General approach to the diagnosis and management of allergic and allergic-like reactions to drugs and therapeutics
Initial Measures
Initially, when an adverse drug reaction is suspected, especially when associated with significant symptoms, the drug should be discontinued (Table General Approach to Diagnosis and Management of Allergic Drug Reactions). Any treatable signs and symptoms should then be promptly attended to. Simple pruritus and urticaria with or without angioedema will usually improve with a H1 antihistamine such as over-the-counter diphehhydramine (Benadryl) 25-50 mg, two to four times daily or loratadine (Claritin) 10 mg 1-2 times daily. Prescribed nonsedating antihistamines such as cetririzine (Zyrtex) 10 mg, fexofenadine 60-180 mg, desloratadine (clarinex) 5 mg, or sedating hyroxyzine (atarax) 10-25 mg are also effective. These latter drugs are usually recommended one time daily, but may be used two times daily if the symptoms are more severe and the drugs are tolerated.
Table General Approach to Diagnosis and Management of Allergic Drug Reactions
| Initial measures |
| 1. Discontinue suspected medication |
| 2. Treat reaction |
| 3. Draw blood for possible confirmation of etiology in select situations (e.g., tryptase in ana-phylaxis/anaphylactoid reactions; complement assay (C3, CH50 levels in serum sickness, Coomb’s test in hemolytic anemia). |
| 4. Substitute appropriate medication whenever possible |
| Follow-up measures |
| 1. Skin test in case of drug allergy (e.g., β-lactam antibiotics,” insulin, vaccines, and latex”) |
| 2. Skin test/subcutaneous drug challenge (local anesthetics) |
| 3. Oral sequential challenge under controlled conditions (nonanaphylactic conditions) |
| 4. Strict avoidance based on presumptive diagnosis |
| 5. In very select cases and when appropriate, desensitize with original medication if no substitute is available (e.g., β-lactam, insulin, TMP-SMX,ASA). |
| 6. Preventive measures for inadvertent exposure in serious situations (e.g., Medic Alert, EpiPen auto-injector) |
aIn vitro tests available to some degree.
In addition, an H2 antihistamine, such as over-the-counter ranitidine (Zantac) 75-150 mg, or cimetidine (Tagamet) 100-200 mg, one to two times daily and/or a prescribed leukotriene antagonist such as motelukast (Singular) 10 mg once daily can be used to enhance the control of itching, rash or swelling. Adrenalin 1:1000,0.1-0.3 mL sc will help the pruritus and the acute rash, or swelling in an office or emergency room situation.
Usually, systemic corticosteroids are prescribed for short periods until out patient follow-up. The type of specific medication, route and dosage will depend upon the situation. Since use of ASA or nonsteroidal anti-inflammatory drugs can intensify pruritus, urticaria, or angioedema regardless of cause, these drugs should be avoided. More complete advice on the management of systemic anaphylaxis/anaphylactoid reactions and urticaria/angioedema can be found in the following chapters
There are few (if any) absolute confirmatory tests available initially when an adverse reaction to a drug is suspected. Diagnosis is usually, therefore, presumptive. Management is important in spite of this fact (e.g., drug discontinuation, treatment of signs and symptoms of the reactions, substitution of another drug if necessary).
One test (if positive) that can help confirm the fact that the reaction involves mediator release is an in vitro mast cell tryptase blood test. In severe cases of systemic anaphylaxis/ anaphylactoid reactions, tryptase is released along with other mast cell chemical mediators. This enzyme remains increased in the bloodstream for several hours after the event, allowing the possibility of confirming a mast cell degranulation (and histamine and other mediator involvement) in the reaction at the time that the patient is seen in the office or emergency room for the acute symptoms.
When serum sickness is suspected, the complement system is usually activated, and low serum levels of C3, C4, and possible CH50 (total hemolytic complement assay at 50%) may in retrospect help confirm the suspicion of this condition. In cases of hemolytic anemia, a positive Coombs test will help confirm the immune nature of this condition.
In almost all cases, the drug or therapeutic agent presumed to be responsible for the adverse reaction can be avoided, and a substitute medication should be available to treat the primary condition. Occasionally, this is not possible if the primary condition is serious and the offending drug is important to therapy. In some of these cases, medication pretreatment (radiocontrast media) graded oral drug challenge or drug desensitization may be necessary.
Drug Allergy Testing
Elective immediate reacting allergy skin testing is usually available only in the case of β-lactam antibiotic sensitivity, insulin sensitivity and with reactions to components of vaccines (e.g., egg, gelatin). It is available experimentally for papain sensitivity and suspected sensitivity to neuromuscular blocking agents. In vitro blood/serum assays are available only to latex, β-lactam antibiotics (penicillin major determinant only) and papain (experimental). These in vitro assays are helpful, if positive. A negative test does not rule out sensitivity. At one time, in vitro cell-mediated drug lymphocyte transformation testing was available in some experimental laboratories. There is little or no current evidence regarding the value of this type of drug reaction testing.
Drug allergy testing (skin testing in vitro studies) usually should be done by allergy-immunology specialists who are knowledgeable about the use and interpretation of such tests. Often investigation and management of drug suspected allergy is restricted to large clinics or hospitals and other academic centers that not only have referrals of complicated cases of this type but also have necessary diagnostic agents and experience in drug challenges or desensitization.
Graded Drug Challenge (Test Dosing)
If it is necessary to verify that an individual can safely take amedication that previously was associated with an allergic or allergic-like reaction, a graded drug challenge or test dosing may be considered. This usually is a situation where there is no test available, symptoms are minor (e.g., maculopapular rash to an antibiotic not associated with systemic symptoms) which usually is not associated with severe, life-threatening types of reactions. In case of suspected local anesthetic reactions, a well-studied protocol consisting of skin testing followed by a graded sc injection challenge helps confirm the safety of local anesthetics for subsequent use (see Table Local Anesthetic Skin Testing and Challenge).
In the case of antibiotics, the recommended initial dose of oral challenge is 1:100(1%) of a single daily therapeutic dose (e.g., 250 mg). Following a suitable interval, further increase (e.g. 10%, 20%, 30%, 40%) of the total challenge dose can be given at 15- to 20-min intervals. Often, this can be done in an office setting, following informal consent, if the allergist-immunologist is prepared for possible systemic allergic-like reaction. Following completion of the challenge, a wait of at least 2 h in the office is recommended and further antibiotic exposure is not advisable for 24 h.
Table Local Anesthetic Skin Testing and Challenge
| Route | Dilution | Dose |
| Prick test3 | Undiluted | 1.0 drop |
| Intradermal test3 | 1:100 | 0.02 mL |
| SC challenge* | 1:100 | 0.1 mL |
| SC | 1:10 | 0. lmL |
| SC | FS | 0.1 mL |
| SC | FS | 0.5 mL |
| SC | FS | 1.0 mL |
| SC (optional) | FS | 2.0 mL |
aSkin test with a battery of local anesthetic types (free of epinephrine) and if indicated, with and without methylparabens.
*Challenge with a single type of local anesthetic (negative result on skin test) sequentially at 15- to 20-min intervals, as recommend by Anderson, and
Follow-Up Measures
In most cases, after a presumptive diagnosis of drug allergy or intolerance has been made the individual is advised to avoid these medications. In some cases of reactions to drugs, drug desensitization is possible and necessary. Example of the use of this procedure will be discussed under the management of B-lactam and sulfonamide sensitivities. In the case of anaphylaxis/anaphylactoid reactions and other serious systemic events (e.g., Stevens-Johnson syndrome, Toxic epidermal necrolysis, or drug hypersensitivity syndromes) re-exposure to the medication is not advised.
In situations in which there are documented life-threatening drug reactions (e.g., systemic anaphylaxis) and inadvertent re-exposure is a risk, the patient should be advised to carry an EpiPen (0.3 mg epinephrine) auto-injector. If the patient is below 6 yr of age, an EpiPen Jr (0.15 mg epinephrine) auto-injector is advised.
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