药物超敏反应综合征

学习,汇报者：涂金伟,Drug-induced hypersensitivity syndrome (DIHS),HISTORY,Drug-Induced Hypersensitivity Syndrome (DIHS), was first recognized in 1950 by Chaiken, in a patient using anticonvulsant.Later,SaItzstein described this kind of drug reaction as pseudo lymphomaIn the 1960s with the development of carbamazepine, the disease named antispasmodic syndromein addition to anticonvulsants,diaphenylsulfone(DDS).allopurinol(别嘌醇),salazosulfapyridine(柳氮磺胺吡啶) and dapsone(氨苯砜) can also cause DIHS,Defition,Drug-Induced Hypersensitivity Syndrome (DIHS) is a severe and rare systemic reaction triggered by a drug (usually an antiepileptic drug).accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, causing damage to several systems, especially to the kidneys, heart, lungs, and pancreasis characterized by late onset, infectious mononucleosis-like symptoms, and herpesvirus 6 (HHV-6) reactivation.,Etiopathogenesis,Drug:deficiency or abnormality of the epoxide hydroxylase enzyme(环氧酶羟化酶) that detoxifies the metabolites of aromaticamine anticonvulsants (metabolic pathway)Herpesvirus:associated sequential reactivation of herpesvirus family.(Recently,accumulating evidence suggests that other HHVs, such as HSV, EBV, HHV-7 and CMV might be reactivated during the course of DIHS)Gene:NAT2 and certain human leukocyte antigen (HLA) alleles (immune response),Clinical manifestations,incubation period(2-6weeks)Fever,：often high (38.5-40oC)Rash:Maculopapular rash developing 3 weeks after starting therapy with a limited number of drugs.The cutaneous eruption consists of a morbilliform rash, which is also common in other less severe drug reactions and both presentations are indistinguishable The face, upper trunk and upper extremities are initially affected, with subsequent progression to the lower extremities.Lymphadenopathy (2mm),The maculopapular eruption later becomes infiltrated with edematous follicular accentuat-ion.Swelling of the face, with marked periorbital involvement. Vesicles may arise and fine vesicles by edema of the dermis can be present.No necrosis of the epidermis like TEN occurs,except in rare cases of overlapping DRESS/DIHS andTEN. Small sterile perifollicular pustules and nonfollicular pustules may appear, which are different from acute generalized exanthematous pustulosis,and does not predominate on the main folds of the skin. Over time the rash becomes purplish, sharply lower limbs andthe resolution is scaling. Another form of presentation is a picture of exfoliative dermatitis, which may be associated with mucosal involvement, such as cheilitis, erosions, pharygitis and enanthematous enlarged,Various hematologic abnormalities:Leukocytosis may be high, up until 11,000 leukocytes/mm3, and eosinophilia reaches values higher than 1500/mm3Hepatitis：hepatomegaly.ALT/AST increased.hepatic necrosis Multiorgan involvement:myocarditis/myositis, pericarditis, interstitial nephritis (11% of cases),necrotizing granulomatous vasculitis in kidney, brain involvement (encephalitis or meningitis), colitis and thyroiditis.the mortality rate is about 10% to 20%,mainly died of severe hepatitis ,Myocarditis may develop at the beginning of the syndrome or up to 40 days after installation.Sym-ptoms include heart failure, chest pain, sudden tachycardia, dyspnea, and hypotension in early DRESS/DIHS.Renal involvement occurs in about 11% of cases, being particularly evident in cases arising from the use of allopurinol. There was an increase in serum creatinine and urea and decreased creatinine clearance. In urine I tests, increased content of eosinophils can de observed.Neurological complications include meningitis and ence-phalitis.occurs about 2 to 4 weeks after onset of the drug reactionpulmonary involvement is rarely reported in DRESS/DIHS,Gastrointestinal bleeding may be an abrupt complication c-aused by ulcers caused by CMV Especially in cases related to advanced age, renal impairment, jaundice and hepatitis with reactivation of CMV. In contrast,cases where there is a reactivation of Epstein-Barr virus (EBV) seems to have less a severe course, but are more likely to have later development (usually after several years) of autoimmune diseases such as diabetes mellitus type 1 and autoimmune hypothyroidism,Auxiliary examination,Complete blood count, ALT, AST, total bilirrubin, GGT, alkaline phosphatase, sodium, potassium, creatinine and creatinine clearance, 24h urine protein and urinary eosinophil count, CPK, LDH, ferritin, triglycerides, calcium and PTH, blood glucose,TAP and TTPA, lipase,protein electrophore-sis, creactive protein, quantitative PCR for HHV-6, 7, EBV and CMV, blood culture,anti-nuclear factor。,Diagnostic caiteria,服用苯妥英钠药物史发热：以中高热为主，体温最高可达40.8oC皮疹：颜面部、躯干、四肢可见散在或弥漫分布的红色斑 丘疹，高出皮面，压之不褪色，伴瘙痒，无脱屑及水泡。淋巴结肿大：颈部可扪及数枚直径约2.0-3.0cm的淋巴结 腋下可扪及1-2枚直径约1.5-2.0cm的淋巴结 腹股沟区可扪及1-2直径约1.5-2.0cm的淋巴结,肝炎：肝大：入院时肋下12cm，剑突下11cm 10.15肋下8cm，剑突下8.5cm 肝功：,辅助检查,血常规：血氨、乳酸 EB-PCR:2.22*106血、痰、咽拭子、骨髓培养：阴性心肌标志物、免疫术前全套胸部平片、心脏彩超、胸腹部B超,Score=6,Differential diagnose,SJS(Johnson综合征) TEN(大疱性表皮松解坏死型药疹)SJSTEN is diagnosed by characteristic skin and mucosal manifestations, but not by organ involvement.However,DIHS is diagnosed based on its characteristic clinical course, multiple organ involvement and detection of herpesvirus reactivationThe onset of SJSTEN was within 3 weeks after the start of drug administration in 67% of cases,In contrast, DIHS developed at 26 weeks in 80% of cases, and occurred most frequently at 4-5weeks.,Complication,Hemophagocytic syndrome (HPS):can rarely be obser-ved in the course of DRESS/DIHS. HPS is associated with and triggered by various conditions,including viral infections, particularly EBV, malignant tu-mors, or autoimmune diseases. When in the course of the DRESS/DIHS, HPS usually occurs two weeks after the onset of drug eruption. There is a decrease in white blood cells and platelets that is detected simultaneously with the elevation of lactate dehydrogenase (LDH).Bone marrow aspirate revealed hemophagocytosis figures in an increased number of macrophages.,The incidence of this syndrome is estimated to vary from one case among 1,000 to 10,000the mortality rate is about 10% to 20% a specific therapy may be necessary,Treatment,systemic corticosteroids (dose equal to or greater than 1 to 1.5 mg/kg /day of prednisone or equivalent) with marked improvement of symptoms and laboratory parameters, but several days after the start of treatment. Systemic corticosteroids should have their dose reduced, after the clinical and laboratory control of the disease, slowly over 6-8 weeks in order to prevent a recurrence of the symptoms of the disease. Abrupt deterioration of various symptoms is observed when the withdrawal is accidental or by rapid reduction of the doses of corticosteroids.,TREATMENT,It should be remembered that theimmunosuppressive therapies may increase the risk of infectious complications and sepsis.Physicians should also pay attention to a proper balance between the needs of corticosteroids for relief of symptoms and clinical signs and their possible negative interference on viral load.Attention:Special attention should be given to a possible reactivation of CMV/EBV, especially in patients with severe DRESS/DIHS. the monitoring of liver function tests should be performed and appropriate tests ordered to rule out the involvement of other organs like lungs, thyroid and heart.,High doses of IVIG :have two immunological effects: (i) compensates for the decrease in concentration of immunoglobulins in the patients blood and the defects of the immune protection against HHV-6(ii) high doses of IVIG have an anti-inflammatory effect that can regulate immune responses, as seen in the treatment of autoimmune diseases.,plasma exchange:especially with low immune or severe cases of infection and unfavorable impact of GC therapy and G C ineffective in patients with severe shock therapy, can be in conjunction with IVIG.Once a day Or 3 times in a row,CsA: CsA can in