Rapid drug desensitization for immediate hypersensitivity reactions

INTRODUCTION — Desensitization is a procedure that alters the immunologic consequences of drug hypersensitivity and results in temporary tolerance, allowing the patient with a drug hypersensitivity reaction to receive an uninterrupted course of the medication safely. Once the medication is discontinued or if treatment is interrupted for a sufficient period of time, the patient's hypersensitivity to the medication returns. Desensitization is only safe and effective for certain types of drug allergy. The terms "drug hypersensitivity" and "drug allergy" are used synonymously in this topic review.

Techniques and protocols for drug desensitization in patients with immediate hypersensitivity reactions and the proposed mechanisms underlying these procedures will be reviewed here. Desensitization for reactions to nonsteroidal antiinflammatory drugs (NSAIDs) are not included in this discussion but are discussed elsewhere. (See "Diagnostic challenge and desensitization protocols for NSAID reactions" and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)

IMMEDIATE DRUG REACTIONS — The World Allergy Organization (WAO) has recommended dividing drug hypersensitivity reactions into two general types [1,2]:

●Immediate/acute reactions – Reactions that begin during the infusion and up to six hours after exposure to the culprit drug.

●Delayed reactions – Reactions that begin after six hours or later after exposure to the culprit drug.

The desensitization techniques described here are appropriate for immediate drug reactions, although they have been applied successfully to delayed types of reaction as well. The following signs and symptoms are typical of immediate-type allergic reactions (table 1):

●Flushing

●Pruritus

●Urticaria (hives)

●Angioedema

●Throat tightening, change in voice quality, stridor

●Wheezing, repetitive dry cough, shortness of breath, chest tightness

●Nausea, vomiting

●Diarrhea

●Hypotension, collapse

●Respiratory or cardiac arrest

●Back pain (observed in reactions to chemotherapeutics and biologics [3,4])

●Fever and rigors (reactions more commonly observed with rituximab and oxaliplatin)

Immediate reactions begin suddenly, within minutes to hours of administration (and occasionally later), with intravenous (IV) or injected medications typically causing reactions within minutes of administration and oral medications causing reactions within several hours. The most severe immediate reaction is anaphylaxis. Diagnostic criteria for anaphylaxis are shown in the table (table 2). (See "Anaphylaxis: Emergency treatment".)

Types of immediate reactions — Immediate drug reactions result from the sudden, massive activation of mast cells and/or basophils or sudden release of cytokines from mast cells and other immune cells, including T cells [5]. These reactions can be further subdivided into immunoglobulin E (IgE) mediated and non-IgE-mediated reactions, depending upon the trigger and the type of cells and receptors activated. The desensitization techniques discussed here are applicable to both types of immediate reactions.

IgE mediated — An IgE-mediated immediate reaction is triggered by binding of the administered drug to drug-specific IgE. Once formed, drug-specific IgE occupies surface receptors on mast cells and basophils throughout the body. If the drug is given again, it can bind these IgE molecules, causing cross-linking of the receptors and activation of the cells, resulting in symptoms. IgE-mediated reactions usually occur in patients who have been exposed to the culprit medication at least once before. Drugs that are well known to cause IgE-mediated allergic reactions include penicillins, cephalosporins, and platinum-based chemotherapy agents (eg, carboplatin, cisplatin, and oxaliplatin) [6,7]. A number of other drugs have been implicated in causing IgE-mediated reactions, albeit less commonly than the three groups mentioned previously.

Although most IgE-mediated reactions require at least one previous exposure to the causative drug, there are notable exceptions:

●Patients may develop anaphylaxis during their first administration of the anti-cancer agent cetuximab. Cetuximab reactions can occur with initial exposure in patients who have sustained prior tick bites and have developed IgE antibodies to the moiety galactose-alpha-1,3-galactose (alpha-gal). Because cetuximab also contains alpha-gal, patients may react the first time they are exposed. (See "Allergy to meats", section on 'Meats and monoclonal antibodies (cetuximab)'.)

●In theory, patients may also react to a medication they have never received because they are sensitized to a common preservative or diluent shared by multiple drugs, but such reactions are very rare.

Non-IgE mediated — Non-IgE-mediated immediate reactions can be as severe as IgE-mediated reactions and may arise by several mechanisms, which result in activation of mast cells and basophils or by cytokine release from mast cells and other immune cells including T cells. Non-IgE-mediated reactions can be clinically identical to IgE-mediated reactions, although some reactions include distinct signs and symptoms, such as sudden severe back pain, chills, and fever. Gradual dose escalation procedures designed for IgE-mediated reactions have been applied to immediate-type non-IgE-mediated reactions as well, with similar outcomes in observational studies [8]. (See "Infusion reactions to systemic chemotherapy", section on 'Taxanes'.)

MRGPRX2 mediated — Mast cells can be activated through a receptor called Mas-related G protein-coupled receptor family member X2 (MRGPRX2), leading to anaphylaxis [9]. Drugs that activate mast cells in this manner include those that contain a THIQ motif (eg, fluoroquinolones and neuromuscular blocking agents, such as atracurium), as well as basic compounds and medications (eg, vancomycin, opioids, and the peptide mastoparan) [9]. (See "Vancomycin hypersensitivity" and "Mast cells: Surface receptors and signal transduction", section on 'MRGPRX2'.)

Cytokine release — Another type of hypersensitivity reaction appears to be caused by release of cytokines, such as tumor necrosis factor (TNF) alpha, interleukin (IL) 6, and IL-1 beta from T cells (figure 1) [10]. These reactions are termed cytokine release reactions (CRRs) and have been described with taxane and oxaliplatin chemotherapy agents, as well as rituximab and several other monoclonal antibodies [11]. Symptoms include chills or rigors, fever, nausea, musculoskeletal pain, and headache, which are distinct from symptoms arising from IgE mast cell-mediated reactions.

Mixed IgE and cytokine release — Patients with mixed IgE/cytokine release reactions to monoclonal antibodies have also been successfully managed with gradual dose escalation (figure 1) [10,12]. These reactions have features of both mast cell-mediated reactions and CRRs.

OTHER TYPES OF DRUG ALLERGY — The term "desensitization" is used somewhat loosely in the medical literature. Various protocols have been used to achieve drug tolerance in patients with delayed hypersensitivity reactions to drugs, although the time course of reintroduction may extend over days or even weeks.

●Desensitizations for delayed reactions to sulfonamides are discussed separately. (See "Sulfonamide allergy in HIV-uninfected patients".)

●Desensitization is also possible for patients with various non-IgE-mediated reactions to nonsteroid antiinflammatory drugs (NSAIDs), and these protocols differ significantly from the standardized protocol presented above. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions" and "Diagnostic challenge and desensitization protocols for NSAID reactions".)

POSSIBLE MECHANISMS OF DESENSITIZATION — Desensitization for IgE-mediated reactions results in temporary tolerance of mast cells and basophils to the specific drug in question. Mast cell activation and inflammatory mediator release are inhibited during desensitization [13,14]. Additionally, reduced skin sensitivity is observed following desensitization in most patients with IgE-mediated reactions, and some become skin test negative at the end of the protocol [15-17].

The mechanism by which temporary tolerance is induced during drug desensitization is not fully explained [15,18,19]. When a patient is sensitized to a drug, the patient's mast cells and basophils are coated with drug-specific IgE bound to IgE receptors, Fc-epsilon-RI (FceRI). If the drug is given normally (ie, not as part of a desensitization protocol), drug allergens bind to the IgE and induce cross-linking of the IgE receptors. Crosslinking triggers the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) within the FceRI receptors, leading to Syk phosphorylation and initiation of an activating signal transduction cascade. Calcium enters the cell and results in the release of various pre-formed proinflammatory mediators, including tryptase and histamine. Activation also stimulates the production of other mediators, such as prostaglandins, leukotrienes, and several cytokines. The allergen/IgE/FceRI complexes are internalized during the activation process.

These processes are interrupted in desensitization. Desensitization involves giving multiple small doses of drug in rapid succession until a full, target dose is given. In an animal model of penicillin allergy and desensitization, mice made allergic to penicillin and then fed a normal target dose consistently develop fatal, penicillin-induced anaphylaxis [20]. Blood taken from these animals showed the expected elevations in histamine, confirming massive mast cell/basophil activation. However, if penicillin-allergic mice were fed small desensitizing doses of penicillin every 15 minutes until they had consumed the target dose, they were completely protected from anaphylaxis and showed no elevations in blood histamine levels.

Possible mechanisms of desensitization involve:

●Inhibitory receptors and phosphatases – There are other receptors on mast cells, such as Fc-gamma-RII (FcgRII) that contain immunoregulatory tyrosine inhibition motifs (ITIMs) and can compete with FceRI receptors. There are also phosphatases, such as Src homology 2 domain-containing inositol phosphatase 1 (SHIP-1), which can dephosphorylate Syk and other early signal transduction molecules, shifting the signal down an inhibitory pathway [21]. Blocking calcium flux and polymerization of actin filaments also appears to be critical to desensitization [22]. Although this mechanism has been demonstrated in vitro by co-crosslinking FcgRIIb with FceRI, it is not known how inhibitory receptors bearing ITIM motifs would be engaged in vivo at the time of drug-specific IgE-mediated activation of mast cells.

In an experimental model of allergen-sensitized humanized mouse mast cells, the phosphorylation of SHIP-1 was selectively increased in the early steps of desensitization, and silencing SHIP-1 increased mediator release and prevented desensitization. These findings suggest that SHIP-1 is a critical molecule in shifting signaling within mast cells away from activation and toward inhibitory pathways [23].

●Alteration in expression of surface receptors – In vitro studies have demonstrated that subthreshold doses of antigen (in this case, the allergenic drug or some form of it) given prior to activating doses can render mast cells and basophils unresponsive to activation by that specific antigen but still responsive to other activating stimuli [24,25]. Subthreshold doses of antigen might result in monomeric binding to the IgE receptor (FceRI), leading to internalization of the antigen-receptor complex (instead of the cross-linking that occurs when there is more antigen present), such that fewer receptors are available on the cell surface, inhibiting activation [26,27]. Alternatively, other research suggested that low doses of antigen might induce rearrangement of the cell membrane in antigen-sensitized mast cells, preventing the internalization of the antigen/IgE/FceRI complex and protecting against anaphylaxis [28].

●Generation of immunoglobulin G (IgG) blocking antibodies – Both IgG and IgE antibodies specific to the culprit allergen increase after desensitization therapy [18]. The rising IgG titer may neutralize drug epitopes and serve a "blocking" function for IgE-dependent reactions, although this has not been conclusively demonstrated.

●Altered cellular signaling in mast cells and basophils – Rapid in vitro desensitization of human mast cells and basophils results in a reduction in levels of certain signaling molecules, such as Syk kinase [29,30]. In keeping with the concept that changes in Syk are important in both normal activation and in desensitization, naturally occurring Syk-deficient basophils are unresponsive to drug antigens [31]. The functions of Syk in mast cell signaling are reviewed in more detail separately. (See "Mast cells: Surface receptors and signal transduction", section on 'Signal transduction'.)

Maintaining the desensitized state is dependent upon continuous exposure to the drug. Basophils can be desensitized in vitro to penicillin, but, if isolated from a patient who was just desensitized and challenged in vitro with penicillin, the basophils will activate, demonstrating that the drug must be physically present to maintain the desensitized state [32]. (See 'Maintaining the desensitized state' below.)

PATIENT SELECTION

Indications — The drug desensitization techniques discussed in this review are appropriate for immediate drug reactions. Desensitization is indicated in patients who are either proven (by positive skin testing or in vitro tests for drug-specific IgE), had elevated tryptase during the initial reaction (indicating mast cell activation), or are strongly suspected to have an immediate-type drug allergy including cytokine release reactions (CRRs) based on clinical history and for whom there are no acceptable alternate drugs. If allergy evaluation or skin testing is not possible, the history of a reaction with the signs and symptoms described above qualifies the patient for a gradual dose escalation protocol as a precaution even though the patient may not be currently immunologically sensitized. Testing procedures for drug allergies are discussed elsewhere. (See "An approach to the patient with drug allergy", section on 'Objective testing'.)

Note that a protocolized graded drug challenge may not be safe in patients whose history strongly suggests that they have immediate IgE-mediated allergy (table 1), so individualized protocols beginning with much smaller doses are warranted when the benefit of drug therapy is high.

Drug desensitization can be performed in patients of any age. Desensitizations have been safely performed in pregnancy when alternative therapies were not possible (eg, in order to administer penicillin to a penicillin-allergic female with syphilis) [33-35].

The overall health care costs of desensitized patients did not exceed that of nondesensitized individuals in one large study [3].

Contraindications — Desensitization is virtually never attempted in patients with histories of the following types of reactions:

●Reactions involving significant skin desquamation, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, because even small doses of the drug may induce irreversible and potentially fatal recurrent desquamative reactions

●Erythema multiforme and diffuse erythroderma with desquamation

●Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS)

●Acute generalized exanthematous pustulosis (AGEP)

●Serum sickness and serum sickness-like reactions

●Nephritis, hepatitis, and other organ-specific reactions

There are also some drug-specific contraindications. (See 'Rare immunologic complications' below.)

REFERRAL — In most situations, drug desensitizations should only be performed by allergy specialists trained in the technique. Desensitization should not be done by other types of specialists not familiar with anaphylaxis, acute cytokine release reactions (CRRs), and mixed reactions, because the possibility of a recurrent severe reaction remains elevated during desensitization under nonexpert guidance.

SAFETY — The main risk during a desensitization procedure is that of a recurrent immediate reaction or a "breakthrough" reaction. The risk of this in any individual patient depends upon the drug in question and the sensitivity of the patient. Most breakthrough reactions are mild and less severe than the patient's initial hypersensitivity reaction. However, clinical judgment and experience is invaluable in determining how to adjust a desensitization procedure if the patient does have breakthrough symptoms and in knowing when to abort a procedure. We know of no published fatalities resulting from failed desensitization procedures.

Risk stratification — It is the approach of one of the authors (MC) to stratify past reactions into three risk categories:

●Grade 1 reactions – Skin only

●Grade 2 reactions – Two organ systems involved (eg, skin and respiratory tract)

●Grade 3 reactions – Includes changes in vital signs with one or more organ systems involved

The grade of reaction is used to choose a protocol (12-steps for grade 1 and 2 reactions; 16-steps for grade 3 reactions). (See 'Protocols' below.)

Setting and staffing — We usually perform desensitizations in patients with past grade 1 or 2 reactions in the outpatient setting under close observation (unless the patient is already hospitalized), and safety data have shown that grade 3 reactions can be safely desensitized in the outpatient setting as well [3]. However, it is not inappropriate to hospitalize all patients for desensitization, and clinicians who are trained in desensitization but perform it infrequently should have a low threshold for hospitalizing the patient. For very high-risk patients, such as those with unstable cardiac disease, those with restrictive or obstructive pulmonary diseases, and those in whom beta blocker therapy cannot be easily discontinued for the procedure, we suggest that desensitization be performed in an intensive care setting.

In one of the author's (MC) center, a supervising allergist is available within minutes of the location where the desensitization is being performed. One-to-one nursing is provided with a nurse who has been specifically trained to monitor desensitization protocols and recognize and treat allergic reactions during the first desensitization and one-to-two nursing for subsequent desensitizations. This nurse has been trained and preauthorized to administer any medications that may be required to treat an allergic reaction, including intramuscular epinephrine for anaphylaxis, so that there will be no delay in treatment.

Complications — Complications include breakthrough allergic reactions, anaphylaxis, and rare immunologic sequelae.

Incidence of breakthrough symptoms — During desensitizations to chemotherapy agents and antibiotics, 70 percent of patients have no reactions, and breakthrough allergic reactions occur in up to 30 percent; less than 10 percent of breakthrough reactions are moderate or severe [3,33,36,37].

Although most reactions are mild in severity, patients with initial grade 3 reactions are at risk for anaphylaxis during desensitization. Similar rates and mostly mild reactions are reported with desensitization to biologic agents (eg, rituximab, infliximab, and trastuzumab), most of which are believed to cause immediate mast cell/basophil-dependent and cytokine release reactions (CRRs) through non-IgE-mediated mechanisms [38].

Rare immunologic complications — Occasionally, late-occurring reactions have been reported following desensitization in patients who required high-dose or extended-duration therapy, including serum sickness, hemolytic anemia, nephritis, and thrombocytopenia [16,39,40].

A rare complication of oxaliplatin desensitization includes thrombocytopenia and bleeding due to pre-formed anti-oxaliplatin antibodies bound to platelets and activated at the time of oxaliplatin infusions [41]. Therefore, patients who have evidence of pre-formed oxaliplatin IgG antibodies are not candidates for desensitization.

Informed consent — Patients should be informed that desensitization involves administration of a drug to which they are known or suspected to be allergic. Accordingly, there is substantial risk of at least a mild allergic reaction. Anaphylaxis is also possible, especially in very sensitive patients.

Patients should also be counseled about what to expect during the desensitization protocol. We explain the procedure in detail to the patient and reassure and inform them that most patients have no reactions or only very mild and treatable reactions. This is critical for reducing patient anxiety and minimizing the likelihood of nonspecific, anxiety-related reactions, which can range from tingling and numbness of the lips and fingers due to hyperventilation, to pruritus, shortness of breath, coughing, nausea, and emesis.

TECHNICAL ASPECTS OF DESENSITIZATION

Overview of the technique — Desensitization is a procedure that alters a patient's immune response to a drug and results in temporary tolerance, allowing the patient with a drug hypersensitivity reaction (ie, a drug allergy) to receive an uninterrupted course of the medication safely. Once the medication is discontinued, the patient's hypersensitivity to the medication returns.

Desensitization is usually performed by starting with a 1/1000^th to 1/100^th dilution of the drug, which is used to administer an initial dose that is 1/10,000^th of the full dose (note the distinction between dilution and dose), typically over 15 minutes. In exquisitely sensitive patients, an even lower dilution that did not produce a positive reaction during skin testing can be used as a starting dilution instead (for patients who had positive results to lower concentrations on skin testing). The dose is progressively doubled every 15 minutes until a full therapeutic dose has been delivered.

Dose increase and time interval for each step — Typically for intravenous (IV) desensitization, the dose is doubled at each step. Increasing the dose faster than doubling is not recommended.

●In IV desensitization for immediate reactions, each step is administered over 15 minutes by continuous infusion. The dose is determined by the concentration of the solution and the rate at which the infusion pump is set. If there is no adverse reaction, we proceed immediately to the next step.

●For oral desensitization, longer intervals may be required to assure complete absorption before increasing the dose, but excessively long periods between doses may allow the cellular effects to be reversed. We suggest allowing 20 to 30 minutes between steps. Longer intervals (ie, 90 minutes) are only used in very specific circumstances, such as oral aspirin desensitization in patients with aspirin-exacerbated respiratory disease (AERD). Aspirin reactions in these patients are not caused by IgE- or mast cell-mediated mechanisms and are discussed separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)

Patient preparation — Prior to desensitization, the patient's underlying medical problems and medications should be reviewed. Evaluation with skin testing when possible, risk stratification, and associated comorbidities should be done in a personalized fashion for each patient at each desensitization [42].

●When possible, beta-adrenergic blocking medications taken for hypertension should be withheld for 24 hours prior to desensitization in case treatment with epinephrine is required. This is usually straightforward if the patient is taking low to medium doses of these agents for hypertension. However, patients taking high-dose beta blockers and individuals taking these medications to control arrhythmias should not stop these medications, unless under the guidance of a cardiology specialist. Beta blockers are continued through the procedure in some cases if stopping them is considered too risky. Angiotensin-converting enzyme (ACE) inhibitors are also not recommended during desensitization, because hypotension during anaphylaxis may be worsened due to unopposed bradykinin generation.

●Patients with asthma, chronic obstructive lung disease, or other lung diseases should be optimally controlled prior to undergoing desensitization in order to minimize the chances of respiratory symptoms during a potential allergic reaction. Patients with active asthma symptoms are sometimes treated with a brief course of oral glucocorticoids prior to desensitization to minimize airway inflammation and reactivity.

Premedications — The authors' approach to premedication depends upon the type of reaction for which desensitization is being performed. When desensitizing to chemotherapy or biologic agents, any premedications (such as glucocorticoids) that would be given to a nonallergic patient should be incorporated into the planned premedications as well.

None for IgE-mediated reactions — Patients undergoing desensitization for a reaction that is known or believed to be IgE mediated (eg, many reactions to penicillins or cephalosporins) are usually not pretreated with glucocorticoids or antihistamines. Antihistamines may mask early signs of breakthrough symptoms, which are important to recognize, and neither antihistamines nor glucocorticoids prevent anaphylaxis.

For non-IgE-mediated reactions — Premedications are given to patients whose initial reaction is suspected to be non-IgE mediated, such as reactions to taxanes, some other chemotherapy agents, and biologic agents [12]. Non-IgE-mediated reactions are believed to result from a variety of mechanisms, some of which may be prevented or reduced by premedication. We usually administer H1 and H2 antihistamines and sometimes montelukast, aspirin, or glucocorticoids as follows (adult dosing shown):

●Cetirizine (10 mg orally) is given 30 to 120 minutes before the start of the procedure [3]. We no longer use short-acting agents (eg, diphenhydramine), which can cause sedation and impair the patient's ability to report symptoms.

●Famotidine (20 mg IV or orally) is given 30 to 60 minutes before the start of the procedure.

●IV fluids are key to successfully tolerating desensitization to reactions that are caused either by cytokine release or mixed IgE/cytokine release mechanisms [43]. IV fluids are given in advance and throughout the procedure.

Additional medications are given based on the symptoms of the patient's initial reaction:

●Aspirin (325 mg orally) is given to patients with flushing during their initial reaction. This is administered the night before the procedure and again one hour before the start of the procedure. Aspirin has been used successfully with desensitization to platinum chemotherapy agents [44].

●Montelukast (10 mg orally) is given to patients who experienced respiratory symptoms during their initial reaction. This is administered the night before the procedure and again one hour before the start of the procedure. Montelukast has been used successfully with desensitization to platinum chemotherapy agents [44].

●Acetaminophen or ibuprofen is given to patients with fever or rigors during their initial reactions.

●Lorazepam may be given to patients with significant anxiety during their first reaction or anxiety related to undergoing desensitization.

●Ondansetron can be given to patients with prominent nausea or vomiting during their previous reaction.

PROTOCOLS — Specific protocols for desensitization by parenteral and oral routes have been published for penicillin, other antibiotics, insulin, and several other drugs [33,45-48]. Desensitization protocols for immediate reactions are provided elsewhere. (See "Vancomycin hypersensitivity", section on 'Desensitization' and "Hypersensitivity reactions to insulins", section on 'Insulin desensitization'.)

Route of administration — Desensitization can be performed by oral, intravenous (IV), intraperitoneal, or subcutaneous routes [16,36,49-51]. The IV route is the most often used for IV medications since it provides control of the rate and amount of drug infusion, which can be stopped at any time during the delivery of drug, in contrast to oral administration [16,34].

The route of desensitization does not need to be the same as the route of administration. As an example, IV desensitization may be used even if subsequent therapy will be oral. Once the patient is successfully desensitized to a given dose, that dose can be administered by any route.

Oral protocols — An oral desensitization protocol for penicillin and other beta-lactam antibiotics has been published, which can be performed in an outpatient setting with IV access and one-to-one nursing (table 3). Staff should have specific training and expertise with desensitization procedures. We recommend that desensitization be performed by allergy experts whenever possible.

Standardized intravenous protocol — A standardized protocol (of 12 steps) has been successful in patients with immediate hypersensitivity reactions to a variety of drugs (table 4) [3,36,38,52-55]. As an example, a 12-step protocol for infliximab desensitization is provided (table 5) [36]. This protocol is appropriate for patients with grade 1 and 2 reactions in the past. This protocol has been used to treat patients with immediate reactions to the following:

●Penicillins and other beta-lactams, including ertapenem, imipenem, and meropenem

●Cephalosporins

●Vancomycin, in patients with severe reactions that have proven refractory to slow infusion and premedication

●Fluoroquinolones

●Trimethoprim

●Platinum chemotherapy agents (carboplatin, cisplatin, oxaliplatin)

●Taxane chemotherapy agents (paclitaxel, docetaxel, cabazitaxel, nabpaclitaxel)

●Pegylated liposomal doxorubicin

●Biologic agents, such as rituximab, trastuzumab, infliximab, and other monoclonal antibodies

●Iron

●Methylprednisolone

●Methotrexate

●Cyclophosphamide

The 12-step standardized protocol requires three solutions (or "bags"): 1, 2, and 3. A volume of 100 to 250 mL of each solution is needed. Solution 3 is the standard therapeutic solution of the drug, as it is normally administered intravenously. Solution 2 is a 10-fold dilution of 3, and solution 1 is a 10-fold dilution of 2 (table 6). The protocol begins with the most dilute solution (solution 1). A single-solution (one bag) desensitization may be possible in less sensitive patients [56].

The standardized protocol is completed in approximately six hours if no pauses for treatment of symptoms are needed.

Protocol for patients with past severe reactions — For patients with severe past reactions (ie, those with grade 3 reactions according to the risk stratification approach described above), a 10-fold more dilute starting solution is recommended. For such patients, a 1000-fold dilution of the standard therapeutic solution is given using a four-bag, 16-step desensitization protocol (table 7) [52]. (See 'Risk stratification' above.)

The typical time required for a four-bag, 16-step protocol is approximately seven hours if no pauses for treatment of symptoms are needed.

Administering the protocol — Once the patient has been premedicated (if appropriate), the protocol is begun with the most dilute solution, solution 1, as shown in the table (table 4). Step 1 consists of solution 1, administered at a rate of 2 mL/hour for 15 minutes. The infusion rate is increased to 5 mL/hour for step 2, 10 mL/hour for step 3, and 20 mL/hour for step 4. Solution 1 is then replaced by solution 2, which is given in the same manner, followed by solution 3. The final step, step 12, is longer in duration and delivers the remainder of the solution required to reach a full therapeutic dose.

Management of symptoms during desensitization — Much of the success of desensitization depends upon the comfort and experience of the supervising allergy specialist in managing breakthrough reactions. Nearly all symptoms can be effectively managed and the protocol ultimately completed. Breakthrough symptoms most typically occur between steps 8 and 12.

If symptoms arise during the procedure, the infusion should be halted temporarily until symptoms have resolved. Sometimes, symptoms will resolve with stopping the infusion alone but if symptoms are significant, do not appear to be resolving spontaneously, or are worsening, then treatment should be administered. Treatment usually consists of antihistamines for pruritus or urticaria, inhaled bronchodilators for chest tightness or wheezing, or epinephrine for uncommon systemic reactions, hypotension, or laryngeal edema. Glucocorticoids are not usually given in this setting, because they are of little benefit in treating acute reactions.

If the patient is receiving IV fluids during the procedure (eg, for cytokine release or mixed IgE/cytokine release reactions) and develops desaturation or hypotension, we treat for anaphylaxis and increase the rate of fluids to >500 mL per hour until blood pressure normalizes [43]. Anaphylaxis treatment is summarized in rapid overview tables for adults and children (table 8 and table 9).

Adjusting the protocol — Once breakthrough symptoms have been treated and have resolved, the protocol is resumed by repeating the step at which the reaction occurred. We do not back up and repeat earlier steps. Not repeating earlier steps is important with drugs for which the target dose is precise, such as chemotherapy agents. With other drugs (eg, antibiotics), the final dose may not need to be as precise.

If the patient reacts again to the same step with severe symptoms (which is unusual), we usually abort the procedure. (See 'When to abort a desensitization' below.)

We have noticed that breakthrough reactions are more common at certain points in the protocol. During desensitizations to chemotherapy agents and antibiotics, breakthrough symptoms occur most often at step 12, whereas, with biologic agents, patients may react at different steps (steps 9 to 12) during infusion of the most concentrated solution.

If the patient experienced a breakthrough reaction and needs repeat desensitization in the future (as is often the case in patients requiring chemotherapy) or if they reacted with hypotension or laryngeal edema that responded rapidly and completely to epinephrine, we then modify the protocol to add an intermediate step before the one at which symptoms occurred. As an example, if a patient reacted during the first few minutes of step 12, we would then add an extra step before that one, and this modified protocol is used for all of the patient's future desensitizations. Usually, we increase the infusion rate less than twofold to create an extra step.

If the patient experienced breakthrough symptoms in the early steps of the protocol, a 16-step protocol could be used in the future for that patient (table 7).

If a patient experienced no symptoms during the final step of the initial desensitization, then the rate of infusion during the final step may be accelerated for repeat desensitizations. The maximum rate of infusion should be that rate at which the drug is normally given. This modification can be helpful by reducing the time required to perform the desensitization.

Patients may present an initial type I reaction and change to cytokine release syndrome as breakthrough during desensitization [10]. In this situation, symptoms are often alleviated by IV fluids and cyclooxygenase 1 (COX-1) inhibitors.

When to abort a desensitization — A desensitization should be aborted if a patient develops hypotension and/or laryngeal edema that is not immediately responsive to intramuscular epinephrine.

●If hypotension or laryngeal edema did resolve with epinephrine and the medication is critical for the patient's treatment, then we continue the protocol, although the supervising clinician must use clinical judgment in this situation.

●In addition, if a step is repeated because symptoms developed and the patient reacts again to this step with severe symptoms, we usually abort the procedure. Recurrence of symptoms when a step is repeated is unusual.

●Another reason to abort a desensitization is an acute hematologic reaction, such as bleeding due to rapidly developing thrombocytopenia (reported with oxaliplatin and some monoclonal antibodies).

OUTCOMES — The overall success rate of desensitization depends upon the protocol used, the sensitivity of the patient, and the type of reaction. Another important factor is the expertise of the supervising clinician in managing any symptoms that occur and adjusting the procedure accordingly. IgE-mediated reactions, such as those to beta-lactam antibiotics and platinum-based chemotherapy agents, have very high rates of success. In experienced hands, virtually all of these desensitizations are successful.

In most cases, patients who experience breakthrough reactions during initial desensitizations display fewer symptoms upon repeat desensitization using the approach described above for modifying the protocol. However, there may be an important subset of patients in whom this is not the case. In a study of desensitizations to infliximab, rituximab, or trastuzumab, a small number of patients undergoing desensitization more than eight times appeared to have a resurgence in their sensitivity to the drug during the procedure [38]. We have also noticed this in a small number of patients requiring repeated desensitizations to one chemotherapy agent or antibiotic. This phenomenon requires further study.

Maintaining the desensitized state — Desensitization induces a temporary state of clinical tolerance. After a patient has been desensitized, the drug is given normally at the usual intervals provided that doses are at least daily. If the drug is stopped, allergic sensitivity will return shortly after the medication is cleared from the bloodstream.

Maintaining the desensitized state is dependent upon the continuous presence of the drug in the patient's system. Accordingly, it is important to give doses regularly and on time so that there is no interruption in exposure. For hospitalized patients, the pharmacy and nursing staff should be informed about the importance of giving subsequent doses on time.

Once the drug is discontinued or doses are missed, the desensitized state dissipates over days to weeks. The speed with which the patient's sensitivity to the medicine returns if the drug is not given is dependent upon multiple variables. These include the half-life of the drug, the formation of drug-containing immune complexes that can delay clearance of the drug, the degree to which the drug binds to serum proteins or other tissues, and the patient's kidney function. In most instances, the patient will remain desensitized for a minimum of 24 to 48 hours so that missing a single dose does not usually necessitate repeat desensitization. Return of the patient's sensitivity is difficult to predict, and repeat desensitization is usually performed if more than 48 hours have elapsed since the last dose.

In the case of drugs that are dosed intermittently based on serum levels, such as vancomycin or the aminoglycosides, levels should be monitored daily to ensure that exposure is ongoing and doses can be given when appropriate for that patient. Although this approach has not been formally studied, it is logical that the patient should remain desensitized as long as the drug is detectable in the serum.

In the case of chemotherapy, most agents are given weekly to every three to four weeks, and the period between doses is too long to maintain desensitization. Thus, for most chemotherapies, desensitization has to be repeated for each dose.

Desensitization is also dose dependent, meaning that, once a patient has been desensitized to a specific dose, a substantial dose increase may result in breakthrough allergic symptoms. Desensitization may also be concentration dependent in some patients, and it is prudent to design the desensitization so that the final (most concentrated) solution is the same concentration at which the drug is normally delivered (for intravenous [IV] medications) [52].

A few reports have described the long-term maintenance of desensitization by chronic daily oral administration for select patients in whom recurrent infections necessitated intermittent antibiotic therapy [16,57] or for whom occupational exposure was unavoidable and disabling [18]. However, published clinical experience with chronic drug desensitization is very limited.

COUNSELING THE PATIENT AFTER DESENSITIZATION — The patient must be counseled that desensitization is not a permanent cure for allergy to the drug in question. The sensitivity returns once the drug is cleared from the bloodstream, and the patient should continue to report an allergy to that agent in the future. If the drug is needed again in the year or two after the desensitization, the procedure should be repeated. If years have elapsed since a patient was desensitized to a drug, the patient's allergic status should be reevaluated if the drug is needed again. For penicillin, many patients lose IgE-mediated allergy over years, so repeat skin testing can help guide whether desensitization needs to be repeated or if the patient has lost the allergy in the interim.

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

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Drug allergy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of rapid drug desensitization – Rapid drug desensitization is a process of inducing temporary tolerance to a specific medication in a patient who has developed a hypersensitivity to that medication. It involves administration of the drug, beginning with very small doses and gradually increasing in a stepwise manner until a full therapeutic dose is reached. Desensitization alters a patient's adverse immune response to the drug temporarily, allowing the patient to receive an uninterrupted course of the medication safely. Once the medication is discontinued, the patient's hypersensitivity to the medication returns. (See 'Introduction' above.)

●Patient selection – The drug desensitization approach described in this topic review can be applied to patients with immediate hypersensitivity reactions. These include immunoglobulin E (IgE) mediated, non-IgE-mediated immediate hypersensitivity reactions, and mixed reactions (figure 1). (See 'Types of immediate reactions' above and 'Patient selection' above.)

●Potential mechanisms – The mechanisms involved in desensitization are not completely understood. Despite this, drug desensitizations have been performed successfully for decades. (See 'Immediate drug reactions' above and 'Patient selection' above.)

●Contraindications – Desensitization is not effective and may be dangerous (even fatal) in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS), acute generalized exanthematous pustulosis (AGEP), diffuse erythroderma with desquamation, and serum sickness reactions. (See 'Contraindications' above.)

●Use of premedications – Premedications are administered before some but not all desensitizations, depending on the mechanism that is believed to underlie the reaction. In addition, any premedications that are normally given before administration in a patient without hypersensitivity, such as premedications before chemotherapy, should also be given before desensitization. (See 'Premedications' above.)

●Protocols – Desensitization can be performed by oral, intravenous (IV), intraperitoneal, or subcutaneous routes, but the IV route is most often used for IV medications. A standardized protocol involving 12 steps and taking approximately six hours to complete has been successful in patients with immediate hypersensitivity reactions to a variety of drugs (table 4). Patients with severe past reactions are more appropriately treated with a slower protocol involving 16 steps (table 7). (See 'Risk stratification' above and 'Protocols' above.)

●Outcomes – The success rate of drug desensitization is very high when performed by experienced drug allergy experts. However, patients may experience breakthrough reactions during as many as 30 percent of desensitizations, although less than 10 percent are moderate or severe. The clinician's experience in managing these reactions is critical. Breakthrough symptoms are managed by stopping the infusion temporarily, administering specific treatments, and restarting the protocol again at the step that elicited symptoms. The protocol should be adjusted to advance through the problematic step more gradually if it is to be performed again in the same patient. (See 'Technical aspects of desensitization' above and 'Protocols' above and 'Outcomes' above.)

●Patient education – The patient must be counseled that desensitization is not a permanent cure for allergy to the drug in question. The sensitivity returns once the drug is cleared from the bloodstream, and the patient should continue to report an allergy to that agent in the future. (See 'Counseling the patient after desensitization' above.)