Druginduced hypersensitvity syndrome課件

1、drug-induced hypersensitivity syndrome (dihs)historydrug-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, th

2、e disease named antispasmodic syndromein addition to anticonvulsants,diaphenylsulfone(dds).allopurinol(別嘌醇),salazosulfapyridine(柳氮磺胺吡啶) and dapsone(氨苯砜) can also cause dihsdefitiondefitiondrug-induced hypersensitivity syndrome (dihs) is a severe and rare systemic reaction triggered by a drug (usuall

3、y 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 cha

4、racterized by late onset, infectious mononucleosis-like symptoms, and herpesvirus 6 (hhv-6) reactivation. etiopathogenesisetiopathogenesisdrugdrug:deficiency or abnormality of the epoxide hydroxylase enzyme(環(huán)氧酶羥化酶) that detoxifies the metabolites of aromaticamine anticonvulsants (metabolic pathway)h

5、erpesvirusherpesvirus: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 (immune response)cli

6、nical 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 morbilliform rash, which is als

7、o 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)the maculopapular eruption later becomes the ma

8、culopapular 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. vesicles may arise and fine vesicl

9、es 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 overlapping dress/dihs andten. s

10、mall 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 exanthematous pustulosis

11、,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 resolution is scaling. a

12、nother 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 enanthematous er

13、osions, pharygitis and enanthematous enlargedenlargedvarious hematologic abnormalities:various hematologic abnormalities:leukocytosis may be high, up until 11,000 leukocytes/mm3, and eosinophilia reaches values higher than 1500/mm3hepatitishepatitis：hepatomegaly.alt/ast increased.hepatic necrosis mu

14、ltiorgan 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 severe he

15、patitis 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 arisi

16、ng 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

17、reactionpulmonary involvement is rarely reported in dress/dihsgastrointestinal 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 rea

18、ctivation 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 hypothyroidismauxiliary examinationauxiliary examinationcom

19、plete 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

20、 protein, quantitative pcr for hhv-6, 7, ebv and cmv, blood culture,anti-nuclear factor。diagnostic caiteria diagnostic caiteria 服用苯妥英鈉藥物史發(fā)熱：以中高熱為主，體溫最高可達(dá)40.8oc皮疹：顏面部、軀干、四肢可見散在或彌漫分布的紅色斑 丘疹，高出皮面，壓之不褪色，伴瘙癢，無脫屑及水泡。淋巴結(jié)腫大：頸部可捫及數(shù)枚直徑約2.0-3.0cm的淋巴結(jié) 腋下可捫及1-2枚直徑約1.5-2.0cm的淋巴結(jié) 腹股溝區(qū)可捫及1-2直徑約1.5-2.0cm的淋巴結(jié) 肝炎：肝大：入

21、院時(shí)肋下12cm，劍突下11cm 10.15肋下8cm，劍突下8.5cm 肝功： 輔助檢查輔助檢查血常規(guī)：eb-pcr:2.22*106血、痰、咽拭子、骨髓培養(yǎng)：陰性 score=6 score=6differential diagnosedifferential diagnosesjs(johnson綜合征) ten(大皰性表皮松解壞死型藥疹)sjsten is diagnosed by characteristic skin and mucosal manifestations, but not by organ involvement.however,dihs is diagnosed

22、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 4-5w

23、eeks.complicationcomplicationhemophagocytic syndrome (hps)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

24、 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 nu

25、mber 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 necessarytreatment treatment systemic corticosteroids systemic corticosteroids (dose equal to or greater than 1 to 1.5 mg/kg /d

26、ay 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

27、 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 treatment it should be remembered that theimmunosuppressive therapies may increase the risk of infectiou

28、s 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,

29、 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 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-inflammatory effect that can regulate