Hypersensitivity reactions to insulins

INTRODUCTION — Several types of hypersensitivity reactions to insulin preparations have been described. These reactions may be caused by the insulin itself or by additives within the preparation. Hypersensitivity reactions to insulin are rare with human insulins and insulin analogs. However, some types of reactions are serious, and even life threatening, and may have a significant detrimental impact on diabetes management. Evaluation requires close collaboration between endocrinology and allergy experts.

The clinical manifestations, classification, diagnosis, and management of hypersensitivity reactions to insulin preparations are discussed in this topic review. Other adverse effects of insulin therapy are discussed separately. (See "General principles of insulin therapy in diabetes mellitus", section on 'Safety'.)

EPIDEMIOLOGY — Hypersensitivity to insulin or insulin analogs can occur in all age groups and in patients with either type 1 or type 2 diabetes and includes local reactions, systemic reactions, and, rarely, true allergic reactions. Although comprehensive epidemiologic studies are lacking, estimates of incidence range from 0.1 to 7.1 percent of patients [1-3], with injection-site reactions in 1.4 percent and insulin-related allergic events in 0.6 percent of patients [4]. Insulin hypersensitivity is rare with the preparations in use today, although it was more common when relatively impure and heterologous porcine and bovine insulins were widely used as these are far more immunogenic. The progressive improvement in purification of nonhuman insulins, use of single-animal species insulins, and the nearly universal adoption of highly purified human insulins beginning in the 1980s all contributed to the reduction in injection-site and systemic allergic reactions to insulin.

When encountering a patient who appears to be reacting to insulin, it is important to understand the other conditions that can mimic insulin hypersensitivity. A retrospective study of 22 patients with suspected insulin allergy determined that 59 percent of patients did not have an allergic cause of their symptoms [5]. This is in keeping with the author's experience. (See 'Differential diagnosis' below.)

Risk factors for immediate allergy — Aside from the use of heterologous porcine and bovine insulins, risk factors for immediate insulin allergy are largely unknown. Possible risk factors include:

●HLA haplotype – In a small case-control study, the frequency of human leukocyte antigen (HLA) A2 among 10 insulin-allergic patients was 80 percent compared with 46 percent in 21 insulin-treated controls without allergy [6].

●Recent COVID-19 or vaccination against COVID-19 – Cases of insulin allergy occurring after coronavirus disease 2019 (COVID-19) infection [7] and COVID-19 vaccination [8] have been described. Theories about possible inciting factors include the proinflammatory state (after infection) or the presence of fatty acid moieties in both the messenger ribonucleic acid (mRNA) of the vaccine and in insulin (after vaccination).

TYPES OF HYPERSENSITIVITY REACTIONS — Hypersensitivity reactions to insulin preparations may be divided into "immediate" and "delayed," based upon how quickly signs and symptoms appear. However, it is not always possible to make this distinction.

Immediate — Immediate hypersensitivity reactions to insulin (or an additive in the insulin preparation) generally develop within one hour after an injection, although the symptoms often appear much more rapidly (sometimes within seconds) [9]. Immediate reactions range from local skin reactions to systemic reactions. The severity of immediate reactions can also vary somewhat from injection to injection, which is true of anaphylaxis caused by any allergen. Cofactors, such as exercise or concomitant infection, can accentuate allergic symptoms or lower the patient's threshold for reacting. Immediate reactions tend to worsen over time and must be actively evaluated and managed in patients who will require ongoing insulin therapy.

●Local immediate reactions – Local skin reactions present as rapidly developing pruritic erythema and/or wheal at the injection site [5]. Sometimes local symptoms increase in intensity over time (days to weeks), ultimately culminating in systemic reactions. This phenomenon has also been described with allergic reactions to other allergens, in which symptoms are initially limited to the skin but then evolve to affect the respiratory and/or gastrointestinal tract, eventually resulting in full anaphylaxis [10].

●Systemic immediate reactions – Systemic reactions may present with generalized urticaria, pruritus (especially of the palms and soles), and angioedema, although a wide range of symptoms are possible (table 1) [11,12]. Sometimes previous injection sites will react (ie, become erythematous) simultaneously [13,14]. Nausea, diarrhea, confusion, tremor, blurry vision, and diplopia have been reported with anaphylaxis to insulin, although these symptoms are not typical of drug-induced anaphylaxis. Cases of severe anaphylaxis have been reported in the past, including fatalities, but not with more purified forms of insulin [15-18].

Immediate reactions to insulin preparations are believed to be immunoglobulin E (IgE) mediated, type I immunologic reactions to insulin or to an additive (table 2A-B). In type I drug allergy, sensitization to the antigen (drug) develops in susceptible individuals prior to the initial allergic reaction. Sensitization refers to the formation of drug-specific IgE molecules and binding of these molecules to high-affinity IgE receptors on mast cells and basophils. However, not all sensitized individuals develop allergic symptoms, and patients treated with human insulin may develop insulin-specific IgE antibodies within the first few months of therapy and remain asymptomatic [19]. Once sensitization has occurred, reexposure to the drug can lead to cross-linking of IgE on the surface of mast cells and basophils and subsequent release of histamine and other inflammatory mediators. Histamine specifically induces vasodilatation, an increase in vessel permeability, and pruritus. In the past, with beef or pork insulins, a typical scenario leading to IgE-mediated insulin allergy was the onset of urticaria, stopping of insulin for weeks or months, and then the development of anaphylaxis when insulin was resumed. In the case of modern insulins, it is not known if interruptions in therapy increase the risk of immediate reactions. Since continuous administration desensitizes at least to some extent, interruption for several days or weeks due to symptoms and subsequent reinduction could lead to more severe reactions. (See "Drug allergy: Pathogenesis", section on 'Type I (IgE-mediated)'.)

Immediate reactions to human insulins typically develop months to years after beginning injection therapy with a specific insulin preparation [20]. However, there are case reports of immediate reactions developing upon the patient's first few injections or in response to an insulin to which the patient had no known previous exposure [18,21,22]. In these unusual cases, it is possible that the culprit antigen is similar to another antigen to which the patient had been previously exposed.

Delayed — Delayed reactions develop later than one hour after injection, and, in most cases, they start several hours to one or two days later. Delayed reactions are usually cutaneous, transient, and resolve spontaneously within a few weeks with continuation of therapy. If they persist, they can be evaluated on a nonurgent basis. (See 'When to refer' below.)

At least two distinct types of delayed reactions have been described:

●Induration and subcutaneous nodules at the site of injections, which are most likely a form of type III reaction (immune complex-mediated reactions). These lesions may be painful and can persist for weeks, although most will eventually resolve.

●Eczematous skin changes or exanthema at the site of injections, which are likely type IV reactions (ie, contact dermatitis). They can be pruritic.

INITIAL ASSESSMENT

Clinical history — The history should focus on the rapidity with which the signs and symptoms develop after injection (ie, within minutes to one hour versus later) to distinguish immediate from delayed reactions, the presence or absence of systemic symptoms to judge the severity, and whether the reactions have become worse over time. Important questions in the evaluation of possible hypersensitivity reaction to insulin include the following:

●What are the specific symptoms following insulin injections?

●How quickly do the symptoms develop with respect to each injection? Immediate reactions begin within one hour of injection for a pure insulin but may occur at the time of peak blood levels in insulins with delayed or prolonged absorption. Delayed reactions start later than one hour after injection, and, in most cases, they start several hours to one or two days later.

●Are the symptoms localized to the injection site, or do they affect more distant parts of the body (ie, systemic)? Does the reaction involve wheals at the injection sites that persist for less than 24 hours, or is the reaction mostly induration that persists for hours or days?

●Have the symptoms been observed by a clinician (or could they be)?

●Are the symptoms the same after each injection, or are they variable and changing over time? If the patient initially had local reactions and now is having systemic symptoms, the possibility of impending anaphylaxis should be considered, and evaluation should be expedited.

●Do the symptoms sometimes occur unrelated to insulin injections? Do reactions occur only when the patient also takes a nonsteroidal antiinflammatory drug? If the patient answers affirmatively to either question, disorders such as chronic urticaria/angioedema should be considered. This is the most common alternative explanation found by allergists to whom patients with "insulin allergy" are referred. Physical exam demonstrating dermatographism can help establish this diagnosis. (See 'Differential diagnosis' below.)

●Which insulins were used in the past, and how well were they tolerated? If any other insulin preparations were used in the past, the additives and types of insulins should be compared. However, the clinician should be mindful that, in patients who have developed a new allergy to an insulin or additive, the fact that a preparation containing that same component was tolerated in the past does not exclude the possibility that the patient has become reactive to it since.

If other dermatologic conditions can be excluded, the clinician should attempt to categorize the reaction. Sometimes it is not clear from the patient's history or examination whether a local reaction is delayed or immediate, and, in this situation, it is prudent to evaluate for both possibilities.

Physical findings — If signs and symptoms are limited to the skin, the injection site and the rest of the integument should be carefully examined. In most cases, skin changes that are suspected to be a manifestation of insulin hypersensitivity have other causes, such as injection-site irritation or a separate dermatologic condition, such as prurigo nodularis simplex subacuta or atopic dermatitis. (See 'Exclude injection-site irritation' below and 'Differential diagnosis' below.)

Exclude injection-site irritation — In most cases, localized symptoms at injection sites of human insulins are mild and are caused by irritation rather than true hypersensitivity. They can be managed by optimizing injection technique and other simple measures. A knowledgeable clinician should observe the patient's injection technique. The following measures can be helpful:

●For patients with eczematous skin changes at the site, discontinue routine use of isopropyl alcohol swabs or other irritating cleansing solutions. Use of cleaners at injection sites is not necessary. In addition, topical antiinflammatory ointments can be applied.

●For patients with induration or subcutaneous nodules, make sure to inject deeply enough, cool the site briefly before injecting, try smaller needles, and/or massage the injection site for a few moments after injecting.

●For patients with localized urticaria at the site, avoid injecting where clothing or belt buckles rub against the skin.

●For any injection-site reaction, change sites regularly.

If these measures do not result in improvement, then further evaluation is appropriate. Proper insulin injection techniques are discussed separately. (See "General principles of insulin therapy in diabetes mellitus", section on 'Injection technique' and "Patient education: Using insulin (The Basics)", section on 'How do I give myself an insulin shot?'.)

DIAGNOSIS

●Immediate reactions – The diagnosis of an immediate hypersensitivity reaction to insulin is based upon a suggestive clinical history, the demonstration of IgE sensitization to insulin (using skin prick/intracutaneous testing and/or IgE immunoassays) or to an additive (very rare), and exclusion of other causes of the symptoms [23,24]. Exclusion of other causes (eg, urticaria/angioedema, other allergies) is important because skin prick/intracutaneous testing with insulins can yield false-positive results. (See 'False-positive results' below.)

●Delayed reactions – The diagnosis of a delayed hypersensitivity reaction to insulin is based upon a suggestive clinical history, testing that is determined by the type of delayed reaction (ie, skin testing with delayed readings or patch testing), characterization of histologic changes on skin biopsy, and exclusion of other causes.

DIFFERENTIAL DIAGNOSIS

●Immediate – The most common disorder that mimics immediate hypersensitivity to insulin is acute or chronic urticaria [5]. However, careful questioning and/or the finding of dermatographism should uncover episodes of urticaria/angioedema that are intermittent or ongoing over a period of time and are only accentuated by insulin injections. Patients should be questioned for other triggers for urticaria, such as intake of nonsteroidal antiinflammatory drugs, bacterial or viral infections, dietary factors, or physical factors (heat, pressure, scratching of the skin). (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Aggravating factors'.)

●Delayed – There are several skin diseases that have been mistaken for delayed insulin hypersensitivity, including prurigo nodularis simplex subacuta, exacerbation of atopic dermatitis, psoriasis, and contact dermatitis unrelated to insulin preparations [5]. (See "Prurigo nodularis" and "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis" and "Psoriasis: Epidemiology, clinical manifestations, and diagnosis" and "Clinical features and diagnosis of allergic contact dermatitis".)

Localized lipodystrophies, or changes in subcutaneous fatty tissue at injection sites, are not usually confused with hypersensitivity. Lipoatrophy (loss of fatty tissue) is believed to be an autoimmune phenomenon that can be aesthetically upsetting but is rare with modern insulins [25,26]. Lipohypertrophy is a consequence of repeated injections at a specific site and results from insulin's known local effects on adipose tissue. It is associated with a decreased response to insulin and fluctuating blood glucose levels [27,28]. Patients should be advised not to inject in areas of lipohypertrophy.

INITIAL INTERVENTIONS

For immediate reactions

Anaphylaxis — Anaphylaxis to human insulin, although rare, is a medical emergency. It is important to recognize early symptoms of potentially severe immediate reactions, like pruritus of palms and soles, hoarseness or dyspnea, or a decrease of blood pressure, since patients with these symptoms require close monitoring in a supervised setting. Patients who have experienced anaphylaxis or have symptoms of impending anaphylaxis should be admitted to the hospital urgently for emergency care and for multidisciplinary management. Stopping insulin therapy in patients who require it can result in ketoacidosis [20]. (See 'Referral for allergy evaluation' below.)

Less severe reactions — Mild-to-moderate immediate reactions, such as localized hives or mild generalized hives and angioedema, can be managed with symptomatic therapy while the patient is referred for allergy evaluation:

●Oral antihistamines can be helpful for patients with urticaria or angioedema [29]. Drugs and doses are similar to those used for chronic urticaria, which are reviewed separately. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Stepwise approach to treatment'.)

●Systemic glucocorticoids might be necessary for patients with urticaria/angioedema in some cases, until the diagnosis is made and a management plan is determined. However, glucocorticoids elevate blood sugars further and complicate management, so they should be given for the shortest amount of time possible.

Empirically change insulin — In patients who require continuation of insulin therapy, the clinician can choose a different insulin preparation or an insulin analog [30-32]. Insulin analogs are options for patients allergic to human insulin [33], although, if the patient has signs or symptoms of a severe systemic immediate allergic reaction, it is important to consider the additives contained in the different preparations as these are often used in both human insulin and analogs. Analogs have been implicated in immediate hypersensitivity reactions as well [34,35].

Use a non-insulin therapy — In patients with type 2 diabetes, there are several non-insulin therapies that could be considered. They include oral hypoglycemic agents and glucagon-like peptide. Some of them have also been implicated in allergic reactions [36-38]. In addition, patients could reduce the need for insulins by implementing lifestyle measures like weight loss. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)

For delayed reactions — Because delayed reactions typically resolve with time, initial measures are intended to minimize symptoms. First, ensure that the patient is injecting deep enough into the subcutaneous layers of the skin, and evaluate for other causes of injection-site irritation. (See 'Exclude injection-site irritation' above.)

For symptomatic relief:

●Local eczematous reactions can be treated with a topical corticosteroid-containing ointment such as triamcinolone.

●Pruritus may respond to local application of a polidocanol-containing urea cream (commercially available in Europe, Asia, and Australia but not in the United States). Oral antihistamines, such as cetirizine 10 to 20 mg once or twice daily, are also helpful for pruritus [3].

FURTHER EVALUATION AND MANAGEMENT

Immediate reactions

Referral for allergy evaluation — Allergy evaluation for immediate reactions to insulin preparations involves a thorough review of the insulins to which the patient has already been exposed, skin testing with insulins and additives to try to identify the culprit allergen, and in vitro testing. This evaluation is usually done by an allergy specialist.

Potential allergens — Immediate allergic reactions to insulin preparations can be elicited by the insulin itself or by additives within the insulin preparation (table 2B).

Insulins — Both human insulins (neutral protamine Hagedorn [NPH] and regular insulin) and insulin analogs (eg, lispro, aspart, glulisine, glargine, detemir, and degludec) can induce allergic reactions. The antigenic epitope may be a nonself-epitope, an altered self-epitope, or an epitope generated by alternate protein folding that can occur during production or purification of insulin preparations. In theory, the degradation of insulin in the subcutaneous depot (eg, by proteases) could expose other epitopes. In most cases, the antigenic epitope is thought to be a determinant unique to recombinant proteins, which have different tertiary structures [39], or a determinant on one of the nonprotein components [40].

Protamine — Protamine sulfate is a protein isolated from fish sperm that can be complexed to insulin to delay absorption. Protamine has been implicated in immediate allergic reactions in patients with diabetes, as well as in anaphylaxis during reversal of heparin in cardiovascular procedures (table 2B) [17,41-43]. Previous exposure to protamine is a risk factor for having protamine allergy. In contrast, fish allergy and prior vasectomy have been proposed as risk factors for protamine allergy, but one prospective study found no evidence for these associations [44]. The pathogenesis of immediate reactions to protamine is not established, and both IgE-mediated and complement-mediated mechanisms have been proposed [45]. Thus, immediate-type skin testing has been successfully used to identify protamine-sensitive patients in some but not all patients [46].

Other additives — Cresol compounds are preservatives present in most insulin preparations that should be considered in immediate reactions (table 2B). Latex has also been implicated in rare cases. Other additives have not been implicated in immediate reactions to insulins.

●Cresol – An unusual case report described a patient with pain, erythema, induration, and urticaria developing at the injection site within five minutes, followed rapidly thereafter by localized skin erosion, with positive skin testing to cresol in saline [29].

●Latex – Trace amounts of latex from vial membranes have been implicated in rare reports of allergic reactions to insulin preparations [47,48]. However, many vial membranes are now latex free. A careful clinical history of other latex exposures should be obtained (table 3). Latex allergy is reviewed in detail separately. (See "Latex allergy: Epidemiology, clinical manifestations, and diagnosis".)

Skin testing — Skin testing for IgE-mediated allergy involves skin prick testing and intracutaneous (ie, intradermal) testing under close monitoring by an allergy expert [49]. Prick testing is performed initially, with appropriate positive (eg, histamine 10 mg/mL) and negative (eg, saline 0.9%) controls. Insulins are applied undiluted for prick testing. If the initial readings of the prick tests are negative, then intradermal (intracutaneous) testing is performed next, using insulin solutions that are diluted in saline 1:100 [50]. Most insulins are commercially available in a 100 unit/mL solution; a 1:100 dilution is equivalent to 1 unit/mL. Prior to undergoing skin testing for immediate reactions, patients must discontinue any antihistamines for a sufficient period of time (seven days for most agents). Other medications and factors that affect skin prick/intracutaneous test results are reviewed separately. (See "Overview of skin testing for IgE-mediated allergic disease", section on 'Factors affecting results'.)

●Prick tests are read after 15 minutes. A wheal with a diameter ≥3 mm is considered a positive reaction (picture 1).

●If the prick tests are negative after 15 minutes, then intradermal testing is performed. Results are measured after 15 minutes. A diameter of the wheal of ≥3 mm greater than the size of the initial injection bleb is considered as a positive reaction.

The sensitivity and specificity of the skin prick testing was 10 and 100 percent, respectively, while that of intradermal testing was 80 and 100 percent, respectively, in a case-control study that also included patients with delayed-type hypersensitivity [6].

Insulin preparations — The author's approach is to perform prick testing with the following (form 1):

●The insulin(s) to which the patient reacted.

●All other insulins that are routinely used to determine if these would be options for the patient.

●The additives that have been most often implicated in immediate reactions (eg, protamine, cresol, and possibly latex).

●An additive-free insulin preparation, if available from the manufacturer.

However, not all of these reagents may be available in all settings, and the clinician may need to modify this approach.

Protamine and other additives — Commercial kits containing various insulin preparations and insulin additives for use in skin testing were available in some European countries in the past, although production has been discontinued in most. If a kit is not available, an insulin-diluting medium that contains the additives or a subset of them in question can be used for testing [29].

●Protamine sulfate for injection (10 mg/mL) may be diluted 30-fold to 333 micrograms/mL for prick skin testing, which is similar to the concentration in undiluted NPH insulin (350 micrograms/mL) [23]. For intradermal testing, the testing solution should be diluted further. Initial concentrations for intradermal testing are generally 10- or 100-fold more dilute than prick testing solutions, and further dilutions are warranted for patients with anaphylaxis. One patient with anaphylaxis had a positive intradermal test to 0.03 nanograms/mL of protamine, so extreme sensitivity is possible [23].

●Skin testing with cresol can be performed with a solution of 1.5 mg/mL for prick testing. Initial concentrations for intradermal testing should be 100- or 10-fold more dilute than prick testing solutions. Some manufacturers may supply solutions containing the additives that are present in the insulin preparations [29].

●Skin testing to latex and/or in vitro testing for latex-specific IgE can be performed. Validated latex skin tests are not available in some countries, including the United States. (See "Latex allergy: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

False-positive results — Note that immediate-type skin testing must be interpreted in the context of the patient's clinical history because false-positive skin prick tests have been documented to both human insulin and protamine in subjects with diabetes without any allergic symptoms [16,23]. Because immediate insulin hypersensitivity is so rare with recombinant human insulins, it is difficult to collect enough patients to perform studies of the sensitivity and specificity of skin testing. A small study of seven patients newly treated with human insulin found that positive prick test results and low insulin-specific IgE titers developed in nearly one-third of subjects, although none had symptoms of hypersensitivity [19].

In vitro allergy tests — It is the author's approach to obtain insulin-specific IgE, latex-specific IgE, and protamine-specific IgE in patients with immediate reactions [51]. Absence of measurable levels of specific IgE antibodies makes an immediate type I allergy unlikely. Delayed reactions, however, are not mediated by IgE and would not be expected to show positive insulin-specific IgE antibodies.

In contrast to allergen-specific IgE antibodies, assessment of neutralizing immunoglobulin G (IgG) antibodies is not relevant to the diagnosis or management of insulin allergy. Neutralizing antibodies have not been shown to have an impact on long-term HbA1c or insulin requirements, as documented in a study investigating insulin aspart [4].

Management of confirmed allergy — Once immediate hypersensitivity has been confirmed to one preparation of insulin or to an additive, it should be carefully documented and explained to the patient. The causative allergen can be avoided by choosing a different insulin preparation suitable for the patient (table 2B) [52,53] or a non-insulin-based therapy. If no alternative preparation can be identified or the patient does not experience adequate control of blood sugars using alternative insulins, desensitization to the desired insulin can be performed. Case reports have described the use of anti-IgE therapy, pancreatic transplant, and immunosuppressants in complicated cases. (See 'Insulin desensitization' below and 'Omalizumab and other options' below.)

Patient education and allergy documentation — Patients with confirmed type I allergy (eg, to insulin or protamine) must be educated about their allergy, and the allergy should be thoroughly documented in the patient's medical record. The patient should be encouraged to obtain a medical identification bracelet or other jewelry stating their allergy. In addition, the patient should be given an allergy card or letter that includes the following information:

●What type of allergy the patient has (ie, a brief description of the type and severity):

•What insulin or additive the patient is allergic to and what other insulins should be avoided.

•Where the culprit insulin or additive is likely to be encountered (especially protamine, which patients should be told is used to reverse the blood thinner heparin).

●What alternative insulin the patient can safely take.

●What treatments should be given if the patient has another reaction. (Eg, patients with anaphylaxis in the past should be provided with an epinephrine autoinjector and trained in proper use. Patients with urticaria should carry a dose of antihistamines and possibly glucocorticoids.) (See "Patient education: How to use an epinephrine autoinjector (The Basics)" and "Patient education: Using an epinephrine autoinjector (Beyond the Basics)" and "Patient education: Anaphylaxis (The Basics)".)

Insulin desensitization — Insulin desensitization should be considered when changing the insulin preparation is not feasible due to multiple sensitizations or when there have been difficulties stabilizing the blood sugar with the insulin preparations the patient does tolerate [54,55]. Most desensitizations have been performed with human insulins, although a few papers describe desensitization with insulin analogs [56].

Insulin desensitization is generally well tolerated and effective in most patients [20,57]. It can be used in patients with severe as well as mild symptoms [58]. The mechanism of insulin desensitization has not been fully elucidated, although the induction of anergy or depletion of specific T cells has been suggested, as well as the induction of T regulatory cells and the modulation of antibody production by cytokines [59]. Desensitization is also associated with a decrease in insulin-specific IgE titers and possibly an increase in IgG antibodies over time [60].

Most published insulin desensitization protocols consist of series of gradually increasing subcutaneous doses, although there are also reports of successful protocols using continuous subcutaneous infusion delivered through insulin pumps [55,61-65]. Continuous infusion has also been used on an emergency basis to manage diabetic ketoacidosis in a patient with insulin allergy [66]. In addition, cases of intravenous desensitization have been described [67,68].

Protocols — The starting dose can be chosen based on the severity of the allergic symptoms. The author usually starts at 0.00001 international units and increases the dose 10-fold every 30 minutes up to 1 unit and then 2, 4, 8, 12, 16, and 20 international units. A protocol used in the author's clinic is provided (table 4). Premedications are not routinely given. The blood glucose is carefully monitored via fingersticks and stabilized by oral antidiabetics, if possible; another insulin preparation intravenously; or via an insulin pump. If necessary, blood glucose can be increased with oral or intravenous glucose.

In the author's experience, most patients can be successfully desensitized.

●If a local reaction occurs at the injection site during desensitization, we wait for it to subside (eg, while applying a cool pack) or treat the reaction, depending on the severity. Then, the same dose is repeated 30 minutes after the dose that caused the local reaction.

●If a systemic reaction occurs, the protocol is suspended, and symptoms are treated. Once the symptoms have resolved, the protocol is restarted at one-half of the dose that caused the reaction.

Although most desensitizations are successful, failures and cases in which the effect was short lived have been reported [11,69]. In severe cases, desensitization has been combined with prednisolone [54,70].

Omalizumab and other options — In selected cases and after desensitization, treatment with omalizumab has been tried, although it is not always effective [71-73]. One case report of a perceived insulin allergy refractory to desensitization described the use of rituximab followed by mycophenolate mofetil and omalizumab [74].

A rarely employed alternative is the transplantation of pancreas tissue and accompanying immunosuppression [75,76] or the transplantation of islet cells.

Delayed reactions

When to refer — Diabetologists have experience in managing local insulin reactions. Delayed reactions are usually transient, resolving spontaneously within a few weeks with continuation of therapy. If the reactions do not improve after one or two months, referral to a dermatology or allergy specialist is appropriate to try to identify the cause of the reaction, as evaluation usually requires skin testing, patch testing, and/or skin biopsy. Once a cause is identified, an insulin preparation lacking this agent should be substituted, if possible.

Testing — Testing depends upon the type of delayed reaction.

●Induration and/or subcutaneous nodules – Evaluation involves one or more of the following:

•Skin testing – A second reading of the skin testing sites after 24 hours is referred to as a "late reading." The presence of induration is considered a positive result, and the site is then examined again at 48 hours. The presence of induration at either time point is considered a positive reaction. Note that late readings of prick or intradermal tests are not standard protocol in the evaluation of immediate-type drug allergies, although the author and others have found this type of testing to be useful in identifying some forms of delayed insulin reactions [5,23]. The initial steps of skin testing are described above. (See 'Skin testing' above.)

•Biopsy – Punch biopsy of the affected skin is helpful to characterize the nature of the cellular infiltrate and determine if vasculitis is present [77]. Leukocytoclastic vasculitis responsive to systemic glucocorticoids was identified in one case [78]. Eosinophilic infiltrates have been described in delayed-type reactions [79] and in reactions after intradermal testing [6]. Granulomatous reactions have also been described and attributed to IgG antibodies directed against insulin, which form immune complexes that precipitate in the tissue [80,81]. These reactions may represent a localized Arthus reaction [77]. The binding of this antibody might also affect the kinetics of insulin action. Biopsy can also exclude other causes of subcutaneous induration or nodules.

•Laboratory tests – Other laboratory tests may provide additional information, although they are not necessary for the diagnosis. Anti-insulin IgG1 antibodies have been reported to be elevated in patients with local hypersensitivity reactions compared with controls. However, it should be noted that anti-insulin IgG antibodies are commonly found in insulin-treated patients and are not necessarily associated with clinical symptoms [82,83]. Lymphocyte transformation tests, where available, can help assess the T cell response to specific drugs [84].

●Erythematous or eczematous skin changes or exanthema – With this presentation, it is important first to make sure that the patient does not have other dermatologic conditions, such as atopic dermatitis. Exanthema can also be associated with infectious disease or reactions to other drugs (eg, antibiotics). (See 'Differential diagnosis' above.)

Patch testing is appropriate for the evaluation of eczematous local reactions or exanthema. Cresol reactions have been demonstrated with patch testing [3]. One report used a solution of medium-containing 3 mg/mL metacresol and glycerol in a Finn chamber for patch testing and tested glycerol alone in parallel [85]. A more general discussion of patch testing is found separately. (See "Patch testing".)

Exanthema have been attributed to delayed-type hypersensitivity reactions involving predominantly T cells (type IVc) or eosinophils (type IVb) [3]. Some patients may additionally experience systemic symptoms, including maculopapular eruptions, headache, nausea, or diarrhea [3]. Systemic symptoms have been attributed to additives within the insulin preparations, such as cresol (or metacresol), protamine, and zinc [3,5,29,51,85-87]. Crystalline zinc solutions can alter immunogenicity by changing the structure of the insulin B chain [84,88]. Protamine may also act as adjuvant [89]. Other reports mentioned additional potential contact allergens in insulin, including parabens, phenol, nickel, and isophane, but specific cases of hypersensitivity to these agents in insulin were not cited [5].

Materials from the catheter pump and application devices can also cause such hypersensitivity reactions [90-95]. Specifically, patients with diabetes have developed contact dermatitis to acrylates in the plastic catheters of infusion sets [90,93] and in the "butterfly" glue (Loctite [brand name]) [92].

Treatment of confirmed allergy — If evaluation identifies a specific allergen as causing a reaction, then avoidance is the primary management. Insulin preparations lacking the culprit component should be used instead. In one report of a patient with documented metacresol hypersensitivity, a short-acting insulin preparation containing methylparabens instead of metacresol was obtained from the manufacturer [85]. This product was not commercially available but was provided for the patient once the hypersensitivity was documented.

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".)

SUMMARY AND RECOMMENDATIONS

●Hypersensitivity reactions to human insulins are rare – Hypersensitivity reactions to human insulins and insulin analogs are uncommon. These reactions may be caused by the insulin itself or by additives within the preparation and can occur in all age groups and in patients with either type 1 or type 2 diabetes. In most cases, skin changes that are suspected to be a manifestation of insulin hypersensitivity have other causes, such as injection-site irritation or a separate dermatologic condition. (See 'Epidemiology' above.)

●Reactions can be immediate or delayed – Hypersensitivity reactions are categorized as immediate or delayed. Clinical history should focus on the rapidity with which the signs and symptoms develop after injection to distinguish immediate from delayed reactions and on the presence or absence of systemic symptoms. (See 'Types of hypersensitivity reactions' above.)

•Immediate reactions generally develop within one hour after an injection and often much more quickly. These rare reactions range from local erythema or a pruritic wheal at the injection site to systemic anaphylaxis that may involve generalized urticaria, pruritus, angioedema, or hypotension (table 1). They are believed to be immunoglobulin E (IgE) mediated, type I immunologic reactions to insulin or to an additive, such as protamine (table 2A and table 2B). Immediate reactions tend to worsen over time and must be actively evaluated and managed.

•Delayed reactions develop later than one hour and typically several hours to one or two days later. Common presentations include eczematous skin changes or induration or nodules at the sites of injection. Delayed reactions usually resolve spontaneously with time.

●Immediate reactions – Initial interventions in the patient suspected of having immediate reactions to insulin preparations depend upon the severity of the reaction. Patients who have experienced anaphylaxis and require ongoing insulin therapy should be admitted to the hospital urgently for multidisciplinary management. For less severe reactions, options include empirically changing insulin preparations and use of a glucagon-like peptide 1 (GLP-1) receptor agonist, symptomatic treatment with antihistamines or glucocorticoids (if the reaction is mild and localized), and discontinuing insulin therapy (feasible in some patients with type 2 diabetes). (See 'Initial Interventions' above.)

•The diagnosis of an immediate hypersensitivity reaction to insulin is based upon a suggestive clinical history, the demonstration of immediate sensitization to insulin (using skin prick/intracutaneous testing and/or IgE immunoassays) or additive (form 1), and exclusion of other causes of the symptoms. Referral to an allergy expert is indicated. An evaluation for immediate hypersensitivity should be performed if the patient's reaction has any features of an immediate reaction. (See 'Referral for allergy evaluation' above.)

•If an immediate allergy is confirmed to a specific insulin or additive, the allergy should be documented and explained to the patient. The causative allergen can be avoided by choosing a different preparation in some cases (table 2B). In patients for whom no alternative preparation can be identified or for those who cannot achieve adequate control of blood sugars using alternative insulins, we suggest desensitization to the desired insulin (table 4) (Grade 2C). Case reports have described the use of anti-IgE therapy, pancreatic transplant, and immunosuppressants in complicated cases. (See 'Management of confirmed allergy' above.)

●Delayed reactions – Delayed reactions at the site of insulin injection are usually transient, resolving spontaneously within a few weeks with continuation of therapy. Initial measures are intended to minimize symptoms and include topical therapies or oral antihistamines. If the reactions do not improve after a couple of months, referral to an allergy or dermatology expert is appropriate to try to identify the cause of the reaction, as evaluation usually requires patch testing, skin testing with delayed readings, and/or skin biopsy (See 'For delayed reactions' above and 'Delayed reactions' above.)