1、Drug-induced hypersensitivity syndrome(DIHS)2021/3/131HISTORYDrug-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 carbamazepi
2、ne,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 DIHS2021/3/1322021/3/1332021/3/134DefitionDefitionDrug-Induced Hypersensitivity Syndrome(DIHS)is a severe and rare systemic react
3、ion 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,lun
4、gs,and pancreasis characterized by late onset,infectious mononucleosis-like symptoms,and herpesvirus 6(HHV-6)reactivation.2021/3/135EtiopathogenesisEtiopathogenesisDrugDrug:deficiency or abnormality of the epoxide hydroxylase enzyme(环氧酶羟化酶)that detoxifies the metabolites of aromaticamine anticonvuls
5、ants(metabolic pathway)HerpesvirusHerpesvirus: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)GeneGene:NAT2 and certain human leukocyte antigen(HLA)alleles(i
6、mmune response)2021/3/136Clinical manifestationsClinical manifestationsincubation period(2-6weeks)incubation period(2-6weeks)FeverFever,：often high(38.5-40oC)RashRash:Maculopapular rash developing 3 weeks after starting therapy with a limited number of drugs.The cutaneous eruption consists of a morb
7、illiform 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.LymphadenopathyLymphadenopathy(2mm)(2mm)2021/3/137The maculopapul
8、ar eruption later becomes The maculopapular eruption later becomes infiltrated with edematous follicular infiltrated with edematous follicular accentuat-ion.Swelling of the face,with accentuat-ion.Swelling of the face,with marked periorbital involvement.Vesicles marked periorbital involvement.Vesicl
9、es may arise and fine vesicles by edema of may arise and fine vesicles by edema of the dermis can be present.No necrosis of the dermis can be present.No necrosis of the epidermis like TEN occurs,except in the epidermis like TEN occurs,except in rare cases of overlapping DRESS/DIHS rare cases of over
10、lapping DRESS/DIHS andTEN.Small sterile perifollicular andTEN.Small sterile perifollicular pustules and nonfollicular pustules may pustules and nonfollicular pustules may appear,which are different from acute appear,which are different from acute generalized exanthematous pustulosis,and generalized
11、exanthematous pustulosis,and does not predominate on the main folds of does not predominate on the main folds of the skin.Over time the rash becomes the skin.Over time the rash becomes purplish,sharply lower limbs andthe purplish,sharply lower limbs andthe resolution is scaling.Another form of resol
12、ution is scaling.Another form of presentation is a picture of exfoliative presentation is a picture of exfoliative dermatitis,which may be associated with dermatitis,which may be associated with mucosal involvement,such as cheilitis,mucosal involvement,such as cheilitis,erosions,pharygitis and enant
13、hematous erosions,pharygitis and enanthematous enlargedenlarged2021/3/138Various hematologic Various hematologic abnormalities:abnormalities:Leukocytosis may be high,up until 11,000 leukocytes/mm3,and eosinophilia reaches values higher than 1500/mm3HepatitisHepatitis：hepatomegaly.ALT/AST increased.h
14、epatic necrosis Multiorgan involvementMultiorgan 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
15、 severe hepatitis 2021/3/139Myocarditis 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
16、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 o
17、f the drug reactionpulmonary involvement is rarely reported in DRESS/DIHS2021/3/1310Gastrointestinal 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 w
18、here 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 autoimmune diseases such as diabetes mellitus type 1 and autoimmune hypothyroidism2021/3/1311Auxiliary examinatio
19、nAuxiliary examinationComplete 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,c
20、reactive protein,quantitative PCR for HHV-6,7,EBV and CMV,blood culture,anti-nuclear factor。2021/3/1312Diagnostic caiteria Diagnostic caiteria 2021/3/13132021/3/1314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，无脱屑与水泡。淋巴结肿大：颈部可扪与数枚直径约2.0-3.0cm的淋巴结 腋下可扪与1-2枚直径约1.5-2.0cm的淋
21、巴结 腹股沟区可扪与1-2直径约1.5-2.0cm的淋巴结 2021/3/1315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：2021/3/1316辅助检查辅助检查血常规：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2021/3/1317 Score=6 Score=62021/3/1318Differential diagnoseDifferential diagnoseSJS(Johnson综合征)TEN(大疱性表皮松解坏死型药疹)SJSTEN is diag
22、nosed 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
23、 in 67%of cases,In contrast,DIHS developed at 26 weeks in 80%of cases,and occurred most frequently at 4-5weeks.2021/3/1319ComplicationComplicationHemophagocytic syndrome(HPS)Hemophagocytic syndrome(HPS):can rarely be obser-ved in the course of DRESS/DIHS.HPS is associated with and triggered by vario
24、us 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 elevat
25、ion of lactate dehydrogenase(LDH).Bone marrow aspirate revealed hemophagocytosis figures in an increased number of macrophages.2021/3/1320The 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 necessary202
26、1/3/1321Treatment Treatment systemic corticosteroids 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
27、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 corticosteroi
28、ds.2021/3/1322TREATMENT 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
29、 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
30、organs like lungs,thyroid and heart.2021/3/1323High doses of IVIGHigh 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-infla
31、mmatory effect that can regulate immune responses,as seen in the treatment of autoimmune diseases.2021/3/1324plasma exchangeplasma 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
32、 conjunction with IVIG.Once a day Or 3 times in a row2021/3/1325CsACsA:CsA can inhibit monocytes and macrophages generated TN F-alpha.Obstacles to T cells,IL-2 receptor expression and transcriptional regulation factor nuclear factor-KB and inhibit T cell activation,prevent apoptosis induced molecula
33、r CD95(ras)and CD95 ligand(FasL)mR NA expression.CSA to outbreaks of CD8+CTL can inhibit proliferation and colony.The dramatic progress in severe DHS,SJS/toxic necrosis loose solution,and accompanied by a weakened immune system or cases of severe infection and unfavorable impact of GC therapy can gi
34、ve CsA treatment,treatment amount for every 3-5 mg/kg,with 8 to 12 d,then reducing sequence until the drug withdrawal.2021/3/13261.激素 甲强龙：10mg/Kg*d *3d,减量为5mg/Kg*d *4，2.5mg/Kg*d *2d2.血浆置换：10.15、10.17进行2次3.免疫球蛋白：10.14 IVIG：12.5mg 10.15 IVIG：17.5mg2021/3/1327经过上述治疗，现患儿无发热、皮疹已退。复查肝功：ALT：167、AST：118。肝肋下8cm，剑突下8.5cm。血常规：WBC：31.07，L：0.5，N：0.4，嗜酸：0.08，HB：90。肺部病变较前有所吸收、心肌标志物阴性2021/3/1328谢谢大家2021/3/1329
