Drug allergy is the unpredictable adverse reaction that occurs as a result of the administration of a drug at a given dose, tolerated by normal subjects and based on an immunological mechanism, either immunoglobulin E (IgE)-mediated or non-IgE-mediated (through IgG or lymphocytes) (1). One or more immune mechanisms can compete in the development of allergic drug reactions (1-3).

In 1977, Rawlins and Thompson proposed the classification of adverse drug reactions into type A (‘augmented’): Predictable, dose-related and based on the pharmacological action of the drug and type B (‘bizarre’): Unpredictable, non-dose reactions or drug action (Table I) (4).

Thirty-seven years later, the World Allergy Organization (WAO) refined the classification of adverse drug reactions in relation to the onset of clinical manifestations, which broadly allows for the differentiation of IgE-mediated type I-type hypersensitivity reactions that typically start in the first hour after exposure, with some exceptions (slow absorption due to oral drug administration or concomitantly with food), and late onset reactions mediated by type II, III or IV hypersensitivity, in which manifestations occur usually after six hours of exposure and, typically, days after the initiation of treatment. WAO also suggests the use of the following terms: Immune-mediated hypersensitivity reactions and non-immune-mediated hypersensitivity reactions. The first category of ‘drug hypersensitivity reactions’ includes clinical signs and symptoms initiated by exposure to a tolerated dose by individuals under physiological conditions. According to WAO, drug allergy defines immunologically mediated hypersensitivity reactions and includes immediate, IgE-mediated and delayed non-IgE-mediated reactions. In the second category, ‘non-allergic hypersensitivity reactions’ include non-immune-mediated immune drug responses. WAO also proposes the differentiation of adverse drug reactions (ADRs) from adverse drug events (ADEs). This latter category includes medical errors, drug side effects, and food-drug interactions (5).

Due to immunomodulatory therapy, the last decade has brought spectacular results in the targeted treatment of inflammatory, autoimmune, and neoplastic diseases, to name a few. The widespread use of biological agents is, however, associated with the increase in the number of adverse drug reactions and implicitly those which are immunologically mediated, which justifies the need for a deeper understanding of this subject.

The adverse reactions associated with biological agents vary widely and include local site reactions, infusion-related reactions, hypersensitivity reactions, blood dyscrasia, serum sickness, vasculitis, demyelinating disease, reactivation of latent infections (tuberculosis, fungal and viral infections), neoplasms or autoimmune diseases. Adverse effects associated with immunomodulatory therapy are thus potentially severe and sometimes life-threatening (6).

Since adverse reactions from biological agents differ from adverse reactions from other drugs, Pichler proposed a new classification of adverse reactions produced by biological agents in 2006, which includes five types of reactions (7).

Drug desensitization is the administration of progressively increasing doses of the specified preparation until reaching the therapeutic dose in order to induce immunological tolerance and is indicated when the drugs are indispensable to the therapeutic regimen in individuals with hypersensitivity reactions to the preparation, with no reasonable alternatives.

Desensitization mechanisms are currently insufficiently elucidated. In the case of IgE-mediated reactions, desensitization induces the temporary immunological tolerance or hyporesponsive state of mast cells and basophils to the incriminated drug (77). In most patients following desensitization for IgE-mediated reactions, the reduction in skin reactivity was documented, while in some individuals, skin testing becomes negative to the incriminated drug once the desensitization protocol has been successfully completed (18,78,79).

One of the mechanisms that could explain the induction of temporary drug tolerance during desensitization is that of altering the level of surface receptor expression. In vitro studies have shown that antigen doses below the tolerance threshold make mast cells and basophils non-responsive to that specific antigen but responsive to other activating stimuli (80,81). Reduced doses of antigen, below the tolerance level, bind monomeric high affinity IgE receptors (FcεRI) from the surface of the sensitized mast cells. The initiation of IgE mediated hypersensitivity reactions involves an essential step of cross-linking at least two adjacent IgE receptor molecules, a situation encountered when exposed to high doses of antigen. Monomeric binding of IgE receptors thus prevents the activation and degranulation of mast cells, events that coincide with the initiation of IgE-mediated, immediate hypersensitivity reactions (77). Studies have shown that reduced doses of an antigen induce structural changes in the cell membrane of sensitized mast cells, and subsequent impairment of the internalization of antigen/IgE/FcεRI complexes from sensitized mast cell surface, which protects against anaphylaxis. Compared to anaphylaxis, where these complexes are internalized, during desensitization, they remain on the surface of the mast cells, preventing their activation (77,82).

Another mechanism of inducing tolerance by desensitization is the skewing of the immune balance in favor of specific immunoglobulin G synthesis. After desensitization, antigen-specific IgE and IgG levels increase. IgE levels increase as a result of antigenic exposure, but the dynamic increase in specific IgG levels generally coincides with the development of immunological tolerance. It is also possible that the high titers of IgG neutralizes drug epitopes and inhibits their ability to induce IgE mediated responses. Some authors have shown that drug desensitization induces increased levels of CD4⁺CD25⁺ T cells and CD4CD25FoxP3 regulators, suggesting the role of allergen-specific regulatory T lymphocytes in inducing drug tolerance (83).

Recent studies have argued in favor of altering some mast cell and basophil signaling pathways (77). In vitro desensitization studies of mast cells and basophils have shown a reduction in the level of signal molecule expression, such as syk kynase (spleen tyrosine kinase). Syk is involved in the activation of mast cells and basophils after cross-linking high affinity immune receptors for IgE with antigens. It has been shown that syk-deficient basophils, which are naturally produced, do not respond to drug antigens, which supports the importance of syk expression in desensitization. In addition, IgG receptors, Fc-gamma-RII can competitively inhibit binding of IgE, Fc-epsilon-RI receptors, and phosphatases can dephosphorize syk and other early signal molecules so that mast cells and basophils receive negative activation signals. Blocking of calcium influx and actin filament polymerization also seems to be also critical in the desensitization process (77,84).

With other adverse reactions, such as type IV hypersensitivity, drug desensitisations have been reported. In such cases, immunological mechanisms are yet to be elucidated.

Rapid desensitization to biological agents may be considered as a treatment strategy for anaphylactic (immediate or delayed) hypersensitivity reactions as well as for severe infusion reactions. Numerous desensitization protocols have been published for various MoAbs (adalimumab, brentuximab, cetuximab, infliximab, omalizumab, rituximab, tocilizumab, trastuzumab) (18,56,83,85-88). Signs and symptoms of immediate hypersensitivity reactions are included in Table II (89).

Desensitization is indicated in sensitized patients, confirmed by positive skin test and/or positive specific IgE (the latter being available for a series of MoAbs, respectively: Infliximab, tocilizumab, cetuximab, rituximab, trastuzumab, natalizumab, muromonab), in those who have documented elevated serum tryptase levels during acute events in the context of MoAbs administration, or when clinical history is highly suggestive of a systemic, IgE-mediated reaction (Table II). Another selection criteria for desensitization is the absence of treatment alternatives, the drug being indispensable to the therapeutic regimen. Drug challenge test is not recommended in patients with a highly suggestive clinical history of systemic IgE-mediated response due to the risk of adverse reactions. In this situation, it is advisable to start with the desensitization protocol.

Drug desensitization can be done at any age. Also, there have been reported cases of desensitization in pregnant women (90).

Desensitization is effective in cases of immediate IgE-mediated reactions, and possibly in delayed type IV hypersensitivity reactions. However, clinical history of severe hypersensitivity reactions, which do not match the typical presentation of anaphylaxis, such as Stevens-Johnson syndrome, Lyell's syndrome, are absolute contraindications for desensitization. In these situations, exposure, even at low doses, may induce severe, potentially fatal reactions. Erythema multiforme and generalized erythroderma also represent contraindications to desensitization (88,91). Desensitization is not indicated in DRESS, acute generalized exanthematous pustulosis (AGEP), serum sickness, drug-related organ damage (nephritis, hepatitis, cytopenias, hemolytic anemias, vasculitis) or other severe, non-IgE-mediated reactions. At the same time, desensitization is carried out only in situations where the patient's comorbidities permit, so that the presence of uncontrolled severe conditions (uncontrolled hypertension, hepatic failure, uncontrolled asthma) constitute contraindications to desensitization (77).

Desensitization involves administering the target drug in progressive incremental doses. The starting dose varies from one to another, ranging from 1/10 to 1/4,000 of the final concentration (92). From the authors' experience, the starting dose for desensitization is adjusted according to the individual reactivity threshold and may need to exceed the initial dilution level of 1/4,000. In some cases, the starting dilution may be that which did not induce a positive skin reaction during cutaneous drug testing.

Brigham and Women's Hospital (Dana Farber Cancer Institute) proposed a 12-step desensitization protocol, which starts with sequential administration of three drug solutions, at a fixed time interval of 15 min, namely 1/100, 1/10 and undiluted preparation. For those experiencing adverse reactions at 1/100, the starting dose is changed to 1/1,000. Some protocols recommend re-administering doses that induce adverse effects until the reaction becomes unresponsive. Desensitization is done subcutaneously or intravenously, depending on the mode of administration of the specific drug, until the therapeutic dose is administered (92).

Because the tolerance status is transient and maintained only in the context of daily drug administration, desensitization to biological agents at a different rate of administration, such as weekly, is a real challenge for both the clinician and the patient alike. For MoAbs, desensitization may be necessary at each administration. Patients should be informed of the temporary nature of desensitization. MoAbs remain in circulation longer than most low-molecular-weight drugs, but their serum clearance is variable and does not correctly predict whether desensitization at each administration is necessary or not. Desensitization is also dose-dependent. Thus, tolerance at higher doses than those achieved with desensitization is unlikely. In some patients, desensitization also depends on the concentration of the substance, it is thus recommended that the final solution is the undiluted substance or the therapeutic concentration (82,88,90).

Premedication is intended to prevent and/or reduce the severity of adverse reactions during desensitisation and varies according to the protocol. Most protocols include anti-H1 and anti-H2 antihistamines, some include steroids, aspirin or montelukast. Some authors advocate for avoiding premedication during desensitization to avoid masking early signs of anaphylaxis (93). Other authors support the efficacy of aspirin and montelukast in the prevention of skin and respiratory manifestations, suggesting the role of prostaglandins and leukotrienes in mediating these reactions (94). Recently published studies advocate the benefit of administering omalizumab as premedication. Omalizumab remains an option for patients who cannot desensitize after the standard protocol (95).

Allergic reactions during desensitization remain a dreadful obstacle. Therefore, desensitization is only done in intensive care units, by trained medical personnel and experienced in emergency therapy of anaphylaxis. If anaphylactic-type adverse reactions occur, rapid serum tryptase dosing is recommended within 30-120 min of the onset of reaction to confirm the IgE-mediated mechanism. In general, desensitization is well tolerated, and most often induces mild, cutaneous reactions (for intravenous agents) or local reactions at the site of administration (for subcutaneous preparations). If the adverse reaction requires treatment, re-administration of the drug will be done after the resolution of the manifestations, starting with the last tolerated dose or with the previous dose. Allergic reactions during biological desensitization (rituximab, inflixmab, trastuzumab) occur in up to 20% of cases. Most of these are mild in severity, but patients with a history of severe systemic reactions have a high risk of anaphylaxis. Occasionally, delayed reactions, including serum sickness, hemolytic anemia, nephritis, thrombocytopenia, have been reported. No fatal anaphylaxis has been reported during desensitization. Regarding the evolution after desensitization, a study by Brennan et al showed a high rate of success with 104 desensitizations from 105 patients in the study (18).

The use of biological agents has inaugurated a new era in the therapy of autoimmune, allergic, and neoplastic diseases. Sometimes the clinical utility of MoAbs is limited due to the occurrence of adverse effects. Immunomodulatory therapy influences immune response as well as other biological functions, which also explains the clinical benefits but also the immune and non-immune adverse effects. Adverse reactions to MoAbs are impediments to first-line treatments. Rapid drug desensitization has the potential to induce transient immunological tolerance, which allows for safe administration of the culprit drug in incremental doses until the full therapeutic dose is reached. Successful immunomodulating therapy is conditioned by appropriate patient selection and knowledge about the potential side effects in correctly addressing the patient with the indication of biological therapy. Moreover, a better understanding of the immune mechanisms underlying drug desensitization is the premise for success of this method.