERGY CLIN IMMUNOL JULY 1986 history of dyspnea ,with inhaled bronchodilator solu- tion. reacted to a blinded oral challenge with Na&O, but was not challenged with an inhalation technique. The authors concluded that, while the vast majority of asthmatics will bronchodilate after inhaling sulfited B-adrenergic aerosol solutions, the presence of sulfites could account for the paradoxical bronchospastic re- sponses seen tn some asthmatics. Further evidence for this apparent paradoxical response to bronchodilator solutions containing sulfites was reported by Koepke et al.” Theii subject. a 3l-year-old, steroid-depen- dent, asthmatic woman, developed airway obstruction from sulfites tontained in isoetharine in a dose-related manner. She had a bronchodilator response to low concentrations of isoetharine; however, with increas- ing concentrations of the material or increasing num- bers of breaths at the same concentration, she devel- oped a paradoxical response (i.e., bronchoconstric- tion). Inhalation of a nonsulfited bronchodilator. terbutaline, produced the expected improvement in pulmonary function. However, when an amount of metabisulfite equivallent to that found in the isoethar- ine was added to the terbutaline, the patient once again had a decline in pulmonary function. In confirming the observations of Koepke et al.,‘” Witek and Schachter “’ showed that sulfited bronchodilator so- lutions generate SO? at concentrations greater than or equal to 2 ppm. Aerosols generated from compressed air sources produced higher levels than did solutions nebulized in a hand-bulb device. Bronchodilator so- lutions without sulfites did not yield detectable SO,. Subjects responding only to aerosolized challenge (not to ingested sulfiting agents) have also been de- scribed. Werthj’ described an individual who failed to respond tcb oral challenge with placebo and doses of as much ;ts 50 rng of K&O,. Nebulized admin- istration of varying (concentrations of K&O, in a ster- ile water solution resulted in a marked fall in FEV,. This subject also reacted with wheezing and flushing when he sniffed a bag of dried apricots. Sulfite inhalation studies in larger series of patients including both sulfite- and non-sulfite-sensitive asth- matics have ileen performed. Koepke et al.” admin- istered 20 inhalations of a sulfite aerosol containing 0.8 to 1.2 ppm of SO, and found that all three sulfite- sensitive subjects tested had a decline in FEV, of greater than 20%. Four of 10 non-sulfite-sensitive asthmatics h.rd similar declines in pulmonary func- tion, and there was a general downward trend in pul- monary function in the remaining subjects. The data suggest that asthmatics sensitive to ingested sulfites also react to inhaleld sulfite-containing aerosols. Ad- ditionally, some asthmatics who do not exhibit sen- sitivity to or.4 ingestion of sulfite do respond to in- haled aeroso’s. Schwartz and Chester” present a different picture from that ‘of Koepke et al. Eight asthmatics with his- tories suggesting sulfite sensitivity underwent oral metabisulfite challenge. Six of the eight developed airway obstruction at doses between IO and SO mg: two did not react to the 50 mg dose. Sub.jects were then exposed to aerosolized solutions of K,S,O, at two different concentrations, 0.5 mg/ml and 5.0 mgiml. No detectable SO, was generated from the 0.5 m&/ml solution, but the 5.0 mg/ml solution generated 1.2 ppm SO?. One patient did not react to either aero- sol or oral challenge, one patient reacted to oral chal- lenge but not to aerosol, one patient was negative to oral challenge but reacted to the aerosol challenge at 5.0 mgiml, and the remaining three reacted to both aerosol and oral challenge. These data suggest that a positive oral sulfite challenge is usually but not in- variably accompanied by a positive aerosol challenge. Although subcutaneous administration of sulfites could theoretically provoke asthma in some individ- uals, no convincing evidence has appeared. Some pharmaceutical agents for intravenous use contain sul- fites, and :he reports of Baker et al.” and Twarog and Leung” suggest that such agents can provoke asthma. However. intravenous challenges have not been per- formed. In summary, it would appear that most individuals identified as sulfite sensitive by challenge with cap- sules or solutions of sullites are likely to respond to inhaled solutions of sulfiting agents as well. SO, gen- erated by the nebulization process most likely ac- counts for the reaction. Conversely, a number of patients have been described who fail to respond to oral challenge yet respond dramatically to inhalation challenge. MECHANISM(S) OF SULFITE SENSITIVITY At present the mechanism(s) of sulfite sensitivity are not completely understood, but their elucidation could offer insights into the cause of asthma. Prenner and Stevensls demonstrated a positive passive transfer test with serum from their patient who developed ur- ticaria from sulfites. This patient also exhibited an immediate skin test reaction to the sulfites, which was not present in control subjects. Although these data are highly suggestive of an IgE-mediated mechanism, IgE antibodies to sulfites have yet to be demonstrated directly. The patient described by Twarog and Leung”’ also had an immediate positive skin test result toward Na,SZOS, as well as in vitro leukocyte histamine re- lease. Although again these data suggest the existence of an I&E-mediated reaction, a specific antibody was not identified. Stevenson and Simon” and Schwartz and Chester” could not demonstrate positive skin test results in t.heir patients. Incubation of peripheral blood
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`VOLUME 78 NUMBEA 1, PAFT 2 Evaluation of trials in reactions to sulfites 197 leukocytes with K$,O, in the patients described by Stevenson and Simon failed to induce histamine re- lease. Thus it would appear that IgE-mediated mech- anisms, if they exist at all, are exceedingly rare in sulfite-sensrtive individuals or are limited to a subset of patients. Nonimmunologic release of mast mediators may play a role in the pathogenesis of sulfite sensitivity. Meggs et al.” found a twofold increase in plasma histamine levels after sulfite challenge in six of seven patients with systemic mastocytosis and 15 of 23 with unexplained anaphylaxis. However, the increase in plasma histamine levels was not associated with clin- ical symptoms. Altman et a1.j” measured neutrophil chemotactic activity in the sera of six asthmatic sub- jects undergoing oral K&O, solution challenges. Three of the six patients had a 20% or greater drop in FEV,. Both groups had an increase in serum neu- trophil chemotactic activity (23% in challenge-posi- tive group and 14% in challenge-negative group). The difference between groups was not statistically sig- nificant, nor did the release of neutrophil chemotactic activity corncide with pulmonary function changes. While these data suggest that nonimmunologic release of mast cell or basophil mediators may occur, the role of this phenomenon in the pathogenesis of sulfite sen- sitivity has yet to be established. Bronchoconstriction after inhalation of low con- centrations of SC)? (0.5 to 5.0 ppm) is a feature of asthma. The mechanism of bronchoconstriction dur- ing inhalation of SO? is a cholinergic reflex response.‘h In animal models, bronchoconstriction to inhaled SO? is blocked by cutting the vagal trunks, which would indicate that SO,! acts through the parasympathetic pathway. f’remedication of six sulfite-sensitive asth- matics with nebulized atropine (1 to 4 mg) inhibited bronchoconstrictilon from capsules of metabisulfite in three subjects and partially abrogated the response in an additional two, lending support to the cholinergic reflex as the mechanism for the bronchoconstrictive response.“‘ Delohery et al.” found that sulfite-sensitive asth- matics who reacted to ingestion of acidic solutions of metabisulhte were no more responsive than were non- sensitive asthmatics to inhaled SO?. These subjects did not respond to metabisulfite instilled into the stom- ach through a nasogastric tube. However, they did respond to a metabisulfite solution administered as a mouthwash that was not swallowed. These sulfite- sensitive subjects were not any more responsive to the effect of inhaled histamine than the group of nonsul- fite-sensitive asthmatics. The authors speculate that asthmatics who respond to ingestion of acidic sulfited solutions svariably inhale quantities of SO:. Further evidence for this comes from the fact that if sulfite- sensitive asthmatics inspire deeply and hold their breath they can swallow acidified sulfite solutions with no reaction. This also suggests that variable inhalation of SO2 is the route of exposure. rather than absorption of sulfite through the oral mucosa. Thus