Management of drug allergy-clinical update : Indian Journal of Allergy, Asthma and Immunology

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Review Article

Management of drug allergy-clinical update

Kathuria, P. C.; Rai, Manisha1

Author Information

National Allergy Centre, BLK Super Speciality Hospital, New Delhi, India

1National Allergy Centre, New Delhi, India

Address for correspondence: Dr. P. C. Kathuria, National Allergy Centre, 1/3 East Patel Nagar, New Delhi - 110 008, India. E-mail: [email protected]

Received September 20, 2022

Accepted December 06, 2022

Indian Journal of Allergy, Asthma and Immunology 36(1):p 4-17, Jan–Jun 2022. | DOI: 10.4103/ijaai.ijaai_34_22
  • Open

Abstract

Drug Allergy-Definitions and phenotypes

Adverse drug reactions (ADRs) are defined as any undesired effect of a drug that occurs at doses used for prevention, diagnosis, and treatment.[1,2] ADRs occur in 10%–20% of all hospitalized patients, among which 0.2%–0.4% can have a fatal outcome.[3] Up to 14% of hospitalized patients have drug allergy labels.[4] Cutaneous reactions are commonly occurring in 2–10 per 1000 patients and are frequently caused by antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs), while SCARs (Severe cutaneous adverse reactions) are uncommon but can result in high morbidity and mortality.[5]

Adverse Drug Reactions

Type A reactions

Type A reactions [Figure 1] which are dose-dependent, predictable, and pharmacologically-mediated (>80%) from mild (headache and gastrointestinal effects, sedative effects of an antihistamine, secondary adverse effects after antibiotics-induced alteration of microbiome such as pseudomembranous colitis or nephrotoxicity with aminoglycosides, etc.,) to life-threatening reactions (warfarin-induced severe bleeding, etc.).

F1-2
Figure 1:
Classification of adverse drug reactions

Type B reactions

Type B reactions [Figure 1] are called drug hypersensitivity reactions (DHRs), which are not dose dependent, unpredictable, and often occur in predisposed patients. They comprise <20% of all ADRs.

Drug Hypersensitivity Reactions [DHRs]: Allergic and Non-allergic

Allergic drug hypersensitivity reactions

Immunologically mediated response to a drug (pharmacological agent and/or excipient) in a sensitized person.

Nonallergic drug hypersensitivity reactions

Nonallergic drug hypersensitivity reactions are the reactions not associated with immunological (humoral or cellular) sensitization and are subdivided into:

  1. Drug intolerance – pharmacologically toxic effect due to underlying abnormalities of metabolism, excretion, or bioavailability of the drug
  2. Drug idiosyncrasies – abnormal unexpected effects unrelated to the intended pharmacological action of the drug
  3. Pseudo-allergy – drug idiosyncrasy of immediate systemic reactions like anaphylaxis due to nonimmunoglobulin E (IgE) mediated release of the mediators from mast cells and basophils
  4. Pharmacological interaction (PI) with the drug (PI reaction) – nonallergic idiosyncratic reaction caused by noncovalent human leukocyte antigen (HLA)-dependent direct activation of T cell receptor.

DHRs- Clinical phenotypes

Allergic DHRs [Figure 1] with prior sensitizations can be classified based on chronology, mechanism, and clinical phenotypes; the chronology is simplified into immediate reactions (1–6 h) or delayed reactions (more than 6 h), while in de novo sensitiztaion, the typical sensitization latency period is 5–10 days. Timeline for ADRs for hypersensitivity reactions (HSR) is shown in Figure 2.

F2-2
Figure 2:
Timeline of drug hypersensitivity reactions

Immediate-type reactions

}With clinical manifestations of flushing, urticaria, angioedema, anaphylaxis, vomiting, abdominal pain, diarrhea, more severe reactions such as dyspnea, bronchospasm, and hypotension, 70% of these reactions have an onset within 5 min. These reactions are due to Mast cell degranulation (antimicrobials, neuromuscular blocking agents [NMBA], proton-pump inhibitors, insulin, and chimeric monoclonal antibodies [MAbs]). They are not only IgE-mediated hypersensitivity reactions on second and subsequent exposure of antigen but also through non-immunological hypersensitivity reactions by complement activation or signal through the Human-G protein-coupled receptors (MRGPRX2), as well as also mediated by Cox-1 inhibitor, for example, NSAID, Vancomycin, Radio contrast Media (RCM), Flouroquinolones (FQs), Opioids [Figure 3]. Anaphylactoid infusion reactions or CRS are non-antibody mediated, typically occur on the initial exposure (within 30-120 minutes) after infusion of the drug, associated with use of monoclonal antibodies and immunomodulating therapy. three specific cytokines: IL-6, IL-10 and IFN-γ have been identified as elevated in CRS during blinatumomab and CD19-specific CAR T- cell therapy.[6]

F3-2
Figure 3:
Mechanism underlying immediate hypersensitive reaction

Delayed type reactions

Delayed type rections [Figure 1], which are likely related to specific T cells (Th1/Th2 and cytotoxic T cell) are Immunological (Type IV) and PI reactions. The latency period is a valuable tool of the type of this reaction, as acute generalized exanthematous pustulosis (AGEP) occurs very quickly to antibiotics, while drug rash with eosinophilia and systemic symptom (DRESS) has a latency period of 2–3 weeks, further subdivided into four sub-groups [Figure 1].

  • Type IVa- macrophage activation induces-contact eczema
  • Type IVb-Th2 cytokine activation (interleukin [IL]-4/5/13) along with IL33/TARC/CCL-47 e.g., DRESS due to sulfonamides, dapsone, vancomycin, minocycline, allopurinol and anti-epileptic, etc
  • Type IVc- due to cytotoxic T cell (CD8) and NK cells and IL-15 cytokine which release granzyme, perforin, and granulysin, which increase the apoptosis and necrosis of keratinocytes and death of epithelial cells. Necroptosis is the key mechanism of keratinocyte death in Stevens-Johnson Syndrome (SJS) and toxic epidermal necroplasia (TEN) due to allopurinol, sulfonamides, lamotrigine, nevirapine, oxicam, dapsone, etc
  • Type IVd- There is a neutrophilic activation by cytokines, IL-8/IL-36/IL-17/IL-22 and TNF/GM-CSF, for example, AGEP due to antibiotics (penicillin and macrolides), anti-malarial and calcium channel blockers.

Other delayed type reactions

(Gell and Coombs Type II/III, immunoglobulin G (IgG)/immunoglobulin A (IgA) or immunoglobulin M (IgM) mediated) which are clinically non-cutaneous but organ-specific drug reaction phenotypes such as cytopenia, serum sickness, allergic vasculitis, and interstitial nephritis due to NSAIDs, antibiotics (trimethoprim + sulfamethoxazole (TMP-SMX), penicillin), dapsone, anti-malarial, barbiturates, etc.

Diagnosis

A comprehensive history and clinical phenotype are essential for correct diagnosis. Clinically, it is important to differentiate whether the reactions are IgE-mediated versus T-cell-mediated reactions. There are five biomarkers in IgE and Non-IgE mediated HSR: (a) Skin testing, (b) Specific IgE, (c) basophil activation test (BAT), (d) Serum Tryptase, and (e) Serum histamine. A high titer of serum tryptase >11.4 mg/dL can confirm the diagnosis of anaphylaxis. If there is a history of severe anaphylaxis, drug-specific IgE test and/or BAT should be considered before skin testing. The combination of skin testing, followed by oral challenge test is generally considered the gold standard for diagnosis of immediate reaction. If T cell-mediated reaction is suspected, then patch test or late-reading intracutaneous testing should be performed. Lymphocyte transformation test (LTT) and enzyme-linked immunosorbent spot assay (ELISpot) test are commercially not available. The various tests [Table 1] have been divided to confirm or exclude DHR.

T1-2
Table 1:
Diagnostic testing for drug hypersensitivity reactions

Diagnosis

Skin test

Guidelines recommend skin prick test (SPT) and intradermal skin test (IDST)/delayed reading intracutaneous testing for both immediate testing and nonimmediate delayed type T cell reaction. Skin testing is safe when performed at least 6 weeks to 6 months after the drug-induced anaphylaxis. Consent should be taken before skin testing. Initially, SPT is done, followed by a more sensitive intacutaneous test. Positive SPT is defined as more than 3 mm wheal and 5 mm erythema bigger than the negative control. IDST is defined as more than 6 mm wheal size and 9 mm erythema bigger than the negative control. Delayed reading intracutaneous test (after 24–48 h) is done by injecting 0.02–0.05 mL to induce baseline bleb of 3–5 mm wheal, is defined as edema/induration of more than 5 mm.[7,8,9,10] A positive SPT suggests that the patient may have IgE-mediated allergy to drugs, but interpretation should always be correlated with the patients' clinical history. Penicillin skin testing has a negative predictive value (NPV) of 97%–99% and specificity of 97%–99% and 70% sensitivity.[11,12,13] Hence, one can change the decision based on the skin test. If skin test is negative with negative oral provocation test (OPT), NPV is 100%. There is hard evidence on penicillin and neuro-muscular blocking agent skin testing, but the rest of the drugs are skin tested by non irritating concentration. Skin testing of drugs (muscle relaxants, NMBA, local anesthetics (LA), and high molecular weight agents such as insulin, vaccines, streptokinase, polyclonal or MAbs, and latex) are also well defined, but their standardized skin test reagents are not commercially available.[14] Contraindications and precautions for skin testing in immediate drug reactions should be considered before the procedure [Table 2].

T2-2
Table 2:
Contraindications to skin testing of immediate drug reactions

Drug challenge test

Drug challenge test (DCT) is also known by the following terms in the literature as drug provocation test (DPT), graded challenge, and graded dose challenge. It is a safe gold standard test to identify the culprit drugs in ADRs. It also determines the tolerance of medication and confirmation of disease, such as aspirin exacerbated respiratory disease (AERD). DCT is performed for both immediate and delayed phenotypes of drug reaction when in vivo/in vitro testing is not reliable, for example, for sulfonamides, quinolones, macrolides, and NSAIDs. DCT is indicated in patients, in whom there is no convincing history of anaphylaxis and also for non-severe delayed drug reactions. If an immediate ADR is concerned, the starting dose of DCT ranges from 1:1000 dilution to full therapeutic dose, with the subsequent dose increased by 10-folds at an interval of 30 min to 1 h. The initial dose depends on the clinical situation, the severity of the initial drug reaction, the route of administration, and the bioavailability of drugs (oral vs. intravenous). In beta-lactam allergy with a positive history but negative skin test, single step therapeutic dose can be done, while in case of a positive skin test, 2 step challenge would entail; first step challenge with 10%–25% of the therapeutic dose and second step challenge after 30 min with 75%–90% of therapeutic dose followed by 1 h observation.[15] In T cell-mediated delayed reaction, the first therapeutic dose is given under medical supervision, then continue the same challenge dose at home for 3–7 days with close monitoring by phone or face-to-face follow-up. DCT is contraindicated in severe anaphylaxis, TEN, SJS, AGEP, Drug-Induced Autoimmune Disease, systemic vasculitis, etc.[Table 3]. Examples of the Immediate Adverse Reaction Drug Challenge Protocol as mentioned in [Table 4].

T3-2
Table 3:
Contraindications to drug challenges
T4-2
Table 4:
Example of immediate adverse reaction drug challenge protocol

In vitro Specific immunoglobulin E tests for drug hypersensitivity reactions

Unfortunately, the sensitivity and specificity of specific IgE for drugs have its limitations. Immunogenic determinants of many drugs are not well defined. Drugs like beta-lactams, NMBA, Chlorhexidine, some NSAIDs, etc., induce mast cell degranulation-releasing mediators (Histamine, PAF, Tryptase, leukotrienes, prostaglandins, etc.,), through cross-linking of FcεR (high-affinity receptors) on second or subsequent exposure of drug antigen. They are useful in those with a history of multiple drug allergy, life-threatening reactions, dermographism, or extensive dermatitis where skin tests or challenge tests are contraindicated. There are limited drugs for specific IgE assays commercially available from Thermo Fisher Scientific, Uppsala, Sweden [Table 5].

T5-2
Table 5:
Fluorescent enzyme immunoassay ImmunoCAP drug-specific IgE assays available for commercial and research purposes

Histamine

Histamine is a principal component in anaphylaxis but has a short half-life (20 min), so blood needs to be collected within the first half-hour. It is not reliable because of its low sensitivity and specificity.

Basophil activation test

It detects the surface expression of activation markers such as CD63 or CD203c. It is useful when skin test and serum-specific IgE testing results are equivocal or ambiguous. It is recommended in life-threatening reactions due to Flouroquinolones, NMBAs, RCM, Pyrazolone, etc.

Serum tryptase

It is serine protease, a preformed mediator comprising of Immature alpha -monomer isoform and a mature beta hetero tetramer isoform. It is detected by immunoassay, having a sensitivity of 30%–94%, a specificity of 92%–94%.[16] Blood must be drawn within 4–6 h of an anaphylactic reaction and to be compared with baseline level within at least 24 h after resolution of anaphylactic symptoms. Serum tryptase level of more than 11.4 ng/mL or increased by 20% plus 2 ng/ml (2 + 1.2 X baseline Tryptase) over the baseline level is indicative of mast cell activation.[17]

How to Assess T-cell Mediated Drug Reaction?

T cell-mediated reactions are dose and concentration dependent. In vivo tests like patch test and intracutaneous tests with delayed reading and in vitro tests like LTT, ELISpot, HLA typing are recommended.

Patch test

It is recommended in MPE, AGEP, FDR, but not useful for SJS or urticarial eruption. It is considered positive if erythema and induration, and vessiculo-papular eruption at the site of patch develop in 48 to72 h of application of the drug.[18] Drugs associated with positive patch tests are anti-convulsants (carbamazepine and phenytoin), beta-lactams (amoxicillin, penicillins), co-trimoxazole, corticosteroids, diltiazem, etc.

Intracutaneous testing with delayed reading

It is done with nonirritating concentration of the drug by injecting 0.02 ml–0.05 ml intracutaneously. Reading is done after 24 h (delayed reading). It is a more sensitive skin test for beta-lactam antibiotic, RCM, and Heparin.

Lymphocyte transformation test

It is an alternative to patch testing but has inconsistent results as compared to patch tests. It has higher variable sensitivity 27%–88.8% and specificity 63%–100% depending on the type of drug.

Enzyme-linked immunosorbent spot assay

This test quantifies the number of cytokines secreting T cells IFN-Y for abacavir and beta-lactam reactions and granulysin or granzyme B for severe cutaneous reactions such as SJS and TEN. The sensitivity of ELISpot for beta-lactam reactions ranges from 13% to 91%. The negative predictive value (NPV) of BAT and LTT was 14.7% and 28.2%, respectively, but when combined, NPV increased to 96.4%.[19,20]

Management

There are three sub-groups of patients:

  1. Multiple Drug Intolerance Syndrome is defined as three or more unrelated drug reactions, with atopic and comorbidities. These patients need special alternative drug treatment
  2. Selective, specific drug allergy, for example, beta-lactam or NSAID or anesthetic agents. These patients need skin tests with a non-irritating dose like amoxicillin 20 mg/mL, ceftriaxone 2 mg/mL, etc., and Drug desensitization (Ds) accordingly.
  3. Selective desensitization where reasonable, alternative drugs are not available, for example, TMP-SMX desensitization in the HIV population, Anti-tubercular drugs, and Anti-cancer drugs, etc.

Drug desensitization

Desensitization is a procedure that results in a temporary tolerance to a drug causing hypersensitivity reaction. Each desensitization protocol is customized to the specific dose till the patient will receive his or her full therapeutic dose. There are three basic fundamentals in Ds: (a) Initiating dose should be 1:1000–1:100 dilution of the therapeutic dose, (b) Increasing doubling dose and (c) fixed time-interval of 15–20 min. The target cell of desentization recation is mast cells and possibly basophil cells, which release inflammatory mediators by IgE-mediated (penicillin, cephalosporin, platinum-based chemotherapeutic drugs-carboplatin) and non-IgE mediated drugs (taxanes-paclitaxel). One should grade the severity of the initial reaction (Grade 1-cutaneous reaction, Grade 2-s/s of cardio-respiratory or gastrointestinal involvement, Grade 3-s/s hypotension or hypoxia, loss of consciousness, and cardiovascular collapse). High-risk patients are those who have an initial reaction of Grade 3, on Beta-blocker and Angiotensin-converting-enzyme inhibitors. The possible mechanism of desensitization is when sub-threshold dose of the drug binds to monomeric binding to the IgE receptor. Then, the cell does not become activated. There is a decreased level of the signal-transducing molecules such as syk.[21] Others suggested that low doses of drug antigens might induce rearrangement of the cell membrane in the antigen-sensitized mast cells which prevents the internalization of the drug antigen - IgE complex and protects against anaphylaxis. There is an increased in IgG antibody titer, which neutralize the drug epitope and serves as a blocking function for IgE-mediated reaction, demonstrating an increase in CD4, CD 25, FoXP3, and Treg cells in the patients after desensitizatiom.[22] Drug desentization is contraindicated in Gell and Coomb classification Type II and Type III hypersensitivity recations (serum sickness, hemolytic anemia, drug-induced interstitial nephritis, pneumonitis, vasculitis, hepatitis, blood cell dyscrasias) and non-mast cell-mediated cutaneous reaction (exfoliative dermatitis syndrome), dermatosis with mucus membrane lesions (SJS, TEN, DRESS, FDE, erythema multiforme, BM, AGEP).[23,24]

Drug desensitization procedure

There are 14-16 steps [Figure 4] during protocol by 3 bag system or 4 bag system:[25]

F4-2
Figure 4:
Drug desensitization procedure

Bag 4- therapeutic dose→Bag 3 × 10-fold dilution→ Bag 2 × 100-fold dilution→ Bag 1 × 1000-fold dilution

Bag 1- (1000-fold dilution × 7 STEPS 10 ml from bag 2 + 90 ml saline)

(volume to be given = 9.25 ml × 4 doses each @ 15 mins interval)

First dose- 0.5 ml @ 2ml/h by infusion

Second dose = 1.25 ml @ 5 ml/h

Third dose = 2.5 ml @ 10 ml/h

Fourth dose = 5 ml @ 20 ml/h

Total dose given = 9.25 ml in 1 hour

Bag 2- (100-fold dilution × 3 STEPS 10 ml from bag 3 + 90 ml saline)

(volume to be given = 18.75 ml × 4 doses each @ 15 mins interval)

First dose- 1.25 ml @ 5ml/h by infusion

Second dose = 2.5 ml @ 10 ml/h

Third dose = 5.0 ml @ 20 ml/h

Fourth dose = 10 ml @ 40 ml/h

Total dose given = 19.675 ml in 1 h

Bag 3

(10-fold dilution × 4 STEPS 10 ml from bag 4 + 90 ml saline)

(volume to be given = 100 ml × 4 doses each @ 15 mins interval)

First dose- 2.5 ml @ 10 ml/h by infusion

Second dose = 5.0 ml @ 20 ml/h

Third dose = 10 ml @ 40 ml/h

Fourth dose = 80 ml @ 80 ml/h over 60.40 mins

Total dose given = 805.325 ml

Penicillin drug allergy

Penicillins are bacteriocidal antibiotics that disrupt bacterial cell walls. Pencilloyl is the major antigenic determinant, a metabolite of the beta-lactam core structure of penicillin. Approximately 10% of patients have a history of penicillin reaction, among which 90% or more of these individuals tolerate penicillin and are unnecessarily labeled as penicillin-allergic. These mislabelling reactions are nonimmunological because of the interaction between infectious agents and the penicillin antigen. They are treated with more toxic, more expensive antibiotics (fluoroquinolones, vancomycin, clindamycin, and late-generation cephalosporins) but are less effective & may develop serious antibiotic-resistant infections (vancomycin-resistant enterococcus, clostridium difficile, MRSA). Every effort should be made to de-lable penicillin allergy. Consensus-based statement 4: A proactive effort should be made to delabel patients with reported penicillin allergy, if possible. Strength of recommendation: Strong, Certainty of Evidence: Moderate.[26]

The direct oral challenge test is done if the reaction is the benign cutaneous reaction, for example, MPE and urticaria and did not involve blistering or exfoliation of the skin or mucus membrane. Single-dose amoxicillin challenge without prior testing should be considered.

Consensus-based statement 8

We recommend against penicillin skin testing before direct amoxicillin challenge in pediatric patients with a history of benign cutaneous reactions (such as MPE and urticaria). Strength of Recommendation: Strong. Certainty of Evidence: Moderate.[26]

Consensus-based statement 9

We suggest that direct amoxicillin challenge be considered in adults with a history of distant and benign cutaneous reactions (such as MPE and urticaria). Strength of Recommendation: Conditional, Certainty of Evidence: Low.[26]

Penicillin skin testing is primarily done with a history of anaphylaxis or recent reaction suspected to be IgE mediated or with patients who are uncomfortable or anxious about the direct oral challenge test. In a patient with a history of anaphylaxis to cephalosporins, penicillin skin testing and drug challenge should be performed before the administration of penicillin therapy. Skin test (SPT/IDST) should be done with a specific dose as per guidelines, (amoxycillin-20 mg/ml, benzylpenicillin-10,000 units/ml, amoxicillin clavulanic acid-20 mg/ml and ampicillin-20 mg/ml). Consensus-Based Statement 6: Penicillin skin testing for patients with a history of anaphylaxis or a recent reaction suspected to be IgE-mediated. Strength of Recommendation: Conditional, Certainty of Evidence: Low.[26] If traditional penicillin skin testing or amoxicillin challenge tests are negative, then skin testing with piperacillin-tazobactam can be done to identify selective sensitivity. 90% of the patients with a negative penicillin test or unverified non-anaphylactic penicillin allergy can safely receive cephalosporin (second or third generation) or structurally dissimilar cephalosporin without testing.

Beta-lactam agents like carbapenems, and monobactams, (aztreonam), can be administered without prior testing unless there is ceftazidime allergy. If penicillin skin testing is positive and needs penicillin for a life-threatening infection, then 12-step penicillin oral desensitization is a safe and effective way.[27,28] If parental penicillin is required, administer it half hour after completion of oral desenstiztaion and then observe at least one hour of the parental dose. The starting oral dose of 0.25 mg is about three-times times the amount of penicillin in an IDST using 0.02 ml of 3.725 mg/ml penicillin G.[27,28]

Cephalosporin allergy

Penicillin and cephalosporin share common structure that are thought to be the source of cross-reaction: (1) Beta-lactam ring and (2) Side chain or R1 and R2 location; for example, patients with allergy to cefepime should avoid ceftriaxone but are unlikely to be allergic to cephalexin based on the side chain. Cephalosporins induce diverse immunologic reactions phenotypes: (1) IgE-mediated anaphylaxis, (2) benign T cell-mediated exanthems, (3) Serum Sickness Like Reaction (SSLR), (4) very rarely severe cutaneous adverse reaction.[29]

Consensus-based statement 10

In patient with a history of non-anaphylactic cephalosporin allergy, direct challenge without prior skin testing to cephalosporin with dissimilar side chains be performed to determine tolerance, the strength of recommendation: Conditional, Certainty of evidence: Moderate.[26]

Consensus-based statement 11

In a patient with a history of anaphylaxis to cephalosporin, a negative cephalosporin skin test should be done prior to administration of parental cephalosporin with a nonidentical R1 side chain, strength of recommendation: Conditional, certainty of evidence: Poor.[26]

Consensus-based statement 12

In patients with a history of anaphylaxis to penicillin, a structurally dissimilar cephalosporin can be administered without testing or additional precautions, the strength of evidence: Conditional, certainty of evidence: Moderate.[26]

Consensus-based statement 13

Patient with a history of unverified non-anaphylactic penicillin allergy, a cephalosporin can be administered without testing or additional precautions, strength of evidence: Conditional, certainty of recommendation: Moderate.[26]

Consensus-based statement 19

Allergists should collaborate with hospitals and healthcare systems to beta-lactam allergy pathways to improve antibiotic stewardship outcomes, strength of recommendation: Strong, certainty of evidence: Moderate.[26]

Quinolones

Although FQs are generally safe and well-tolerated antibiotics, but HSR, phototoxicity, and acute exanthematous reaction/SJS/TEN can occur. The most common type of allergic reaction to FQs is a delayed onset maculopapular eruption (MPE).

The most important FQs involved in DHRs are ciprofloxacin, followed by moxifloxacin, ofloxacin, and levofloxacin.[30,31,32,33] If clinical history is unreliable and skin tests have a high rate of false positivity and low sensitivity, DPT is the only way to diagnose DHR and is generally accepted as a gold standard. Consensus-Based statement 21: 1-or 2-step drug challenge without preceding skin testing to confirm tolerance in patients with a history of non-anaphylactic reactions to FQs. Strength of recommendation: Conditional, certainty of evidence-low.[26]

Ofloxacin and levofloxacin are cross-reactive, but Ciprofloxacin, Moxifloxacin, and Gemifloxacin are not cross-reactive. OPT should be done accordingly:

  1. If allergic to Ciprofloxacin-OPT with moxifloxacin, levofloxacin, and Gemifloxacin
  2. If allergic to moxifloxacin-OPT with Cipro, levofloxacin, and Gemifloxacin
  3. If allergic to levofloxacin/Ofloxacin-OPT with Ciprofloxacin, Moxifloxacin, and Gemifloxacin
  4. If allergic to Gemifloxacin-OPT with Ciprofloxacin, moxifloxacin, and Levofloxacin.

Macrolide Drug Allergy

They are classified according to the number of carbon atoms in their lactone ring: 14 membered (erythromycin, troleandomycin, roxithromycin, and clarithromycin), 15 membered (azithromycin), and 16 membered (spiramycin).

Acute urticaria is the most frequent immediate reaction, while MPE, FDR. AGEP and vasculitis have also been reported due to macrolide reactions. Skin tests have not been validated due to poor sensitivity and specificity. Patch testing at a concentration of crushed tablets in petroleum is done for FDR, contact dermatitis to erythromycin and azithromycin.[34,35] DPT (with 1- or 2-step drug challenge) is the most important diagnostic tool to rule out macrolide reactions.

Sulfonamides Drug Allergy

After beta-lactam antibiotics, sulfonamide antibiotics are the most commonly implicated antibiotic in DHR. Delayed reactions involving the skin, are the most common in clinical practice, example, Morbilliform/MPE/Urticarial rash/SJS/TEN/DRESS, etc. In HIV patients, 24%–50% get MPE reaction in 8 to 12 days and it lasts for 3-5 days. There is no specific test for diagnosis, but combination of SPT, IDST for immediate reaction, Delayed Intradermal testing, and patch testing has shown good sensitivity. 5-methyl-3 isoxazole group on SMX molecule has antigenic determinant which is responsible for immediate reaction to TMP-SMX.[36] Patients who are at a higher risk and still require treatment with TMP-SMX, Dd protocol has significant successful outcomes.

Consensus-based statement 20

Patients with a history of benign cutaneous reactions (e.g., MPE, urticaria) to sulfonamide antibiotics that occurred more than five years ago, a 1-step drug challenge with trimethoprim-sulfamethoxazole be performed when there is a need to de-label a sulfonamide antibiotic allergy. Strength of Recommendation: Conditional, Certainty of Evidence-Low.[26]

Nonsteroidal Anti-inflammatory Drugs Hypersensitivity

NSAID are unique, not only induce an immunological reaction but also a non-immunological reaction [Tables 6 and 7]:

T6-2
Table 6:
Classification of nonsteroid anti-inflammatory drug hypersensitivity reactions
T7-2
Table 7:
Nonsteroidal anti-inflammatory drug classification based on chemical structure
  • The immunological reaction occurs as Single NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA), and Single NSAID-induced delayed reactions (SNIDRs), have no history of comorbidities
  • Nonimmunological reaction occurs in preexisting disease of adult-onset asthma, rhino-sinusitis, recurrent nasal polyp, chronic spontaneous urticaria, etc. These produce an increase in cysteinyl leukotrienes, (Cys LTs), prostaglandins (PG) D2, 15-hydroxy eicosateteranoic acid (15-HETE), with overexpression of leukotrienes (LTC4) synthase and decrease in PGE2 & increase serum tryptase level, classified as NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous disease (NECD) and NSAID-induced urticaria/angioedema (NIUA) [Table 6].

One has to differentiate by aspirin provocation test, whether the patient is cross-reactive (non-immunological), or cross-selective (immunological). If the aspirin provocation test is positive, it suggests cross-reactive non-immunological and if negative, it suggests a selective immunological reaction, where the patient can take selectively different structural class NSAIDS.

Consensus-based statement 24

An oral aspirin challenge to confirm the diagnosis of AERD in cases of diagnostic uncertainty. Strength of Recommendation: Conditional, Certainty of Evidence: Moderate.[26]

Consensus-based statement 25

A challenge procedure is used to diagnose AERD when there is diagnostic uncertainty but that a desensitization protocol is used when the intention is to place a patient on a daily therapeutic aspirin dose for cardio-protection, pain relief, or to control polyp regrowth. Strength of Recommendation: Conditional, Certainty of Evidence: Moderate.[26]

Selective Cox-2 inhibitor may be used as an alternative analgesic: (a) If there is diagnostic uncertainty of diagnosis of NERD, (b) If there is a history of any NSAID hypersensitivity phenotype, (c) if the patient needs a therapeutic dose for cardio-protection, analgesics or to control nasal polyp regrowth; oral aspirin challenge is gold standard for diagnosis of NERD and desensitization protocol can be used. If there is a history of multiple NSAID-induced urticaria and angioedema, without comorbidities, aspirin oral challenge is done to differentiate whether the reaction is cross-reactive or selective reaction. In NERD and NECD, there is no place for immunoassays seeking specific IgE antibodies, but histamine and leukotriene release assays have been used.

In NIUA, no specific immunological mechanism is involved, neither skin tests nor in vitro tests are available for diagnosis. The only alternative is DPT. Most of these patients have a history of repeated episodes of urticaria, and angioedema with more than 2–3 groups of NSAIDs, not only with Cox-1 inhibitor NSAID but also Cox-2 inhibitor NSAID.[37] SNIUAA is suspected when there is a history of anaphylaxis to one or more NSAID but good tolerance to Acetyl salicylic acid (ASA), therefore, BAT in vitro test will confirm the diagnosis. Alternative drugs from the same group can be safely administered.

SNIDRs include reaction due to T-cell mediated response, patch testing, and delayed reading; intradermal testing has been used for diagnosis. It is further divided into:

  1. Type IV a-contact eczema, e.g., arylpropionic acid derivative, oxicam, and diclofenac
  2. Type IV b-MPE with bullae formation, DRESS, e.g., pyrozolones, paracetamol, and propionic acid Cox-2 inhibitor
  3. Type IV c-MPE with bullae formation, e.g., ibuprofen, paracetamol, and selective Cox-2 inhibitor
  4. Type IV d-AGEP, e.g., ibuprofen and selective Cox-2 inhibitor.

Consensus-based statement 22

A selective COX-2 inhibitor may be used as an alternative analgesic in patients with any NSAID hypersensitivity phenotype when an NSAID is needed. Strength of Recommendation: Conditional, Certainty of Evidence: Low.[26]

Aspirin Drug Desensitization

Aspirin desensitization has been successful in NERD. Pretreatment with oral montelukast 10 mg helps patients to tolerate subsequent desensitization. However in NECD, Ds is not well established.[38,39] The clinical characteristics which determine the need for desensitization versus challenge test in AERD as mentioned in Table 8.

T8-2
Table 8:
Clinical characteristics determining the need for challenge versus desensitization in AERD

Ds to the other NSAIDs can be done in special indications. In a selective immunological reaction to a single Cox-2 inhibitor, alternative drugs from the same group can be given. While in a cross-reactive non-immunological reaction, following drugs Paracetamol, meloxicam, nimusulide, benzydamine, rofecoxib, etoricoxib, celecoxib can be given.

Chemotherapy Hypersensitivity

There are two types of immediate reaction, (a) IgE mediated and (b) Non-IgE-mediated (Cytokine Release Syndrome) with atypical systemic signs and symptoms of malaise, chills, and fever. Taxane-based chemotherapeutic agents (paclitaxel, docetaxel, and cabazitaxel) with a history of immediate reaction, only initial hypersensitivity reaction determines risk stratification and management. Cremophor, which is a solubilizing lipid agent present in paclitaxel and docetaxel, can activate complement leading to the generation of anaphylatoxin and mast-cell activation.

In platin-based chemotherapy agents with a history of immediate reaction, the initial severity of hypersensitivity reaction and skin testing determines the management. Skin testing with non-irritant concentration to platins (carboplatin, cisplatin, oxaliplatin) has been safely done (IDST for cisplatin 0.1 mg/ml and 1 mg/ml), carboplatin has a positive predictive value (PPV) of 87%. In patients with negative skin tests and normal tryptase levels, but positive reaction during the challenge, desensitization is recommended. In patients with a history of immediate anaphylactic reaction to mAbs, drug desenstization should be considered. While patients with non-immediate reactions or inconsistent reactions to mAbs should be treated with a slowed infusion graded dose escalation and/or premedications without desenstization. Specific IgE and BAT are the future tools to predict the severity of reaction during desensitization with appropriate premedication.

Consensus-based statement 28

Patients with immediate reactions to chemotherapeutics a Ds may be performed when the implicated drug is the preferred therapy. Strength of Recommendation: Conditional, Certainty of Evidence: Low.[26]

Consensus-based statement 29

Patients with non-immediate reactions or a history of reactions inconsistent with chemotherapeutic hypersensitivity may be treated with a slowed infusion rate, graded dose escalation, and/or pre-medications without desensitization. Strength of Recommendation: Conditional Certainty of Evidence: Low.[26]

Biological Hypersensitivity

Almost all the biological agents are either engineered antibodies, targeted against specific antibodies, or mimics of human protein agonist blocking or effective function through a specific pathway. Allergists should be aware of DHRs by IgE-mediated reaction, cytokine release syndrome (CRS), and the possibility for serious, non-immediate adverse reaction, e.g., AGEP, SJS. Most common are typical infusion reactions (TIRs), which range from mild-to-severe fatal reactions with a combination of signs/symptoms of fever, and/or rigors, flushing, hemodynamic changes: hypotension or tachycardia, shortness of breath, chest tightness, GIT symptoms, and back pain. TIRs and CRS typically occur in the first or second infusion, while IgE-mediated reaction develop in the second or subsequent exposure who are pre-sensitized, for example, cetuximab via alpha-gal. Serum tryptase should be done if immediate type of HSRs is suspected after the onset of symptoms. Elevation of tryptase produced by mast cells confirms the mast cell-mediated anaphyaxis, but normal tryptase level does not rule out drug-induced anaphylaxis. Drug-specific IgG, IgE, and BAT for monoclonal antibody anaphylaxis are not validated for clinical use. Rapid desensitization can be considered for anaphylaxis in HSRs and severe TIRs.

Omalizumab

Omalizumab is a humanized anti-IgE antibody that primarily binds free IgE and indirectly reduces the concentration of high-affinity IgE receptors. Omalizumab-induced anaphylaxis of immediate and delayed type is of great concern, found in 0.1% to 0.2% of patients (25% after 2 h, 30% after 6 h, and 5% more than 24 h after the injection.[40,41,42] It is a standard practice in US, after 2 h of observation period following an omalizumab injection, that patients should carry epinephrine auto-injector for 24 h. History and IDST with the nonirritating concentration of 1:1,00,000 (1.25 ug/mL) confirm the diagnosis, but excipient, polysorbate can also induce anaphylaxis.[43] There are reports of successful desensitization to omalizumab.

Infliximab

HSRs occur in approximately 10% of patients during the first or subsequent exposure; testing for Alpha-gal specific IgE should be considered to confirm cross-reactivity in patients with Alpha-gal allergy.

Cetuximab

Most of the severe HSRs are associated with preexisting IgE antibodies against Galactose-alpha-1,3-galactose, a carbohydrate (Alpha-gal) attached to cetuximab. Alpha-gal is a blood group substance of non-primate mammals which is nonfunctional, but its synthesis needs an enzyme, α1,3 galactosyltransferase (α1,3GT) glycosylated with Alpha-gal found in most mammalian or red meat, therefore likely to induce delayed red meat anaphylaxis.[44]

Rituximab

Rituximab is a mouse-human chimeric mAb directed against CD20 used in several rheumatologic diseases and hematologic malignancies. Infusion reactions (TIRs) are more common in hematological malignancies (50%–80%) than rheumatological disorders (12%–30%), respectively.[45]

Consensus-based statement 32

We suggest that patients with nonimmediate reactions or a history of reactions inconsistent with mAb hypersensitivity may be treated with a slowed infusion, graded dose escalation, and/or pre-medications without desensitization. Strength of Recommendation: Conditional, Certainty of Evidence: Low.[26]

Consensus-based statement 33

We suggest that patients with immediate reactions or a history consistent with anaphylaxis to mAbs Ds should be considered when the implicated drug is the preferred therapy. Strength of Recommendation: Conditional, Certainty of Evidence: Low.[26]

Perioperative Anaphylaxis

There are more complex reactions, varying from a mild skin reaction to severe life-threatening reactions with multi-organ involvement. Most of these reactions are non-allergic, which may mimic pre-operative allergic reaction. If reaction is intraoperative, common drugs are antibiotics (amikacin, ciprofloxacin, linezolid), Analgesics (paracetamol, tramadol), Colloids (Gelatin, Heta-starch [Hydroxyethyl starches]), Dextran, Latex gloves, Colorant and Chlorhexidine. If reaction occurs at the end of the surgery or during recovery, common drugs are intravenous opiates, colloids, anesthetic reversing agents like neostigmine, glycopyrrolate, and Latex.

Clinically, the patient may develop generalized urticaria with or without angioedema, increased peak airway pressure, decreased oxygen saturation, wheeze on auscultation, associated with tachycardia and hypotension during peri-operative HSRs.

The main aim of the investigation is to rule-out IgE-mediated allergic reactions:

  1. Serum tryptase-it is very stable both in serum and plasma and increase in its level from the time of reaction compared with baseline serum tryptase level (2 + 1.2 X baseline tryptase) is very useful in the diagnosis of peri-operative HSRs
  2. Specific IgE-there are limited number of drugs for specific IgE e.g., chlorhexidine, NMBAs, ethylene oxide, penicillin, but negative specific IgE below 0.35 kUA/L does not rule-out clinical HSRs
  3. BAT has been useful in suspected NMBA anaphylaxis to assess cross-reactivity within the drug group
  4. Skin test should be performed at 6 weeks to 6 months after an episode of anaphylaxis.

Local Anesthetics

Peri-operative allergic reactions to LA are rare. IDST and sub-cutaneous provocation has been recommended as the best diagnostic test in a suspected HSRs.

Opioids and Other Analgesics

HSRs to opioids and especially to fentanyl derivatives are rare; morphine and other drugs such as codeine, and meperidine are more likely to induce nonspecific histamine release than IgE-mediated reaction.

Neuro Muscular Blocking Agents

They are the most common cause of peri-operative HSRs due to IgE, and Non-IgE mediated reactions, as NMBA are structurally similar, so the risk of cross-sensitization is as high as 60%–70%. SPT and ISDT are done with five perioperative drugs (rocuronium, vecuronium, propofol, mepivacaine, and midazolam) diluted to 1:100 concentration. SPT is to be done with undiluted concentration and IDST with 1:1000, 1:100, and 1:10, each tested at an interval of 20-30 min.

Protocol for Anti-allergic pre-medication regimens for patients with high-risk factors for perioperative anaphylaxis are mentioned in [Table 9].

T9-2
Table 9:
Anti-allergic premedication regimens

Radio Contrast Media

RCM reactions [Table 10] are more common with ionic but less with non-ionic. Here, the pre-medication with anti-histamines and corticosteroids is given in high-risk patients (history of asthma, cardiovascular disease, beta-blocker). In patients with mild to moderate ICM-induced Immediate hypersensitivity reaction (IHR) limited to skin, there is less than 1% risk of developing severe anaphylaxis. Diagnosis is confirmed by the severity of the reaction and allergic work-up (SPT undiluted, IDST with a dilution of at least 1:10, DPT (if needed). There is no role of pre-medication (Fist generation anti-histamines and glucocorticoids) in moderate to severe IHR, but it is controversial in mild to moderate IHR. CT-Visipaque and Omnipaque (Iodixanol/Iohexol) are safe. In MRI-Gadodiamide (Omniscan)-the most serious adverse reaction is nephrogenic systemic fibrosis or in those, who have reduced GFR from either acute or chronic kidney disease.

T10-2
Table 10:
Radiological contrast media-classification

Corticosteroids

Immediate HSRs to glucocorticoids (GC) have been reported in 0.1%–0.3%, while delayed T-cell mediated reactions have been found in 0.5%–5%.[46] Succinate ester in intravenous GCs accounts for HSRs, but no reactions have been reported with sodium phosphate and acetate esters, which are used to solubilize for intra-articular and soft tissue administration. Skin testing should be performed with nonirritating concentration of methylprednisolone (40 mg/mL for SPT and 0.4–4 mg/mL for IDST) with methylprednisolone succinate, Methylprednisolone sodium phosphate, polyethylene glycol (10 mg/mL for SPT and 0.1 mg/mL for IDST), carboxymethylcellulose (5 mg/mL for SPT and 0.005/0.05 mg/mL for IDST).

Patch test by Thin layer Rapid use Epicutaneous Test, includes Group A Corticosteroids-Tixocortol-21-Pivalate (0.1% petroleum) and Group B corticosteroid-Budesonide (0.01% petrolatum) is done to identify causative corticosteroids in contact dermatitis.[47]

Excipient Allergy

Excipient HSRs should be suspected in patients with a history of anaphylaxis to more than two structurally unrelated drugs but share a common excipient (injectable corticosteroids and laxatives, both containing PEG-based excipients). It is an inactive substance of coloring agents, preservatives, stabilizers, and filters formulated with active ingredients of drugs. Lactose, mannitol, gelatin, and cornstarch are food excipients while polymers such as PEG and its derivatives such as dyes and coloring agents and CMC are other ingredients in drugs.

Conclusion

The new understanding of the phenotypes, endotypes, and molecular biomarkers has expanded our classification, which not only includes DHRs from Gell and Coombs but also cytokine storm-like reactions. Diagnostic tests for DHRs are primarily based on immediate skin testing and drug challenges in patients with a history of drug-induced anaphylaxis. The accuracy of delayed skin testing for delayed DHRs is still unclear and cannot be reliably calculated. Rapid Ds is proved to be a safe and effective way for patients where no other alternative drug is available. Medications such as epinephrine, anti-histamines, and bronchodilators at the bedside are required during severe HSRs. Further studies are required to better understand the mechanism of rapid Ds and also the reduction of severe HSRs in the high-risk group of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

Acute generalized exanthematous pustulosis; adverse drug reaction; desensitization models; desensitization; drug allergy; drug hypersensitivity reaction; drug rash with eosinophilia and systemic symptoms; high-affinity immunoglobulin E fcε receptor I; immunoglobulin E; SCAR; stevens-johnson syndrome; toxic epidermal necroplasia

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