[Pathogenic Mechanism and Diagnostic Testing for Drug Allergies].

　Three stages of the pathogenic mechanism of drug allergies can be considered: antigen formation, immune reaction and inflammation/disorder reaction. Drugs are thought to form 4 types of antigens: drug only, polymers, drug-carrier conjugates, and metabolite-carrier complexes. Antigens are recognized by B cell receptors and T cell receptors. Helper T cells (Th) are differentiated into four subsets, namely, Th1, Th2, Th17 and regulatory T cells (Treg). Th1 produces interleukin (IL)-2 and interferon (IFN)-γ, and activates macrophages and cytotoxic T cells (Tc). Macrophages induce type IV allergies, and Tc lead to serious type IV allergies. On the other hand, Th2 produces IL-4, IL-5, and IL-6, etc., and activates B cells. B cells produce IgE antibodies, and the IgE antibody affects mast cells and induces type I allergies. Activated eosinophil leads to the chronic state of type I allergy. Diagnostic testing for allergenic drugs is necessary for patients with drug allergies. Because in vivo diagnostic tests for allergenic drugs are associated with a risk and burden to the patient, in vitro allergy tests are recommended to identify allergenic drugs. In allergy tests performed in vitro, cytological tests are more effective than serological tests, and the leukocyte migration test (LMT) presently has the highest efficacy. An LMT-chamber is better than LMT-agarose in terms of usability and sensitivity, and it can detect about 80% of allergenic drugs.

Examination of patients suspected as having hypersensitivity to iodinated contrast media with leukocyte migration test.

In vivo tests may be used for the diagnosis of allergy to iodinated contrast media (ICM); however, the tests do not provide definitive diagnosis and are associated with risks for patients. Diagnoses based on in vitro tests are limited, and there are almost no relevant studies. Herein, the authors examined involvement of allergic reaction from a multilateral standpoint in 39 patients suspected of having ICM allergies using leukocyte migration test (LMT). The positive rate of LMT was 44%. A comparison with the positive rate of LMT in drugs other than ICM (74%) indicated 30% difference, which was significantly low value, suggesting that there is poor involvement of these drugs in the allergic reaction. In LMT positives, 76% of hypersensitivity reactions were skin rash mainly erythema, and 18% was anaphylactic reactions. Cases considered as non-immediate hypersensitivity accounted for about 4 times as many as immediate-type hypersensitivity. In examination of relevancy between a history of drugs or food allergies, the incidence of ICM allergies was 35%. There is a high possibility that these adverse reactions were caused by pseudoallergy to drug. It was suggested that most hypersensitivity reactions were skin rash related to non-immediate hypersensitivity, and approximately 20% of the reaction was immediate anaphylactic reaction. Therefore attention should be paid not only to immediate-type hypersensitivity but also delayed reactions. Moreover, it was considered that patients with past history of drug or food allergies have a high potential for manifestation of the reactions.

Study on patients who underwent suspected diagnosis of allergy to amide-type local anesthetic agents by the leukocyte migration test.

BACKGROUND: There are problems in diagnosis of allergy to amide-type local anesthetic agents (ALAs), because definitive diagnosis is not obtained by in vivo tests, which are used for the diagnosis. Consequently, patients may be exposed to risk. There are few diagnoses based on in vitro tests, and there are almost no relevant studies. METHODS: Authors examined involvement of allergic reaction using the leukocyte migration test (LMT) through multiple standpoints in 43 patients who underwent suspected diagnosis of allergy to ALAs. RESULTS: Rate of LMT-positives was 54%, and especially the positive rate of lidocaine hydrochloride preparations was significantly high. In 15 positives to lidocaine hydrochloride preparations, all cases were indicated as positive in a test with drugs containing antiseptic agent, but only 3 cases were indicated as positive in a test with lidocaine hydrochloride alone. In addition, test with paraben was conducted in 4 cases; 2 cases were confirmed as positive. In relevance of histories of drug or food allergies, development rates of ALAs-allergies were the highest in both allergies, and were 35% and 13%, respectively. CONCLUSIONS: There is a high possibility that these adverse reactions were caused by pseudoallergy to drug. Even by allergic reactions, it was assumed that 80% of them might be caused by antiseptic agents such as paraben. In addition, it was suggested that ALAs, especially lidocaine hydrochloride preparations have high antigenicity (sensitizing property). Furthermore, it was considered that patients with past history of drug or food allergies have a high potential for manifestation of the reactions.

A study of elevated interleukin-8 (CXCL8) and detection of leukocyte migration inhibitory activity in patients allergic to beta-lactam antibiotics.

BACKGROUND: The leukocyte migration test (LMT) is effective in identifying the causative drug in drug allergies. Both leukocyte migration activating activity (LMAA) and leukocyte migration inhibitory activity (LMIA) are involved in the development of drug allergies. However, no cytokines associated with LMIA have been identified to date. Because CXCL8 played an important role in neutrophil infiltration and activation, we performed the LMT and measured CXCL8 levels in patients with hypersensitivity to beta-lactam antibiotics (beta-lactams) and antipyretic analgesics (APAs) and investigated the pathogenic mechanism of hypersensitivity to these drugs. METHODS: The LMT was performed according to an improved version of the agarose plate method and CXCL8 levels in the reacted solution that had been stored as described were measured using a solid-phase sandwich enzyme-linked immunosorbent assay. RESULTS: Migration index (MI) values for the LMT were 77.7 ± 11.7 for patients with hypersensitivity to beta-lactams and 83.6 ± 1.9 for those with hypersensitivity to APAs. The CXCL8 concentrations were significantly higher in patients after beta-lactams administration (175.9 ± 71.2 ng/mL) than those without beta-lactams administration (48.3 ± 34.9 ng/mL). The CXCL8 concentrations were significantly lower in patients after APAs administration (41.7 ± 24.3 ng/mL) than those without APAs administration (63.1 ± 30.2 ng/mL). CONCLUSIONS: Increased CXCL8 levels produced by beta-lactams administration were accompanied by LMIA. CXCL8 may be involved in LMIA and play a role in beta-lactam allergies. In contrast, the LMIA detected in patients with allergies to APAs may be a cytokine or chemokine other than CXCL8.

Comparative study of the usefulness of the drug-induced lymphocyte stimulation test and the leukocyte migration test in drug allergies.

In 133 patients suspected of hypersensitivity to drugs and 102 control patients without hypersensitivity to drugs, the identification of allergenic drugs was performed by the drug-induced lymphocyte stimulation test (DLST) and the leukocyte migration test (LMT) to compare their usefulness in identifying drug allergies. In the 133 subject patients, the positive rate was 24.8% on the DLST and 60.9% on the LMT (agreement rate; 77.4%); thus, the LMT showed a significantly higher positive rate than the DLST (p<0.000001, chi(2)-test). In the 102 control patients, the positive rates on the DLST and LMT were 6.9%. In addition, the LMT showed a higher positive rate than the DLST for many hypersensitivity symptoms such as skin eruptions and hepatic injury, and for many drug efficacy categories of the suspected drugs such as antibacterial drugs, etc. Furthermore, the positive rate of the DLST did not change when adjusted for the patients' serum and sex, while that of the LMT increased when adjusted for the patients' serum and was found to be higher in females than in males. Our findings indicate that the LMT may be more useful than the DLST in identifying the causative drug in drug allergies and that its interpretation is influenced by the patient's serum and sex.

Clinical application of the leukocyte migration test and new diagnostic criteria for identifying causative agents in patients with drug-induced liver injury.

BACKGROUND/AIMS: We examined the usefulness of the leukocyte migration test (LMT) in the identification of agents causing drug-induced liver injury (DILI). METHODOLOGY: In 14 patients who were tentatively diagnosed as having DILI in Kitasato Institute Hospital, pharmacists collected and evaluated drug information and patients' medication histories to identify causative agents. Simultaneously, LMT and drug lymphocyte stimulation test (DLST) were performed. Furthermore, scoring was performed according to the diagnostic criteria established by the International Consensus Meeting (ICM) and the Digestive Disease Week-Japan 2004 (DDW-J). RESULTS: LMT-positive agents showed a higher ICM score compared to DLST-positive agents. The rate of LMT-positive agents was examined with respect to ICM assessment, and 0%, 25%, 33%, and 100% of agents regarded as unrelated/unlikely, possible, probable, and highly probable showed positive reactions on LMT, respectively; the rate of LMT-positive agents increased with the degree of the agent's involvement. When the results of LMT were applied to the DDW-J criteria, there was a correlation with the ICM criteria in comparison to scoring based on the results of DLST. CONCLUSIONS: LMT may be useful for identifying agents causing DILI. Furthermore, the collection and evaluation of drug and patient information and in vitro testing in the identification of causative agents may support more reliable diagnosis.

Liver injury induced by a Japanese herbal medicine, sairei-to (TJ-114, Bupleurum and Hoelen Combination, Chai-Ling-Tang) R1.

The case is reported of a man who showed acute hepatitis with jaundice after he was given a Japanese herbal medicine, sairei-to (TJ-114, Bupleurum and Hoelen Combination, Chai-Ling-Tang). Unusually, the component thought to be responsible for the observed drug-induced liver injury was able to be identified. Lymphocyte migration inhibition testing indicated that the tuber of the perennial herbage Pinellia ternate was the causative agent.