Drug eruption caused by azathioprine: value of using the drug-induced lymphocytes stimulation test for diagnosis

Azathioprine (AZA) is an immunosuppressant commonly used for organ transplantation and autoimmune diseases. Allergic side effects of AZA are rare, and reported allergic skin eruptions from AZA are very limited in Japan. We report AZA-induced drug eruption that developed in two cases of systemic scleroderma with polymyositis. One case presented with Stevens-Johnson syndrome, and the other had systemic papular erythema. The stimulation indices of the drug-induced lymphocyte stimulation test (DLST) for AZA in these two patients were as high as 2,180% and 430%, respectively, but those of healthy volunteers were under 120% without nonspecific suppression of lymphocyte proliferation. Other drugs used simultaneously were ruled out by patch and challenge tests. The challenge test for Stevens-Johnson syndrome type drug allergy is very risky. DLST is a good diagnostic tool for AZA allergy, especially for severe drug allergy cases.     

Stevensjohnson Syndrome Caused by a Health Drink (Eberu®) Containing Ophiopogonis Tuber

Stevens-Johnson syndrome is considered to be a severe type of erythema exsudativum multiforme. It is characterized by erythema with bullous and eroded lesions of skin and mucous membranes. We report a case of Stevenjohnson syndrome following consumption of a health drink containing ophiopogonis tuber. A 66-year-old female took an O.T.C. health drink for fever. The next morning, she noted erythema and swelling of her face, neck, and chest. She started to develop bullous and eroded lesions on the skin of her entire body and the mucous membranes of her oral cavity, conjunctiva, and cornea, and she became feverish. She had high degrees of corneal erosion and liver dysfunction. Skin biopsy showed diffuse necrosis of the epidermis. After admission to the hospital, steroid pulse therapy (1000 mg/day of methylprednisolone sodium succinate) was continued for 5 days. The health drink induced a positive drug lymphocyte stimulation test (DLST) and patch test. A challenge test was done with a one hundredth dose, and it was positive. We did patch tests with all components of the drink and found that Mai-Meu-Dong-Tang (ophiopogonis) alone was positive at 72 hours. There is no previous report of Stevens-Johnson syndrome caused by a health drink or Mai-Meu-Dong-Tang. Even though it is a health drink, we should be aware of the possibility of a severe reaction.     

Photosensitivity with sulfasalazopyridine hypersensitivity syndrome.

Five weeks after the start of treatment with an association of sulfasalazopyridine and piroxicam, a 30-year-old woman presented with an eczematous eruption in light-exposed areas, hepatomegaly and fever (38 degrees C). Laboratory studies showed leukocytosis, eosinophilia and hepatic cytolysis. Treatment consisted of withdrawing the two drugs and topical steroids. The clinical signs regressed in 6 days. An increase in eosinophilia and hepatic cytolysis was observed until the tenth day, after which the trend reversed. Laboratory parameters were normal on the twentieth day. One month later, photopatch testing was performed. A patch test with sulfanilamide irradiated with UVA was positive. Clinical and laboratory findings were highly suggestive of drug hypersensitivity syndrome. The positive result from the UVA photopatch test with sulfanilamide suggests that sulfasalazopyridine was involved in the occurrence of hypersensitivity syndrome in our patient. We conclude that photodistributed eruptions can be observed in drug hypersensitivity syndrome with photosensitizing drugs.     

Drug eruption caused by ranitidine hydrochloride (Zantac) which showed a strong reaction in a drug-induced lymphocyte stimulation test

An 80-year-old male who developed a generalized papular erythema-type drug eruption after being treated with ranitidine hydrochloride is herein reported. The duration from the intake of the medicine to the onset of the eruption was 3 days, and the eruption remained unchanged for a week after withdrawal of the medicine and even after the eruption itself was treated. A diagnosis of drug eruption by ranitidine hydrochloride was confirmed based on a strongly-positive reaction of a drug-induced lymphocyte stimulation test (DLST).     

Tegafur/gimeracil/oteracil (TS-1) induced Stevens–Johnson syndrome: Case report

TS-1 is an oral fluoropyrimidine anticancer drug that contains tegafur, gimeracil, and oteracil. A 78-year-old Japanese male who was diagnosed with carcinoma of the oral floor (rT4aN0M0) was prescribed a standard dose of TS-1 (80 mg/day). On Day 8 after administration of TS-1, an eruption developed. There was erythema, along with vesicles and erosions involving the lip, face, neck, trunk, limbs, and genitals. The drug-induced lymphocyte stimulation test (DLST) for TS-1 was negative on the 23^rd day, but positive on the 43^rd day (20 days after discontinuing prednisolone). The condition was diagnosed as Stevens–Johnson syndrome due to TS-1 because of the clinical course and laboratory results. This case and 24 cases previously reported in the literature were analyzed. The types of drug eruption were drug-related lupus (9 cases), acral erythema (7 cases), scleroderma-like skin lesion (2 cases), Stevens–Johnson syndrome (2 cases), lichenoid eruption (1 case), purpura (1 case), lichen planus (1 case), erythema multiforme (1 case), hypopigmentation (1 case) and toxic epidermal necrolysis (1 case), respectively. In view of the increasing usage of TS-1 in several common cancers, clinicians should be aware of drug eruptions due to TS-1.     

Fixed eruption due to quinine: report of two cases

Fixed eruption is a characteristic condition with recurrent an erythematous macule in the same location. Because fixed eruption is caused by medical drugs in the majority of cases, it is not so difficult to identify suspicious material by interview. However, it may be difficult in cases in which food additives are responsible. We report two rare cases of fixed eruption due to quinine contained in tonic water. In case 1, a 37-year-old man had repeated erythema on the same sites after drinking a variety of cocktails. We suspected tonic water as the causative material. Oral challenge test of tonic water was positive and patch test with quinine sulfate was positive also. In case 2, a 24-year-old woman in had noticed that her eruption appeared after drinking liquor, especially cocktails as in case 1. She was also positive upon an oral challenge test of tonic water and in a patch test of quinine sulfate.     

Pustular Drug Eruption Due to Bacampicilin Hydrochloride in a Patient with Psoriasis

We report a case of pustular drug eruption due to bacampicilin hydrochloride which developed in a patient with pustular psoriasis. The patient was a 45-year-old Japanese woman with psoriasis which started as pustular psoriasis twenty years previously. In 1994, she developed generalized erythema with pustules accompanied by high fever and liver injury. Clinical and histological findings of this pustular eruption were different from her previous episodes of pustular psoriasis. Erythemas and pustules disappeared and her abnormal transaminase returned to normal rapidly when she discontinued bacampicilin hydrochloride. Her positive reaction to a patch test and a lymphocyte stimulation test also suggested that our case had a pustular drug eruption rather than pustular psoriasis induced by a drug.     

Macrophage migration inhibition factor (MIF) in drug eruption

A controlled study was conducted to evaluate the macrophage migration inhibition factor test as a diagnostic aid in 50 patients with drug eruption. Two groups of patients served as controls: group A, 110 patients being treated with drugs without known cutaneous adverse reactions, and group B, 15 patients suffering from dermatologic disorders unrelated to drugs being taken. Positive macrophage migration inhibition factor responses were found toward a variety of drugs in 35 (70%) of the patients with drug eruptions, with no relation to the type of eruption or the duration of drug intake. The percentage of positive macrophage migration inhibition factor responses toward drugs in the patients with drug eruptions was higher than that in the two control groups (4.5% and 6.7%, respectively). The percentage of positive macrophage migration inhibition factor responses recorded for clinically "suspected" drugs was significantly higher than that recorded for the "nonsuspected" drugs.     

63例重症药疹住院患者发热及肝损伤特征分析

【摘要】 目的 了解重症药疹住院患者的发热及药物性肝损伤（DILI）的特点。方法 回顾分析滨州医学院附属医院2007年6月至2020年6月收住院治疗的63例重症药疹患者的发热及DILI情况。计量资料组间比较采用两独立样本t检验或Kruskal-Wallis H检验；计数资料组间比较采用χ2检验或Fisher精确检验。结果 63例重症药疹患者中，54例出现发热，低、中、高热/超高热者各占约1/3，16例高热/超高热者（16/17）发生于Stevens-Johnson综合征（SJS）、中毒性表皮坏死松解症（TEN）和药物超敏反应综合征（DHS）。45例热型为不规则热；51例热程1 ~ 14 d；不同临床类型药疹患者间热度及热程差异均无统计学意义（P分别为0.303、0.719）；92.59%的患者皮疹早于发热或与发热同时出现。11例患者出现DILI，入院时肝细胞损伤型8例，其中DHS 5例、SJS 2例、TEN 1例；6例伴有发热，低、中、高热均可见，热程（7.33 ± 4.97） d，均为1级肝损伤；出院时复查肝功能5例痊愈，1例好转，1例演变为混合型，1例自动出院未复查肝功能。另3例DILI为胆汁淤积型，均为DHS患者，皆伴有高热或超高热，热程（8.33 ± 3.51） d，其中1例为4级肝损伤（急性肝衰竭）；出院时肝功能均好转。结论 重症药疹热型多样，不规则热多见，热程多 ≤ 2周；皮疹常早于发热或与其同时出现。DILI多合并发热，以肝细胞损伤型更为多见，恢复较快，而胆汁淤积型临床症状重，病程长，好发于DHS。     

Hydralazine-Induced Fixed Drug Eruption

A 62-year-old man had known hypertension for the past 6 years and had been under medical supervision for its control. Three years ago, his therapeutic regimen had included dihydralazine sulfate for the control of hypertension. He had responded favorably for the initial 3 months. Subsequently, he noticed an erythematous eruption confined to the nose and upper lip. It was preceded and accompanied by the burning sensation. The attending physician took cognizance of this episode and henceforth stopped dihydralazine sulfate. In a couple of weeks, symptoms and signs subsided, leaving behind pigmentation. The patient did not consume this particular drug for a couple of years. Two days prior to reporting to us, he had once again taken the same drug and had a flare-up precisely confined to the earlier site.
Examination of skin surface revealed a bluish-black, edematous, irregular macule surrounded by an erythematous halo. It was confined to the bridge of the nose, extending to involve the right ala nasi, nasolabial fold, and adjoining part of the upper lip.
Before embarking on a provocation test, a detailed drug history was elicited again. It was revealed that the patient had been taking propranolol and diazepam regularly. Dihydralazine sulfate was taken only as a complement to the regular treatment without any instruction from the attending physician, who was surprised this time by the exacerbation of the lesion. This prompted us to identify dihydralazine sulfate as the offending drug. Accordingly, the provocation with this drug was initiated with 12.5 mg orally, and the dose was increased to 37.5 mg on the third day. With the latter dose, 2 hours after the administration of drug, the patient experienced burning, erythema, and edema in the lesion, and an erythematous halo appeared around the lesion, corresponding to the previous site. The other drugs did not evoke any positive response.     

The role of macrophage migration inhibition factor in toxic epidermal necrolysis

Patient A A 60-year-old man developed toxic epidermal necrolysis (TEN) following several weeks of treatment with two kinds of drug: co-trimoxazole and acetazolamide. On the basis of time relationship data, both drugs could be considered as the inducers of the cutaneous reaction.¹ Guide fables indicated that co-trimoxazole is one of the most common inducers of TEN, whereas acetazolamide has been reported as a possible uncommon inducer of TEN.^1–3 Drug intake was stopped, and treatment with prednisone (120 mg/day) was instituted, followed by a gradual tapering of the dosage. A month later, complete remission of the skin lesions was observed. A macrophage migration inhibition factor (MIF) test was performed towards the drugs taken, in an attempt to identify the offending drug. The macrophage migration inhibition factor (MIF) test was positive towards co-trimoxazole and negative for acetazolamide. Positive MIF responses towards co-trimoxazole were not recorded in ten control patients (control I) treated with the drug with no manifestations of drug eruption. Patient B TEN was diagnosed in an 84-year-old man treated prior to the appearance of the eruption with two kinds of drug: furosemide, which had been taken for several weeks, and nitrofurantoin, which had been taken for 3 months. On the basis of time relationship data, furosemide was suspected to be the offending drug; however, guide tables indicated nitrofurantoin as a possible inducer of TEN,³ whereas the role of furosemide (a sulfa drug) as an inducer of TEN has not yet been reported. Drug intake was stopped, and following supportive treatment, without the addition of corticosteroids, the skin lesions disappeared 3 weeks later. A MIF test was performed towards furosemide and nitrofurantoin. The MIF test was positive towards furosemide and negative for nitrofurantoin. Positive MIF responses towards furosemide were not recorded in seven control patients (control II) treated with the drug with no manifestations of drug eruption. The MIF test technique The MIF test was performed according to the modified method of Livni et al.⁴ A migration index of 0.80 or less at one or more of the drug concentrations was considered to be a positive MIF test. Statistical analysis Statistical analysis of MIF test results in TEN patients and controls was performed using Fisher's exact test (F.E.T.). The occurrence of positive MIF responses towards drugs recorded in TEN patients (2/4) was significantly higher (P<0.05) than that recorded in the controls (0/17). The MIF test results in TEN patients and controls are summarized in Table 1.     

Co-sensitization to drugs belonging to different chemical classes during the same episode of cutaneous adverse drug reaction: two cases

BACKGROUND: For the first time, 2 cases highlight the fact that, in the event of cutaneous adverse drug reactions under treatment associating 2 drugs, a positive test with one of the 2 does not authorize further readministration of the remaining drug without hospital surveillance. PATIENTS AND METHODS: A man had urticaria during treatment with pristinamycin subsequently replaced by ceftriaxon. All the patch-tests with synergistins were positive, whereas patch-tests, prick-tests and intradermal tests with betalactams were negative. The oral challenge with ceftriaxon was positive. A woman taking spiramycin developed a maculopapular rash which was slowly regressive despite substitution with cefixim and corticotherapy. Patch-tests, prick-tests and intradermal tests with macrolides and betalactams were negative. An oral challenge with spiramycin was positive. DISCUSSION: Sensitization to two antibiotics without shared chemical structures can occur during the same episode of a cutaneous adverse drug reaction, even without prior indication of sensitization to these drug classes. The mechanisms at play in this phenomenon are still debated, but this highlights the fact that reintroduction of any drug suspected at the time of a cutaneous adverse drug reaction must be performed under hospital surveillance, whatever the degree of imputability and even if skin tests with other drugs taken simultaneously were positive.     

The predominant drug-specific T-cell population may switch from cytotoxic T cells to regulatory T cells during the course of anticonvulsant-induced hypersensitivity

Background

Delayed hypersensitivity is responsible for severe cutaneous adverse drug reactions (cADRs), especially in Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome (DIHS) (also known as drug rash with eosinophilia and systemic symptoms [DRESS] syndrome). The drug-induced lymphocyte stimulation test (DLST), or lymphocyte transformation test (LTT), is used to identify the culprit drug in severe cADR cases.

Objective

The aim of this study was to examine the immune reactions in cADR patients through the identification of the drug-specific proliferating cells by flow cytometric DLST (FCM-DLST).

Methods

The peripheral blood mononuclear cells of 16 anticonvulsant-induced cADR patients were investigated by conventional DLST and a FCM-DLST protocol in which CFSE dilution and BrdU incorporation were combined. FCM-DLST allowed for the identification of the drug-specific proliferating cells in six cases. Three of these cases were DIHS cases, whereas there was one case of SJS, one case of maculopapular rash (MP), and one case of erythema multiforme (EM) among the six cases.

Results

In FCM-DLST, drug-specific proliferating T cells were detected as CFSE^low BrdU^high cells. These cells corresponded to the cells incorporating ³H-thymidine in conventional DLST. Although CD4⁺ T-cell proliferation dominated the observed proliferation in most of the cases (in the recovery stage of the three DIHS cases, the MP case, and the EM case), drug-specific CD8⁺ cytotoxic T lymphocytes (CTLs) were detected, especially in the acute stages of the SJS case and one of the DIHS cases. There was a dramatic switch in the predominant drug-specific proliferating T-cell population in the course of one of the cases of DIHS in which CD8⁺ CTLs were predominant initially, whereas CD4⁺ T cells were predominant later. Moreover, drug-specific CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells (Tregs) proliferated during the recovery stage in one DIHS case.

Conclusions

FCM-DLST revealed that the cell proliferation detected by conventional DLST is a heterogeneous proliferation of both CD8⁺ CTLs and CD4⁺ T cells that likely includes Tregs. However, the number of cADR cases in this study was limited, which limits the conclusions that can be drawn from it.     

The usefulness of skin tests to prove drug hypersensitivity

BACKGROUND: Suspected drug hypersensitivity is common. Only a minority of cutaneous adverse drug reactions (CADRs) are allergic in origin and will reappear after the next exposure. Methods to confirm suspected CADRs are needed and skin testing could serve as one possibility. OBJECTIVES: To analyse the usefulness of skin tests in revealing drug allergy. The relevance of skin test results was evaluated with drug provocation studies. METHODS: During 1989-2001, 947 patients with a history of suspected CADR were examined with skin tests including patch tests (PTs) (826 patients), skin prick tests (SPTs) (935 patients) and photopatch tests (12 patients). The occurrence of positive and negative test reactions to different drugs was correlated with clinical history. Drug provocation was carried out in 246 patients. RESULTS: Antimicrobial drugs were suspected and tested most often. A positive PT reaction to one or more drug was seen in 89 of 826 (10.8%), most often to beta-lactams, clindamycin and trimethoprim. A positive SPT reaction was seen in 10 of 935 (1.1%) patients. Challenge was carried out in 17 patients with positive skin test results. Thirteen of 16 (81.2%) PT positives developed exanthema, three remained negative and one SPT-positive patient developed urticaria. Among skin test negatives, 207 of 229 (90.4%) challenges were negative and 22 of 229 (9.6%) were positive, 12 with exanthema, three with fixed drug eruptions and seven with urticaria. CONCLUSIONS: Skin testing, especially the PT, was a useful screening method to find a cause of CADR if the reaction was exanthema and if antimicrobial, cardiovascular or antiepileptic drugs were suspected. The SPT detected occasional positives with antimicrobials. In cases of fixed drug eruption, PTs performed at the earlier reaction site were useful. When skin tests are negative or dubious, oral challenge should be carried out to confirm the association.     

Anticonvulsant hypersensitivity syndrome

Anticonvulsant hypersensitivity syndrome is an acute, life-threatening, idiosyncratic drug reaction seen with the aromatic antiepileptic drugs, phenytoin, carbamazepine, phenobarbital, and primidone, with frequent cross sensitivity. It usually occurs 2-8 weeks after initiation of therapy and the hallmark clinical features are fever, rash, and lymphadenopathy. Hematologic abnormalities such as eosinophilia, atypical lymphocytes, and internal organ involvement also occur with varying severity. A case of hypersensitivity syndrome due to carbamazepine with cross sensitivity to phenytoin is reported. It is emphasized that this serious drug reaction with diverse clinical presentations should be recognized and treated promptly.     

Relevance of skin tests with drugs in investigating cutaneous adverse drug reactions

Skin tests with drugs can be of value in investigating patients who have developed cutaneous adverse drug reactions (CADR), but their specificity and relevance remain to be determined. A false-positive result on skin testing can happen if it is not compared to results in control subjects. When performing intradermal tests (IDT), we have determined the lowest concentrations that induce false-positive results for many drugs, including betalactam antibiotics, cephalosporins, other antibiotics or non-steroidal anti-inflammatory drugs. Some drugs in their commercialized form contain sodium lauryl sulfate and can induce irritation when patch tested as such. When patch tested with colchicine at 10% in pet. or with a Cytotec pill (containing misoprostol) at 30% in pet., respectively, 80% of the 29 and 9 of the 10 negative controls developed false-positive results. Lastly, positive results of patch tests with drugs can be related to contact allergy to one of the components of the commercialized form of the drug, without any relevance to the investigation of a CADR, as observed in 2 cases with iodine or avocado oil.     

Oral challenge in patients with suspected cutaneous adverse drug reactions: findings in 784 patients during a 25-year-period

The aim of this study was to analyse the usefulness of oral challenge test with different drugs in confirming cutaneous adverse drug reactions in routine clinical practice. During the years 1975-2000 a total of 1,001 challenges were carried out in 784 patients. Patients with serious drug reactions were excluded and those with positive skin test reactions were challenged only in dubious cases. Of 1,001 challenges, 136 (13%) patients developed a positive challenge reaction. Antimicrobial drugs were most commonly suspected, accounting for 67% of challenges and 66% of the positive reactions. Exanthema was the most common skin reaction (72%), followed by fixed drug eruption (16%) and urticaria (12%). One serious challenge reaction with salazosulfapyridine was seen. We conclude that the challenge test is most useful as a tolerance test or to exclude drug hypersensitivity. It may be useful to complete studies of adverse drug reactions in patients with a history of exanthema, if other diagnostic methods are not available or if other diagnostic tests yield negative results. Out-patient protocol can be used in most cases.     

A Case of Drug Eruption Caused by the Crude Drug Boi® (Sinomenium Stem/Sinomeni Caulis et Rhizoma)

We report a case of drug eruption caused by the crude drug Boi®. A 41-year-old female patient had been diagnosed with chronic rheumatoid arthritis in the department of internal medicine. After ingestion of a decoction of the crude drug Boi® for the alleviation of arthralgia, a slight fever developed, which was followed by systemic edematous erythema with itching. HPLC showed that the main components of the crude drug Boi® are sinomenine and magnoflorine. The results of patch tests were negative for all oral drugs that the patient had been taking. Oral ingestion tests showed that the patient showed positive reactions to the as-is Boi® boiling-water decoction and 1/10-volume sinomenine. Based on this, the drug eruption was judged to be caused by sinomenine. It is considered the first time that the causative component of a drug eruption was confirmed by oral ingestion tests with components of a crude drug of Kampo medicine (Sino-Japanese traditional medicine).     

Minoxidil sulfate is the active metabolite that stimulates hair follicles

An important step in understanding minoxidil's mechanism of action on hair follicles was to determine the drug's active form. We used organ-cultured vibrissa follicles to test whether it is minoxidil or its sulfated metabolite, minoxidil sulfate, that stimulates hair growth. Follicles from neonatal mice were cultured with or without drugs and effects were assessed by measuring incorporation of radiolabeled cysteine in hair shafts of the treated follicles. Assays of minoxidil sulfotransferase activity indicated that vibrissae follicles metabolize minoxidil to minoxidil sulfate. Dose-response studies showed that minoxidil sulfate is 14 times more potent than minoxidil in stimulating cysteine incorporation in cultured follicles. Three drugs that block production of intrafollicular minoxidil sulfate were tested for their effects on drug-induced hair growth. Diethylcarbamazine proved to be a noncompetitive inhibitor of sulfotransferase and prevented hair growth stimulation by minoxidil but not by minoxidil sulfate. Inhibiting the formation of intracellular PAPS with chlorate also blocked the action of minoxidil but not of minoxidil sulfate. Acetaminophen, a potent sulfate scavenger blocked cysteine incorporation by minoxidil. It also blocked follicular stimulation by minoxidil sulfate apparently by directly removing the sulfate from the drug. Experiments with U-51,607, a potent minoxidil analog that also forms a sulfated metabolite, showed that its activity was inhibited by both chlorate and diethylcarbamazine. These studies show that sulfation is a critical step for hair-growth effects of minoxidil and that it is the sulfated metabolite that directly affects hair follicles.     

Hypersensitivity syndrome due to 2 anticonvulsant drugs

Drug-induced hypersensitivity syndrome is a multiorgan-system reaction characterized by fever, pleomorphic eruption, lymphadenopathy, eosinophilia, lymphocytosis and hepatitis. We report a drug hypersensitivity syndrome in a 6-year-old Tunisian child treated for epileptic absences with sodium valproate and ethosuximide. Imputability of these 2 drugs is probable because of the chronological and clinical features. Positive rechallenge with ethosuximide confirmed the toxicity of this drug. Sodium valproate was also responsible because patch testing was positive and followed by a generalized eruption. Human herpesvirus 6 (HHV6) antibody titers increased significantly within 15 days. There was a favourable outcome after discontinuation of the drugs and corticosteroid therapy. Our case is interesting because this drug hypersensitivity syndrome occurred with non-aromatic anticonvulsant drugs. It is the 1st case with ethosuximide and the 2nd with sodium valproate. We also observed a reactivation of HHV6 infection that may contribute to the development of this hypersensitivity syndrome.