Diagnostic challenge and desensitization protocols for NSAID reactions

INTRODUCTION — Nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin, can cause several distinct types of allergic and pseudoallergic reactions. These reactions are categorized by the presumed underlying mechanism and whether the reaction is elicited by multiple NSAIDs or by a single agent. Challenge procedures are used in the diagnosis of some NSAID reactions, and desensitization protocols are used in management of patients who require NSAID therapy despite a history of adverse reactions.

The various challenge and desensitization protocols used by allergy specialists will be reviewed here. A protocol to introduce low-dose (ie, 75 to 100 mg) aspirin to patients reporting aspirin hypersensitivity but who require aspirin for a cardiovascular or neurologic intervention is provided separately. (See "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions".)

The clinical features of NSAID reactions and the use of alternative medications, either medications that are highly selective inhibitors of the enzyme cyclooxygenase (COX) 2 (eg, celecoxib, others) or NSAIDs that weakly inhibit COX-1, are presented separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

REACTION TYPES — To determine if a diagnostic challenge and/or desensitization is appropriate for a patient with a history of NSAID reaction, the clinician must first attempt to classify the patient's past reaction. This is done by reviewing the clinical history in detail. The most important elements of the history are:

●The signs and symptoms of the reaction

●Whether the reaction has been elicited by a single NSAID or multiple NSAIDs

●The presence of several underlying medical disorders (specifically asthma, chronic rhinosinusitis, nasal polyps, and chronic urticaria)

The different types of pseudoallergic and allergic reactions to NSAIDs are summarized briefly here and reviewed in more detail separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'History'.)

Pseudoallergic — Pseudoallergic reactions are nonimmunologic reactions that occur in susceptible individuals and are related to cyclooxygenase (COX) 1 inhibition.

Pseudoallergic reactions are elicited by multiple NSAIDs. These typically occur in patients who have either asthma and chronic sinus disease (often with nasal polyposis) or chronic urticaria (table 1).

●Type 1 – Respiratory reactions to multiple NSAIDs in patients with asthma and chronic rhinosinusitis with nasal polyposis (also called aspirin-exacerbated respiratory disease [AERD]).

●Type 2 – Urticaria/angioedema to multiple NSAIDs in patients with underlying chronic urticaria.

●Type 3 – Urticaria/angioedema to multiple NSAIDs in otherwise asymptomatic individuals.

●Type 4 – Blended (involving both the respiratory tract and skin) reactions to multiple NSAIDs in otherwise asymptomatic individuals. Some patients with type 4 reactions have underlying AERD and experience both respiratory and cutaneous symptoms (urticaria-like pruritic rash, angioedema) during NSAID reactions. Others do not have AERD but develop cutaneous symptoms that are not classic urticaria/angioedema and can be quite variable.

Allergic — Allergic reactions are presumed to be immunoglobulin E (IgE) mediated and are elicited by a single NSAID or, rarely, by more than one agent with similar chemical structures. Interestingly, allergic reactions have not been reported to aspirin itself but have been described to several other NSAIDS [1-4].

●Type 5 – Allergic reactions (usually urticaria, pruritus, or angioedema) to a single NSAID.

●Type 6 – Anaphylaxis (ie, a more severe allergic reaction involving multiple organ systems) to a single NSAID.

REFERRAL — Referral to an allergy specialist with experience in drug allergy should be considered for patients who had severe reactions in the past and for those who would benefit from being able to take other NSAIDs if it were safe to do so. NSAID reactions are challenging to diagnose and manage for several reasons:

●Some NSAID reactions can be severe or life threatening.

●NSAID reactions can be challenging to classify based on history alone because the signs and symptoms of the various types of reactions may be overlapping.

●Patients have sometimes avoided all NSAIDs since the initial reaction, so it is not possible to determine if the symptoms are elicited by one or multiple agents.

●Most patients develop NSAID sensitivity at some point after initially tolerating these drugs, so the history of having tolerated a different NSAID prior to the first reaction does not mean that the patient would tolerate that agent again in the future.

GENERAL ISSUES IN NSAID CHALLENGE AND DESENSITIZATION

Indications for challenge — There are no in vitro assays or skin tests available to diagnose NSAID reactions. Therefore, a provocative challenge is the only means of obtaining a definitive diagnosis of current sensitivity if there is a legitimate medical need for future NSAID therapy. Challenge protocols involve cautiously administering gradually increasing doses of an NSAID, usually aspirin, in an appropriately monitored medical setting. These procedures are also used to desensitize patients to NSAIDs in some situations.

Drug challenges are not without risk. Therefore, the benefits of the information gathered from the challenge must be weighed against the risks for each patient individually. The following are general guidelines:

●Performing an NSAID challenge simply to determine if a person with a suggestive history is sensitive to an NSAID is not recommended.

●In contrast, if a patient has a medical indication for NSAID therapy (eg, cardiovascular risk factors, confirmed coronary heart disease, or a chronic inflammatory condition, such as arthritis), it is usually appropriate to determine the specific type of reaction present. The information can then be used to determine what other NSAIDs the patient may safely take.

Indication for desensitization — Patients with NSAID reactions can sometimes be desensitized to an NSAID, which is accomplished by continuing the challenge procedure. Following desensitization, the patient must continue to take the NSAID in question daily to maintain the desensitized state. Two common indications for desensitization are the need for daily aspirin in patients with cardiovascular disease and the need for daily NSAIDs in patients with rheumatologic disease.

Contraindications — Any concurrent cardiopulmonary conditions should be under optimal control before a patient is challenged or desensitized. In patients with asthma, it is our practice to proceed with these procedures only if the prebronchodilator forced expiratory volume in one second (FEV₁) is ≥70 percent of the patient's best and ≥1.5 liters. However, if aspirin desensitization is needed urgently (eg, after a cardiovascular event or procedure), systemic glucocorticoids can be given to rapidly control asthma. (See "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions".)

Patients with past NSAID reactions that involved possible anaphylaxis should not be on any medications that may increase the likelihood of anaphylaxis or interfere with treatment of anaphylaxis, such as angiotensin-converting enzyme (ACE) inhibitors or beta blockers, although there may be individual exceptions to this.

NSAIDs can cause other types of reactions that are not considered here. These include severe cutaneous reactions, such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Patients who have experienced such reactions should not receive the culprit drug again, and any form of reexposure, including challenge and desensitization, is contraindicated. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Safety issues

●NSAID challenges should only be performed by clinicians with the expertise to manage any resultant symptoms and in settings equipped with the necessary medications, equipment, and support staff. (See "Anaphylaxis: Emergency treatment" and "Aspirin-exacerbated respiratory disease", section on 'Signs and symptoms'.)

●In some patients, intravenous access should be obtained prior to challenge in case emergency medications or fluids are required. This is indicated in patients believed to be at risk for moderate-to-severe symptoms during the challenge procedure, in those with past anaphylaxis, and in those with significant underlying cardiopulmonary disease.

●Informed consent should be obtained from all adult patients or from the guardians of children under 18 years of age.

Setting — The appropriate setting is determined by the historical features of past reactions and the clinician's knowledge about what types of reactions are in the differential diagnosis. In most cases, these protocols may be safely performed in specially equipped outpatient allergy clinics, while, in other cases, admission to the hospital or intensive care unit (ICU) is indicated. Oral challenges in patients with previous anaphylaxis should be performed in an ICU or in an area where ICU transfer is readily available, although severe reactions are generally avoidable. The decision about where to perform challenges requires clinical judgment, and each case must be considered individually.

PROTOCOLS FOR ORAL CHALLENGES — There are several basic oral challenge procedures, which differ in the starting dose and the time interval between doses (table 2) [5,6]. The choice of protocol depends on the patient's past reaction. The clinician must categorize the patient's past reaction based on reported symptoms and underlying disorders in order to choose the most appropriate protocol. (See 'Reaction types' above.)

The protocols described in this section were intended to be performed as elective procedures. A somewhat different approach is used for urgent desensitization after cardiac procedures. (See "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions".)

Choice of NSAID — At the author's institution and many others, aspirin is the drug most often utilized in oral challenges. There is more experience with aspirin than any other NSAID, and aspirin has the additional advantage of not having been implicated in any confirmed cases of anaphylaxis. The few instances in which we perform challenges with NSAIDs other than aspirin are pointed out in the discussions below.

Use of placebo doses — We do not usually include placebos when a challenge is performed solely for the purposes of patient management. However, there are some situations in which the use of placebo doses is clinically useful. As an example, placebo doses are helpful in the evaluation of the patient who is suspected of not having sensitivity to NSAIDs at all, in whom challenge is indicated to prove that the patient tolerates NSAIDs. We sometimes give such patients an initial dose of placebo and also end the challenge with one or more placebo doses (so that the patient receives placebo when expecting the largest dose of the day) with one or more placebo doses in between. Informed consent should be obtained for inclusion of placebos.

In contrast, placebo doses are essential in research studies in which challenge is performed for the purposes of confirming the diagnosis. Many protocols include an initial day in which only placebos are administered to control for nonspecific changes in pulmonary function that some patients demonstrate in a challenge environment.

APPROACH TO SPECIFIC TYPES OF REACTIONS

Respiratory reactions — Patients who experienced rhinorrhea or bronchospasm (often with nasal and ocular symptoms) following exposure to an NSAID most often have type 1 pseudoallergy. If the patient develops cutaneous symptoms (urticaria and/or angioedema or other cutaneous findings) during NSAID reactions, they may have type 4 pseudoallergy. Patients with types 1 and 4 pseudoallergy have underlying asthma and chronic rhinosinusitis with nasal polyposis, although the polyposis may not have been detected unless the patient has undergone evaluation for their sinus disease. The combination of asthma, chronic rhinosinusitis with nasal polyposis, and respiratory reactions to NSAIDs is called aspirin-exacerbated respiratory disease (AERD). It is important to recognize patients with AERD because they have potentially severe reactions to NSAIDs, and, if aspirin challenge is attempted, it must be done with appropriate safeguards in place (discussed below). AERD is reviewed in more detail separately. (See "Aspirin-exacerbated respiratory disease".)

Occasionally, a non-AERD patient with past bronchospasm following NSAID exposure has IgE-mediated anaphylaxis to that NSAID (type 6, allergic reaction). This should be suspected if the patient had a severe reaction to a single agent in the past and does not have a history of asthma or sinus disease.

Type 1 (respiratory reactions to multiple NSAIDs) — The most common reason for performing aspirin challenge in a patient with AERD is to determine if the patient is sensitive to aspirin and therefore might benefit from daily aspirin therapy. In most cases, patients are premedicated with antileukotriene agents prior to undergoing aspirin challenges to reduce or eliminate the potentially severe pulmonary symptoms that can occur during challenge. A more detailed discussion of challenge and desensitization in patients with AERD is found elsewhere. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)

Patients with type 1 pseudoallergy can undergo the oral aspirin challenge described in row 1 of the table (table 2), following premedication with a leukotriene-modifying drug (LTMD). The starting dose is 40.5 mg, and this is doubled at intervals of three hours until the patient reacts or the desired therapeutic dose is reached.

If the patient does not react, then they either do not have NSAID allergy or pseudoallergy or their reaction requires higher doses to elicit. Most patients with type 1 pseudoallergy react to between 60 and 100 mg of aspirin, so, if the final dose was only 81 mg, it is possible that it was below the dose needed to provoke a reaction. However, if the patient only requires low doses for therapy, then they can safely continue on 81 mg daily, although they should not take higher doses or other NSAIDs other than aspirin.

Desensitization — NSAID desensitization is a process of inducing tolerance to NSAIDs in a patient with pseudoallergic reactions. Desensitization is essentially a continuation of the challenge procedure until the patient reaches the desired dose without reacting further to the drug (table 2). Desensitization to aspirin is nearly always successful in patients with type 1 pseudoallergy. Following desensitization, aspirin or another NSAID must be taken daily since tolerance is lost if exposure is interrupted. This is discussed elsewhere. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)

Type 4 (respiratory and cutaneous symptoms to multiple NSAIDs) — Patients with type 4 pseudoallergy can undergo the oral aspirin challenge described in row 1 of the table (table 2) following premedication with an LTMD. The starting dose is 40.5 mg, and this is doubled at intervals of three hours, until the patient reacts.

Desensitization — Patients with type 4 pseudoallergic reactions generally can be desensitized. However, the process may be prolonged, and the patient may react at several different aspirin doses. It is our approach to premedicate with a nonsedating oral antihistamine and an LTMD, such as montelukast. If a reaction occurs, we administer additional antihistamines, wait for the symptoms to subside, repeat the provoking dose, and continue the desensitization process. This process can take hours to days. The interval between doses can be extended by several hours (not to exceed 48 hours), if needed, to allow symptoms to resolve before continuing. Systemic glucocorticoids may be necessary for resistant cases. When the desired dose is reached without symptoms, the patient is desensitized. Once desensitized, the antihistamine and LTMD can be discontinued (tapering the dose or discontinuing gradually is not necessary). Although studies of desensitization for type 4 pseudoallergic reactions are lacking, it is the author's experience that nearly all patients can be desensitized if the clinician is persistent and makes judicious use of antihistamines and LTMDs as described [7].

Type 6 (anaphylaxis to a single NSAID) — If a patient had a past severe reaction to an NSAID that included respiratory symptoms and stopped taking NSAIDs at that point in time, it can be difficult to determine from the history if the patient had anaphylaxis to that single agent or if they have a form of pseudoallergy.

For patients who have a history suggestive of single NSAID reactivity with anaphylaxis (type 6), performing an oral challenge to aspirin is a safe first step in the evaluation (row 4 of the table) (table 2) since anaphylaxis to aspirin has not been described. A typical starting dose in these patients is 81 mg of aspirin, which is then doubled every three hours [5].

●If the patient does not react to aspirin, then their initial reaction was likely anaphylaxis to the specific NSAID in question. In order to determine if a similar but not identical NSAID could be safely taken, a challenge with the desired alternative NSAID would subsequently be performed.

●If the patient does react to aspirin, then they have a type of pseudoallergy and not a type 6 reaction.

There may be uncommon clinical situations in which a challenge is performed to an NSAID other than aspirin. In this situation, the starting dose should be much lower (ie, 1/1000^th or 1/100^th of a dose), which is then increased 10-fold every three hours, since anaphylaxis to other NSAIDs has been reported. This scenario may arise if a patient has experienced possible anaphylaxis to a specific NSAID and needs NSAIDs for occasional use but cannot tolerate other chemically different groups of NSAIDs for various reasons. In this situation, an aspirin challenge would be performed first to exclude the possibility of pseudoallergy.

Desensitization — Desensitization is rarely indicated for patients with type 6 reactions (ie, presumed IgE-mediated reactions to a single NSAID), because an array of different NSAIDs are available that can be used instead of the culprit drug. Patients with these types of reactions should avoid the causative agent and other NSAIDs in the same chemical group (table 3). NSAIDs that are structurally dissimilar to the drug that caused the initial reaction may be safely taken. It is the author's practice to give a full tablet of the alternative NSAID to demonstrate to the patient that it is tolerated and dispel any fears the patient may have about taking it. The first dose can be given under observation as a precaution. Other options for management are discussed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Management'.)

Urticaria/angioedema reactions — Isolated urticaria and angioedema may be seen in types 2, 3, 4, and 5 reactions.

Type 2 (patients with chronic urticaria) — Patients who react to multiple NSAIDs with symptoms of urticaria/angioedema and have a history consistent with chronic urticaria may undergo the oral aspirin challenge described in row 2 of the table (table 2).

Premedications are not normally given prior to this type of challenge. Antihistamines are normally withheld prior to NSAID challenges as these agents could obscure detection of early or mild allergic symptoms. Both H1 and H2 antihistamines should be discontinued at least 48 hours before the challenge.

The starting dose is either 81 or 162 mg, and this is doubled at intervals of 90 minutes until the patient reacts or the desired therapeutic dose is reached. The diagnosis of a type 2 or 3 reaction is confirmed in patients who develop urticaria and/or angioedema as a result of challenge.

If a patient does not develop symptoms, then pseudoallergy is excluded, and the patient is only sensitive to the drug that caused the initial reaction and has a type 5 or 6 reaction. The patient can safely receive an NSAID that is structurally different from the one that caused the initial reaction.

Desensitization — Patients with type 2 pseudoallergic reactions (ie, aspirin/NSAID-induced urticaria/angioedema with underlying chronic urticaria) are the most difficult to desensitize. Even when desensitization is initially successful, tolerance is often lost over time. In addition, if the patient's urticaria is more active for a period of time, the aspirin is likely to make it more difficult to control.

Despite this, patients with type 2 reactions who need aspirin for cardioprotection can sometimes tolerate 81 mg dose of aspirin daily without significant worsening of their symptoms. To determine this, we usually give one-half of a tablet (ie, 40.5 mg) initially, wait approximately three hours, and then give 81 mg. If the patient reacts to either step, we repeat that step at three-hour intervals until it is tolerated. The process can be interrupted overnight and continued for several days, if needed. A second option, if aspirin therapy is considered important for that patient, is to repeat the procedure on another day after the patient has been pretreated with H1 antihistamines (if the patient is already taking these for chronic urticaria, the dose can be increased), montelukast, and sometimes misoprostol [7]. Other management options, such as use of acetaminophen, selective cyclooxygenase (COX) 2 inhibitors, or weak COX-1 inhibitors, are reviewed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Types 1 to 4: Treatment options'.)

Type 3 (patients without chronic urticaria) — For patients who reacted to a single NSAID with urticaria and/or angioedema and do not have a history of underlying chronic urticaria, performing an oral challenge to aspirin is the most prudent approach (using row 2 of the table) (table 2).

●If a patient does not develop symptoms, then pseudoallergy is excluded, and either the initial history was incorrect or the patient is only sensitive to the drug that caused the initial reaction and has a type 5 or 6 reaction. The patient can safely receive an NSAID that is structurally different from the one that caused the initial reaction.

●If a patient without a history of chronic urticaria develops urticaria or angioedema in response to aspirin challenge, then the diagnosis is type 3 pseudoallergy.

Desensitization — Many patients with type 3 pseudoallergic reactions (urticaria/angioedema in an otherwise asymptomatic person) may tolerate 81 mg or even 325 mg without developing urticaria/angioedema or other symptoms and may be able to continue on these doses long term.

Type 3 patients can usually be desensitized, although this can be challenging because the urticaria and/or angioedema that develop during the procedure may be difficult to control. It is our approach to begin the desensitization without premedications and then, if the patient reacts, to initiate therapy with both a nonsedating oral antihistamine and an LTMD. If a reaction occurs, we administer additional antihistamines, wait for the symptoms to subside, repeat the provoking dose, and continue the desensitization process, continuing at three-hour intervals. Systemic glucocorticoids may be necessary for resistant cases. When the desired dose is reached without symptoms, the patient is desensitized. Once desensitized, the antihistamine and LTMD can be discontinued (tapering the dose or discontinuing gradually is not necessary). This approach has been successful in the author's experience [7], although it has not been formally studied.

Other treatment options for these patients are reviewed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Types 1 to 4: Treatment options'.)

Type 5 (patients without chronic urticaria) — For patients who reacted to a single NSAID with pruritus, urticaria, and/or angioedema and do not have a history of underlying chronic urticaria, performing an oral challenge to aspirin is the most prudent approach (row 3 of the table) (table 2). The starting dose is 162 mg, and this is doubled at three-hour intervals.

Patients with type 5 reactions would not be expected to react to aspirin, because IgE-mediated allergy to aspirin has not been documented. If the patient does react, then the diagnosis is a type 3 reaction.

Desensitization is rarely indicated for patients with type 5 reactions, as mentioned previously, because an array of different NSAIDs are available that can be used instead of the culprit drug. Patients with these types of reactions should avoid the causative agent and other NSAIDs in the same chemical group (table 3). NSAIDs that are structurally dissimilar to the drug that caused the initial reaction may be safely taken. It is the author's practice to simply give a full tablet of the alternative NSAID to demonstrate to the patient that it is tolerated and dispel any fears the patient may have about taking it. The first dose can be given under observation as a precaution, although this is not the practice in the author's clinic, where there is extensive experience with these reactions. Other options for management are discussed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Management'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

SUMMARY AND RECOMMENDATIONS

●Types of pseudoallergic and allergic reactions to NSAIDs – To determine whether a diagnostic challenge and/or desensitization is appropriate for a patient with a history of a nonsteroidal antiinflammatory drug (NSAID) reaction, the clinician must first attempt to classify the patient's past reaction based on the clinical history and the patient's comorbidities (table 1). (See 'Reaction types' above.)

●Referral to a drug allergy specialist – Challenges and desensitizations to NSAIDs should be performed by allergy specialists with experience in drug allergy. (See 'Referral' above and 'General issues in NSAID challenge and desensitization' above.)

●Protocols for patients who require aspirin urgently – Occasionally, patients who report aspirin hypersensitivity require aspirin urgently in conjunction with a cardiovascular or neurologic intervention. An approach to introducing low-dose aspirin in this situation is described elsewhere. (See "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions".)

●Indications for challenge and desensitization:

•Provocative NSAID challenges are required to make a definitive diagnosis of a pseudoallergic or allergic NSAID reaction because validated skin tests or in vitro tests are not available. Challenge is usually indicated only in patients who have a legitimate medical need for future NSAID therapy. Simple avoidance of NSAIDs is a more practical option for patients who have no specific need for these mediations. (See 'Indications for challenge' above.)

•Desensitization is most often performed to allow patients to take daily NSAID therapy. Once patients are desensitized to aspirin (or another NSAID), they must continue to take that agent daily to maintain the desensitized state and avoid recurrent reactions.

●Choice of protocol:

•Most challenge protocols use oral aspirin because reactions to aspirin are well characterized, and aspirin has not been convincingly implicated in causing immunoglobulin E (IgE) mediated anaphylaxis. The characteristics of the past NSAID reaction determine the protocol that should be used for challenge (table 2). (See 'Protocols for oral challenges' above.)

•Patients with underlying aspirin-exacerbated respiratory disease (AERD) who develop respiratory reactions (type 1 reactions) or both respiratory reactions and urticaria/angioedema (type 4 reactions) to multiple NSAIDs can be challenged with the protocol shown in row 1 of the table (table 2). Challenge is expected to induce respiratory symptoms and premedication with leukotriene-modifying drugs (LTMDs) before oral challenge is recommended to minimize the severity of the symptoms, as reviewed in detail separately. Desensitization involves extending the diagnostic challenge procedure and is nearly always successful in patients with type 1 pseudoallergy. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)

•Patients with urticaria and/or angioedema in response to NSAIDs should be challenged with the protocol in row 2 of the table. These patients may have a history of underlying chronic urticaria (type 2 reaction) or no such history (type 3 reaction) (table 2). Desensitization in patients with type 2 reactions is usually not successful long term, although some of these individuals will tolerate low-dose aspirin. Desensitization is variably successful in patients with type 3 reactions. (See 'Urticaria/angioedema reactions' above.)

•Patients with allergic symptoms to a single NSAID (type 5 reaction) may be challenged with aspirin, using the protocol in row 3 of the table (table 2). Patients with anaphylaxis in response to an NSAID in the past (type 6 reaction) should be challenged with aspirin using the protocol in row 4 of the table (table 2). Desensitization is rarely indicated for patients with types 5 or 6 reactions because an array of different NSAIDs are available that can be used instead of the culprit drug. (See 'Type 5 (patients without chronic urticaria)' above and 'Type 6 (anaphylaxis to a single NSAID)' above.)