《药物超敏反应综合征ppt课件》由会员分享，可在线阅读，更多相关《药物超敏反应综合征ppt课件（30页珍藏版）》请在金锄头文库上搜索。
1、学习1Drug-inducedhypersensitivitysyndrome(DIHS)2HISTORYDrug-InducedHypersensitivitySyndrome(DIHS),wasfirstrecognizedin1950byChaiken,inapatientusinganticonvulsant.Later,SaItzsteindescribedthiskindofdrugreactionaspseudolymphomaInthe1960swiththedevelopmentofcarbamazepine,thediseasenamedantispasmodicsyndr
2、omeinadditiontoanticonvulsants,diaphenylsulfone(DDS).allopurinol(别嘌醇),salazosulfapyridine(柳氮磺胺吡啶)anddapsone(氨苯砜)canalsocauseDIHS345DefitionDefitionDrug-InducedHypersensitivitySyndrome(DIHS)isasevereandraresystemicreactiontriggeredbyadrug(usuallyanantiepilepticdrug).accompaniedbyfever,lymphadenopathy
3、,hepatitis,hematologic abnormalities with eosinophilia andatypicallymphocytes,andmayinvolveotherorganswitheosinophilicinfiltration,causingdamagetoseveralsystems,especiallytothekidneys,heart,lungs,andpancreasischaracterizedbylateonset,infectiousmononucleosis-like symptoms, and herpesvirus 6(HHV-6)rea
4、ctivation.6EtiopathogenesisEtiopathogenesisDrugDrug:deficiency or abnormality of the epoxidehydroxylaseenzyme(环氧酶羟化酶)thatdetoxifiesthe metabolites of aromaticamine anticonvulsants(metabolicpathway)HerpesvirusHerpesvirus:associated sequential reactivation ofherpesvirusfamily.(Recently,accumulatingevi
5、dencesuggeststhatotherHHVs,suchasHSV,EBV,HHV-7andCMVmightbereactivatedduringthecourseofDIHS)GeneGene:NAT2 and certain human leukocyte antigen(HLA)alleles(immuneresponse)7Clinical manifestationsClinical manifestationsincubationperiod(2-6weeks)incubationperiod(2-6weeks)FeverFever,：oftenhigh(38.5-40oC)
6、RashRash:Maculopapularrashdeveloping3weeksafterstartingtherapy with a limited number of drugs.The cutaneouseruption consists of a morbilliform rash, which is alsocommon in other less severe drug reactions and bothpresentations are indistinguishable The face, upper trunkandupperextremitiesareinitiall
7、yaffected,withsubsequentprogressiontothelowerextremities.LymphadenopathyLymphadenopathy(2mm)(2mm)8The The maculopapular maculopapular eruption eruption later later becomes becomes infiltrated infiltrated with with edematous edematous follicular follicular accentuat-ion.Swelling accentuat-ion.Swellin
8、g of of the the face, face, with with marked marked periorbital periorbital involvement. involvement. Vesicles Vesicles may may arise arise and and fine fine vesicles vesicles by by edema edema of of the the dermis dermis can can be be present.No present.No necrosis necrosis of of the the epidermis
9、epidermis like like TEN TEN occurs,except occurs,except in in rare rare cases cases of of overlapping overlapping DRESS/DIHS DRESS/DIHS andTEN. andTEN. Small Small sterile sterile perifollicular perifollicular pustules pustules and and nonfollicular nonfollicular pustules pustules may may appear, ap
10、pear, which which are are different different from from acute acute generalized generalized exanthematous exanthematous pustulosis,and pustulosis,and does does not not predominate predominate on on the the main main folds folds of of the the skin. skin. Over Over time time the the rash rash becomes
11、becomes purplish, purplish, sharply sharply lower lower limbs limbs andthe andthe resolution resolution is is scaling. scaling. Another Another form form of of presentation presentation is is a a picture picture of of exfoliative exfoliative dermatitis, dermatitis, which which may may be be associat
12、ed associated with with mucosal mucosal involvement, involvement, such such as as cheilitis, cheilitis, erosions, erosions, pharygitis pharygitis and and enanthematous enlargedenanthematous enlarged9VariousVarioushematologichematologicabnormalities:abnormalities:Leukocytosismaybe high, up until 11,0
13、00 leukocytes/mm3, andeosinophiliareachesvalueshigherthan1500/mm3HepatitisHepatitis：hepatomegaly.ALT/ASTincreased.hepaticnecrosisMultiorganMultiorganinvolvementinvolvement:myocarditis/myositis,pericarditis, interstitial nephritis (11% ofcases),necrotizing granulomatous vasculitis inkidney,braininvol
14、vement(encephalitisormeningitis),colitisandthyroiditis.themortalityrate is about 10% to 20%,mainly died of severehepatitis10Myocarditismaydevelopatthebeginningofthesyndromeorup to 40 days after installation.Sym-ptoms include heartfailure, chest pain, sudden tachycardia, dyspnea, andhypotensioninearl
15、yDRESS/DIHS.Renal involvement occurs in about 11% of cases, beingparticularly evident in cases arising from the use ofallopurinol.Therewasanincreaseinserumcreatinineandureaanddecreasedcreatinineclearance.InurineItests,increasedcontentofeosinophilscandeobserved.Neurological complications include meni
16、ngitis and ence-phalitis.occursabout2to4weeksafteronsetofthedrugreactionpulmonaryinvolvementisrarelyreportedinDRESS/DIHS11Gastrointestinalbleedingmaybeanabruptcomplicationc-ausedbyulcerscausedbyCMVEspecially in cases related to advanced age, renal impairment, jaundice and hepatitis with reactivation
17、 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 hypothyroidism12Auxiliary examin
18、ationAuxiliary examinationCompletebloodcount,ALT,AST,totalbilirrubin,GGT, alkaline phosphatase, sodium, potassium,creatinine and creatinine clearance, 24h urineprotein and urinary eosinophil count, CPK, LDH,ferritin, triglycerides, calcium and PTH, bloodglucose,TAPandTTPA,lipase,proteinelectrophore-
19、sis,creactiveprotein,quantitativePCRforHHV-6, 7, EBV and CMV, blood culture,anti-nuclearfactor。13Diagnostic caiteria Diagnostic caiteria 1415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
20、淋巴结16肝炎：肝大：入院时肋下12cm，剑突下11cm10.15肋下8cm，剑突下8.5cm肝功：17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18Score=6Score=619Differential diagnoseDifferential diagnoseSJS(Johnson综合征)TEN(大疱性表皮松解坏死型药疹)SJSTEN is diagnosed by characteristic skin andmucosalmanifestations,butnotbyorgani
21、nvolvement.However,DIHSisdiagnosedbasedonitscharacteristic clinical course, multiple organinvolvementanddetectionofherpesvirusreactivationTheonsetofSJSTENwaswithin3weeksafterthestart of drug administration in 67% of cases,Incontrast, DIHS developed at 26 weeks in 80% ofcases,andoccurredmostfrequentl
22、yat4-5weeks.20ComplicationComplicationHemophagocyticHemophagocyticsyndromesyndrome(HPS)(HPS):canrarelybeobser-vedinthecourseofDRESS/DIHS.HPSisassociatedwithandtriggeredbyvariousconditions,includingviralinfections,particularlyEBV,malignanttu-mors,orautoimmunediseases.Wheninthecourseof the DRESS/DIHS,
23、 HPS usually occurs two weeksafter the onset of drug eruption. There is adecreaseinwhitebloodcellsandplateletsthatisdetectedsimultaneouslywiththeelevationoflactate dehydrogenase (LDH).Bone marrow aspiraterevealedhemophagocytosisfiguresinanincreasednumberofmacrophages.21The incidence of this syndrome
24、 is estimated tovaryfromonecaseamong1,000to10,000themortalityrateisabout10%to20%aspecifictherapymaybenecessary22Treatment 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 an
25、d 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 va
26、rious symptoms is observed when the withdrawal is accidental or by rapid reduction of the doses of corticosteroids. 23TREATMENT TREATMENT Itshouldberememberedthattheimmunosuppressivetherapiesmay increase the risk of infectious complications andsepsis.Physicians should also pay attention to a properb
27、alancebetweentheneedsofcorticosteroidsforreliefofsymptoms and clinical signs and their possible negativeinterferenceonviralload.Attention:Special attention should be given to a possiblereactivationofCMV/EBV,especiallyinpatientswithsevereDRESS/DIHS.themonitoringofliverfunctiontestsshouldbeperformedan
28、dappropriatetestsorderedtoruleouttheinvolvementofotherorganslikelungs,thyroidandheart.24HighHigh dosesdoses ofof IVIGIVIG :have two immunologicaleffects:(i)compensatesforthedecreaseinconcentrationofimmunoglobulins in the patients blood and thedefectsoftheimmuneprotectionagainstHHV-6(ii) high doses o
29、f IVIG have an anti-inflammatoryeffectthatcanregulateimmuneresponses,asseeninthetreatmentofautoimmunediseases.25plasma 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 b
30、e in conjunction with IVIG.Once a day Or 3 times in a row26CsACsA: CsA can inhibit monocytes and macrophagesgeneratedTNF-alpha.ObstaclestoTcells,IL-2receptorexpressionandtranscriptionalregulationfactornuclearfactor-KBandinhibitT cell activation, prevent apoptosis inducedmolecularCD95(ras)andCD95liga
31、nd(FasL)mRNAexpression.CSA to outbreaks of CD8 + CTL caninhibit proliferation and colony.The dramaticprogressinsevereDHS,SJS/toxicnecrosisloosesolution, and accompanied by a weakened immunesystemorcasesofsevereinfectionandunfavorable impact of GC therapy can give CsAtreatment,treatmentamountforevery
32、3-5mg/kg,with8to12d,thenreducingsequenceuntilthedrugwithdrawal.271.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：17.5mg28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29谢谢大家30
