Insulin allergy is now very rare, and when it does occur, management is often difficult. Since insulin often plays an irreplaceable role in the treatment of some diabetic patients and the prevalence of diabetes is increasing, it is necessary to discuss the diagnosis and management of insulin allergy.
Insulin allergy has been reported repeatedly as one of the adverse reactions to insulin since 1922, when insulin extracted by Banting and Best was first used clinically. However, compared to the immediate efficacy of insulin, insulin allergy was not an important event. At that time, insulin allergy was actually a more common phenomenon. The main reason, on the one hand, is the genus of insulin, whether it is dog insulin, bovine insulin or porcine insulin, there are differences in protein genus with human insulin; on the other hand, it is the purity problem, the purification technology at that time is really not the same as now. In 1936, fish protein became a component of long-acting insulin preparations, and fish protein was added to the list of allergens. This situation changed by the 1970s. The introduction of single-peaked pure insulin was a sign of the development of protein purification technology, and since then the cases of insulin allergy caused by impurities have been greatly reduced. 1982 saw the introduction of genetically recombinant human insulin, which completely solved the problem of insulin species, so that allergy caused by differences in protein species disappeared from the theory. The incidence of insulin allergy was greatly reduced, and many believed that the problem had been completely solved.
However, it was soon discovered that insulin allergy still occurs in a very small number of patients and is very persistent and difficult to manage. The reason for this was thought to be due to the fact that although the primary structure of human insulin in commercial preparations is consistent with the primary structure of insulin secreted by humans under physiological conditions, the highly concentrated preparations make the tertiary structure of human insulin different from that in physiological conditions. If this change happens to lead to the production of antigenic determinant clusters, insulin allergy may occur. Since then, the management of insulin allergy has relied almost exclusively on conventional desensitization therapy until the advent of insulin analogs and the widespread use of portable insulin pumps improved the situation. In recent years, the emerging anti-IgE therapy in the field of allergology and the use of pancreatic transplantation in the field of diabetes therapeutics for the management of insulin allergy have been reported in the literature, but the combination of efficacy, safety and health economics can only be considered as second- and third-line options.
Clinical features of insulin allergy
Insulin allergy, which can be strictly referred to as insulin preparation allergy, is a special category of allergic disease among protein-based drug allergies. The vast majority of insulin allergies belong to type I allergic reactions, and very few cases can show clinical manifestations of type III allergic reactions, and there are also reports of type IV allergic reactions. However, the allergens that cause type IV allergic reactions are almost always the additive components in insulin preparations. The author mainly discusses type I allergic reactions caused by insulin preparations.
Type I allergic reactions caused by insulin preparations have a sensitization phase, usually between 3 months and 6 months; however, some patients have clinical manifestations of allergy that occur rapidly after insulin use. These clinical manifestations are similar to other protein-based injectable drug allergies and can be divided into local and systemic manifestations. Generally, it appears a few minutes after insulin injection, and most patients only have local manifestations, while very few patients may have systemic manifestations. Local manifestations mainly include the appearance of a wind cluster centered on the injection site, sometimes with pseudopods and pronounced local pruritus. Systemic manifestations include urticaria, asthma, and anaphylaxis. Although systemic manifestations rarely occur, they are life-threatening when they do occur and require high attention.
Diagnosis and differentiation of insulin allergy
Diagnosis of insulin allergy
According to the diagnostic principles of allergology, the diagnosis of drug allergy requires detailed medical history, in vivo test, in vitro test, withdrawal of the suspected drug, and the diagnosis of insulin allergy. In vitro tests and reactions after withdrawal of suspected drugs are examined in four aspects. The diagnosis of insulin allergy includes: whether the patient is allergic, what clinical manifestations appear after insulin injection; skin test; specific IgE determination; whether the clinical manifestations of the patient subside after stopping insulin injection.
Medical history: Many insulin allergic patients can be found to be allergic from their medical history, with previous allergy to a variety of substances; and the clinical manifestations after insulin injection need to be collected and analyzed in detail to understand the emergence of symptoms and signs, the trend of development and the relationship between the time of insulin injection, etc.
2. Skin test: Commonly used skin tests are divided into two types: intradermal test and prick test. Although puncture test is mostly used in the Department of Allergic reactions, the training of special puncture needles and puncture techniques is required, so the intradermal test is mostly used in general wards. At present, when there are many types of insulin preparations, the skin test is not only helpful for diagnosis, but also beneficial for the selection of insulin preparations for desensitization therapy. In addition, foreign literature reports that the additive components of various insulin preparations can be used for skin test to help diagnosis, but there are no corresponding mature samples available for clinical use in China.
3.Specific IgE determination: If available, the level of insulin-specific IgE in serum and the level of fisetin-specific IgE can be determined to help diagnosis. If you are allergic to the additives in insulin preparations, the above specific IgE – in general – is negative. Higher total serum IgE is not very helpful for diagnosis.
4. Post-discontinuation reaction: It is very important to observe whether the clinical symptoms and signs of the patient subside after stopping insulin injection. Of course, if there is a history of symptoms appearing after injection, disappearing after discontinuation and the same symptoms and signs appearing again with insulin will be more significant for diagnosis, but patients with systemic manifestations especially with the possibility of anaphylaxis need to be very cautious when injecting insulin again.
In addition to insulin allergy, another common problem is how to exclude the diagnosis of insulin allergy in clinical work. In China, a small percentage of diabetic patients have strong resistance to insulin therapy, and after being forced to receive insulin therapy, they have some physical symptoms due to psychological unacceptability and often describe themselves as “allergic”. In addition, some patients may happen to be allergic to other substances (such as pollen) at the time of insulin treatment.
These conditions usually have the following characteristics.
(1) Symptoms are significantly worse than the signs, or there are no signs at all.
(2) There is no local reaction at the injection site, but there are systemic symptoms.
(3) The relationship between the appearance of symptoms and the time of insulin injection is not clear.
The management of such patients can generally be judged by testing the relevant insulin-specific IgE level and combining it with clinical manifestations, and in most cases an adequate explanation is sufficient. However, some patients are still convinced that they are allergic to insulin, in which case the following tests can be performed if necessary.
(1) Configure several different concentrations of insulin solutions (diluted with the original solution plus saline), prepare saline in addition and number them.
(2) Under the condition of double-blinded injector and patient, subcutaneous injection of the configured solution to the patient and observation and recording of the patient’s discomfort.
(3) At the end of the test, the numbered person can “unblind” the patient and analyze the relationship between the clinical performance of the patient and the concentration of the injected insulin.
It should be noted that if the patient complains of extremely severe clinical manifestations, this test is not appropriate for identification. In addition, since the complaints of most of these patients are usually similar to type I allergic reactions, i.e., symptoms appear soon after insulin injection, the test is usually completed within 1 d to exclude the diagnosis of insulin allergy; however, if the patient’s symptoms are similar to delayed allergic reactions, careful observation and treatment are still required.
If the patient complains of life-threatening symptoms such as respiratory distress or has indeed experienced anaphylaxis, a very low concentration of insulin solution should be configured for patch test first, and if no reaction occurs, the concentration of insulin solution should be gradually increased until the original insulin solution is applied for patch test. If there is still no corresponding clinical manifestation, the above steps can only be attempted.
Response to insulin allergy
After insulin allergy is diagnosed, if the patient’s condition allows treatment with oral hypoglycemic agents, it is preferred to switch to oral hypoglycemic agents in accordance with the principle of avoiding contact with allergens. However, in most cases, it is unavoidable for patients to be treated with insulin, so for patients who cannot tolerate the symptoms of insulin allergy, the following treatment must be considered.
First-line treatment
The first-line treatment is still desensitization therapy. The indications for desensitization therapy are for patients who must use insulin and cannot tolerate the symptoms of insulin allergy.
Conventional desensitization therapy generally uses dilution to 10-4 to 10-6 of the original insulin solution as the starting dose, followed by subcutaneous injection at gradually increasing concentrations every 15 to 30 minutes. For the convenience of clinical operation, it is generally administered in 2, 5, and 10-fold sequential increments, with 3 concentrations tested at each order of magnitude. If the patient responds, the dose is returned to the first or second level and the interval between injections is increased; the dose increase is then reduced to facilitate successful desensitization.
Second-line therapy
Several more new drugs for diabetes treatment are currently available, including glucagon-like peptide (GLP-1) analogs, which have a strong hypoglycemic effect. If a patient needs insulin therapy only because of poor glycemic control, this class of drugs, exenatide or liraglutide, can be tried in combination with oral hypoglycemic agents (dipeptidyl peptidase IV inhibitors can also be tried). However, these drugs are relatively more expensive to treat.
Anti-IgE antibody therapy, which is theoretically effective for all type I reactions, including insulin allergy. It has been reported internationally, but this therapy requires sequential treatment with rituximab and omalizumab, which is extremely expensive and difficult to be widely used in the short term.
Third-line therapy
Islet cell transplantation or pancreas transplantation may be the last resort when all treatments fail and the patient is at high risk of developing acute complications of diabetes. It is generally only considered in patients with type 1 diabetes combined with insulin hypersensitivity, and only in cases where desensitization therapy is completely ineffective and ketoacidosis is recurrent.
Advances in desensitization therapy
The introduction of various insulin analogues has greatly increased the choice of insulin preparations for desensitization therapy. Since the main cause of insulin allergy is the conformational change of its tertiary structure in highly concentrated preparations, insulin analogs may be beneficial for insulin desensitization therapy precisely because of the difference in the type or order of amino acids that may have some change in insulin conformation. The special case is that no allergic manifestation occurs after changing to insulin analogues, and in this case desensitization therapy is not required; however, even if the preparation is negative in skin test, the clinical practice usually does not take the risk to use the therapeutic dose directly, but usually starts from a very small dose with reference to the program of desensitization therapy, and the dose can be increased more rapidly until the clinical therapeutic dose under close observation (conceptually this case is not (this is not conceptually desensitization therapy).
Ultra-short-acting insulin analogues
The emergence of ultra-short-acting insulin analogues is due to the formation of hexamers in highly concentrated preparations of human insulin, which require a period of time to be fully absorbed into the blood after being injected subcutaneously to exert glucose-lowering effects. Therefore, the clinical use of short-acting human insulin preparations must be injected 15-30 min before meals, which causes great inconvenience. To solve this problem, ultra-short-acting human insulin analogues have been developed, such as lysine insulin, which changes the order of proline at position 28 and lysine at position 29 of the B chain of human insulin; and menthol insulin, which changes the 28th position of the B chain to menthol, so that the hexamer is not easily formed, thus making the time of subcutaneous absorption of insulin preparations shorter. The change in conformation of insulin analogs may make highly concentrated insulins less immunogenic, increasing the likelihood of successful desensitization therapy. Since the introduction of lysergic insulin in 1996, a large number of cases of successful treatment of insulin allergy using fast-acting insulin analogs have been reported, and our hospital has had several cases of successful treatment since 2004.
Super-long-acting insulin analogues
The ideal mode of insulin replacement therapy is close to the physiological state basal-mealtime mode, and ultra-short-acting insulin analogues can more ideally mimic the situation of mealtime insulin. For the requirement of simulating basal insulin (i.e. insulin required by human physiology in the absence of energy intake), ultra-long-acting insulin analogues have also been successfully addressed by modifying the primary structure of insulin. Currently, glargine insulin and detergent insulin have entered clinical application, and in clinical trials is degludec insulin. Since these preparations achieve their effects by modifying the tertiary structure of insulin, their immunogenicity is likely to be altered and they can naturally be used for desensitization treatment. successful treatment of insulin-allergic patients with glargine insulin has been reported since 2000 and has also been reported in our hospital. At present, with a variety of insulin preparations available, the principle of desensitization therapy is to select the one with the mildest local reaction for desensitization therapy based on skin tests with a variety of insulin and insulin analogue preparations.
Another progress in desensitization therapy is the continuous improvement of insulin pumps, and continuous subcutaneous insulin infusion (CSII) technology has become a more convenient method of desensitization therapy. The invention of the insulin pump was based on the fact that the insulin injection mode is difficult to achieve close to the physiological mode, and the form of subcutaneous pumping is used to simulate human insulin secretion. In this way, the pump speed is adjusted to achieve the purpose of simulating human insulin secretion pattern as much as possible, which is crucial for the treatment of type 1 diabetes patients with large blood glucose fluctuations.
Through years of technical improvement, insulin pumps have evolved into portable multifunctional small instruments whose fine adjustment of insulin pump speed makes them apt for an improved form of desensitization therapy. The insulin pump achieves the effect of accurate micro-release of insulin by adjusting the pump speed, so gradually increasing the pump speed is equivalent to gradually increasing the dose of insulin injected, achieving the same effect as the traditional multiple subcutaneous injections of desensitization and more accurate. The successful use of CSII technology for desensitization treatment was reported as early as 1988, and our hospital has also experienced many successful cases.
According to our experience, the routine sequential procedure is.
1.Pump insulin at 0.01IU/h (insulin diluted to 1% of the original solution with saline) as the starting basal rate, and increase the pumping rate by 0.01U every th. i.e., the pumping rate of insulin increases from 0.01IU/h to 0.24IU/h on the first day.
2.On the 2nd day, the pumping insulin rate was increased from 0.25IU/h to more than 1IU/h with 10 times diluted insulin solution.
3.On the 3rd day, the original insulin preparation is pumped, and the basal rate can be set to 1IU/h during the day and 0.5IU/h during the night; under close observation, the temporary basal rate function of the insulin pump (i.e. the function of pumping insulin at a fixed pumping rate for a certain period of time in advance) is used to continue to gradually increase the dose and observe the patient’s response.
4.Enable the pre-meal high-dose pumping function of the insulin pump after the 4th day and observe the patient’s response.
5.If the patient’s condition is stable, consider trying to change to subcutaneous insulin injection mode.
Attention should be paid to avoid the occurrence of hypoglycemia during the above treatment.
In conclusion, desensitization treatment with CSII technology is simple and easy, and less painful for patients. In foreign countries, insulin pump treatment is usually continued after successful desensitization, but in China, due to economic factors, most patients require multiple insulin subcutaneous injections for treatment. In conclusion, the diagnosis and treatment of insulin allergy is a very difficult problem in clinical practice. However, through detailed clinical observation, targeted skin tests and specific IgE testing, it is generally possible to make a correct diagnosis of insulin allergic patients. According to the different results of the patient’s skin test, the appropriate insulin preparation is selected for desensitization therapy, using the CSII technique if necessary. Second-line treatment options need to be considered for patients who cannot be successfully treated with desensitization.