Drug Allergies - Thong B, Vervloet D, Torres Jaen, MJ (Updated 2021)

Drug Allergies

Updated: April 2021
Updated: 2014
Originally Posted: January 2007

 

Original Authors:

Bernard Thong MBBS, MRCP (UK), FRCP (Edin), FAAAAI
Tan Tock Seng Hospital
11, Jalan Tan Tock Seng
Singapore 308433
SINGAPORE

Daniel Vervloet MD FAAAAI
Hopital Sainte Marguerite
Service De Pneumo-allergologie
Marseille Cedex 9 132 74
FRANCE

 

Updated By:

Maria José Torres Jaén
Head of Unit of Allergic Diseases, Malaga Regional University Hospital
Coordinator of the Spanish Allergy Network ARADyAL
Full Professor of Medicine, Malaga University
Spain

 

DEFINITION AND CLASSIFICATION

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).

ADRs should be differentiated from adverse drug events (ADEs). ADEs extend beyond ADRs to include harm related to medication errors and drug/food interactions. While knowledge of ADEs is important in efforts to improve patient safety, ADRs are the primary focus of regulatory agencies and post-marketing surveillance.

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. It is a type of unpredictable ADR and includes reactions induced by immune or inflammatory cells as well as other non-immunological mechanisms. The term "drug allergy" refers to a specific immunologically mediated drug hypersensitivity reaction (DHRs) [1-3]. DHRs are clinically classified as immediate reactions (IRs) (appearing 1-6 hours after drug intake) or nonimmediate reactions (NIRs) (appearing >1 hour after drug intake) [3]. IRs cause urticaria, angioedema, or anaphylaxis, and NIRs induce heterogenous manifestations ranging from maculopapular exanthema (MPE) or fixed drug eruption (FDE) to severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) or single-organ reactions such as drug-induced liver disease (DILI) and drug-specific reactions such as abacavir hypersensitivity síndrome [4].

 

MECHANISMS

DHRs can be classified as allergic and non-allergic reactions based on the mechanism involved [3].

Allergic reactions are mediated by a specific immune response to a drug acting as hapeten that can lead to all types of Coombs and Gell-mediated immune reactions: types I (IgE-mediated, produced by B cells), type II (IgG/IgM-mediated cytotoxicity), type III (immunocomplex) and IV (T cell-mediated). The most common are type I and IV, involved in IRs and NIRs, respectively.

Non-allergic reactions include all other IRs without an underlying demonstrated immune mechanism. They are clinically indistinguishable from allergic reactions and they are produced after drug interaction with inflammatory cells as mast cells, basophils, and neutrophils through mechanisms based on (i) over-inhibition of specific enzymes such as the COX-1 inhibition (pharmacological effect) in non-steroidal anti-inflammatory drugs reactions or (ii) the off-target occupation of receptors by drugs (direct stimulation) such as the Mas-related G-protein receptor (MRGPRX2) on mast cells by neuromuscular blocking agent (NMBAs) and fluoroquinolones.

According to the more recent classification [2], the mechanism involved in each reaction could be determined by how drugs interact with the immune system.

There are three main processes by which T cells are stimulated by drugs [2]:

• 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.

In toxic epidermal necrolysis (TEN), there is a specific drug hypersensitivity restricted to HLA class I antigens, resulting in clonal expansion of CD8⁺ cytotoxic T lymphocytes (CTLs). Cytotoxicity is mediated by CTL granzymes and possibly death receptor (DR) ligand (DR-L) and Fas ligand (FasL). Particular to TEN, there is then an amplification sequence involving further DR-L expression.

 

EPIDEMIOLOGY

ADRs account for 3% to 6% of all hospital admissions and occur in 10% to 15% of hospitalized patients and up to 25% of outpatients. Drug allergy is relatively uncommon, accounting for less than 10% of all ADRs. Drug allergy, occurs in 1% to 2% of all admissions and 3% to 5% of hospitalized patients, respectively but the true incidence of drug allergy in the community, and among children and adults, is unknown. Many children are misdiagnosed as being “allergic” to various medications, particularly antibiotics and end up carrying this label into adulthood. These patients are frequently treated with alternate medication that may be more toxic, less effective and more expensive – this in turn may result in increased morbidity, mortality and cost (economic) [5].

The true incidence of drug-induced anaphylaxis is also unknown, as most studies have been based on all causes of anaphylaxis or all causes (both allergic and nonallergic) of ADRs.

The estimated incidence of SJS, which may occur secondary to ADR, is 0.4 to 1.2 per 1 million people per year; the estimated incidence for TEN is 1.2 to 6 per 1 million people per year. An increase in SCARs among children (reaching 100 cases/year) has been observed, probably due to the active pharmacovigilance programmes [6].

 

RISK FACTORS FOR DRUG ALLERGY

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 [5]. These factors may be drug related or host (patient) related (Table 1)

 

Table 1 RISK FACTORS FOR DRUG ALLERGY

Drug Factors Nature of the drug Degree of exposure (dose, duration, frequency) Route of administration Cross-sensitization Host Factors Age and Sex Genetic factors (HLA type, Acetylator status) Concurrent medical illness (e.g. Ebstein-Barr Virus (EBV), human immunodeficiency virus (HIV), asthma) Previous drug reaction Multiple allergy syndrome

Drug Factors

• Nature of the drug
  The ability to elicit a complete immune response is based on two features of the drug: antigenicity and immunogenicity. However, there is still a need of a better understanding of the different aspects related to the immunological mechanism and the drug determinants that are finally presented. Moreover, the interaction may also depend on metabolites generated, that may be much more reactive than the native drug, being responsible for clinical sensitization [2, 7].
  Although numerous drugs have been implicated in the production of allergic reactions, antibiotics and analgesics are the drug classes most commonly implicated in drug allergy. However, geographical differences exist likely caused by local prescription patterns. Therefore, in the USA antibiotics are by far the most frequent culprit drugs in anaphylaxis (including penicillin, sulphinamides, cephalosporins macrolides and fluoroquinolones), and the analgesics (nonsteroidal anti-inflammatory drugs (NSAIDs), opiates and local anaesthetics) the largest group. In Europe, the most frequently involved drugs are antibiotics (penicillins, cephalosporins ad quinolones) and NSAIDs. In Latin America, NSAIDS are the most frequent drugs involved in anaphylaxis. In China, the most frequently implicated cause is antibiotics followed by traditional Chinese medicines [8].
   
• Degree of exposure (dose, duration, frequency)
  Although there are no rigorous studies, it has been reported that intermittent courses of moderate drug doses clearly predispose to sensitization; whereas prolonged treatment without free intervals is less likely to do so.
   
• Route of Administration
  Topical application of a drug is associated with a high incidence of sensitization and should be avoided with certain agents, especially on inflamed skin. Penicillin and sulfonamides are no longer used topically because of this risk. Oral administration of a drug is generally safer than any type of parenteral administration; however, severe reactions have followed this mode of administration. Cross-Sensitization
  Once sensitization to a drug has occurred, the possibility exists of reactivity either to drugs with a close structural chemical relationship or to immunochemically similar metabolites. The range of cross-sensitization varies greatly among individuals and is often impossible to predict. Familiar examples include substances having a free amino group in the para acid, para-aminobenzoic acid, and sulfonamides; phenothiazine derivatives such as chlorpromazine, prochlorperazine, promethazine, trifluoperazone, trimeprazine, and triflupromazine; and the cross-reactivity seen among penicillins and cephalosporins. Pholcodine is hypothesized to be a source of cross-sensitization among patients who developed hypersensitivity reactions to neuromuscular blocking agents.
   
• Cross-Sensitization
  Once sensitization to a drug has occurred, the possibility exists of reactivity either to drugs with a close structural chemical relationship or to immunochemically similar metabolites. The range of cross-sensitization varies greatly among individuals and is often impossible to predict. Familiar examples include substances having a free amino group in the para acid, para-aminobenzoic acid, and sulfonamides; phenothiazine derivatives such as chlorpromazine, prochlorperazine, promethazine, trifluoperazone, trimeprazine, and triflupromazine; and the cross-reactivity seen among penicllins and cephalopsporins. Pholcodine is hypothesized to be a source of cross-sensitization among patients who developed hypersensitivity reactions to neuromuscular blocking agents.

 

Host Factors

• Age and sex
  Some allergic reactions to drugs are probably less frequent in children possibly owing to immaturity of the immune response and lower drug consumption. However, in elderly patients prevalence increases up to 30%, being more severe, probably due to comorbidities and the use of multiple medications [9]. There is no conclusive evidence, with the possible exception of cutaneous reactions, that allergic drug reactions are more common in females than in males, probably due to the higher drug consumption in women compared to men, genetic and epigenetic factors, and discrepant hormonal interactions with immune cells [10]. However, the differences regarding age and sex are not significant determinants in the selection of a drug for therapy.
   
• Genetic factors (HLA type, Acetylator status)
  Allergic drug reactions occur in only a small percentage of patients treated with a given drug. It is likely that many factors, both genetic and environmental, are involved in determining which individuals in a large random population will develop an allergic reaction to a given drug. The presence of atopy is not a risk factor for drug allergy, although patients with uncontrolled asthma may be more prone to having severe reactions (as is the case with food allergies). Theoretically, genetic factors of various kinds, operating at different levels, may need to coexist in an individual before an allergic drug reaction occurs. The patient may require genetic information to form reactive metabolites, to produce specific types of antibodies, and to elaborate various pharmacologically active mediators. As the probability of coexistence of all these factors is probably quite low, this would explain the low incidence of allergic drug reactions in the general population. A number of genetic associations in DHRs have been found, mainly in Asian populations, that have been discovered as valid pharmacogenetic markers for prediction of these reactions [11, 12]:
  • HLA-B*13:01 associated with dapsone-induced SJS/TEN and DRESS in Thai and Han Chinese populations
  • HLA B*1502 associated with carbamazepine induced SJS/TEN in Han Chinese in Taiwan, Hong Kong, Thais and Indians; but neither in Japanese nor Europeans of non-Asian ancestry
  • HLA B*1502 associated with phenytoin induced SJS in Han Chinese in Hong Kong and Thais but not with MPE among Han Chinese from Hong Kong
  • HLA-A*32:01 in vancomycin-induced DRESS in a European ancestry population
  • HLA-B*56:02/04 in phenytoin-induced DRESS in Thai population
  • HLA-A*24:02 in anticonvulsants-induced SCARs in Han Chinese
  • HLA-B*35:05 allele correlates nevirapine patch test results in Thai population
  • HLA B*5801 and allopurinol induced SJS/TEN in Han Chinese from Taiwan, Thais, Japanese and Europeans
  • HLA B*5701 and abacavir drug hypersensitivity in Caucasian males and females but not blacks. This haplotype has been found to be uncommon in Taiwanese Chinese and Korean populations.
  • IgE mediated penicillin allergy: E237G variant of FceR1b (high affinity IgE receptor b chain) gene, IL-4RaQ576R polymorphism, IL-4 IL-13-SNP polymorphisms in Chinese
  • Immediate allergic reactions to beta-lactams: IL-13 (R130Q and -1055C>T variants) and IL-4RA (150V, S478P, and Q551R variants) polymorphisms in Italians; lle75Val variant of IL-4Ra gene two linked IL-10 promotor gene polymorphisms (-819C>T and -592C>A) in Causasians, and HLA-B* 48:01 in Thai children.
  • NIRs to beta-lactams: HLA-C*04:06, HLA-C*08:01 and HLA-DRB1*04:06 in Thai children.
  • Antituberculous drug induced hepatitis: CYP2E1 in the Chinese (but not in Korean and British), NAT2 (N-acetyltransferase) in Koreans and GST (glutathione-S-transferase) genotypes in Caucasians.
  • CYP2C19*3 associated to phenytoin-induced SJS in Thai populaation
  
  
  Pharmacogenetic testing for HLA-B*57:01 is now standard of care prior to prescription of abacavir in Caucasian populations. In certain countries in East and South East Asia, testing for HLA-B*15:02 has been mandated/ recommended prior to prescription of carbamazepine.
   
• Concurrent medical illness (e.g. Ebstein-Barr Virus (EBV), human immunodeficiency virus (HIV), asthma)
  The disease state may affect the development of allergic drug reactions by altering metabolic pathways and inducing variations in the immunologic responses to drugs. Drug reactions should occur less frequently among individuals whose immunologic responsiveness is impaired. For example hypogammaglobulinemia, drug allergy due to antibodies is rare, but cell-mediated reactions, such as contact dermatitis caused by topically applied drugs, may be easily induced. Conversely, patients with sarcoidosis have impaired cellular hypersensitivity, and are less likely to develop contact dermatitis and some drug exanthems, but may develop urticaria and other antibody-mediated allergic drug reactions.
  Moreover, the underlying disease may influence in the appearance of drug allergy as the disease may imply an increased frequency of exposure to high-drug doses, as occurrs in cystic fibrosis patients, in whom the incidence of beta-lactam allergy is significantly higher compared with noncystic fibrosis patients as they are often exposure to an increased frequency of high-drug doses. However, the nature and mechanisms of beta-lactam allergy in cystic fibrosis patients is thought to be the same as in non-cystic fibrosis patients [13]. Similarly, ADRs are frequently encountered in patients with HIV and AIDS, particularly those on co-trimoxazole (trimethoprim– sulfamethoxazole). Whether these frequent reactions are due to increased propensity or increase use of certain drugs is unclear.
  Regarding chemotherapeutic agents, it has been observed that disease severity, histological type, malignant ascites, past drug allergies and cumulative dose can induce an earlier onset and be a risk of hypersensitivity reaction development.
  Previous cardiovascular morbidity, systemic mastocytosis and asthma have also shown to be a risk for developing DHRs.
  Certain infections appear to be associated with the increased likelihood of drug hypersensitivity. For example, ampicillin maculopapular rashes arise commonly in patients with infectious. It is also well known that human herpesvirus-6 plays an important role in DRESS/DIHS, as this viral reactivation in patients with DRESS may increase T cell activity after the initiation of the drug eruption and induce the synthesis of proinflammatory cytokines [14]
   
• Previous drug exposure
  There is some evidence that patients who have demonstrated drug hypersensitivity in the past may have an increased tendency to develop sensitivity to new drugs, and one should be more cautious in medicating such patients. Obviously, if the drug is somewhat related to the one causing difficulty in the past, one must be on the alert for cross-sensitization.
   
• Multiple Drug Allergy Syndrome
  Patients with ‘multiple drug allergy syndrome” may have a predilection to more than one non-cross-reacting medication. It is a rare condition, being the estimated prevalence of 2.5% of the total suspected DHRs and 0.5% of the confirmed ones [15].
  Well-defined case series of patients where multiple drug allergies have been proven with in-vivo and in-vitro tests have been described [15].

 

DIAGNOSIS

The diagnosis of DHR is based on a detailed history of the onset of symptoms/signs combined with a temporal relationship between the appearance of those symptoms and drug use/discontinuation. The clinical diagnosis is followed by carefully selected diagnostic tests depending on whether the reaction is IgE or non-IgE mediated.

A few of the important principles of drug allergy include:

1. Drug allergy usually occurs in the presence of previous/adequate sensitization to the drug.  However, non-allergic DHRs may occurr after the first dose as no sensitization is required, because drugs directly activate effector mechanism of inflammation without the involvement of adaptive immune mechanism sometimes at the first encounter with the drug [2].
2. A drug allergy may take the form of a cutaneous reaction or a systemic reaction with major organ involvement, or both. P-i stimulation leads to NIRs which skin involvemtent, being sometimes severe due to systemic implication. The majority of pseudo‐allergic reactions are mild (acute urticaria), but some cause anaphylaxis and can even be lethal.
3. Potentially life-threatening drug allergies include anaphylaxis, SJS and TEN.

 

Clinical Diagnosis: Pattern of reactions

The morphology and distribution of the drug eruption is important. Disease extent can be described as generalized (widespread; no major regions of skin are exempt), disseminated (several skin regions are involved) or localized (limited to a certain area of the body) [4].

1. Clinical phenotypes of generalized or disseminated DHR:

   The term Drug-induced hypersensitivity syndrome (DIHS) is now used synonymously with other nomenclature including DRESS and Drug Hypersensitivity Syndrome (DHS).

   1.1. Urticaria, angioedema: wheals (circumscribed areas of raised erythema and oedema of the superficial dermis) in variable number and size accompanied or not by angioedema).
   
   1.2. Anaphylaxis: this is a severe life-threatening reaction. Mostly comes with skin lesions such as urticaria or a generalized flush, accompanied by systemic involvement (normally cardiovascular or respiratory involvement).
   
   1.3. MPE: erythematous macules and infiltrated papules that may widespread with different degrees of confluence.
   
   1.4. Bullous exanthems: small isolated vesicles and pustules in any MPE. The more severe bullous entities are called SJS and TEN. SJS and TEN are considered as severity variants of the same disease entity. The lesions are macules and flat atypical targets that do show confluence and on which blisters occur leading to various amounts of skin detachment: in SJS detachment is less than 10% of the body surface area, in TEN Detachment is greater than 30% of the body surface area, and in overlapping SJS and TEN the detachment is of 10% to 30% of the body surface area.
   
   1.5. AGEP: nonfollicular, small sterile pustules on the background of a widespread confluent exanthem.
   
   1.6. Vasculitis: palpable purpura, petechiae, bullae which can lead to necrosis and is indistinguishable from vasculitis due to other causes.
   
   1.7. DRESS: severe condition that often starts with MPE that also involves internal organs. Fever, malaise and lymphadenopathy are mostly present. In the peripheral blood, eosinophilia, leukocytosis and atypical lymphocytes are often found.
   
   It comprises the following features, with the diagnosis confirmed by the presence of any five of the six criteria:
   1. Human herpes virus (HHV)–6 reactivation
   2. Hepatitis (alanine aminotransferase [ALT] ≥100 U/L)
   3. Leukocytosis (≥10 ´ 10⁹/L), atypical lymphocytosis or eosinophilia
   4. Fever (≥38°C)
   5. Lymphadenopathy
   6. Maculopapular rash developing ≥3 weeks after starting therapy with a limited number of drugs
      
      1.8. Symmetrical drug-related intertriginous and flexural exanthem: Special pattern of a MPE with a characteristic distribution pattern involving flexural and intertriginous areas.
      
       
2. Clinical phenotypes of localized DHR:
   
   2.1. Fixed drug eruption: erythematous to violaceous plaque, which may become bullous centrally, that always arises at the same site after re-exposure to the culprit drug. The lesion characteristically resolves with residual hyperpigmentation. Multisite FDEs may also occur.
   
   2.2. Systemic photoallergic reactions: it occurrs after ingestion of the sensitizer medication where light initiates an immune or a phototoxic response. It is manifested as dermatitis predominantly affecting the sun-exposed areas.

 

Diagnostic Tests

Clinical history is the first approach in the diagnosis of DHRs. Predictive models based on decision tree methods based only on clinical history have been designed for the diagnosis of beta-lactam allergy. Although it has shown a similar specificity, positive and negative predictive values compared to the allergological workup, its lower sensitivity makes these models to have a limited value for accurately predicting beta-lactam allergy [16].

Diagnostic tests [17-19] should be used as an adjunct to the clinical history and examination. The type of diagnostic test depends on whether the initial reaction was IgE or non-IgE mediated.

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, suxamethonium, neuromuscular blocking agents (NMBAs) and chlorhexidine. 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, NSAIDs, fluoroquinolones, iodinated contrast media, proton pump inhibitors, NMBAs and chemotherapeutical agents) hypersensitivity.

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 [18,19] 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 [20] 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) [21,22] 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.

DPT may be used in the following four instances:

1. To exclude drug hypersensitivity when the history is nonsuggestive or the symptoms nonspecific
2. To provide safe pharmacologically and/or structurally nonrelated drugs in cases of proven hypersensitivity (e.g., beta-lactam antibiotics)
3. To exclude cross-reactivity of related drugs in cases of proven hypersensitivity (e.g., cephalosporin in a penicillin-allergic individual)
4. To definitively diagnose drug allergy when the clinical history is suggestive but allergological tests are negative, inconclusive or unavailable

Specific contraindications to DPT include pregnancy; comorbidities in which DPT may provoke the medical situation beyond the ability to control it (e.g., acute infections; uncontrolled asthma; or underlying cardiac, hepatic or renal diseases); immunobullous drug eruptions; and cases in which the initial reaction was a severe cutaneous and/or systemic reaction (e.g., SJS and TEN).

The risks and benefits of any DPT must be explained to the patient and informed consent obtained. Short-acting antihistamines (e.g., chlorpheniramine or hydroxyzine) should be stopped for 3 days and long-acting antihistamines (e.g., cetirizine, loratidine or fexofenadine) for 7 days before performing any DPT. Patients should also be fasted overnight and carefully observed at all times during the DPT for symptoms or signs of an adverse reaction. Resuscitation equipment should be available at all times, and staff should be trained in the management of acute anaphylaxis.

 

Other investigations for drug hypersensitivity

In drug induced pneumonitis, a plain chest x-ray, pulmonary function tests and high resolution CT thorax may be useful. Bronchoalveolar lavage and open lung biopsy for histological diagnosis are usually not necessary.

 

TREATMENT

Apart from immediate cessation of the putative drug, the following measures should also be taken:

Acute Immediate Management of IRs

• Nonserious (mild cutaneous) reactions: antihistamines.
• Serious reactions (anaphylaxis) [23]: emergency management, including securing the airway; maintaining breathing and circulation; and use of drugs, including:

• First line treatment: Intramuscular epinephrine 0.3-0.5 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. If cardiorespiratory arrest occurs, cardiopulmonary resuscitation should be immediately instituted.
• Second-line intervention: high flow oxygen, for patients with cardiovascular instability, fluid support should be initiated promptly and inhaled short‐acting beta‐2 agonists can be additionally given to relieve symptoms of bronchoconstriction.
• Third line intervention: H1‐ and H2 antihistamines, and glucocorticoids. 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.

It is recommended to observe the patient for at least 6‐8 hours in case of respiratory compromise and at least 12‐24 hours for patients who presented with hypotension. This will facilitate the recognition and treatment of biphasic reaction.

Acute Immediate Management of NIRs

• Nonserious reactions: antihistamines 
• Serious reactions

The use of tapered doses of systemic corticosteroids is not uniformly practiced by all specialists in drug allergy due to variable outcomes, potential side-effects and the lack of data from well-designed, randomized prospective studies [24].

In SJS/TEN, oropharyngeal hygiene and gargle solutions, as well as eye care (sterile eye management, use of topical corticosteroids), and skin care should be ensured. , 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.

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 [25]. 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 [26].

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 [26].

The methods of inducing tolerance are all similar but specifics vary. Assuming that there is a need for the drug that cannot be met in any other way and warrants the risks of desensitization, a schedule is prepared that is appropriate for the clinical circumstances. In some situations, rapid desensitization in a few hours may be required. Desensitization over a period of days to weeks may be acceptable if the need is for prophylaxis or more chronic treatment. A beginning dose can be selected as a fraction, possibly 0.1-1%, of the subject’s known tolerance of the agent or by arbitrarily starting with 1 per 100 to 1 per 1 000 or even less of a therapeutic concentration. Subsequent doses are then increased by approximate doubling. After the therapeutic concentration (dose) is reached, the patient should continue to receive the agent.

Induction of tolerance to the offending drug is temporary - patients should still be regarded “allergic” to that particular drug. Should the patient require the medication 3-7 days after cessation, the desensitization process should be reinstituted.

Regimes have been described for many drugs including penicillins, cephalosporins, cotrimoxazole, allopurinol and the chemotherapeutic agents. Following is a list of drugs for which desensitization protocols have been described in the literature: (Table 3)

Table 3 AGENTS FOR WHICH DESENSITIZATION PROTOCOLS AVAILABLE

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.

 

INDICATIONS FOR ALLERGIST REFERRAL

Referral mandatory [27]

• When there is a history of severe DHR for any drugs such as anaphylaxis or severe non-immediate cutaneous reaction to a drug (e.g. DRESS, SJS, TEN), in order to confirm the culprit and protect the patient from future reactions
• Patients with a history of betalactam 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 or general 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
• For others drugs, when they are required depending on an individual medical need

Referral recommended [27]

• Patients with a suspected non-severe DHR to beta-lactam antibiotics; Although at the moment of the reaction the patient may have no condition that requires beta-lactam antibiotics, they are among the most commonlyprescribed antibiotics and they are likely to be prescribed in future

Patients with a suspected nonsevere DHR to NSAIDs: Although at the moment of the reaction the patient may have no condition that requires NSAIDs, they are among the most commonly prescribed drugs and they are likely to be prescribed in future.

 

COURSE AND PROGNOSIS

The outcome of most cutaneous drug allergies is good after immediate cessation of the drug and symptom relief.

Drug-induced anaphylaxis is potentially fatal, as it is characterized by a high frequency of rapid-onset (within minutes) cardiovascular collapse, especially in older patients. Other risk factors for death include cardiopathies associated with beta-blocker therapy. The true prevalence of fatal drug-induced anaphylaxis is unknown, as the patients studied varied from children to adults, and from emergency room attendees to inpatients, and most studies included all causes of anaphylaxis rather than drug-induced anaphylaxis specifically.

In SJS/TEN, the reported mortality rate varies from 30% to 50%. The effect of IVIG on mortality in patients with TEN remains indeterminate. Ocular complications (i.e., nonhealing epithelial defects and visual impairment) are major but relatively uncommon long-term sequelae of SJS/TEN. A persistent dry eye is the most common.

Drug allergy may result in anxiety and impairment in health related quality of life for sufferers. Health care professionals involved in the care of patients with a history of drug allergy/hypersensitivity must be aware of potential long-term psychological sequelae and effects on the doctor-patient relationships especially when new drugs have to be prescribed again.

 

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Helpful Links: Patient Information on Drug Allergies

American College of Allergy Asthma and Immunology (ACAAI) Public Education on Drug Reactions
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American Academy of Allergy Asthma and Immunology (AAAAI) Adverse reactions to medications
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