3. What are drug mediated allergies?
The term "drug hypersensitivity" refers to objectively reproducible symptoms or signs
initiated by exposure to a drug at a dose normally tolerated by non-hypersensitive
persons. "Drug allergy" refers to immunologically mediated drug hypersensitivity reactions.
These may be either immunoglobulin E (IgE)–mediated (immediate) or non–IgE-mediated
(delayed) hypersensitivity reactions.
4.
5. Types of Drug Sensitivity
IgE-mediated reactions
Urticaria
Angioedema
anaphylaxis
non–IgE-mediated drug allergy
cytotoxic/cytolytic reactions involving the interaction of IgG or IgM antibodies and complement
with a drug allergen associated with cell membranes (e.g., immune hemolytic anemia,
thrombocytopenia),
drug immune complex reactions (e.g., serum sickness and drug-induced lupus), and
T-cell–mediated reactions. THEY ARE MOST PREVALENT AND DISCUSSED FURTHER IN THE
PRESENTAION
6.
7.
8. T-Cell Mediated Reactions
Hapten concept
Pro-hapten concept
Pi (pharmacologic interaction with immune receptors) concept
9. RISK FACTORS FOR DRUG ALLERGY
DRUG FACTORS HOST FACTORS
Nature of the drug Age and Sex
Degree of exposure (dose, duration,
frequency)
Genetic factors (HLA type, Acetylator status)
Cross-sensitization Concurrent medical illness (e.g. Ebstein-Barr
Virus (EBV), human immunodeficiency virus
(HIV), asthma)
Route of administration Multiple allergy syndrome
Previous drug reaction
10.
11. Diagnosis:
Clinical Diagnosis
Severe cutaneous reactions
SJS: detachment of less than 10% of the body surface area plus widespread purpuric macules or flat atypical
targets with at least two mucosal surfaces involved (i.e., oral, conjunctival or genital)
Overlapping SJS and TEN: Detachment of 10% to 30% of the body surface area plus widespread purpuric macules
or flat atypical targets
TEN: Detachment of more than 30% of the body surface area plus widespread purpuric macules or flat atypical
targets
Drug-induced hypersensitivity syndrome (DIHS) comprises the following features, with the diagnosis confirmed
by the presence of any five of the six criteria:
Maculopapular rash developing ≥3 weeks after starting therapy with a limited number of drugs
Lymphadenopathy
Fever (≥38°C)
Leukocytosis (≥10 ´ 109/L), atypical lymphocytosis or eosinophilia
Hepatitis (alanine aminotransferase [ALT] ≥100 U/L)
Human herpes virus (HHV)–6 reactivation
Anaphylaxis
12. Diagnostic Tests:
Diagnostic
Tests
In Vitro Tests
The
lymphocyte
transformation
test (LTT)
CAST–
enzyme-linked
immunosorbe
nt assay
(ELISA)
Flow
cytometry–
based
basophil
activation
assays
Allergen-
specific IgE
levels
Measurement
of mediators
(histamine,
tryptase,
leukotrienes)
In Vivo Tests
Skin tests skin biopsy
Drug
provocation
(challenge)
tests (DPTs)
Patch tests
14. IgE-Mediated Reactions
Acute Immediate
Management of
IgE-Mediated
Reactions
Non- serious
Reactions
antihistamines
Serious Reaction
Intramuscular
epinephrine
Intramuscular
promethazine or
intravenous
diphenhydramine
Intravenous fluids
(colloids or
crystalloids)
Systemic
corticosteroids
15. Non IgE-Mediated Reactions
Acute Immediate
Management of
Non-IgE-Mediated
Reactions
Non- serious
Reactions
antihistamines
Serious Reaction
SJS TEN DIHS
16. Specific Treatment
Drug Desensitization
Desensitization is a process in which the drug to which the patient is allergic is administered to the
patient in small, incremental doses to induce a state of temporary tolerance to the drug. This
should only be attempted if the offending drug is deemed essential and no alternatives are
available.
This treatment has been well established for IgE-mediated drug allergy, specifically to penicillins.
Hypotheses as to the mechanisms underlying successful of drug desensitization include mast cell
desensitization, hapten inhibition, IgE consumption and mediator depletion.
Drug desensitization for non–IgE-mediated drug allergy has also been described for various drugs. Although
treatment has been shown to be effective, the underlying mechanisms for its success remain unknown.
17. PREVENTION
Patients and family members should be educated on the generic names of the drugs they
are allergic to and other potentially cross-reacting drugs.
In addition, the patient should be given a Medic Alert® card or bracelet to avoid future
accidental prescription/dispensing of any drugs to which he or she is allergic.
Through the use of electronic medical records, pharmacovigilance in the form of adverse
drug reaction reporting to drug regulatory agencies and accurate labelling to avoid
future reactions should be constantly emphasized.
Adverse drug reactions (ADRs) are broadly divided into predictable (related to pharmacologic actions of the drug in otherwise normal individuals) and unpredictable reactions (related to individual’s immunological response and, on occasion, to genetic differences in susceptible patients). Drug allergy is a type of unpredictable reaction.
IgE primes the IgE-mediated allergic response by binding to Fc receptors found on the surface of mast cells and basophils. Fc receptors are also found on eosinophils, monocytes, macrophages and platelets in humans. There are two types of Fcε receptors:
FcεRI (type I Fcε receptor), the high-affinity IgE receptor
FcεRII (type II Fcε receptor), also known as CD23, the low-affinity IgE receptor
Unlike immune-mediated drug reactions, pseudoallergic
reactions are not associated with the production of
antibodies or sensitized T cells, but are often clinically
indistinguishable from drug hypersensitivity reactions.
During these reactions, the drug has the ability, via its
chemistry or pharmacology, to directly stimulate the
release or activation of inflammatory mediators such as
histamine (from mast cells, basophils), prostaglandins,
leukotrienes, or kinins. Non-steroidal anti-inflammatory
drugs (NSAIDs), narcotics, and angiotensin-converting
enzyme (ACE) inhibitors are common causes of these
non-allergic reactions
Hapten concept: Haptens are chemically reactive small compounds (<1000 d) that bind to proteins/peptides and modify them covalently. These subsequently may
stimulate the innate immune system by covalently binding to cellular proteins, thereby transmitting a danger signal, which in turn results in stimulation; or
stimulate the specific immune system by forming hapten-carrier complexes, which in turn can form neoantigens. The hapten-protein complexes are processed and then presented as hapten-modified peptides to T cells, which can react with these peptides.
Pro-hapten concept: Pro-haptens are not chemically reactive and cannot form a covalent bond with a peptide. To become chemically reactive, they must first be converted into a hapten by being metabolized into a compound that is chemically reactive.
Pi (pharmacologic interaction with immune receptors) concept: A chemically inert drug, unable to covalently bind to proteins, is still able to "fit" to some of the many immune receptors (as it does to other proteins/receptors). Under certain circumstances, this reversible drug–receptor interaction can activate immune cells specific for peptide antigens, which then expand and cause inflammatory reactions of different types. A primary immune response to the drug is not necessary for such a reaction to occur, but an expansion of drug-reactive cells may be required before symptoms appear.
While the development of drug hypersensitivity is impossible to predict with any certainty, some factors have been elucidated which, when present, increase the likelihood of such a reaction occurring. [3] These factors may be drug related or host (patient) related
Anaphylaxis
This is a severe life-threatening, generalized or systemic hypersensitivity reaction which may be IgE or non-IgE mediated. It is usually characterized by one or more of the following: generalized erythema, or flushing, urticaria, angioedema of the face, lip, tongue or uvula, stridor, rhonchi and/or hypotension. Anaphylaxis is a clinical diagnosis for which drug-induced anaphylaxis is one of the most easily avoidable causes.
In Vitro Tests
Measurement of mediators (histamine, tryptase, leukotrienes) released in peripheral blood, nasal or bronchial secretions or urine may be useful in the diagnosis of immediate hypersensitivity type allergic reactions. Levels may be measured at baseline and after allergen challenge. One commercially available test measures
serum total tryptase levels, with serial specimens taken at 1 and 6 hours after an acute anaphylactic reaction. Although elevated levels support a diagnosis of anaphylaxis, this criterion is not completely reliable; normal levels have been found even in cases of fatal anaphylaxis. In addition, these tests are expensive. Although histamine levels have been described to correlate better with symptoms and signs of anaphylaxis, plasma histamine levels remain elevated for only 1 hour after symptom onset - therefore, this test is not reliable.
Allergen-specific IgE levels are measured by either radioallergosorbent tests (RASTs) or radioimmunoassay (RIA). These tests are commercially available in the form of ImmunoCAP® fluorescent enzyme immunoassay (FEIA) tests for a limited number of drugs, including penicilloyl, amoxicilloyl, ampicilloyl, cefaclor, protamine, insulin and suxamethonium. In general, these tests although generally specific, lack sensitivity compared to clinical history and/or skin tests. They have not been well validated even for beta-lactam antibiotics for which studies are the most commonly available. Thus in clinical practice, utility for these tests is limited.
Flow cytometry–based basophil activation assays (also known as flow cellular antigen stimulation tests [CASTs]), which measure levels of CD 63 and CD 203c on activated basophils, are currently not widely used because of technical concerns, false-positive results, and lack of sensitivity and specificity. They have been used in research in the diagnosis of drug (beta-lactam and NSAID) hypersensitivity.
The CAST–enzyme-linked immunosorbent assay (ELISA) can be considered an in vitro allergy provocation test. The patient's collected leukocyte blood fraction is exposed in vitro to the suspected specific allergen. After incubation, the cellular supernatant is tested for the de novo synthesis of sulfidoleukotrienes by a highly specific ELISA. Although commercially available, the test is not widely used in the diagnosis of drug allergy because of inconsistent results from various research studies.
The presence or absence of peripheral blood eosinophilia or elevated total IgE levels is not useful in the diagnosis or exclusion or drug allergy. However, eosinophilia may be present in drug hypersensitivity syndromes.
For hematological manifestations of drug hypersensitivity (e.g. haemolytic anaemia, leukopaenia, thrombocytopaenia), there is usually no specific diagnostic test or serological test apart from recovery of the cytopaenia following withdrawal of the putative drug. A positive direct Coomb’s test is useful in screening for immune-mediated hemolytic anaemia. Drug-induced IgM and IgG have not been found to be clinically useful.
The lymphocyte transformation test (LTT) has been shown to be useful in the diagnosis of T-cell mediated delayed hypersensitivity reactions in a wide variety of delayed reactions with a wide variety of drugs. Although a positive LTT is useful in confirming the diagnosis, a negative test cannot exclude drug hypersensitivity. Positive LTT are usually drug-specific, and reaction-specific.
In Vivo Tests
Skin tests [6] are useful in the diagnosis of IgE-mediated allergy. A positive skin prick test (SPT) is defined as mean weal diameter >e;3 mm (associated with a flare response) compared to the negative control after 15 to 20 minutes.
A positive intradermal test (IDT) is defined as an increase in the mean weal diameter of ≥3 mm compared to the baseline diameter for the negative control after 15 to 20 minutes. An IDT is accomplished by injecting 0.02 to 0.05 mL of an allergen intradermally, raising a small bleb measuring 3 mm in diameter. The IDT is more sensitive than the SPT, but also carries a higher risk for inducing an irritative, falsely positive reaction and might even lead to anaphylaxis in IgE-dependent reactions. Readings should be taken after 15 to 20 minutes for evaluation of immediate reactions, and after 24 and 72 hours for evaluation of nonimmediate (late) reactions.
Patch tests [7] are used in specialized centers for the diagnosis of delayed hypersensitivity drug reactions. In these tests a patch imbedded with the suspected allergen is fixed on the back of the patient for 1 to 2 days and the result is read after 1 day and/or after 2 to 3 days. A photopatch test is a modification of the patch test used when photoallergic or phototoxic reactions are suspected. After 1 day the test patch is removed and the skin is irradiated with ultraviolet A light 5 or 10 J/cm2. This test is read after 2, 3 and 4 days.
Recommendations on non-irritating skin test concentrations for SPT, IDT and patch tests have been published.
A skin biopsy per se may not be helpful in the diagnosis of drug allergy because there are no absolute histopathologic or immunohistochemical findings in most drug exanthems. However, it may be useful when the differential diagnoses include other skin conditions with typical histologic patterns. For instance, drug-induced maculopapular exanthems may be differentiated from secondary syphilis characterized by plasma cell–rich mononuclear cell infiltrates, or from connective tissue disease characterized by interface dermatitis with epidermal atrophy, focal parakeratosis, dermal mucinosis and fibrinoid deposition in dermis.
Drug provocation (challenge) tests (DPTs) [8,9] are used to objectively reproduce the patient’s symptoms and signs of hypersensitivity using the suspected agent. A positive test does not confirm allergy (i.e. an immune-mediated reaction).
DPT involves administering the drug using slow, incremental dose escalations at fixed time intervals and observing for the presence or absence of an objective reaction. It is not without risk to the patient and should be done only under the strict supervision of clinicians/nurses with allergy training and with resuscitative equipment available.
Intramuscular epinephrine 0.3 mL of a 1:1,000 concentration up to every 5 minutes in adults or 0.01 mg/kg in children up to a maximum dose of 0.3 mg
Systemic corticosteroids may be used to prevent the delayed-phase reaction in acute anaphylaxis and to prevent/treat associated angioedema and lower airway inflammation. This has been extrapolated from its use in acute asthma, with a recent Cochrane systematic review failing to identify any evidence from randomized, controlled trials to confirm the effectiveness of corticosteroids in acute anaphylaxis.
SJS: The use of tapered doses of systemic corticosteroids is not uniformly practiced by all specialists in drug allergy. Oropharyngeal hygiene and gargle solutions, as well as eye care (sterile eye management, use of topical corticosteroids), should be ensured.
TEN: Skin care, eye care (sterile eye management, topical corticosteroids), adequate hydration and nutrition and respiratory care are paramount. High-dose intravenous immunoglobulin (IVIG 1 g/kg/d for 2 days) has been used at various centers with generally good outcomes, especially in improving skin re-epithelialization. However, the evidence remains controversial, and the original hypothesis on the anti-apoptotic effect of IVIG now does not appear to be so. Other immunosuppressive therapies, including cyclophosphamide, plasmapharesis and systemic corticosteroids, have not been found to be uniformly useful. Recent interest has re-emerged on the possible benefits of ciclosporin provided patients have not developed acute kidney injury and uncontrolled infection.
DIHS: The use of tapered doses of systemic corticosteroids is not uniformly practiced by all specialists in drug allergy.
INDICATIONS FOR ALLERGIST REFERRAL
Patients with a history of penicillin allergy who have a significant probability of requiring future antibiotic therapy
Patients with a history of penicillin allergy in which a penicillin-class antibiotic is the drug of choice
Patients with histories of multiple drug allergy/intolerance
Patients who might be allergic to protein-based biotherapeutic agents and require use of these materials
Patients with histories of adverse reactions to NSAIDs who require aspirin or other NSAIDs
Patients who require chemotherapy medications for cancer or other severe conditions and have experienced a previous hypersensitivity reaction to those medications
Patients with a history of possible allergic reactions to local anesthetics
HIV-infected patients with a history of adverse reactions to co-trimoxazole who need this therapy
Patients with a history of reactions to induction agents or to nonpenicillin antibiotics
