Allopurinol hypersensitivity syndrome with acute generalized exanthematous pustulosis manifestations

Allopurinol hypersensitivity syndrome(AHS) is a severe form of cutaneous adverse reaction that is associated with significant morbidity and mortality. We report a case of AHS with the cutaneous manifestation of acute generalised exanthematous pustulosis(AGEP). A 47 year old gentleman, with no previous skin disease, presented with a generalized mildly pruritic erythematous rash on the trunk and all 4 limbs, with patches of superficial non-follicular pustules. Our patient fulfilled both criteria for AGEP and AHS.     

Acute generalized exanthematous pustulosis caused by terazosin hydrochloride

Acute generalized exanthematous pustulosis (AGEP) is a rare cutaneous eruption mainly provoked by drugs. A case of AGEP in a 74-year-old male that was attributed to the ingestion of terazosin hydrochloride is presented. This is the first reported case of this association in medical literature. The history, clinical presentation, and pathogenesis of AGEP are discussed.     

Acute generalized exanthematous pustulosis with lymphangitis triggered by a spider bite

Acute generalized exanthematous pustulosis (AGEP) is a rare, severe cutaneous reaction pattern that, in the majority (>90%) of cases, is related to administration of medication. It can be seen in both genders and in all ages. The cutaneous manifestations of AGEP are usually seen 1–14 days after drug administration. A 39-year-old woman presented to our outpatient clinic with the complaint of generalized erythema, burning, and rash. She explained that 2 days before presentation a spider bite had occurred on her left forearm, after which she had experienced pain and erythema spreading gradually to the left upper extremity. On her dermatologic examination, she had an indurated necrotic plaque on the left forearm, which had an upward-spreading linear erythema. Additionally, she had diffuse erythema on her body and small pustules over erythematous skin, especially located on the left popliteal fossa and gluteal region. Based on the clinical and histopathologic findings, she was diagnosed as having AGEP. Because there was no drug use in her history, we attributed her AGEP lesions to the spider bite. This case is interesting, because the patient also had lymphangitis. Herein, we present the fifth case reported in the literature of AGEP caused by a spider bite.     

Hydroxychloroquine-induced acute generalized exanthematous pustulosis with positive patch-testing

Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction, mostly induced by drugs. Hydroxychloroquine have been rarely reported in literature as a causative drug of this reaction. We report a case of AGEP induced by hydroxychloroquine with systemic involvement and confirmed by positive patch testing.KEY WORDS: Hydroxychloroquine, patch test, pustulosis     

Acute generalized exanthematous pustulosis induced by piroxicam: A case report

Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous reaction characterized by an acute episode of sterile pustules over erythematous-edematous skin. The main triggering drugs are antibiotics, mainly beta-lactam and macrolides. Non-steroid anti-inflammatory drugs may rarely be responsible. We describe a case of a woman with AGEP, who presented with generalized pustulosis lesions after the use of piroxicam for renal colic. The diagnosis was confirmed by the clinical and histological correlations and the dermatosis resolved after withdrawal of the drug.KEY WORDS: Acute generalized exanthematous pustulosis, adverse drug reactions, piroxicam, pustulosis     

Anticonvulsant hypersensitivity syndrome in children: incidence, prevention and management

Anticonvulsant hypersensitivity syndrome (AHS) is a rare, but potentially fatal, adverse reaction that occurs in patients, including children, who are treated with anticonvulsants. During metabolism of the anticonvulsant, toxic arene-oxide compounds are produced. AHS is associated with both cutaneous and systemic symptoms and is associated with multiorgan involvement. Liver damage, in particular, seems to be associated with fatal outcomes. The pathophysiology of AHS is still uncertain but it may be linked to a genetically determined inability to detoxify reactive drug metabolites. The prompt recognition of the first clinical signs of AHS, and the rapid withdrawal of the anticonvulsant, often avoids the progression of symptoms. Pharmacological treatment is essentially based on systemic corticosteroids in association with enteral nutrition, intravenous fluid augmentation, pain relief and ocular care. Intravenous immunoglobulins may also have a possible therapeutic role in some cases. Diagnostic tests, such as patch tests or in vitro assays, for AHS could help to identify patients at risk of developing the syndrome and could represent a first step of primary prevention when applied to relatives of patients.     

Acute generalized exanthematous pustulosis (AGEP) due to exposure to sulfuric acid and bromic acid vapor: a case report

Acute generalized exanthematous pustulosis (AGEP, toxic pustuloderma, pustular drug eruption) is a not uncommon cutaneous reaction pattern that is usually related to drug administration. The eruption is of sudden onset and appears 7-10 days after the medication is started. A 22-year-old male patient who was a student at a chemical faculty attended our outpatient clinic with a complaint of pustular eruption on his face. According to his history, the eruption started with pruritus and erythema on his chin 3 days ago and spread to his face and chest. He explained that he had performed an experiment with sulfuric acid and bromic acid and was exposed to their vapor. His dermatological examination revealed erythema and pustules on his cheeks, on his chin, above his upper lip, and on his eyebrows. He also had a few pustules on his chest. There were no ocular, mucous membrane, or pulmonary symptoms. Histopathological examination of the skin biopsy specimen revealed superficial orthokeratosis, focal subcorneal pustule formation, and perivascular chronic inflammatory cell infiltration in superficial dermis. After administration of systemic antihistamines and wet dressing topically, we observed rapid healing of the lesions. Because there was no systemic drug intake in his history, we were concerned that exposure to sulfuric acid and bromic acid vapor caused AGEP in this patient. We present this rare case to show that the vapor of chemical materials may cause AGEP or other drug eruptions.     

Generalized pustules in a healthy woman

A healthy 47-year-old woman developed diffuse pustules and edema of the skin after exposure to diltiazem and cephalexin. Bacterial, fungal and viral cultures were sterile suggesting a noninfectious etiology. A skin biopsy showed spongiosis, subcorneal collections of neutrophils, papillary dermal edema and a superficial perivascular mixed cell infiltrate. The clinical and histopathologic findings were consistent with acute generalized exanthematous pustulosis (AGEP). The patient was treated with supportive care and the pustular dermatitis cleared. AGEP is a rare complication of drug therapy and should be considered in the differential diagnosis of patients presenting with acute onset pustular dermatitis. Drug reactions are an uncommon and unpredictable complication of medical therapy. Cutaneous drug reaction rates occur with a frequency of 1% to 8% and can be higher for certain classes of drugs. They can range from mild morbilliform eruptions to more severe forms such as drug-hypersensitivity syndrome, toxic epidermal necrolysis or anaphylaxis. Acute generalized exanthermatous pustulosis (AGEP) is a rare presentation of a drug reaction and can be difficult to distinguish from other pustular dermatoses. Herein we review a case of AGEP and include a discussion of salient clinical and histological features of AGEP.     

Cutaneous allergic drug reactions: update on pathophysiology,diagnostic procedures and differential diagnosic

Important changes in the understanding and management of drug hypersensitivity reactions during the last years result from the increasing importance of biologics in medical practice, which differ in their spectrum of adverse drug reactions (ADRs) from the classical covalent drugs. With regard to covalent drugs, ampicillin and amoxicillin as well as clavulanic acid play an increasing role among ADRs to betalactam antibiotics. Fluoroquinolones are mainly the cause of anaphylactic and photosensitivity reactions. Especially in allergic reactions to NSAIDs, pseudoallergic reactions should be considered in the differential diagnosis. In opposite to the main cutaneous allergic drug reactions such as urticaria or maculopapular skin rash, in which antibiotics are the main culprits, in severe drug allergic reactions such as SJS (Stevens-Johnson Syndrome), TEN (Toxic Epidermal Necrolysis), or DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) Syndrome, compounds like allopurinol and anticonvulsants are the main causes. Similar mutations in the IL36R gene, which were found in both patients with an AGEP (Acute Generalized Exanthematous Pustulosis) and pustular psoriasis, make the differential diagnosis more difficult and raise the question whether there is a difference between these diseases or whether AGEP is not just a drug induced pustular psoriasis. Finally, some special aspects of side effects of biologics and targeted therapies respectively are discussed.     

Clinical heterogeneity of drug hypersensitivity

Skin is the most frequent target of drug reactions that are reported, may be because they are easily detected. Most (probably more than 90%) are related to drug hypersensitivity, i.e. an individually tailored, unexpected effect mediated by a drug specific activation of the immune response. The clinical presentation of "drug eruptions" is highly variable, from the most common transient and benign erythema that occurs 6-9 days after the introduction of a new drug in 1 to 3 % of users to the most severe forms, that fortunately affect less than 1/10,000 users. Even though there are some overlapping or unclassifiable cases, it is important for clinicians to recognize and categorize severe cutaneous adverse reactions/SCAR (bullous fixed drug eruptions/bFDE, acute generalized exanthematous pustulosis/AGEP, drug reaction with eosinophilia and systemic symptoms/DRESS, Stevens-Johnson syndrome/SJS, toxic epidermal necrolysis/TEN). First they must suspect rapidly that an unusual eruption with high fever and severe constitutional symptoms is caused by a medication and not by an infection. Second they have to look for involvement of organs that differ according to the type of reaction. Third they can determine a prognosis, the mortality rate being virtually 0 for bFDE, 5% for AGEP, 10% for "hypersensitivity syndrome"/DRESS and 25% for SJS or TEN. In addition if some medications are "usual suspects" for all types (e.g. anticonvulsants), some other are more specific of a given pattern (pristinamycine, hydroxychloroquine, diltiazem for AGEP, minocycline for DRESS, anti-infectious sulfonamides, allopurinol for epidermal necrolysis). The "phenotypic" diversity of the final expression drug reactions can be explained by the engagement of a variety of cytokines and inflammatory cells and by regulatory mechanisms. For example, memory cytotoxic T-Cells are key effectors in both localized blisters of bFDE and in extensive blisters of epidermal necrolysis.     

Clearance of increased serum advanced glycosylation end products in patients with end stage renal disease by hemodialysis

AIM: To study the effect of removal of hemodialysis using acetate membrane on serum advanced glycosylation end products (AGEP) in 36 patients (59.1 +/- 1.6) with end stage renal disease (ESRD). METHODS: Serum AGEP levels were determined with quantitative fluorescence spectrometry, flow injection analysis (FIA), and competitive enzyme-linked immunosorbent assay (ELISA) using a polyclonal antibody directed against AGEP. RESULTS: The serum AGEP levels in patients with ESRD quantified by fluorescence spectrometry, FIA, and ELISA were higher than those in controls [(25 +/- 5) vs (7.5 +/- 1.5), (6.1 +/- 1.8) vs (1.4 +/- 0.5), and (37 +/- 20) vs (9 +/- 10) kU/L, respectively] and markedly reduced to [(22 +/- 6), (4.2 +/- 1.4), and (19 +/- 14) kU/L, respectively] after hemodialysis. CONCLUSION: Increased serum AGEP levels in the circulation of patients with ESRD were reduced effectively by hemodialysis.     

Acute generalized exanthematous pustulosis induced by iodixanol (Visipaque): a serious reaction to a commonly used drug

Acute generalized exanthematous pustulosis (AGEP) is an acute sterile pustular eruption most commonly induced by medications. Although antibiotics are the most commonly accused drugs in AGEP, non-antibiotic agents may also cause this disease. We present a case of AGEP following use of iodixanol for coronary angiography in a 61-year-old woman. Given the wide use of this substance in cardiology, clinicians should be aware of this potential complication.     

培养的大鼠主动脉平滑肌细胞表达糖基化终产物受体和地尔硫Zh…

目的：探讨培养的主动脉平滑肌细胞（ＡＳＭＣ）上是否表达糖基化终产物（ＡＧＥＰ）高亲性受体和地尔硫Ｚｈｕｏ对ＡＧＥＰ升高胞浆游离钙的抑制。方法：用放射配基结合方法研究ＡＳＭＣ与ＡＧＥＰ的相互作用；用钙离子荧光指示剂Ｆｕｒａ２－ＡＭ测定ＡＳＭＣ胞浆游离钙。结果：ＡＳＭＣ上有ＡＧＥＰ高亲和性受体表达，其解离常数为６５．３±１．５ｍｏｌ·Ｌ＾－１，最大结合容量１．５７±０．０４ｎｍｏｌ／ｇ细胞蛋白；通过该     

糖基化终产物对培养的大鼠主动脉平滑肌细胞增殖及胞浆游离钙含…

目的：研究糖基化终产物（ＡＧＥＰ）对主动脉平滑肌细胞增殖的影响及其与［Ｃａ＾２＋］ｉ的关系。方法：采用同位素掺入法分别测定ＤＮＡ和蛋白质合成；Ｆｕｒａ２－ＡＭ测定［Ｃａ＾２＋］ｉ。结果：ＡＧＥＰ以浓度、时间相关的方式促进［＾３Ｈ］ＴｄＲ与［＾Ｈ］Ｌｅｕ掺入细胞，随ＡＧＥＰ作用时间、糖化时间延长，掺入率增加明显，ＡＧＥＰ增加［Ｃａ＾２＋］ｉ，与时间、浓度相关，但随ＡＧＥＰ作用时间延长（４０分钟后）而     

Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care

Anticonvulsant hypersensitivity syndrome (AHS) is a delayed adverse drug reaction associated with the use of aromatic anticonvulsant drugs. It has been most commonly reported with the use of phenytoin, carbamazepine, and phenobarbital. Although its occurrence is rare, 1 in every 1000-10,000 exposures, AHS is a serious adverse event often resulting in hospitalization and even death. The clinical manifestations of AHS include a triad of symptoms consisting of dermatologic rashes, fever, and evidence of systemic organ involvement. Diagnosis is most frequently based on the recognition of this triad of symptoms and clinical judgment. The exact mechanism of AHS remains to be determined but is thought to have at least three components: deficiency or abnormality of the epoxide hydroxylase enzyme that detoxifies the metabolites of aromatic amine anticonvulsants, associated reactivation of herpes-type viruses, and ethnic predisposition with certain human leukocyte antigen subtypes. Arene oxides, the toxic intermediaries in the metabolism of anticonvulsant drugs, can accumulate and directly bind to macromolecules, causing cell death, as well as act as prohaptens that bind to T cells, initiating an immune response and systemic reactions. Management of AHS primarily includes discontinuation of the associated anticonvulsant drug. Systemic corticosteroids are usually required for full recovery. An important issue regarding AHS is the cross-sensitivity among aromatic anticonvulsant drugs, which has been reported to be 40-80%. This means that patients with a history of AHS should avoid further use of any aromatic anticonvulsant drug. In addition, a familial association with AHS exists, and family members of the patient with AHS should be educated that they may be at increased risk for developing AHS if they use aromatic anticonvulsant drugs. Anticonvulsant drugs that are generally considered safe are valproic acid and benzodiazepines. Other nonaromatic anticonvulsant drugs should also be acceptable. Pharmacists as health care providers can play an important role in the diagnosis, treatment, and prevention of AHS.     

Pathogenesis and clinical approaches to anticonvulsant hypersensitivity syndrome: current state of knowledge

Anticonvulsant hypersensitivity syndrome (AHS) is a rare, but severe and potentially fatal, adverse reaction that occurs in patients who are treated with commonly used older anticonvulsant drugs (phenytoin, carbamazepine and phenobarbital) and/or with some newer agents (lamotrigine). Paediatric patients are at an increased risk for the development of AHS for the higher incidence of seizure disorder in the first decade of life. Hypersensitivity reactions range from simple maculopapular skin eruptions to a severe life-threatening disorder. AHS is typically associated with the development of skin rash, fever and internal organ dysfunctions. Recent evidence suggests that AHS is the result of a chemotoxic and immunologically-mediated injury, characterized by skin and mucosal bioactivation of antiepileptic drugs and by major histocompatibility complex-dependent clonal expansion of T cells. Early recognition of AHS and withdrawal of anticonvulsant therapy are essential for a successful outcome. In vivo and vitro tests can be helpful for the diagnosis that actually depends essentially on clinical recognition.     

Cross Hypersensitivity Syndrome between Phenytoin and Carbamazepine

Objective: To evaluate the incidence of cross anticonvulsant hypersensitivity syndrome (AHS) between phenytoin (PHT) and carbamazepine (CBZ) in hospitalized patients.Method: Retrospective chart review about the cross AHS was retrieved from pharmacy adverse drug reaction program from 1998 to 2002 in a 450-bed teaching hospital.Main outcome measures: AHS was defined as the appearance of at least two symptoms with the first anticonvulsant drug (ACD). Cross AHS was considered if after withdrawal of a first ACD because of hypersensitivity symptoms, a new episode with similar or new symptoms appeared after exposure to a second ACD. The following symptoms were considered– rash, fever, hepatotoxicity, lymphadenopathies or hematological disturbances.Results: Cross AHS between PHT and CBZ was observed in nine cases (45). After the cross-reaction event, four of them were treated with valproic acid, two with vigabatrin, two with phenobarbital and one with no treatment without developing further AHS.Conclusions: AHS is a severe complication of aromatic ACD that can compromise the future choice of therapy. Because of the high incidence of clinical cross-reaction between these two drugs, non-aromatic ACD alternatives, must be considered.     

Anticonvulsant hypersensitivity syndrome: a review

Anticonvulsant hypersensitivity syndrome (AHS), characterised by fever, rash and internal organ involvement, is a rare, but potentially fatal adverse event that occurs most commonly with first-line aromatic anticonvulsants, but can also occur with non-aromatic anticonvulsants such as lamotrigine and valproic acid. AHS can begin anywhere from 1 to 12 weeks after commencement of therapy and has been estimated to occur at a frequency of 1/1000 to 1/ 10,000 exposures. Its true incidence, however, remains unknown due to under-reporting. The disease has protean manifestations mimicking several other conditions, and the diagnosis is thus difficult. Several hypotheses have been put forward to explain the pathogenesis of AHS. These include accumulation of toxic metabolites, graft versus host disease, antibody production and viral infections. The one based on toxic metabolites has found the greatest acceptance, perhaps due to the fact that it can be proven by an in vitro test; the lymphocyte toxicity assay. Discontinuation of the offending agent with supportive, symptomatic therapy forms the mainstay of management of AHS. In addition, counselling of both the patient and first degree relatives for susceptibility to AHS is an important aspect of management. In the last decade, several new anticonvulsants have been introduced for epilepsy. In addition, for resource-poor countries, inexpensive and effective first-line drugs such as phenytoin and phenobarbitone will continue to remain important treatment options. Thus, the problem of AHS will continue, and attempts should be made to further understand the molecular basis of and individual susceptibility to AHS. Adverse event monitoring programs must also actively seek AHS reports to estimate its true incidence.     

Anticonvulsant hypersensitivity syndrome: a review

Anticonvulsant hypersensitivity syndrome (AHS), characterised by fever, rash and internal organ involvement, is a rare, but potentially fatal adverse event that occurs most commonly with first-line aromatic anticonvulsants, but can also occur with non-aromatic anticonvulsants such as lamotrigine and valproic acid. AHS can begin anywhere from 1 to 12 weeks after commencement of therapy and has been estimated to occur at a frequency of 1/1000 to 1/10,000 exposures. Its true incidence, however, remains unknown due to under-reporting. The disease has protean manifestations mimicking several other conditions, and the diagnosis is thus difficult. Several hypotheses have been put forward to explain the pathogenesis of AHS. These include accumulation of toxic metabolites, graft versus host disease, antibody production and viral infections. The one based on toxic metabolites has found the greatest acceptance, perhaps due to the fact that it can be proven by an in vitro test; the lymphocyte toxicity assay. Discontinuation of the offending agent with supportive, symptomatic therapy forms the mainstay of management of AHS. In addition, counselling of both the patient and first degree relatives for susceptibility to AHS is an important aspect of management. In the last decade, several new anticonvulsants have been introduced for epilepsy. In addition, for resource-poor countries, inexpensive and effective first-line drugs such as phenytoin and phenobarbitone will continue to remain important treatment options. Thus, the problem of AHS will continue, and attempts should be made to further understand the molecular basis of and individual susceptibility to AHS. Adverse event monitoring programs must also actively seek AHS reports to estimate its true incidence.     

Possible atypical cross-sensitivity between phenytoin and carbamazepine in the anticonvulsant hypersensitivity syndrome

Anticonvulsant hypersensitivity syndrome (AHS) is a rare but potentially life-threatening reaction that occurs in response to common anticonvulsants in predisposed individuals. It is often characterized by fever, rash, lymphadenopathy, hepatitis, and laboratory abnormalities. Consequently, it often is overlooked or even misdiagnosed by practitioners unfamiliar with AHS. Cross-sensitivity manifests frequently between phenytoin, phenobarbital, and carbamazepine as an exacerbation of presenting signs and symptoms. We report a case of AHS in a patient whose clinical features changed significantly when switching from phenytoin to carbamazepine. Physicians and pharmacists must become aware of the extreme variability in AHS manifestation so that the offending anticonvulsant regimen can be discontinued in a timely manner.