- Email: [email protected]
ORAL DIAGNOSTIC CHALLENGES
COMPREHENSIVE CARE
IN THE ALLERGY/ASTHMA OFFICE
0889-8561/99 $8.00
+ .OO
ORAL DIAGNOSTIC CHALLENGES Marilyn A. Daniels, BSE, RN
Over 2000 years ago in ancient Greece, Hippocrates (460-375/351 recorded his observations of an adverse food reaction (i.e., milkinduced),18and in his treatise on ancient medicine, admonished patients to “search out food befitting their nature.’17 Writings from Galen, physician and philosopher (130-200 AD), indicate that the Romans were also well aware that foods safely consumed by most of the population could not be tolerated by some and could initiate many forms of adverse reactions.16 Centuries later, in 1921, Carl Prausnitz and Heinz Kustner, in a significant breakthrough contribution, demonstrated the passive transfer (P-IS) test. By injecting his own serum into Prausnitz, who had a known sensitivity to fish, Kustner was able to provoke a wheal and flare response at the injection site following fish ingestion by Pra~snitz.‘~ Although now used only for special purposes because of the risk of transmitting AIDS and other diseases, the test succeeded in establishing substances in blood serum as the causative factor in food allergy. Blinded, placebo-controlled food trials were introduced in 1950 by Loveless who incorporated ”food masking” techniques to disguise a suspected food in a safe food, thereby avoiding detection by the patient.l0,l1 At that same symposium, Graham et a1 presented a paper examining the placebo effect.Patients in this study reacted more to what they believed was being administered than to the actual food, showing once again the human mind’s ability to conjure up and to remand symptom^.^, l5 BC)
From Northwest Asthma and Allergy Center, Seattle, Washington
IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA VOLUME 19 * NUMBER 1 FEBRUARY 1999
75
76
DANlELS
Further pioneering work by May, in 1976, used the double-blind, placebo-controlled food challenge (DBPCFC),14a procedure that continues to be recognized as the standard in diagnosing food allergy.18 PRELIMINARY PROCEDURES
To determine the need and design considerations for an appropriate oral challenge, preliminary procedures generally consist of some or all of the following: (1) a thorough physical examination evaluating acute and chronic problems with emphasis on the gastrointestinal, cutaneous, and respiratory systems; (2) a carefully focused, complete medical history pinpointing the suspected item(s), quantity consumed, length of time between ingestion and development of symptoms, description of symptoms including duration, reproducibility, frequency, timing, the most recent occurrence of the reaction, whether an accompanying component such as exercise or behavioral,€actors is required to elicit the reaction, and family history; (3) a diet diary kept by the patient (or adult family member) in which all ingested substances and subsequently incurred symptoms are recorded, as well as timing of symptoms, quantity consumed, reproducibility, and medications taken; (4) an elimination diet prior to the challenge to determine if omitting the suspect substance brings resolution of symptoms or to-manage symptoms of adverse reactions and promote a stable baseline; (5) prick skin testing to screen patients with suspected IgE-mediated food hypersensitivity; and (6) radioallergosorbent tests (RAST) and other immunologic testing, biochemical testing, and additional laboratory studies as appropriate.8 OPEN CHALLENGES
Open food challenges in which the patient and the nurse administering the challenge know the content of the food being ingested are useful in the practice setting, especially with very young children likely to have a minimal psychogenic component. Open food challenges are most often used when the skin test is negative, the history is vague or doubtful, the elimination diet has failed to produce a definitive result, or the patient has been avoiding the food. Because the majority of challenges do not reproduce the symptoms and therefore disprove the history: open challenges in the clinic office are valuable and very practical with the considerable advantages of being time efficient and comparatively inexpensive to administer. Prior to the challenge, the suspected food should be eliminated from the diet for a minimum of 24 hours up to 7 to 14 days. Most patients will already be avoiding the substance thought to be medically harmful to them. Antihistamines are generally discontinued for a long enough time to elicit a normal histamine skin test. Other medications are reduced to minimum levels that are believed adequate to curtail
ORAL DIAGNOSTIC CHALLENGES
77
eruptions of acute symptoms.ls Those to consider avoiding prior to the challenge are P-agonists (12 hours), theophylline (12 hours), cromolyn (12 hours), and tricyclic antidepressants (96 hours or longer).2 The open challenge is optimally made when no symptoms are present, and is conducted early in the day (following an overnight fast), attended by well-qualified staff capable of providing individual attention and skilled at administering emergency treatment. Whether to perform the challenge in the clinic office or in a hospital setting depends on the patient’s history of reaction, the response time to engage paramedic assistance, and proximity to hospitals or emergency care facilities. Foods are introduced one at a time while the patient is carefully monitored for recurrence of symptoms. Although most often individualized, the initial challenge is made with a safe dose unlikely to cause symptoms, generally 20 mg to 2 g of dried food or one quarter teaspoon to 1 tablespoon of fresh food, depending on the history reported. The quantity of food is then increased incrementally (doubling is common) at timed intervals, again determined by patient history, until a reaction is provoked or the ingested amount reaches either 8 to 10 g of dried food, a standard portion of fresh food, or an amount equal to or greater than the prior symptom-provoking p0rti0n.l~ As in all oral challenges, the signs and symptoms recorded should mimic those gleaned from the patient history before considering the provocation reaction positive.
SINGLE-BLIND, PLACEBO-CONTROLLED CHALLENGES General principles of the open challenge are repeated in the singleblind, placebo-controlled food challenge; however, to eliminate a possible source of bias, the patient receives unidentifiable encapsulated dried or powdered food or suspect food disguised in safe food along with similarly camouflaged placebos. Obviously, the administrator of the challenge must exercise caution not to show undue concern or give unintended messages through body language or other expression when the incriminated food is ingested by the subject. Such challenges are considered to be a safe, practical approach; they are easy and speedy to administer and allow the tester to individualize doses and to use additional placebos when warranted. They are a useful screening tool in the clinic setting to document the absence of symptoms and to refute an unclear history or subjective symptoms, especially when a single substance is implicated.2A positive result (reproducing the patient’s historical signs and symptoms) may be confirmed later through a DBPCFC. Ideally, a negative result of any blinded challenge calls for reintroducing the food openly into the patient’s diet in the usual portions and customary manner under observation of the physician.
78
DANIELS
DOUBLE-BLIND, PLACEBO-CONTROLLED CHALLENGES
Because of its diagnostic accuracy, as illustrated by Bock and Sampson, the DBPCFC currently is state-of-the-art for diagnosing food allergy.3,l9 Whereas inclusive of oral provocation general principles discussed previously, the defining characteristic of the DBPCFC is that patient, nurse, and physician are all blinded to test substances and placebos in their disguised form, ensuring elimination of bias on all levels. This challenge is necessary in research studies, in equivocal clinical situations, and to confirm positive reactions elicted from open or single-blind challenges. All single- and double-blind challenges must be appropriately controlled. Two commonly used techniques are (1) to conduct a straight placebo challenge on a separate day for the same length of time as the proposed active challenge, and (2) to randomly intermingle approximately equal numbers of placebos and active agents during the actual ~ha1lenge.l~ A single positive outcome from a DBPCFC is considered adequate to establish a diagnosis if only objective symptoms are being investigated; evaluation of subjective symptoms calls for two or more sets of challenges because of the strong possibilitl (up to 50%) that the patient will experience symptoms during the provo~ation.'~ Additionally, when investigating subjective symptoms, the placebo and food must be crossed over several times to ensure reproducibility, and a repeat challenge is called for after several months to determine if the problem is ongoing.' Anecdotal claims aside, the literature is supportive of the position that delayed-onset food reactions caused by immunologic responses are rare and limited primarily to diarrheal responses in young children.' Generally, patients experience a prompt onset of symptoms, usually minutes to hours, following ingestion during provocation.' CHALLENGING PATIENTS WITH ANAPHYLAXIS
Because patient safety is paramount in any challenge, many allergists believe that no patient with a convincing profile of anaphylaxis should undergo a provocative oral challenge. A history consistent with a severe life-threatening allergic reaction developing after the isolated ingestion of a suspected food and requiring emergency treatment by a physician, coupled with in vitro IgE food-specific antibodies or a positive in vivo skin test, is considered sufficient for a presumptive diagnosis. Situations that may prompt oral challenge of patients with food anaphylaxis are to unequivocally identify the suspect food and to determine whether a young child who appears to have outgrown previously diagnosed life-threatening food anaphylaxis has really done so.* Such patients should only be challenged under the most rigid and strictly
ORAL DIAGNOSTIC CHALLENGES
79
controlled circumstances with well-trained personnel and appropriate equipment for resuscitation present at all times. Patients with a history of anaphylaxis must be challenged using very small doses with incremental increases adjusted downward from the usual doubled dose. Often a liquid vehicle with good masking ability is preferred for the following reasons: it may be more easily administered to young children; it may be easier to control the amount of food consumed; the problem of slow dissolution of capsules is eliminated; and in cases of oral allergy syndrome when all reported symptoms involve only the oropharynx (pruritus or swelling of the tongue or pharyngeal structures) and liquids provide the needed contact of food to mouth. Before each dose, subjective complaints and physical findings are noted on a clinical manifestation recording sheet. Vital signs including pulse and blood pressure are consistently monitored to differentiate a vasovagal (decreased pulse and blood pressure) from a genuine anaphylactic (increased pulse and decreased blood pressure) reaction. Peak flow rates are carefully measured, and the challenge is discontinued if the flow rate or blood pressure drops.20% or more from baseline or if the patient experiences systemic sympt0ms.b Withholding medications from patients who have recurring anaphylaxis may sometimes be necessary if they are totally effective in controlling anaphylaxis.20In extreme cases, hospitalization may be warranted with intravenous access in place before beginning the challenge. CHALLENGING PATIENTS WITH ASTHMA
Safety issues dictate that challenges in patients with asthma should be performed only when the subject’s asthma is stable and the forced expiratory volume in 1 second (FEV,) is greater than 1.5 L and greater than 70% of predicted normal values or the patient’s personal best?, To ensure continued bronchial stability, Simon suggests continued use of oral bronchodilators and corticosteroids; discontinued use of inhaled bronchodilators, including ipratropium bromide, the morning of the study; discontinued use of cromolyn and nedocromil 48 hours prior to challenge; and discontinued use of traditional antihistamines 24 hours prior to challenge.20 The same controls previously mentioned for anaphylaxis patients are appropriately used here. To further decrease the possibility of falsepositive results in unstable patients with asthma, some allergists recommend that patients undergo a prior, separate-day single-blind, straightplacebo challenge using the same time frame as that of the proposed challenge. During this placebo provocation phase, the FEVl value should not fall more than 10% below baseline. Pulmonary function tests are performed before each challenge dose or earlier if symptoms occur, with a 20%drop in the FEV, from baseline considered a positive challenge?1,zz An extra margin of safety can be provided for asthmatic patients by
80
DANIELS
using the single-blind challenge to allow tailoring incremental increases to prevent sharp drops in the FEV, value. A double-blind challenge protocol would obviously not accommodate this flexibility of dosingz0 Patients should be carefully monitored for a minimum of 2 hours following completion of the challenge because most major allergic reactions would take place in this time frame.l CHALLENGING PATIENTS WITH URTICARIA AND ANGIOEDEMA
Possible underlying causes of urticaria and angioedema are multiple and often difficult to pinpoint. In most reviews, fewer than 20% of patients have a known cause for their condition? Of the myriad determinants, drugs, foods, and food and drug additives are commonly identified causative agents. An extensive evaluation may not be necessary when the incidence is limited to a single episode or a few mild recurring ones. Severe reactions or frequent bouts, however, justify a thorough investigation to determine an avoidable cause or one yielding to treatment. To further investigate and establish causality, a provocation test is necessary. As always, evaluation of the patient begins with a complete, carefully detailed history followed by the clinician’s choice of the most suitable preliminary measures discussed previously, all of which together guide the selection of challenge substances. Although it is difficult to make sound conclusions without a hivefree baseline: there appears to be a paradoxic element involved in those patients who have chronic idiopathic urticaria as the primary diagnosis: A threshold degree of reactivity at the time of the challenge determines the skin’s further ability to respond.20Lumry et a1 found in a 1982 study that only 1 in 15 patients reacted to aspirin when in a state of urticarial remission, whereas 7 to 10 patients experiencing active urticaria at the time of challenge reacted to the aspirin.12 In these situations, Simonz0 suggests tapering antihistamines to the lowest effective dose (measured by a positive histamine skin test) to allow some disease activity with room to discern additional reactions. This method would not be a consideration with acute urticaria. Reaction criteria in some studies have been criticized for being poorly defined and often subjective. Employing use of the nine thermal injury zones to assess urticarial activity through an assigned point system is at least a partially objective scoring method.I2 Bosso and Simon also suggest use of a one-day baseline period of pure observation with skin scoring followed by one-day placebo challenge with skin scoring to determine the spontaneous variability of urticaria in a challenge setting.* Because exacerbations of urticaria may be stress-provoked or suggestioninduced, administration of a placebo first and last in single-blind fashion is advisable.2O Positive results can later be followed by a confirmatory double-blind challenge.
ORAL DIAGNOSTIC CHALLENGES
81
CONCLUSION
With use of a carefully focused historical appraisal of the patient, appropriate screening tools, a well-designed procedure protocol emphasizing safety, baseline evaluation, strict controls, elimination of bias, reproducibility of patient’s symptoms, and stringent reaction criteria, oral diagnostic challenges can be employed successfully and practically in the clinic setting for a wide variety of symptoms, including those prompted by foods and drugs, additives, sulfites, monosodium glutamate (MSG), tartrazine and dyes, and aspirin or nonsteroidal anti-inflammatory drugs. If one is able to reproduce a scenario consistent with the patient’s previous exposure and repeatedly provoke the same symptoms and signs, avoidance of the offending substance is obviously the treatment of choice along with mandatory education, including recognition of hidden substances, emergency measures for accidental ingestion, and sources of further information or aid, such as the Food Allergy Network and Medic Alert. It is safe to say that in most cases, there is no reaction to the maligned substance, and many allergists, as a final aid in dispelling lingering misconceptions, reintroduce the product to the patient in the confines of the clinic in an open manner.
References 1. Bock SA, Sampson HA, Atkins FM, et a1 Double-blind, placebo-controlled food challenge as an office procedure: A manual. J Allergy Clin Immunol82:98&997, 1988 2. Bock S A In vivo diagnosis: Skin testing and oral challenge procedures. In Metcalfe D, Sampson H, Simon R (eds): Adverse Reactions to Foods and Food Additives, ed 2. Cambridge, Blackwell Science, 1997, pp 151-164 3. Bock SA, Lee W-Y, Remigio LK, et al: Studies of hypersensitivity reactions to foods in infants and children. J Allergy Clin Immunol 62327-334, 1978 4. Bosso JV,Simon RA: Urticaria, angioedema, and anaphylaxis provoked by food additives. In Schocket AL (ed): Clinical Management of Urticaria and Anaphylaxis. New York, Marcel Dekker, 1993 5. Graham DT, Wolf S, Wolff HG: Changes in tissue sensitivity associated with varying life situations and emotions: Their relevance to allergy. J Allergy 21:478486, 1950 6 . Hamilos D, Oppenheimer J, Nelson H, et al: Suggested approaches for research protocols involving the potential for life-threatening reactions. J Allergy Clin Immunol 91:6, 1993 7. Hippocratic Writings: Great Books of the Western World. Translated by Francis Adams, Encyclopedia Britannica, Inc. The University of Chicago, 1952, p 2 8. Hobbs K, Schocket A: Urticaria and angioedema. In Bierman CS, Pearlman D, Shapiro G, et a1 (eds): Allergy, Asthma, and Immunology from Infancy to Adulthood, ed 3. Philadelphia, WB Saunders, 1996, pp 646-647 9. Hoffman K, Sampson H: Evaluation and management of patients with adverse food reactions. In Bierman CS, Pearlman D, Shapiro G, et a1 (eds): Allergy, Asthma, and Immunology from Infancy to Adulthood, ed 3. Philadelphia, WB Saunders, 1996, pp 665-684 10. Loveless MH. Allergy for corn and its derivatives: Experiments with a masked ingestion test for its diagnosis. J Allergy 21:500-509, 1950
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DANIELS
11. Loveless MH: Milk allergy: A survey of its incidence. Experiments with a masked ingestion test. J Allergy 21:489499, 1950 12. Lumry W, Mathison D, Stevenson D, et a1 Aspirin in chronic urticaria and/or angioedema: Studies of sensitivity and desensitization. J Allergy Clin Immunol 69(suppl):135,1982 13. Mahan L, Arlin M: Krause's Food, Nutrition, and Diet Therapy, ed 8. Philadelphia, WB Saunders, 1992, pp 662-663 14. May C Objective clinical and laboratory studies of immediate hypersensitivity reactions to foods in asthmatic children. J Allergy Clin Immunol5850CL515,1976 15. Metcalfe D, Sampson H, Simon R Food Allergy: Adverse Reactions to Foods and Food Additives, ed 2. Cambridge, Blackwell Science, 1997, pp 159-161 16. On The Natural Faculties: Great Books of the Western World. Translated by Arthur John Brock, MD, Encyclopedia Brittanica. The University of Chicago, 1952, pp 202-203 17. Prausnitz C, Kustner H: Studies on supersensitivity.Centrabl Bakteriol86:160-169,1921 18. Sampson H Adverse reactions to foods. In Middleton E, Reed C, Ellis E, et a1 (eds): Allergy Principles and Practice, ed 4. St. Louis, Mosby-Year Book, 1993, pp 1661-1677 19. Sampson H. Immunologically mediated food allergy: The importance of food challenge procedures. Ann Allergy 60262-269, 1988 20. Simon RA: Diagnostic Challenges. In Bierman CS, Pearlman DS, Shapiro GG, et al (eds): Allergy Asthma, and Immunology from Infancy to Adulthood, ed 3. Philadelphia, WB Saunders, 1996, pp 187-193 21. Simon R, Stephenson D Adverse reactions to food and drug additives. In Middleton E Jr, Reed C, Ellis E, et a1 (eds): Allergy Principles and Practice. St. Louis, Mosby YearBook, 1993, pp 1787-1702 22. Stephenson D, Simon R: Sensitivity to aspirin and nonsteroidal anti-inflammatory drugs. In Middleton E Jr, Reed C, Ellis E, et a1 ( 4 s ) : Allergy Principles and Practice. St. Louis, Mosby Year-Book, 1993, pp 1747-1766
Address reprint requests to Marilyn A. Daniels, BSE, RN Northwest Asthma and Allergy Center 4540 Sand Point Way NE, Suite 200 Seattle, WA 98105
IN THE ALLERGY/ASTHMA OFFICE
0889-8561/99 $8.00
+ .OO
ORAL DIAGNOSTIC CHALLENGES Marilyn A. Daniels, BSE, RN
Over 2000 years ago in ancient Greece, Hippocrates (460-375/351 recorded his observations of an adverse food reaction (i.e., milkinduced),18and in his treatise on ancient medicine, admonished patients to “search out food befitting their nature.’17 Writings from Galen, physician and philosopher (130-200 AD), indicate that the Romans were also well aware that foods safely consumed by most of the population could not be tolerated by some and could initiate many forms of adverse reactions.16 Centuries later, in 1921, Carl Prausnitz and Heinz Kustner, in a significant breakthrough contribution, demonstrated the passive transfer (P-IS) test. By injecting his own serum into Prausnitz, who had a known sensitivity to fish, Kustner was able to provoke a wheal and flare response at the injection site following fish ingestion by Pra~snitz.‘~ Although now used only for special purposes because of the risk of transmitting AIDS and other diseases, the test succeeded in establishing substances in blood serum as the causative factor in food allergy. Blinded, placebo-controlled food trials were introduced in 1950 by Loveless who incorporated ”food masking” techniques to disguise a suspected food in a safe food, thereby avoiding detection by the patient.l0,l1 At that same symposium, Graham et a1 presented a paper examining the placebo effect.Patients in this study reacted more to what they believed was being administered than to the actual food, showing once again the human mind’s ability to conjure up and to remand symptom^.^, l5 BC)
From Northwest Asthma and Allergy Center, Seattle, Washington
IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA VOLUME 19 * NUMBER 1 FEBRUARY 1999
75
76
DANlELS
Further pioneering work by May, in 1976, used the double-blind, placebo-controlled food challenge (DBPCFC),14a procedure that continues to be recognized as the standard in diagnosing food allergy.18 PRELIMINARY PROCEDURES
To determine the need and design considerations for an appropriate oral challenge, preliminary procedures generally consist of some or all of the following: (1) a thorough physical examination evaluating acute and chronic problems with emphasis on the gastrointestinal, cutaneous, and respiratory systems; (2) a carefully focused, complete medical history pinpointing the suspected item(s), quantity consumed, length of time between ingestion and development of symptoms, description of symptoms including duration, reproducibility, frequency, timing, the most recent occurrence of the reaction, whether an accompanying component such as exercise or behavioral,€actors is required to elicit the reaction, and family history; (3) a diet diary kept by the patient (or adult family member) in which all ingested substances and subsequently incurred symptoms are recorded, as well as timing of symptoms, quantity consumed, reproducibility, and medications taken; (4) an elimination diet prior to the challenge to determine if omitting the suspect substance brings resolution of symptoms or to-manage symptoms of adverse reactions and promote a stable baseline; (5) prick skin testing to screen patients with suspected IgE-mediated food hypersensitivity; and (6) radioallergosorbent tests (RAST) and other immunologic testing, biochemical testing, and additional laboratory studies as appropriate.8 OPEN CHALLENGES
Open food challenges in which the patient and the nurse administering the challenge know the content of the food being ingested are useful in the practice setting, especially with very young children likely to have a minimal psychogenic component. Open food challenges are most often used when the skin test is negative, the history is vague or doubtful, the elimination diet has failed to produce a definitive result, or the patient has been avoiding the food. Because the majority of challenges do not reproduce the symptoms and therefore disprove the history: open challenges in the clinic office are valuable and very practical with the considerable advantages of being time efficient and comparatively inexpensive to administer. Prior to the challenge, the suspected food should be eliminated from the diet for a minimum of 24 hours up to 7 to 14 days. Most patients will already be avoiding the substance thought to be medically harmful to them. Antihistamines are generally discontinued for a long enough time to elicit a normal histamine skin test. Other medications are reduced to minimum levels that are believed adequate to curtail
ORAL DIAGNOSTIC CHALLENGES
77
eruptions of acute symptoms.ls Those to consider avoiding prior to the challenge are P-agonists (12 hours), theophylline (12 hours), cromolyn (12 hours), and tricyclic antidepressants (96 hours or longer).2 The open challenge is optimally made when no symptoms are present, and is conducted early in the day (following an overnight fast), attended by well-qualified staff capable of providing individual attention and skilled at administering emergency treatment. Whether to perform the challenge in the clinic office or in a hospital setting depends on the patient’s history of reaction, the response time to engage paramedic assistance, and proximity to hospitals or emergency care facilities. Foods are introduced one at a time while the patient is carefully monitored for recurrence of symptoms. Although most often individualized, the initial challenge is made with a safe dose unlikely to cause symptoms, generally 20 mg to 2 g of dried food or one quarter teaspoon to 1 tablespoon of fresh food, depending on the history reported. The quantity of food is then increased incrementally (doubling is common) at timed intervals, again determined by patient history, until a reaction is provoked or the ingested amount reaches either 8 to 10 g of dried food, a standard portion of fresh food, or an amount equal to or greater than the prior symptom-provoking p0rti0n.l~ As in all oral challenges, the signs and symptoms recorded should mimic those gleaned from the patient history before considering the provocation reaction positive.
SINGLE-BLIND, PLACEBO-CONTROLLED CHALLENGES General principles of the open challenge are repeated in the singleblind, placebo-controlled food challenge; however, to eliminate a possible source of bias, the patient receives unidentifiable encapsulated dried or powdered food or suspect food disguised in safe food along with similarly camouflaged placebos. Obviously, the administrator of the challenge must exercise caution not to show undue concern or give unintended messages through body language or other expression when the incriminated food is ingested by the subject. Such challenges are considered to be a safe, practical approach; they are easy and speedy to administer and allow the tester to individualize doses and to use additional placebos when warranted. They are a useful screening tool in the clinic setting to document the absence of symptoms and to refute an unclear history or subjective symptoms, especially when a single substance is implicated.2A positive result (reproducing the patient’s historical signs and symptoms) may be confirmed later through a DBPCFC. Ideally, a negative result of any blinded challenge calls for reintroducing the food openly into the patient’s diet in the usual portions and customary manner under observation of the physician.
78
DANIELS
DOUBLE-BLIND, PLACEBO-CONTROLLED CHALLENGES
Because of its diagnostic accuracy, as illustrated by Bock and Sampson, the DBPCFC currently is state-of-the-art for diagnosing food allergy.3,l9 Whereas inclusive of oral provocation general principles discussed previously, the defining characteristic of the DBPCFC is that patient, nurse, and physician are all blinded to test substances and placebos in their disguised form, ensuring elimination of bias on all levels. This challenge is necessary in research studies, in equivocal clinical situations, and to confirm positive reactions elicted from open or single-blind challenges. All single- and double-blind challenges must be appropriately controlled. Two commonly used techniques are (1) to conduct a straight placebo challenge on a separate day for the same length of time as the proposed active challenge, and (2) to randomly intermingle approximately equal numbers of placebos and active agents during the actual ~ha1lenge.l~ A single positive outcome from a DBPCFC is considered adequate to establish a diagnosis if only objective symptoms are being investigated; evaluation of subjective symptoms calls for two or more sets of challenges because of the strong possibilitl (up to 50%) that the patient will experience symptoms during the provo~ation.'~ Additionally, when investigating subjective symptoms, the placebo and food must be crossed over several times to ensure reproducibility, and a repeat challenge is called for after several months to determine if the problem is ongoing.' Anecdotal claims aside, the literature is supportive of the position that delayed-onset food reactions caused by immunologic responses are rare and limited primarily to diarrheal responses in young children.' Generally, patients experience a prompt onset of symptoms, usually minutes to hours, following ingestion during provocation.' CHALLENGING PATIENTS WITH ANAPHYLAXIS
Because patient safety is paramount in any challenge, many allergists believe that no patient with a convincing profile of anaphylaxis should undergo a provocative oral challenge. A history consistent with a severe life-threatening allergic reaction developing after the isolated ingestion of a suspected food and requiring emergency treatment by a physician, coupled with in vitro IgE food-specific antibodies or a positive in vivo skin test, is considered sufficient for a presumptive diagnosis. Situations that may prompt oral challenge of patients with food anaphylaxis are to unequivocally identify the suspect food and to determine whether a young child who appears to have outgrown previously diagnosed life-threatening food anaphylaxis has really done so.* Such patients should only be challenged under the most rigid and strictly
ORAL DIAGNOSTIC CHALLENGES
79
controlled circumstances with well-trained personnel and appropriate equipment for resuscitation present at all times. Patients with a history of anaphylaxis must be challenged using very small doses with incremental increases adjusted downward from the usual doubled dose. Often a liquid vehicle with good masking ability is preferred for the following reasons: it may be more easily administered to young children; it may be easier to control the amount of food consumed; the problem of slow dissolution of capsules is eliminated; and in cases of oral allergy syndrome when all reported symptoms involve only the oropharynx (pruritus or swelling of the tongue or pharyngeal structures) and liquids provide the needed contact of food to mouth. Before each dose, subjective complaints and physical findings are noted on a clinical manifestation recording sheet. Vital signs including pulse and blood pressure are consistently monitored to differentiate a vasovagal (decreased pulse and blood pressure) from a genuine anaphylactic (increased pulse and decreased blood pressure) reaction. Peak flow rates are carefully measured, and the challenge is discontinued if the flow rate or blood pressure drops.20% or more from baseline or if the patient experiences systemic sympt0ms.b Withholding medications from patients who have recurring anaphylaxis may sometimes be necessary if they are totally effective in controlling anaphylaxis.20In extreme cases, hospitalization may be warranted with intravenous access in place before beginning the challenge. CHALLENGING PATIENTS WITH ASTHMA
Safety issues dictate that challenges in patients with asthma should be performed only when the subject’s asthma is stable and the forced expiratory volume in 1 second (FEV,) is greater than 1.5 L and greater than 70% of predicted normal values or the patient’s personal best?, To ensure continued bronchial stability, Simon suggests continued use of oral bronchodilators and corticosteroids; discontinued use of inhaled bronchodilators, including ipratropium bromide, the morning of the study; discontinued use of cromolyn and nedocromil 48 hours prior to challenge; and discontinued use of traditional antihistamines 24 hours prior to challenge.20 The same controls previously mentioned for anaphylaxis patients are appropriately used here. To further decrease the possibility of falsepositive results in unstable patients with asthma, some allergists recommend that patients undergo a prior, separate-day single-blind, straightplacebo challenge using the same time frame as that of the proposed challenge. During this placebo provocation phase, the FEVl value should not fall more than 10% below baseline. Pulmonary function tests are performed before each challenge dose or earlier if symptoms occur, with a 20%drop in the FEV, from baseline considered a positive challenge?1,zz An extra margin of safety can be provided for asthmatic patients by
80
DANIELS
using the single-blind challenge to allow tailoring incremental increases to prevent sharp drops in the FEV, value. A double-blind challenge protocol would obviously not accommodate this flexibility of dosingz0 Patients should be carefully monitored for a minimum of 2 hours following completion of the challenge because most major allergic reactions would take place in this time frame.l CHALLENGING PATIENTS WITH URTICARIA AND ANGIOEDEMA
Possible underlying causes of urticaria and angioedema are multiple and often difficult to pinpoint. In most reviews, fewer than 20% of patients have a known cause for their condition? Of the myriad determinants, drugs, foods, and food and drug additives are commonly identified causative agents. An extensive evaluation may not be necessary when the incidence is limited to a single episode or a few mild recurring ones. Severe reactions or frequent bouts, however, justify a thorough investigation to determine an avoidable cause or one yielding to treatment. To further investigate and establish causality, a provocation test is necessary. As always, evaluation of the patient begins with a complete, carefully detailed history followed by the clinician’s choice of the most suitable preliminary measures discussed previously, all of which together guide the selection of challenge substances. Although it is difficult to make sound conclusions without a hivefree baseline: there appears to be a paradoxic element involved in those patients who have chronic idiopathic urticaria as the primary diagnosis: A threshold degree of reactivity at the time of the challenge determines the skin’s further ability to respond.20Lumry et a1 found in a 1982 study that only 1 in 15 patients reacted to aspirin when in a state of urticarial remission, whereas 7 to 10 patients experiencing active urticaria at the time of challenge reacted to the aspirin.12 In these situations, Simonz0 suggests tapering antihistamines to the lowest effective dose (measured by a positive histamine skin test) to allow some disease activity with room to discern additional reactions. This method would not be a consideration with acute urticaria. Reaction criteria in some studies have been criticized for being poorly defined and often subjective. Employing use of the nine thermal injury zones to assess urticarial activity through an assigned point system is at least a partially objective scoring method.I2 Bosso and Simon also suggest use of a one-day baseline period of pure observation with skin scoring followed by one-day placebo challenge with skin scoring to determine the spontaneous variability of urticaria in a challenge setting.* Because exacerbations of urticaria may be stress-provoked or suggestioninduced, administration of a placebo first and last in single-blind fashion is advisable.2O Positive results can later be followed by a confirmatory double-blind challenge.
ORAL DIAGNOSTIC CHALLENGES
81
CONCLUSION
With use of a carefully focused historical appraisal of the patient, appropriate screening tools, a well-designed procedure protocol emphasizing safety, baseline evaluation, strict controls, elimination of bias, reproducibility of patient’s symptoms, and stringent reaction criteria, oral diagnostic challenges can be employed successfully and practically in the clinic setting for a wide variety of symptoms, including those prompted by foods and drugs, additives, sulfites, monosodium glutamate (MSG), tartrazine and dyes, and aspirin or nonsteroidal anti-inflammatory drugs. If one is able to reproduce a scenario consistent with the patient’s previous exposure and repeatedly provoke the same symptoms and signs, avoidance of the offending substance is obviously the treatment of choice along with mandatory education, including recognition of hidden substances, emergency measures for accidental ingestion, and sources of further information or aid, such as the Food Allergy Network and Medic Alert. It is safe to say that in most cases, there is no reaction to the maligned substance, and many allergists, as a final aid in dispelling lingering misconceptions, reintroduce the product to the patient in the confines of the clinic in an open manner.
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